Left ventricular (LV) contraction dyssynchrony is common among patients with heart failure and is often associated with significantly greater cardiac risks. Cardiac resynchronization therapy (CRT) is clinically used to treat dyssynchrony by simultaneously activating the ventricles using a cardiac pacemaker. Although a promising therapy, ∼30% of patients fail to respond to CRT, possibly due to the following issues: limited knowledge regarding mechanisms underlying the detrimental mechano-energetic effects of dyssynchrony, lack of robust algorithms for quantifying dyssynchrony, and inadequate patient selection criteria. The goal of the present research was to address some of these issues.;In an isolated heart model, dyssynchrony resulted in depressed LV mechanical function and increased myocardial oxygen consumption. This adverse mechano-energetic effect of dyssynchrony can be reconciled by the hypothesis that the observed mechanical activity at the global level underestimated internal cellular work, which is likely to be the true determinant of myocardial oxygen consumption.;Using data from canine models, cross-correlation analysis was developed to quantify dyssynchrony, both at the integrated and segmental levels. This fully automated, robust tool took into account the entire systolic portion of the cardiac cycle. As a result, this methodology was associated with less intra-group variability compared to current methods that focus on manually chosen time points, which are subject to user interpretability. The segmental cross-correlation analysis provided insight into the integrated LV contraction pattern.;Changes in radial synchrony did not always predict changes in global LV function. For example, in some instances, global LV depression was associated with longitudinal dyssynchrony and preserved radial synchrony, indicating that multi-faceted dyssynchrony analysis is necessary for comprehensive evaluation of contraction.;In a chronic canine model, dyssynchrony and its adverse functional effects were exaggerated as heart failure progressed. In contrast, resynchronization using LV free-wall pacing was equally efficacious regardless of the degree of heart failure.;Preliminary clinical studies indicated that dyssynchrony was better characterized using cross-correlation analysis compared to standard indices. Although these results are promising, additional studies with a larger patient cohort is necessary to translate cross-correlation analysis into the clinical realm as a standard tool to quantify dyssynchrony and identify patients for CRT.