Exercise: Great for Heart Health, Just as Great for Cardiac Preco
Clinical & Experimental Cardiology

Clinical & Experimental Cardiology
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Editorial - (2013) Volume 4, Issue 2

Exercise: Great for Heart Health, Just as Great for Cardiac Preconditioning Research

John C. Quindry*
Cardioprotection Laboratory, Department of Kinesiology, Auburn University, Auburn, AL, USA
*Corresponding Author: John C. Quindry, PhD, FACSM, Associate Professor, Cardioprotection Laboratorym Department of Kinesiology, Auburn University, Auburn, AL, USA, Tel: (334) 8441421 Email:

Ischemic heart disease remains a leading cause of morbidity and mortality in the United States and other industrialized countries [1]. Ongoing research efforts within the biomedical science community seek to discover counter therapies that will mitigate ischemic damage in those with coronary artery disease. Candidate therapies are intended to invoke cardioprotection by pharmacologic activation of endogenous mechanisms of cellular protection [2]. In concept the process of pharmacologic development is fundamentally simple: a cardioprotective pathway against ischemic injury is discovered, animal-based experiments provide proof of concept for pharmacologic induction of cardioprotection, and then clinical trials are undertaken. The reality, however, is somewhat more complicated. Within the context of discovery at different organizational levels (isolated cells, isolated organs, whole animal), numerous cellular pathways that elicit robust cardioprotection against ischemic injury are now well characterized [3]. Translation of this knowledge into clinical practice has proven far more difficult than expected. The point is famously articulated in a 2004 position paper by preeminent physicians and scientists is Circulation Research, “over the past 30 years, hundreds of experimental interventions (both pharmacologic and nonpharmacologic) have been reported to protect the ischemic myocardium in experimental animals; however, with the exception of early reperfusion, none has been translated into clinical practice” [4]. Given the collective effort to date, this is the central question: What scientific breakthrough is needed to translate our understanding of cardiac preconditioning into clinical practice? The underlying premise of this editorial is that the major limitation of cardiac preconditioning research is the nature of the stimulus, which traditionally has been derived from ischemia-induced adaptations.

Ischemic preconditioning research is historically founded on the classic 1986 Murry study, which was the first to demonstrate that brief intervals of sub-lethal ischemia conferred a subsequent window of protection against an ischemic insult of longer duration [5]. Twenty five years later, the ischemic preconditioning phenotype is well characterized as a polygenic response with redundant protective mediators including up-regulation of myocardial inducible nitric oxide synthase (iNOS), heat shock proteins (HSP) including HSP- 72, cyclooxygenase-2 (COX-2), and the sarcolemmal ATP-sensitive potassium channel (KATP) (reviewed in [6]). Activation of these and other protective mediators appear to converge upon the mitochondrial KATP channel, often heralded as the ‘holy grail’ protective mediators [3]. Experimental evidence clearly demonstrates that pharmacologic agonists for these various mechanisms elicit transient cardioprotection (reviewed in [7]). It’s the transient nature of this protection that may best explain why an ischemic stimulus has proved so difficult to translate clinically.

The fundamental hindrances to translating ischemic preconditioning research into clinically viable solutions are evident by multiple caveats. First, heart attacks, even in high risk individuals, are currently impossible to predict accurately. Common sense might suggest that prophylactic use of cardioprotective agonists in high risk individuals is the obvious answer to the unpredictable nature of cardiac events. However, another hurdle preventing the translation of ischemic preconditioning research is the fact that pharmacologic induction of cardioprotection is itself transient. The initially protected myocardium is rapidly adaptable and quickly habituates to the pharmacologic stimulus within a matter of days, and comparatively “sustainable” cardioprotection dissipates after a maximum of 7 days [8]. Perhaps most importantly, the canonical cellular mediators of cardioprotection are inflammatory in nature. Thus, activated by the signaling molecules NFkB and TNFα, hormetic up-regulation of iNOS and COX-2is not “biologically intended” as a sustainable solution to cellular dyshomeostasis [9]. Given this rationale, we have sought to investigate the mechanisms of cardioprotection against ischemic insults using a scientific model of exercise preconditioning.

