Pro Arrhythmia
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PROARRHYTHMIA
Transcript of Pro Arrhythmia
PROARRHYTHMIA
Low IKs, ++ density of Ito++ late INa, +++ INa-Ca
Variable ventricular K channels expression:Heterogeneous Repolarization
+++ density of Itof , IKr
High density of Itof , IKur , IKr
High density of Itof
*+ density of Itof
ECG and IKs Ito Heterogeneity
+
_ Vm
+
_
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Δ
EFFECTS OF CHANGE OF EXTRCELLULAR [K]
IKr conductance directly related to [K]oEffect quantitatively greater in M cellsDecrease Vm gradient in hypoK, increase in hyperK
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TRANSMURAL V DIFFERENCES
Also elevation of resting Vm, decreased Vmax, elevated [K]o
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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
Circulation 1989;79:1000
Exercise induced VT with Flecanide
Rest 65 msec
Peak exercise 103 msec
VT
Flecanide Proarrhythmia
Proarrhythmia Class I
• IA TdPmore likely with: HypoK, hypoMg, concomitant class III drugs, bradycardiaProlongation of QT greater than 500 msecStructural HDHistory of sustained VTIschemia
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
Gima, K. et al. Circ Res 2002;90:889-896
IKr block slows M repolarizationas they have less IKs to complete repolarization
IKs block induces an homogeneous depolarization prolongation butno 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 βstimulation persistence of IKs at faster rates)
K channel block and pro-arrhythmia
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
EAD underlies the premature beat initiating TdPPhase 2 EAD Ca dependent phase 3 Na dependent
TDR creates a vulnerable window for re-entryIntrinsic heterogeneity amplified by drugs, electrolytes, ischemia, β agonists etc
MECHANISM of TDP
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%
*CYP3A
Fexofenadine
Terfenadine Story
NEJM 2004;350:1013
ProarrhythmiaRed 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
Prolong phase 2:Increase INa or ICa or reducing IKs
Slow phase 3:block IK1 or IKr
PROLONGING APD
CIRCULATION 2001;103:2013
Too much time in the Ca reactivation windowToo long in Na channel Reactivation V
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
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The wavelength of the tachycardia is determined byConduction velocity X refractory period
Schematic of re-entrant circuit
Class I AA drugs affect VmaxClass III AA drugs affect ERP
EFFECTS OF AA DRUGS ON TACHYCARDIA CIRCUIT
TERMINATING THE TACHYCARDIA
