1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Physiology
  4. Volume 77, 2015
  5. Article

Annual Review of Physiology

Volume 77, 2015

Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence

Abstract

Ventricular arrhythmias have complex causes and mechanisms. Despite extensive investigation involving many clinical, experimental, and computational studies, effective biological therapeutics are still very limited. In this article, we review our current understanding of the mechanisms of ventricular arrhythmias by summarizing the state of knowledge spanning from the molecular scale to electrical wave behavior at the tissue and organ scales and how the complex nonlinear interactions integrate into the dynamics of arrhythmias in the heart. We discuss the challenges that we face in synthesizing these dynamics to develop safe and effective novel therapeutic approaches.

Keyword(s): chaos, multiscale dynamics, nonlinear dynamics, sudden cardiac death, ventricular arrhythmias
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-021014-071622
2015-02-10
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/physiol/77/1/annurev-physiol-021014-071622.html?itemId=/content/journals/10.1146/annurev-physiol-021014-071622&mimeType=html&fmt=ahah

Literature Cited

  1. Janse MJ, Rosen MR. 1.  2006. History of arrhythmias. Handb. Exp. Pharmacol. 2006:1–39 [Google Scholar]
  2. Jalife J. 2.  2000. Ventricular fibrillation: mechanisms of initiation and maintenance. Annu. Rev. Physiol. 62:25–50 [Google Scholar]
  3. Zipes DP, Wellens HJ. 3.  1998. Sudden cardiac death. Circulation 98:2334–51 [Google Scholar]
  4. Priori SG, Napolitano C. 4.  2004. Genetics of cardiac arrhythmias and sudden cardiac death. Ann. N. Y. Acad. Sci. 1015:96–110 [Google Scholar]
  5. Marsman RF, Tan HL, Bezzina CR. 5.  2014. Genetics of sudden cardiac death caused by ventricular arrhythmias. Nat. Rev. Cardiol. 11:96–111 [Google Scholar]
  6. CAST I. 6.  1989. Effect of encainide and flecainide on mortality in a random trial of arrhythmia suppression after myocardial infarction. N. Engl. J. Med. 321:406–12 [Google Scholar]
  7. Waldo AL, Camm AJ, deRuyter H, Friedman PL, Macneil DJ. 7.  et al. 1996. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 348:7–12 [Google Scholar]
  8. Myerburg RJ, Mitrani R, Interian A, Castellanos A. 8.  1998. Interpretation of outcomes of antiarrhythmic clinical trials: design features and population impact. Circulation 97:1514–21 [Google Scholar]
  9. Tung R, Zimetbaum P, Josephson ME. 9.  2008. A critical appraisal of implantable cardioverter-defibrillator therapy for the prevention of sudden cardiac death. J. Am. Coll. Cardiol. 52:1111–21 [Google Scholar]
  10. Qu Z, Hu G, Garfinkel A, Weiss JN. 10.  2014. Nonlinear and stochastic dynamics in the heart. Phys. Rep. 543:61–162 [Google Scholar]
  11. O'Reilly CM, Fogarty KE, Drummond RM, Tuft RA, Walsh JV. 11.  2003. Quantitative analysis of spontaneous mitochondrial depolarizations. Biophys. J. 85:3350–57 [Google Scholar]
  12. Aon MA, Cortassa S, Marban E, O'Rourke B. 12.  2003. Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J. Biol. Chem. 278:44735–44 [Google Scholar]
  13. Xie Y, Sato D, Garfinkel A, Qu Z, Weiss JN. 13.  2010. So little source, so much sink: requirements for afterdepolarizations to propagate in tissue. Biophys. J. 99:1408–15 [Google Scholar]
  14. Sato D, Xie LH, Sovari AA, Tran DX, Morita N. 14.  et al. 2009. Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias. PNAS 106:2983–88 [Google Scholar]
  15. Asano Y, Davidenko JM, Baxter WT, Gray RA, Jalife J. 15.  1997. Optical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart. J. Am. Coll. Cardiol. 29:831–42 [Google Scholar]
  16. Choi B-R, Burton F, Salama G. 16.  2002. Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J. Physiol. 543:615–31 [Google Scholar]
  17. de Lange E, Xie Y, Qu Z. 17.  2012. Synchronization of early afterdepolarizations and arrhythmogenesis in heterogeneous cardiac tissue models. Biophys. J. 103:365–73 [Google Scholar]
  18. Sato D, Xie LH, Nguyen TP, Weiss JN, Qu Z. 18.  2010. Irregularly appearing early afterdepolarizations in cardiac myocytes: random fluctuations or dynamical chaos?. Biophys. J. 99:765–73 [Google Scholar]
  19. Qu Z. 19.  2011. Chaos in the genesis and maintenance of cardiac arrhythmias. Prog. Biophys. Mol. Biol. 105:247–57 [Google Scholar]
  20. Cerrone M, Noujaim SF, Tolkacheva EG, Talkachou A, O'Connell R. 20.  et al. 2007. Arrhythmogenic mechanisms in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circ. Res. 101:1039–48 [Google Scholar]
  21. Baher AA, Uy M, Xie F, Garfinkel A, Qu Z, Weiss JN. 21.  2011. Bidirectional ventricular tachycardia: ping pong in the His–Purkinje system. Heart Rhythm 8:599–605 [Google Scholar]
