ADVERTISEMENT

Congenital long QT syndrome: Considerations for primary care physicians

Cleveland Clinic Journal of Medicine. 2008 August;75(8):591-600
August 1, 2008|Cleveland Clinic Journal of Medicine
Ethan Levine, DO;Spencer Z. Rosero, MD;Adam S. Budzikowski, MD;Arthur J. Moss;MD;Wojciech Zareba, MD;James P. Daubert, MD
Author and Disclosure Information

Ethan Levine, DO
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY

Spencer Z. Rosero, MD
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY

Adam S. Budzikowski, MD
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY

Arthur J. Moss, MD
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY

Wojciech Zareba, MD
Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY

James P. Daubert, MD
Associate Professor of Medicine, and Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY

Address: James P. Daubert, MD, University of Rochester Medical Center, Box 679-Cardiology Division, 601 Elmwood Avenue, Rochester, NY 14642-8679; e-mail James_Daubert@URMC.Rochester.edu

Dr. Daubert has disclosed that he has received consulting fees from Medtronic and CryoCor corporations and has ownership interest in Boston Scientific.

ABSTRACTCongenital long QT syndrome is an inherited disorder of cardiac repolarization that predisposes to syncope and to sudden death from polymorphic ventricular tachycardia. The disorder should be suspected when the electrocardiogram shows characteristic QT abnormalities, or when there is a family history of long QT syndrome or of an event that raises suspicion of long QT syndrome, such as sudden death, syncope, or ill-defined “seizure” disorder. We can now classify some types of congenital long QT syndrome according to their genetic mutations and their triggers, such as exercise, rest, or startle.

 

KEY POINTS

  • Because of the heterogeneity of the syndrome, genotyping is often useful in making therapeutic decisions, such as avoiding alarm clocks in bedrooms in patients with long QT genetic type 2, or restricting physical activity (particularly swimming) in patients with genetic type 1.
  • When patients on beta-blocker therapy experience further syncopal episodes or aborted cardiac arrest and are considered at high risk, implantation of a cardioverter-defibrillator is appropriate.
  • In a select few patients, left cervical-thoracic sympathetic denervation may be appropriate.

Analyzing T wave morphology

After analysis of the QT interval, attention is directed to the T wave morphology. Abnormalities such as low amplitude, inversion, or notches support the diagnosis of long QT syndrome and are helpful if the QTc is borderline-long.34 Moss et al35 showed that characteristic patterns of the ST segment and T wave yield clues to the genotype in patients with long QT syndrome. In their study of patients of known genotype, they provided one of the earliest indications of genotype-specific patterns in this syndrome.35 In addition, if possible, one should look for dynamic changes in the QTc with exercise, as this too can provide insight not only to the diagnosis, but also to the particular genotype. In the absence of exercise electrocardiography, provocative testing with infusion of epinephrine (with ready availability of external defibrillation) has also proven informative.19,33,36

What is the clinical picture and family history?

Naturally, the above information needs to be analyzed in the context of the larger clinical picture (Table 1). Specifically, is there a history of syncope or ill-defined seizure disorder? Convulsive syncope due to polymorphic ventricular tachycardia from QT prolongation is sometimes misinterpreted as a seizure. Are family members similarly affected, or is there a history of sudden death in the family?

What are event triggers?

When symptoms or events are identified, it is often illuminating to discern the circumstances surrounding the events, with attention to possible triggers. Clearly, when events are associated with swimming or loud noises or startling situations, the clinical likelihood of long QT syndrome increases dramatically. In the absence of a positive genotype, the diagnosis is often measured in probabilities (Table 1). If a patient has been genotyped as positive, then he or she is called “genotypically affected”; the phenotype depends on whether the QTc is prolonged, but beta-blockade is advisable in genotype-positive patients regardless.

Could it be another repolarization abnormality?

Finally, one needs to be vigilant for other re-polarization abnormalities, such as those seen in the Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, or even short QT syndrome, as well as normal variants. While the diagnosis of these disorders is beyond the scope of this review, they are seen in a similar demographic group and have similar symptoms. Short QT syndrome is due to a gain of function of one of the potassium channels, the opposite of what is seen in long QT syndrome. Also, whereas LQT3 is caused by a gain of function of the sodium channel (SCN5A), the opposite functional change in the sodium channel (ie, a loss of function) produces Brugada syndrome (or conduction system disease).

STRATIFYING THE RISK OF AN EVENT

Once the diagnosis has been made, the next objective is to determine the patient’s risk of a serious arrhythmic event, information that helps in choosing one therapeutic alternative over another.

Several studies have analyzed the differing clinical courses of the three main phenotypes. In 1998, Zareba and colleagues37 published an analysis of cardiac events among 541 genotyped patients from the international long QT registry. Included were 112 patients with LQT1, 72 with LQT2, and 62 with LQT3. The authors evaluated several factors, including the likelihood of having an event (syncope, cardiac arrest, or sudden death) before age 40, the influence of gender and QTc on the event rate, and the lethality of events. Although the likelihood of an event was significantly higher with LQT1 and LQT2, the death rate from the events was essentially the same across all three groups, reflecting the higher likelihood of fatal events in those with LQT3. Furthermore, within each genotype, the longer the QTc, the greater the event rate.37 These findings underscore the heterogeneity of long QT syndrome and the need to consider factors such as genotype (when available) and QTc when making clinical decisions.

In 2003, Priori et al38 revisited the issue of risk stratification, this time looking at 647 patients drawn from 196 families genotyped with long QT syndrome and followed for a mean of 28 years.38 They evaluated the influence of QTc, genotype, and gender on the risk of a first long-QT-related event occurring before age 40. Without therapy, by age 40, 13% of patients had died suddenly or had had a cardiac arrest, thus defining the “natural history” of the disease. A QTc longer than 500 ms was the single most powerful predictor of events. Also, in those with LQT2, females fared worse than their male counterparts, while the opposite was true in the cohort with LQT3, and no sex bias was observed in the cohort with LQT1.38 Unlike the situation in the study of Zareba et al, events in patients with LQT3 were not more likely to be lethal.

‘Silent carriers’

Another finding of the study38 was that the cohort with LQT1 had a 36% prevalence of a “silent carrier” state, ie, having a mutation but a normal QTc. Although the risk of events was lower in silent carriers, it was not zero. This underscores the importance of genetic screening of family members of symptomatic individuals, even if the family members have normal electrocardiograms.

A risk stratification scheme

Priori et al38 proposed a risk stratification scheme to aid in clinical decision-making, emphasizing the high risk of events, including death, associated with a QTc greater than 500 ms in LQT1 or LQT2, as well as in males with LQT3. Table 2 incorporates data from these and other studies into a novel risk-stratification scheme.3,37–40

In a recent study in 812 adults ages 18 to 40 who had long QT syndrome mutations,41 predictors of life-threatening events including aborted cardiac arrest or death due to QT prolongation included female sex (males had many fewer events after age 18), a QTc interval exceeding 500 ms, and recent syncopal events. Adults with LQT2 had more events when syncope was included. Beta-blockers reduced the rate of aborted cardiac arrest or death by 60%.

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT