(Circulation. 2001;103:2876.)
© 2001 American Heart Association, Inc.
Editorial |
Nitroglycerin and Delayed Preconditioning in Humans
Yet Another New Mechanism for an Old Drug?
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 adenosine9 10 or bradykinin11 and the prevention of ischemic preconditioning by the ATP-sensitive calcium channel (KATP) 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 KATP channels, whereas the protection of ischemic preconditioning is induced through the activation of mitochondrial KATP 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 collaterals15 16 is not sufficient to exclude significant collateral recruitment, and more rigorous approaches such as the pressure-derived collateral flow index5 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.
References
1.
Yellon DM,
Baxter GF, Garcia-Dorado D, et al. Ischaemic preconditioning:
present position and future directions.
Cardiovasc Res. 1998;37:21–33.
2.
Yellon DM, Dana A.
The preconditioning phenomenon: a tool for the scientist or a clinical
reality? Circ Res. 2000;87:543–550.
3.
Deutsch E, Berger
M, Kussmaul WG, et al. Adaptation to ischemia during
percutaneous transluminal coronary angioplasty:
clinical, hemodynamic, and metabolic
features. Circulation. 1990;82:2044–2051.
4.
Tomai F, Crea F,
Gaspardone A, et al. Ischemic preconditioning during
coronary angioplasty is prevented by glibenclamide, a selective
ATP-sensitive K+ channel blocker.
Circulation. 1994;90:700–705.
5.
Billinger M,
Fleisch M, Eberli FR, et al. Is the development of myocardial tolerance
to repeated ischemia in humans due to preconditioning or to
collateral recruitment? J Am Coll
Cardiol. 1999;33:1027–1035.
6.
Laskey WK.
Beneficial impact of preconditioning during PTCA on creatine kinase
release. Circulation. 1999;99:2085–2089.
7. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993;342:276–277.[Medline] [Order article via Infotrieve]
8.
Jenkins DP, Pugsley
WB, Alkhulaifi AM, et al. Ischaemic preconditioning reduces troponin T
release in patients undergoing coronary artery bypass surgery.
Heart. 1997;77:314–318.
9.
Leesar MA, Stoddard
M, Ahmed M, et al. Preconditioning in human myocardium with
adenosine during coronary angioplasty.
Circulation. 1997;95:2500–2507.
10. Heidland UE, Heintzen MP, Michel CJ, et al. Effect of adjunctive intracoronary adenosine on myocardial ischemia, hemodynamic function and left ventricular performance during percutaneous transluminal coronary angioplasty: clinical access to ischemic preconditioning? Coron Artery Dis. 2000;11:421–428.[Medline] [Order article via Infotrieve]
11.
Leesar MA,
Stoddard MF, Manchikalapudi S, et al. Bradykinin-induced
preconditioning in patients undergoing coronary angioplasty.
J Am Coll Cardiol. 1999;34:639–650.
12.
Tomai F, Crea F,
Gaspardone A, et al. Effects of naloxone on myocardial ischemic
preconditioning in humans. J Am Coll
Cardiol. 1999;33:1863–1869.
13.
Jaffe AS,
Ravkilde J, Roberts R, et al. It’s time for a change to a troponin
standard. Circulation. 2000;102:1216–1220.
14. Birincioglu M, Yang X-M, Critz SD, et al. S-T segment voltage during sequential coronary occlusions is an unreliable marker of preconditioning. Am J Physiol. 1999;277:H2435–H2441.
15. Cribier A, Korsatz L, Koning R, et al. Improved myocardial ischemic response and enhanced collateral circulation with long repetitive coronary occlusion during angioplasty: a prospective study. J Am Coll Cardiol. 1992;20:578–586.[Abstract]
16. Hirai T, Fujita M, Yoshida N, et al. Importance of ischemic preconditioning and collateral circulation for left ventricular functional recovery in patients with successful intracoronary thrombolysis for acute myocardial infarction. Am Heart J. 1993;126:827–831.[Medline] [Order article via Infotrieve]
17.
Seiler C, Fleisch
M, Garachemani A, et al. Coronary collateral quantitation in
patients with coronary artery disease using intravascular flow
velocity or pressure measurements. J
Am Coll Cardiol. 1998;32:1272–1279.
