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

Remote Ischemic Conditioning: From Bench to Bedside

Remote ischemic conditioning (RIC) is a therapeutic strategy for protecting organs or tissue against the detrimental effects of acute ischemia-reperfusion injury (IRI). It describes an endogenous phenomenon in which the application of one or more brief cycles of non-lethal ischemia and reperfusion to an organ or tissue protects a remote organ or tissue from a sustained episode of lethal IRI. Although RIC protection was first demonstrated to protect the heart against acute myocardial infarction, its beneficial effects are also seen in other organs (lung, liver, kidney, intestine, brain) and tissues (skeletal muscle) subjected to acute IRI. The recent discovery that RIC can be induced non-invasively by simply inflating and deflating a standard blood pressure cuff placed on the upper arm or leg, has facilitated its translation into the clinical setting, where it has been reported to be beneficial in a variety of cardiac scenarios. In this review article we provide an overview of RIC, the potential underlying mechanisms, and its potential as a novel therapeutic strategy for protecting the heart and other organs from acute IRI

Clinical benefit of adenosine as an adjunct to reperfusion in ST-elevation myocardial infarction patients: An updated meta-analysis of randomized controlled trials

Background: Adenosine administered as an adjunct to reperfusion can reduce coronary no-reflow and limit myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients. Whether adjunctive adenosine therapy can improve clinical outcomes in reperfused STEMI patients is not clear and is investigated in this meta-analysis of 13 randomized controlled trials (RCTs). Methods: We performed an up-to-date search for all RCTs investigating adenosine as an adjunct to reperfusion in STEMI patients. We calculated pooled relative risks using a fixed-effect meta-analysis assessing the impact of adjunctive adenosine therapy on major clinical endpoint including all-cause mortality, non-fatal myocardial infarction, and heart failure. Surrogate markers of reperfusion were also analyzed. Results: 13 RCTs (4273 STEMI patients) were identified and divided into 2 subgroups: intracoronary adenosine versus control (8 RCTs) and intravenous adenosine versus control (5 RCTs). In patients administered intracoronary adenosine, the incidence of heart failure was significantly lower (risk ratio [RR] 0.44 [95% CI 0.25–0.78], P = 0.005) and the incidence of coronary no-reflow was reduced (RR for TIMI flow<3 postreperfusion 0.68 [95% CI 0.47–0.99], P = 0.04). There was no difference in heart failure incidence in the intravenous adenosine group but most RCTs in this subgroup were from the thrombolysis era. There was no difference in non-fatal MI or all-cause mortality in both subgroups. Conclusion: We find evidence of improved clinical outcome in terms of less heart failure in STEMI patients administered intracoronary adenosine as an adjunct to reperfusion. This finding will need to be confirmed in a large adequately powered prospective RCT

Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning

It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2.Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 +/- 2% WT vs. 17 +/- 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 +/- 9% WT vs. 56 +/- 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 +/- 3.5% HPC vs. 43.7 +/- 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 +/- 1.4% HPC vs. 24.4 +/- 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts.The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway

The Diabetic Heart: Too Sweet for Its Own Good?

Diabetes mellitus is a major risk factor for ischemic heart disease (IHD). Patients with diabetes and IHD experience worse clinical outcomes, suggesting that the diabetic heart may be more susceptible to ischemia-reperfusion injury (IRI). In contrast, the animal data suggests that the diabetic heart may be either more, equally, or even less susceptible to IRI. The conflicting animal data may be due to the choice of diabetic and/or IRI animal model. Ischemic conditioning, a phenomenon in which the heart is protected against IRI by one or more brief nonlethal periods of ischemia and reperfusion, may provide a novel cardioprotective strategy for the diabetic heart. Whether the diabetic heart is amenable to ischemic conditioning remains to be determined using relevant animal models of IRI and/or diabetes. In this paper, we review the limitations of the current experimental models used to investigate IRI and cardioprotection in the diabetic heart

Defining Peri-Operative Myocardial Injury during Cardiac Surgery Using High-Sensitivity Troponin T

