J波综合征发生机制的研究进展
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摘要
目的 J波综合征是引起自发性室颤导致心脏性猝死的一个重要原因。虽然J波综合征有多种表型,但其发生机制与心电图表现具有相似性。J波是动作电位1相复极的结果,主要由I_(to)介导的瞬时外向钾电流产生。由于心内膜与心外膜I_(to)通道密度不同,构成了J波产生的生理基础。除了I_(to)外,其它离子通道如I_(Na)、I_(ca)、I_k也参与J波的形成,这提示任何一种离子通道异常都可产生J波。其中,最常见的离子通道病变是基因突变。已有大量实验表明J波综合征与多种离子通道基因突变相关,如SCN5A、CACNA1C、CACNB2、SCNIB、KCNE3。这些突变的离子通道影响心外膜复极,产生2相折返而引发室颤。因此,充分了解J波综合征的发生机制,有助于临床诊断和治疗,降低死亡率。
J wave syndrome has emerged as a significant cause of idiopathic ventricular fibrillation(IVF) responsible for sudden cardiac death. Although J-wave syndrome involves a variety of types, but its mechanism and ECG performance are similar. The J wave is the result of the 1-phase repolarization of the action potential. which is mainly generated by the I_(to)-mediated transient outward potassium flow. Because of the heterogeneity of I_(to) density between the endocardium and epicardium, its heterogeneity constitutes the physiological basis of J wave. In addition to I_(to),other ion channels such as I_(Na),I_(ca),I_k are also related to the generation of J waves. So any of anomalies of these ion channels can cause J waves appearing. The most common lesion of ion channel is gene mutation. A large number of experiments have shown that J wave syndrome is associated with a variety of ion channel gene mutations such as SCN5A, CACNA1C, CACNB2,SCN1B, KCNE3 and so on. The mutation affects the epicardium repolarization, resulting in 2-phase reentry,triggering ventricular fibrillation. Therefore, a full understanding the pathomechanism of J wave syndrome,contributing to clinical diagnosis and treatment, reducing the mortality as much as possible.
J wave syndrome has emerged as a significant cause of idiopathic ventricular fibrillation(IVF) responsible for sudden cardiac death. Although J-wave syndrome involves a variety of types, but its mechanism and ECG performance are similar. The J wave is the result of the 1-phase repolarization of the action potential. which is mainly generated by the I_(to)-mediated transient outward potassium flow. Because of the heterogeneity of I_(to) density between the endocardium and epicardium, its heterogeneity constitutes the physiological basis of J wave. In addition to I_(to),other ion channels such as I_(Na),I_(ca),I_k are also related to the generation of J waves. So any of anomalies of these ion channels can cause J waves appearing. The most common lesion of ion channel is gene mutation. A large number of experiments have shown that J wave syndrome is associated with a variety of ion channel gene mutations such as SCN5A, CACNA1C, CACNB2,SCN1B, KCNE3 and so on. The mutation affects the epicardium repolarization, resulting in 2-phase reentry,triggering ventricular fibrillation. Therefore, a full understanding the pathomechanism of J wave syndrome,contributing to clinical diagnosis and treatment, reducing the mortality as much as possible.
引文
[1]Badri M,Patel A,Yan GX.Cellular and ionic basis of J-wave syndromes[J].Trends Cardiovasc Med,2015,25(1):12-21.
[2]Antzelevitch C,Yan GX.J wave syndromes[J].Heart Rhythm,2010,7(4):549-558.
[3]Yan GX,Antzelevitch C.Cellular basis for the electrocardiographic J wave[J].Circulation,1996,93(2):372-379.
[4]Niwa N,Nerbonne JM.Molecular determI_(Na)nts of cardiac transient outward potassium current(I(to))expression and regulation[J].J Mol Cell Cardiol,2010,48(1):12-25.
[5]Wettwer E,Amos G J,Posival H,et al.Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin[J].Circ Res,1994,75(3):473-482.
[6]Nabauer M,Beuckelmann D J,Uberfuhr P,et al.Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle[J].Circulation,1996,93(1):168-177.
