Plasma dipeptidyl-peptidase-4 activity is associated with left ventricular systolic function in patients with ST-segment elevation myocardial infarction

Abstract

Plasma dipeptidyl-peptidase-4 activity (DPP4a) is inversely associated with left ventricular function in patients with heart failure (HF) or diabetes. However, the association between DPP4a and left ventricular function in ST-segment elevation myocardial infarction (STEMI) patients has not been reported. We studied this association in 584 consecutive STEMI patients at a tertiary referral center from July 2014 to October 2015. DPP4a and plasma N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels were quantified by enzymatic assays. The median serum NT-proBNP levels were highest in patients of the lowest tertile (T1) of DPP4a compared with that of the highest tertile (T3) (p = 0.028). The STEMI patients in T1 exhibited lower left ventricular systolic function (T1 vs. T3: left ventricular ejection fraction (LVEF): 50.13 ± 9.12 vs. 52.85 ± 6.82%, p = 0.001). Multivariate logisticregression analyses (adjusted for confounding variables) showed that a 1 U/L increase in DPP4a was associated with a decreased incidence of left ventricular systolic dysfunction (LVSD) (adjusted odds ratio: 0.90; 95% CI: 0.87-0.94; p < 0.01). In conclusion, low DPP4a is independently associated with LVSD in STEMI patients, which suggests that DPP4 may be involved in the mechanisms of LVSD in STEMI patients.Left ventricular systolic dysfunction (LVSD), whose representative indicator is left ventricular ejection fraction (LVEF), is an important marker of poorer prognosis in patients after an acute myocardial infarction (AMI), for both in-hospital and long-term follow-up 1, 2 . Plasma biomarkers may provide insight into the pathogenesis of LVSD while also providing prognostic information in MI patients.Dipeptidyl-peptidase-4 (DPP4) is a widely expressed enzyme, cleaving off proteins containing a position 2 alanine or proline, and thus inactivating peptides 3 . DPP4 plays an important role in glucose metabolism and is responsible for the degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide. DPP4 regulates immune responses via cleavage of many cytokines and chemokines, such as stromal-cell-derived factor-1 (SDF-1) 4 . Inhibition of DPP4 enhances endothelial regeneration and reduces atherosclerotic progression via the SDF1/chemokine receptor (CXCR)-4 axis 5 . Soluble DPP4 circulating in the plasma exerts catalytic activity cleaving oxyntomodulin 6 and SDF-1 7 , as does membrane-type DPP4. Soluble DPP4 plays a role in the development of insulin resistance, smooth muscle cell (SMC) proliferation, inflammation, and vasorelaxation 8 . Increased soluble DPP4 levels are associated with coronary artery disease 9 and heart failure (HF) 10 . We found that plasma DPP4 activity (DPP4a) is decreased in patients with MI compared with those with only chest pain or unstable angina pectoris. Also, we found that elevated DPP4a is associated with no-reflow phenomenon and a decreased rate of major bleeding events in ST-segment elevation myocardial infarction (STEMI) patients treated with percutaneous coronary ...

Reduced post-operative DPP4 activity associated with worse patient outcome after cardiac surgery

“…However, in our study cohort, no significant correlation was detected between BMI and serum DPP4 activity. This is in accordance with previous findings in STEMI patients, in whom no difference was detected in BMI among different quartiles of plasma DPP4 activity 39 , 54 . In contrast, as mentioned earlier, patients with a recent myocardial infarction exhibited a significantly reduced pre-operative DDP4 activity when compared to patients without recent infarction.…”

“…The latter became also obvious in a recent study by Li et al . demonstrating low plasma DPP4 activity to be independently associated with left ventricular systolic dysfunction in patients with ST-segment elevation myocardial infarction (STEMI) 39 . These findings are in line with our study reporting low post-operative DPP4 activity to be associated with a worse patient outcome after cardiac surgery, while the myocardial I/R injury following surgery may be in analogy to STEMI patients.…”

“…The differential findings of these studies vs. the study of Li et al . 39 and our study could be explained by the differential patient group examined with different pathophysiology of the underlying disease: as our data show that DPP4 activity is decreased by prior myocardial infarction and a larger intra-operative decrease in DPP4 activity is observed for an increased duration of aortic cross clamping, it is likely that the degree of DPP4 activity decrease after myocardial infarction or cardiac surgery reflects the severity of myocardial ischemia, and that thereby low DPP4 activity levels are associated with worse patients’ short term outcome. In our study this is further underlined by the inverse correlation of post-operative DPP4 activity with i) high levels of lactate as marker for insufficient oxygen supply, which may result from inadequate myocardial function, and ii) given the importance of the cardio-renal link 36 , with high creatinine levels as marker of kidney dysfunction.…”

A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study

“…Interestingly, although there was no difference in cardiac function between the groups, sitagliptin significantly decreased LVEF and %FS from baseline to 12 weeks. Similarly, Mulvihill et al demonstrated that a DPP-4 inhibitor impaired cardiac function in a rodent model [ 49 ] and Li et al reported that DPP-4 activity was positively correlated with LV systolic function, suggesting that DPP-4 inhibition is correlated with LV systolic dysfunction in humans [ 50 ]. Furthermore, various CVD outcome trials have indicated that DPP-4 inhibitors increase the risk of hospitalizations due to heart failure [ 9 , 51 ].…”