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Right arrow Myocardial protection

Ann Thorac Surg 2003;75:S700-S708
© 2003 The Society of Thoracic Surgeons

II: Surgical myocardial protection

Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection

Robert M. Mentzer, Jr, MDa*, Robert D. Lasley, PhDa, Andreas Jessel, MDb, Morris Karmazyn, PhDc

a Department of Surgery, University of Kentucky, Lexington, Kentucky, USA
b Aventis Inc, Bridgewater, New Jersey, USA
c Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada

* Address reprint requests to Dr Mentzer, Professor and Chairman, Department of Surgery, University of Kentucky, MV 264 UKMC, 800 Rose St, Lexington, KY 40536, USA
e-mail: mentzer{at}pop.uky.edu

Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.

Abstract

Although the mechanisms underlying ischemia/reperfusion injury remain elusive, evidence supports the etiologic role of intracellular calcium overload and oxidative stress induced by reactive oxygen species. Activation of the sodium hydrogen exchanger (NHE) is associated with intracellular calcium accumulation. Inhibition of the NHE-1 isoform may attenuate the consequences of this injury. Although there is strong preclinical and early clinical evidence that NHE inhibitors may be cardioprotective, definitive proof of this concept in humans awaits the results of ongoing clinical trials.


Drs Mentzer, Lasley, and Jessel disclose that they have a financial relationship with Aventis Inc.

 

Protecting the heart during reparative or replacement heart surgery has been the focus of intense basic science and clinical research over the past 50 years [1–4]. Although numerous methodologies and surgical techniques such as fibrillatory arrest and the single clamp technique have been developed, the mainstays remain hypothermic arrest and use of crystalloid or blood cardioplegia [2, 5, 6]. Despite these advances, however, the clinical problem of ischemia/reperfusion injury persists.

The mechanisms underlying ischemia/reperfusion injury remain elusive; however, considerable evidence shows that its etiology is associated with intracellular calcium overload during ischemia and reperfusion and with oxidative stress induced by reactive oxygen species released at the onset of reperfusion [7, 8]. The injury may result in myocardial stunning (reversible injury), myocardial infarction (MI; necrosis), or myocardial apoptosis. Clinically, this injury may be associated with hypotension and low cardiac output acutely or ventricular remodeling and heart failure months to years later. Although the frequency of this reperfusion injury varies with the duration of ischemia and the underlying nature of the heart disease, the incidence of myocardial stunning may range between 20% and 80% after coronary artery bypass grafting (CABG) alone [9–12]. Likewise, the incidence of non–Q-wave and Q-wave infarction after CABG ranges from 5% to 7%; necrosis-related postischemic myocardial dysfunction ranges from 3% to 7%; severe myocardial dysfunction in high-risk patients ranges from 15% to 20%; and in-hospital death after CABG ranges from 3% to 4.5% [13–15]. The magnitude of the problem is immense if one considers that almost 62 million individuals in the United States have at least one form of cardiovascular disease and more than 12 million of these have coronary artery disease [16]. In 1999, it was reported that more than 750,000 patients underwent open-heart surgery and that 571,000 bypass procedures were performed on 355,000 patients [16]. (A mortality rate of 3% in 355,000 patients receiving CABG per year would yield an expected mortality of approximately 10,650 persons per year.) Assuming that 10% of the patients undergoing surgery experience cardiac death, MI, severe ventricular dysfunction or heart failure, it has been estimated that these complications consume an additional $2 billion in US health care resources each year [13].

