Exhaustive Exercise-Induced Cardiac Conduction System Injury and Changes of cTnT and Cx43

Abstract

Up to now, studies of exercise-induced cardiac arrhythmia have focused primarily on the working myocardium, with few studies examining to the cardiac conduction system where the rhythmic and synchronized contraction of the heart is initiated. To explore whether the cardiac conduction system is involved in the exercise-induced cardiac injury, we performed histological analysis of sinoatrial node, atrioventricular node and Purkinje fibers and tested the level of structural protein cardiac troponin T and Connexin 43 in Sprague Dawley rats following repeated exhaustive exercise. We found increased collagen deposition, hyperplasia interstitialis, and enhanced activity of lactate dehydrongenase and acid phosphatase in the cardiac conduction system following repeated exhaustive exercise. Mitochondrial alterations, enlarged area of intercalated disc and disappearance of gap junctions were additionally observed through electron transmission microscopy. In addition, significant decreases in cardiac troponin T and Connexin 43 were present in the cardiac conduction system in response to repeated exhaustive exercise. All of these findings demonstrate that repeated exhaustive exercise induces ischemic alterations, damage to cytoskeleton and gap junctions, and tissue fibrosis in the cardiac conduction system in rats. These data may shed a new light on the mechanism of exercised-induced cardiac injury and arrhythmia.

Key words

repeated exhaustive exercise - cardiac conduction system - exercise-induced arrhythmia - cardiac troponin T - connexin 43

