(Circulation. 2000;101:2874.)
© 2000 American Heart Association, Inc.
Editorial |
Myocardial Cell Protection
A Challenging Time for Action and a Challenging Time for Clinical Research
From the Department of Medicine, Montreal Heart Institute and University of Montreal, Quebec, Canada.
Key Words: Editorials • myocardial infarction • cariporide • reperfusion
Left ventricular dysfunction, most often the consequence of coronary artery disease and acute myocardial infarction (MI) in our society, is the primary determinant of prognosis in coronary artery disease and the major cause of cardiac disability. The principles for cell protection have long been established: on one hand, metabolic preservation; on the other, restoration of flow. Reperfusion therapy led most progress in the past 2 decades, leaving in the shadow other means of cell protection. The success of reperfusion therapy is measured in clinical trials in terms of lives saved. The more subtle benefits of direct cell intervention are difficult to assess in humans, given the large interindividual variability in infarct size, the small to moderate benefit expected from interventions, and the lack of a sensitive method to quantify exactly the area of necrosis versus the area at risk. Meanwhile, mechanisms involved in the progression of ischemia to necrosis have become better defined, opening new therapeutic perspectives. Some of the new or renewed concepts are ischemic insult, reperfusion damage, no-reflow, stunning, hibernation, and ischemic preconditioning.
Cell necrosis involves multiple mechanisms, including metabolic changes, ionic shifts, complement activation and generation of cytotoxic substances, inflammation, tissue edema, apoptosis, and matrix degradation. The respective roles of these mechanisms differ at various stages of ischemia and reperfusion and are cumulative. Unless interrupted, the process leads to irreversible damage. Early interventions will profit more and late interventions less; multiple interventions acting at different levels will probably be more successful.
The time constraints of 15 minutes to 3 hours for saving the jeopardized myocardium, learned from experimental models, apply only to a limited extent in humans.1 Reperfusion therapy saves life for up to 12 hours after onset of symptoms. Less profound ischemia associated with hibernation extends the period of time for salvage, whereas stunning delays recovery of function.2 Paradoxically, extensive necrosis can occur prematurely, despite early restoration of blood flow, as a result of no-reflow at the tissue level.3
Clinical research on cell protection may target ischemia, reperfusion, prevention in high-risk situations, or reversible dysfunction. Rupprecht et al,4 in their study published in this issue of Circulation, set optimal conditions for detecting benefit of an intervention during an evolving infarct. Patients with anterior ST-segment-elevation MI and no flow through the culprit lesion who were undergoing primary angioplasty within 6 hours of onset of symptoms were enrolled. Success was measured as change in function on paired contrast ventriculograms obtained before and 3 weeks after the intervention. They studied cariporide, an inhibitor of the sodium-potassium exchanger (NHE) that is highly effective for reducing infarct size in experimental models of ischemia-reperfusion.5 Although the laboratory studies have shown maximal benefit when the drug was applied before or early during ischemia, higher doses administered before reperfusion are still effective.6 7 Rupprecht et al administered relatively low doses of the drug just before reperfusion. Yet, the drug improved global ejection fraction, end-systolic and end-diastolic volumes, and indices of regional function, such as percentage of left ventricular contour with akinesis, dyskinesis, or hypokinesis. The improvement was not statistically significant or was of borderline significance in the presence of an imbalance between groups at baseline, treated patients showing less severe wall motion abnormalities and better left ventricular function than placebo patients. In addition, 45% of enrolled patients had no control angiographic study, and the clinical characteristics of these patients are not provided. Nevertheless, all results, including enzyme release, converge to suggest a true benefit of cariporide.
