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.
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Identification
Copyright
© 2020 Published by Elsevier Inc.
