Abstract Body (Do not enter title and authors here): Background: Post-translational histone modifications wield significant influence over cardiac hypertrophy and dysfunction. Apabetalone (APA), a selective inhibitor of BET proteins, effectively disrupts the interactions between bromodomain-containing protein 4 (BRD4) and chromatin, exerting modulation over transcriptional programs across various organs.
Aim: We aim to investigate if APA could be beneficial in cardiometabolic heart failure with preserved ejection fraction (cHFpEF).
Methods:Comprehensive assessments including histology, mouse echocardiography, and treadmill exhaustion tests were performed on mice subjected to high-fat diet and L-NAME for 15 weeks to induce cHFpEF. Unbiased gene expression profiling via PCR array and proteomics were conducted on left ventricular (LV) myocardial of HFpEF mice and control ones. Cultured cardiomyocytes (CMs) treated with palmitic acid (PA) served as an in vitro model of metabolic stress. cHFpEF mice received chronic treatment with APA (150mg/kg/day) or vehicle (DMSO). To bridge these findings to human relevance, passive stiffness of skinned CMs from cHFpEF patients was evaluated before and after APA treatment.
Results: HFpEF mice exhibited notable characteristics including LV hypertrophy, diastolic dysfunction, myocardial fibrosis, lung congestion, and compromised exercise tolerance. APA treatment significantly ameliorated diastolic dysfunction, as evidenced by improvements in the E/A ratio and isovolumic relaxation time (IVRT), alongside a reduction in lung congestion, and enhancement in exercise tolerance. Transcriptomic analysis of PA-treated CMs and LV specimens of cHFpEF mice revealed a profound dysregulation of genes involved in inflammation, particularly IL-6, TNF-alpha, and IL-1beta. Chromatin immunoprecipitation assays demonstrated BRD4 occupancy on the promoters of various inflammatory genes, including IL6, with APA treatment resulting in the suppression of most inflammatory genes, notably impacting IL6 expression. APA led to a decrease in circulating levels of several inflammatory chemokines. The beneficial effects of APA were elucidated through the modulation of the IL-6/CaMKII/STAT3 pathway in both cHFpEF hearts and PA-treated CMs. Notably, in skinned CMs obtained from cHFpEF patients, both APA treatment and IL6 blockade exhibited a capacity to attenuate passive stiffness.
Conclusions: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF.