Ischemic Preconditioning: The Concept of Endogenous Cardioprotection

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Cardiovascular disease is the leading cause of mortality and morbidity in the United States. Cardiac preconditioning, an endogenous phenomenon, has been shown to protect the heart from acute myocardial infarction by subjecting it to brief cycles of ischemia and reperfusion.

The concept of ischemic preconditioning has led to a group of cardiac conditioning strategies that include preconditioning, postconditioning, and remote conditioning. Other than complete reperfusion, cardiac conditioning is considered the most powerful intervention available for reducing infarct size in animal models and in clinical trials. A comprehensive investigation into the mechanisms underlying cardiac conditioning has led to the identification of several therapeutic targets for pharmacological intervention, including the ATP-dependent potassium channel.

Remote cardiac conditioning has garnered a great deal of attention as a noninvasive method to deliver conditioning. Several signaling mechanisms have been investigated, including humoral communication and neuronal stimulation. Although the cardioprotective pathways of remote conditioning are widely studied, the translation to clinical practice has been controversial.

Two recent, large, and well-designed clinical trials highlight the challenges of implementing remote conditioning. However, a number of cardioprotective therapies involving conditioning have shown promising results. Future research should continue to explore the potential of remote conditioning.

Involvement of endogenous prostaglandins in ischemic preconditioning in pigs.

Advanced Search. Heart disease and stroke statistics update: A report from the American Heart Association. Circulation ;e2-e Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation ; Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Liver Transpl ; Transient limb ischemia induces remote ischemic preconditioning in vivo.

Mechanism of cardioprotection by early ischemic preconditioning.

Effect of remote ischemic preconditioning on hepatic microcirculation and function in a rat model of hepatic ischemia reperfusion injury. HPB Oxford ; The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system. Br J Pharmacol ; The mitochondrial K ATP channel-fact or fiction? J Mol Cell Cardiol ; Comparison of in vitro preconditioning responses of isolated pig and rabbit cardiomyocytes: Effects of a protein phosphatase inhibitor, fostriecin. Mitochondrial ATP-dependent potassium channels: Novel effectors of cardioprotection?

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Biochim Biophys Acta ; Das M, Das DK. Molecular mechanism of preconditioning. Int Rev Cell Mol Biol ; Role of endothelial cells in myocardial ischemia-reperfusion injury.

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Vasc Dis Prev ; Preconditioning decreases Bax expression, PMN accumulation and apoptosis in reperfused rat heart. Cardiovasc Res ; Improved myocardial ischemic response and enhanced collateral circulation with long repetitive coronary occlusion during angioplasty: A prospective study. J Am Coll Cardiol ; Ischaemic preconditioning during cardiac surgery: Systematic review and meta-analysis of perioperative outcomes in randomised clinical trials.

Eur J Cardiothorac Surg ; Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? There is, however, an inherently unique aspect of remote conditioning not shared by pre- and postconditioning: the cardioprotective signaling cascades are initiated by communication or transfer of a protective signal from the site of the conditioning stimulus to the heart. Of note, these two hypotheses are not mutually exclusive, are in all likelihood model-dependent, and, in at least some models, both humoral and neuronal communication may be involved 5 , 44 , 45 , 53 , As summarized in the preceding paragraphs, intensive interest and attention has focused on the involvement of RISK and SAFE signaling in the infarct-sparing effect of ischemic pre-, post- and remote conditioning.

However, additional and less well-characterized mediators have also been postulated to contribute to conditioning-induced cardioprotection, either in concert with or as possible alternatives to the RISK and SAFE cascades. Generation of low, sub-lethal levels of reactive oxygen species ROS and signaling via nitric oxide have, similarly, been proposed to integrate with both PKC and the RISK and STAT pathways as mediators of pre- and post-conditioning 27 , 56 , 57 , 59 - A long-standing concept that may be relevant to the issue of cardioprotection in diabetic cohorts, particularly for ischemic preconditioning, is that alterations in myocardial metabolism play a causal role.

Metabolic hallmarks of cardiac ischemia include the rapid within seconds-minutes shift from aerobic to anaerobic metabolism and the resultant, progressive temporal decline in myocardial ATP concentration as ATP synthesis via anaerobic glycolysis is insufficient to meet the diminished, residual energy consumption of the ischemic tissue The first report of infarct size reduction with preconditioning was accompanied by evidence of an increase in metabolic efficiency: i.

Ensuing studies argued against the concept of a cause-and-effect relationship between reduced energy demand during prolonged ischemia and infarct size reduction with preconditioning Nonetheless, there is evidence for a mechanistic link between metabolism and preconditioning-induced cardioprotection.

