Reduced post-operative DPP4 activity associated with worse patient outcome after cardiac surgery.
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.
Project description:The chemokine CXCL16 and its receptor CXCR6 have been linked to the pathogenesis of acute and chronic cardiovascular disease. However, data on the clinical significance of CXCL16 in patients undergoing cardiac surgery with acute myocardial ischemia/reperfusion (I/R) are still lacking. Therefore, we determined CXCL16 in the serum of cardiac surgery patients and investigated its kinetics and association with the extent of organ dysfunction. 48 patients underwent conventional cardiac surgery with myocardial I/R and the use of cardiopulmonary bypass (CPB) were consecutively enrolled in the present study. We investigated the peri- and post-operative profile of CXCL16. Clinical relevant data were assessed and documented throughout the entire observation period. To identify the influence of myocardial I/R and CPB on CXCL16 release data were compared to those received from patients that underwent off-pump procedure. Pre-operative serum CXCL16 levels were comparable to those obtained from healthy volunteers (1174 ± 55.64 pg/ml versus 1225 ± 70.94). However, CXCL16 levels significantly increased during surgery (1174 ± 55.64 versus 1442 ± 75.42 pg/ml; P = 0.0057) and reached maximum levels 6 hrs after termination of surgery (1174 ± 55.64 versus 1648 ± 74.71 pg/ml; P < 0.001). We revealed a positive correlation between the intraoperative serum levels of CXCL16 and the extent of organ dysfunction (r(2) = 0.356; P = 0.031). Patients with high CXCL16 release showed an increased extent of organ dysfunction compared to patients with low CXCL16 release. Our study shows that CXCL16 is released into the circulation as a result of cardiac surgery and that high post-operative CXCL16 levels are associated with an increased severity of post-operative organ dysfunctions.
Project description:Cardiovascular disease is the leading cause of death in patients with peripheral arterial disease (PAD). Coronary artery disease (CAD) is highly prevalent, and often times coexist, in patients with PAD. The management of patients with PAD that requires a high-risk vascular surgical procedure for intermittent claudication, critical limb ischemia or expanding abdominal aortic aneurysm requires risk stratification with the revised cardiac risk index, optimization of medical therapies, and limited use of cardiac imaging prior to surgery. Preventive revascularization in patients with stable CAD, with the sole intention to mitigate the risk of cardiac complications in the peri-operative period, is not effective and may be associated with significant bleeding and thrombotic risks, in particular if stents are used. A strategy of universal use of cardiac troponins in the perioperative period for active surveillance of myocardial ischemia may be more reasonable and cost-effective than the current standard of care of widespread use of cardiac imaging prior to high-risk surgery. An elevated cardiac troponin after vascular surgery is predictive of long-term mortality risk. Medical therapies such as aspirin and statins are recommended for patients with post-operative myocardial ischemia. Ongoing trials are assessing the role of novel anticoagulants. Additional research is needed to define the role of cardiac imaging and invasive angiography in this population.
Project description:Glucagon-like peptide-1 (7-36)amide (GLP-1) is cleaved by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9-36)amide. We examined whether chemical inhibition or genetic elimination of DPP-4 activity affects cardiovascular function in normoglycemic and diabetic mice after experimental myocardial infarction.Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (Dpp4(-/-)) mice versus wild-type (Dpp4(+/+)) littermate controls and after left anterior descending (LAD) coronary artery ligation-induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sitagliptin versus treatment with metformin were ascertained after experimental MI in a high-fat diet-streptozotocin model of murine diabetes. Functional recovery from ischemia-reperfusion (I/R) injury was measured in isolated hearts from Dpp4(-/-) versus Dpp4(+/+) littermates and from normoglycemic wild-type (WT) mice treated with sitagliptin or metformin. Cardioprotective signaling in the murine heart was examined by RT-PCR and Western blot analyses.Dpp4(-/-) mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic Dpp4(-/-) mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3beta, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4(-/-) heart, and HO-1, ANP, and pGSK3beta proteins were induced in nonischemic hearts from diabetic mice treated with sitagliptin or metformin. Sitagliptin and metformin treatment of wild-type diabetic mice reduced mortality after myocardial infarction. Sitagliptin improved functional recovery after I/R injury ex vivo in WT mice with similar protection from I/R injury also manifest in hearts from Dpp4(-/-) versus Dpp4(+/+) mice.Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.