[7]Fish J M,Antzelevitch C.Role of sodium and calcium channel block in unmasking the Brugada syndrome[J].Heart Rhythm,2004,1(2):210-217.
[8]Antzelevitch C.Genetic,molecular and cellular mechanisms underlying the J wave syndromes[J].Circ J,2012,76(5):1054-1065.
[9]Badri M,Patel A,Yan GX.Cellular and ionic basis of J-wave syndromes[J].Trends Cardiovasc Med.2015,25(1):12-21.
[10]Antzelevitch CJ wave syndromes:molecular and cellular mechanisms[J].J Electrocardiol,2013,46(6):510-518.
[11]Yan G X,Antzelevitch C.Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation[J].Circulation,1999,100(15):1660-1666.
[12]Yan GX,Lankipalli RS,Burke JF,et al.Ventricular repolarization components on the electrocardiogram:cellular basis and clinical significance[J].J Am Coll Cardiol,2003,42(3):401-409.
[13]Bloch TP,Joergensen RM,Kanters JK,et al.Phase 2 reentry in man[J].Heart Rhythm,2005,2(8):797-803.
[14]RuDusky BM.Right bundle branch block,persistent ST-segment elevation,and sudden death[J].Am J Cardiol,1998,82(3):407-408.
[15]Sethi KK,Sethi K,Chutani SK.Early repolarisation and J wave syndromes[J].Indian Heart J,2014,66(4):443-452.
[16]Gellens ME,George AJ,Chen LQ,et al.Primary structure and functional expression of the human cardiac tetrodotoxininsensitive voltage-dependent sodium channel[J].Proc Natl Acad Sci U S A,1992,89(2):554-558.
[17]Antzelevitch C,Brugada P,Borggrefe M,et al.Brugada syndrome:report of the second consensus conference[J].Heart Rhythm,2005,2(4):429-440.
[18]Vatta M,Dumaine R,Antzelevitch C,et al.Novel mutations in domain I of SCN5A cause Brugada syndrome[J].Mol Genet Metab,2002,75(4):317-324.
[19]Hedley P L,Jorgensen P,Schlamowitz S,et al.The genetic basis of Brugada syndrome:a mutation update[J].Hum Mutat,2009,30(9):1256-1266.
[20]Rivolta I,Abriel H,Tateyama M,et al.Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes[J].J Biol Chem,2001,276(33):30623-30630.
[21]London B,Michalec M,Mehdi H,et al.Mutation in glycerol-3-phosphate dehydrogenase 1 like gene(GPD1-L)decreasescardiac Na~+current and causes inherited arrhythmias[J].Circulation,2007,116(20):2260-2268.
[22]Makita N,Sloan-Brown K,Weghuis D O,et al.Genomic organization and chromosomal assignment of the human voltagegated Na~+channel beta 1 subunit gene(SCN1B)[J].Genomics,1994,23(3):628-634.
[23]Qin N,D'Andrea M R,Lubin M L,et al.Molecular cloning and functional expression of the human sodium channel betalB subunit,a novel splicing variant of the betal subunit[J].Eur J Biochem,2003,270(23):4762-4770.
[24]Watanabe H,Koopmann T T,Le Scouarnec S,et al.Sodium channel betal subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans[J].J Clin Invest,2008,118(6):2260-2268.
[25]Morgan K,Stevens E B,Shah B,et al.beta 3:an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics[J].Proc Natl Acad Sci U S A,2000,97(5):2308-2313.
[26]Hu D,Barajas-Martinez H,Burashnikov E,et al.A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype[J].Circ Cardiovasc Genet,2009,2(3):270-278.
[27]Van Petegem F,Clark K A,Chatelain F C,et al.Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain[J].Nature,2004,429(6992):671-675.
[28]Catterall WA,Perez-Reyes E,Snutch T P,et al.International Union of Pharmacology.XLⅧ.Nomenclature and structurefunction relationships of voltage-gated calcium channels[J].Pharmacol Rev,2005,57(4):411-425.
[29]Cardiocyte Cytoskeleton in Hypertrophied Myocardium[Z].
