Born and raised in Scotland, Euan Angus Ashley graduated with 1st class Honors in Physiology and Medicine from the University of Glasgow. He completed medical residency and a PhD in molecular cardiology at the University of Oxford before moving to Stanford University where he trained in cardiology and advanced heart failure joining the faculty in 2006. His group is focused on the application of genomics to medicine. In 2010, he led the team that carried out the first clinical interpretation of a human genome. The paper published in the Lancet was the focus of over 300 news stories, became one of the most cited articles in clinical medicine that year, and was featured in the Genome Exhibition at the Smithsonian in DC. The team extended the approach in 2011 to a family of four and now routinely apply genome sequencing to the diagnosis of patients at Stanford hospital where Dr Ashley directs the Clinical Genome Service and the Center for Inherited Cardiovascular Disease. In 2013, Dr Ashley was recognized by the White House Office of Science and Technology Policy for his contributions to Personalized Medicine. In 2014, Dr Ashley became co-chair of the steering committee for the NIH Undiagnosed Diseases Network. Dr Ashley is a recipient of the National Innovation Award from the American Heart Association (AHA) and a National Institutes of Health (NIH) Director’s New Innovator Award. He is a member of the AHA Council on Functional Genomics, and the Institute of Medicine (IOM) of the National Academy of Sciences Roundtable on Translating Genomic-Based Research for Health. He is a peer reviewer for the NIH and the AHA as well as journals including Nature, the New England Journal of Medicine, the Lancet and the Journal of Clinical Investigation. He is co-founder of Personalis Inc, a genome scale genetic diagnostics company.
Father to three young Americans, in his ‘spare’ time, he tries to understand American football, plays the saxophone, and conducts research on the health benefits of single malt Scotch whisky.
- Inherited cardiovascular disease
- Heart Failure
- Genomic medicine
- Hypertrophic Cardiomyopathy
- Cardiomyopathy, Dilated
- Arrhythmogenic Right Ventricular Dysplasia
Co-chair, Steering Committee, NIH Undiagnosed Diseases Network (2014 - Present)
Co-chair, Cardiovascular Working Group, Clinical Genome Resource (Clingen) (2014 - Present)
Co-Director, Stanford Clinical Genomics Service (2013 - Present)
Director, Stanford Center for Inherited Cardiovascular Disease (2010 - Present)
Co-Director, Stanford Research Training Program in Myocardial Biology (T32) (2010 - Present)
Member, Institute of Medicine Roundtable on Translating Genomic-based Research for Health (2012 - Present)
Leadership committee, AHA Council on Functional Genomics and Translational Biology (2009 - Present)
Director, Stanford Cardiopulmonary Exercise Testing Laboratory (2007 - Present)
Honors & Awards
NIH Director's New Innovator Award, National Institutes of Health (2009)
Innovative Research Award, American Heart Association (2008)
Faculty Scholar, Donald E. and Delia B. Baxter Foundation (2009)
Career Development Award (K08), National Institutes of Health (2006)
Western Affiliates Young Investigator Award, American Heart Association (2004)
Cardiovascular Medicine Basic Science Award, Stanford University (2004)
Young Investigator Award (Basic), Astra-Zeneca (2003)
Young Investigator Award, European Society of Cardiology (2002)
Young Investigator Prize in Cardiovascular Medicine, UK Medical Research Society (2002)
Residency:University of Oxford (1996) UK
Internship:University of Glasgow (1997) Scotland
Medical Education:University of Glasgow (1996) Scotland
Fellowship:University of Oxford (2002) UK
Fellowship:Stanford University Medical Center (2006) CA
DPhil, University of Oxford, Molecular Cardiology (2002)
MRCP (UK), Royal College of Physicians (UK), Medicine (1999)
MB ChB, University of Glasgow, Medicine (1996)
BSc (Hons), University of Glasgow, Physiology (1993)
Community and International Work
Arbor Free Cardiology Clinic
Opportunities for Student Involvement
Current Research and Scholarly Interests
The Ashley lab is focused on the application of genomics to medicine. We develop methods for the interpretation of whole genome sequencing data to improve diagnosis of genetic disease and to personalize the practice of medicine. We love big data questions and are obsessed with systems approaches to biology especially analysis of network graphs. The wet bench is where we test causality of key genes and investigate the biology of network modules. It is also the focus of our translational efforts. Therapeutic development is a near term goal and several of our discoveries are the focus of patents or are being actively pursued by pharmaceutical and biotechnology partners.
Personal Genomics for Preventive Cardiology
The purpose of this study is to see if providing information to a person on their inherited (genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their diet, lifestyle or medication regimen to alter their risk.
Stanford is currently not accepting patients for this trial. For more information, please contact Josh Knowles, 650-804-2526.
Study of Exercise Training in Hypertrophic Cardiomyopathy
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 and quality of life, with neutral effects on the clinical characteristics.
Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
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.
Exercise Study Including Patients With Hypertrophic Cardiomyopathy
The long term health and cardiovascular benefits of a regular exercise program have been well-established. National guidelines recommend involvement in moderate aerobic fitness (i.e. walking, bicycling, light jogging, swimming) for patients with hypertrophic cardiomyopathy (HCM). However, data on potential benefits of recreational exercise, useful parameters for risk stratification, and methods of devising individual exercise prescriptions are completely lacking. The specific aims of this study are: 1) to devise a safe moderate intensity exercise training program in patients with HCM, and 2) to determine whether exercise training improves ability to perform activities and tasks, heart size and function, and quality of life in patients with HCM.
Independent Studies (8)
- Biomedical Informatics Teaching Methods
BIOMEDIN 290 (Aut, Win, Spr, Sum)
- Directed Reading and Research
BIOMEDIN 299 (Aut, Win, Spr, Sum)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum)
- Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum)
- Graduate Research
MED 399 (Aut, Win, Spr, Sum)
- Medical Scholars Research
BIOMEDIN 370 (Aut, Win, Spr, Sum)
- Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum)
- Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Biomedical Informatics Teaching Methods
Graduate and Fellowship Programs
Biomedical Informatics (Phd Program)
Human Genetics and Genetic Counseling (Masters Program)
Medical Genetics (Fellowship Program)
Molecular and Genetic Medicine (Fellowship Program)
Pediatric Cardiology (Fellowship Program)
Sports Medicine (Fellowship Program)
Guidelines for investigating causality of sequence variants in human disease
2014; 508 (7497): 469-476
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
View details for DOI 10.1038/nature13127
View details for Web of Science ID 000334741600026
View details for PubMedID 24759409
Clinical interpretation and implications of whole-genome sequencing.
JAMA-the journal of the American Medical Association
2014; 311 (10): 1035-1045
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
Molecular Diagnosis of Long-QT syndrome at 10 Days of Life by Rapid Whole Genome Sequencing.
Heart rhythm : the official journal of the Heart Rhythm Society
The advent of clinical next generation sequencing is rapidly changing the landscape of rare disease medicine. Molecular diagnosis of long QT syndrome (LQTS) can impact clinical management, including risk stratification and selection of pharmacotherapy based on the type of ion channel affected, but results from current gene panel testing requires 4 to 16 weeks before return to clinicians.A term female infant presented with 2:1 atrioventricular block and ventricular arrhythmias consistent with perinatal LQTS, requiring aggressive treatment including epicardial pacemaker, and cardioverter-defibrillator implantation and sympathectomy on day of life two. We sought to provide a rapid molecular diagnosis for optimization of treatment strategies.We performed CLIA-certified rapid whole genome sequencing (WGS) with a speed-optimized bioinformatics platform to achieve molecular diagnosis at 10 days of life.We detected a known pathogenic variant in KCNH2 that was demonstrated to be paternally inherited by followup genotyping. The unbiased assessment of the entire catalog of human genes provided by whole genome sequencing revealed a maternally inherited variant of unknown significance in a novel gene.Rapid clinical WGS provides faster and more comprehensive diagnostic information by 10 days of life than standard gene-panel testing. In selected clinical scenarios such as perinatal LQTS, rapid WGS may be able to provide more timely and clinically actionable information than a standard commercial test.
View details for DOI 10.1016/j.hrthm.2014.06.030
View details for PubMedID 24973560
APJ acts as a dual receptor in cardiac hypertrophy
2012; 488 (7411): 394-398
Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate G?i and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of ?-arrestins or by pharmacological doses of apelin acting through G?i. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.
View details for DOI 10.1038/nature11263
View details for Web of Science ID 000307501000045
View details for PubMedID 22810587
Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence
2011; 7 (9)
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 Web of Science ID 000295419100031
View details for PubMedID 21935354
Clinical assessment incorporating a personal genome
2010; 375 (9725): 1525-1535
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
Whole-Exome Sequencing Reveals TopBP1 as a Novel Gene in Idiopathic Pulmonary Arterial Hypertension
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2014; 189 (10): 1260-1272
Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. While mutations in the bone morphogenetic receptor (BMPR) 2 are found in 80% of heritable and ±15% of IPAH patients, their low penetrance (±20%) suggests that other as-yet unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH but whether WES can also accelerate gene discovery in IPAH remains unknown. Objectives: To determine whether WES can help identify novel gene modifiers in IPAH patients. Methods and Measurements: Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated IPAH patients lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR. Main Results: A total of 10 genes were identified as high priority candidates. Our top hit was TopBP1, a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from IPAH patients. While TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival. Conclusions: WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibly to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.
View details for DOI 10.1164/rccm.201310-17490C
View details for Web of Science ID 000336017200018
Latent Obstruction and Left Atrial Size Are Predictors of Clinical Deterioration Leading to Septal Reduction in Hypertrophic Cardiomyopathy
JOURNAL OF CARDIAC FAILURE
2014; 20 (4): 236-243
Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.
View details for DOI 10.1016/j.cardfail.2014.01.014
View details for Web of Science ID 000334650600003
- Clinical Interpretation and Implications of Whole-Genome Sequencing JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 2014; 311 (10): 1035-1044
Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement.
Echocardiography (Mount Kisco, N.Y.)
2014; 31 (3): E80-4
In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.
View details for DOI 10.1111/echo.12467
View details for PubMedID 24299065
- Unexplained Double-Chambered Left Ventricle Associated with Contracting Right Ventricular Aneurysm and Right Atrial Enlargement ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES 2014; 31 (3): E80-E84
A neural network approach to predicting outcomes in heart failure using cardiopulmonary exercise testing
INTERNATIONAL JOURNAL OF CARDIOLOGY
2014; 171 (2): 265-269
To determine the utility of an artificial neural network (ANN) in predicting cardiovascular (CV) death in patients with heart failure (HF).ANNs use weighted inputs in multiple layers of mathematical connections in order to predict outcomes from multiple risk markers. This approach has not been applied in the context of cardiopulmonary exercise testing (CPX) to predict risk in patients with HF.2635 patients with HF underwent CPX and were followed for a mean of 29±30months. The sample was divided randomly into ANN training and testing sets to predict CV mortality. Peak VO2, VE/VCO2 slope, heart rate recovery, oxygen uptake efficiency slope, and end-tidal CO2 pressure were included in the model. The predictive accuracy of the ANN was compared to logistic regression (LR) and a Cox proportional hazards (PH) score. A multi-layer feed-forward ANN was used and was tested with a single hidden layer containing a varying number of hidden neurons.There were 291 CV deaths during the follow-up. An abnormal VE/VCO2 slope was the strongest predictor of CV mortality using conventional PH analysis (hazard ratio 3.04; 95% CI 2.2-4.2, p<0.001). After training, the ANN was more accurate in predicting CV mortality compared to LR and PH; ROC areas for the ANN, LR, and PH models were 0.72, 0.70, and 0.69, respectively. Age and BMI-adjusted odds ratios were 4.2, 2.6, and 2.9, for ANN, LR, and PH, respectively.An ANN model slightly improves upon conventional methods for estimating CV mortality risk using established CPX responses.
View details for DOI 10.1016/j.ijcard.2013.12.031
View details for Web of Science ID 000329982200047
View details for PubMedID 24387896
Prevalence and Clinical Correlates of Right Ventricular Dysfunction in Patients With Hypertrophic Cardiomyopathy
AMERICAN JOURNAL OF CARDIOLOGY
2014; 113 (2): 361-367
Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.
View details for DOI 10.1016/j.amjcaid.2013.09.045
View details for Web of Science ID 000330253900027
Rat model of veno-arterial extracorporeal membrane oxygenation.
Journal of translational medicine
2014; 12: 37-?
We aim to develop a rat model of veno-arterial extracorporeal membrane oxygenation (VA-ECMO).VA-ECMO was established in twelve Male Sprague-Dawley rats (250-350 g) through cannulation of the right jugular vein for venous drainage and the right femoral artery for arterial reinfusion. Arterial blood pressure was measured using a conductance catheter through cannulation of the left carotid artery. Heart rate was monitored by electrocardiography and arterial blood gas parameters with a blood gas analyzer. The VA-ECMO circuit was tested by subjecting the rats to hypoxic cardiac arrest with resuscitation using VA-ECMO. Both load-dependent and load-independent measures of myocardial contractility were measured using pressure-volume loop analysis to confirm restoration of myocardial function post-resuscitation.Following hypoxic cardiac arrest VA-ECMO provided sufficient oxygenation to support the circulation. The haemodynamic and blood gas parameters were maintained at transition and during ECMO. All animals were resuscitated, regained cardiac function and were able to be weaned off ECMO post-resuscitation.We have established a safe, high-throughput, economical, functioning rat model of VA-ECMO.
View details for DOI 10.1186/1479-5876-12-37
View details for PubMedID 24507588
How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience.
2014; 4 (6)
It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.Tertiary referral centre from Stanford, California, USA.383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Echocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).Reverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E'<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E' was similarly elevated (E/E': 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m(2) was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m(2) (OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E'>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E'<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.In HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.
View details for DOI 10.1136/bmjopen-2014-004814
View details for PubMedID 24928584
Identification of a New Target of miR-16, Vacuolar Protein Sorting 4a.
2014; 9 (7)
The rationale was to utilize a bioinformatics approach to identify miRNA binding sites in genes with single nucleotide mutations (SNPs) to discover pathways in heart failure (HF).The objective was to focus on the genes containing miRNA binding sites with miRNAs that were significantly altered in end-stage HF and in response to a left ventricular assist device (LVAD).BEDTools v2.14.3 was used to discriminate SNPs within predicted 3'UTR miRNA binding sites. A member of the miR-15/107 family, miR-16, was decreased in the circulation of end-stage HF patients and increased in response to a LVAD (p<0.001). MiR-16 decreased Vacuolar Protein Sorting 4a (VPS4a) expression in HEK 293T cells (p<0.01). The SNP rs16958754 was identified in the miR-15/107 family binding site of VPS4a which abolished direct binding of miR-16 to the 3'UTR of VPS4a (p<0.05). VPS4a was increased in the circulation of end-stage HF patients (p<0.001), and led to a decrease in the number of HEK 293T cells in vitro (p<0.001).We provide evidence that miR-16 decreases in the circulation of end-stage HF patients and increases with a LVAD. Modeling studies suggest that miR-16 binds to and decreases expression of VPS4a. Overexpression of VPS4a decreases cell number. Together, these experiments suggest that miR-16 and VPS4a expression are altered in end-stage HF and in response to unloading with a LVAD. This signaling pathway may lead to reduced circulating cell number in HF.