Project description:Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that exerts protective effects during myocardial ischemia/reperfusion injury. We hypothesized that elevated MIF levels in the early postoperative time course might be inversely associated with postoperative organ dysfunction as assessed by the simplified acute physiology score (SAPS) II and sequential organ failure assessment (SOFA) score in patients after cardiac surgery. A total of 52 cardiac surgical patients (mean age [± SD] 67 ± 10 years; EuroScore: 7) were enrolled in this monocenter, prospective observational study. Serum levels of MIF and clinical data were obtained after induction of anesthesia, at admission to the intensive care unit (ICU), 4 h after admission and at the first and second postoperative day. To characterize the magnitude of MIF release, we compared blood levels of samples from cardiac surgical patients with those obtained from healthy volunteers. We assessed patient outcomes using the SAPS II at postoperative d 1 and SOFA score for the first 3 d of the eventual ICU stay. Compared to healthy volunteers, patients had already exhibited elevated MIF levels prior to surgery (64 ± 50 versus 13 ± 17 ng/mL; p < 0.05). At admission to the ICU, MIF levels reached peak values (107 ± 95 ng/mL; p < 0.01 versus baseline) that decreased throughout the observation period and had already reached preoperative values 4 h later. Postoperative MIF values were inversely correlated with SAPS II and SOFA scores during the early postoperative stay. Moreover, MIF values on postoperative d 1 were related to the calculated cardiac power index (r = 0.420, p < 0.05). Elevated postoperative MIF levels are inversely correlated with organ dysfunction in patients after cardiac surgery.
Project description:BACKGROUND: Severe obesity is associated with an increased risk of coronary artery disease (CAD). Bariatric surgery is an effective procedure for long term weight management as well as reduction of comorbidities. Preoperative evaluation of cardiac operative risk may often be necessary but unfortunately standard imaging techniques are often suboptimal in these subjects. The purpose of this study was to demonstrate the feasibility, safety and utility of transesophageal dobutamine stress echocardiography (TE-DSE) using an adapted accelerated dobutamine infusion protocol in severely obese subjects with comorbidities being evaluated for bariatric surgery for assessing the presence of myocardial ischemia. METHODS: Subjects with severe obesity [body mass index (BMI) >40 kg/m2] with known or suspected CAD and being evaluated for bariatric surgery were recruited. RESULTS: Twenty subjects (9M/11F), aged 50 +/- 8 years (mean +/- SD), weighing 141 +/- 21 kg and with a BMI of 50 +/- 5 kg/m2 were enrolled in the study and underwent a TE-DSE. The accelerated dobutamine infusion protocol used was well tolerated. Eighteen (90%) subjects reached their target heart rate with a mean intubation time of 13 +/- 4 minutes. Mean dobutamine dose was 31.5 +/- 9.9 ug/kg/min while mean atropine dose was 0.5 +/- 0.3 mg. TE-DSE was well tolerated by all subjects without complications including no significant arrhythmia, hypotension or reduction in blood arterial saturation. Two subjects had abnormal TE-DSE suggestive of myocardial ischemia. All patients underwent bariatric surgery with no documented cardiovascular complications. CONCLUSIONS: TE-DSE using an accelerated infusion protocol is a safe and well tolerated imaging technique for the evaluation of suspected myocardial ischemia and cardiac operative risk in severely obese patients awaiting bariatric surgery. Moreover, the absence of myocardial ischemia on TE-DSE correlates well with a low operative risk of cardiac event.
