Cardiac preconditioning and cardiovascular diseases

William A Li; Yuchuan Ding

doi:10.4103/hm.hm_4_17

REVIEW ARTICLE

Year : 2017 | Volume : 1 | Issue : 1 | Page : 17-21

Cardiac preconditioning and cardiovascular diseases

William A Li, Yuchuan Ding
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA

Date of Web Publication

24-May-2017

Correspondence Address:
William A Li
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48202
USA

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/hm.hm_4_17

Abstract

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.

Keywords: ATP-dependent potassium channel, cardiac function, humoral communication, infarct size, ischemia, myocardial infarction, preconditioning, remote conditioning, reperfusion

How to cite this article:
Li WA, Ding Y. Cardiac preconditioning and cardiovascular diseases. Heart Mind 2017;1:17-21

How to cite this URL:
Li WA, Ding Y. Cardiac preconditioning and cardiovascular diseases. Heart Mind [serial online] 2017 [cited 2023 Mar 23];1:17-21. Available from: http://www.heartmindjournal.org/text.asp?2017/1/1/17/206967

Introduction

Cardiovascular disease is the leading cause of mortality and morbidity in the United States, accounting for more than 600,000 deaths every year.^[1] Currently, the treatment of choice for acute myocardial infarction (MI) is percutaneous coronary intervention or coronary artery bypass graft (CABG) surgery for patients with multivessel coronary artery disease or obstruction involving the left main coronary artery. In both clinical settings, the myocardium is subjected to detrimental and irreversible consequences, including cardiomyocyte loss, impaired cardiac contractility, and compromised cardioconduction. With a rising number of patients with comorbidities, including kidney disease, pulmonary diseases, and diabetes, morbidity and mortality rates have not improved despite advancements in medical management. Apart from complete reperfusion, preconditioning has emerged as the most powerful intervention known for minimizing MI-induced injuries. Ischemic preconditioning is the concept that a brief episode(s) of controlled ischemia and reperfusion applied in the past renders the myocardium resistant to a subsequent sustained episode of ischemia. This well-documented endogenous phenomenon can paradoxically protect the heart is well documented and is one of the most potent procedures available for reducing infarct size. In this review, we will discuss the several molecular mechanisms underlying cardiac preconditioning, their clinical relevance, the concept of remote ischemic preconditioning (RIPC), and future direction for research.

Historical Perspective

The endogenous cardioprotective effects of ischemic precondition were first described by Murry et al. in 1986. They proposed that multiple brief ischemic episodes protect the heart from subsequent sustained ischemic insult. In their investigation, Murry et al. preconditioned canines by subjecting them to four 5-min circumflex occlusions, each separated by 5 min of reperfusion. Sustained ischemia was induced by 40 min of occlusion. Animals were allowed 4 days of reperfusion. Histologic infarct size was then measured and showed preconditioning reduced infarct size by 75%.^[2] Collateral blood flow was minimal, indicating compensatory increase in angiogenesis and arteriogenesis were not significant contributory factors in preconditioning. In a 1993 landmark study, Przyklenk et al. demonstrated that brief episodes of ischemia in one vascular bed, the circumflex coronary artery, protected remote, virgin myocardium (left anterior descending artery) from subsequent sustained coronary artery occlusion.^[3]

RIPC has been gaining increased interest since Abu-Amara et al. demonstrated that brief renal occlusion and reperfusion reduces myocardial infarct size in rabbit models. Subsequent experimental studies have reported that preconditioning stimulus could be applied to several different organs/areas remote from the heart, including the mesentery, brain, liver, and upper and lower extremities as previously reviewed.^[4],[5],[6]

Possible Mechanisms

There is a biphasic relationship between preconditioning and cardioprotection. The first phase is immediate. It begins minutes postpreconditioning and lasts up to 2 h. Immediate myocardial adaptation is also termed “classical preconditioning” or “early adaptation.” Evidence suggests ATP-dependent potassium channel (K_ATP) is an important component of this pathway. This is supported by data demonstrating that K_ATP channel inducers, including cromakalim, bimakalim, or pinacidil mimic protection induced by preconditioning while K_ATP inhibitors, glibenclamide and 5-hydroxydecanoate (5-HD), blocks preconditioning-induced cardioprotection. Based on these studies, a mechanistic hypothesis was formed where K_ATP was the putative main end-effect of preconditioning. There has been substantial focus on the role of cardiac sarcolemma K_ATP channel specifically in preconditioning-induced cardioprotection. Sarcolemmal K_ATP channels are closed under normal metabolic conditions and do not play a role in the depolarization of the myocardiocyte and energy transfer. However, exposure to metabolic stressful conditions, including during hypoxia and ischemia, causes sarcolemmal K_ATP channels to open up. The opening of K_ATP channels is a protective mechanism that occurs from increasing potassium conductance, which stabilizes the resting membrane potential, shortens the action potential, and reduces calcium influx, and the subsequently calcium overload.^[7]