View details for DOI 10.1371/journal.pone.0101509
View details for PubMedID 25033200
Effects of respiratory exchange ratio on the prognostic value of peak oxygen consumption and ventilatory efficiency in patients with systolic heart failure.
JACC. Heart failure
2013; 1 (5): 427-432
The purpose of this analysis was to evaluate the prognostic characteristics of peak oxygen consumption (Vo2) and the minute ventilation/carbon dioxide (VE/Vco2) slope of different peak respiratory exchange ratios (RERs) obtained from cardiopulmonary exercise testing in patients with heart failure (HF).For patients with HF, peak Vo2 and the VE/Vco2 slope are used for assessing prognosis. Peak Vo2 is assessed in association with peak RER ≥1.10, indicating maximal effort and prognostic sensitivity. Conversely, the VE/Vco2 slope provides effort-independent prognostic discrimination.Patients with HF scheduled to undergo cardiopulmonary exercise testing were enrolled. Patients were subclassified by peak RER (RER <1.00, RER 1.00 to 1.04, RER 1.05 to 1.09, RER ≥1.10) and followed for up to 3 years for major cardiac-related events (death, left ventricular assist device implantation, or cardiac transplantation).Included were 1,728 patients with HF (75% males; 40% ischemic etiology; age: 55 ± 14 years; left ventricular ejection fraction: 28 ± 10%). Two hundred seventy major events occurred, with no proportional differences across the RER subgroups. Multivariate Cox regression analysis indicated that the VE/Vco2 slope and peak Vo2 remained prognostic within each subgroup; the VE/Vco2 slope remained the strongest predictor. Receiver-operating characteristic analysis demonstrated equitable prognostic cutoffs for the VE/Vco2 slope (range: 34.9 to 35.7; area under the curve [AUC] range: 0.69 to 0.75) and peak Vo2 (range: 13.8 to 14.0 ml·kg(-1)·min(-1); AUC range: 0.68 to 0.75).Peak Vo2 provided a sensitive assessment of prognosis in patients with HF in all RER subgroups. The VE/Vco2 slope provided greater prognostic discrimination in all RER subgroups. Clinical consideration may be warranted for patients with low RER, low peak Vo2, and an elevated VE/Vco2 slope.
View details for DOI 10.1016/j.jchf.2013.05.008
View details for PubMedID 24621975
The prognostic significance of heart rate recovery is not dependent upon maximal effort in patients with heart failure
INTERNATIONAL JOURNAL OF CARDIOLOGY
2013; 168 (2): 1496-1501
Heart rate recovery (HRR) has been observed to be a significant prognostic measure in patients with heart failure (HF). However, the prognostic value of HRR has not been examined in regard to the level of patient effort during exercise testing. Using the peak respiratory exchange ratio (RER) and a large multicenter HF database we examined the prognostic utility of HRR.Cardiopulmonary exercise testing (CPX) was performed in 806 HF patients who then underwent an active cool-down of at least 1 min. Peak oxygen consumption (VO2), ventilatory efficiency (VE/VCO2 slope), and peak RER were determined with subjects categorized into subgroups according to peak RER (<1.00, 1.00-1.09, ≥ 1.10). HRR was defined as the difference between heart rate at peak exercise and 1 min following test termination. Patients were followed for major cardiac events for up to four years post-CPX.There were 163 major cardiac events (115 deaths, 20 left ventricular assist device implantations, and 28 transplantations) during the four year tracking period. Univariate Cox regression analysis results identified HRR as a significant (p<0.05) univariate predictor of adverse events regardless of the RER achieved. Multivariate Cox regression analysis in the overall group revealed that the VE/VCO2 slope was the strongest predictor of adverse events (chi-square: 110.9, p<0.001) with both HRR (residual chi-square: 16.7, p<0.001) and peak VO2 (residual chi-square: 10.4, p<0.01) adding significant prognostic value.HRR after symptom-limited exercise testing performed at sub-maximal efforts using RER to categorize level of effort is as predictive as HRR after maximal effort in HF patients.
View details for DOI 10.1016/j.ijcard.2012.12.102
View details for Web of Science ID 000325412800152
View details for PubMedID 23391698
Race Differences in Ventricular Remodeling and Function Among College Football Players
AMERICAN JOURNAL OF CARDIOLOGY
2013; 112 (1): 128-134
Athletic training is associated with increases in ventricular mass and volume. Recent studies have shown that left ventricular mass increases proportionally in white athletes with a mass/volume ratio approaching unity. The objective of this study was to compare the proportionality in ventricular remodeling and ventricular function in black versus white National Collegiate Athletic Association Division I football players. From 2008 to 2011, football players at Stanford University underwent cardiovascular screening with a 12-point history and physical examination, electrocardiography, and focused echocardiography. Compared with white players, black players had on average higher left ventricular mass indexes (77 ± 11 vs 71 ± 11 g/m(2), p = 0.009), higher mass/volume ratios (1.18 ± 0.16 vs 1.06 ± 0.09 g/ml, p <0.001), and higher QRS vector magnitudes (3.2 ± 0.7 vs 2.7 ± 0.8, p = 0.002). Black race had an odds ratio of 14 (95% confidence interval 5 to 42, p <0.001) for a mass/volume ratio >1.2. Mass/volume ratio was inversely related to early diastolic tissue Doppler velocity e' (r = -0.50, p <0.001) but not to QRS vector magnitude (r = 0.065, p = 0.034). With regard to systolic indexes, there was no significant difference in the left ventricular ejection fraction, velocity of circumferential shortening, and isovolumic acceleration. In conclusion, black college football players exhibit more concentric ventricular remodeling, lower early diastolic annular velocities, and increased ventricular voltage compared with white players. Ventricular mass increases proportionally to volume in white players but not in black players.
View details for DOI 10.1016/j.amjcard.2013.02.065
View details for Web of Science ID 000321677200023
View details for PubMedID 23602691
- Taming Rare Variation With Known Biology in Long QT Syndrome. Circulation. Cardiovascular genetics 2013; 6 (3): 227-229
Validation of a cardiopulmonary exercise test score in heart failure.
Circulation. Heart failure
2013; 6 (2): 211-218
Cardiopulmonary exercise test (CPX) responses are strong predictors of outcomes in patients with heart failure. We recently developed a CPX score that integrated the additive prognostic information from CPX. The purpose of this study was to validate the score in a larger, independent sample of patients.A total of 2625 patients with heart failure underwent CPX and were followed for cardiovascular (CV) mortality and major CV events (death, transplantation, left ventricular assist device implantation). Net reclassification improvement (NRI) for the score and each of its components were determined at 3 years. The VE/VCO2 slope was the strongest predictor of risk and was attributed a relative weight of 7, with weighted scores for abnormal heart rate recovery, oxygen uptake efficiency slope, end-tidal CO2 pressure, and peak VO2 having scores of 5, 3, 3, and 2, respectively. A summed score of >15 was associated with an annual mortality rate of 12.2% and a relative risk >9 for total events, whereas a score of <5 was associated with an annual mortality rate of 1.2%. The composite score was the most accurate predictor of CV events among all CPX responses considered (C indexes, 0.70 for CV mortality and 0.72 for the composite outcome). Each component of the score provided significant NRI compared with peak VO2 (category-free NRI, 0.61-0.77), and the score provided significant NRI above clinical risk factors for both CV events and mortality (NRI, 0.63 and 0.65 for CPX score compared with clinical variables alone).These results validate the application of a simple, integrated multivariable score based on readily available CPX responses.
View details for DOI 10.1161/CIRCHEARTFAILURE.112.000073
View details for PubMedID 23392791
Impact of Cardiorespiratory Fitness on the Obesity Paradox in Patients With Heart Failure
MAYO CLINIC PROCEEDINGS
2013; 88 (3): 251-258
To determine the impact of cardiorespiratory fitness (FIT) on survival in relation to the obesity paradox in patients with systolic heart failure (HF).We studied 2066 patients with systolic HF (body mass index [BMI] ≥18.5 kg/m(2)) between April 1, 1993 and May 11, 2011 (with 1784 [86%] tested after January 31, 2000) from a multicenter cardiopulmonary exercise testing database who were followed for up to 5 years (mean ± SD, 25.0±17.5 months) to determine the impact of FIT (peak oxygen consumption <14 vs ≥14 mL O2 ∙ kg(-1) ∙ min(-1)) on the obesity paradox.There were 212 deaths during follow-up (annual mortality, 4.5%). In patients with low FIT, annual mortality was 8.2% compared with 2.8% in those with high FIT (P<.001). After adjusting for age and sex, BMI was a significant predictor of survival in the low FIT subgroup when expressed as a continuous (P=.03) and dichotomous (<25.0 vs ≥25.0 kg/m(2)) (P=.01) variable. Continuous and dichotomous BMI expressions were not significant predictors of survival in the overall and high FIT groups after adjusting for age and sex. In patients with low FIT, progressively worse survival was noted with BMI of 30.0 or greater, 25.0 to 29.9, and 18.5 to 24.9 (log-rank, 11.7; P=.003), whereas there was no obesity paradox noted in those with high FIT (log-rank, 1.72; P=.42).These results indicate that FIT modifies the relationship between BMI and survival. Thus, assessing the obesity paradox in systolic HF may be misleading unless FIT is considered.
View details for DOI 10.1016/j.mayocp.2012.11.020
View details for Web of Science ID 000317331800009
View details for PubMedID 23489451
Cardiopulmonary and Noninvasive Hemodynamic Responses to Exercise Predict Outcomes in Heart Failure
JOURNAL OF CARDIAC FAILURE
2013; 19 (2): 101-107
An impaired cardiac output response to exercise is a hallmark of chronic heart failure (HF). We determined the extent to which noninvasive estimates of cardiac hemodynamics during exercise in combination with cardiopulmonary exercise test (CPX) responses improved the estimation of risk for adverse events in patients with HF.CPX and impedance cardiography were performed in 639 consecutive patients (mean age 48 ± 14 years), evaluated for HF. Clinical, hemodynamic, and CPX variables were acquired at baseline and subjects were followed for a mean of 460 ± 332 days. Patients were followed for the composite outcome of cardiac-related death, hospitalization for worsening HF, cardiac transplantation, and left ventricular assist device implantation. Cox proportional hazards analyses including clinical, noninvasive hemodynamic, and CPX variables were performed to determine their association with the composite endpoint. There were 113 events. Among CPX variables, peak oxygen uptake (VO(2)) and the minute ventilation (VE)/carbon dioxide production (VCO(2)) slope were significant predictors of risk for adverse events (age-adjusted hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.05-1.11 for both; P < .001). Among hemodynamic variables, peak cardiac index was the strongest predictor of risk (HR 1.08, 95% CI 1.0-1.16; P = .01). In a multivariate analysis including CPX and noninvasively determined hemodynamic variables, the most powerful predictive model included the combination of peak VO(2), peak cardiac index, and the VE/VCO(2) slope, with each contributing significantly and independently to predicting risk; an abnormal response for all 3 yielded an HR of 5.1 (P < .001).These findings suggest that noninvasive indices of cardiac hemodynamics complement established CPX measures in quantifying risk in patients with HF.
View details for DOI 10.1016/j.cardfail.2012.11.010
View details for Web of Science ID 000315017600006
- A Clinical Approach to Inherited Hypertrophy The Use of Family History in Diagnosis, Risk Assessment, and Management CIRCULATION-CARDIOVASCULAR GENETICS 2013; 6 (1): 118-131
Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells
CELL STEM CELL
2013; 12 (1): 101-113
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
A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure
HEART FAILURE REVIEWS
2013; 18 (1): 79-94
The objective of the study is to assess the role of cardiopulmonary exercise testing (CPX) variables, including peak oxygen consumption (VO(2)), which is the most recognized CPX variable, the minute ventilation/carbon dioxide production (VE/VCO(2)) slope, the oxygen uptake efficiency slope (OUES), and exercise oscillatory ventilation (EOV) in a current meta-analysis investigating the prognostic value of a broader list of CPX-derived variables for major adverse cardiovascular events in patients with HF. A search for relevant CPX articles was performed using standard meta-analysis methods. Of the initial 890 articles found, 30 met our inclusion criteria and were included in the final analysis. The total subject populations included were as follows: peak VO(2) (7,319), VE/VCO(2) slope (5,044), EOV (1,617), and OUES (584). Peak VO(2), the VE/VCO(2) slope and EOV were all highly significant prognostic markers (diagnostic odds ratios ≥ 4.10). The OUES also demonstrated promise as a prognostic marker (diagnostic odds ratio = 8.08) but only in a limited number of studies (n = 2). No other independent variables (including age, ejection fraction, and beta-blockade) had a significant effect on the meta-analysis results for peak VO(2) and the VE/VCO(2) slope. CPX is an important component in the prognostic assessment of patients with HF. The results of this meta-analysis strongly confirm this and support a multivariate approach to the application of CPX in this patient population.
View details for DOI 10.1007/s10741-012-9332-0
View details for Web of Science ID 000312882800007
View details for PubMedID 22733204
Cardiac Structural and Sarcomere Genes Associated With Cardiomyopathy Exhibit Marked Intolerance of Genetic Variation
2012; 5 (6): 602-610
The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation.We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute's Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of in silico algorithms to distinguish between a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected.Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.
View details for DOI 10.1161/CIRCGENETICS.112.963421
View details for Web of Science ID 000312774800008
View details for PubMedID 23074333
Prognostic value of capnography during rest and exercise in patients with heart failure.
Congestive heart failure (Greenwich, Conn.)
2012; 18 (6): 302-307
New variables obtained from cardiopulmonary exercise testing (CPX) have received attention in recent years, in particular the partial pressure of end-tidal carbon dioxide (P(ET) CO(2) ). The purpose of this study was to therefore comprehensively assess the ability of resting and exercise P(ET) CO(2) to predict major cardiac events in a heart failure (HF) cohort referred for CPX. A total of 963 patients with systolic HF undergoing symptom-limited CPX were included in the analysis. Resting and exercise P(ET) CO(2) along with other CPX variables were determined, and patients were followed for major adverse events. With regard to resting measures, multivariate analysis revealed that left ventricular ejection fraction was the most robust prognostic marker (P<.001) while resting P(ET) CO(2) added significant predictive value and was retained in the regression (P<.001). When exercise data were considered, the multivariate analysis revealed that the P(ET) CO(2) apex during exercise added predictive value and was retained (P<.05). In what is the largest evaluation of P(ET) CO(2) in the assessment of systolic HF patients to date, the authors substantiate prior (smaller) studies showing prognostic utility of P(ET) CO(2) , both as a resting measure (an important potential screening tool) and during exercise. These data add to the rationale to incorporate P(ET) CO(2) as a routine monitoring component in HF management.
