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REVIEW ARTICLE

Na⁺/h⁺ exchange inhibitors for cardioprotective therapy: progress, problems and prospects

^a Centre for Cardiovascular Biology and Medicine and Department of Cardiology, King’s College London, The Rayne Institute, St Thomas’ Hospital, London, United Kingdom

Manuscript received September 25, 2001; revised manuscript received December 4, 2001, accepted December 14, 2001.

^* Reprint requests and correspondence: Professor Metin Avkiran, Centre for Cardiovascular Biology and Medicine, The Rayne Institute, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom
metin.avkiran{at}kcl.ac.uk

	Abstract

Top Abstract A novel pharmacologic approach... Clinical studies with NHE... NHE inhibitors for... NHE inhibitors for... Conclusions References

 
Extensive pre-clinical work indicates that inhibition of the sarcolemmal Na⁺/H⁺ exchanger (NHE) affords significant protection to myocardium subjected to ischemia and reperfusion, predominantly through reduced intracellular accumulation of Na⁺ and consequently Ca²⁺. In contrast, recent clinical studies with the NHE inhibitors cariporide and eniporide in patients with evolving myocardial infarction (MI) and those at risk of MI have provided mixed and somewhat contradictory data. The experimental evidence suggests that the key mechanism through which NHE inhibitors afford protection consists in slowing the progression of myocardial injury during ischemia and thereby enhancing myocardial salvage by reperfusion. It follows from this that, to obtain maximum cardioprotective benefit, 1) the NHE inhibitor must be present in jeopardized myocardium, at a concentration sufficient to inhibit NHE activity, before (or as soon as possible after) the onset of ischemia, and 2) ischemia must be terminated by timely reperfusion. Thus, in the GUARDIAN trial, the cardioprotective efficacy of cariporide was limited to the subset of high-risk patients who underwent coronary artery bypass graft surgery, in whom both prerequisites could be readily fulfilled. In contrast, no cardioprotective benefit was observed in the ESCAMI trial, in which eniporide was administered late as an adjunct to reperfusion therapy in patients with evolving MI. Ongoing clinical studies will determine whether NHE inhibition will find therapeutic application in the setting of cardiac surgery, while pre-clinical investigations continue to test the potential of NHE inhibitors in the treatment of other cardiovascular diseases such as heart failure.

Abbreviations and Acronyms   CABG = coronary artery bypass graft   CK = creatine kinase   CK-MB = creatine kinase-MB isoform   ECG = electrocardiogram   ESCAMI = Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction   EXPEDITION = Na+/H+ Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions   GUARDIAN = Guard During Ischemia Against Necrosis   MI = myocardial infarction   NCX = Na+/Ca2+ exchanger   NHE = Na+/H+ exchanger   PCI = percutaneous coronary intervention

	A novel pharmacologic approach to cardioprotection

Top Abstract A novel pharmacologic approach... Clinical studies with NHE... NHE inhibitors for... NHE inhibitors for... Conclusions References

 
Among the wide range of putative cardioprotective drugs that have been tested in experimental studies of myocardial ischemia and reperfusion, those that specifically target and inhibit the Na⁺/H⁺ exchanger (NHE) isoform 1, a ubiquitously expressed protein that is the molecular homolog of the cardiac sarcolemmal NHE, have shown particular promise. This growing family of NHE inhibitors, which include cariporide (3), eniporide (4) and zoniporide (5), have been found to afford substantial protection in animal models of myocardial ischemia and reperfusion, with an unusual degree of conformity between different investigators, species and models (see recent reviews by Avkiran [6] and Karmazyn et al. [7]). Indeed, some laboratory findings suggest that NHE inhibition may provide cardioprotective benefit that is equivalent, or perhaps even superior, to that afforded by ischemic preconditioning (8–10).

The potential mechanisms that are likely to underlie the protection afforded by NHE inhibitors during myocardial ischemia and reperfusion have been reviewed recently (11). As illustrated in Figure 1 , the available experimental evidence suggests that such protection is likely to arise primarily from the attenuation of intracellular Na⁺ accumulation during ischemia, which in turn would attenuate intracellular Ca²⁺ accumulation (through reduced Ca²⁺ efflux and/or increased Ca²⁺ influx via the sarcolemmal Na⁺/Ca²⁺ exchanger) during both ischemia and subsequent reperfusion (11). In some settings additional mechanisms, such as the attenuation of neutrophil accumulation (12,13) and coronary endothelial dysfunction (14) within the jeopardized tissue, may also contribute to the protection afforded by NHE inhibitors, through the inhibition of NHE activity in non-myocardial cells (11).

