Dysfunctional EAT thickness may promote maladaptive heart remodeling in CVD patients through the ST2-IL33 system, directly related to EPAC protein expression.

Dysfunctional epicardial adipose tissue (EAT) secretome can influence the heart's stretch response. However, the molecular mechanisms are still poorly understood. The aim of this study was to clarify how dysfunctional EAT promotes maladaptive heart remodeling in cardiovascular disease (CVD) through ST2 production associated with exchange protein directly activated by cAMP (EPAC) proteins. A series of 55 CVD males were enrolled and their EAT thickness, LV mass and volumes were measured by echocardiography. Blood, plasma and EAT biopsies were collected for molecular and proteomic assays. Taking EAT thickness as a continuous variable there was a direct correlation between the ST2 cardiac stretch mediator and EAT thickness (r = 0.54, p < 0.01) and an inverse relation between the ST2 gene and IL-33 expression (r -0.50, p < 0.01). In the CVD population EPAC2 expression directly correlated with the ST2 gene (r = 0.74, p < 0.0001) causing an ST2/IL-33 system local (p < 0.001) and systemic (sST2 = 57.33 ± 3.22 and IL-33 = 0.53 ± 017 pg/mL; p < 0.0001) protein imbalance associated with maladaptive remodeling. This indicated that dysfunctional EAT is a source of both EPAC and ST2 protein and an EPAC2 isoform seems involved in ST2 production in adipose tissue. Both EPAC2 and ST2 expression were directly related to maladaptive heart remodeling indices, suggesting EAT measurements could be useful in the early assessment of CVD complications.