  22. Mines GR. 22.  1914. On circulating excitation on heart muscles and their possible relation to tachycardia and fibrillation. Trans. R. Soc. Can. 4:43–52 [Google Scholar]
  23. Winfree AT. 23.  1972. Spiral waves of chemical activity. Science 175:634–36 [Google Scholar]
  24. Davidenko JM, Pertsov AM, Salomonsz R, Baxter W, Jalife J. 24.  1992. Stationary and drifting spiral waves of excitation in isolated cardiac muscle. Nature 355:349–51 [Google Scholar]
  25. Qu Z, Xie F, Garfinkel A, Weiss JN. 25.  2000. Origins of spiral wave meander and breakup in a two-dimensional cardiac tissue model. Ann. Biomed. Eng. 28:755–71 [Google Scholar]
  26. Wu TJ, Lin SF, Weiss JN, Ting CT, Chen PS. 26.  2002. Two types of ventricular fibrillation in isolated rabbit hearts—importance of excitability and action potential duration restitution. Circulation 106:1859–66 [Google Scholar]
  27. Moe GK, Rheinboldt WC, Abildskov JA. 27.  1964. A computer model of atrial fibrillation. Am. Heart J. 67:200–20 [Google Scholar]
  28. Chang MG, Sato D, de Lange E, Lee J-H, Karagueuzian HS. 28.  et al. 2012. Bi-stable wave propagation and early afterdepolarization–mediated cardiac arrhythmias. Heart Rhythm 9:115–22 [Google Scholar]
  29. Chang MG, de Lange E, Calmettes G, Garfinkel A, Qu Z, Weiss JN. 29.  2013. Pro- and antiarrhythmic effects of ATP-sensitive potassium current activation on reentry during early afterdepolarization–mediated arrhythmias. Heart Rhythm 10:575–82 [Google Scholar]
  30. Vandersickel N, Kazbanov IV, Nuitermans A, Weise LD, Pandit R, Panfilov AV. 30.  2014. A study of early afterdepolarizations in a model for human ventricular tissue. PLOS ONE 9:e84595 [Google Scholar]
  31. Gadsby DC, Cranefield PF. 31.  1977. Two levels of resting potential in cardiac Purkinje fibers. J. Gen. Physiol. 70:725–46 [Google Scholar]
  32. Yan G-X, Wu Y, Liu T, Wang J, Marinchak RA, Kowey PR. 32.  2001. Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome: direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 103:2851–56 [Google Scholar]
  33. Nguyen TP, Qu Z, Weiss JN. 33.  2014. Cardiac fibrosis and arrhythmogenesis: The road to repair is paved with perils. J. Mol. Cell. Cardiol. 70C:83–91 [Google Scholar]
  34. Rohr S, Kucera JP, Fast VG, Kleber AG. 34.  1997. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science 275:841–44 [Google Scholar]
  35. Janse MJ, Wit AL. 35.  1989. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol. Rev. 69:1046–169 [Google Scholar]
  36. Maruyama M, Lin SF, Xie Y, Chua SK, Joung B. 36.  et al. 2011. Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome. Circ. Arrhythm. Electrophysiol. 4:103–11 [Google Scholar]
  37. Lukas A, Antzelevitch C. 37.  1996. Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia. Cardiovasc. Res. 32:593–603 [Google Scholar]
  38. Yan GX, Antzelevitch C. 38.  1999. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 100:1660–66 [Google Scholar]
  39. Yan GX, Joshi A, Guo D, Hlaing T, Martin J. 39.  et al. 2004. Phase 2 reentry as a trigger to initiate ventricular fibrillation during early acute myocardial ischemia. Circulation 110:1036–41 [Google Scholar]
  40. Echebarria B, Karma A. 40.  2002. Instability and spatiotemporal dynamics of alternans in paced cardiac tissue. Phys. Rev. Lett. 88:208101 [Google Scholar]
  41. Qu Z, Garfinkel A, Chen PS, Weiss JN. 41.  2000. Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation 102:1664–70 [Google Scholar]
  42. Rosenbaum DS, Jackson LE, Smith JM, Garan H, Ruskin JN, Cohen RJ. 42.  1994. Electrical alternans and vulnerability to ventricular arrhythmias. N. Engl. J. Med. 330:235–41 [Google Scholar]
  43. Verrier RL, Klingenheben T, Malik M, El-Sherif N, Exner DV. 43.  et al. 2011. Microvolt T-wave alternans physiological basis, methods of measurement, and clinical utility—consensus guideline by International Society for Holter and Noninvasive Electrocardiology. J. Am. Coll. Cardiol. 58:1309–24 [Google Scholar]
  44. Qu Z, Xie Y, Garfinkel A, Weiss JN. 44.  2010. T-wave alternans and arrhythmogenesis in cardiac diseases. Front. Physiol. 1:154 [Google Scholar]
  45. Qu Z, Shiferaw Y, Weiss JN. 45.  2007. Nonlinear dynamics of cardiac excitation-contraction coupling: an iterated map study. Phys. Rev. E 75:011927 [Google Scholar]
  46. Chialvo DR, Gilmour RF, Jalife J. 46.  1990. Low dimensional chaos in cardiac tissue. Nature 343:653–57 [Google Scholar]
  47. Mahajan A, Shiferaw Y, Sato D, Baher A, Olcese R. 47.  et al. 2008. A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates. Biophys. J. 94:392–410 [Google Scholar]
  48. Lukas A, Antzelevitch C. 48.  1993. Differences in the electrophysiological response of canine ventricular epicardium and endocardium to ischemia. Role of the transient outward current. Circulation 88:2903–15 [Google Scholar]
