Long QT Syndrome: Diagnosis and Management

Ijaz A. Khan, MD, FACP, FACC

Disclosures

Am Heart J. 2002;143(1) 

In This Article

Diagnosis of LQT Syndrome

The diagnosis of LQT primarily depends on the clinical features, the family history, and the ECG findings of the patient. Unexplained syncope or sudden cardiac death in a child or young adult should raise a high suspicion of the possibility of presence of LQT. Electrophysiologic testing is not helpful in making the diagnosis of LQT. Genetic testing has not become a routine part of the diagnostic workup in patients with LQT, although it could be of assistance in the borderline cases or in cases where a new mutation is suspected. Schwartz[12] and Schwartz et al[13] have proposed a set of criteria to assist in diagnosing the LQT ( Table I ).

These criteria provide a quantitative approach to the diagnosis of LQT by allocating numerical points to the clinical features, family history, and ECG findings and divide the possibility of LQT into low, intermediate, and high probability ranges. In the borderline cases, exercise testing may be performed to assist in the diagnosis. The QT interval may lengthen abnormally during the recovery phase of exercise testing in patients with LQT.[14,15] In a controlled study,[15] at heart rates of 110 or 100 beats/min during recovery, 100% of LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the control subjects.

Clinical Features

The clinical features of LQT are a result of the precipitation of torsades, and range from minor symptoms, such as dizziness, to seizure, syncope, and sudden death. An individual episode of the torsades is generally short lived, usually terminates spontaneously, and may go unrecognized. However, it has a tendency to recur in rapid succession and therefore may cause syncope and death. The characteristic electrocardiographic features of torsades include a markedly prolonged QT interval in the last sinus beat preceding the onset of the arrhythmia, progressive twisting of the QRS complex polarity around an imaginary baseline, a complete 180-degree twist of the QRS complexes in 10 to 12 beats, changing amplitude of the QRS complexes in each cycle in a sinusoidal fashion, a heart rate between 150 to 300 beats/min, and irregular RR intervals.[16,17] The initiation of torsades is usually dependent on a pause in the electrical activity created by a longer cycle length, which may be the result of bradycardia or an extrasystole. The longer cycle length usually precedes the last supraventricular beat before initiation of the torsades. In a typical short-long-short sequence, a sinus beat is followed by an extrasystole (short cycle), this extrasystole is followed by a sinus beat after a long postextrasystolic pause (long cycle), and this sinus beat, which has a longer QT interval than the preceding sinus beats, is then followed by a ventricular beat, which is the first beat of the torsades. In cases with congenital LQT, a sudden intense adrenergic stimulation can precipitate torsades.[18] The sudden intense adrenergic stimulation probably results in an extrasystole, which is followed by a long postextrasystolic pause that precipitates arrhythmia in the setting of underlying long QT interval.[19]

The congenital LQT usually manifests before the age of 40 years, chiefly in childhood and adolescence. The age at which disease manifests the first time in an individual patient depends on the genotype of the family. According to the International Long QT Syndrome Registry data, the median age at which the first cardiac event occurred was 9, 12, and 16 years in subjects with LQT1 (n = 112 subjects), LQT2 (n = 72 subjects), and LQT3 (n = 62 subjects), respectively.[20] Men are less prone to the development of cardiac events because of shorter QT intervals compared with women, boys, and girls, especially in LQT1 and LQT2 groups.[21,22,23] The shorter QT interval for men is most evident for heart rates <60 beats/min. The risk of torsades and sudden death is highest at the early waking hours, which correlates with the diurnal peak of the QT interval at that time.

The prolongation of QT interval is a risk factor for sudden cardiac death independent of the patient's age, history of myocardial infarction, heart rate, and history of drug use; the patients with a QTc interval of >440 milliseconds are at 2 to 3 times higher risk for sudden cardiac death than those with a QTc interval of <440 milliseconds.[24] The mortality rate in untreated patients with LQT is in the range of 1% to 2% per year. The incidence of sudden death varies from family to family as a function of the genotype.[20,25] In the data published from the International Long-QT Syndrome Registry, the frequency of cardiac events was significantly higher among subjects with LQT1 (63%) or LQT2 (46%) than among subjects with LQT3 (18%).[20] The cumulative mortality through the age of 40 years was similar among subjects of all 3 genotypes, but the likelihood of dying during a cardiac event was significantly higher among the subjects with LQT3 (20%) than among those with LQT1 (4%) or LQT2 (4%). The mean QTc interval was significantly longer in the LQT3 group (510 ± 48 ms) than that in the LQT1 (490 ± 43 ms) or LQT2 (495 ± 43 ms) groups. Sudden cardiac death in patients with congenital LQT is often precipitated by a triggering event, such as physical exercise, swimming, sleep deprivation, auditory stimuli, and sudden intense sympathetic stimuli including grief, fright, pain, anger, fear, or startle.[26,27] These events tend to cluster in families as a function of the genotype.[26] Physical exercise is more prone to precipitate cardiac events in patients with LQT1, auditory stimuli in patients with LQT2, and rest and sleep in patients with LQT3.[26,27,28] Although the cause of death during rest and sleep in patients with LQT3 is not well established, it well reflects bradyarrhythmia-induced torsades because bradycardia and pauses have been reported with LQT3. The high-risk predictors of sudden cardiac death in patients with congenital LQT include recurrent episodes of syncope, failure on conventional medical therapy, survival from cardiac arrest, congenital deafness, female sex, QTc >600 milliseconds, relative bradycardia, kinship with a symptomatic patient, and sudden cardiac death in a family member at an early age.[29]

