Associate Editor: O. Binah
Pharmacological and non-pharmacological management of the congenital long QT syndrome: The rationale

https://doi.org/10.1016/j.pharmthera.2011.03.001Get rights and content

Abstract

The congenital long QT syndrome (LQTS) is a familial disorder characterized by a prolongation of the QT interval on the ECG and occurrence of life-threatening cardiac arrhythmias especially, but not only, under conditions of increased sympathetic activity. Symptomatic untreated patients are at high risk for sudden cardiac death. Twelve LQTS genes have been identified and most of them encode cardiac ion channels. Very effective therapies are available and in carefully treated patients mortality is around 0.5–1% over 20 years.

The initial treatment should always involve β-blockers, with propranolol and nadolol being the two most effective ones. With few exceptions all mutation carriers should be treated because of the risk of sudden death during the first cardiac event. Approximately 20% of patients continue to have syncope despite the β-blockers and the most rationale next level of therapy is represented by Left Cardiac Sympathetic Denervation (LCSD), which is highly effective and can complement any other therapy. One important limitation of LCSD is that, without valid reasons, it is available only in a few selected centers. Whenever syncope recurs despite LCSD, or whenever an aborted cardiac arrest has occurred, it becomes logical to resort to the implantation of a cardioverter defibrillator (ICD). The latter, however, is burdened by a high rate (31%) of adverse events including severe ones such as endocarditis, inappropriate shocks, and by the need of frequent battery replacements. A scoring system, based on simple clinical variables, can identify the patients more and less likely to benefit from ICD implantation.

Introduction

The congenital long QT syndrome (LQTS) is a relatively uncommon but important clinical disorder of genetic origin. Since 1975 (Schwartz et al., 1975), under the unifying name of "Long QT Syndrome" it includes two hereditary variants. The Jervell and Lange-Nielsen syndrome (J–LN) is associated with deafness (Jervell and Lange-Nielsen, 1957, Schwartz et al., 2006) and the Romano–Ward syndrome (R–W) is not (Romano et al., 1963, Ward, 1964).

The interest for LQTS has progressively increased, reaching an almost exponential growth during the last 15 years. The reasons are multiple, including two which are not novel. One is represented by the dramatic manifestations of the disease, namely syncopal episodes which often result in cardiac arrest and sudden death and usually occur in conditions of either physical or emotional stress in otherwise healthy young individuals, mostly children and teenagers. Another is that, while LQTS is a disease with a very high mortality rate among untreated patients, very effective therapies are available; this makes unacceptable and inexcusable the existence of symptomatic and undiagnosed or misdiagnosed patients. Since 1995 the identification of several genes responsible for LQTS, and moreover the realization that so far most of them encode ion channels, has provided a new stimulus for clinical cardiologists and basic scientists. The impressive correlation between specific mutations and critical alterations in the ionic control of ventricular repolarization makes this syndrome a unique paradigm which allows to correlate genotype and phenotype, thus providing a direct bridge between molecular biology and clinical cardiology in the area of sudden cardiac death.

Here, I will focus primarily on therapy. As generalities go, details on clinical manifestations can be found in a recent review (Schwartz & Crotti, 2009), the prevalence of LQTS is close to 1/2000 live births based on a prospective ECG study complemented by molecular screening in 44,000 infants (Schwartz et al., 2009a), and even though 12 LQTS genes have been identified the most important remain the first 3 identified which encode the IKs, the IKr, and the INa current (Schwartz and Crotti, 2009, Schwartz, in press).

Section snippets

Management and therapy for long QT syndrome

The cardinal aspects of LQTS therapy and management are essentially four: the two types of antiadrenergic interventions (β-blockers and left cardiac sympathetic denervation, LCSD), the implantable cardioverter defibrillator (ICD), and gene-specific management, which is still in its infancy.

Overview on therapy

The clear data available, and decades of clinical experience, dictate the therapeutic approach to the patient affected by LQTS who already has had a syncopal episode. Treatment should always begin with β-blockers, unless there are valid contraindications. If the patient has one more syncope despite full dose β-blockade, LCSD should be performed without hesitation and ICD implant should be considered with the final decision being based on the individual patient characteristics (age, sex,

Acknowledgments

This work was supported by National Institutes of Health grant HL-68880 and by the Telethon Italy grants GGP07016 and GGP09247. I am grateful Pinuccia De Tomasi for expert editorial support.

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