Mitochondrial K_ATP channels role in cardioprotection has been investigated. Employing the selectivity of diazoxide as a mitoK_ATP inducer and 5-HD as a mitoK_ATP inhibitor, Garlid et al. concluded that cardioprotective effect of K_ATP inducer may be attributed to mitochondrial K_ATP channels more than sarcolemmal K_ATP channels.^[8] Similar results have been observed by other groups.^[9],[10] However, the role of mitoK_ATP in preconditioning-induced cardioprotection is not unanimous as others have shown that mitoK_ATP may not be a significant contributor of preconditioning as reviewed by Tinker et al.^[7],[11]

The concept that the activation of protein kinase C (PKC), an upstream of K_ATP, underlays cardiac preconditioning brought greater clarity to this pathway. PKC can be activated by G-proteins, phospholipids, diacylglycerol, increased intracellular calcium levels, nitric oxide as well as reactive oxygen species (ROS) from the mitochondria. PKC subsequently opens K_ATP channels. PKC inhibition, on the other hand, attenuated infarct reduction produced by preconditioning suggesting PKC pathway is crucial for immediate myocardial adaptation.

On the other hand, delayed type ischemic preconditioning lasts 24–72 h after the brief ischemic period. Compared to classical preconditioning, it appears gradually and lasts 72 h or more following the ischemic preconditioning stimulus. Although the protection is longer lasting, it is less pronounced compared to that afforded by classical preconditioning and often requires multiple episodes of ischemia-reperfusion preconditioning. Studies suggest delayed type ischemic preconditioning is conveyed by newly synthesized cardioprotective proteins. PKC activation and its translocation have been shown to be integral in the intracellular signaling processes. PKC, nitric oxide, and radical oxygen species have been observed to be part of this common pathway. Furthermore, activation of nuclear factor-KB (NF-KB), which leads to sustained expression of several proteins, is responsible for the delayed protection. NF-KB is a well-known redox-sensitive transcription factor and a regulator for gene expression in cell stress signals, including ischemic stresses. While NF-KB binding activity is very low in nonischemic cardiomyocytes, preconditioning, and ischemia/reperfusion, significantly increase the translocation of NF-KB from cytosol to nucleus.^[12]

Infarct size is the most important prognostic factor of MI in the research setting and is the “gold standard” measurement of the efficacy of preconditioning. In fact, decreases in arrhythmias and increases in cardiac contractility are attributed as secondary effects of infarct size reduction. Not surprisingly then, how preconditioning provides myocardiocyte resistance to death is an important area of research. Preconditioning has been observed to inhibit myocardiocyte apoptosis by reducing ROS generated from inflammatory cells, local endothelial cells, and myocytes.^[13],[14] Preconditioning also tilts the balance between antiapoptotic and proapoptotic proteins. Ischemic preconditioning decreases proapoptotic Bax expression and increases antiapoptotic Bcl-2 proteins, resulting in an elevated Bcl-2/Bax ratio; this subsequently attenuates cytochrome c release from the mitochondria and ultimately cell apoptosis.^[15] The caveat is that preconditioning does not actually prevent myocardial death. Preconditioning only delays injury, thus it only demonstrates a benefit when coupled with timely reperfusion.

Clinical Relevance

While infarct size is the key end-point in determining the effectiveness of preconditioning in animal models, it is not an applicable end-point in the clinical setting. Surrogate measurements are used in the clinical setting, including, creatine kinase or troponin release substitute for infarct size, electrocardiogram to look for tachycardia and ventricular fibrillation, and clinical examination to detect the onset of MI.

While ischemic preconditioning has been shown to reliably reduce the detrimental effects of sustained MI in animal models, it has not readily translated to routine clinical use. The most substantial obstacle is that there is no reliable way to predict when a MI will occur, and hence no way to administer ischemic preconditioning or a preconditioning mimetic agent. However, there are situations where preconditioning (e.g., ischemia/reperfusion) are planned and thus can be studied. These situations include coronary artery balloon angioplasty, CABG surgery, and exercise in patient with known stable angina. More specifically, Cribier et al. showed that multiple balloon inflation and deflation to simulate ischemia and reperfusion reduces ST-segment elevation and lactate production on subsequent balloon inflations compared with initial balloon inflation.^[16] Similarly, Walsh et al. conducted a meta-analysis concluding that ischemic preconditioning through intermittent aorta cross-clamping reduces postoperative ventricular arrhythmias, inotrope requirements, and Intensive Care Unit stay.^[17]

