Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient

Teerapat Nantsupawat, Wanwarang Wongcharoen, Siriporn C Chattipakorn, Nipon Chattipakorn, Teerapat Nantsupawat, Wanwarang Wongcharoen, Siriporn C Chattipakorn, Nipon Chattipakorn

Abstract

Metformin has been shown to have various cardiovascular benefits beyond its antihyperglycemic effects, including a reduction in stroke, heart failure, myocardial infarction, cardiovascular death, and all-cause mortality. However, the roles of metformin in cardiac arrhythmias are still unclear. It has been shown that metformin was associated with decreased incidence of atrial fibrillation in diabetic patients with and without myocardial infarction. This could be due to the effects of metformin on preventing the structural and electrical remodeling of left atrium via attenuating intracellular reactive oxygen species, activating 5' adenosine monophosphate-activated protein kinase, improving calcium homeostasis, attenuating inflammation, increasing connexin-43 gap junction expression, and restoring small conductance calcium-activated potassium channels current. For ventricular arrhythmias, in vivo reports demonstrated that activation of 5' adenosine monophosphate-activated protein kinase and phosphorylated connexin-43 by metformin played a key role in ischemic ventricular arrhythmias reduction. However, metformin failed to show anti-ventricular arrhythmia benefits in clinical trials. In this review, in vitro and in vivo reports regarding the effects of metformin on both atrial arrhythmias and ventricular arrhythmias are comprehensively summarized and presented. Consistent and controversial findings from clinical trials are also summarized and discussed. Due to limited numbers of reports, further studies are needed to elucidate the mechanisms and effects of metformin on cardiac arrhythmias. Furthermore, randomized controlled trials are needed to clarify effects of metformin on cardiac arrhythmias in human.

Keywords: Arrhythmias; Atrial arrhythmias; Atrial fibrillation; Metformin; Ventricular arrhythmias.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Effects of metformin on atrial arrhythmias. Atrial fibrillation, obesity, insulin resistance, and diabetes mellitus can cause atrial structural, electrical, electromechanical, and autonomic adverse remodeling. These remodelings become arrhythmogenic substrates and set out a vicious cycle known as “AF begets AF”. Metformin exerts protective effects through various mechanisms. Red arrow shows adverse effects from atrial fibrillation, obesity, insulin resistance, and diabetes. Green rectangle shows pathway that metformin blocked. Solid green arrow shows protective mechanisms of metformin directly demonstrated from the studies in Tables 1 and 2. Dotted green arrow indicates protective mechanism of metformin from other studies in the text
Fig. 2
Fig. 2
Effects of metformin on ventricular arrhythmias. Ischemia causes reduction in myocardial ATP and finally results in ventricular fibrillation. Chronic metformin use exerts its energy guardian effects mainly via AMPK activation. Additionally, metformin prevents QT interval prolongation, QT dispersion, and conduction velocity delay by regulating microRNA-1 and L-type calcium channels. Only the combination of metformin and vildagliptin could increase p-Cx43 and subsequently reduce ventricular fibrillation. Green rectangle and arrow shows protective mechanisms of metformin

References

    1. Bristol-Myers Squibb Company. Metformin HCL (Glucophage) [package insert]. U.S. Food and Drug Administration website. . Initial approval 1995.
    1. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5(1):6. doi: 10.1186/1758-5996-5-6.
    1. Mohan M, Al-Talabany S, McKinnie A, Mordi IR, Singh JSS, Gandy SJ, Baig F, Hussain MS, Bhalraam U, Khan F, et al. A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: the MET-REMODEL trial. Eur Heart J. 2019;40(41):3409–17. doi: 10.1093/eurheartj/ehz203.
    1. Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, Lee SD, Kao CL. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis. 2014;23(2):e99–105. doi: 10.1016/j.jstrokecerebrovasdis.2013.09.001.
    1. Nichols GA, Koro CE, Gullion CM, Ephross SA, Brown JB. The incidence of congestive heart failure associated with antidiabetic therapies. Diabetes Metab Res Rev. 2005;21(1):51–7. doi: 10.1002/dmrr.480.
    1. Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, Atreja A, Zimmerman RS. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009;46(2):145–54. doi: 10.1007/s00592-008-0090-3.
    1. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998, 352(9131):854–865.
    1. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13(3):221–8. doi: 10.1111/j.1463-1326.2010.01349.x.