View details for DOI 10.1111/j.1751-7133.2012.00296.x
View details for PubMedID 22537025
Ventilatory Power A Novel Index That Enhances Prognostic Assessment of Patients With Heart Failure
2012; 5 (5): 621-626
Minute ventilation/CO(2) production (VE/Vco(2)) slope is an index determined by cardiopulmonary exercise testing, which incorporates pertinent cardiac, pulmonary, and skeletal muscle physiology into a substantive composite assessment. The VE/Vco(2) slope has many applications, including utility as a well-validated prognostic gauge for patients with heart failure (HF). In this study, we combine VE/Vco(2) slope with systolic blood pressure, creating a novel index that we labeled ventilatory power. Ventilatory power links the combined physiology inherent in the VE/Vco(2) slope to peripheral pressure, adding an additional dimension pertinent to HF assessment. Whereas the related concept of circulatory power links peak oxygen consumption with peak systolic blood pressure as a prognostic index, we hypothesized that ventilatory power would provide greater prognostic discrimination than VE/Vco2 slope, peak oxygen consumption, and circulatory power for patients with systolic HF.Patients with systolic HF (left ventricular ejection fraction ?35%) underwent symptom-limited cardiopulmonary exercise testing as part of routine management and were followed for up to 4 years for major cardiac events (mortality, left ventricular assist device implantation, and heart transplantation). Eight hundred seventy-five patients with HF (left ventricular ejection fraction, 26±9%; mean age, 55±14) were studied. Cardiopulmonary exercise testing indices peak oxygen consumption, VE/Vco(2) slope, circulatory power, and ventilatory power were all predictive of cardiac events (P<0.001). Multivariate analysis demonstrated that ventilatory power was the strongest indicator of prognosis.Although circulatory power and traditional cardiopulmonary exercise testing parameters can be used to predict prognosis among patients with HF, ventilatory power provides relatively greater prognostic discrimination and may constitute a relatively more useful composite tool.
View details for DOI 10.1161/CIRCHEARTFAILURE.112.968529
View details for Web of Science ID 000313579500014
View details for PubMedID 22899767
In Situ Optical Mapping of Voltage and Calcium in the Heart
2012; 7 (8)
Electroanatomic mapping the interrelation of intracardiac electrical activation with anatomic locations has become an important tool for clinical assessment of complex arrhythmias. Optical mapping of cardiac electrophysiology combines high spatiotemporal resolution of anatomy and physiological function with fast and simultaneous data acquisition. If applied to the clinical setting, this could improve both diagnostic potential and therapeutic efficacy of clinical arrhythmia interventions. The aim of this study was to explore this utility in vivo using a rat model. To this aim, we present a single-camera imaging and multiple light-emitting-diode illumination system that reduces economic and technical implementation hurdles to cardiac optical mapping. Combined with a red-shifted calcium dye and a new near-infrared voltage-sensitive dye, both suitable for use in blood-perfused tissue, we demonstrate the feasibility of in vivo multi-parametric imaging of the mammalian heart. Our approach combines recording of electrophysiologically-relevant parameters with observation of structural substrates and is adaptable, in principle, to trans-catheter percutaneous approaches.
View details for DOI 10.1371/journal.pone.0042562
View details for Web of Science ID 000307184700055
View details for PubMedID 22876327
A public resource facilitating clinical use of genomes
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (30): 11920-11927
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
The Prognostic Utility of Cardiopulmonary Exercise Testing Stands the Test of Time in Patients With Heart Failure
JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION
2012; 32 (4): 198-202
While the medical management strategy for patients with heart failure (HF) has dramatically changed, cardiopulmonary exercise testing (CPX) procedures and the data obtained have remained relatively stable. We are unaware of any previous investigation that has assessed differences in the prognostic utility of CPX in HF according to time period, reflecting differences in the clinical management of systolic HF.Subjects (n = 381) underwent CPX between April 1, 1993, and December 31, 2005, and the remaining 511 were tested between January 1, 2006, and October 28, 2010. Peak oxygen uptake ((Equation is included in full-text article.)O2) and the minute ventilation/carbon dioxide production ((Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2) slope were ascertained for all tests.Both the (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slope and peak (Equation is included in full-text article.)O2 were strong univariate predictors of adverse events in both subgroups. In the multivariate analysis, the (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slope was the strongest predictive marker while peak (Equation is included in full-text article.)O2 added predictive value and was retained in the regression for all scenarios. In subjects undergoing CPX before 2006, a (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slope 45 or greater and a peak (Equation is included in full-text article.)O2 of less than 10 mL · kg · min generated a hazard ratio of 4.2 (95% CI: 1.9-9.1, P < .001) when considering only mortality as an endpoint. In subjects undergoing CPX after 2006, a (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slope 45 or greater and a peak (Equation is included in full-text article.)O2 of less than 10 mL · kg · min generated a hazard ratio of 8.2 (95% CI: 4.7-14.3, P < .001) when considering only mortality as an endpoint.The results of this study indicate that CPX continues to be a valuable clinical assessment in the present-day HF management.
View details for DOI 10.1097/HCR.0b013e318259f153
View details for Web of Science ID 000306115400005
View details for PubMedID 22760244
Prognostic Implications of Q Waves and T-Wave Inversion Associated With Early Repolarization
MAYO CLINIC PROCEEDINGS
2012; 87 (7): 614-619
To evaluate the prevalence of early polarization (ER) in a stable population and to evaluate the prognostic significance of the association or absence of Q waves or T-wave inversion (TWI).In this retrospective study performed at the university-affiliated Palo Alto Veterans Affairs Health Care Center from March 1, 1987, through December 31, 1999, we evaluated outpatient electrocardiograms. Vital status and cause of death were determined in all patients, with a mean ± SD follow-up of 7.6±3.8 years.Of the 29,281 patients, 87% were men and 13% were African American. Inferior or lateral ER was present in 664 patients (2.3%): in inferior leads in 185 (0.6%), in lateral leads in 479 (1.6%) , and in both inferior and lateral leads in 163 (0.6%). Only when Q waves or TWI accompanied ER was there an increased risk of cardiovascular death (Cox proportional hazards regression model, 5.0; 95% confidence interval, 3.4-7.2; P<.001).Common patterns of ER without concomitant Q waves or TWI are not associated with increased risk of cardiovascular death; however, when either occurs with ER, there is a hazard ratio of 5.0. These findings confirm that ER is a benign entity; however, the presence of Q waves or TWI with ER is predictive of increased cardiovascular death.
View details for DOI 10.1016/j.mayocp.2012.04.009
View details for Web of Science ID 000306872800003
View details for PubMedID 22766081
Personalized medicine: hope or hype?
EUROPEAN HEART JOURNAL
2012; 33 (13): 1564-U29
Medicine has always been personalized. For years, physicians have incorporated environmental, behavioural, and genetic factors that affect disease and drug response into patient management decisions. However, until recently, the 'genetic' data took the form of family history and self-reported race/ethnicity. As genome sequencing declines in cost, the availability of specific genomic information will no longer be limiting. Rather, our ability to parse these data and our decision whether to use it will become primary. As our understanding of genetic association with drug responses and diseases continues to improve, clinically useful genetic tests may emerge to improve upon our previous methods of assessing genetic risks. Indeed, genetic tests for monogenic disorders have already proven useful. Such changes may usher in a new era of personalized medicine. In this review, we will discuss the utility and limitations of personal genomic data in three domains: pharmacogenomics, assessment of genetic predispositions for common diseases, and identification of rare disease-causing genetic variants.
View details for DOI 10.1093/eurheartj/ehs112
View details for Web of Science ID 000306143000014
View details for PubMedID 22659199
Cell-Intrinsic Functional Effects of the alpha-Cardiac Myosin Arg-403-Gln Mutation in Familial Hypertrophic Cardiomyopathy
2012; 102 (12): 2782-2790
Human familial hypertrophic cardiomyopathy is the most common Mendelian cardiovascular disease worldwide. Among the most severe presentations of the disease are those in families heterozygous for the mutation R403Q in ?-cardiac myosin. Mice heterozygous for this mutation in the ?-cardiac myosin isoform display typical familial hypertrophic cardiomyopathy pathology. Here, we study cardiomyocytes from heterozygous 403/+ mice. The effects of the R403Q mutation on force-generating capabilities and dynamics of cardiomyocytes were investigated using a dual carbon nanofiber technique to measure single-cell parameters. We demonstrate the Frank-Starling effect at the single cardiomyocyte level by showing that cell stretch causes an increase in amplitude of contraction. Mutant 403/+ cardiomyocytes exhibit higher end-diastolic and end-systolic stiffness than +/+ cardiomyocytes, whereas active force generation capabilities remain unchanged. Additionally, 403/+ cardiomyocytes show slowed relaxation dynamics. These phenotypes are consistent with increased end-diastolic and end-systolic chamber elastance, as well as diastolic dysfunction seen at the level of the whole heart. Our results show that these functional effects of the R403Q mutation are cell-intrinsic, a property that may be a general phenomenon in familial hypertrophic cardiomyopathy.
View details for DOI 10.1016/j.bpj.2012.04.049
View details for Web of Science ID 000305546500012
View details for PubMedID 22735528
Apelin Enhances Directed Cardiac Differentiation of Mouse and Human Embryonic Stem Cells
2012; 7 (6)
Apelin is a peptide ligand for an orphan G-protein coupled receptor (APJ receptor) and serves as a critical gradient for migration of mesodermal cells fated to contribute to the myocardial lineage. The present study was designed to establish a robust cardiac differentiation protocol, specifically, to evaluate the effect of apelin on directed differentiation of mouse and human embryonic stem cells (mESCs and hESCs) into cardiac lineage. Different concentrations of apelin (50, 100, 500 nM) were evaluated to determine its differentiation potential. The optimized dose of apelin was then combined with mesodermal differentiation factors, including BMP-4, activin-A, and bFGF, in a developmentally specific temporal sequence to examine the synergistic effects on cardiac differentiation. Cellular, molecular, and physiologic characteristics of the apelin-induced contractile embryoid bodies (EBs) were analyzed. It was found that 100 nM apelin resulted in highest percentage of contractile EB for mESCs while 500 nM had the highest effects on hESCs. Functionally, the contractile frequency of mESCs-derived EBs (mEBs) responded appropriately to increasing concentration of isoprenaline and diltiazem. Positive phenotype of cardiac specific markers was confirmed in the apelin-treated groups. The protocol, consisting of apelin and mesodermal differentiation factors, induced contractility in significantly higher percentage of hESC-derived EBs (hEBs), up-regulated cardiac-specific genes and cell surface markers, and increased the contractile force. In conclusion, we have demonstrated that the treatment of apelin enhanced cardiac differentiation of mouse and human ESCs and exhibited synergistic effects with mesodermal differentiation factors.
View details for DOI 10.1371/journal.pone.0038328
View details for Web of Science ID 000305339900024
View details for PubMedID 22675543
- Systems-Based Approaches to Cardiovascular Biomarker Discovery CIRCULATION-CARDIOVASCULAR GENETICS 2012; 5 (3): 360-367
- Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS 2012; 5 (3): 368-376
Whole-Genome Sequencing in Personalized Therapeutics
CLINICAL PHARMACOLOGY & THERAPEUTICS
2012; 91 (6): 1001-1009
Eleven years since the initial drafts of the human genome were published, we have begun to see the first examples of the application of whole-genome sequencing to personalized diagnosis and therapeutics. The exponential decline in sequencing costs and the constant improvement in these technologies promise to further advance the use of a patient's full genetic profile in the clinic. However, realizing the potential benefit of such sequencing will require a concerted effort by science, medicine, law, and management. In this review, we discuss current approaches to decoding the 6 billion-letter genetic code of a whole genome in a clinical context, give current examples of translating this information into therapy-guiding knowledge, and list the challenges that will need to be surmounted before these powerful data can be fully exploited to forward the goals of personalized medicine.
View details for DOI 10.1038/clpt.2012.51
View details for Web of Science ID 000304245800018
View details for PubMedID 22549284
Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated Cardiomyopathy
SCIENCE TRANSLATIONAL MEDICINE
2012; 4 (130)
Characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure, dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy in patients. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific cellular models, investigating underlying mechanisms, and optimizing therapy. Here, we generated cardiomyocytes from iPSCs derived from patients in a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to control healthy individuals in the same family cohort, cardiomyocytes derived from iPSCs from DCM patients exhibited altered regulation of calcium ion (Ca(2+)), decreased contractility, and abnormal distribution of sarcomeric ?-actinin. When stimulated with a ?-adrenergic agonist, DCM iPSC-derived cardiomyocytes showed characteristics of cellular stress such as reduced beating rates, compromised contraction, and a greater number of cells with abnormal sarcomeric ?-actinin distribution. Treatment with ?-adrenergic blockers or overexpression of sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (Serca2a) improved the function of iPSC-derived cardiomyocytes from DCM patients. Thus, iPSC-derived cardiomyocytes from DCM patients recapitulate to some extent the morphological and functional phenotypes of DCM and may serve as a useful platform for exploring disease mechanisms and for drug screening.
View details for DOI 10.1126/scitranslmed.3003552
View details for Web of Science ID 000303045900004
View details for PubMedID 22517884
The prognostic value of early repolarization with ST-segment elevation in African Americans
2012; 9 (4): 558-565
Increased prevalence of classic early repolarization, defined as ST-segment elevation (STE) in the absence of acute myocardial injury, in African Americans is well established. The prognostic value of this pattern in different ethnicities remains controversial.Measure association between early repolarization and cardiovascular mortality in African Americans.The resting electrocardiograms of 45,829 patients were evaluated at the Palo Alto Veterans Affairs Hospital. Subjects with inpatient status or electrocardiographic evidence of acute myocardial infarction were excluded, leaving 29,281 subjects. ST-segment elevation, defined as an elevation of >0.1 mV at the end of the QRS, was electronically flagged and visually adjudicated by 3 observers blinded to outcomes. An association between ethnicity and early repolarization was measured by using multivariate logistic regression. We analyzed associations between early repolarization and cardiovascular mortality by using the Cox proportional hazards regression analysis.Subjects were 13% women and 13.3% African Americans, with an average age of 55 years and followed for an average of 7.6 years, resulting in 1995 cardiovascular deaths. There were 479 subjects with lateral STE and 185 with inferior STE. After adjustment for age, sex, heart rate, and coronary artery disease, African American ethnicity was associated with lateral or inferior STE (odds ratio 3.1; P = .0001). While lateral or inferior STE in non-African Americans was independently associated with cardiovascular death (hazard ratio 1.6; P = .02), it was not associated with cardiovascular death in African Americans (hazard ratio 0.75; P = .50).Although early repolarization is more prevalent in African Americans, it is not predictive of cardiovascular death in this population and may represent a distinct electrophysiologic phenomenon.
View details for DOI 10.1016/j.hrthm.2011.11.020
View details for Web of Science ID 000302258100020
View details for PubMedID 22094072
Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes
2012; 148 (6): 1293-1307
Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.
