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01-05-2017 | Original Contribution

Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction

Authors: Thomas Ravn Lassen, Jan Møller Nielsen, Jacob Johnsen, Steffen Ringgaard, Hans Erik Bøtker, Steen Buus Kristiansen

Published in: Basic Research in Cardiology | Issue 3/2017

Abstract

Left ventricular (LV) remodeling following a myocardial infarction (MI) involves formation of reactive oxygen species (ROS). Paroxetine, a selective serotonin reuptake inhibitor, has an antioxidant effect in the vascular wall. We investigated whether paroxetine reduces myocardial ROS formation and LV remodeling following a MI. In a total of 32 Wistar rats, MI was induced by a 30-min ligation of the left anterior descending artery followed by 7- or 28-day reperfusion. During the 28 days of reperfusion, LV remodeling was evaluated by magnetic resonance imaging (MRI) and echocardiography (n = 20). After 28 days of reperfusion, the susceptibility to ventricular tachycardia was evaluated prior to sacrifice and histological assessment of myocyte cross-sectional area, fibrosis, and presence of myofibroblasts. Myocardial ROS formation was measured with dihydroethidium after 7 days of reperfusion in separate groups (n = 12). Diastolic LV volume, evaluated by MRI (417 ± 60 vs. 511 ± 64 µL, p < 0.05), and echocardiography (515 ± 80 vs. 596 ± 83 µL, p < 0.05) as well as diastolic LV internal diameter evaluated with echocardiography (7.2 ± 0.6 vs. 8.1 ± 0.7 mm, p < 0.05) were lower in the paroxetine group than in controls. Furthermore, myocyte cross-sectional area was reduced in the paroxetine group compared with controls (277 ± 26 vs. 354 ± 23 mm³, p < 0.05) and ROS formation was reduced in the remote myocardium (0.415 ± 0.19 normalized to controls, p < 0.05). However, no differences in the presence of fibrosis or myofibroblasts were observed. Finally, paroxetine reduced the susceptibility to ventricular tachycardia (induced in 2/11 vs. 6/8 rats, p < 0.05). Paroxetine treatment following MI decreases LV remodeling and susceptibility to arrhythmias, probably by reducing ROS formation.

Angermann CE, Gelbrich G, Störk S et al (2016) Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: the MOOD-HF randomized clinical trial. JAMA 315:2683–2693. doi:10.1001/jama.2016.7635 CrossRefPubMed

Arroyo CM, Kramer JH, Dickens BF, Weglicki WB (1987) Identification of free radicals in myocardial ischemia/reperfusion by spin trapping with nitrone DMPO. FEBS Lett 221:101–104. doi:10.1016/0014-5793(87)80360-5 CrossRefPubMed

Carney RM, Blumenthal JA, Freedland KE, Stein PK, Howells WB, Berkman LF, Watkins LL, Czajkowski SM, Hayano J, Domitrovich PP, Jaffe AS (2005) Low heart rate variability and the effect of depression on post-myocardial infarction mortality. Arch Intern Med 165:1486–1491. doi:10.1001/archinte.165.13.1486 CrossRefPubMed

de Bakker JM, van Capelle FJ, Janse MJ, Wilde AA, Coronel R, Becker AE, Dingemans KP, van Hemel NM, Hauer RN (1988) Reentry as a cause of ventricular tachycardia in patients with chronic ischemic heart disease: electrophysiologic and anatomic correlation. Circulation 77:589–606. doi:10.1161/01.cir.77.3.589 CrossRefPubMed

Doughty RN, Whalley GA, Walsh HA, Gamble GD, Lopez-Sendon J, Sharpe N, Investigat CES (2004) Effects of carvedilol on left ventricular remodeling after acute myocardial infarction—the CAPRICORN echo substudy. Circulation 109:201–206. doi:10.1161/01.cir.0000108928.25690.94 CrossRefPubMed

Frey A, Saxon V-M, Popp S, Lehmann M, Mathes D, Pachel C, Hofmann U, Ertl G, Lesch K-P, Frantz S (2016) Early citalopram treatment increases mortality due to left ventricular rupture in mice after myocardial infarction. J Mol Cell Cardiol 98:28–36. doi:10.1016/j.yjmcc.2016.07.002 CrossRefPubMed

Gaudron P, Eilles C, Kugler I, Ertl G (1993) Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Circulation 87:755–763. doi:10.1161/01.CIR.87.3.755 CrossRefPubMed

Gero D, Szoleczky P, Suzuki K, Modis K, Olah G, Coletta C, Szabo C (2013) Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction. Diabetes 62:953–964. doi:10.2337/db12-0789/-/DC1 CrossRefPubMedPubMedCentral

Heiberg E, Sjogren J, Ugander M, Carlsson M, Engblom H, Arheden H (2010) Design and validation of segment—freely available software for cardiovascular image analysis. BMC Med Imaging 10:1. doi:10.1186/1471-2342-10-1 CrossRefPubMedPubMedCentral

10.

