Bio


I am a physician scientist with interests in cardiomyopathies, rare and undiagnosed diseases, therapeutics and genomics. I have research training in both myocardial and skeletal muscle biology and genetics, genomics, and multi-scale networks. In addition to my research training, I am a physician with interest and experience treating patients with hypertrophic cardiomyopathy and other inherited cardiomyopathies. I have clinical training in medicine, cardiology, cardiovascular genetics, and advanced heart failure. I have extensive translational science efforts, participating in several ongoing clinical trials for hypertrophic cardiomyopathy, dilated cardiomyopathy, ATTR cardiac amyloidosis, and mechanical circulatory support. I am Co-PI of Stanford’s NIH-funded Center for Undiagnosed Diseases a clinical site of the Undiagnosed Diseases Network. I am also a co-Investigator of the Bioinformatics Center of the Molecular Transducers of Physical Activity Consortium. I pursue projects and collaborations at the intersection of striated muscle genetics, genomics, and clinical investigation.

Clinical Focus


  • Cardiology
  • Cardiomyopathy, Hypertrophic, Familial
  • Heart Failure
  • Cardiovascular Disease
  • Mechanical Circulatory Support
  • Undiagnosed Diseases
  • Myotonic Dystrophy associated Cardiomyopathy
  • Cardiovascular Genetics
  • Cardiac Amyloid
  • Heart Transplantation
  • Arrhythmogenic Right Ventricular Cardiomyopathy
  • Dilated Cardiomyopathies
  • Muscular Dystrophy associated Cardiomyopathy

Administrative Appointments


  • Executive Director, Center for Undiagnosed Diseases at Stanford (2014 - Present)
  • Adult Medical Director, Center for Undiagnosed Diseases at Stanford (2015 - Present)

Boards, Advisory Committees, Professional Organizations


  • Member, American Heart Association (2012 - Present)
  • Member, American College of Cardiology (2017 - Present)
  • Member, American Society of Human Genetics (2016 - Present)

Professional Education


  • Medical Education:Pritzker School of Medicine University of Chicago Registrar (2005) IL
  • Board Certification: Advanced Heart Failure and Transplant Cardiology, American Board of Internal Medicine (2014)
  • Residency:Stanford University Hospital -Clinical Excellence Research Center (2007) CA
  • Fellowship:Stanford University School of Medicine (2013) CA
  • Fellowship:Stanford University School of Medicine (2012) CA
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2012)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2008)
  • Bachelor of Arts, Williams College, History and Biology (1998)

Community and International Work


  • Undiagnosed Diseases - Latin America

    Topic

    Undiagnosed Diseases and Genetics

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Current Research and Scholarly Interests


Translational research in rare and undiagnosed diseases. Basic and clinical research in cardiomyopathy genetics, mechanisms, screening, and treatment. Investigating novel agents for treatment of hypertrophic cardiomyopathy and new mechanisms in heart failure. Cardiovascular screening and genetics in competitive athletes, disease gene discovery in cardiomyopathy and rare disease. Informatics approaches to rare disease and multiomics. Molecular transducers of physical activity bioinformatics.

Clinical Trials


  • A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy (nHCM) Recruiting

    This is a multicenter, exploratory, randomized, double-blind study of the administration of mavacamten in 60 participants with symptomatic nHCM randomized to receive a 16-week course of mavacamten doses titrated to achieve 1 of 2 target drug concentrations.

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  • A Study of ARRY-371797 in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation Recruiting

    This is a randomized, double-blind, placebo-controlled study in patients with dilated cardiomyopathy (DCM) due to a gene encoding the lamin A/C protein (LMNA) mutation. The study will further evaluate a dose level of ARRY-371797 that has shown preliminary efficacy and safety in this patient population. After the primary analysis has been performed, eligible patients may receive open-label treatment with ARRY-371797.

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  • Clinical and Genetic Evaluation of Individuals With Undiagnosed Disorders Through the Undiagnosed Diseases Network Recruiting

    Background: - Without an explanation for severe and sometimes life-threatening symptoms, patients and their families are left in a state of unknown. The NIH helped create a network of medical research centers, called the Undiagnosed Diseases Network (UDN), to provide care and answers for these individuals. Objectives: - To improve diagnosis and care for people with undiagnosed diseases. Eligibility: - People with undiagnosed diseases, and their relatives. Design: - Participants will travel to one of the UDN medical centers for a 5-day clinical and research visit. - As part of the visit, UDN healthcare providers may ask participants to have: - Clinically indicated tests and procedures performed including: - A physical exam - Blood and urine tests - A review of health and family history - X-rays and body scans - Surveys - Photographs of the face and body - A special diet to see if the body can handle the food without having a reaction, like vomiting - Video or voice recordings - Other tests and procedures to help reach a diagnosis - Research tests and procedures performed including: - A skin biopsy. For this, a small piece of skin will be taken. - Surveys - Other tests and procedures for research that may not be related to a diagnosis or treatment. - Most participants will be asked to give samples for genetic testing. - Participants may be contacted after their visit to discuss test results. They may also be contacted in the future for interviews and surveys. - Relatives of participants may be asked to give samples for genetic testing. They may be asked to have parts of their visit recorded and to have additional tests. They may also be contacted in the future for interviews and surveys. - Clinical and research information collected will be stored in a database. - Information and samples collected will be shared with others for research purposes.

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  • Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Recruiting

    This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM). Approximately 220 participants will be randomized to receive placebo or mavacamten.

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  • DCM Precision Medicine Study Recruiting

    The aims of the DCM Precision Medicine Study are to test the hypothesis that DCM has substantial genetic basis and to evaluate the effectiveness of a family communication intervention in improving the uptake and impact of family member clinical screening.

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  • Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction Recruiting

    The purpose of this study is to determine if treatment with omecamtiv mecarbil/AMG 423 when added to standard of care is well tolerated and superior to placebo in reducing the risk of cardiovascular death or heart failure events in subjects with chronic HFrEF.

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  • Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy Not Recruiting

    This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ed Finn, 650-724-6167.

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  • Study of Exercise Training in Hypertrophic Cardiomyopathy Not Recruiting

    The investigators propose a pilot randomized controlled trial to determine the safety and potential benefits of moderate intensity exercise in patients with hypertrophic cardiomyopathy. The investigators hypotheses are that exercise parameters derived from a baseline cardiopulmonary exercise test will target an appropriately safe level of exercise intensity that will not cause significant arrhythmias or exacerbate symptoms and that exercise training for 4 months will result in significant improvements in peak oxygen consumption (peak VO2) and quality of life, with neutral effects on the clinical characteristics.

    Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Salisbury, BS, RN, MSN, 650-736-7878.

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  • The HeartWare™ Ventricular Assist System as Destination Therapy of Advanced Heart Failure: the ENDURANCE Trial Not Recruiting

    The purpose of this study is to determine the safety and effectiveness of the HeartWare Ventricular Assist System in patients with chronic Stage D/ New York Heart Association (NYHA) Class IIIB/IV left ventricular failure who have received and failed optimal medical therapy, and who are ineligible for cardiac transplantation.

    Stanford is currently not accepting patients for this trial. For more information, please contact Philip Oyer, (650) 725-3820.

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  • Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM Not Recruiting

    The purpose of this trial is to determine whether treatment with valsartan will have beneficial effect in early hypertrophic cardiomyopathy (HCM) by assessing many domains that reflect myocardial structure, function and biochemistry.

    Stanford is currently not accepting patients for this trial. For more information, please contact Euan Ashley, MD, PhD, 650-498-4900.

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2018-19 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder AMERICAN JOURNAL OF HUMAN GENETICS Olahova, M., Yoon, W., Thompson, K., Jangam, S., Fernandez, L., Davidson, J. M., Kyle, J. E., Grove, M. E., Fisk, D. G., Kohler, J. N., Holmes, M., Dries, A. M., Huang, Y., Zhao, C., Contrepois, K., Zappala, Z., Fresard, L., Waggott, D., Zink, E. M., Kim, Y., Heyman, H. M., Stratton, K. G., Webb-Robertson, B. M., Snyder, M., Merker, J. D., Montgomery, S. B., Fisher, P. G., Feichtinger, R. G., Mayr, J. A., Hall, J., Barbosa, I. A., Simpson, M. A., Deshpande, C., Waters, K. M., Koeller, D. M., Metz, T. O., Morris, A. A., Schelley, S., Cowan, T., Friederich, M. W., McFarland, R., Van Hove, J. K., Enns, G. M., Yamamoto, S., Ashley, E. A., Wangler, M. F., Taylor, R. W., Bellen, H. J., Bernstein, J. A., Wheeler, M. T., Undiagnosed Diseases Network 2018; 102 (3): 494–504

    Abstract

    ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.

    View details for PubMedID 29478781

  • Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. The New England journal of medicine Splinter, K., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., Eng, C. M., Esteves, C., Gahl, W. A., Hamid, R., Jacob, H. J., Kikani, B., Koeller, D. M., Kohane, I. S., Lee, B. H., Loscalzo, J., Luo, X., McCray, A. T., Metz, T. O., Mulvihill, J. J., Nelson, S. F., Palmer, C. G., Phillips, J. A., Pick, L., Postlethwait, J. H., Reuter, C., Shashi, V., Sweetser, D. A., Tifft, C. J., Walley, N. M., Wangler, M. F., Westerfield, M., Wheeler, M. T., Wise, A. L., Worthey, E. A., Yamamoto, S., Ashley, E. A. 2018

    Abstract

    Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

    View details for PubMedID 30304647

  • Effect of Moderate-Intensity Exercise Training on Peak Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Saberi, S., Wheeler, M., Bragg-Gresham, J., Hornsby, W., Agarwal, P. P., Attili, A., Concannon, M., Dries, A. M., Shmargad, Y., Salisbury, H., Kumar, S., Herrera, J., Myers, J., Helms, A. S., Ashley, E. A., Day, S. M. 2017; 317 (13): 1349-1357

    Abstract

    Formulating exercise recommendations for patients with hypertrophic cardiomyopathy is challenging because of concern about triggering ventricular arrhythmias and because a clinical benefit has not been previously established in this population.To determine whether moderate-intensity exercise training improves exercise capacity in adults with hypertrophic cardiomyopathy.A randomized clinical trial involving 136 patients with hypertrophic cardiomyopathy was conducted between April 2010 and October 2015 at 2 academic medical centers in the United States (University of Michigan Health System and Stanford University Medical Center). Date of last follow-up was November 2016.Participants were randomly assigned to 16 weeks of moderate-intensity exercise training (n = 67) or usual activity (n = 69).The primary outcome measure was change in peak oxygen consumption from baseline to 16 weeks.Among the 136 randomized participants (mean age, 50.4 [SD, 13.3] years; 42% women), 113 (83%) completed the study. At 16 weeks, the change in mean peak oxygen consumption was +1.35 (95% CI, 0.50 to 2.21) mL/kg/min among participants in the exercise training group and +0.08 (95% CI, -0.62 to 0.79) mL/kg/min among participants in the usual-activity group (between-group difference, 1.27 [95% CI, 0.17 to 2.37]; P = .02). There were no occurrences of sustained ventricular arrhythmia, sudden cardiac arrest, appropriate defibrillator shock, or death in either group.In this preliminary study involving patients with hypertrophic cardiomyopathy, moderate-intensity exercise compared with usual activity resulted in a statistically significant but small increase in exercise capacity at 16 weeks. Further research is needed to understand the clinical importance of this finding in patients with hypertrophic cardiomyopathy, as well as the long-term safety of exercise at moderate and higher levels of intensity.clinicaltrials.gov Identifier: NCT01127061.