Equally important is the increasing evidence that the long-term consequences of inadequate myocardial protection are also associated with medium-term cardiovascular adverse events [17, 18]. Klatte and colleagues [19] reported an association between increased unadjusted 6-month mortality rates for 2,918 patients after CABG and postoperative peak creatine kinase myocardial band isozyme (CK-MB) ratios (peak CK-MB value/upper limits of normal) (Fig 1) . This relationship remained significant after adjusting for a number of variables including ejection fraction, congestive heart failure, cardiac arrhythmias, and method of cardioplegia delivery. Thus, progressive elevation of the CK-MB ratio in clinically high-risk CABG patients is associated with significant elevations of medium-term mortality [20–22]. These findings are consistent with a report by Steuer and colleagues [23] that enzyme elevations in 4,911 consecutive patients who underwent isolated, first-time CABG and were followed for 5 years were associated with the risk of both early and late death (Fig 2). Thus, compelling evidence shows a real need to improve current methodologies to protect the heart against ischemia/reperfusion injury during surgery and demonstrates that the deleterious consequences of inadequate intraoperative myocardial protection may manifest long after the immediate effects of the operation.



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  		Fig 1. Cumulative 6-month survival rates according to the peak creatine kinase–myocardial band (CK-MB) ratio category (p < 0.0001). Reprinted with permission from [19].

 


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  		Fig 2. Survival in relation to day 1 serum creatine kinase–myocardial band (CK-MB). Survival of more than 7 years is shown among groups of patients with CK-MB of 61 µg/L or more and CK-MB less than 61 µg/L on postoperative day 1. Reprinted with permission from [23].

 
One therapeutic modality that holds considerable promise for the immediate future is the use of sodium-hydrogen exchange (NHE) inhibitors [24]. The concept behind these agents is that they make it possible to limit ischemia-induced intracellular acidosis and excessive intracellular calcium accumulation, which in turn is etiologic in the phenomenon of ischemia/reperfusion injury.

Intracellular pH regulation in the cardiac cell

Changes in intracellular pH (pHi) can have profound effects on cardiac contractility through a variety of mechanisms. These mechanisms become very important when the pHi increases as a consequence of myocardial ischemia. Although the regulation of pHi reflects a net balance of alkalinization and acidification processes, the two major alkalinizing exchangers that are important for controlling intracellular acidosis are the Na-H exchanger (NHE) and a Na-HCO3 symport [25].

The NHE is one of the key mechanisms for restoring pHi after ischemia-induced acidosis by extruding protons concomitantly with Na influx in an electroneutral process. At present, seven NHE isoforms (termed NHE-1 through NHE-7) have been identified [26–28]. These seven isoforms represent distinct gene products and exhibit distinct differences in their primary structures, patterns of tissue expression, membrane localization, number of transmembrane spanning regions, functional properties, physiologic roles, and sensitivities to pharmacologic inhibition [26, 27]. In virtually all mammalian cells NHE-1 is expressed, whereas a more restricted pattern of expression is shown for NHE-2 through NHE-5. Both NHE-6 and NHE-7 are intracellularly localized, although their functions are not currently known. The various isoforms show marked differences in their sensitivities to pharmacologic inhibition by the agent amiloride and its derivatives, which represent the prototypical NHE inhibitors. They are not, however, specific for NHE subtypes [29]. Because the NHE-1 is the primary form identified in the mammalian myocardium, it represents the major subtype that is the focus of preclinical and clinical work designed to minimize the adverse consequences associated with ischemia/reperfusion injury.

NHE-1 isoform structure and cellular localization

The NHE-1 isoform is a glycoprotein containing 815 amino acids and can be separated into two distinct functional domains: (1) a 500–amino acid transmembrane domain made up of 12 transmembrane spanning segments, and (2) a 315–amino acid hydrophilic cytoplasmic carboxy-terminal domain [26, 27]. The 500–amino acid transmembrane domain is primarily responsible for proton extrusion [30], and the 315–amino acid C-terminal domain is responsible for modulation of NHE-1 activity, primarily through phosphorylation-dependent reactions [26, 31]. Although the predicted molecular weight of the exchanger is 91 kDa, the actual weight is 110 kDa given that it is glycosylated; however, this does not seem to be essential for transport function [32].

