Inherited Arrhythmias: Long QT Syndrome

The Challenge
Long QT syndrome (LQTS) is a disorder of cardiac repolarization. It is characterized by a prolongation of the QT interval, and a predisposition to ventricular tachyarrhythmias, which are associated with syncope, arrhythmic events, and sudden cardiac death (SCD). In recent years, there have been significant advances in understanding the genetic basis of the syndrome. Newer genetic forms of LQTS have been identified, too, plus a laboratory test has become available to help in the diagnosis of the syndrome. As knowledge of LQTS continues to expand, clinical applications of this growing body of information need further study

LQTS usually presents with cardiac events in childhood, adolescence, or early adulthood. The syndrome runs in families; thus, when SCD (or an aborted sudden death) has occurred in one family member, electrocardiograms of other family members is advisable, and could lead to multiple presymptomatic (pre-syncope) diagnoses.

Numerous genetic loci of long QT syndrome have been identified, with the initial LQTS types labeled LQT1 through LQT6; most are potassium channel mutations. More recently, newer complex forms of long QT have been identified, notably the LQT7 type, which is associated with Andersen Syndrome (AS). In addition to a prolonged QT interval with ventricular arrhythmias, this rare variant of hereditary-familial LQTS is characterized by periodic paralysis and abnormalities in physical development (e.g., micrognathia, clinodactyly). Long QT has been identified in 71% of all gene carriers of AS, and some researchers have proposed that AS be considered a subtype of LQTS.1

Another newly identified gene has been associated with Timothy Syndrome, another complicated disorder characterized by long QT. Timothy Syndrome is also a rare condition with multiorgan dysfunction, including lethal arrhythmias, autism, and syndactyly (webbing of fingers and toes).2 The syndrome’s genetic mutations interfere with the calcium channels that regulate cardiac activity.

Using genetic testing, along with knowledge of the patient’s personal and family history, some patients may be considered for an implantable cardioverter defibrillator (ICD). However, there is limited long-term clinical experience with the ICDs in this setting. Available data are encouraging. In one trial, patients who were cardiac arrest survivors or had recurrent syncope were followed for a mean of 8 years. LQTS patients with an ICD had a 1.3% death rate compared with 16% in controls who did not receive an implant.3

Even with a careful personal and family history, plus meticulous inspection with a 12-lead electrocardiogram, there are still numerous challenges facing the clinician trying to unmask this potentially silent killer. Once diagnosed, risk stratification is necessary given the profound heterogeneity of this syndrome, but it can be exceedingly difficult. The effort is important, however, considering that some patients may be destined for asymptomatic longevity while others will be walking time bombs waiting for the right trigger to detonate. (Triggers may be related to physical activity or emotional distress, or may even be auditory in nature.) The greatest challenge may be to discern which of these divergent outcomes is most likely in a given patient and the appropriate therapy to reduce this risk, which may be greatly influenced by the specific genotype of LQTS.

According to Jeffrey A. Towbin, MD, FACC, individuals who have had an aborted SCD should be strongly considered for an ICD. The need for an ICD also should be evaluated in families where long QT syndrome has been associated with sudden death in multiple family members. It’s still not clear which other patients might benefit from ICD placement. “Research is ongoing,” he said, “and over the next few years, I think there will be more stringent criteria available so that clinicians can make wise decisions about ICD use.”

Until then, clinicians may be able to answer some important questions about individual patients with a new genetic test for LQTS. Genaissance Pharmaceuticals (New Haven, CT) has intellectual property rights relating to the five genes that have been identified as explaining the majority of familial LQTS and Brugada Syndrome. (Like LQTS, Brugada Syndrome is caused by abnormalities in cardiac ion channels and can result in abnormal electrical activity in the heart, particularly ventricular fibrillation.) Genaissance Pharmaceuticals started offering the new test at its CLIA laboratory in 2004.

While the test is expensive, Dr. Towbin said, “The cost decreases dramatically when you test other family members after identifying the gene mutation in the index case. Once you have a presymptomatic diagnosis, it can be life saving over the long term.” One possible benefit of the new genetic test: more specific information regarding genotype and a better assessment of individual patient risk may lead to fewer ICDs used in this population.

Source

Guidelines
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—summary article:
a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Am Coll Cardiol 2002;40:1703-19.

References

• Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome) J Clin Invest 2002;110:381-388.
• Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism Cell 2004;119:19-31.
• Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients J Cardiovasc Electrophysiol 2003;14:337-41.