Coronary artery disease (CAD) is one of the leading causes of death and disability in Europe and worldwide. For patients with multi-vessel CAD, coronary artery bypass graft (CABG) surgery is a common approach for coronary revascularization, and is of proven symptomatic and prognostic benefit. Due to an aging population, higher prevalence of co-morbidities (such as diabetes mellitus, heart failure, hypertension, and renal failure), and a growing requirement for concomitant surgical procedures (such as valve and aortic surgery), higher risk patients are undergoing surgery. ^1–3 This has resulted in an increased risk of peri-operative myocardial injury (PMI) ⁴ and Type 5 myocardial infarction (MI), both of which are associated with worsened clinical outcomes following CABG surgery. The aetiology and determinants of PMI and Type 5 MI are multi-factorial (see Tables 1 and 2 for summary). Although diagnostic criteria have been proposed for Type 5 MI (based on an elevation in cardiac biomarkers in the 48-h post-operative period and electrocardiogram/angiography/imaging evidence of MI ^{5, 13}), there is currently no clear definition for prognostically significant PMI, in terms of the level of post-operative cardiac biomarker elevation, which is associated with worsened clinical outcomes following CABG surgery.

Background: The catalytic subunit of telomerase, Telomerase Reverse Transcriptase (TERT) has protective functions in the cardiovascular system. TERT is not only present in the nucleus, but also in mitochondria. However, it is unclear whether nuclear or mitochondrial TERT is responsible for the observed protection and appropriate tools are missing to dissect this. Methods: We generated new mouse models containing TERT exclusively in the mitochondria (mitoTERT mice) or the nucleus (nucTERT mice) to finally distinguish between the functions of nuclear and mitochondrial TERT. Outcome after ischemia/reperfusion, mitochondrial respiration in the heart as well as cellular functions of cardiomyocytes, fibroblasts, and endothelial cells were determined. Results: All mice were phenotypically normal. While respiration was reduced in cardiac mitochondria from TERT-deficient and nucTERT mice, it was increased in mitoTERT animals. The latter also had smaller infarcts than wildtype mice, whereas nucTERT animals had larger infarcts. The decrease in ejection fraction after one, two and four weeks of reperfusion was attenuated in mitoTERT mice. Scar size was also reduced and vascularization increased. Mitochondrial TERT protected a cardiomyocyte cell line from apoptosis. Myofibroblast differentiation, which depends on complex I activity, was abrogated in TERT-deficient and nucTERT cardiac fibroblasts and completely restored in mitoTERT cells. In endothelial cells, mitochondrial TERT enhanced migratory capacity and activation of endothelial NO synthase. Mechanistically, mitochondrial TERT improved the ratio between complex I matrix arm and membrane subunits explaining the enhanced complex I activity. In human right atrial appendages, TERT was localized in mitochondria and there increased by remote ischemic preconditioning. The Telomerase activator, TA-65 evoked a similar effect in endothelial cells, thereby increasing their migratory capacity, and enhanced myofibroblast differentiation. Conclusions: Mitochondrial, but not nuclear TERT, is critical for mitochondrial respiration and during ischemia/reperfusion injury. Mitochondrial TERT improves complex I subunit composition. TERT is present in human heart mitochondria, and remote ischemic preconditioning increases its level in those organelles. TA-65 has comparable effects ex vivo and improves migratory capacity of endothelial cells and myofibroblast differentiation. We conclude that mitochondrial TERT is responsible for cardioprotection and its increase could serve as a therapeutic strategy.

Background: Acute kidney injury (AKI) affects up to 30% of patients undergoing cardiac surgery, leading to increased in-hospital and long-term morbidity and mortality. Teprasiran is a novel small interfering RNA that temporarily inhibits p53-mediated cell death that underlies AKI. Methods: This prospective, multicenter, double-blind, randomized, controlled phase 2 trial evaluated the efficacy and safety of a single 10 mg/kg dose of teprasiran versus placebo (1:1), in reducing the incidence, severity, and duration of AKI after cardiac surgery in high-risk patients. The primary end point was the proportion of patients who developed AKI determined by serum creatinine by postoperative day 5. Other end points included AKI severity and duration using various prespecified criteria. To inform future clinical development, a composite end point of major adverse kidney events at day 90, including death, renal replacement therapy, and ≥25% reduction of estimated glomerular filtration rate was assessed. Both serum creatinine and serum cystatin-C were used for estimated glomerular filtration rate assessments. Results: A total of 360 patients were randomly assigned in 41 centers; 341 dosed patients were 73±7.5 years of age (mean±SD), 72% were men, and median European System for Cardiac Operative Risk Evaluation score was 2.6%. Demographics and surgical parameters were similar between groups. AKI incidence was 37% for teprasiran- versus 50% for placebo-treated patients, a 12.8% absolute risk reduction, P =0.02; odds ratio, 0.58 (95% CI, 0.37–0.92). AKI severity and duration were also improved with teprasiran: 2.5% of teprasiran- versus 6.7% of placebo-treated patients had grade 3 AKI; 7% teprasiran- versus 13% placebo-treated patients had AKI lasting for 5 days. No significant difference was observed for the major adverse kidney events at day 90 composite in the overall population. No safety issues were identified with teprasiran treatment. Conclusions: The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration. A phase 3 study with a major adverse kidney event at day 90 primary outcome that has recently completed enrollment was designed on the basis of these findings (NCT03510897). Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02610283.

There are few data assessing factors, which identify patients with liver cirrhosis (LC) facing high risk for open-heart surgery. We sought to compare the Model for End-Stage Liver Disease (MELD) score, the Child-Turcotte-Pugh (CTP) classification and the European system for cardiac operative risk evaluation (EuroSCORE) for risk prediction in cirrhotic patients. Fifty-seven consecutive patients with non-cardiac LC, who underwent open-heart surgery with the use of cardiopulmonary bypass between 1998 and 2008, were studied at our institution. Potential preoperative predictors of outcome, as well as preoperative MELD score, CTP classification and EuroSCORE were calculated. The primary study end points were all-cause in-hospital and long-term mortality. MELD score and CTP classification both differed significantly between survivors and non-survivors for in-hospital (P<0.0001) and long-term mortality (P<0.0001). Univariate predictors of in-hospital mortality were emergency surgery (odds ratio (OR), 4.9; 95% confidence interval (CI), 1.2-20.6; P=0.03), ascites (OR, 7.2; 95% CI, 2.0-25.5; P=0.002), total serum protein (OR, 0.4; 95% CI, 0.2-0.8; P=0.01), CTP class (OR, 5.5; 95% CI, 1.4-21.5; P=0.04) and MELD score (OR, 1.4; 95% CI, 1.1-1.6; P=0.001). Multivariable exact logistic regression analyses revealed MELD score (OR, 1.3; 95% CI, 1.005-1.6; P=0.04) as the only independent factor associated with in-hospital mortality. Receiver operating characteristic curve (ROC) analysis showed MELD score to be highly predictive with an optimal cut-off value of 13.5 (sensitivity: 82.0%, specificity: 78.5%) for postoperative in-hospital mortality (area under curve (AUC): 85.1 ± 0.05%) and superior compared to the CTP classification (AUC: 75.7±0.08%) and EuroSCORE (AUC: 65.9 ± 0.08%). The mortality of patients with liver cirrhosis undergoing open-heart surgery progressively increases with the severity of liver dysfunction. Therefore, the MELD score most reliably identifies those cirrhotic patients who are at high risk for open-heart surgery.