Whereas ischemic preconditioning has been invaluable in understanding the fundamental principles of ischemic injury and cardioprotection, exercise preconditioning may prove essential in discovering therapeutic translation. From a clinical perspective the differences between ischemic and exercise stimuli are obvious. Cardioprotective exercise is a long established lifestyle intervention for improved heart health, while sustained exposure to periodic ischemia promotes heart failure in clinical populations [10]. Recent animal-based research reveals important differences between ischemic and exercise models of cardiac preconditioning. One of the first key discoveries was that a few days of moderate intensity exercise elicits profound ischemic protection in rats, and longer duration (months) exercise regimens confer no additional protection [11-13].

Chronic exercise, in the longitudinal context of a lifestyle, is among the most well established interventions for improved heart health. However, a few consecutive days of moderate intensity exercise is insufficient to remodel the cardiac vasculature or architecture. The observed infarct resistance must then be attributed to short term upregulation of protective biochemical factors in the exercised heart. Ample evidence from multiple labs now indicates that the exercise and ischemic stimuli exhibit several important differences. In contrast to ischemic preconditioning that confers a 3-4 day window of cardioprotection [3], Three days of exercise elicits an ischemic injury resistant phenotype that persists for at least nine days following exercise cessation [14]. The mechanisms responsible for exercise-induced cardioprotection have been described through a series of reductionist studies conducted over the last decade. Key biochemical mediators of exercise induced cardioprotection include manganese superoxide dismutase (MnSOD) [12,15-17], calcium handling proteins [15,18], endogenous opioids [19], and sarcolemmal and mitochondrial KATP channels [20-23]. It is a notable fact that the identified mechanisms of exercise preconditioning are not central to ischemic-based protection. Moreover, the aforementioned mechanisms responsible for ischemic preconditioning, including iNOS, COX-2 and HSP-72 have been ruled out as mediators of exercise-induced cardioprotection [24-27]. The clinical relevance of these animal-based studies is punctuated by the fact that both ischemic and pharmacologic approaches to cardioprotection are ineffective in aged rodents [28]. In contrast, several investigations clearly demonstrate that the aged heart is thoroughly cardioprotected against ischemic insults by a few days of moderate intensity exercise [26,29,30].

Medical advances over the last 40 years have yielded incremental improvements in treating and preventing ischemic heart disease, and yet the clinical, financial, and personal burdens of heart disease remain [1]. Exercise is cardioprotective in that regular exercise participation reduces the incidence and severity of heart disease, modifies risk factors for cardiovascular disease, and beneficially remodels the heart [10]. In contrast to these ‘exercise for improved heart health’ points of interest, the current editorial presents a rationale whereby exercise is employed as a novel scientific model for understanding cardioprotection within the biomedical sciences. The proposed exercise-based approach is pragmatic, sustainable, and cost effective. Given the increased competition for federal research dollars, exercise-based research studies offer a high potential return. This editorial focus on exerciseinduced preconditioning against ischemia reperfusion injury serves as a prime example why additional funds from federal source should be directed to high quality investigations designed to understand protective mechanisms and translational potential of exercise.