• References

• 1 Alexander AM. Atrial fibrillation in the athlete. Curr Sports Med Rep 2013; 12: 86-92
• 2 Axelsson A, Ruwald MH, Dalsgaard M, Rossing K, Steffensen R, Iversen K. Serial measurements of high-sensitivity cardiac troponin T after exercise stress test in stable coronary artery disease. Biomarkers 2013; 18: 304-309
• 3 Baldesberger S, Bauersfeld U, Candinas R, Seifert B, Zuber M, Ritter M, Jenni R, Oechslin E, Luthi P, Scharf C, Marti B, Attenhofer Jost CH. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J 2008; 29: 71-78
• 4 Benito B, Gay-Jordi G, Serrano-Mollar A, Guasch E, Shi Y, Tardif JC, Brugada J, Nattel S, Mont L. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011; 123: 13-22
• 5 Boengler K. Stimulation of cardiac beta-adrenoceptors targets connexin 43. Br J Pharmacol 2009; 158: 195-197
• 6 Calvo N, Brugada J, Sitges M, Mont L. Atrial fibrillation and atrial flutter in athletes. Br J Sports Med 2012; 46 (Suppl. 01) i37-i43
• 7 Carranza-Garcia LE, George K, Serrano-Ostariz E, Casado-Arroyo R, Caballero-Navarro AL, Legaz-Arrese A. Cardiac biomarker response to intermittent exercise bouts. Int J Sports Med 2011; 32: 327-331
• 8 Chen Y, Serfass RC, Mackey-Bojack SM, Kelly KL, Titus JL, Apple FS. Cardiac troponin T alterations in myocardium and serum of rats after stressful, prolonged intense exercise. J Appl Physiol 2000; 88: 1749-1755
• 9 Cutler MJ, Jeyaraj D, Rosenbaum DS. Cardiac electrical remodeling in health and disease. Trends Pharmacol Sci 2011; 32: 174-180
• 10 de Jong S, van Veen TA, van Rijen HV, de Bakker JM. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol 2011; 57: 630-638
• 11 Duttaroy S, Thorell D, Karlsson L, Borjesson M. A single-bout of one-hour spinning exercise increases troponin T in healthy subjects. Scand Cardiovasc J 2012; 46: 2-6
• 12 Fontes MS, van Veen TA, de Bakker JM, van Rijen HV. Functional consequences of abnormal Cx43 expression in the heart. Biochim Biophys Acta 2012; 1818: 2020-2029
• 13 Gerber Y, Jaffe AS, Weston SA, Jiang R, Roger VL. Prognostic value of cardiac troponin T after myocardial infarction: a contemporary community experience. Mayo Clin Proc 2012; 87: 247-254
• 14 Greener ID, Sasano T, Wan X, Igarashi T, Strom M, Rosenbaum DS, Donahue JK. Connexin43 gene transfer reduces ventricular tachycardia susceptibility after myocardial infarction. J Am Coll Cardiol 2012; 60: 1103-1110
• 15 Harriss DJ, Atkinson G. Ethical standards in sport and exercise science research: 2014 update. Int J Sports Med 2013; 34: 1025-1028
• 16 Hatanaka K, Kawata H, Toyofuku T, Yoshida K. Down-regulation of connexin43 in early myocardial ischemia and protective effect by ischemic preconditioning in rat hearts in vivo. Jpn Heart J 2004; 45: 1007-1019
• 17 Jansen JA, van Veen TA, de Jong S, van der Nagel R, van Stuijvenberg L, Driessen H, Labzowski R, Oefner CM, Bosch AA, Nguyen TQ, Goldschmeding R, Vos MA, de Bakker JM, van Rijen HV. Reduced Cx43 expression triggers increased fibrosis due to enhanced fibroblast activity. Circ Arrhythm Electrophysiol 2012; 5: 380-390
• 18 Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M. Lone atrial fibrillation in vigorously exercising middle aged men: case-control study. BMJ 1998; 316: 1784-1785
• 19 Laughlin MH, Bowles DK, Duncker DJ. The coronary circulation in exercise training. Am J Physiol 2012; 302: H10-H23
• 20 Lerner DL, Yamada KA, Schuessler RB, Saffitz JE. Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 2000; 101: 547-552
• 21 Lindsay MM, Dunn FG. Biochemical evidence of myocardial fibrosis in veteran endurance athletes. Br J Sports Med 2007; 41: 447-452
• 22 Matsushita S, Kurihara H, Watanabe M, Okada T, Sakai T, Amano A. Alterations of phosphorylation state of connexin 43 during hypoxia and reoxygenation are associated with cardiac function. J Histochem Cytochem 2006; 54: 343-353
• 23 Metra M, Bettari L, Pagani F, Lazzarini V, Lombardi C, Carubelli V, Bonetti G, Bugatti S, Parrinello G, Caimi L, Felker GM, Dei Cas L. Troponin T levels in patients with acute heart failure: clinical and prognostic significance of their detection and release during hospitalisation. Clin Res Cardiol 2012; 101: 663-672
• 24 Mont L, Sambola A, Brugada J, Vacca M, Marrugat J, Elosua R, Pare C, Azqueta M, Sanz G. Long-lasting sport practice and lone atrial fibrillation. Eur Heart J 2002; 23: 477-482
• 25 Morris JN, Everitt MG, Pollard R, Chave SP, Semmence AM. Vigorous exercise in leisure-time: protection against coronary heart disease. Lancet 1980; 2: 1207-1210
• 26 Nie J, Close G, George KP, Tong TK, Shi Q. Temporal association of elevations in serum cardiac troponin T and myocardial oxidative stress after prolonged exercise in rats. Eur J Appl Physiol 2010; 110: 1299-1303
• 27 Noorman M, Hakim S, Kessler E, Groeneweg JA, Cox MG, Asimaki A, van Rijen HV, van Stuijvenberg L, Chkourko H, van der Heyden MA, Vos MA, de Jonge N, van der Smagt JJ, Dooijes D, Vink A, de Weger RA, Varro A, de Bakker JM, Saffitz JE, Hund TJ, Mohler PJ, Delmar M, Hauer RN, van Veen TA. Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disc in patients with arrhythmogenic cardiomyopathy. Heart Rhythm 2013; 10: 412-419
• 28 Parissis JT, Papadakis J, Kadoglou NP, Varounis C, Psarogiannakopoulos P, Rafouli-Stergiou P, Ikonomidis I, Paraskevaidis I, Dimopoulou I, Zerva A, Dima K, Anastasiou-Nana M, Filippatos G. Prognostic value of high sensitivity troponin T in patients with acutely decompensated heart failure and non-detectable conventional troponin T levels. Int J Cardiol 2013; 168: 3609-3612
• 29 Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 1997; 95: 988-996
• 30 Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, Martinez Ubago JL, Diez J. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation 2004; 110: 1263-1268
• 31 Querejeta R, Varo N, Lopez B, Larman M, Artinano E, Etayo JC, Martinez Ubago JL, Gutierrez-Stampa M, Emparanza JI, Gil MJ, Monreal I, Mindan JP, Diez J. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000; 101: 1729-1735
• 32 Remo BF, Giovannone S, Fishman GI. Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models. J Membr Biol 2012; 245: 275-281
• 33 Scharhag J, George K, Shave R, Urhausen A, Kindermann W. Exercise-associated increases in cardiac biomarkers. Med Sci Sports Exerc 2008; 40: 1408-1415
• 34 Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 2008; 80: 9-19
• 35 Sturek M. Ca2+  regulatory mechanisms of exercise protection against coronary artery disease in metabolic syndrome and diabetes. J Appl Physiol 2011; 111: 573-586
• 36 Thomas DP, Marshall KI. Effects of repeated exhaustive exercise on myocardial subcellular membrane structures. Int J Sports Med 1988; 9: 257-260
• 37 Tian Y, Nie J, Huang C, George KP. The kinetics of highly sensitive cardiac troponin T release after prolonged treadmill exercise in adolescent and adult athletes. J Appl Physiol 2012; 113: 418-425
• 38 Twerenbold R, Jaffe A, Reichlin T, Reiter M, Mueller C. High-sensitive troponin T measurements: what do we gain and what are the challenges?. Eur Heart J 2012; 33: 579-586