  49. Hopenfeld B. 49.  2006. Mechanism for action potential alternans: the interplay between L-type calcium current and transient outward current. Heart Rhythm 3:345–52 [Google Scholar]
  50. Wegener FT, Ehrlich JR, Hohnloser SH. 50.  2008. Amiodarone-associated macroscopic T-wave alternans and torsade de pointes unmasking the inherited long QT syndrome. Europace 10:112–13 [Google Scholar]
  51. Antzelevitch C. 51.  2001. Heterogeneity of cellular repolarization in LQTS: the role of M cells. Eur. Heart J. Suppl. 3:K2–16 [Google Scholar]
  52. Qu Z, Chung D. 52.  2012. Mechanisms and determinants of ultralong action potential duration and slow rate-dependence in cardiac myocytes. PLOS ONE 7:e43587 [Google Scholar]
  53. Wagner S, Ruff HM, Weber SL, Bellmann S, Sowa T. 53.  et al. 2011. Reactive oxygen species–activated Ca/calmodulin kinase IIδ is required for late INa augmentation leading to cellular Na and Ca overload. Circ. Res. 108:555–65 [Google Scholar]
  54. Wasserstrom JA, Sharma R, O'Toole MJ, Zheng J, Kelly JE. 54.  et al. 2009. Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated intact heart. J. Pharmacol. Exp. Ther. 331:382–91 [Google Scholar]
  55. Song Y, Shryock JC, Belardinelli L. 55.  2008. An increase of late sodium current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes. Am. J. Physiol. Heart Circ. Physiol. 294:H2031–39 [Google Scholar]
  56. Qu Z, Nivala M, Weiss JN. 56.  2013. Calcium alternans in cardiac myocytes: order from disorder. J. Mol. Cell. Cardiol. 58:100–9 [Google Scholar]
  57. Escobar AL, Valdivia HH. 57.  2014. Cardiac alternans and ventricular fibrillation: a bad case of ryanodine receptors reneging on their duty. Circ. Res. 114:1369–71 [Google Scholar]
  58. Eisner DA, Choi HS, Diaz ME, O'Neill SC, Trafford AW. 58.  2000. Integrative analysis of calcium cycling in cardiac muscle. Circ. Res. 87:1087–94 [Google Scholar]
  59. Shiferaw Y, Watanabe MA, Garfinkel A, Weiss JN, Karma A. 59.  2003. Model of intracellular calcium cycling in ventricular myocytes. Biophys. J. 85:3666–86 [Google Scholar]
  60. Diaz ME, O'Neill SC, Eisner DA. 60.  2004. Sarcoplasmic reticulum calcium content fluctuation is the key to cardiac alternans. Circ. Res. 94:650–56 [Google Scholar]
  61. Li Y, Diaz ME, Eisner DA, O'Neill S. 61.  2009. The effects of membrane potential, SR Ca2+ content and RyR responsiveness on systolic Ca2+ alternans in rat ventricular myocytes. J. Physiol. 587:1283–92 [Google Scholar]
  62. Xie LH, Sato D, Garfinkel A, Qu Z, Weiss JN. 62.  2008. Intracellular Ca alternans: coordinated regulation by sarcoplasmic reticulum release, uptake, and leak. Biophys. J. 95:3100–10 [Google Scholar]
  63. Picht E, DeSantiago J, Blatter LA, Bers DM. 63.  2006. Cardiac alternans do not rely on diastolic sarcoplasmic reticulum calcium content fluctuations. Circ. Res. 99:740–48 [Google Scholar]
  64. Shkryl VM, Maxwell JT, Domeier TL, Blatter LA. 64.  2012. Refractoriness of sarcoplasmic reticulum Ca release determines Ca alternans in atrial myocytes. Am. J. Physiol. Heart Circ. Physiol. 302:H2310–20 [Google Scholar]
  65. Rovetti R, Cui X, Garfinkel A, Weiss JN, Qu Z. 65.  2010. Spark-induced sparks as a mechanism of intracellular calcium alternans in cardiac myocytes. Circ. Res. 106:1582–91 [Google Scholar]
  66. Nivala M, Qu Z. 66.  2012. Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load. Am. J. Physiol. Heart Circ. Physiol. 303:H341–52 [Google Scholar]
  67. Restrepo JG, Weiss JN, Karma A. 67.  2008. Calsequestrin-mediated mechanism for cellular calcium transient alternans. Biophys. J. 95:3767–89 [Google Scholar]
  68. Pastore JM, Girouard SD, Laurita KR, Akar FG, Rosenbaum DS. 68.  1999. Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. Circulation 99:1385–94 [Google Scholar]
  69. Hayashi H, Shiferaw Y, Sato D, Nihei M, Lin SF. 69.  et al. 2007. Dynamic origin of spatially discordant alternans in cardiac tissue. Biophys. J. 92:448–60 [Google Scholar]
  70. Mironov S, Jalife J, Tolkacheva EG. 70.  2008. Role of conduction velocity restitution and short-term memory in the development of action potential duration alternans in isolated rabbit hearts. Circulation 118:17–25 [Google Scholar]
  71. Pu JL, Balser JR, Boyden PA. 71.  1998. Lidocaine action on Na+ currents in ventricular myocytes from the epicardial border zone of the infarcted heart. Circ. Res. 83:431–40 [Google Scholar]
  72. Qu Z, Karagueuzian HS, Garfinkel A, Weiss JN. 72.  2004. Effects of Na+ channel and cell coupling abnormalities on vulnerability to reentry: a simulation study. Am. J. Physiol. Heart Circ. Physiol. 286:H1310–21 [Google Scholar]
  73. Keating MT, Sanguinetti MC. 73.  2001. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569–80 [Google Scholar]
