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Editorials |
From the Oates Institute for Experimental Therapeutics and Division of Clinical Pharmacology, Departmentsts of Medicine and Pharmacology (T.S., B.C.K.), Medical Center, Nashville, Tenn.
Correspondence to Björn C. Knollmann, MD, PhD, Associate Professor of Medicine and Pharmacology, Oates Institute for Experimental Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 1265 Medical Research Building IV, Nashville, TN 37232-0575. E-mail bjorn.knollmann{at}vanderbilt.edu
See related article, pages 10791088
Key Words: exercise training myocardial infarction Ca2+ handling myofilament Ca2+ sensitivity cardiac arrhythmias
| Impaired Myofilament Function After Myocardial Infarction |
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| Benefit of Exercise Training Post MI |
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In the current issue of Circulation Research, de Waard et al8 present remarkable data addressing the question of exercise training early post MI. After a large MI, mice were subjected to 8 weeks of "voluntary" exercise training. Exercise had no detrimental effects on mortality and minimal effects on myocardial hypertrophy and left ventricular remodelling. Furthermore, there was a clear benefit in pump function and general exercise capacity. On the cellular level, exercise improved cell shortening and lowered elevated end-diastolic Ca2+, wheras Ca2+ transient amplitudes and Ca2+ handling proteins (SERCA2a, phospholamban, Na+/Ca2+ exchanger) were relatively unaffected. Moreover, exercise normalized the depressed maximum developed force and also normalized the increased myofilament Ca2+ sensitivity of the post-MI myocardium. The authors conclude that improved contractility with early exercise training following MI is because of improved myofilament function rather than the restoration of depressed Ca2+ transients. The reduction in myofilament Ca2+ sensitivity is presumably caused by improved ß1-adrenergic signaling.
| Voluntary Exercise Is Better |
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| Exercise Decreases Myofilament Ca2+ Sensitivity |
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| Exercise Benefits Beyond Improved Myofilament Function? |
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The most common cause of mortality after MI is sudden cardiac death (SCD) because of arrhythmic events. About 60% of acute MI mortality is attributed to ventricular tachycardia or fibrillation, accounting for more than 250 000 deaths annually in the United States alone.10 The link between ischemia and arrhythmia has been known since the 1840s.11 Arrhythmias remain the major cause of mortality even long after the MI event, as evidenced by the increasing use of highly effective (but expensive) implantable cardioverter-defibrillators.12 In humans, exercise not only significantly decreases cardiac mortality, but also improves markers of electrical instability that are good predictors of malignant ventricular arrhythmias and SCD.13
So why dont we see an effect on mortality in the de Waard et al study? The reason probably lies in the experimental model: Although mice clearly develop ventricular tachyarrhythmias,14,15 they simply do not die from them as easily as humans or other big mammals do.16 The survival plot in Figure 1C illustrates this point: After the high mortality rate during the first few days after coronary ligation, the line remains completely flat. No further deaths are observed. In contrast, a similar study in dogs reported that 21% of the animals in the sedentary group died between the sixth and tenth week following ischemia,17 and in this regard people are more like dogs than mice. It would have been helpful to record the incidence of ventricular arrhythmias during the 8-week observation period even in the present mouse study. Unfortunately, these data are not available, and may be quite difficult to get. Short of repeating the study, what can be deduced from the presented effects of exercise on Ca2+ cycling and myofilament function with respect to arrhythmogenesis?
First, MI significantly increases diastolic intracellular Ca2+, especially at fast heart rates. Exercise reversed this effect and lowered end-diastolic Ca2+ significantly. This has at least 2 important implications1: Increased diastolic Ca2+ is a known independent trigger of delayed afterdepolarizations and triggered arrhythmia18; and2 more long-term, increased end-diastolic Ca2+ will induce ventricular remodelling by activating regulatory proteins such as calcineurin and calmodulin-dependent protein kinase-II (CaMKII). Upregulation of CaMKII in turn has been shown to be arrhythmogenic even after normalization of basal Ca2+. Together with the normalization of ß-adrenergic responsiveness after exercise, these results suggest that exercise may reduce the incidence of ventricular arrhythmia post MI, as has been demonstrated convincingly in a dog study.17
The second key finding is the increase in myofilament Ca2+ sensitivity after MI and its reduction with exercise. The effect of increased Ca2+ sensitivity on arrhythmogenesis is not known. However, mutations in sarcomeric proteins that increase myofilament Ca2+ sensitivity cause familial hypertrophic cardiomyopathy, a disease characterized by high rates of ventricular arrhythmias in humans and animal models.14 Although speculative at this point, the data by de Waard et al8 nevertheless raise interesting questions regarding the role of altered myofilament Ca2+ sensitivity in the context of post-MI contractility and arrhythmogenesis.