View larger version (45K): [in this window] [in a new window]   Figure 1 Potential mechanism through which Na+/H+ exchanger (NHE) inhibition preserves intracellular ion homeostasis and thereby myocardial integrity and function after ischemia and reperfusion. (A) Under basal conditions, NHE is relatively quiescent, the Na+/K+ ATPase (Na+ pump) utilizes ATP to extrude Na+, and the bidirectional Na+/Ca2+ exchanger (NCX) works predominantly in forward (Ca2+ efflux) mode. (B) During ischemia, NHE becomes activated in response to intracellular acidosis and possibly by other NHE-stimulatory factors (26). The resulting influx of Na+, occurring in the presence of ischemia-induced attenuation of Na+ pump activity, causes the intracellular accumulation of Na+. Such a rise in the intracellular Na+ concentration during ischemia alters the reversal potential of the NCX in a manner that inhibits its operation in forward mode but favors its operation in reverse (Ca2+ influx) mode, thus producing intracellular Ca2+ accumulation (Ca2+ overload) during both ischemia and subsequent reperfusion. (C) NHE inhibitors are likely to afford a cardioprotective effect during ischemia and reperfusion by inhibiting this sequence at an early stage, through the limitation of Na+ influx during ischemia. Note that the illustration has been simplified for clarity, and that mechanisms other than NHE activity are also likely to contribute to the intracellular accumulation of Na+ and consequently Ca2+ during ischemia and reperfusion.

	Clinical studies with NHE inhibitors: results and reflections

Top Abstract A novel pharmacologic approach... Clinical studies with NHE... NHE inhibitors for... NHE inhibitors for... Conclusions References

 
A recent issue of the Journal of the American College of Cardiology includes a report of the main findings of a clinical study with eniporide (18), which follows the earlier publication of the results of two other clinical studies with cariporide (16,17). Two of these studies (17,18) involved patients with acute myocardial infarction (MI) in whom the NHE inhibitor was used as an adjunct to reperfusion therapy (by primary coronary angioplasty or thrombolysis), and the other study (16) tested the cardioprotective efficacy of NHE inhibition in a large number of patients at risk of MI during spontaneous or iatrogenic ischemia.

NHE inhibition in patients with MI.   Rupprecht et al. (17) determined the effects of cariporide in patients with anterior MI who were expected to receive reperfusion therapy by primary coronary angioplasty within 6 h of the onset of symptoms. One hundred patients were randomized to receive placebo or 40 mg cariporide as an intravenous bolus 10 min before reperfusion, and placebo or drug administration was completed within approximately 4 h after the onset of symptoms. Cardiac enzymes (creatine kinase [CK], creatine kinase-MB isoform [CK-MB] and lactate dehydrogenase) were determined in blood samples obtained before and 4, 12, 24, 36 and 72 h after reperfusion in 85 patients (placebo n = 43, cariporide n = 42). Left ventricular function was determined by contrast ventriculography before treatment and at three-week follow-up in 46 patients (placebo n = 21, cariporide n = 25). The main findings of the study were that, after reperfusion: 1) ejection fraction remained unchanged in the placebo group but increased in the cariporide group, such that the change from baseline to follow-up was greater in the latter group (p = 0.045); 2) regional left ventricular wall-motion abnormalities tended to resolve in both groups, but the change from baseline to follow-up was greater in the cariporide group (p = 0.045); and 3) the cumulative release of CK-MB (the area under the curve) was reduced in the cariporide group relative to the placebo group (p = 0.047). The authors concluded that these data were consistent with the notion that reperfusion injury contributed to MI in humans and should be a target for interventions such as NHE inhibition (17). They further suggested that large-scale clinical trials were warranted to establish this therapeutic principle (17).