  74. Liu GX, Choi B-R, Ziv O, Li W, de Lange E. 74.  et al. 2012. Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. J. Physiol. 590:1171–80 [Google Scholar]
  75. Nuss HB, Kaab S, Kass DA, Tomaselli GF, Marban E. 75.  1999. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am. J. Physiol. Heart Circ. Physiol. 277:H80–91 [Google Scholar]
  76. Li GR, Lau CP, Ducharme A, Tardif JC, Nattel S. 76.  2002. Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. Am. J. Physiol. Heart Circ. Physiol. 283:H1031–41 [Google Scholar]
  77. Damiano BP, Rosen MR. 77.  1984. Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation 69:1013–25 [Google Scholar]
  78. January CT, Riddle JM. 78.  1989. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ. Res. 64:977–90 [Google Scholar]
  79. January CT, Moscucci A. 79.  1992. Cellular mechanisms of early afterdepolarizations. Ann. N. Y. Acad. Sci. 644:23–32 [Google Scholar]
  80. Zeng J, Rudy Y. 80.  1995. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys. J. 68:949–64 [Google Scholar]
  81. Roden DM. 81.  1998. Taking the “idio” out of “idiosyncratic”: predicting torsades de pointes. Pacing Clin. Electrophysiol. 21:1029–34 [Google Scholar]
  82. Qu Z, Xie L-H, Olcese R, Karagueuzian HS, Chen P-S. 82.  et al. 2013. Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve. Cardiovasc. Res. 99:6–15 [Google Scholar]
  83. Volders PG, Vos MA, Szabo B, Sipido KR, de Groot SH. 83.  et al. 2000. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc. Res. 46:376–92 [Google Scholar]
  84. Zhao Z, Wen H, Fefelova N, Allen C, Baba A. 84.  et al. 2012. Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: predominant by Ca waves or Ca currents?. Am. J. Physiol. Heart Circ. Physiol. 302:H1636–44 [Google Scholar]
  85. Burashnikov A, Antzelevitch C. 85.  2003. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization–induced triggered activity. Circulation 107:2355–60 [Google Scholar]
  86. Maruyama M, Ai T, Chua S-K, Park H-W, Lee Y-S. 86.  et al. 2014. Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles. Heart Rhythm 11:697–706 [Google Scholar]
  87. Yeh YH, Wakili R, Qi XY, Chartier D, Boknik P. 87.  et al. 2008. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ. Arrhythm. Electrophysiol. 1:93–102 [Google Scholar]
  88. ter Keurs HEDJ, Boyden PA. 88.  2007. Calcium and arrhythmogenesis. Physiol. Rev. 87:457–506 [Google Scholar]
  89. Xie L-H, Chen F, Karagueuzian HS, Weiss JN. 89.  2009. Oxidative stress–induced afterdepolarizations and calmodulin kinase II signaling. Circ. Res. 104:79–86 [Google Scholar]
  90. Maruyama M, Joung B, Tang L, Shinohara T, On YK. 90.  et al. 2010. Diastolic intracellular calcium-membrane voltage coupling gain and postshock arrhythmias: role of Purkinje fibers and triggered activity. Circ. Res. 106:399–408 [Google Scholar]
  91. Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM. 91.  2001. Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual β-adrenergic responsiveness. Circ. Res. 88:1159–67 [Google Scholar]
  92. Pogwizd SM, Bers DM. 92.  2002. Calcium cycling in heart failure: the arrhythmia connection. J. Cardiovasc. Electrophysiol. 13:88–91 [Google Scholar]
  93. Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ. 93.  et al. 2010. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J. Mol. Cell. Cardiol. 48:293–301 [Google Scholar]
  94. Lehnart SE, Mongillo M, Bellinger A, Lindegger N, Chen BX. 94.  et al. 2008. Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J. Clin. Investig. 118:2230–45 [Google Scholar]
  95. Jiang D, Xiao B, Yang D, Wang R, Choi P. 95.  et al. 2004. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). PNAS 101:13062–67 [Google Scholar]
  96. Dirksen WP, Lacombe VA, Chi M, Kalyanasundaram A, Viatchenko-Karpinski S. 96.  et al. 2007. A mutation in calsequestrin, CASQ2D307H, impairs sarcoplasmic reticulum Ca2+ handling and causes complex ventricular arrhythmias in mice. Cardiovasc. Res. 75:69–78 [Google Scholar]
  97. Nivala M, Ko CY, Nivala M, Weiss JN, Qu Z. 97.  2012. Criticality in intracellular calcium signaling in cardiac myocytes. Biophys. J. 102:2433–42 [Google Scholar]
  98. Nivala M, Ko CY, Nivala M, Weiss JN, Qu Z. 98.  2013. The emergence of subcellular pacemaker sites for calcium waves and oscillations. J. Physiol. 591:5305–20 [Google Scholar]
  99. Rosen MR, Wit AL, Hoffman BF. 99.  1975. Electrophysiology and pharmacology of cardiac arrhythmias. IV. Cardiac antiarrhythmic and toxic effects of digitalis. Am. Heart J. 89:391–99 [Google Scholar]
  100. Surawicz B. 100.  1998. U wave: facts, hypotheses, misconceptions, and misnomers. J. Cardiovasc. Electrophysiol. 9:1117–28 [Google Scholar]
  101. di Bernardo D, Murray A. 101.  2002. Origin on the electrocardiogram of U-waves and abnormal U-wave inversion. Cardiovasc. Res. 53:202–8 [Google Scholar]