Project description:Remote ischaemic preconditioning (RIPC) by inducing brief ischaemia in distant tissues protects the heart against myocardial ischaemia-reperfusion injury (IRI) in children undergoing open-heart surgery, although its effectiveness in adults with comorbidities is controversial. The effectiveness and mechanism of RIPC with respect to myocardial IRI in children with tetralogy of Fallot (ToF), a severe cyanotic congenital cardiac disease, undergoing open heart surgery are unclear. We hypothesized that RIPC can confer cardioprotection in children undergoing ToF repair surgery.Overall, 112 ToF children undergoing radical open cardiac surgery using cardiopulmonary bypass (CPB) were randomized to either a RIPC group (n?=?55) or a control group (n?=?57). The RIPC protocol consisted of three cycles of 5-min lower limb occlusion and 5-min reperfusion using a cuff-inflator. Serum inflammatory cytokines and cardiac injury markers were measured before surgery and after CPB. Right ventricle outflow tract (RVOT) tissues were collected during the surgery to assess hypoxia-inducible factor (Hif)-1? and other signalling proteins. Cardiac mitochondrial injury was assessed by electron microscopy. The primary results showed that the length of stay in the intensive care unit (ICU) was longer in the control group than in the RIPC group (52.30?±?13.43?h vs. 47.55?±?10.34?h, respectively, P?=?0.039). Patients in the control group needed longer post-operative ventilation time compared to the RIPC group (35.02?±?6.56?h vs. 31.96?±?6.60?h, respectively, P?=?0.016). The levels of post-operative serum troponin-T at 12 and 18?h, CK-MB at 24?h, as well as the serum h-FABP levels at 6?h, after CPB were significantly lower, which was coincident with significantly higher protein expression of cardiac Hif-1?, p-Akt, p-STAT3, p-STAT5, and p-eNOS and less vacuolization of mitochondria in the RIPC group compared to the control group.In ToF children undergoing open heart surgery, RIPC attenuates myocardial IRI and improves the short-term prognosis.
Project description:Background:Coronary ostial stenosis is an uncommon but potentially lethal complication following aortic root replacement with or without aortic valve replacement (including Bentall and David procedures). This manifests clinically as acute myocardial ischaemia in the early or late post-operative period. Traditionally, this might be managed with redo open-heart surgery. Case summary:This case series describes two presentations where urgent percutaneous coronary intervention was used to manage myocardial infarction complicating aortic root surgery with coronary reimplantation. Discussion:This series highlights the risk of acute myocardial infarction after cardiac surgery involving coronary reimplantation. Emergency percutaneous coronary intervention is feasible and illustrates the importance of shared post-operative care involving the cardiac surgeons and the cardiology team.
Project description:A low plasma glutamine level was found in 34% of patients after elective cardiothoracic surgery. This could be a result of the inflammation caused by surgical stress or the use of extracorporeal circulation (ECC). But it is also possible that plasma glutamine levels were already lowered before surgery and reflect an impaired metabolic state and a higher likelihood to develop complications. In the present study plasma glutamine levels were measured before and after cardiac surgery and we questioned whether there is a relation between plasma glutamine levels and duration of ECC and the occurrence of postoperative infections.We performed a single-centre prospective, observational study in a closed-format, 20-bed, mixed ICU in a tertiary teaching hospital. We included consecutive patients after elective cardiac surgery with use of extracorporeal circulation. Blood samples were collected on the day prior to surgery and at admission on the ICU. The study was approved by the local Medical Ethics Committee (Regional Review Committee Patient-related Research, Medical Centre Leeuwarden, nWMO 115, April 28th 2015).Ninety patients were included. Pre-operative plasma glutamine level was 0.42?±?0.10 mmol/l and post-operative 0.38?±?0.09 mmol/l (p?<?0.001). There was no relation between duration of extracorporeal circulation or aortic occlusion time and changes in plasma glutamine levels. A logistic regression analysis showed a significant correlation between the presence of a positive culture during the post-operative course and pre-operative plasma glutamine levels (p?=?0.04).Plasma glutamine levels are significantly lower just after cardiac surgery compared to pre-operative levels. We did not find a relation between the decrease in plasma glutamine levels and the duration of extracorporeal circulation or aortic clamp time. There was a correlation between pre-operative plasma glutamine levels and the presence of a positive culture after cardiac surgery.ClinicalTrials.gov, number NCT02444780 .