The results of such a trial, in the form of the ESCAMI (Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction) trial, have been reported recently (18). This study employed a two-stage design and recruited patients with anterior or inferior MI who were expected to receive reperfusion therapy, by primary coronary angioplasty or thrombolysis (at the physician’s discretion), within 6 h of the onset of symptoms. Blood samples were collected before and 4, 8, 12, 16, 24, 36, 48, 60 and 72 h after the start of reperfusion therapy for assessment of -hydroxybutyrate dehydrogenase, CK and CK-MB content. Ejection fraction or regional wall motion were not assessed. In stage 1, patients (n = 430) were randomized to receive placebo (n = 88) or 50 mg (n = 86), 100 mg (n = 91), 150 mg (n = 74) or 200 mg (n = 91) eniporide, as a 10-min intravenous infusion that had to be completed at least 10 min before the start of coronary angioplasty or within 15 min after the start of thrombolysis. Data from this stage indicated reductions in cumulative enzyme release of approximately 15% with 100 mg eniporide and 30% with 150 mg eniporide, although no effect was seen with the 200 mg dose. On the basis of these findings, the study was extended into stage 2, during which additional patients (n = 959) were randomized to receive placebo (n = 322) or 100 mg (n = 321) or 150 mg (n = 316) eniporide in an identical manner to stage 1. However, the results of stage 2 of the trial, when considered alone or in combination with those of stage 1, revealed no effect of eniporide on cumulative enzyme release. Furthermore, this lack of effect of active treatment persisted across various predefined subgroups (e.g., reperfusion by thrombolysis [n = 590] vs. coronary angioplasty [n = 363]; anterior [n = 389] vs. inferior [n = 513] infarction; early [4 h from the onset of symptoms, n = 696] vs. late [>4 h from the onset of symptoms, n = 229] reperfusion). Thus, the overall results of this study oppose the hypothesis that NHE inhibition, used as an adjunct to reperfusion, reduces MI by attenuating reperfusion injury.

Clearly, the outcome of the ESCAMI trial with eniporide (18) contradicts the findings of the earlier study with cariporide (17) with respect to the effects of NHE inhibition, as an adjunct to reperfusion therapy, on cardiac enzyme release. This difference in outcome is unlikely to have a pharmacologic basis, because eniporide is a more potent NHE inhibitor than cariporide (19) and the doses of eniporide used in the ESCAMI trial (18) were up to five times greater than the dose of cariporide used by Rupprecht et al. (17). It might be argued that NHE inhibition during reperfusion reduces myocardial enzyme release only in a highly selected group of patients who have large anterior infarcts and receive reperfusion by primary coronary angioplasty (17). However, this is also unlikely because, in the ESCAMI study, cumulative enzyme release did not differ between placebo and eniporide treatment even in the subgroup of patients who had anterior infarcts and received reperfusion by primary coronary angioplasty (18). The most likely explanation for the apparent discrepancy appears to be a chance finding in the study by Rupprecht et al. (17), arising as a consequence of the small sample size. Indeed, such a finding is also likely to have been responsible for the ultimately misleading results of stage 1 of the ESCAMI trial (18).

Is the lack of efficacy of NHE inhibition as an adjunct to reperfusion in patients with acute MI surprising, given what is known about the nature of reperfusion injury and the data from extensive pre-clinical work with NHE inhibitors? First, the existence of "lethal" reperfusion injury (defined as myocardial cell death arising from reperfusion rather than from the preceding period of ischemia) and its clinical relevance in the setting of acute MI are open to debate (20,21). Second, as reviewed in depth previously (6), the majority of available pre-clinical data show that NHE inhibitors limit infarct size dramatically when given before or soon after the onset of ischemia, but not when administered shortly before or at the time of reperfusion, suggesting that NHE activity does not contribute significantly to any lethal reperfusion injury. Indeed, even in the early experiments in pigs that demonstrated a limitation of infarct size with NHE inhibition from shortly before reperfusion, significantly greater benefit was observed when the NHE inhibitor was administered before the onset of ischemia (22). A recent study by Klein et al. (23), in pigs that were instrumented to receive residual flow (through an extracorporeal circuit) during a 60-min period of regional ischemia, has sought to determine definitively the key period during which NHE activity contributes to MI. As illustrated in Figure 2 , this study showed that infarct size measured after 24 h of reperfusion was significantly reduced by the intracoronary infusion of cariporide during the first 30 min of ischemia or throughout the entire 60 min of ischemia plus the first 10 min of reperfusion, but not by such infusion during the last 15 min of ischemia plus the first 10 min of reperfusion (23). In the light of such data and with the benefit of hindsight, a strong case may be made that the negative overall outcome of the ESCAMI trial was in fact predictable and that the unexpected findings were the positive indications from the earlier, smaller clinical studies. Indeed, when considered together, the clinical and pre-clinical data reinforce the concept that NHE activity during early ischemia (rather than during reperfusion) is the principal determinant of the extent of myocardial injury, such that early (ideally pre-ischemic) treatment is a prerequisite to obtain maximum cardioprotective benefit with NHE inhibitors (6,11).