  102. Fujiwara K, Tanaka H, Mani H, Nakagami T, Takamatsu T. 102.  2008. Burst emergence of intracellular Ca2+ waves evokes arrhythmogenic oscillatory depolarization via the Na+-Ca2+ exchanger: simultaneous confocal recording of membrane potential and intracellular Ca2+ in the heart. Circ. Res. 103:509–18 [Google Scholar]
  103. Wasserstrom JA, Shiferaw Y, Chen W, Ramakrishna S, Patel H. 103.  et al. 2010. Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load. Circ. Res. 107:1117–26 [Google Scholar]
  104. Di Diego JM, Sun ZQ, Antzelevitch C. 104.  1996. I(to) and action potential notch are smaller in left versus right canine ventricular epicardium. Am. J. Physiol. Heart Circ. Physiol. 271:H548–61 [Google Scholar]
  105. Greenstein JL, Wu R, Po S, Tomaselli GF, Winslow RL. 105.  2000. Role of the calcium-independent transient outward current Ito1 in shaping action potential morphology and duration. Circ. Res. 87:1026–33 [Google Scholar]
  106. Maoz A, Krogh-Madsen T, Christini DJ. 106.  2009. Instability in action potential morphology underlies phase 2 reentry: a mathematical modeling study. Heart Rhythm 6:813–22 [Google Scholar]
  107. Cantalapiedra IR, Penaranda A, Mont L, Brugada J, Echebarria B. 107.  2009. Reexcitation mechanisms in epicardial tissue: role of Ito density heterogeneities and INa inactivation kinetics. J. Theor. Biol. 259:850–59 [Google Scholar]
  108. Miyoshi S, Mitamura H, Fujikura K, Fukuda Y, Tanimoto K. 108.  et al. 2003. A mathematical model of phase 2 reentry: role of L-type Ca current. Am. J. Physiol. Heart Circ. Physiol. 284:H1285–94 [Google Scholar]
  109. Di Diego JM, Antzelevitch C. 109.  1994. High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry. Circulation 89:1839–50 [Google Scholar]
  110. Antzelevitch C. 110.  1999. Ion channels and ventricular arrhythmias: cellular and ionic mechanisms underlying the Brugada syndrome. Curr. Opin. Cardiol. 14:274–79 [Google Scholar]
  111. Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJG, Verkerk AO. 111.  et al. 2005. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation 112:2769–77 [Google Scholar]
  112. Scherf D. 112.  1947. Studies on auricular tachycardia caused by aconitine administration. Proc. Soc. Exp. Biol. Med. 64:839–44 [Google Scholar]
  113. Silva J, Rudy Y. 113.  2003. Mechanism of pacemaking in IK1-downregulated myocytes. Circ. Res. 92:261–63 [Google Scholar]
  114. Miragoli M, Salvarani N, Rohr S. 114.  2007. Myofibroblasts induce ectopic activity in cardiac tissue. Circ. Res. 101:755–58 [Google Scholar]
  115. Lakatta EG, Maltsev VA, Vinogradova TM. 115.  2010. A coupled system of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ. Res. 106:659–73 [Google Scholar]
  116. Nguyen TP, Xie Y, Garfinkel A, Qu Z, Weiss JN. 116.  2012. Arrhythmogenic consequences of myofibroblast-myocyte coupling. Cardiovasc. Res. 93:242–51 [Google Scholar]
  117. Xie Y, Garfinkel A, Weiss JN, Qu Z. 117.  2009. Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models. Am. J. Physiol. Heart Circ. Physiol. 297:H775–84 [Google Scholar]
  118. Keener JP. 118.  2003. Model for the onset of fibrillation following coronary artery occlusion. J. Cardiovasc. Electrophysiol. 14:1225–32 [Google Scholar]
  119. Pinto JM, Boyden PA. 119.  1999. Electrical remodeling in ischemia and infarction. Cardiovasc. Res. 42:284–97 [Google Scholar]
  120. Madhvani RV, Xie Y, Pantazis A, Garfinkel A, Qu Z. 120.  et al. 2011. Shaping a new Ca2+ conductance to suppress early afterdepolarizations in cardiac myocytes. J. Physiol. 589:6081–92 [Google Scholar]
  121. Nerbonne JM. 121.  2000. Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J. Physiol. 525:Part 2285–98 [Google Scholar]
  122. Tuteja D, Xu D, Timofeyev V, Lu L, Sharma D. 122.  et al. 2005. Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 289:H2714–23 [Google Scholar]
  123. Chua SK, Chang PC, Maruyama M, Turker I, Shinohara T. 123.  et al. 2011. Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. Circ. Res. 108:971–79 [Google Scholar]
  124. Chang P-C, Hsieh Y-C, Hsueh C-H, Weiss JN, Lin S-F, Chen P-S. 124.  2013. Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium. Heart Rhythm 10:1516–24 [Google Scholar]
  125. Zhao Z, Xie Y, Wen H, Xiao D, Allen C. 125.  et al. 2012. Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells. Cardiovasc. Res. 95:308–16 [Google Scholar]
  126. Kaufman ES. 126.  2009. Mechanisms and clinical management of inherited channelopathies: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. Heart Rhythm 6:S51–55 [Google Scholar]
  127. Akar FG, Aon MA, Tomaselli GF, O'Rourke B. 127.  2005. The mitochondrial origin of postischemic arrhythmias. J. Clin. Investig. 115:3527–35 [Google Scholar]
