A Key Driver in Obesity-Related HFpEF
The link between obesity & HFpEF is critical.
Epicardial adipose tissue (EAT)
is not just storage— it’s an active organ promoting myocardial dysfunction.
EAT drives:
➡️Fibrosis
➡️Inflammation
➡️Oxidative stress
➡️Diastolic dysfunction
Understanding EAT’s is crucial for developing new personalized therapies.
Heart failure with preserved ejection fraction (HFpEF)
is a growing global health problem characterized by high morbidity and mortality, with limited effective therapies available.
Obesity significantly influences haemodynamic and structural changes in the myocardium and vasculature, primarily through the accumulation and action of visceral adipose tissue.
Particularly, epicardial adipose tissue (EAT) contributes to HFpEF through inflammationand lipotoxic infiltration of the myocardium.
However, the precise signalling pathways leading to diastolic stiffness in HFpEF require further elucidation.
This review explores the dynamic role of EAT in health and disease.
Drawing upon insights from studies in other conditions, we discuss potential
EAT-mediated inflammatory pathways in HFpEF and
how they may contribute to functional and structural myocardial and endothelial derangements, including
•intramyocardial lipid infiltration, •fibrosis,
•endothelial dysfunction, •cardiomyocyte stiffening, and
•left ventricular hypertrophy.
Lastly, we propose potential targets for novel therapeutic avenues.
EAT as a therapeutic target in HFpEF
The phenotypic diversity of HFpEF and the interplay with different comorbiditieswarrant a tailored treatment approach.
In the context of the obesity-related HFpEF phenotype, targeting the pathological transformation and underlying inflammatory pathways mediated by EAT may present new therapeutic avenues.
We therefore present therapeutic options that pose a clinical benefit that arise from changes to EAT or EAT-mediated pathways.
1) Sodium-glucose cotransporter-2 inhibitors(SGLT2i), like dapagliflozin and empagliflozin, are the first type of pharmacological drugs to reduce the risk of heart failure–related hospitalization in HFpEF trials.
Given the low expression of SGLT2 in cardiomyocytes, it is likely that SGLT2i mediate their positive effects in HFpEF by off-target mechanisms in the myocardium.
At least in part, these effects might be mediated by EAT.
Upon SGLT2i administration, EAT volume decreases and glucose uptake by EAT is enhanced, suggesting that these types of drugs might improve EAT’s secretome and may improve metabolic regulation associated with insulin resistance in obesity.
Furthermore, SGLT2i-treated patients show a reduction of ECM and cardiomyocyte volume, along with a decrease in inflammatory biomarkers, such as FABP4, IL-1, IL-6, and TGF-β, indicating a role in improving myocardial inflammation and fibrosis.
Additionally, SGLT2i show a mild, sustained diuretic effect that can improve volume overload and congestion seen in HFpEF, while reducing the need for diuretics use.
2)Glucagon-like peptide 1 agonists (GLP-1a), such as semaglutide and liraglutide, are a class of anti-diabetic drugs known for their glucose-lowering effects and insulin sensitization, which show a rapid and significant reduction of EAT thickness independent of body weight loss.
Clinical trials in patients with HFpEF show symptom reduction and exercise capacity improvement after GLP-1a administration, across the entire obesity spectrum.
It is suggested that part of the effect of GLP-1a might be mediated by EAT, given that this fat depot expresses specific GLP-1 receptors.
While GLP-1a primarily enhances insulin sensitivity, in EAT, it induces adipocyte browning through activation of the AMPK pathway and reduces local adipogenesis by improving FFA oxidation.
However, a reduction in EAT is likely accompanied by simultaneous reductions in other fat depots. GLP-1a reduces both VAT and SAT in equal proportions, and these reductions correspond with overall weight loss.
However, due to the presence of specific GLP-1 receptors on EAT, these agonists may directly remodel EAT into a more cardioprotective fat depot, and therefore have a direct effect mediated by EAT, independent of overall weight loss.
3)Bariatric surgery causes drastic and often lasting weight loss, triggering favourable metabolic changes in obese patients.
Significant weight loss is typically accompanied by a reduction of abdominal and visceral fat depots, including EAT.
Although robust and longitudinal data in patients with HFpEF is lacking, significant weight loss may improve haemodynamics, exercise capacity, and symptoms.
This effect could be mediated, at least in part, by reducing EAT-mediated pericardial constraint, which may alleviate pressure on the LV and improve its (diastolic) function.
4)Statins, particularly atorvastatin, show improved cholesterol profiles and reduction in EAT.
Known for their lipid-lowering and anti-inflammatory effects, statins could influence EAT expansion and hamper the secretion of proinflammatory molecules, contributing to improvements in cardiovascular health.
While statins are not recommended in the guidelines for HFpEF treatment, they are often prescribed for patients with HFpEF to address cardiovascular comorbidities, such as hypertension, CAD, and dyslipidaemia.
Furthermore, some suggest that early initiation of statin use is associated with improved outcomes in HFpEF, although this is a topic of current debate.
