Bio


Dr. Marco Perez's research goal is to better understand the fundamental causes of cardiovascular disease through the study of genetics and epidemiology. His group studies the genetic variations and environmental exposures that are associated with conditions such as atrial fibrillation and heart failure. He has led the studies of atrial fibrillation in Women's Health Initiative, one of the largest nation-wide population-based cohorts. He is currently conducting a large study monitoring for silent or asymptomatic atrial fibrillation in women from the WHI randomized to exercise intervention, and was co-PI of the Apple Heart Study, a clinical trial that validated the ability of a smartwatch to detect atrial fibrillation. He is now PI of the Clinical Coordinating Center at Stanford for the REACT-AF which is a clinical trial to evaluate efficacy and safety of a "pill-in-the pocket" approach to anticoagulation for AF using a smartwatch. He is interested in understanding the paradox that atrial fibrillation is less common in African Americans and Hispanics, despite a greater burden of risk factors such as hypertension. As director of the Stanford Inherited Arrhythmia Clinic, he evaluates families with rare inherited arrhythmias associated with sudden death such as Long QT and Brugada Syndromes and explores their links with novel genes. He also studies the genetic causes of very early onset atrial fibrillation. He also studies how best to use the electrocardiogram and imaging modalities using Machine Learning techniques to identify patients at risk for cardiovascular disease. Dr. Perez receives funding from the NIH/NHLBI, Apple Inc., Janssen and the Colson Foundation.

Clinical Focus


  • Atrial Fibrillation
  • Arrhythmias, Cardiac
  • Channelopathies (Long QT, Brugada, CPVT)
  • Clinical Cardiac Electrophysiology
  • Inherited Cardiomyopathies (HCM, ARVD, LVNC)

Academic Appointments


Administrative Appointments


  • Director, Stanford Cardiac Electrocardiography Laboratory (2017 - Present)
  • Director, Stanford Inherited Cardiac Arrhythmia Clinic (2013 - Present)

Honors & Awards


  • National Research Service Award, NIH (2006-2008)
  • R01 Research Project Grant (1R01HL136390-01 ), NIH/NHLBI (2017-2022)
  • Dean's Fellow Research Award, Stanford University (2006-2008)
  • Loan Repayment Program Award, NIH (2010-2014)
  • Fellow to Faculty Award, American Heart Association (2011-2016)
  • Harold Amos Faculty Development Award, Robert Wood Johnson Foundation (2012-2016)
  • Finalist, FGTB Young Investigator Award, American Heart Association (2013)
  • Department of Medicine Teaching Award, Stanford University (2014)
  • SPARK Award, Stanford University (2014-2015)

Boards, Advisory Committees, Professional Organizations


  • Member, AHA Research Committee (2014 - Present)
  • Medical Director, Racing Hearts Community AED Program (2014 - Present)

Professional Education


  • Board Certification: American Board of Internal Medicine, Clinical Cardiac Electrophysiology (2011)
  • Fellowship: Stanford University Medical Center (2010) CA
  • Fellowship: Stanford University School of Medicine (2007) CA
  • Residency: Massachusetts General Hospital (2004) MA
  • Internship: Massachusetts General Hospital (2002) MA
  • Medical Education: Harvard University Health Services (2001) MA
  • Fellowship, Stanford, Electrophysiology (2010)
  • Fellowship, Stanford, Cardiology (2007)
  • Residency, Massachusetts General Hospital, Internal Medicine (2004)

Clinical Trials


  • Apple Heart Study: Assessment of Wristwatch-Based Photoplethysmography to Identify Cardiac Arrhythmias Not Recruiting

    The Apple Heart Study (AHS) is a research study conducted to evaluate whether the Apple Heart Study App can use data collected on the Apple Watch to identify irregular heart rhythms, including those from potentially serious heart conditions such as atrial fibrillation. Up to 500,000 can participate in the study.

    Stanford is currently not accepting patients for this trial.

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  • Attain Performa(TM) Quadripolar Lead Study Not Recruiting

    The purpose of the study is to evaluate the safety and efficacy of the Medtronic Attain Performa Quadripolar Leads (Model 4298, 4398, and 4598) during and post the implant procedure. This study will also assess the interactions of the Attain Performa leads with the entire Medtronic CRT-D system.

    Stanford is currently not accepting patients for this trial. For more information, please contact Linda Norton, RN, MSN, (650) 725-5597.

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  • Evaluation of the Use of Apple Watch Features for Identification of Cardiac Arrhythmias Not Recruiting

    This post-marketing study is conducted to characterize the ability of Apple Watch rhythm analysis software to identify Atrial Fibrillation (AF) and facilitate subsequent clinical evaluation among users who contact AppleCare.

    Stanford is currently not accepting patients for this trial. For more information, please contact SCCR, 650-723-9363.

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  • Women's Health Initiative Silent Atrial Fibrillation Recording Study Not Recruiting

    The purpose of the WHISH STAR study is to investigate whether or not those who are randomized to exercise intervention have higher rates of atrial fibrillation on review of medical records and, in a subset, on screening with a cardiac ECG patch monitor. We will also study whether those with a known history of AF have any changes in AF hospitalizations due to exercise.

    Stanford is currently not accepting patients for this trial.

    View full details

2023-24 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines CIRCULATION Joglar, J. A., Chung, M. K., Armbruster, A. L., Benjamin, E. J., Chyou, J. Y., Cronin, E. M., Deswal, A., Eckhardt, L. L., Goldberger, Z. D., Gopinathannair, R., Gorenek, B., Hess, P. L., Hlatky, M., Hogan, G., Ibeh, C., Indik, J. H., Kido, K., Kusumoto, F., Link, M. S., Linta, K. T., Marcus, G. M., McCarthy, P. M., Patel, N., Patton, K. K., Perez, M. V., Piccini, J. P., Russo, A. M., Sanders, P., Streur, M. M., Thomas, K. L., Times, S., Tisdale, J. E., Valente, A., Van Wagoner, D. R. 2024; 149 (1): e1-e156

    Abstract

    The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation.A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate.Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

    View details for DOI 10.1161/CIR.0000000000001193

    View details for Web of Science ID 001149820500001

    View details for PubMedID 38033089

  • A deep learning-based electrocardiogram risk score for long term cardiovascular death and disease. NPJ digital medicine Hughes, J. W., Tooley, J., Torres Soto, J., Ostropolets, A., Poterucha, T., Christensen, M. K., Yuan, N., Ehlert, B., Kaur, D., Kang, G., Rogers, A., Narayan, S., Elias, P., Ouyang, D., Ashley, E., Zou, J., Perez, M. V. 2023; 6 (1): 169

    Abstract

    The electrocardiogram (ECG) is the most frequently performed cardiovascular diagnostic test, but it is unclear how much information resting ECGs contain about long term cardiovascular risk. Here we report that a deep convolutional neural network can accurately predict the long-term risk of cardiovascular mortality and disease based on a resting ECG alone. Using a large dataset of resting 12-lead ECGs collected at Stanford University Medical Center, we developed SEER, the Stanford Estimator of Electrocardiogram Risk. SEER predicts 5-year cardiovascular mortality with an area under the receiver operator characteristic curve (AUC) of 0.83 in a held-out test set at Stanford, and with AUCs of 0.78 and 0.83 respectively when independently evaluated at Cedars-Sinai Medical Center and Columbia University Irving Medical Center. SEER predicts 5-year atherosclerotic disease (ASCVD) with an AUC of 0.67, similar to the Pooled Cohort Equations for ASCVD Risk, while being only modestly correlated. When used in conjunction with the Pooled Cohort Equations, SEER accurately reclassified 16% of patients from low to moderate risk, uncovering a group with an actual average 9.9% 10-year ASCVD risk who would not have otherwise been indicated for statin therapy. SEER can also predict several other cardiovascular conditions such as heart failure and atrial fibrillation. Using only lead I of the ECG it predicts 5-year cardiovascular mortality with an AUC of 0.80. SEER, used alongside the Pooled Cohort Equations and other risk tools, can substantially improve cardiovascular risk stratification and aid in medical decision making.

    View details for DOI 10.1038/s41746-023-00916-6

    View details for PubMedID 37700032

    View details for PubMedCentralID 8145781

  • Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early-Onset Atrial Fibrillation. Circulation. Genomic and precision medicine Goodyer, W. R., Dunn, K., Caleshu, C., Jackson, M., Wylie, J., Moscarello, T., Platt, J., Reuter, C., Smith, A., Trela, A., Ceresnak, S. R., Motonaga, K. S., Ashley, E., Yang, P., Dubin, A. M., Perez, M. 2019

    Abstract

    Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting approximately 34 million worldwide. The pathophysiology of AF remains incompletely understood but is clearly complex with multiple underlying genetic, physiologic and environmental factors. Very early-onset AF (vEAF) (defined here as onset <45 years and without significant comorbidities), while rare (only ~0.5-3% of AF cases), is highly heritable, with a greater prevalence of rare variants in genes previously associated with AF. Patients with vEAF, therefore, represent an ideal population for discovering novel genes involved in the underlying genetic basis of AF. Notably, the Framingham study showed that patients with AF without comorbidities have a three-fold higher risk for heart failure. Conversely, several forms of inherited cardiomyopathy have been strongly associated with AF suggestive of a shared etiology.

    View details for DOI 10.1161/CIRCGEN.119.002713

    View details for PubMedID 31638414

  • Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. The New England journal of medicine Perez, M. V., Mahaffey, K. W., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P., Talati, N., Nag, D., Gummidipundi, S. E., Beatty, A., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. P., Apple Heart Study Investigators, Perez, M. V., Turakhia, M. P., Lhamo, K., Smith, S., Berdichesky, M., Sharma, B., Mahaffey, K., Parizo, J., Olivier, C., Nguyen, M., Tallapalli, S., Kaur, R., Gardner, R., Hung, G., Mitchell, D., Olson, G., Datta, S., Gerenrot, D., Wang, X., McCoy, P., Satpathy, B., Jacobsen, H., Makovey, D., Martin, A., Perino, A., O'Brien, C., Gupta, A., Toruno, C., Waydo, S., Brouse, C., Dorfman, D., Stein, J., Huang, J., Patel, M., Fleischer, S., Doll, E., O'Reilly, M., Dedoshka, K., Chou, M., Daniel, H., Crowley, M., Martin, C., Kirby, T., Brumand, M., McCrystale, K., Haggerty, M., Newberger, J., Keen, D., Antall, P., Holbrook, K., Braly, A., Noone, G., Leathers, B., Montrose, A., Kosowsky, J., Lewis, D., Finkelmeier, J. R., Bemis, K., Mahaffey, K. W., Desai, M., Talati, N., Nag, D., Rajmane, A., Desai, S., Caldbeck, D., Cheung, L., Granger, C., Rumsfeld, J., Kowey, P. R., Hills, M. T., Russo, A., Rockhold, F., Albert, C., Alonso, A., Wruck, L., Friday, K., Wheeler, M., Brodt, C., Park, S., Rogers, A., Jones, R., Ouyang, D., Chang, L., Yen, A., Dong, J., Mamic, P., Cheng, P., Shah, R., Lorvidhaya, P. 2019; 381 (20): 1909–17

    Abstract

    BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

    View details for DOI 10.1056/NEJMoa1901183

    View details for PubMedID 31722151

  • Lean body mass and risk of incident atrial fibrillation in post-menopausal women EUROPEAN HEART JOURNAL Azarbal, F., Stefanick, M. L., Assimes, T. L., Manson, J. E., Bea, J. W., Li, W., Hlatky, M. A., Larson, J. C., LeBlanc, E. S., Albert, C. M., Nassir, R., Martin, L. W., Perez, M. V. 2016; 37 (20): 1606-1613

    Abstract

    High body mass index (BMI) is a risk factor for atrial fibrillation (AF). The aim of this study was to determine whether lean body mass (LBM) predicts AF.The Women's Health Initiative is a study of post-menopausal women aged 50-79 enrolled at 40 US centres from 1994 to 1998. A subset of 11 393 participants at three centres underwent dual-energy X-ray absorptiometry. Baseline demographics and clinical histories were recorded. Incident AF was identified using hospitalization records and diagnostic codes from Medicare claims. A multivariable Cox hazard regression model adjusted for demographic and clinical risk factors was used to evaluate associations between components of body composition and AF risk. After exclusion for prevalent AF or incomplete data, 8832 participants with an average age of 63.3 years remained for analysis. Over the 11.6 years of average follow-up time, 1035 women developed incident AF. After covariate adjustment, all measures of LBM were independently associated with higher rates of AF: total LBM [hazard ratio (HR) 1.24 per 5 kg increase, 95% confidence intervals (CI) 1.14-1.34], central LBM (HR 1.51 per 5 kg increase, 95% CI 1.31-1.74), and peripheral LBM (HR 1.39 per 5 kg increase, 95% CI 1.19-1.63). The association between total LBM and AF remained significant after adjustment for total fat mass (HR 1.22 per 5 kg increase, 95% CI 1.13-1.31).Greater LBM is a strong independent risk factor for AF. After adjusting for obesity-related risk factors, the risk of AF conferred by higher BMI is primarily driven by the association between LBM and AF.

    View details for DOI 10.1093/eurheartj/ehv423

    View details for Web of Science ID 000376168100013

    View details for PubMedID 26371115

  • Systems Genomics Identifies a Key Role for Hypocretin/Orexin Receptor-2 in Human Heart Failure JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Perez, M. V., Pavlovic, A., Shang, C., Wheeler, M. T., Miller, C. L., Liu, J., Dewey, F. E., Pan, S., Thanaporn, P. K., Absher, D., Brandimarto, J., Salisbury, H., Chan, K., Mukherjee, R., Konadhode, R. P., Myers, R. M., Sedehi, D., Scammell, T. E., Quertermous, T., Cappola, T., Ashley, E. A. 2015; 66 (22): 2522-2533

    Abstract

    The genetic determinants of heart failure (HF) and response to medical therapy remain unknown. We hypothesized that identifying genetic variants of HF that associate with response to medical therapy would elucidate the genetic basis of cardiac function.This study sought to identify genetic variations associated with response to HF therapy.This study compared extremes of response to medical therapy in 866 HF patients using a genome-wide approach that informed the systems-based design of a customized single nucleotide variant array. The effect of genotype on gene expression was measured using allele-specific luciferase reporter assays. Candidate gene transcription-deficient mice underwent echocardiography and treadmill exercise. The ability of the target gene agonist to rescue mice from chemically-induced HF was assessed with echocardiography.Of 866 HF patients, 136 had an ejection fraction improvement of 20% attributed to resynchronization (n = 83), revascularization (n = 7), tachycardia resolution (n = 2), alcohol cessation (n = 1), or medications (n = 43). Those with the minor allele for rs7767652, upstream of hypocretin (orexin) receptor-2 (HCRTR2), were less likely to have improved left ventricular function (odds ratio: 0.40 per minor allele; p = 3.29 × 10(-5)). In a replication cohort of 798 patients, those with a minor allele for rs7767652 had a lower prevalence of ejection fraction >35% (odds ratio: 0.769 per minor allele; p = 0.021). In an HF model, HCRTR2-deficient mice exhibited poorer cardiac function, worse treadmill exercise capacity, and greater myocardial scarring. Orexin, an HCRTR2 agonist, rescued function in this HF mouse model.A systems approach identified a novel genetic contribution to human HF and a promising therapeutic agent efficacious in an HF model.

    View details for DOI 10.1016/j.jacc.2015.09.061

    View details for Web of Science ID 000366094500009

    View details for PubMedID 26653627

  • Characteristics of Contemporary Atrial Fibrillation Clinical Trials and Their Association With Industry Sponsorship. Heart rhythm Lan, R. H., Paranjpe, I., Saeed, M., Perez, M. V. 2024

    Abstract

    Industry sponsorship is an important source of funding for atrial fibrillation (AF) clinical trials, the implications of which have not been analyzed.The purpose of this study is to describe the characteristics of contemporary AF clinical trials and to evaluate their association with funding source.We systematically assessed all completed AF trials registered in the ClinicalTrials.gov database between conception to October 31, 2023, and extracted publicly available information including funding source, trial size, demographic distribution, intervention, location, and publication status. Trial characteristics were compared using the Wilcoxon rank sum test and Fisher's exact test for continuous and categorical variables, respectively.Of the 253 clinical trials assessed, 171 (68%) reported industry funding. Industry funding was associated with a greater median number of patients enrolled (172 vs. 80; P < 0.001), publication rate (56.7% vs. 42.7%; P = 0.04), probability of being product-focused (48.0% vs. 24.4%; P < 0.001), and multicontinental recruitment location (25.2% vs. 2.4%; P < 0.001) when compared to non-industry funded trials. However, industry funding was not associated with a significant difference in median impact factor (7.7 vs. 7.7; P = 0.723). The overall proportion of industry funded trials did not change over time (P = 1.00).Industry funded clinical trials in AF are often larger, more frequently published, multicontinental, and product-focused. Industry funding was found to be associated with significant differences in study enrollment and publication metrics.

    View details for DOI 10.1016/j.hrthm.2024.03.001

    View details for PubMedID 38453036

  • Expedited Loading with Intravenous Sotalol is Safe and Feasible - Primary Results of the Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry. Heart rhythm Steinberg, B. A., Holubkov, R., Deering, T., Groh, C. A., Mittal, S., Kennedy, R., Pokharel, P., Perez, M., Savona, S., Verma, N., Watt, K., Piccini, J. P., Bunch, T. J. 2024

    Abstract

    Loading oral sotalol for atrial fibrillation (AF) requires 3 days, frequently in-hospital, to achieve steady state. The FDA approved loading with intravenous (IV) sotalol through model-informed development, without patient data.We present results of the first multicenter evaluation of this recent labeling for IV sotalol.The Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) Registry was a multicenter observational registry of patients undergoing elective IV sotalol load for atrial arrhythmias. Outcomes, measured from hospital admission until first outpatient follow-up, included adverse arrhythmia events, efficacy, and length of stay.Among 167 consecutively enrolled patients, 23% were female, the median age was 68 (IQR: 61,74), and the median CHA2DS2-VASc was 3 (IQR 2,4). Overall, 99% were admitted for sotalol initiation (1% for dose escalation), with a target oral sotalol dose of either 80 mg bid (85[51%]) or 120 mg bid (78[47%]); 62 patients (37%) had an estimated creatinine clearance <90 mL/min. On presentation, 40% of patients were in sinus rhythm whereas 26% underwent cardioversion prior to sotalol infusion. In two patients, sotalol infusion was stopped for bradycardia or hypotension. In six subjects, sotalol was discontinued prior to discharge due to QTc prolongation (3), bradycardia (1), or recurrent atrial arrhythmia (2). The mean length of stay was 1.1 days and 95%(n=159) were discharged within 1 night.Intravenous sotalol loading is safe and feasible for atrial arrhythmias, with low rates of adverse events, and yields shorter hospitalizations. More data are needed on the minimal duration required for monitoring in-hospital.

    View details for DOI 10.1016/j.hrthm.2024.02.046

    View details for PubMedID 38417598

  • Prevalence of frequent premature ventricular contractions and nonsustained ventricular tachycardia in older women screened for atrial fibrillation in the Women's Health Initiative. Heart rhythm Gomez, S. E., Larson, J., Hlatky, M. A., Rodriguez, F., Wheeler, M., Greenland, P., LaMonte, M., Froelicher, V., Stefanick, M. L., Wallace, R., Kooperberg, C., Tinker, L. F., Schoenberg, J., Soliman, E. Z., Vitolins, M. Z., Saquib, N., Nuño, T., Haring, B., Perez, M. V. 2024

    Abstract

    Frequent premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) have been associated with cardiovascular disease and mortality. Their prevalence, especially in ambulatory populations, is under-studied and limited by few female participants and the use of short-duration (24-48 hour) monitoring.Report the prevalence of frequent PVCs and NSVT in a community-based population of women likely to undergo ECG screening using sequential patch monitoring.Participants from the Women's Health Initiative Strong and Healthy (WHISH) trial with no history of atrial fibrillation (AF) but 5-year predicted risk of incident AF ≥ 5% by CHARGE-AF score were randomly selected to undergo screening with 7-day ECG patch monitors at baseline, 6 months, and 12 months. Recordings were reviewed for PVCs and NSVT (> 5 beats); data was analyzed using multivariate regression models.There were 1,067 participants who underwent ECG screening at baseline, 866 at 6-months and 777 at 12-months. Frequent PVCs were found on at least one patch from 4.3% of participants and one or more episodes of NSVT was found in 12 (1.1%) women. PVC frequency directly correlated with CHARGE-AF score and NSVT on any patch. Detection of frequent PVCs increased with sequential monitoring.Among postmenopausal women at high risk for AF, frequent PVCs were relatively common (4.3%), and correlated with higher CHARGE-AF score. As strategies for AF screening continue to evolve, particularly in those individuals at high risk of AF, the prevalence of incidental ventricular arrhythmias is an important benchmark to guide clinical decision-making.

    View details for DOI 10.1016/j.hrthm.2024.02.040

    View details for PubMedID 38403238

  • Arrhythmias including Atrial Fibrillation and Congenital Heart Disease in Kleefstra Syndrome: a possible epigenetic link. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology Vasireddi, S. K., Draksler, T. Z., Bouman, A., Kummeling, J., Wheeler, M., Reuter, C., Srivastava, S., Harris, J., Fisher, P. G., Narayan, S. M., Wang, P. J., Badhwar, N., Kleefstra, T., Perez, M. V. 2024

    Abstract

    BACKGROUND: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown.METHODS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands, and GenIDA (163 patients) based on world-wide surveys of patient families.RESULTS: Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median(IQR) age was considerably younger; GenIDA/Radboudumc at 10/13.5 (12/13) years respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one AF, two with supraventricular tachycardias (SVTs), and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia. In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (3 AF and 1 AT) without structural heart disease.CONCLUSION: In addition to a high prevalence of CHD, evolving data reveals early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

    View details for DOI 10.1093/europace/euae003

    View details for PubMedID 38195854

  • Race, Sex, and Age Disparities in the Performance of ECG Deep Learning Models Predicting Heart Failure. Circulation. Heart failure Kaur, D., Hughes, J. W., Rogers, A. J., Kang, G., Narayan, S. M., Ashley, E. A., Perez, M. V. 2023: e010879

    Abstract

    Deep learning models may combat widening racial disparities in heart failure outcomes through early identification of individuals at high risk. However, demographic biases in the performance of these models have not been well-studied.This retrospective analysis used 12-lead ECGs taken between 2008 and 2018 from 326 518 patient encounters referred for standard clinical indications to Stanford Hospital. The primary model was a convolutional neural network model trained to predict incident heart failure within 5 years. Biases were evaluated on the testing set (160 312 ECGs) using the area under the receiver operating characteristic curve, stratified across the protected attributes of race, ethnicity, age, and sex.There were 59 817 cases of incident heart failure observed within 5 years of ECG collection. The performance of the primary model declined with age. There were no significant differences observed between racial groups overall. However, the primary model performed significantly worse in Black patients aged 0 to 40 years compared with all other racial groups in this age group, with differences most pronounced among young Black women. Disparities in model performance did not improve with the integration of race, ethnicity, sex, and age into model architecture, by training separate models for each racial group, or by providing the model with a data set of equal racial representation. Using probability thresholds individualized for race, age, and sex offered substantial improvements in F1 scores.The biases found in this study warrant caution against perpetuating disparities through the development of machine learning tools for the prognosis and management of heart failure. Customizing the application of these models by using probability thresholds individualized by race, ethnicity, age, and sex may offer an avenue to mitigate existing algorithmic disparities.

    View details for DOI 10.1161/CIRCHEARTFAILURE.123.010879

    View details for PubMedID 38126168

  • Clinical Management of Brugada Syndrome: Commentary From the Experts. Circulation. Arrhythmia and electrophysiology Cutler, M. J., Eckhardt, L. L., Kaufman, E. S., Arbelo, E., Behr, E. R., Brugada, P., Cerrone, M., Crotti, L., DeAsmundis, C., Gollob, M. H., Horie, M., Huang, D. T., Krahn, A. D., London, B., Lubitz, S. A., Mackall, J. A., Nademanee, K., Perez, M. V., Probst, V., Roden, D. M., Sacher, F., Sarquella-Brugada, G., Scheinman, M. M., Shimizu, W., Shoemaker, B., Sy, R. W., Watanabe, A., Wilde, A. A. 2023: e012072

    Abstract

    Although there is consensus on the management of patients with Brugada Syndrome with high risk for sudden cardiac arrest, asymptomatic or intermediate-risk patients present clinical management challenges. This document explores the management opinions of experts throughout the world for patients with Brugada Syndrome who do not fit guideline recommendations. Four real-world clinical scenarios were presented with commentary from small expert groups for each case. All authors voted on case-specific questions to evaluate the level of consensus among the entire group in nuanced diagnostic and management decisions relevant to each case. Points of agreement, points of controversy, and gaps in knowledge are highlighted.

    View details for DOI 10.1161/CIRCEP.123.012072

    View details for PubMedID 38099441

  • Utility of smart watches for identifying arrhythmias in children. Communications medicine Zahedivash, A., Chubb, H., Giacone, H., Boramanand, N. K., Dubin, A. M., Trela, A., Lencioni, E., Motonaga, K. S., Goodyer, W., Navarre, B., Ravi, V., Schmiedmayer, P., Bikia, V., Aalami, O., Ling, X. B., Perez, M., Ceresnak, S. R. 2023; 3 (1): 167

    Abstract

    Arrhythmia symptoms are frequent complaints in children and often require a pediatric cardiology evaluation. Data regarding the clinical utility of wearable technologies are limited in children. We hypothesize that an Apple Watch can capture arrhythmias in children.We present an analysis of patients ≤18 years-of-age who had signs of an arrhythmia documented by an Apple Watch. We include patients evaluated at our center over a 4-year-period and highlight those receiving a formal arrhythmia diagnosis. We evaluate the role of the Apple Watch in arrhythmia diagnosis, the results of other ambulatory cardiac monitoring studies, and findings of any EP studies.We identify 145 electronic-medical-record identifications of Apple Watch, and find arrhythmias confirmed in 41 patients (28%) [mean age 13.8 ± 3.2 years]. The arrythmias include: 36 SVT (88%), 3 VT (7%), 1 heart block (2.5%) and wide 1 complex tachycardia (2.5%). We show that invasive EP study confirmed diagnosis in 34 of the 36 patients (94%) with SVT (2 non-inducible). We find that the Apple Watch helped prompt a workup resulting in a new arrhythmia diagnosis for 29 patients (71%). We note traditional ambulatory cardiac monitors were worn by 35 patients (85%), which did not detect arrhythmias in 10 patients (29%). In 73 patients who used an Apple Watch for recreational or self-directed heart rate monitoring, 18 (25%) sought care due to device findings without any arrhythmias identified.We demonstrate that the Apple Watch can record arrhythmia events in children, including events not identified on traditionally used ambulatory monitors.

    View details for DOI 10.1038/s43856-023-00392-9

    View details for PubMedID 38092993

    View details for PubMedCentralID 4937287

  • Electrocardiographic deep learning for predicting post-procedural mortality: a model development and validation study. The Lancet. Digital health Ouyang, D., Theurer, J., Stein, N. R., Hughes, J. W., Elias, P., He, B., Yuan, N., Duffy, G., Sandhu, R. K., Ebinger, J., Botting, P., Jujjavarapu, M., Claggett, B., Tooley, J. E., Poterucha, T., Chen, J. H., Nurok, M., Perez, M., Perotte, A., Zou, J. Y., Cook, N. R., Chugh, S. S., Cheng, S., Albert, C. M. 2023

    Abstract

    Preoperative risk assessments used in clinical practice are insufficient in their ability to identify risk for postoperative mortality. Deep-learning analysis of electrocardiography can identify hidden risk markers that can help to prognosticate postoperative mortality. We aimed to develop a prognostic model that accurately predicts postoperative mortality in patients undergoing medical procedures and who had received preoperative electrocardiographic diagnostic testing.In a derivation cohort of preoperative patients with available electrocardiograms (ECGs) from Cedars-Sinai Medical Center (Los Angeles, CA, USA) between Jan 1, 2015 and Dec 31, 2019, a deep-learning algorithm was developed to leverage waveform signals to discriminate postoperative mortality. We randomly split patients (8:1:1) into subsets for training, internal validation, and final algorithm test analyses. Model performance was assessed using area under the receiver operating characteristic curve (AUC) values in the hold-out test dataset and in two external hospital cohorts and compared with the established Revised Cardiac Risk Index (RCRI) score. The primary outcome was post-procedural mortality across three health-care systems.45 969 patients had a complete ECG waveform image available for at least one 12-lead ECG performed within the 30 days before the procedure date (59 975 inpatient procedures and 112 794 ECGs): 36 839 patients in the training dataset, 4549 in the internal validation dataset, and 4581 in the internal test dataset. In the held-out internal test cohort, the algorithm discriminates mortality with an AUC value of 0·83 (95% CI 0·79-0·87), surpassing the discrimination of the RCRI score with an AUC of 0·67 (0·61-0·72). The algorithm similarly discriminated risk for mortality in two independent US health-care systems, with AUCs of 0·79 (0·75-0·83) and 0·75 (0·74-0·76), respectively. Patients determined to be high risk by the deep-learning model had an unadjusted odds ratio (OR) of 8·83 (5·57-13·20) for postoperative mortality compared with an unadjusted OR of 2·08 (0·77-3·50) for postoperative mortality for RCRI scores of more than 2. The deep-learning algorithm performed similarly for patients undergoing cardiac surgery (AUC 0·85 [0·77-0·92]), non-cardiac surgery (AUC 0·83 [0·79-0·88]), and catheterisation or endoscopy suite procedures (AUC 0·76 [0·72-0·81]).A deep-learning algorithm interpreting preoperative ECGs can improve discrimination of postoperative mortality. The deep-learning algorithm worked equally well for risk stratification of cardiac surgeries, non-cardiac surgeries, and catheterisation laboratory procedures, and was validated in three independent health-care systems. This algorithm can provide additional information to clinicians making the decision to perform medical procedures and stratify the risk of future complications.National Heart, Lung, and Blood Institute.

    View details for DOI 10.1016/S2589-7500(23)00220-0

    View details for PubMedID 38065778

  • Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer Carvedilol. Circulation Seo, K., Yamamoto, Y., Kirillova, A., Kawana, M., Yadav, S., Huang, Y., Wang, Q., Lane, K. V., Pruitt, B. L., Perez, M. V., Bernstein, D., Wu, J. C., Wheeler, M. T., Parikh, V. N., Ashley, E. A. 2023

    Abstract

    Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ [myosin heavy chain 6]) and iPSC cardiomyocytes derived from patients with HCM (MYH7R403Q/+) [myosin heavy chain 7]).We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ induced pluripotent stem cell cardiomyocytes.R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

    View details for DOI 10.1161/CIRCULATIONAHA.123.065017

    View details for PubMedID 37850394

  • Association Between Insomnia, Stress Events, and Other Psychosocial Factors and Incident Atrial Fibrillation in Postmenopausal Women: Insights From the Women's Health Initiative. Journal of the American Heart Association Zhao, S. X., Tindle, H. A., Larson, J. C., Woods, N. F., Crawford, M. H., Hoover, V., Salmoirago-Blotcher, E., Shadyab, A. H., Stefanick, M. L., Perez, M. V. 2023: e030030

    Abstract

    Background The association between psychosocial factors and atrial fibrillation (AF) is poorly understood. Methods and Results Postmenopausal women from the Women's Health Initiative were retrospectively analyzed to identify incident AF in relation to a panel of validated psychosocial exposure variables, as assessed by multivariable Cox proportional hazard regression and hierarchical cluster analysis. Among the 83736 women included, the average age was 63.9±7.0years. Over an average of 10.5±6.2years follow-up, there were 23954 cases of incident AF. Hierarchical cluster analysis generated 2 clusters of highly correlated psychosocial variables: the Stress Cluster included stressful life events, depressive symptoms, and insomnia, and the Strain Cluster included optimism, social support, social strain, cynical hostility, and emotional expressiveness. Incident AF was associated with higher values in the Stress Cluster (hazard ratio [HR], 1.07 per unit cluster score [95% CI, 1.05-1.09]) and the Strain Cluster (HR, 1.03 per unit cluster score [95% CI, 1.00-1.05]). Of the 8 individual psychosocial predictors that were tested, insomnia (HR, 1.04 [95% CI, 1.03-1.06]) and stressful life events (HR, 1.02 [95% CI, 1.01-1.04]) were most strongly associated with increased incidence of AF in Cox regression analysis after multivariate adjustment. Subgroup analyses showed that the Strain Cluster was more strongly associated with incident AF in those with lower traditional AF risks (P for interaction=0.02) as determined by the cohorts for heart and aging research in genomic epidemiology for atrial fibrillation score. Conclusions Among postmenopausal women, 2 clusters of psychosocial stressors were found to be significantly associated with incident AF. Further research is needed to validate these associations.