Immunohistochemical studies have revealed that cardiac NHE-1 isoform is predominantly localized at the intercalated disk region of atrial and ventricular myocytes in close proximity to the gap junction protein, connexin 43 and, to a lesser extent, along the transverse tubular system [33]. Connexin 43 and the sarcoplasmic reticulum calcium release channel (ie, ryanodine receptor) are highly pHi-sensitive. Thus it has been speculated that because of its apparent localization, NHE-1 regulates the pH microenvironment of these pHi-sensitive proteins and thereby influences cell-to-cell ion-dependent communication and intracellular calcium levels [33].

NHE-1 isoform activation

The major stimulus that regulates NHE-1 activity under normal physiologic conditions is acidic pHi [34]. Within the normal physiologic pHi range (7.1 to 7.3), NHE-1 activity is negligible; but as pHi decreases, which occurs during myocardial ischemia, the exchanger becomes rapidly activated. The reason for this rapid activation is the so-called proton sensor, which is found on the cytoplasmic surface of the exchanger and accounts for the sensitivity of the exchanger to pHi. Extrinsic factors such as hormones, growth factors, cytokines, and autocrine/paracrine regulators modulate NHE-1 activity by increasing the sensitivity of the proton sensor to intracellular protons, thus causing a shift of NHE-1 activity toward an alkaline range; that is, NHE-1 activity increases at a less acidic pHi. Examples of such factors include endothelin-1 [35, 36], angiotensin II [37, 38], {alpha}1-adrenergic agonists [39, 40], thrombin [41], and growth factors [42–44]. As most of these are elevated in plasma as a consequence of myocardial ischemia, it can be readily appreciated that NHE-1 can thus be stimulated not only by increased acidosis in the ischemic cell but also by external stimuli such as these paracrine, autocrine, and hormonal factors. In addition, cardiotoxic ischemic metabolites such as hydrogen peroxide [45] and lysophosphatidylcholine [46] have also been reported to stimulate NHE-1 activity, a phenomenon that likely contributes to the deleterious effects of these factors.

NHE-1 isoform and its contribution to ischemia/reperfusion injury

The basis for NHE-1 involvement in ischemia/reperfusion injury is the myocyte’s inability to extrude sodium by the ischemic cardiac cell and the ultimate injurious accumulation of intracellular calcium. This is due, in part, to the inhibition of sodium-potassium ATPase during ischemia, which occurs in concert with NHE-1 activation (because of increased proton generation). In this sense, inhibition of sodium-potassium ATPase (the sodium-pump) is a prerequisite for NHE-1 involvement in ischemia/reperfusion injury. The sequence of events that leads to myocardial injury through NHE-1 activation has been reviewed in a number of recent publications [47, 48]. Briefly, stimulation of NHE-1 during ischemia enhances sodium influx that enters the cell through NHE-1 in exchange for proton extrusion. Because of the inhibition of the sodium pump, sodium cannot be effectively removed and consequently accumulates within the cardiac cell. This results in a reduction in the transmembrane sodium gradient, a major regulator of the sodium–calcium exchanger. This cell membrane exchanger is the major route of calcium removal from the cardiac cell and is driven by the sodium gradient. Thus, as the gradient is reduced owing to accumulation of intracellular sodium, the removal of calcium through the sodium–calcium exchanger is slowed and intracellular calcium accumulates. In addition, the sodium–calcium exchanger is a bidirectional transporter that can function in reverse mode under certain conditions. Accordingly, active calcium influx through reverse-mode sodium–calcium exchange may also contribute to calcium overloading and cardiomyocyte injury. Thus, it is not the NHE-1 activation per se that directly results in myocyte injury and death but, rather, its indirect effect associated with sodium potassium ATPase inhibition and intracellular calcium overload (Fig 3) [28].