    View details for DOI 10.1001/jama.2017.2503

    View details for Web of Science ID 000398434200019

    View details for PubMedID 28306757

  • Value of Strain Imaging and Maximal Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy. The American journal of cardiology Moneghetti, K. J., Stolfo, D., Christle, J. W., Kobayashi, Y., Finocchiaro, G., Sinagra, G., Myers, J., Ashley, E. A., Haddad, F., Wheeler, M. T. 2017; 120 (7): 1203–8

    Abstract

    Longitudinal strain (LS) has been shown to be predictive of outcome in hypertrophic cardiomyopathy (HC). Percent predicted peak oxygen uptake (ppVO2), among other cardiopulmonary exercise testing (CPX) metrics, is a strong predictor of prognosis in HC. However, there has been limited investigation into the combination of LS and CPX metrics. This study sought to determine how LS and parameters of exercise performance contribute to prognosis in HC. One hundred and thirty-one consecutive patients with HC who underwent CPX and stress echocardiography were included. Global, septal, and lateral LS were assessed at rest and stress. Eighty matched individuals were used as controls. Patients were followed for the composite end point of death and worsening heart failure. All absolute LS components were lower in patients with HC than in controls (global 14.3 ± 4.0% vs 18.8 ± 2.2%, p <0.001; septal 11.9 ± 4.9% vs 17.9 ± 2.7%, p <0.001; lateral 16.0 ± 4.7% vs 19.4 ± 3.1%, p = 0.001). Global strain reserve was also reduced in patients with HC (13 ± 5% vs 19 ± 8%, p = 0.002). Over a median follow-up of 56 months (interquartile range 14 to 69), the composite end point occurred in 53 patients. Global LS was predictive of outcome on univariate analysis (0.55 [0.41 to 0.74], p <0.001). When combined with CPX metrics, lateral LS was the only strain variable predictive of outcome along with indexed left atrial volume (LAVI) and ppVO2. The worst outcomes were observed for patients with lateral LS <16.1%, LAVI >52 ml/m2, and ppVO2 <80%. The combination of lateral LS, LAVI, and ppVO2 presents a simple model for outcome prediction.

    View details for PubMedID 28802509

  • Cost-Effectiveness of Preparticipation Screening for Prevention of Sudden Cardiac Death in Young Athletes ANNALS OF INTERNAL MEDICINE Wheeler, M. T., Heidenreich, P. A., Froelicher, V. F., Hlatky, M. A., Ashley, E. A. 2010; 152 (5): 276-W91

    Abstract

    Inclusion of 12-lead electrocardiography (ECG) in preparticipation screening of young athletes is controversial because of concerns about cost-effectiveness.To evaluate the cost-effectiveness of ECG plus cardiovascular-focused history and physical examination compared with cardiovascular-focused history and physical examination alone for preparticipation screening.Decision-analysis, cost-effectiveness model.Published epidemiologic and preparticipation screening data, vital statistics, and other publicly available data.Competitive athletes in high school and college aged 14 to 22 years.Lifetime.Societal.Nonparticipation in competitive athletic activity and disease-specific treatment for identified athletes with heart disease.Incremental health care cost per life-year gained.Addition of ECG to preparticipation screening saves 2.06 life-years per 1000 athletes at an incremental total cost of $89 per athlete and yields a cost-effectiveness ratio of $42 900 per life-year saved (95% CI, $21 200 to $71 300 per life-year saved) compared with cardiovascular-focused history and physical examination alone. Compared with no screening, ECG plus cardiovascular-focused history and physical examination saves 2.6 life-years per 1000 athletes screened and costs $199 per athlete, yielding a cost-effectiveness ratio of $76 100 per life-year saved ($62 400 to $130 000).Results are sensitive to the relative risk reduction associated with nonparticipation and the cost of initial screening.Effectiveness data are derived from 1 major European study. Patterns of causes of sudden death may vary among countries.Screening young athletes with 12-lead ECG plus cardiovascular-focused history and physical examination may be cost-effective.Stanford Cardiovascular Institute and the Breetwor Foundation.

    View details for PubMedID 20194233

  • Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. Z., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bican, A., Bick, D. P., Birch, C. L., Bonner, D., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Eckstein, D. J., Emrick, L. T., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Fernandez, L., Ferreira, C., Fieg, E. L., Fogel, B. L., Friedman, N. D., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Murphy, J. L., Muzny, D. M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Pena, L. M., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Staler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 179 (6): 966–77
  • Targeted Long-Read RNA Sequencing Demonstrates Transcriptional Diversity Driven by Splice-Site Variation in MYBPC3. Circulation. Genomic and precision medicine Dainis, A., Tseng, E., Clark, T. A., Hon, T., Wheeler, M., Ashley, E. 2019; 12 (5): e002464

    View details for DOI 10.1161/CIRCGEN.119.002464

    View details for PubMedID 31112421

  • Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students JOURNAL OF GENETIC COUNSELING Grove, M. E., White, S., Fisk, D. G., Rego, S., Dagan-Rosenfeld, O., Kohler, J. N., Reuter, C. M., Bonner, D., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K., Undiagnosed Dis Network 2019; 28 (2): 466–76

    View details for DOI 10.1002/jgc4.1094

    View details for Web of Science ID 000463993600030

  • A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing JOURNAL OF GENETIC COUNSELING Zastrow, D. B., Kohler, J. N., Bonner, D., Reuter, C. M., Fernandez, L., Grove, M. E., Fisk, D. G., Yang, Y., Eng, C. M., Ward, P. A., Bick, D., Worthey, E. A., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Ashley, E. A., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bernstein, J. A., Bican, A., Bick, D. P., Birch, C. L., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Dries, A. M., Eckstein, D. J., Emrick, L. T., Eng, C. M., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Ferreira, C., Fieg, E. L., Fisher, P. G., Fogel, B. L., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Huang, Y., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M. V., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Postlethwait, J. H., Potocki, L., Pusey, B. N., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Stoler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Waggott, D. M., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wheeler, M. T., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yang, Y., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 28 (2): 213–28

    View details for DOI 10.1002/jgc4.1119

    View details for Web of Science ID 000463993600005

  • Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review. American journal of medical genetics. Part A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. R., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Undiagnosed Diseases Network, Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A. 2019

    Abstract

    Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p=.0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

    View details for PubMedID 30920161

  • Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy PLOS ONE Kahn-Kirby, A. H., Amagata, A., Maeder, C. I., Mei, J. J., Sideris, S., Kosaka, Y., Hinman, A., Malone, S. A., Bruegger, J. J., Wang, L., Kim, V., Shrader, W. D., Hoff, K. G., Latham, J. C., Ashley, E. A., Wheeler, M. T., Bertini, E., Carrozzo, R., Martinelli, D., Dionisi-Vici, C., Chapman, K. A., Enns, G. M., Gahl, W., Wolfe, L., Saneto, R. P., Johnson, S. C., Trimmer, J. K., Klein, M. B., Holst, C. R. 2019; 14 (3)
  • Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy CIRCULATION-HEART FAILURE Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L. C., Ingles, J., Garcia, J., McCaleb, K., Adesiyun, T., Sedaghat-Hamedani, F., Kumar, S., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A. Y., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L. M., Lakdawala, N. K., Taylor, M. G., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. 2019; 12 (3)
  • Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Circulation. Heart failure Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L. C., Ingles, J., Garcia, J., McCaleb, K., Adesiyun, T., Sedaghat-Hamedani, F., Kumar, S., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A. Y., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L. M., Lakdawala, N. K., Taylor, M. R., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. 2019; 12 (3): e005371

    Abstract

    Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.

    View details for PubMedID 30871351

  • Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nature medicine Frésard, L., Smail, C., Ferraro, N. M., Teran, N. A., Li, X., Smith, K. S., Bonner, D., Kernohan, K. D., Marwaha, S., Zappala, Z., Balliu, B., Davis, J. R., Liu, B., Prybol, C. J., Kohler, J. N., Zastrow, D. B., Reuter, C. M., Fisk, D. G., Grove, M. E., Davidson, J. M., Hartley, T., Joshi, R., Strober, B. J., Utiramerur, S., Lind, L., Ingelsson, E., Battle, A., Bejerano, G., Bernstein, J. A., Ashley, E. A., Boycott, K. M., Merker, J. D., Wheeler, M. T., Montgomery, S. B. 2019

    Abstract

    It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.

    View details for DOI 10.1038/s41591-019-0457-8

    View details for PubMedID 31160820

  • 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., 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

    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

  • A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing. Journal of genetic counseling Zastrow, D. B., Kohler, J. N., Bonner, D., Reuter, C. M., Fernandez, L., Grove, M. E., Fisk, D. G., Yang, Y., Eng, C. M., Ward, P. A., Bick, D., Worthey, E. A., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 2019; 28 (2): 213–28

    Abstract

    There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%-41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.

    View details for PubMedID 30964584

  • A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis. Journal of general internal medicine Hom, J., Marwaha, S., Postolova, A., Kittle, J., Vasquez, R., Davidson, J., Kohler, J., Dries, A., Fernandez-Betancourt, L., Majcherska, M., Dearlove, J., Raghavan, S., Vogel, H., Bernstein, J. A., Fisher, P., Ashley, E., Sampson, J., Wheeler, M. 2019

    Abstract

    We discuss a challenging case of a 58-year-old Vietnamese-American woman who presented to her new primary care provider with an 8-year history of slowly progressive dysphagia, hoarseness, muscle weakness with associated frequent falls, and weight loss. She eventually reported dry eyes and dry mouth, and she was diagnosed with Sjogren's syndrome. Subsequently, she was additionally diagnosed with inclusion body myositis and gastric light-chain (AL) amyloidosis. Although inclusion body myositis has been previously associated with Sjogren's syndrome, inclusion body myositis is rare in non-Caucasians, and the trio of Sjogren's syndrome, inclusion body myositis, and AL amyloidosis has not been previously reported. Sjogren's syndrome is a systemic autoimmune condition characterized by ocular and oral dryness. It is one of the most common rheumatologic disorders in the USA and worldwide. Early diagnosis of Sjogren's is particularly important given the frequency and variety of associated autoimmune diseases and extraglandular manifestations. Furthermore, although inclusion body myositis has a low prevalence, it is the most common inflammatory myopathy in older adults and is unfortunately associated with long delays in diagnosis, so knowledge of this disorder is also crucial for practicing internists.

    View details for PubMedID 30887439

  • Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. PloS one Miller, R. J., Heidary, S., Pavlovic, A., Schlachter, A., Dash, R., Fleischmann, D., Ashley, E. A., Wheeler, M. T., Yang, P. C. 2019; 14 (6): e0217612

    Abstract

    HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing.Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death.We included 273 patients, mean age 51.2 ± 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 ± 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020).We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM.

    View details for DOI 10.1371/journal.pone.0217612

    View details for PubMedID 31199839

  • Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students. Journal of genetic counseling Grove, M. E., White, S., Fisk, D. G., Rego, S., Dagan-Rosenfeld, O., Kohler, J. N., Reuter, C. M., Bonner, D., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K. 2019

    Abstract

    With the wide adoption of next-generation sequencing (NGS)-based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture-based learning around these topics is important, there has been growing need for the inclusion of case-based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice.

    View details for PubMedID 30706981

  • The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation. Journal of cardiac failure Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y. J., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823–32

    Abstract

    BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.METHODS AND RESULTS: From 2009 to 2015, 158 patients who underwent implantation of continuous-flow devices who had complete echocardiographic and hemodynamic data were included. Quantitative RV parameters included RV end-diastolic (RVEDAI) and end-systolic area index, RV free-wall longitudinal strain (RVLS), fractional area change, tricuspid annular plane systolic excursion, and right atrial area and pressure. Independent correlates of early RHF (<30 days) were determined with the use of logistic regression analysis. Mean age was 56 ± 13 years, with 79% male; 49% had INTERMACS profiles ≤2. RHF occurred in 60 patients (38%), with 20 (13%) requiring right ventricular assist device. On multivariate analysis, INTERMACS profiles (adjusted odds ratio 2.38 [95% confidence interval [CI] 1.47-3.85]), RVEDAI (1.61 [1.08-2.32]), and RVLS (2.72 [1.65-4.51]) were independent correlates of RHF (all P < .05). Both RVLS and RVEDAI were incremental to validated risk scores (including the EUROMACS score) for early RHF after LVAD (all P < .01).CONCLUSIONS: RV end-diastolic and strain are complementary prognostic markers of RHF after LVAD implantation.

