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(Circulation. 2001;103:2876.)
© 2001 American Heart Association, Inc.

Editorial

Nitroglycerin and Delayed Preconditioning in Humans

Yet Another New Mechanism for an Old Drug?

Gerd Heusch, MD

From the Department of Pathophysiology, Center of Internal Medicine, University School of Medicine, Essen, Germany.

Correspondence to Prof. Dr. Med. Dr. h. c. Gerd Heusch, Direktor der Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstr 55, 45122 Essen, Germany. E-mail gerd.heusch{at}uni-essen.de

Key Words: Editorials • heart diseases • pharmacology • ischemia • reperfusion

Short episodes of ischemia and reperfusion protect the myocardium from the damage induced by episodes of sustained ischemia. Such ischemic preconditioning is apparent within minutes and lasts for 2 to 3 hours; a second phase of delayed preconditioning reappears 12 to 24 hours later and lasts for 3 to 4 days. Ischemic preconditioning, in its early and delayed form, is currently the prevailing paradigm for experimental studies aiming to reduce infarct size and other deleterious consequences of ischemia/reperfusion.¹ A more detailed analysis of the underlying signal transduction is expected to provide better insight into the basic pathophysiology of myocardial ischemia/reperfusion injury and to help develop more potent and specific pharmacological treatments.

The existence and significance of ischemic preconditioning in humans are less clear,² largely because the most rigorous end point, infarct size, is not easily available in controlled, prospective studies in humans, for obvious ethical reasons. Prospective clinical studies with short episodes of fully reversible myocardial ischemia, such as that induced by percutaneous transluminal coronary angioplasty (PTCA)^{3 4 5 6} or by brief surgical ischemic cardiac arrest,^{7 8} are available. Certain parts of the experimentally established signal transduction of ischemic preconditioning have been verified using PTCA; these include preconditioning by adenosine^{9 10} or bradykinin¹¹ and the prevention of ischemic preconditioning by the ATP-sensitive calcium channel (K_ATP) blocker glibenclamide⁴ or the opioid antagonist naloxone.¹² Surrogate end points in such studies include ST-segment shifts in the surface or intracoronary ECG, metabolic markers such as lactate and ATP, or the release of creatine kinase and troponin. Although new troponin assays seem to provide reliable clinical markers of myocardial injury,¹³ the association of alterations in energy and substrate metabolism with infarct size reduction, even in the experiment, is still elusive.

Importantly, in animal experiments, attenuation of ischemic ST-segment elevation seems to be an unreliable marker of ischemic preconditioning that reflects the activation of sarcolemmal K_ATP channels, whereas the protection of ischemic preconditioning is induced through the activation of mitochondrial K_ATP channels.¹⁴ Apart from potentially unreliable end points, these clinical studies using PTCA are confounded by the potential of collateral recruitment, which may attenuate ischemia and its consequences independently of any preconditioning. Clearly, the exclusion of angiographically visible collaterals^{15 16} is not sufficient to exclude significant collateral recruitment, and more rigorous approaches such as the pressure-derived collateral flow index^{5 17} are required. This concern does not apply to global ischemia during surgical cardiac arrest. All existing clinical studies using PTCA or ischemic cardiac arrest address only the early phase of ischemic preconditioning.

Support for the existence of ischemic preconditioning in humans is also derived from retrospective analyses of patients undergoing thrombolysis who had preinfarction angina. Patients with preinfarction angina seem to have reduced infarct size, as estimated by reduced creatine kinase release and fewer Q waves on their ECG,^{18 19} better functional recovery,²⁰ and better prognosis.¹⁸ These earlier retrospective studies were confirmed in an ancillary study to the Thrombolysis In Myocardial Infarction (TIMI)-9B trial in a prospective study design, although only in terms of improved prognosis.²¹ However, patients with preinfarction angina also have more rapid thrombolysis and possibly therefore smaller infarcts and better prognosis.²² The time frame of occurrence of angina before myocardial infarction in those studies varied widely, and the protection observed can therefore not be attributed to either early or delayed preconditioning.