  128. Tang L, Joung B, Ogawa M, Chen P-S, Lin S-F. 128.  2012. Intracellular calcium dynamics, shortened action potential duration, and late-phase 3 early afterdepolarization in Langendorff-perfused rabbit ventricles. J. Cardiovasc. Electrophysiol. 23:1364–71 [Google Scholar]
  129. Sugai Y, Miura M, Hirose M, Wakayama Y, Endoh H. 129.  et al. 2009. Contribution of Na+/Ca2+ exchange current to the formation of delayed afterdepolarizations in intact rat ventricular muscle. J. Cardiovasc. Pharmacol. 53:517–22 [Google Scholar]
  130. Rosen M, Danilo Jr P. 130.  1980. Digitalis-induced delayed afterdepolarizations. The Slow Inward Current and Cardiac Arrhythmias D Zipes, J Bailey, V Elharrar 417–35 Dordrecht, Neth.: Springer [Google Scholar]
  131. Verkerk AO, Tan HL, Kirkels JH, Ravesloot JH. 131.  2003. Role of Ca2+-activated Cl− current during proarrhythmic early afterdepolarizations in sheep and human ventricular myocytes. Acta Physiol. Scand. 179:143–48 [Google Scholar]
  132. Reed A, Kohl P, Peyronnet R. 132.  2014. Molecular candidates for cardiac stretch-activated ion channels. Glob. Cardiol. Sci. Pract. 2014:19 [Google Scholar]
  133. Bers DM. 133.  2008. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol. 70:23–49 [Google Scholar]
  134. Cheng H, Lederer WJ. 134.  2008. Calcium sparks. Physiol. Rev. 88:1491–545 [Google Scholar]
  135. Stern MD, Rios E, Maltsev VA. 135.  2013. Life and death of a cardiac calcium spark. J. Gen. Physiol. 142:257–74 [Google Scholar]
  136. Sobie EA, Song LS, Lederer WJ. 136.  2006. Restitution of Ca2+ release and vulnerability to arrhythmias. J. Cardiovasc. Electrophysiol. 17:Suppl. 164–70 [Google Scholar]
  137. Winslow RL, Greenstein JL. 137.  2013. Extinguishing the sparks. Biophys. J. 104:2115–17 [Google Scholar]
  138. Gaeta SA, Bub G, Abbott GW, Christini DJ. 138.  2009. Dynamical mechanism for subcellular alternans in cardiac myocytes. Circ. Res. 105:335–42 [Google Scholar]
  139. Tian Q, Kaestner L, Lipp P. 139.  2012. Noise-free visualization of microscopic calcium signaling by pixel-wise fitting. Circ. Res. 111:17–27 [Google Scholar]
  140. Cheng H, Lederer MR, Lederer WJ, Cannell MB. 140.  1996. Calcium sparks and [Ca2+]i waves in cardiac myocytes. Am. J. Physiol. Cell Physiol. 270:C148–59 [Google Scholar]
  141. Wier WG, ter Keurs HE, Marban E, Gao WD, Balke CW. 141.  1997. Ca2+ “sparks” and waves in intact ventricular muscle resolved by confocal imaging. Circ. Res. 81:462–69 [Google Scholar]
  142. Belevych AE, Terentyev D, Terentyeva R, Ho HT, Gyorke I. 142.  et al. 2012. Shortened Ca2+ signaling refractoriness underlies cellular arrhythmogenesis in a postinfarction model of sudden cardiac death. Circ. Res. 110:569–77 [Google Scholar]
  143. O'Rourke B, Maack C. 143.  2007. The role of Na dysregulation in cardiac disease and how it impacts electrophysiology. Drug Discov. Today Dis. Models 4:207–17 [Google Scholar]
  144. Webster G, Berul CI. 144.  2013. An update on channelopathies: from mechanisms to management. Circulation 127:126–40 [Google Scholar]
  145. Clancy CE, Rudy Y. 145.  2002. Na+ channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation 105:1208–13 [Google Scholar]
  146. Wagner S, Rokita AG, Anderson ME, Maier LS. 146.  2013. Redox regulation of sodium and calcium handling. Antioxid. Redox Signal. 18:1063–77 [Google Scholar]
  147. Dobrev D, Wehrens XHT. 147.  2014. Role of RyR2 phosphorylation in heart failure and arrhythmias: controversies around ryanodine receptor phosphorylation in cardiac disease. Circ. Res. 114:1311–19 [Google Scholar]
  148. Jeong E-M, Liu M, Sturdy M, Gao G, Varghese ST. 148.  et al. 2012. Metabolic stress, reactive oxygen species, and arrhythmia. J. Mol. Cell. Cardiol. 52:454–63 [Google Scholar]
  149. Swaminathan PD, Purohit A, Hund TJ, Anderson ME. 149.  2012. Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias. Circ. Res. 110:1661–77 [Google Scholar]
  150. Boyden PA, Dun W, Barbhaiya C, Ter Keurs HE. 150.  2004. 2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart. Heart Rhythm 1:218–26 [Google Scholar]
  151. Lipp P, Niggli E. 151.  1993. Microscopic spiral waves reveal positive feedback in subcellular calcium signaling. Biophys. J. 65:2272–76 [Google Scholar]
  152. Xie F, Qu Z, Yang J, Baher A, Weiss JN, Garfinkel A. 152.  2004. A simulation study of the effects of cardiac anatomy in ventricular fibrillation. J. Clin. Investig. 113:686–93 [Google Scholar]
/content/journals/10.1146/annurev-physiol-021014-071622
Loading
Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence
Annual Review of Physiology 77, 29 (2015); https://doi.org/10.1146/annurev-physiol-021014-071622
/content/journals/10.1146/annurev-physiol-021014-071622
/content/journals/10.1146/annurev-physiol-021014-071622
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Download Supplemental Text (PDF).