View details for DOI 10.1016/j.cell.2012.02.009
View details for Web of Science ID 000301889500023
View details for PubMedID 22424236
- DNA Sequencing Clinical Applications of New DNA Sequencing Technologies CIRCULATION 2012; 125 (7): 931-944
- Performance comparison of whole-genome sequencing platforms NATURE BIOTECHNOLOGY 2012; 30 (1): 78-U118
- Exercise oscillatory ventilation reflects diminished quality of life and perceived functional capacity in patients with heart failure INTERNATIONAL JOURNAL OF CARDIOLOGY 2011; 153 (2): 213-214
Early Repolarization in an Ambulatory Clinical Population
2011; 124 (20): 2208-2214
The significance of early repolarization, particularly regarding the morphology of the R-wave downslope, has come under question.We evaluated 29 281 resting ambulatory ECGs from the VA Palo Alto Health Care System. With PR interval as the isoelectric line and amplitude criteria ?0.1 mV, ST-segment elevation is defined at the end of the QRS, J wave as an upward deflection, and slur as a conduction delay on the QRS downstroke. Associations of ST-segment elevation patterns, J waves, and slurs with cardiovascular mortality were analyzed with Cox analysis. With a median follow-up of 7.6 years, there were 1995 cardiac deaths. Of 29 281 subjects, 87% were male (55±14 years) and 13% were female (56±17 years); 13% were black, 6% were Hispanic, and 81% were white or other. Six hundred sixty-four (2.3%) had inferior or lateral ST-segment elevation: 185 (0.6%) in inferior leads and 479 (1.6%) in lateral leads, 163 (0.6%) in both, and 0.4% had global elevation. A total of 4041 ECGs were analyzed with enhanced display, and 583 (14%) had J waves or slurring, which were more prevalent in those with than in those without ST-segment elevation (61% versus 13%; P<0.001). ST-segment elevation occurred more in those with than in those without J waves or slurs (12% versus 1.3%; P<0.001). Except when involving only inferior leads, all components of early repolarization were more common in young individuals, male subjects, blacks, and those with bradycardia. All patterns and components of early repolarization were associated with decreased cardiovascular mortality, but this was not significant after adjustment for age.We found no significant association between any components of early repolarization and cardiac mortality.
View details for DOI 10.1161/CIRCULATIONAHA.111.047191
View details for Web of Science ID 000297060700013
View details for PubMedID 21986288
The Impact of ST Elevation on Athletic Screening
CLINICAL JOURNAL OF SPORT MEDICINE
2011; 21 (5): 433-440
To demonstrate the prevalence and patterns of ST elevation (STE) in ambulatory individuals and athletes and compare the clinical outcomes.Retrospective cohort study. ST elevation was measured by computer algorithm and defined as ?0.1 mV at the end of the QRS complex. Elevation was confirmed, and J waves and slurring were coded visually.Veterans Affairs Palo Alto Health Care System and Stanford University varsity athlete screening evaluation.Overall, 45 829 electrocardiograms (ECGs) were obtained from the clinical patient cohort and 658 ECGs from athletes. We excluded inpatients and those with ECG abnormalities, leaving 20 901 outpatients and 641 athletes.Electrocardiogram evaluation and follow-up for vital status.All-cause and cardiovascular mortality and cardiac events.ST elevation in the anterior and lateral leads was more prevalent in men and in African Americans and inversely related to age and resting heart rate. Athletes had a higher prevalence of early repolarization even when matched for age and gender with nonathletes. ST elevation greater than 0.2 mV (2 mm) was very unusual. ST elevation was not associated with cardiac death in the clinical population or with cardiac events or abnormal test results in the athletes.Early repolarization is not associated with cardiac death and has patterns that help distinguish it from STE associated with cardiac conditions, such as myocardial ischemia or injury, pericarditis, and the Brugada syndrome.
View details for DOI 10.1097/JSM.0B013E31822CF105
View details for Web of Science ID 000294485000009
View details for PubMedID 21892017
- Interpretation of the Electrocardiogram of Young Athletes CIRCULATION 2011; 124 (6): 746-757
Hearts From DCD Donors Display Acceptable Biventricular Function After Heart Transplantation in Pigs
AMERICAN JOURNAL OF TRANSPLANTATION
2011; 11 (8): 1621-1632
Cardiac transplantation is in decline, in contrast to other solid organs where the number of solid organ transplants from donors after circulatory death (DCD) is increasing. Hearts from DCD donors are not currently utilized due to concerns that they may suffer irreversible cardiac injury with resultant poor graft function. Using a large animal model, we tested the hypothesis that hearts from DCD donors would be suitable for transplantation. Donor pigs were subjected to hypoxic cardiac arrest (DCD) followed by 15 min of warm ischemia and resuscitation on cardiopulmonary bypass, or brainstem death (BSD) via intracerebral balloon inflation. Cardiac function was assessed through load-independent measures and magnetic resonance imaging and spectroscopy. After resuscitation, DCD hearts had near normal contractility, although stroke volume was reduced, comparable to BSD hearts. DCD hearts had a significant decline in phosphocreatine and increase in inorganic phosphate during the hypoxic period, with a return to baseline levels after reperfusion. After transplantation, cardiac function was comparable between BSD and DCD groups. Therefore, in a large animal model, the DCD heart maintains viability and recovers function similar to that of the BSD heart and may be suitable for clinical transplantation. Further study is warranted on optimal reperfusion strategies.
View details for DOI 10.1111/j.1600-6143.2011.03622.x
View details for Web of Science ID 000293340900015
View details for PubMedID 21749639
Systems biology of heart failure, challenges and hopes
CURRENT OPINION IN CARDIOLOGY
2011; 26 (4): 314-321
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
The concept of ventricular reserve in heart failure and pulmonary hypertension: an old metric that brings us one step closer in our quest for prediction
CURRENT OPINION IN CARDIOLOGY
2011; 26 (2): 123-131
Ventricular reserve is emerging a strong predictor of outcome in heart failure and cardiovascular disease. Ventricular reserve is the term used to describe the extent of increase or change in ventricular function that occurs during exercise or pharmacological stress (typically with dobutamine).The interest in ventricular reserve lies in its ability to assess viability in coronary artery disease, to predict clinical outcome and response to therapy in patients with heart failure and to screen patients for early cardiovascular disease.In this paper, we will review the emerging role of ventricular reserve in heart failure and pulmonary hypertension. We will also explore the mechanisms involved in the pathophysiology of impaired ventricular reserve and discuss future directions of research in the field.
View details for DOI 10.1097/HCO.0b013e3283437485
View details for Web of Science ID 000287189400008
View details for PubMedID 21297465
Gene Coexpression Network Topology of Cardiac Development, Hypertrophy, and Failure
2011; 4 (1): 26-U129
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 Web of Science ID 000287353200014
View details for PubMedID 21127201
BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways
JOURNAL OF CELL BIOLOGY
2011; 192 (1): 171-188
We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-?-catenin (?C) and Wnt-planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt-dependent manner, induces ?C transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via ?4-integrins. ILK-1 then induces the Wnt-PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1-mediated motility. Transfection of a Dvl mutant that binds ?C without activating RhoA-Rac1 not only prevents BMP-2-mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent ?C activity. Interfering with the Dvl-dependent Wnt-PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2-mediated tandem activation of Wnt-?C and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.
View details for DOI 10.1083/jcb.201008060
View details for Web of Science ID 000287778600015
View details for PubMedID 21220513
Drug Discovery in a Multidimensional World: Systems, Patterns, and Networks
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2010; 3 (5): 438-447
Despite great strides in revealing and understanding the physiological and molecular bases of cardiovascular disease, efforts to translate this understanding into needed therapeutic interventions continue to lag far behind the initial discoveries. Although pharmaceutical companies continue to increase investments into research and development, the number of drugs gaining federal approval is in decline. Many factors underlie these trends, and a vast number of technological and scientific innovations are being sought through efforts to reinvigorate drug discovery pipelines. Recent advances in molecular profiling technologies and development of sophisticated computational approaches for analyzing these data are providing new, systems-oriented approaches towards drug discovery. Unlike the traditional approach to drug discovery which is typified by a one-drug-one-target mindset, systems-oriented approaches to drug discovery leverage the parallelism and high-dimensionality of the molecular data to construct more comprehensive molecular models that aim to model broader bimolecular systems. These models offer a means to explore complex molecular states (e.g., disease) where thousands to millions of molecular entities comprising multiple molecular data types (e.g., proteomics and gene expression) can be evaluated simultaneously as components of a cohesive biomolecular system. In this paper, we discuss emerging approaches towards systems-oriented drug discovery and contrast these efforts with the traditional, unidimensional approach to drug discovery. We also highlight several applications of these system-oriented approaches across various aspects of drug discovery, including target discovery, drug repositioning and drug toxicity. When available, specific applications to cardiovascular drug discovery are highlighted and discussed.
View details for DOI 10.1007/s12265-010-9214-6
View details for Web of Science ID 000284694700003
View details for PubMedID 20677029
Chromatin regulation by Brg1 underlies heart muscle development and disease
2010; 466 (7302): 62-U74
Cardiac hypertrophy and failure are characterized by transcriptional reprogramming of gene expression. Adult cardiomyocytes in mice primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6), whereas embryonic cardiomyocytes express beta-MHC (also known as Myh7). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. Here we show that Brg1, a chromatin-remodelling protein, has a critical role in regulating cardiac growth, differentiation and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 and suppressing p57(kip2) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylase (HDAC) and poly (ADP ribose) polymerase (PARP) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathological alpha-MHC to beta-MHC shift. Preventing Brg1 re-expression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Our studies show that Brg1 maintains cardiomyocytes in an embryonic state, and demonstrate an epigenetic mechanism by which three classes of chromatin-modifying factors-Brg1, HDAC and PARP-cooperate to control developmental and pathological gene expression.
View details for DOI 10.1038/nature09130
View details for Web of Science ID 000279343800035
View details for PubMedID 20596014
Upregulation of the apelin-APJ pathway promotes neointima formation in the carotid ligation model in mouse
2010; 87 (1): 156-165
To investigate apelin-APJ (angiotensin receptor-like 1) signalling in vascular remodelling, we have examined the pathophysiological response to carotid ligation in apelin knockout mice.Apelin null animals compared with wild-type mice had significantly decreased neointimal lesion area (1.17 +/- 0.17 vs. 3.33 +/- 1.04 x 10(4) microm(2), P < 0.05) and intima/media ratio (0.81 +/- 0.23 vs. 1.49 +/- 0.44, P < 0.05), averaged over four sites 0.5-2 mm from the ligation. Exogenous apelin infusion rescued the apelin-KO phenotype, promoting neointima formation in the null animals. Apelin null animals showed decreased smooth muscle positive area in the neointima (82.3 +/- 2.4 vs. 63.9 +/- 8.4, P < 0.05), and a smaller percentage BrdU positive cells in the neointima and media (11.06 +/- 1.00 vs. 6.53 +/- 0.86, P < 0.05). Apelin mRNA expression increased initially (5.2-fold, P < 0.01) followed by increased apelin receptor expression (10.1-fold, P < 0.05) in the ligated artery. Cytochemistry studies localized apelin expression to luminal endothelial cells and apelin receptor upregulation to smooth muscle cells (SMC) in the media and neointima. In vitro experiments with cultured rat aortic SMC revealed that apelin stimulation increased migration. In contrast to the increased expression of apelin and apelin receptor in carotid remodelling, expression was not upregulated in the apoE high fat model, and correlated with the known disease-inhibitory effect in this model.These data suggest that increased apelin receptor expression by SMC provides a paracrine pathway in injured vessels that allows endothelial-derived apelin to stimulate their division and migration into the neointima.
View details for DOI 10.1093/cvr/cvq052
View details for Web of Science ID 000278690000021
View details for PubMedID 20176814
Effect of Gender on Computerized Electrocardiogram Measurements in College Athletes
PHYSICIAN AND SPORTSMEDICINE
2010; 38 (2): 156-164
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 2010; 375 (9727): 1749-1751
Measurement Precision in the Optimization of Cardiac Resynchronization Therapy
2010; 3 (3): 395-404
Cardiac resynchronization therapy improves morbidity and mortality in appropriately selected patients. Whether atrioventricular (AV) and interventricular (VV) pacing interval optimization confers further clinical improvement remains unclear. A variety of techniques are used to estimate optimum AV/VV intervals; however, the precision of their estimates and the ramifications of an imprecise estimate have not been characterized previously.An objective methodology for quantifying the precision of estimated optimum AV/VV intervals was developed, allowing physiologic effects to be distinguished from measurement variability. Optimization using multiple conventional techniques was conducted in individual sessions with 20 patients. Measures of stroke volume and dyssynchrony were obtained using impedance cardiography and echocardiographic methods, specifically, aortic velocity-time integral, mitral velocity-time integral, A-wave truncation, and septal-posterior wall motion delay. Echocardiographic methods yielded statistically insignificant data in the majority of patients (62%-82%). In contrast, impedance cardiography yielded statistically significant results in 84% and 75% of patients for AV and VV interval optimization, respectively. Individual cases demonstrated that accepting a plausible but statistically insignificant estimated optimum AV or VV interval can result in worse cardiac function than default values.Consideration of statistical significance is critical for validating clinical optimization data in individual patients and for comparing competing optimization techniques. Accepting an estimated optimum without knowledge of its precision can result in worse cardiac function than default settings and a misinterpretation of observed changes over time. In this study, only impedance cardiography yielded statistically significant AV and VV interval optimization data in the majority of patients.
View details for DOI 10.1161/CIRCHEARTFAILURE.109.900076
View details for Web of Science ID 000277825800009
View details for PubMedID 20176716
- Defining the Limits of Athlete's Heart Implications for Screening in Diverse Populations CIRCULATION 2010; 121 (9): 1066-1068
Cost-Effectiveness of Preparticipation Screening for Prevention of Sudden Cardiac Death in Young Athletes
ANNALS OF INTERNAL MEDICINE
2010; 152 (5): 276-W91
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 Web of Science ID 000275329600002
View details for PubMedID 20194233
Addition of the Electrocardiogram to the Preparticipation Examination of College Athletes
CLINICAL JOURNAL OF SPORT MEDICINE
2010; 20 (2): 98-105
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 Web of Science ID 000275481500005
View details for PubMedID 20215891
New insights for the diagnosis and management of right ventricular failure, from molecular imaging to targeted right ventricular therapy
CURRENT OPINION IN CARDIOLOGY
2010; 25 (2): 131-140
Despite the recognition of a critical role of the right ventricle (RV) in many aspects of cardiovascular medicine, there has been surprisingly little interest in right ventricular-targeted imaging and therapeutic approaches. Compared with the left ventricle, the RV has a different embryologic origin, undergoes a dramatic change during the transition from the fetal to the adult circulation and normally operates in a low resistance or impedance arterial system. Here, we review new insights on the pathophysiology, assessment and management of right ventricular failure.Our understanding of the mechanisms underlying right ventricular failure has improved. As in the left ventricle, decrease in alpha-myosin heavy chain and a switch towards glycolysis from fatty acid oxidation is observed in the stressed RV, but the key question remains unanswered: why is the RV so much more vulnerable to failure upon afterload increase compared with the left ventricle? In assessing the RV, it is becoming increasingly important to consider the RV and pulmonary artery as a unit. New therapies that could specifically target the RV, such as metabolic modulators and phosphodiesterase type 5 inhibitors, are now being considered.A better understanding of the molecular mechanisms of right ventricular failure will lead to the development of new strategies for the diagnosis and management of right ventricular failure. Right ventricular-targeted therapies are needed in a number of diseases in which only the RV fails.