Objective: Cut-offs for high-sensitivity troponin (hs-Tn) elevations to define prognostically significant peri-operative myocardial injury (PMI) in cardiac surgery is not well-established. We evaluated the associations between peri-operative high-sensitivity troponin T (hs-TnT) elevations and 1-year all-cause mortality in patients undergoing cardiac surgery. Methods: The prognostic significance of baseline hs-TnT and various thresholds for post-operative hs-TnT elevation at different time-points on 1-year all-cause mortality following cardiac surgery were assessed after adjusting for baseline hs-TnT and EuroSCORE in a post-hoc analysis of the ERICCA trial. Results: 1206 patients met the inclusion criteria. Baseline elevation in hs-TnT &gt;x1 99th percentile upper reference limit (URL) was significantly associated with 1-year all-cause mortality (adjusted hazard ratio 1.90, 95% confidence interval 1.15–3.13). In the subgroup with normal baseline hs-TnT (n = 517), elevation in hs-TnT at all post-operative time points was associated with higher 1-year mortality, reaching statistical significance for elevations above: ≥100 × URL at 6 h; ≥50 × URL at 12 and 24 h; ≥35 × URL at 48 h; and ≥30 × URL at 72 h post-surgery. Elevation in hs-TnT at 24 h ≥ 50 × URL had the optimal sensitivity and specificity (73% and 75% respectively). When the whole cohort of patients was analysed, including those with abnormal baseline hs-TnT (up to 10 × URL), the same threshold had optimal sensitivity and specificity (66% and 70%). Conclusions: Both baseline and post-operative hs-TnT elevations are independently associated with 1-year all-cause mortality in patients undergoing cardiac surgery. The optimal threshold to define a prognostically significant PMI in our study was ≥50 × URL elevation in hs-TnT at 24 h

Effect of remote ischaemic conditioning on platelet reactivity and endogenous fibrinolysis in ST-elevation myocardial infarction- a substudy of the CONDI-2/ERIC4 PPCI randomised controlled trial

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly citedBackground: Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in animal models of myocardial infarction. Platelet thrombus formation is a critical determinant of outcome in ST-segment elevation myocardial infarction (STEMI). Whether the beneficial effects of RIC are related to thrombotic parameters is unclear. Methods and Results: In a pre-specified substudy of the Effect of Remote Ischaemic Conditioning on clinical outcomes in STEMI patients undergoing Primary Percutaneous Coronary Intervention (ERIC-PPCI) trial, we assessed the effect of RIC on thrombotic status. Patients presenting with STEMI were randomised to immediate RIC consisting of an automated autoRICTM cuff on the upper arm inflated to 200mmHg for 5 minutes and deflated for 5 minutes for 4 cycles (n=53) or sham (n=47). Venous blood was tested at presentation, discharge (48 h) and 6-8 weeks, to assess platelet reactivity, coagulation and endogenous fibrinolysis using the Global Thrombosis Test and thromboelastography (TEG). Baseline thrombotic status was similar in the 2 groups. At discharge, there was some evidence that the time to in vitro thrombotic occlusion under high shear stress was longer with RIC compared to sham (454±105s vs. 403±105s; mean difference 50.1s; 95% confidence interval [CI] 93.7- 6.4, P=0.025), but this was no longer apparent at 6-8 weeks. There was no difference in clot formation or endogenous fibrinolysis between the study arms at any time-point. Conclusion: RIC may reduce platelet reactivity in the first 48h post-STEMI. Further research is needed to delineate mechanisms through which RIC may reduce platelet reactivity, and whether it may improve outcomes in patients with persistent high on-treatment platelet reactivity.Peer reviewedFinal Accepted Versio

Cardiovascular magnetic resonance in acute ST-segment-elevation myocardial infarction: recent advances, controversies, and future directions

Although mortality after ST-segment elevation myocardial infarction (MI) is on the decline, the number of patients developing heart failure as a result of MI is on the rise. Apart from timely reperfusion by primary percutaneous coronary intervention, there is currently no established therapy for reducing MI size. Thus, new cardioprotective therapies are required to improve clinical outcomes after ST-segment-elevation MI. Cardiovascular magnetic resonance has emerged as an important imaging modality for assessing the efficacy of novel therapies for reducing MI size and preventing subsequent adverse left ventricular remodeling. The recent availability of multiparametric mapping cardiovascular magnetic resonance imaging has provided new insights into the pathophysiology underlying myocardial edema, microvascular obstruction, intramyocardial hemorrhage, and changes in the remote myocardial interstitial space after ST-segment-elevation MI. In this article, we provide an overview of the recent advances in cardiovascular magnetic resonance imaging in reperfused patients with ST-segment-elevation MI, discuss the controversies surrounding its use, and explore future applications of cardiovascular magnetic resonance in this setting