    Download Supplemental Figures 1-6 as a single PDF (also reproduced below).

    Supplemental Figure 1. Complex focal excitations and reentry in tissue. a. Multiple shifting foci (stars) in a homogeneous tissue due to dynamic instabilities, in which the foci continuously disappear and reborn, shifting in space and time. b. Spiral wave breakup, in which the waves are unstable, continuously disappear and reborn through breaks of the existing ones. c. Mother-rotor fibrillation, in which a stable rotor (indicated by the arrow) emanates wavefronts which fail to be 1:1 conduction due to heterogeneities in refractoriness, resulting in wavebreaks away from the rotor. d. Scroll wave breakup in in three-dimensional tissue slab. e. Scroll wave breakup in a model of dog ventricles. The panels shown are voltage snapshots from computer simulations, with voltage levels indicated by the color bar. Panels a-c are simulations of two-dimensional tissue models; panel d is a simulation of a three-dimensional tissue slab; and panel e is a simulation of a dog ventricle model. The left panel in e is a voltage snapshot of the heart surface and the right panel is voltage snapshot of the entire ventricle in which voltage higher than a certain value is colored red (otherwise no color) for three-dimensional visualization.



    Supplemental Figure 2. Restitution and alternans. a. Voltage traces showing the protocol used for measuring S1S2 APD restitution curve, i.e., a train of S1 stimulus with a certain cycle length is applied to pace the cell into a steady state and then an S2 stimulus is applied for a certain S1S2 interval. The same pacing protocol is repeated with different S1S2 intervals which give rise to different diastolic intervals (DIs) preceding the S2 stimulus and APDs of S2 beat. By plotting APD against the preceding DI, one obtains the S1S2 APD restitution curve. b. An S1S2 APD restitution curve (APD vs preceding DI) from a rabbit ventricular myocyte. c. Conduction velocity (CV) restitution curve (CV vs preceding DI) which can be measured using a similar protocol as the S1S2 APD restitution curve but needs to be carried out in tissue.



