Yellon, Derek M., and James M. Downey. Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology. Physiol Rev 83: 1113-1151, 2003; 10.1152/physrev.00009.2003.—The phenomenon o...

Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology

—Unlike the early phase of preconditioning (PC), which lasts 2 to 3 hours and protects against infarction but not against stunning, the late phase of PC lasts 3 to 4 days and protects against both infarction and stunning, suggesting that it may have greater clinical relevance. It is now clear that late PC is a polygenic phenomenon that requires the simultaneous activation of multiple stress-responsive genes. Chemical signals released by a sublethal ischemic stress (such as NO, reactive oxygen species, and adenosine) trigger a complex cascade of signaling events that includes the activation of protein kinase C, Src protein tyrosine kinases, and nuclear factor κB and culminates in increased synthesis of inducible NO synthase, cyclooxygenase-2, aldose reductase, Mn superoxide dismutase, and probably other cardioprotective proteins. An analogous sequence of events can be triggered by a variety of stimuli, such as heat stress, exercise, and cytokines. Thus, late PC appears to be a universal response of the heart to stress in general. Importantly, the cardioprotective effects of late PC can be reproduced pharmacologically with clinically relevant agents (eg, NO donors, adenosine receptor agonists, endotoxin derivatives, or opioid receptor agonists), suggesting that this phenomenon might be exploited for therapeutic purposes. The purpose of this review is to summarize current information regarding the pathophysiology and mechanism of late PC.

The late phase of preconditioning.

Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult. Additionally, the application of brief repetitive episodes of ischemia/reperfusion at the immediate onset of reperfusion, which has been termed "postconditioning," reduces the extent of reperfusion injury. Ischemic pre- and postconditioning share some but not all parts of the proposed signal transduction cascade, including the activation of survival protein kinase pathways. Most experimental studies on cardioprotection have been undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, aging is an important modifying condition. In these diseases and aging, the pathological processes are associated with fundamental molecular alterations that can potentially affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Among many other possible mechanisms, for example, in hyperlipidemia and diabetes, the pathological increase in reactive oxygen and nitrogen species and the use of the ATP-sensitive potassium channel inhibitor insulin secretagogue antidiabetic drugs and, in aging, the reduced expression of connexin-43 and signal transducer and activator of transcription 3 may disrupt major cytoprotective signaling pathways thereby significantly interfering with the cardioprotective effect of pre- and postconditioning. The aim of this review is to show the potential for developing cardioprotective drugs on the basis of endogenous cardioprotection by pre- and postconditioning (i.e., drug applied as trigger or to activate signaling pathways associated with endogenous cardioprotection) and to review the evidence that comorbidities and aging accompanying coronary disease modify responses to ischemia/reperfusion and the cardioprotection conferred by preconditioning and postconditioning. We emphasize the critical need for more detailed and mechanistic preclinical studies that examine car-dioprotection specifically in relation to complicating disease states. These are now essential to maximize the likelihood of successful development of rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions.

Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning

On July 2–3, 1996, the National Heart, Lung, and Blood Institute sponsored a workshop in Columbia, Md, entitled “The Medical and Cellular Implications of Myocardial Stunning, Hibernation, and Preconditioning.” The goals of this workshop were to identify and discuss the areas of agreement and controversy regarding these important phenomena and in particular to identify areas of future research for each. One aspect of these goals included determination of the mechanisms of these phenomena. Stunning is a form of prolonged contractile dysfunction that occurs after relief of a discrete episode or episodes of ischemia; hibernation is a form of prolonged contractile dysfunction associated with ongoing low blood flow, although controversy exists as to whether absolute blood flow or coronary reserve is reduced and whether it may represent repetitive bouts of stunning. Preconditioning is a cardioprotective mechanism in which the heart is exposed to a controlled, short period of sublethal ischemia that attenuates cellular damage from a subsequent prolonged lethal episode of ischemia. Research efforts have not yet provided a clear understanding of all aspects of these conditions. The workshop presented the current state of both basic science knowledge and clinical knowledge of these disorders, promoted discussions between basic and clinical scientists, and identified likely mechanisms and new directions for research.

The meeting was chaired by Eugene Braunwald and cochaired by Roberto Bolli, Eduardo Marban, and Robert A. Kloner and was coordinated by Leslie Reinlib. Twenty participants represented a broad spectrum of expertise: basic and clinical scientists, pathologists, and surgeons. (A list of conference participants is provided in the Appendix.)

The purpose of this article is to review some of the points made at the workshop in regard to areas of general agreement and controversy and, most importantly, to summarize the areas that need further research. The following discussions briefly review the …

Medical and cellular implications of stunning, hibernation, and preconditioning - An NHLBI Workshop

https://www.onlinejacc.org/content/accj/46/3/450.full.pdf

Remote Ischemic Preconditioning Provides Early and Late Protection Against Endothelial Ischemia-Reperfusion Injury in Humans: Role of the Autonomic Nervous System

The delayed phase (‘second window’) of protection induced by ischemic preconditioning in rabbit heart is observed as enhanced resilience to infarction 24 hours after repetitive brief cycles of ischemia. Here we provide a fuller physiological characterisation of this phenomenon in the open-chest rabbit model, examining temporal characteristics and dose-dependency of this adaptation. For examination of the timecourse of delayed protection, rabbits were pretreated with four 5 minute coronary artery occlusions (PC) or sham operation (SHAM). Twenty four, 48, 72 or 96 hours later, infarct size after 30 min coronary occlusion and 120 minutes reperfusion was assessed with TTC staining and expressed as a percentage of myocardial risk volume (I/R). I/R was reduced at 24 hours (SHAM 48.1±3.9% v PC31.4±3.0%, P<0.01), 48 hours (SHAM 41.9±3.0% v PC 19.6±6.3%, P<0.01), and 72 hours (SHAM 39.8±3.4% v PC 17.2±2.5%, P<0.01). No protection was observed 96 hours after preconditioning (SHAM 35.0±4.8% v PC 36.9±3.8%). In a further study, animals were pretreated with one, two or four 5 minute coronary occlusions (1×5 PC, 2×5 PC, 4×5 PC) and subjected to the infarction protocol 48 hours later. I/R was 44.5±4.3% in SHAM, 24.8±4.4% in 1×5 PC (P<0.01), 27.4±2.9% in 2×5 PC (P<0.05) and 24.4±4.8 in 4×5 PC (P<0.01). Delayed protection in this rabbit model is prolonged, extending between 24 and 72 hours after the preconditioning stimulus. The threshold for eliciting the second window of protection in this model is as low as one 5 minute coronary occlusion.

F. M. Goma

Papers

Characterisation of the infarct-limiting effect of delayed preconditioning: timecourse and dose-dependency studies in rabbit myocardium.