Nitric Oxide in Ischemic Preconditioning

Nitrate therapy (amylnitrite) for angina pectoris was first recommended by Brunton in 1867.²³ Since then, the efficacy of nitric oxide (NO) donors, most notably nitroglycerin, in coronary artery disease has been well established. Apart from preload reduction and coronary vasodilation, a number of beneficial effects of NO and NO donors have emerged more recently, such as improved endothelial function,^{24 25} inhibition of platelet aggregation and cyclic flow variations,²⁶ improvement of the efficiency of energy use, and preservation of contractile function during myocardial ischemia.²⁷ The role of NO as a trigger and mediator of ischemic preconditioning is not entirely clear. Although endogenous NO seems not to be important in classic/early ischemic preconditioning’s protection against myocardial infarction,^{28 29} exogenous NO reduces infarct size through a free radical mechanism.²⁹ In contrast, NO acts as a trigger and mediator in delayed preconditioning’s protection against both myocardial infarction and stunning,³⁰ and nitroglycerin induces delayed preconditioning against myocardial stunning through a protein kinase C–dependent pathway.³¹ There are no studies on the role of NO in ischemic preconditioning in humans thus far.

Nitroglycerin-Induced Delayed Preconditioning in Humans

In the current issue of Circulation, Leesar et al³² report that a 4-hour intravenous infusion of nitroglycerin provided protection during PTCA 24 hours later, as evidenced by reduced ST-segment elevation, attenuated contractile dysfunction, and less pain. This study is important for several reasons. (1) It is the first study to demonstrate delayed preconditioning in humans and is, as such, innovative. (2) It is founded on a solid pathophysiological concept that has been thoroughly established in animal studies. (3) Collateral recruitment as a confounding variable is carefully excluded. (4) It uses a clinically feasible tool, ie, nitroglycerin, to induce protection. (5) After >130 years of clinical use, this study identifies a new mechanism of action for nitrates in humans. (6) It compares the nitroglycerin-induced delayed preconditioning to PTCA-induced early preconditioning. Surprisingly and somewhat different from the prior animal studies, the magnitude of protection by delayed preconditioning was as great as that by early preconditioning. In addition, the effects of nitroglycerin-induced delayed and PTCA-induced early preconditioning were not additive, suggesting that either elicited maximal protection.

As outlined above, the use of end points remains a critical issue; this is also true in the study by Leesar et al.³² In contrast to animal experiments in which infarct size and postischemic dysfunction/stunning were used as end points to establish the role of NO and nitroglycerin in delayed preconditioning, the study by Leesar et al³² used ST-segment elevation, ischemic dysfunction, and pain as end points. It is certainly laudable that 3 different and independent end points were used to assess protection, and I have no idea how to do better in the clinical scenario at present. Nevertheless, it seems that experimental studies rely on end points that are consequences of ischemia/reperfusion (infarct size and stunning), whereas clinical studies use end points that reflect the severity of ischemia per se (ST-segment elevation and ischemic dysfunction). Of note, in contrast to the present study by Leesar et al,³² the degree of ischemic dysfunction was not attenuated by nitroglycerin-induced delayed preconditioning in the conscious rabbit, but the degree of postischemic dysfunction was reduced.³¹ It is possible that the surprising finding of equally potent protection by nitroglycerin-induced delayed preconditioning and by PTCA-induced early preconditioning relates to the use of end points.

What is expected from further studies? PTCA is a fairly innocuous and well-controlled scenario, and the present beneficial results must be confirmed during more serious conditions, such as cardiac surgery, and in daily life, where patients really benefit in terms of outcome. In particular, the potential development of tolerance against nitroglycerin-induced delayed preconditioning will have to be addressed in future studies.

Acknowledgments

I am grateful to my friends and colleagues Michael Cohen, James Downey, and Rainer Schulz for many fruitful discussions on preconditioning.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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