This R21 grant application is submitted in response to Innovative Research Grant Program Announcement (PA-06-239) for analyses of existing clinical databases with newer parameters or methodologies. Recent investigations have found that statin therapy is associated with a lower risk of ventricular arrhythmias and cardiac mortality including sudden cardiac death. However, the mechanisms are not well understood. The Vascular Basis for Treatment of Myocardial Ischemia Study, a randomized, double- blind, controlled trial, recently reported in stable coronary artery disease (CAD) patients that statin therapy was associated with reduction in ischemic episodes and duration of ischemia compared with pretreatment baseline. Autonomic and cardiac electrophysiologic effects remain to be evaluated. We propose to employ newly developed noninvasive ambulatory-ECGs (AECG) indices to assess baroreceptor reflexes (by heart rate turbulence (HRT) analysis), autonomic tone (by heart rate variability (HRV) analysis), and cardiac electrical instability (by T-wave alternans (TWA) analysis) to evaluate effects of intensive as compared with moderate statin therapy on autonomic and cardiac electrophysiologic factors in 300 patients in Vascular Basis trial.
SPECIFIC AIMS : 1) To determine whether intensive statin therapy with atorvastatin to a target LDL of 80 mg/dL with or without supplemental antioxidant vitamins C and E improves autonomic tone (HRV) and reflexes (HRT) in patients with stable CAD, compared with moderate statin therapy with diet and low- dose lovastatin as needed to reach an LDL goal of 130 mg/dL. 2) To quantify the effects of intensive versus moderate statin therapy on cardiac electrical instability as measured by TWA magnitude. At the time of AECG monitoring, patients were free of antiischemic and antiarrhythmic medications. Our analysis would constitute the largest investigation of effects of statins on autonomic tone and reflexes and on cardiac electrophysiologic function. This proposal will examine the effects of intensive as compared with moderate statin therapy on autonomic function and cardiac electrophysiologic function using newly developed noninvasive ambulatory-ECGs (AECG) indices in patients enrolled in the Vascular Basis trial. Ultimately, the present proposal could provide novel insights into mechanisms whereby statin therapy may reduce risk for life-threatening arrhythmias and thereby impact the major public health problem of sudden cardiac death. ? ? ?
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