    View details for PubMedID 30539717

  • Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic acids research Kohler, S., Carmody, L., Vasilevsky, N., Jacobsen, J. O., Danis, D., Gourdine, J., Gargano, M., Harris, N. L., Matentzoglu, N., McMurry, J. A., Osumi-Sutherland, D., Cipriani, V., Balhoff, J. P., Conlin, T., Blau, H., Baynam, G., Palmer, R., Gratian, D., Dawkins, H., Segal, M., Jansen, A. C., Muaz, A., Chang, W. H., Bergerson, J., Laulederkind, S. J., Yuksel, Z., Beltran, S., Freeman, A. F., Sergouniotis, P. I., Durkin, D., Storm, A. L., Hanauer, M., Brudno, M., Bello, S. M., Sincan, M., Rageth, K., Wheeler, M. T., Oegema, R., Lourghi, H., Della Rocca, M. G., Thompson, R., Castellanos, F., Priest, J., Cunningham-Rundles, C., Hegde, A., Lovering, R. C., Hajek, C., Olry, A., Notarangelo, L., Similuk, M., Zhang, X. A., Gomez-Andres, D., Lochmuller, H., Dollfus, H., Rosenzweig, S., Marwaha, S., Rath, A., Sullivan, K., Smith, C., Milner, J. D., Leroux, D., Boerkoel, C. F., Klion, A., Carter, M. C., Groza, T., Smedley, D., Haendel, M. A., Mungall, C., Robinson, P. N. 2018

    Abstract

    The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

    View details for PubMedID 30476213

  • A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay. Circulation Seeger, T., Shrestha, R., Lam, C. K., Chen, C., McKeithan, W. L., Lau, E., Wnorowski, A., McMullen, G., Greenhaw, M., Lee, J., Oikonomopoulos, A., Lee, S., Yang, H., Mercola, M., Wheeler, M., Ashley, E. A., Yang, F., Karakikes, I., Wu, J. C. 2018

    Abstract

    BACKGROUND: Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in myosin binding protein C3 ( MYBPC3) resulting in a premature termination codon (PTC). The underlying mechanisms of how PTC mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. This study's aim was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 PTC mutations by utilizing human isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).METHODS: Isogenic iPSC lines were generated from patients harboring MYBPC3 PTC mutations (p.R943x; p.R1073P_Fsx4) using genome editing and then differentiated into cardiomyocytes. Comprehensive phenotypical and transcriptome analyses were performed.RESULTS: We observed aberrant calcium handling properties with prolonged decay kinetics and elevated diastolic calcium levels in HCM iPSC-CMs compared to isogenic controls without structural abnormalities or contractile dysfunction. The mRNA expression levels of MYBPC3 were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not contribute to the pathogenesis of HCM in vitro. Furthermore, truncated MYBPC3 peptides were not detected. At the molecular level, the nonsense-mediated decay (NMD) pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro. Specific inhibition of the NMD pathway in mutant iPSC-CMs resulted in reversal of the molecular phenotype and normalization of calcium handling abnormalities.CONCLUSIONS: iPSC-CMs carrying MYBPC3 PTC mutations displayed aberrant calcium signaling and molecular dysregulations in the absence of significant haploinsufficiency of MYBPC3 protein. Here we provided the first evidence of the direct connection between the chronically activated NMD pathway and HCM disease development.

    View details for PubMedID 30586709

  • Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations. Journal of genetic counseling Subas, T., Luiten, R., Hanson-Kahn, A., Wheeler, M., Caleshu, C. 2018

    Abstract

    Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

    View details for PubMedID 30220053

  • Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. The New England journal of medicine Maurer, M. S., Schwartz, J. H., Gundapaneni, B., Elliott, P. M., Merlini, G., Waddington-Cruz, M., Kristen, A. V., Grogan, M., Witteles, R., Damy, T., Drachman, B. M., Shah, S. J., Hanna, M., Judge, D. P., Barsdorf, A. I., Huber, P., Patterson, T. A., Riley, S., Schumacher, J., Stewart, M., Sultan, M. B., Rapezzi, C., ATTR-ACT Study Investigators 2018

    Abstract

    Background Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis. Methods In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status. Results In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups. Conclusions In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

    View details for PubMedID 30145929

  • Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Bouajila, S., Stolfo, D., Finocchiaro, G., Kuznetsova, T., Liang, D., Schnittger, I., Ashley, E., Wheeler, M., Haddad, F. 2018

    Abstract

    Aims: The myocardial performance index (MPI) is a time-based index of global myocardial performance. In this study, we sought to compare the prognostic value of the MPI with other strain and remodelling indices in hypertrophic cardiomyopathy (HCM).Methods and results: We enrolled 126 patients with HCM and 50 age- and sex-matched controls. Along with traditional echocardiographic assessment, MPI, left ventricular global longitudinal strain (LVGLS), E/e' ratio, and total left atrial (LA) global strain (LAS) were also measured. Time-based MPI was calculated from flow or tissue-based pulse wave Doppler (PWD and TDI) as the (isovolumic-relaxation and contraction time)/systolic-time. We used hierarchical clustering and network analysis to better visualize the relationship between parameters. The primary endpoint was the composite of all-cause death, heart transplantation, left ventricular assist device implantation, and clinical worsening. Left ventricular outflow tract (LVOT) obstruction was present in 56% of patients. Compared with controls, patients with HCM had worse LVGLS (-14.0±3.4% vs. -19.6±1.5%), higher E/e' (12.9±7.2 vs. 6.1±1.5), LA volume index (LAVI) (36.4±13.8ml/m2 vs. 25.6±6.7ml/m2), and MPI (0.55±0.17 vs. 0.40±0.11 for PWD and 0.59±0.22 vs. 0.46±0.09 for TDI) (all P<0.001). During a median follow-up of 55months, 47 endpoints occurred. PWD or TDI-based MPI was not associated with outcome, while LAVI, LAS, LVGLS, and E/e' were (all P<0.01). On multivariable analysis, LVOT obstruction (P<0.001), LAS (P<0.001), and E/e' (P=0.02) were retained as independent associates. They were in different clusters suggesting complemental relationship between them.Conclusion: Time-based index is less predictive of outcome than strain or tissue Doppler indices. LAS may be a promising prognostic marker in HCM.

    View details for PubMedID 30060097

  • Genome Sequencing in HypertrophicCardiomyopathy. Journal of the American College of Cardiology Ashley, E. A., Reuter, C. M., Wheeler, M. T. 2018; 72 (4): 430–33

    View details for PubMedID 30025579

  • Applying current normative data to prognosis in heart failure: The Fitness Registry and the Importance of Exercise National Database (FRIEND) INTERNATIONAL JOURNAL OF CARDIOLOGY Moneghetti, K. J., Hock, J., Kaminsky, L., Arena, R., Lui, G. K., Haddad, F., Wheeler, M., Froelicher, V., Ashley, E., Myers, J., Christle, J. W. 2018; 263: 75–79

    Abstract

    Percent of predicted peak VO2 (ppVO2) is considered a standard measure for establishing disease severity, however, there are known limitations to traditional normative values. This study sought to compare ppVO2 from the newly derived "Fitness Registry and the Importance of Exercise: a National Database" (FRIEND) registry equation to conventional prediction equations in a clinical cohort of patients undergoing cardiopulmonary exercise testing (CPX).We selected 1094 patients referred for evaluation of heart failure (HF) symptoms who underwent CPX. ppVO2 was calculated using the FRIEND, Wasserman/Hansen and Jones equations. Participants were followed for a median of 4.5 years [Interquartile range 3.5-6.0] for the composite endpoint of death, advanced HF therapy, or acute decompensated HF requiring hospital admission. Mean age was 48 ± 15 years and 62% were female. The FRIEND registry equation predicted the lowest ppVO2 (measured/predicted; 71 ± 31%), compared to the Wasserman/Hansen (74 ± 29%) and Jones equations (83 ± 33%) (p < 0.001). All expressions of peak VO2 were significant as univariate predictors of outcome with no significant differences between equations on pairwise analysis of receiver operating characteristic curves. When compared at a similar threshold of ppVO2 the event rate was significantly lower in the FRIEND registry equation versus the currently used Wasserman and Jones equations.The use of the newly derived FRIEND registry equation predicts HF outcomes; however, it appears to predict a higher predicted VO2; the clinical implication being a lower threshold of percent predicted peak VO2 should be considered when risk stratifying patients with HF.

    View details for PubMedID 29525067

  • Electrocardiographic left atrial abnormalities predict cardiovascular mortality JOURNAL OF ELECTROCARDIOLOGY Ha, L., Grober, A. F., Hock, J., Wheeler, M., Elbadawi, A., Biniwale, N., Baig, B., Froelicher, V. 2018; 51 (4): 652–57

    Abstract

    Clinical utilization of electrocardiography for diagnosis of left atrial abnormalities is hampered by variable P-wave morphologies, multiple empiric criteria, and lack of an imaging "gold standard". Our aim was to determine the prevalence of P-wave patterns and demonstrate which components have associations with cardiovascular death (CVD).This is a retrospective analysis of 20,827 veterans <56 years of age who underwent electrocardiograms at a Veteran's Affairs Medical Center from 1987 to 1999, followed for a median duration of 17.8 years for CVD. Receiver Operating Characteristic, Kaplan-Meier and Cox Hazard analyses were applied, the latter with adjustment for age, gender and electrocardiography abnormalities.The mean age was 43.3 ± 8 years, and 888 CVD (4.3%) occurred. A single positive deflection of the P-wave (Pattern 1) was present in 29% for V1 and 81% for V2. A singular negative P-wave (Pattern 2) was present in 4.6% for V1 and 1.6% in V2. A P-wave with an upward component followed by downward component (Pattern 3) was present in 64.5% for V1 and 17.5% for V2. When the downward component in Patterns 2 and/or 3 is at least -100 μV, a significant association is observed with CVD (adjusted hazard ratios [HRs] 2.9-4.1, P < 0.001). Total P-wave duration ≥140 ms was also associated with CVD (adjusted HR 2.2, P < 0.001).A negative P-wave in V1 or V2 ≤-100 μV, and P-wave with a duration of ≥140 ms, all have independent and significant associations with CVD, with HRs comparable to other electrocardiography abnormalities.

    View details for PubMedID 29997006

  • 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

  • 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., Giraldeau, G., Finocchiaro, G., Kobayashi, Y., Wheeler, M., Perez, M., Moneghetti, K., Oxborough, D., George, K. P., Myers, J., Ashley, E., Haddad, F. 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

  • ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis. Genetics in medicine : official journal of the American College of Medical Genetics Deisseroth, C. A., Birgmeier, J., Bodle, E. E., Kohler, J. N., Matalon, D. R., Nazarenko, Y., Genetti, C. A., Brownstein, C. A., Schmitz-Abe, K., Schoch, K., Cope, H., Signer, R., Martinez-Agosto, J. A., Shashi, V., Beggs, A. H., Wheeler, M. T., Bernstein, J. A., Bejerano, G. 2018

    Abstract

    Diagnosing monogenic diseases facilitates optimal care, but can involve the manual evaluation of hundreds of genetic variants per case. Computational tools like Phrank expedite this process by ranking all candidate genes by their ability to explain the patient's phenotypes. To use these tools, busy clinicians must manually encode patient phenotypes from lengthy clinical notes. With 100 million human genomes estimated to be sequenced by 2025, a fast alternative to manual phenotype extraction from clinical notes will become necessary.We introduce ClinPhen, a fast, high-accuracy tool that automatically converts clinical notes into a prioritized list of patient phenotypes using Human Phenotype Ontology (HPO) terms.ClinPhen shows superior accuracy and 20× speedup over existing phenotype extractors, and its novel phenotype prioritization scheme improves the performance of gene-ranking tools.While a dedicated clinician can process 200 patient records in a 40-hour workweek, ClinPhen does the same in 10 minutes. Compared with manual phenotype extraction, ClinPhen saves an additional 3-5 hours per Mendelian disease diagnosis. Providers can now add ClinPhen's output to each summary note attached to a filled testing laboratory request form. ClinPhen makes a substantial contribution to improvements in efficiency critically needed to meet the surging demand for clinical diagnostic sequencing.