    1. Han Y, Xie H, Liu Y, Gao P, Yang X, Shen Z. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol. 2019;18(1):96. doi: 10.1186/s12933-019-0900-7.
    1. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28(10):2345–51. doi: 10.2337/diacare.28.10.2345.
    1. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2010;162(2):193–212. doi: 10.1530/EJE-09-0733.
    1. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20(6):953–66. doi: 10.1016/j.cmet.2014.09.018.
    1. Young LH. AMP-activated protein kinase conducts the ischemic stress response orchestra. Circulation. 2008;117(6):832–40. doi: 10.1161/CIRCULATIONAHA.107.713115.
    1. Solskov L, Lofgren B, Kristiansen SB, Jessen N, Pold R, Nielsen TT, Botker HE, Schmitz O, Lund S. Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration. Basic Clin Pharmacol Toxicol. 2008;103(1):82–7. doi: 10.1111/j.1742-7843.2008.00234.x.
    1. Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Goncalves L, Providencia L, Rongen GA, Smits P, Mocanu MM, et al. Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol. 2009;53(5):373–8. doi: 10.1097/FJC.0b013e31819fd4e7.
    1. Peart JN, Headrick JP. Adenosinergic cardioprotection: multiple receptors, multiple pathways. Pharmacol Ther. 2007;114(2):208–21. doi: 10.1016/j.pharmthera.2007.02.004.
    1. El Messaoudi S, Rongen GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol. 2011;22(6):445–53. doi: 10.1097/MOL.0b013e32834ae1a7.
    1. Whittington HJ, Hall AR, McLaughlin CP, Hausenloy DJ, Yellon DM, Mocanu MM. Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther. 2013;27(1):5–16. doi: 10.1007/s10557-012-6425-x.
    1. Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy TM, Lang JE, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;50(7):856–61. doi: 10.1053/meta.2001.24192.
    1. Goldberg R, Temprosa M, Otvos J, Brunzell J, Marcovina S, Mather K, Arakaki R, Watson K, Horton E, Barrett-Connor E. Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program. J Clin Endocrinol Metab. 2013;98(10):3989–98. doi: 10.1210/jc.2013-1452.
    1. Luo F, Das A, Chen J, Wu P, Li X, Fang Z. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc Diabetol. 2019;18(1):54. doi: 10.1186/s12933-019-0860-y.
    1. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37(5):1344–50. doi: 10.1016/S0735-1097(01)01129-9.
    1. Forouzandeh F, Salazar G, Patrushev N, Xiong S, Hilenski L, Fei B, Alexander RW. Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. J Am Heart Assoc. 2014;3(6):e001202. doi: 10.1161/JAHA.114.001202.
    1. Luo F, Guo Y, Ruan GY, Long JK, Zheng XL, Xia Q, Zhao SP, Peng DQ, Fang ZF, Li XP. Combined use of metformin and atorvastatin attenuates atherosclerosis in rabbits fed a high-cholesterol diet. Sci Rep. 2017;7(1):2169. doi: 10.1038/s41598-017-02080-w.
    1. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care. 1993;16(4):621–9. doi: 10.2337/diacare.16.4.621.
    1. Sobel BE, Hardison RM, Genuth S, Brooks MM, McBane RD, III, Schneider DJ, Pratley RE, Huber K, Wolk R, Krishnaswami A, et al. Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation. 2011;124(6):695–703. doi: 10.1161/CIRCULATIONAHA.110.014860.
    1. Huikuri HV, Stein PK. Heart rate variability in risk stratification of cardiac patients. Prog Cardiovasc Dis. 2013;56(2):153–9. doi: 10.1016/j.pcad.2013.07.003.
    1. Manzella D, Grella R, Esposito K, Giugliano D, Barbagallo M, Paolisso G. Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration. Am J Hypertens. 2004;17(3):223–7. doi: 10.1016/j.amjhyper.2003.11.006.
    1. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–962. doi: 10.1093/eurheartj/ehw210.
    1. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339(10):659–66. doi: 10.1056/NEJM199809033391003.
    1. Cox JL, Canavan TE, Schuessler RB, Cain ME, Lindsay BD, Stone C, Smith PK, Corr PB, Boineau JP. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg. 1991;101(3):406–26. doi: 10.1016/S0022-5223(19)36723-6.
    1. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J. 1959;58(1):59–70. doi: 10.1016/0002-8703(59)90274-1.
