Ischemic and postischemic conditioning of the myocardium in clinical practice: Challenges, expectations and obstacles

Conditioning refers to endogenous mechanisms rendering the myocardium more tolerant against reperfusion injury. Application of brief ischemia-reperfusion cycles prior to the index ischemia has a beneficial effect and limits the infarct size. This is called preconditioning and is mainly mediated by activation of adenosine, bradykinin, opioid and other receptors, with subsequent activation of intracellular mediators leading to mitochondrial protection. A clinical equivalent of preconditioning is preinfarction angina. Benefits for the ischemic and reperfused myocardium are also provided by repetitive short-lived cycles of ischemia-reperfusion applied after the index ischemia. This is termed postconditioning, shares a common pathway with preconditioning, and is more useful and relevant in clinical practice. Finally, benefits are also derived from remote conditioning, i.e. ischemia applied in a remote vascular territory parallel with or immediately after the index myocardial ischemia. Several pharmacological interventions may interfere with these mechanisms leading to enhanced protection of the myocardium and limitation of the infarct size. Despite the huge interest and the great body of evidence that verify the effectiveness of conditioning, clinical application has remained limited due to controversies over the appropriate intervention protocol, but also interference of medication, comorbidities and other factors that may enhance or blur the protective effect. © 2014 S. Karger AG, Basel

Hydrogen sulfide and PKG in ischemia–reperfusion injury: sources, signaling, accelerators and brakes

Over the past decade, hydrogen sulfide has emerged as an important cardioprotective molecule with potential for clinical applications. Although several pathways have been proposed to mediate the beneficial effects of H2S, the NO/cGMP axis has attracted significant attention. Recent evidence has suggested that cGMP-dependent protein kinase can lie both downstream and upstream of H2S. The current literature on this topic is reviewed and data from recent studies are integrated to propose a unifying model. © 2015, Springer-Verlag Berlin Heidelberg

Myocardial infarction or acute coronary syndrome with non-obstructive coronary arteries and sudden cardiac death: A missing connection

Myocardial infarction with non-obstructive coronary arteries or any acute coronary syndrome (ACS) with normal or near-normal (non-obstructive) coronary arteries (ACS-NNOCA) is an heterogeneous clinical entity, which includes different pathophysiology mechanisms and is challenging to treat. Sudden cardiac death (SCD) is a catastrophic manifestation of ACS that is crucial to prevent and treat urgently. The concurrence of the two conditions has not been adequately studied. This narrative review focuses on the existing literature concerning ACS-NNOCA pathophysiology, with an emphasis on SCD, together with risk and outcome data from clinical trials. There have been no large-scale studies to investigate the incidence of SCD within ACS-NNOCA patients, both early and late in the disease. Some pathophysiology mechanisms that are known to mediate ACS-NNOCA, such as atheromatous plaque erosion, anomalous coronary arteries, and spontaneous coronary artery dissection are documented causes of SCD. Myocardial ischaemia, inflammation, and fibrosis are probably at the core of the SCD risk in these patients. Effective treatments to reduce the relevant risk are still under research. ACS-NNOCA is generally considered as an ACS with more 'benign' outcome compared to ACS with obstructive coronary artery disease, but its relationship with SCD remains obscure, especially until its incidence and effective treatment are evaluated. © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology

Pharmacological pre- and post- conditioning agents: Reperfusion-injury of the heart revisited

Ischemic preconditioning (PC) and postconditioning (PostC) are endogenous mechanisms of protection of the ischemic heart. In brief, short cycles of sublethal ischemia separated by brief periods of reperfusion render the heart resistant to infarction from a subsequent lethal episode of prolonged ischemia. Although PC is a powerful form of protection, its clinical application is limited because of ethical and practical reasons. It is of interest that multiple very short periods of ischemia and reperfusion applied at the onset of reperfusion are also capable in limiting the infarct size. In fact, the short ischemic insults in PC have to be applied before the onset of sustained period of ischemia which cannot be precisely anticipated. On the contrary, the very brief insults in postconditioning (PostC) have to be applied immediately after the end of the long ischemia thus making the intervention more easily applicable. Both mechanisms reduce the infarct size by limiting the reperfusion injury. Pharmacological PC and PostC represent ideal alternatives that may substitute the short ischemic insults for pharmaceuticals means. The components of PC share two pathways, one that involves the mitochondrial KATP channels- free radicals and PKC and another one that involves adenosine and PKC. Reperfusion injury salvage kinases (RISK) prevent the mitochondrial permeability transition pores (mPTP) which destroy the mitochondria and cause cell death. PC via PKC and PostC via gradual restoration of pH at reperfusion up-regulate RISK and preserve viable part of the ischemic region of the heart. In order to confer pharmacological protection, novel therapeutic strategies, based on the knowledge of the ligands, of the receptors and of the intracellular signaling pathways have emerged. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. Furthermore, agents that increase RISK or directly prevent mPTP are also under investigation as PostC analogues. We summarize recent studies focused on the pharmacological interventions and on the discovery of novel agents that may reduce the infarct size. © 2008 Bentham Science Publishers Ltd