View details for DOI 10.1097/HCO.0b013e328335febd
View details for Web of Science ID 000274797100010
View details for PubMedID 20130456
A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2009; 2 (4): 381-391
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
Insights into Human beta-Cardiac Myosin Function from Single Molecule and Single Cell Studies
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2009; 2 (4): 426-440
beta-Cardiac myosin is a mechanoenzyme that converts the energy from ATP hydrolysis into a mechanical force that drives contractility in muscle. Thirty percent of the point mutations that result in hypertrophic cardiomyopathy are localized to MYH7, the gene encoding human beta-cardiac myosin heavy chain (beta-MyHC). Force generation by myosins requires a tight and highly conserved allosteric coupling between its different protein domains. Hence, the effects of single point mutations on the force generation and kinetics of beta-cardiac myosin molecules cannot be predicted directly from their location within the protein structure. Great insight would be gained from understanding the link between the functional defect in the myosin protein and the clinical phenotypes of patients expressing them. Over the last decade, several single molecule techniques have been developed to understand in detail the chemomechanical cycle of different myosins. In this review, we highlight the single molecule techniques that can be used to assess the effect of point mutations on beta-cardiac myosin function. Recent bioengineering advances have enabled the micromanipulation of single cardiomyocyte cells to characterize their force-length dynamics. Here, we briefly review single cell micromanipulation as an approach to determine the effect of beta-MyHC mutations on cardiomyocyte function. Finally, we examine the technical challenges specific to studying beta-cardiac myosin function both using single molecule and single cell approaches.
View details for DOI 10.1007/s12265-009-9129-2
View details for Web of Science ID 000284691000010
View details for PubMedID 20560001
Endogenous regulation of cardiovascular function by apelin-APJ
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2009; 297 (5): H1904-H1913
Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.
View details for DOI 10.1152/ajpheart.00686.2009
View details for Web of Science ID 000271143400045
View details for PubMedID 19767528
- The Medical Device Safety Act of 2009: Clarifying Preemption AMERICAN JOURNAL OF THERAPEUTICS 2009; 16 (6): 471-474
Electrocardiographic predictors of atrial fibrillation
AMERICAN HEART JOURNAL
2009; 158 (4): 622-628
Atrial fibrillation (AF) is the most prevalent arrhythmia in the United States and accounts for more than 750,000 strokes per year. Noninvasive predictors of AF may help identify patients at risk of developing AF. Our objective was to identify the electrocardiographic characteristics associated with onset of AF.This was a retrospective cohort analysis of 42,751 patients with electrocardiograms (ECGs) ordered by physician's discretion and analyzed using a computerized system. The population was followed for detection of AF on subsequent ECGs. Cox proportional hazard regression analysis was performed to test the association between these ECG characteristics and development of AF.For a mean follow-up of 5.3 years, 1,050 (2.4%) patients were found to have AF on subsequent ECG recordings. Several ECG characteristics, such as P-wave dispersion (the difference between the widest and narrowest P waves), premature atrial contractions, and an abnormal P axis, were predictive of AF with hazard ratio of approximately 2 after correcting for age and sex. P-wave index, the SD of P-wave duration across all leads, was one of the strongest predictors of AF with a concordance index of 0.62 and a hazard ratio of 2.7 (95% CI 2.1-3.3) for a P-wave index >35. These were among the several independently predictive markers identified on multivariate analysis.Several ECG markers are independently predictive of future onset of AF. The P index, a measurement of disorganized atrial depolarization, is one of the strongest predictors of AF. The ECG contains valuable prognostic information that can identify patients at risk of AF.
View details for DOI 10.1016/j.ahj.2009.08.002
View details for Web of Science ID 000270706100020
View details for PubMedID 19781423
- Re: A prospective randomized evaluation of VV delay optimization in CRT-D recipients: echocardiographic observations from the RHYTHM II ICD study. Pacing and clinical electrophysiology : PACE 2009; 32 (10): 1360-1361
Mechanisms of exercise intolerance in patients with hypertrophic cardiomyopathy
AMERICAN HEART JOURNAL
2009; 158 (3): E27-E34
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
The ageing athlete: screening prior to vigorous exertion in asymptomatic adults without known cardiovascular disease
BRITISH JOURNAL OF SPORTS MEDICINE
2009; 43 (9): 696-701
The exercise electrocardiogram (ECG) is widely considered the best available test for screening asymptomatic adults without known cardiovascular (CV) disease prior to initiating a vigorous exercise programme due to its prognostic value, widespread availability and low cost. Observational studies have demonstrated an increased relative risk of CV events with positive screening exercise ECG tests in men with diabetes, advanced age, or multiple cardiac risk factors. Recent observational studies have not demonstrated similar prognostic value for exercise ECG testing in asymptomatic healthy women. Despite the predictive ability of exercise ECG testing in several groups, there have been no studies demonstrating a significant impact of screening on morbidity and mortality in completely asymptomatic patients, leading to significant discordance in consensus guidelines on screening. One prospective observational study is ongoing in Italy that may for the first time demonstrate the ability to decrease incident CV events using preparticipation screening exercise ECG testing in adult athletes with targeted exclusion from athletics. Until more conclusive data is available the authors currently recommend screening exercise ECG testing in asymptomatic men with diabetes and asymptomatic men over age 45 with two or more CV risk factors prior to initiating a vigorous exercise programme. Consideration should also be given to screening asymptomatic patients younger than 45 with particularly strong risk factor exposure or elderly patients with fewer than two risk factors.
View details for DOI 10.1136/bjsm.2008.054783
View details for Web of Science ID 000270517800014
View details for PubMedID 19734505
Apelin prevents aortic aneurysm formation by inhibiting macrophage inflammation
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2009; 296 (5): H1329-H1335
Apelin is a potent inodilator with recently described antiatherogenic properties. We hypothesized that apelin might also attenuate abdominal aortic aneurysm (AAA) formation by limiting disease-related vascular wall inflammation. C57BL/6 mice implanted with osmotic pumps filled with apelin or saline were treated with pancreatic elastase to create infrarenal AAAs. Mice were euthanized for aortic PCR analysis or followed ultrasonographically and then euthanized for histological analysis. The cellular expression of inflammatory cytokines and chemokines in response to apelin was also assessed in cultured macrophages, smooth muscle cells, and fibroblasts. Apelin treatment resulted in diminished AAA formation, with a 47% reduction in maximal cross-sectional area (0.74 vs. 1.39 mm(2), P < 0.03) and a 57% reduction in macrophage infiltrate (113 vs. 261.3 cells/high-power field, P < 0.0001) relative to the saline-treated group. Apelin infusion was also associated with significantly reduced aortic macrophage colony-stimulating factor expression and decreased monocyte chemattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha mean mRNA levels. Apelin stimulation of cultured macrophages significantly reduced MCP-1 and TNF-alpha mRNA levels relative to baseline (2.03- and 1.89-fold reduction, P < 0.03, respectively) but did not affect intimal adhesion molecule expression or medial or adventitial cell cytokine production. Apelin significantly reduces aneurysm formation in the elastase model of human AAA disease. The mechanism appears to be decreased macrophage burden, perhaps related to an apelin-mediated decrease in proinflammatory cytokine and chemokine activation.
View details for DOI 10.1152/ajpheart.01341.2008
View details for Web of Science ID 000265659100020
View details for PubMedID 19304942
- Should the exercise ECG be used to screen for sudden cardiac death? EUROPEAN HEART JOURNAL 2009; 30 (5): 528-529
Statin Use and Ventricular Arrhythmias During Clinical Treadmill Testing
JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY
2009; 20 (2): 193-199
Premature ventricular complexes (PVCs) during exercise are associated with adverse prognosis, particularly in patients with intermediate treadmill test findings. Statin use reduces the incidence of resting ventricular arrhythmias in patients with coronary artery disease; however, the relationship between statin use and exercise-induced ventricular arrhythmias has not been investigated.We evaluated the association between statin use and PVCs in 1,847 heart-failure-free patients (mean age 58, 95% male) undergoing clinical exercise treadmill testing between 1997 and 2004 in the VA Palo Alto Health Care System. PVCs were quantified in beats per minute and frequent PVCs were defined as PVC rates greater than the median value (0.43 and 0.60 PVCs per minute for exercise and recovery, respectively). Propensity-adjusted logistic regression was used to evaluate the odds of developing PVCs during exercise and recovery periods associated with statin use. There were 431 subjects who developed frequent PVCs during exercise and 284 subjects had frequent recovery PVCs. After propensity score adjustment, subjects treated with statins (n = 145) had 42% lower odds of developing frequent PVCs during exercise (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.37-0.93) and 44% lower odds of developing frequent PVCs during recovery (OR 0.56, 95% CI 0.30-0.94). These effects were not modified by age, prior coronary disease, hypercholesterolemia, exercise-induced angina, or exercise capacity.Statin use was associated with reduced odds of frequent PVCs during and after clinical exercise testing in a manner independent of associations with coronary disease or ischemia in our study population.
View details for DOI 10.1111/j.1540-8167.2008.01284.x
View details for Web of Science ID 000262889000012
View details for PubMedID 18775041
A general framework for dose optimization.
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium
2009; 2009: 656-660
Dose optimization is a ubiquitous challenge in clinical practice and includes both pharmacologic and non-pharmacologic interventions. Methods for the statistical assessment of optimum dosing are lacking. We developed a generic framework for dose titration and demonstrated its application in two domains. Optimum warfarin dose was estimated from clinical titration data. In addition, cardiac pacemaker interval optimization was conducted using three conventional techniques. For both data types, optima were obtained from mathematical functions fit to the raw data. The precision of the estimated optima was quantified using bootstrapping. In pacing optimization, the observed precision varied significantly among the techniques, suggesting that impedance cardiography is superior to commonly used echocardiographic methods. The average 95% confidence interval of the estimated optimum warfarin dose was +/-18%, suggesting that titration within this range is of limited utility. By identifying statistically ineffective interventions, objective analysis of optimization data may both improve outcomes and reduce healthcare costs.
View details for PubMedID 20351936
Age and Double Product (Systolic Blood Pressure x Heart Rate) Reserve-Adjusted Modification of the Duke Treadmill Score Nomogram in Men
AMERICAN JOURNAL OF CARDIOLOGY
2008; 102 (10): 1407-1412
The Duke Treadmill Score (DTS) is an established clinical tool for risk stratification. Our aim was to determine if other variables could improve the prognostic power of the DTS and if so, to modify the DTS nomogram. From a total of 1,959 patients referred for exercise testing at the Palo Alto VA Medical Center from 1997 to 2006 (a mean follow-up of 5.4 years), we studied 1,759 male veterans (age 57 +/- 12 years) free of heart failure. Double product (DP) was calculated by multiplying systolic blood pressure and heart rate; variables and their products were subtracted to obtain the differences between at rest and maximal exercise (reserve) and recovery. Of all the hemodynamic measurements, DP reserve was the strongest predictor of cardiovascular death (CVD) (Wald Z-score -3.84, p <0.001) after adjustment for potential confounders. When the components of DTS were entered in the Cox hazard model with DP reserve and age, only DP reserve and age were chosen (p <0.00001). Using the Cox coefficients, a score calculated by [age - DTS - 3 x (DP reserve/1,000)] yielded an area under the curve of 0.84 compared with 0.76 for the DTS. Using this equation, a nomogram was constructed by adding age and DP reserve to the original DTS nomogram improving estimation of annual CVD. In conclusion, we propose an age and DP reserve-adjusted DTS nomogram that improves the prognostic estimates of average annual CVD over the DTS alone.
View details for DOI 10.1016/j.amjcard.2008.07.020
View details for Web of Science ID 000261194000023
View details for PubMedID 18993164
Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis
JOURNAL OF CLINICAL INVESTIGATION
2008; 118 (10): 3343-3354
Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function and a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. Here we investigated whether the apelin-APJ pathway can directly antagonize vascular disease-related Ang II actions. In ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II-mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II-mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling.
View details for DOI 10.1172/JCI34871
View details for Web of Science ID 000259828600016
View details for PubMedID 18769630
Progressive dyspnea after CABG: Complication of retained epicardial pacing wires
ANNALS OF THORACIC SURGERY
2008; 86 (4): 1352-1354
We report a case of progressive dyspnea and recurrent pneumonia after uneventful coronary artery bypass graft surgery caused by migration of retained epicardial pacing wires into the right upper lobe of the lung. Removal of the wires by open thoracotomy resulted in significant improvement in dyspnea and near complete resolution of the bronchiectasis and consolidation.
View details for DOI 10.1016/j.athoracsur.2008.03.013
View details for Web of Science ID 000259848000044
View details for PubMedID 18805194
Low-dose growth hormone is cardioprotective in uremia
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2008; 19 (9): 1774-1783
Growth hormone (GH) is required to maintain normal cardiac structure and function and has a positive effect on cardiac remodeling in experimental and possibly human disease. Cardiac resistance to GH develops in the uremic state, perhaps predisposing to the characteristic cardiomyopathy associated with uremia. It was hypothesized that administration of low-dosage GH may have a salutary effect on the cardiac remodeling process in uremia, but because high levels of GH have adverse cardiac effects, administration of high-dosage GH may worsen uremic cardiomyopathy. In rats with chronic renal failure, quantitative cardiac morphology revealed a decrease in total capillary length and capillary length density and an increase in mean intercapillary distance and fibroblast volume density evident. Low-dosage GH prevented these changes. Collagen and TGF-beta immunostaining, increased in chronic renal failure, were also reduced by GH, suggesting a mechanism for its salutary action. Low-dosage GH also prevented thickening of the carotid artery but did not affect aortic pathology. In contrast, high-dosage GH worsened several of these variables. These results suggest that low-dosage GH may benefit the heart and possibly the carotid arteries in chronic renal failure.
View details for DOI 10.1681/ASN.2007121386
View details for Web of Science ID 000259167000021
View details for PubMedID 18650479
Genetics of Arrhythmia: Disease Pathways Beyond Ion Channels
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2008; 1 (2): 155-165
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
Does size matter? Clinical applications of scaling cardiac size and function for body size
2008; 117 (17): 2279-2287
Extensive evidence is available that cardiovascular structure and function, along with other biological properties that span the range of organism size and speciation, scale with body size. Although appreciation of such factors is commonplace in pediatrics, cardiovascular measurements in the adult population, with similarly wide variation in body size, are rarely corrected for body size. In this review, we describe the critical role of body size measurements in cardiovascular medicine. Using examples, we illustrate the confounding effects of body size. Current cardiovascular scaling practices are reviewed, as are limitations and alternative relationships between body and cardiovascular dimensions. The experimental evidence, theoretical basis, and clinical application of scaling of various functional parameters are presented. Appropriately scaled parameters aid diagnostic and therapeutic decision making in specific disease states such as hypertrophic cardiomyopathy and congestive heart failure. Large-scale studies in clinical populations are needed to define normative relationships for this purpose. Lack of appropriate consideration of body size in the evaluation of cardiovascular structure and function may adversely affect recognition and treatment of cardiovascular disease states in the adult patient.
