PROARRHYTHMIA

Variable ventricular K channels expression:

Heterogeneous Repolarization

High density of Itof , IKur , IKr

High density of Itof

+ density of Itof

* Low IKs, ++ density of Ito

++ late INa, +++ INa-Ca
+++ density of Itof , IKr
 ECG and IKs Ito Heterogeneity

Δ
Vm
_ _

+ +

Circ Res 2002;90:889

 EFFECTS OF CHANGE OF EXTRCELLULAR [K]

IKr conductance directly related to [K]o

Effect quantitatively greater in M cells
Decrease Vm gradient in hypoK, increase in hyperK
Circ Res 2002;90:889
TRANSMURAL V DIFFERENCES
Also elevation of resting Vm,
decreased Vmax, elevated [K]o

Circ Res 2002;90:889

 Proarrhythmia

• Worsening of pre-existing arrhythmias or

induction of new forms of arrhythmia
• Most important factor limiting use of AAD
• A number of studies demonstrate
increased mortality with AAD use
 Proarrhythmia
• Worsening of clinical arrhythmia:
NS to Sustained
• Induction of new arrhythmia:
Bradyarrhythmias (SN, AVN, HPS)
SVT (Aflutter)
Ventricular (TdP, VT, incessant VT)
 Proarrhythmia
Class I
• Facilitation of re-entry due to slowing of
conduction
• Post MI conduction slowing in ischemic
zone facilitating re-entry
• AAD needs to be present prior to acute MI
to reach sufficient concentration in
ischemic area (CAST: increase SCD in pts
with non fatal MI)
 Proarrhythmia
Class I

• In absence of cardiac pathology AAD safe

(2% in normal CV, 7 to 17% in CAD)
• Transformation of AF in AFL with fast V
rates (slow AFL cl and vagolitic effect of
class Ia)
• Class IA can also induce proarrhythmia
due to AP prolongation (class III effect)
Encanide Proarrhythmia
Exercise induced VT with Flecanide

Rest 65 msec

Peak exercise 103 msec

VT

Circulation 1989;79:1000
Flecanide Proarrhythmia
 Proarrhythmia
Class I

• IA TdPmore likely with:

HypoK, hypoMg, concomitant class III
drugs, bradycardia
Prolongation of QT greater than 500 msec
Structural HD
History of sustained VT
Ischemia
Quinidine Proarrhythmia
 Proarrhythmia
Class III

• SD during ECG monitoring shows 55% pt

had prolonged QT and 60% were on AAD
• Early after AAD initiation
• 30-50% cases greater than 4 days
• Bradycardia, HypoK, HypoMg, concomitant
QT prolonging drugs increase proarrhythmia
 K channel block and pro-arrhythmia

IKr block slows M repolarization

as they have less IKs to complete
repolarization

IKs block induces an homogeneous

depolarization prolongation but
no arrhythmia

Isoproterenol shortens epi and

endocardial APD inducing TdP (increase
of IKs)

Augmentation of late INa increase M cells

APD with TdP

Slow HR increases and fast HR

decreases TdR (IKs stimulated by β
stimulation persistence of IKs at faster
rates)
Gima, K. et al. Circ Res 2002;90:889-896
 Proarrhythmia
Class III
• Class III prolonging QT by more than 50
msec have TdP risk of more than 1%
• No linear relationship between QT
prolongation and risk
• QT >500 msec considered high risk
 Proarrhythmia
Class III

• Prolongation of QT also associated with

VT, VF, polymorphous VT
• TdP degenerates into VF in 20% cases
• Mortality of TdP is 10-17%
 Proarrhythmia
Class III
• Short QT can also be proarhythmic (i.e.
congenital or due to mexiletine)
• AAD induced QT prolongation not reliable
marker of proarrhythmia

Typical TdP

Short coupling TdP

 Proarrhythmia
Class III

• Class III AAD prolong APD and induce

Transmural Dispersion of Repolarization
(TDR) and/or EAD-TdP
• QT prolongation reflects AP repolarization
• QT prolongation = TdP
 Proarrhythmia
Class III
• Imperfect link between molecular effect of
AAD, prolongation of APD and TdP
• Drugs may block IKr (Amiodarone,
Verapamil) and not cause TdP
• Terfanadine blocks IKr does not causes QT
prolongation or TdP experimentally
• QT is FDA yardstick for torsedogenicity
• QT correction for rate difficult and imperfect
 Proarrhythmia
Class III
• Alternative measure of TDR:
• QT dispersion (inter-lead difference
between longest and shortest QT in 12
lead ECG)
• Tpeak Tend
• T wave alternans
 MECHANISM of TDP

EAD underlies the premature beat initiating TdP

Phase 2 EAD Ca dependent phase 3 Na dependent

TDR creates a vulnerable window for re-entry

Intrinsic heterogeneity amplified by drugs, electrolytes, ischemia, β agonists etc
76 Female, CRF, AF on Sotalol
 Proarrhythmia
Class III
• Reduced repolarization reserve due to:

Subclinical LQTs (5-10% of pts developing

TdP on AAD)
Common polymorphism causing variations
in gene function manifest on AAD, HF hypoK
Polymorphism variants present in up to 15%
 Terfenadine Story

*CYP3A

Fexofenadine

NEJM 2004;350:1013
 Proarrhythmia
Red Flags
• Elderly women, pts with CV disease,
concomitant drugs prolonging QT, family
history of SD, polypharmacy
• Report syncope, pre-syncope, palpitations,
conditions potentially causing hypoK
(diuretics, GI problems)
• Baseline ECG , follow up ECGs

Circulation 2000;101:1749
THE END
 PROLONGING APD
Prolong phase 2:
Slow phase 3: Increase INa or ICa
block IK1 or IKr or reducing IKs

Too much time in the

Ca reactivation window
Too long in Na channel
Reactivation V

CIRCULATION 2001;103:2013
 Proarrhythmia
Class III
• EADs are induced by one or combination of:
Reduction in repolarization currents
Increased in ICa availability
Increased Na/Ca exchange current
due to increased intracellular Ca
Increase in late INa
• This causes Ca mediated current initiating a
propagated response
HYPOTHERMIA and Ito

Circ Res 2002;90:889

EFFECTS OF AA DRUGS ON TACHYCARDIA CIRCUIT

Schematic of re-entrant circuit

The wavelength of the tachycardia is determined by

Conduction velocity X refractory period

Class I AA drugs affect Vmax

Class III AA drugs affect ERP

TERMINATING THE TACHYCARDIA