18.
Kloner RA, Shook
T, Przyklenk K, et al. Previous angina alters in-hospital outcome in
TIMI 4: a clinical correlate to preconditioning?
Circulation. 1995;91:37–47.
19.
Ottani F, Galvani
M, Ferrini D, et al. Prodromal angina limits infarct size: a role for
ischemic preconditioning.
Circulation. 1995;91:291–297.
20. Nakagawa Y, Ito H, Kitakaze M, et al. Effect of angina pectoris on myocardial protection in patients with reperfused anterior wall myocardial infarction: retrospective clinical evidence of "preconditioning." J Am Coll Cardiol. 1995;25:1076–1083.[Abstract]
21.
Kloner RA, Shook
T, Antman EM, et al, and the TIMI-9B Investigators. Prospective
temporal analysis of the onset of preinfarction angina versus
outcome: an ancillary study in TIMI-9B.
Circulation. 1998;97:1042–1045.
22.
Andreotti F,
Pasceri V, Hackett DR, et al. Preinfarction as a predictor of more
rapid coronary thrombolysis in patients with
acute myocardial infarction. N Engl
J Med. 1996;334:7–12.
23. Brunton TL. Use of nitrite of amyl in angina pectoris. Lancet.. 1867;97:97–98.
24.
Drexler H. Nitric
oxide and coronary endothelial dysfunction in
humans. Cardiovasc Res. 1999;43:572–579.
25. Fleming I, Busse R. Endothelial dysfunction: a novel therapeutic target: NO: the primary EDRF. J Mol Cell Cardiol. 1999;31:5–14.[Medline] [Order article via Infotrieve]
26.
Yao S-K, Ober JC,
Krishnaswami A, et al. Endogenous nitric oxide protects
against platelet aggregation and cyclic flow variations in stenosed
and endothelium-injured arteries.
Circulation. 1992;86:1302–1309.
27.
Heusch G, Post H,
Michel MC, et al. Endogenous nitric oxide and myocardial
adaptation to ischemia. Circ
Res. 2000;87:146–152.
28. Post H, Schulz R, Behrends M, et al. No involvement of endogenous nitric oxide in classical ischemic preconditioning in swine. J Mol Cell Cardiol. 2000;32:725–733.[Medline] [Order article via Infotrieve]
29. Nakano A, Liu GS, Heusch G, et al. Exogenous nitric oxide can trigger a preconditioned state through a free radical mechanism, but endogenous nitric oxide is not a trigger of classical ischemic preconditioning. J Mol Cell Cardiol. 2000;32:1159–1167.[Medline] [Order article via Infotrieve]
30. Bolli R, Dawn B, Tang X-L, et al. The nitric oxide hypothesis of late preconditioning. Basic Res Cardiol. 1998;93:325–338.[Medline] [Order article via Infotrieve]
31. Banerjee S, Tang X-L, Qiu Y, et al. Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway. Am J Physiol. 1999;277:H2488–H2494.
32.
Leesar MA,
Stoddard MF, Dawn B, et al. Delayed preconditioning- mimetic action of
nitroglycerin in patients undergoing coronary
angioplasty. Circulation.. 2001;103:2935–2941.
