TORSADES DE POINTES

Dalmo Antonio Moreira Ribeiro MD, PhD

Dante Pazzanese Institute os Cardiology, São Paulo

Itajubá Medical School, Minas Gerais

It is a type of polymorphic ventricular tachycardia that is associated with prolongation of

the QT interval (QT interval corrected for heart rate > 440 ms) and can be acquired or
congenital in origin, unlike the polymorphic ventricular tachycardia that occurs in acute
myocardial infarction, when the QT interval is not prolonged. This distinction is important
because the tachycardia can be treated with drugs that prolong the QT interval, such as
procainamide, without risk to patients whose arrhythmia is not associated with long QT
interval, while they are contraindicated when this interval is prolonged during sinus
rhythm.

Electrocardiographically it is characterized by the appearance of premature ventricular

contractions, polymorphic or mono, which cause the appearance of pauses of varying
length, which most often is interrupted by a normal beat (figure 1 A). The QT interval of
this beat is prolonged by the previous pause, predisposing to a new ventricular extra-
systole, which often falls on the vulnerable period of the T wave. At this time, cardiac cells
are in different stages of repolarization, some already completed, others still in full
evolution. Such discrepancies predispose to fragmentation of ventricular activation and
the consequent emergence of a polymorphic tachycardia characterized by QRS
complexes with tips oriented upward and downward, as if turning around its baseline
(figure 1 B to D) . Tachycardia is usually self-limited (5 to 20 or 30 QRS complexes),
breaking up spontaneously or degenerating into ventricular fibrillation. Not yet determined
what degree of QT prolongation that is associated with the onset of ventricular
tachycardia, however, values> 550 ms should be considered high risk, particularly in
patients taking drugs that prolong the QT interval.
Torsades de Pointes Caused by Drugs

One of the most important concepts acquired in recent years about the antiarrhythmic
therapy, is that the drugs prescribed for the treatment of cardiac arrhythmia, ventricular or
supraventricular origin, can cause death, and the mechanism involved in this condition is
a polymorphic ventricular tachycardia called torsades de pointes. The most important
predisposing factors for triggering of arrhythmia by antiarrhythmic agents are: long QT
interval, ventricular dysfunction, myocardial ischemia, complex ventricular arrhythmias,
bradycardia, electrolyte imbalance (particularly hypokalemia and hypomagnesemia),
history of torsades de pointes. Women seem to be more vulnerable than men.

Besides antiarrhythmic drugs, other pharmacologic agents are involved with torsades de
pointes, and may be cited: a) psychotropic drugs (phenothiazines, tricyclic
antidepressants), b) antibiotics (erythromycin, trimethoprim-sulfamethoxazole,
pentamidine), c) antihistamines (astemizole, terfenadine) .

Torsades de Pointes and Congenital Long QT Interval Syndrome

Classically, it is described the Jervell and Lange-Nielsen long QT interval syndrome,

whose electrocardiographic change is associated with congenital deafness; the Romano-
Ward syndrome, is not associated with deafness, in which the QT is prolonged and there
is a propensity with syncope and sudden death.

The pathophysiological mechanisms are not yet finally clarified. One hypothesis is the
discrepancy of ventricular autonomic innervation, with a predominance of sympathetic
activity in the left ventricle and hypoactivity over the right ventricle. It is based on this
theory the concept of using beta-blockers and resection of the left stellate ganglion in the
treatment of the affected patients. Another theory is related to genetic abnormality,
specifically located on chromosome 11, in which mutations in related genes encoding
proteins involved in the structure of channels that transport potassium currents
A

B
C

Figure 1 - Holter 24 hours after a patient of 75 years, with chronic atrial fibrillation with quinidine
600 mg / day for maintenance of sinus rhythm. The tracing shows sinus rhythm with ventricular
extrasystoles and QT interval of up to 680 ms (measured in channel A). Plots B, C and D are
continuous showing start and finish of polymorphic ventricular tachycardia of torsades de
pointes. Note the oscillation of the tip of the QRS complexes around the baseline, typical of this
arrhythmia. As in most cases, the episodes are self-limiting, stopping spontaneously. In this case,
the patient was hospitalized, the medication was suspended and administered magnesium
sulfate, with improvement in clinical status.
(genes KVLQT1 and HERG currents to slow and fast correction of potassium
respectively) or sodium (SCN5A) prolong repolarization and consequently, the QT
interval. In asymptomatic patients with not apparent ECG changes, the arrhythmia may
present when they use drugs that prolong the QT interval.

Electrophysiological mechanisms
Triggered activity by early after-potential is the main mechanism responsible for
arrhythmogenic polymorphic ventricular tachycardia of torsades de pointes observed in
patients with LQTS. This mechanism involves changes in the functioning of certain ion
channels (K channels or Na) and transmembrane protein (protein kinase II, Ca /
calmodulin dependent) which prolong the action potential duration, allowing recovery
through the inactivation or reactivation of calcium current ICa-L, with consequent triggered
activity by early after-potential (plateau phase or the early phase of repolarization). Some
studies have shown that this event usually occurs in cells of Purkinje fibers and
intramyocardial cells of M type.

In recent years, it was found the close relationship between the autonomic nervous
system and LQTS. Sympathetic activity can exacerbate the input current through the
calcium channels (ICa-L), raising the likelihood of early after-potential. Recent data indicate
that patients with mutations in KCNQ1 or KCNE1 are at increased risk of fatal ventricular
arrhythmias associated with high sympathetic activity. Moreover, other studies have
demonstrated a relationship between the LQTS subtype-2 and adrenergic stress. Such
patients usually have sinus bradycardia and have prolonged action potentials during
sleep. Upon awakening suddenly, a release of large amounts of epinephrine, may cause

polymorphic ventricular tachycardia, ventricular fibrillation and sudden death.

The main mechanism involved in the genesis of torsades de pointes in the context of
acquired LQTS is the blockade of IKr current, the main responsible for the ventricular
repolarization phase. Drugs that specifically block this current, without acting on other ion
channels, are more likely to induce tachycardia. M cells and Purkinje fibers are more
often affected than other cardiac myocytes, which explains the increased dispersion of
repolarization observed in this syndrome, whose consequence is the development of
torsades de pointes by triggered activity due to early after depolarization (initial phase of
repolarization).

Regarding the anti-arrhythmic drugs, the risk of torsades de pointes with amiodarone is
much smaller than with quinidine or sotalol. This fact is explained by the action of
amiodarone in blocking multiple ion channels, K (IKr), calcium (ICA-L) and Na channels
(INa), reducing thus the dispersion of repolarization.

The degree of QTc prolongation may vary depending on the serum levels of the drug, the
combination of drugs that prolong the QTc interval, and the interaction among drugs that
interfere with metabolism through the CYP2D6 and CYP450. With respect to quinidine,
the risk of torsades de pointes is higher precisely in subtherapeutic plasma
concentrations, since at low concentration there is greater blockade of IKr current, and
lower blockade of the sodium channels INa).

Initial studies of genetic analysis suggest that some patients have a higher genetic
predisposition to the development of torsades de pointes associated with acquired long
QTc.. Women are more vulnerable to this arrhythmic complication.

In summary, the early post-depolarization secondary to triggered activity would be

responsible for torsades de pointes, both with congenital and acquired form. In this
condition, before repolarization is complete, oscillations of the early action potentials
reach the threshold potential causing ventricular ectopy. Catecholamines and calcium
currents make cells more vulnerable. The arrhythmia could be maintained by this
mechanism, or by reentry secondary to dispersion of repolarization.

Treatment

In the acquired form, it is indicated the immediate suspension of the drug involved. In
addition, potassium replacement when indicated, and administration of magnesium
sulfate bolus (2 g, followed by 2 to 4 grams after 15 minutes, if necessary, and continuous
infusion of 3 to 30 mg / minute in the next 24/48 hours ). The implantation of temporary
pacemaker for ventricular pacing at frequencies ranging between 90 and 110 beats per
minute, reduce episodes of tachycardia due to a reduction in QT interval and the
homogenization of ventricular repolarization. The administration of isoproterenol is
indicated when there is no available temporary pacemaker. Prevention is done by
avoiding the administration of drugs that cause QT prolongation.

In the congenital form, in patients with symptoms such as syncope or pre-syncope is

indicated administration of beta-blockers. If symptoms persist, it is associated with
surgical resection of the left stellate ganglion. In refractory cases, when the tachycardia
becomes recurrent, or when there is a history of sudden death, even with the therapy
described above, it is indicated the implant of the automatic cardioverter defibrillator.

The prognosis is good in those in whom symptoms are controlled with medication and
become more reserved in patients with recurrent tachycardias, when the risk of death is
greatest.

The therapy is controversial in asymptomatic patients with long QT interval. Family history
of syncope or sudden death, are factors that increase the tendency of the preventive
treatment of these patients. There is no additional investigation with good predictive
value in identifying asymptomatic patients at higher risk of sudden death. Genetic studies
can identify asymptomatic carriers of chromosomal abnormalities with the risk for
arrhythmia. The latter however are not yet widely employed, being reserved only for
family members of individuals affected.