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SCIENCE CHINA Life Sciences, Volume 60, Issue 4: 348-355(2017) https://doi.org/10.1007/s11427-016-9005-6

Mechanistic and therapeutic perspectives for cardiac arrhythmias: beyond ion channels

Yufei Wu1,2,3, Jun Li1,2,3, Liang Xu1,2, Li Lin1,2,*, Yi-Han Chen1,2,3,4,*
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  • ReceivedNov 11, 2016
  • AcceptedDec 20, 2016
  • PublishedMar 24, 2017

Abstract

Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness, and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias.


Funded by

Major International Joint Research Program of China(81120108004 to Yi-Han Chen)

General Program of National Natural Science Foundation of China(81170224)

Key Program of National Natural Science Foundation of China(81530017 to Yi-Han Chen)

National Natural Science Foundation of China(81670295 to Li Lin)

National Innovative Research Groups Program of the National Natural Science Foundation of China(81221001 to Yi-Han Chen)

National Key Basic Research Program of China(2013CB531100 to Yi-Han Chen)


Acknowledgment

This work was supported by the National Key Basic Research Program of China (2013CB531100 to Yi-Han Chen), the Major International Joint Research Program of China (81120108004 to Yi-Han Chen), the Key Program of National Natural Science Foundation of China (81530017 to Yi-Han Chen), the National Innovative Research Groups Program of the National Natural Science Foundation of China (81221001 to Yi-Han Chen), the General Program of National Natural Science Foundation of China (81170224, 81270313 to Jun Li, 31271214 to Yi-Han Chen), and the National Natural Science Foundation of China (81670295 to Li Lin).


Interest statement

The author(s) declare that they have no conflict of interest.


References

[1] Ackerman M.J., Clapham D.E.. Ion channels—basic science and clinical disease. N Engl J Med, 1997, 336: 1575-1586 CrossRef PubMed Google Scholar

[2] Ai X., Curran J.W., Shannon T.R., Bers D.M., Pogwizd S.M.. Ca2+/Calmodulin-dependent protein kinase modulates cardiac ryanodine receptor phosphorylation and sarcoplasmic reticulum Ca2+ leak in heart failure. Circulation Res, 2005, 97: 1314-1322 CrossRef PubMed Google Scholar

[3] Akar F.G., Aon M.A., Tomaselli G.F., O'Rourke B.. The mitochondrial origin of postischemic arrhythmias. J Clinical Investigation, 2005, 115: 3527-3535 CrossRef PubMed Google Scholar

[4] Akhmanova A., Steinmetz M.O.. Control of microtubule organization and dynamics: two ends in the limelight. Nat Rev Mol Cell Biol, 2015, 16: 711-726 CrossRef PubMed Google Scholar

[5] Bell J.R., Raaijmakers A.J.A., Curl C.L., Reichelt M.E., Harding T.W., Bei A., Ng D.C.H., Erickson J.R., Vila Petroff M., Harrap S.B., Delbridge L.M.D.. Cardiac CaMKIIδ splice variants exhibit target signaling specificity and confer sex-selective arrhythmogenic actions in the ischemic-reperfused heart. Int J Cardiology, 2015, 181: 288-296 CrossRef PubMed Google Scholar

[6] Bers D.M.. Cardiac excitation—contraction coupling. Nature, 2002, 415: 198-205 CrossRef PubMed ADS Google Scholar

[7] Brenyo A., Aktas M.K.. Review of complementary and alternative medical treatment of arrhythmias. Am J Cardiology, 2014, 113: 897-903 CrossRef PubMed Google Scholar

[8] Brown D.A., O'Rourke B.. Cardiac mitochondria and arrhythmias. Cardiovascular Res, 2010, 88: 241-249 CrossRef PubMed Google Scholar

[9] Chen W., Wang R., Chen B., Zhong X., Kong H., Bai Y., Zhou Q., Xie C., Zhang J., Guo A., Tian X., Jones P.P., O'Mara M.L., Liu Y., Mi T., Zhang L., Bolstad J., Semeniuk L., Cheng H., Zhang J., Chen J., Tieleman D.P., Gillis A.M., Duff H.J., Fill M., Song L.S., Chen S.R.W.. The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias. Nat Med, 2014, 20: 184-192 CrossRef PubMed Google Scholar