    View details for DOI 10.1161/JAHA.123.030030

    View details for PubMedID 37646212

  • From Founder to Function: can we unravel phenotype from genotype? Heart rhythm Weldy, C. S., Perez, M. V. 2023

    View details for DOI 10.1016/j.hrthm.2023.08.030

    View details for PubMedID 37625473

  • The evolving role of data & safety monitoring boards for real-world clinical trials. Journal of clinical and translational science Bunning, B. J., Hedlin, H., Chen, J. H., Ciolino, J. D., Ferstad, J. O., Fox, E., Garcia, A., Go, A., Johari, R., Lee, J., Maahs, D. M., Mahaffey, K. W., Opsahl-Ong, K., Perez, M., Rochford, K., Scheinker, D., Spratt, H., Turakhia, M. P., Desai, M. 2023; 7 (1): e179

    Abstract

    Clinical trials provide the "gold standard" evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources - data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor.Three examples of real-world trials that leverage different types of data sources - wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived.Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity.Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.

    View details for DOI 10.1017/cts.2023.582

    View details for PubMedID 37745930

    View details for PubMedCentralID PMC10514684

  • Expanding the stdpopsim species catalog, and lessons learned for realistic genome simulations. eLife Lauterbur, M. E., Cavassim, M. I., Gladstein, A. L., Gower, G., Pope, N. S., Tsambos, G., Adrion, J., Belsare, S., Biddanda, A., Caudill, V., Cury, J., Echevarria, I., Haller, B. C., Hasan, A. R., Huang, X., Iasi, L. N., Noskova, E., Obsteter, J., Pavinato, V. A., Pearson, A., Peede, D., Perez, M. F., Rodrigues, M. F., Smith, C. C., Spence, J. P., Teterina, A., Tittes, S., Unneberg, P., Vazquez, J. M., Waples, R. K., Wohns, A. W., Wong, Y., Baumdicker, F., Cartwright, R. A., Gorjanc, G., Gutenkunst, R. N., Kelleher, J., Kern, A. D., Ragsdale, A. P., Ralph, P. L., Schrider, D. R., Gronau, I. 2023; 12

    Abstract

    Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic datasets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than threefold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed the best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

    View details for DOI 10.7554/eLife.84874

    View details for PubMedID 37342968

  • Vigorous Exercise in Patients With Hypertrophic Cardiomyopathy. JAMA cardiology Lampert, R., Ackerman, M. J., Marino, B. S., Burg, M., Ainsworth, B., Salberg, L., Tome Esteban, M. T., Ho, C. Y., Abraham, R., Balaji, S., Barth, C., Berul, C. I., Bos, M., Cannom, D., Choudhury, L., Concannon, M., Cooper, R., Czosek, R. J., Dubin, A. M., Dziura, J., Eidem, B., Emery, M. S., Estes, N. A., Etheridge, S. P., Geske, J. B., Gray, B., Hall, K., Harmon, K. G., James, C. A., Lal, A. K., Law, I. H., Li, F., Link, M. S., McKenna, W. J., Molossi, S., Olshansky, B., Ommen, S. R., Saarel, E. V., Saberi, S., Simone, L., Tomaselli, G., Ware, J. S., Zipes, D. P., Day, S. M., LIVE Consortium, Abrahms, D., Ashley, E., Aziz, P., Batra, A., Cerrone, M., Colan, S., Erickson, C., Ferhaan, A., Gollob, M. J., Johnsrude, C., Kannankeril, P., Kanter, R., Li, W., Masri, A., Murphy, A., Nandi, D., Perez, M., Perry, J., Popjes, E., Rao, R., Rosenthal, D., Sanatani, S., Semsarian, C., Shah, M., Skinner, J., Tardif, J., Towbin, J., Turer, A., Webster, G., Wever-Pinzon, O., Wong, T. 2023

    Abstract

    Importance: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown.Objective: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity.Design, Setting, and Participants: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled.Exposures: Amount and intensity of physical activity.Main Outcomes and Measures: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category.Results: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority.Conclusions and Relevance: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

    View details for DOI 10.1001/jamacardio.2023.1042

    View details for PubMedID 37195701

  • Generation of two induced pluripotent stem cell lines from catecholaminergic polymorphic ventricular tachycardia patients carrying RYR2 mutations. Stem cell research Kong, X., Belbachir, N., Zeng, W., Yan, C. D., Navada, S., Perez, M. V., Wu, J. C. 2023; 69: 103111

    Abstract

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a congenital arrhythmic syndrome caused by the RYR2 gene encoded ryanodine receptor. Mutations on RYR2 are commonly associated with ventricular tachycardia after adrenergic stimulation, leading to lethal arrhythmias and sudden cardiac death. We generated two human induced pluripotent stem cell (iPSC) lines from CPVT affected patients carrying single missense heterozygote RYR2 mutations, c.1082 G > A and c.100 A > C. Pluripotency and differentiation capability into derivatives of three germ layers were evaluated along with karyotype stability in the report. The generated patient-specific iPSC lines provide a reliable tool to investigate the CPVT phenotype and understand underlaying mechanisms.

    View details for DOI 10.1016/j.scr.2023.103111

    View details for PubMedID 37210947

  • Arrhythmogenic Cardiomyopathy and Athletes - A Dangerous Relationship. Current problems in cardiology de la Guía-Galipienso, F., Ugedo-Alzaga, K., Grazioli, G., Quesada-Ocete, F. J., Feliu-Rey, E., Perez, M. V., Quesada-Dorador, A., Sanchis-Gomar, F. 2023: 101799

    Abstract

    Arrhythmogenic cardiomyopathy (ACM) is a disease characterized by a progressive replacement of myocardium by fibro-adipose material, predisposing to ventricular arrhythmias (VA) and sudden cardiac death (SCD). Its prevalence is estimated at 1:2000 to 1:5000, with a higher incidence in males, and clinical onset is usually between the 2nd and 4th decade of life. The prevalence of ACM in SCD victims is relatively high, making it one of the most common etiologies in young patients with SCD, especially if they are athletes. Cardiac events occur more frequently in individuals with ACM who participate in competitive sports and/or high-intensity training. In effect, exercise activity can worsen RV function in cases of hereditary ACM. Estimating the incidence of SCD caused by ACM in athletes remains challenging, being reported frequency ranging from 3-20%. Here, we review the potential implications of exercising on the clinical course of the classical genetic form of ACM, as well as the diagnostic tools, risk stratification, and the different therapeutic tools available for managing ACM.

    View details for DOI 10.1016/j.cpcardiol.2023.101799

    View details for PubMedID 37172878

  • Using wearables to manage atrial fibrillation: Pushing the boundaries with consumer devices. Journal of cardiovascular electrophysiology Perez, M. V. 2023

    View details for DOI 10.1111/jce.15903

    View details for PubMedID 37087674

  • Maladaptive versus adaptative cardiovascular phenotype in response to exercise training: Expert opinion of the evidence HEART AND MIND Sanchis-Gomar, F., Perez-Quilis, C., Eijsvogels, T. H., Guia-Galipienso, F., Christle, J. W., Perez, M. V., Lavie, C. J. 2023; 7 (2): 57-61
  • Evaluation of the Association Between Circulating IL-1β and Other Inflammatory Cytokines and Incident Atrial Fibrillation in a Cohort of Postmenopausal Women. American heart journal Gomez, S. E., Parizo, J., Ermakov, S., Larson, J., Wallace, R., Assimes, T., Hlatky, M., Stefanick, M., Perez, M. V. 2023

    Abstract

    Inflammatory cytokines play a role in atrial fibrillation (AF). Interleukin (IL)-1β, which is targeted in the treatment of ischemic heart disease, has not been well-studied in relation to AF.Postmenopausal women from the Women's Health Initiative were included. Cox proportional hazards regression models were used to evaluate the association between log-transformed baseline cytokine levels and future AF incidence. Models were adjusted for body mass index, age, race, education, hypertension, diabetes, hyperlipidemia, current smoking, and history of coronary heart disease, congestive heart failure, or peripheral artery disease.Of 16,729 women, 3,943 developed AF over an average of 8.5 years. Racial and ethnic groups included White (77.4%), Black/African-American (16.1%), Asian (2.7%), American Indian/Alaska Native (1.0%), and Hispanic (5.5%). Baseline IL-1β log continuous levels were not significantly associated with incident AF (HR 0.86 per 1 log (pg/mL) increase, p=0.24), similar to those of other inflammatory cytokines, IL-7, IL-8, IL-10, IGF-1, and TNF-α. There were significant associations between C-reactive protein (CRP) and IL-6 with incident AF.In this large cohort of postmenopausal women, there was no significant association between IL-1β and incident AF, although downstream effectors, CRP and IL-6, were associated with incident AF.

    View details for DOI 10.1016/j.ahj.2023.01.010

    View details for PubMedID 36646198

  • Development and validation of a rapid visual technique for left ventricular hypertrophy detection from the electrocardiogram. Frontiers in cardiovascular medicine Somani, S., Hughes, J. W., Ashley, E. A., Witteles, R. M., Perez, M. V. 2023; 10: 1251511

    Abstract

    Introduction: Left ventricular hypertrophy (LVH) detection techniques on by electrocardiogram (ECG) are cumbersome to remember with modest performance. This study validated a rapid technique for LVH detection and measured its performance against other techniques.Methods: This was a retrospective cohort study of patients at Stanford Health Care who received ECGs and resting transthoracic echocardiograms (TTE) from 2006 through 2018. The novel technique, Witteles-Somani (WS), assesses for S- and R-wave overlap on adjacent precordial leads. The WS, Sokolow-Lyon, Cornell, and Peguero-Lo Presti techniques were algorithmically implemented on ECGs. Classification metrics, receiver-operator curves, and Pearson correlations measured performance. Age- and sex-adjusted Cox proportional hazard models evaluated associations between incident cardiovascular outcomes and each technique.Results: A total of 53,333 ECG-TTE pairs from 18,873 patients were identified. Of all ECG-TTE pairs, 21,638 (40.6%) had TTE-diagnosed LVH. The WS technique had a sensitivity of 0.46, specificity of 0.66, and AUROC of 0.56, compared to Sokolow-Lyon (AUROC 0.55), Cornell (AUROC 0.63), and Peguero-Lo Presti (AUROC 0.63). Patients meeting LVH by WS technique had a higher risk of cardiovascular mortality [HR 1.18, 95% CI (1.12, 1.24), P<0.001] and a higher risk of developing any cardiovascular disease [HR 1.29, 95% CI (1.22, 1.36), P<0.001], myocardial infarction [HR 1.60, 95% CI (1.44, 1.78), P<0.005], and heart failure [HR 1.24, 95% CI (1.17, 1.32), P<0.001].Conclusions: The WS criteria is a rapid visual technique for LVH detection with performance like other LVH detection techniques and is associated with incident cardiovascular outcomes.

    View details for DOI 10.3389/fcvm.2023.1251511

    View details for PubMedID 37711561

  • The development of a mobile app-focused deduplication strategy for the Apple Heart Study that informs recommendations for future digital trials. Stat (International Statistical Institute) Garcia, A., Lee, J., Balasubramanian, V., Gardner, R., Gummidipundi, S. E., Hung, G., Ferris, T., Cheung, L., Desai, S., Granger, C. B., Hills, M. T., Kowey, P., Nag, D., Rumsfeld, J. S., Russo, A. M., Stein, J. W., Talati, N., Tsay, D., Mahaffey, K. W., Perez, M. V., Turakhia, M. P., Hedlin, H., Desai, M., Apple Heart Study Investigators 2022; 11 (1): e470

    Abstract

    An app-based clinical trial enrolment process can contribute to duplicated records, carrying data management implications. Our objective was to identify duplicated records in real time in the Apple Heart Study (AHS). We leveraged personal identifiable information (PII) to develop a dissimilarity score (DS) using the Damerau-Levenshtein distance. For computational efficiency, we focused on four types of records at the highest risk of duplication. We used the receiver operating curve (ROC) and resampling methods to derive and validate a decision rule to classify duplicated records. We identified 16,398 (4%) duplicated participants, resulting in 419,297 unique participants out of a total of 438,435 possible. Our decision rule yielded a high positive predictive value (96%) with negligible impact on the trial's original findings. Our findings provide principled solutions for future digital trials. When establishing deduplication procedures for digital trials, we recommend collecting device identifiers in addition to participant identifiers; collecting and ensuring secure access to PII; conducting a pilot study to identify reasons for duplicated records; establishing an initial deduplication algorithm that can be refined; creating a data quality plan that informs refinement; and embedding the initial deduplication algorithm in the enrolment platform to ensure unique enrolment and linkage to previous records.

    View details for DOI 10.1002/sta4.470

    View details for PubMedID 36589778

  • Serial 7-Day Electrocardiogram PatchScreening for AF inHigh-Risk Older Women by the CHARGE-AF Score. JACC. Clinical electrophysiology Lin, J. Y., Larson, J., Schoenberg, J., Sepulveda, A., Tinker, L., Wheeler, M., Albert, C., Manson, J. E., Wells, G., Martin, L. W., Froelicher, V., LaMonte, M., Kooperberg, C., Hlatky, M. A., Greenland, P., Stefanick, M. L., Perez, M. V. 2022; 8 (12): 1523-1534

    Abstract

    BACKGROUND: Asymptomatic atrial fibrillation (AF) is associated with an increased risk of stroke. The yield of serial electrocardiographic (ECG) screening for AF is unknown.OBJECTIVES: The aim of this study was to determine the frequency of AF detected by serial, 7-day ECG patch screenings in older women identified as having an elevated risk of AF according to the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology)-AF clinical prediction score.METHODS: Postmenopausal women with a 5-year predicted risk of new-onset AF≥5% according to CHARGE-AF were recruited from the ongoing WHISH (Women's Health Initiative Strong and Healthy) randomized trial of a physical activity intervention. Participants with AF at baseline by self-report or medical records review were excluded. Screening with 7-day ECG patch monitors was performed at baseline, 6months, and 12months from study enrollment.RESULTS: On baseline monitoring, 2.5% of the cohort had AF detected, increasing to 3.7% by 6months and 4.9% cumulatively by 12months. Yield of patch screening was higher among participants with a higher (≥10%) CHARGE-AF score: 4.2% had AF detected at baseline, 5.9% at 6months, and 7.2% at 12months. Most participants with patch-identified AF never had a clinical diagnosis of AF (36 of 46 [78%]).CONCLUSIONS: Older women with an elevated CHARGE-AF score had a high prevalence of AF on 7-day ECG patch screening. Serial screening over 12months substantially increased the detection of AF. These data can be useful in helping identify high-risk participants for enrollment in future studies of the management of asymptomatic AF.(Women'sHealth Initiative Silent Atrial Fibrillation Recording Study [WHISH STAR]; NCT05366803.).

    View details for DOI 10.1016/j.jacep.2022.08.024

    View details for PubMedID 36543503

  • Consumer-Led Screening for Atrial Fibrillation: Frontier Review of the AF-SCREEN International Collaboration. Circulation Brandes, A., Stavrakis, S., Freedman, B., Antoniou, S., Boriani, G., Camm, A. J., Chow, C. K., Ding, E., Engdahl, J., Gibson, M. M., Golovchiner, G., Glotzer, T., Guo, Y., Healey, J. S., Hills, M. T., Johnson, L., Lip, G. Y., Lobban, T., Macfarlane, P. W., Marcus, G. M., McManus, D. D., Neubeck, L., Orchard, J., Perez, M. V., Schnabel, R. B., Smyth, B., Steinhubl, S., Turakhia, M. P. 2022; 146 (19): 1461-1474

    Abstract

    The technological evolution and widespread availability of wearables and handheld ECG devices capable of screening for atrial fibrillation (AF), and their promotion directly to consumers, has focused attention of health care professionals and patient organizations on consumer-led AF screening. In this Frontiers review, members of the AF-SCREEN International Collaboration provide a critical appraisal of this rapidly evolving field to increase awareness of the complexities and uncertainties surrounding consumer-led AF screening. Although there are numerous commercially available devices directly marketed to consumers for AF monitoring and identification of unrecognized AF, health care professional-led randomized controlled studies using multiple ECG recordings or continuous ECG monitoring to detect AF have failed to demonstrate a significant reduction in stroke. Although it remains uncertain if consumer-led AF screening reduces stroke, it could increase early diagnosis of AF and facilitate an integrated approach, including appropriate anticoagulation, rate or rhythm management, and risk factor modification to reduce complications. Companies marketing AF screening devices should report the accuracy and performance of their products in high- and low-risk populations and avoid claims about clinical outcomes unless improvement is demonstrated in randomized clinical trials. Generally, the diagnostic yield of AF screening increases with the number, duration, and temporal dispersion of screening sessions, but the prognostic importance may be less than for AF detected by single-time point screening, which is largely permanent, persistent, or high-burden paroxysmal AF. Consumer-initiated ECG recordings suggesting possible AF always require confirmation by a health care professional experienced in ECG reading, whereas suspicion of AF on the basis of photoplethysmography must be confirmed with an ECG. Consumer-led AF screening is unlikely to be cost-effective for stroke prevention in the predominantly young, early adopters of this technology. Studies in older people at higher stroke risk are required to demonstrate both effectiveness and cost-effectiveness. The direct interaction between companies and consumers creates new regulatory gaps in relation to data privacy and the registration of consumer apps and devices. Although several barriers for optimal use of consumer-led screening exist, results of large, ongoing trials, powered to detect clinical outcomes, are required before health care professionals should support widespread adoption of consumer-led AF screening.

    View details for DOI 10.1161/CIRCULATIONAHA.121.058911

    View details for PubMedID 36343103

  • Premature ventricular contractions (PVCs) in young athletes. Progress in cardiovascular diseases Gomez, S. E., Hwang, C. E., Kim, D. S., Froelicher, V. F., Wheeler, M. T., Perez, M. V. 2022

    Abstract

    There is a growing body of literature focusing on the morphology, management, and outcomes of PVCs in athletes. This review summarizes this literature and establishes recommendations on management, treatment, and indications for specialist referral in this patient population. The sports medicine physician's responses and recommendation should be made in conjunction with the athletes wishes. Medications or ablations are not always necessary in all athletes if they are followed with regular evaluations.

    View details for DOI 10.1016/j.pcad.2022.10.011

    View details for PubMedID 36309100

  • Multimodal deep learning enhances diagnostic precision in left ventricular hypertrophy. European heart journal. Digital health Soto, J. T., Weston Hughes, J., Sanchez, P. A., Perez, M., Ouyang, D., Ashley, E. A. 2022; 3 (3): 380-389

    Abstract

    Aims: Determining the aetiology of left ventricular hypertrophy (LVH) can be challenging due to the similarity in clinical presentation and cardiac morphological features of diverse causes of disease. In particular, distinguishing individuals with hypertrophic cardiomyopathy (HCM) from the much larger set of individuals with manifest or occult hypertension (HTN) is of major importance for family screening and the prevention of sudden death. We hypothesized that an artificial intelligence method based joint interpretation of 12-lead electrocardiograms and echocardiogram videos could augment physician interpretation.Methods and results: We chose not to train on proximate data labels such as physician over-reads of ECGs or echocardiograms but instead took advantage of electronic health record derived clinical blood pressure measurements and diagnostic consensus (often including molecular testing) among physicians in an HCM centre of excellence. Using more than 18000 combined instances of electrocardiograms and echocardiograms from 2728 patients, we developed LVH-fusion. On held-out test data, LVH-fusion achieved an F1-score of 0.71 in predicting HCM, and 0.96 in predicting HTN. In head-to-head comparison with human readers LVH-fusion had higher sensitivity and specificity rates than its human counterparts. Finally, we use explainability techniques to investigate local and global features that positively and negatively impact LVH-fusion prediction estimates providing confirmation from unsupervised analysis the diagnostic power of lateral T-wave inversion on the ECG and proximal septal hypertrophy on the echocardiogram for HCM.Conclusion: These results show that deep learning can provide effective physician augmentation in the face of a common diagnostic dilemma with far reaching implications for the prevention of sudden cardiac death.

    View details for DOI 10.1093/ehjdh/ztac033

    View details for PubMedID 36712167

  • Deep Learning Electrocardiographic Analysis for Detection of Left-Sided Valvular Heart Disease. Journal of the American College of Cardiology Elias, P., Poterucha, T. J., Rajaram, V., Moller, L. M., Rodriguez, V., Bhave, S., Hahn, R. T., Tison, G., Abreau, S. A., Barrios, J., Torres, J. N., Hughes, J. W., Perez, M. V., Finer, J., Kodali, S., Khalique, O., Hamid, N., Schwartz, A., Homma, S., Kumaraiah, D., Cohen, D. J., Maurer, M. S., Einstein, A. J., Nazif, T., Leon, M. B., Perotte, A. J. 2022; 80 (6): 613-626

    Abstract

    Valvular heart disease is an important contributor to cardiovascular morbidity and mortality and remains underdiagnosed. Deep learning analysis of electrocardiography (ECG) may be useful in detecting aortic stenosis (AS), aortic regurgitation (AR), and mitral regurgitation (MR).This study aimed to develop ECG deep learning algorithms to identify moderate or severe AS, AR, and MR alone and in combination.A total of 77,163 patients undergoing ECG within 1 year before echocardiography from 2005-2021 were identified and split into train (n = 43,165), validation (n = 12,950), and test sets (n = 21,048; 7.8% with any of AS, AR, or MR). Model performance was assessed using area under the receiver-operating characteristic (AU-ROC) and precision-recall curves. Outside validation was conducted on an independent data set. Test accuracy was modeled using different disease prevalence levels to simulate screening efficacy using the deep learning model.The deep learning algorithm model accuracy was as follows: AS (AU-ROC: 0.88), AR (AU-ROC: 0.77), MR (AU-ROC: 0.83), and any of AS, AR, or MR (AU-ROC: 0.84; sensitivity 78%, specificity 73%) with similar accuracy in external validation. In screening program modeling, test characteristics were dependent on underlying prevalence and selected sensitivity levels. At a prevalence of 7.8%, the positive and negative predictive values were 20% and 97.6%, respectively.Deep learning analysis of the ECG can accurately detect AS, AR, and MR in this multicenter cohort and may serve as the basis for the development of a valvular heart disease screening program.

    View details for DOI 10.1016/j.jacc.2022.05.029

    View details for PubMedID 35926935

  • Contributions of the Women's Health Initiative to Cardiovascular Research: JACC State-of-the-Art Review. Journal of the American College of Cardiology LaMonte, M. J., Manson, J. E., Anderson, G. L., Baker, L. D., Bea, J. W., Eaton, C. B., Follis, S., Hayden, K. M., Kooperberg, C., LaCroix, A. Z., Limacher, M. C., Neuhouser, M. L., Odegaard, A., Perez, M. V., Prentice, R. L., Reiner, A. P., Stefanick, M. L., Van Horn, L., Wells, G. L., Whitsel, E. A., Rossouw, J. E. 2022; 80 (3): 256-275

    Abstract

    The WHI (Women's Health Initiative) enrolled 161,808 racially and ethnically diverse postmenopausal women, ages 50-79 years, from 1993 to 1998 at 40 clinical centers across the United States. In its clinical trial component, WHI evaluated 3 randomized interventions (menopausal hormone therapy; diet modification; and calcium/vitamin D supplementation) for the primary prevention of major chronic diseases, including cardiovascular disease, in older women. In the WHI observational study, numerous clinical, behavioral, and social factors have been evaluated as predictors of incident chronic disease and mortality. Although the original interventions have been completed, the WHI data and biomarker resources continue to be leveraged and expanded through ancillary studies to yield novel insights regarding cardiovascular disease prevention and healthy aging in women.

    View details for DOI 10.1016/j.jacc.2022.05.016

    View details for PubMedID 35835498

  • Lessons learned in the Apple Heart Study and implications for the data management of future digital clinical trials. Journal of biopharmaceutical statistics Garcia, A., Balasubramanian, V., Lee, J., Gardner, R., Gummidipundi, S., Hung, G., Ferris, T., Cheung, L., Granger, C., Kowey, P., Rumsfeld, J., Russo, A., Hills, M. T., Talati, N., Nag, D., Stein, J., Tsay, D., Desai, S., Mahaffey, K., Turakhia, M., Perez, M., Hedlin, H., Desai, M. 2022: 1-15

    Abstract

    The digital clinical trial is fast emerging as a pragmatic trial that can improve a trial's design including recruitment and retention, data collection and analytics. To that end, digital platforms such as electronic health records or wearable technologies that enable passive data collection can be leveraged, alleviating burden from the participant and study coordinator. However, there are challenges. For example, many of these data sources not originally intended for research may be noisier than traditionally obtained measures. Further, the secure flow of passively collected data and their integration for analysis is non-trivial. The Apple Heart Study was a prospective, single-arm, site-less digital trial designed to evaluate the ability of an app to detect atrial fibrillation. The study was designed with pragmatic features, such as an app for enrollment, a wearable device (the Apple Watch) for data collection, and electronic surveys for participant-reported outcomes that enabled a high volume of patient enrollment and accompanying data. These elements led to challenges including identifying the number of unique participants, maintaining participant-level linkage of multiple complex data streams, and participant adherence and engagement. Novel solutions were derived that inform future designs with an emphasis on data management. We build upon the excellent framework of the Clinical Trials Transformation Initiative to provide a comprehensive set of guidelines for data management of the digital clinical trial that include an increased role of collaborative data scientists in the design and conduct of the modern digital trial.

    View details for DOI 10.1080/10543406.2022.2080698

    View details for PubMedID 35695137

  • Getting Smart About Wearable ECG Interpretation in the Clinic. JACC. Clinical electrophysiology Perez, M. V. 2022; 8 (6): 792-794

    View details for DOI 10.1016/j.jacep.2022.03.018

    View details for PubMedID 35738856

  • Sedentary Behavior and Atrial Fibrillation in Older Women: The OPACH Study. Journal of the American Heart Association Boursiquot, B. C., Bellettiere, J., LaMonte, M. J., LaCroix, A. Z., Perez, M. V. 2022: e023833

    Abstract

    Background Sedentary behavior is associated with cardiovascular disease, but its association with incident atrial fibrillation is not well studied. Our aim was to measure the association between objectively measured sedentary behavior and incident atrial fibrillation. Methods and Results Sedentary behavior was measured by a triaxial accelerometer worn on a belt for 1week. Incident atrial fibrillation was ascertained from Medicare claims. The associations between total sedentary time (or patterns of sedentary behavior) and incident atrial fibrillation were assessed using Cox proportional hazards models adjusted for demographic and clinical covariates. Among 2675 participants (mean age, 78.2years), there were 268 (10.0%) cases of incident atrial fibrillation at a rate of 31 cases per 1000 person-years. Greater total sedentary time was associated with a higher risk of incident atrial fibrillation after adjustment for age, race and ethnicity, body mass index, education, smoking history, hypertension, diabetes, stroke, heart disease, and other chronic conditions (quartile 4 versus quartile 1: hazard ratio, 1.20, [95% CI, 0.81-1.78]; P for trend=0.05). After adjusting for physical function and self-rated health, this was no longer statistically significant. Both longer mean sedentary bout duration and more continuous sedentary periods (versus frequent breaks in sedentary time) were also associated with higher risks of incident atrial fibrillation, but these associations were also attenuated with serial adjustment. Conclusions Total sedentary time and prolonged patterns of sedentary accumulation were associated with a higher risk of atrial fibrillation in this prospective study of community-dwelling older women, but these associations were attenuated by adjustment for physical function and self-reported health. This suggests that associations between sedentary behavior and atrial fibrillation may be attributable to global measures of overall function and health.

    View details for DOI 10.1161/JAHA.121.023833

    View details for PubMedID 35253465

  • Generation of two induced pluripotent stem cell lines from Brugada syndrome affected patients carrying SCN5A mutations. Stem cell research Belbachir, N., Lai, C., Rhee, J., Zhuge, Y., Perez, M. V., Sallam, K., Wu, J. C. 2021; 57: 102605

    Abstract

    SCN5A gene loss-of-function mutations are commonly associated with Brugada syndrome, which represents a risk of lethal arrhythmias and sudden cardiac death. The present report describes the generation of two human induced pluripotent stem cell (iPSC) lines reprogrammed from two Brugada syndrome affected patients carrying SCN5A mutations, c.53506 G>A and c.2102 C>T, respectively. Pluripotency markers, karyotype stability, and differentiation capability into derivatives of the three germ layers were assessed and described in the present report. These lines can be used as a reliable cell model for Brugada syndrome investigations and characterization of leading cellular mechanisms.

    View details for DOI 10.1016/j.scr.2021.102605

    View details for PubMedID 34856468

  • Disruption of Protein Quality Control of Human Ether-a-go-go Related Gene K+ Channel Results in Profound Long QT Syndrome. Heart rhythm Ledford, H. A., Ren, L., Thai, P. N., Park, S., Timofeyev, V., Sirish, P., Xu, W., Emigh, A. M., Priest, J. R., Perez, M. V., Ashley, E. A., Yarov-Yarovoy, V., Yamoah, E. N., Zhang, X., Chiamvimonvat, N. 2021

    Abstract

    BACKGROUND: Long QT syndrome (LQTS) is a hereditary disease that predisposes patients to life-threatening cardiac arrhythmias and sudden cardiac death. Our previously study of human ether-a-go-go related gene (hERG)-encoded K+ channel (Kv11.1) supports an association between hERG and RING Finger Protein 207 (RNF207) variants in aggravating the onset and severity of LQTS, specifically T613M hERG (hERGT613M) and RNF207 frameshift (RNF207G603fs) mutations. However, the underlying mechanistic underpinning remains unknown.OBJECTIVE: The purpose of the current study is to test the role of RNF207 on the function of hERG-encoded K+ channel subunits.METHODS AND RESULTS: Here, we demonstrate that RNF207 serves as an E3 ubiquitin ligase and targets misfolded hERGT613M proteins for degradation. RNF207G603fs exhibits decreased activity and hinders the normal degradation pathway; this increases the levels of hERGT613M subunits and their dominant-negative effect on the wild-type (WT) subunits, ultimately resulting in decreased current density. Similar findings are shown for hERGA614V, a known dominant-negative mutant subunit. Finally, the presence of RNF207G603fs with hERGT613M results in significantly prolonged action potential durations and reduced hERG current in human pluripotent stem cell-derived cardiomyocytes.CONCLUSIONS: Our study establishes RNF207 as an interacting protein serving as a ubiquitin ligase for hERG-encoded K+ channel subunits. Normal function of RNF207 is critical for the quality control of hERG subunits and, consequently, cardiac repolarization. Moreover, our study provides evidence for protein quality control as a new paradigm in life-threatening cardiac arrhythmias in LQTS patients.

