Heart failure with preserved ejection fraction (HFpEF) constitutes half of all HF and lacks effective therapy, yet myocardial biological data from HFpEF patients is nearly non-existent.
We prospectively obtained right ventricular septal endomyocardial biopsies in HFpEF. Myocardial tissue from HFpEF (n=41), heart failure with reduced ejection fraction (HFrEF, n=30) and control (CON, n=24) were analyzed by RNA sequencing.
HFpEF patients were older, more often African American (68%), with more diabetes (63%) and higher body mass index (median 41 kg/m2 [36-46]), compared to HFrEF. Agnostic principal component and hierarchical gene clustering analyses separated HFpEF, HFrEF and CON with minimal overlap (Figure 1A, 1B). HFpEF uniquely upregulated genes clustered in mitochondrial ATP synthesis/electron transport pathways that correlated with obesity; these pathways were downregulated in HFrEF. HFpEF uniquely down-regulated genes in endoplasmic reticulum stress, autophagy, and angiogenesis, uncorrelated with obesity. A subset of downregulated genes in HFpEF (upregulated in HFrEF) were functionally tested by knock-down in Drosophila; 65% altering fractional shortening and/or delaying relaxation. Three transcriptome-derived HFpEF subgroups were identified with distinct clinical correlates and clinical outcomes (Figure 1C, 1D): 1) mostly male with pulmonary hypertension, elevated cardiac biomarkers, altered stress/sarcomere genes, and worse event-free survival; 2) female with low cardiac biomarkers and inflammatory signaling; and 3) mixed sex with altered extracellular matrix genes. Obesity, hypertension, and hypertrophy were similar.
HFpEF has a distinct transcriptional profile from HFrEF, involving pathways both dependent and independent of obesity. These transcriptome signatures defined molecular-subgroups within HFpEF and highlight new signaling targets that may prove valuable for precision therapeutics.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Cardiac Failure
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
© 2020 Published by Elsevier Inc.