稳心颗粒抗室性心侓失常的机制 Gan-Xin Yan Professor, Lankenau Institute for Medical...

稳心颗粒抗室性心侓失常的机制稳心颗粒抗室性心侓失常的机制

Gan-Xin YanGan-Xin YanProfessor, Lankenau Institute for Medical ResearchProfessor, Lankenau Institute for Medical ResearchProfessor of Medicine, Thomas Jefferson UniversityProfessor of Medicine, Thomas Jefferson University

When we use a sodium channel blocker for suppression of cardiac When we use a sodium channel blocker for suppression of cardiac arrhythmias, which effects we expect are antiarrhythmic?arrhythmias, which effects we expect are antiarrhythmic?

Slow conduction velocity;Slow conduction velocity;

Prolong Effective Refractory Period; therefore, Prolong Effective Refractory Period; therefore, prolong the wavelength and abolish the reentry prolong the wavelength and abolish the reentry circle circle （（±±）） ;;

Reduce intracellular calcium overloading via Na-Reduce intracellular calcium overloading via Na-Ca exchangeCa exchange;;

Blunt rate-dependent change in ventricular Blunt rate-dependent change in ventricular repolarization;repolarization;

Reduce dispersion of repolarization, particularly Reduce dispersion of repolarization, particularly during bradycardia.during bradycardia.

When we use a sodium channel blocker for When we use a sodium channel blocker for suppression of cardiac arrhythmias, which effects suppression of cardiac arrhythmias, which effects

we expect are antiarrhythmic?we expect are antiarrhythmic?

Slow conduction velocitySlow conduction velocity

传导速度减慢传导速度减慢

折返波长折返波长 == 传导速度 x x 有效不应期有效不应期

折返心侓失常的机制

(1) Late Sodium Current (I(1) Late Sodium Current (INa,LNa,L) Contributes to ) Contributes to Ventricular RepolarizationVentricular Repolarization

Late Sodium Channel CurrentLate Sodium Channel Current

SodiumCurrent

0

Late INa

Peak

NormalNormal(Physiologic)(Physiologic)

0

Late INa

Peak

AbnormalAbnormal(Pathophysiologic)(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+

Na+Impaired

Inactivation

(40 to < 100 pA)

Late INa

1. Slowly inactivating INa

2. Late Reopenings

3. Bursting Behavior

• Single NaCh Current

Late Sodium Current Feature 1Feature 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 There may be species-dependent differences in left ventricular Idifferences in left ventricular INa,LNa,L

Human > Dog > Rabbit> RatHuman > Dog > Rabbit> Rat

Weight (Kg)

10-1 100 101 102 103 104 105

QT

c (

ms

)

0

200

400

600

800

1000

Whale

Elephant

HumanCamel

Horse

DogKoala

Rabbit

Guinea pigRat

Donkey

Rhinoceros

Each Species has its own ventricular Each Species has its own ventricular repolarization time (QTc) repolarization time (QTc)

Wang, Cui and Yan: Pharmacol.Ther 2008; 119:141-151

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

Bazett's FormulaBazett's Formula: : QTc= QT Interval / √ (RR interval)QTc= QT Interval / √ (RR interval)

HR 60 70 80 90 100RR (s) 1 0.86 0.75 0.67 0.6

QT (ms) 400400 370 346 327 310

ΔQT:225 ms/ ΔRR per secondΔQT:225 ms/ ΔRR per second

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

Ion Mechanism for Rate Adaptation of Ion Mechanism for Rate Adaptation of RepolarizationRepolarization

Classic IClassic IKsKs Hypothesis should be Abandoned: Hypothesis should be Abandoned:

IIKsKs does not play a significant role in rate adaptation does not play a significant role in rate adaptation of ventricular repolarization of ventricular repolarization