    View details for DOI 10.1016/j.hrthm.2021.10.005

    View details for PubMedID 34634443

  • Epigenetic Age and the Risk of Incident Atrial Fibrillation. Circulation Roberts, J. D., Vittinghoff, E., Lu, A. T., Alonso, A., Wang, B., Sitlani, C. M., Mohammadi-Shemirani, P., Fornage, M., Kornej, J., Brody, J. A., Arking, D. E., Lin, H., Heckbert, S. R., Prokic, I., Ghanbari, M., Skanes, A. C., Bartz, T. M., Perez, M. V., Taylor, K. D., Lubitz, S. A., Ellinor, P. T., Lunetta, K. L., Pankow, J. S., Pare, G., Sotoodehnia, N., Benjamin, E. J., Horvath, S., Marcus, G. M. 2021

    Abstract

    Background: The most prominent risk factor for atrial fibrillation (AF) is chronological age, however underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge, a phenomenon termed epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. Methods: Measures for 4 epigenetic clocks (Horvath, Hannum, DNAm PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 levels (DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analysis. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. Results: Among 5,600 individuals (mean age: 65.5 years; 60.1% female; 50.7% black), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. Following multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR]: 1.19; 95% confidence intervals [CI]: 1.09-1.31; p<0.01) and 15% (adjusted HR: 1.15; 95% CI: 1.05-1.25; p<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. Conclusions: Our study identified adjusted associations between EAA measures and incident AF, suggesting biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

    View details for DOI 10.1161/CIRCULATIONAHA.121.056456

    View details for PubMedID 34587750

  • Exercise Effects On Cardiovascular Disease: From Basic Aspects To Clinical Evidence. Cardiovascular research Sanchis-Gomar, F., Lavie, C. J., Marin, J., Perez-Quilis, C., Eijsvogels, T. M., O'Keefe, J. H., Perez, M. V., Blair, S. N. 2021

    Abstract

    Cardiovascular (CV) disease (CVD) remains the leading cause of major morbidity and CVD- and all-cause mortality in most of the world. It is now clear that regular physical activity (PA) and exercise training (ET) induces a wide range of direct and indirect physiologic adaptations and pleiotropic benefits for human general and CV health. Generally, higher levels of PA, ET, and cardiorespiratory fitness (CRF) are correlated with reduced risk of CVD, including myocardial infarction, CVD-related death, and all-cause mortality. Although exact details regarding the ideal doses of ET, including resistance and, especially, aerobic ET, as well as the potential adverse effects of extreme levels of ET, continue to be investigated, there is no question that most of the world's population have insufficient levels of PA/ET, and many also have lower than ideal levels of CRF. Therefore, assessment and promotion of PA, ET, and efforts to improve levels of CRF should be integrated into all health professionals' practices worldwide. In this state-of-the-art review, we discuss the exercise effects on many areas related to CVD, from basic aspects to clinical practice.

    View details for DOI 10.1093/cvr/cvab272

    View details for PubMedID 34478520

  • Long-Term Exposures to Air Pollution and the Risk of Atrial Fibrillation in the Women's Health Initiative Cohort. Environmental health perspectives Hart, J. E., Hohensee, C., Laden, F., Holland, I., Whitsel, E. A., Wellenius, G. A., Winkelmayer, W. C., Sarto, G. E., Warsinger Martin, L., Manson, J. E., Greenland, P., Kaufman, J., Albert, C., Perez, M. V. 2021; 129 (9): 97007

    Abstract

    BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence.OBJECTIVES: Our objective was to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S. women.METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant.RESULTS: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure-response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [HazardRatio(HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, p-for-trend=<0.0001]. Women living closer to roadways were at higher risk of AF (e.g., HR=1.07; 95% CI: 1.01, 1.13 for living within 50m of A3 roads, compared with ≥1,000m, p-for-trend=0.02), but we did not observe adverse associations with exposures to PM10, PM2.5, or SO2. There were adverse associations with PM10 (top quartile HR=1.10; 95% CI: 1.05, 1.16, p-for-trend=<0.0001) and PM2.5 (top quartile HR=1.09; 95% CI: 1.03, 1.14, p-for-trend=0.002) in sensitivity models adjusting for census region.DISCUSSION: In this study of postmenopausal women, NO2 and distance to road were consistently associated with higher risk of AF. https://doi.org/10.1289/EHP7683.

    View details for DOI 10.1289/EHP7683

    View details for PubMedID 34523977

  • Generation of three induced pluripotent stem cell lines (SCVIi014-A, SCVIi015-A, and SCVIi016-A) from patients with LQT1 caused by heterozygous mutations in the KCNQ1 gene. Stem cell research Zhang, H., Jahng, J. W., Liu, Y., Chase, A. J., Perez, M. V., Wu, J. C. 2021; 55: 102492

    Abstract

    Congenital long QT syndrome type 1 (LQT1) results from KCNQ1 mutations that cause loss of Kv7.1 channel function, leading to arrhythmias, syncope, and sudden cardiac death. Here, we generated three human-induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of LQT1 patients carrying pathogenic variants (c.569 G>A, c.585delG, and c.573_577delGCGCT) in KCNQ1. All lines show typical iPSC morphology, high expression of pluripotent markers, normal karyotype, and are able to differentiate into three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of LQT1 caused by KCNQ1 mutations.

    View details for DOI 10.1016/j.scr.2021.102492

    View details for PubMedID 34411974

  • Role of digital health in detection and management of atrial fibrillation. Heart (British Cardiac Society) Tooley, J. E., Perez, M. V. 2021

    Abstract

    Atrial fibrillation is a common arrhythmia associated with significant morbidity, mortality and decreased quality of life. Mobile health devices marketed directly to consumers capable of detecting atrial fibrillation through methods including photoplethysmography, single-lead ECG as well as contactless methods are becoming ubiquitous. Large-scale screening for atrial fibrillation is feasible and has been shown to detect more cases than usual care-however, controversy still exists surrounding screening even in older higher risk populations. Given widespread use of mobile health devices, consumer-driven screening is happening on a large scale in both low-risk and high-risk populations. Given that young people make up a large portion of early adopters of mobile health devices, there is the potential that many more patients with early onset atrial fibrillation will come to clinical attention requiring possible referral to genetic arrythmia clinic. Physicians need to be familiar with these technologies, and understand their risks, and limitations. In the current review, we discuss current mobile health devices used to detect atrial fibrillation, recent and upcoming trials using them for diagnosis of atrial fibrillation, practical recommendations for patients with atrial fibrillation diagnosed by a mobile health device and special consideration in young patients.

    View details for DOI 10.1136/heartjnl-2020-318262

    View details for PubMedID 34344729

  • Rare Coding Variants Associated with Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-ancestry Analysis. Circulation. Genomic and precision medicine Choi, S. H., Jurgens, S. J., Haggerty, C. M., Hall, A. W., Halford, J. L., Morrill, V. N., Weng, L., Lagerman, B., Mirshahi, T., Pettinger, M., Guo, X., Lin, H. J., Alonso, A., Soliman, E. Z., Kornej, J., Lin, H., Moscati, A., Nadkarni, G., Brody, J. A., Wiggins, K. L., Cade, B. E., Lee, J., Austin-Tse, C., Blackwell, T., Chaffin, M. D., Lee, C. J., Rehm, H. L., Roselli, C., Redline, S., Mitchell, B. D., Sotoodehnia, N., Psaty, B. M., Heckbert, S. R., Loos, R. J., Vasan, R. S., Benjamin, E. J., Correa, A., Boerwinkle, E., Arking, D. E., Rotter, J. I., Rich, S. S., Whitsel, E. A., Perez, M. V., Kooperberg, C., Fornwalt, B. K., Lunetta, K. L., Ellinor, P. T., Lubitz, S. A. 2021

    Abstract

    Background - Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between ECG intervals and rare genetic variation at a population level are poorly understood. Methods - Using a discovery sample of 29,000 individuals with whole-genome sequencing from TOPMed and replication in nearly 100,000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured ECG traits (RR, P-wave, PR, and QRS intervals and corrected QT interval [QTc]). Results - We found that rare variants associated with population-based ECG intervals identify established monogenic SCD genes (KCNQ1, KCNH2, SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM, MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of first-degree atrioventricular block (P=8.4x10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked QTc prolongation (P=4x10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal ECG intervals. Conclusions - Our findings indicate that large-scale high-depth sequence data and ECG analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked ECG interval prolongation.

    View details for DOI 10.1161/CIRCGEN.120.003300

    View details for PubMedID 34319147

  • Management of Congenital Long-QT Syndrome: Commentary From the Experts. Circulation. Arrhythmia and electrophysiology Kaufman, E. S., Eckhardt, L. L., Ackerman, M. J., Aziz, P. F., Behr, E. R., Cerrone, M., Chung, M. K., Cutler, M. J., Etheridge, S. P., Krahn, A. D., Lubitz, S. A., Perez, M. V., Priori, S. G., Roberts, J. D., Roden, D. M., Schulze-Bahr, E., Schwartz, P. J., Shimizu, W., Shoemaker, M. B., Sy, R. W., Towbin, J. A., Viskin, S., A M Wilde, A., Zareba, W. 2021: CIRCEP120009726

    Abstract

    While published guidelines are useful in the care of patients with long-QT syndrome, it can be difficult to decide how to apply the guidelines to individual patients, particularly those with intermediate risk. We explored the diversity of opinion among 24 clinicians with expertise in long-QT syndrome. Experts from various regions and institutions were presented with 4 challenging clinical scenarios and asked to provide commentary emphasizing why they would make their treatment recommendations. All 24 authors were asked to vote on case-specific questions so as to demonstrate the degree of consensus or divergence of opinion. Of 24 authors, 23 voted and 1 abstained. Details of voting results with commentary are presented. There was consensus on several key points, particularly on the importance of the diagnostic evaluation and of beta-blocker use. There was diversity of opinion about the appropriate use of other therapeutic measures in intermediate-risk individuals. Significant gaps in knowledge were identified.

    View details for DOI 10.1161/CIRCEP.120.009726

    View details for PubMedID 34238011

  • Antiarrhythmic drug loading at home using remote monitoring: a virtual feasibility study during COVID-19 social distancing. European heart journal. Digital health Shah, R. L., Kapoor, R., Bonnett, C., Ottoboni, L. K., Tacklind, C., Tsiperfal, A., Perez, M. V. 2021; 2 (2): 259-262

    Abstract

    The epidemiological necessity for distancing during the COVID-19 pandemic has resulted in postponement of non-emergent hospitalizations and increase use of telemedicine. The feasibility of virtual antiarrhythmic drug (AAD) loading specifically with digital QTc electrocardiographic monitoring (EM) in conjunction with telemedicine video visits is not well established. We tested the hypothesis that existing digital health technologies and virtual communication platforms could provide EM and support medically guided AAD loading for patients with symptomatic tachyarrhythmia in the ambulatory setting, while reducing physical contact between patient and healthcare system. A prospective pilot, case series was approved by the institutional ethics committee, entailing three subjects with symptomatic arrhythmia during the COVID-19 pandemic who were enrolled for virtual AAD loading at home. Clinicians met with participants twice daily via video visits conducted after QTc analysis (Kardia 6L mobile sensor) and telemetry review (Mobile Cardiac Outpatient Telemetry of silent arrhythmias). Participants received direct instruction to either terminate the study or proceed with the next single dose of AAD. All participants completed contactless loading of five AAD doses, without untoward event. Scheduled video visits allowed dialogue and participant counselling where decision-making was guided by remote review of EM. Participant adherence with transmissions and scheduled visits was 98.3%; a single electrocardiogram was delayed beyond the 2 hours of post-dose schedule. This virtual approach reduced overall expenditures based on retrospective comparison with previous AAD load hospitalizations. We found that a 'virtual hospitalization' for AAD loading with remote EM and twice-daily virtual rounding is feasible using existing digital health technologies.

    View details for DOI 10.1093/ehjdh/ztab034

    View details for PubMedID 37155657

    View details for PubMedCentralID PMC8083679

  • Generation of three heterozygous KCNH2 mutation-carrying human induced pluripotent stem cell lines for modeling LQT2 syndrome. Stem cell research Mondejar-Parreno, G., Jahng, J. W., Belbachir, N., Wu, B. C., Zhang, X., Perez, M. V., Badhwar, N., Wu, J. C. 2021; 54: 102402

    Abstract

    Congenital long QT syndrome type 2 (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function which can lead to arrhythmias, syncope, and sudden death. Here, we generated three human-induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of two LQT2 patients carrying pathogenic variants (c.1714G>A and c.2960del) and one LQT2 patient carrying a variant of uncertain significance (c.1870A>T) in KCNH2. All lines show typical iPSC morphology, high expression of pluripotent markers, normal karyotype, and differentiate into three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of LQTS caused by caused by KCNH2 mutations.

    View details for DOI 10.1016/j.scr.2021.102402

    View details for PubMedID 34051449

  • Generation of three induced pluripotent stem cell lines, SCVIi003-A, SCVIi004-A, SCVIi005-A, from patients with ARVD/C caused by heterozygous mutations in the PKP2 gene. Stem cell research Jahng, J. W., Black, K. E., Liu, L., Bae, H. R., Perez, M., Ashley, E. A., Sallam, K., Wu, J. C. 2021; 53: 102284

    Abstract

    Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease which can cause life-threatening ventricular arrhythmias and cardiac dysfunction. The autosomal dominant form of ARVD/C is caused by mutations in the cardiac desmosome, such as those in the plakoglobin plakophilin-2 (PKP2) gene. Here, we generated three human induced pluripotent stem cell (iPSC) lines from the peripheral blood mononuclear cells (PBMCs) of three ARVD/C patients carrying pathogenic variants in their PKP2 genes (c.2065_2070delinsG; c.235C>T; c.1725_1728dup). All lines show the typical morphology of pluripotent stem cells, demonstrate high expression of pluripotent markers, display normal karyotype, and differentiate into all three germ layers in vitro. These lines are valuable resources for studying the pathological mechanisms of ARVD/C caused by PKP2 mutation.

    View details for DOI 10.1016/j.scr.2021.102284

    View details for PubMedID 33743362

  • Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature Taliun, D., Harris, D. N., Kessler, M. D., Carlson, J., Szpiech, Z. A., Torres, R., Taliun, S. A., Corvelo, A., Gogarten, S. M., Kang, H. M., Pitsillides, A. N., LeFaive, J., Lee, S., Tian, X., Browning, B. L., Das, S., Emde, A., Clarke, W. E., Loesch, D. P., Shetty, A. C., Blackwell, T. W., Smith, A. V., Wong, Q., Liu, X., Conomos, M. P., Bobo, D. M., Aguet, F., Albert, C., Alonso, A., Ardlie, K. G., Arking, D. E., Aslibekyan, S., Auer, P. L., Barnard, J., Barr, R. G., Barwick, L., Becker, L. C., Beer, R. L., Benjamin, E. J., Bielak, L. F., Blangero, J., Boehnke, M., Bowden, D. W., Brody, J. A., Burchard, E. G., Cade, B. E., Casella, J. F., Chalazan, B., Chasman, D. I., Chen, Y. I., Cho, M. H., Choi, S. H., Chung, M. K., Clish, C. B., Correa, A., Curran, J. E., Custer, B., Darbar, D., Daya, M., de Andrade, M., DeMeo, D. L., Dutcher, S. K., Ellinor, P. T., Emery, L. S., Eng, C., Fatkin, D., Fingerlin, T., Forer, L., Fornage, M., Franceschini, N., Fuchsberger, C., Fullerton, S. M., Germer, S., Gladwin, M. T., Gottlieb, D. J., Guo, X., Hall, M. E., He, J., Heard-Costa, N. L., Heckbert, S. R., Irvin, M. R., Johnsen, J. M., Johnson, A. D., Kaplan, R., Kardia, S. L., Kelly, T., Kelly, S., Kenny, E. E., Kiel, D. P., Klemmer, R., Konkle, B. A., Kooperberg, C., Kottgen, A., Lange, L. A., Lasky-Su, J., Levy, D., Lin, X., Lin, K., Liu, C., Loos, R. J., Garman, L., Gerszten, R., Lubitz, S. A., Lunetta, K. L., Mak, A. C., Manichaikul, A., Manning, A. K., Mathias, R. A., McManus, D. D., McGarvey, S. T., Meigs, J. B., Meyers, D. A., Mikulla, J. L., Minear, M. A., Mitchell, B. D., Mohanty, S., Montasser, M. E., Montgomery, C., Morrison, A. C., Murabito, J. M., Natale, A., Natarajan, P., Nelson, S. C., North, K. E., O'Connell, J. R., Palmer, N. D., Pankratz, N., Peloso, G. M., Peyser, P. A., Pleiness, J., Post, W. S., Psaty, B. M., Rao, D. C., Redline, S., Reiner, A. P., Roden, D., Rotter, J. I., Ruczinski, I., Sarnowski, C., Schoenherr, S., Schwartz, D. A., Seo, J., Seshadri, S., Sheehan, V. A., Sheu, W. H., Shoemaker, M. B., Smith, N. L., Smith, J. A., Sotoodehnia, N., Stilp, A. M., Tang, W., Taylor, K. D., Telen, M., Thornton, T. A., Tracy, R. P., Van Den Berg, D. J., Vasan, R. S., Viaud-Martinez, K. A., Vrieze, S., Weeks, D. E., Weir, B. S., Weiss, S. T., Weng, L., Willer, C. J., Zhang, Y., Zhao, X., Arnett, D. K., Ashley-Koch, A. E., Barnes, K. C., Boerwinkle, E., Gabriel, S., Gibbs, R., Rice, K. M., Rich, S. S., Silverman, E. K., Qasba, P., Gan, W., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Papanicolaou, G. J., Nickerson, D. A., Browning, S. R., Zody, M. C., Zollner, S., Wilson, J. G., Cupples, L. A., Laurie, C. C., Jaquish, C. E., Hernandez, R. D., O'Connor, T. D., Abecasis, G. R., Abe, N., Almasy, L., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Assimes, T., Avramopoulos, D., Barron-Casella, E., Beaty, T., Beck, G., Becker, D., Beitelshees, A., Benos, T., Bezerra, M., Bis, J., Bowler, R., Broeckel, U., Broome, J., Bunting, K., Bustamante, C., Buth, E., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Castaldi, P., Chaffin, M., Chang, C., Chang, Y., Chavan, S., Chen, B., Chen, W., Chuang, L., Chung, R., Comhair, S., Cornell, E., Crandall, C., Crapo, J., Curtis, J., Damcott, C., David, S., Davis, C., Fuentes, L. d., DeBaun, M., Deka, R., Devine, S., Duan, Q., Duggirala, R., Durda, J. P., Eaton, C., Ekunwe, L., El Boueiz, A., Erzurum, S., Farber, C., Flickinger, M., Fornage, M., Frazar, C., Fu, M., Fulton, L., Gao, S., Gao, Y., Gass, M., Gelb, B., Geng, X. P., Geraci, M., Ghosh, A., Gignoux, C., Glahn, D., Gong, D., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Gupta, N., Haessler, J., Hawley, N. L., Heavner, B., Herrington, D., Hersh, C., Hidalgo, B., Hixson, J., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Hsiung, C. A., Hung, Y., Huston, H., Hwu, C. M., Jackson, R., Jain, D., Jhun, M. A., Johnson, C., Johnston, R., Jones, K., Kathiresan, S., Khan, A., Kim, W., Kinney, G., Kramer, H., Lange, C., Lange, E., Lange, L., Laurie, C., LeBoff, M., Lee, J., Lee, S. S., Lee, W., Levine, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Liu, S., Liu, Y., Liu, Y., Luo, J., Mahaney, M., Make, B., Manson, J., Margolin, L., Martin, L., Mathai, S., May, S., McArdle, P., McDonald, M., McFarland, S., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Min, N., Minster, R. L., Moll, M., Moscati, A., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Nekhai, S., Neltner, B., Ochs-Balcom, H., Paik, D., Pankow, J., Parsa, A., Peralta, J. M., Perez, M., Perry, J., Peters, U., Phillips, L. S., Pollin, T., Becker, J. P., Boorgula, M. P., Preuss, M., Qiao, D., Qin, Z., Rafaels, N., Raffield, L., Rasmussen-Torvik, L., Ratan, A., Reed, R., Regan, E., Reupena, M. S., Roselli, C., Russell, P., Ruuska, S., Ryan, K., Sabino, E. C., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Sankaran, V. G., Scheller, C., Schmidt, E., Schwander, K., Sciurba, F., Seidman, C., Seidman, J., Sherman, S. L., Shetty, A., Sheu, W. H., Silver, B., Smith, J., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Storm, G., Streeten, E., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Tang, H., Taub, M., Taylor, M., Taylor, S., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H., Tong, C., Tsai, M., Vaidya, D., VandeHaar, P., Walker, T., Wallace, R., Walts, A., Wang, F. F., Wang, H., Watson, K., Wessel, J., Williams, K., Williams, L. K., Wilson, C., Wu, J., Xu, H., Yanek, L., Yang, I., Yang, R., Zaghloul, N., Zekavat, M., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X. 2021; 590 (7845): 290–99

    Abstract

    The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

    View details for DOI 10.1038/s41586-021-03205-y

    View details for PubMedID 33568819

  • Palpitations in an Elite Running Athlete: When to Run Through the Beat? A Case Report. Current sports medicine reports Giacomazzi, C., Diaz, R., Syrop, I., Perez, M., Froelicher, V. F., Fredericson, M. 2021; 20 (2): 84–86

    View details for DOI 10.1249/JSR.0000000000000806

    View details for PubMedID 33560031

  • Research Priorities in Atrial Fibrillation Screening: A Report From a National Heart, Lung, and Blood Institute Virtual Workshop. Circulation Benjamin, E. J., Go, A. S., Desvigne-Nickens, P., Anderson, C. D., Casadei, B., Chen, L. Y., Crijns, H. J., Freedman, B., Hills, M. T., Healey, J. S., Kamel, H., Kim, D., Link, M. S., Lopes, R. D., Lubitz, S. A., McManus, D. D., Noseworthy, P. A., Perez, M. V., Piccini, J. P., Schnabel, R. B., Singer, D. E., Tieleman, R. G., Turakhia, M. P., Van Gelder, I. C., Cooper, L. S., Al-Khatib, S. M. 2021; 143 (4): 372–88

    Abstract

    Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.

    View details for DOI 10.1161/CIRCULATIONAHA.120.047633

    View details for PubMedID 33493033

  • Arrhythmias Other Than Atrial Fibrillation in Those With an Irregular Pulse Detected With a Smartwatch: Findings From the Apple Heart Study. Circulation. Arrhythmia and electrophysiology Perino, A. C., Gummidipundi, S. E., Lee, J., Hedlin, H., Garcia, A., Ferris, T., Balasubramanian, V., Gardner, R. M., Cheung, L., Hung, G., Granger, C. B., Kowey, P., Rumsfeld, J. S., Russo, A. M., True Hills, M., Talati, N., Nag, D., Tsay, D., Desai, S., Desai, M., Mahaffey, K. W., Turakhia, M. P., Perez, M. V. 2021: CIRCEP121010063

    Abstract

    The Apple watch irregular pulse detection algorithm was found to have a positive predictive value of 0.84 for identification of atrial fibrillation (AF). We sought to describe the prevalence of arrhythmias other than AF in those with an irregular pulse detected on a smartwatch.The Apple Heart Study investigated a smartwatch-based irregular pulse notification algorithm to identify AF. For this secondary analysis, we analyzed participants who received an ambulatory ECG patch after index irregular pulse notification. We excluded participants with AF identified on ECG patch and described the prevalence of other arrhythmias on the remaining participant ECG patches. We also reported the proportion of participants self-reporting subsequent AF diagnosis.Among 419 297 participants enrolled in the Apple Heart Study, 450 participant ECG patches were analyzed, with no AF on 297 ECG patches (66%). Non-AF arrhythmias (excluding supraventricular tachycardias <30 beats and pauses <3 seconds) were detected in 119 participants (40.1%) with ECG patches without AF. The most common arrhythmias were frequent PACs (burden ≥1% to <5%, 15.8%; ≥5% to <15%, 8.8%), atrial tachycardia (≥30 beats, 5.4%), frequent PVCs (burden ≥1% to <5%, 6.1%; ≥5% to <15%, 2.7%), and nonsustained ventricular tachycardia (4-7 beats, 6.4%; ≥8 beats, 3.7%). Of 249 participants with no AF detected on ECG patch and patient-reported data available, 76 participants (30.5%) reported subsequent AF diagnosis.In participants with an irregular pulse notification on the Apple Watch and no AF observed on ECG patch, atrial and ventricular arrhythmias, mostly PACs and PVCs, were detected in 40% of participants. Defining optimal care for patients with detection of incidental arrhythmias other than AF is important as AF detection is further investigated, implemented, and refined.

    View details for DOI 10.1161/CIRCEP.121.010063

    View details for PubMedID 34565178

  • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. European heart journal Walsh, R., Adler, A., Amin, A. S., Abiusi, E., Care, M., Bikker, H., Amenta, S., Feilotter, H., Nannenberg, E. A., Mazzarotto, F., Trevisan, V., Garcia, J., Hershberger, R. E., Perez, M. V., Sturm, A. C., Ware, J. S., Zareba, W., Novelli, V., Wilde, A. A., Gollob, M. H. 2021

    Abstract

    Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

    View details for DOI 10.1093/eurheartj/ehab687

    View details for PubMedID 34557911

  • Antiarrhythmic Drug Loading at Home Using Remote Monitoring: A Virtual Feasibility Study During COVID-19 Social Distancing European Heart Journal Digital Health Shah, R. L., Kapoor, R., Bonnett, C., Ottoboni, L. K., Tacklind, C., Tsiperfal, A., Perez, M. V. 2021

    View details for DOI 10.1093/ehjdh/ztab034

  • Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals with Atrial Fibrillation. Circulation. Genomic and precision medicine O'Sullivan, J. W., Shcherbina, A., Justesen, J. M., Turakhia, M., Perez, M., Wand, H., Tcheandjieu, C., Clarke, S. L., Rivas, M. A., Ashley, E. A. 2021

    Abstract

    Background - Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA2DS2-VASc) don't include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS). Methods - Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank, both independently and integrated with clinical risk factors. The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Results - Compared with the currently recommended risk tool (CHA2DS2-VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Using this improved tool, >115,000 people with AF would have improved risk classification in the US. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.06 to 1.23)). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson's correlation coefficient: -0.018). Conclusions - In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.

    View details for DOI 10.1161/CIRCGEN.120.003168

    View details for PubMedID 34029116

  • Consumer wearable technologies to identify and monitor exercise-related arrhythmias in athletes. Current opinion in cardiology Sanchis-Gomar, F., Lavie, C. J., Perez, M. V. 2020

    Abstract

    PURPOSE OF REVIEW: The aim of this study was to synthesize the current evidence supporting and against the use of wearable devices to detect underlying heart conditions in athletes and the most significant limitations.RECENT FINDINGS: Although several large studies have been conducted to evaluate the ability of wearables devices to identify atrial fibrillation among the general population, no studies evaluating their ability to detect other exercise-related arrhythmias in athletes are very sparse. Most of the studies or case reports are focused on the wearables' reliability and accuracy compared with standard ECG. Only small studies evaluating the accuracy of one wearable device in athletes have been carried out to date. Unfortunately, none of them have investigated their ability to detect specific arrhythmias in the athletic population.SUMMARY: Rapidly detecting dangerous arrhythmias in a symptomatic athlete continues to be an elusive goal. The use of smartphone ECG monitors can provide diagnostic data in athletes with symptoms that could represent a helpful instrument. However, many uncertainties remain and need to be addressed and validated in large-scale trials to incorporate these devices into the healthcare system and be part of an athlete's daily monitoring and healthcare.

    View details for DOI 10.1097/HCO.0000000000000817

    View details for PubMedID 33074935

  • Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature Bick, A. G., Weinstock, J. S., Nandakumar, S. K., Fulco, C. P., Bao, E. L., Zekavat, S. M., Szeto, M. D., Liao, X., Leventhal, M. J., Nasser, J., Chang, K., Laurie, C., Burugula, B. B., Gibson, C. J., Lin, A. E., Taub, M. A., Aguet, F., Ardlie, K., Mitchell, B. D., Barnes, K. C., Moscati, A., Fornage, M., Redline, S., Psaty, B. M., Silverman, E. K., Weiss, S. T., Palmer, N. D., Vasan, R. S., Burchard, E. G., Kardia, S. L., He, J., Kaplan, R. C., Smith, N. L., Arnett, D. K., Schwartz, D. A., Correa, A., de Andrade, M., Guo, X., Konkle, B. A., Custer, B., Peralta, J. M., Gui, H., Meyers, D. A., McGarvey, S. T., Chen, I. Y., Shoemaker, M. B., Peyser, P. A., Broome, J. G., Gogarten, S. M., Wang, F. F., Wong, Q., Montasser, M. E., Daya, M., Kenny, E. E., North, K. E., Launer, L. J., Cade, B. E., Bis, J. C., Cho, M. H., Lasky-Su, J., Bowden, D. W., Cupples, L. A., Mak, A. C., Becker, L. C., Smith, J. A., Kelly, T. N., Aslibekyan, S., Heckbert, S. R., Tiwari, H. K., Yang, I. V., Heit, J. A., Lubitz, S. A., Johnsen, J. M., Curran, J. E., Wenzel, S. E., Weeks, D. E., Rao, D. C., Darbar, D., Moon, J., Tracy, R. P., Buth, E. J., Rafaels, N., Loos, R. J., Durda, P., Liu, Y., Hou, L., Lee, J., Kachroo, P., Freedman, B. I., Levy, D., Bielak, L. F., Hixson, J. E., Floyd, J. S., Whitsel, E. A., Ellinor, P. T., Irvin, M. R., Fingerlin, T. E., Raffield, L. M., Armasu, S. M., Wheeler, M. M., Sabino, E. C., Blangero, J., Williams, L. K., Levy, B. D., Sheu, W. H., Roden, D. M., Boerwinkle, E., Manson, J. E., Mathias, R. A., Desai, P., Taylor, K. D., Johnson, A. D., NHLBI Trans-Omics for Precision Medicine Consortium, Auer, P. L., Kooperberg, C., Laurie, C. C., Blackwell, T. W., Smith, A. V., Zhao, H., Lange, E., Lange, L., Rich, S. S., Rotter, J. I., Wilson, J. G., Scheet, P., Kitzman, J. O., Lander, E. S., Engreitz, J. M., Ebert, B. L., Reiner, A. P., Jaiswal, S., Abecasis, G., Sankaran, V. G., Kathiresan, S., Natarajan, P., Abe, N., Albert, C., Almasy, L., Alonso, A., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Arking, D., Ashley-Koch, A., Aslibekyan, S., Assimes, T., Avramopoulos, D., Barnard, J., Barr, R. G., Barron-Casella, E., Barwick, L., Beaty, T., Beck, G., Becker, D., Beer, R., Beitelshees, A., Benjamin, E., Benos, P., Bezerra, M., Bielak, L., Bowler, R., Brody, J., Broeckel, U., Bunting, K., Bustamante, C., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Casella, J., Castaldi, P., Chaffin, M., Chang, C., Chang, Y., Chasman, D., Chavan, S., Chen, B., Chen, W., Choi, S. H., Chuang, L., Chung, M., Chung, R., Clish, C., Comhair, S., Cornell, E., Crandall, C., Crapo, J., Curtis, J., Damcott, C., Das, S., David, S., Davis, C., DeBaun, M., Deka, R., DeMeo, D., Devine, S., Duan, Q., Duggirala, R., Dutcher, S., Eaton, C., Ekunwe, L., Boueiz, A. E., Emery, L., Erzurum, S., Farber, C., Flickinger, M., Franceschini, N., Frazar, C., Fu, M., Fullerton, S. M., Fulton, L., Gabriel, S., Gan, W., Gao, S., Gao, Y., Gass, M., Gelb, B., Priscilla Geng, X., Geraci, M., Germer, S., Gerszten, R., Ghosh, A., Gibbs, R., Gignoux, C., Gladwin, M., Glahn, D., Gong, D., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Gupta, N., Haessler, J., Hall, M., Harris, D., Hawley, N. L., Heavner, B., Hernandez, R., Herrington, D., Hersh, C., Hidalgo, B., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Agnes Hsiung, C., Hung, Y., Huston, H., Hwu, C. M., Jackson, R., Jain, D., Jaquish, C., Jhun, M. A., Johnson, C., Johnston, R., Jones, K., Kang, H. M., Kelly, S., Kessler, M., Khan, A., Kim, W., Kinney, G., Kramer, H., Lange, C., LeBoff, M., Lee, S. S., Lee, W., LeFaive, J., Levine, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Lin, X., Liu, S., Liu, Y., Lunetta, K., Luo, J., Mahaney, M., Make, B., Manichaikul, A., Margolin, L., Martin, L., Mathai, S., May, S., McArdle, P., McDonald, M., McFarland, S., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Mikulla, J., Min, N., Minear, M., Minster, R. L., Moll, M., Montgomery, C., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Nekhai, S., Nelson, S. C., Neltner, B., Nickerson, D., O'Connell, J., O'Connor, T., Ochs-Balcom, H., Paik, D., Pankow, J., Papanicolaou, G., Parsa, A., Perez, M., Perry, J., Peters, U., Peyser, P., Phillips, L. S., Pollin, T., Post, W., Becker, J. P., Boorgula, M. P., Preuss, M., Qasba, P., Qiao, D., Qin, Z., Rasmussen-Torvik, L., Ratan, A., Reed, R., Regan, E., Sefuiva Reupena, M., Rice, K., Roselli, C., Ruczinski, I., Russell, P., Ruuska, S., Ryan, K., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Scheller, C., Schmidt, E., Schwander, K., Sciurba, F., Seidman, C., Seidman, J., Sheehan, V., Sherman, S. L., Shetty, A., Shetty, A., Silver, B., Smith, J., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Sotoodehnia, N., Stilp, A. M., Storm, G., Streeten, E., Su, J. L., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Taliun, D., Tang, H., Taylor, M., Taylor, S., Telen, M., Thornton, T. A., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H., Tong, C., Tsai, M., Vaidya, D., Berg, D. V., VandeHaar, P., Vrieze, S., Walker, T., Wallace, R., Walts, A., Wang, H., Watson, K., Weir, B., Weng, L., Wessel, J., Willer, C., Williams, K., Wilson, C., Wu, J., Xu, H., Yanek, L., Yang, R., Zaghloul, N., Zhang, Y., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X., Zody, M., Zoellner, S. 2020

    Abstract

    Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon istermed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIPdriver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

    View details for DOI 10.1038/s41586-020-2819-2

    View details for PubMedID 33057201

  • Digital Health and the Care of the Arrhythmia Patient; What Every Electrophysiologist Needs to Know. Circulation. Arrhythmia and electrophysiology Tarakji, K. G., Silva, J. N., Chen, L. Y., Turakhia, M. P., Perez, M. V., Attia, Z. I., Passman, R., Boissy, A., Cho, D. J., Majmudar, M., Mehta, N., Wan, E. Y., Chung, M. K. 2020

    Abstract

    The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and healthcare apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.

