Time to Give Up on Cardioprotection?

Abstract

Abstract:The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of postmyocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-ofconcept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection. (Circ Res. 2016;119:676-695.

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

“…Despite extension of the concept to ischemic postconditioning [460] and remote ischemic conditioning [202, 344] and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps [199], so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients [155, 200]. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies [54, 195], and poor design and conduct of clinical trials [196, 206]. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial.…”

Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning

“…Recently, the first prospective, randomized trial on patients with reperfused acute myocardial infarction confirmed improved clinical outcome as a primary end point of remote ischemic conditioning during follow‐up for 3.6 years 13. Even if there is good evidence for cardioprotection by remote ischemic conditioning in patients, not all studies are positive,16 and the underlying signaling is not well understood. Obviously, remote ischemic conditioning induces a systemic response because it protects also organs other than the heart.…”

Remote Limb Ischaemic Postconditioning Protects Against Myocardial Ischaemia/Reperfusion Injury in Mice: Activation of JAK/STAT3-Mediated Nrf2-Antioxidant Signalling

“…However, there have been some clinical trials showing that ischaemic pre-, post- and remote conditioning have no effect on patients with acute myocardial infarction, given that patients receiving cardiac surgery almost always have comorbidities such as diabetes, ageing, and obesity that comprise the beneficial effects of cardioprotective interventions (e.g., remote ischaemic postconditioning). It is not yet time to give up on cardioprotection through conditioning interventions; efforts should be made to further explore the underlying mechanism of these cardioprotective interventions [9, 10]. According to recent studies, the mechanism of RIPostC cardioprotection may involve autophagy [11] and transient receptor potential vanilloid 1 activation [12] in animal models.…”