  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, et al. (2012) Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation.
  2. Lefer DJ, Bolli R (2011) Development of an NIH consortium for preclinicAl AssESsment of CARdioprotective therapies (CAESAR): a paradigm shift in studies of infarct size limitation. J Cardiovasc Pharmacol Ther 16: 332-339.
  3. Bolli R, Li QH, Tang XL, Guo Y, Xuan YT, et al. (2007) The late phase of preconditioning and its natural clinical application--gene therapy. Heart Fail Rev 12: 189-199.
  4. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, et al. (2004) Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 95: 125-134.
  5. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74: 1124-1136.
  6. Hausenloy DJ, Yellon DM (2010) The second window of preconditioning (SWOP) where are we now? Cardiovasc Drugs Ther 24: 235-254.
  7. Gross ER, Gross GJ (2007) Pharmacologic therapeutics for cardiac reperfusion injury. Expert Opin Emerg Drugs 12: 367-388.
  8. Peart JN, Hoe LE, Gross GJ, Headrick JP (2011) Sustained ligand-activated preconditioning via δ-opioid receptors. J Pharmacol Exp Ther 336: 274-281.
  9. Wilson EM, Diwan A, Spinale FG, Mann DL (2004) Duality of innate stress responses in cardiac injury, repair, and remodeling. J Mol Cell Cardiol 37: 801-811.
  10. Marcus BH, Williams DM, Dubbert PM, Sallis JF, King AC, et al. (2006) Physical activity intervention studies: what we know and what we need to know: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity); Council on Cardiovascular Disease in the Young; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research. Circulation 114: 2739-2752.
  11. Demirel HA, Powers SK, Zergeroglu MA, Shanely RA, Hamilton K, et al. (2001) Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. J Appl Physiol 91: 2205-2212.
  12. Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, et al. (1999) Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med 189: 1699-1706.
  13. Powers SK, Demirel HA, Vincent HK, Coombes JS, Naito H, et al. (1998) Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat. Am J Physiol 275: R1468-R1477.
  14. Lennon SL, Quindry J, Hamilton KL, French J, Staib J, et al. (2004) Loss of exercise-induced cardioprotection after cessation of exercise. J Appl Physiol 96: 1299-1305.
  15. French JP, Hamilton KL, Quindry JC, Lee Y, Upchurch PA, et al. (2008) Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. FASEB J 22: 2862-2871.
  16. Hamilton K, Quindry J, French J, Lee Y, Powers S (2006) MnSOD antisense oligonucleotide treatment attenuates exercise induced protection against infarction and apoptosis following ischemia-reperfusion. In Review.
  17. Hamilton KL, Quindry JC, French JP, Staib J, Hughes J, et al. (2004) MnSOD antisense treatment and exercise-induced protection against arrhythmias. Free Radic Biol Med 37: 1360-1368.
  18. French JP, Quindry JC, Falk DJ, Staib JL, Lee Y, et al. (2005) Ischemia-reperfusion induced calpain activation and SERCA2a degradation are attenuated by exercise training and calpain inhibition. Am J Physiol Heart Circ Physiol 290: H128-136.
  19. Dickson EW, Hogrefe CP, Ludwig PS, Ackermann LW, Stoll LL, et al. (2008) Exercise enhances myocardial ischemic tolerance via an opioid receptor-dependent mechanism. Am J Physiol Heart Circ Physiol 294: H402-408.
  20. Jew KN, Moore RL (2001) Glibenclamide improves postischemic recovery of myocardial contractile function in trained and sedentary rats. J Appl Physiol 91: 1545-1554.
  21. Chicco AJ, Johnson MS, Armstrong CJ, Lynch JM, Gardner RT, et al. (2007) Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal KATP channel blockade in the rat heart. Am J Physiol Heart Circ Physiol 292: H2432-2437.
  22. Brown DA, Lynch JM, Armstrong CJ, Caruso NM, Ehlers LB, et al. (2005) Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. J Physiol 564: 619-630.
  23. Quindry JC, Miller L, McGinnis G, Kliszczewicz B, Irwin JM, et al. (2012) Ischemia reperfusion injury, KATP channels, and exercise-induced cardioprotection against apoptosis. J Appl Physiol 113: 498-506.
  24. Hamilton KL, Staib JL, Phillips T, Hess A, Lennon SL, et al. (2003) Exercise, antioxidants, and HSP72: protection against myocardial ischemia/reperfusion. Free Radic Biol Med 34: 800-809.
  25. Lennon SL, Quindry JC, Hamilton KL, French JP, Hughes J, et al. (2004) Elevated MnSOD is not required for exercise-induced cardioprotection against myocardial stunning. Am J Physiol Heart Circ Physiol 287: H975-980.
  26. Quindry JC, French J, Hamilton KL, Lee Y, Selsby J, et al. (2010) Exercise does not increase cyclooxygenase-2 myocardial levels in young or senescent hearts. J Physiol Sci 60: 181-186.
  27. Quindry JC, Hamilton KL, French JP, Lee Y, Murlasits Z, et al. (2007) Exercise-induced HSP-72 elevation and cardioprotection against infarct and apoptosis. J Appl Physiol 103: 1056-1062.
  28. Schulman D, Latchman DS, Yellon DM (2001) Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 281: H1630-1636.
  29. Quindry J, French J, Hamilton K, Lee Y, Mehta JL, et al. (2005) Exercise training provides cardioprotection against ischemia-reperfusion induced apoptosis in young and old animals. Exp Gerontol 40: 416-425.
  30. Starnes JW, Taylor RP, Park Y (2003) Exercise improves postischemic function in aging hearts. Am J Physiol Heart Circ Physiol 285: H347-351.
Citation: Quindry JC (2013) Exercise: Great for Heart Health, Just as Great for Cardiac Preconditioning Research. J Clin Exp Cardiolog 4:e119.

Copyright: © 2013 Quindry JC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.