Similar articles

Abstract: T-wave alternans, a specific form of cardiac alternans, has been associated with the increased susceptibility to cardiac arrhythmias and sudden cardiac death (SCD). Plenty of evidence has related cardiac alternans at the tissue level to the instability of voltage kinetics or ca²⁺ handling dynamics at the cellular level. However, to date, none of the existing experiments could identify the exact cellular mechanism of cardiac alternans due to the bi-directional coupling between voltage kinetics and ca²⁺ handling dynamics. Either of these systems could be the origin of alternans and the other follows as a secondary change, therefore making the cellular mechanism of alternans a difficult chicken or egg problem. In this context, theoretical analysis combined with experimental techniques provides a possibility to explore this problem. In this review, we will summarize the experimental and theoretical advances in understanding the cellular mechanism of alternans. We focus on the roles of action potential duration (APD) restitution and ca²⁺ handling dynamics in the genesis of alternans and show how the theoretical analysis combined with experimental techniques has provided us a new insight into the cellular mechanism of alternans. We also discuss the possible reasons of increased propensity for alternans in heart failure (HF) and the new possible therapeutic targets. Finally, according to the level of electrophysiological recording techniques and theoretical strategies, we list some critical experimental or theoretical challenges which may help to determine the origin of alternans and to find more effective therapeutic targets in the future.

心脏电交替现象的细胞机制：先有鸡还是先有蛋的谜团

研究目的：探索心脏电交替（alternans）现象的细胞支持机制，从而能够更有针对性地抑制alternans，进而优化治疗心律失常。
创新要点：采用理论方法系统探索离子流以及钙循环系统异常对alternans形成的影响。由于两个系统的互相影响，实验上无法有效地对二者的作用分别进行定量研究。
研究方法：结合实验数据，建立理论模型，并结合非线性动力学知识，定量分析离子流和钙循环各成分对alternans形成的相对贡献。
重要结论：理论分析结合实验数据对于认识alternans发生机制有着重要意义，对未来更有针对性治疗心律失常提供了一种新的路径。

关键词：交替（Alternans）；心律失常；离子流；钙循环；模型

[1] Baddeley, D., Jayasinghe, I.D., Lam, L., 2009. Optical single-channel resolution imaging of the ryanodine receptor distribution in rat cardiac myocytes. PNAS, 106(52):22275-22280. 

[2] Banville, I., Gray, R.A., 2002. Effect of action potential duration and conduction velocity restitution and their spatial dispersion on alternans and the stability of arrhythmias. J Cardiovasc Electrophysiol, 13(11):1141-1149. 

[3] Benson, A.P., Aslanidi, O.V., Zhang, H., 2008. The canine virtual ventricular wall: a platform for dissecting pharmacological effects on propagation and arrhythmogenesis. Prog Biophys Mol Biol, 96(1-3):187-208. 

[4] Chen, Y., Escoubet, B., Prunier, F., 2004. Constitutive cardiac overexpression of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase delays myocardial failure after myocardial infarction in rats at a cost of increased acute arrhythmias. Circulation, 109(15):1898-1903. 

[5] Cheng, H., Lederer, W.J., Cannell, M.B., 1993. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science, 262(5134):740-744. 

[6] Chudin, E., Goldhaber, J., Garfinkel, A., 1999. Intracellular Ca²⁺ dynamics and the stability of ventricular tachycardia. Biophys J, 77(6):2930-2941. 

[7] Cordeiro, J.M., Malone, J.E., di Diego, J.M., 2007. Cellular and subcellular alternans in the canine left ventricle. Am J Physiol Heart Circ Physiol, 293(6):H3506-H3516. 

[8] Cutler, M.J., Wan, X., Laurita, K.R., 2009. Targeted SERCA2a gene expression identifies molecular mechanism and therapeutic target for arrhythmogenic cardiac alternans. Circ Arrhythm Electrophysiol, 2(6):686-694. 

[9] Cutler, M.J., Wan, X., Plummer, B.N., 2012. Targeted sarcoplasmic reticulum Ca²⁺ ATPase 2a gene delivery to restore electrical stability in the failing heart. Circulation, 126(17):2095-2104. 

[10] Diaz, M.E., Trafford, A.W., ONeill, S.C., 1997. Measurement of sarcoplasmic reticulum Ca²⁺ content and sarcolemmal Ca²⁺ fluxes in isolated rat ventricular myocytes during spontaneous Ca²⁺ release. J Physiol, 501(1):3-16. 

[11] Diaz, M.E., ONeill, S.C., Eisner, D.A., 2004. Sarcoplasmic reticulum calcium content fluctuation is the key to cardiac alternans. Circ Res, 94(5):650-656. 

[12] Dumitrescu, C., Narayan, P., Efimov, I.R., 2002. Mechanical alternans and restitution in failing SHHF rat left ventricles. Am J Physiol Heart Circ Physiol, 282(4):H1320-H1326. 

[13] Eisner, D.A., Diaz, M.E., Li, Y., 2005. Stability and instability of regulation of intracellular calcium. Exp Physiol, 90(1):3-12. 