[10] Curran J., Brown K.H., Santiago D.J., Pogwizd S., Bers D.M., Shannon T.R.. Spontaneous Ca waves in ventricular myocytes from failing hearts depend on Ca2+-calmodulin-dependent protein kinase II. J Mol Cellular Cardiology, 2010, 49: 25-32 CrossRef PubMed Google Scholar

[11] Curran J., Hinton M.J., Ríos E., Bers D.M., Shannon T.R.. b-Adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase. Circulation Res, 2007, 100: 391-398 CrossRef PubMed Google Scholar

[12] Curran J., Mohler P.J.. Alternative paradigms for ion channelopathies: disorders of ion channel membrane trafficking and posttranslational modification. Annu Rev Physiol, 2015, 77: 505-524 CrossRef PubMed Google Scholar

[13] Delisle B.P., Anson B.D., Rajamani S., January C.T.. Biology of cardiac arrhythmias: ion channel protein trafficking. Circulation Res, 2004, 94: 1418-1428 CrossRef PubMed Google Scholar

[14] Drago I., De Stefani D., Rizzuto R., Pozzan T.. Mitochondrial Ca2+ uptake contributes to buffering cytoplasmic Ca2+ peaks in cardiomyocytes. Proc Natl Acad Sci USA, 2012, 109: 12986-12991 CrossRef PubMed ADS Google Scholar

[15] Erickson J.R., He B.J., Grumbach I.M., Anderson M.E.. CaMKII in the cardiovascular system: sensing redox states. Physiol Rev, 2011, 91: 889-915 CrossRef PubMed Google Scholar

[16] Ferguson, S.M., and De Camilli, P. (2012). Dynamin, a membrane remodelling GTPase. Nat Rev Mol Cell Biol 13, 75–88.. Google Scholar

[17] Fischer T.H., Eiringhaus J., Dybkova N., Förster A., Herting J., Kleinwächter A., Ljubojevic S., Schmitto J.D., Streckfuß-Bömeke K., Renner A., Gummert J., Hasenfuss G., Maier L.S., Sossalla S.. Ca2+/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca2+ leak in human ischaemic and dilated cardiomyopathy. Eur J Heart Fail, 2014, 16: 1292-1300 CrossRef PubMed Google Scholar

[18] Grimm M., Ling H., Willeford A., Pereira L., Gray C.B.B., Erickson J.R., Sarma S., Respress J.L., Wehrens X.H.T., Bers D.M., Brown J.H.. CaMKII d mediates b-adrenergic effects on RyR2 phosphorylation and SR Ca2+ leak and the pathophysiological response to chronic b-adrenergic stimulation. J Mol Cellular Cardiology, 2015, 85: 282-291 CrossRef PubMed Google Scholar

[19] Harkcom W.T., Abbott G.W.. Emerging concepts in the pharmacogenomics of arrhythmias: ion channel trafficking. Expert Rev Cardiovascular Therapy, 2010, 8: 1161-1173 CrossRef PubMed Google Scholar

[20] Hilliard F.A., Steele D.S., Laver D., Yang Z., Le Marchand S.J., Chopra N., Piston D.W., Huke S., Knollmann B.C.. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J Mol Cellular Cardiology, 2010, 48: 293-301 CrossRef PubMed Google Scholar

[21] Hubner C.A., Jentsch T.J.. Ion channel diseases. Human Mol Genets, 2002, 11: 2435-2445 CrossRef Google Scholar

[22] Li H., Guo W., Mellor R.L., Nerbonne J.M.. KChIP2 modulates the cell surface expression of Kv1.5-encoded K channels. J Mol Cellular Cardiology, 2005, 39: 121-132 CrossRef PubMed Google Scholar

[23] Li J., Li C., Liang D., Lv F., Yuan T., The E., Ma X., Wu Y., Zhen L., Xie D., Wang S., Liu Y., Huang J., Shi J., Liu Y., Shi D., Xu L., Lin L., Peng L., Cui J., Zhu W., Chen Y.H.. LRP6 acts as a scaffold protein in cardiac gap junction assembly. Nat Commun, 2016, 7: 11775 CrossRef PubMed ADS Google Scholar