View larger version (41K): [in this window] [in a new window]   Figure 2 Effects on infarct size of intracoronary infusion of the Na+/H+ exchanger (NHE) inhibitor cariporide during various periods, in pig hearts subjected to 60 min of regional low-flow ischemia and 24 h of reperfusion. Infarct size was measured at the end of 24 h of reperfusion by both histochemical and histologic methods. The top panel illustrates the experimental protocol, with the vertically hatched bars indicating the periods of cariporide infusion and the arrows showing the coronary sinus cariporide concentrations (in µmol/l) after 30 min 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 min of ischemia or throughout the entire 60 min of ischemia plus the first 10 min of reperfusion. In contrast, infusion of cariporide during the last 15 min of ischemia plus the first 10 min 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, appears to be the principal determinant of the extent of myocardial infarction. I = ischemia; R = reperfusion, * = p < 0.05 versus control. The figure is based on data from Klein et al. (23).

A laudable feature of the design of the GUARDIAN trial is the attempt to treat patients with the NHE inhibitor before the onset of an episode of myocardial ischemia that might culminate in infarction, reflecting the knowledge gained from pre-clinical work. However, the pre-clinical work also indicates that the key mechanism through which NHE inhibitors afford protection is by delaying the progression of myocardial injury during ischemia and thereby enhancing myocardial salvage by reperfusion (6). It follows from this that a further prerequisite to obtain maximum cardioprotective benefit with NHE inhibitors is timely reperfusion, in whose absence severely ischemic myocardium will eventually succumb to infarction regardless of treatment (6). It is probably not a coincidence therefore that the prerequisites of early treatment and timely reperfusion are both fulfilled in the setting of CABG surgery, where significant cardioprotective benefit was afforded by NHE inhibition in the GUARDIAN trial (16). As discussed by Théroux et al. (16), in the other entry diagnostic groups included in the GUARDIAN trial, evolving new infarcts would be reperfused only if ST-segment elevation developed (in patients admitted with unstable angina or non-Q-wave MI) or abrupt vessel closure ensued (in patients undergoing high-risk PCI). It is reasonable to speculate that the tendency in these cohorts toward a reduced incidence of Q-wave MI in response to high-dose cariporide treatment (16) may be a reflection of infarct size limitation by NHE inhibition in patients who exhibited such events and therefore received reperfusion therapy.

In addition to the presence or absence of timely reperfusion, a further issue to consider in interpreting the data from the GUARDIAN trial is the lack of a discernible dose-response relationship, even among patients who underwent CABG surgery (16). This raises the possibility that the optimal dose of cariporide may be higher than the maximum dose used in the GUARDIAN trial, barring unacceptable adverse effects. Indeed, pharmacokinetic modeling based on information from the GUARDIAN trial has indicated that, for therapeutic efficacy, a threshold plasma drug concentration of 550 ng/ml (approximately 1.4 µmol/l) needs to be exceeded during the period of risk (16). The model has also predicted that this would have occurred in only 67% of patients who received the highest (120 mg) dose of cariporide before CABG surgery (16). Of relevance to this issue, our recent studies in rat ventricular myocytes indicate that, in the presence of a physiologic Na⁺ concentration, 1 µmol/l cariporide is required for effective inhibition of sarcolemmal NHE activity (24). Thus, future clinical studies will need to consider using higher doses or modified drug administration protocols to ensure that the myocardial drug concentration during the period of risk is sufficient for effective inhibition of sarcolemmal NHE activity.

	NHE inhibitors for cardioprotection in acute ischemia: what next?

Top Abstract A novel pharmacologic approach... Clinical studies with NHE... NHE inhibitors for... NHE inhibitors for... Conclusions References

 
The positive findings of the GUARDIAN trial in the setting of CABG surgery were revealed by retrospective analysis of subgroup data (16). Clearly, therefore, there is an important need for further trial(s) that are designed prospectively to determine whether NHE inhibition affords cardioprotective benefit in patients undergoing high-risk CABG surgery. In an effort to fulfill this need, the objective of the recently initiated EXPEDITION (Na⁺/H⁺ Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions) trial is to test the hypothesis that NHE inhibition results in a reduction in myocardial injury in such patients, using a modified dosing regimen of cariporide. If the hypothesis is proven by the eventual findings of the EXPEDITION trial, then it will be necessary to consider whether there are other clinical settings in which NHE inhibitors may be given to patients before the onset of myocardial ischemia, in order to preserve myocardial viability during such ischemia and improve salvage by subsequent reperfusion. An immediate application may be in non-CABG cardiac surgery where the heart is also subjected to global ischemia and reperfusion. Additionally, consideration needs to be given to the possibility of using NHE inhibitors for perioperative cardioprotection in patients who are at high risk of cardiac events, such as MI, during non-cardiac surgery.

