Dysregulated Epicardial Adipose Tissue as a Risk Factor and Potential Therapeutic Target of Heart Failure with Preserved Ejection Fraction in Diabetes

Abstract

Cardiovascular (CV) disease and heart failure (HF) are the leading cause of mortality in type 2 diabetes (T2DM), a metabolic disease which represents a fast-growing health challenge worldwide. Specifically, T2DM induces a cluster of systemic metabolic and non-metabolic signaling which may promote myocardium derangements such as inflammation, fibrosis, and myocyte stiffness, which represent the hallmarks of heart failure with preserved ejection fraction (HFpEF). On the other hand, several observational studies have reported that patients with T2DM have an abnormally enlarged and biologically transformed epicardial adipose tissue (EAT) compared with non-diabetic controls. This expanded EAT not only causes a mechanical constriction of the diastolic filling but is also a source of pro-inflammatory mediators capable of causing inflammation, microcirculatory dysfunction and fibrosis of the underlying myocardium, thus impairing the relaxability of the left ventricle and increasing its filling pressure. In addition to representing a potential CV risk factor, emerging evidence shows that EAT may guide the therapeutic decision in diabetic patients as drugs such as metformin, glucagon-like peptide‑1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is), have been associated with attenuation of EAT enlargement.

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

“…The reduced mass and inflammation of perivisceral adipose tissue induced by SGLT2-Is may minimize the inflammatory paracrine actions on visceral organs such as the heart and kidney to promote cardiac fibrosis and renal glomerulosclerosis [ 263 ]. In particular, SGLT2-Is exert a drug class effect of reduction of epicardial adipose tissue, the true visceral fat of heart, associated with attenuated inflammation and less secretion of deleterious adipokines, that can positively affect both structure and function of adjacent myocardium [ 264 , 265 ]. A particularly relevant role seems to be played by attenuation of leptin secretion and related paracrine effects [ 266 , 267 ].…”

Epicardial adipose tissue thickness is associated with reduced peak oxygen consumption and systolic reserve in patients with type 2 diabetes and normal heart function

“…Individuals with type 2 diabetes (T2D) are at a high risk of developing heart failure with preserved ejection fraction (HFpEF), a heterogeneous and complex syndrome that, despite its growing prevalence and incidence with significant morbidity and mortality, still retains important knowledge gaps and therapeutic challenges 1 . In recent years, excessive epicardial adipose tissue (EAT) has been regarded as a one among the main actors in myocardial disease by promoting inflammation, micro‐vasculopathy, fibrosis and stiffness of myocardium, all findings corresponding to the hallmarks of HFpEF 2 . Its quantification is easy and reproducible during standard transthoracic echocardiography 3 .…”

Diabetes Mellitus and Heart Failure: Epidemiology, Pathophysiologic Mechanisms, and the Role of SGLT2 Inhibitors

“…Another explanatory concept is the decrease in epicardial fat caused by leptin downregulation [ 128 , 133 ]. Epicardial adipose tissue growth is linked to poor left ventricular relaxation and diastolic filling, either directly through constriction or indirectly through the regulation of pro-inflammatory molecule release, resulting in inflammation, microcirculatory dysfunction, and fibrosis [ 134 ]. SGLT2 expression has been established in human epicardial adipose tissue, and the majority of the data on individuals with type 2 DM show a decrease in epicardial adipose tissue mass after SGLT2 inhibition [ 134 , 135 ].…”

“…Epicardial adipose tissue growth is linked to poor left ventricular relaxation and diastolic filling, either directly through constriction or indirectly through the regulation of pro-inflammatory molecule release, resulting in inflammation, microcirculatory dysfunction, and fibrosis [ 134 ]. SGLT2 expression has been established in human epicardial adipose tissue, and the majority of the data on individuals with type 2 DM show a decrease in epicardial adipose tissue mass after SGLT2 inhibition [ 134 , 135 ]. The newly published randomized, placebo-controlled EMPA-TROPISM study found that empagliflozin decreased epicardial fat content in individuals without T2DM, HF, and a lower LVEF [ 128 ].…”