A review published in Frontiers in Cardiovascular Medicine synthesizes how epicardial adipose tissue undergoes pathological remodeling during obesity and evaluates emerging pharmacological strategies to reverse this damage in heart failure with preserved ejection fraction. Unlike traditional cardiovascular treatments that primarily address hemodynamics and neurohormonal axes, addressing epicardial fat targets an upstream driver of disease. Positioned directly between the visceral pericardium and the myocardium, epicardial adipose tissue shares coronary circulation with cardiac muscle and lacks an intervening fascial barrier, establishing the most direct, fascia-free tissue interface of any visceral fat depot in the human body.

Healthy epicardial fat plays an essential role in sustaining cardiac metabolic homeostasis by buffering fatty acids, generating heat through thermogenesis, and secreting protective adipokines via paracrine pathways. However, the review details how obesity drives a pathological transformation structured along an asynchronous quantity-quality dual axis. On the quantity axis, the depot expands significantly in overall volume and measurable thickness. Simultaneously, the quality axis deteriorates through the loss of tissue browning, excessive lipotoxic lipid accumulation, an imbalanced inflammatory microenvironment, and a critical secretome shift that swaps anti-inflammatory signaling molecules for harmful pro-inflammatory mediators.

This dual-axis remodeling damages adjacent myocardium through four interconnected pathological pathways: direct mechanical constraint, paracrine and vasocrine inflammatory cascades, cardiomyocyte lipotoxicity, and coronary microvascular dysfunction. These destructive processes converge to accelerate myocardial fibrosis and elevate cardiomyocyte stiffness, pathological structural alterations that are closely associated with left ventricular diastolic dysfunction and the clinical onset of heart failure with preserved ejection fraction.

To counteract this adverse progression, researchers evaluated several pharmacological drug classes capable of reversing remodeling across the dual axes. Incretin analogs, including semaglutide and tirzepatide, currently demonstrate the most complete evidence chain, which spans basic mechanistic investigations, cardiac imaging findings, and clinical endpoints. Nevertheless, the review notes a key limitation: evidence has not yet definitively established whether the observed clinical benefits of incretin therapies are directly mediated by alterations in epicardial adipose tissue. Meanwhile, sodium-glucose cotransporter 2 inhibitors offer the most systematic structural evidence specifically addressing the quantity axis.

Additional therapeutic candidates, such as statins, thiazolidinediones, metformin, beta-3 adrenergic receptor agonists, and microRNA-based therapies, also display potential to target both quantity and quality remodeling axes.

Subject of Research: Pharmacological reversal of epicardial adipose tissue remodeling in heart failure

Article Title: From cushion to culprit: pharmacological reversal of epicardial adipose tissue remodeling in obesity-related heart failure with preserved ejection fraction

Article References: Li, Y., Chang, J., Liu, Z., & Liu, J. (2026). From cushion to culprit: pharmacological reversal of epicardial adipose tissue remodeling in obesity-related heart failure with preserved ejection fraction. Frontiers in Cardiovascular Medicine, 13, Article 1986624. https://doi.org/10.3389/fcvm.2026.1986624

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1986624

Keywords: epicardial adipose tissue, heart failure with preserved ejection fraction, HFpEF, obesity, myocardial fibrosis, cardiomyocyte stiffness, incretin analogs, semaglutide, tirzepatide, SGLT2 inhibitors, left ventricular diastolic dysfunction, paracrine secretion, microvascular dysfunction, adipokines, cardiomyocyte lipotoxicity, visceral pericardium, thermogenesis, statins