    Supplemental Figure 3. Bi-excitability. a. An INa-mediated spiral wave in which the voltage recovers fully to around -80 mV after each excitation (black trace) and INa is activated to generate the upstroke (red trace). Note that the color changes from blue to red in the voltage snapshot. b. In the same tissue as in a, a different initiation protocol produces an ICa,L-mediated spiral wave, in which the voltage recovers only partially to around -50 mV (black trace) and the upstroke is mediated by ICa,L without INa activation (red trace). Note that the color changes from green to red in the voltage snapshot. c. Two snapshots showing mixed INa- and ICa,L-mediated conduction (different parameter settings from a and b). White arrows point to INa-mediated conduction. All computer simulations are from homogeneous two-dimensional tissue models (From Chang et al, Ref.28 with permission), indicating that the patterns are dynamic in origin and do not require pre-existing heterogeneity.



    Supplemental Figure 4. Spike-and-dome action potential morphology initiating phase-2 reentry. a. Action potentials with no Ito (black), intermediate Ito (red), and large Ito (blue). b. APD versus Ito conductance. c. Phase-2 reentry (modified from Ref. 107). Green arrow indicates the direction of a pacing beat. Red arrow indicates that the AP dome in the upper region re-excites the repolarized cells near the middle, which then propagates retrogradely, resulting in phase-2 reentry.



    Supplemental Figure 5. EAD dynamics. a. Voltage traces showing a 1 ms delay in S2 stimulus from an S1 action potential result in an EAD (red trace). b. APD restitution in the presence of EADs. The steep and discontinuous change in the APD restitution curve is caused by the all-or-nothing property shown in a. c. APD vs. beat number showing a chaotic behavior. The result was obtained by iterating the following equation: , where PCL is the pacing cycle length and f is the restitution function from b. (From Ref.14 with permission) d. Voltage traces showing irregular EAD appearance. Upper trace is a recording from dog Purkinje fiber (Courtesy of Robert Gilmour). Lower trace is a recording from an isolated rabbit ventricular myocyte subjected to hypokalemia ([K+]o=2.7 mM) (from Ref.18 with permission).



    Supplemental Figure 6. DADs. a. A DAD (arrow) caused by a spontaneous Ca2+ wave in a Ca2+-overloaded ventricular myocyte with EADs (arrows), illustrating voltage (upper), whole-cell Ca2+ fluorescence (middle), and a line scan of Ca2+ fluorescence (bottom). Asterisk and the white arrows indicate the origin of the Ca2+ wave from the center of the cell and its propagation to the ends, respectively. Reproduced from Xie et al. (from Ref.89 with permission). b. Voltage traces showing pacing-induced DADs in HF cells (indicated by arrows), but not in the normal cell, reproduced from Yeh et al (from Ref.87 with permission).

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error