View details for DOI 10.1161/CIRCULATIONAHA.107.736785
View details for Web of Science ID 000255394300014
View details for PubMedID 18443249
Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2008; 1 (1): 25-36
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
Ventricular arrhythmias during clinical treadmill testing and prognosis
ARCHIVES OF INTERNAL MEDICINE
2008; 168 (2): 225-234
Although exercise-associated ventricular arrhythmias are frequently observed during exercise testing, their prognostic significance remains uncertain. Therefore, we aimed to evaluate the clinical correlates and prognostic significance of exercise-associated premature ventricular complexes (PVCs) during and after exercise testing.We studied 1847 heart failure-free patients who underwent clinical treadmill testing between March 13, 1997, and January 15, 2004, in the Veterans Affairs Palo Alto Health Care System. Logistic regression was used to evaluate the clinical and exercise test associations of exercise and recovery PVCs. Propensity score-adjusted Cox survival analyses were used to evaluate the prognostic significance of exercise-associated PVCs.Of the 1847 subjects, 850 (46.0%) developed exercise PVCs (median rate, 0.43 per minute) and 620 (33.6%) had recovery PVCs (median rate, 0.60 per minute). Resting PVCs, age, and systolic blood pressure were key predictors of both exercise and recovery PVCs. Whereas exercise PVCs were related to the heart rate increase with exercise, recovery PVCs were related to coronary disease (previous myocardial infarction, coronary revascularization procedure, or pathological Q waves on resting electrocardiogram) and ST-segment depression. During a 5.4-year mean follow-up, 161 subjects (8.7%) died, and 53 of these deaths (32.9%) were due to cardiovascular causes. Recovery PVCs, but not exercise PVCs, were associated with 71% to 96% greater propensity-adjusted mortality rates (hazard ratio, 1.96 [95% confidence interval, 1.31-2.91] for infrequent PVCs; hazard ratio, 1.71 [95% confidence interval, 1.07-2.73] for frequent PVCs compared with subjects without PVCs), and occurrence of recovery PVCs reclassified 33.2% of subjects with intermediate-risk Duke Treadmill Scores into higher-risk subgroups.In our heart failure-free population, recovery PVCs were associated with increased mortality and augmented established risk markers.
View details for Web of Science ID 000252593800018
View details for PubMedID 18227372
Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease
AMERICAN HEART JOURNAL
2007; 154 (6): 1043-1051
The aim of this study was to assess systematic differences between patients with acute myocardial infarction (MI) and patients with stable angina in matrix metalloproteinase (MMP) circulating levels and genetic polymorphisms.We identified adults in a large integrated health care delivery system whose initial clinical presentation of coronary disease was either an acute MI or stable exertional angina. A total of 909 patients with acute MI, 466 patients with stable angina, and 1023 healthy older control subjects were genotyped. Serum levels of pro-MMP1, MMP2, MMP3, MMP9, and MMP10 were measured in 199 randomly selected patients from each group.At a median of 15 weeks after initial clinical presentation, higher circulating levels of MMP2 and MMP9 were independently associated with acute MI after statistical adjustment for conventional risk factors, hs-CRP levels, and cardiac medications. By contrast, none of the polymorphisms in MMP1, MMP2, MMP3, MMP9, or MMP10 was significantly associated with either acute MI compared with angina, or with coronary disease compared with controls.Circulating levels of MMP2 and MMP9 are independently associated with development of an acute MI rather than stable angina as the initial clinical presentation of coronary artery disease.
View details for DOI 10.1016/j.ahj.2007.06.042
View details for Web of Science ID 000251396200007
View details for PubMedID 18035073
Frontiers in nephrology: Genomic approaches to understanding the molecular basis of atherosclerosis
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2007; 18 (11): 2853-2862
Atherosclerosis is a complex multicellular disease that is responsible for pathology in various organ systems. The understanding of its initiation and progression has been enhanced in recent years by the application of high-throughput genomic tools such as the microarray. Increasing in genomic coverage, such tools allow a view of the disease unaffected by previous conjecture as to the primary signal of interest. New statistical tools and pathway modeling techniques have established definitively for the first time the central role of inflammation in this process. This article reviews the genomic literature relating to atherosclerosis from cell culture, animal models, and human tissues. In this comparison of these differing approaches, the available data are synthesized to reach a new understanding of the complex interplay between vascular wall and immune system components.
View details for DOI 10.1681/ASN.2007040514
View details for Web of Science ID 000250737600012
View details for PubMedID 17942952
Emerging role of the apelin system in cardiovascular homeostasis
BIOMARKERS IN MEDICINE
2007; 1 (1): 37-43
The angiotensin receptor-like 1 (APJ) and its novel ligand, apelin, share similarities in structure and anatomical distribution with that of angiotensin II and the angiotensin II type 1 receptor. However, apelin has positive inotropic, vasodilatory and diuretic properties. Differential expression and synthesis of apelin and the APJ receptor in normal and failing hearts suggest that the apelin system may contribute to the pathophysiology of human heart failure and has potential therapeutic use in treatment of heart failure.
View details for DOI 10.2217/175203184.108.40.206
View details for Web of Science ID 000252123800012
View details for PubMedID 20477459
Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2007; 292 (5): H2106-H2118
The db/db mouse is a well-established model of diabetes. Previous reports have documented contractile dysfunction (i.e., cardiomyopathy) in these animals, although the extant literature provides limited insights into cardiac structure and function as they change over time. To better elucidate the natural history of cardiomyopathy in db/db mice, we performed cardiac magnetic resonance (CMR) scans on these animals. CMR imaging was conducted with a 4.7-T magnet on female db/db mice and control db/+ littermates at 5, 9, 13, 17, and 22 wk of age. Gated gradient echo sequences were used to obtain cineographic short-axis slices from apex to base. From these images left ventricular (LV) mass (LVM), wall thickness, end-diastolic volume (LVEDV), and ejection fraction (LVEF) were determined. Additionally, cardiac [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET scanning, pressure-volume loops, and real-time quantitative PCR on db/db myocardium were performed. Relative to control, db/db mice developed significant increases in LVM and wall thickness as early as 9 wk of age. LVEDV diverged slightly later, at 13 wk. Interestingly, compared with the baseline level, LVEF in the db/db group did not decrease significantly until 22 wk. Additionally, [(18)F]FDG metabolic imaging showed a 40% decrease in glucose uptake in db/db mice. Furthermore, contractile dysfunction was observed in 15-wk db/db mice undergoing pressure-volume loops. Finally, real-time quantitative PCR revealed an age-dependent recapitulation of the fetal gene program, consistent with a myopathic process. In summary, as assessed by CMR, db/db mice develop characteristic structural and functional changes consistent with cardiomyopathy.
View details for DOI 10.1152/ajpheart.00856.2006
View details for Web of Science ID 000247777200012
View details for PubMedID 17122193
Prognostic value of heart rate increase at onset of exercise testing
2007; 115 (4): 468-474
The initial response of heart rate to dynamic exercise has been proposed as having prognostic value in limited studies that have used modalities other than the treadmill. Our aim was to evaluate the prognostic value of early heart rate parameters in patients referred for routine clinical treadmill testing.The heart rate rise at the onset of exercise was measured in 1959 patients referred for clinical treadmill testing at the Palo Alto (Calif) Veterans Affairs Medical Center from 1997 to 2004. Multivariable Cox survival analysis was performed for 197 all-cause and 74 cardiovascular deaths that accrued during a mean follow-up of 5.4+/-2.1 years. Decreased heart rate changes at all initial relative exercise workloads were associated with significantly increased all-cause mortality. The heart rate rise at one-third total exercise capacity, however, was the only early heart rate variable that significantly predicted both all-cause and cardiovascular risk after adjustment for confounders. Failing to reach 1 SD in the heart rate rise at one-third total exercise capacity was associated with a 28% increased all-cause mortality rate (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001) and a 35% cardiovascular mortality rate (hazard ratio, 0.65; 95% CI, 0.49 to 0.86; P=0.003). Of all heart rate measurements considered (initial and recovery), the heart rate increase at peak exercise was the most powerful predictor of cardiovascular prognosis after adjustment for potential confounders. The Duke treadmill score, however, was superior to all heart rate measurements in the prediction of cardiovascular mortality.In the present study population, a rapid initial heart rate rise was associated with improved survival, but the heart rate increase at peak exercise and other conventional measurements such as exercise capacity and the Duke treadmill score were more powerful predictors of prognosis.
View details for DOI 10.1161/CIRCULATIONAHA.106.666388
View details for Web of Science ID 000243853400010
View details for PubMedID 17242274
Emerging therapies for the management of decompensated heart failure - From bench to bedside
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2006; 48 (12): 2397-2409
While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart failure, this has not been matched by similar success in decompensated heart failure syndromes. Despite outstanding issues over definitions and end points, we argue in this paper that an unprecedented wealth of pharmacologic innovation may soon transform the management of these challenging patients. Agents that target contractility, such as cardiac myosin activators and novel adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote free water excretion without compromising renal function and may simultaneously inhibit myocardial remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production from free fatty acids to glucose, a unique and conceptually appealing approach to the management of heart failure. These advances allow optimism not only for the advancement of our understanding and management of decompensated heart failure syndromes but for the translational research effort in heart failure biology in general.
View details for DOI 10.1016/j.jacc.2006.08.039
View details for Web of Science ID 000242916100001
View details for PubMedID 17174176
Network analysis of human in-stent restenosis
2006; 114 (24): 2644-2654
Recent successes in the treatment of in-stent restenosis (ISR) by drug-eluting stents belie the challenges still faced in certain lesions and patient groups. We analyzed human coronary atheroma in de novo and restenotic disease to identify targets of therapy that might avoid these limitations.We recruited 89 patients who underwent coronary atherectomy for de novo atherosclerosis (n=55) or in-stent restenosis (ISR) of a bare metal stent (n=34). Samples were fixed for histology, and gene expression was assessed with a dual-dye 22,000 oligonucleotide microarray. Histological analysis revealed significantly greater cellularity and significantly fewer inflammatory infiltrates and lipid pools in the ISR group. Gene ontology analysis demonstrated the prominence of cell proliferation programs in ISR and inflammation/immune programs in de novo restenosis. Network analysis, which combines semantic mining of the published literature with the expression signature of ISR, revealed gene expression modules suggested as candidates for selective inhibition of restenotic disease. Two modules are presented in more detail, the procollagen type 1 alpha2 gene and the ADAM17/tumor necrosis factor-alpha converting enzyme gene. We tested our contention that this method is capable of identifying successful targets of therapy by comparing mean significance scores for networks generated from subsets of the published literature containing the terms "sirolimus" or "paclitaxel." In addition, we generated 2 large networks with sirolimus and paclitaxel at their centers. Both analyses revealed higher mean values for sirolimus, suggesting that this agent has a broader suppressive action against ISR than paclitaxel.Comprehensive histological and gene network analysis of human ISR reveals potential targets for directed abrogation of restenotic disease and recapitulates the results of clinical trials of existing agents.
View details for DOI 10.1161/CIRCULATIONAHA.106.637025
View details for Web of Science ID 000243477800015
View details for PubMedID 17145989
- Opposing cardiovascular roles for the angiotensin and apelin signaling pathways JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 2006; 41 (5): 778-781
Perioperative cardiac risk: pathophysiology, assessment and management.
Expert review of cardiovascular therapy
2006; 4 (5): 731-743
Cardiac complications are the leading cause of perioperative morbidity and mortality following noncardiac surgery. The annual cost of perioperative cardiovascular events exceeds 20 billion US dollars. A strategic preoperative evaluation holds the potential to reduce perioperative cardiac events and healthcare costs; however, our current understanding of the pathophysiological basis of postoperative acute coronary syndromes is limited. Although significant advances continue to facilitate early and reliable noninvasive detection of high-risk coronary anatomy, the most appropriate interventions remain unclear. Pharmacotherapy, revascularization, safer anesthesia and early detection of perioperative heart failure may all reduce perioperative morbidity and mortality, although the evidence base is incomplete and controversial. A close working relationship between the primary care physician, cardiologist, surgeon and anesthesiologist will facilitate rational, tailored and optimized management decisions that constitute our best opportunity to reduce perioperative cardiovascular risk.
View details for PubMedID 17081095
Angiotensin-converting enzyme genotype predicts cardiac and autonomic responses to prolonged exercise
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2006; 48 (3): 523-531
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 Web of Science ID 000239401500017
View details for PubMedID 16875979
Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure
EUROPEAN JOURNAL OF HEART FAILURE
2006; 8 (4): 355-360
Apelin, the novel endogenous ligand for the G-protein-coupled receptor APJ, has shown positive inotropic, vasodilatory and diuretic properties in animal studies. Differential expression and synthesis of apelin and APJ receptors have been observed in normal and failing human hearts, suggesting a possible role in cardiovascular homeostasis. Changes in plasma apelin concentrations in relation to heart failure have been described in small studies with conflicting results. Our aim was to evaluate plasma apelin concentrations in a large cohort of patients with chronic heart failure (CHF) across a broad spectrum of disease severity.Plasma apelin concentrations were measured in 202 patients with CHF secondary to left ventricular systolic dysfunction and 22 age-matched controls. Plasma apelin concentrations were significantly lower in patients with CHF, irrespective of NYHA class, ejection fraction or aetiology when compared to age-matched controls (0.85 [0.53-2.04] versus 3.76 [0.85-5.13] ng/ml, p<0.001). Apelin concentrations were correlated with peak VO(2) and right ventricular ejection fraction, but not with age, sex, body mass index, renal function or NT-proBNP concentrations.Plasma apelin concentrations are decreased in patients with CHF. The Apelin-APJ signaling pathway may be a potentially important mediator in the pathophysiological processes of heart failure and may therefore have potential therapeutic implications.
View details for DOI 10.1016/j.ejheart.2005.10.007
View details for Web of Science ID 000238750400004
View details for PubMedID 16464638
Pathway analysis of coronary atherosclerosis
2005; 23 (1): 103-118
Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected "nexus" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.
View details for DOI 10.1152/physiolgenomics.00101.2005
View details for Web of Science ID 000232065200012
View details for PubMedID 15942018
Signature patterns of gene expression in mouse atherosclerosis and their correlation to human coronary disease
2005; 22 (2): 213-226
The propensity for developing atherosclerosis is dependent on underlying genetic risk and varies as a function of age and exposure to environmental risk factors. Employing three mouse models with different disease susceptibility, two diets, and a longitudinal experimental design, it was possible to manipulate each of these factors to focus analysis on genes most likely to have a specific disease-related function. To identify differences in longitudinal gene expression patterns of atherosclerosis, we have developed and employed a statistical algorithm that relies on generalized regression and permutation analysis. Comprehensive annotation of the array with ontology and pathway terms has allowed rigorous identification of molecular and biological processes that underlie disease pathophysiology. The repertoire of atherosclerosis-related immunomodulatory genes has been extended, and additional fundamental pathways have been identified. This highly disease-specific group of mouse genes was combined with an extensive human coronary artery data set to identify a shared group of genes differentially regulated among atherosclerotic tissues from different species and different vascular beds. A small core subset of these differentially regulated genes was sufficient to accurately classify various stages of the disease in mouse. The same gene subset was also found to accurately classify human coronary lesion severity. In addition, this classifier gene set was able to distinguish with high accuracy atherectomy specimens from native coronary artery disease vs. those collected from in-stent restenosis lesions, thus identifying molecular differences between these two processes. These studies significantly focus efforts aimed at identifying central gene regulatory pathways that mediate atherosclerotic disease, and the identification of classification gene sets offers unique insights into potential diagnostic and therapeutic strategies in atherosclerotic disease.
