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Aerobic interval training reduces inducible ventricular arrhythmias in diabetic mice after myocardial infarction

Abstract

Diabetes mellitus (DM) increases the risk of heart failure after myocardial infarction (MI), and aggravates ventricular arrhythmias in heart failure patients. Although exercise training improves cardiac function in heart failure, it is still unclear how it benefits the diabetic heart after MI. To study the effects of aerobic interval training on cardiac function, susceptibility to inducible ventricular arrhythmias and cardiomyocyte calcium handling in DM mice after MI (DM-MI). Male type 2 DM mice (C57BLKS/J Lepr db /Lepr db) underwent MI or sham surgery. One group of DM-MI mice was submitted to aerobic interval training running sessions during 6 weeks. Cardiac function and structure were assessed by echocardiography and magnetic resonance imaging, respectively. Ventricular arrhythmias were induced by high-frequency cardiac pacing in vivo. Protein expression was measured by Western blot. DM-MI mice displayed increased susceptibility for inducible ventricular arrhythmias and impaired diastolic function when compared to wild type-MI, which was associated with disruption of cardiomyocyte calcium handling and increased calcium leak from the sarcoplasmic reticulum. High-intensity exercise recovered cardiomyocyte function in vitro, reduced sarcoplasmic reticulum diastolic calcium leak and significantly reduced the incidence of inducible ventricular arrhythmias in vivo in DM-MI mice. Exercise training also normalized the expression profile of key proteins involved in cardiomyocyte calcium handling, suggesting a potential molecular mechanism for the benefits of exercise in DM-MI mice. High-intensity aerobic exercise training recovers cardiomyocyte function and reduces inducible ventricular arrhythmias in infarcted diabetic mice.

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References

  1. Ai X, Curran JW, Shannon TR, Bers DM, Pogwizd SM (2005) Ca2+/calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circ Res 97:1314–1322. doi:10.1161/01.RES.0000194329.41863.89

    CAS  PubMed  Article  Google Scholar 

  2. Anderson ME, Brown JH, Bers DM (2011) CaMKII in myocardial hypertrophy and heart failure. J Mol Cell Cardiol 51:468–473. doi:10.1016/j.yjmcc.2011.01.012

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  3. Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47:693–700. doi:10.1016/j.jacc.2005.09.050

    CAS  PubMed  Article  Google Scholar 

  4. Ather S, Wang W, Wang Q, Li N, Anderson ME, Wehrens XH (2013) Inhibition of CaMKII phosphorylation of RyR2 prevents inducible ventricular arrhythmias in mice with Duchenne muscular dystrophy. Heart Rhythm 10:592–599. doi:10.1016/j.hrthm.2012.12.016

    PubMed Central  PubMed  Article  Google Scholar 

  5. Bauters C, Lamblin N, Mc Fadden EP, Van Belle E, Millaire A, de Groote P (2003) Influence of diabetes mellitus on heart failure risk and outcome. Cardiovasc Diabetol 2:1. doi:10.1186/1475-2840-2-1

    PubMed Central  PubMed  Article  Google Scholar 

  6. Bers DM (2006) Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda, Md.) 21:380–387. doi:10.1152/physiol.00019.2006

    CAS  Article  Google Scholar 

  7. Curran J, Brown KH, Santiago DJ, Pogwizd S, Bers DM, Shannon TR (2010) Spontaneous Ca waves in ventricular myocytes from failing hearts depend on Ca(2+)-calmodulin-dependent protein kinase II. J Mol Cell Cardiol 49:25–32. doi:10.1016/j.yjmcc.2010.03.013

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. Czyzk A, Krolewski AS, Szablowska S, Alot A, Kopczynski J (1980) Clinical course of myocardial infarction among diabetic patients. Diabetes Care 3:526–529. doi:10.2337/diacare.3.4.526

    CAS  PubMed  Article  Google Scholar 

  9. De Groote P, Lamblin N, Mouquet F, Plichon D, McFadden E, Van Belle E, Bauters C (2004) Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J 25:656–662. doi:10.1016/j.ehj.2004.01.010

