Abstract
Cardiac surgery with cardiopulmonary bypass (CPB) triggers myocardial ischemia/reperfusion injury contributing to organ dysfunction. Preclinical studies revealed that dipeptidyl peptidase (DPP4) inhibition is protective during myocardial infarction. Here, we assessed for the first time the relation of peri-operative DPP4-activity in serum of 46 patients undergoing cardiac surgery with patients’ post-operative organ dysfunction during intensive care unit (ICU) stay. Whereas a prior myocardial infarction significantly reduced pre-operative DDP4-activity, patients with preserved left ventricular function showed an intra-operative decrease of DPP4-activity. The latter correlated with aortic cross clamping time, indicative for the duration of surgery-induced myocardial ischemia. As underlying mechanism, mass-spectrometry revealed increased DPP4 oxidation by cardiac surgery, with DPP4 oxidation reducing DPP4-activity in vitro. Further, post-operative DPP4-activity was negatively correlated with the extent of post-operative organ injury as measured by SAPS II and SOFA scoring, circulating levels of creatinine and lactate, as well as patients’ stay on the ICU. In conclusion, cardiac surgery reduces DPP4-activity through oxidation, with low post-operative DPP4-activity being associated with organ dysfunction and worse outcome of patients during the post-operative ICU stay. This likely reflects the severity of myocardial ischemia/reperfusion injury and may suggest potential beneficial effects of anti-oxidative treatments during cardiac surgery.
Highlights
Worldwide cardiovascular disease (CVD) is considered a major cause of morbidity and mortality, being responsible for 45% of non-communicable diseases[1]
Since glucagon-like peptide (GLP)-1 plays a major role in glucose metabolism, dipeptidyl peptidase 4 (DPP4) inhibitors are used for the treatment of type 2 diabetes mellitus (T2DM) with the aim to reduce the rate of GLP-1 inactivation and thereby reduce blood glucose levels[13]
In contrast to the wealth of animal studies focusing on DPP4 in inflammation and myocardial infarction, no data are available on the kinetics and clinical significance of DPP4 activity in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB)
Summary
Worldwide cardiovascular disease (CVD) is considered a major cause of morbidity and mortality, being responsible for 45% of non-communicable diseases[1]. Large-scale clinical trials examining the cardiovascular-protective effect of long-term DPP4 inhibitor treatment could not detect a reduction of cardiovascular events in patients with diabetes[22,23,24,25,26,27], and some studies even surprisingly reported an increased hospitalization rate for heart failure[23,24,28]. This indicates that, despite attractive clinical features observed in animal models, the relation of DPP4 activity to clinical outcome requires further investigation in clinical practice. Before advancing to a large-scale analysis to evaluate the effect of DPP4 inhibitors in this population, we aimed to provide first evidence about the peri-operative DDP4 activity and resulting clinical significance in patients undergoing cardiac surgery
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