Abstract 13050: Dysfunctional Endothelial-Subcutaneous Adipocyte Cross-Talk in Patients With Reduced Ejection Fraction Heart Failure and Type 2 Diabetes Mellitus

Abstract

Introduction: Normal subcutaneous adipose tissue (SAT) function is critical to metabolic homeostasis and is dependent on normal microvascular endothelial cell (MVEC) function. Heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes mellitus (T2DM) have a synergistic deleterious relationship and of relevance to this metabolic dysregulation may drive HFrEF progression in T2DM. Detailed phenotyping of SAT microvasculature in this population is lacking. Aims: To examine SAT MVEC function and cross talk between SAT MVEC and adipocytes in patients with HFrEF and T2DM. Methods: Pectoral SAT biopsies were taken from HFrEF patients with and without T2DM undergoing pacemaker implant. SAT was examined for angiogenic potential, vascularity, adipocyte morphology and inflammatory markers. MVEC were isolated from SAT and characterised for metabolic, mitochondrial and proliferative capacity, angiogenic potential and senescence. The direct effect of altered SAT MVEC physiology in T2DM on healthy adipocytes was examined using indirect (conditioned media) and direct (co-culture) techniques. Results: We recruited 51 people with HFrEF of whom 21 (41%) had T2DM (HFDM). There was no difference in age, sex, or body mass index between groups. Macroscopically, SAT from patients with HFDM had impaired angiogenesis and increased fibrosis compared to SAT from HFrEF patients alone. SAT MVEC from patients with HFDM had lower metabolic activity, ATP production, proliferation; increased senescence and impaired angiogenesis. Healthy adipocytes co-cultured with SAT MVEC from HFDM patients had significantly increased expression of interleukin-6 and reduced uptake of 2-NBD-glucose compared to HFrEF alone. Conclusions: Cross talk between SAT MVEC from HFDM patients and healthy adipocytes leads to a deleterious alteration in adipocyte phenotype. Future work identifying the mechanism of SAT MVEC to adipocyte cross talk may identify novel therapeutic targets for patients with HFrEF and/or T2DM.