    PubMed  Article  Google Scholar 

  10. Erickson JR, Anderson ME (2008) CaMKII and its role in cardiac arrhythmia. J Cardiovasc Electrophysiol 19:1332–1336. doi:10.1111/j.1540-8167.2008.01295.x

    PubMed  Article  Google Scholar 

  11. Erickson JR, Pereira L, Wang L, Han G, Ferguson A, Dao K, Copeland RJ, Despa F, Hart GW, Ripplinger CM, Bers DM (2013) Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502:372–376. doi:10.1038/nature12537

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. Fein F, Scheuer J (1990) Heart disease in diabetes mellitus: theory and practice. In: Porte DJ (ed) Rifkin H. Elsevier, New York, pp 812–823

    Google Scholar 

  13. George CH (2008) Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res 77:302–314. doi:10.1093/cvr/cvm006

    CAS  PubMed  Article  Google Scholar 

  14. Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L (2014) Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 383:1933–1943. doi:10.1016/S0140-6736(14)60107-0

    PubMed Central  PubMed  Article  Google Scholar 

  15. Hollekim-Strand SM, Bjorgaas MR, Albrektsen G, Tjonna AE, Wisloff U, Ingul CB (2014) High-intensity interval exercise effectively improves cardiac function in patients with type 2 diabetes mellitus and diastolic dysfunction: a randomized controlled trial. J Am Coll Cardiol 64:1758–1760. doi:10.1016/j.jacc.2014.07.971

    PubMed  Article  Google Scholar 

  16. Li N, Wehrens XHT (2010) Programmed electrical stimulation in mice. J Vis Exp. doi:10.3791/1730

    Google Scholar 

  17. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J (1998) Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care 21:69–75. doi:10.2337/diacare.21.1.69

    CAS  PubMed  Article  Google Scholar 

  18. Milberg P, Pott C, Frommeyer G, Fink M, Ruhe M, Matsuda T, Baba A, Klocke R, Quang TH, Nikol S, Stypmann J, Osada N, Muller FU, Breithardt G, Noble D, Eckardt L (2012) Acute inhibition of the Na(+)/Ca(2+) exchanger reduces proarrhythmia in an experimental model of chronic heart failure. Heart Rhythm 9:570–578. doi:10.1016/j.hrthm.2011.11.004

    PubMed  Article  Google Scholar 

  19. Oort RJv, McCauley MD, Dixit SS, Pereira L, Yang Y, Respress JL, Wang Q, Almeida ACD, Skapura DG, Anderson ME, Bers DM, Wehrens XHT (2010) Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failureclinical perspective. Circulation 122:2669–2679. doi:10.1161/CIRCULATIONAHA.110.982298

    PubMed Central  PubMed  Article  Google Scholar 

  20. Porter KE, Turner NA (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther 123:255–278. doi:10.1016/j.pharmthera.2009.05.002

    CAS  PubMed  Article  Google Scholar 

  21. Regan TJ, Wu CF, Yeh CK, Oldewurtel HA, Haider B (1981) Myocardial composition and function in diabetes. The effects of chronic insulin use. Circ Res 49:1268–1277. doi:10.1161/01.RES.49.6.1268

    CAS  PubMed  Article  Google Scholar 

  22. Robinson E, Cassidy RS, Tate M, Zhao Y, Lockhart S, Calderwood D, Church R, McGahon MK, Brazil DP, McDermott BJ, Green BD, Grieve DJ (2015) Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix. Basic Res Cardiol 110:20. doi:10.1007/s00395-015-0476-7

    PubMed Central  PubMed  Article  Google Scholar 

  23. Rytter L, Troelsen S, Beck-Nielsen H (1985) Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 8:230–234. doi:10.2337/diacare.8.3.230

    CAS  PubMed  Article  Google Scholar 

  24. Shao CH, Wehrens XH, Wyatt TA, Parbhu S, Rozanski GJ, Patel KP, Bidasee KR (2009) Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol 106:1280–1292. doi:10.1152/japplphysiol.91280.2008

