ARTICLE: Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction

AUTHORS: Virginia S. HahnHildur KnutsdottirXin LuoKenneth BediKenneth B. MarguliesSaptarsi M. HaldarMaria StolinaJun YinAarif Y. Khakoo, Joban Vaishnav, Joel S. BaderDavid A. Kass, and Kavita Sharma

JOURNAL: Circulation. 2020 Oct 29. doi: 10.1161/CIRCULATIONAHA.120.050498. Online ahead of print.

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) constitutes half of all HF yet lacks effective therapy. Understanding its myocardial biology remains limited due to a paucity of heart tissue molecular analysis.

Methods: We performed RNA sequencing on right ventricular septal endomyocardial biopsies prospectively obtained from patients with consensus criteria for HFpEF (n=41) and contrasted to RV-septal tissue from HF with reduced EF (HFrEF, n=30) and donor controls (CON, n=24). Principal component analysis (PCA) and hierarchical clustering tested for transcriptomic distinctiveness between groups and impact of co-morbidities, and differential gene expression with pathway enrichment contrasted HF groups to CON. Within HFpEF, non-negative matrix factorization (NMF) and weighted gene co-expression analysis (WGCNA) identified molecular subgroups and the resulting clusters were correlated with hemodynamic and clinical data.

Results: HFpEF patients were more often women (59%), African American (68%), obese (median BMI 41), and hypertensive (98%), with clinical HF characterized by 65% NYHA III-IV, nearly all on a loop diuretic, and 70% with a HF hospitalization in the prior year. PCA separated HFpEF from HFrEF and CON with minimal overlap and this persisted after adjusting for primary co-morbidities: BMI, sex, age, diabetes, and renal function. Hierarchical clustering confirmed group separation. Nearly half the significantly altered genes in HFpEF versus CON (1882 up, 2593 down) changed in the same direction in HFrEF; however, 5745 genes were uniquely altered between HF groups. Compared to CON, uniquely upregulated genes in HFpEF were enriched in mitochondrial ATP synthesis/electron transport, pathways downregulated in HFrEF. HFpEF-specific down-regulated genes engaged endoplasmic reticulum stress, autophagy, and angiogenesis. BMI differences largely accounted for HFpEF upregulated genes whereas neither this nor broader co-morbidity adjustment altered pathways enriched in downregulated genes. NMF identified three HFpEF transcriptomic subgroups with distinctive pathways and clinical correlates, including a group closest to HFrEF with higher mortality, and a mostly female group with smaller hearts and pro-inflammatory signaling. These groupings remained after sex adjustment. WGCNA analysis yielded analogous gene-clusters and clinical groupings.

Conclusions: HFpEF exhibits distinctive broad transcriptomic signatures and molecular subgroupings with particular clinical features and outcomes. The data reveal new signaling targets to consider for precision therapeutics.

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