[30]Abbott GW,Butler M H,Bendahhou S,et al.MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis[J].Cell,2001,104(2):217-231.
[31]Delpon E,Cordeiro J M,Nunez L,et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome[J].Circ Arrhythm Electrophysiol,2008,1(3):209-218.
[32]Yokoshiki H,Sunagawa M,Seki T,et al.ATP-sensitive K+channels in pancreatic,cardiac,and vascular smooth muscle cells[J].Am J Physiol,1998,274(1 Pt 1):C25-C37.
[33]Medeiros-Domingo A,Tan B H,Crotti L,et al.Gain-offunction mutation S422L in the KCNJ8-encoded cardiac K(ATP)channel Kir6.1 as a pathogenic substrate for J-wave syndromes[J].Heart Rhythm,2010,7(10):1466-1471.
[34]Gurabi Z,Koncz I,Patocskai B,et al.Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine,cilostazol,and milrinone[J].Circ Arrhythm Electrophysiol,2014,7(1):134-142.
[35]Yan GX,Joshi A,Guo D,et al.Phase 2 reentry as a trigger to initiate ventricular fibrillation during early acute myocardial ischemia[J].Circulation,2004,110(9):1036-1041.
[36]Carmeliet E.Cardiac ionic currents and acute ischemia:from channels to arrhythmias[J].Physiol Rev,1999,79(3):917-1017.
[37]Ehlert FA,Goldberger JJ.Cellular and pathophysiological mechanisms of ventricular arrhythmias in acute ischemia and infarction[J].Pacing Clin Electrophysiol,1997,20(4 Pt 1):966-975.
[2]Antzelevitch C,Yan GX.J wave syndromes[J].Heart Rhythm,2010,7(4):549-558.
[3]Yan GX,Antzelevitch C.Cellular basis for the electrocardiographic J wave[J].Circulation,1996,93(2):372-379.
[4]Niwa N,Nerbonne JM.Molecular determI_(Na)nts of cardiac transient outward potassium current(I(to))expression and regulation[J].J Mol Cell Cardiol,2010,48(1):12-25.
[5]Wettwer E,Amos G J,Posival H,et al.Transient outward current in human ventricular myocytes of subepicardial and subendocardial origin[J].Circ Res,1994,75(3):473-482.
[6]Nabauer M,Beuckelmann D J,Uberfuhr P,et al.Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle[J].Circulation,1996,93(1):168-177.
[7]Fish J M,Antzelevitch C.Role of sodium and calcium channel block in unmasking the Brugada syndrome[J].Heart Rhythm,2004,1(2):210-217.
[8]Antzelevitch C.Genetic,molecular and cellular mechanisms underlying the J wave syndromes[J].Circ J,2012,76(5):1054-1065.
[9]Badri M,Patel A,Yan GX.Cellular and ionic basis of J-wave syndromes[J].Trends Cardiovasc Med.2015,25(1):12-21.
[10]Antzelevitch CJ wave syndromes:molecular and cellular mechanisms[J].J Electrocardiol,2013,46(6):510-518.
[11]Yan G X,Antzelevitch C.Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation[J].Circulation,1999,100(15):1660-1666.
[12]Yan GX,Lankipalli RS,Burke JF,et al.Ventricular repolarization components on the electrocardiogram:cellular basis and clinical significance[J].J Am Coll Cardiol,2003,42(3):401-409.
[13]Bloch TP,Joergensen RM,Kanters JK,et al.Phase 2 reentry in man[J].Heart Rhythm,2005,2(8):797-803.
[14]RuDusky BM.Right bundle branch block,persistent ST-segment elevation,and sudden death[J].Am J Cardiol,1998,82(3):407-408.
[15]Sethi KK,Sethi K,Chutani SK.Early repolarisation and J wave syndromes[J].Indian Heart J,2014,66(4):443-452.
[16]Gellens ME,George AJ,Chen LQ,et al.Primary structure and functional expression of the human cardiac tetrodotoxininsensitive voltage-dependent sodium channel[J].Proc Natl Acad Sci U S A,1992,89(2):554-558.