[24] Li J., Xiao J., Liang D., Zhang H., Zhang G., Liu Y., Zhang Y., Liu Y., Yu Z., Yan B., Jiang B., Li F., Peng L., Zhou Z.N., Chen Y.H.. Inhibition of mitochondrial translocator protein prevents atrial fibrillation. Eur J Pharmacology, 2010, 632: 60-64 CrossRef PubMed Google Scholar

[25] Li J., Xie D., Huang J., Lv F., Shi D., Liu Y., Lin L., Geng L., Wu Y., Liang D., Chen Y.H.. Cold-inducible RNA-binding protein regulates cardiac repolarization by targeting transient outward potassium channels. Circulation Res, 2015, 116: 1655-1659 CrossRef PubMed Google Scholar

[26] Li J., Xu J., Xiao J., Zhang H., Liang D., Liu Y., Zhang Y., Liu Y., Wen W., Hu Y., Yu Z., Yan B., Jiang B., Zhou Z.N., Chen Y.H.. Preservation of TSPO by chronic intermittent hypobaric hypoxia confers antiarrhythmic activity. J Cellular Mol Med, 2011, 15: 134-140 CrossRef PubMed Google Scholar

[27] Li, J., Xu, L., Ye, J., Li, X., Zhang, D., Liang, D., Xu, X., Qi, M., Li, C., Zhang, H., Wang, J., Liu, Y., Zhang, Y., Zhou, Z., Liang, X., Peng, L., Zhu, W., and Chen, Y.H. (2013a). Aberrant dynamin 2-dependent Na(+) /H(+) exchanger-1 trafficking contributes to cardiomyocyte apoptosis. J Cell Mol Med 17, 1119–1127. Google Scholar

[28] Li J., Zhang D.S., Ye J.C., Li C.M., Qi M., Liang D.D., Xu X.R., Xu L., Liu Y., Zhang H., Zhang Y.Y., Deng F.F., Feng J., Shi D., Chen J.J., Li L., Chen G., Sun Y.F., Peng L.Y., Chen Y.H.. Dynamin-2 mediates heart failure by modulating Ca2+-dependent cardiomyocyte apoptosis. Int J Cardiology, 2013b, 168: 2109-2119 CrossRef PubMed Google Scholar

[29] Liu G.S., Morales A., Vafiadaki E., Lam C.K., Cai W.F., Haghighi K., Adly G., Hershberger R.E., Kranias E.G.. A novel human R25C-phospholamban mutation is associated with super-inhibition of calcium cycling and ventricular arrhythmia. Cardiovascular Res, 2015, 107: 164-174 CrossRef PubMed Google Scholar

[30] Liu N., Ruan Y., Denegri M., Bachetti T., Li Y., Colombi B., Napolitano C., Coetzee W.A., Priori S.G.. Calmodulin kinase II inhibition prevents arrhythmias in RyR2R4496C+/− mice with catecholaminergic polymorphic ventricular tachycardia. J Mol Cellular Cardiology, 2011, 50: 214-222 CrossRef PubMed Google Scholar

[31] Luo, X., Zhang, H., Xiao, J., and Wang, Z. (2010). Regulation of human cardiac ion channel genes by microRNAs: theoretical perspective and pathophysiological implications. Cell Physiol Biochem 25, 571–586. Google Scholar

[32] Marx S.O., Reiken S., Hisamatsu Y., Jayaraman T., Burkhoff D., Rosemblit N., Marks A.R.. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor). Cell, 2000, 101: 365-376 CrossRef Google Scholar

[33] Mitchell P.. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature, 1961, 191: 144-148 CrossRef ADS Google Scholar

[34] Montaigne D., Maréchal X., Lacroix D., Staels B.. From cardiac mitochondrial dysfunction to clinical arrhythmias. Int J Cardiology, 2015, 184: 597-599 CrossRef PubMed Google Scholar

[35] Murphy, M.P. (2009). How mitochondria produce reactive oxygen species. Biochem J 4171, 13. Google Scholar

[36] Nattel S.. Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Cardiovascular Res, 1998, 37: 567-577 CrossRef Google Scholar

[37] Orchard, C., and Brette, F. (2008). t-Tubules and sarcoplasmic reticulum function in cardiac ventricular myocytes. Cardiovasc Res 77, 237-244.. Google Scholar