Hemeryck A, Belpaire FM (2002) Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 3:13–37. doi:10.2174/1389200023338017 CrossRefPubMed

11.

Heusch G, Libby P, Gersh B, Yellon D, Böhm 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 CrossRefPubMedPubMedCentral

12.

Kawai K, Qin FZ, Shite J, Mao WK, Fukuoka S, Liang CS (2004) Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy. Am J Physiol Heart Circ Physiol 287:H1003–H1012. doi:10.1152/ajpheart.00797.2003 CrossRefPubMed

13.

Kawara T, Derksen R, de Groot JR, Coronel R, Tasseron S, Linnenbank AC, Hauer RNW, Kirkels H, Janse MJ, de Bakker JMT (2001) Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis. Circulation 104:3069–3075. doi:10.1161/hc5001.100833 CrossRefPubMed

14.

Kinugawa S, Tsutsui H, Hayashidani S, Ide T, Suematsu N, Satoh S, Utsumi H, Takeshita A (2000) Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress. Circ Res 87:392–398. doi:10.1161/01.res.87.5.392 CrossRefPubMed

15.

Kitamura H, Ohnishi Y, Yoshida A, Okajima K, Azumi H, Ishida A, Galeano EJ, Kubo S, Hayashi Y, Itoh H, Yokoyama M (2002) Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia. J Cardiovasc Electrophysiol 13:865–870. doi:10.1046/j.1540-8167.2002.00865.x CrossRefPubMed

16.

Kukielka GL, Smith CW, Manning AM, Youker KA, Michael LH, Entman ML (1995) Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury. Circulation 92:1866–1875. doi:10.1161/01.CIR.92.7.1866 CrossRefPubMed

17.

Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E (2011) Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ 183:1835–1843. doi:10.1503/cmaj.100912 CrossRefPubMedPubMedCentral

18.

Leftheriotis D, Flevari P, Ikonomidis I, Douzenis A, Liapis C, Paraskevaidis I, Iliodromitis E, Lykouras L, Kremastinos DT (2010) The role of the selective serotonin re-uptake inhibitor sertraline in nondepressive patients with chronic ischemic heart failure: a preliminary study. Pacing Clin Electrophysiol 33:1217–1223. doi:10.1111/j.1540-8159.2010.02792.x CrossRefPubMed

19.

Machackova J, Sanganalmath SK, Elimban V, Dhalla NS (2011) beta-adrenergic blockade attenuates cardiac dysfunction and myofibrillar remodelling in congestive heart failure. J Cell Mol Med 15:545–554. doi:10.1111/j.1582-4934.2010.01015.x CrossRefPubMed

20.

McFarlane A, Kamath MV, Fallen EL, Malcolm V, Cherian F, Norman G (2001) Effect of sertraline on the recovery rate of cardiac autonomic function in depressed patients after acute myocardial infarction. Am Heart J 142:617–623. doi:10.1068/mhj/2001.116766 CrossRefPubMed

21.

Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Flaxman A, Murray CJL, Naghavi M (2014) The global burden of ischemic heart disease in 1990 and 2010. Circulation 129:1493–1501. doi:10.1161/circulationaha.113.004046 CrossRefPubMedPubMedCentral

22.

Nakamura Y, Yoshiyama M, Omura T, Yoshida K, Izumi Y, Takeuchi K, Kim S, Iwao H, Yoshikawa J (2003) Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction. Cardiovasc Res 57:48–54. doi:10.1016/s0008-6363(02)00644-2 CrossRefPubMed

23.

Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE (2010) Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart Rhythm 7:1438–1445. doi:10.1016/j.hrthm.2010.04.030 CrossRefPubMed

24.