    View details for PubMedID 30514889

  • A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network. The Journal of pediatrics Reuter, C. M., Brimble, E., DeFilippo, C., Dries, A. M., Enns, G. M., Ashley, E. A., Bernstein, J. A., Fisher, P. G., Wheeler, M. T. 2018

    View details for PubMedID 29331327

  • PHACOMATOSIS PIGMENTOVASCULARIS: A CASE WITH SOMATIC MUTATION IN GNAQ AND ATYPICAL PHENOTYPIC FEATURES Kumar, A., Zastrow, D., Prybol, C., Manning, M., Huang, Y., Fisher, P., Ashley, E., Teng, J., Wheeler, M., Bernstein, J. BMJ PUBLISHING GROUP. 2018: 202
  • Exercise for Patients With Hypertrophic Cardiomyopathy Reply JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Saberi, S., Wheeler, M., Day, S. M. 2017; 318 (5): 481–82

    View details for PubMedID 28763545

  • Repeats and Survival in Myotonic Dystrophy Type 1 CIRCULATION-CARDIOVASCULAR GENETICS Wheeler, M. T. 2017; 10 (3)
  • Accuracy in Wrist-Worn, Sensor-Based Measurements of Heart Rate and Energy Expenditure in a Diverse Cohort. Journal of personalized medicine Shcherbina, A., Mattsson, C. M., Waggott, D., Salisbury, H., Christle, J. W., Hastie, T., Wheeler, M. T., Ashley, E. A. 2017; 7 (2)

    Abstract

    The ability to measure physical activity through wrist-worn devices provides an opportunity for cardiovascular medicine. However, the accuracy of commercial devices is largely unknown. The aim of this work is to assess the accuracy of seven commercially available wrist-worn devices in estimating heart rate (HR) and energy expenditure (EE) and to propose a wearable sensor evaluation framework. We evaluated the Apple Watch, Basis Peak, Fitbit Surge, Microsoft Band, Mio Alpha 2, PulseOn, and Samsung Gear S2. Participants wore devices while being simultaneously assessed with continuous telemetry and indirect calorimetry while sitting, walking, running, and cycling. Sixty volunteers (29 male, 31 female, age 38 ± 11 years) of diverse age, height, weight, skin tone, and fitness level were selected. Error in HR and EE was computed for each subject/device/activity combination. Devices reported the lowest error for cycling and the highest for walking. Device error was higher for males, greater body mass index, darker skin tone, and walking. Six of the devices achieved a median error for HR below 5% during cycling. No device achieved an error in EE below 20 percent. The Apple Watch achieved the lowest overall error in both HR and EE, while the Samsung Gear S2 reported the highest. In conclusion, most wrist-worn devices adequately measure HR in laboratory-based activities, but poorly estimate EE, suggesting caution in the use of EE measurements as part of health improvement programs. We propose reference standards for the validation of consumer health devices (http://precision.stanford.edu/).

    View details for DOI 10.3390/jpm7020003

    View details for PubMedID 28538708

  • 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

  • The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease AMERICAN JOURNAL OF HUMAN GENETICS Ramoni, R. B., Mulvihill, J. J., Adams, D. R., Allard, P., Ashley, E. A., Bernstein, J. A., Gahl, W. A., Hamid, R., Loscalzo, J., McCray, A. T., Shashi, V., Tifft, C. J., Wise, A. L. 2017; 100 (2): 185-192

    Abstract

    Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

    View details for DOI 10.1016/j.athg.2017.01.006

    View details for PubMedID 28157539

  • Simultaneous ramp right heart catheterization and echocardiography in a ReliantHeart left ventricular assist device. World journal of cardiology Banerjee, D., Dutt, D., Duclos, S., Sallam, K., Wheeler, M., Ha, R. 2017; 9 (1): 55-59

    Abstract

    Many clinicians caring for patients with continuous flow left ventricular assist devices (CF-LVAD) use ramp right heart catheterization (RHC) studies to optimize pump speed and also to troubleshoot CF-LVAD malfunction. An investigational device, the ReliantHeart Heart Assist 5 (Houston, TX), provides the added benefit of an ultrasonic flow probe on the outflow graft that directly measures flow through the CF-LVAD. We performed a simultaneous ramp RHC and echocardiogram on a patient who received the above CF-LVAD to optimize pump parameters and investigate elevated flow through the CF-LVAD as measured by the flow probe. We found that the patient's hemodynamics were optimized at their baseline pump speed, and that the measured cardiac output via the Fick principle was lower than that measured by the flow probe. Right heart catheterization may be useful to investigate discrepancies between flow measured by a CF-LVAD and a patient's clinical presentation, particularly in investigational devices where little clinical experience exists. More data is needed to elucidate the correlation between the flow measured by an ultrasonic probe and cardiac output as measured by RHC.

    View details for DOI 10.4330/wjc.v9.i1.55

    View details for PubMedID 28163837

    View details for PubMedCentralID PMC5253195

  • in a patient with a complex connective tissue phenotype. Cold Spring Harbor molecular case studies Zastrow, D. B., Zornio, P. A., Dries, A., Kohler, J., Fernandez, L., Waggott, D., Walkiewicz, M., Eng, C. M., Manning, M. A., Farrelly, E., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 2017; 3 (1)

    Abstract

    Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants in FBN1 and TRPS1 were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 (FBN1) mutations are associated with Marfan syndrome and a spectrum of similar phenotypes. TRPS1 mutations are associated with trichorhinophalangeal syndrome types I and III. Features of both conditions are evident in the patient reported here. Discrepant features of the conditions (e.g., stature) and the young age of the patient may have made a clinical diagnosis more difficult in the absence of exome-wide genetic testing.

    View details for DOI 10.1101/mcs.a001388

    View details for PubMedID 28050602

  • Autoantibody profiling on a plasmonic nano-gold chip for the early detection of hypertensive heart disease. Proceedings of the National Academy of Sciences of the United States of America Li, X., Kuznetsova, T., Cauwenberghs, N., Wheeler, M., Maecker, H., Wu, J. C., Haddad, F., Dai, H. 2017; 114 (27): 7089–94

    Abstract

    The role of autoimmunity in cardiovascular (CV) diseases has been increasingly recognized. Autoimmunity is most commonly examined by the levels of circulating autoantibodies in clinical practices. Measurement of autoantibodies remains, however, challenging because of the deficiency of reproducible, sensitive, and standardized assays. The lack of multiplexed assays also limits the potential to identify a CV-specific autoantibody profile. To overcome these challenges, we developed a nanotechnology-based plasmonic gold chip for autoantibody profiling. This approach allowed simultaneous detection of 10 CV autoantibodies targeting the structural myocardial proteins, the neurohormonal regulatory proteins, the vascular proteins, and the proteins associated with apoptosis and coagulation. Autoantibodies were measured in four groups of participants across the continuum of hypertensive heart diseases. We observed higher levels of all 10 CV autoantibodies in hypertensive subjects (n= 77) compared with healthy participants (n= 30), and the autoantibodies investigated were related to each other, forming a highly linked network. In addition, we established that autoantibodies to troponin I, annexin-A5, and beta 1-adrenegic receptor best discriminated hypertensive subjects with adverse left ventricular (LV) remodeling or dysfunction (n= 49) from hypertensive subjects with normal LV structure and function (n= 28). By further linking these three significant CV autoantibodies to the innate and growth factors, we revealed a positive but weak association between autoantibodies to troponin I and proinflammatory cytokine IL-18. Overall, we demonstrated that this platform can be used to evaluate autoantibody profiles in hypertensive subjects at risk for heart failure.

    View details for PubMedID 28630342

  • Functional Cardiac Recovery and Hematologic Response to Chemotherapy in Patients With Light-Chain Amyloidosis (from the Stanford University Amyloidosis Registry). The American journal of cardiology Tuzovic, M., Kobayashi, Y., Wheeler, M., Barrett, C., Liedtke, M., Lafayette, R., Schrier, S., Haddad, F., Witteles, R. 2017; 120 (8): 1381–86

    Abstract

    Cardiac involvement is common in patients with light-chain (AL) amyloidosis and portends a poor prognosis, although little is known about the changes in cardiac mechanics after chemotherapy. We sought to explore the relation between amyloidosis staging and baseline cardiac mechanics and to investigate short-term changes in cardiac mechanics after chemotherapy. We identified 41 consecutive patients from the Stanford Amyloid Center who had echocardiograms and free light-chain values before and after chemotherapy, along with 40 age- and gender-matched controls. Echocardiographic assessment included left ventricular global longitudinal strain, E/e' ratio, and left atrial (LA) stiffness. Hematologic response to chemotherapy was defined as ≥50% reduction in the difference between the involved and the uninvolved free light chain (dFLC). The mean age was 66.9 ± 8.4 years and 66% were men. Before chemotherapy, global longitudinal strain, E/e' ratio, and LA stiffness were impaired in patients with amyloidosis compared with controls, and the severity of impairment worsened with advanced staging. After chemotherapy, hematologic response was observed in 30 (73%) patients. There was a significant association between the change in dFLC and cardiac function (E/e' ratio: r = -0.43, p = 0.01; LA stiffness: r = -0.35, p = 0.05). There was no significant improvement in cardiac mechanics in patients without a hematologic response to chemotherapy. In conclusion, amyloidosis stage correlated with noninvasive measurements of cardiac mechanics, and improvement in dFLC correlated with cardiac improvement on short-term follow-up echocardiography.

    View details for PubMedID 28844519

  • Repeats and Survival in Myotonic Dystrophy Type 1. Circulation. Cardiovascular genetics Wheeler, M. T. 2017; 10 (3)

    View details for PubMedID 28611033

  • Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy. European heart journal cardiovascular Imaging Moneghetti, K. J., Giraldeau, G., Wheeler, M. T., Kobayashi, Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashley, E., Haddad, F. 2017

    Abstract

    Risk stratification in heart failure (HF) relies on several established clinical risk scores, however, myocardial deformation, right heart metrics, and exercise performance have not usually been considered. This study sought to assess the incremental value of advanced echocardiographic and cardiopulmonary exercise testing (CPX) parameters to validated risk scores in HF.The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) and Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI) scores were applied to 208 ambulatory patients with dilated cardiomyopathy (DCM) who completed echocardiography in conjunction with CPX as part of the Stanford Exercise Testing registry. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation, and hospitalization for acute HF. Mean age, left ventricular ejection fraction (LVEF), and left ventricular global longitudinal strain (LVGLS) were 47 ± 13 years, 33 ± 13%, and -10.6 ± 4.4%, respectively, while right ventricular free-wall longitudinal strain was -18.8 ± 5.5%. Partial correlation mapping identified strong correlations between LVEF, LVGLS, and LV systolic strain rate, with a moderate correlation between these metrics and peak VO2. Over a median follow up of 5.3 years, the composite end point occurred in 60 patients. Cox proportional hazards identified MAGGIC score [hazard ratio (HR) (2.04 [1.39-3.01], P < 0.01], peak VO2 HR (0.52 [0.28-0.97], P = 0.04), and right atrial volume indexed (RAVI) HR (1.31 [1.07-1.61], P < 0.01) as independent correlates of outcome. RAVI remained an independent correlate when combined with the MECKI score (2.21 [1.59-3.07]), P < 0.01, RAVI, 1.33 [1.06-1.67], P = 0.01).Our study demonstrates that RAVI is complementary to well-validated HF risk scores and highlights the importance of exercise performance in DCM.