    1. Haissaguerre M, Hocini M, Denis A, Shah AJ, Komatsu Y, Yamashita S, Daly M, Amraoui S, Zellerhoff S, Picat MQ, et al. Driver domains in persistent atrial fibrillation. Circulation. 2014;130(7):530–8. doi: 10.1161/CIRCULATIONAHA.113.005421.
    1. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol. 2012;60(7):628–36. doi: 10.1016/j.jacc.2012.05.022.
    1. Carlisle MA, Fudim M, DeVore AD, Piccini JP. Heart failure and atrial fibrillation, like fire and fury. JACC Heart Fail. 2019;7(6):447–56. doi: 10.1016/j.jchf.2019.03.005.
    1. Wang A, Green JB, Halperin JL, Piccini JP. Atrial fibrillation and diabetes mellitus: JACC review topic of the week. J Am Coll Cardiol. 2019;74(8):1107–15. doi: 10.1016/j.jacc.2019.07.020.
    1. Chan YH, Chang GJ, Lai YJ, Chen WJ, Chang SH, Hung LM, Kuo CT, Yeh YH. Atrial fibrillation and its arrhythmogenesis associated with insulin resistance. Cardiovasc Diabetol. 2019;18(1):125. doi: 10.1186/s12933-019-0928-8.
    1. Casaclang-Verzosa G, Gersh BJ, Tsang TS. Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol. 2008;51(1):1–11. doi: 10.1016/j.jacc.2007.09.026.
    1. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92(7):1954–68. doi: 10.1161/01.CIR.92.7.1954.
    1. Harada M, Tadevosyan A, Qi X, Xiao J, Liu T, Voigt N, Karck M, Kamler M, Kodama I, Murohara T, et al. Atrial fibrillation activates AMP-dependent protein kinase and its regulation of cellular calcium handling: potential role in metabolic adaptation and prevention of progression. J Am Coll Cardiol. 2015;66(1):47–58. doi: 10.1016/j.jacc.2015.04.056.
    1. Bai F, Liu Y, Tu T, Li B, Xiao Y, Ma Y, Qin F, Xie J, Zhou S, Liu Q. Metformin regulates lipid metabolism in a canine model of atrial fibrillation through AMPK/PPAR-alpha/VLCAD pathway. Lipids Health Dis. 2019;18(1):109. doi: 10.1186/s12944-019-1059-7.
    1. Li J, Li B, Bai F, Ma Y, Liu N, Liu Y, Wang Y, Liu Q. Metformin therapy confers cardioprotection against the remodeling of gap junction in tachycardia-induced atrial fibrillation dog model. Life Sci. 2020;254:117759. doi: 10.1016/j.lfs.2020.117759.
    1. Qiu J, Zhou S, Liu Q. Energy metabolic alterations in the progression of atrial fibrillation: Potential role of AMP-activated protein kinase as a critical regulator. Int J Cardiol. 2016;212:14–5. doi: 10.1016/j.ijcard.2016.03.014.
    1. Chang SH, Wu LS, Chiou MJ, Liu JR, Yu KH, Kuo CF, Wen MS, Chen WJ, Yeh YH, See LC. Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies. Cardiovasc Diabetol. 2014;13:123. doi: 10.1186/s12933-014-0123-x.
    1. Li B, Po SS, Zhang B, Bai F, Li J, Qin F, Liu N, Sun C, Xiao Y, Tu T, et al. Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability. J Cell Mol Med. 2020 doi: 10.1111/jcmm.15407.
    1. He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–62. doi: 10.1016/j.cmet.2015.01.003.
    1. Bikou O, Thomas D, Trappe K, Lugenbiel P, Kelemen K, Koch M, Soucek R, Voss F, Becker R, Katus HA, et al. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc Res. 2011;92(2):218–25. doi: 10.1093/cvr/cvr209.
    1. Igarashi T, Finet JE, Takeuchi A, Fujino Y, Strom M, Greener ID, Rosenbaum DS, Donahue JK. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation. 2012;125(2):216–25. doi: 10.1161/CIRCULATIONAHA.111.053272.
    1. Qiu J, Zhou S, Liu Q. Phosphorylated AMP-activated protein kinase slows down the atrial fibrillation progression by activating Connexin43. Int J Cardiol. 2016;208:56–7. doi: 10.1016/j.ijcard.2016.01.201.
