Background: The gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its regulatory effects in glucose metabolism GLP-1 has been found to improve left ventricular function in models of ischemic and hypertrophic cardiomyopathy while activation of the GLP-1 system by GLP-1 receptor agonists decrease cardiovascular endpoints in patients with diabetes and high cardiovascular risk. The functional relevance of GIP (the other main incretin) for cardiac remodeling and heart failure is largely unknown. The aim of the study was to investigate the role of GIP in cardiac remodeling and heart failure.

Methods: GIP (1-42) and LacZ (as control) were overexpressed with a viral adeno-associated vector system (AAV) in C57BL/6J mice (n=9/group). To investigate the effects of GIP on pressure overload-induced hypertensive cardiomyopathy we performed transaortic constriction (TAC) in C57BL/6J mice with GIP or LacZ overexpression and analysed cardiac function 5 weeks later (Millar catheter). In addition, circulating GIP serum levels of 852 patients with acute myocardial infarction were measured after hospital admission (median follow-up: 310 days).

Results: Overexpression of GIP significantly reduced aortic banding-induced left ventricular hypertrophy (30 ± 7% reduction; p<0.05; left ventricular and septal thickness), while there was a non-significant trend for decreased fibrosis (49 ± 9% reduction; p=0.055; histological quantification of collagen content) and improved parameters of diastolic myocardial function (60 ±.2% reduction in LVEDP; p<0.05; analysed by Millar catheter). Mechanistically, GIP overexpression reduced cardiac expression of the profibrotic factor TGF-β and diminished cardiac proinflammatory signaling by reducing myocardial IL-6, TNF-α and IL-1β expression, which was paralleled by an inhibition of p38 phosphorylation. Consistently, cardiac genome-wide transcriptome analysis revealed downregulation of proinflammatory networks (chemokine- and type II interferon signaling) in GIP overexpressing mice. In the clinical part of our study Kaplan-Meier curves (GIP median; cut-off: 69 pg/mL) and univariable Cox-regression analyses showed that higher GIP levels are associated with a favourable prognosis (logarithmized GIP values  HR: 0.520; p=0.020 for cardiovascular mortality) in patients with acute myocardial infarction. This association remained significant after adjustment for age, sex, smoking, previous cardiovascular disease, diabetes, hypertension, hypercholesterolemia, serum creatinin, hs-CRP, Troponin T and NT-proBNP (HR: 0.42; p=0.0495). 

Conclusion: GIP has antiinflammatory and cardioprotective effects in murine heart failure and is associated with a favourable prognosis in patients with acute myocardial infarction. Thus, targeting the GIP system might open novel therapeutical approaches for the treatment of cardiovascular disease.