[38] Page, R.L., and Roden, D.M. (2005). Drug therapy for atrial fibrillation: where do we go from here? Nat Rev Drug Discov 4, 899-910.. Google Scholar

[39] Podrid P.J., Lampert S., Graboys T.B., Blatt C.M., Lown B.. Aggravation of arrhythmia by antiarrhythmic drugs—Incidence and predictors. Am J Cardiology, 1987, 59: E38-E44 CrossRef Google Scholar

[40] Priori S.G., Chen S.R.W.. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circulation Res, 2011, 108: 871-883 CrossRef PubMed Google Scholar

[41] Priori S.G., Napolitano C., Tiso N., Memmi M., Vignati G., Bloise R., Sorrentino V., Danieli G.A.. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation, 2001, 103: 196-200 CrossRef Google Scholar

[42] Purohit A., Rokita A.G., Guan X., Chen B., Koval O.M., Voigt N., Neef S., Sowa T., Gao Z., Luczak E.D., Stefansdottir H., Behunin A.C., Li N., El-Accaoui R.N., Yang B., Swaminathan P.D., Weiss R.M., Wehrens X.H.T., Song L.S., Dobrev D., Maier L.S., Anderson M.E.. Oxidized Ca2+/calmodulin-dependent protein kinase II triggers atrial fibrillation. Circulation, 2013, 128: 1748-1757 CrossRef PubMed Google Scholar

[43] Roden D.M.. Cellular basis of drug-induced torsades de pointes. British J Pharmacology, 2008, 154: 1502-1507 CrossRef PubMed Google Scholar

[44] Sacherer M., Sedej S., Wakuła P., Wallner M., Vos M.A., Kockskämper J., Stiegler P., Sereinigg M., von Lewinski D., Antoons G., Pieske B.M., Heinzel F.R., Heinzel F.R.. JTV519 (K201) reduces sarcoplasmic reticulum Ca2+leak and improves diastolic functionin vitro in murine and human non-failing myocardium. British J Pharmacology, 2012, 167: 493-504 CrossRef PubMed Google Scholar

[45] Sato H., Hori M., Kitakaze M., Iwai K., Takashima S., Kurihara H., Inoue M., Kamada T.. Reperfusion after brief ischemia disrupts the microtubule network in canine hearts. Circulation Res, 1993, 72: 361-375 CrossRef Google Scholar

[46] Schaper J., Meiser E., Stammler G.. Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice, and from human hearts. Circulation Res, 1985, 56: 377-391 CrossRef Google Scholar

[47] Schramm, M., Klieber, H.G., and Daut, J. (1994). The energy expenditure of actomyosin-ATPase, Ca(2+)-ATPase and Na+, K(+)-ATPase in guinea-pig cardiac ventricular muscle. J Physiol 481(Pt 3), 647–662. Google Scholar

[48] Shattock M.J., Ottolia M., Bers D.M., Blaustein M.P., Boguslavskyi A., Bossuyt J., Bridge J.H.B., Chen-Izu Y., Clancy C.E., Edwards A., Goldhaber J., Kaplan J., Lingrel J.B., Pavlovic D., Philipson K., Sipido K.R., Xie Z.J.. Na+/Ca2+exchange and Na+/K+ -ATPase in the heart. J Physiol, 2015, 593: 1361-1382 CrossRef Google Scholar

[49] Shi D., Xie D., Zhang H., Zhao H., Huang J., Li C., Liu Y., Lv F., The E., Liu Y., Yuan T., Wang S., Chen J., Pan L., Yu Z., Liang D., Zhu W., Zhang Y., Li L., Peng L., Li J., Chen Y.H.. Reduction in dynamin-2 is implicated in ischaemic cardiac arrhythmias. J Cell Mol Med, 2014, 18: 1992-1999 CrossRef PubMed Google Scholar

[50] Shibata R., Misonou H., Campomanes C.R., Anderson A.E., Schrader L.A., Doliveira L.C., Carroll K.I., Sweatt J.D., Rhodes K.J., Trimmer J.S.. A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels. J Biol Chem, 2003, 278: 36445-36454 CrossRef PubMed Google Scholar

[51] Sumitomo N.. Current topics in catecholaminergic polymorphic ventricular tachycardia. J Arrhythmia, 2016, 32: 344-351 CrossRef PubMed Google Scholar