    1. Kim YG, Han KD, Choi JI, Boo KY, Kim DY, Oh SK, Lee KN, Shim J, Kim JS, Kim YH. The impact of body weight and diabetes on new-onset atrial fibrillation: a nationwide population based study. Cardiovasc Diabetol. 2019;18(1):128. doi: 10.1186/s12933-019-0932-z.
    1. Packer M. Disease-treatment interactions in the management of patients with obesity and diabetes who have atrial fibrillation: the potential mediating influence of epicardial adipose tissue. Cardiovasc Diabetol. 2019;18(1):121. doi: 10.1186/s12933-019-0927-9.
    1. Zhang XD, Lieu DK, Chiamvimonvat N. Small-conductance Ca2+ -activated K + channels and cardiac arrhythmias. Heart Rhythm. 2015;12(8):1845–51. doi: 10.1016/j.hrthm.2015.04.046.
    1. Fu X, Pan Y, Cao Q, Li B, Wang S, Du H, Duan N, Li X. Metformin restores electrophysiology of small conductance calcium-activated potassium channels in the atrium of GK diabetic rats. BMC Cardiovasc Disord. 2018;18(1):63. doi: 10.1186/s12872-018-0805-5.
    1. Zhang XD, Timofeyev V, Li N, Myers RE, Zhang DM, Singapuri A, Lau VC, Bond CT, Adelman J, Lieu DK, et al. Critical roles of a small conductance Ca(2)(+)-activated K(+) channel (SK3) in the repolarization process of atrial myocytes. Cardiovasc Res. 2014;101(2):317–25. doi: 10.1093/cvr/cvt262.
    1. Liou YS, Yang FY, Chen HY, Jong GP. Antihyperglycemic drugs use and new-onset atrial fibrillation: a population-based nested case control study. PLoS One. 2018;13(8):e0197245. doi: 10.1371/journal.pone.0197245.
    1. Davis TM, Parsons RW, Broadhurst RJ, Hobbs MS, Jamrozik K. Arrhythmias and mortality after myocardial infarction in diabetic patients. Relationship to diabetes treatment. Diabetes Care. 1998;21(4):637–40. doi: 10.2337/diacare.21.4.637.
    1. Chen HY, Yang FY, Jong GP, Liou YS. Antihyperglycemic drugs use and new-onset atrial fibrillation in elderly patients. Eur J Clin Invest. 2017;47(5):388–93. doi: 10.1111/eci.12754.
    1. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, Heckbert SR. Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J Gen Intern Med. 2010;25(8):853–8. doi: 10.1007/s11606-010-1340-y.
    1. Anyukhovsky EP, Sosunov EA, Chandra P, Rosen TS, Boyden PA, Danilo P, Jr, Rosen MR. Age-associated changes in electrophysiologic remodeling: a potential contributor to initiation of atrial fibrillation. Cardiovasc Res. 2005;66(2):353–63. doi: 10.1016/j.cardiores.2004.10.033.
    1. Anyukhovsky EP, Sosunov EA, Plotnikov A, Gainullin RZ, Jhang JS, Marboe CC, Rosen MR. Cellular electrophysiologic properties of old canine atria provide a substrate for arrhythmogenesis. Cardiovasc Res. 2002;54(2):462–9. doi: 10.1016/S0008-6363(02)00271-7.
    1. Mostafa A, El-Haddad MA, Shenoy M, Tuliani T. Atrial fibrillation post cardiac bypass surgery. Avicenna J Med. 2012;2(3):65–70. doi: 10.4103/2231-0770.102280.
    1. Oktay V, Baydar O, Sinan UY, Kocas C, Abaci O, Yildiz A, Yigit Z, Yildiz CE, Hatemi A, Cetin G, et al. The effect of oxidative stress related with ischemia-reperfusion damage on the pathogenesis of atrial fibrillation developing after coronary artery bypass graft surgery. Turk Kardiyol Dern Ars. 2014;42(5):419–25. doi: 10.5543/tkda.2014.84032.
    1. Apaijai N, Chinda K, Palee S, Chattipakorn S, Chattipakorn N. Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats. PLoS One. 2014;9(7):e102374. doi: 10.1371/journal.pone.0102374.
    1. Chakraborty A, Chowdhury S, Bhattacharyya M. Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract. 2011;93(1):56–62. doi: 10.1016/j.diabres.2010.11.030.
