In the preceding grant cycle our work on the long QT syndrome (LQTS) progressed rapidly from genetics through ion channel biophysics in clinical studies. The discovery in Keating's laboratory of the gene defect in LQT2 led rapidly to the discovery in Sanguinetti's laboratory that LQT is due to l/Kr defects. Our first clinical study of intravenous potassium in a patient with LQT2 took place within four months of the discovery of the abnormal gene. Project 6 continues our effort to develop gene-specific therapy for arrhythmias secondary to repolarization abnormalities. Subproject 3.1 is a multicenter feasibility trial of potassium for prevention of arrhythmia in patients with l/Kr mutations. We have already shown that acutely increased serum potassium improves repolarization in patients with this form of LQTS. We intend to investigate whether this finding can be applied clinically. In this pilot study, we will determine the feasibility of multicenter identification and genotyping of affected families, recruitment of both children and adults with inherited LQTS, compliance with prolonged therapy, and effectiveness of multicenter data collection and protocol enforcement. In a sub-study, we will test the specificity of therapies that have been considered gene-specific in LQT2 and LQT3. We hypothesize that QT reduction by non-specific therapy has less therapeutic efficacy than gene-specific therapy, which we expect to effect a much greater improvement in ST segment and T wave (STT) abnormalities than non-specific therapy. Subproject 3.2 is a clinical investigation of idiopathic ventricular fibrillation (IVF) and VF associated with anti-arrhythmic drug pro- arrhythmia (pIVF) in patients displaying the Brugada syndrome phenotype. Many of these patients have SCN5A mutations. We will investigate conduction and transmural repolarization differences in order to understand how presumed sodium channel dysfunction disturbs the normal transmural activation and recovery processes. We will also evaluate the ability of pharmacologic therapy to correct the abnormalities. Some therapies have already been envisioned, while others will be conceptualized on the electrophysiological observations in this Project. We will subsequently evaluate long term efficacy of potential treatments for this disease.
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