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Pronounced echocardiographically measured mechanical dyssynchrony is a positive predictor of response to cardiac resynchronization therapy (CRT), whereas right ventricular (RV) dysfunction is a negative predictor. The aim of this study was to investigate how RV dysfunction influences the association between mechanical dyssynchrony and left ventricular (LV) volumetric remodeling following CRT.One hundred twenty-two CRT candidates (mean LV ejection fraction, 19 ± 6%; mean QRS width, 168 ± 21 msec) were prospectively enrolled and underwent echocardiography before and 6 months after CRT. Volumetric remodeling was defined as percentage reduction in LV end-systolic volume. RV dysfunction was defined as RV fractional area change < 35%. Mechanical dyssynchrony was assessed as time to peak strain between the septum and LV lateral wall, interventricular mechanical delay, and septal systolic rebound stretch. Simulations of heart failure with an LV conduction delay in the CircAdapt computer model were used to investigate how LV and RV myocardial contractility influence LV dyssynchrony and acute CRT response.In the entire patient cohort, higher baseline septal systolic rebound stretch, time to peak strain between the septum and LV lateral wall, and interventricular mechanical delay were all associated with LV volumetric remodeling in univariate analysis (R = 0.599, R = 0.421, and R = 0.410, respectively, P < .01 for all). The association between septal systolic rebound stretch and LV volumetric remodeling was even stronger in patients without RV dysfunction (R = 0.648, P < .01). However, none of the mechanical dyssynchrony parameters were associated with LV remodeling in the RV dysfunction subgroup. The computer simulations showed that low RV contractility reduced CRT response but hardly affected mechanical dyssynchrony. In contrast, LV contractility changes had congruent effects on mechanical dyssynchrony and CRT response.Mechanical dyssynchrony parameters do not reflect the negative impact of reduced RV contractility on CRT response. Echocardiographic prediction of CRT response should therefore include parameters of mechanical dyssynchrony and RV function.The authors investigated the associations among RV function, dyssynchrony, and CRT response.In patients with RV dysfunction, dyssynchrony was not associated with CRT response.In computer simulations, dyssynchrony was not affected by RV myocardial dysfunction.In the simulations, RV myocardial dysfunction limited CRT response.Measuring RV function can improve prediction of response by mechanical dyssynchrony.