    1. Diaz-Morales N, Rovira-Llopis S, Banuls C, Lopez-Domenech S, Escribano-Lopez I, Veses S, Jover A, Rocha M, Hernandez-Mijares A, Victor VM. Does metformin protect diabetic patients from oxidative stress and leukocyte-endothelium interactions? Antioxid Redox Signal. 2017;27(17):1439–45. doi: 10.1089/ars.2017.7122.
    1. Esteghamati A, Eskandari D, Mirmiranpour H, Noshad S, Mousavizadeh M, Hedayati M, Nakhjavani M. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr. 2013;32(2):179–85. doi: 10.1016/j.clnu.2012.08.006.
    1. Malinska H, Oliyarnyk O, Skop V, Silhavy J, Landa V, Zidek V, Mlejnek P, Simakova M, Strnad H, Kazdova L, et al. Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein. PLoS One. 2016;11(3):e0150924. doi: 10.1371/journal.pone.0150924.
    1. El Messaoudi S, Nederlof R, Zuurbier CJ, van Swieten HA, Pickkers P, Noyez L, Dieker HJ, Coenen MJ, Donders AR, Vos A, et al. Effect of metformin pretreatment on myocardial injury during coronary artery bypass surgery in patients without diabetes (MetCAB): a double-blind, randomised controlled trial. Lancet Diabetes Endocrinol. 2015;3(8):615–23. doi: 10.1016/S2213-8587(15)00121-7.
    1. Basnet S, Kozikowski A, Sun H, Troup M, Urrutia LE, Pekmezaris R. Metformin therapy and postoperative atrial fibrillation in diabetic patients after cardiac surgery. J Intensive Care. 2017;5:60. doi: 10.1186/s40560-017-0254-8.
    1. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;15(10):e190–252. doi: 10.1016/j.hrthm.2017.10.035.
    1. Prenner SB, Shah SJ, Goldberger JJ, Sauer AJ. Repolarization heterogeneity: beyond the QT interval. J Am Heart Assoc. 2016;5(5):e003607. doi: 10.1161/JAHA.116.003607.
    1. Nishiyama A, Ishii DN, Backx PH, Pulford BE, Birks BR, Tamkun MM. Altered K(+) channel gene expression in diabetic rat ventricle: isoform switching between Kv4.2 and Kv1.4. Am J Physiol Heart Circ Physiol. 2001;281(4):H1800–H1807. doi: 10.1152/ajpheart.2001.281.4.H1800.
    1. Shimoni Y, Severson D, Ewart HS. Insulin resistance and the modulation of rat cardiac K(+) currents. Am J Physiol Heart Circ Physiol. 2000;279(2):H639–49. doi: 10.1152/ajpheart.2000.279.2.H639.
    1. Yada H, Murata M, Shimoda K, Yuasa S, Kawaguchi H, Ieda M, Adachi T, Murata M, Ogawa S, Fukuda K. Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2 + channels in the heart. Circ Res. 2007;101(1):69–77. doi: 10.1161/CIRCRESAHA.106.146399.
    1. Brown DW, Giles WH, Greenlund KJ, Valdez R, Croft JB. Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the Third National Health and Nutrition Examination Survey. J Cardiovasc Risk. 2001;8(4):227–33. doi: 10.1097/00043798-200108000-00007.
    1. Christensen PK, Gall MA, Major-Pedersen A, Sato A, Rossing P, Breum L, Pietersen A, Kastrup J, Parving HH. QTc interval length and QT dispersion as predictors of mortality in patients with non-insulin-dependent diabetes. Scand J Clin Lab Invest. 2000;60(4):323–32. doi: 10.1080/003655100750046486.
    1. Sawicki PT, Kiwitt S, Bender R, Berger M. The value of QT interval dispersion for identification of total mortality risk in non-insulin-dependent diabetes mellitus. J Intern Med. 1998;243(1):49–56. doi: 10.1046/j.1365-2796.1998.00259.x.
    1. Costa EC, Goncalves AA, Areas MA, Morgabel RG. Effects of metformin on QT and QTc interval dispersion of diabetic rats. Arq Bras Cardiol. 2008;90(4):232–8. doi: 10.1590/S0066-782X2008000400004.
    1. Wang H, Wang C, Lu Y, Yan Y, Leng D, Tian S, Zheng D, Wang Z, Bai Y. Metformin shortens prolonged QT interval in diabetic mice by inhibiting L-type calcium current: a possible therapeutic approach. Front Pharmacol. 2020;11:614. doi: 10.3389/fphar.2020.00614.