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  25. Shehadeh A, Regan TJ (1995) Cardiac consequences of diabetes mellitus. Clin Cardiol 18:301–305. doi:10.1002/clc.4960180604

    CAS  PubMed  Article  Google Scholar 

  26. Stolen TO, Hoydal MA, Kemi OJ, Catalucci D, Ceci M, Aasum E, Larsen T, Rolim N, Condorelli G, Smith GL, Wisloff U (2009) Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy. Circ Res 105:527–536. doi:10.1161/CIRCRESAHA.109.199810

    CAS  PubMed  Article  Google Scholar 

  27. Tjønna AE, Lee SJ, Rognmo Ø, Stølen TO, Bye A, Haram PM, Loennechen JP, Al-Share QY, Skogvoll E, Slørdahl SA, Kemi OJ, Najjar SM, Wisløff U (2008) Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome a pilot study. Circulation 118:346–354. doi:10.1161/CIRCULATIONAHA.108.772822

    PubMed Central  PubMed  Article  Google Scholar 

  28. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FW, Wijns W, Task Force on the Management of Acute Myocardial Infarction of the European Society of C (2003) Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 24:28–66. doi:10.1016/S0195-668X(02)00618-8

    PubMed  Google Scholar 

  29. Wisløff U, Najjar SM, Ellingsen Ø, Haram PM, Swoap S, Al-Share Q, Fernström M, Rezaei K, Lee SJ, Koch LG, Britton SL (2005) Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307:418–420. doi:10.1126/science.1108177

    PubMed  Article  Google Scholar 

  30. Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo Ø, Haram PM, Tjønna AE, Helgerud J, Slørdahl SA, Lee SJ, Videm V, Bye A, Smith GL, Najjar SM, Ellingsen Ø, Skjærpe T (2007) Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients. Circulation 115:3086–3094. doi:10.1161/CIRCULATIONAHA.106.675041

    PubMed  Article  Google Scholar 

  31. Yue L, Xie J, Nattel S (2011) Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res 89:744–753. doi:10.1093/cvr/cvq329

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. Zethelius B, Gudbjornsdottir S, Eliasson B, Eeg-Olofsson K, Cederholm J, Swedish National Diabetes R (2014) Level of physical activity associated with risk of cardiovascular diseases and mortality in patients with type-2 diabetes: report from the Swedish National Diabetes Register. Eur J Prev Cardiol 21:244–251. doi:10.1177/2047487313510893

    CAS  PubMed  Article  Google Scholar 

  33. Zhao Z, Fefelova N, Shanmugam M, Bishara P, Babu GJ, Xie LH (2011) Angiotensin II induces afterdepolarizations via reactive oxygen species and calmodulin kinase II signaling. J Mol Cell Cardiol 50:128–136. doi:10.1016/j.yjmcc.2010.11.001

    CAS  PubMed Central  PubMed  Article  Google Scholar 

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Acknowledgments

We thank R. Røsbjørgen for technical assistance, J. Nauman for statistical support, and G. J. J. Silva, and J. B. N. Moreira for very helpful advices. This study was funded by K.G. Jebsen Foundation, The Norwegian Council on Cardiovascular Disease, The Research Council of Norway and Liaison Committee between the Central Norway Regional Health Authority (RHA), the Norwegian University of Science and Technology (NTNU), and the European Commission (FP7-Health-2013; OPTIMEX-602405).

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On behalf of all the authors, the corresponding author states that there is no conflict of interest.

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Correspondence to Natale Rolim.

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Rolim, N., Skårdal, K., Høydal, M. et al. Aerobic interval training reduces inducible ventricular arrhythmias in diabetic mice after myocardial infarction. Basic Res Cardiol 110, 44 (2015). https://doi.org/10.1007/s00395-015-0502-9

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  • DOI: https://doi.org/10.1007/s00395-015-0502-9

Keywords

  • Diabetes mellitus
  • Myocardial infarction
  • Arrhythmias
  • Calcium
  • Aerobic interval training