Remote Ischemic Conditioning in Ischemic Stroke and Myocardial Infarction: Similarities and Differences

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Remote Ischemic Conditioning in Ischemic Stroke and Myocardial Infarction: Similarities and Differences

Luigi F. Saccaro^1,2*, Alberto Aimo^2,3, Michele Emdin^2,3 and Fernando Pico^1,4

• ¹Neurology and Stroke Care Unit, Versailles Hospital, Le Chesnay, France
• ²Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
• ³Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
• ⁴Neurology Department, Versailles Saint-Quentin-en–Yvelines and Paris Saclay University, Versailles, France

Acute myocardial infarction and ischemic stroke are leading causes of morbidity and mortality worldwide. Although reperfusion therapies have greatly improved the outcomes of patients with these conditions, many patients die or are severely disabled despite complete reperfusion. It is therefore important to identify interventions that can prevent progression to ischemic necrosis and limit ischemia-reperfusion injury. A possible strategy is ischemic conditioning, which consists of inducing ischemia – either in the ischemic organ or in another body site [i.e., remote ischemic conditioning (RIC), e.g., by inflating a cuff around the patient's arm or leg]. The effects of ischemic conditioning have been studied, alone or in combination with revascularization techniques. Based on the timing (before, during, or after ischemia), RIC is classified as pre-, per-/peri-, or post-conditioning, respectively. In this review, we first highlight some pathophysiological and clinical similarities and differences between cardiac and cerebral ischemia. We report evidence that RIC reduces circulating biomarkers of myocardial necrosis, infarct size, and edema, although this effect appears not to translate into a better prognosis. We then review cutting-edge applications of RIC for the treatment of ischemic stroke. We also highlight that, although RIC is a safe procedure that can easily be implemented in hospital and pre-hospital settings, its efficacy in patients with ischemic stroke remains to be proven. We then discuss possible methodological issues of previous studies. We finish by highlighting some perspectives for future research, aimed at increasing the efficacy of ischemic conditioning for improving tissue protection and clinical outcomes, and stratifying myocardial infarction and brain ischemia patients to enhance treatment feasibility.

Introduction

Myocardial infarction (MI) and ischemic stroke are leading causes of morbidity and mortality (1, 2). Both conditions have an acute onset and are due to blood vessel occlusion leading to a certain extent of ischemic necrosis.

MI usually follows thrombotic occlusion of a coronary artery due to a vulnerable plaque rupture. Ischemia-dependent mitochondrial and metabolic alterations lead to systolic function depression and, when persistent, to cardiomyocyte necrosis followed by tissue scarring (3). Similarly, ischemic stroke results from a lack of blood flow to the brain, which reduces oxygen, glucose and nutrient supply, as well as, secondarily, catabolite removal. Blood deprivation is typically caused by large artery atherosclerosis, cardiac embolic events, small vessel occlusion, or stroke of other etiologies (4).

In cardiac, as in brain ischemia, there is a clear major effect of early restoration of blood flow through reperfusion therapies on outcomes. These include pharmacologic (i.e., fibrinolytic therapy) or mechanical interventions, namely primary percutaneous coronary intervention (PPCI) or endovascular thrombectomy. More than 90% of MI patients receive reperfusion therapy against ~10% of acute ischemic stroke patients (5). Among the factors that account for this difference, the different time windows from symptom onset for beneficial reperfusion treatment should be taken in account. These are usually <12 h (or between 12 and 48 h in some patients with persisting symptoms) for fibrinolytic therapy for ST-segment elevation MI (STEMI), 4.5 h (9 h in some patients with radiological signs of salvageable brain tissue) for thrombolysis of brain ischemia, and <24 h for mechanical thrombectomy in brain ischemia. Furthermore, an arterial occlusive thrombus accessible to catheter-based intervention is found in about 90% of MI patient, but only about half of computed tomography (CT) angiograms performed for acute ischemic stroke (5). Indeed, while there are few contraindications to coronary catheter-based interventions, reperfusion therapies for ischemic stroke are absolutely contraindicated if there is intracranial bleeding or advanced ischemia. Another reason possibly accounting for the difference in the percentage of patients that receive reperfusion therapy between ischemic stroke and MI may be that time to treatment is often longer in the former condition (6). Finally, biomarkers of brain ischemia are missing (while troponins are widely used in cardiovascular medicine), and neurological diagnostic methods [CT or magnetic resonance imaging (MRI)] are expensive, time-consuming, and not routinely performed outside hospital or at the bedside (contrary to an electrocardiogram) (5), although technological advances (such as mobile CT or bedside MRI) may change this (7, 8).

