1. 稳心颗粒抗室性心侓失常的机制 Gan-Xin Yan Professor, Lankenau Institute for Medical Research Professor of Medicine, Thomas Jefferson University

2. When we use a sodium channel blocker for suppression of cardiac arrhythmias, which effects we expect are antiarrhythmic? Slow conduction velocity; Prolong Effective Refractory Period; therefore, prolong the wavelength and abolish the reentry circle （ ± ） ; Reduce intracellular calcium overloading via Na- Ca exchange; Blunt rate-dependent change in ventricular repolarization; Reduce dispersion of repolarization, particularly during bradycardia.

3. When we use a sodium channel blocker for suppression of cardiac arrhythmias, which effects we expect are antiarrhythmic? Slow conduction velocity 传导速度减慢 折返波长 =x 有效不应期 折返波长 = 传导速度 x 有效不应期

4. 折返心侓失常的机制

5. (1) Late Sodium Current (I Na,L ) Contributes to Ventricular Repolarization

14. Late Sodium Channel Current Sodium Current 0 Late I Na Peak Normal(Physiologic) 0 Late I Na Peak Abnormal(Pathophysiologic) Whole Cell NaCh Current Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.Modified from: Kiyosue, T & Arita, M. Circ Res 64:389-397, 1989. Na + Impaired Inactivation (40 to < 100 pA) Late I Na 1.Slowly inactivating I Na 2.Late Reopenings 3.Bursting Behavior Single NaCh Current

15. Feature 1 Late Sodium Current Feature 1 Lasting for a few hundreds of milliseconds; Therefore, late sodium current contributes importantly to repolarization; Any factor that prolongs repolarization will enhance the late sodium current because of the unique kinetics of the late sodium current!!!

16. There may be species-dependent differences in left ventricular I Na,L Human > Dog > Rabbit> Rat

17. Each Species has its own ventricular repolarization time (QTc) Wang, Cui and Yan: Pharmacol.Ther 2008; 119:141-151

18. Rate Adaptation of Ventricular Repolarization is a Universal Phenomenon seen in Almost All Mammals Species Including Humans

26. Bazett's Formula: QTc= QT Interval / √ (RR interval) HR 60708090100 RR (s) 10.860.750.670.6 QT (ms)400370346327310 ΔQT:225 ms/ ΔRR per second

28. Should We need to correct a mouse’s QT on rate?

29. Ion Mechanism for Rate Adaptation of Repolarization Classic I Ks Hypothesis should be Abandoned: I Ks does not play a significant role in rate adaptation of ventricular repolarization of ventricular repolarization

30. Guo, Kowey, Yan; Heart Rhythm 2011;8:762-769 Contribution of I Na,L to Rate-dependent change in APD

31. Why? Guo, Kowey, Yan; Heart Rhythm 2011;8:762-769

32. Feature 2: Late sodium current is the key current underlying rate adaptation of repolarization

33. Suppression by TTX of Torsades de Pointes Induced by E-4031 A. Control B. E-4031 (60 nM) Spontaneous TdP C. E-4031 (60 nM) + TTX (0.6 µM) 3-sec pause

34. Feature 3: Heterogeneous Distribution of I Na,L, Resulting in Dispersion of Repolarization under Physiological Condition Transmural (left ventricle): M cells > endocardium > epicardium; Regional: LV > RV > atria, leading to regional heterogeneous dispersion of repolarization. Yan and Antzelevitch: Circ 1998;98:1268-1236

35. Yan et al Circ 2001; 103:2851-2856 Since I Na,L is Larger in M cells than in epicardium, QT prolongation during bradycardia is accompanied by Tp-e prolongation

36. Pause-dependent QT and Tp-e prolongation----- TdP

38. A Pathophysiological Paradigm: Sodium Channelopathy Enhanced late I Na Ca 2+ Overload Ca 2+ Overload Na + i Impaired Na Ch inactivation Enhanced late I Na Modified from Belardinelli L. et al. Heart. 92 (Suppl. IV):IV6-IV14, 2006. Pathological Conditions Acquired Congenital Late I Na Peak I Na normal abnormal Sodium Current (I Na )

