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Published online before print November 29, 2007

0031-6997/07/5904-418-458$7.00
Pharmacol Rev 59:418-458, 2007

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

Peter Ferdinandy, Rainer Schulz and Gary F. Baxter

Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Szeged, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Institut für Pathophysiologie, Zentrum für Innere Medizin, Universitasklinikum Essen, Universität Duisburg-Essen, Essen, Germany (R.S.); and Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, UK (G.F.B.)

Abstract
I. Introduction
    A. Ischemic Heart Disease and Cardioprotection
    B. Risk Factors for Ischemic Heart Disease
II. Introduction to Endpoints of Ischemia/Reperfusion Injury and Experimental Approaches to Cardioprotection
    A. Clinical and Experimental Endpoints of Injury
        1. Irreversible Cellular Injury and Infarction.
        2. Contractile Dysfunction and Ventricular Arrhythmias.
    B. Experimental Approaches to Infarct Size Limitation
        1. Historical Background.
        2. The Reperfusion Injury Paradigm of Irreversible Injury.
        3. Cardioprotection through Classic Preconditioning.
            a. The role of protein kinases in classic preconditioning.
            b. ATP-sensitive potassium channels and classic preconditioning.
            c. The evolving model of signal transduction in classic preconditioning.
        4. Cardioprotection through Late Preconditioning.
        5. Cardioprotection through Postconditioning.
            a. Autacoid mediators of postconditioning.
            b. Role of the NO/cGMP pathway in postconditioning.
            c. ATP-sensitive potassium channels and postconditioning.
            d. The reperfusion injury salvage kinase pathway.
III. Animal Models and Human Studies of Cardioprotective Strategies
    A. Classic Preconditioning
        1. Duration and Severity of Ischemia and Reperfusion in Preconditioning.
    B. Remote Preconditioning
    C. Late Preconditioning
    D. Postconditioning
        1. Pharmacological Postconditioning.
IV. Effects of Major Risk Factors on Ischemia/Reperfusion Injury and Cardioprotective Strategies
    A. Left Ventricular Hypertrophy
        1. Hypertensive Left Ventricular Hypertrophy as a Risk Factor.
        2. Hypertensive Left Ventricular Hypertrophy and Myocardial Ischemia/Reperfusion.
            a. Effects of left ventricular hypertrophy on the coronary circulation.
            b. Experimental ischemia/reperfusion injury in left ventricular hypertrophy.
            c. Arrhythmias in left ventricular hypertrophy models.
        3. Experimental Cardioprotection in Hypertensive Left Ventricular Hypertrophy.
            a. Ischemic preconditioning in left ventricular hypertrophy.
            b. Pharmacological preconditioning in left ventricular hypertrophy.
        4. Hyperthyroid Left Ventricular Hypertrophy.
    B. Cardioprotection and Myocardial Infarction, Remodeling, and Heart Failure
        1. Postinfarction Remodeling.
        2. Postinfarction Heart Failure.
    C. Hyperlipidemia and Atherosclerosis
        1. Hyperlipidemia as a Risk Factor.
        2. Ischemia/Reperfusion Injury in Hyperlipidemia.
        3. Cardioprotection by Pre- and Postconditioning in Hyperlipidemia.
            a. Classic preconditioning in hyperlipidemia.
            b. Late preconditioning in hyperlipidemia.
            c. Postconditioning in hyperlipidemia.
        4. Interaction of Hyperlipidemia and Antihyperlipidemic Statins with Cardioprotective Cellular Mechanisms.
    D. Diabetes
        1. Diabetes as a Risk Factor.
        2. Ischemia/Reperfusion Injury in Diabetes.
            a. Preclinical studies.
            b. Clinical studies.
        3. Cardioprotection by Pre- and Postconditioning in Diabetes.
            a. Preclinical studies.
            b. Clinical studies.
        4. Interaction of Diabetes and Antidiabetic Drugs with Cardioprotective Cellular Mechanisms.
    E. Aging and Cardioprotection
        1. Aging and Ischemia/Reperfusion Injury.
        2. Aging and Ischemic Preconditioning.
        3. Aging and Pharmacological Preconditioning.
V. Conclusions and Perspectives
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.

Address correspondence to: Dr. Peter Ferdinandy, Cardiovascular Research Group, Department of Biochemistry, University of Szeged, Dóm tér 9, Szeged, H-6720, Hungary. E-mail: peter.ferdinandy{at}pharmahungary.com




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