Peters NS, Coromilas J, Severs NJ, Wit AL (1997) 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 95:988–996. doi:10.1161/01.CIR.95.4.988 CrossRefPubMed

25.

Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E (1988) Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 319:80–86. doi:10.1056/nejm198807143190204 CrossRefPubMed

26.

Pung YF, Rocic P, Murphy MP, Smith RA, Hafemeister J, Ohanyan V, Guarini G, Yin L, Chilian WM (2012) Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats. Arterioscler Thromb Vasc Biol 32:325–334. doi:10.1161/ATVBAHA.111.241802 CrossRefPubMed

27.

Sauer WH, Berlin JA, Kimmel SE (2001) Selective serotonin reuptake inhibitors and myocardial infarction. Circulation 104:1894–1898. doi:10.1161/hc4101.097519 CrossRefPubMed

28.

Sauer WH, Berlin JA, Kimmel SE (2003) Effect of antidepressants and their relative affinity for the serotonin transporter on the risk of myocardial infarction. Circulation 108:32–36. doi:10.1161/01.CIR.0000079172.43229.CD CrossRefPubMed

29.

Spijkerman T, de Jonge P, van den Brink RHS, Jansen JHC, May JF, Crijns H, Ormel J (2005) Depression following myocardial infarction: first-ever versus ongoing and recurrent episodes. Gen Hosp Psychiatry 27:411–417. doi:10.1016/j.genhosppsych.2005.05.007 CrossRefPubMed

30.

St John Sutton M, Lee D, Rouleau JL, Goldman S, Plappert T, Braunwald E, Pfeffer MA (2003) Left ventricular remodeling and ventricular arrhythmias after myocardial infarction. Circulation 107:2577–2582. doi:10.1161/01.CIR.0000070420.51787.A8 CrossRefPubMed

31.

Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A (2003) Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 107:1418–1423. doi:10.1161/01.CIR.0000055318.09997.1F CrossRefPubMed

32.

Thompson SA, Copeland CR, Reich DH, Tung L (2011) Mechanical coupling between myofibroblasts and cardiomyocytes slows electric conduction in fibrotic cell monolayers. Circulation 123:2083–2093. doi:10.1161/CIRCULATIONAHA.110.015057 CrossRefPubMedPubMedCentral

33.

van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J (2010) Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7:30–37. doi:10.1038/nrcardio.2009.199 CrossRefPubMed

34.

van Melle JP, Buikema H, van den Berg MP, van Buiten A, van Veldhuisen DJ, Boonstra PW, van Gilst WH (2004) Sertraline causes strong coronary vasodilation: possible relevance for cardioprotection by selective serotonin reuptake inhibitors. Cardiovasc Drugs Ther 18:441–447. doi:10.1007/s10557-004-6222-2 CrossRefPubMed

35.

Wang X-X, Wang X-L, M-m Tong, Gan L, Chen H, S-s Wu, Chen J-X, Li R-L, Wu Y, H-y Zhang, Zhu Y, Y-x Li, J-h He, Wang M, Jiang W (2016) SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3α-dependent antioxidant defense mechanisms. Basic Res Cardiol 111:13. doi:10.1007/s00395-016-0531-z CrossRefPubMed

36.

Wei M, Xin P, Li S, Tao J, Li Y, Li J, Liu M, Li J, Zhu W, Redington AN (2011) Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res 108:1220–1225. doi:10.1161/CIRCRESAHA.110.236190 CrossRefPubMed

37.

Xu XH, Wan WH, Powers AS, Li J, Ji LL, Lao SH, Wilson B, Erikson JM, Zhang JQ (2008) Effects of exercise training on cardiac function and myocardial remodeling in post myocardial infarction rats. J Mol Cell Cardiol 44:114–122. doi:10.1016/j.yjmcc.2007.10.004 CrossRefPubMed

38.

Zhao W, Zhao T, Chen Y, Ahokas RA, Sun Y (2009) Reactive oxygen species promote angiogenesis in the infarcted rat heart. Int J Exp Pathol 90:621–629. doi:10.1111/j.1365-2613.2009.00682.x CrossRefPubMedPubMedCentral

Title: Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction
Authors: Thomas Ravn Lassen
Jan Møller Nielsen
Jacob Johnsen
Steffen Ringgaard
Hans Erik Bøtker
Steen Buus Kristiansen
Publication date: 01-05-2017
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 3/2017
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-017-0614-5

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Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction

Abstract

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Abstract

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