The mechanisms by which cardiac resynchronization therapy improves mechanical LV function in patients with heart failure and ventricular dyssynchrony are not completely understood. Electrical resynchronization can reduce the LBBB-induced mechanical interventricular dyssynchrony between the right and the left ventricle and the intraventricular dyssynchrony within the left ventricle. Minimizing intraventricular dyssynchrony has been shown to improve global LV function; that is, cardiac resynchronization therapy increases LV filling time, decreases septal dyskinesis, and reduces mitral regurgitation, thus improving hemodynamics17, 18 (Figure 1). These acute mechanical effects of cardiac resynchronization therapy can be accompanied by more chronic adaptations that lead to long-term benefit in the patient experiencing heart failure. For example, cardiac resynchronization therapy can improve the deranged neurohormonal milieu associated with chronic heart failure. 19 Early work on resynchronization therapy demonstrated a normalization of plasma norepinephrine levels, although this was not replicated in work from the same investigator. 20 There is increasing evidence from unpublished investigations suggesting improvement of brain natriuretic peptide and a variety of other neurohormones in more recent studies. There is also an indication that cardiac resynchronization therapy restores autonomic balance in heart failure. In 2 prospective studies, biventricular pacing resulted in a significant improvement in heart rate variability, suggesting a decrease in cardiac adrenergic activity or an increase in parasympathetic activity, or a combination of both. 3, 21

Several studies demonstrate the beneficial effects of cardiac resynchronization therapy on LV remodeling. Yu and colleagues22 evaluated 25 NYHA class III or IV heart failure patients with baseline ejection fractions 40% and QRS durations 140 ms treated with biventricular pacing therapy. The subjects were assessed serially during 3 months of pacing and when pacing was withheld for 4 weeks. During cardiac resynchronization therapy, there was a progressive improvement in ventricular structure and function. At 3 months, significant improvements were noted in ejection fraction, dP/dt, myocardial performance index, and mitral regurgitation. LV end-diastolic and end-systolic volumes were significantly reduced (from 20568 to 16867 mL and from 16254 to 12242 mL, respectively). These benefits appeared to be dependent on continued pacing because withholding pacing resulted in a progressive but not immediate loss of effect. The authors concluded that biventricular pacing reverses the adverse LV remodeling seen in chronic heart failure and suggested that improvement of LV mechanical synchrony was the predominant mechanism. Such observations have been confirmed in studies of hundreds of patients experiencing heart failure. In the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial, serial Doppler echocardiograms were obtained at baseline, 3, and 6 months in 323 optimally treated patients with NYHA class III and IV heart failure. 1 Cardiac resynchronization therapy for 6 months was associated with reduced end-diastolic and end-systolic volumes (both P 0.001), reduced LV mass (P 0.01), increased ejection fraction (P 0.001), reduced mitral regurgitant blood flow (P 0.001), and improved myocardial performance index (P 0.001) as compared with controls.