Pro Arrhythmia

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 Slow phase 3: block IK1 or IKr

Prolong phase 2: Increase INa or ICa 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