ABSTRACT: BACKGROUND: The end-systolic pressure-volume relationship is often considered as a load-independent property of the heart and, for this reason, is widely used as an index of ventricular contractility. However, many criticisms have been expressed against this index and the underlying time-varying elastance theory: first, it does not consider the phenomena underlying contraction and second, the end-systolic pressure volume relationship has been experimentally shown to be load-dependent. METHODS: In place of the time-varying elastance theory, a microscopic model of sarcomere contraction is used to infer the pressure generated by the contraction of the left ventricle, considered as a spherical assembling of sarcomere units. The left ventricle model is inserted into a closed-loop model of the cardiovascular system. Finally, parameters of the modified cardiovascular system model are identified to reproduce the hemodynamics of a normal dog. RESULTS: Experiments that have proven the limitations of the time-varying elastance theory are reproduced with our model: (1) preload reductions, (2) afterload increases, (3) the same experiments with increased ventricular contractility, (4) isovolumic contractions and (5) flow-clamps. All experiments simulated with the model generate different end-systolic pressure-volume relationships, showing that this relationship is actually load-dependent. Furthermore, we show that the results of our simulations are in good agreement with experiments. CONCLUSIONS: We implemented a multi-scale model of the cardiovascular system, in which ventricular contraction is described by a detailed sarcomere model. Using this model, we successfully reproduced a number of experiments that have shown the failing points of the time-varying elastance theory. In particular, the developed multi-scale model of the cardiovascular system can capture the load-dependence of the end-systolic pressure-volume relationship.