[14] Fox, J.J., McHarg, J.L., Gilmour, R.F., 2002. Ionic mechanism of electrical alternans. Am J Physiol Heart Circ Physiol, 282(2):H516-H530. 

[15] Gaeta, S.A., Bub, G., Abbott, G.W., 2009. Dynamical mechanism for subcellular alternans in cardiac myocytes. Circ Res, 105(4):335-342. 

[16] Gilmour, R.F., Otani, N.F., Watanabe, M.A., 1997. Memory and complex dynamics in cardiac Purkinje fibers. Am J Physiol, 272(4 Pt 2):H1826-H1832. 

[17] Gold, M.R., Ip, J.H., Costantini, O., 2008. Role of microvolt T-wave alternans in assessment of arrhythmia vulnerability among patients with heart failure and systolic dysfunction: primary results from the T-wave alternans sudden cardiac death in heart failure trial substudy. Circulation, 118(20):2022-2028. 

[18] Greenstein, J.L., Winslow, R.L., 2011. Integrative systems models of cardiac excitation-contraction coupling. Circ Res, 108(1):70-84. 

[19] Hoffman, B.F., Suckling, E.E., 1954. Effect of heart rate on cardiac membrane potentials and the unipolar electrogram. Am J Physiol, 179(1):123-130. 

[20] Hund, T.J., Rudy, Y., 2004. Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model. Circulation, 110(20):3168-3174. 

[21] Huser, J., Wang, Y.G., Sheehan, K.A., 2000. Functional coupling between glycolysis and excitation-contraction coupling underlies alternans in cat heart cells. J Physiol, 524(3):795-806. 

[22] Jordan, P.N., Christini, D.J., 2007. Characterizing the contribution of voltage- and calcium-dependent coupling to action potential stability: implications for repolarization alternans. Am J Physiol Heart Circ Physiol, 293(4):H2109-H2118. 

[23] Karagueuzian, H.S., Khan, S.S., Hong, K., 1993. Action potential alternans and irregular dynamics in quinidine-intoxicated ventricular muscle cells. Implications for ventricular proarrhythmia. Circulation, 87(5):1661-1672. 

[24] Kihara, Y., Morgan, J.P., 1991. Abnormal Ca_i ²⁺ handling is the primary cause of mechanical alternans: study in ferret ventricular muscles. Am J Physiol, 261(6 Pt 2):H1746-H1755. 

[25] Kirchhof, P., Fabritz, L., Kilic, A., 2004. Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice. J Mol Cell Cardiol, 36(5):691-700. 

[26] Kleinfeld, M., Stein, E., Kossmann, C.E., 1963. Electrical alternans with emphasis on recent observations made by means of single-cell electrical recording. Am Heart J, 65(4):495-500. 

[27] Kockskamper, J., Blatter, L.A., 2002. Subcellular Ca²⁺ alternans represents a novel mechanism for the generation of arrhythmogenic Ca²⁺ waves in cat atrial myocytes. J Physiol, 545(1):65-79. 

[28] Koller, M.L., Riccio, M.L., Gilmour, R.F., 1998. Dynamic restitution of action potential duration during electrical alternans and ventricular fibrillation. Am J Physiol, 275(5 Pt 2):H1635-H1642. 

[29] Konta, T., Ikeda, K., Yamaki, M., 1990. Significance of discordant ST alternans in ventricular fibrillation. Circulation, 82(6):2185-2189. 

[30] Lehnart, S.E., Terrenoire, C., Reiken, S., 2006. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias. PNAS, 103(20):7906-7910. 

[31] Li, Y., Diaz, M.E., Eisner, D.A., 2009. The effects of membrane potential, SR Ca²⁺ content and RyR responsiveness on systolic Ca²⁺ alternans in rat ventricular myocytes. J Physiol, 587(6):1283-1292. 

[32] Livshitz, L.M., Rudy, Y., 2007. Regulation of Ca²⁺ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents. Am J Physiol Heart Circ Physiol, 292(6):H2854-H2866. 

[33] Lu, L., Xia, L., Ye, X., 2010. Simulation of the effect of rogue ryanodine receptors on a calcium wave in ventricular myocytes with heart failure. Phys Biol, 7(2):026005

[34] Lyon, A.R., Bannister, M.L., Collins, T., 2011. SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circ Arrhythm Electrophysiol, 4(3):362-372. 

[35] Narayan, S.M., 2007. Is T-wave alternans as good or better than programmed ventricular stimulation?. Heart Rhythm, 4(7):913-915. 

[36] Nolasco, J.B., Dahlen, R.W., 1968. A graphic method for the study of alternation in cardiac action potentials. J Appl Physiol, 25(2):191-196. 

[37] ORourke, B., Kass, D.A., Tomaselli, G.F., 1999. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies. Circ Res, 84(5):562-570. 

[38] Pastore, J.M., Rosenbaum, D.S., 2000. Role of structural barriers in the mechanism of alternans-induced reentry. Circ Res, 87(12):1157-1163. 

[39] Picht, E., DeSantiago, J., Blatter, L.A., 2006. Cardiac alternans do not rely on diastolic sarcoplasmic reticulum calcium content fluctuations. Circ Res, 99(7):740-748. 