[52] Swaminathan P.D., Purohit A., Soni S., Voigt N., Singh M.V., Glukhov A.V., Gao Z., He B.J., Luczak E.D., Joiner M.A., Kutschke W., Yang J., Donahue J.K., Weiss R.M., Grumbach I.M., Ogawa M., Chen P.S., Efimov I., Dobrev D., Mohler P.J., Hund T.J., Anderson M.E.. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J Clin Invest, 2011, 121: 3277-3288 CrossRef PubMed Google Scholar

[53] Vaughan Williams, E.M. (1970). The experimental basis for the choice of an anti-arrhythmic drug. Adv Cardiol 4, 275–289. Google Scholar

[54] Watanabe H., Chopra N., Laver D., Hwang H.S., Davies S.S., Roach D.E., Duff H.J., Roden D.M., Wilde A.A.M., Knollmann B.C.. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med, 2009, 15: 380-383 CrossRef PubMed Google Scholar

[55] Wehrens X.H.T., Lehnart S.E., Reiken S.R., Deng S.X., Vest J.A., Cervantes D., Coromilas J., Landry D.W., Marks A.R.. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science, 2004, 304: 292-296 CrossRef PubMed ADS Google Scholar

[56] Xiao J., Cao H., Liang D., Liu Y., Zhang H., Zhao H., Liu Y., Li J., Yan B., Peng L., Zhou Z., Chen Y.H.. Taxol, a microtubule stabilizer, prevents ischemic ventricular arrhythmias in rats. J Cellular Mol Med, 2011, 15: 1166-1176 CrossRef PubMed Google Scholar

[57] Xiao, J., Liang, D., Liu, Y., Zhang, H., Zhao, H., Li, J., Peng, L., Zhou, Z., and Chen, Y.H. (2012). Taxol, a microtubule stabilizer, improves cardiac functional recovery during postischemic reperfusion in rat in vitro. Cardiovasc Ther 30, 12–30. Google Scholar

[58] Xiao J., Liang D., Zhang H., Liu Y., Li F., Chen Y.H.. 4′-Chlorodiazepam, a translocator protein (18 kDa) antagonist, improves cardiac functional recovery during postischemia reperfusion in rats. Exp Biol Med, 2010a, 235: 478-486 CrossRef PubMed Google Scholar

[59] Xiao, J., Zhang, H., Liang, D., Liu, Y., Zhao, H., Li, J., Peng, L., and Chen, Y.H. (2010b). Taxol, a microtubule stabilizer, prevents atrial fibrillation in in vitro atrial fibrillation models using rabbit hearts. Med Sci Monit 16, BR353–360. Google Scholar

[60] Yang K.C., Bonini M.G., Dudley Jr. S.C.. Mitochondria and arrhythmias. Free Radical Biol Med, 2014, 71: 351-361 CrossRef PubMed Google Scholar

[61] Yang K.C., Kyle J.W., Makielski J.C., Dudley S.C.. Mechanisms of sudden cardiac death: oxidants and metabolism. Circulation Res, 2015, 116: 1937-1955 CrossRef PubMed Google Scholar

[62] Zhao, Y., Huang, Y., Li, W., Wang, Z., Zhan, S., Zhou, M., Yao, Y., Zeng, Z., Hou, Y., Chen, Q., Tu, X., Wang, Q., and Huang, Z. (2015). Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p. Biochim Biophys Acta 1852, 2024–2034. Google Scholar

[63] Zhou Q., Xiao J., Jiang D., Wang R., Vembaiyan K., Wang A., Smith C.D., Xie C., Chen W., Zhang J., Tian X., Jones P.P., Zhong X., Guo A., Chen H., Zhang L., Zhu W., Yang D., Li X., Chen J., Gillis A.M., Duff H.J., Cheng H., Feldman A.M., Song L.S., Fill M., Back T.G., Chen S.R.W.. Carvedilol and its new analogs suppress arrhythmogenic store overload—induced Ca2+ release. Nat Med, 2011, 17: 1003-1009 CrossRef PubMed Google Scholar

[64] Zipes, D.P., and Jalife, J. (2004). Cardiac Electrophysiology: From Cell to Bedside (4th edn). (Philadelphia: Saunders). Google Scholar

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