    View details for PubMedID 28977353

  • Contractile reserve and cardiopulmonary exercise parameters in patients with dilated cardiomyopathy, the two dimensions of exercise testing. Echocardiography (Mount Kisco, N.Y.) Moneghetti, K. J., Kobayashi, Y., Christle, J. W., Ariyama, M., Vrtovec, B., Kouznetsova, T., Wilson, A., Ashley, E., Wheeler, M. T., Myers, J., Haddad, F. 2017

    Abstract

    Left ventricular (LV) contractile reserve assessed using imaging and cardiopulmonary exercise testing (CPX) has been shown to predict outcome in patients with dilated cardiomyopathy (DCM). Few clinical studies have, however, analyzed the relationship between them.A cohort of 75 ambulatory patients with DCM underwent stress treadmill echocardiography with CPX. LV contractile reserve was calculated as absolute change (ΔLVEF=LVEFpeak -LVEFrest ) and percent change (%LVEF=[(LVEFpeak -LVEFrest )/LVEFpeak) ]×100) in LVEF, circumferential and longitudinal strain (LS). Exercise capacity was measured as peak oxygen uptake (peak VO2 ) and ventilatory efficiency as the slope of minute ventilation to CO2 production (VE/VCO2 slope). Values of contractile reserve were compared to matched controls. We also explored which metric of ventricular response (absolute or percent change) was less dependent on baseline LV function.Patients with DCM had a mean age, rest and peak LVEF of 44±10 years, 42±10% and 50±12%, respectively. Among parameters of contractile reserve, peak cardiac output was the strongest parameter associated with peak VO2 (r=.63, P<.001). Along with age, sex, and BMI, it explained more than 70% of the variance in peak VO2 . In contrast, LVEF and LS were only weakly related to peak VO2 . With regard to ventilatory efficiency, the strongest parameter that emerged was right atrial volume index (r=.36, P<.001). Percent change in LVEF was more independent of baseline function than absolute change.Echocardiographic contractile reserve and CPX provide complementary information. Percent change in contractile reserve was most independent of baseline function, therefore may be preferred when analyzing the ventricular response to exercise.

    View details for PubMedID 28681553

  • Incremental value of right heart metrics and exercise performance to well-validated risk scores in dilated cardiomyopathy European Heart Journal - Cardiovascular Imaging Moneghetti , K. J., Giraldeau, G., Wheeler, M. T., Kobayashi , Y., Vrtovec, B., Boulate, D., Kuznetsova, T., Schnittger, I., Wu, J. C., Myers, J., Ashely, E., Haddad , F. 2017

    View details for DOI 10.1093/ehjci/jex187

  • Long-read genome sequencing identifies causal structural variation in a Mendelian disease. Genetics in medicine : official journal of the American College of Medical Genetics Merker, J. D., Wenger, A. M., Sneddon, T., Grove, M., Zappala, Z., Fresard, L., Waggott, D., Utiramerur, S., Hou, Y., Smith, K. S., Montgomery, S. B., Wheeler, M., Buchan, J. G., Lambert, C. C., Eng, K. S., Hickey, L., Korlach, J., Ford, J., Ashley, E. A. 2017

    Abstract

    PurposeCurrent clinical genomics assays primarily utilize short-read sequencing (SRS), but SRS has limited ability to evaluate repetitive regions and structural variants. Long-read sequencing (LRS) has complementary strengths, and we aimed to determine whether LRS could offer a means to identify overlooked genetic variation in patients undiagnosed by SRS.MethodsWe performed low-coverage genome LRS to identify structural variants in a patient who presented with multiple neoplasia and cardiac myxomata, in whom the results of targeted clinical testing and genome SRS were negative.ResultsThis LRS approach yielded 6,971 deletions and 6,821 insertions > 50 bp. Filtering for variants that are absent in an unrelated control and overlap a disease gene coding exon identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. RNA sequencing demonstrated decreased PRKAR1A expression. The deletion was classified as pathogenic based on guidelines for interpretation of sequence variants.ConclusionThis first successful application of genome LRS to identify a pathogenic variant in a patient suggests that LRS has significant potential for the identification of disease-causing structural variation. Larger studies will ultimately be required to evaluate the potential clinical utility of LRS.GENETICS in MEDICINE advance online publication, 22 June 2017; doi:10.1038/gim.2017.86.

    View details for PubMedID 28640241

  • Exercise restrictions trigger psychological difficulty in active and athletic adults with hypertrophic cardiomyopathy OPEN HEART Luiten, R. C., Ormond, K., Post, L., Asif, I. M., Wheeler, M. T., Caleshu, C. 2016; 3 (2)
  • Sports genetics moving forward: lessons learned from medical research. Physiological genomics Mattsson, C. M., Wheeler, M. T., Waggott, D., Caleshu, C., Ashley, E. A. 2016; 48 (3): 175-182

    Abstract

    Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, we can magnify the breadth and depth of knowledge in the field. We present an outline of challenges facing sports genetics in the light of experiences from medical research. Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. To find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved. Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between sexes and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology, which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.

    View details for DOI 10.1152/physiolgenomics.00109.2015

    View details for PubMedID 26757801

  • Athlome Project Consortium: a concerted effort to discover genomic and other "omic" markers of athletic performance. Physiological genomics Pitsiladis, Y. P., Tanaka, M., Eynon, N., Bouchard, C., North, K. N., Williams, A. G., Collins, M., Moran, C. N., Britton, S. L., Fuku, N., Ashley, E. A., Klissouras, V., Lucia, A., Ahmetov, I. I., de Geus, E., Alsayrafi, M. 2016; 48 (3): 183-190

    Abstract

    Despite numerous attempts to discover genetic variants associated with elite athletic performance, injury predisposition, and elite/world-class athletic status, there has been limited progress to date. Past reliance on candidate gene studies predominantly focusing on genotyping a limited number of single nucleotide polymorphisms or the insertion/deletion variants in small, often heterogeneous cohorts (i.e., made up of athletes of quite different sport specialties) have not generated the kind of results that could offer solid opportunities to bridge the gap between basic research in exercise sciences and deliverables in biomedicine. A retrospective view of genetic association studies with complex disease traits indicates that transition to hypothesis-free genome-wide approaches will be more fruitful. In studies of complex disease, it is well recognized that the magnitude of genetic association is often smaller than initially anticipated, and, as such, large sample sizes are required to identify the gene effects robustly. A symposium was held in Athens and on the Greek island of Santorini from 14-17 May 2015 to review the main findings in exercise genetics and genomics and to explore promising trends and possibilities. The symposium also offered a forum for the development of a position stand (the Santorini Declaration). Among the participants, many were involved in ongoing collaborative studies (e.g., ELITE, GAMES, Gene SMART, GENESIS, and POWERGENE). A consensus emerged among participants that it would be advantageous to bring together all current studies and those recently launched into one new large collaborative initiative, which was subsequently named the Athlome Project Consortium.

    View details for DOI 10.1152/physiolgenomics.00105.2015

    View details for PubMedID 26715623

    View details for PubMedCentralID PMC4773890

  • Medical implications of technical accuracy in genome sequencing. Genome medicine Goldfeder, R. L., Priest, J. R., Zook, J. M., Grove, M. E., Waggott, D., Wheeler, M. T., Salit, M., Ashley, E. A. 2016; 8 (1): 24-?

    Abstract

    As whole exome sequencing (WES) and whole genome sequencing (WGS) transition from research tools to clinical diagnostic tests, it is increasingly critical for sequencing methods and analysis pipelines to be technically accurate. The Genome in a Bottle Consortium has recently published a set of benchmark SNV, indel, and homozygous reference genotypes for the pilot whole genome NIST Reference Material based on the NA12878 genome.We examine the relationship between human genome complexity and genes/variants reported to be associated with human disease. Specifically, we map regions of medical relevance to benchmark regions of high or low confidence. We use benchmark data to assess the sensitivity and positive predictive value of two representative sequencing pipelines for specific classes of variation.We observe that the accuracy of a variant call depends on the genomic region, variant type, and read depth, and varies by analytical pipeline. We find that most false negative WGS calls result from filtering while most false negative WES variants relate to poor coverage. We find that only 74.6% of the exonic bases in ClinVar and OMIM genes and 82.1% of the exonic bases in ACMG-reportable genes are found in high-confidence regions. Only 990 genes in the genome are found entirely within high-confidence regions while 593 of 3,300 ClinVar/OMIM genes have less than 50% of their total exonic base pairs in high-confidence regions. We find greater than 77 % of the pathogenic or likely pathogenic SNVs currently in ClinVar fall within high-confidence regions. We identify sites that are prone to sequencing errors, including thousands present in publicly available variant databases. Finally, we examine the clinical impact of mandatory reporting of secondary findings, highlighting a false positive variant found in BRCA2.Together, these data illustrate the importance of appropriate use and continued improvement of technical benchmarks to ensure accurate and judicious interpretation of next-generation DNA sequencing results in the clinical setting.

    View details for DOI 10.1186/s13073-016-0269-0

    View details for PubMedID 26932475

    View details for PubMedCentralID PMC4774017

  • 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

  • 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

  • Letter by Wheeler et al Regarding Article, "Recognition and Significance of Pathological T-Wave Inversions in Athletes" CIRCULATION Wheeler, M. T., Adelfattah, R., Froelicher, V. F. 2015; 132 (14): E180

    View details for PubMedID 26438774

  • Sequence to Medical Phenotypes: A Framework for Interpretation of Human Whole Genome DNA Sequence Data PLOS GENETICS Dewey, F. E., Grove, M. E., Priest, J. R., Waggott, D., Batra, P., Miller, C. L., Wheeler, M., Zia, A., Pan, C., Karzcewski, K. J., Miyake, C., Whirl-Carrillo, M., Klein, T. E., Datta, S., Altman, R. B., Snyder, M., Quertermous, T., Ashley, E. A. 2015; 11 (10)

    Abstract

    High throughput sequencing has facilitated a precipitous drop in the cost of genomic sequencing, prompting predictions of a revolution in medicine via genetic personalization of diagnostic and therapeutic strategies. There are significant barriers to realizing this goal that are related to the difficult task of interpreting personal genetic variation. A comprehensive, widely accessible application for interpretation of whole genome sequence data is needed. Here, we present a series of methods for identification of genetic variants and genotypes with clinical associations, phasing genetic data and using Mendelian inheritance for quality control, and providing predictive genetic information about risk for rare disease phenotypes and response to pharmacological therapy in single individuals and father-mother-child trios. We demonstrate application of these methods for disease and drug response prognostication in whole genome sequence data from twelve unrelated adults, and for disease gene discovery in one father-mother-child trio with apparently simplex congenital ventricular arrhythmia. In doing so we identify clinically actionable inherited disease risk and drug response genotypes in pre-symptomatic individuals. We also nominate a new candidate gene in congenital arrhythmia, ATP2B4, and provide experimental evidence of a regulatory role for variants discovered using this framework.

    View details for DOI 10.1371/journal.pgen.1005496

    View details for Web of Science ID 000364401600008

    View details for PubMedID 26448358

    View details for PubMedCentralID PMC4598191

  • 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

  • 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

  • Examining QRS amplitude criteria for electrocardiographic left ventricular hypertrophy in recommendations for screening criteria in athletes. Journal of electrocardiology Singla, V., Jindal, A., Pargaonkar, V., Soofi, M., Wheeler, M., Froelicher, V. 2015; 48 (3): 368-372

    Abstract

    Current guidelines for interpretation of the ECGs of athletes recommend that isolated R and S wave amplitudes that exceed traditional criteria for left ventricular hypertrophy be accepted as a physiological response to exercise training. This is based on training and echocardiographic studies but not on long term follow up. Demonstration of the prognostic characteristics of the amplitude criteria in a non-athletic population could support the current guidelines.To evaluate the prognostic value of the R and S wave voltage criteria for electrocardiographic left ventricular hypertrophy (ECG-LVH) in an ambulatory clinical population.The target population consisted of 20,903 ambulatory subjects who had ECGs recorded between 1987 and 1999 and were followed for cardiovascular death until 2013. During the mean follow up of 17years, there were 881 cardiovascular deaths.The mean age was 43±10, 91% were male and 16% were African American. Of the 2482 (12%) subjects who met the Sokolow-Lyon criteria, 241 (1.2%) subjects with left ventricular (LV) strain had an HR of 5.4 (95% CI 4.1-7.2, p<0.001), while 2241 (11%) subjects without strain had an HR of 1.4 (95% CI 1.2-1.8, p<0.001). Of the 4836 (23%) subjects who met the Framingham voltage criteria, 350 (2%) subjects with LV strain had an HR of 5.1 (95% CI 4.0-6.5, p<0.001), while 4486 (22%) subjects without strain had an HR of 1.1 (95% CI 0.9-1.3, p=0.26). The individual components of the Romhilt-Estes had HRs ranging from 1.4 to 3.6, with only the voltage component not being significant (HR 1.1, 95% CI 0.9-1.5, p=0.35).This study demonstrates that the R and S wave voltage criteria components of most of the original classification schema for electrocardiographic left ventricular hypertrophy are not predictive of CV mortality. Our findings support the current guidelines for electrocardiographic screening of athletes.

