This research proposal seeks to address a major unanswered question in the clinical application of the analysis of heart rate variability (HRV), whether a pharmacological intervention which decreases HRV in a particular patient also increases the risk of mortality for that patient. The rationale underlying this study is that decreased HRV has been shown to be a risk factor for increased mortality in various populations, and cardioactive medications have been shown to affect HRV. Also, in the absence of any intervention, indices of HRV have been shown to be stable in both normals and in stable cardiac patients. Moreover, our own investigation of moricizine has shown that its effect on HRV is not uniform in magnitude or direction across subjects. The Cardiac Arrhythmia Suppression Trail (CAST) database may prove invaluable for addressing the relationship between individual change in HRV and risk, because it contains baseline and post-treatment 24-hour Holter recordings and outcomes for patients treated with encainide, flecainide and moricizine. CAST also has a placebo control group. Moreover, while answering the central question of the relationship of individual changes in HRV and mortality, further information will be obtained about the relationship of baseline HRV and other clinical parameters and mortality, about the effects of treatment with the CAST drugs on HRV, and about clinical characteristics of patients who have HRV reduced by treatment. Our primary aim is to: Investigate the relationship between mortality and the change in HRV resulting from treatment with encainide, flecainide and moricizine (considered separately and grouped together for greater statistical power). Our secondary aims are to: 1) Investigate the association between baseline predictor variables (age, gender, LVEF, mean HR, VPC's per hour, time from Ml, concurrent drugs (digitalis, beta- blockers, calcium channel blockers)] and indices of HRV from baseline recording in CAST, 2) Investigate the relationship between baseline HRV, and HRV in combination with other predictor variables, and mortality in each of the treatment arms of the CAST study, 3) Determine if the relationship between baseline HRV and mortality differs in the placebo arm of the CAST study, 4) Determine the separate effects of treatment with encainide, flecainide and moricizine on HRV, 5) Investigate the association between baseline predictor variables and changes in indices of HRV resulting from each treatment (encainide, flecainide and moricizine).
