Ischemic Preconditioning and the Role of Antifibrinolytic Drugs: Translation From Bench to Bedside

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Preconditioning refers to a diverse group of biologic phenomena in which myocardial tissue is rendered ischemic for a short, nonlethal period and subsequently exhibits reduced injury in response to ischemia.1 This phenomenon, first discovered over 30 years ago,2 has become a major subject of laboratory research. Myocardial preconditioning can be induced with short periods of coronary occlusion known as ischemic preconditioning or by rendering a distant tissue ischemic, such as with an arm tourniquet, known as remote ischemic preconditioning. Preconditioning can also be induced pharmacologically by certain agents3 whereas others are known to interfere with preconditioning.4–6 A wealth of cellular mechanisms has been discovered that contributes to the development of preconditioning including changes in phosphoinositol-3, protein kinase C, reactive oxygen species, electron transport chain complex III, nitric oxide synthases, mitochondrial ATP-dependent potassium channels, and the mitochondrial permeability transition pore.
Remote ischemic preconditioning is a reproducible phenomenon that has been observed and extensively studied in multiple species.7,8 In laboratory models, remote ischemic preconditioning can reliably decrease myocardial infarct size by 20%–50%. Despite the ongoing interest in using remote ischemic preconditioning in cardiac surgery based on extensive animal data, only a small number of clinical trials has produced promising results.9–13 These preliminary trials prompted 2 large randomized clinical trials of remote ischemic preconditioning in cardiac surgical patients, Remote Ischemic Preconditioning in Heart Surgery (RIPHeart) and Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patients Undergoing Coronary Artery Bypass Graft Surgery (ERICCA), that were both completed in 2015 but to the disappointment of many, both trials were negative reporting no beneficial effect of remote ischemic preconditioning.14,15 How could such a robust laboratory effect be ineffective in a clinical trial?
Ischemic preconditioning is most commonly shown in laboratory models of ischemia–reperfusion where animals are anesthetized, usually with barbiturates, anesthetics which only weakly induce pharmacologic preconditioning in laboratory animals.16,17 In the cardiac operating room, patients are given a balanced anesthetic consisting of drugs known to more potently induce preconditioning such as volatile anesthetics and opioids, either of which may eclipse the protective effect of ischemic preconditioning by providing more robust pharmacologic preconditioning.18–22 Many of these drugs induce changes in gene and protein expression that are remarkably similar to those changes wrought by ischemic preconditioning.23,24 This knowledge led RIPHeart investigators to make the use of volatile anesthetics in patients enrolled in their study an exclusion criteria. Additionally, patients undergoing cardiac surgery may receive postoperative sedation, analgesics, β-blockade, statins, and antifibrinolytic drugs, some of which are known to induce or interfere with preconditioning. As a large number of drugs has been noted in the laboratory to induce or modify preconditioning we have included, the Table highlights some of the commonly used drugs that alter myocardial protection. While no large prospective randomized trials exist that clearly demonstrate a benefit to pharmacologic preconditioning, 2 meta-analyses show a clinical benefit to cardiac anesthesia that incorporates volatile anesthetic known to induce preconditioning.19,20 Additionally, a review of Danish registry data showed a clinical benefit of exposure to volatile anesthetics in patients who did not experience preceding ischemia, reported as angina.21 Taken together, these studies suggest that preconditioning can be induced by nonlethal ischemia, a host of pharmacologic agents, and can be enhanced or inhibited by a number of other drugs; however, it seems that pharmacologic preconditioning cannot be superimposed on ischemic preconditioning or vice versa. That brings us to the present study in the journal of the carefully conducted experiments by van Caster et al,32 which have endeavored to clarify the role of the antifibrinolytic drug, tranexamic acid (TXA), in ischemic preconditioning and remote ischemic preconditioning.
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