    View details for DOI 10.1161/CIRCEP.120.007953

    View details for PubMedID 33021815

  • Apelin increases atrial conduction velocity, refractoriness, and prevents inducibility of atrial fibrillation. JCI insight Kim, Y. M., Lakin, R., Zhang, H., Liu, J., Sachedina, A., Singh, M., Wilson, E., Perez, M., Verma, S., Quertermous, T., Olgin, J., Backx, P. H., Ashley, E. A. 2020; 5 (17)

    Abstract

    Previous studies have shown an association between elevated atrial NADPH-dependent oxidative stress and decreased plasma apelin in patients with atrial fibrillation (AF), though the basis for this relationship is unclear. In the current study, RT-PCR and immunofluorescence studies of human right atrial appendages (RAAs) showed expression of the apelin receptor, APJ, and reduced apelin content in the atria, but not in plasma, of patients with AF versus normal sinus rhythm. Disruption of the apelin gene in mice increased (2.4-fold) NADPH-stimulated superoxide levels and slowed atrial conduction velocities in optical mapping of a Langendorff-perfused isolated heart model, suggesting that apelin levels may influence AF vulnerability. Indeed, in mice with increased AF vulnerability (induced by chronic intense exercise), apelin administration reduced the incidence and duration of induced atrial arrhythmias in association with prolonged atrial refractory periods. Moreover, apelin decreased AF induction in isolated atria from exercised mice while accelerating conduction velocity and increasing action potential durations. At the cellular level, these changes were associated with increased atrial cardiomyocyte sodium currents. These findings support the conclusion that reduced atrial apelin is maladaptive in fibrillating human atrial myocardium and that increasing apelin bioavailability may be a worthwhile therapeutic strategy for treating and preventing AF.

    View details for DOI 10.1172/jci.insight.126525

    View details for PubMedID 32879139

  • Genetic Determinants of Electrocardiographic P-wave Duration and Relation to Atrial Fibrillation. Circulation. Genomic and precision medicine Weng, L., Hall, A. W., Choi, S. H., Jurgens, S. J., Haessler, J., Bihlmeyer, N. A., Grarup, N., Lin, H., Teumer, A., Li-Gao, R., Yao, J., Guo, X., Brody, J. A., Muller-Nurasyid, M., Schramm, K., Verweij, N., van den Berg, M. E., van Setten, J., Isaacs, A., Ramirez, J., Warren, H. R., Padmanabhan, S., Kors, J. A., de Boer, R. A., van der Meer, P., Sinner, M. F., Waldenberger, M., Psaty, B. M., Taylor, K. D., Volker, U., Kanters, J. K., Li, M., Alonso, A., Perez, M. V., Vaartjes, I., Bots, M. L., Huang, P. L., Heckbert, S. R., Lin, H. J., Kornej, J., Munroe, P. B., van Duijn, C. M., Asselbergs, F. W., Stricker, B. H., van der Harst, P., Kaab, S., Peters, A., Sotoodehnia, N., Rotter, J. I., Mook-Kanamori, D. O., Dorr, M., Felix, S. B., Linneberg, A., Hansen, T., Arking, D. E., Kooperberg, C., Benjamin, E. J., Lunetta, K. L., Ellinor, P. T., Lubitz, S. A. 2020

    Abstract

    Background - The P-wave duration (PWD) is an electrocardiographic (ECG) measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome chip data to examine the associations between common and rare variants with PWD. Methods - Fifteen studies comprising 64,440 individuals (56,943 European, 5,681 African, 1,186 Hispanic, 630 Asian), and ~230,000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and SKAT tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF GWAS. Results - We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (e.g., PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions - Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

    View details for DOI 10.1161/CIRCGEN.119.002874

    View details for PubMedID 32822252

  • Amiodarone in the COVID-19 Era: Treatment for Symptomatic Patients Only, or Drug to Prevent Infection? American journal of cardiovascular drugs : drugs, devices, and other interventions Sanchis-Gomar, F., Lavie, C. J., Morin, D. P., Perez-Quilis, C., Laukkanen, J. A., Perez, M. V. 2020

    Abstract

    Amiodarone, one of the most widely prescribed antiarrhythmic drugs to treat both ventricular and supraventricular arrhythmias, has been identified as a candidate drug for use against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We present the rationale of using amiodarone in the COVID-19 scenario, as well as whether or not amiodarone administration represents a potential strategy to prevent SARS-CoV-2 infection, rather than simply used to treat patients already symptomatic and/or with severe coronavirus disease 2019 (COVID-19), based on current evidence.

    View details for DOI 10.1007/s40256-020-00429-7

    View details for PubMedID 32737841

  • Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology. Circulation. Arrhythmia and electrophysiology Feeny, A. K., Chung, M. K., Madabhushi, A., Attia, Z. I., Cikes, M., Firouznia, M., Friedman, P. A., Kalscheur, M. M., Kapa, S., Narayan, S. M., Noseworthy, P. A., Passman, R. S., Perez, M. V., Peters, N. S., Piccini, J. P., Tarakji, K. G., Thomas, S. A., Trayanova, N. A., Turakhia, M. P., Wang, P. J. 2020

    Abstract

    Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.

    View details for DOI 10.1161/CIRCEP.119.007952

    View details for PubMedID 32628863

  • How Will Genetics Inform the Clinical Care of Atrial Fibrillation? CIRCULATION RESEARCH Shoemaker, M., Shah, R. L., Roden, D. M., Perez, M. 2020; 127 (1): 111–27
  • A Smartwatch to Identify Atrial Fibrillation REPLY NEW ENGLAND JOURNAL OF MEDICINE Turakhia, M. P., Desai, M., Perez, M. V. 2020; 382 (10): 975–76
  • An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition. Circulation Roberts, J. D., Asaki, S. Y., Mazzanti, A. n., Bos, J. M., Tuleta, I. n., Muir, A. R., Crotti, L. n., Krahn, A. D., Kutyifa, V. n., Shoemaker, M. B., Johnsrude, C. L., Aiba, T. n., Marcondes, L. n., Baban, A. n., Udupa, S. n., Dechert, B. n., Fischbach, P. n., Knight, L. M., Vittinghoff, E. n., Kukavica, D. n., Stallmeyer, B. n., Giudicessi, J. R., Spazzolini, C. n., Shimamoto, K. n., Tadros, R. n., Cadrin-Tourigny, J. n., Duff, H. J., Simpson, C. S., Roston, T. M., Wijeyeratne, Y. D., El Hajjaji, I. n., Yousif, M. D., Gula, L. J., Leong-Sit, P. n., Chavali, N. n., Landstrom, A. P., Marcus, G. M., Dittmann, S. n., Wilde, A. A., Behr, E. R., Tfelt-Hansen, J. n., Scheinman, M. M., Perez, M. V., Kaski, J. P., Gow, R. M., Drago, F. n., Aziz, P. F., Abrams, D. J., Gollob, M. H., Skinner, J. R., Shimizu, W. n., Kaufman, E. S., Roden, D. M., Zareba, W. n., Schwartz, P. J., Schulze-Bahr, E. n., Etheridge, S. P., Priori, S. G., Ackerman, M. J. 2020

    Abstract

    Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multi-center collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc > 460ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, p<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR]: 11.6, 95% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 patients relative to the overall heterozygous cohort (10.5% [2/19]; HR: 1.7, 95% CI: 0.3-10.8, p=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database (gnomAD), which is a human database of exome and genome sequencing data from now over 140,000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs. 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT-prolongation, however the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for JLNS2 patients.

    View details for DOI 10.1161/CIRCULATIONAHA.119.043114

    View details for PubMedID 31941373

  • Exercise-induced right ventricular injury or arrhythmogenic cardiomyopathy (ACM): The bright side and the dark side of the moon. Progress in cardiovascular diseases Leischik, R. n., Strauss, M. n., Horlitz, M. n., Pareja-Galeano, H. n., de la Guía-Galipienso, F. n., Lippi, G. n., Lavie, C. J., Perez, M. V., Sanchis-Gomar, F. n. 2020

    Abstract

    There is still debate on the range of normal physiologic changes of the right ventricle or ventricular (RV) function in athletes. Genetic links to arrhythmogenic cardiomyopathy (ACM) are well-established. There is no current consensus on the importance of extensive exercise and exercise-induced injury to the RV. During the intensive exercise of endurance sports, the cardiac structures adapt to athletic load over time. Some athletes develop RV cardiomyopathy possibly caused by genetic predisposition, whilst others develop arrhythmias from the RV. Endurance sports lead to increased volume and pressure load in both ventricles and increased myocardial mass. The extent of volume increase and changes in myocardial structure contribute to impairment of RV function and pose a challenge in cardiovascular sports medicine. Genetic predisposition to ACM may play an important role in the risk of sudden cardiac death of athletes. In this review, we discuss and evaluate existing results and opinions. Intensive training in competitive dynamic/power and endurance sports leads to specific RV adaptation, but physiological adaptation without genetic predisposition does not necessarily lead to severe complications in endurance sports. Discriminating between physiological adaptation and pathological form of ACM or RV impairment provoked by reinforced exercise presents a challenge to clinical sports cardiologists.

    View details for DOI 10.1016/j.pcad.2020.03.015

    View details for PubMedID 32224113

  • A Smartwatch to Identify Atrial Fibrillation. Reply. The New England journal of medicine Turakhia, M. P., Desai, M. n., Perez, M. V. 2020; 382 (10): 975–76

    View details for DOI 10.1056/NEJMc1916858

    View details for PubMedID 32130828

  • An International, Multicentered, EvidenceBased Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation Adler, A. n., Novelli, V. n., Amin, A. S., Abiusi, E. n., Care, M. n., Nannenberg, E. A., Feilotter, H. n., Amenta, S. n., Mazza, D. n., Bikker, H. n., Sturm, A. C., Garcia, J. n., Ackerman, M. J., Hershberger, R. E., Perez, M. V., Zareba, W. n., Ware, J. S., Wilde, A. A., Gollob, M. H. 2020

    View details for DOI 10.1161/CIRCULATIONAHA.119.043132

    View details for PubMedID 31983240

  • Accuracy of Smartphone Camera Applications for Detecting Atrial Fibrillation: A Systematic Review and Meta-analysis. JAMA network open O'Sullivan, J. W., Grigg, S. n., Crawford, W. n., Turakhia, M. P., Perez, M. n., Ingelsson, E. n., Wheeler, M. T., Ioannidis, J. P., Ashley, E. A. 2020; 3 (4): e202064

    Abstract

    Atrial fibrillation (AF) affects more than 6 million people in the United States; however, much AF remains undiagnosed. Given that more than 265 million people in the United States own smartphones (>80% of the population), smartphone applications have been proposed for detecting AF, but the accuracy of these applications remains unclear.To determine the accuracy of smartphone camera applications that diagnose AF.MEDLINE and Embase were searched until January 2019 for studies that assessed the accuracy of any smartphone applications that use the smartphone's camera to measure the amplitude and frequency of the user's fingertip pulse to diagnose AF.Bivariate random-effects meta-analyses were constructed to synthesize data. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) of Diagnostic Test Accuracy Studies reporting guideline.Sensitivity and specificity were measured with bivariate random-effects meta-analysis. To simulate the use of these applications as a screening tool, the positive predictive value (PPV) and negative predictive value (NPV) for different population groups (ie, age ≥65 years and age ≥65 years with hypertension) were modeled. Lastly, the association of methodological limitations with outcomes were analyzed with sensitivity analyses and metaregressions.A total of 10 primary diagnostic accuracy studies, with 3852 participants and 4 applications, were included. The oldest studies were published in 2016 (2 studies [20.0%]), while most studies (4 [40.0%]) were published in 2018. The applications analyzed the pulsewave signal for a mean (range) of 2 (1-5) minutes. The meta-analyzed sensitivity and specificity for all applications combined were 94.2% (95% CI, 92.2%-95.7%) and 95.8% (95% CI, 92.4%-97.7%), respectively. The PPV for smartphone camera applications detecting AF in an asymptomatic population aged 65 years and older was between 19.3% (95% CI, 19.2%-19.4%) and 37.5% (95% CI, 37.4%-37.6%), and the NPV was between 99.8% (95% CI, 99.83%-99.84%) and 99.9% (95% CI, 99.94%-99.95%). The PPV and NPV increased for individuals aged 65 years and older with hypertension (PPV, 20.5% [95% CI, 20.4%-20.6%] to 39.2% [95% CI, 39.1%-39.3%]; NPV, 99.8% [95% CI, 99.8%-99.8%] to 99.9% [95% CI, 99.9%-99.9%]). There were methodological limitations in a number of studies that did not appear to be associated with diagnostic performance, but this could not be definitively excluded given the sparsity of the data.In this study, all smartphone camera applications had relatively high sensitivity and specificity. The modeled NPV was high for all analyses, but the PPV was modest, suggesting that using these applications in an asymptomatic population may generate a higher number of false-positive than true-positive results. Future research should address the accuracy of these applications when screening other high-risk population groups, their ability to help monitor chronic AF, and, ultimately, their associations with patient-important outcomes.

    View details for DOI 10.1001/jamanetworkopen.2020.2064

    View details for PubMedID 32242908

  • Structural Abnormalities on Cardiac Magnetic Resonance Imaging in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia. JACC. Clinical electrophysiology Gerber, D. A., Dubin, A. M., Ceresnak, S. R., Motonaga, K. S., Bussineau, M. n., Dunn, K. n., Caleshu, C. n., Shoemaker, M. B., Lubitz, S. A., Perez, M. V. 2020; 6 (6): 741–42

    View details for DOI 10.1016/j.jacep.2020.03.006

    View details for PubMedID 32553227

  • Apple Watch App Identifies Clinically Important Arrhythmias Other Than Atrial Fibrillation: Results From the Apple Heart Study Perez, M. V., Mahaffey, K., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P. R., Talati, N., Nag, D., Gummidipundi, S., Beatty, A. L., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E988
  • Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study. European heart journal Larsson, S. C., Bäck, M., Rees, J. M., Mason, A. M., Burgess, S. 2019

    Abstract

    The causal role of adiposity for several cardiovascular diseases (CVDs) is unclear. Our primary aim was to apply the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 CVDs and arterial hypertension. We also assessed the roles of fat mass and fat-free mass on the same outcomes.Single-nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instrumental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was significantly positively associated with eight outcomes, including and with decreasing magnitude of association: aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio (OR) per 1 kg/m2 increase in BMI ranged from 1.06 [95% confidence interval (CI) 1.02-1.11; P = 2.6 × 10-3] for pulmonary embolism to 1.13 (95% CI 1.05-1.21; P = 1.2 × 10-3) for aortic valve stenosis. There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes (P < 0.05). The strongest magnitude of association was with aortic valve stenosis (OR per 1 kg/m2 increase in fat mass index 1.46, 95% CI 1.13-1.88; P = 3.9 × 10-3). There was suggestive evidence of inverse associations of fat-free mass index with atrial fibrillation, ischaemic stroke, and abdominal aortic aneurysm.This study provides evidence that higher BMI and particularly fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions.

    View details for DOI 10.1093/eurheartj/ehz388

    View details for PubMedID 31195408

  • Comparison of QT Interval Measurement Methods and Correction Formulas in Atrial Fibrillation AMERICAN JOURNAL OF CARDIOLOGY Tooley, J., Ouyang, D., Hadley, D., Turakhia, M., Wang, P., Ashley, E., Froelicher, V., Perez, M. 2019; 123 (11): 1822–27
  • No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation DIABETOLOGIA Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019; 62 (5): 800–804
  • Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited CLINICAL JOURNAL OF SPORT MEDICINE Kooreman, Z., Giraldeau, G., Finocchiaro, G., Kobayashi, Y., Wheeler, M., Perez, M., Moneghetti, K., Oxborough, D., George, K. P., Myers, J., Ashley, E., Haddad, F. 2019; 29 (3): 224–31
  • Body composition and atrial fibrillation: a Mendelian randomization study EUROPEAN HEART JOURNAL Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S., Ingelsson, E. 2019; 40 (16): 1277-+
  • Comparison of QT Interval Measurement Methods and Correction Formulas in Atrial Fibrillation. The American journal of cardiology Tooley, J., Ouyang, D., Hadley, D., Turakhia, M., Wang, P., Ashley, E., Froelicher, V., Perez, M. 2019

    Abstract

    Antiarrhythmic drugs used in atrial fibrillation (AF) cause QT prolongation and are associated with torsades de pointes, a deadly ventricular arrhythmia. No consensus exists on the optimal method of QT measurement or correction in AF. Therefore, we compared common methods to measure and correct QT in AF to identify the most accurate approach. We identified patients who had electrocardiograms done at Stanford Hospital (Stanford, California) between January 2014 and October 2016 with conversion from AF to sinus rhythm (SR) within a 24-hour period. QT intervals were determined using different measurement methods and corrected using the Bazett's, Framingham, Fridericia, or Hodges formulas for heart rate (HR). Comparisons were made between QT in a patient's last instance of AF to SR. Computerized measurements were taken from 715 patients. Manual measurements were taken from a 50-patient subset. Bazett's formula produced the longest corrected QT in AF compared with other formulas (p <0.005). Measuring QT as an average over multiple beats resulted in a smaller difference between AF and SR than choosing a single beat. Determining QT from a 5-beat average resulted in a QTc that was 19.0ms higher (interquartile range 0.30 to 43.7) in AF than SR. After correcting for residual effect of HR on QTc, there was not a significant difference between QTc in AF to SR. In conclusion, measuring QT over multiple beats produces a more accurate measurement of QT in AF. Differences between QTc in AF and SR exist because of imperfect HR correction formula and not due to an independent effect of AF.

    View details for PubMedID 30961909

  • Vitamin D with calcium supplementation and risk of atrial fibrillation in postmenopausal women AMERICAN HEART JOURNAL Boursiquot, B. C., Larson, J. C., Shalash, O. A., Vitolins, M. Z., Soliman, E. Z., Perez, M. 2019; 209: 68–78
  • No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E., Knowles, J. W. 2019

    Abstract

    AIMS/HYPOTHESIS: Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.METHODS: Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA1c on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.RESULTS: Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p=0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p=0.49) or HbA1c (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p=0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA1c, respectively, for associations with atrial fibrillation.CONCLUSIONS/INTERPRETATION: This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA1c and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.DATA AVAILABILITY: The datasets analysed during the current study are available from the following repository: Nielsen JB, Thorolfsdottir RB, Fritsche LG, et al (2018) GWAS summary statistics for AF (N=60,620 AF cases and 970,216 controls). Center for Statistical Genetics: http://csg.sph.umich.edu/willer/public/afib2018/nielsen-thorolfsdottir-willer-NG2018-AFib-gwas-summary-statistics.tbl.gz.

    View details for PubMedID 30810766

  • Body composition and atrial fibrillation: a Mendelian randomization study. European heart journal Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S., Ingelsson, E. 2019

    Abstract

    Aims: Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.Methods and results: We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N=487404, N events=10365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR)=1.77, 95% confidence interval (CI) 1.72-1.83; HR=1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).Conclusion: Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.

    View details for PubMedID 30721963

  • Athletic Remodeling in Female College Athletes: The "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z. n., Giraldeau, G. n., Finocchiaro, G. n., Kobayashi, Y. n., Wheeler, M. n., Perez, M. n., Moneghetti, K. n., Oxborough, D. n., George, K. P., Myers, J. n., Ashley, E. n., Haddad, F. n. 2019; 29 (3): 224–31

    Abstract

    There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

    View details for PubMedID 31033616

  • Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study AMERICAN HEART JOURNAL Turakhia, M. P., Desai, M., Hedlin, H., Rajmane, A., Talati, N., Ferris, T., Desai, S., Nag, D., Patel, M., Kowey, P., Rumsfeld, J. S., Russo, A. M., Hills, M., Granger, C. B., Mahaffey, K. W., Perez, M. V. 2019; 207: 66–75
  • Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes NEUROLOGY-GENETICS Pulit, S. L., Weng, L., McArdle, P. F., Trinquart, L., Choi, S., Mitchell, B. D., Rosand, J., de Bakker, P. W., Benjamin, E. J., Ellinor, P. T., Kittner, S. J., Lubitz, S. A., Anderson, C. D., Christophersen, I. E., Rienstra, M., Roselli, C., Yin, X., Geelhoed, B., Barnard, J., Lin, H., Arking, D. E., Smith, A., Albert, C. M., Chaffin, M., Tucker, N. R., Li, M., Klarin, D., Bihlmeyer, N. A., Low, S., Weeke, P. E., Mueller-Nurasyid, M., Smith, J., Brody, J. A., Niemeijer, M. N., Doerr, M., Trompet, S., Huffman, J., Gustafsson, S., Schurmann, C., Kleber, M. E., Lyytikainen, L., Seppala, I., Malik, R., Horimoto, A. R., Perez, M., Sinisalo, J., Aeschbacher, S., Theriault, S., Yao, J., Radmanesh, F., Weiss, S., Teumer, A., Clauss, S., Deo, R., Rader, D. J., Shah, S., Sun, A., Hopewell, J. C., Debette, S., Chauhan, G., Yang, Q., Worrall, B. B., Pare, G., Kamatani, Y., Hagemeijer, Y. P., Verweij, N., Siland, J. E., Kubo, M., Smith, J. D., Van Wagoner, D. R., Bis, J. C., Perz, S., Psaty, B. M., Ridker, P. M., Magnani, J. W., Harris, T. B., Launer, L. J., Shoemaker, M., Padmanabhan, S., Haessler, J., Bartz, T. M., Waldenberger, M., Lichtner, P., Arendt, M., Krieger, J. E., Kahonen, M., Risch, L., Mansur, A. J., Peters, A., Smith, B. H., Lind, L., Scott, S. A., Lu, Y., Bottinger, E. B., Hernesniemi, J., Lindgren, C. M., Wong, J. A., Huang, J., Eskola, M., Morris, A. P., Ford, I., Reiner, A. P., Delgado, G., Chen, L. Y., Chen, Y., Sandhu, R. K., Li, M., Boerwinkle, E., Eisele, L., Lannfelt, L., Rost, N., Taylor, K. D., Campbell, A., Magnusson, P. K., Porteous, D., Hocking, L. J., Vlachopoulou, E., Pedersen, N. L., Nikus, K., Orho-Melander, M., Hamsten, A., Heeringa, J., Denny, J. C., Kriebel, J., Darbar, D., Newton-Cheh, C., Shaffer, C., Macfarlane, P. W., Heilmann, S., Almgren, P., Huang, P. L., Sotoodehnia, N., Soliman, E. Z., Uitterlinden, A. G., Hofman, A., Franco, O. H., Voelker, U., Joeckel, K., Sinner, M. F., Lin, H. J., Guo, X., Dichgans, M., Ingelsson, E., Kooperberg, C., Melander, O., Loos, R. F., Laurikka, J., Conen, D., van der Harst, P., Lokki, M., Kathiresan, S., Pereira, A., Jukema, J., Hayward, C., Rotter, J., Maerz, W., Lehtimaki, T., Stricker, B. H., Chung, M. K., Felix, S. B., Gudnason, V., Alonso, A., Roden, D. M., Kaeaeb, S., Chasman, D., Heckbert, S. R., Tanaka, T., Lunetta, K. L., Smoller, S., Sorkin, J., Wang, X., Selim, M., Pikula, A., Wolf, P., Seshadri, S., de Bakker, P., Chasman, D., Rexrode, K., Chen, I., Rotter, J., Luke, M., Sale, M., Lee, T., Chang, K., Elkind, M., Goldstein, L., James, M., Breteler, M., O'Donnell, C., Leys, D., Carty, C., Kidwell, C., Olesen, J., Sharma, P., Rich, S., Tatlisumak, T., Happola, O., Bijlenga, P., Soriano, C., Giralt, E., Roquer, J., Jimenez-Conde, J., Cotlarcius, I., Hardy, J., Korostynski, M., Boncoraglio, G., Ballabio, E., Parati, E., Mateusz, A., Urbanik, A., Dziedzic, T., Jagiella, J., Gasowski, J., Wnuk, M., Olszanecki, R., Pera, J., Slowik, A., Juchniewicz, K., Levi, C., Nyquist, P., Cendes, I., Cabral, N., Franca, P., Goncalves, A., Keller, L., Crisby, M., Kostulas, K., Lemmens, R., Ahmadi, K., Opherk, C., Duering, M., Gonik, M., Staals, J., Burri, P., Sadr-Nabavi, A., Romero, J., Biffi, A., Anderson, C., Falcone, G., Brouwers, B., Du, R., Kourkoulis, C., Battey, T., Lubitz, S., Mueller-Myhsok, B., Meschia, J., Brott, T., Pichler, A., Enzinger, C., Schmidt, H., Schmidt, R., Seiler, S., Blanton, S., Yamada, Y., Bersano, A., Rundek, T., Sacco, R., Chan, Y., Gschwendtner, A., Deng, Z., Barr, T., Gwinn, K., Corriveau, R., Singleton, A., Waddy, S., Launer, L., Chen, C., Le, K., Lee, W., Tan, E., Olugbodi, A., Rothwell, P., Schilling, S., Mok, V., Lebedeva, E., Jern, C., Jood, K., Olsson, S., Kim, H., Lee, C., Kilarski, L., Markus, H., Peycke, J., Bevan, S., Sheu, W., Chiou, H., Chern, J., Giraldo, E., Taqi, M., Jain, V., Lam, O., Howard, G., Woo, D., Kittner, S., Mitchell, B., Cole, J., O'Connell, J., Milewicz, D., Illoh, K., Worrall, B., Stine, C., Karaszewski, B., Werring, D., Sofat, R., Smalley, J., Lindgren, A., Hansen, B., Norrving, B., Smith, G., Jose Martin, J., Thijs, V., Klijn, K., van't Hof, F., Algra, A., Macleod, M., Perry, R., Arnett, D., Pezzini, A., Padovani, A., Cramer, S., Fisher, M., Saleheen, D., Broderick, J., Kissela, B., Doney, A., Sudlow, C., Rannikmae, K., Silliman, S., McDonough, C., Walters, M., Pedersen, A., Nakagawa, K., Chang, C., Dobbins, M., McArdle, P., Chang, Y., Brown, R., Brown, D., Holliday, E., Kalaria, R., Maguire, J., Attia, J., Farrall, M., Giese, A., Fornage, M., Majersik, J., Cushman, M., Keene, K., Bennett, S., Tirschwell, D., Psaty, B., Reiner, A., Longstreth, W., Spence, D., Montaner, J., Fernandez-Cadenas, I., Langefeld, C., Bushnell, C., Heitsch, L., Lee, J., Sheth, K., Atrial Fibrillation Genetics Conso, Int Stroke Genetics Consortium 2018; 4 (6): e293

    Abstract

    We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk.We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10-4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10-48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1).Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

    View details for DOI 10.1212/NXG.0000000000000293

    View details for Web of Science ID 000455099800017

    View details for PubMedID 30584597

    View details for PubMedCentralID PMC6283455

  • Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study. American heart journal Turakhia, M. P., Desai, M., Hedlin, H., Rajmane, A., Talati, N., Ferris, T., Desai, S., Nag, D., Patel, M., Kowey, P., Rumsfeld, J. S., Russo, A. M., Hills, M. T., Granger, C. B., Mahaffey, K. W., Perez, M. V. 2018

    Abstract

    BACKGROUND: Smartwatch and fitness band wearable consumer electronics can passively measure pulse rate from the wrist using photoplethysmography (PPG). Identification of pulse irregularity or variability from these data has the potential to identify atrial fibrillation or atrial flutter (AF, collectively). The rapidly expanding consumer base of these devices allows for detection of undiagnosed AF at scale.METHODS: The Apple Heart Study is a prospective, single arm pragmatic study that has enrolled 419,093 participants (NCT03335800). The primary objective is to measure the proportion of participants with an irregular pulse detected by the Apple Watch (Apple Inc, Cupertino, CA) with AF on subsequent ambulatory ECG patch monitoring. The secondary objectives are to: 1) characterize the concordance of pulse irregularity notification episodes from the Apple Watch with simultaneously recorded ambulatory ECGs; 2) estimate the rate of initial contact with a health care provider within 3 months after notification of pulse irregularity. The study is conducted virtually, with screening, consent and data collection performed electronically from within an accompanying smartphone app. Study visits are performed by telehealth study physicians via video chat through the app, and ambulatory ECG patches are mailed to the participants.CONCLUSIONS: The results of this trial will provide initial evidence for the ability of a smartwatch algorithm to identify pulse irregularity and variability which may reflect previously unknown AF. The Apple Heart Study will help provide a foundation for how wearable technology can inform the clinical approach to AF identification and screening.

