Distinct Myocardial Gene Expression Signatures in Heart Failure with Preserved Ejection Fraction

Background 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. Methods 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. Results 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. Conclusions 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.