Arrhythmias remain a major health problem, causing at least 250,000 deaths annually in the United States. Pharmacological treatments often do more harm than good, and device therapies are limited by high cost and effects on quality of life. Ion channel mutations cause rare inherited arrhythmopathies, but account for only a small fraction of patients with life-threatening arrhythmias and sudden death. Most arrhythmias occur during myocardial ischemia, following myocardial infarction, and in patients with poor left ventricular (LV) function of any etiology. Aside from ejection fraction (EF), few clinically useful indicators to stratify the risk of sudden death have been identified. The role of subtle differences in ion channel expression and/or structure in predisposing patients to arrhythmias and modulating the risk of sudden death is unknown. In an ischemic cardiomyopathy population, we have found that a common polymorphism in the K+ channel HERG (K897T) worsens survival and increases sudden death. A polymorphism of the beta1-adrenergic receptor (S49G) also modulates the risk of pump failure vs. arrhythmic death. In this proposal, we will prospectively test whether polymorphisms in ion channel and ion channel modifying genes are associated with arrhythmias in a population with internal cardioverter-defibrillators (ICDs) and poor LV function. We will: 1) Directly test the hypothesis that the HERG K897T polymorphism predicts arrhythmia susceptibility in 1700 individuals with an EF below 30 percent and ICD implants. The subjects will be followed prospectively for a period of up to five years with freedom from appropriate ICD shock as the primary endpoint. 2) Test the hypothesis that the HERG K897T polymorphism selectively promotes arrhythmias in the setting of ischemia via alterations in channel turnover and or phosphorylation. Biochemical and electrophysiological studies will be performed in-vitro using cell lines and in-vivo using a rabbit MI model. 3) Test whether functional polymorphisms in the coding sequences and promoter regions of other cardiac genes (e.g. ion channels, beta-adrenergic receptors, connexins) predispose individuals to arrhythmias and/or heart failure progression. We hope to identify genetic predictors for the common forms of sudden cardiac death. This would allow the identification of a subpopulation of heart failure patients that would benefit most from ICD placement.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077398-03
Application #
7102791
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Lathrop, David A
Project Start
2004-08-15
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$534,675
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zhang, Xiaoming; Yoon, Jin-Young; Morley, Michael et al. (2018) A common variant alters SCN5A-miR-24 interaction and associates with heart failure mortality. J Clin Invest 128:1154-1163
Aleong, Ryan G; Mulvahill, Matthew J; Halder, Indrani et al. (2015) Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function. J Am Heart Assoc 4:e001566
AlJaroudi, Wael A; Refaat, Marwan M; Habib, Robert H et al. (2015) Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study). Am J Cardiol 115:924-31
London, Barry (2013) Searching for sudden death snps in calcium handling genes. J Am Heart Assoc 2:e000541
Refaat, Marwan M; Tanaka, Toshikazu; Kormos, Robert L et al. (2012) Survival benefit of implantable cardioverter-defibrillators in left ventricular assist device-supported heart failure patients. J Card Fail 18:140-5
McNamara, Dennis M; London, Barry (2010) GWAS applied to heart failure: bigger will be better...eventually. Circ Cardiovasc Genet 3:226-8
Frangiskakis, J Michael; London, Barry (2010) Targeting device therapy: genomics of sudden death. Heart Fail Clin 6:93-100
Frangiskakis, J Michael; Hravnak, Marilyn; Crago, Elizabeth A et al. (2009) Ventricular arrhythmia risk after subarachnoid hemorrhage. Neurocrit Care 10:287-94
Pretorius, Mias; Donahue, Brian S; Yu, Chang et al. (2007) Plasminogen activator inhibitor-1 as a predictor of postoperative atrial fibrillation after cardiopulmonary bypass. Circulation 116:I1-7
Neuman, Robert B; Bloom, Heather L; Shukrullah, Irfan et al. (2007) Oxidative stress markers are associated with persistent atrial fibrillation. Clin Chem 53:1652-7

Showing the most recent 10 out of 12 publications