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  		Fig 3. The role of the Na-H exchanger NHE-1 in mediating cell injury during ischemia and reperfusion involves an interaction with other ion-regulatory pathways. Activation of the exchanger during ischemia occurs primarily because of intracellular acidosis. Ischemia depresses the Na+, K+-ATPase, which prevents effective removal of Na+ that has entered because of NHE-1 activation. The bidirectional Na+, Ca++ exchanger, although generally functioning to extrude Ca++, is shown operating in its reverse mode, which can likely occur under intracellular Na+ loading conditions, thus contributing to elevations in intracellular Ca++ levels. Reprinted with permission from [28].

 
NHE inhibition using pharmacologic agents

The first series of drugs reported to inhibit NHE were the potassium-sparing diuretic amiloride and its derivatives [49, 50]. However, despite the ability of these agents to inhibit NHE, their eventual therapeutic development has been restricted by various nonspecific actions, lack of selectivity against NHE-1, and relatively low potency. This has led to the development of novel benzoylguanidine compounds that are targeted specifically against NHE-1 and thereby increase the potential for treatment of patients with heart disease and of those at risk for ischemia/reperfusion injury [28, 51, 52]. The first such compound was 3-methylsulphonyl-4-piperidinobenzoyl-guanidine methanesulphonate (HOE 694), which was followed by 4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate (HOE 642, cariporide). These compounds at therapeutic doses specifically target the NHE-1 isoform, and they have little or no effect on the other NHE isoforms. To date, there is little evidence that these agents affect other cellular regulatory processes aside from NHE. Because these agents have high specificity for NHE-1 and NHE-1 is generally inactive in the normal cell, there is a relatively low risk of this group of drugs exhibiting undesirable side effects.

Experimental evidence that NHE inhibition protects the ischemic heart in animals

Extensive preclinical evidence shows that NHE inhibitors are cardioprotective and that the antiporter is involved in mediating ischemia/reperfusion injury. The cardioprotective effects have recently been summarized in a number of review articles [47, 48, 53]. Some of these effects include the amelioration of myocardial necrosis, arrhythmias, postischemic stunning, and apoptosis. The earliest studies used the diuretic amiloride or amiloride analogues to demonstrate the cardioprotective properties of NHE inhibition. In one of the first such studies, Karmazyn [49] reported the effects of amiloride in isolated rat hearts subjected to 60 minutes of low-flow global ischemia followed by reperfusion. They found that amiloride significantly reduced the release of creatine kinase and significantly enhanced the recovery of force, rate of force development, and rate of relaxation during reperfusion. As shown in Figure 4, these benefits required that the NHE inhibitor be present during early ischemia, as amiloride had no effect when its administration was delayed until the time of reperfusion [49].



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  		Fig 4. Effects of amiloride (40 µg/mL) during ischemia and reperfusion on rate of force development in isolated rat hearts, measured as the rate of force divided by the rate of time in grams per second (df/dt [g/sec]). Control buffer (closed circles) or amiloride (open circles) was present through (A) ischemia only, (B) reperfusion only, or (C) both ischemia and reperfusion. Reprinted with permission from [49]. * p < 0.05 from control.

 
More recently, others have confirmed the beneficial effects of NHE inhibition on recovery of myocardial function after ischemia and reperfusion. Hartmann and Decking [54] showed that NHE inhibition with cariporide prevented sodium overload and delayed the pH change in isolated guinea pig hearts subjected to ischemia and reperfusion (Fig 5). Yasutake and colleagues [55] demonstrated that NHE inhibition with an amiloride analogue or HOE 694 protected against the arrhythmias often associated with ischemia and reperfusion. Both NHE inhibitors prevented ventricular fibrillation in a dose-dependent manner in an isolated rat heart preparation when given before ischemia and reperfusion (Fig 6) [55]. In a recent study by Klein and colleagues [56], NHE inhibition was shown to reduce infarct size in pigs subjected to experimental MI by means of a defined regional ischemia (60 minutes) and reperfusion (24 hours). As shown in Figure 7, infarct size measured after 24 hours of reperfusion was significantly reduced by an intracoronary infusion of the NHE inhibitor cariporide during the first 30 minutes of ischemia or throughout the entire 60 minutes of ischemia plus the first 10 minutes of reperfusion [53, 56]. No effect was seen when cariporide was infused during the last 15 minutes of ischemia plus the first 10 minutes of reperfusion.



