Effects Of Acute Ischaemia-reperfusion Injury Research Articles

Effect of hyperglycaemia and diabetes on acute myocardial ischaemia-reperfusion injury and cardioprotection by ischaemic conditioning protocols.

Diabetic patients are at increased risk of developing coronary artery disease and experience worse clinical outcomes following acute myocardial infarction. Novel therapeutic strategies are required to protect the myocardium against the effects of acute ischaemia-reperfusion injury (IRI). These include one or more brief cycles of non-lethal ischaemia and reperfusion prior to the ischaemic event (ischaemic preconditioning [IPC]) or at the onset of reperfusion (ischaemic postconditioning [IPost]) either to the heart or to extracardiac organs (remote ischaemic conditioning [RIC]). Studies suggest that the diabetic heart is resistant to cardioprotective strategies, although clinical evidence is lacking. We overview the available animal models of diabetes, investigating acute myocardial IRI and cardioprotection, experiments investigating the effects of hyperglycaemia on susceptibility to acute myocardial IRI, the response of the diabetic heart to cardioprotective strategies e.g. IPC, IPost and RIC. Finally we highlight the effects of anti-hyperglycaemic agents on susceptibility to acute myocardial IRI and cardioprotection. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.23/issuetoc.

Preconditioning and postconditioning: from bench to bedside

Coronary heart disease (CHD) is the leading cause of death world-wide. Since 1990, more people in the world have diedfrom CHD than from any other disease (World Health Organisation, WHO). “Conditioning” the heart to render it more resistant to the detrimental effects of acute ischaemia-reperfusion injury harnesses the endogenous ability of the heart to protect itself. This can be achieved using various mechanical strategies including the application of brief episodes of ischaemia and reperfusion to either the heart itself (ischaemic preconditioning) or an organ/tissue remote from the heart (remote ischaemic preconditioning) prior to the sustained ischaemic insult. Importantly, this form of protection can be mimicked by pharmacological agents capable of recapitulating the protective effect of IPC(pharmacological preconditioning). Preconditioning-induced cardioprotection is clearly restricted to patients undergoing an anticipated ischaemic insult such as in patients undergoing cardiac surgery. In contrast, the other major form of “conditioning” termed postconditioning can be implemented in patients presenting with an acute myocardial infarction after the onset of the sustained ischaemic insult. In this setting, myocardial reperfusion is interrupted with intermittent short-lived episodes of myocardial ischaemia applied to the heart itself (ischaemic postconditioning) or an organ or tissue remote from the heart (remote ischaemic postconditioning) – an effect which can again be mimicked by pharmacological agents (pharmacological postconditioning).This article will briefly review these various forms of“conditioning” examining the underlying mechanistic pathways and their clinical application.

Cardiac troponins and volatile anaesthetics in coronary artery bypass graft surgery: A systematic review, meta-analysis and trial sequential analysis.

Reports from animal studies indicate that volatile anaesthetics protect the myocardium against the effects of acute ischaemia-reperfusion injury by reducing infarct size. This cardioprotective effect in the clinical setting of coronary artery bypass graft (CABG) surgery, where the heart is subjected to global ischaemia-reperfusion injury, remains controversial. The objective was to demonstrate that clinical studies investigating the cardioprotective effect of volatile anaesthetics on cardiac troponins in CABG are no longer warranted. We also investigated the effect of volatile anaesthetics on cardiac enzymes in off-pump cardiac surgery. Systematic review of randomised clinical trials, meta-analyses and trial sequential analysis (TSA). Trials between January 1985 and March 2015 were obtained from electronic databases (Medline, Excerpta Medica Database (EMBASE), Cochrane Controlled Trial Register, abstracts from major anaesthesiology and cardiology journals and reference lists of relevant randomised trials and review articles. Relevant randomised clinical trials were included. We investigated the effect of volatile anaesthetics in both off-pump and on-pump CABG surgery with respect to troponin release [peak postoperative cardiac troponin I (cTnI) and cardiac troponin T (cTnT), cTnI/cTnT] and performed two separate meta-analyses. TSA was used to overcome the weakness of a type-1 error associated with repeated meta-analyses. From 30 studies, 2578 patients were pooled for the meta-analysis. The outcome significantly favours the use of peroperative volatile over non-volatile anaesthetics during on-pump CABG surgery with regard to peak postoperative cTnI (0.995 mg l; standard mean difference, 95% confidence interval, -1.316 to -0.673; P < 0.001). Meta-analysis of 11 off-pump studies showed no difference in peak postoperative cTnI (0.385 mg l; standard mean difference, 95% confidence interval, -0.857 to 0.087; P = 0.11). TSA indicated that the required information size for on-pump surgery was 1072 patients, and for off-pump surgery it was 1442; this latter figure has not yet been reached. Studies investigating the cardioprotective effect of volatile anaesthetics on cardiac troponins in on-pump CABG surgery are no longer warranted. This is not yet the case for off-pump surgery.

Remote ischaemic conditioning: cardiac protection from afar.

For patients with ischaemic heart disease, remote ischaemic conditioning may offer an innovative, non‐invasive and virtually cost‐free therapy for protecting the myocardium against the detrimental effects of acute ischaemia‐reperfusion injury, preserving cardiac function and improving clinical outcomes. The intriguing phenomenon of remote ischaemic conditioning was first discovered over 20 years ago, when it was shown that the heart could be rendered resistant to acute ischaemia‐reperfusion injury by applying one or more cycles of brief ischaemia and reperfusion to an organ or tissue away from the heart – initially termed ‘cardioprotection at a distance’. Subsequent pre‐clinical and then clinical studies made the important discovery that remote ischaemic conditioning could be elicited non‐invasively, by inducing brief ischaemia and reperfusion to the upper or lower limb using a cuff. The actual mechanism underlying remote ischaemic conditioning cardioprotection remains unclear, although a neuro‐hormonal pathway has been implicated. Since its initial discovery in 1993, the first proof‐of‐concept clinical studies of remote ischaemic conditioning followed in 2006, and now multicentre clinical outcome studies are underway. In this review article, we explore the potential mechanisms underlying this academic curiosity, and assess the success of its application in the clinical setting.

