Congenital long QT syndrome

Abstract

Congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias. Disease prevalence is estimated at close to 1 in 2,500 live births. The two cardinal manifestations of LQTS are syncopal episodes, that may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities, including prolongation of the QT interval and T wave abnormalities. The genetic basis of the disease was identified in the mid-nineties and all the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in these genes (KCNQ1, KCNH2, KCNE1, KCNE2, CACNA1c, CAV3, SCN5A, SCN4B) cause the disease by prolonging the duration of the action potential. The most prevalent LQTS variant (LQT1) is caused by mutations in the KCNQ1 gene, with approximately half of the genotyped patients carrying KCNQ1 mutations. Given the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in specific diagnostic criteria. Additionally, molecular screening is now part of the diagnostic process. Treatment should always begin with beta-blockers, unless there are valid contraindications. If the patient has one more syncope despite a full dose beta-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation and implantable cardioverter defibrillator (ICD) therapy should be considered with the final decision being based on the individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, presence of ECG signs - including 24-hour Holter recordings - indicating high electrical instability). The prognosis of the disease is usually good in patients that are correctly diagnosed and treated. However, there are a few exceptions: patients with Timothy syndrome, patients with Jervell Lange-Nielsen syndrome carrying KCNQ1 mutations and LQT3 patients with 2:1 atrio-ventricular block and very early occurrence of cardiac arrhythmias.

Figure 1

Different T wave morphologies in affected members of the same family. The proband had a documented cardiac arrest as first manifestation of LQTS. The basal ECG shows deep negative T waves in the precordial leads and a very prolonged QTc. His sister is still asymptomatic with typical bi-phasic T waves. His father, with notched T waves and a QTc 584 ms, has had 2 syncopal episodes. The arrows point to examples of notched T wave. [Reprinted from: Schwartz PJ, Priori SG, Napolitano C: The long QT syndrome. In: CARDIAC ELECTROPHYSIOLOGY. FROM CELL TO BEDSIDE. III EDITION (Zipes DP and Jalife J, Eds.) WB Saunders Co., Philadelphia, pp. 597–615, 2000 – with permission from Elsevier].

Figure 2

5-year-old patient affected by LQTS with congenital deafness. Tracing recorded during a syncopal episode. T wave alternans precedes the onset of torsade de pointes. In this case, it is also evident that TdP is not preceded by a pause. (From C. Pernot: Le syndrome cardio-auditif de Jervell et Lange-Nielsen. Aspects electrocardiographiques. Proc Ass Europ Paediat Cardiol 1972, 8:28–36).

Figure 3

Differential risk for arrhythmic events among Mutation Carriers (MCs) according to resting heart rate off- βB and QTc. The dashed horizontal line represents the predefined cut-off for QTc (≤ or > 500 ms) whereas the dashed vertical line corresponds to the first tertile (≤ 60 bpm) of the heart rate values distribution. It is evident that in the group of patients with a QTc ≤ 500 ms those the first tertile (heart rate ≤ 60 bpm) were less frequently symptomatic compared to MCs in the other two tertiles (OR 0.19, 95%CI 0.04–0.79, p = 0.023). This figure also provides evidence that a QTc > 500 ms represents a more severe arrhythmogenic substrate in our population based on the fact that 15 of 16 (94%) MCs with a QTc > 500 ms were symptomatic. (Reprinted from ref. [25] with permission from Lippincott Williams and Wilkins).

Figure 4

(A) Kaplan-Meier curves of event-free survival comparing JLN patients vs LQT1, LQT2 and LQT3 symptomatic patients.(Modified from ref. [3] with permission from Lippincott Williams and Wilkins). (B) Kaplan-Meier curve of event-free survival in JLN patients with mutations in KCNQ1 or KCNE1 genes. (Reprinted from ref. [3] with permission from Lippincott Williams and Wilkins).

Figure 5

Kaplan-Meier curves of event-free survival and survival according to QTc interval after left cardiac sympathetic denervation in patients with only syncope, or aborted cardiac arrest before left cardiac sympathetic denervation. (Modified from ref. [65] with permission from Lippincott Williams and Wilkins).

Figure 6

LQT3 patient aged 17-yrs, major QTc prolongation (QTc 516 ms) not modified by β-blocker therapy. The addition of oral chronic therapy with mexiletine (200 mg b.i.d.) produced a major shortening of QTc by over 100 ms persisting over time. (Reprinted from ref. [78] with permission from Elsevier).