    View details for PubMedID 30392584

  • Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy. Circulation. Heart failure Lee, S., Ashley, E. A., Homburger, J., Caleshu, C., Green, E. M., Jacoby, D., Colan, S. D., Arteaga-Fernandez, E., Day, S. M., Girolami, F., Olivotto, I., Michels, M., Ho, C. Y., Perez, M. V., SHaRe Investigators 2018; 11 (9): e005191

    Abstract

    Background Although atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) patients, the relationship between genetic variation and AF has been poorly defined. Characterizing genetic subtypes of HCM and their associations with AF may help to improve personalized medical care. We aimed to investigate the link between sarcomeric gene variation and incident AF in HCM patients. Methods and Results Patients from the multinational Sarcomeric Human Cardiomyopathy Registry were followed for incident AF. Those with likely pathogenic or pathogenic variants in sarcomeric genes were included. The AF incidence was ascertained by review of medical records and electrocardiograms at each investigative site. One thousand forty adult HCM patients, without baseline AF and with likely pathogenic or pathogenic variation in either MYH7 (n=296), MYBPC3 (n=659), or thin filament genes (n=85), were included. Compared with patients with variation in other sarcomeric genes, those with MYH7 variants were younger on first clinical encounter at the Sarcomeric Human Cardiomyopathy Registry site and more likely to be probands than the MYBPC3 variants. During an average follow-up of 7.2 years, 198 incident AF events occurred. Patients with likely pathogenic or pathogenic mutations in MYH7 had the highest incidence of AF after adjusting for age, sex, proband status, left atrial size, maximal wall thickness, and peak pressure gradient (hazard ratio, 1.7; 95% CI, 1.1-2.6; P=0.009). Conclusions During a mean follow-up of 7.2 years, new-onset AF developed in 19% of HCM patients with sarcomeric mutations. Compared with other sarcomeric genes, patients with likely pathogenic or pathogenic variation in MYH7 had a higher rate of incident AF independent of clinical and echocardiographic factors.

    View details for PubMedID 30354366

  • Effects of reproductive period duration and number of pregnancies on midlife ECG indices: a secondary analysis from the Women's Health Initiative Clinical Trial BMJ OPEN Parikh, N. I., Kapphahn, K., Hedlin, H., Olgin, J. E., Allison, M. A., Magnani, J. W., Ryckman, K. R., Waring, M. E., Perez, M., Howard, B. V. 2018; 8 (8): e019129

    Abstract

    Pregnancy, menses and menopause are related to fluctuations in endogenous sex hormones in women, which cumulatively may alter cardiac electrical conduction. Therefore, we sought to study the association between number of pregnancies and reproductive period duration (RD, time from menarche to menopause) with ECG intervals in the Women's Health Initiative Clinical Trials.Secondary analysis of multicentre clinical trial.USA.ECGintervals: PR interval, P-wave duration, P-wave dispersion, QTc interval.n=40 687 women (mean age=62 years) participating in the Women's Health Initiative Clinical Trials. 82.5% were white, 9.3% black, 4% Hispanic and 2.7% Asian.In primary analysis, we employed multivariable linear regression models relating number of pregnancies and RD with millisecond changes in intervals from enrolment ECG. We studied effect modification by hormone therapy use.Among participants, 5+ live births versus 0 prior pregnancies was associated with a 1.32 ms increase in PR interval (95% CI 0.25 to 2.38), with a graded association with longer QTc interval (ms) (none (prior pregnancy, no live births)=0.66 (-0.56 to 1.88), 1=0.15 (-0.71 to 1.02), 2-4=0.25 (-0.43 to 0.94) and 5+ live births=1.15 (0.33 to 1.98), p=0.008). RD was associated with longer PR interval and maximum P-wave duration (but not P-wave dispersion) among never users of hormone therapy: (PR (ms) per additional RD year: 0.10 (0.04 to 0.16); higher P-wave duration (ms): 0.09 (0.06 to 0.12)). For every year increase in reproductive period, QTc decreased by 0.04 ms (-0.07 to -0.01).An increasing number of live births is related to increased and RD to decreased ventricular repolarisation time. Both grand multiparity and longer RD are related to increased atrial conduction time. Reproductive factors that alter midlife cardiac electrical conduction system remodelling in women may modestly influence cardiovascular disease risk in later life.NCT00000611; Post-results.

    View details for PubMedID 30121588

  • Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6 GENOME BIOLOGY Prins, B. P., Mead, T. J., Brody, J. A., Sveinbjornsson, G., Ntalla, I., Bihlmeyer, N. A., van den Berg, M., Bork-Jensen, J., Cappellani, S., Van Duijvenboden, S., Klena, N. T., Gabriel, G. C., Liu, X., Gulec, C., Grarup, N., Haessler, J., Hall, L. M., Iorio, A., Isaacs, A., Li-Gao, R., Lin, H., Liu, C., Lyytikainen, L., Marten, J., Mei, H., Mueller-Nurasyid, M., Orini, M., Padmanabhan, S., Radmanesh, F., Ramirez, J., Robino, A., Schwartz, M., van Setten, J., Smith, A. V., Verweij, N., Warren, H. R., Weiss, S., Alonso, A., Arnar, D. O., Bots, M. L., de Boer, R. A., Dominiczak, A. F., Eijgelsheim, M., Ellinor, P. T., Guo, X., Felix, S. B., Harris, T. B., Hayward, C., Heckbert, S. R., Huang, P. L., Jukema, J. W., Kahonen, M., Kors, J. A., Lambiase, P. D., Launer, L. J., Li, M., Linneberg, A., Nelson, C. P., Pedersen, O., Perez, M., Peters, A., Polasek, O., Psaty, B. M., Raitakari, O. T., Rice, K. M., Rotter, J. I., Sinner, M. F., Soliman, E. Z., Spector, T. D., Strauch, K., Thorsteinsdottir, U., Tinker, A., Trompet, S., Uitterlinden, A., Vaartjes, I., van der Meer, P., Voelker, U., Voelzke, H., Waldenberger, M., Wilson, J. G., Xie, Z., Asselbergs, F. W., Doerr, M., van Duijn, C. M., Gasparini, P., Gudbjartsson, D. F., Gudnason, V., Hansen, T., Kaeaeb, S., Kanters, J. K., Kooperberg, C., Lehtimaki, T., Lin, H. J., Lubitz, S. A., Mook-Kanamori, D. O., Conti, F. J., Newton-Cheh, C. H., Rosand, J., Rudan, I., Samani, N. J., Sinagra, G., Smith, B. H., Holm, H., Stricker, B. H., Ulivi, S., Sotoodehnia, N., Apte, S. S., van der Harst, P., Stefansson, K., Munroe, P. B., Arking, D. E., Lo, C. W., Jamshidi, Y. 2018; 19: 87

    Abstract

    Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

    View details for PubMedID 30012220

  • Genome Editing of Induced PluripotentStem Cells to Decipher CardiacChannelopathy Variant. Journal of the American College of Cardiology Garg, P., Oikonomopoulos, A., Chen, H., Li, Y., Lam, C. K., Sallam, K., Perez, M., Lux, R. L., Sanguinetti, M. C., Wu, J. C. 2018; 72 (1): 62–75

    Abstract

    BACKGROUND: The long QT syndrome (LQTS) is an arrhythmogenic disorder of QT interval prolongation that predisposes patients to life-threatening ventricular arrhythmias such as Torsades de pointes and sudden cardiac death. Clinical genetic testing has emerged as the standard of care to identify genetic variants in patients suspected of having LQTS. However, these results are often confounded by the discovery of variants of uncertain significance (VUS), for which there is insufficient evidence of pathogenicity.OBJECTIVES: The purpose of this study was to demonstrate that genome editing of patient-specific induced pluripotent stem cells (iPSCs) can be a valuable approach to delineate the pathogenicity of VUS in cardiac channelopathy.METHODS: Peripheral blood mononuclear cells were isolated from a carrier with a novel missense variant (T983I) in the KCNH2 (LQT2) gene and an unrelated healthy control subject. iPSCs were generated using an integration-free Sendai virus and differentiated to iPSC-derived cardiomyocytes (CMs).RESULTS: Whole-cell patch clamp recordings revealed significant prolongation of the action potential duration (APD) and reduced rapidly activating delayed rectifier K+ current (IKr) density in VUS iPSC-CMs compared with healthy control iPSC-CMs. ICA-105574, a potent IKr activator, enhanced IKr magnitude and restored normal action potential duration in VUS iPSC-CMs. Notably, VUS iPSC-CMs exhibited greater propensity to proarrhythmia than healthy control cells in response to high-risk torsadogenic drugs (dofetilide, ibutilide, and azimilide), suggesting a compromised repolarization reserve. Finally, the selective correction of the causal variant in iPSC-CMs using CRISPR/Cas9 gene editing (isogenic control) normalized the aberrant cellular phenotype, whereas the introduction of the homozygous variant in healthy control cells recapitulated hallmark features of the LQTS disorder.CONCLUSIONS: The results suggest that the KCNH2T983I VUS may be classified as potentially pathogenic.

    View details for PubMedID 29957233

  • Thiazolidinediones and Risk of Atrial Fibrillation Among Patients with Diabetes and Coronary Disease AMERICAN JOURNAL OF MEDICINE Pallisgaard, J., Brooks, M., Chaitman, B. R., Boothroyd, D. B., Pere, M., Hlatk, M. A., Bypass Angioplasty Revascularizati 2018; 131 (7): 805–12

    Abstract

    We sought to determine whether insulin-sensitizing therapy (thiazolidinediones or metformin) decreased the risk of developing atrial fibrillation compared with insulin-providing therapy (insulin, sulfonylurea, or a meglitinide). Thiazolidinediones are insulin sensitizers that also decrease the inflammatory response. Because inflammation is a risk factor for atrial fibrillation, we hypothesized that treating diabetes with thiazolidinediones might decrease the risk of developing atrial fibrillation.The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial enrolled patients with type 2 diabetes and documented coronary artery disease. All patients were randomized to insulin-sensitizing therapy or insulin-providing therapy.A total of 2319 patients entered the study, with 1160 assigned to the insulin-sensitization strategy and 1159 assigned to the insulin-provision strategy. Over a median follow-up of 4.2 years, 90 patients (3.9%) developed new-onset atrial fibrillation. In the intention-to-treat analysis, the incidence of atrial fibrillation was 8.7 per 1000 person-years in patients assigned to insulin sensitization compared with 9.5 in patients assigned to insulin provision with a hazard ratio (HR) of 0.91 (95% confidence interval [CI], 0.60-1.38, P = .66). In a time-varying exposure analysis, the incidence rate per 1000 person-years was 7.2 while exposed to thiazolidinediones and 9.7 while not exposed to thiazolidinediones with an adjusted HR of 0.80 (95% CI, 0.33-1.94, P = .62). In a subset of patients matched on propensity to receive a thiazolidinediones, the HR was 0.75 (95% CI, 0.43-1.30, P = .30).We did not find a significant reduction of atrial fibrillation incidence with use of thiazolidinediones.

    View details for PubMedID 29581079

  • Atrial Fibrillation Burden: Moving Beyond Atrial Fibrillation as a Binary Entity: A Scientific Statement From the American Heart Association. Circulation Chen, L. Y., Chung, M. K., Allen, L. A., Ezekowitz, M., Furie, K. L., McCabe, P., Noseworthy, P. A., Perez, M. V., Turakhia, M. P. 2018; 137 (20): e623-e644

    Abstract

    Our understanding of the risk factors and complications of atrial fibrillation (AF) is based mostly on studies that have evaluated AF in a binary fashion (present or absent) and have not investigated AF burden. This scientific statement discusses the published literature and knowledge gaps related to methods of defining and measuring AF burden, the relationship of AF burden to cardiovascular and neurological outcomes, and the effect of lifestyle and risk factor modification on AF burden. Many studies examine outcomes by AF burden classified by AF type (paroxysmal versus nonparoxysmal); however, quantitatively, AF burden can be defined by longest duration, number of AF episodes during a monitoring period, and the proportion of time an individual is in AF during a monitoring period (expressed as a percentage). Current guidelines make identical recommendations for anticoagulation regardless of AF pattern or burden; however, a review of recent evidence suggests that higher AF burden is associated with higher risk of stroke. It is unclear whether the risk increases continuously or whether a threshold exists; if a threshold exists, it has not been defined. Higher burden of AF is also associated with higher prevalence and incidence of heart failure and higher risk of mortality, but not necessarily lower quality of life. A structured and comprehensive risk factor management program targeting risk factors, weight loss, and maintenance of a healthy weight appears to be effective in reducing AF burden. Despite this growing understanding of AF burden, research is needed into validation of definitions and measures of AF burden, determination of the threshold of AF burden that results in an increased risk of stroke that warrants anticoagulation, and discovery of the mechanisms underlying the weak temporal correlations of AF and stroke. Moreover, developments in monitoring technologies will likely change the landscape of long-term AF monitoring and could allow better definition of the significance of changes in AF burden over time.

    View details for DOI 10.1161/CIR.0000000000000568

    View details for PubMedID 29661944

  • Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. Circulation. Genomic and precision medicine Lin, H., van Setten, J., Smith, A. V., Bihlmeyer, N. A., Warren, H. R., Brody, J. A., Radmanesh, F., Hall, L., Grarup, N., Muller-Nurasyid, M., Boutin, T., Verweij, N., Lin, H. J., Li-Gao, R., van den Berg, M. E., Marten, J., Weiss, S., Prins, B. P., Haessler, J., Lyytikainen, L., Mei, H., Harris, T. B., Launer, L. J., Li, M., Alonso, A., Soliman, E. Z., Connell, J. M., Huang, P. L., Weng, L., Jameson, H. S., Hucker, W., Hanley, A., Tucker, N. R., Chen, Y. I., Bis, J. C., Rice, K. M., Sitlani, C. M., Kors, J. A., Xie, Z., Wen, C., Magnani, J. W., Nelson, C. P., Kanters, J. K., Sinner, M. F., Strauch, K., Peters, A., Waldenberger, M., Meitinger, T., Bork-Jensen, J., Pedersen, O., Linneberg, A., Rudan, I., de Boer, R. A., van der Meer, P., Yao, J., Guo, X., Taylor, K. D., Sotoodehnia, N., Rotter, J. I., Mook-Kanamori, D. O., Trompet, S., Rivadeneira, F., Uitterlinden, A., Eijgelsheim, M., Padmanabhan, S., Smith, B. H., Volzke, H., Felix, S. B., Homuth, G., Volker, U., Mangino, M., Spector, T. D., Bots, M. L., Perez, M., Kahonen, M., Raitakari, O. T., Gudnason, V., Arking, D. E., Munroe, P. B., Psaty, B. M., van Duijn, C. M., Benjamin, E. J., Rosand, J., Samani, N. J., Hansen, T., Kaab, S., Polasek, O., van der Harst, P., Heckbert, S. R., Jukema, J. W., Stricker, B. H., Hayward, C., Dorr, M., Jamshidi, Y., Asselbergs, F. W., Kooperberg, C., Lehtimaki, T., Wilson, J. G., Ellinor, P. T., Lubitz, S. A., Isaacs, A. 2018; 11 (5): e002037

    Abstract

    BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.METHODS: We performed large-scale meta-analyses of the PR interval that included 83367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2*10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9*10-11) and SCN5A (P=1.1*10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus.CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

    View details for PubMedID 29748316

  • Large Q and S waves in lead III on the electrocardiogram distinguish patients with hypertrophic cardiomyopathy from athletes. Heart (British Cardiac Society) Chen, A. S., Bent, R. E., Wheeler, M., Knowles, J. W., Haddad, F., Froelicher, V., Ashley, E., Perez, M. V. 2018

    Abstract

    OBJECTIVE: To identify electrocardiographic findings, especially deep Q and S waves in lead III, that differentiate athletes from patients with hypertrophic cardiomyopathy (HCM).METHODS: Digital ECGs of athletes and patients with HCM followed at the Stanford Center for Inherited Cardiovascular Disease were studied retrospectively. All patients with HCM had an echocardiogram performed. A multivariable logistic regression model was used to calculate ORs for various demographic and ECG characteristics. Linear regression was used to correlate ECG characteristics with echocardiogram findings.RESULTS: We studied 1124 athletes and 240 patients with HCM. The average Q+Swave amplitude in lead III (IIIQ+S) was significantly higher in patients with HCM compared with athletes (0.71±0.69mV vs 0.21±0.17mV, p<0.001). In patients with HCM, IIIQ+S directly correlated with interventricular septal (IVS) thickness on echocardiography (rho=0.45, p<0.001). In a multivariable analysis adjusted for demographic and ECG characteristics, higher IIIQ+S values remained independently associated with HCM compared with athletes (OR=4.2 per 0.5mV, p<0.001). In subgroup analyses of young patients, African-American subjects and subjects without left axis deviation (LAD), IIIQ+S remained associated with HCM. The addition of IIIQ+S>1.0 mV as an abnormal finding to the International Criteria for athletic ECG interpretation improved sensitivity from 64.2% to 70.4%, with a minimal decrease in specificity.CONCLUSION: Large Q and S waves in lead III distinguished athletes from patients with HCM, independent of axis and well-known ECG markers associated with HCM. The correlation between IVS thickness in patients with HCM and IIIQ+S suggests a partial explanation for this association.

    View details for PubMedID 29680808

  • Ring Finger Protein 207 Degrades T613M Kv11.1 Channel Ledford, H. A., Park, S., Sirish, P., Xu, W., Emigh, A. M., Timofeyev, V., Priest, J. R., Perez, M. V., Ashley, E. A., Yarov-Yarovoy, V., Zhang, X., Chiamvimonvat, N. CELL PRESS. 2018: 625A
  • Athletic Remodeling in Female College Athletes, the "Morganroth Hypothesis" Revisited. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Kooreman, Z. n., Giraldeau, G. n., Finocchiaro, G. n., Kobayashi, Y. n., Wheeler, M. n., Perez, M. n., Moneghetti, K. n., Oxborough, D. n., George, K. P., Myers, J. n., Ashley, E. n., Haddad, F. n. 2018

    Abstract

    There is limited data regarding ventricular remodeling in college female athletes, especially when appropriate scaling of cardiac dimensions to lean body mass (LBM) is considered. Moreover, it is not well established whether cardiac remodeling in female athletes is a balanced process with proportional increase in left ventricular (LV) mass and volume or the right and LV size.During the preparticipation competitive screening, 72 female college athletes volunteered to undergo dual energy x-ray absorptiometry scan for quantification of LBM and comprehensive 2D echocardiography including assessment of longitudinal myocardial strain. The athletes were divided in 2 groups according to the intensity of the dynamic and static components of their sport categories, ie, a higher intensity dynamic and resistive group (n = 37 participating in rowing, water polo and lacrosse) and a lower intensity group (n = 35, participating in short distance running, sailing, synchronized swimming, and softball). In addition, we recruited a group of 31 age-matched nonathlete controls.The mean age of the study population was 18.7 ± 1.0 years. When scaled to body surface area, the higher intensity group had 17.1 ± 3.6% (P < 0.001) greater LV mass when compared with the lower intensity group and 21.7 ± 4.0% (P < 0.001) greater LV mass than the control group. The differences persisted after scaling to LBM with 14.2 ± 3.2% (P < 0.001) greater LV mass in the higher intensity group. By contrast, there was no difference in any of the relative remodeling indices including the LV mass to volume ratio, right to LV area ratio, or left atrial to LV volume ratio (P > 0.50 for all). In addition, no significant difference was noted among the 3 groups in LV ejection fraction (P = 0.22), LV global longitudinal strain (P = 0.55), LV systolic strain rate (P = 0.62), or right ventricular global longitudinal strain (P = 0.61).Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.

    View details for PubMedID 29369833

  • Vitamin D with calcium supplementation and risk of atrial fibrillation in postmenopausal women. American heart journal Boursiquot, B. C., Larson, J. C., Shalash, O. A., Vitolins, M. Z., Soliman, E. Z., Perez, M. V. 2018; 209: 68–78

    Abstract

    Atrial fibrillation (AF) is the most common arrhythmia in adults. Although vitamin D deficiency is associated with AF risk factors, retrospective studies of association with AF have shown mixed results. We sought to determine the efficacy of calcium and vitamin D (CaD) supplementation for AF prevention in a randomized trial.We performed a secondary analysis of the Women's Health Initiative trial on CaD supplementation versus placebo. We linked participants to their Medicare claims to ascertain incident AF.Among 16,801 included participants, there were 1,453 (8.6%) cases of incident AF over an average of 4.5 years, at an average rate of 19.9 events per 1,000 person-years. We found no significant difference in incident AF rates between the CaD and placebo arms (hazard ratio 1.02 for CaD vs placebo, 95% CI 0.92-1.13). After multivariate adjustment, there was no significant association between baseline 25-hydroxyvitamin D serum levels and incident AF (hazard ratio 0.92 for lowest subgroup vs highest subgroup, 95% CI 0.66-1.28).We present the first analysis of a large randomized trial of daily vitamin D supplementation for AF prevention. We found that CaD had no effect on incidence of AF in Women's Health Initiative CaD trial participants. We also found that baseline serum 25-hydroxyvitamin D level was not predictive of long-term incident AF risk.

    View details for PubMedID 30685677

  • ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals CIRCULATION-CARDIOVASCULAR GENETICS Bihlmeyer, N. A., Brody, J. A., Smith, A., Warren, H. R., Lin, H., Isaacs, A., Liu, C., Marten, J., Radmanesh, F., Hall, L. M., Grarup, N., Mei, H., Muller-Nurasyid, M., Huffman, J. E., Verweij, N., Guo, X., Yao, J., Li-Gao, R., van den Berg, M., Weiss, S., Prins, B. P., van Setten, J., Haessler, J., Lyytikainen, L., Li, M., Alonso, A., Soliman, E. Z., Bis, J. C., Austin, T., Chen, Y., Psaty, B. M., Harrris, T. B., Launer, L. J., Padmanabhan, S., Dominiczak, A., Huang, P. L., Xie, Z., Ellinor, P. T., Kors, J. A., Campbell, A., Murray, A. D., Nelson, C. P., Tobin, M. D., Bork-Jensen, J., Hansen, T., Pedersen, O., Linneberg, A., Sinner, M. F., Peters, A., Waldenberger, M., Meitinger, T., Perz, S., Kolcic, I., Rudan, I., de Boer, R. A., van der Meer, P., Lin, H. J., Taylor, K. D., de Mutsert, R., Trompet, S., Jukema, J., Maan, A. C., Stricker, B. C., Rivadeneira, F., Uitterlinden, A., Volker, U., Homuth, G., Volzke, H., Felix, S. B., Mangino, M., Spector, T. D., Bots, M. L., Perez, M., Raitakari, O. T., Kahonen, M., Mononen, N., Gudnason, V., Munroe, P. B., Lubitz, S. A., van Duijn, C. M., Newton-Cheh, C. H., Hayward, C., Rosand, J., Samani, N. J., Kanters, J. K., Wilson, J. G., Kaab, S., Polasek, O., van der Harst, P., Heckbert, S. R., Rotter, J. I., Mook-Kanamori, D. O., Eij-Gelsheim, M., Dorr, M., Jamshidi, Y., Asselbergs, F. W., Kooperberg, C., Lehtimaki, T., Arking, D. E., Sotoodehnia, N. 2018; 11 (1)
  • Video-assisted thoracoscopic surgery to displace the phrenic nerve during endocardial ablation of right atrial tachycardia. HeartRhythm case reports Mesquita, J. n., Bisla, J. n., Lee, A. n., Perez, M. n. 2018; 4 (7): 304–6

    View details for PubMedID 30023277

  • Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts HEART RHYTHM Kerr, K. F., Avery, C. L., Lin, H. J., Raffield, L. M., Zhang, Q. S., Browning, B. L., Browning, S. R., Conomos, M. P., Gogarten, S. M., Laurie, C. C., Sofer, T., Thornton, T. A., Hohensee, C., Jackson, R. D., Kooperberg, C., Li, Y., Mendez-Giraldez, R., Perez, M. V., Peters, U., Reiner, A. P., Zhang, Z., Yao, J., Sotoodehnia, N., Taylor, K. D., Guo, X., Lange, L. A., Soliman, E. Z., Wilson, J. G., Rotter, J. I., Heckbert, S. R., Jain, D., Whitsel, E. A. 2017; 14 (11): 1675–84

    Abstract

    Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized.The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767).We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10-8) or suggestive (P <10-6) significance thresholds.Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms.This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

    View details for PubMedID 28610988

    View details for PubMedCentralID PMC5671896

  • The Expressed Genome in Cardiovascular Diseases and Stroke: Refinement, Diagnosis, and Prediction: A Scientific Statement From the American Heart Association. Circulation. Cardiovascular genetics Musunuru, K., Ingelsson, E., Fornage, M., Liu, P., Murphy, A. M., Newby, L. K., Newton-Cheh, C., Perez, M. V., Voora, D., Woo, D. 2017; 10 (4)

    Abstract

    There have been major advances in our knowledge of the contribution of DNA sequence variations to cardiovascular disease and stroke. However, the inner workings of the body reflect the complex interplay of factors beyond the DNA sequence, including epigenetic modifications, RNA transcripts, proteins, and metabolites, which together can be considered the "expressed genome." The emergence of high-throughput technologies, including epigenomics, transcriptomics, proteomics, and metabolomics, is now making it possible to address the contributions of the expressed genome to cardiovascular disorders. This statement describes how the expressed genome can currently and, in the future, potentially be used to diagnose diseases and to predict who will develop diseases such as coronary artery disease, stroke, heart failure, and arrhythmias.

    View details for DOI 10.1161/HCG.0000000000000037

    View details for PubMedID 28760750

  • Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. Nature genetics Christophersen, I. E., Rienstra, M., Roselli, C., Yin, X., Geelhoed, B., Barnard, J., Lin, H., Arking, D. E., Smith, A. V., Albert, C. M., Chaffin, M., Tucker, N. R., Li, M., Klarin, D., Bihlmeyer, N. A., Low, S., Weeke, P. E., Müller-Nurasyid, M., Smith, J. G., Brody, J. A., Niemeijer, M. N., Dörr, M., Trompet, S., Huffman, J., Gustafsson, S., Schurmann, C., Kleber, M. E., Lyytikäinen, L., Seppälä, I., Malik, R., Horimoto, A. R., Perez, M., Sinisalo, J., Aeschbacher, S., Thériault, S., Yao, J., Radmanesh, F., Weiss, S., Teumer, A., Choi, S. H., Weng, L., Clauss, S., Deo, R., Rader, D. J., Shah, S. H., Sun, A., Hopewell, J. C., Debette, S., Chauhan, G., Yang, Q., Worrall, B. B., Paré, G., Kamatani, Y., Hagemeijer, Y. P., Verweij, N., Siland, J. E., Kubo, M., Smith, J. D., Van Wagoner, D. R., Bis, J. C., Perz, S., Psaty, B. M., Ridker, P. M., Magnani, J. W., Harris, T. B., Launer, L. J., Shoemaker, M. B., Padmanabhan, S., Haessler, J., Bartz, T. M., Waldenberger, M., Lichtner, P., Arendt, M., Krieger, J. E., Kähönen, M., Risch, L., Mansur, A. J., Peters, A., Smith, B. H., Lind, L., Scott, S. A., Lu, Y., Bottinger, E. B., Hernesniemi, J., Lindgren, C. M., Wong, J. A., Huang, J., Eskola, M., Morris, A. P., Ford, I., Reiner, A. P., Delgado, G., Chen, L. Y., Chen, Y. I., Sandhu, R. K., Li, M., Boerwinkle, E., Eisele, L., Lannfelt, L., Rost, N., Anderson, C. D., Taylor, K. D., Campbell, A., Magnusson, P. K., Porteous, D., Hocking, L. J., Vlachopoulou, E., Pedersen, N. L., Nikus, K., Orho-Melander, M., Hamsten, A., Heeringa, J., Denny, J. C., Kriebel, J., Darbar, D., Newton-Cheh, C., Shaffer, C., Macfarlane, P. W., Heilmann-Heimbach, S., Almgren, P., Huang, P. L., Sotoodehnia, N., Soliman, E. Z., Uitterlinden, A. G., Hofman, A., Franco, O. H., Völker, U., Jöckel, K., Sinner, M. F., Lin, H. J., Guo, X., Dichgans, M., Ingelsson, E., Kooperberg, C., Melander, O., Loos, R. J., Laurikka, J., Conen, D., Rosand, J., van der Harst, P., Lokki, M., Kathiresan, S., Pereira, A., Jukema, J. W., Hayward, C., Rotter, J. I., März, W., Lehtimäki, T., Stricker, B. H., Chung, M. K., Felix, S. B., Gudnason, V., Alonso, A., Roden, D. M., Kääb, S., Chasman, D. I., Heckbert, S. R., Benjamin, E. J., Tanaka, T., Lunetta, K. L., Lubitz, S. A., Ellinor, P. T. 2017; 49 (6): 946-952

    Abstract

    Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

    View details for DOI 10.1038/ng.3843

    View details for PubMedID 28416818

  • Left atrial function and phenotypes in asymmetric hypertrophic cardiomyopathy. Echocardiography (Mount Kisco, N.Y.) Kobayashi, Y., Wheeler, M., Finocchiaro, G., Ariyama, M., Kobayashi, Y., Perez, M. V., Liang, D., Kuznetsova, T., Schnittger, I., Ashley, E., Haddad, F. 2017

    Abstract

    Few studies have analyzed changes in left atrial (LA) function associated with different phenotypes of asymmetric hypertrophic cardiomyopathy (HCM). We sought to demonstrate the association of impairments in LA function with disease phenotype in patients with obstructive and nonobstructive HCM.From Stanford Cardiomyopathy Registry, we randomly selected 50 age-/sex-matched healthy controls, 35 patients with nonobstructive HCM (HCM 1), 35 patients with obstructive HCM (HCM 2), and 35 patients with obstructive HCM requiring septal reduction therapy (HCM 3). Echocardiography was performed to evaluate left ventricular (LV) strain as well as LA function including LA emptying fraction and LA strain.The mean age was 51±14 years and 57% were male. LA volume index differed among all four predefined groups (25.6±6.7 mL/m(2) in controls, 32.2±13.3 mL/m(2) in HCM 1, 42.0±12.9 mL/m(2) in HCM 2, 52.4±15.2 mL/m(2) for HCM 3, and P<.05 all between groups). All measurement of LA function was impaired in patients with HCM than controls. Total and passive LA function was further impaired in HCM 2 or 3 compared with HCM 1, while active LA function was not different among the three groups. Among LV strains, only septal longitudinal strain differed among all groups (-18.5±1.9% in controls, -14.5±1.9% in HCM 1, -13.3±1.8% in HCM 2, -11.6±2.3% in HCM 3, and P<.05 all between groups).LA function was impaired in patients with HCM even in minimally symptomatic nonobstructive phenotype. Total and passive LA function was further impaired in patients with obstructive HCM.

