Genetic architecture of heart failure with preserved versus reduced ejection fraction

• Type of Material: Article
• Authors: Jacob Joseph, VA Boston Healthcare System; Chang Liu, Emory University; Qin Hui, Emory University; Krishna Aragam, VA Boston Healthcare System; Zeyuan Wang, Rollins School of Public Health; Brian Charest, VA Boston Healthcare System; Jennifer E. Huffman, VA Boston Healthcare System; Jacob M. Keaton, National Human Genome Research Institute (NHGRI); Todd L. Edwards, Vanderbilt University Medical Center; Serkalem Demissie, VA Boston Healthcare System; Luc Djousse, VA Boston Healthcare System; Juan P. Casas, VA Boston Healthcare System; J. Michael Gaziano, VA Boston Healthcare System; Kelly Cho, VA Boston Healthcare System; Peter Wilson, Emory University; Lawrence Phillips, Emory University; Christopher J. O Donnell, VA Boston Healthcare System; Yan Sun, Emory University
• Language: English
• Date: 2022-12-01
• Publisher: Nature
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-35323-0
• Title of Journal or Parent Work: Nature Communications
• Volume: 13
• Issue: 1
• Start Page: 7753
• End Page: 7753
• Grant/Funding Information: This research is supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant I01-CX001737 (PI: Phillips) and I01-BX004821 (PI: Wilson). This publication does not represent the views of the Department of Veterans Affairs or the United States Government.
• Keywords: Stroke Volume; Ventricular Dysfunction, Left; Heart Failure; Humans
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition.