A unique and priced ppt on Proarrhythmias

1. PROARRHYTHMIA
Dr. D SUNIL REDDY

2. DEFINITION
• Proarrhythmia is defined as the provocation of a new
arrhythmia or the aggravation of a pre-existing one
during therapy (with a drug below its toxic doses)
• Suggested criteria@ for proarrhythmia include
(1) The new appearance of a sustained ventricular
tachyarrhythmia
(2) Change from a nonsustained to a sustained
tachyarrhythmia
(3) Acceleration of tachycardia rate or
(4) The new appearance of a clinically significant
bradyarrhythmia or conduction defect
(5) A worsening or change of a preexisting arrhythmia
@ Zipes, DP. Proarrhythmic effects of antiarrhythmic drugs. Am J Cardiol 1987; 59:26E

3. TYPES OF PROARRHYTHMIA
1 VENTRICULAR PROARRHYTHMIA
• Torsade de pointes (VW type IA and type III drugs)
• Sustained monomorphic VT (usually type IC drugs)
• Sustained polymorphic VT/VF without long QT
(types IA, IC, and III drugs)
2 ATRIAL PROARRHYTHMIA
• Conversion of AF to flutter (usually type IC drugs or
amiodarone)
• Increase of defibrillation threshold ( type IC )

4. 3 ABNORMALITIES OF CONDUCTION OR
IMPULSE FORMATION
• Sinus node dysfunction, AV block (almost all
drugs)
• Accelerate conduction over accessory
pathway (digoxin, I/V verapamil, or diltiazem)
• Acceleration of ventricular rate during AF
(type IA and type IC drugs).

5. PROARRHYTHMIAS AND
ANTIARRHYTHMICS
• Proarrhythmic events can occur in as many as
5 to 10 percent of patients receiving
antiarrhythmic agents
• Concomitant Structural heart disease
increases this risk
• Antiarrhythmic agents decrease conduction
velocity and increase refractoriness.
• Degree of block with antiarrhythmic agents is
increased progressively at faster heart rates

6. • They vary with respect to rate of development of
block during repetitive stimulation or rate of
recovery from block (kinetics), as well as saturation
behaviour ; based on these properties they can be
divided into three subgroups
• Group 1 - fast onset kinetics and saturation level of
block at rapid rates (῀300 beats/min)
• Group 2 - slow onset kinetics and saturation level at
rapid rates ( ῀ 300 beats/min); Encainide, Flecainide,
Procainamide,Quinidine
• Group 3 - slow onset kinetics and saturation level of
frequency dependent block at slower heart rates ( ῀
100 beats/min). Propafenone and disopyramide
Muqtada et al ; Antiarrhythmic agents and proarrhythmia ;Crit Care Med
2010 Vol. 28, No. 10 (Suppl.)

7. Vaughan-Williams Classification of Antiarrhythmic Drugs
Class Action Drugs
I SODIUM CHANNEL BLOCKADE
Ia Moderate phase 0 depression and
conduction slowing, prolonging of
action potential duration
Quinidine, procainamide,
disopyramide
Ib Minimal effect on phase 0 upstroke
No change or shortening of APD
Lidocaine, mexiletine, tocainide
Ic Marked phase 0 depression and
conduction slowing, little effect on
repolarization
Flecainide, propafenone,
moricizine
II B - ADRENERGIC BLOCKADE Propranolol, metoprolol, atenolol,
esmolol, acebutolol
III POTASSIUM CHANNEL BLOCKADE d,l-Sotalol, dofetilide, amiodarone,
bretylium, ibutilide
IV CALCIUM CHANNEL BLOCKADE Verapamil, diltiazem

8. Torsade de Pointes
• Torsade de pointes is polymorphic VT
associated with prolongation of the QT interval.
• EAD of action potential in phase III are thought
to be the mechanism
• Bradyarrhythmia and hypokalemia are the
most common precipitating factors

9. DRUGS WITH A RISK OF TDP
ARSENIC TRIOXIDE DROPERIDOL
ASTEMIZOLE ERYTHROMYCIN
AZITHROMYCIN HALOPERIDOL
CHLOROQUINE METHADONE
CHLORPROMAZINE PROCAINAMIDE
CISAPRIDE QUINIDINE
CLARITHROMYCIN SEVOFLURANE
DISOPYRAMIDE SOTALOL
DOFETILIDE SPARFLOXACIN
DOMPERIDONE TERFENADINE
FLECAINIDE THIORIDAZINE
IBUTILIDE HALOFANTRINE
MOXIFLOXACIN PENTAMIDINE

10. Characteristic pattern of a TDP
• First, a change in the amplitude and morphology
(twisting) of the QRS complexes around the
isoelectric line is a typical feature of the
arrhythmia
• Second, episodes of drug-induced TdP usually
start with a short-long-short pattern of R-R cycles
consisting of a short-coupled premature
ventricular complex (PVC) followed by a
compensatory pause and then another PVC that
typically falls close to the peak of the T wave

11. • Third, TdP episodes usually show a warm-up
phenomenon, with the first few beats of
ventricular tachycardia exhibiting longer cycle
lengths than subsequent arrhythmia complexes.
• The rate of TdP ranges from 160 to 240 beats per
minute, which is slower than ventricular
fibrillation.
• Fourth, in contrast to ventricular fibrillation that
does not terminate without defibrillation, TdP
frequently terminates spontaneously, with the
last 2 to 3 beats showing slowing of the
arrhythmia.

12. Characteristics of TDP

13. Premonitory ECG Signs of TDP
• Each 10-ms increase in QTc contributes approximately a
5% to 7% exponential increase in risk for TdP
• QTc 500 ms is associated with a 2- to 3-fold higher risk for
TdP.
• ECG sign of impending TdP is macroscopic T-wave
alternans
• Exaggerated QT-interval prolongation with T-U distortion
after a pause should be considered a strong marker of
risk for TdP.

14. • In a patient with drug-induced LQTS, the QT interval may
be prolonged during normal sinus rhythm without
adverse effect, but after a pause , QT-interval
prolongation and T-U deformity become markedly
exaggerated, and TdP is triggered.
• Some reports ( Topilski et al ) indicate that TdP is
especially likely when the QT interval is prolonged
because of an increase in the terminal portion of the T
wave, from the peak of the T wave to its end (Tpeak-
Tend)
• QT prolongation alone is insufficient and a heterogeneity
of repolarization is also necessary to produce an
arrhythmogenic response in some cases .

15. ECG before the onset of TdP shows extreme
prolongation of the QT interval (QTc in cycles with
larger T waves730 ms), a ventricular couplet ( ), )
and macroscopic T-wave alternans (vertical arrows)

16. Risk Factors for TDP
• QTc > 500 ms
• Use of QT-prolonging drugs
• Congestive heart failure
• Myocardial infarction
• Advanced age
• Female sex
• Hypokalemia
• Hypomagnesemia
• Hypocalcemia
• Treatment with diuretics
• Impaired hepatic drug
metabolism
• Bradycardia
– Sinus bradycardia, heart
block, incomplete heart
block with pauses
– Premature complexes
leading to short-long-
short cycles

17. Monomorphic Ventricular Tachycardia
• Marked slowing of conduction with sodium channel
blockade can activate potential circuits for ventricular
tachycardia, which can be difficult or impossible to
terminate.
• Drugs with the capability to depress conduction velocity
(class IC agents) are the worst offenders
• Management includes withdrawal of the drug ,
Amiodarone and attempts at cardioversion.
• Intravenous NaCl can be used to counter Na channel
blockade with mass effect.

18. Altered A-V Conduction
• In patients with WPW syndrome and atrial fibrillation, rapid
ventricular rates can be seen with conduction via the bypass
tract.
• Use of class II and IV agents, as well as digoxin can be
associated with decreased conduction over the A-V node and
thus, a lesser degree of retrograde penetration at the
ventricular insertion site of the accessory pathway
• Digoxin may decrease the refractory period of almost 30% of
accessory pathways resulting in extremely rapid ventricular
rates, which might transform into ventricular fibrillation and
precipitate sudden death.