[17]Antzelevitch C,Brugada P,Borggrefe M,et al.Brugada syndrome:report of the second consensus conference[J].Heart Rhythm,2005,2(4):429-440.
[18]Vatta M,Dumaine R,Antzelevitch C,et al.Novel mutations in domain I of SCN5A cause Brugada syndrome[J].Mol Genet Metab,2002,75(4):317-324.
[19]Hedley P L,Jorgensen P,Schlamowitz S,et al.The genetic basis of Brugada syndrome:a mutation update[J].Hum Mutat,2009,30(9):1256-1266.
[20]Rivolta I,Abriel H,Tateyama M,et al.Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes[J].J Biol Chem,2001,276(33):30623-30630.
[21]London B,Michalec M,Mehdi H,et al.Mutation in glycerol-3-phosphate dehydrogenase 1 like gene(GPD1-L)decreasescardiac Na~+current and causes inherited arrhythmias[J].Circulation,2007,116(20):2260-2268.
[22]Makita N,Sloan-Brown K,Weghuis D O,et al.Genomic organization and chromosomal assignment of the human voltagegated Na~+channel beta 1 subunit gene(SCN1B)[J].Genomics,1994,23(3):628-634.
[23]Qin N,D'Andrea M R,Lubin M L,et al.Molecular cloning and functional expression of the human sodium channel betalB subunit,a novel splicing variant of the betal subunit[J].Eur J Biochem,2003,270(23):4762-4770.
[24]Watanabe H,Koopmann T T,Le Scouarnec S,et al.Sodium channel betal subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans[J].J Clin Invest,2008,118(6):2260-2268.
[25]Morgan K,Stevens E B,Shah B,et al.beta 3:an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics[J].Proc Natl Acad Sci U S A,2000,97(5):2308-2313.
[26]Hu D,Barajas-Martinez H,Burashnikov E,et al.A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype[J].Circ Cardiovasc Genet,2009,2(3):270-278.
[27]Van Petegem F,Clark K A,Chatelain F C,et al.Structure of a complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit domain[J].Nature,2004,429(6992):671-675.
[28]Catterall WA,Perez-Reyes E,Snutch T P,et al.International Union of Pharmacology.XLⅧ.Nomenclature and structurefunction relationships of voltage-gated calcium channels[J].Pharmacol Rev,2005,57(4):411-425.
[29]Cardiocyte Cytoskeleton in Hypertrophied Myocardium[Z].
[30]Abbott GW,Butler M H,Bendahhou S,et al.MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis[J].Cell,2001,104(2):217-231.
[31]Delpon E,Cordeiro J M,Nunez L,et al.Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome[J].Circ Arrhythm Electrophysiol,2008,1(3):209-218.
[32]Yokoshiki H,Sunagawa M,Seki T,et al.ATP-sensitive K+channels in pancreatic,cardiac,and vascular smooth muscle cells[J].Am J Physiol,1998,274(1 Pt 1):C25-C37.
[33]Medeiros-Domingo A,Tan B H,Crotti L,et al.Gain-offunction mutation S422L in the KCNJ8-encoded cardiac K(ATP)channel Kir6.1 as a pathogenic substrate for J-wave syndromes[J].Heart Rhythm,2010,7(10):1466-1471.
[34]Gurabi Z,Koncz I,Patocskai B,et al.Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine,cilostazol,and milrinone[J].Circ Arrhythm Electrophysiol,2014,7(1):134-142.
[35]Yan GX,Joshi A,Guo D,et al.Phase 2 reentry as a trigger to initiate ventricular fibrillation during early acute myocardial ischemia[J].Circulation,2004,110(9):1036-1041.
[36]Carmeliet E.Cardiac ionic currents and acute ischemia:from channels to arrhythmias[J].Physiol Rev,1999,79(3):917-1017.
[37]Ehlert FA,Goldberger JJ.Cellular and pathophysiological mechanisms of ventricular arrhythmias in acute ischemia and infarction[J].Pacing Clin Electrophysiol,1997,20(4 Pt 1):966-975.