ESC working group cellular biology of the heart: position paper: improving the preclinical assessment of novel cardioprotective therapies.

Ischaemic heart disease (IHD) remains the leading cause of death and disability worldwide. As a result, novel therapies are still needed to protect the heart from the detrimental effects of acute ischaemia–reperfusion injury, in order to improve clinical outcomes in IHD patients. In this regard, although a large number of novel cardioprotective therapies discovered in the research laboratory have been investigated in the clinical setting, only a few of these have been demonstrated to improve clinical outcomes. One potential reason for this lack of success may have been the failure to thoroughly assess the cardioprotective efficacy of these novel therapies in suitably designed preclinical experimental animal models. Therefore, the aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to provide recommendations for improving the preclinical assessment of novel cardioprotective therapies discovered in the research laboratory, with the aim of increasing the likelihood of success in translating these new treatments into improved clinical outcomes.

Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Ischaemic heart disease (IHD) is the leading cause of death and disability worldwide. The pathophysiological effects of IHD on the heart most often result from the detrimental effects of acute ischaemia-reperfusion injury (IRI) on the myocardium. Therefore, novel therapeutic targets for protecting the myocardium against acute IRI are required to reduce injury to the heart, preserve cardiac function and improve clinical outcomes in patients with IHD. In this regard, the mitochondrial permeability transition pore (mPTP) has emerged as a critical target for cardioprotection which is readily amenable to intervention at the time of myocardial reperfusion. The formation and opening of the mPTP at the onset of myocardial reperfusion is a major determinant of mitochondrial dysfunction and cardiomyocyte death in the setting of acute IRI. The seminal discovery in the late 1980s that mPTP opening could be pharmacologically inhibited by the immunosuppressive agent, cyclosporin A (CsA), has been fundamental in the elucidation of the critical role of the mPTP as a mediator of acute IRI and, therefore, a viable target for cardioprotection. Its initial role as an investigative tool was used to identify mitochondrial cyclophilin D to be a regulatory component of the mPTP. The mPTP as a viable target for cardioprotection has recently been translated into the clinical setting with CsA reducing myocardial infarct size in patients. In this article, we review the intriguing role of CsA as a tool for investigating the mPTP as a target for cardioprotection and its potential role as a therapeutic agent for patients with IHD.

Cardiac preconditioning for ischaemia: lost in translation

Coronary heart disease (CHD) is the leading cause of death worldwide. The development of novel treatment strategies for protecting the myocardium against the detrimental effects of acute ischaemia-reperfusion injury, termed cardioprotection, and for improving clinical outcomes in patients with CHD requires the use of appropriate animal disease models. The concept of cardioprotection was first conceived in the late 1960s and has evolved to include the endogenous cardioprotective phenomenon of ischaemic conditioning, a concept in which the heart can be protected from an episode of acute lethal ischaemia-reperfusion injury by applying brief non-lethal episodes of ischaemia and reperfusion either to the heart itself or to an organ or tissue that is remote from the heart. The brief conditioning episodes of ischaemia and reperfusion can be applied prior to the index ischaemic episode (ischaemic preconditioning), after the onset of the index ischaemic episode (ischaemic perconditioning), or at the onset of reperfusion (ischaemic postconditioning). Elucidation of the signal transduction pathways underlying ischaemic conditioning has identified a variety of pharmacological agents that are capable of reproducing its cardioprotective actions. Despite a wealth of preclinical, experimental animal data demonstrating clear cardioprotective benefits with these treatment strategies, their translation into clinical therapy has been hugely disappointing. This review explores the potential reasons behind this failure; it will focus primarily on the inadequacy of the experimental animal disease models that are currently being used to investigate novel cardioprotective strategies, which on the whole are not adequately representative of the clinical scenario, and finally, we will discuss potential solutions to remedy this problem.

Cardioprotective growth factors

Many of the originally identified cardiovascular 'growth factors' have been demonstrated to exert a diverse variety of actions within the cardiovascular system, the majority of which are unrelated to their initially proposed mechanism of action. Interestingly, several of these growth factors have been demonstrated to protect the cardiomyocyte from the detrimental effects of acute ischaemia-reperfusion injury, through the activation of a variety of cell-surface receptors and the subsequent recruitment of a number of intracellular signal transduction pathways, which include components of the reperfusion injury salvage kinase pathway. This article will review several of these cardioprotective growth factors with respect to their ability to confer direct myocardial protection, focusing on the underlying signalling pathways involved and their potential for clinical application.

Drug discovery possibilities from visfatin cardioprotection?

The adipocytokine, visfatin, exerts a diverse variety of effects that include the ability to mimic the glucose-lowering effects of insulin. In addition to its anti-hyperglycaemic action, recent evidence suggests that visfatin may be responsible for a number of different cardiovascular effects, depending on the cell type and the duration of therapy, one of which includes the ability to protect the myocardium from the detrimental effects of acute ischaemia-reperfusion injury. As such visfatin may not only provide a potential new target for acute cardioprotection but it may also act as an anti-diabetic agent with a unique mechanism of action, thereby offering a potentially novel drug target for the diabetic patient that experiences an episode of acute myocardial ischaemia-reperfusion injury.