Is angina a clinical correlate to preconditioning? In support of this idea, Kloner et al. demonstrated that previous angina, a form of preconditioning, offers a beneficial effect on in-hospital outcome after acute MI and thrombolytic therapy as measured by in-hospital mortality, congestive heart failure, cardiogenic shock, and creatine kinase-determined infarct size.^[18] However, others have questioned the mechanism underlying the beneficial effect of preconditioning. After reviewing the study, Andreotti et al. attributed the benefits to earlier coronary thrombolysis instead of preconditioning for the improved outcome.^[19]

Remote Ischemic Preconditioning

The concept of RIPC involves brief episodes of ischemia/reperfusion applied in distant tissues or organs rendering the myocardium protection against sustained episode of ischemia. The interest in RIPC has been increasing, especially in the clinical setting, as it does not require an invasive procedure to induce ischemia within the heart and possibly dislodging atherosclerotic plaque and showering downstream coronaries with emboli. RIPC have been observed to elicit cardioprotection in a variety of settings, including during CABG surgery and valve replacement surgery.^[20],[21] Interestingly, in vitro studies have shown that the magnitude of reduction in infarct volume in RIPC is comparable to that achieved with classic ischemic preconditioning.^{[22],[23],[24],[25]} Similarly, in vivo studies demonstrated that brief episodes of ischemia applied to remote organs, including skeletal muscle, kidney, and mesentery have consistently provided profound infarct resistance in the myocardium.^{[5],[26],[27]}

More recently, the concept of remote preconditioning involving limb ischemia has been gaining traction as a noninvasive method of inducing ischemia. Animal models have demonstrated that limb ischemia-induced preconditioning, can be performed noninvasively by simply inflating and deflating a blood-pressure cuff to induce transient ischemia and reperfusion, is effective in exert cardioprotection.^[5],[28] These findings raise the question, what are these protective factors released from both the heart and distant organs that initiate protection at remote sites? The mechanism underlying RIPC is not well understood although the current concepts suggest blood-borne factors, including adenosine, bradykinin, and norepinephrine may play a role. These blood-borne factors ultimately activate K_ATP channels to exert cardioprotection similar to the mechanism underlying local classical preconditioning. However, the intermediators between blood-borne factors and K_ATP channels in this pathway are also not well understood. It is hypothesized that adenosine binds to extracellular receptors, activating G-protein. Activated G-protein induces the activation of PKC. PKC subsequently activates ATP-sensitive potassium channels, exerting cardioprotective effects. This hypothesis is confirmed in rabbit, rat, and human models.^{[29],[30],[31]} However, studies involving dog and pig models have cast some doubt on the universal importance of PKC in this pathway.^{[32],[33],[34],[35]}

The clinical application and efficacy of remote limb ischemic preconditioning have been equivocal. Candilio et al. observed RIPC reduced the extent of perioperative myocardial injury in patients undergoing CABG or valve surgery in the short-term clinical outcomes, and Thielmann et al. concluded that RIPC provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgeries in longer term.^[26],[36] The clinical applicability of RPIC is buttressed by other clinical studies.^{[21],[36],[37],[38],[39],[40],[41]} However, Hausenloy et al. and Meybohm et al. did not observe cardioprotective effects following RIPC in the most recent and most comprehensive clinical trial.^[42],[43] Possible explanations for the divergent results as follows: (1) remote ischemic conditioning does not add additional protection in cardiac surgery, and (2) patients in the studies already received hypothermia, opioids, and cardioplegia, which are known to be cardioprotective. Perhaps, further RIPC protection is impossible to achieve in these cases. Furthermore, concomitant medications, including propofol, a known inhibitor of the preconditioning pathway, may have attenuated the cardioprotective efficacy of RIPC. However, the most recent clinical trials showed negative results. Future studies should include other cohorts such as patients in other clinical settings and explore the use of other RIPC protocols, including lower-limb RIPC, longer duration of ischemia, or increase the number of cycles of ischemia, which may still be protective.

Conclusion

Ischemic preconditioning is an endogenous phenomenon for which the value and limitation for cardioprotection remain ambiguous. Although several components in the signal transduction cascade have been elucidated, the comprehensive understanding of the mechanism underlying preconditioning remains unclear. While animal models showed clear efficacy of preconditioning, clinical translation has been challenging. Classical preconditioning is difficult to administer due to both medical and ethical concerns. Nonetheless, some clinical trials showed promising results in surrogate surgical conditions. Recently, RIPC has gained popularity as a none-invasive alternative to classical preconditioning. Although several clinical trials observed positive results, two multicenter and well-conceived clinical studies have been disappointing. Currently, there is no effective cardioprotective therapy used in clinical practice. However, future clinical trials employing a different cohort or a different RPIC protocol may yield positive results.

Acknowledgment

This work was partially supported by the Medical Student Research Fellowship, American Heart Association Grant-in-Aid (14GRNT20460246) (YD), Merit Review Award (I01RX-001964-01) from the US Department of Veterans Affairs Rehabilitation R&D Service (YD).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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