    View details for DOI 10.1111/echo.13533

    View details for PubMedID 28370331

  • International criteria for electrocardiographic interpretation in athletes. British journal of sports medicine Drezner, J. A., Sharma, S., Baggish, A., Papadakis, M., Wilson, M. G., Prutkin, J. M., Gerche, A. L., Ackerman, M. J., Borjesson, M., Salerno, J. C., Asif, I. M., Owens, D. S., Chung, E. H., Emery, M. S., Froelicher, V. F., Heidbuchel, H., Adamuz, C., Asplund, C. A., Cohen, G., Harmon, K. G., Marek, J. C., Molossi, S., Niebauer, J., Pelto, H. F., Perez, M. V., Riding, N. R., Saarel, T., Schmied, C. M., Shipon, D. M., Stein, R., Vetter, V. L., Pelliccia, A., Corrado, D. 2017

    Abstract

    Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

    View details for DOI 10.1136/bjsports-2016-097331

    View details for PubMedID 28258178

  • The Associations of Atrial Fibrillation With the Risks of Incident Invasive Breast and Colorectal Cancers AMERICAN JOURNAL OF EPIDEMIOLOGY Wassertheil-Smoller, S., McGinn, A. P., Martin, L., Rodriguez, B. L., Stefanick, M. L., Perez, M. 2017; 185 (5): 372-384

    View details for DOI 10.1093/aje/kww185

    View details for Web of Science ID 000397245800007

  • International Recommendations for Electrocardiographic Interpretation in Athletes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Sharma, S., Drezner, J. A., Baggish, A., Papadakis, M., Wilson, M. G., Prutkin, J. M., La Gerche, A., Ackerman, M. J., Borjesson, M., Salerno, J. C., Asif, I. M., Owens, D. S., Chung, E. H., Emery, M. S., Froelicher, V. F., Heidbuchel, H., Adamuz, C., Asplund, C. A., Cohen, G., Harmon, K. G., Marek, J. C., Molossi, S., Niebauer, J., Pelto, H. F., Perez, M. V., Riding, N. R., Saarel, T., Schmied, C. M., Shipon, D. M., Stein, R., Vetter, V. L., Pelliccia, A., Corrado, D. 2017; 69 (8): 1057-1075

    Abstract

    Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

    View details for DOI 10.1016/j.jacc.2017.01.015

    View details for PubMedID 28329355

  • International Recommendations for Electrocardiographic Interpretation in Athletes. Journal of the American College of Cardiology Sharma, S., Drezner, J. A., Baggish, A., Papadakis, M., Wilson, M. G., Prutkin, J. M., La Gerche, A., Ackerman, M. J., Borjesson, M., Salerno, J. C., Asif, I. M., Owens, D. S., Chung, E. H., Emery, M. S., Froelicher, V. F., Heidbuchel, H., Adamuz, C., Asplund, C. A., Cohen, G., Harmon, K. G., Marek, J. C., Molossi, S., Niebauer, J., Pelto, H. F., Perez, M. V., Riding, N. R., Saarel, T., Schmied, C. M., Shipon, D. M., Stein, R., Vetter, V. L., Pelliccia, A., Corrado, D. 2017; 69 (8): 1057-1075

    Abstract

    Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural, or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly over the last decade; pushed by a growing body of scientific data that both tests proposed criteria sets and establishes new evidence to guide refinements. On February 26-27, 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington, to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD.

    View details for DOI 10.1016/j.jacc.2017.01.015

    View details for PubMedID 28231933

  • Orexin: a Missing Link Between Sleep Disorders and Heart Failure? Current heart failure reports Pan, S., Cabral, C. S., Ashley, E. A., Perez, M. V. 2017

    Abstract

    Sleep disorders represent a significant comorbidity in the heart failure population, and there is mounting evidence that treatment of sleep disorders such as obstructive sleep apnea can significantly improve cardiac function. However, the link between these two disorders is still not entirely clear.Recently, a novel neurohormonal pathway has been elucidated involving signaling molecules now collectively known as the orexins, which have been implicated in regulating autonomic function during sleep/wake cycles. Further evidence has mounted that orexin signaling is deeply perturbed in the setting of sleep disorders, and furthermore that abnormal orexin signaling may be implicated in the pathology of heart failure. The orexin signaling pathway represents an enticing novel target for both the treatment of sleep disorders as well as heart failure, and may represent one facet of the "missing link" between these two prevalent and often comorbid diseases.

    View details for DOI 10.1007/s11897-017-0322-3

    View details for PubMedID 28215031

  • Safety and Clinical Outcomes of Catheter Ablation of Atrial Fibrillation in Patients With Chronic Kidney Disease JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Ullal, A. J., Kaiser, D. W., Fan, J., Schmitt, S. K., Than, C. T., Winkelmayer, W. C., Heidenreich, P. A., Piccini, J. P., Perez, M. V., Wang, P. J., Turakhia, M. P. 2017; 28 (1): 39-48

    Abstract

    Data regarding catheter ablation of atrial fibrillation (AF) in patients with chronic kidney disease (CKD) is limited. We therefore assessed the association of CKD with common safety and clinical outcomes in a nationwide sample of ablation recipients.Using MarketScan(®) Commercial Claims and Medicare Supplemental Databases, we evaluated 30-day safety and 1-year clinical outcomes in patients who underwent a first AF ablation procedure between 2007 and 2011. We calculated frequency of common 30-day complications and calculated frequencies, incidence rates, and Cox proportional hazards for outcomes at 1-year postablation.Of 21,091 patients included, 1,593 (7.6%) had CKD. Patients with CKD were older (64 years vs. 59 years, P < 0.001) with higher CHA2 DS2 -VASc scores (3.2 vs. 1.8, P < 0.001). At 30 days postablation, patients with CKD had similar rates of stroke/TIA (0.13% vs. 0.13%, P = 0.99), perforation/tamponade (3.2% vs. 3.1%, P = 0.83), and vascular complications (2.4% vs. 2.2%, P = 0.59) as patients without CKD, but were more likely to be hospitalized for heart failure (2.1% vs. 0.4%, P < 0.001). In multivariate analysis, there were no significant differences in hazards of AF hospitalization (adjusted HR: 1.02, 95%CI: 0.87-1.20), cardioversion (adjusted HR: 0.99, 95%CI: 0.87-1.12), or repeat AF ablation (adjusted HR: 0.89, 95%CI: 0.76-1.06) at 1 year.Among patients selected for AF ablation, those with and without CKD had similar rates of postprocedural complications although they were more likely to be re-admitted for heart failure. CKD was not independently associated with AF hospitalization, cardioversion, and repeat ablation. These findings can inform clinical decision-making in patients with AF and CKD.

    View details for DOI 10.1111/jce.13118

    View details for Web of Science ID 000393901900004

  • Early somatic mosaicism is a rare cause of long-QT syndrome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Priest, J. R., Gawad, C., Kahlig, K. M., Yu, J. K., O'Hara, T., Boyle, P. M., Rajamani, S., Clark, M. J., Garcia, S. T., Ceresnak, S., Harris, J., Boyle, S., Dewey, F. E., Malloy-Walton, L., Dunn, K., Grove, M., Perez, M. V., Neff, N. F., Chen, R., Maeda, K., Dubin, A., Belardinelli, L., West, J., Antolik, C., Macaya, D., Quertermous, T., Trayanova, N. A., Quake, S. R., Ashley, E. A. 2016; 113 (41): 11555-11560

    Abstract

    Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband. Genotyping of single circulating leukocytes demonstrated the mutation in the genomes of 8% of patient cells, and RNA sequencing of cardiac tissue from the infant confirmed the expression of the mutant allele at mosaic ratios. Heterologous expression of the mutant channel revealed significantly delayed sodium current with a dominant negative effect. To investigate the mechanism by which mosaicism might cause arrhythmia, we built a finite element simulation model incorporating Purkinje fiber activation. This model confirmed the pathogenic consequences of cardiac cellular mosaicism and, under the presenting conditions of this case, recapitulated 2:1 AV block and arrhythmia. To investigate the extent to which mosaicism might explain undiagnosed arrhythmia, we studied 7,500 affected probands undergoing commercial gene-panel testing. Four individuals with pathogenic variants arising from early somatic mutation events were found. Here we establish cardiac mosaicism as a causal mechanism for LQTS and present methods by which the general phenomenon, likely to be relevant for all genetic diseases, can be detected through single-cell analysis and next-generation sequencing.

    View details for DOI 10.1073/pnas.1607187113

    View details for PubMedID 27681629

  • The associations of leptin, adiponectin and resistin with incident atrial fibrillation in women. Heart Ermakov, S., Azarbal, F., Stefanick, M. L., LaMonte, M. J., Li, W., Tharp, K. M., Martin, L. W., Nassir, R., Salmoirago-Blotcher, E., Albert, C. M., Manson, J. E., Assimes, T. L., Hlatky, M. A., Larson, J. C., Perez, M. V. 2016; 102 (17): 1354-1362

    Abstract

    Higher body mass index (BMI) is an important risk factor for atrial fibrillation (AF). The adipokines leptin, adiponectin and resistin are correlates of BMI, but their association with incident AF is not well known. We explored this relationship in a large cohort of postmenopausal women.We studied an ethnically diverse cohort of community-dwelling postmenopausal women aged 50-79 who were nationally recruited at 40 clinical centres as part of the Women's Health Initiative investigation. Participants underwent measurements of baseline serum leptin, adiponectin and resistin levels and were followed for incident AF. Adipokine levels were log transformed and normalised using inverse probability weighting. Cox proportional hazard regression models were used to estimate associations with adjustment for known AF risk factors.Of the 4937 participants included, 892 developed AF over a follow-up of 11.1 years. Those with AF had higher mean leptin (14.9 pg/mL vs 13.9 pg/mL), adiponectin (26.3 ug/mL vs 24.5 ug/mL) and resistin (12.9 ng/mL vs 12.1 ng/mL) levels. After multivariable adjustment, neither log leptin nor log adiponectin levels were significantly associated with incident AF. However, log resistin levels remained significantly associated with incident AF (HR=1.57 per 1 log (ng/mL) increase, p=0.006). Additional adjustment for inflammatory cytokines only partially attenuated the association between resistin and incident AF (HR=1.43, p=0.06 adjusting for C-reactive protein (CRP); HR=1.39, p=0.08 adjusting for IL-6). Adjusting for resistin partially attenuated the association between BMI and incident AF (HR=1.14 per 5 kg/m(2), p=0.006 without resistin; HR=1.12, p=0.02 with resistin).In women, elevated levels of serum resistin are significantly associated with higher rates of incident AF and partially mediate the association between BMI and AF. In the same population, leptin and adiponectin levels are not significantly associated with AF.

    View details for DOI 10.1136/heartjnl-2015-308927

    View details for PubMedID 27146694

  • Whole Exome Sequencing in Atrial Fibrillation PLOS GENETICS Lubitz, S. A., Brody, J. A., Bihlmeyer, N. A., Roselli, C., Weng, L., Christophersen, I. E., Alonso, A., Boerwinkle, E., Gibbs, R. A., Bis, J. C., Cupples, L. A., Mohler, P. J., Nickerson, D. A., Muzny, D., Perez, M. V., Psaty, B. M., Soliman, E. Z., Sotoodehnia, N., Lunetta, K. L., Benjamin, E. J., Heckbert, S. R., Arking, D. E., Ellinor, P. T., Lin, H. 2016; 12 (9)

    Abstract

    Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

    View details for DOI 10.1371/journal.pgen.1006284

    View details for PubMedID 27589061

  • Optimizing QT Interval Measurement for the Preparticipation Screening of Young Athletes. Medicine and science in sports and exercise Pickham, D., Hsu, D., Soofi, M., Goldberg, J. M., Saini, D., Hadley, D., Perez, M., Froelicher, V. F. 2016; 48 (9): 1745-1750

    Abstract

    Sudden cardiac death is the leading cause of death in athletes. Long QT syndrome (LQTS) is one of the most common cardiogenetic diseases that can lead to sudden cardiac death and is identified by QT interval prolongation on an ECG. Recommendations for QT monitoring in athletes are adopted from nonathlete populations. To improve screening, ECG data of athletes are assessed to determine a more appropriate method for QT interval estimation.ECG (CardeaScreen) data were collected from June 2010 to March 2015. ECG data with HR greater than 100 bpm were excluded. Fiducial points of outliers were manually corrected if the QRS onset or the T wave offset was misidentified. A model of best fit was determined and compared across four QT correction factors. Classification analysis was used to compare the Bazett's corrected QT interval to the 99th percentile of uncorrected QT interval.High school (n = 597), college (n = 1207), and professional athletes (n = 273) (N = 2077) were analyzed. Mean age was 19 ± 3.5 yr. QT interval varied by cohort (HS = 388 ± 30, Col = 410 ± 33, Pro = 407 ± 27, p < 0.0001). A nonlinear power function with a cubic exponent of -0.349 fit the data the best (R = 0.64). Of the four common correction factors, Fridericia had the lowest residual dependence to HR (m = -0.10). With standard screening, 75% of athletes within the top 1% for QT interval were not identified for further investigation for LQTS.Up to 75% of athletes possessing an uncorrected QT interval greater than 99% of the population are not identified for investigation for LQTS using the recommended criteria. We propose a new method of risk stratification that replaces QT interval correction. Further study is needed to establish QT interval distributions and risk thresholds in athletes.

    View details for DOI 10.1249/MSS.0000000000000962

    View details for PubMedID 27116644

  • Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals. JAMA cardiology Roberts, J. D., Hu, D., Heckbert, S. R., Alonso, A., Dewland, T. A., Vittinghoff, E., Liu, Y., Psaty, B. M., Olgin, J. E., Magnani, J. W., Huntsman, S., Burchard, E. G., Arking, D. E., Bibbins-Domingo, K., Harris, T. B., Perez, M. V., Ziv, E., Marcus, G. M. 2016; 1 (4): 442-50

    Abstract

    White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors.To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon.Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015.Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data.A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified.The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.

    View details for DOI 10.1001/jamacardio.2016.1185

    View details for PubMedID 27438321

    View details for PubMedCentralID PMC5395094

  • Racial and ethnic differences in atrial fibrillation risk factors and predictors in women: Findings from the Women's Health Initiative AMERICAN HEART JOURNAL Rodriguez, F., Stefanick, M. L., Greenland, P., Soliman, E. Z., Manson, J. E., Parikh, N., Martin, L. W., Larson, J. C., Hlatky, M., Nassir, R., Cene, C. W., Rodriguez, B. L., Albert, C., Perez, M. V. 2016; 176: 70-77

    Abstract

    The incidence of atrial fibrillation (AF) is higher in non-Hispanic whites (NHWs) compared with other race-ethnic groups, despite more favorable cardiovascular risk profiles. To explore reasons for this paradox, we compared the hazards of AF from traditional and other risk factors between 4 race-ethnic groups in a large cohort of postmenopausal women.We included 114,083 NHWs, 11,876 African Americans, 5,174 Hispanics, and 3,803 Asians from the Women's Health Initiative free of AF at baseline. Women, averaging 63 years old, were followed up for incident AF using hospitalization records and diagnostic codes from Medicare claims.Over a mean of 13.7 years, 19,712 incident cases of AF were recorded. Despite a higher burden of hypertension, diabetes, and obesity, annual AF incidence was lower among nonwhites (0.7%, 0.4%, and 0.4% for African American, Hispanic, and Asian participants, respectively, compared with 1.2% for NHWs). The hazards of AF from hypertension, diabetes, obesity, heart failure, and coronary artery disease were similar across race-ethnic groups. Major risk factors, including hypertension, obesity, diabetes, smoking, peripheral arterial disease, coronary artery disease, and heart failure, accounted for an attributable risk of 50.3% in NHWs, 83.1% in African Americans, 65.6% in Hispanics, and 37.4% in Asians. Established AF prediction models performed comparably across race-ethnic groups.In this large study of postmenopausal women, traditional cardiovascular risk factors conferred a similar degree of individual risk of AF among 4 race-ethnic groups. However, major AF risk factors conferred a higher-attributable risk in African Americans and Hispanics compared with NHWs and Asians.

    View details for DOI 10.1016/j.ahj.2016.03.004

    View details for Web of Science ID 000377472000013

    View details for PubMedID 27264222

  • Long-Term Prognosis of Early Repolarization With J-Wave and QRS Slur Patterns on the Resting Electrocardiogram: A Cohort Study. Annals of internal medicine Pargaonkar, V. S., Perez, M. V., Jindal, A., Mathur, M. B., Myers, J., Froelicher, V. F. 2015; 163 (10): 747-755

    Abstract

    The prognostic value of early repolarization with J waves and QRS slurs remains controversial. Although these findings are more prevalent in patients with idiopathic ventricular fibrillation, their ability to predict cardiovascular death has varied across studies.To test the hypothesis that J waves and QRS slurs on electrocardiograms (ECGs) are associated with increased risk for cardiovascular death.Retrospective cohort.Veterans Affairs Palo Alto Health Care System.Veterans younger than 56 years who had resting 12-lead electrocardiography, 90.5% of whom were men.Electrocardiograms were manually measured and visually coded using criteria of 0.1 mV or greater in at least 2 contiguous leads. J waves were measured at the peak of an upward deflection or notch at the end of QRS, and QRS slurs were measured at the top of conduction delay on the QRS downstroke. Absolute risk differences at 10 years were calculated to study the associations between J waves or QRS slurs and the primary outcome of cardiovascular death.Over a median follow-up of 17.5 years, 859 cardiovascular deaths occurred. Of 20 661 ECGs, 4219 (20%) had J waves or QRS slurs in the inferior and/or lateral territories; of these, 3318 (78.6%) had J waves or QRS slurs in inferior leads and 1701 (40.3%) in lateral leads. The upper bound of differences in risk for cardiovascular death from any of the J-wave or QRS slur patterns suggests that an increased risk can be safely ruled out (inferior, -0.77% [95% CI, -1.27% to -0.27%]; lateral, -1.07% [CI, -1.72% to -0.43%]).The study consisted of predominantly men, and deaths could be classified as cardiovascular but not arrhythmic.J waves and QRS slurs did not exhibit a clinically meaningful increased risk for cardiovascular death in long-term follow-up.None.

    View details for DOI 10.7326/M15-0598

    View details for PubMedID 26501238

  • Gender Differences in Ventricular Remodeling and Function in College Athletes, Insights from Lean Body Mass Scaling and Deformation Imaging AMERICAN JOURNAL OF CARDIOLOGY Giraldeau, G., Kobayashi, Y., Finocchiaro, G., Wheeler, M., Perez, M., Kuznetsova, T., Lord, R., George, K. P., Oxborough, D., Schnittger, T., Froelicher, V., Liang, D., Ashley, E., Haddad, F. 2015; 116 (10): 1610-1616

    Abstract

    Several studies suggest gender differences in ventricular dimensions in athletes. Few studies have, however, made comparisons of data indexed for lean body mass (LBM) using allometry. Ninety Caucasian college athletes (mixed sports) who were matched for age, ethnicity, and sport total cardiovascular demands underwent dual-energy x-ray absorptiometry scan for quantification of LBM. Athletes underwent comprehensive assessment of left and right ventricular and atrial structure and function using 2-dimensional echocardiography and deformation imaging using the TomTec analysis system. The mean age of the study population was 18.9 ± 1.9 years. Female athletes (n = 45) had a greater fat free percentage (19.4 ± 3.7%) compared to male athletes (11.5 ± 3.7%). When scaled to body surface area, male had on average 19 ± 3% (p <0.001) greater left ventricular (LV) mass; in contrast, when scaled to LBM, there was no significant difference in indexed LV mass -1.4 ± 3.0% (p = 0.63). Similarly, when allometrically scaled to LBM, there was no significant gender-based difference in LV or left atrial volumes. Although female athletes had mildly higher LV ejection fraction and LV global longitudinal strain in absolute value, systolic strain rate and allometrically indexed stroke volume were not different between genders (1.5 ± 3.6% [p = 0.63] and 0.0 ± 3.7% [p = 0.93], respectively). There were no differences in any of the functional atrial indexes including strain or strain rate parameters. In conclusion, gender-related differences in ventricular dimensions or function (stroke volume) appear less marked, if not absent, when indexing using LBM allometrically.

    View details for DOI 10.1016/j.amjcard.2015.08.026

    View details for PubMedID 26456207

  • Limitations of Current AHA Guidelines and Proposal of New Guidelines for the Preparticipation Examination of Athletes CLINICAL JOURNAL OF SPORT MEDICINE Dunn, T. P., Pickham, D., Aggarwal, S., Saini, D., Kumar, N., Wheeler, M. T., Perez, M., Ashley, E., Froelicher, V. F. 2015; 25 (6): 472-477

    Abstract

    To examine the prevalence of athletes who screen positive with the preparticipation examination guidelines from the American Heart Association, the AHA 12-elements, in combination with 3 screening electrocardiogram (ECG) criteria.Observational cross-sectional study.Stanford University Sports Medicine Clinic.Total of 1596 participants, including 297 (167 male; mean age, 16.2 years) high school athletes, 1016 (541 male; mean age, 18.8 years) collegiate athletes, and 283 (mean age, 26.3 years) male professional athletes.Athletes were screened using the 8 personal and family history questions from the AHA 12-elements. Electrocardiograms were obtained for all participants and interpreted using Seattle criteria, Stanford criteria, and European Society of Cardiology (ESC) recommendations.Approximately one-quarter of all athletes (23.8%) had at least 1 positive response to the AHA personal and family history elements. High school and college athletes had similar rates of having at least 1 positive response (25.9% vs 27.4%), whereas professional athletes had a significantly lower rate of having at least 1 positive response (8.8%, P < 0.05). Females reported more episodes of unexplained syncope (11.4% vs 7.5%, P = 0.017) and excessive exertional dyspnea with exercise (11.1% vs 6.1%, P = 0.001) than males. High school athletes had more positive responses to the family history elements when compared with college athletes (P < 0.05). The percentage of athletes who had an abnormal ECG varied between Seattle criteria (6.0%), Stanford criteria (8.8%), and ESC recommendations (26.8%).Many athletes screen positive under current screening recommendations, and ECG results vary widely by interpretation criteria.In a patient population without any adverse cardiovascular events, the currently recommended AHA 12-elements have an unacceptably high rate of false positives. Newer screening guidelines are needed, with fewer false positives and evidence-based updates.

    View details for Web of Science ID 000364310700003

    View details for PubMedID 25915146

  • Reply to van Oosten et al: "P-Wave Characteristics on Routine Preoperative Electrocardiogram Improve Prediction of New-Onset Postoperative Atrial Fibrillation in Cardiac Surgery". Journal of cardiothoracic and vascular anesthesia Wong, J. K., Maxwell, B. G., Perez, M. V. 2015; 29 (5): e63-4

    View details for DOI 10.1053/j.jvca.2015.04.011

    View details for PubMedID 26260908

  • Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology Bent, R. E., Wheeler, M. T., Hadley, D., Knowles, J. W., Pavlovic, A., Finocchiaro, G., Haddad, F., Salisbury, H., Race, S., Shmargad, Y., Matheson, G. O., Kumar, N., Saini, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 65 (22): 2462-2463

    View details for DOI 10.1016/j.jacc.2015.03.559

    View details for PubMedID 26046742

  • Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment. JACC. Heart failure Finocchiaro, G., Haddad, F., Knowles, J. W., Caleshu, C., Pavlovic, A., Homburger, J., Shmargad, Y., Sinagra, G., Magavern, E., Wong, M., Perez, M., Schnittger, I., Myers, J., Froelicher, V., Ashley, E. A. 2015; 3 (5): 408-418

    Abstract

    This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.

    View details for DOI 10.1016/j.jchf.2014.11.011

    View details for PubMedID 25863972

  • Computerized Q wave dimensions in athletes and hypertrophic cardiomyopathy patients JOURNAL OF ELECTROCARDIOLOGY Bent, R. E., Wheeler, M. T., Hadley, D., Froelicher, V., Ashley, E., Perez, M. V. 2015; 48 (3): 362-367

    Abstract

    There is controversy regarding Q wave criteria for assessing risk for hypertrophic cardiomyopathy (HCM) in young athletes.The 12-lead ECGs from Preparticipation screening in healthy athletes and patients with HCM were studied retrospectively. All 12 leads were measured using the same automated ECG analysis program.There were a total of 225 HCM patients and 1124 athletes with 12-lead electrocardiograms available for analysis. Athletes were on average 20 years of age, 65% were male and 24% were African-American. Patients with HCM were on average 51 years of age, 56% were male and 5.8% were African-American. Q waves by either amplitude, duration or area criteria were more prevalent in males than females, in lateral leads than inferior and in HCM patients than athletes. The most striking difference in Q waves between the groups was in Limb lead I and in the females. Tall, skinny Q waves were rare in athletes and had the highest prevalence of only 3.7% in male HCM patients.Q waves are more common in males compared to females and in patients with HCM compared to athletes. Q waves of 30 ms or more in limb lead I appear to offer the greatest discriminatory value for separating patients with HCM from athletes.

    View details for DOI 10.1016/j.jelectrocard.2015.01.009

    View details for PubMedID 25732098

  • Race and ethnicity, obesity, metabolic health, and risk of cardiovascular disease in postmenopausal women. Journal of the American Heart Association Schmiegelow, M. D., Hedlin, H., Mackey, R. H., Martin, L. W., Vitolins, M. Z., Stefanick, M. L., Perez, M. V., Allison, M., Hlatky, M. A. 2015; 4 (5)

    Abstract

    It is unclear whether obesity unaccompanied by metabolic abnormalities is associated with increased cardiovascular disease risk across racial and ethnic subgroups.We identified 14 364 postmenopausal women from the Women's Health Initiative who had data on fasting serum lipids and serum glucose and no history of cardiovascular disease or diabetes at baseline. We categorized women by body mass index (in kg/m(2)) as normal weight (body mass index 18.5 to <25), overweight (body mass index 25 to <30), or obese (body mass index ≥30) and by metabolic health, defined first as the metabolic syndrome (metabolically unhealthy: ≥3 metabolic abnormalities) and second as the number of metabolic abnormalities. We used Cox proportional hazards regression to assess associations between baseline characteristics and cardiovascular risk. Over 13 years of follow-up, 1101 women had a first cardiovascular disease event (coronary heart disease or ischemic stroke). Among black women without metabolic syndrome, overweight women had higher adjusted cardiovascular risk than normal weight women (hazard ratio [HR] 1.49), whereas among white women without metabolic syndrome, overweight women had similar risk to normal weight women (HR 0.92, interaction P=0.05). Obese black women without metabolic syndrome had higher adjusted risk (HR 1.95) than obese white women (HR 1.07; interaction P=0.02). Among women with only 2 metabolic abnormalities, cardiovascular risk was increased in black women who were overweight (HR 1.77) or obese (HR 2.17) but not in white women who were overweight (HR 0.98) or obese (HR 1.06). Overweight and obese women with ≤1 metabolic abnormality did not have increased cardiovascular risk, regardless of race or ethnicity.Metabolic abnormalities appeared to convey more cardiovascular risk among black women.

    View details for DOI 10.1161/JAHA.114.001695

    View details for PubMedID 25994446

  • Feasibility of Extended Ambulatory Electrocardiogram Monitoring to Identify Silent Atrial Fibrillation in High-risk Patients: The Screening Study for Undiagnosed Atrial Fibrillation (STUDY-AF) CLINICAL CARDIOLOGY Turakhia, M. P., Ullal, A. J., Hoang, D. D., Than, C. T., Miller, J. D., Friday, K. J., Perez, M. V., Freeman, J. V., Wang, P. J., Heidenreich, P. A. 2015; 38 (5): 285-292

    Abstract

    Identification of silent atrial fibrillation (AF) could prevent stroke and other sequelae.Screening for AF using continuous ambulatory electrocardiographic (ECG) monitoring can detect silent AF in asymptomatic in patients with known risk factors.We performed a single-center prospective screening study using a wearable patch-based device that provides up to 2 weeks of continuous ambulatory ECG monitoring (iRhythm Technologies, Inc.). Inclusion criteria were age ≥55 years and ≥2 of the following risk factors: coronary disease, heart failure, hypertension, diabetes, sleep apnea. We excluded patients with prior AF, stroke, transient ischemic attack, implantable pacemaker or defibrillator, or with palpitations or syncope in the prior year.Out of 75 subjects (all male, age 69 ± 8.0 years; ejection fraction 57% ± 8.7%), AF was detected in 4 subjects (5.3%; AF burden 28% ± 48%). Atrial tachycardia (AT) was present in 67% (≥4 beats), 44% (≥8 beats), and 6.7% (≥60 seconds) of subjects. The combined diagnostic yield of sustained AT/AF was 11%. In subjects without sustained AT/AF, 11 (16%) had ≥30 supraventricular ectopic complexes per hour.Outpatient extended ECG screening for asymptomatic AF is feasible, with AF identified in 1 in 20 subjects and sustained AT/AF identified in 1 in 9 subjects, respectively. We also found a high prevalence of asymptomatic AT and frequent supraventricular ectopic complexes, which may be relevant to development of AF or stroke. If confirmed in a larger study, primary screening for AF could have a significant impact on public health.

    View details for DOI 10.1002/clc.22387

    View details for PubMedID 25873476

  • Genetic risk for atrial fibrillation could motivate patient adherence to warfarin therapy: a cost effectiveness analysis. BMC cardiovascular disorders Shiffman, D., Perez, M. V., Bare, L. A., Louie, J. Z., Arellano, A. R., Devlin, J. J. 2015; 15 (1): 104-?

    View details for DOI 10.1186/s12872-015-0100-7

    View details for PubMedID 26419225

  • Genetic risk for atrial fibrillation could motivate patient adherence to warfarin therapy: a cost effectiveness analysis. BMC cardiovascular disorders Shiffman, D., Perez, M. V., Bare, L. A., Louie, J. Z., Arellano, A. R., Devlin, J. J. 2015; 15: 104-?

    Abstract

    Atrial fibrillation (AF) increases risk of stroke, and although this stroke risk can be ameliorated by warfarin therapy, some patients decline to adhere to warfarin therapy. A prospective clinical study could be conducted to determine whether knowledge of genetic risk for AF could increase adherence to warfarin therapy for patients who initially declined therapy. As a prelude to a potential prospective clinical study, we investigated whether the use of genetic information to increase adherence could be cost effective.Markov model assessed costs and utilities of two care strategies for AF patients who declined warfarin therapy. In the usual care strategy patients received aspirin. In the test strategy genetic risk for AF was assessed (genotype of the 4q25 locus) and some patients with a positive genetic test (≥1 risk allele) were assumed to adhere to warfarin therapy. The remaining patients received aspirin. The incremental cost-effectiveness ratio (ICER) was the ratio of the costs differential and the quality adjusted life-years (QALYs) differential for the two strategies.We found that the 4q25 genetic testing strategy, compared with the usual care strategy (aspirin therapy), would be cost-effective (ICER $ 47,148) if 2.1 % or more of the test positive patients were to adhere to warfarin therapy. The test strategy would become a cost saving strategy if 5.3 % or more of the test positive patients were to adhere to warfarin therapy. If 20 % of test positive patients were to adhere to warfarin therapy in a hypothetical cohort of 1000 patients, 7 stroke events would be prevented and 3 extra-cranial major bleeding events would be caused over 5 years, resulting in a cost savings of ~ $250,000 and a net gain of 9 QALYs.A clinical study to assess the impact of patient knowledge of genetic risk of AF on adherence to warfarin therapy would be merited because even a modest increase in patient adherence would make a genetic testing strategy cost-effective.Providing patients who declined warfarin therapy with information about their genetic risk of AF would be cost effective if this genetic risk information resulted in modest increases in adherence.

    View details for DOI 10.1186/s12872-015-0100-7

    View details for PubMedID 26419225

    View details for PubMedCentralID PMC4587718

  • P-Wave Characteristics on Routine Preoperative Electrocardiogram Improve Prediction of New-Onset Postoperative Atrial Fibrillation in Cardiac Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Wong, J. K., Lobato, R. L., Pinesett, A., Maxwell, B. G., Mora-Mangano, C. T., Perez, M. V. 2014; 28 (6): 1497-1504

    Abstract

    To test the hypothesis that including preoperative electrocardiogram (ECG) characteristics with clinical variables significantly improves the new-onset postoperative atrial fibrillation prediction model.Retrospective analysis.Single-center university hospital.Five hundred twenty-six patients,≥18 years of age, who underwent coronary artery bypass grafting, aortic valve replacement, mitral valve replacement/repair, or a combination of valve surgery and coronary artery bypass grafting requiring cardiopulmonary bypass.Retrospective review of medical records.Baseline characteristics and cardiopulmonary bypass times were collected. Digitally-measured timing and voltages from preoperative electrocardiograms were extracted. Postoperative atrial fibrillation was defined as atrial fibrillation requiring therapeutic intervention. Two hundred eight (39.5%) patients developed postoperative atrial fibrillation. Clinical predictors were age, ejection fraction<55%, history of atrial fibrillation, history of cerebral vascular event, and valvular surgery. Three ECG parameters associated with postoperative atrial fibrillation were observed: Premature atrial contraction, p-wave index, and p-frontal axis. Adding electrocardiogram variables to the prediction model with only clinical predictors significantly improved the area under the receiver operating characteristic curve, from 0.71 to 0.78 (p<0.01). Overall net reclassification improvement was 0.059 (p = 0.09). Among those who developed postoperative atrial fibrillation, the net reclassification improvement was 0.063 (p = 0.03).Several p-wave characteristics are independently associated with postoperative atrial fibrillation. Addition of these parameters improves the postoperative atrial fibrillation prediction model.

