Project description:Background On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia–reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. Methods We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia–reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia–reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. Findings In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32–0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68–0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning–afternoon variation in hypoxia–reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia–reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia–reperfusion injury modulator CDKN1a/p21. Interpretation Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery.

Project description:Myocardial infarction (MI), an undesirable clinical outcome of coronary artery disease (CAD), triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, which is necessary for myocardial healing. However, when in excess, causes pathological tissue remodeling and eventual heart failure. Timely repression of MI-induced inflammatory response are critical to prevent and minimize cardiac tissue injuries, nonetheless, progression in this aspect remains clinically challenging. The well documentation on the ability of EVs to trigger a functional response with the delivery of bioactive cargos carried within, have made them clinically attractive as diagnostic biomarkers and drug vectors for therapeutic interventions. Using label-free quantitative proteomics approach, we compared the protein cargo of plasma EVs between patients with (MI) and from control patients with stable angina (NMI). We report, for the first time, the expression proteomics profiling on 252 plasma EV proteins that were modulated with >1.2-fold in myocardial injury. We identified a panel of six strongly up-regulated biomarkers with significant potential for clinical applications; these reflected post-infarct pathways of complement activation (Complement C1q subcomponent subunit A [C1QA], ~3.23-fold change, p = 0.012; Complement C5 [C5], ~1.27-fold change, p = 0.087), lipoprotein metabolism (Apoliporotein D [APOD], ~1.86-fold change, p = 0.033; Apolipoprotein C-III [APOCC3], ~2.63-fold change, p = 0.029) and platelet activation (Platelet glycoprotein Ib alpha chain [GP1BA], ~9.18-fold change, p < 0.0001; Platelet basic protein [PPBP], ~4.72-fold change, p = 0.027). The data have been deposited to the ProteomeXchange with identifier PXD002950. This novel biomarker panel was successfully validated in a separate cohort of 43 individual angina patients using Luminex analysis of the representative EV proteins C1QA (p = 0.005) and C5 (p = 0.0021), which act as critical regulators of complement activity in MI. We further present that all EV-derived fibrinogen components detected were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, and indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data urge the further development of novel EV-based diagnostic and therapeutic strategies to benefit patients with CAD.

Dataset Information

Plasma microRNA signatures for perioperative myocardial injury.

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