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  		Fig 5. Influence of cariporide (10 µmol/L) on (A) intracellular sodium and (B) pH in total global ischemia (15 minutes duration) and reperfusion. Cariporide was administered 3 minutes after data acquisition and 9 minutes before onset of ischemia ({ddagger}p < 0.01 vs control). Reprinted with permission from [54].

 


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  		Fig 6. Effects of (A) 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and (B) HOE-694 when given before ischemia plus during reperfusion on overall incidence of reperfusion-induced ventricular fibrillation (VF). *p < 0.05 vs control (0 µmol/L). Reprinted with permission from [55].

 


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  		Fig 7. Effects on infarct size of intracoronary infusion of the Na+/H+ exchanger (NHE) inhibitor cariporide during various periods, in pig hearts subjected to 60 minutes of regional low-flow ischemia and 24 hours of reperfusion. Infarct size was measured at the end of 24 hours of reperfusion by both histochemical and histologic methods. Top panel illustrates experimental protocol, with vertically hatched bars indicating the periods of cariporide infusion and arrows showing coronary sinus cariporide concentrations (in µmol/L) after 30 minutes of ischemia, immediately before reperfusion and immediately after reperfusion, in the various study groups. Note that a minimum concentration of approximately 1 µmol/L cariporide is required for effective inhibition of sarcolemmal NHE activity in cardiac ventricular myocytes [24]. As shown, infarct size was significantly limited by the intracoronary infusion of cariporide during the first 30 minutes of ischemia or throughout the entire 60 minutes of ischemia plus the first 10 minutes of reperfusion. In contrast, infusion of cariporide during the last 15 minutes of ischemia plus the first 10 minutes of reperfusion provided no benefit, even though the coronary sinus cariporide concentrations at the end of ischemia and the beginning of reperfusion were sufficient to inhibit NHE activity. Thus NHE activity during early ischemia, rather than that during late ischemia and early reperfusion, seems to be the principal determinant of the extent of myocardial infarction. I = ischemia; R = reperfusion, *p < 0.05 vs control. Reprinted with permission from [53] based on data from [56].

 
In a different study in our laboratory, we subjected open-chested anesthetized pigs to 60 minutes of normothermic coronary artery occlusion. Infarct size was estimated by triphenyltetrazolium chloride staining after 3 hours reperfusion. As illustrated in Figure 8, cariporide treatment 10 minutes before the onset of ischemia was associated with a dose-dependent reduction in infarct size with the higher dose (3 mg/kg), producing a greater than 60% reduction in infarct size. Furthermore, cariporide treatment was associated with no hemodynamic effects. Together, these findings consistently demonstrate excellent and reproducible protection in a wide variety of experimental preparations, animal species, and conditions.



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  		Fig 8. Effect of cariporide on infarct size in anesthetized pigs. Open-chest, anesthetized pigs were subjected to 60 minutes normothermic coronary artery occlusion. Infarct size was estimated by triphenyltetrazolium chloride staining after 3 hours of reperfusion. Individual data points represent individual animals. Solid circles represent group mean (± SEM). Cariporide treatment 10 minutes before onset of ischemia was associated with a dose-dependent reduction in infarct size, with the higher dose (3 mg/kg) producing a greater than 60% reduction in infarct size. Cariporide treatment was associated with no hemodynamic effects.