    View details for DOI 10.1016/j.jelectrocard.2014.12.012

    View details for PubMedID 25661864

  • Outcomes after heart transplantation for amyloid cardiomyopathy in the modern era. American journal of transplantation Davis, M. K., Kale, P., Liedtke, M., Schrier, S., Arai, S., Wheeler, M., Lafayette, R., Coakley, T., Witteles, R. M. 2015; 15 (3): 650-658

    Abstract

    We conducted a review of patients undergoing heart transplantation (HT) at our institution for amyloid cardiomyopathy (ACM) between 2008 and 2013. Complete follow-up was available for all patients. Nineteen patients with ACM underwent HT during the study period, accounting for 9.4% of all HT performed at our institution during this period. Amyloid subtype was light chain (AL) in 9 patients and transthyretin (ATTR) in 10 (2 wild-type, 7 familial, 1 unknown). Eight of nine patients with AL amyloidosis began chemotherapy prior to HT, six have resumed chemotherapy since HT, and five have undergone autologous stem cell transplantation. Most recent free light chain levels in AL patients decreased by a median of 85% from peak values. Only one patient developed recurrent graft amyloidosis, occurring at 3.5 years post-HT and asymptomatic. After a median follow-up of 380 days, 17 (89.5%) patients are alive. To our knowledge, this is the largest single-center series reported of ACM patients undergoing HT in the modern era. Our results suggest that acceptable outcomes following HT can be achieved in the short-to-intermediate term and that this is a feasible option for end-stage ACM with careful patient selection and aggressive control of amyloidogenic light chains in AL patients.

    View details for DOI 10.1111/ajt.13025

    View details for PubMedID 25648766

  • Hypertrophic cardiomyopathy: can the horse be put back in the barn? Journal of the American College of Cardiology Wheeler, M. T., Ashley, E. A. 2015; 65 (6): 570-572

    View details for DOI 10.1016/j.jacc.2014.12.004

    View details for PubMedID 25677316

  • Personalized preventive medicine: genetics and the response to regular exercise in preventive interventions. Progress in cardiovascular diseases Bouchard, C., Antunes-Correa, L. M., Ashley, E. A., Franklin, N., Hwang, P. M., Mattsson, C. M., Negrao, C. E., Phillips, S. A., Sarzynski, M. A., Wang, P., Wheeler, M. T. 2015; 57 (4): 337-346

    Abstract

    Regular exercise and a physically active lifestyle have favorable effects on health. Several issues related to this theme are addressed in this report. A comment on the requirements of personalized exercise medicine and in-depth biological profiling along with the opportunities that they offer is presented. This is followed by a brief overview of the evidence for the contributions of genetic differences to the ability to benefit from regular exercise. Subsequently, studies showing that mutations in TP53 influence exercise capacity in mice and humans are succinctly described. The evidence for effects of exercise on endothelial function in health and disease also is covered. Finally, changes in cardiac and skeletal muscle in response to exercise and their implications for patients with cardiac disease are summarized. Innovative research strategies are needed to define the molecular mechanisms involved in adaptation to exercise and to translate them into useful clinical and public health applications.

    View details for DOI 10.1016/j.pcad.2014.08.005

    View details for PubMedID 25559061

  • BEST IN PHYSICS (THERAPY) - Stereotactic Radiotherapy for Renal Sympathetic Ablation for the Treatment of Refractory Hypertension Maxim, P., Wheeler, M., Maguire, P., Loo, B. WILEY. 2014: 503–4
  • Clinical interpretation and implications of whole-genome sequencing. JAMA Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., Merker, J. D., Goldfeder, R. L., Enns, G. M., David, S. P., Pakdaman, N., Ormond, K. E., Caleshu, C., Kingham, K., Klein, T. E., Whirl-Carrillo, M., Sakamoto, K., Wheeler, M. T., Butte, A. J., Ford, J. M., Boxer, L., Ioannidis, J. P., Yeung, A. C., Altman, R. B., Assimes, T. L., Snyder, M., Ashley, E. A., Quertermous, T. 2014; 311 (10): 1035-1045

    Abstract

    Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

    View details for DOI 10.1001/jama.2014.1717

    View details for PubMedID 24618965

  • Genetic Variation Near HCRTR2 Associates With Dramatic Improvement of Heart Function in Patients With Heart Failure Perez, M. V., Pavlovic, A., Wheeler, M. T., Miller, C. L., Thanaporn, P., Dewey, F. E., Pan, S., Absher, D., Cretti, E., Southwick, A., Heidenreich, P., Sedehi, D., Brandimarto, J., Kao, D., Salisbury, H., Chan, K., Rosenthal, D., Bernstein, D., Fowler, M. B., Robbins, R. C., Meyers, R., Meyers, R., Quertermous, T., Cappola, T., Ashley, E. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Physical Activity and Other Health Behaviors in Adults With Hypertrophic Cardiomyopathy AMERICAN JOURNAL OF CARDIOLOGY Reineck, E., Rolston, B., Bragg-Gresham, J. L., Salberg, L., Baty, L., Kumar, S., Wheeler, M. T., Ashley, E., Saberi, S., Day, S. M. 2013; 111 (7): 1034-1039

    Abstract

    The clinical expression of hypertrophic cardiomyopathy (HC) is undoubtedly influenced by modifying genetic and environmental factors. Lifestyle practices such as tobacco and alcohol use, poor nutritional intake, and physical inactivity are strongly associated with adverse cardiovascular outcomes and increased mortality in the general population. Before addressing the direct effect of such modifiable factors on the natural history of HC, it is critical to define their prevalence in this population. A voluntary survey, drawing questions in part from the 2007 to 2008 National Health and Nutrition Examination Survey (NHANES), was posted on the HC Association website and administered to patients with HC at the University of Michigan. Propensity score matching to NHANES participants was used. Dichotomous and continuous health behaviors were analyzed using logistic and linear regression, respectively, and adjusted for body mass index and propensity score quintile. Compared to the matched NHANES participants, the patients with HC reported significantly less alcohol and tobacco use but also less time engaged in physical activity at work and for leisure. Time spent participating in vigorous or moderate activity was a strong predictor of self-reported exercise capacity. The body mass index was greater in the HC cohort than in the NHANES cohort. Exercise restrictions negatively affected emotional well-being in most surveyed subjects. In conclusion, patients with HC are less active than the general United States population. The well-established relation of inactivity, obesity, and cardiovascular mortality might be exaggerated in patients with HC. More data are needed on exercise in those with HC to strike a balance between acute risks and the long-term health benefits of exercise.

    View details for DOI 10.1016/j.amjcard.2012.12.018

    View details for Web of Science ID 000316923700018

    View details for PubMedID 23340032

  • Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells CELL STEM CELL Lan, F., Lee, A. S., Liang, P., Sanchez-Freire, V., Nguyen, P. K., Wang, L., Han, L., Yen, M., Wang, Y., Sun, N., Abilez, O. J., Hu, S., Ebert, A. D., Navarrete, E. G., Simmons, C. S., Wheeler, M., Pruitt, B., Lewis, R., Yamaguchi, Y., Ashley, E. A., Bers, D. M., Robbins, R. C., Longaker, M. T., Wu, J. C. 2013; 12 (1): 101-113

    Abstract

    Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca(2+)) imaging indicated dysregulation of Ca(2+) cycling and elevation in intracellular Ca(2+) ([Ca(2+)](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca(2+) homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

    View details for DOI 10.1016/j.stem.2012.10.010

    View details for Web of Science ID 000313839500014

    View details for PubMedID 23290139

    View details for PubMedCentralID PMC3638033

  • A public resource facilitating clinical use of genomes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ball, M. P., Thakuria, J. V., Zaranek, A. W., Clegg, T., Rosenbaum, A. M., Wu, X., Angrist, M., Bhak, J., Bobe, J., Callow, M. J., Cano, C., Chou, M. F., Chung, W. K., Douglas, S. M., Estep, P. W., Gore, A., Hulick, P., Labarga, A., Lee, J., Lunshof, J. E., Kim, B. C., Kim, J., Li, Z., Murray, M. F., Nilsen, G. B., Peters, B. A., Raman, A. M., Rienhoff, H. Y., Robasky, K., Wheeler, M. T., Vandewege, W., Vorhaus, D. B., Yang, J. L., Yang, L., Aach, J., Ashley, E. A., Drmanac, R., Kim, S., Li, J. B., Peshkin, L., Seidman, C. E., Seo, J., Zhang, K., Rehm, H. L., Church, G. M. 2012; 109 (30): 11920-11927

    Abstract

    Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved "open consent" process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain-we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.

    View details for DOI 10.1073/pnas.1201904109

    View details for Web of Science ID 000306992700018

    View details for PubMedID 22797899

    View details for PubMedCentralID PMC3409785

  • DNA Sequencing Clinical Applications of New DNA Sequencing Technologies CIRCULATION Dewey, F. E., Pan, S., Wheeler, M. T., Quake, S. R., Ashley, E. A. 2012; 125 (7): 931-944
  • Cardiovascular Magnetic Resonance Imaging Elucidates Genotype-Phenotype Relationships in Patients with Hypertrophic Cardiomyopathy Scientific Sessions of the American-Heart-Association/Resuscitation Science Symposium Heidary, S., Wheeler, M. T., Bennett, M. V., Chung, J., Pavlovic, A., Parent, M., Dash, R., McConnell, M. V., Ashley, E. A., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2011
  • Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence PLOS GENETICS Dewey, F. E., Chen, R., Cordero, S. P., Ormond, K. E., Caleshu, C., Karczewski, K. J., Whirl-Carrillo, M., Wheeler, M. T., Dudley, J. T., Byrnes, J. K., Cornejo, O. E., Knowles, J. W., Woon, M., Sangkuhl, K., Gong, L., Thorn, C. F., Hebert, J. M., Capriotti, E., David, S. P., Pavlovic, A., West, A., Thakuria, J. V., Ball, M. P., Zaranek, A. W., Rehm, H. L., Church, G. M., West, J. S., Bustamante, C. D., Snyder, M., Altman, R. B., Klein, T. E., Butte, A. J., Ashley, E. A. 2011; 7 (9)

    Abstract

    Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.

    View details for DOI 10.1371/journal.pgen.1002280

    View details for PubMedID 21935354

  • 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

  • Systems biology of heart failure, challenges and hopes CURRENT OPINION IN CARDIOLOGY Dewey, F. E., Wheeler, M. T., Ashley, E. A. 2011; 26 (4): 314-321

    Abstract

    Heart failure remains a leading cause of morbidity and mortality in developed nations. Our current understanding of molecular pathways involved in heart failure reveals little of the multiscale biological systems at work. Here we consider recent advances in understanding the integrative multiscale biology, or systems biology, of heart failure and present a framework for future work in the area.Multiplexed assays of gene expression and the complex dynamics of protein-protein interactions in heart failure have illuminated key pathways important to myocardial adaptation. Modeling of complex systems has advanced to incorporate these dynamic data sources into networks that capture fundamental interactions on different biological scales. The complex syndrome of heart failure, like other complex disease syndromes, can be viewed as an emergent property of these multiscale systems.A comprehensive understanding of adaptive mechanisms in heart failure requires integration of multiple data sources on several biological scales. A combination of holistic systems biology approaches and traditional reductionist experimentation will be required for a nuanced understanding of this multifaceted disease process.

