ARTICLE: Myocardial Gene Expression Signatures in Human Heart Failure with Preserved Ejection Fraction
AUTHORS: Virginia S. Hahn, Hildur Knutsdottir, Xin Luo, Kenneth Bedi, Kenneth B. Margulies, Saptarsi M. Haldar, Maria Stolina, Jun Yin, Aarif Y. Khakoo, Joban Vaishnav, Joel S. Bader, David A. Kass, and Kavita Sharma
JOURNAL: Circulation. 2020 Oct 29. doi: 10.1161/CIRCULATIONAHA.120.050498. Online ahead of print.
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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