Heart failure (HF) is the leading cause of adult hospitalization in the industrialized world and imposes a substantial burden on the public health. Over the past two decades, a large body of research using transgenic models has implicated a growing number of transcription factors and microRNAs as mediators of myocardial hypertrophy and dysfunction. Because few of these mediators have been confirmed in human hearts, there has been minimal progress in applying these insights to human HF therapeutics. We propose to overcome these barriers by leveraging unique bioresources at three U.S. transplant centers that have amassed repositories of high-quality myocardium from more than 1,900 human subjects over the past 15 years. The overall goals of this proposal are to use integrative genomics to test whether transcriptional regulatory programs identified in animal models are relevant in human HF and to perform unbiased screens for regulators of myocardial gene expression in human subjects. Integrative genomics elucidates disease mechanism by combining phenotype data with whole-genome genotypes and gene expression in a tissue of interest. To apply these approaches to the human heart, we have assembled a multidisciplinary team of experts in heart failure, clinical investigation, cardiac biology, and the genetics of complex disorders.
In Aim 1, we will perform a case-control study (n=1000) using integrated SNP and expression data to test which of 40 pre-specified transcriptional regulators contribute to advanced HF in humans.
In Aim 2, we will perform a cross-sectional study (n=1000) using integrated SNP and expression data across a broad range of myocardial phenotypes to test whether the same candidate regulators contribute to pathological remodeling. In both aims, secondary analyses and network modeling will enable genome-wide screens for unanticipiated mechanisms of transcriptional regulation in the human heart.
In Aim 3, we will test whether our most promising results identify genetic risk factors for cardiac remodeling in the general population through collaboration with EchoGen, a genome-wide association meta-analysis of echocardiographic traits in seven community-based cohorts (N=18,000). This research will test the relevance of knowledge derived from years of animal research while employing an unbiased discovery approach to reveal unanticipated mechanisms of human myocardial disease. Doing so will accelerate the translation of scientific knowledge to HF therapeutics. Moreover, all data and biosamples will be made available to the scientific community to promote a broad and durable impact on HF research.

Public Health Relevance

In the midst of an ongoing heart failure epidemic, this research will determine the clinical relevance of heart failure mechanisms identified in animal models, help identify new therapeutic targets, and define mechanisms through which genetic variation influences the development of heart failure. By advancing clinical research in myocardial mechanisms of disease progression, this project will accelerate the development of therapeutic applications to improve the care of patients with heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105993-04
Application #
8695454
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Larkin, Jennie E
Project Start
2011-08-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$2,154,089
Indirect Cost
$427,495
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bennett, Mosi K; Sweet, Wendy E; Baicker-McKee, Sara et al. (2014) S100A1 in human heart failure: lack of recovery following left ventricular assist device support. Circ Heart Fail 7:612-8
Lin, Honghuang; Dolmatova, Elena V; Morley, Michael P et al. (2014) Gene expression and genetic variation in human atria. Heart Rhythm 11:266-71
Kapoor, Ashish; Sekar, Rajesh B; Hansen, Nancy F et al. (2014) An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval. Am J Hum Genet 94:854-69
Despa, Sanda; Sharma, Savita; Harris, Todd R et al. (2014) Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model. J Am Heart Assoc 3:
Mohmand-Borkowski, Adam; Tang, W H Wilson (2014) Atrial fibrillation as manifestation and consequence of underlying cardiomyopathies: from common conditions to genetic diseases. Heart Fail Rev 19:295-304
Ritter, Scott; Margulies, Kenneth B (2014) Emerging Tools for Computer-Aided Diagnosis and Prognostication. J Clin Trials 4:e117
Dunn, Kyla E; Caleshu, Colleen; Cirino, Allison L et al. (2013) A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management. Circ Cardiovasc Genet 6:118-31
Anand, Priti; Brown, Jonathan D; Lin, Charles Y et al. (2013) BET bromodomains mediate transcriptional pause release in heart failure. Cell 154:569-82
Johnson, J A; Roden, D M; Lesko, L J et al. (2012) Clopidogrel: a case for indication-specific pharmacogenetics. Clin Pharmacol Ther 91:774-6