Project description:Introduction: Post-operative delirium remains a significant problem, particularly in the older surgical patient. Previous evidence suggests that the provision of supplementary visual feedback about ones environment via the use of a mirror may positively impact on mental status and attention (core delirium diagnostic domains). We aimed to explore whether use of an evidence-based mirrors intervention could be effective in reducing delirium and improving post-operative outcomes such as factual memory encoding of the Intensive Care Unit (ICU) environment in older cardiac surgical patients. Methods: This was a pilot time-cluster randomized controlled trial at a 32-bed ICU, enrolling 223 patients aged 70 years and over, admitted to ICU after elective or urgent cardiac surgery from October 29, 2012 to June 23, 2013. The Mirrors Group received a structured mirrors intervention at set times (e.g., following change in mental status). The Usual Care Group received the standard care without mirrors. Primary outcome was ICU delirium incidence; secondary outcomes were ICU delirium days, ICU days with altered mental status or inattention, total length of ICU stay, physical mobilization (balance confidence) at ICU discharge, recall of factual and delusional ICU memories at 12 weeks, Health-Related Quality of Life at 12 weeks, and acceptability of the intervention. Results: The intervention was not associated with a significant reduction in ICU delirium incidence [Mirrors: 20/115 (17%); Usual Care: 17/108 (16%)] or duration [Mirrors: 1 (1-3); Usual Care: 2 (1-8)]. Use of the intervention on ICU was predictive of significantly higher recall of factual (but not delusional) items at 12 weeks after surgery (p = 0.003) and acceptability was high, with clinicians using mirrors at 86% of all recorded hourly observations. The intervention did not significantly impact on other secondary outcomes. Conclusion: Use of a structured mirrors intervention on the post-operative ICU does not reduce delirium, but may result in improved factual memory encoding in older cardiac surgical patients. This effect may occur via mechanisms unrelated to delirium, altered mental status, or inattention. The intervention may provide a new means of improving outcomes in patients at risk of post-ICU anxiety and/or Post-Traumatic Stress Disorder. Trial Registration: Clinicaltrials.gov identifier NCT01599689.
Project description:BACKGROUND:Impaired cardiac vagal function, quantified preoperatively as slower heart rate recovery (HRR) after exercise, is independently associated with perioperative myocardial injury. Parasympathetic (vagal) dysfunction may also promote (extra-cardiac) multi-organ dysfunction, although perioperative data are lacking. Assuming that cardiac vagal activity, and therefore heart rate recovery response, is a marker of brainstem parasympathetic dysfunction, we hypothesized that impaired HRR would be associated with a higher incidence of morbidity after noncardiac surgery. METHODS:In two prospective, blinded, observational cohort studies, we established the definition of impaired vagal function in terms of the HRR threshold that is associated with perioperative myocardial injury (HRR ? 12 beats min-1 (bpm), 60 seconds after cessation of cardiopulmonary exercise testing. The primary outcome of this secondary analysis was all-cause morbidity three and five days after surgery, defined using the Post-Operative Morbidity Survey. Secondary outcomes of this analysis were type of morbidity and time to become morbidity-free. Logistic regression and Cox regression tested for the association between HRR and morbidity. Results are presented as odds/hazard ratios [OR or HR; (95% confidence intervals). RESULTS:882/1941 (45.4%) patients had HRR?12bpm. All-cause morbidity within 5 days of surgery was more common in 585/822 (71.2%) patients with HRR?12bpm, compared to 718/1119 (64.2%) patients with HRR>12bpm (OR:1.38 (1.14-1.67); p = 0.001). HRR?12bpm was associated with more frequent episodes of pulmonary (OR:1.31 (1.05-1.62);p = 0.02)), infective (OR:1.38 (1.10-1.72); p = 0.006), renal (OR:1.91 (1.30-2.79); p = 0.02)), cardiovascular (OR:1.39 (1.15-1.69); p<0.001)), neurological (OR:1.73 (1.11-2.70); p = 0.02)) and pain morbidity (OR:1.38 (1.14-1.68); p = 0.001) within 5 days of surgery. CONCLUSIONS:Multi-organ dysfunction is more common in surgical patients with cardiac vagal dysfunction, defined as HRR ? 12 bpm after preoperative cardiopulmonary exercise testing. CLINICAL TRIAL REGISTRY:ISRCTN88456378.