    View details for DOI 10.1053/j.jvca.2014.04.034

    View details for PubMedID 25263779

  • Evidence of Heterogeneity by Race/Ethnicity in Genetic Determinants of QT Interval. Epidemiology (Cambridge, Mass.) Seyerle, A. A., Young, A. M., Jeff, J. M., Melton, P. E., Jorgensen, N. W., Lin, Y., Carty, C. L., Deelman, E., Heckbert, S. R., Hindorff, L. A., Jackson, R. D., Martin, L. W., Okin, P. M., Perez, M. V., Psaty, B. M., Soliman, E. Z., Whitsel, E. A., North, K. E., Laston, S., Kooperberg, C., Avery, C. L. 2014; 25 (6): 790-8

    Abstract

    QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

    View details for DOI 10.1097/EDE.0000000000000168

    View details for PubMedID 25166880

  • Evidence of Heterogeneity by Race/Ethnicity in Genetic Determinants of QT Interval EPIDEMIOLOGY Seyerle, A. A., Young, A. M., Jeff, J. M., Melton, P. E., Jorgensen, N. W., Lin, Y., Carty, C. L., Deelman, E., Heckbert, S. R., Hindorff, L. A., Jackson, R. D., Martin, L. W., Okin, P. M., Perez, M. V., Psaty, B. M., Soliman, E. Z., Whitsel, E. A., North, K. E., Laston, S., Kooperberg, C., Avery, C. L. 2014; 25 (6): 790-798

    Abstract

    QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations.Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test.Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity.These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

    View details for DOI 10.1097/EDE.0000000000000168

    View details for Web of Science ID 000343122000002

  • Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencing. Heart rhythm Priest, J. R., Ceresnak, S. R., Dewey, F. E., Malloy-Walton, L. E., Dunn, K., Grove, M. E., Perez, M. V., Maeda, K., Dubin, A. M., Ashley, E. A. 2014; 11 (10): 1707-1713

    Abstract

    The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians.A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies.We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene.Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.

    View details for DOI 10.1016/j.hrthm.2014.06.030

    View details for PubMedID 24973560

  • Association Between Success Rate and Citation Count of Studies of Radiofrequency Catheter Ablation for Atrial Fibrillation Possible Evidence of Citation Bias CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Perino, A. C., Hoang, D. D., Holmes, T. H., Santangeli, P., Heidenreich, P. A., Perez, M. V., Wang, P. J., Turakhia, M. P. 2014; 7 (5): 687-692

    Abstract

    The preferential citation of studies with the highest success rates could exaggerate perceived effectiveness, particularly for treatments with widely varying published success rates such as radiofrequency catheter ablation for atrial fibrillation.We systematically identified observational studies and clinical trials of radiofrequency catheter ablation of atrial fibrillation between 1990 and 2012. Generalized Poisson regression was used to estimate association between study success rate and total citation count, adjusting for sample size, journal impact factor, time since publication, study design, and whether first or last author was a consensus-defined pre-eminent expert. We identified 174 articles meeting our inclusion criteria (36 289 subjects). After adjustment only for time since publication, a 10-point increase above the mean in pooled reported success rates was associated with a 17.8% increase in citation count at 5 years postpublication (95% confidence interval, 7.1-28.4%; P<0.001). After additional adjustment for impact factor, sample size, randomized trial design, and pre-eminent expert authorship, the association remained significant (18.6% increase in citation count; 95% confidence interval, 7.6-29.6%; P<0.0001). In this full model, time since publication, impact factor, and pre-eminent expert authorship were significant covariates, whereas randomized control trial design and study sample size were not.Among studies of radiofrequency catheter ablation of atrial fibrillation, high success rate was independently associated with citation count, which may indicate citation bias. To readers of the literature, radiofrequency catheter ablation of atrial fibrillation could be perceived to be more effective than the data supports. These findings may have implications for a wide variety of novel cardiovascular therapies.

    View details for DOI 10.1161/CIRCOUTCOMES.114.000912

    View details for Web of Science ID 000342365200011

  • Association between success rate and citation count of studies of radiofrequency catheter ablation for atrial fibrillation: possible evidence of citation bias. Circulation. Cardiovascular quality and outcomes Perino, A. C., Hoang, D. D., Holmes, T. H., Santangeli, P., Heidenreich, P. A., Perez, M. V., Wang, P. J., Turakhia, M. P. 2014; 7 (5): 687-692

    Abstract

    The preferential citation of studies with the highest success rates could exaggerate perceived effectiveness, particularly for treatments with widely varying published success rates such as radiofrequency catheter ablation for atrial fibrillation.We systematically identified observational studies and clinical trials of radiofrequency catheter ablation of atrial fibrillation between 1990 and 2012. Generalized Poisson regression was used to estimate association between study success rate and total citation count, adjusting for sample size, journal impact factor, time since publication, study design, and whether first or last author was a consensus-defined pre-eminent expert. We identified 174 articles meeting our inclusion criteria (36 289 subjects). After adjustment only for time since publication, a 10-point increase above the mean in pooled reported success rates was associated with a 17.8% increase in citation count at 5 years postpublication (95% confidence interval, 7.1-28.4%; P<0.001). After additional adjustment for impact factor, sample size, randomized trial design, and pre-eminent expert authorship, the association remained significant (18.6% increase in citation count; 95% confidence interval, 7.6-29.6%; P<0.0001). In this full model, time since publication, impact factor, and pre-eminent expert authorship were significant covariates, whereas randomized control trial design and study sample size were not.Among studies of radiofrequency catheter ablation of atrial fibrillation, high success rate was independently associated with citation count, which may indicate citation bias. To readers of the literature, radiofrequency catheter ablation of atrial fibrillation could be perceived to be more effective than the data supports. These findings may have implications for a wide variety of novel cardiovascular therapies.

    View details for DOI 10.1161/CIRCOUTCOMES.114.000912

    View details for PubMedID 25205786

  • Obesity, physical activity, and their interaction in incident atrial fibrillation in postmenopausal women. Journal of the American Heart Association Azarbal, F., Stefanick, M. L., Salmoirago-Blotcher, E., Manson, J. E., Albert, C. M., LaMonte, M. J., Larson, J. C., Li, W., Martin, L. W., Nassir, R., Garcia, L., Assimes, T. L., Tharp, K. M., Hlatky, M. A., Perez, M. V. 2014; 3 (4)

    Abstract

    Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased risk of stroke and death. Obesity is an independent risk factor for AF, but modifiers of this risk are not well known. We studied the roles of obesity, physical activity, and their interaction in conferring risk of incident AF.The Women's Health Initiative (WHI) Observational Study was a prospective observational study of 93 676 postmenopausal women followed for an average of 11.5 years. Incident AF was identified using WHI-ascertained hospitalization records and diagnostic codes from Medicare claims. A multivariate Cox's hazard regression model adjusted for demographic and clinical risk factors was used to evaluate the interaction between obesity and physical activity and its association with incident AF. After exclusion of women with prevalent AF, incomplete data, or underweight body mass index (BMI), 9792 of the remaining 81 317 women developed AF. Women were, on average, 63.4 years old, 7.8% were African American, and 3.6% were Hispanic. Increased BMI (hazard ratio [HR], 1.12 per 5-kg/m(2) increase; 95% confidence interval [CI], 1.10 to 1.14) and reduced physical activity (>9 vs. 0 metabolic equivalent task hours per week; HR, 0.90; 95% CI, 0.85 to 0.96) were independently associated with higher rates of AF after multivariate adjustment. Higher levels of physical activity reduced the AF risk conferred by obesity (interaction P=0.033).Greater physical activity is associated with lower rates of incident AF and modifies the association between obesity and incident AF.

    View details for DOI 10.1161/JAHA.114.001127

    View details for PubMedID 25142057

  • Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy. Journal of cardiac failure Finocchiaro, G., Haddad, F., Pavlovic, A., Sinagra, G., Schnittger, I., Knowles, J. W., Perez, M., Magavern, E., Myers, J., Ashley, E. 2014; 20 (4): 236-243

    Abstract

    Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.

    View details for DOI 10.1016/j.cardfail.2014.01.014

    View details for PubMedID 24486928

  • Exercise capacity and paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy. Heart Azarbal, F., Singh, M., Finocchiaro, G., Le, V., Schnittger, I., Wang, P., Myers, J., Ashley, E., Perez, M. 2014; 100 (8): 624-630

    Abstract

    Atrial fibrillation (AF) is the most common arrhythmia among patients with hypertrophic cardiomyopathy (HCM). The relationship between paroxysmal AF and exercise capacity in this population is incompletely understood.Patients with HCM underwent symptom-limited cardiopulmonary testing with expired gas analysis at Stanford Hospital between October 2006 and October 2012. Baseline demographics, medical histories and resting echocardiograms were obtained for all subjects. Diagnosis of AF was established by review of medical records and baseline ECG. Those with paroxysmal AF were in sinus rhythm at the time of cardiopulmonary testing with expired gas analysis. Exercise intolerance was defined as peak VO2<20 mL/kg/min. We used multivariate logistic regression to evaluate the association between exercise intolerance and paroxysmal AF.Among the 265 patients recruited, 55 had AF (28 paroxysmal and 27 permanent). Compared with those without AF, subjects with paroxysmal AF were older, more likely to use antiarrhythmic and anticoagulant medications, and had larger left atria. Patients with paroxysmal AF achieved lower peak VO2 (21.9±9.2 mL/kg/min vs 26.9±10.8 mL/kg/min, p=0.02) and were more likely to have exercise intolerance (61% vs 28%, p<0.001) compared with those without AF. After adjustment for age, sex and body mass index (BMI) exercise intolerance remained significantly associated with paroxysmal AF (OR 4.65, 95% CI 1.83 to 11.83, p=0.001).Patients with HCM and paroxysmal AF demonstrate exercise intolerance despite being in sinus rhythm at the time of exercise testing.

    View details for DOI 10.1136/heartjnl-2013-304908

    View details for PubMedID 24326897

  • Patterns and prognosis of all components of the J-wave pattern in multiethnic athletes and ambulatory patients. American heart journal Muramoto, D., Yong, C. M., Singh, N., Aggarwal, S., Perez, M., Ashley, E., Hadley, D., Froelicher, V. 2014; 167 (2): 259-266

    Abstract

    Despite recent concern about the significance of the J-wave pattern (also often referred to as early repolarization) and the importance of screening in athletes, there are limited rigorous prognostic data characterizing the 3 components of the J-wave pattern (ST elevation, J waves, and QRS slurs). We aim to assess the prevalence, patterns, and prognosis of the J-wave pattern among both stable clinical and athlete populations.We retrospectively studied 4,041 electrocardiograms from a multiethnic clinical population from 1997 to 1999 at the Veterans Affairs Palo Alto Health Care System. We also examined preparticipation electrocardiograms of 1,114 Stanford University varsity athletes from 2007 to 2008. Strictly defined criteria for components of the J-wave pattern were examined. In clinical subjects, prognosis was assessed using the end point of cardiovascular death after 7 years of follow-up.Components of the J-wave pattern were most prevalent in males; African Americans; and, particularly, athletes, with the greatest variations demonstrated in the lateral leads. ST elevation was the most common. Inferior J waves and slurs, previously linked to cardiovascular risk, were observed in 9.6% of clinical subjects and 12.3% of athletes. J waves, slurs, or ST elevation was not associated with time to cardiovascular death in clinical subjects, and ST-segment slope abnormalities were not prevalent enough in conjunction with them to reach significance.J waves, slurs, or ST elevation was not associated with increased hazard of cardiovascular death in our large multiethnic, ambulatory population. Even subsets of J-wave patterns, recently proposed to pose a risk of arrhythmic death, occurred at such a high prevalence as to negate their utility in screening.

    View details for DOI 10.1016/j.ahj.2013.10.027

    View details for PubMedID 24439988

  • Prevalence and clinical correlates of right ventricular dysfunction in patients with hypertrophic cardiomyopathy. American journal of cardiology Finocchiaro, G., Knowles, J. W., Pavlovic, A., Perez, M., Magavern, E., Sinagra, G., Haddad, F., Ashley, E. A. 2014; 113 (2): 361-367

    Abstract

    Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.

    View details for DOI 10.1016/j.amjcard.2013.09.045

    View details for PubMedID 24230980

  • Use of Medicare data to identify coronary heart disease outcomes in the Women's Health Initiative. Circulation. Cardiovascular quality and outcomes Hlatky, M. A., Ray, R. M., Burwen, D. R., Margolis, K. L., Johnson, K. C., Kucharska-Newton, A., Manson, J. E., Robinson, J. G., Safford, M. M., Allison, M., Assimes, T. L., Bavry, A. A., Berger, J., Cooper-DeHoff, R. M., Heckbert, S. R., Li, W., Liu, S., Martin, L. W., Perez, M. V., Tindle, H. A., Winkelmayer, W. C., Stefanick, M. L. 2014; 7 (1): 157-162

    Abstract

    . Unique identifier: NCT00000611.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000373

    View details for PubMedID 24399330

  • Electrocardiographic Repolarization-Related Variables as Predictors of Coronary Heart Disease Death in the Women's Health Initiative Study. Journal of the American Heart Association Rautaharju, P. M., Zhang, Z., Vitolins, M., Perez, M., Allison, M. A., Greenland, P., Soliman, E. Z. 2014; 3 (4)

    Abstract

    We evaluated 25 repolarization-related ECG variables for the risk of coronary heart disease (CHD) death in 52 994 postmenopausal women from the Women's Health Initiative study.Hazard ratios from Cox regression were computed for subgroups of women with and without cardiovascular disease (CVD). During the average follow-up of 16.9 years, 941 CHD deaths occurred. Based on electrophysiological considerations, 2 sets of ECG variables with low correlations were considered as candidates for independent predictors of CHD death: Set 1, Ѳ(Tp|Tref), the spatial angle between T peak (Tp) and normal T reference (Tref) vectors; Ѳ(Tinit|Tterm), the angle between the initial and terminal T vectors; STJ depression in V6 and rate-adjusted QTp interval (QTpa); and Set 2, TaVR and TV1 amplitudes, heart rate, and QRS duration. Strong independent predictors with over 2-fold increased risk for CHD death in women with and without CVD were Ѳ(Tp|Tref) >42° from Set 1 and TaVR amplitude >-100 μV from Set 2. The risk for these CHD death predictors remained significant after multivariable adjustment for demographic/clinical factors. Other significant predictors for CHD death in fully adjusted risk models were Ѳ(Tinit|Tterm) >30°, TV1 >175 μV, and QRS duration >100 ms.Ѳ(Tp|Tref) angle and TaVR amplitude are associated with CHD mortality in postmenopausal women. The use of these measures to identify high-risk women for further diagnostic evaluation or more intense preventive intervention warrants further study.http://www.clinicaltrials.gov. Unique identifier: NCT00000611.

    View details for DOI 10.1161/JAHA.114.001005

    View details for PubMedID 25074699

  • Does CHA2DS2-VASc improve stroke risk stratification in postmenopausal women with atrial fibrillation? American journal of medicine Abraham, J. M., Larson, J., Chung, M. K., Curtis, A. B., Lakshminarayan, K., Newman, J. D., Perez, M., Rexrode, K., Shara, N. M., Solomon, A. J., Stefanick, M. L., Torner, J. C., Wilkoff, B. L., Wassertheil-Smoller, S. 2013; 126 (12): 1143 e1-8

    Abstract

    Risk stratification of atrial fibrillation patients with a congestive heart failure (C), hypertension (H), age ≥ 75 (A), diabetes (D), stroke or transient ischemic attack (TIA) (S2) (CHADS2) score of <2 remains imprecise, particularly in women. Our objectives were to validate the CHADS2 and congestive heart failure (C), hypertension (H), age ≥ 75 (A2), diabetes (D), stroke, TIA or prior thromboembolic disease (S2)- vascular disease (V), age 65-74 (A), female gender (S) (CHA2DS2-VASc) stroke risk scores in a healthy cohort of American women with atrial fibrillation and to determine whether CHA2DS2-VASc further risk-stratifies individuals with a CHADS2 score of <2.We identified a cohort of 5981 women with atrial fibrillation not on warfarin at baseline (mean age 65.9 ± 7.2 years) enrolled in the Women's Health Initiative and followed for a median of 11.8 years. Univariate and multivariate proportional hazards analyses were used to examine these 2 risk scores, with main outcome measures being annualized event rates of ischemic stroke or transient ischemic attack stratified by risk score.Annualized stroke/transient ischemic attack rates ranged from 0.36% to 2.43% with increasing CHADS2 score (0-4+) (hazard ratio [HR] 1.57; 95% confidence interval [CI], 1.45-1.71 for each 1-point increase) and 0.20%-2.02% with increasing CHA2DS2-VASc score (1-6+) (HR 1.50; 95% CI, 1.41-1.60 for each 1-point increase). CHA2DS2-VASc had a higher c statistic than CHADS2: 0.67 (95% CI, 0.65-0.69) versus 0.65 (95% CI, 0.62-0.67), P <.01. For CHADS2 scores <2, stroke risk almost doubled with every additional CHA2DS2-VASc point.Although both CHADS2, and CHA2DS2-VASc are predictive of stroke risk in postmenopausal women with atrial fibrillation, CHA2DS2-VASc further risk-stratifies patients with a CHADS2 score <2.

    View details for DOI 10.1016/j.amjmed.2013.05.023

    View details for PubMedID 24139523

  • Variation in Use of Left Ventriculography in the Veterans Affairs Health Care System CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Heidenreich, P. A., Lin, S., Knowles, J. W., Perez, M., Maddox, T. M., Ho, M. P., Rumsfeld, J. S., Sahay, A., Massie, B. M., Tsai, T. T., Witteles, R. M. 2013; 6 (6): 687-693

    Abstract

    Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System.We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases.There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000199

    View details for Web of Science ID 000330362400017

    View details for PubMedID 24192569

  • Prognostic implications of the J wave ECG patterns. Journal of electrocardiology Yong, C. M., Perez, M., Froelicher, V. 2013; 46 (5): 408-410

    View details for DOI 10.1016/j.jelectrocard.2013.06.010

    View details for PubMedID 23870660

  • African American race but not genome-wide ancestry is negatively associated with atrial fibrillation among postmenopausal women in the Women's Health Initiative. American heart journal Perez, M. V., Hoffmann, T. J., Tang, H., Thornton, T., Stefanick, M. L., Larson, J. C., Kooperberg, C., Reiner, A. P., Caan, B., Iribarren, C., Risch, N. 2013; 166 (3): 566-572

    Abstract

    Atrial fibrillation (AF) is the most common arrhythmia in women and is associated with higher rates of stroke and death. Rates of AF are lower in African American subjects compared with European Americans, suggesting European ancestry could contribute to AF risk.The Women's Health Initiative (WHI) Observational Study (OS) followed up 93,676 women since the mid 1990s for various cardiovascular outcomes including AF. Multivariate Cox hazard regression analysis was used to measure the association between African American race and incident AF. A total of 8,119 African American women from the WHI randomized clinical trials and OS were genotyped on the Affymetrix Human SNP Array 6.0. Genome-wide ancestry and previously reported single nucleotide polymorphisms associated with AF in European cohorts were tested for association with AF using multivariate logistic regression analyses.Self-reported African American race was associated with lower rates of AF (hazard ratio 0.43, 95% CI 0.32-0.60) in the OS, independent of demographic and clinical risk factors. In the genotyped cohort, there were 558 women with AF. By contrast, genome-wide European ancestry was not associated with AF. None of the single nucleotide polymorphisms previously associated with AF in European populations, including rs2200733, were associated with AF in the WHI African American cohort.African American race is significantly and inversely correlated with AF in postmenopausal women. The etiology of this association remains unclear and may be related to unidentified environmental differences. Larger studies are necessary to identify genetic determinants of AF in African Americans.

    View details for DOI 10.1016/j.ahj.2013.05.024

    View details for PubMedID 24016508

  • J wave patterns and their prognostic value in African Americans. Journal of electrocardiology Perez, M. V., Froelicher, V. 2013; 46 (5): 442-445

    View details for DOI 10.1016/j.jelectrocard.2013.06.015

    View details for PubMedID 23885885

  • Risk factors for atrial fibrillation and their population burden in postmenopausal women: the Women's Health Initiative Observational Study. Heart Perez, M. V., Wang, P. J., Larson, J. C., Soliman, E. Z., Limacher, M., Rodriguez, B., Klein, L., Manson, J. E., Martin, L. W., Prineas, R., Connelly, S., Hlatky, M., Wassertheil-Smoller, S., Stefanick, M. L. 2013; 99 (16): 1173-1178

    Abstract

    OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia in women. Large studies evaluating key AF risk factors in older women are lacking. We aimed to identify risk factors for AF in postmenopausal women and measure population burden of modifiable risk factors. DESIGN: Prospective observational study. SETTING: The Women's Health Initiative (WHI) Observational Study. PATIENTS: 93 676 postmenopausal women were followed for an average of 9.8 years for cardiovascular outcomes. After exclusion of women with prevalent AF or incomplete data, 8252 of the remaining 81 892 women developed incident AF. MAIN OUTCOME MEASURES: Incident AF was identified by WHI-ascertained hospitalisation records and diagnosis codes from Medicare claims. Multivariate Cox hazard regression analysis identified independent risk factors for incident AF. RESULTS: Age, hypertension, obesity, diabetes, myocardial infarction and heart failure were independently associated with incident AF. Hypertension and overweight status accounted for 28.3% and 12.1%, respectively, of the population attributable risk. Hispanic and African-American participants had lower rates of incident AF (HR 0.58, 95% CI 0.47 to 0.70 and HR 0.59, 95% CI 0.53 to 0.65, respectively) than Caucasians. CONCLUSIONS: Caucasian ethnicity, traditional cardiovascular risk factors and peripheral arterial disease were independently associated with higher rates of incident AF in postmenopausal women. Hypertension and overweight status accounted for a large proportion of population attributable risk. Measuring burden of modifiable AF risk factors in older women may help target interventions.

    View details for DOI 10.1136/heartjnl-2013-303798

    View details for PubMedID 23756655

  • Different patterns of bundle-branch blocks and the risk of incident heart failure in the Women's Health Initiative (WHI) study. Circulation. Heart failure Zhang, Z., Rautaharju, P. M., Soliman, E. Z., Manson, J. E., Martin, L. W., Perez, M., Vitolins, M., Prineas, R. J. 2013; 6 (4): 655-661

    Abstract

    We evaluated the risk of incident heart failure (HF) associated with bundle-branch blocks (BBBs) in postmenopausal women.Cox's regression was used to evaluate hazard ratios with 95% confidence intervals for HF among 65975 participants of the Women's Health Initiative (WHI) study during an average follow-up of 14 years. BBBs observed in 1676 women at baseline were categorized into left, right, and indetermined-type BBBs (LBBB, RBBB, and intraventricular conduction defect, respectively). Compared with women with no BBB, LBBB, and intraventricular conduction defect were strong predictors of incident HF in multivariable-adjusted risk models (hazard ratio, 3.79; confidence interval, 2.95-4.87 for LBBB and hazard ratio, 3.53; confidence interval, 2.14-5.81 for intraventricular conduction defect). RBBB was not a significant predictor of incident HF in multivariable-adjusted risk model, but the combination of RBBB and left anterior fascicular block was a strong predictor (hazard ratio, 2.96; confidence interval, 1.77-4.93). QRS duration was an independent predictor of incident HF only in LBBB, with more pronounced risk at QRS ≥ 140 ms than at <140 ms. QRS nondipolar voltage (RNDPV) was an independent predictor in both RBBB and LBBB and, in addition, in LBBB, QRS/STT angle and ST J-point depression in aVL were independent predictors.LBBB, intraventricular conduction defect, and RBBB combined with left anterior fascicular block are strong predictors of incident HF in multivariable-adjusted risk models, but RBBB is not a significant predictor. QRS duration ≥ 140 ms may warrant consideration in LBBB as an indication for further diagnostic evaluation for possible therapeutic and preventive action. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.

    View details for DOI 10.1161/CIRCHEARTFAILURE.113.000217

    View details for PubMedID 23729198

  • Taming Rare Variation With Known Biology in Long QT Syndrome. Circulation. Cardiovascular genetics Perez, M. V., Ashley, E. A. 2013; 6 (3): 227-229

    View details for DOI 10.1161/CIRCGENETICS.113.000199

    View details for PubMedID 23778589

  • From bedside to bench JOURNAL OF ELECTROCARDIOLOGY Perez, M., Froelicher, V. 2013; 46 (2): 114-115
  • Pacemaker Therapy in Atrial Fibrillation Journal of Cardiology and Vascular Medicine Park, S., Wang, P. J., Zei, P. C., Hsia, H. H., Turakhi, M., Perez, M. V., Al-Ahmad, A. A. 2013; 1: 1-7
  • Effects of Postmenopausal Hormone Therapy on Incident Atrial Fibrillation The Women's Health Initiative Randomized Controlled Trials CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Perez, M. V., Wang, P. J., Larson, J. C., Virnig, B. A., Cochrane, B., Curb, J. D., Klein, L., Manson, J. E., Martin, L. W., Robinson, J., Wassertheil-Smoller, S., Stefanick, M. L. 2012; 5 (6): 1108-1116

    Abstract

    Atrial fibrillation (AF) is less prevalent in women versus men, but associated with higher risks of stroke and death in women. The role hormone therapy plays in AF is not well understood.The Women's Health Initiative randomized postmenopausal women to placebo or conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) if they had a uterus (N=16 608) or to conjugated equine estrogens only if they had prior hysterectomy (N=10 739). Incident AF was identified by ECG and diagnosis codes from Medicare claims or hospitalization records. Hazard ratios for incident AF were estimated using Cox proportional hazards regression. After excluding participants with baseline AF, there were 611 incident AF cases over a mean of 5.6 years among 16 128 estrogen plus progestin participants, and 683 cases over a mean of 7.1 years among 10 251 conjugated equine estrogens alone participants. Incident AF was more frequent in the active groups of both trials, reaching statistical significance in the trial of conjugated equine estrogens alone in women with prior hysterectomy (hazard ratio, 1.17; CI, 1.00-1.36; P=0.045) and in the pooled analysis (hazard ratio, 1.12; CI, 1.00-1.24; P=0.05), but not in the estrogen plus progestin trial (hazard ratio, 1.07; CI, 0.91-1.25; P=0.44). These results were only minimally affected by adjustment for incident stroke, coronary heart disease, and heart failure.Incident AF was modestly elevated in hysterectomized women randomized to postmenopausal E-alone, and in the pooled group randomized to E-alone or estrogen plus progestin. The trend in women with intact uterus receiving estrogen plus progestin, considered separately, was not statistically significant.ClinicalTrials.gov; Identifier: NCT00000611.

    View details for DOI 10.1161/CIRCEP.112.972224

    View details for Web of Science ID 000313586900018

    View details for PubMedID 23169946

  • Semantic Confusion: The Case of Early Repolarization and the J Point AMERICAN JOURNAL OF MEDICINE Perez, M. V., Friday, K., Froelicher, V. 2012; 125 (9): 843-844

    View details for DOI 10.1016/j.amjmed.2011.08.024

    View details for PubMedID 22340816

  • Prognostic Implications of Q Waves and T-Wave Inversion Associated With Early Repolarization MAYO CLINIC PROCEEDINGS Uberoi, A., Sallam, K., Perez, M., Jain, N. A., Ashley, E., Froelicher, V. 2012; 87 (7): 614-619

    Abstract

    To evaluate the prevalence of early polarization (ER) in a stable population and to evaluate the prognostic significance of the association or absence of Q waves or T-wave inversion (TWI).In this retrospective study performed at the university-affiliated Palo Alto Veterans Affairs Health Care Center from March 1, 1987, through December 31, 1999, we evaluated outpatient electrocardiograms. Vital status and cause of death were determined in all patients, with a mean ± SD follow-up of 7.6±3.8 years.Of the 29,281 patients, 87% were men and 13% were African American. Inferior or lateral ER was present in 664 patients (2.3%): in inferior leads in 185 (0.6%), in lateral leads in 479 (1.6%) , and in both inferior and lateral leads in 163 (0.6%). Only when Q waves or TWI accompanied ER was there an increased risk of cardiovascular death (Cox proportional hazards regression model, 5.0; 95% confidence interval, 3.4-7.2; P<.001).Common patterns of ER without concomitant Q waves or TWI are not associated with increased risk of cardiovascular death; however, when either occurs with ER, there is a hazard ratio of 5.0. These findings confirm that ER is a benign entity; however, the presence of Q waves or TWI with ER is predictive of increased cardiovascular death.

    View details for DOI 10.1016/j.mayocp.2012.04.009

    View details for PubMedID 22766081

  • Use and overuse of left ventriculography AMERICAN HEART JOURNAL Witteles, R. M., Knowles, J. W., Perez, M., Morris, W. M., Spettell, C. M., Brennan, T. A., Heidenreich, P. A. 2012; 163 (4): 617-?

    Abstract

    Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography.Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort.Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test.

    View details for DOI 10.1016/j.ahj.2011.12.018

    View details for PubMedID 22520528

  • The prognostic value of early repolarization with ST-segment elevation in African Americans HEART RHYTHM Perez, M. V., Uberoi, A., Jain, N. A., Ashley, E., Turakhia, M. P., Froelicher, V. 2012; 9 (4): 558-565

    Abstract

    Increased prevalence of classic early repolarization, defined as ST-segment elevation (STE) in the absence of acute myocardial injury, in African Americans is well established. The prognostic value of this pattern in different ethnicities remains controversial.Measure association between early repolarization and cardiovascular mortality in African Americans.The resting electrocardiograms of 45,829 patients were evaluated at the Palo Alto Veterans Affairs Hospital. Subjects with inpatient status or electrocardiographic evidence of acute myocardial infarction were excluded, leaving 29,281 subjects. ST-segment elevation, defined as an elevation of >0.1 mV at the end of the QRS, was electronically flagged and visually adjudicated by 3 observers blinded to outcomes. An association between ethnicity and early repolarization was measured by using multivariate logistic regression. We analyzed associations between early repolarization and cardiovascular mortality by using the Cox proportional hazards regression analysis.Subjects were 13% women and 13.3% African Americans, with an average age of 55 years and followed for an average of 7.6 years, resulting in 1995 cardiovascular deaths. There were 479 subjects with lateral STE and 185 with inferior STE. After adjustment for age, sex, heart rate, and coronary artery disease, African American ethnicity was associated with lateral or inferior STE (odds ratio 3.1; P = .0001). While lateral or inferior STE in non-African Americans was independently associated with cardiovascular death (hazard ratio 1.6; P = .02), it was not associated with cardiovascular death in African Americans (hazard ratio 0.75; P = .50).Although early repolarization is more prevalent in African Americans, it is not predictive of cardiovascular death in this population and may represent a distinct electrophysiologic phenomenon.