    View details for DOI 10.1097/HCO.0b013e328346597d

    View details for Web of Science ID 000291424400007

    View details for PubMedID 21478745

  • 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

  • Extremely elevated lipoprotein(a), combined hyperlipidemia, and premature atherosclerosis in a Chinese family JOURNAL OF CLINICAL LIPIDOLOGY deGoma, E. M., Wheeler, M. T., Marcovina, S. M., Ashley, E. A. 2010; 4 (6): 543–47

    View details for DOI 10.1016/j.jacl.2010.09.002

    View details for Web of Science ID 000285702800013

    View details for PubMedID 21122702

  • Effect of Gender on Computerized Electrocardiogram Measurements in College Athletes PHYSICIAN AND SPORTSMEDICINE Mandic, S., Fonda, H., Dewey, F., Vy-van Le, Stein, R., Wheeler, M., Ashley, E. A., Myers, J., Froelicher, V. F. 2010; 38 (2): 156-164

    Abstract

    Background Broad criteria for classifying an electrocardiogram (ECG) as abnormal and requiring additional testing prior to participating in competitive athletics have been recommended for the preparticipation examination (PPE) of athletes. Because these criteria have not considered gender differences, we examined the effect of gender on the computerized ECG measurements obtained on Stanford student athletes. Currently available computer programs require a basis for "normal" in athletes of both genders to provide reliable interpretation. Methods During the 2007 PPE, computerized ECGs were recorded and analyzed on 658 athletes (54% male; mean age, 19 +/- 1 years) representing 22 sports. Electrocardiogram measurements included intervals and durations in all 12 leads to calculate 12-lead voltage sums, QRS amplitude and QRS area, spatial vector length (SVL), and the sum of the R wave in V5 and S wave in V2 (RSsum). Results By computer analysis, male athletes had significantly greater QRS duration, PR interval, Q-wave duration, J-point amplitude, and T-wave amplitude, and shorter QTc interval compared with female athletes (all P < 0.05). All ECG indicators of left ventricular electrical activity were significantly greater in males. Although gender was consistently associated with indices of atrial and ventricular electrical activity in multivariable analysis, ECG measurements correlated poorly with body dimensions. Conclusion Significant gender differences exist in ECG measurements of college athletes that are not explained by differences in body size. Our tables of "normal" computerized gender-specific measurements can facilitate the development of automated ECG interpretation for screening young athletes.

    View details for Web of Science ID 000290808000025

    View details for PubMedID 20631475

  • Challenges in the clinical application of whole-genome sequencing LANCET Ormond, K. E., Wheeler, M. T., Hudgins, L., Klein, T. E., Butte, A. J., Altman, R. B., Ashley, E. A., Greely, H. T. 2010; 375 (9727): 1749-1751
  • Clinical assessment incorporating a personal genome LANCET Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., Pushkarev, D., Neff, N. F., Hudgins, L., Gong, L., Hodges, L. M., Berlin, D. S., Thorn, C. F., Sangkuhl, K., Hebert, J. M., Woon, M., Sagreiya, H., Whaley, R., Knowles, J. W., Chou, M. F., Thakuria, J. V., Rosenbaum, A. M., Zaranek, A. W., Church, G. M., Greely, H. T., Quake, S. R., Altman, R. B. 2010; 375 (9725): 1525-1535

    Abstract

    The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

    View details for Web of Science ID 000277655100025

    View details for PubMedID 20435227

  • 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

  • A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Wheeler, M., Pavlovic, A., deGoma, E., Salisbury, H., Brown, C., Ashley, E. A. 2009; 2 (4): 381-391

    Abstract

    Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

    View details for DOI 10.1007/s12265-009-9139-0

    View details for Web of Science ID 000284691000005

    View details for PubMedID 20559996

  • 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

  • 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

  • Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Wheeler, M. T., Ho, M., Knowles, J. W., Pavlovic, A., Ashley, E. A. 2008; 1 (1): 25-36

    Abstract

    Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the beta1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.

    View details for DOI 10.1007/s12265-007-9007-8

    View details for Web of Science ID 000207734400008

    View details for PubMedID 20559955

  • Angiotensin-converting enzyme genotype predicts cardiac and autonomic responses to prolonged exercise JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ashley, E. A., Kardos, A., Jack, E. S., Habenbacher, W., Wheeler, M., Kim, Y. M., Froning, J., Myers, J., Whyte, G., Froelicher, V., Douglas, P. 2006; 48 (3): 523-531

    Abstract

    The purpose of this study was to investigate the phenomenon of left ventricular (LV) dysfunction after ultraendurance exercise.Subclinical LV dysfunction in response to endurance exercise up to 24 h duration has been described, but its mechanism remains elusive.We tested 86 athletes before and after the Adrenalin Rush Adventure Race using echocardiography, impedance cardiography, and plasma immunoassay.At baseline, athletes demonstrated physiology characteristic of extreme endurance training. After 90 to 120 h of almost-continuous exercise, LV systolic and diastolic function declined (fractional shortening before the race, 39.6 +/- 0.65%; after, 32.2 +/- 0.84%, p < 0.001; mitral inflow E-wave deceleration time before the race, 133 +/- 5 ms; after, 160 +/- 5 ms, n = 48, p < 0.001) without change in loading conditions as defined by LV end-diastolic dimension and total peripheral resistance estimated by thoracic impedance. There was a compensatory increase in heart rate (before, 55 +/- 1.3 beats/min; after, 59 +/- 1.5 beats/min, p = 0.05), which left cardiac output unchanged, as well as significant-but-subclinical increases in brain natriuretic peptide and troponin I. In addition, we found that athletes who were homozygous for the intron-16 insertion polymorphism of the angiotensin-converting enzyme (ACE) gene exhibited a significantly greater decrease in fractional shortening than athletes who were homozygous for the deletion allele. Heterozygotes showed an intermediate phenotype. In addition, the deletion group manifest an enhanced sympathovagal balance after the race, as evidenced by greater power in the low-frequency component of blood pressure variability.The ACE genotype predicts the extent of reversible subclinical LV dysfunction after prolonged exercise and is associated with a differential postactivity augmentation of sympathetic nervous system function that may explain it.

    View details for DOI 10.1016/j.jacc.2006.02.071

    View details for PubMedID 16875979

  • The interaction of coronary tone and cardiac fibrosis. Current atherosclerosis reports Wheeler, M. T., McNally, E. M. 2005; 7 (3): 219-226

    Abstract

    Regulation of coronary vascular tone is critical for proper perfusion and function of the myocardium. Many disease processes result in compromised regulation of coronary vascular tone and impaired myocardial perfusion. A common result of coronary vascular dysfunction is the development of areas of replacement fibrosis within the myocardium and surrounding the vasculature. Both intravascular processes, such as coronary atherosclerosis and endothelial dysfunction, and extravascular processes, including compromised myocardial metabolism, hormone excesses, and altered local signaling, may result in coronary vascular dysregulation. Coronary occlusion events, in turn, lead to myocardial damage and the activation of inflammatory cells and fibroblasts. The role of fibroblasts in regulating myocardial fibrosis and the contribution of myofibroblasts, cells that have limited contractile potential while retaining many of the extracellular matrix regulating processes of the fibroblast, may also contribute to the development of myocardial disease. In this review we examine the recent literature on myocardial fibrosis and myofibroblast activity, highlighting the effects of several classes of cardiovascular agents on the remodeling process.

    View details for PubMedID 15811257

  • The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses NATURE IMMUNOLOGY Boone, D. L., Turer, E. E., Lee, E. G., Ahmad, R. C., Wheeler, M. T., Tsui, C., Hurley, P., Chien, M., Chai, S., Hitotsumatsu, O., McNally, E., Pickart, C., Ma, A. 2004; 5 (10): 1052-1060

    Abstract

    A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)-induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor-induced activity of the transcription factor NF-kappaB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.

    View details for DOI 10.1038/ni1110

    View details for Web of Science ID 000224156600029

    View details for PubMedID 15334086

  • Secondary coronary artery vasospasm promotes cardiomyopathy progression AMERICAN JOURNAL OF PATHOLOGY Wheeler, M. T., Korcarz, C. E., Collins, K. A., Lapidos, K. A., Hack, A. A., Lyons, M. R., Zarnegar, S., Earley, J. U., Lang, R. M., McNally, E. M. 2004; 164 (3): 1063-1071

    Abstract

    Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of gamma-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of gamma-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated gamma-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, gamma-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 +/- 13.3% treated versus 37.4 +/- 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 +/- 27.9 cm/second versus 92.8 +/- 22.7 cm/second), and cardiac index (1.06 +/- 0.30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression.

    View details for Web of Science ID 000189164300031

    View details for PubMedID 14982859

  • Smooth muscle cell-extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy JOURNAL OF CLINICAL INVESTIGATION Wheeler, M. T., Allikian, M. J., Heydemann, A., Hadhazy, M., Zarnegar, S., McNally, E. M. 2004; 113 (5): 668-675

    Abstract

    Vascular spasm is a poorly understood but critical biomedical process because it can acutely reduce blood supply and tissue oxygenation. Cardiomyopathy in mice lacking gamma-sarcoglycan or delta-sarcoglycan is characterized by focal damage. In the heart, sarcoglycan gene mutations produce regional defects in membrane permeability and focal degeneration, and it was hypothesized that vascular spasm was responsible for this focal necrosis. Supporting this notion, vascular spasm was noted in coronary arteries, and disruption of the sarcoglycan complex was observed in vascular smooth muscle providing a molecular mechanism for spasm. Using a transgene rescue strategy in the background of sarcoglycan-null mice, we replaced cardiomyocyte sarcoglycan expression. Cardiomyocyte-specific sarcoglycan expression was sufficient to correct cardiac focal degeneration. Intriguingly, successful restoration of the cardiomyocyte sarcoglycan complex also eliminated coronary artery vascular spasm, while restoration of smooth muscle sarcoglycan in the background of sarcoglycan-null alleles did not. This mechanism, whereby tissue damage leads to vascular spasm, can be partially corrected by NO synthase inhibitors. Therefore, we propose that cytokine release from damaged cardiomyocytes can feed back to produce vascular spasm. Moreover, vascular spasm feeds forward to produce additional cardiac damage.

    View details for DOI 10.1172/JCI200420410

    View details for Web of Science ID 000189379500008

    View details for PubMedID 14991064

  • Functional nitric oxide synthase mislocalization in cardiomyopathy JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY Heydemann, A., Huber, J. M., Kakkar, R., Wheeler, M. T., McNally, E. M. 2004; 36 (2): 213-223

    Abstract

    Mutations in the dystrophin glycoprotein complex, and in particular the sarcoglycan subcomplex, lead to cardiomyopathy and muscular dystrophy. Mice with mutations in gamma-sarcoglycan or delta-sarcoglycan develop cardiomyopathy that is characterized by focal regions of tissue damage. These focally damaged regions constitute 0-5% of cardiac tissue. In cardiomyopathy arising from sarcoglycan mutations, we found that endothelial nitric oxide synthase (eNOS) was significantly increased in focally damaged cardiac myocytes. In addition, we noted that nitric oxide (NO) was also increased in regions of tissue damage and altered membrane permeability. In sarcoglycan mutant mice, regionally increased cardiac NO was associated with hypersensitivity to carbachol and decreased sensitivity to adrenergic stimulation. Inhibition of NO production in sarcoglycan mutant mice was associated with improved recovery after carbachol and isoproterenol infusion. These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients.

