Calcium Handling Defects and Cardiac Arrhythmia Syndromes

The objectives of this study were to present data on eight patients with recurrent episodes of aborted sudden death unexplainable by currently known diseases whose common clinical and electrocardiographic (ECG) features define them as having a distinct syndrome different from idiopathic ventricular fibrillation. Among patients with ventricular arrhythmias who have no structural heart disease, several subgroups have been defined. The present patients constitute an additional subgroup with these findings. The study group consisted of eight patients, six male and two female, with recurrent episodes of aborted sudden death. Clinical and laboratory data and results of electrocardiography, electrophysiology, echocardiography, angiography, histologic study and exercise testing were available in most cases. The ECG during sinus rhythm showed right bundle branch block, normal QT interval and persistent ST segment elevation in precordial leads V1 to V2-V3 not explainable by electrolyte disturbances, ischemia or structural heart disease. No histologic abnormalities were found in the four patients in whom ventricular biopsies were performed. The arrhythmia leading to (aborted) sudden death was a rapid polymorphic ventricular tachycardia initiating after a short coupled ventricular extrasystole. A similar arrhythmia was initiated by two to three ventricular extrastimuli in four of the seven patients studied by programmed electrical stimulation. Four patients had a prolonged HV interval during sinus rhythm. One patient receiving amiodarone died suddenly during implantation of a demand ventricular pacemaker. The arrhythmia of two patients was controlled with a beta-adrenergic blocking agent. Four patients received an implantable defibrillator that was subsequently used by one of them, and all four are alive. The remaining patient received a demand ventricular pacemaker and his arrhythmia is controlled with amiodarone and diphenylhydantoin. Common clinical and ECG features define a distinct syndrome in this group of patients. Its causes remain unknown.

Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca2+]i). Normal function requires that [Ca2+]i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca2+]i.

Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.