Comparative evaluation of class IIa HDAC inhibition with standard-of-care therapies in HFpEF
Introduction
Heart failure with preserved ejection fraction (HFpEF) remains a major clinical challenge characterized by diastolic dysfunction, systemic inflammation, and metabolic abnormalities. Inhibition of histone deacetylase 4 (HDAC4), has emerged as a potential therapeutic approach influencing cardiac remodeling and metabolic regulation. This study compares two class IIa HDAC4 inhibitors with distinct pharmacological mechanisms (active site inhibition by RT1 and allosteric inhibition by RT2) to the current standard HFpEF therapies—Empagliflozin (SGLT2 inhibitor) and Semaglutide (GLP-1 receptor agonist)—to delineate common and divergent pathways underlying therapeutic efficacy.
Methodology
Experimental HFpEF in mice was induced by a high-fat diet (HFD) combined with L-NAME administration. Treatment groups received RT1, RT2, Empagliflozin, or Semaglutide. Cardiac function was assessed by echocardiography and invasive hemodynamics; Syetemic features of HFpEF were evaluated by exercise capacity testing, blood pressure, and body composition analysis. Planned metabolic cage studies will assess energy expenditure and respiratory exchange ratio. Transcriptomic analyses ofheart muscle tissue, adipose tissue and skeletal muscle tissues will identify common and distinct pathways affected by the different treatments.
Results
Both class IIa HDAC4 inhibitors significantly improved diastolic function, exercise capacity, glycemic control, renal function, and blood pressure compared to untreated HFpEF controls. RT2 and standard therapies induced pronounced weight loss, while RT1 showed a moderate effect on weight. Fat but not lean mass reduction paralleled total body weight changes. Notably, Semaglutide-treated control mice exhibited a reduction in lean mass, whereas HFpEF + Semaglutide mice preserved lean mass but showed limited improvement in physical performance, implying potential side effects on skeletal muscle function.
Conclusions
Class IIa HDAC4-inhibition provides therapeutic benefits comparable to standard-of-care agents in HFpEF, improving both cardiac function and metabolic homeostasis. The benefits appear to involve enhanced cardiac energy utilization and modulation of adipose and skeletal muscle metabolism, supporting HDAC4 as a novel and mechanistically relevant target for HFpEF treatment.
Future Work
Ongoing metabolic cage experiments will clarify whether class IIa HDAC4-inhibition increases energy expenditure or alters substrate oxidation patterns. Integrated transcriptomic analyses of heart muscle, adipose tissue and skeletal muscle will further define molecular pathways mediating class IIa HDAC4-related cardiometabolic improvement, paving the way for refined therapeutic strategies in HFpEF.