    View details for DOI 10.1016/j.yjmcc.2003.09.020

    View details for Web of Science ID 000189264800007

    View details for PubMedID 14871549

  • Sarcoglycans in vascular smooth and striated muscle TRENDS IN CARDIOVASCULAR MEDICINE Wheeler, M. T., McNally, E. M. 2003; 13 (6): 238-243

    Abstract

    Sarcoglycans are transmembrane proteins important in the maintenance of proper muscle function. Together, the sarcoglycans form a heteromeric complex that interacts with dystrophin, dystroglycan, and filamin C to form a mechanosignaling complex. Mutations in the genes encoding sarcoglycan can produce cardiomyopathy and muscular dystrophy. Studies of patients and animal models have emphasized the variability in penetrance and severity of cardiomyopathy. In animal models of sarcoglycan mutations, muscular dystrophy develops owing to loss of the sarcoglycan complex at the membrane of skeletal myocytes. Cardiomyopathy similarly develops with evidence of focal areas of degeneration and necrosis, as well as loss of sarcoglycan at the cardiomyocyte membrane. Vascular spasm has been noted as a feature of sarcoglycan-mediated cardiomyopathy. Recent evidence suggests that disruption of the smooth muscle sarcoglycan complex is not required for the development of vascular spasm and that vascular spasm arises from a vascular smooth muscle cell-extrinsic process.

    View details for Web of Science ID 000184950300005

    View details for PubMedID 12922020

  • Cytoskeletal defects in cardiomyopathy JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY McNally, E., Allikian, M., Wheeler, M. T., Mislow, J. M., Heydemann, A. 2003; 35 (3): 231-241

    Abstract

    Genetic studies of cardiomyopathy and muscular dystrophy have emphasized the importance of the striated myocyte cytoskeleton. Cytoskeletal defects produce myopathies through a combination of structural and signaling mechanisms. Broadly, the cytoskeletal proteins defective in these myopathic syndromes can be classified into categories based on their intracellular locations. The first category includes proteins of the plasma membrane that interact with both subsarcolemmal and extracellular matrix proteins. The second category, generally associated with hypertrophic cardiomyopathies, includes proteins of the sarcomere. The last, newly emerging, category includes proteins of the inner nuclear membrane. In this review, we will examine the genetic defects that lead to cardiomyopathy and the potential means by which these varied proteins normally maintain the structural integrity of myocytes.

    View details for DOI 10.1016/S0022-2828(03)00018-X

    View details for Web of Science ID 000182212600002

    View details for PubMedID 12676538

  • zeta-Sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy HUMAN MOLECULAR GENETICS Wheeler, M. T., Zarnegar, S., McNally, E. M. 2002; 11 (18): 2147-2154

    Abstract

    The dystrophin glycoprotein complex (DGC) is found at the plasma membrane of muscle cells, where it provides a link between the cytoskeleton and the extracellular matrix. A subcomplex within the DGC, the sarcoglycan complex, associates with dystrophin and mediates muscle membrane stability. Mutations in sarcoglycan genes lead to muscular dystrophy and cardiomyopathy in both humans and mice. In invertebrates, there are three sarcoglycan genes, while in mammals there are additional sarcoglycan genes that probably arose from gene duplication events. We identified a novel mammalian sarcoglycan, zeta-sarcoglycan, that is highly related to gamma-sarcoglycan and delta-sarcoglycan. We generated a zeta-sarcoglycan-specific antibody and found that zeta-sarcoglycan associated with other members of the sarcoglycan complex at the plasma membrane. Additionally, zeta-sarcoglycan was reduced at the membrane in muscular dystrophy, consistent with a role in mediating membrane stability. zeta-Sarcoglycan was also found as a component of the vascular smooth muscle sarcoglycan complex. Together, these data demonstrate that zeta-sarcoglycan is an integral component of the sarcoglycan complex and, as such, is important in the pathogenesis of muscular dystrophy.

    View details for Web of Science ID 000177590700008

    View details for PubMedID 12189167

  • Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K-ATP channels JOURNAL OF CLINICAL INVESTIGATION Chutkow, W. A., Pu, J. L., Wheeler, M. T., Wada, T., Makielski, J. C., Burant, C. F., McNally, E. M. 2002; 110 (2): 203-208

    Abstract

    K(ATP) channels couple the intracellular energy state to membrane excitability and regulate a wide array of biologic activities. K(ATP) channels contain a pore-forming inwardly rectifying potassium channel and a sulfonylurea receptor regulatory subunit (SUR1 or SUR2). To clarify the role of K(ATP) channels in vascular smooth muscle, we studied Sur2 gene-targeted mice (Sur2(-/-)) and found significantly elevated resting blood pressures and sudden death. Using in vivo monitoring, we detected transient, repeated episodes of coronary artery vasospasm in Sur2(-/-) mice. Focal narrowings in the coronary arteries were present in Sur2(-/-) mice consistent with vascular spasm. We treated Sur2(-/-) mice with a calcium channel antagonist and successfully reduced vasospastic episodes. The intermittent coronary artery vasospasm seen in Sur2(-/-) mice provides a model for the human disorder Prinzmetal variant angina and demonstrates that the SUR2 K(ATP) channel is a critical regulator of episodic vasomotor activity.

    View details for DOI 10.1172/JCI200215672

    View details for Web of Science ID 000176872600011

    View details for PubMedID 12122112

  • Cardiomyopathy is independent of skeletal muscle disease in muscular dystrophy. FASEB journal Zhu, X., Wheeler, M. T., Hadhazy, M., Lam, M. J., McNally, E. M. 2002; 16 (9): 1096-1098

    Abstract

    Dystrophin and its associated proteins, the sarcoglycans, are normally expressed in heart and skeletal muscle. Mutations that alter the expression of these membrane-associated proteins lead to muscular dystrophy (MD) and cardiomyopathy in humans. Because of the timing and nature of the accompanying cardiomyopathy, it has been suggested that cardiomyopathy develops as a secondary consequence of skeletal muscle dysfunction in the muscular dystrophies. To determine whether skeletal muscle dystrophy contributes to the development of sarcoglycan-mediated cardiomyopathy, we used mice lacking gamma-sarcoglycan and inserted a transgene that "rescued" gamma-sarcoglycan expression only in skeletal muscle. Gamma-sarcoglycan was expressed in skeletal muscle under the control of the skeletal muscle-specific myosin light chain 1/3 promoter. Gamma-sarcoglycan-null mice expressing this transgene fully restore gamma-sarcoglycan expression. Furthermore, the transgene-rescued mice lack the focal necrosis and membrane permeability defects that are a hallmark of MD. Despite correction of the skeletal muscle disease, focal degeneration and membrane permeability abnormalities persisted in cardiac muscle, and notably persisted in the right ventricle. Therefore, heart and skeletal muscle defects are independent processes in sarcoglycan-mediated muscular dystrophies and, as such, therapy should target both skeletal and cardiac muscle correction to prevent sudden death due to cardiomyopathy in the muscular dystrophies.

    View details for PubMedID 12039854

  • Cardiomyopathy is independent of skeletal muscle disease in muscular dystrophy FASEB JOURNAL Zhu, X. L., Wheeler, M. T., Hadhazy, M., Lam, M. Y., McNally, E. M. 2002; 16 (7): 1096-?
  • The sarcoglycan complex in striated and vascular smooth muscle Cold Spring Harbor Symposium on Quantitative Biology Wheeler, M. T., Allikian, M. J., Heydemann, A., McNally, E. M. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. 2002: 389–397

    View details for Web of Science ID 000183780700049

    View details for PubMedID 12858564

  • Overexpression of gamma-sarcoglycan induces severe muscular dystrophy - Implications for the regulation of sarcoglycan assembly JOURNAL OF BIOLOGICAL CHEMISTRY Zhu, X. L., Hadhazy, M., Groh, M. E., Wheeler, M. T., Wollmann, R., McNally, E. M. 2001; 276 (24): 21785-21790

    Abstract

    The sarcoglycan complex is found normally at the plasma membrane of muscle. Disruption of the sarcoglycan complex, through primary gene mutations in dystrophin or sarcoglycan subunits, produces membrane instability and muscular dystrophy. Restoration of the sarcoglycan complex at the plasma membrane requires reintroduction of the mutant sarcoglycan subunit in a manner that will permit normal assembly of the entire sarcoglycan complex. To study sarcoglycan gene replacement, we introduced transgenes expressing murine gamma-sarcoglycan into muscle of normal mice. Mice expressing high levels of gamma-sarcoglycan, under the control of the muscle-specific creatine kinase promoter, developed a severe muscular dystrophy with greatly reduced muscle mass and early lethality. Marked gamma-sarcoglycan overexpression produced cytoplasmic aggregates that interfered with normal membrane targeting of gamma-sarcoglycan. Overexpression of gamma-sarcoglycan lead to the up-regulation of alpha- and beta-sarcoglycan. These data suggest that increased gamma-sarcoglycan and/or mislocalization of gamma-sarcoglycan to the cytoplasm is sufficient to induce muscle damage and provides a new model of muscular dystrophy that highlights the importance of this protein in the assembly, function, and downstream signaling of the sarcoglycan complex. Most importantly, gene dosage and promoter strength should be given serious consideration in replacement gene therapy to ensure safety in human clinical trials.

    View details for Web of Science ID 000169297900129

    View details for PubMedID 11287429

  • Cardiomyopathy in animal models of muscular dystrophy CURRENT OPINION IN CARDIOLOGY Heydemann, A., Wheeler, M. T., McNally, E. M. 2001; 16 (3): 211-217

    Abstract

    Arrhythmia and cardiomyopathy frequently accompany muscular dystrophy. In the last year, the cardiovascular consequences of muscular dystrophy gene mutations have been established through studies of murine models. These models have highlighted the potential role of primary defects in cardiac muscle as well as those secondary cardiovascular outcomes that arise from severe muscle disease. This review focuses on three areas. Recent studies using mouse models have shown that the dystrophin-associated proteins, the sarcoglycans and alpha-dystrobrevin, are critical for both cardiac and skeletal muscle membrane function, yet may exert their roles by different molecular mechanisms. New findings have shown that cytoskeletal proteins at the nuclear membrane, such as emerin and lamin AC, cause muscular dystrophy and cardiomyopathy with cardiac conduction system disease. Finally, the mechanism of cardiac and muscle degeneration in myotonic dystrophy has been re-evaluated through a series of studies using murine models. Implications for human therapy are considered in light of these new findings.

    View details for Web of Science ID 000169006500009

    View details for PubMedID 11357018

  • An E-box within the MHC IIB gene is bound by MyoD and is required for gene expression in fast muscle AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY Wheeler, M. T., Snyder, E. C., Patterson, M. N., Swoap, S. J. 1999; 276 (5): C1069-C1078

    Abstract

    The myosin heavy chain (MHC) IIB gene is selectively expressed in skeletal muscles, imparting fast contractile kinetics. Why the MHC IIB gene product is expressed in muscles like the tibialis anterior (TA) and not expressed in muscles like the soleus is currently unclear. It is shown here that the mutation of an E-box within the MHC IIB promoter decreased reporter gene activity in the fast-twitch TA muscle 90-fold as compared with the wild-type promoter. Reporter gene expression within the TA required this E-box for activation of a heterologous construct containing upstream regulatory regions of the MHC IIB promoter linked to the basal 70-kDa heat shock protein TATA promoter. Electrophoretic mobility shift assays demonstrated that mutation of the E-box prevented the binding of both MyoD and myogenin to this element. In cotransfected C2C12 myotubes and Hep G2 cells, MyoD preferentially activated the MHC IIB promoter in an E-box-dependent manner, whereas myogenin activated the MHC IIB promoter to a lesser extent, and in an E-box-independent manner. A time course analysis of hindlimb suspension demonstrated that the unweighted soleus muscle activated expression of MyoD mRNA before the de novo expression of MHC IIB mRNA. These data suggest a possible causative role for MyoD in the observed upregulation of MHC IIB in the unweighted soleus muscle.

    View details for Web of Science ID 000080245000009

    View details for PubMedID 10329954