    View details for DOI 10.1016/j.hrthm.2011.11.020

    View details for PubMedID 22094072

  • Catheter ablation of atrial fibrillation: state-of-the-art techniques and future perspectives JOURNAL OF CARDIOVASCULAR MEDICINE Santangeli, P., Di Biase, L., Burkhardt, D. J., Horton, R., Sanchez, J., Bai, R., Pump, A., Perez, M., Wang, P. J., Natale, A., Al-Ahmad, A. 2012; 13 (2): 108-124

    Abstract

    The impact of atrial fibrillation on the healthcare systems of Western countries is overwhelming, due to its independent association with death, systemic thromboembolism, impaired quality of life and hospitalizations. Catheter ablation is the only treatment thus far demonstrated capable of achieving cure in a substantial proportion of patients. Pulmonary vein antrum isolation (PVAI) is the cornerstone of current atrial fibrillation ablation techniques, with the greatest efficacy as a stand-alone procedure in patients with paroxysmal atrial fibrillation. Use of general anesthesia, open-irrigated ablation catheters and maintenance of periprocedural therapeutic warfarin has been demonstrated to increase the safety and effectiveness of PVAI. In patients with paroxysmal atrial fibrillation, the systematic addition of superior vena cava isolation increases the long-term freedom from atrial fibrillation recurrence. A more extensive ablation approach extending to the entire left atrial posterior wall and to complex fractionated electrograms (CFAEs) is warranted in nonparoxysmal atrial fibrillation patients, in whom nonpulmonary vein trigger sites are frequently identified. Up to one-third of these patients experiencing atrial fibrillation recurrence after ablation have evidence of triggers from the left atrial appendage. Isolation of this structure is the best treatment strategy to improve the long-term success rate. In recent years, in addition to the development of ablation techniques to increase the success rate, outcomes of atrial fibrillation treatment trials have been reconsidered. In particular, reduction of hospitalization, stroke and mortality, as well as economic factors, have all been considered relevant to evaluate the effectiveness of atrial fibrillation treatment. Large ongoing trials are specifically evaluating the impact of atrial fibrillation ablation on these outcomes. This article will summarize the state-of-the art techniques for atrial fibrillation ablation, and will discuss the contribution of ongoing studies to the future of atrial fibrillation ablation.

    View details for DOI 10.2459/JCM.0b013e32834f2371

    View details for Web of Science ID 000299652200004

    View details for PubMedID 22193837

  • Early Repolarization in an Ambulatory Clinical Population CIRCULATION Uberoi, A., Jain, N. A., Perez, M., Weinkopff, A., Ashley, E., Hadley, D., Turakhia, M. P., Froelicher, V. 2011; 124 (20): 2208-2214

    Abstract

    The significance of early repolarization, particularly regarding the morphology of the R-wave downslope, has come under question.We evaluated 29 281 resting ambulatory ECGs from the VA Palo Alto Health Care System. With PR interval as the isoelectric line and amplitude criteria ≥0.1 mV, ST-segment elevation is defined at the end of the QRS, J wave as an upward deflection, and slur as a conduction delay on the QRS downstroke. Associations of ST-segment elevation patterns, J waves, and slurs with cardiovascular mortality were analyzed with Cox analysis. With a median follow-up of 7.6 years, there were 1995 cardiac deaths. Of 29 281 subjects, 87% were male (55±14 years) and 13% were female (56±17 years); 13% were black, 6% were Hispanic, and 81% were white or other. Six hundred sixty-four (2.3%) had inferior or lateral ST-segment elevation: 185 (0.6%) in inferior leads and 479 (1.6%) in lateral leads, 163 (0.6%) in both, and 0.4% had global elevation. A total of 4041 ECGs were analyzed with enhanced display, and 583 (14%) had J waves or slurring, which were more prevalent in those with than in those without ST-segment elevation (61% versus 13%; P<0.001). ST-segment elevation occurred more in those with than in those without J waves or slurs (12% versus 1.3%; P<0.001). Except when involving only inferior leads, all components of early repolarization were more common in young individuals, male subjects, blacks, and those with bradycardia. All patterns and components of early repolarization were associated with decreased cardiovascular mortality, but this was not significant after adjustment for age.We found no significant association between any components of early repolarization and cardiac mortality.

    View details for DOI 10.1161/CIRCULATIONAHA.111.047191

    View details for PubMedID 21986288

  • The Impact of ST Elevation on Athletic Screening CLINICAL JOURNAL OF SPORT MEDICINE Leo, T., Uberoi, A., Jain, N. A., Garza, D., Chowdhury, S., Freeman, J. V., Perez, M., Ashley, E., Froelicher, V. 2011; 21 (5): 433-440

    Abstract

    To demonstrate the prevalence and patterns of ST elevation (STE) in ambulatory individuals and athletes and compare the clinical outcomes.Retrospective cohort study. ST elevation was measured by computer algorithm and defined as ≥0.1 mV at the end of the QRS complex. Elevation was confirmed, and J waves and slurring were coded visually.Veterans Affairs Palo Alto Health Care System and Stanford University varsity athlete screening evaluation.Overall, 45 829 electrocardiograms (ECGs) were obtained from the clinical patient cohort and 658 ECGs from athletes. We excluded inpatients and those with ECG abnormalities, leaving 20 901 outpatients and 641 athletes.Electrocardiogram evaluation and follow-up for vital status.All-cause and cardiovascular mortality and cardiac events.ST elevation in the anterior and lateral leads was more prevalent in men and in African Americans and inversely related to age and resting heart rate. Athletes had a higher prevalence of early repolarization even when matched for age and gender with nonathletes. ST elevation greater than 0.2 mV (2 mm) was very unusual. ST elevation was not associated with cardiac death in the clinical population or with cardiac events or abnormal test results in the athletes.Early repolarization is not associated with cardiac death and has patterns that help distinguish it from STE associated with cardiac conditions, such as myocardial ischemia or injury, pericarditis, and the Brugada syndrome.

    View details for DOI 10.1097/JSM.0B013E31822CF105

    View details for PubMedID 21892017

  • Interpretation of the Electrocardiogram of Young Athletes CIRCULATION Uberoi, A., Stein, R., Perez, M. V., Freeman, J., Wheeler, M., Dewey, F., Peidro, R., Hadley, D., Drezner, J., Sharma, S., Pelliccia, A., Corrado, D., Niebauer, J., Estes, M., Ashley, E., Froelicher, V. 2011; 124 (6): 746-757

    View details for DOI 10.1161/CIRCULATIONAHA.110.013078

    View details for PubMedID 21824936

  • Gene Coexpression Network Topology of Cardiac Development, Hypertrophy, and Failure CIRCULATION-CARDIOVASCULAR GENETICS Dewey, F. E., Perez, M. V., Wheeler, M. T., Watt, C., Spin, J., Langfelder, P., Horvath, S., Hannenhalli, S., Cappola, T. P., Ashley, E. A. 2011; 4 (1): 26-U129

    Abstract

    Network analysis techniques allow a more accurate reflection of underlying systems biology to be realized than traditional unidimensional molecular biology approaches. Using gene coexpression network analysis, we define the gene expression network topology of cardiac hypertrophy and failure and the extent of recapitulation of fetal gene expression programs in failing and hypertrophied adult myocardium.We assembled all myocardial transcript data in the Gene Expression Omnibus (n=1617). Because hierarchical analysis revealed species had primacy over disease clustering, we focused this analysis on the most complete (murine) dataset (n=478). Using gene coexpression network analysis, we derived functional modules, regulatory mediators, and higher-order topological relationships between genes and identified 50 gene coexpression modules in developing myocardium that were not present in normal adult tissue. We found that known gene expression markers of myocardial adaptation were members of upregulated modules but not hub genes. We identified ZIC2 as a novel transcription factor associated with coexpression modules common to developing and failing myocardium. Of 50 fetal gene coexpression modules, 3 (6%) were reproduced in hypertrophied myocardium and 7 (14%) were reproduced in failing myocardium. One fetal module was common to both failing and hypertrophied myocardium.Network modeling allows systems analysis of cardiovascular development and disease. Although we did not find evidence for a global coordinated program of fetal gene expression in adult myocardial adaptation, our analysis revealed specific gene expression modules active during both development and disease and specific candidates for their regulation.

    View details for DOI 10.1161/CIRCGENETICS.110.941757

    View details for PubMedID 21127201

  • Personalized Medicine and Cardiovascular Disease: From Genome to Bedside Current Cardiovascular Risk Reports S. Pan, F. E. Dewey, M. V. Perez, J. W. Knowles, R. Chen, A. J. Butte, E. A. Ashley 2011; 5: 542-551
  • Cost-Effectiveness of Genetic Testing in Family Members of Patients With Long-QT Syndrome CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Perez, M. V., Kumarasamy, N. A., Owens, D. K., Wang, P. J., Hlatky, M. A. 2011; 4 (1): 76-84

    Abstract

    Family members of patients with established long-QT syndrome (LQTS) often lack definitive clinical findings, yet may have inherited an LQTS mutation and be at risk of sudden death. Genetic testing can identify mutations in 75% of patients with LQTS, but genetic testing of family members remains controversial.We used a Markov model to assess the cost-effectiveness of 3 strategies for treating an asymptomatic 10-year-old, first-degree relative of a patient with clinically evident LQTS. In the genetic testing strategy, relatives undergo genetic testing only for the mutation identified in the index patient, and relatives who test positive for the mutation are treated with β-blockers. This strategy was compared with (1) empirical treatment of relatives with β-blockers and (2) watchful waiting, with treatment only after development of symptoms. The genetic testing strategy resulted in better survival and quality-adjusted life years at higher cost, with a cost-effectiveness ratio of $67 400 per quality-adjusted life year gained compared with watchful waiting. The cost-effectiveness of the genetic testing strategy improved to less than $50 000 per quality-adjusted life year gained when applied selectively either to (1) relatives with higher clinical suspicion of LQTS (pretest probability 65% to 81%), or to (2) families with a higher than average risk of sudden death, or to (3) larger families (2 or more first-degree relatives tested).Genetic testing of young first-degree relatives of patients with definite LQTS is moderately expensive, but can reach acceptable thresholds of cost-effectiveness when applied to selected patients.

    View details for DOI 10.1161/CIRCOUTCOMES.110.957365

    View details for PubMedID 21139095

  • Inappropriate pacing in a patient with managed ventricular pacing: What is the cause? HEART RHYTHM Perez, M. V., Al-Ahmad, A. A., Wang, P. J., Turakhia, M. P. 2010; 7 (9): 1336-1337

    Abstract

    A case of inappropriate atrial pacing in a patient with a pacemaker programmed with Managed Ventricular Pacing (MVP) mode, a proprietary algorithm in Medtronic devices, is presented. The patient was an 84-year-old woman who presented in sinus rhythm with complete atrioventricular block. A dual-chamber pacemaker was implanted and programmed to an MVP pacing mode. After the implant, the patient developed a relatively slow atrial tachyarrhythmia with 2:1 atrioventricular block and inappropriate atrial pacing, followed by a delay in tracking of the atrial tachyarrhythmia. The mechanisms for these behaviors are described.

    View details for DOI 10.1016/j.hrthm.2010.04.028

    View details for PubMedID 20435165

  • Addition of the Electrocardiogram to the Preparticipation Examination of College Athletes CLINICAL JOURNAL OF SPORT MEDICINE Le, V., Wheeler, M. T., Mandic, S., Dewey, F., Fonda, H., Perez, M., Sungar, G., Garza, D., Ashley, E. A., Matheson, G., Froelicher, V. 2010; 20 (2): 98-105

    Abstract

    Although the use of standardized cardiovascular (CV) system-focused history and physical examination is recommended for the preparticipation examination (PPE) of athletes, the addition of the electrocardiogram (ECG) has been controversial. Because the impact of ECG screening on college athletes has rarely been reported, we analyzed the findings of adding the ECG to the PPE of Stanford athletes.For the past 15 years, the Stanford Sports Medicine program has mandated a PPE questionnaire and physical examination by Stanford physicians for participation in intercollegiate athletics. In 2007, computerized ECGs with digital measurements were recorded on athletes and entered into a database.Although the use of standardized CV-focused history and physical examination are recommended for the PPE of athletes, the addition of the ECG has been controversial. Because the feasibility and outcomes of ECG screening on college athletes have rarely been reported, we present findings derived from the addition of the ECG to the PPE of Stanford athletes. For the past 15 years, the Stanford Sports Medicine program has mandated a PPE questionnaire and physical examination by Stanford physicians for participation in intercollegiate athletics. In 2007, computerized ECGs with digital measurements were recorded on athletes and entered into a database.Six hundred fifty-eight recordings were obtained (54% men, 10% African-American, mean age 20 years) representing 24 sports. Although 68% of the women had normal ECGs, only 38% of the men did so. Incomplete right bundle branch block (RBBB) (13%), right axis deviation (RAD) (10%), and atrial abnormalities (3%) were the 3 most common minor abnormalities. Sokolow-Lyon criteria for left ventricular hypertrophy (LVH) were found in 49%; however, only 27% had a Romhilt-Estes score of >or=4. T-wave inversion in V2 to V3 occurred in 7%, and only 5 men had abnormal Q-waves. Sixty-three athletes (10%) were judged to have distinctly abnormal ECG findings possibly associated with conditions including hypertrophic cardiomyopathy or arrhythmogenic right ventricular dysplasia/cardiomyopathy. These athletes were offered further testing but this was not mandated according to the research protocol.Six hundred fifty-three recordings were obtained (54% men, 7% African American, mean age 20 years), representing 24 sports. Although 68% of the women had normal ECGs, only 38% of the men did so. Incomplete RBBB (13%), RAD (10%), and atrial abnormalities (3%) were the 3 most common minor abnormalities. Sokolow-Lyon criteria for LVH were found in 49%; however, only 27% had a Romhilt-Estes score of >or=4. T-wave inversion in V2 to V3 occurred in 7% and only 5 men had abnormal Q-waves. Sixty-five athletes (10%) were judged to have distinctly abnormal ECG findings suggestive of arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, and/or biventricular hypertrophy. These athletes will be submitted to further testing.Mass ECG screening is achievable within the collegiate setting by using volunteers when the appropriate equipment is available. However, the rate of secondary testing suggests the need for an evaluation of cost-effectiveness for mass screening and the development of new athlete-specific ECG interpretation algorithms.

    View details for DOI 10.1097/JSM.0b013e3181d44705

    View details for PubMedID 20215891

  • Adding an Electrocardiogram to the Pre-participation Examination in Competitive Athletes: A Systematic Review CURRENT PROBLEMS IN CARDIOLOGY Perez, M., Fonda, H., Le, V., Mitiku, T., Ray, J., Freeman, J. V., Ashley, E., Froelicher, V. F. 2009; 34 (12): 586-662

    Abstract

    No matter how rare, the death of young athletes is a tragedy. Can it be prevented? The European experience suggests that adding the electrocardiogram (ECG) to the standard medical and family history and physical examination can decrease cardiac deaths by 90%. However, there has not been a randomized trial to demonstrate such a reduction. While there are obvious differences between the European and American experiences with athletes including very differing causes of athletic deaths, some would highlight the European emphasis on public welfare vs the protection of personal rights in the USA. Even the authors of this systematic review have differing interpretation of the data: some of us view screening as a hopeless battle against Bayes, while others feel that the ECG can save lives. What we all agree on is that the USA should implement the American Heart Association 12-point screening recommendations and that, before ECG screening is mandated, we need to gather more data and optimize ECG criteria for screening young athletes.

    View details for DOI 10.1016/j.cpcardiol.2009.08.002

    View details for Web of Science ID 000271915700002

    View details for PubMedID 19887232

  • Electrocardiographic predictors of atrial fibrillation AMERICAN HEART JOURNAL Perez, M. V., Dewey, F. E., Marcus, R., Ashley, E. A., Al-Ahmad, A. A., Wang, P. J., Froelicher, V. F. 2009; 158 (4): 622-628

    Abstract

    Atrial fibrillation (AF) is the most prevalent arrhythmia in the United States and accounts for more than 750,000 strokes per year. Noninvasive predictors of AF may help identify patients at risk of developing AF. Our objective was to identify the electrocardiographic characteristics associated with onset of AF.This was a retrospective cohort analysis of 42,751 patients with electrocardiograms (ECGs) ordered by physician's discretion and analyzed using a computerized system. The population was followed for detection of AF on subsequent ECGs. Cox proportional hazard regression analysis was performed to test the association between these ECG characteristics and development of AF.For a mean follow-up of 5.3 years, 1,050 (2.4%) patients were found to have AF on subsequent ECG recordings. Several ECG characteristics, such as P-wave dispersion (the difference between the widest and narrowest P waves), premature atrial contractions, and an abnormal P axis, were predictive of AF with hazard ratio of approximately 2 after correcting for age and sex. P-wave index, the SD of P-wave duration across all leads, was one of the strongest predictors of AF with a concordance index of 0.62 and a hazard ratio of 2.7 (95% CI 2.1-3.3) for a P-wave index >35. These were among the several independently predictive markers identified on multivariate analysis.Several ECG markers are independently predictive of future onset of AF. The P index, a measurement of disorganized atrial depolarization, is one of the strongest predictors of AF. The ECG contains valuable prognostic information that can identify patients at risk of AF.

    View details for DOI 10.1016/j.ahj.2009.08.002

    View details for PubMedID 19781423

  • Mechanisms of exercise intolerance in patients with hypertrophic cardiomyopathy AMERICAN HEART JOURNAL Le, V., Perez, M. V., Wheeler, M. T., Myers, J., Schnittger, I., Ashley, E. A. 2009; 158 (3): E27-E34

    Abstract

    To determine the relation between echocardiogram findings and exercise capacity in hypertrophic cardiomyopathy (HCM).Sixty-three patients (48 +/- 15 years) were referred for cardiopulmonary testing and exercise echocardiography. They were classified by morphology: proximal (n = 11), reverse curvature (n = 32), apical (n = 7), and concentric HCM (n = 13). There were more women in proximal and reverse curvature groups. Proximal HCM patients were older. Maximal left ventricular thickness was highest in reverse curvature group. At peak exercise, concentric HCM achieved the lowest percent predicted maximal Vo2. Excluding apical group, no significant differences in gradient were noted between groups. Overall, no statistically significant correlation was found between peak Vo2, wall thickness, and gradient. Significant correlations were noted between peak Vo2 and indexed left atrial (LA) volume (r = -0.52), lateral E' (r = 0.50), and lateral E/E' ratio (r = -0.46). A multivariate model including age, lateral E', indexed LA volume, and mitral A wave explained 46% of the variance in peak Vo2 (P = .01).Lateral E' and indexed LA volume are negatively correlated with functional capacity. Although patients with concentric morphology achieved the lowest peak Vo2, wall thickness and gradient did not predict exercise capacity.

    View details for DOI 10.1016/j.ahj.2009.06.006

    View details for Web of Science ID 000269641200027

    View details for PubMedID 19699847

  • Statin Use and Ventricular Arrhythmias During Clinical Treadmill Testing JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Dewey, F. E., Perez, M., Hadley, D., Freeman, J. V., Wang, P., Ashley, E. A., Myers, J., Froelicher, V. F. 2009; 20 (2): 193-199

    Abstract

    Premature ventricular complexes (PVCs) during exercise are associated with adverse prognosis, particularly in patients with intermediate treadmill test findings. Statin use reduces the incidence of resting ventricular arrhythmias in patients with coronary artery disease; however, the relationship between statin use and exercise-induced ventricular arrhythmias has not been investigated.We evaluated the association between statin use and PVCs in 1,847 heart-failure-free patients (mean age 58, 95% male) undergoing clinical exercise treadmill testing between 1997 and 2004 in the VA Palo Alto Health Care System. PVCs were quantified in beats per minute and frequent PVCs were defined as PVC rates greater than the median value (0.43 and 0.60 PVCs per minute for exercise and recovery, respectively). Propensity-adjusted logistic regression was used to evaluate the odds of developing PVCs during exercise and recovery periods associated with statin use. There were 431 subjects who developed frequent PVCs during exercise and 284 subjects had frequent recovery PVCs. After propensity score adjustment, subjects treated with statins (n = 145) had 42% lower odds of developing frequent PVCs during exercise (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37-0.93) and 44% lower odds of developing frequent PVCs during recovery (OR 0.56, 95% CI 0.30-0.94). These effects were not modified by age, prior coronary disease, hypercholesterolemia, exercise-induced angina, or exercise capacity.Statin use was associated with reduced odds of frequent PVCs during and after clinical exercise testing in a manner independent of associations with coronary disease or ischemia in our study population.

    View details for DOI 10.1111/j.1540-8167.2008.01284.x

    View details for PubMedID 18775041

  • Added Value of a Resting ECG Neural Network That Predicts Cardiovascular Mortality ANNALS OF NONINVASIVE ELECTROCARDIOLOGY Perez, M. V., Dewey, F. E., Tan, S. Y., Myers, J., Froelicher, V. F. 2009; 14 (1): 26-34

    Abstract

    The resting 12-lead electrocardiogram (ECG) remains the most commonly used test in evaluating patients with suspected cardiovascular disease. Prognostic values of individual findings on the ECG have been reported but may be of limited use.The characteristics of 45,855 ECGs ordered by physician's discretion were first recorded and analyzed using a computerized system. Ninety percent of these ECGs were used to train an artifical neural network (ANN) to predict cardiovascular mortality (CVM) based on 132 ECG and four demographic characteristics. The ANN generated a Resting ECG Neural Network (RENN) score that was then tested in the remaining ECGs. The RENN score was finally assessed in a cohort of 2189 patients who underwent exercise treadmill testing and were followed for CVM.The RENN score was able to better predict CVM compared to individual ECG markers or a traditional Cox regression model in the testing cohort. Over a mean of 8.6 years, there were 156 cardiovascular deaths in the treadmill cohort. Among the patients who were classified as intermediate risk by Duke Treadmill Scoring (DTS), the third tertile of the RENN score demonstrated an adjusted Cox hazard ratio of 5.4 (95% CI 2.0-15.2) compared to the first RENN tertile. The 10-year CVM was 2.8%, 8.6% and 22% in the first, second and third RENN tertiles, respectively.An ANN that uses the resting ECG and demographic variables to predict CVM was created. The RENN score can further risk stratify patients deemed at moderate risk on exercise treadmill testing.

    View details for DOI 10.1111/j.1542-474X.2008.00270.x

    View details for PubMedID 19149790

  • Isolated Disease of the Proximal Left Anterior Descending Artery Comparing the Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Surgery JACC-CARDIOVASCULAR INTERVENTIONS Kapoor, J. R., Gienger, A. L., Ardehali, R., Varghese, R., Perez, M. V., Sundaram, V., McDonald, K. M., Owens, D. K., Hlatky, M. A., Bravata, D. M. 2008; 1 (5): 483-491

    Abstract

    This study sought to systematically compare the effectiveness of percutaneous coronary intervention and coronary artery bypass surgery in patients with single-vessel disease of the proximal left anterior descending (LAD) coronary artery.It is uncertain whether percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG) surgery provides better clinical outcomes among patients with single-vessel disease of the proximal LAD.We searched relevant databases (MEDLINE, EMBASE, and Cochrane from 1966 to 2006) to identify randomized controlled trials that compared outcomes for patients with single-vessel proximal LAD assigned to either PCI or CABG.We identified 9 randomized controlled trials that enrolled a total of 1,210 patients (633 received PCI and 577 received CABG). There were no differences in survival at 30 days, 1 year, or 5 years, nor were there differences in the rates of procedural strokes or myocardial infarctions, whereas the rate of repeat revascularization was significantly less after CABG than after PCI (at 1 year: 7.3% vs. 19.5%; at 5 years: 7.3% vs. 33.5%). Angina relief was significantly greater after CABG than after PCI (at 1 year: 95.5% vs. 84.6%; at 5 years: 84.2% vs. 75.6%). Patients undergoing CABG spent 3.2 more days in the hospital than those receiving PCI (95% confidence interval: 2.3 to 4.1 days, p < 0.0001), required more transfusions, and were more likely to have arrhythmias immediately post-procedure.In patients with single-vessel, proximal LAD disease, survival was similar in CABG-assigned and PCI-assigned patients; CABG was significantly more effective in relieving angina and led to fewer repeat revascularizations.

    View details for DOI 10.1016/j.jcin.2008.07.001

    View details for PubMedID 19463349

  • Genetics of Arrhythmia: Disease Pathways Beyond Ion Channels JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Perez, M. V., Wheeler, M., Ho, M., Pavlovic, A., Wang, P., Ashley, E. A. 2008; 1 (2): 155-165

    Abstract

    Diseases of the electrical conduction system that lead to irregularities in cardiac rhythm can have morbid and often lethal clinical outcomes. Linkage analysis has been the principal tool used to discover the genetic mutations responsible for Mendelian arrhythmic disease. Although the majority of arrhythmias can be accounted for by mutations in genes encoding ion channels, linkage analysis has also uncovered the role of other gene families such as those encoding members of the desmosome. With a list of candidates in mind, mutational analysis has helped confirm the suspicion that proteins found in caveolae or gap junctions also play a role in arrhythmogenesis. Atrial fibrillation and sudden cardiac death are relatively common arrhythmias that may be caused by multiple factors including common genetic variants. Genome-wide association studies are already revealing the important and poorly understood role of intergenic regions in atrial fibrillation. Despite the great advancements that have been made in our understanding of the genetics of these diseases, we are still far from able to routinely use genomic data to make clinical management decisions. There remain several hurdles in the study of genetics of arrhythmia, including the costs of genotyping, the need to find large affected families for linkage analysis, or to recruit large numbers of patients for genome-wide studies. Novel techniques that incorporate epigenetic information, such as known gene-gene interactions, biologic pathways, and experimental gene expression, will need to be developed to better interpret the large amount of genetic data that can now be generated. The study of arrhythmia genetics will continue to elucidate the pathophysiology of disease, help identify novel therapies, and ultimately allow us to deliver the individualized medical therapy that has long been anticipated.

    View details for DOI 10.1007/s12265-008-9030-4

    View details for Web of Science ID 000207734800012

    View details for PubMedID 20559910

  • Systematic review: The comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft surgery ANNALS OF INTERNAL MEDICINE Bravata, D. M., Gienger, A. L., McDonald, K. M., Sundaram, V., Perez, M. V., Varghese, R., Kapoor, J. R., Ardehali, R., Owens, D. K., Hlatky, M. A. 2007; 147 (10): 703-U139

    Abstract

    The comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) for patients in whom both procedures are feasible remains poorly understood.To compare the effectiveness of PCI and CABG in patients for whom coronary revascularization is clinically indicated.MEDLINE, EMBASE, and Cochrane databases (1966-2006); conference proceedings; and bibliographies of retrieved articles.Randomized, controlled trials (RCTs) reported in any language that compared clinical outcomes of PCI with those of CABG, and selected observational studies.Information was extracted on study design, sample characteristics, interventions, and clinical outcomes.The authors identified 23 RCTs in which 5019 patients were randomly assigned to PCI and 4944 patients were randomly assigned to CABG. The difference in survival after PCI or CABG was less than 1% over 10 years of follow-up. Survival did not differ between PCI and CABG for patients with diabetes in the 6 trials that reported on this subgroup. Procedure-related strokes were more common after CABG than after PCI (1.2% vs. 0.6%; risk difference, 0.6%; P = 0.002). Angina relief was greater after CABG than after PCI, with risk differences ranging from 5% to 8% at 1 to 5 years (P < 0.001). The absolute rates of angina relief at 5 years were 79% after PCI and 84% after CABG. Repeated revascularization was more common after PCI than after CABG (risk difference, 24% at 1 year and 33% at 5 years; P < 0.001); the absolute rates at 5 years were 46.1% after balloon angioplasty, 40.1% after PCI with stents, and 9.8% after CABG. In the observational studies, the CABG-PCI hazard ratio for death favored PCI among patients with the least severe disease and CABG among those with the most severe disease.The RCTs were conducted in leading centers in selected patients. The authors could not assess whether comparative outcomes vary according to clinical factors, such as extent of coronary disease, ejection fraction, or previous procedures. Only 1 small trial used drug-eluting stents.Compared with PCI, CABG was more effective in relieving angina and led to fewer repeated revascularizations but had a higher risk for procedural stroke. Survival to 10 years was similar for both procedures.

    View details for PubMedID 17938385

  • Prognostic value of the computerized ECG in Hispanics CLINICAL CARDIOLOGY Perez, M. V., Yaw, T. S., Myers, J., Froelicher, V. F. 2007; 30 (4): 189-194

    Abstract

    The prevalence and prognostic values of electrocardiogram (ECG) abnormalities in Hispanics have not been compared to other ethnicities in a large population. Despite a worse cardiovascular risk profile, the prevalence of cardiovascular disease is lower in Hispanics compared to non-Hispanics.We hypothesized that ECG abnormalities were less common in Hispanics and were not as strongly associated with cardiovascular mortality.45,563 ECGs ordered for usual clinical indications in a Veteran's hospital were available for analysis. 1,392 patients who died within one week of the ECG were excluded. Demographic characteristics were recorded and the population was followed for an average of 7.5 years using the California Death Index. The presence of baseline ECG characteristics were recorded and analyzed using the GE/Marquette computerized ECG system. Age, sex and heart rate adjusted Cox hazard ratio analyses were performed.Being Hispanic was associated with lower cardiovascular death, with a hazard ratio (HR) of 0.76 (95% CI 0.65-0.89). Findings such as atrial fibrillation, presence of Q-waves, left ventricular hypertrophy (LVH), upright T-waves in aortic valve replacement (aVR) and cardiac Infarction Injury Scores > 6 were significantly less prevalent in Hispanics than in non-Hispanics. These findings were similarly associated with increased cardiovascular mortality in both groups, each with a HR of approximately 2.The lower prevalence of ECG characteristics associated with coronary heart disease, atrial fibrillation and left ventricular hypertrophy support prior observations that cardiovascular disease is less prevalent in the Hispanic population. These findings, however, are similarly associated with increased mortality compared to non-Hispanics.

    View details for DOI 10.1002/clc.20053

    View details for PubMedID 17443659

  • Giant coronary aneurysms in heart transplantation: an unusual presentation of cardiac allograft vasculopathy JOURNAL OF HEART AND LUNG TRANSPLANTATION Haddad, F., Perez, M., Fleischmann, D., Valantine, H., Hunt, S. A. 2006; 25 (11): 1367-1370

    Abstract

    Cardiac allograft vasculopathy is a leading cause of death during long-term follow-up of heart transplant recipients. We report 2 cases of cardiac allograft vasculopathy associated with giant coronary aneurysms. To our knowledge, these are the first reported cases of spontaneous giant coronary aneurysms in heart transplant recipients.

    View details for DOI 10.1016/j.healun.2006.07.006

    View details for Web of Science ID 000242222100015

    View details for PubMedID 17097503

  • p300/MDM2 complexes participate in MDM2-mediated p53 degradation MOLECULAR CELL Grossman, S. R., Perez, M., Kung, A. L., Joseph, M., Mansur, C., Xiao, Z. X., Kumar, S., Howley, P. M., Livingston, D. M. 1998; 2 (4): 405-415

    Abstract

    Control of p53 turnover is critical to p53 function. E1A binding to p300/CBP translates into enhanced p53 stability, implying that these coactivator proteins normally operate in p53 turnover control. In this regard, the p300 C/H1 region serves as a specific in vivo binding site for both p53 and MDM2, a naturally occurring p53 destabilizer. Moreover, most of the endogenous MDM2 is bound to p300, and genetic analysis implies that specific interactions of p53 and MDM2 with p300 C/H1 are important steps in the MDM2-directed turnover of p53. A specific role for p300 in endogenous p53 degradation is underscored by the p53-stabilizing effect of overproducing the p300 C/H1 domain. Taken together, the data indicate that specific interactions between p300/CBP C/H1, p53, and MDM2 are intimately involved in the MDM2-mediated control of p53 abundance.

    View details for Web of Science ID 000076678900001

    View details for PubMedID 9809062