A computer-implemented method for predicting and/or optimizing the response of patients with dyssynchronous heart failure to cardiac resynchronization therapy, comprising: (a) determining indices derived from the regional distribution of myocardial external work density (RDMW) prior to treatment, wherein the indices determined are selected from the group consisting of: (i) the fraction of ventricular wall mass or volume, or a part thereof, optionally left ventricle, right ventricle, or septum, performing negative work (myocardial negative work density fraction, or MNWF), optionally having work done on it by the surrounding heart wall, (ii) the coefficient of variation of external work density (COVW) or other measures of work dispersion or heterogeneity, (iii) the fraction of the septal wall performing negative work (change in STNW or ΔSTNW), wherein a decrease in the fraction of the septal wall performing negative work (ΔSTNM) computed after simulated CRT is a predictor of pump function improvement and CRT response, and (iv) a combination thereof, (b) computing the change in these indices of work heterogeneity following the simulated application of CRT in a computational model, and (c) performing computational simulations of possible therapeutic interventions including the cardiac resynchronization therapy, the computational simulations being performed using different possible therapeutic parameters including at least one of alternative pacing lead locations and ventriculo-ventricular pacing delay times. (a) determining indices derived from the regional distribution of myocardial external work density (RDMW) prior to treatment, wherein the indices determined are selected from the group consisting of: (i) the fraction of ventricular wall mass or volume, or a part thereof, optionally left ventricle, right ventricle, or septum, performing negative work (myocardial negative work density fraction, or MNWF), optionally having work done on it by the surrounding heart wall, (ii) the coefficient of variation of external work density (COVW) or other measures of work dispersion or heterogeneity, (iii) the fraction of the septal wall performing negative work (change in STNW or ΔSTNW), wherein a decrease in the fraction of the septal wall performing negative work (ΔSTNM) computed after simulated CRT is a predictor of pump function improvement and CRT response, and (iv) a combination thereof, (i) the fraction of ventricular wall mass or volume, or a part thereof, optionally left ventricle, right ventricle, or septum, performing negative work (myocardial negative work density fraction, or MNWF), optionally having work done on it by the surrounding heart wall, (ii) the coefficient of variation of external work density (COVW) or other measures of work dispersion or heterogeneity, (iii) the fraction of the septal wall performing negative work (change in STNW or ΔSTNW), wherein a decrease in the fraction of the septal wall performing negative work (ΔSTNM) computed after simulated CRT is a predictor of pump function improvement and CRT response, and (iv) a combination thereof, (b) computing the change in these indices of work heterogeneity following the simulated application of CRT in a computational model, and (c) performing computational simulations of possible therapeutic interventions including the cardiac resynchronization therapy, the computational simulations being performed using different possible therapeutic parameters including at least one of alternative pacing lead locations and ventriculo-ventricular pacing delay times.