View details for DOI 10.1152/physiolgenomics.00001.2005
View details for Web of Science ID 000230987900011
View details for PubMedID 15870398
Preoperative cardiac evaluation: mechanisms, assessment, and reduction of risk.
Thoracic surgery clinics
2005; 15 (2): 263-275
The changing paradigm in cardiovascular disease in which atherosclerotic lesions exist in a spectrum of stable to unstable, the lack of a perfect prediction tool, and the paucity of randomized controlled data on appropriate intervention make protection of cardiac patients undergoing thoracic surgery challenging. Nociception-related sympathetic drive combines with inflammatory stimuli and the cardiodepressant effects of anesthesia to create a window of maximum risk in the early postoperative period (8-24 hours), and although multivariate models have shown that a combination of surgery-specific risk, patient-specific cardiovascular history, and estimated functional capacity best determine the need for further investigation, the optimal choice of investigation is unclear. Exercise or dobutamine stress echocardiography provide the best validated investigations, and in the case of poor images, dobutamine MR imaging is increasingly used. When disease is found, medical and interventional options are available. PCI is often used, but the risk of converting a stable flow-limiting lesion into a less stable non-flow-limiting lesion must be considered, along with a delay for anti-platelet therapy and endothelialization of the stent. Alternatively, medical protection with acute beta-blockade or alpha2-agonists reduces risk (although beta-blockade often is avoided in chronic lung disease, even nonselective agents are safe in patients with non-airways reactive COPD). In addition, it is likely that statin use reduces risk, probably by stabilizing plaques, but patients with cardiac risk are increasingly likely to be taking this medication already. The assessment and management of cardiac risk in the perioperative thoracic surgery patient is challenging. With focused, rational, and individually tailored management; tight monitoring of postoperative pain; and a close working relationship between the surgeon, anesthesiologist, and cardiologist, patient care can be optimized, and risk can be effectively controlled.
View details for PubMedID 15999524
Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2005; 25 (2): 302-308
Different strains of inbred mice exhibit different susceptibility to the development of atherosclerosis. The C3H/HeJ and C57Bl/6 mice have been used in several studies aimed at understanding the genetic basis of atherosclerosis. Under controlled environmental conditions, variations in susceptibility to atherosclerosis reflect differences in genetic makeup, and these differences must be reflected in gene expression patterns that are temporally related to the development of disease. In this study, we sought to identify the genetic pathways that are differentially activated in the aortas of these mice.We performed genome-wide transcriptional profiling of aortas from C3H/HeJ and C57Bl/6 mice. Differences in gene expression were identified at baseline as well as during normal aging and longitudinal exposure to high-fat diet. The significance of these genes to the development of atherosclerosis was evaluated by observing their temporal pattern of expression in the well-studied apolipoprotein E model of atherosclerosis.Gene expression differences between the 2 strains suggest that aortas of C57Bl/6 mice have a higher genetic propensity to develop inflammation in response to appropriate atherogenic stimuli. This study expands the repertoire of factors in known disease-related signaling pathways and identifies novel candidate genes for future study. To gain insights into the molecular pathways that are differentially activated in strains of mice with varied susceptibility to atherosclerosis, we performed comprehensive transcriptional profiling of their vascular wall. Genes identified through these studies expand the repertoire of factors in disease-related signaling pathways and identify novel candidate genes in atherosclerosis.
View details for DOI 10.1161/011.ATV.0000151372.86863.a5
View details for Web of Science ID 000226594000009
View details for PubMedID 15550693
The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo
2005; 65 (1): 73-82
The endogenous peptide apelin is differentially regulated in cardiovascular disease but the nature of its role in cardiac function remains unclear.We investigated the functional relevance of this peptide using ECG and respiration gated magnetic resonance imaging, conductance catheter pressure-volume hemodynamic measurements, and echocardiography in vivo. In addition, we carried out histology and immunohistochemistry to assess cardiac hypertrophy and to localize apelin and APJ in the adult and embryonic mouse heart.Intraperitoneal injection of apelin (300 microg/kg) resulted in a decrease in left ventricular end diastolic area (pre: 0.122+/-0.007; post: 0.104+/-0.005 cm(2), p=0.006) and an increase in heart rate (pre: 537+/-20; post: 559+/-19 beats per minute, p=0.03). Hemodynamic measurements revealed a marked increase in ventricular elastance (pre: 3.7+/-0.9; post: 6.5+/-1.4 mm Hg/RVU, p=0.018) and preload recruitable stroke work (pre: 27.4+/-8.0; post: 51.8+/-3.1, p=0.059) with little change in diastolic parameters following acute infusion of apelin. Chronic infusion (2 mg/kg/day) resulted in significant increases in the velocity of circumferential shortening (baseline: 5.36+/-0.401; 14 days: 6.85+/-0.358 circ/s, p=0.049) and cardiac output (baseline: 0.142+/-0.019; 14 days: 0.25+/-0.019 l/min, p=0.001) as determined by 15 MHz echocardiography. Post-mortem corrected heart weights were not different between apelin and saline groups (p=0.5) and histology revealed no evidence of cellular hypertrophy in the apelin group (nuclei per unit area, p=0.9). Immunohistochemistry studies revealed APJ staining of myocardial cells in all regions of the adult mouse heart. Antibody staining, as well as quantitative real time polymerase chain reaction identified expression of both APJ and apelin in embryonic myocardium as early as embryonic day 13.5.Apelin reduces left ventricular preload and afterload and increases contractile reserve without evidence of hypertrophy. These results associate apelin with a positive hemodynamic profile and suggest it as an attractive target for pharmacotherapy in the setting of heart failure.
View details for DOI 10.1016/j.cardiores.2004.08.018
View details for Web of Science ID 000226477600011
View details for PubMedID 15621035
Transcriptional profiling of in vitro smooth muscle cell differentiation identifies specific patterns of gene and pathway activation
2004; 19 (3): 292-302
Mesodermal and epidermal precursor cells undergo phenotypic changes during differentiation to the smooth muscle cell (SMC) lineage that are relevant to pathophysiological processes in the adult. Molecular mechanisms that underlie lineage determination and terminal differentiation of this cell type have received much attention, but the genetic program that regulates these processes has not been fully defined. Study of SMC differentiation has been facilitated by development of the P19-derived A404 embryonal cell line, which differentiates toward this lineage in the presence of retinoic acid and allows selection for cells adopting a SMC fate through a differentiation-specific drug marker. We sought to define global alterations in gene expression by studying A404 cells during SMC differentiation with oligonucleotide microarray transcriptional profiling. Using an in situ 60-mer array platform with more than 20,000 mouse genes derived from the National Institute on Aging clone set, we identified 2,739 genes that were significantly upregulated after differentiation was completed (false-detection ratio <1). These genes encode numerous markers known to characterize differentiated SMC, as well as many unknown factors. We further characterized the sequential patterns of gene expression during the differentiation time course, particularly for known transcription factor families, providing new insights into the regulation of the differentiation process. Changes in genes associated with specific biological ontology-based pathways were evaluated, and temporal trends were identified for functional pathways. In addition to confirming the utility of the A404 model, our data provide a large-scale perspective of gene regulation during SMC differentiation.
View details for DOI 10.1152/physiolgenomics.00148.2004
View details for Web of Science ID 000225840800007
View details for PubMedID 15340120
Electrocardiographic arrhythmia risk testing
CURRENT PROBLEMS IN CARDIOLOGY
2004; 29 (7): 365-432
Among the most compelling challenges facing cardiologists today is identification of which patients are at highest risk for sudden death. Automatic implantable cardioverter-defibrillators are now indicated in many of these patients, yet the role of noninvasive risk stratification in classifying patients at high risk is not well defined. The purpose of this review is to evaluate the various electrocardiographic (ECG) techniques that appear to have potential in assessment of risk for arrhythmia. The resting ECG (premature ventricular contractions, QRS duration, damage scores, QT dispersion, and ST segment and T wave abnormalities), T wave alternans, late potentials identified on signal-averaged ECGs, and heart rate variability are explored. Unequivocal evidence to support the widespread use of any single noninvasive technique is lacking; further research in this area is needed. It is likely that a combination of risk evaluation techniques will have the greatest predictive power in enabling identification of patients most likely to benefit from device therapy.
View details for DOI 10.1016/j.cpcardiol.2004.02.007
View details for Web of Science ID 000222170600002
View details for PubMedID 15192691
Nitric oxide control of cardiac function: is neuronal nitric oxide synthase a key component?
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
2004; 359 (1446): 1021-1044
Nitric oxide (NO) has been shown to regulate cardiac function, both in physiological conditions and in disease states. However, several aspects of NO signalling in the myocardium remain poorly understood. It is becoming increasingly apparent that the disparate functions ascribed to NO result from its generation by different isoforms of the NO synthase (NOS) enzyme, the varying subcellular localization and regulation of NOS isoforms and their effector proteins. Some apparently contrasting findings may have arisen from the use of non-isoform-specific inhibitors of NOS, and from the assumption that NO donors may be able to mimic the actions of endogenously produced NO. In recent years an at least partial explanation for some of the disagreements, although by no means all, may be found from studies that have focused on the role of the neuronal NOS (nNOS) isoform. These data have shown a key role for nNOS in the control of basal and adrenergically stimulated cardiac contractility and in the autonomic control of heart rate. Whether or not the role of nNOS carries implications for cardiovascular disease remains an intriguing possibility requiring future study.
View details for DOI 10.1098/rstb.2004.1477
View details for Web of Science ID 000222444800012
View details for PubMedID 15306414
- Cardiology Explained ISBN: 1901346226 2004
Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction
2003; 108 (12): 1432-1439
Apelin is among the most potent stimulators of cardiac contractility known. However, no physiological or pathological role for apelin-angiotensin receptor-like 1 (APJ) signaling has ever been described.We performed transcriptional profiling using a spotted cDNA microarray with 12 814 unique clones on paired samples of left ventricle obtained before and after placement of a left ventricular assist device in 11 patients. The significance analysis of microarrays and a novel rank consistency score designed to exploit the paired structure of the data confirmed that natriuretic peptides were among the most significantly downregulated genes after offloading. The most significantly upregulated gene was the G-protein-coupled receptor APJ, the specific receptor for apelin. We demonstrate here using immunoassay and immunohistochemical techniques that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading. These findings imply an important paracrine signaling pathway in the heart. We additionally extend the clinical significance of this work by reporting for the first time circulating human apelin levels and demonstrating increases in the plasma level of apelin in patients with left ventricular dysfunction.The apelin-APJ signaling pathway emerges as an important novel mediator of cardiovascular control.
View details for DOI 10.1161/01.CIR.0000091235.94914.75
View details for Web of Science ID 000185467400005
View details for PubMedID 12963638
Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling
2003; 92 (5): E52-E59
A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.
View details for DOI 10.1161/01.RES.0000064585.95749.6D
View details for Web of Science ID 000181711300017
View details for PubMedID 12623875
Exercise testing scores as an example of better decisions through science
MEDICINE AND SCIENCE IN SPORTS AND EXERCISE
2002; 34 (8): 1391-1398
The application of common statistical techniques to clinical and exercise test data has the potential to become a useful tool for assisting in the diagnosis of coronary artery disease, assessing prognosis, and reducing the cost of evaluating patients with suspected coronary disease. Since general practitioners function as gatekeepers and decide which patients must be referred to the cardiologist, they need to optimally use the basic tools they have available (i.e., history, physical exam, and the exercise test).Review of the literature with a focus on the scientific techniques for aiding the decision-making process.Scores derived from multivariable statistical techniques considering clinical and exercise data have demonstrated superior discriminating power when compared using receiver-operating-characteristic curves with the ST segment response. In addition, by stratifying patients as to probability of disease and prognosis, they provide a management strategy. While computers as part of information management systems can calculate complicated equations to provide scores, physicians are reluctant to trust them. Thus, these scores have been represented as nomograms or simple additive tables so physicians are comfortable with their application. Scores have also been compared with physician judgment and been found to estimate the presence of coronary disease and prognosis as well as expert cardiologists, and often better than nonspecialists.Multivariate scores can empower the clinician to assure the cardiac patient with access to appropriate and cost-effective cardiological care.
View details for Web of Science ID 000177291000023
View details for PubMedID 12165697
Cardiac nitric oxide synthase 1 regulates basal and beta-adrenergic contractility in murine ventricular myocytes
2002; 105 (25): 3011-3016
Evidence indicates that myocardial NO production can modulate contractility, but the source of NO remains uncertain. Here, we investigated the role of a type 1 NO synthase isoform (NOS1), which has been recently localized to the cardiac sarcoplasmic reticulum, in the regulation of basal and beta-adrenergic myocardial contraction.Contraction was assessed in left ventricular myocytes isolated from mice with NOS1 gene disruption (NOS1(-/-) mice) and their littermate controls (NOS1(+/+) mice) at 3 stimulation frequencies (1, 3, and 6 Hz) in basal conditions and during beta-adrenergic stimulation with isoproterenol (2 nmol/L). In addition, we examined the effects of acute specific inhibition of NOS1 with vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO, 500 micromol/L). NOS1((-/-)) myocytes exhibited greater contraction at all frequencies (percent cell shortening at 6 Hz, 10.7+/-0.92% in NOS1(-/-) myocytes versus 7.21+/-0.8% in NOS1(+/+) myocytes; P<0.05) with a flat frequency-contraction relationship. Time to 50% relaxation was increased in NOS1(-/-) myocytes at all frequencies (at 6 Hz, 26.53+/-1.4 ms in NOS1(-/-) myocytes versus 21.27+/-1.3 ms in NOS1(+/+) myocytes; P<0.05). L-VNIO prolonged time to 50% relaxation at all frequencies (at 6 Hz, 21.28+/-1.7 ms in NOS1(+/+) myocytes versus 26.45+/-1.4 ms in NOS1(+/+)+L-VNIO myocytes; P<0.05) but did not significantly increase basal contraction. However, both NOS1(-/-) myocytes and NOS1(+/+) myocytes treated with L-VNIO showed a greatly enhanced contraction in response to beta-adrenergic stimulation (percent increase in contraction at 6 Hz, 25.2+/-10.8 in NOS1(+/+) myocytes, 68.2+/-11.2 in NOS1(-/-) myocytes, and 65.1+/-13.2 in NOS1(+/+)+L-VNIO myocytes; P<0.05).NOS1 disruption enhances basal contraction and the inotropic response to beta-adrenergic stimulation in murine ventricular myocytes. These findings indicate that cardiac NOS1-derived NO plays a significant role in the autocrine regulation of myocardial contractility.