19. • Intravenous procainamide or amiodarone, or
preferably, cardioversion is the management of
choice in such patients
• In patients with atrial fibrillation, organization into
atrial flutter may result in loss of concealed A-V
nodal penetration and faster ventricular rates. Class
IC, class IA, and occasionally amiodarone is
associated with such effects.
• Ablation of flutter circuit and continued drug therapy
is a useful management option in such patients

20. AMIODARONE
• Chronic administration of amiodarone markedly prolongs
the QT interval, yet it is very rarely a/w TdP (<1%) .
• It has been postulated that unlike high-risk drugs that
selectively prolong repolarization in myocytes located in
the mid myocardium (M cells), amiodarone uniformly
delays repolarization in all layers of the myocardial wall.
• As a result, there is only QT prolongation and no
transmural heterogeneity of repolarization, which is the
necessary substrate for the development of a reentrant
arrhythmia.

21. ICD AND PROARRHYTHMIA
• ICD-induced proarrhythmic events are rarely fatal but
increase the morbidity associated with device therapy
• Careful reprogramming of the pacemaker parameters is
needed in order to avoid pacing-facilitated
proarrhythmia.
• CLASSIFICATION
 Clinically Appropriate Therapies
• ATP or shocks leading to:
– Acceleration of VT
– Deceleration of VT
– Induction of supraventricular tachyarrhythmias

22.  Clinically Inappropriate Therapies
• Antitachycardia therapies (ATP, cardioversion,
defibrillation)
– Failure to discriminate between SVT and VT
– Committed behavior for nonsustained VTs
– Signal oversensing
• Antibradycardia pacing
• Undersensing of spontaneous beats

23. ICD INDUCED BRADYARRHYTHMIAS
• Postshock bradyarrhythmias
• Postshock increase in pacing threshold leading to
noncapture
• Postshock reset of a separate pacemaker
• Inhibition of antibradycardia pacing caused by T-
wave oversensing

24. CRT – PROARRHYTHMIC ?
• Experimental studies suggest that change in transmural
activation in CRT can result in remodeling of cardiac
repolarization
• The development of polymorphic VT following CRT
seems to occur in the early postoperative period.
• The Tpeak-Tend interval provides a measure of the TDR.
• A prolonged Tpeak-Tend has been linked to
spontaneous development of ventricular tachycardia
and, interestingly, with increased inducibility.
• In effect, a prolonged Tpeak-Tend marks the presence
of an arrhythmogenic substrate

25. THANK
YOU

27. Sweeney et al's VT/VF categories
 NON-PACING ASSOCIATED: No pacing or S-L-S sequence within
five cycles of the onset of VT/VF.
 PACING-ASSOCIATED: Pacing present within five cycles before
VT/VF initiation, but no S-L-S sequence.
 PACING-PERMITTED: VT/VF is initiated by an S-L-S sequence not
caused by pacing stimuli but passively allowed by the device
mode.
 PACING-FACILITATED: Single ventricular-pacing stimuli initiate or
terminate pauses prematurely, producing an S-L-S sequence
followed by VT/VF.

28. Pacing-facilitated VT with S-L-S, pacemaker in the VVI mode: The red star
indicates a ventricular premature beat that creates the first short interval; the
bracket indicates the long interval, or pause; and the arrow points to the second
short interval and initiation of VT. [Provided by Dr Michael O Sweeney]

29. Subgroup of patients with VT/VF DDDR
n=88
VVIR,
n=53
MVP
n=63
With
any
n=204
Those with only non-pacing-
facilitated VT/VF (%)
71.6 88.7 84.1 79.9
Those with only pacing-facilitated
VT/VF with S-L-S initiation (%)
6.8 3.8 9.5 6.9
Those with pacing-facilitated VT/VF
with S-L-S initiation plus non-pacing-
facilitated VT/VF (%)
21.6 7.5 5.3 13.2

31. Evidence for increased mortality with antiarrhythmics
CAST - I Increased total and sudden death mortality with
flecainide and encainide.
CAST - II Increased total and sudden death with moricizine
IMPACT Increased mortality with mexiletine.
SWORD Increased total and sudden death with D-sotalol.
Coplen et al Increased mortality with quinidine ( AF )
Flaker et al Excess mortality for AF patients with heart failure
receiving antiarrhythmic drugs.
Nattel et al. Increased mortality with quinidine, disopyramide,
flecainide, and sotalol ( AF )
Moosvi et al.
(Cardiac arrest )
Increased rate of recurrent cardiac arrest in pts
receiving empiric quinidine procainamide.