This metabolic signaling is purportedly required for the infarct-sparing effect of ischemic preconditioning 66 - 70 , and has been implicated to play a secondary role in postconditioning For example, p66Shc is a pro-oxidant protein, reportedly associated with the mPTP, which has been proposed to serve as a nexus for the deleterious effects of hyperglycemia and obesity-induced impairment in molecular signaling in multiple cell types including cardiomyocytes 75 - Moreover, there is evidence that genetic knockout of p66Shc renders the heart resistant to infarction, possibly via attenuation of mitochondrial ROS production Interestingly, recent data have revealed that remote perconditioning fails to inhibit arginase 2 signaling in a rat model of type-1 diabetes Whether a similar response is seen in the setting of type-2 diabetes is, at present, unknown.

Indeed, CVD is the leading cause of death and disability among diabetics, a poor prognosis that has not been appreciably influenced by the current trend of an overall reduction in mortality associated with AMI 1 , 16 , 82 , 83 , 92 , This anticipated escalation in the numbers of patients with diabetes may have the potential to diminish the gains that have been made attenuating the overall prevalence of CVD-related death 1 , 94 - The hallmarks of type-2 diabetes are insulin resistance and accompanying metabolic dysregulation.

Reduced insulin sensitivity has both direct effects on glucose uptake and insulin-mediated signaling in cardiac cells, and indirect cellular effects that are secondary to the accompanying hyperglycemia, hyperinsulinemia and hyperlipidemia 97 - The effect of type-2 diabetes on the infarct-sparing effect of ischemic conditioning has, almost exclusively, been assessed in the aforementioned rodent models.

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Accordingly, meaningful discussion of conditioning-induced cardioprotection in these models first requires an understanding of the effect of type-2 diabetes on infarct size in untreated control animals. In contrast to the clinical consensus that diabetes is associated with larger infarct sizes and poor outcomes when compared with non-diabetic patients 1 , 82 - 93 , data obtained in preclinical models are mixed: diabetes has been reported to increase, decrease or have no effect on cardiomyocyte death 19 , - Among the small number of studies that have addressed this issue, a spectrum of rat and mouse models of type-2 diabetes have been utilized Table 1.

Nonetheless, irrespective of the model used and variations in study design, there is an emerging consensus: both pre- and post-conditioning either fail to reduce infarct size Figure 2 22 , , , , - , or the efficacy of conditioning is attenuated such that an amplified stimulus i.

Ischaemic conditioning and reperfusion injury

Loss of conditioning-induced cardioprotection has been described in both lean and obese type-2 diabetic rat models and in obese rats before the onset of significant hyperglycemia Moreover, similar outcomes a diminished responsiveness to the infarct-sparing effect of ischemic conditioning have also been reported in models of type-1 diabetes 14 , 17 - 19 , 22 , 69 , 79 - 81 , - , suggesting that the refractoriness of the diabetic heart to ischemic conditioning is not a simple consequence of hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity or, in all likelihood, any single pathophysiological feature of the disease.

Nascent mechanistic insight has, however, been obtained into the cellular mechanisms that may contribute to the compromised efficacy of ischemic conditioning in diabetic models. Potential diabetes-associated defects in mitochondrial end-effectors have also been identified, including impaired activation of mitochondrial K ATP channels , Finally, there is a notable and fundamental gap in our current knowledge of the efficacy of ischemic conditioning in models of type-2 diabetes.

All previous discussion has focused exclusively on pre- and postconditioning; to date, no published studies have utilized remote conditioning as the cardioprotective trigger Table 1. There is, however, one piece of evidence that diabetes may have a complex, confounding effect on the production or release of the as-yet unidentified humoral factor s from the site of the conditioning stimulus For both cohorts, serum collected after the conditioning stimulus rendered the rabbit hearts resistant to infarction: i.

However, in the subset of diabetic subjects with peripheral neuropathy, the transferred serum failed to reduce infarct size in acceptor rabbit hearts, implicating the requisite involvement of a diabetes-sensitive neurogenic component in this model of humorally-mediated remote conditioning The consequences of type-2 diabetes in standard in vivo models of remote conditioning, and the concept that persistent efficacy of remote conditioning in diabetic models may depend on the intact innervation of the effector organ, are topics of ongoing study by our group and others.

As preconditioning is, by definition, a pretreatment—thereby limiting its potential for clinical use to planned ischemic events such as cardiac surgery and elective percutaneous intervention PCI —current attention is focused largely on postconditioning and remote conditioning. In addition, recent meta-analyses of pooled data from multiple trials underscored the variability among studies and concluded that, at present, there is borderline evidence, or no evidence, for cardioprotection with either postconditioning or remote conditioning , In addition to differences in patient demographics and enrollment criteria, protocol logistics including the number and timing of the conditioning stimuli and duration of sustained ischemia , choice of endpoints, etc.

Indeed, in an effort to mitigate this concern, some investigators have prospectively excluded the enrollment of diabetic patients - Initial evidence appears to support of the concept that conditioning-induced cardioprotection may be impaired or lost in patients with diabetes.

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For example, in two clinical trials in which prospective subset analyses were performed and cardiac enzyme release served as the surrogate for infarct size, preconditioning triggered by prodromal angina had no beneficial effect, while postconditioning tended to exacerbate myocardial injury in diabetic cohorts ,