In the non-surgical sphere, it may be opportune to determine whether long-term NHE inhibition affords functional and/or symptomatic benefit in patients with stable angina through direct myocardial protection. Recent data in conscious pigs subjected to repetitive cycles of sublethal regional ischemia (2 min) and reperfusion (8 min) have shown that the ensuing regional contractile dysfunction is attenuated by NHE inhibition (25). In addition to a potential benefit during the transient episodes of ischemia, NHE inhibition in patients with angina would be expected to provide further benefit if spontaneous coronary occlusion ensues, by delaying the progression of ischemic injury and thereby enhancing myocardial salvage by subsequent reperfusion, as discussed earlier.

	NHE inhibitors for cardioprotection beyond acute ischemia?

Top Abstract A novel pharmacologic approach... Clinical studies with NHE... NHE inhibitors for... NHE inhibitors for... Conclusions References

 
Emerging experimental evidence suggests that sarcolemmal NHE activity may play an important pathophysiologic role beyond its contribution to the development of myocardial injury during acute ischemia and reperfusion. In this context, it is notable that although sarcolemmal NHE activity is regulated primarily by intracellular pH, it is also subject to regulation by a variety of neurohormonal mediators (26). Intriguingly, several myocardial G protein-coupled receptors whose activation by their cognate ligands has been associated with the induction of a hypertrophic phenotype in vitro, such as ₁-adrenergic (27), endothelin (28), angiotensin II (29) and thrombin (30) receptors, have also been shown to mediate increased sarcolemmal NHE activity (31–35). Furthermore, the induction of myocyte hypertrophy in vitro, in response to neurohormonal (36) or mechanical (37) stimuli, has been shown to be attenuated by NHE inhibition. Importantly, recent in vivo evidence in the rat indicates that NHE inhibition with cariporide attenuates myocardial hypertrophy and the development of heart failure after infarction, independently of infarct size limitation or afterload reduction (38,39). Of potential clinical relevance, our recent work has shown that ventricular myocytes from explanted human hearts with end-stage heart failure exhibit significantly greater sarcolemmal NHE activity than their counterparts from unused donor hearts, probably through altered posttranslational regulation of the exchanger (40). Thus, the available evidence points toward a causal or permissive role for sarcolemmal NHE activity in the development of cardiac hypertrophy and its progression to heart failure, suggesting that NHE inhibitors might find a novel therapeutic application in this setting.

Before the therapeutic potential of NHE inhibitors in the management of heart failure is tested in clinical trials, further experimental investigation may need to be performed. At present, the distal mechanism(s) through which NHE regulates myocardial growth and remodeling are unclear, and there is some controversy regarding the relative contributions of Na⁺ influx versus H⁺ efflux as mediators of such regulation. In addition, there is a paucity of information on the efficacy of NHE inhibition relative to, or in combination with, established therapies such as angiotensin-converting enzyme inhibition and beta-adrenergic receptor blockade in animal models of heart failure. In this context, a potential advantage of NHE inhibition over other therapies may be the direct attenuation of myocyte hypertrophy and remodeling in the absence of significant hemodynamic effects (39).

	Conclusions

Top Abstract A novel pharmacologic approach... Clinical studies with NHE... NHE inhibitors for... NHE inhibitors for... Conclusions References

 
The mixed results of recent clinical studies with NHE inhibitors contrast with the highly encouraging data from pre-clinical investigations and serve to highlight the enormous challenge of translating therapeutic potential into therapeutic reality. Nevertheless, a valid case may be made that the design of the clinical studies that have been completed to date did not reflect optimally the current knowledge from extensive pre-clinical work, particularly on the mechanism of action of NHE inhibitors. Indeed, with perfect hindsight, it is relatively straightforward to provide a scientific rationale for the disappointing outcomes of these clinical studies.

On the positive side, the clinical studies have shown that NHE inhibitors are well tolerated by patients (at least over a short period of treatment) and have provided a strong indication that, in the appropriate setting, they can indeed protect the human myocardium from injury during ischemia and reperfusion. Furthermore, animal experiments continue to support the cardioprotective potential of these agents in acute myocardial ischemia and have indicated that NHE inhibition may provide benefit beyond the preservation of acutely ischemic and reperfused myocardium. The very considerable challenge remains the translation of this potential into reality. This goal may be achieved only through pre-clinical work that improves our understanding of the pathophysiologic roles of the NHE system and the consequences of its inhibition, and complementary clinical trials that reflect such understanding.

	Acknowledgments

 
We thank Dr. Uwe Zeymer (Klinikum Kassel, Germany) for allowing us access to reference 18 before its publication.

	Footnotes

 
Metin Avkiran is the recipient of a Basic Science Award (BS/93002) from the British Heart Foundation.

	References

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