Transcript Late Sodium Current (I Na,L ) Contributes to Ventricular Repolarization

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!