Alaric Franzos, MD, Erich F Wedam, MD, Mark Haigney, MD
A 95-year-old man with coronary artery disease, an ischemic cardiomyopathy (left ventricular ejection fraction 45%), and atrial fibrillation (without anticoagulation) presented to the emergency department after multiple episodes of syncope. He was initially responsive but suddenly developed altered mental status. His Glasgow coma score fell from 15 (ie, fully awake and responsive) to 4 (indicating coma). The subject simultaneously developed fixed pinpoint pupils, extensor posturing, roving gaze, and Cheyne-Stokes breathing. Except for an elevated pro-BNP of 1386 ng/ml (reference range 5.0-450), laboratory analysis was normal including a serum potassium 4.5 mEq/L (3.6-5.0) and a serum digoxin level of 0.6 ng/ml (0.8-1.2). A noncontrast CT suggested an initial diagnosis of mid pons ischemic stroke due to basilar artery occlusion. Tissue plasminogen activator was administered with restoration of the patient basilar artatus to normal, and the patient transferred to the medical intensive care unit. A brain magnetic resonance imagery (MRI) showed no evidence of acute stroke. An electrocardiogram revealed atrial fibrillation, complete heart block, a QTc of 540 ms, and a right bundle branch morphology escape rhythm (Figure 67-1)—a significant change from prior electrocardiograms showing atrial fibrillation, a QTc of 450 ms, and left bundle branch block (Figure 67-2). Episodes of polymorphic ventricular tachycardia or “torsades de pointes” (TdP) were evident on telemetry (Figure 67-3). Magnesium sulfate (two grams) was administered, and the patient was emergently transported to the electrophysiology lab where a temporary pacemaker was placed, suppressing further episodes of TdP. Placement of a permanent pacemaker prevented further TdP.
FIGURE 67-1 The 12-lead ECG recorded in the MICU showing complete heart block and QTc prolongation.
FIGURE 67-2 The 12-lead ECG recorded at prior visit showing LBBB and a QTc of 450 ms. In the presence of LBBB, this is a normal QTc.
FIGURE 67-3 Telemetry strip showing onset and offset of TdP.
The patient presented with recurrent syncope complicated by a basilar artery thrombosis. While it is impossible to be certain, it seems likely that the syncope was caused by either the onset of complete heart block or the development of TdP, and the onset of coma appears to be attributable to the basilar artery occlusion. While the etiology of the complete heart block is likewise uncertain, the presence of preexisting left bundle branch block suggests significant infra-His conduction disease. The manifestation of a new right bundle branch block and regularization of the ventricular response is most consistent with complete atrioventricular block. The etiology of the polymorphic ventricular tachycardia is not mysterious, however, and is due to the new onset of severe bradycardia and resultant QT interval prolongation associated with the escape rhythm. The immediate and permanent resolution of the arrhythmia with the institution of ventricular pacing, the absence of a history of QT prolongation, and the lack of a QT-prolonging drug indicate that this is pause-dependent TdP, although some contribution from the cerebral insult cannot be ruled out.
• The prevalence of true pause-dependent TdP is unknown but is likely rare. Sporadic case reports document QT prolongation and TdP in children and adults after congenital or acquired complete heart block.1-3
In its “pure” form, it is associated with a normal QT interval prior to the pause.
• TdP commonly presents as two syndromes: syncope and sudden cardiac death (SCD).
Syncope is a common syndrome, with an incidence of 6.2 cases per 1000 person-years, with a cardiac cause identified in 9.5%, but the percentage of cases attributable to pause-dependent TdP is likely very small.4
At autopsy, a long QT (LQT) associated gene mutation (a congenital predisposition to TdP) was identified in approximately one-third of cases of SCD without structural heart disease.5
TdP is also associated with structural heart disease, with an odd’s ratio of 3.9 in NYHA Class III or IV dilated cardiomyopathy exposed to dofetilide, a potent inhibitor of the rapid component of the delayed rectifier potassium current, IKr.6
In 60 cases collected over 11 years, the most common causes of TdP include QT-prolonging drugs (38%), hypokalemia (27%), and severe bradycardia (35%).7
ETIOLOGY AND PATHOPHYSIOLOGY
• Torsades de pointes (TdP) is a polymorphic ventricular tachycardia typified by continuous change in the QRS axis in the setting of a prolonged QT interval, often occurring in short bursts.
• The long QT interval can be congenital or acquired and reflects increased heterogeneity of repolarization, a necessary requirement for induction of reentrant arrhythmias.
• TdP is typically—perhaps always—multifactorial in origin, requiring interaction of depressed “repolarization reserve”8 due to drugs, structural heart disease, ischemia, electrolyte imbalances, female gender, altered calcium handling, or bradycardia combined with a trigger in the form of a premature beat (Table 67-1).
TABLE 67-1 Loss of Repolarization Reserve: Risk Factors for Torsades de Pointes
hERG mutation (0.1%-1% of population)
QT-prolonging drug use, particularly at high dose
Preexisting QTc >450 ms
Electrolyte disturbances ↓ K+, ↓ Mg2+
Combination of QT-prolonging drugs
Inhibition of drug metabolism
Cardiac ischemia/congestive heart failure
Liver disease, eg, cirrhosis
• Pause-dependent TdP is an acquired cause of QT prolongation.
Some degree of heart rate slowing may contribute to the induction of arrhythmia in the presence of a preexisting long QT interval (acquired or congenital).
■ Even in normal individuals, substantial prolongation of the QT interval can be seen at slower heart rates (Figure 67-4).
FIGURE 67-4 Decremental atrial pacing from a heart rate of 50 to 90 shortens the QT interval by 45 msec in a healthy subject.
■ In subjects with depressed repolarization reserve, slowing of the heart rate may be the final insult that allows TdP to occur.
■ Viskin and coworkers found that an increase of the RR interval of >100 ms preceded the onset of TdP in 82% of congenital long QT patients with documented pause-dependent TdP, and some degree of pause-dependence was manifested by 46 of 52 subjects above the age of 3.9
■ Subjects with congenital LQTS due to loss of function mutations in KCNH2 (IKr) appear to have a particular predisposition to pause-dependent TdP, seen in 68% of LQT2 subjects experiencing TdP but 0% of LQT1.10
■ In subjects receiving the IKr blocker quinidine, a “long-short” sequence whereby a premature beat followed by a compensatory pause resulted in a premature beat initiating TdP in 90% of cases 11
Sudden iatrogenic reductions of heart rate may result in TdP after ablation of the atrioventricular node in atrial fibrillation for rapid ventricular rates, and maintaining ventricular pacing at 80 to 90 bpm suppresses the arrhythmia by shortening the QT and preventing premature beats.12
■ In a meta-analysis of 26 subjects experiencing cardiac arrest following atrioventricular node ablation, 23 were paced at a rate less than 80 bpm, and 19 had significant structural heart disease contributing to their reduced repolarization reserve.
Case reports suggest that bradycardia may be sufficient to cause enough loss of repolarization reserve to induce TdP. Proof of this concept in the animal model is lacking.
■ In dogs subjected to complete atrioventricular block and the IKr blocker dofetilide, TdP could not be induced acutely but only after development of chronic changes in ventricular chamber size and action potential prolongation due to down-regulation of IKr.13
■ Experimental data from rabbits shows that slow heart rates result in:
• Increased calcium loading of the sarcoplasmic reticulum.14
• Leakage of calcium from the sarcoplasmic reticulum.
• Early and delayed afterdepolarizations through activation of sodium-calcium exchange.15
• If large enough, this instability in the membrane potential can trigger premature beats that that can serve to initiate TdP.
Whether bradycardia-induced premature beats can be sufficient to trigger TdP alone is unclear, and in any suspected case of pause-dependent TdP, a search for other causes of reduced repolarization reserve should be undertaken.
• Torsades de pointes has characteristic morphologic features (Figure 67-5):
FIGURE 67-5. Intermittent high degree atrioventricular block resulting in a pause-dependent prolongation in the QT interval and initiation of triggering premature ventricular complex, followed by TdP. Note the “long-short” RR interval preceding the TdP.
Wide, polymorphic QRS.
Three or more beats.
Alternating polarity (axis) in a sinusoidal pattern.
Prolonged QT interval (ie, at least >450 msecs but >500 msec more definitive).
Presence of a “long-short R-R interval” preceding the onset of tachycardia
If the arrhythmia is not preceded by a long QT interval, it is known simply as polymorphic ventricular tachycardia.
• Pause-dependent TdP is a diagnosis of exclusion, and the presence of other contributing factors such as an unrecognized ion channelopathy, QT-prolonging drug, or structural heart disease must be excluded, as ventricular pacing may not be adequate to prevent TdP in these conditions.
• Acute myocardial ischemia
• Drug-induced or congenital long QT syndrome
• Catecholaminergic polymorphic ventricular tachycardia
• “Coarse” Ventricular fibrillation
• Takotsubo cardiomyopathy
• Atrial fibrillation and Wolff-Parkinson-White syndrome
• Acute management of pause-dependent TdP focuses on elimination of pauses, which are usually a consequence of bradycardia or intermittent heart block.
• Continuous intravenous isoproterenol can be administered to achieve a goal heart rate >90 bpm.
• Increased heart rate decreases the QT interval, and therefore decreases the heterogeneity of repolarization and the likelihood of triggering premature complexes (Figure 67-5).
• Temporary transvenous pacing may be required.
• Intravenous magnesium has been shown to suppress after depolarizations with a small increase (0.5-1.0 mmol/liter) in extracellular magnesium, but magnesium is unlikely to completely suppress TdP in subjects with severe bradycardia.16
• Potentially treatable underlying causes include:
Excessive nodal blockade (via β-blockers or nondihydropyridine calcium channel blockers).
• Placement of a permanent pacemaker may be required if an underlying cause for the slow stimulation rate (bradycardia or pauses) cannot be identified and treated.
Placement of a permanent pacemaker effectively eliminates true pause-dependent TdP, but the clinician must be confident that other causes of reduced repolarization reserve have been addressed.
Implantation of cardioverter-defibrillator may be more appropriate if other causes of reduced repolarization reserve cannot be addressed.
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