Family History and Genetics

A family history of unexplained syncope or sudden death, especially in the young family members of a patient with unexplained syncope or sudden death, should raise a strong suspicion of congenital LQT. Initially, the 2 well-described forms of the congenital LQT were the Jervell Lange-Nielsen syndrome and the Romano Ward syndrome. The Jervell Lange-Nielsen syndrome is a rare cardioauditory syndrome where the deafness is inherited in an autosomal recessive pattern, and the marked QTc prolongation reflects the double-dominant inheritance of 2 mutant alleles.[30] The more common Romano Ward syndrome, associated with normal hearing, is inherited in an autosomal dominant pattern.[31,32]

During last decade, significant advancements have been made in determining the genetic basis of the congenital LQT, and on the basis of ion channel and the gene involved, 6 subtypes of congenital LQT have been characterized. Mutations in the KCNQ1 (KVLQT1) gene, located on chromosome 11, cause LQT1. The KCNQ1 gene encodes the a-subunit of a cardiac potassium channel IKs -- the slowly activating potassium-delayed rectifier.[33] The LQT1 is the principal gene responsible for both Jervell Lange-Nielsen and Romano Ward syndromes, and it accounts for approximately 50% of the genotyped LQT families.[34] The mutations in the HERG gene, located on chromosome 7, cause LQT2. The HERG gene encodes for another cardiac potassium channel IKr -- the rapidly activating potassium-delayed rectifier.[35] The LQT2 accounts for approximately 45% of the genotyped LQT families. The mutations in the SCN5A gene, located on chromosome 3, cause LQT3. The SCN5A gene encodes a cardiac sodium channel INa -- the cardiac voltage-dependent sodium channel.[36] The LQT3 accounts for approximately 5% of the genotyped LQT families. Interestingly, mutations in the same gene but at different loci result in Brugada syndrome and progressive conduction system disease (Lenegre-Lev disease). However, these mutations are loss of function type mutations contrary to the gain in function type mutations in LQT3. The LQT4 locus has been identified at chromosome 4 in one large French kindred but the responsible gene has not been identified yet.[37] The mutations in the KCNE1 (minK) gene, located on chromosome 21, cause LQT5. The KCNE1 gene encodes the ß-subunit of the cardiac potassium channel IKs.[38] The KCNQ1 (LQT1) and KCNE1 (LQT5) gene products assemble to form a complete IKs channel protein. The LQT5 accounts for only a small number of the genotyped LQT families. The mutations in the KCNE2 (MiRP1) gene, located on chromosome 21 cause LQT6.[39] The KCNE2 (MiRP1) gene encodes a small membrane protein, which is considered a part of the IKr channel.[39] The HERG (LQT2) and KCNE2 (LQT6) gene products assemble to form a complete IKr channel protein. Although currently >300 mutations have been discovered in the 5 known LQT genes, not all the genes responsible for LQT have been identified. In addition, the sporadic cases of LQT occur as a result of spontaneous mutations. Therefore a lack of family history does not entirely preclude the diagnosis of congenital LQT.

ECG Findings

In the majority of patients with congenital LQT, the QTc interval is >440 milliseconds, but in 6% to 12% of patients the QTc interval is within normal limits, and about one third of the patients have a QTc interval <=460 milliseconds.[20,40] The other ECG features, especially accompanying T-wave and U-wave abnormalities, may assist in diagnosis, especially in cases where the QTc interval is within normal limits or is borderline high.[40] Sinus bradycardia with sinus pauses has been reported in up to one third of the patients with congenital LQT, especially so in patients with LQT3.[41] Another ECG feature of the LQT is increased QT interval dispersion, which is due to labile repolarization in LQT.[42]

The T wave could be larger, prolonged, and bizarre looking and may display a notched, bifid, biphasic, or alternans appearance.[40,43] T-wave alternans is a diagnostic feature of the LQT and reflects an enhanced electrical instability during repolarization.[43] The different genotypes of LQT may display specific ECG phenotypes. Zhang et al[40] identified 10 ST-T wave repolarization patterns in LQT (4 in LQT1 genotype, 4 in LQT2 genotype, 2 in LQT3 genotype). The repolarization patterns identified in LQT1 were of infantile ST-T wave, broad-based T wave, normal-appearing T wave, and late-onset normal-appearing T wave; those identified in LQT2 were of obvious bifid T wave, subtle bifid T wave with second component on top of T wave in limb and left precordial leads, subtle bifid T wave with second component on down slope of T wave in inferior and mid precordial leads, and low-amplitude bifid T wave with second component merged with U wave; and those identified with LQT3 were of late-onset peaked/biphasic T wave and asymmetric peaked T wave. These repolarization patterns had sensitivity of 61% to 100%, 62% to 100%, and 33% to 100%; and specificity of 71% to 100%, 87% to 100%, and 98% to 100% for identifying LQT1, LQT2, and LQT3, respectively. However, overlap existed among the repolarization patterns of 3 genotypes, and one third of LQT3 gene carriers had repolarization patterns similar to those of LQT1 gene carriers. The sensitivities and specificities were higher with family-grouped analysis. The U-wave abnormalities reported in LQT include prominent bizarre looking U waves and U-wave alternans. The T- and U-wave abnormalities in LQT have been reported to exaggerate with excessive sympathetic stimulation.[43]

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