Christina T. Hampton, PA-C, MMSc

Clinician Reviews 13(1):40-46, 2003. © 2003 Clinicians Group, LLC

Abstract

Long QT syndrome (LQTS) is an inherited disease that affects sodium and potassium channels in the heart, leading to abnormal functioning in the heart's electrical system. To date, researchers have identified six ion channel gene loci with multiple potential mutations linked to LQTS. Prolongation of the QT interval causes ventricular arrhythmias, such as torsades de pointes and ventricular fibrillation -- which can lead to sudden cardiac death. Episodes of syncope and arrhythmia can be triggered by extreme emotion, loud noise, or exertion; by use of specific medications; or by an electrolyte imbalance. Variations in presentation create a significant clinical challenge to primary care providers. This article will address the diagnosis of LQTS and the connections between its causes and effective patient management.

Introduction

Inherited long QT syndrome (LQTS), once thought to be a rare disease, may occur in one in every 5,000 persons and may cause 3,000 to 4,000 sudden deaths in children and young adults each year in the United States.[1] If even 50,000 US cases currently exist, this congenital or acquired disease occurs three times more often than acute lymphoblastic leukemia (the most common childhood leukemia), one third as often as cystic fibrosis, and twice as often as phenylketonuria.[2] Yet large numbers of LQTS cases go undiagnosed due to the complexity of the diagnosis, the variety of presentations, and many clinicians' lack of familiarity with the disease (see Figure 1).

Figure 1. A 12-year-old girl with a history of syncopal episodes was diagnosed with exercise-induced asthma and given ß-agonist therapy. The child later experienced torsades de pointes after mild exertion, followed by ventricular fibrillation and cardiac arrest. In a postmortem investigation, her older sister was found to have a prolonged QT interval on resting electrocardiogram. Later, fourteen members of the extended family were diagnosed with long QT syndrome. Courtesy of the author.

On the surface electrocardiogram (ECG), the QT interval reflects the total duration of the depolarization and repolarization phases in the heart. Thus, a prolonged QT interval represents an abnormal slowing of cardiac electrical impulses resulting from mutations that create structural defects in the potassium and sodium channels.[3,4]

A prolonged QT interval can be caused by numerous conditions other than LQTS[3] (eg, use of certain medications or of cocaine, hypokalemia, hypocalcemia, hypomagnesemia, myocardial ischemia, subarachnoid hemorrhage). By the same token, a long QT interval is not always evident on resting ECG in every patient with LQTS.

The Role of Genetics

Congenital LQTS is an inherited disease caused by a mutation in one of the genes that code for the transmembrane sodium or potassium ion-channel proteins.[5-7] (See "The Genetics of Long QT Syndrome,"[8-19].) Research is ongoing to coordinate genotypes with their respective clinical presentations. Patients cannot yet be routinely screened for an abnormal long-QT gene, because only about half of persons diagnosed with LQTS can be genotyped.[4,20,21] Recently, however, ST-T-wave patterns, enhanced by family-grouped ECG analysis, have been shown to be a promising means of identifying patients with genotypes LQT1 and LQT2 (and possibly LQT3).[22]

LQTS is divided into four major categories: Romano-Ward syndrome, Jervell and Lange-Nielsen syndrome, sporadic LQTS, and acquired LQTS.[5]Romano-Ward syndrome is characterized by autosomal-dominant inheritance of one of multiple gene mutations in five different genes that code for ion channels in the myocardium.[15] Patients with this form of the disease present with symptoms of LQTS without any additional organ involvement. Children of a person with Romano-Ward syndrome have a 50% chance of inheriting the abnormal long-QT gene.[4]

In contrast, patients with Jervell and Lange-Nielsen syndrome usually present first with congenital sensorineural deafness, and a prolonged QT is detected later.[23] This syndrome is autosomal-recessive for deafness but autosomal-dominant for LQTS. Jervell and Lange-Nielsen syndrome is thought to be a combination of two different LQTS genes that are seen in Romano-Ward syndrome.[15]

In sporadic LQTS, the patient who presents with LQTS is the first and only case in the family.[24] These cases are attributed to spontaneous mutation.[3]

Finally, acquired LQTS is a syndrome of a prolonged QT that is associated with use of a specific medication (see Table 1,[5,15,25]) or to an electrolyte imbalance. However, recent evidence suggests that persons with acquired LQTS secondary to drug therapy are genetically predisposed to prolonged QT intervals.[15,17]

Patients may present with a history of syncopal episodes, bradycardia, or a near-drowning event. As many as one third of patients will have sudden cardiac death as the presenting symptom, while another third are completely asymptomatic.[26] The first cardiac event usually takes place during childhood or adolescence but may occur at any age.[4]

Syncopal episodes and sudden cardiac death are often precipitated by a sudden increase in sympathetic activity, as with profuse emotion, a loud noise, or demanding physical activity.[26] (Swimming, for example, has recently been found to be a specific trigger for LQTS in approximately 15% of patients.[2]) Often patients are in a self-terminating torsades de pointes rhythm; sudden cardiac death occurs when this rhythm degenerates into ventricular fibrillation.[4]

For a small subset of patients, the first symptom is sudden cardiac death during sleep. It is unclear what precipitates prolongation of the QT interval in these patients, but genetic variation is the suspected cause.[5]

Clinical Findings

Ordinarily, the prolonged QT interval is found on a resting ECG (see Figure 2). The QTc (corrected QT) interval may be considered prolonged if it exceeds 0.44 seconds. (The QTc can be determined by using Bazett's formula, that is, dividing QT by the square root of R-R [the duration of the previous QRS-to-QRS interval in seconds].[27]) In a recent study, Vincent[15] found that a QTc of 0.47 seconds in men and 0.48 in women was diagnostic for LQTS in 100% of cases, while a QTc below 0.40 seconds in men and 0.42 in women would completely exclude the diagnosis. The study author suggested using a QTc of 0.46 seconds as diagnostic.

Figure 2. This electrocardiogram of a 40-year-old man shows a normal sinus rhythm, left-axis deviation, and a prolonged QT interval of 0.46 seconds. Courtesy of Lyle Larson, PhD, PA-C.

Approximately 40% of patients with LQTS will not present with a prolonged resting QTc but will require exercise stimulation to trigger prolongation of the QT interval (possibly during the recovery phase of exercise testing).[3,15] Symptomatic patients with a normal or borderline QTc on resting ECG or those with a positive family history for sudden cardiac death, seizures, or syncope should undergo 24-hour Holter monitoring, a treadmill stress test, and a repeat ECG in the sitting/standing position.[2]

Schwartz et al[27] created and later updated a system to determine the probability of presence of LQTS. This system assigns a point value to various aspects of the patient's clinical and family history and to specific findings on the ECG. Some criteria (eg, presence of torsades de pointes) are weighted more heavily than others (low heart rate for the patient's age).

One focus of molecular and clinical research is the possibility of tailoring treatment to each patient's genotype.[5,28] Even without this knowledge, optimal management with currently available resources is essential: Mortality in untreated, symptomatic LQTS is greater than 20% within one year of the patient's first syncopal episode and 50% within 10 years.[5]

Generally, referral to a specialist should be considered at the first indication that a patient may have LQTS -- any unexplained syncopal episodes, sudden cardiac death in the family history, or a resting ECG with a prolonged QT interval. For the primary care provider of the patient with LQTS,[29] long-term management is intended to prevent cardiac events and occurrences of torsades de pointes by shortening the QTc interval.[4] Patients' medications must be reviewed at the outset, and those known to cause prolongation of the QT interval should be discontinued.[2] Likewise, patients should be advised to avoid prescription and over-the-counter medications that stimulate the sympathetic nervous system (see Table 1[5,15,25]).

First-line therapy with ß-blockers is effective in 80% to 90% of patients,[15] with a significant reduction in sudden cardiac death (down to 4% to 5% in the five years after presentation). New episodes of syncope are prevented in 75% of patients.[5] However, patients with LQT3 who take ß-blockers may experience decreased efficacy or even adverse effects.[15]

When ß-blocker therapy fails (ie, the patient continues to experience syncopal episodes), the addition of a sodium channel blocker (eg, mexiletine, flecainide) may be helpful -- particularly in patients with LQT3.[4,26] Other mutation-specific therapies include potassium for persons with LQT2, calcium channel blockers, and potassium channel activators.[4,10]

If medication fails to control symptoms, placement of a permanent pacemaker or of a cardioverter/ defibrillator should be considered. Pacemaker placement is especially beneficial in patients who present with bradycardia exacerbated by ß-blocker therapy,[15] and implantable cardioverter/defibrillator therapy may be particularly helpful for adolescents who do not comply with their medication regimens or for patients with LQT3 who do not respond to ß-blockers.[30] But defibrillator placement, it should be noted, remains controversial because shocks from the device can lead to further emotional stress and even precipitate episodes of torsades de pointes.[5] ß-blocker therapy should be continued after placement of either device.[4]

Imbalance in electrolytes demands close attention. Even mild hypokalemia, for example, must be corrected in LQTS patients. In fact, research is currently under way to test the long-term effects of potassium loading in these patients. One small trial demonstrated impressive shortening of the QT interval and normalization of T-wave morphology as a result of potassium loading.[31]

Currently, left cervicothoracic sympathetic ganglionectomy is the only available surgical option. Surgery is reserved for patients who fail to respond to other treatments.[15]

Acute Management

Acute therapy of arrhythmia or prolonged QT might include emergency monitoring and administration of magnesium.[32] Acute management of a prolonged episode of torsades de pointes includes performing immediate cardioversion, removing all QT-prolonging drugs, and correcting hypokalemia.[4]

Pacing may be achieved with a temporary transvenous pacemaker; if this is not possible, continuous intravenous infusion of isoproterenol is initiated to increase the heart rate to 90 beats/min or more; this controls acute recurrences of torsades de pointes.[4] If the rhythm degenerates into ventricular fibrillation, defibrillation is necessary.[33]

Lifestyle Considerations

In addition to avoiding specified medications and complying with prescribed therapy,[4] patients with LQTS should be urged to avoid competitive sports. Recreational sports are permissible in moderation and only in the presence of someone who knows of the patient's condition. Since swimming has been shown to be a particular trigger, LQTS patients should never swim alone.[2]

Conclusion

LQTS is a complicated genetic disorder with varied presentations. More common than once suspected, it should remain high on the differential diagnosis of a young healthy person with unexplained syncope. It is hoped that future research will make the diagnosis of LQTS easier and help simplify genotyping and appropriate individualized management.