In subjects with heart failure, genetic variation will affect clinical outcomes and the response to therapy. Heart failure is a polygenic disorder, and the impact of specific genetic polymorphisms will be influenced by genetic background. For several genes critical to heart failure pathogenesis, the prevalence of adverse alleles differs significantly between white and black cohorts. The current proposal will enroll one thousand subjects with heart failure due to systolic dysfunction including 500 white subjects and 500 black subjects, and will examine the impact of racial differences in genetic background on left ventricular function and clinical outcomes.
Specific Aim 1 will evaluate the impact of genetic background on left ventricular ejection fraction (LVEF) and LV diastolic diameter in 500 black subjects with chronic heart failure and a matched cohort of 500 white subjects. The proposal will focus on adverse alleles of key heart failure mediators including the ACE deletion, aldosterone synthase promoter -344C, NOS3 Asp298, and betal Arg389 variants.
Specific Aim 2 will investigate the impact of the adverse alleles from aim 1 on survival in the overall cohort and separately in the black and white subsets.
Specific aim 3 will explore gene-gene interactions to examine whether the impact of the ACE D allele is modified by coinheritance of the GNB3 T haplotype. This polymorphism is linked to increased alpha adrenergic activation and low plasma renin and is far more prevalent in black cohorts.
Specific Aim 3 will explore in the black heart failure cohort the use of Mapping by Admixture Linkage Disequilibrium (MALD), which utilizes comparisons of genomic DMA of African and European orgin, to determine the potential contributions of genomics to apparent racial differences in remodeling and heart failure outcomes. This proposal will address an important clinical question and will provide an ideal program for mentoring young investigators in the methodologies involved in genetics outcomes research.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL069912-09
Application #
8213754
Study Section
Special Emphasis Panel (ZHL1-CSR-R (O1))
Program Officer
Scott, Jane
Project Start
2002-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$161,032
Indirect Cost
$11,928
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Cooper, Leslie T; Mather, Paul J; Alexis, Jeffrey D et al. (2012) Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women. J Card Fail 18:28-33
McNamara, Dennis M; Starling, Randall C; Cooper, Leslie T et al. (2011) Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Coll Cardiol 58:1112-8
Simon, Marc A; Primack, Brian A; Teuteberg, Jeffrey et al. (2010) Left ventricular remodeling and myocardial recovery on mechanical circulatory support. J Card Fail 16:99-105
McNamara, Dennis M; London, Barry (2010) GWAS applied to heart failure: bigger will be better...eventually. Circ Cardiovasc Genet 3:226-8
McNamara, Dennis M (2010) Genomic variation and neurohormonal intervention in heart failure. Heart Fail Clin 6:35-43
McNamara, Dennis M; Tam, S William; Sabolinski, Michael L et al. (2009) Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail 15:191-8
Ishizawar, David C; Janosko, Karen M; Teuteberg, Jeffrey J et al. (2008) The beta1-adrenergic receptor mediates the pharmacogenetic interaction of the ACE D allele and beta-blockers. Clin Transl Sci 1:151-4
Bedi, Maninder S; Alvarez Jr, Rene J; Kubota, Toru et al. (2008) Myocardial Fas and cytokine expression in end-stage heart failure: impact of LVAD support. Clin Transl Sci 1:245-8
McNamara, Dennis M (2008) Pharmacogenomics for neurohormonal intervention in heart failure. Cardiol Clin 26:127-35, viii

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