 
NHE-1 inhibition and ischemic preconditioning

To date, one of the most effective methods for enhancing the heart’s tolerance to ischemia is first to expose the heart to a brief period of ischemia and reperfusion. This phenomenon is referred to as ischemic preconditioning (IPC) [57]. Although the precise mechanism(s) underlying ischemic preconditioning have yet to be determined, there is little evidence to suggest that the NHE is involved. In fact, NHE-1 inhibition has been reported to offer added protection when administered to preconditioned hearts [58]. Evidence also suggests that NHE inhibition confers the same degree of myocardial protection as IPC. Gumina and colleagues [59] reported that NHE inhibition in dogs subjected to 60 minutes of coronary artery occlusion conferred the same reduction in infarct size as IPC. However, when the period of occlusion was extended to 90 minutes, IPC failed to protect the myocardium, whereas NHE-1 inhibition reduced infarct size by approximately 70%. This suggests that cardioprotection by NHE-1 inhibition in dogs is actually superior to IPC.

Other salutary effects of NHE-I inhibition

Recent evidence suggests that inhibition of NHE-1 may also be associated with other cardioprotective effects. For example, some reports assert that NHE-1 inhibition blunts the deleterious effects of reperfusion-induced neutrophil activation through a pH-dependent mechanism [60–62]. Other evidence suggests that NHE inhibition preserves endothelial function, which can be compromised under pathologic conditions. Specifically, NHE inhibition has been reported to preserve endothelial function, as measured by the vasodilatory response to acetylcholine in various models of myocardial ischemia/reperfusion injury [63, 64]. Protection of the endothelium may also be relevant to the observations pertaining to neutrophil activation, as it is likely that endothelial preservation results in reduced neutrophil adhesion to the vascular wall, thus further reducing tissue damage [62, 65].

Timing of treatment

A major focus of preclinical and clinical studies has been the demonstration of drug efficacy when administered at the time of reperfusion. An agent that can attenuate myocardial necrosis and postischemic dysfunction when administered at the onset of reperfusion would be of considerable importance to patients undergoing percutaneous coronary intervention (PCI) for the treatment of an acute MI. Although experimental evidence shows that many NHE inhibitors administered at the time of reperfusion exert some degree of myocardial protection, such protection generally is markedly less than that seen when the agent is administered preischemia [47, 48]. From a mechanistic perspective, this is not surprising, because NHE-1 activation during ischemia contributes substantially to the sodium and calcium overloading, with further NHE-1 activation occurring immediately upon reflow. As such, optimal protective effects of NHE-1 inhibitors would predictably be realized when treatment can be initiated before onset of ischemia, as well as during both ischemia and reperfusion.

NHE inhibition and myocardial protection in humans

One of the first studies in humans tested the hypothesis that NHE inhibition would limit infarct size and improve myocardial function in patients with acute anterior MI treated with PCI [66]. A total of 100 patients were randomized to receive placebo (n = 51) or a 40-mg intravenous bolus of the NHEi cariporide (n = 49) before reperfusion. Left ventriculography was performed before and 21 days after PCI to assess functional differences. Creatine kinase, CK-MB, and lactate dehydrogenase levels were measured as enzyme markers of myocardial injury. At follow-up, the ejection fraction was greater (50% vs 40%; p < 0.05) and the enzyme release less in the treated patients.

This cardioprotective effect of an NHE inhibitor in humans was not realized, however, in the Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction (ESCAMI) Trial [67]. In this two-stage study, eniporide, a specific NHE-1 isoform inhibitor, was administered to patients undergoing thrombolytic therapy or primary angioplasty for acute ST-elevation MI. Efficacy was assessed in terms of infarct size reduction (the primary end point), which was measured by the cumulative release of {alpha}-hydroxybutyrate dehydrogenase. The study was carried out in two stages, with 433 patients in stage 1 and 2,998 patients in stage 2. In stage 1, the 100- and 150-mg eniporide dosage regimens were associated with smaller infarct sizes; however, the positive findings were not confirmed in stage 2.

