Molecular analysis at the Harvey Ras-1 gene in patients with long QT syndrome.

Patients with long QT syndrome (LQTS; MIM 1921500) frequently suffer from syncope and are threatened by sudden cardiac death due to ventricular arrhythmias, typically of the torsade de pointes type. Initial progress in revealing the molecular basis of the disease was made by the observation of genetic linkage of the disease locus to the Harvey Ras-1 gene (HRAS 1) on chromosome 11p15.5. More recently loci on chromosomes 3, 4, and 7 have also been found to be linked to LQTS, thus demonstrating heterogeneity in the causes for this disease. The present study performed sequence analysis on the HRAS 1 gene in patients with congenital and acquired LQTS to determine the frequency of HRAS 1 mutations in patients with this disease. In neither group were no mutations identified in the coding regions or in the splice donor and acceptor sites. Alleles characterized by a T to C transition in exon 1 and an insertion/deletion polymorphism upstream of exon 1 showed no significant difference in their frequencies between LQTS patients and normal controls. No quantitative influence of the such characterized genotypes on the QT duration was observed. These results demonstrate that structural mutations in the HRAS 1 gene are not a frequent cause of LQTS. Also, since there was no association of different alleles at the HRAS 1 locus with changes in QT duration, it appears unlikely that this gene is a major contributor to this disease.

Torsade de pointes secondary to d,l-sotalol after catheter ablation of incessant atrioventricular reentrant tachycardia--evidence for a significant contribution of the "cardiac memory".

Radiofrequency catheter ablation of a right septal accessory pathway was performed in a 66-year-old patient with incessant orthodromic atrioventricular reentrant tachycardia. Intravenous administration of flecainide, ajmaline, verapamil, and d,l-sotalol had been ineffective in controlling the tachycardia. After the ablation procedure, precordial T-wave inversion was observed during sinus rhythm. These repolarization abnormalities persisted and were suggested to represent "cardiac memory." Three days later, atrial fibrillation with a fast ventricular response developed and oral d,l-sotalol, which had been well tolerated previously on a long-term basis, was started again. However, at this time, and in the presence of the persisting repolarization abnormalities, the T waves became deeper and broader within a few hours after the introduction of d,l-sotalol. Marked QT prolongation that was paralleled by the occurrence of repeated episodes of torsade de pointes developed. Serum electrolytes were normal. Direct current cardioversion was necessary due to the degeneration of torsade de pointes into ventricular fibrillation. Further sustained arrhythmia episodes were suppressed by temporary endocardial ventricular pacing. The patient recovered without any sequela. This case demonstrates that repolarization abnormalities after catheter ablation, which may be due, at least in part, to the "cardiac memory," are not always benign but may contribute significantly to proarrhythmia.

[The idiopathic QT syndrome as the cause of epileptic and nonepileptic seizures]. / Das idiopathische QT-Syndrom als Ursache epileptischer und nicht epileptischer Anfälle.

The long QT syndrome (LQTS) is characterized by a pathological lengthening of the corrected QT interval on the surface ECG and the occurrence of syncopal attacks, sometimes presenting as a seizure disorder. They are caused by ventricular tachycardia of the torsade de pointes type, an arrhythmia that is also responsible for the high incidence of sudden death among these patients. Besides the acquired forms of LQTS which are transient (e.g. therapy with QT-prolonging drugs), congenital variants (Romano-Ward syndrome, Jervell/Lange-Nielsen syndrome, sporadic form) can occur as well. The latter mostly become manifest during childhood or adolescence. Because the syndrome is rare, it is often not included in the primary differential diagnosis of syncope. Thus, misinterpretation as epilepsy may occur. Especially if siblings are affected, a genetic epilepsy may be diagnosed. However, the correct diagnosis can be made by standard ECG methods. Early recognition of the syndrome is very importance because of prognostic and therapeutic consequences. In this article, two cases of idiopathic LQTS are presented. Problems regarding differential diagnosis and therapy are discussed.

[Torsade de pointes]. / Torsade de pointes.

Torsade de pointes (TDP) is a polymorphic ventricular tachycardia with a particular electrocardiographic pattern of continuously changing ("twisting") morphology of the QRS complex occurring in the setting of delayed myocardial repolarization (i.e., prolongation of the QT interval). TDP may develop in the setting of an idiopathic disorder (Jervell/Lange-Nielsen syndrome, Romano-Ward syndrome, sporadic long QT syndrome) or may be induced by pharmacologic agents which prolong the QT interval, as well as by other clinical circumstances under which repolarization is delayed (e.g., hypokalemia, hypomagnesemia, bradycardia) (acquired long QT syndrome). Since the treatment of TDP strongly differs from that of conventional ventricular tachycardia, correct diagnosis is critical as it guides the treating physician in selecting the appropriate mode of therapy. In this paper mainly the electrocardiographic criteria presently used for the correct identification of this unusual form of ventricular arrhythmia are presented. Additionally, the potential mechanisms and therapeutic modalities of TDP are discussed.

[The pro-arrhythmic effects of anti-arrhythmia agents]. / Proarrhythmische Effekte von Antiarrhythmika.

Proarrhythmia is defined as the provocation of new cardiac arrhythmias or the aggravation of preexisting arrhythmias by antiarrhythmic drugs. The possible types of manifestation of proarrhythmia are manifold. With respect to prognosis, drug-induced ventricular tachyarrhythmias seem to be of particular importance. Monomorphic ventricular tachycardia and ventricular tachycardias of the torsade de pointes type have to be distinguished. The former seem to be mainly based on reentrant mechanisms, while the later is supposed to result from triggered activity. Drug-induced monomorphic tachycardia is most often observed during therapy with drugs which slow conduction (class I agents, proarrhythmic potency: IC > IA > IB). Patients with depressed left ventricular function and previously documented life-threatening tachyarrhythmias are the most susceptible candidates. Torsade de pointes can be preferentially observed during therapy with antiarrhythmic drugs which prolong myocardial repolarization (i.e. class IA and class III agents). Electrolyte abnormalities and/or bradycardia are factors which often predispose to the development of this particular type of proarrhythmia. The physician who prescribes antiarrhythmic drugs must be aware of the different types and clinical manifestations of proarrhythmia. This is necessary to assess the degree of proarrhythmic risk and to determine the benefit/risk ratio before the start of drug therapy.

Autosomal recessive long-QT syndrome (Jervell Lange-Nielsen syndrome) is genetically heterogeneous.

Jervell Lange-Nielsen syndrome (JLNS) is a recessive disorder with congenital deafness and long-QT syndrome (LQTS 1). Mutations in the potassium-channel gene KVLQT1 (LQTS 1) have been identified in JLNS and in autosomal-dominant LQTS as well. We performed haplotype analysis with microsatellite markers in a Lebanese family with JLNS, but failed to detect linkage at LQTS 1. Moreover, using this approach, we excluded two other ion-channel genes involved in autosomal-dominant LQTS, HERG (LQTS 2) and SCN5A (LQTS 3). Our findings indicate that JLNS is genetically heterogeneous and that, in this family, an unknown LQTS gene causes the disease.