This article has been cited by other articles:
 |
|
 |
|
  G. Ambrosio, M. Del Pinto, I. Tritto, G. Agnelli, M. Bentivoglio, C. Zuchi, F. A. Anderson, J. M. Gore, J. Lopez-Sendon, A. Wyman, et al. Chronic nitrate therapy is associated with different presentation and evolution of acute coronary syndromes: insights from 52 693 patients in the Global Registry of Acute Coronary Events Eur. Heart J., November 10, 2009; (2009) ehp457v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Heusch, P. Kleinbongard, D. Bose, B. Levkau, M. Haude, R. Schulz, and R. Erbel Coronary Microembolization: From Bedside to Bench and Back to Bedside Circulation, November 3, 2009; 120(18): 1822 - 1836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch A BEAUTIFUL lesson--ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more? Eur. Heart J., October 1, 2009; 30(19): 2300 - 2301. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Heusch and R. Schulz Neglect of the coronary circulation: some critical remarks on problems in the translation of cardioprotection Cardiovasc Res, October 1, 2009; 84(1): 11 - 14. [Full Text] [PDF]
|
|
|
|
|
|
K. Boengler, R. Schulz, and G. Heusch Loss of cardioprotection with ageing Cardiovasc Res, July 15, 2009; 83(2): 247 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Peart and J. P. Headrick Clinical cardioprotection and the value of conditioning responses Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1705 - H1720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch, K. Boengler, and R. Schulz Cardioprotection: Nitric Oxide, Protein Kinases, and Mitochondria Circulation, November 4, 2008; 118(19): 1915 - 1919. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Niccoli, L. Altamura, A. Fabretti, G. A. Lanza, L. M. Biasucci, A. G. Rebuzzi, A. M. Leone, I. Porto, F. Burzotta, C. Trani, et al. Ethanol Abolishes Ischemic Preconditioning in Humans J. Am. Coll. Cardiol., January 22, 2008; 51(3): 271 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ferdinandy, R. Schulz, and G. F. Baxter Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning Pharmacol. Rev., December 1, 2007; 59(4): 418 - 458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dragoni, T. Gori, M. Lisi, G. Di Stolfo, A. Pautz, H. Kleinert, and J. D. Parker Pentaerythrityl Tetranitrate and Nitroglycerin, but not Isosorbide Mononitrate, Prevent Endothelial Dysfunction Induced by Ischemia and Reperfusion Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1955 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Leesar, H. Jneid, X.-L. Tang, and R. Bolli Pretreatment with intracoronary enalaprilat protects human myocardium during percutaneous coronary angioplasty. J. Am. Coll. Cardiol., April 17, 2007; 49(15): 1607 - 1610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Boengler, R Schulz, and G Heusch Connexin 43 signalling and cardioprotection Heart, December 1, 2006; 92(12): 1724 - 1727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Guo, A. B. Stein, W.-J. Wu, X. Zhu, W. Tan, Q. Li, and R. Bolli Late preconditioning induced by NO donors, adenosine A1 receptor agonists, and {delta}1-opioid receptor agonists is mediated by iNOS Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2251 - H2257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boengler, G. Dodoni, A. Rodriguez-Sinovas, A. Cabestrero, M. Ruiz-Meana, P. Gres, I. Konietzka, C. Lopez-Iglesias, D. Garcia-Dorado, F. Di Lisa, et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning Cardiovasc Res, August 1, 2005; 67(2): 234 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wang, D. A. Liem, T. M. Vondriska, H. M. Honda, P. Korge, D. M. Pantaleon, X. Qiao, Y. Wang, J. N. Weiss, and P. Ping Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1290 - H1295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Heusch Postconditioning: Old wine in a new bottle? J. Am. Coll. Cardiol., September 1, 2004; 44(5): 1111 - 1112. [Full Text] [PDF]
|
|
|
|
|
|
A. Crisafulli, F. Melis, F. Tocco, U. M. Santoboni, C. Lai, G. Angioy, L. Lorrai, G. Pittau, A. Concu, and P. Pagliaro Exercise-induced and nitroglycerin-induced myocardial preconditioning improves hemodynamics in patients with angina Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H235 - H242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-L. Tang, Y.-T. Xuan, Y. Zhu, G. Shirk, and R. Bolli Nicorandil induces late preconditioning against myocardial infarction in conscious rabbits Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1273 - H1280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. Lambiase, R. J. Edwards, M. R. Cusack, C. A. Bucknall, S. R. Redwood, and M. S. Marber Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1174 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shinmura, E. Kodani, Y. u-T. Xuan, B. Dawn, X.-L. Tang, and R. Bolli Effect of aspirin on late preconditioning against myocardial stunning in conscious rabbits J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1183 - 1194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Przyklenk and G. Heusch Late preconditioning against myocardial stunning: Does aspirin close the "second window" of endogenous cardioprotection? J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1195 - 1197. [Full Text] [PDF]
|
|
|
|
|
|
A. Skyschally, R. Schulz, P. Gres, H.-G. Korth, and G. Heusch Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H698 - H703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Gres, R. Schulz, J. Jansen, C. Umschlag, and G. Heusch Involvement of endogenous prostaglandins in ischemic preconditioning in pigs Cardiovasc Res, August 15, 2002; 55(3): 626 - 632. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||