Guo, Kowey, Yan; Heart Rhythm 2011;8:762-769

Contribution of INa,L to Rate-dependent change in APD

Why?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

2750.25028 2755.25028 2760.25028 2765.25028 2770.25028

seconds

-0.565592

0.000000

0.565592

1.131185

Volts

-0.871175

-0.653381

-0.435588

-0.217794

Volts

2750.25028 2755.25028 2760.25028 2765.25028 2770.25028

seconds

-0.565592

0.000000

0.565592

1.131185

Volts

-0.871175

-0.653381

-0.435588

-0.217794

Volts

65.25028 70.25028 75.25028 80.25028

seconds

-0.265503

-0.132751

0.000000

0.132751

Vo

lts

-1.132813

-0.991211

-0.849609

-0.708008

Vo

lts

65.25028 70.25028 75.25028 80.25028

seconds

-0.265503

-0.132751

0.000000

0.132751

Volts

-1.132813

-0.991211

-0.849609

-0.708008

Volts

A. Control

B. E-4031 (60 nM)Spontaneous TdP

4125.25028 4130.25028 4135.25028 4140.25028

seconds

-0.268046

-0.252279

-0.236511

-0.220744

Volts

106.076218

117.862465

129.648711

141.434957

Volts

C. E-4031 (60 nM) + TTX (0.6 µM)

3-sec pause

4125.25028 4130.25028 4135.25028 4140.25028

seconds

-0.268046

-0.252279

-0.236511

-0.220744

Volts

106.076218

117.862465

129.648711

141.434957

Volts

Feature 3:Feature 3: Heterogeneous Distribution of I Heterogeneous Distribution of INa,LNa,L, Resulting in , Resulting in

Dispersion of Repolarization under Physiological ConditionDispersion of Repolarization under Physiological Condition

Transmural (left ventricle): M cells > Transmural (left ventricle): M cells > endocardium > epicardium;endocardium > epicardium;

Regional: LV > RV > atria, Regional: LV > RV > atria, leading to regional leading to regional heterogeneous dispersion of repolarizationheterogeneous dispersion of repolarization..

Yan and Antzelevitch:Yan and Antzelevitch:Circ 1998;98:1268-1236Circ 1998;98:1268-1236

Yan et al Circ 2001; 103:2851-2856

Since ISince INa,L Na,L is Larger in M cells than in epicardium, QT prolongation is Larger in M cells than in epicardium, QT prolongation

during bradycardia is accompanied by Tp-e prolongationduring bradycardia is accompanied by Tp-e prolongation

Pause-dependent QT and Tp-e Pause-dependent QT and Tp-e prolongation----- TdPprolongation----- TdP

A Pathophysiological Paradigm: Sodium ChannelopathyA Pathophysiological Paradigm: Sodium Channelopathy

Enhanced late INa

Ca2+

OverloadCa2+

Overload

NaNa++ii

Impaired Na Ch inactivation

Enhanced late INa

Modified from Belardinelli L. et al. Heart. 92 (Suppl. IV):IV6-IV14, 2006.

Pathological Conditions

• Acquired• Congenital

Late INa

Peak INa

normal

abnormal

Sodium Current (INa)

IINa,LNa,L, TWA and EAD, TWA and EADEffect of RanolazineEffect of Ranolazine

IINa,LNa,L, TWA,EAD and R-on-T, TWA,EAD and R-on-TEffect of RanolazineEffect of Ranolazine

Case 1: 2 year old infant with LQT8 (Timothy Syndrome).Case 1: 2 year old infant with LQT8 (Timothy Syndrome). Pathophysiology: gain of function in L-type calcium currentPathophysiology: gain of function in L-type calcium current

Syndactyly Syndactyly

2:1 AV block2:1 AV block

T Wave T Wave AlternansAlternans

Mexiletine, a pure sodium channel blocker, shortens Mexiletine, a pure sodium channel blocker, shortens

QT and abolishes 2:1 AV block and T wave alternansQT and abolishes 2:1 AV block and T wave alternans

Mexiletine RR-QT slopeMexiletine RR-QT slope

Case 2Case 2: TWA and TdP in Takotsubo: TWA and TdP in Takotsubo

Recent Progress in J Wave SyndromesRecent Progress in J Wave Syndromes

J Wave Syndromes: J Wave Syndromes: ECG features of ECG features of accentuatedaccentuated J wavesJ waves accompanied byaccompanied by ST segment elevation and/or early repolarization.ST segment elevation and/or early repolarization.