To prevent, protect and save the ischemic heart: Antioxidants revisited

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) formation increases in the post-ischemic myocardium and represents a mechanism of post ischemic injury. ROS, which are formed during reperfusion, trigger lipid peroxidation, oxidize proteins and cause DNA strand breaks, all interfering with and potentially damaging normal cellular function. Oxidative stress is associated with poor recovery of left ventricular function after a sustained period of ischemia and, according to several studies, it contributes significantly to the acceleration of necrosis and thus extension of infarction, apoptosis, arrhythmiogenesis and endothelial dysfunction. Accordingly, targeting the generation of ROS with various antioxidants has been shown to improve left ventricular function after the restoration of flow. Apart from mechanical or pharmacological interventions that open the occluded artery, the heart has endogenous mechanisms of protection, called ischemic pre-conditioning and ischemic post-conditioning. Opening of the mitochondrial ATP-sensitive potassium channels and subsequent generation of ROS is considered to be a pivotal step in the mechanisms of pre- and post- conditioning. Notably, ROS play an ambiguous role in the protection of myocardium and can be both effective and harmful. Thus, the role of antioxidants in the attenuation of the effects of pre-and post-conditioning in vivo remains controversial. © 2009 Informa UK Ltd. All rights reserved

What is the optimal postconditioning algorithm?

Ischemic postconditioning has emerged as a clinically feasible intervention for limiting infarction in the setting of percutaneous intervention. In ischemic postconditioning, a number of cycles of a brief period of reperfusion followed by a brief period of occlusion are applied immediately upon reperfusion of the ischemic heart. Although ischemic postconditioning is protective in both animals and man, the animal studies reveal that the algorithm used in selecting the duration of the occlusion and reperfusion periods is critical to the degree of protection realized and it varies with species. The question then arises what is the best algorithm for man? The available animal and clinical data are examined in an attempt to shed light on this perplexing problem

Alternative pharmacological interventions that limit myocardial infarction

Despite current optimal treatment, the morbidity and mortality of coronary heart disease remain significant worldwide and open the way for the development of novel cardioprotective therapies. In the last two decades, a remarkable scientific effort has focused on the limitation of infarct size. Important input from experimental studies has led the way in this direction. However, clinical and preclinical results using various cardioprotective strategies to attenuate reperfusion injury have generally not been applicable for every day clinical practice. Protection of the ischemic myocardium is known to occur as a result of ischemic preconditioning (PC), in which repetitive brief periods of ischemia protect the heart from a subsequent prolong ischemic insult. Although PC is a powerful form of protection, it is of limited clinical application for obvious ethical and practical reasons. Another endogenous form of cardioprotection, similar to PC but applicable at the time of reperfusion, termed postconditioning (PostC), has been recently described. Short series of repetitive cycles of brief reperfusion and re-occlusion of the coronary artery applied at the onset of reperfusion, reduce the infarct size and coronary artery endothelial dysfunction. At present, pharmacological PC and PostC are possible alternative methods that may substitute pharmaceutical treatments the short ischemic insults. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. We summarize the recent research efforts on novel therapeutic strategies and on the design of new compounds, based on the accumulated knowledge of the ligands, receptors and intracellular signaling pathways of PC and PostC. © 2008 Bentham Science Publishers Ltd

Acute administration of vitamin C abrogates protection from ischemic preconditioning in rabbits

Vitamin C is considered to be an antioxidant agent that is broadly used. Free radicals are involved in the protective mechanism of preconditioning (PC), but some antioxidant compounds abolish this benefit. The aim of the present study was to evaluate the effect of vitamin C on the protective effect of PC with respect to infarct size and oxidative stress in anesthetized rabbits. Male rabbits were randomly divided into six groups and subjected to 30 min of myocardial ischemia and 3 h of reperfusion with the following interventions per group: (1) Control (no intervention), (2) Vit C 150 group (i.v. vitamin C at a total dose of 150 mg/kg for 75 min, starting 40 min before the onset of long ischemia and lasting up to the 5th min of reperfusion), (3) Vit C 300 group (i.v. vitamin C at a total dose of 300 mg/kg as previously described), (4) PC group (two cycles of 5 min ischemia and 10 min reperfusion), (5) combined PC-Vit C 150 group and (6) combined PC-Vit C 300 group. Blood samples were taken at different time points for malondialdehyde (MDA) assessment as a lipid peroxidation marker and for superoxide dismutase (SOD) activity. At the end of the experiment the infarct size was determined. Vitamin C, at both doses, did not reduce the infarct size (35.5 ± 4.1%, 38.3 ± 7.0% vs. 44.9 ± 3.3% in the control group) and diminished the protection afforded by PC (32.0 ± 2.7%, 43.8 ± 3.3% vs. 15.7 ± 2.9% in the PC group, P < 0.05). At reperfusion there was an elevation of circulating MDA levels in the control and PC groups while in both vitamin C groups the levels were decreased. SOD activity was enhanced in the PC group compared to the controls; vitamin C did not change SOD activity during ischemia-reperfusion. Vitamin C abrogates the beneficial effect of ischemic PC on infarct size and elicits antioxidant properties during ischemia-reperfusion. © 2008 Elsevier Ltd. All rights reserved