The observation that there was no effect of treatment on either the primary or overall secondary end points (death, cardiogenic shock, heart failure, or life-threatening arrhythmias) in the ESCAMI Trial may not be so surprising in that the preponderance of preclinical evidence indicates that the beneficial effect of NHE inhibition is realized only when it is initiated before the ischemic event. This also provides a strong rationale for why there was a significant clinical benefit in patients at risk of myocardial necrosis undergoing CABG in the GUARD During Ischemia Against Necrosis (GUARDIAN) Trial [68]. In this study, 11,590 patients who had unstable angina or who underwent high-risk PCI or surgical revascularization (CABG) were randomized to receive placebo or one of three doses of cariporide. Although the overall trial failed to demonstrate a benefit of NHE inhibition over placebo on the primary end point of death or MI, post hoc analysis of CABG patient cohort data revealed that the 120-mg dose was associated with a 25% relative risk reduction in the primary end point (16.2% with placebo vs 12.2% with cariporide; p = 0.027). This risk reduction was maintained through 6 months and was associated with less of an increase in CK-MB and a reduction in Q-wave and non–Q-wave MIs.

As a consequence of these findings, the multinational, double-blind, randomized, placebo-controlled Na+/H+ Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions (EXPEDITION) Trial was initiated in 2000. The purpose of this investigation is to test the hypothesis that the NHE inhibitor cariporide will reduce all-cause mortality and nonfatal MI after CABG surgery. Patients at an increased risk of myocardial injury, as evidenced by either the need for urgent or repeat CABG surgery, or the presence of multivessel disease and at least one additional risk factor (age >65 years, female sex, diabetes mellitus, ejection fraction <35%) are randomized in a double-blind manner to receive cariporide or placebo. The study drug is administered more than 49 hours, starting approximately 2 hours before induction of anesthesia. Other clinical end points address the incidence of newly developed left ventricular dysfunction and life-threatening arrhythmia. These end points are complemented by documentation of need for inotropic support or mechanical ventricular assist devices to address clinically relevant indicators of myocardial stunning. The results of this trial are expected in 2003.

Summary

Perhaps nowhere else is there greater need to enhance the heart’s tolerance to ischemia and to minimize the consequences of ischemia/reperfusion injury than in the field of heart surgery. Although elucidation of the mechanisms underlying early and late phase ischemic preconditioning may well lead to pharmacomimetic agents that can achieve the same degree of protection as IPC, currently the most promising mechanism for clinical use is that associated with NHE. The clinical impact of global myocardial injury during cardiac surgery may not be immediately evident in the early postoperative phase, unless unmasked by early hemodynamic instability and need for inotropic support or ventricular assist devices. However, long-term studies identified heart failure as the leading cause of death in the months after bypass grafting, accounting for more than 60% of deaths during this period [69]. Furthermore, postoperative elevation of CK-MB has been shown to be a strong predictor of 6-month to 5-year mortality [70–73]. These findings clearly emphasize the clinical need for improved perioperative cardioprotection.

Strong preclinical and early clinical evidence support the rationale for additional studies in humans using NHE inhibitors that are currently ongoing. The aim of these trials is to prove conclusively the therapeutic concept that NHE-1 inhibition in humans can reduce the incidence of myocardial necrosis. Should this be the case, it is conceivable that NHE inhibition therapy could be tailored to treat all patients who are vulnerable to ischemia/reperfusion injury, not only those about to undergo cardiac surgery. On the other hand, if these clinical studies do not confirm the efficacy of NHE inhibitors in reducing the incidence of myocardial infarction in humans, basic and clinical scientists will need to reassess the hypothesis that intracellular calcium overload is etiologic in ischemia/reperfusion injury.

Acknowledgments

Doctors Mentzer and Lasley are supported by National Heart, Lung, and Blood Institute Grants RO1HL34759 (RMM Jr), RO1HL66132 (RDL), and a research grant from Aventis Inc. Work cited from Dr Karmazyn’s laboratory was supported by the Canadian Institutes of Health Research; Dr Karmazyn is a recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario.

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