    1. Lv L, Zheng N, Zhang L, Li R, Li Y, Yang R, Li C, Fang R, Shabanova A, Li X, et al. Metformin ameliorates cardiac conduction delay by regulating microRNA-1 in mice. Eur J Pharmacol. 2020;881:173131. doi: 10.1016/j.ejphar.2020.173131.
    1. Danik SB, Rosner G, Lader J, Gutstein DE, Fishman GI, Morley GE. Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts. FASEB J. 2008;22(4):1204–12. doi: 10.1096/fj.07-8974com.
    1. Poelzing S, Rosenbaum DS. Altered connexin43 expression produces arrhythmia substrate in heart failure. Am J Physiol Heart Circ Physiol. 2004;287(4):H1762–70. doi: 10.1152/ajpheart.00346.2004.
    1. Roell W, Lewalter T, Sasse P, Tallini YN, Choi BR, Breitbach M, Doran R, Becher UM, Hwang SM, Bostani T, et al. Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature. 2007;450(7171):819–24. doi: 10.1038/nature06321.
    1. Surinkaew S, Kumphune S, Chattipakorn S, Chattipakorn N. Inhibition of p38 MAPK during ischemia, but not reperfusion, effectively attenuates fatal arrhythmia in ischemia/reperfusion heart. J Cardiovasc Pharmacol. 2013;61(2):133–41. doi: 10.1097/FJC.0b013e318279b7b1.
    1. Jackson PE, Feng QP, Jones DL. Nitric oxide depresses connexin 43 after myocardial infarction in mice. Acta Physiol (Oxf) 2008;194(1):23–33. doi: 10.1111/j.1748-1716.2008.01858.x.
    1. Yin M, van der Horst IC, van Melle JP, Qian C, van Gilst WH, Sillje HH, de Boer RA. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol. 2011;301(2):H459–68. doi: 10.1152/ajpheart.00054.2011.
    1. Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes. 2008;57(3):696–705. doi: 10.2337/db07-1098.
    1. Lu L, Ye S, Scalzo RL, Reusch JEB, Greyson CR, Schwartz GG. Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs. Diabetologia. 2017;60(8):1550–8. doi: 10.1007/s00125-017-4287-2.
    1. Weidner K, Behnes M, Schupp T, Rusnak J, Reiser L, Bollow A, Taton G, Reichelt T, Ellguth D, Engelke N, et al. Type 2 diabetes is independently associated with all-cause mortality secondary to ventricular tachyarrhythmias. Cardiovasc Diabetol. 2018;17(1):125. doi: 10.1186/s12933-018-0768-y.
    1. Marfella R, Rossi F, Giugliano D. QTc dispersion, hyperglycemia, and hyperinsulinemia. Circulation. 1999;100(25):e149. doi: 10.1161/01.CIR.100.25.e149.
    1. Tran HV, Gore JM, Darling CE, Ash AS, Kiefe CI, Goldberg RJ. Hyperglycemia and risk of ventricular tachycardia among patients hospitalized with acute myocardial infarction. Cardiovasc Diabetol. 2018;17(1):136. doi: 10.1186/s12933-018-0779-8.
    1. Jardine DL, Charles CJ, Frampton CM, Richards AM. Cardiac sympathetic nerve activity and ventricular fibrillation during acute myocardial infarction in a conscious sheep model. Am J Physiol Heart Circ Physiol. 2007;293(1):H433–9. doi: 10.1152/ajpheart.01262.2006.
    1. Najeed SA, Khan IA, Molnar J, Somberg JC. Differential effect of glyburide (glibenclamide) and metformin on QT dispersion: a potential adenosine triphosphate sensitive K + channel effect. Am J Cardiol. 2002;90(10):1103–6. doi: 10.1016/S0002-9149(02)02776-5.
    1. Cacciapuoti F, Spiezia R, Bianchi U, Lama D, D’Avino M, Varricchio M. Effectiveness of glibenclamide on myocardial ischemic ventricular arrhythmias in non-insulin-dependent diabetes mellitus. Am J Cardiol. 1991;67(9):843–7. doi: 10.1016/0002-9149(91)90617-T.
    1. Targeting Risk Interventions and Metformin for Atrial Fibrillation (TRIM-AF). .
    1. Metformin as an Upstream Therapy in Atrial Fibrillation. .

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere