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Circulation. 2006;113:e1-e3
doi: 10.1161/CIRCULATIONAHA.105.569863
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(Circulation. 2006;113:e1-e3.)
© 2006 American Heart Association, Inc.

Clinician Update

Preconditioning

A New Concept About the Benefit of Exercise

Raúl J. Domenech, MD

From Instituto de Ciencias Biomédicas, Facultad de Medicina Universidad de Chile, Santiago, Chile.

Correspondence to Raúl J. Domenech, Instituto de Ciencias Biomédicas, Facultad de Medicina Universidad de Chile, Casilla 16038, Avenida Salvador 486 (Providencia), Santiago 9, Chile. E-mail rdomenec{at}med.uchile.cl


*    Introduction
up arrowTop
 *Introduction
down arrowBenefits of Exercise
 down arrowReferences
 
Case presentation: A 45-year-old man with coronary artery disease is found to be in good condition after his annual medical checkup, and his doctor advises him to continue with the same drugs, a prudent diet, entertainment, and regular exercise; however, the patient is afraid that he will not have time to exercise regularly.


*    Benefits of Exercise
up arrowTop
 up arrowIntroduction
 *Benefits of Exercise
down arrowReferences
 
Clinicians have learned about the beneficial effects of several factors that may prevent a myocardial infarction (MI), including avoidance of smoking; treatment of high blood pressure, diabetes, dyslipidemia, and obesity; and regular performance of exercise. This last factor is based on epidemiological observations such as a decrease in the incidence of MI in men who perform heavy work1,2; however, it is only in the last few years that the beneficial effect of exercise has obtained plausible explanations of its own, that is, apart from its effect on other risk factors. There are at least 3 distinct mechanisms for this benefit: (1) Improvement of endothelial function, thereby preventing atherosclerosis and coronary occlusion3; (2) prevention of remodeling after MI through the expression of oxidative metabolism-related genes4; and (3) delaying acute ischemic injury after a coronary occlusion by preconditioning.

Since the discovery of ischemic preconditioning by Murry et al5 in 1986, studies have appeared in the literature searching for its mechanisms and for alternative ways to trigger it. The concept that 1 or 2 episodes of brief ischemia (&5 minutes in duration each), induced a few minutes or a few hours (early preconditioning) or 24 to 72 hours (late preconditioning or second window) before a prolonged coronary occlusion, followed by reperfusion substantially decreases the speed of the ischemic injury and limits infarct size is firmly established in all animal species studied in the experimental laboratory.6 It is one of the most powerful means of protecting the myocardium with the exception of early reperfusion. Several lines of evidence in coronary patients suggest but do not prove that the human myocardium is also protected by ischemic preconditioning. For example, preinfarction angina is associated with a smaller infarct size; a lower incidence of congestive heart failure, shock, and ventricular arrhythmias; and decreased mortality.7–9 The ST-segment elevation observed during angioplasty decreases after subsequent occlusions,10 which suggests that each occlusion provides preconditioning for the ischemic effect of the next one. Protocols of ischemic preconditioning before coronary artery bypass grafting preserve ATP levels during the subsequent global ischemic period11 and decrease serum levels of troponin T, thereby suggesting a smaller infarct size.12 Finally, the progressive decrease in the magnitude of ischemia during several consecutive episodes of exercise in patients with demand angina (warm-up phenomenon) suggests the preconditioning effect of each episode.13

The protective effect of ischemic preconditioning can be reproduced by several drugs, thus avoiding the necessity of ischemic periods to induce it. Pharmacological preconditioning is potentially a strong therapeutic tool. For example, the opening of mitochondrial ATP-sensitive potassium channels appears to be an important mediator of ischemic preconditioning. The administration of a mitochondrial ATP-sensitive potassium channel opener before planned procedures that involve a potentially ischemic insult (such as coronary artery surgery or angioplasty in the presence of a non-ST-elevation acute coronary syndrome that includes unstable angina) has been proposed to "buy time" before proceeding to reperfusion.6 Thus, pharmacological preconditioning may be considered "insurance" to protect the heart against ischemia.6

Among the maneuvers that induce preconditioning is exercise. Experiments in pigs14 and dogs15 showed that brief episodes of tachycardia that do not induce ischemia before a prolonged coronary occlusion decrease the infarct size (Figure) by a mechanism similar to that of ischemic preconditioning and that is mediated through modifications of sarcoplasmic reticulum and mitochondrial ATP-sensitive potassium channels.16,17 Subsequent experiments in rats18 and in dogs19 showed, as expected, that brief episodes of exercise also induced preconditioning of the infarct size. Interestingly, exercise induces early as well as late preconditioning and the magnitude of reduction in infarct size observed in dogs is much larger than that obtained with ischemic and tachycardia preconditioning (Figure). As yet, there are no studies that show this effect of exercise in humans. In light of these findings, the need for well-designed studies in humans to search for evidence of myocardial preconditioning by exercise is clear.



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  		Effect of tachycardia (A) and exercise (B) on myocardial infarct size in dogs. C indicates control; T, preconditioning with tachycardia; EP, early preconditioning with exercise; LP, late preconditioning with exercise; and NV/RV (%), infarct size expressed in terms of necrotic region volume as percent of the risk region volume. *P at least <0.05. Modified from Domenech et al15 (A) and Domenech et al19 (B).