Inherited J Wave SyndromesInherited J Wave Syndromes are associated with a risk of sudden are associated with a risk of sudden cardiac death in apparently healthy young people.cardiac death in apparently healthy young people. Acquired J Wave SyndromesAcquired J Wave Syndromes are more common and can be seen in a are more common and can be seen in a variety of pathophysiological conditions.variety of pathophysiological conditions.

J wave, ST elevation and Early J wave, ST elevation and Early RepolarizationRepolarization

J waveJ wave

ST Elevation and Early RepolarizationST Elevation and Early Repolarization

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

In PhilippinesIn Philippines capital city Malina, a total of capital city Malina, a total of 722 apparently healthy young males died 722 apparently healthy young males died during sleep during 1948 to 1982, a during sleep during 1948 to 1982, a disease called “Bangungut” (to rise and disease called “Bangungut” (to rise and moan during sleep) in native language. In moan during sleep) in native language. In 1982, the incidence is about 26.3/100,000 1982, the incidence is about 26.3/100,000 per year. per year.

If there were a similar incidence in China, If there were a similar incidence in China, this syndrome would take approximately this syndrome would take approximately 320,000 young lives in China a year. 320,000 young lives in China a year.

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

Nocturnal and Pause-Dependent Amplification of J Nocturnal and Pause-Dependent Amplification of J Wave (29 yo Asian Male)Wave (29 yo Asian Male)

Journal of Cardiovascular Electrophysiologypages no-no, 7 JUL 2011 DOI: 10.1111/j.1540-8167.2011.02124.x

5 AM5 AM

J wave with Ventricular FibrillationJ wave with Ventricular Fibrillation

Kalla, Yan and Marinchak: JCE 2000:11:95-97Kalla, Yan and Marinchak: JCE 2000:11:95-97

J wave and Phase 2 ReentryJ wave and Phase 2 Reentry

Aizawa, et al. Am Heart J 1993; 126:1473-4

Features of IFeatures of Itoto-mediated epicardial action potential -mediated epicardial action potential

spike and dome ---- J wavespike and dome ---- J wave

J wave is the consequence of IJ wave is the consequence of Itoto-mediated action potential -mediated action potential spike and dome in epicardium but not in endocardium; The J spike and dome in epicardium but not in endocardium; The J wave size is amplified during wave size is amplified during bradycardiabradycardia or by an or by an enhanced vagal tone;enhanced vagal tone;

IItoto-mediated action potential spike and dome is more -mediated action potential spike and dome is more prominent in prominent in right right ventricular epicardium; ventricular epicardium;

IItoto-mediated action potential spike and dome is more -mediated action potential spike and dome is more prominent in prominent in malesmales than in females; than in females;

IItoto-mediated action potential spike and dome predisposes -mediated action potential spike and dome predisposes the the loss or depressionloss or depression of action potential dome in epicardium, of action potential dome in epicardium, resulting in ST segment elevation; therefore, Iresulting in ST segment elevation; therefore, I toto-mediated ST -mediated ST segment elevation shares the features with J wave.segment elevation shares the features with J wave.

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

Are other racial groups, like white or Are other racial groups, like white or black people, immune to this black people, immune to this

problem?problem?

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

The Findings by Brugada Brothers in 1992The Findings by Brugada Brothers in 1992

12

RBBB ? RBBB ?

AreAre the cases reported by Brugada and Brugada from Europe 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?

Thank Thank You!You!

稳心颗粒抗室性心侓失常的机制 Gan-Xin Yan Professor, Lankenau Institute for Medical...

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