39. I Na,L, TWA and EAD Effect of Ranolazine

48. I Na,L, TWA,EAD and R-on-T Effect of Ranolazine

58. Case 1: 2 year old infant with LQT8 (Timothy Syndrome). Pathophysiology: gain of function in L-type calcium current Syndactyly 2:1 AV block T Wave Alternans

59. Mexiletine, a pure sodium channel blocker, shortens QT and abolishes 2:1 AV block and T wave alternans

60. Mexiletine RR-QT slope

61. Case 2: TWA and TdP in Takotsubo

64. Recent Progress in J Wave Syndromes

65. J Wave Syndromes: ECG features of accentuated J waves accompanied by ST segment elevation and/or early repolarization. Inherited J Wave Syndromesare associated with a risk of sudden cardiac death in apparently healthy young people. Inherited J Wave Syndromes are associated with a risk of sudden cardiac death in apparently healthy young people. Acquired J Wave Syndromesare more common and can be seen in a variety of pathophysiological conditions. Acquired J Wave Syndromes are more common and can be seen in a variety of pathophysiological conditions.

66. J wave, ST elevation and Early Repolarization J wave ST Elevation and Early Repolarization

67. The inherited disease targets Asian males at age of late 20s and early 30s during sleep The inherited disease targets Asian males at age of late 20s and early 30s during sleep

68. In Philippines capital city Malina, a total of 722 apparently healthy young males died during sleep during 1948 to 1982, a disease called “Bangungut” (to rise and moan during sleep) in native language. In 1982, the incidence is about 26.3/100,000 per year. If there were a similar incidence in China, this syndrome would take approximately 320,000 young lives in China a year.

69. It was believed that widow ghosts might spirit young, healthy and handsome men away during their sleep

70. Nocturnal and Pause-Dependent Amplification of J Wave (29 yo Asian Male) Journal of Cardiovascular Electrophysiology pages no-no, 7 JUL 2011 DOI: 10.1111/j.1540-8167.2011.02124.x 5 AM

71. J wave with Ventricular Fibrillation Kalla, Yan and Marinchak: JCE 2000:11:95-97

72. J wave and Phase 2 Reentry Aizawa, et al. Am Heart J 1993; 126:1473-4

73. Features of I to -mediated epicardial action potential spike and dome ---- J wave J wave is the consequence of I to -mediated action potential spike and dome in epicardium but not in endocardium; The J wave size is amplified during bradycardia or by an enhanced vagal tone; I to -mediated action potential spike and dome is more prominent in right ventricular epicardium; I to -mediated action potential spike and dome is more prominent in males than in females; I to -mediated action potential spike and dome predisposes the loss or depression of action potential dome in epicardium, resulting in ST segment elevation; therefore, I to -mediated ST segment elevation shares the features with J wave.

74. Summary It appears that this problem exclusively involves “Asian males”; It appears that J wave and ST segment elevation (or early repolarization) in the inferior leads (II, III, aVF), in absence of myocardial ischemia, are potential ECG markers of this problem.

75. Are other racial groups, like white or black people, immune to this problem?

76. In 1992, Brugada and Brugada brothers reported 8 cases (6 males/2 females) of sudden deaths resulting from ventricular fibrillation in European countries. ECG features include so called “RBBB”, ST segment elevation in V1 to V3 in the absence of a structural heart disease. The Findings by Brugada Brothers in 1992 The Findings by Brugada Brothers in 1992 RBBB ?

77. Arethe cases reported by Brugada and Brugada from Europe Are the cases reported by Brugada and Brugada from Europe similar in etiology to those SCD cases in Asia? similar in etiology to those SCD cases in Asia?

78. Thank You!