Patients with MI or ischemic stroke who receive successful reperfusion therapies are still exposed to certain risks, as reperfusion itself is an important determinant of end-organ damage. Indeed, ischemia triggers a vicious cycle of cell death, inflammation, and oxidative stress, which is perpetuated by reperfusion and may increase the extent of infarction in otherwise viable brain or cardiac tissue (9, 10), also in association with cerebral edema and blood–brain barrier disruption (11). Reperfusion injury is much more common and more often leads to hemorrhagic transformation in brain infarct than MI (5). Intracranial hemorrhage exposes the patient to life-threatening intracranial hypertension, with the risk of brain herniation (5).

The risk of these detrimental effects is usually counterbalanced by the fact that reperfusion therapies can save the border (or marginal) zone of MI or the ischemic penumbra in ischemic stroke, if administered promptly. The border zone (or penumbra in ischemic stroke) is the salvageable tissue around the ischemic core, in which reduced blood flow causes loss of cell function with normal structural morphology, before irreversible damage, which occurs instead in the ischemic core (12, 13). However, the recanalization rate with thrombolysis in brain ischemia is lower than with endovascular thrombectomy (14). Penumbral salvage becomes more likely with endovascular thrombectomy, which considerably improves clinical outcomes. Despite this, only about half of successful thrombectomies lead to patients' functional independence (15), mainly because the ischemic core is already too large at the time of recanalization. This may partially explain why most stroke patients are still disabled 3 months after treatment (15). As for MI patients, despite the fact that timely PPCI is associated with better outcomes than fibrinolysis, a significant number of patients with reperfused STEMI display the no-reflow phenomenon, which predicts a worse outcome, specifically a greater risk of ventricular wall rupture and arrhythmias, adverse ventricular remodeling with heart failure development, and cardiac death (3).

Reducing the burden of cardiac and cerebral ischemia-related death disability requires the identification of interventions able to “freeze the penumbra,” i.e., prevent the growth of the necrotic ischemic core until partial or complete reperfusion, as well as techniques to protect the ischemic tissue from subsequent reperfusion injury (12, 13, 16). However, interventions that aim to improve ischemic stroke and MI prognosis have, so far, shown an inconsistent benefit (17–20). Alternative cytoprotective strategies are being studied (21), but strong evidence on the efficacy of any proposed mechanism is lacking.

An interesting paradigm may be ischemic conditioning (22), first described in 1986 by Murry et al. (23) in the setting of experimental MI. In ischemic conditioning, transient, intermittent ischemia without necrosis is induced either in the organ undergoing spontaneous ischemia (i.e., conventional conditioning), or at a distance from the affected organ [i.e., indirect or remote ischemic conditioning (RIC)]. According to the timing of the intervention (before, during, or after ischemia), remote ischemic pre-, per-/peri-, and post-conditioning, respectively, can be defined. Pre-conditioning has been defined as “an adaptive process of endogenous protection in which small, sublethal doses of a harmful agent protect the organism against a later lethal dose of the same agent” (24). In the settings of acute MI and ischemic stroke, per- or post-ischemic conditioning is more easily realized. This can be achieved by the application of an inflatable cuff around the patient's arm or leg (22). After extensive evaluation in the field of cardiac ischemia, the paradigm of RIC has recently been translated to ischemic stroke (20), and seems to apply to other organs and tissues. Plasma dialysate obtained from animals and humans treated with RIC has been shown to reduce MI size after ligation of a coronary artery and subsequent reperfusion in isolated heart preparations (25, 26), indicating that the effect may be mediated (at least partially) by humoral substances released from the tissues exposed to intermittent ischemia. In animal models, remote ischemic pre- and post-conditioning have been shown to reduce MI size and biomarkers of myocardial necrosis (27–29). Similarly, in rat models of middle cerebral artery occlusion, brain infarct size was reduced by remote pre-conditioning (30).

This review aims to discuss the existing clinical evidence on RIC in brain and myocardial ischemia. We will first of all synthetically recapitulate potential mechanisms of RIC, then discuss main clinical findings in MI, first, and in ischemic stroke, then, highlight the differences and similarities, as well as future perspectives and therapeutic implications.

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