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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Paltoo, Dina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bec, Julien; Phipps, Jennifer E; Gorpas, Dimitris et al. (2017) In vivo label-free structural and biochemical imaging of coronary arteries using an integrated ultrasound and multispectral fluorescence lifetime catheter system. Sci Rep 7:8960
Wild, Philipp S; Felix, Janine F; Schillert, Arne et al. (2017) Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. J Clin Invest 127:1798-1812
Narayan, Hari K; Finkelman, Brian; French, Benjamin et al. (2017) Detailed Echocardiographic Phenotyping in Breast Cancer Patients: Associations With Ejection Fraction Decline, Recovery, and Heart Failure Symptoms Over 3 Years of Follow-Up. Circulation 135:1397-1412
Parikh, Victoria N; Ashley, Euan A (2017) Next-Generation Sequencing in Cardiovascular Disease: Present Clinical Applications and the Horizon of Precision Medicine. Circulation 135:406-409
Liu, Miao; Verma, Nirmal; Peng, Xiaoli et al. (2016) Hyperamylinemia Increases IL-1? Synthesis in the Heart via Peroxidative Sarcolemmal Injury. Diabetes 65:2772-83
Horton, Julie L; Martin, Ola J; Lai, Ling et al. (2016) Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2:
Hou, Ning; Ye, Bo; Li, Xiang et al. (2016) Transcription Factor 7-like 2 Mediates Canonical Wnt/?-Catenin Signaling and c-Myc Upregulation in Heart Failure. Circ Heart Fail 9:
Robison, Patrick; Caporizzo, Matthew A; Ahmadzadeh, Hossein et al. (2016) Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes. Science 352:aaf0659
Bedi Jr, Kenneth C; Snyder, Nathaniel W; Brandimarto, Jeffrey et al. (2016) Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure. Circulation 133:706-16
Altman, Russ B; Ashley, Euan A (2015) Using ""big data"" to dissect clinical heterogeneity. Circulation 131:232-3

Showing the most recent 10 out of 34 publications