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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 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 NaCa exchange; Blunt rate-dependent change in ventricular repolarization; Reduce dispersion of repolarization, particularly during bradycardia. 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=传导速度x 有效不应期 折返心侓失常的机制 (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization (1) Late Sodium Current (INa,L) Contributes to Ventricular Repolarization Late Sodium Channel Current Na+ Normal Abnormal (Physiologic) Na+ • Single NaCh Current (Pathophysiologic) Impaired Inactivation • Whole Cell NaCh Current Late INa 0 Sodium Current Peak Late INa (40 to < 100 pA) 0 1. Slowly inactivating INa 2. Late Reopenings 3. Bursting Behavior Modified from: Kiyosue, T & Arita, M. Circ Res 64:389-397, 1989. Late INa Peak Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7. 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!!! There may be species-dependent differences in left ventricular INa,L Human > Dog > Rabbit> Rat Each Species has its own ventricular repolarization time (QTc) 1000 Whale QTc (ms) 800 600 Elephant Rhinoceros Horse 400 Dog Human Koala Camel Donkey Rabbit 200 Rat Guinea pig 0 10-1 100 101 102 103 104 105 Weight (Kg) Wang, Cui and Yan: Pharmacol.Ther 2008; 119:141-151 Rate Adaptation of Ventricular Repolarization is a Universal Phenomenon seen in Almost All Mammals Species Including Humans Bazett's Formula: QTc= QT Interval / √ (RR interval) HR RR (s) QT (ms) 60 1 400 70 0.86 370 80 0.75 346 90 0.67 327 100 0.6 310 ΔQT:225 ms/ ΔRR per second Should We need to correct a mouse’s QT on rate? Ion Mechanism for Rate Adaptation of Repolarization Classic IKs Hypothesis should be Abandoned: IKs does not play a significant role in rate adaptation of ventricular repolarization Contribution of INa,L to Rate-dependent change in APD Guo, Kowey, Yan; Heart Rhythm 2011;8:762-769 Why? Guo, Kowey, Yan; Heart Rhythm 2011;8:762-769 Feature 2: Late sodium current is the key current underlying rate adaptation of repolarization Suppression by TTX of Torsades de Pointes Induced by E-4031 A. Control Channel 12 3-sec pause s ec onds 25028 70.25028 25028 70.25028 75.25028 80.25028 75.25028 80.25028 s ec onds Spontaneous TdP Channel 6 Channel 6 Channel 12 B. E-4031 (60 nM) s ec onds 2750.25028 2755.25028 2760.25028 C. E-4031 (60 nM) + TTX (0.6 µM) 2750.25028 2755.25028 2765.25028 s ec onds 2760.25028 2765.25028 s ec onds 4125.25028 4130.25028 4135.25028 4140.25028 s ec onds 4125.25028 4130.25028 4135.25028 4140.25028 Feature 3: Heterogeneous Distribution of INa,L, Resulting in Dispersion of Repolarization under Physiological Condition Transmural (left ventricle): M cells > endocardium > epicardium; Yan and Antzelevitch: Circ 1998;98:1268-1236 Regional: LV > RV > atria, leading to regional heterogeneous dispersion of repolarization. Since INa,L is Larger in M cells than in epicardium, QT prolongation during bradycardia is accompanied by Tp-e prolongation Yan et al Circ 2001; 103:2851-2856 Pause-dependent QT and Tp-e prolongation----- TdP A Pathophysiological Paradigm: Sodium Channelopathy Pathological Conditions • Acquired • Congenital Ca2+ Overload Sodium Current (INa) normal Impaired Na Ch inactivation abnormal Late INa Enhanced late INa Peak INa Modified from Belardinelli L. et al. Heart. 92 (Suppl. IV):IV6-IV14, 2006. Na+i INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA and EAD Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine INa,L, TWA,EAD and R-on-T Effect of Ranolazine 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 Mexiletine, a pure sodium channel blocker, shortens QT and abolishes 2:1 AV block and T wave alternans Mexiletine RR-QT slope Case 2: TWA and TdP in Takotsubo Recent Progress in J Wave Syndromes J Wave Syndromes: ECG features of accentuated J waves accompanied by ST segment elevation and/or early repolarization. Inherited J Wave Syndromes are associated with a risk of sudden cardiac death in apparently healthy young people. Acquired J Wave Syndromes are more common and can be seen in a variety of pathophysiological conditions. J wave, ST elevation and Early Repolarization J wave ST Elevation and Early Repolarization The inherited disease targets Asian males at age of late 20s and early 30s during sleep 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. It was believed that widow ghosts might spirit young, healthy and handsome men away during their sleep Nocturnal and Pause-Dependent Amplification of J Wave (29 yo Asian Male) 5 AM Journal of Cardiovascular Electrophysiology pages no-no, 7 JUL 2011 DOI: 10.1111/j.1540-8167.2011.02124.x J wave with Ventricular Fibrillation Kalla, Yan and Marinchak: JCE 2000:11:95-97 J wave and Phase 2 Reentry Aizawa, et al. Am Heart J 1993; 126:1473-4 Features of Ito-mediated epicardial action potential spike and dome ---- J wave J wave is the consequence of Ito-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; Ito-mediated action potential spike and dome is more prominent in right ventricular epicardium; Ito-mediated action potential spike and dome is more prominent in males than in females; Ito-mediated action potential spike and dome predisposes the loss or depression of action potential dome in epicardium, resulting in ST segment elevation; therefore, Ito-mediated ST segment elevation shares the features with J wave. 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. Are other racial groups, like white or black people, immune to this problem? The Findings by Brugada Brothers in 1992 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. RBBB ? 12 Are the cases reported by Brugada and Brugada from Europe similar in etiology to those SCD cases in Asia? Thank You!