The NHEs compose a family of membrane proteins involved in the transport of H+ in exchange for Na+, the driving force being the transmembrane Na+ gradient.8 It is regulated by the intracellular pH through interaction of H+ with a sensor site on the exchanger protein. Six NHE isoforms have been recognized. NHE-1 and NHE-6 are ubiquitously distributed in tissue, whereas NHE-2 through NHE-5 have limited expression. Myocyte sarcolemma is composed predominantly of the NHE-1 isoform. The system protects against acidosis; paradoxically, it can be deleterious. As the ATP-dependent Na+/K+ transport system becomes inoperative during ischemia, Na+ is exchanged for Ca2+. Elevated intracellular Ca2+ concentrations directly mediate cell death by activating various proteases and causing cell contracture, membrane rupture, and gap junction disjunction. Reperfusion washes out the extracellular metabolites to accelerate the ionic exchanges; Ca2+ then enters the cell massively to cause the reperfusion injury. A burst of free radicals is also generated on reperfusion, contributing to cell necrosis. NHE inhibition has consistently prevented cell contracture and necrosis, stunning, reperfusion arrhythmias, and mortality in various models of ischemia/reperfusion.5
The sensitivity of the exchanger to intracellular H+ is influenced by numerous extracellular signals, such as those induced by catecholamines, angiotensin II, thrombin, endothelin-1, and free radical species. Thus, NHE inhibition has the potential of counteracting many morbid processes associated with ischemia, some manifested acutely and some long-term as remodeling.9 10 NHE inhibition interferes with leukotriene B4 production, and agonists induced platelet activation and reduced platelet and leukocyte activation to minimize microvascular plugging and the no-reflow damage.11 The inhibition can also prevent apoptosis in hearts submitted to an ischemic insult.12 It does not interfere with the mechanisms of ischemic preconditioning and can possibly enhance them.13
Cariporide was recently investigated in the GUArd During Ischemia Against Necrosis (GUARDIAN) trial, which enrolled close to 12 000 patients.14 The phase 2/3 trial was designed to assess drug safety and efficacy in preventing necrosis in various clinical situations at risk of MI. These were unstable angina or non–Q-wave MI and high-risk coronary angioplasty and coronary artery bypass surgery. Three doses of cariporide were evaluated against placebo. The trial showed a very favorable safety profile but did not support the hypothesis that cariporide would prevent progression of ischemia to necrosis through a large spectrum of patients at risk. A significant gain could nevertheless be shown with the high dose in patients undergoing CABG.
The studies by Rupprecht et al4 and by the GUARDIAN Research Group14 are early investigation of a novel pharmacological approach that opens new therapeutic perspectives and raises new challenges. Pressing clinical issues to explore are (1) effective doses and how much inhibition of the system is required for efficacy; (2) relative usefulness when administered during ischemia, during reperfusion, or during both; (3) optimal duration of administration, an oral therapy being available; and (4) functional aspects of the inhibition in prolonged or repetitive ischemia. The dose selection in humans remains empirical, based on experimental assessment of the degree of inhibition achieved in noncardiac cells. No direct measurement of activity has been made in the diseased human heart. In the rabbit model, the reduction in infarct size is dose-dependent and correlates with plasma levels and drug effects in isolated myocytes.5 7 A single dose of 40 mg was used by Rupprecht et al and doses of 20, 80, and 120 mg TID for 2 to 7 days in GUARDIAN. These doses were probably suboptimal. The GUARDIAN data suggest that nearly complete inhibition of NHE activity will probably be required for benefit in humans.14 The effective doses may differ in different clinical situations and could be influenced by the amount of drug delivery in the ischemic myocardium through opened or closed arteries or through collaterals. A reperfusion strategy will also very likely be required within the following hours to extend the benefit.4 14 Furthermore, the role of the NHE system may differ in large and small infarcts, during the early versus late stages of ischemia or reperfusion, and with different causes of MI, such as spontaneous occlusion, percutaneous interventions, or global ischemia.
