Abstract Body (Do not enter title and authors here): Background: The development of effective treatments for heart failure with preserved ejection fraction (HFpEF) remains an urgent, unmet need. Multi-omics studies have identified numerous heart failure (HF)-associated genes, but many remain unvalidated. Reported biological processes implicated in HF pathophysiology may offer promising clinically actionable targets for HFpEF patients.
Research Question: The aim of this study was to identify HFpEF-relevant genes consistently reported in HF omics studies as potential candidates for therapeutic targets.
Methods: A multi-tiered strategy was used for candidate gene selection, prioritizing directionally consistent associations reported across multiple, independent omics studies, supported by mechanistic plausibility. Relative gene expression (quantified via 2^-ΔCt) was assessed in left ventricular (LV) and visceral adipose tissue from a validated preclinical HFpEF model (n=10 AKR/J mice fed a high-fat diet vs. n=10 controls) using Wilcoxon rank sum tests. Clinical data from HF patients (n=327) were then analyzed for coding SNPs or eQTLs in candidate gene regions (minor allele frequency ≥5%). Associations between variants and clinical outcomes were evaluated with multivariable Cox regression models, corrected for multiple testing (P ≤0.0013). The primary outcome was a composite of CV hospitalization or all-cause mortality, with all-cause mortality as a secondary outcome.
Results: Four candidate genes were prioritized (BAG3, BCAT2, GILZ, MAPT). Gilz expression was significantly upregulated in both LV and adipose tissue of HFpEF mice compared to control (fold change [FC]: 2.93, P<0.001; FC: 1.56, P=0.005, respectively). Bag3 expression was increased in the LV (FC: 1.25, P=0.049) and Bcat2 expression was decreased in adipose tissue (FC: 0.47, P=0.008) compared to control. There were no SNPs associated with the primary outcome. However, the eQTL variant rs10886530 was nominally associated with increased BAG3 expression in GTEx and all-cause mortality risk in HF patients, but did not meet the correction threshold (HR: 1.83 [95% CI: 1.25-2.68], P=0.002).
Conclusions: Increased expression of BAG3 consistently demonstrates an elevated risk of HF development and worse clinical outcomes across multi-omics, preclinical, and clinical analyses. Tissue-specific expression differences in Bcat2 and Gilz additionally support further investigation. Collectively, these findings identify potential therapeutic candidates for HFpEF.