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Aims: Recent studies have found circulating concentrations of the gastrointestinal hormone GLP-1 to be an excellent predictor of cardiovascular risk in patients with myocardial infarction. This illustrates a yet not appreciated crosstalk between the gastrointestinal and cardiovascular systems, which requires further investigation. The gut-derived hormone Peptide YY (PYY) is secreted from the same intestinal L-cells as GLP-1. Relevance of PYY in the context of cardiovascular disease has not been explored. In this study, we aimed to investigate PYY serum concentrations in patients with acute myocardial infarction and to evaluate their association with cardiovascular events. Material and Methods: PYY levels were assessed in 834 patients presenting with acute myocardial infarction (553 Non-ST-Elevation Myocardial Infarction (NSTEMI) and 281 ST-Elevation Myocardial Infarction (STEMI)) at the time of hospital admission. The composite outcomes of first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke (3-P-MACE), and all-cause mortality were assessed with a median follow-up of 338 days. Results: PYY levels were significantly associated with age and cardiovascular risk factors, including hypertension, diabetes, and kidney function in addition to biomarkers of heart failure (NT-pro BNP) and inflammation (hs-CRP). Further, PYY was significantly associated with 3-P-MACE (HR: 1.7, 95% CI: 1&ndash, 2.97, p = 0.0495) and all-cause mortality (HR: 2.69, 95% CI: 1.61&ndash, 4.47, p = 0.0001) by univariable Cox regression analyses, which was however lost after adjusting for multiple confounders. Conclusions: PYY levels are associated with parameters of cardiovascular risk as well as cardiovascular events and mortality in patients presenting with acute myocardial infarction. However, this significant association is lost after adjustment for further confounders.

Myocardial infarction causes rapid impairment of left ventricular function and requires a hypercontractile response of non-infarcted tissue areas to maintain haemodynamic stability. This compensatory adaptation is mediated by humoral, inflammatory and neuronal signals. GLP-1 is an incretin hormone with glucoregulatory and cardioprotective capacities and is secreted in response to nutritional and inflammatory stimuli. Inactivation of GLP-1 is caused by the ubiquitously present enzyme DPP-4. In this study, circulating concentrations of GLP-1 were assessed after myocardial infarction and were evaluated in the light of metabolism, left ventricular contractility and mitochondrial function. Circulating GLP-1 concentrations were markedly increased in patients with acute myocardial infarction. Experimental myocardial infarction by permanent LAD ligation proved sufficient to increase GLP-1 secretion in mice. This took place in a time-dependent manner, which coincided with the capacity of DPP-4 inhibition, by linagliptin, to augment left ventricular contractility in a GLP-1 receptor-dependent manner. Mechanistically, DPP-4 inhibition increased AMPK activity and stimulated the mitochondrial respiratory capacity of non-infarcted tissue areas. We describe a new functional relevance of inflammatory GLP-1 secretion for left ventricular contractility during myocardial infarction.

Objectives Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy. Background SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart. Methods We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress. Results Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected. Conclusions In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.

DPP-4 inhibitors are a class of antidiabetic drugs which act by augmentation of the GLP-1 system and insulin secretion. Despite similar glucose lowering efficacy within the class, only saxagliptin increased heart failure hospitalization in diabetic patients. This unexpected effect might relate to the metabolism of saxagliptin (saxa). Here, we directly compare linagliptin (lina, 3 mg/kg, p.o.), saxa (10 mg/kg, p.o.), and its metabolite 5-hydroxy-saxagliptin (OH-saxa, 10 mg/kg, p.o.) to the sulfonylurea glimepiride (glim, 2 mg/kg, p.o.) and control during acute myocardial infarction in mice. Millar catheter analysis under dobutamin stress 6h post (permanent) LAD ligation were performed. Drugs were given 3 days prior infarction. Active GLP-1 was significantly increased by Lina (1,69 fold), saxa (1,49 fold) and OH-saxa (2,27 fold) vs. control (each p < 0.05), but not by glim. Despite similar GLP-1 levels, only lina and saxa but not OH-saxa or glim increased left ventricular contractility (Lina: 11.549 ± 795 dp/dt max; p < 0.0001; n=9. Saxa: 10.121 ± 200 dp/dt max; p < 0.05; n=12. OH-saxa: 8.201 ± 567 dp/dt max; n=7. Glim: 9.947 ± 813 dp/dt max; n=6 relative to control: 8.764 ± 284 dp/dt max; n=21). We further isolated mitochondria from non-infarcted myocardial tissue and found for lina 2.89 fold (p < 0.0001; n=3), saxa 1.78 fold (p < 0.05; n=8) and OH-saxa 2.2 fold (p < 0.01; n=4) increase in mitochondrial respiration by Clark electrode, but not for glim. In conclusion, only linagliptin and saxagliptin increased left ventricular contractility and myocardial mitochondrial respiration following LAD ligation; 5-hydroxy-saxagliptin had no effect on contractility despite increasing mitochondrial respiration. Glimepiride had no effect on contractility and mitochondrial function. Metabolism of saxagliptin might be linked to differences found in the DPP-4 class regarding heart failure. Disclosure E. Haj-Yehia: None. S. Diebold: None. J. Moellmann: None. F. Kahles: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. M. Mark: Employee; Self; Boehringer Ingelheim GmbH. N. Marx: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K..