Other Approaches to Cell Protection
The multiplicity of mechanisms involved in ischemia and in the progression of ischemia to necrosis lends itself to a multifactorial approach to management. The mismatch between glucose oxidation and anaerobic glycolysis that results in accumulation of lactates, pyruvates, and protons can be favorably influenced by glucose-insulin-potassium infusion and other interventions promoting glucose transport and ATP production. Such interventions are a reduction in plasma fatty acids levels and their mitochondria uptake and stimulation of glycolysis and of pyruvate dehydrogenase activity.15 NHE inhibition prevents the deleterious effect of protons once accumulated, whereas the toxic effects of calcium can be directly blocked, at least experimentally, at the actin-myosin coupling and at the gap junction levels.16
Other targets for treatment are free radical toxicity, neutrophil infiltration causing cellular edema, plugging of small arteries and no-reflow, the inflammation process, and matrix degradation. Antioxidants and free radical scavengers, antibody against cytokines, the complement system, and selectins and integrins and perfluorochemicals are all potentially useful interventions, as well as modulation of the activity of the matrix degradation molecules. GP IIb/IIIa antagonists interfere with the binding of neutrophils and platelets and, possibly, the interactions between inflammation and thrombosis.17
Ongoing Clinical Research
On the basis of strong and consistent effects in experimental studies, large clinical trials on cell protection are actually ongoing in coronary artery bypass surgery and in ST-segment-elevation MI with various NHE antagonists, with anti-integrins and anti-selectins and anti-C5 component of the complement system, with agonists to the adenosine receptors A1 and A3, and with ATP-sensitive potassium channel openers, which mediate preconditioning. Adenosine has a broad spectrum of physiological effects, including preservation of energy phosphate stores, inhibition of neutrophil activity and of free radical formation. Inhibition of the cleavage of C5 prevents the generation of the complement byproducts C5a and C5b-9, which promote inflammation, induce procoagulant activity, and cause direct myocardial tissue damage.
Clinical Application
Cell protection is more than a promise for the future; it is already a leitmotiv in current practice. Left ventricular dysfunction in a patient with an acute coronary syndrome dictates investigation of its reversibility. Acute ischemia, stunning, and hibernation are reversible causes of dysfunction. Current anti-ischemic therapy protects by reducing myocardial oxygen needs. Restoration of blood flow, however, is still required in most instances, urgently when hemodynamic compromise is present. Stunning usually recovers rapidly unless new ischemia supervenes. Hibernation, which may represent repeated episodes of stunning, needs revascularization. Ischemic preconditioning is probably underused during reperfusion procedures, and the potential of pharmacological reconditioning has been little explored.18
Cell protection is the new challenge for patient management in coronary care units, the catheterization laboratory, and the operating room, broadening our management strategies for acute coronary syndromes. Cell protection may be the next breakthrough in clinical cardiology. Yet, now is a time for clinical application.
Footnotes
Reprint requests to Pierre Théroux, MD, 5000 Belanger E, Montreal, Quebec, Canada H1T 1C8.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Reimer KA, Jennings RB. The "wavefront phenomenon" of myocardial ischemic cell death, II: transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40:633–644.[Medline] [Order article via Infotrieve]
2.
Kloner RA, Bolli R, Marban E, et al. Medical and
cellular implications of stunning, hibernation, and preconditioning: an
NHLBI workshop. Circulation. 1998;97:1848–1867.
3. Kloner RA, Ganote CE, Jennings RB. The "no-reflow phenomenon" after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–1508.
4.
Rupprecht HJ, vom Dahl J, Terres W, et al. Protective
effects of the Na+/H+
exchange inhibitor cariporide in patients with anterior
myocardial infarction undergoing direct PTCA. Circulation. 2000;101:2902–2908.
5. Scholz W, Albus U, Counillon L, et al. Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischemia and reperfusion. Cardiovasc Res. 1995;29:260–268.[Medline] [Order article via Infotrieve]
6.
Gumina RJ, Mizumura T, Beier N, et al. A new
sodium/hydrogen inhibitor, EMD 85131, limits infarct size
in dogs when administered before and after coronary artery
occlusion. J Pharmacol Exp Ther. 1998;286:175–183.
7. Linz W, Albus U, Crause P, et al. Dose dependent reduction of myocardial infarct mass in rabbits by the NHE-1 inhibitor cariporide (HOE642). Clin Exp Hypertens. 1998;20:733–749.
8. Frölich O, Karmazyn M. The Na-H exchanger revisited: an update on Na-H exchange regulation and the role of the exchanger in hypertension and cardiac function in health and disease. Cardiovasc Res. 1997;36:138–148.[Medline] [Order article via Infotrieve]
9. Avkiran M, Snabaitis AK. Regulation of cardiac sarcolemma Na+/H+ exchanger activity: potential pathophysiological significance of endogenous mediators and oxidant stress. J Thromb Thrombolysis. 1999;8:21–25.
