Epicardial Adipose Tissue

: Relationship with Cardiovascular Disease and the Effect of Therapeutic Interventions

Abstract

Background
Until recently, research has been directed towards the intra-abdominal visceral fat and its relationship with metabolic syndrome and the role of inflammatory mediators. However, recent research has shown that mediastinal visceral fat and, in particular, epicardial adipose tissue (EAT) may play a vital role in the pathophysiology of atherosclerosis and atherothrombosis. A predominant hypothesis in these studies was that EAT, because of its proximity to the coronary arteries, may contribute to the development of atherosclerosis locally due to paracrine effects, thus leading to adverse cardiovascular outcome, however, few studies have shown that EAT may exert a more systemic effect. EAT is metabolically active and secretes numerous substances associated with cardiovascular disease (CVD) such as TNFα, IL-6, IL-1β and resistin amongst others. Having considered evidence of the possible effect of EAT in the development of atherosclerosis, which is hugely limited to few studies, implied the importance of studying various drug therapies on EAT.

Methodology
Using cardiac magnetic resonance images, EAT area was measured for patients from SUMMIT, METREMODEL and REFORM studies. In SUMMIT study a combination of patients with type 2 diabetes (T2DM) and without T2DM patients with or without CVD were recruited and the measured EAT area was compared between the different groups and the correlations with a vascular assessment like pulse wave velocity (PWV) and a wide range of biomarkers were investigated.
In MET-REMODEL Study in which metformin was given to patients with insulin resistance identified to have ischaemic heart disease and left ventricular hypertrophy for 12 months and in REFORM Study in which an SGLT2 inhibitor, dapagliflozin, was given to patients with T2DM and heart failure for 12 months, the impact of these two drugs on EAT area were examined by measuring the EAT area pre and post intervention.

Results
In SUMMIT study, EAT area was found to be larger in patients with CVD with and without T2DM in comparison to T2DM only patients and controls with no T2DM/ no CVD (CVD with T2DM: 15.9 ± 5.5 cm², n =34, T2DM: 15.1 ± 4.3, n =54, CVD without T2DM: 15.1 ± 4.3cm², n =28 versus control 11.8 ± 4.1 cm2, n =29, P =0.001). EAT was an independently associated with arterial stiffness estimated by PWV in the SUMMIT study cohort. (EAT r=0.1; p=0.026, multivariable linear regression for prediction of PWV). There was an incremental independent association of both EAT and interleukin-6 (IL-6) with PWV in SUMMIT study (EAT r=0.1; p=0.03, IL-6 r=0.5; p=0.005, multivariable linear regression for prediction of PWV).
In METREMODEL and REFORM studies, no effect of metformin and dapagliflozin on EAT area (metformin -0.1 ± 3.8 cm² vs. placebo -0.5 ± 2.9 cm² p= 0.7), (dapagliflozin -1.00 ± 3.6 cm² vs. placebo -0.7 ± 3.1 p=0.8), respectively was estimated.

Conclusion
EAT was significantly increased in patients with overt cardio-metabolic disease compared to those without it and it appears to be associated with systemic inflammation and increase cardiovascular risk in the same cohort. As metformin and dapagliflozin showed no effect on EAT, the reported cardiovascular benefits of these 2 diabetic therapies are not likely to be mediated by effects on EAT and Therefore, trials of both metformin and dapagliflozin that are adequately powered statistically and designed to examine the impact of metformin and SGLT2 inhibitors on EAT are mandatory.

Date of Award	2019
Original language	English
Awarding Institution	University of Dundee
Supervisor	Chim Lang (Supervisor) & Faisel Khan (Supervisor)