In summary, the study by de Waard et al is a remarkable piece of work, which, as any good study, answers 1 and raises 5 new questions. The answers will have to wait until the authors present us with data from a similar study in pigs or dogs, ideally from a strain that has an inherent urge to exercise. Meanwhile, the odds are low that patients will start exercising voluntarily.
| Acknowledgments |
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Dr Knollmann is partly supported by NIH grants HL071670 and HL46681.
Disclosures
None.
| Footnotes |
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| References |
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2. van der Velden J, Merkus D, Klarenbeek BR, James AT, Boontje NM, Dekkers DH, Stienen GJ, Lamers JM, Duncker DJ. Alterations in myofilament function contribute to left ventricular dysfunction in pigs early after myocardial infarction. Circ Res. 2004; 95: e85e95.
3. van der Velden J, Papp Z, Zaremba R, Boontje NM, de Jong JW, Owen VJ, Burton PB, Goldmann P, Jaquet K, Stienen GJ. Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovasc Res. 2003; 57: 3747.
4. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2001: CD001800.
5. Kubo N, Ohmura N, Nakada I, Yasu T, Katsuki T, Fujii M, Saito M. Exercise at ventilatory threshold aggravates left ventricular remodeling in patients with extensive anterior acute myocardial infarction. Am Heart J. 2004; 147: 113120.[CrossRef][Medline] [Order article via Infotrieve]
6. Hochman JS, Healy B. Effect of exercise on acute myocardial infarction in rats. J Am Coll Cardiol. 1986; 7: 126132.[Abstract]
7. Kloner RA, Kloner JA. The effect of early exercise on myocardial infarct scar formation. Am Heart J. 1983; 106: 10091013.[CrossRef][Medline] [Order article via Infotrieve]
8. de Waard M, van der Velden J, Bito V, Ozdemir S, Biesmans L, Boontje N, Dekkers D, Schoonderwoerd K, Schuurbiers H, de Crom R, Stienen G, Sipido K, Lamers J, Duncker D Early exercise training normalizes myofilament function and attenuates left ventricular pump dysfunction in mice with a large myocardial infarction. Circ Res. 2007; 100: 10791088.
9. Wisloff U, Loennechen JP, Currie S, Smith GL, Ellingsen O. Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility, Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction. Cardiovasc Res. 2002; 54: 162174.[CrossRef][Medline] [Order article via Infotrieve]
10. Pratt CM, Waldo AL, Camm AJ. Can antiarrhythmic drugs survive survival trials? Am J Cardiol. 1998; 81: 24D34D.[CrossRef][Medline] [Order article via Infotrieve]
11. Erichsen JE. On the influence of the coronary circulation on the action of the heart. Lond. Med. Gazette. 1842; 2: 561573.
12. Wilber DJ, Zareba W, Hall WJ, Brown MW, Lin AC, Andrews ML, Burke M, Moss AJ. Time dependence of mortality risk and defibrillator benefit after myocardial infarction. Circulation. 2004; 109: 10821084.
13. Kalapura T, Lavie CJ, Jaffrani W, Chilakamarri V, Milani RV. Effects of cardiac rehabilitation and exercise training on indexes of dispersion of ventricular repolarization in patients after acute myocardial infarction. Am J Cardiol. 2003; 92: 292294.[CrossRef][Medline] [Order article via Infotrieve]
14. Knollmann BC, Kirchhof P, Sirenko SG, Degen H, Greene AE, Schober T, Mackow JC, Fabritz L, Potter JD, Morad M. Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling. Circ Res. 2003; 92: 428436.
15. Knollmann BC, Chopra N, Hlaing T, Akin B, Yang T, Ettensohn K, Knollmann BE, Horton KD, Weissman NJ, Holinstat I, Zhang W, Roden DM, Jones LR, Franzini-Armstrong C, Pfeifer K. Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J Clin Invest. 2006; 116: 25102520.[CrossRef][Medline] [Order article via Infotrieve]
16. London B. Cardiac arrhythmias: from (transgenic) mice to men. J Cardiovasc Electrophysiol. 2001; 12: 10891091.[CrossRef][Medline] [Order article via Infotrieve]
17. Billman GE, Kukielka M. Effects of endurance exercise training on heart rate variability and susceptibility to sudden cardiac death: protection is not due to enhanced cardiac vagal regulation. J Appl Physiol. 2006; 100: 896906.
18. Bers DM. Calcium and cardiac rhythms: physiological and pathophysiological. Circ Res. 2002; 90: 1417.
Related Article:
Circ. Res. 2007 100: 1079-1088.
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