10. Hoque AN, Karmazyn M. Effect of sodium-hydrogen exchange inhibition on functional and metabolic impairment produced by oxidative stress on the isolated rat heart. Can J Physiol Pharmacol. 1997;75:326–334.[Medline] [Order article via Infotrieve]
11. Ito Y, Imai S, Ui G, et al. A Na+-H+ exchange inhibitor (SM-20550) protects from microvascular deterioration and myocardial injury after reperfusion. Eur J Pharmacol. 1999;374:355–366.[Medline] [Order article via Infotrieve]
12. Chakrabarti S, Hoque AN, Karmazyn M. A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE-642 (cariporide). J Mol Cell Cardiol. 1997;29:3169–3174.[Medline] [Order article via Infotrieve]
13.
Shipolini AR, Yokoyama H, Galiñanes M, et al.
Na+/H+ exchanger activity
does not contribute to protection by ischemic preconditioning
in the isolated rat heart. Circulation. 1997;96:3617–3625.
14. Theroux P, Chaitman BR, Danchin N, et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations: main results of the GUARDIAN trial. Circulation. In press.
15. Lopaschuk GD. Treating ischemic heart disease by pharmacologically improving cardiac energy metabolism. Am J Cardiol. 1998;82:14K–17K.[Medline] [Order article via Infotrieve]
16.
Garcia-Dorado D, Theroux P, Duran JM, et al. Selective
inhibition of the contractile apparatus: a new approach to
modification of infarct size, infarct composition, and infarct geometry
during coronary artery occlusion and reperfusion.
Circulation. 1992;85:1160–1174.
17. Xiao Z, Theroux P, Frojmovic M. Modulation of platelet-neutrophil interaction with pharmacological inhibition of fibrinogen binding to platelet GPIIb/IIIa receptor. Thromb Haemost. 1999;81:281–285.[Medline] [Order article via Infotrieve]
18. Mentzer RM Jr, Birjiniuk V, Khuri S, et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial. Ann Surg. 1999;229:643–649.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. G. Lloyd, P. Wang, H. Zeng, and J. C. Chatham Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H351 - H362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Brar, A. K. Jonassen, E. M. Egorina, A. Chen, A. Negro, M. H. Perrin, O. D. Mjos, D. S. Latchman, K.-F. Lee, and W. Vale Urocortin-II and Urocortin-III Are Cardioprotective against Ischemia Reperfusion Injury: An Essential Endogenous Cardioprotective Role for Corticotropin Releasing Factor Receptor Type 2 in the Murine Heart Endocrinology, January 1, 2004; 145(1): 24 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Reshkin, A. Bellizzi, R. A. Cardone, M. Tommasino, V. Casavola, and A. Paradiso Paclitaxel Induces Apoptosis via Protein Kinase A- and p38 Mitogen-activated Protein-dependent Inhibition of the Na+/H+ Exchanger (NHE) NHE Isoform 1 in Human Breast Cancer Cells Clin. Cancer Res., June 1, 2003; 9(6): 2366 - 2373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Dae, D. W. Gao, D. I. Sessler, K. Chair, and C. A. Stillson Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1584 - H1591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Redlin, J. Werner, H. Habazettl, W. Griethe, H. Kuppe, and A. R. Pries Cariporide (HOE 642) Attenuates Leukocyte Activation in Ischemia and Reperfusion Anesth. Analg., December 1, 2001; 93(6): 1472 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Zeymer, H. Suryapranata, J. P. Monassier, G. Opolski, J. Davies, G. Rasmanis, G. Linssen, U. Tebbe, R. Schroder, R. Tiemann, et al. The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1644 - 1650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. B. A. Menown and A. A. J. Adgey Cardioprotective therapy and sodium-hydrogen exchange inhibition: current concepts and future goals J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1651 - 1653. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Marzilli and M. Mariani About EMIP-FR and reperfusion damage in AMI: a comment to the comment Eur. Heart J., June 1, 2001; 22(11): 973 - 975. [PDF]
|
|
|
|
|
|
J. Soler-Soler and D. Garcia-Dorado Trimetazidine and reperfusion injury Eur. Heart J., June 1, 2001; 22(11): 975 - 975. [PDF]
|
|
|
|
 |
|
 R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 15, 2001; (2001) 51599198. [Abstract] [Full Text]
|
|
|
|
|
|
R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 27, 2001; 98(5): 2855 - 2859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Jonassen, M. N. Sack, O. D. Mjos, and D. M. Yellon Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling Circ. Res., December 7, 2001; 89(12): 1191 - 1198. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||