[40] Pruvot, E.J., Katra, R.P., Rosenbaum, D.S., 2004. Role of calcium cycling versus restitution in the mechanism of repolarization alternans. Circ Res, 94(8):1083-1090. 

[41] Qian, Y.W., Sung, R.J., Lin, S.F., 2003. Spatial heterogeneity of action potential alternans during global ischemia in the rabbit heart. Am J Physiol Heart Circ Physiol, 285(6):H2722-H2733. 

[42] Qu, Z., Garfinkel, A., Chen, P.S., 2000. Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue. Circulation, 102(14):1664-1670. 

[43] Riccio, M.L., Koller, M.L., Gilmour, R.F., 1999. Electrical restitution and spatiotemporal organization during ventricular fibrillation. Circ Res, 84(8):955-963. 

[44] Rosenbaum, D.S., Jackson, L.E., Smith, J.M., 1994. Electrical alternans and vulnerability to ventricular arrhythmias. N Engl J Med, 330(4):235-241. 

[45] Rovetti, R., Cui, X., Garfinkel, A., 2010. Spark-induced sparks as a mechanism of intracellular calcium alternans in cardiac myocytes. Circ Res, 106(10):1582-1591. 

[46] Saitoh, H., Bailey, J.C., Surawicz, B., 1988. Alternans of action potential duration after abrupt shortening of cycle length: differences between dog Purkinje and ventricular muscle fibers. Circ Res, 62(5):1027-1040. 

[47] Sato, D., Shiferaw, Y., Qu, Z., 2007. Inferring the cellular origin of voltage and calcium alternans from the spatial scales of phase reversal during discordant alternans. Biophys J, 92(4):L33-L35. 

[48] Shannon, T.R., Ginsburg, K.S., Bers, D.M., 2000. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys J, 78(1):334-343. 

[49] Shannon, T.R., Pogwizd, S.M., Bers, D.M., 2003. Elevated sarcoplasmic reticulum Ca²⁺ leak in intact ventricular myocytes from rabbits in heart failure. Circ Res, 93(7):592-594. 

[50] Shannon, T.R., Wang, F., Bers, D.M., 2005. Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model. Biophys J, 89(6):4096-4110. 

[51] Shiferaw, Y., Watanabe, M.A., Garfinkel, A., 2003. Model of intracellular calcium cycling in ventricular myocytes. Biophys J, 85(6):3666-3686. 

[52] Shiferaw, Y., Sato, D., Karma, A., 2005. Coupled dynamics of voltage and calcium in paced cardiac cells. Phys Rev E, 71(2 Pt 1):021903

[53] Tao, T., O'Neill, S.C., Diaz, M.E., 2008. Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study. Am J Physiol Heart Circ Physiol, 295(2):H598-H609. 

[54] ten Tusscher, K.H., Panfilov, A.V., 2006. Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol, 291(3):H1088-H1100. 

[55] Traube, L., 1872. Ein Fall von Pulsus bigeminus nebst Bemerkungen über die Leberschwellungen bei Klappenfehlern und über acute Leberatrophie. Berlin Klin Wochenschr, (in German),9:185-188. 

[56] Wagner, S., Dybkova, N., Rasenack, E.C., 2006. Ca²⁺/calmodulin-dependent protein kinase II regulates cardiac Na⁺ channels. J Clin Invest, 116(12):3127-3138. 

[57] Walker, M.L., Rosenbaum, D.S., 2003. Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death. Cardiovasc Res, 57(3):599-614. 

[58] Wan, X., Laurita, K.R., Pruvot, E.J., 2005. Molecular correlates of repolarization alternans in cardiac myocytes. J Mol Cell Cardiol, 39(3):419-428. 

[59] Wilson, L.D., Jeyaraj, D., Wan, X., 2009. Heart failure enhances susceptibility to arrhythmogenic cardiac alternans. Heart Rhythm, 6(2):251-259. 

[60] Windle, J.D., 1911. The incidence and prognostic value of the pulsus alternans in myocardial and arterial disease. Quart J Med, 6(2617):453-462. 

[61] Wohlfart, B., 1982. Analysis of mechanical alternans in rabbit papillary muscle. Acta Physiol Scand, 115(4):405-414. 

[62] Wu, Y., Temple, J., Zhang, R., 2002. Calmodulin kinase II and arrhythmias in a mouse model of cardiac hypertrophy. Circulation, 106(10):1288-1293. 

[63] Xie, L.H., Sato, D., Garfinkel, A., 2008. Intracellular Ca alternans: coordinated regulation by sarcoplasmic reticulum release, uptake, and leak. Biophys J, 95(6):3100-3110. 

[64] Zang, Y., Dai, L., Zhan, H., 2013. Theoretical investigation of the mechanism of heart failure using a canine ventricular cell model: especially the role of up-regulated CaMKII and SR Ca²⁺ leak. J Mol Cell Cardiol, 56:34-43. 

[65] Zhao, X., Yamazaki, D., Park, K.H., 2010. Ca²⁺ overload and sarcoplasmic reticulum instability in tric-a null skeletal muscle. J Biol Chem, 285(48):37370-37376.