Regular moderate exercise activity may protect against the effect of myocardial ischemia if a plaque rupture in a coronary artery occurs in an individual with or without previous clinical and laboratory evidence of coronary artery disease, delaying the injury, providing more time for revascularization, and thus yielding a smaller infarct size. Regular exercise may constitute a physiological "insurance policy" against the progression of ischemia. From a physiological point of view, it may be speculated that the myocardium is being preconditioned regularly by common daily physical activity. If tachyphylaxis exists for this protective action, as described for ischemic and pharmacological preconditioning, then episodes of moderate or heavy exercise should be needed to promote the late preconditioning effect.

Clinical Recommendations
Accordingly, the recommendation for the patient under discussion should be to perform exercise that is at least of moderate magnitude but that is performed regularly,20 not only to obtain the beneficial effects of exercise on cardiovascular risk factors but also to obtain the "insurance" it provides.


*    Acknowledgments
 
Some of the studies cited in this report were funded by FONDECYT, Santiago, Chile.

Disclosures

None.


*    References
up arrowTop
 up arrowIntroduction
 up arrowBenefits of Exercise
 *References
 

  1. Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Goldberg RJ, Muller JE, for the Determinants of Myocardial Infarction Onset Study Investigators. Triggering of acute myocardial infarction by heavy exertion: protection against triggering by regular exertion. N Engl J Med. 1993; 329: 1677–1683.[Abstract/Free Full Text]
  2. Willich SN, Lewis M, Lowel H, Arntz HR, Schubert F, Schroder R, for the Triggers and Mechanism of Myocardial Infarction Study Group. Physical exertion as a trigger of acute myocardial infarction. N Engl J Med. 1993; 329: 1684–1690.[Abstract/Free Full Text]
  3. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005; 111: 363–368.[Free Full Text]
  4. Freiman S, Scheinowitz M, Yekutieli D, Feinberg MS, Eldar M, Kessler-Icekson G. Prior exercise training improves the outcome of acute myocardial infarction in the rat. J Am Coll Cardiol. 2005; 45: 931–938.[Abstract/Free Full Text]
  5. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124–1136.[Abstract/Free Full Text]
  6. Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol. Rev. 2003; 83: 1113–1151.[Abstract/Free Full Text]
  7. Kloner RA, Shook T, Przyklenk K, Davis VS, Junio L, Matthews RV, Burstein S, Gibson CM, Poole WK, Cannon CP, McCabe CH, Braunwald E. Previous angina alters in-hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation. 1995; 91: 37–45.[Abstract/Free Full Text]
  8. Tamura K, Tsuji H, Nishiue T Tokunaga S, Iwasaka T. Association of preceding angina with in hospital life threatening ventricular tachyarrhythmias and late potentials in patients with a first acute myocardial infarction. Am Heart J. 1997; 133: 297–301.[CrossRef][Medline] [Order article via Infotrieve]
  9. Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, Yoo K, McCabe CH, Braunwald E, 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.[Abstract/Free Full Text]
  10. Tomai F, Crea F, Chiariello L, Gioffre PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation. 1999; 100: 559–563.[Abstract/Free Full Text]
  11. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993; 342: 276–277.[CrossRef][Medline] [Order article via Infotrieve]
  12. Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischemic preconditioning reduces troponin T release in patients undergoing coronary artery by-pass surgery. Heart. 1997; 77: 314–318.[Abstract/Free Full Text]
  13. Marber MS, Joy MD, Yellon DM. Warm-up angina: is it ischemic preconditioning? Br Heart J. 1994; 72: 213–215.Editorial.[Free Full Text]
  14. Koning MMG, Gho BCG, van Klaarwater E, Opstal RLJ, Duncker DJ, Verdouw PD. Rapid ventricular pacing produces myocardial protection by nonischemic activation of ATP potassium channels. Circulation. 1996; 93: 178–186.[Abstract/Free Full Text]
  15. Domenech RJ, Macho P, Velez D, Sanchez G, Liu X, Dhalla L. Tachycardia preconditions infarct size in dogs: role of adenosine and protein kinase C. Circulation. 1998; 97: 786–794.[Abstract/Free Full Text]
  16. Domenech RJ, Sanchez G, Donoso P, Parra V, Macho P. Effect of tachycardia on myocardial sarcoplasmic reticulum and calcium dynamics: a mechanism for preconditioning? J Mol Cell Cardiol. 2003; 35: 1429–1437.[CrossRef][Medline] [Order article via Infotrieve]
  17. Macho P, Solis E, Sanchez G, Schwarze H, Domenech R. Mitochondrial ATP-dependent potassium channels mediate nonischemic preconditioning by tachycardia in dogs. Mol Cell Biochem. 2001; 216: 129–136.[CrossRef][Medline] [Order article via Infotrieve]
  18. Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, Hori M. Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med. 1999; 189: 1699–1706.[Abstract/Free Full Text]
  19. Domenech RJ, Macho P, Schwarze H, Sanchez G. Exercise induces early and late myocardial preconditioning in dogs. Cardiovasc Res. 2002; 55: 561–566.[Abstract/Free Full Text]
  20. Myers J. Exercise and cardiovascular health. Circulation. 2003; 107: e2–e5.[Medline] [Order article via Infotrieve]

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Issue Highlights
Circulation 2006 113: 1. [Full Text]




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