View details for DOI 10.1161/01.CIR.0000019516.31040.2D
View details for Web of Science ID 000176818800026
View details for PubMedID 12081996
Diagnosing coronary artery disease in diabetic patients
DIABETES-METABOLISM RESEARCH AND REVIEWS
2002; 18 (3): 201-208
Although several diagnostic modalities are available to the clinician interested in diagnosing coronary artery disease, very few have been validated in diabetic populations. This review discusses the non-invasive diagnosis of coronary disease in diabetic patients. Evidence regarding the prevalence and prognostic significance of silent ischemia is reviewed and the potential impact of silent ischemia on the diagnostic characteristics of the exercise treadmill test discussed. Other diagnostic tools are considered, and recommendations are made with respect to screening asymptomatic diabetic patients for coronary artery disease.
View details for DOI 10.1002/dmrr.297
View details for Web of Science ID 000176838800005
View details for PubMedID 12112938
Better decisions through science: Exercise testing scores
PROGRESS IN CARDIOVASCULAR DISEASES
2002; 44 (5): 395-414
Statistical tools can be used to create scores for assisting in the diagnosis of coronary artery disease and assessing prognosis. General practitioners and internists frequently function as gatekeepers, deciding which patients must be referred to the cardiologist. Therefore, they need to use the basic tools they have available (ie, history, physical examination and the exercise test) in an optimal fashion. Scores derived from multivariable statistical techniques considering clinical and exercise data have demonstrated superior discriminating power compared with diagnosis only using the ST segment response. In addition, by stratifying patients as to probability of disease and prognosis, they provide a more practical management strategy than a response of normal or abnormal. Although computers, as part of information management systems, can calculate complicated equations and derive these scores, physicians are reluctant to trust them. However, when represented as nomograms or simple additive discrete pieces of information, scores are more readily accepted. The scores have been compared with physician judgment and have been found to estimate the presence of coronary disease and prognosis as well as expert cardiologists and often better than nonspecialists. However, the discriminating power of specific variables from the medical history and exercise test remains unclear because of inadequate study design and differences in study populations. Should expired gases be substituted for estimated METs? Should ST/heart rate index be used instead of putting ST depression and heart rate separately into the models? Should right-sided chest leads and heart rate in recovery be considered? There is a need for further evaluation of these easily obtained variables to improve the accuracy of prediction algorithms, especially in women. The portability and reliability of scores must be ensured because access to specialized care must be safeguarded. Assessment of the clinical and exercise test data and application of the newer scores can empower the clinician to assure the cardiac patient access to appropriate and cost-effective cardiologic care.
View details for DOI 10.1053/pcad.2002.122693
View details for Web of Science ID 000175790200007
View details for PubMedID 12024337
An evidence-based review of the resting electrocardiogram as a screening technique for heart disease
PROGRESS IN CARDIOVASCULAR DISEASES
2001; 44 (1): 55-67
Given renewed interest in the primary prevention of cardiovascular disease, we comprehensively reviewed the utility of the electrocardiogram (ECG) for screening considering the seminal epidemiologic studies. It appears that conventional risk factors relate to long-term risk, while ECG abnormalities are better predictors of short-term risk. For individual ECG abnormalities as well as for pooled categories of ECG abnormalities, the sensitivity of the ECG for future events was too low for it to be practical as a screening tool. This almost certainly relates to the low prevalence of these abnormalities. However, all ECG abnormalities increase with age and pre-test risk. Also screening with the ECG is of minimal cost and likely to decrease further as stand-alone machines are replaced by integration into personal computers (PC). Another potential impact on performing screening ECGs would be distribution and availability of digitized ECG data via the World Wide Web. For clinical utility of ECG data, comparison with previous ECGs can be critical but is currently limited. PC based ECG systems could very easily replace many of the ECG machines in use that only have paper output. PC-ECG systems would also permit interaction with computerized medical information systems, facilitate emailing and faxing of ECGs as well as storage at a centralized web-server. Web-enabled ECG recorders similar to the new generation of home appliances could follow this quick PC solution. A serious goal for the medical industry should be to end the morass of proprietary ECG digital formats and follow a standardized format. This could lead to a network of web-servers from which every patient's ECGs would be available. Such a situation could have a dramatic effect on the advisability of performing screening ECGs.
View details for DOI 10.1053/pcad.2001.24683
View details for Web of Science ID 000170847500005
View details for PubMedID 11533927
Sex, the heart, and sildenafil.
Current problems in cardiology
2001; 26 (6): 388-415
View details for PubMedID 11391247
- The post myocardial infarction exercise test: still worthy after all of these years EUROPEAN HEART JOURNAL 2001; 22 (4): 273-276
Exercise testing in clinical medicine
2000; 356 (9241): 1592-1597
Exercise-induced changes in the electrocardiogram have been used to identify coronary artery disease for almost a century. Over the past decade, however, clinicians have increasingly focused on more expensive diagnostic tools believing them to offer improved diagnostic accuracy. In fact, by incorporating historical data, the simple exercise test can in most cases outperform the newer tests. The use of prediction equations and non-staged exercise protocols can improve the test still further, while advances in the use of the test for prognosis, with the discovery of novel risk factors and the addition of gas analysis, may in the future shift the primary emphasis away from diagnosis. Brief, inexpensive, and done in most cases without the presence of a cardiologist, the exercise test offers the highest value for predictive accuracy of any of the non-invasive tests for coronary artery disease.
View details for Web of Science ID 000165134500038
View details for PubMedID 11075788
Computer applications in the interpretation of the exercise electrocardiogram
2000; 30 (4): 231-248
The exercise electrocardiogram remains the noninvasive diagnostic test of first choice in patients with coronary artery disease. While new technology offers novel diagnostic possibilities and the ability to assess patients unsuitable for exercise testing, no other investigation has to this point furnished the quality of functional information and value-for-predictive accuracy of exercise electrocardiography. In this article, we describe how this central position in the work up of the cardiac patient has been secured through the evolution of the microprocessor. Particularly important has been its ability to harness and present large volumes of raw data, to derive and manipulate multivariate equations for diagnostic prediction, and to run 'expert' systems which can pool demographic and exercise test data, calculate risk scores, and prompt the nonexpert with advice on current management. These key features explain the pivotal role of the exercise test in the diagnostic, and increasingly prognostic, armoury of the cardiovascular clinician.
View details for Web of Science ID 000089841100001
View details for PubMedID 11048772
Medical education - beyond tomorrow? The new doctor - Asclepiad or Logiatros?
2000; 34 (6): 455-459
Against a background of the theoretical basis for the contextual approach to medical education, this paper examines and supports the changes that are occurring in undergraduate medical education throughout the world, before putting up for discussion the suggestion that the changes have not gone far enough. Consideration is given to a model of apprenticeship learning within undergraduate medical education, to the benefits it may offer, and to some of the challenges inherent in its implementation.
View details for Web of Science ID 000086920800011
View details for PubMedID 10792686
The prevalence and prognostic significance of electrocardiographic abnormalities.
Current problems in cardiology
2000; 25 (1): 1-72
View details for PubMedID 10705558
The prevalence and prognostic significance of electrocardiographic abnormalities
CURRENT PROBLEMS IN CARDIOLOGY
2000; 25 (1): 7-72
View details for Web of Science ID 000085137200002
Dangerous curves - A perspective on exercise, lactate, and the anaerobic threshold
1997; 111 (3): 787-795
A number of general observations can be made from these recent studies. Lactate is a ubiquitous substance that is produced and removed from the body at all times, even at rest, both with and without the availability of oxygen. It is now recognized that lactate accumulates in the blood for several reasons, not just the fact that oxygen supply to the muscle is inadequate. Lactate production and removal is a continuous process; it is a change in the rate of one or the other that determines the blood lactate level. Rather than a specific threshold, there is most likely a period of time during which lactate production begins to exceed the body's capacity to remove it (through buffering or oxidation in other fibers). It may be appropriate to replace the term "anaerobic threshold" to a more functional description, since the muscles are never entirely anaerobic nor is there always a distinct threshold ("oxygen independent glycolysis" among others has been suggested) Lactate plays a major role as a metabolic substrate during exercise, is the preferred fuel for slow-twitch muscle fibers, and is a precursor for liver gluconeogenesis. The point at which lactate begins to accumulate in the blood, causing an increase in ventilation, is important to document clinically. Irrespective of the underlying mechanism or specific model that describes the process, the physiologic changes associated with lactate accumulation have significant import for cardiopulmonary performance. These include metabolic acidosis, impaired muscle contraction, hyperventilation, and altered oxygen kinetics, all of which contribute to an impaired capacity to perform work. Thus, any delay in the accumulation of blood lactate which can be attributed to an intervention (drug, exercise training, surgical, etc) may add important information concerning the efficacy of the intervention. A substantial body of evidence is available demonstrating that lactate accumulation occurs later (shifting to a higher percentage of Vo2max) after a period of endurance training. In athletes, the level of work that can be sustained prior to lactate accumulation, visually determined, is an accurate predictor of endurance performance. Presumably, these concepts have implications related to vocation/disability among patients with cardiovascular and pulmonary disease, but few such applied studies have been performed outside the laboratory. Blood lactate during exercise and its associated ventilatory changes maintain useful and interesting applications in both the clinical exercise laboratory and the sport sciences. However, the mechanism, interpretation, and application of these changes continue to rely more on tradition and convenience than science.
View details for Web of Science ID A1997WM94600041
View details for PubMedID 9118720
Hormonal responses to graded-resistance, PES-assisted strength training in spinal cord-injured
1996; 34 (5): 264-267
Functional electrical stimulation (FES) assisted resistance training has been effective in increasing muscular strength and endurance in spinal cord injured men and women in preparation for FES-assisted cycle programs and for FES-assisted standing and walking. Increases in blood pressure and a concomitant bradycardia suggestive of autonomic dysreflexia have been reported during FES-assisted resistance training. Self-induced autonomic dysreflexia in athletes who use wheelchairs suppressed the normal exercise induced serum testosterone increase. We, therefore, examined the changes in hematocrit and circulating levels of testosterone, sex hormone binding globulin (SHBG), cortisol, prolactin, norepinephrine and epinephrine during FES assisted resistance exercise in five high spinal cord injured men (SCI) and comparable maximal exercise in five able bodied controls (AB). Mean serum testosterone levels significantly increased with FES-assisted resistance training in SCI and maximal resistance exercise in AB with no significant change in hematocrit or SHBG. Prolactin, cortisol and epinephrine levels were unchanged while norepinephrine levels were significantly increased in SCI and AB. These findings suggest that there is no concern over inadequate physiological androgen response to an exercise stimulus in SCI. The data do not support the previous findings that elevated levels of norepinephrine in autonomic dysreflexia suppress testosterone response to exercise.
View details for Web of Science ID A1996UR61200003
View details for PubMedID 8963972
EVIDENCE OF AUTONOMIC DYSREFLEXIA DURING FUNCTIONAL ELECTRICAL-STIMULATION IN INDIVIDUALS WITH SPINAL-CORD INJURIES
1993; 31 (9): 593-605
The purpose of the investigation was to examine the safety and efficacy of functional electrical stimulation (FES)-assisted hydraulic resistance training in improving cardiovascular fitness in persons with spinal cord injuries. The cardiopulmonary responses of 10 high spinal cord injured (SCI) and five able bodied (AB) subjects were assessed during three bouts of FES-assisted leg extension exercise. The protocol involved three 30-minute tests: (1) unloaded leg extension, (2) hydraulically-resisted leg extension (loaded), and (3) a reproduction of the unloaded and loaded protocols to measure cardiac output (Q). Pre-measurements were made of body mass, mean limb weight, maximal force output and maximal oxygen uptake (incremental arm ergometry). Oxygen uptake (VO2), minute ventilation (Ve), respiratory exchange ratio (RER), heart rate (HR), blood pressure (BP) were recorded before, during and after tests. There was a significant difference in VO2 max between SCI and AB subjects. Cardiac output significantly increased between the loaded and unloaded tests. The significant increases from rest to unloaded and loaded exercise pointed to the potential value of adding resistance to a leg extension training regime. Heart rate and BP of the participants with SCI consistently demonstrated a response suggestive of autonomic dysreflexia. Upon stimulation an immediate increase in (predominantly systolic) BP was observed, followed by a fall in HR. On cessation of stimulation HR exhibited a substantial rebound effect and BP returned to normal levels. This response was highly reproducible and suggests caution be exercised in the use of FES for people with SCI with lesion levels above the major splanchnic outflow (T6).
View details for Web of Science ID A1993LX59600006
View details for PubMedID 8247602
ELECTRICAL STIMULATION-ASSISTED ROWING EXERCISE IN SPINAL-CORD INJURED PEOPLE - A PILOT-STUDY
1993; 31 (8): 534-541
Recently a FES (functional electrical stimulation)-assisted rowing machine was developed to enhance cardiovascular training in people with spinal cord injuries. The machine was assessed in terms of its efficacy as a training tool. Six patients who were quadriplegic (C6-T1) and 2 who were paraplegic (T3-6) completed a series of three tests in succession: (1) leg stimulation only (quadriceps and hamstring groups)--'Stim', (2) arm row only--'Row' and (3) simultaneous row and stimulation--'R & S'. Measurements recorded included oxygen uptake (VO2), minute ventilation (Ve), respiratory exchange ratio (RER), heart rate (HR) and blood pressure (BP). In addition, 6 out of the 8 subjects took part in a qualitative assessment comprising a guided interview exploring the subject's perception of the machine and test. Significant increases in VO2 were demonstrated between the three tests with R & S producing mean steady-state values of 16.34 nm (+/- 0.74) ml/kg/min (83% of maximum). These values represented a 12% increase over Row alone. Of interest was the qualitative assessment which revealed that subjects perceived R & S to be easier than Row despite the higher levels of VO2 observed. The results suggest that the rowing machine represents a potentially valuable hybrid training device that may significantly reduce risk factors for cardiovascular disease and improve the quality of life of people with SCI.
View details for Web of Science ID A1993LR02900009
View details for PubMedID 8414639
Genetic Analysis in Cardiovascular Disease A Clinical Perspective
LIPPINCOTT WILLIAMS & WILKINS. 2011: 81-89
Many forms of cardiovascular disease (CVD) demonstrate heritability and thus a genetic contribution is likely. This is most evident when considering the "simple" Mendelian traits such as hypertrophic cardiomyopathy. However, family history also influences our assessment of patients with complex traits such as coronary artery disease, hypertension, and common forms of hypercholesterolemia, as observed in clinical practice. Recent research has led to advances in our understanding of the genetic basis of both the simple and complex forms of CVD. This review presents the current state of knowledge regarding major gene disorders, as well as more common, complex forms of CVD such as coronary artery disease. It discusses the fundamental approaches being used to identify the genetic basis of the various disease states, as well as the practical implications of the discoveries to clinicians. It also focuses on our need to assess the extent by which genetic analysis can alter our calculation of an individual's risk of disease, and our ability to successfully target treatment that will modify this process.
View details for DOI 10.1097/CRD.0b013e318207ffac
View details for Web of Science ID 000286875000009
View details for PubMedID 21285668