Long QT syndrome and arrhythmogenesis

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The idiopathic Long QT Syndrome (LQTS) is a genetically transmitted disease characterized by prolongation of the QT interval and by syncope or cardiac arrest, usually triggered by emotional or physical stress, due to Torsades de Pointes ventricular tachycardia often degenerating into ventricular fibrillation. There is a very high mortality (20% within one year from the first syncope) for untreated patients. In most cases the disease manifests itself in the first two decades of life. As the available therapies are very effective, it is extremely important that no patient remains undiagnosed. LQTS has genetic heterogeneity and linkage has been demonstrated on chromosomes 3, 4, 7, and 11; this implies that a diversity of molecular defects underlie the LQTS phenotype. Recently, two of the genes for LQTS have been identified. A mutation within SCN5A, the cardiac sodium channel gene, has been detected in families linked to chromosome 3; the deleted sequences affect a region important for channel inactivation. Several different mutations in the human eag-related gene (HERG), a putative potassium channel (I(kr)), appear to cause LQTS in families linked to chromosome 7. With few exceptions, it is an abrupt activation of the sympathetic nervous system that represents the trigger for the life-threatening arrhythmias of LQTS. The left cardiac sympathetic nerves are quantitatively dominant and, when activated, they release in the ventricles larger amounts of norepinephrine compared to the right sympathetic nerves. These considereations have guided the rational implementation of the therapeutic strategy for LQTS, and since 1975 we have suggested the use of β-adrenergic blocking agents as first choice therapy and left cardiac sympathetic denervation (LCSD) when pharmacological therapy fails or is contraindicated. The results available, and largely based on the International Registry that we have initiated in 1979 and that has already enrolled more than 500 families with 7.000 members world-wide, are highly encouraging. Beta-blockers, propranolol or nadolol (3-4 mg/kg/day), are effective in 75-80% of the patients. When they fail, LCSD is extremely effective. Our current data in 123 patients, with an average follow-up before (from the first syncope) and after surgery that exceeds 6 years, show a dramatic reduction in the incidence of syncope or cardiac arrest from 21 ± 31 to 1 ± 3 episodes per patient. Whereas the 10-year mortality in the untreated patients is approximately 60%, the institution of either pharmacological or surgical antiadrenergic therapy has reduced mortality to approximately 3-4%. The use of a pace-maker is indicated in the presence of either pause- or bradycardia-dependent arrhythmias. Therapies used in a few and unusual cases, and not yet clearly validated, include L-type calcium channel blockers, potassium openers, the sodium channel blocker pentisomide, and bilateral cardiac sympathetic denervation. The use of the implantable cardioverter defibrillators is seldom justified because the attacks are not prevented and major psychologic consequences have been reported; on the other hand, in high risk cases refractory to antiadrenergic interventions it may serve as bridge therapy and be life-saving. In summary, the therapies currently available have radically modified the prognosis of patients affected by LQTS; this makes inexcusable the existence of undiagnosed and thereby untreated patients.

Original languageEnglish
Pages (from-to)266-273
Number of pages8
JournalOspedale Maggiore
Issue number3
Publication statusPublished - 1995


  • human genetics
  • molecular biology
  • sudden cardiac death
  • sympathetic nervous system

ASJC Scopus subject areas

  • Medicine(all)


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