The purpose of this investigation was to develop a theoretical framework to predict stroke volume (and therefore cardiac output) when the ventricle is coupled with the arterial impedance. The ultimate objective is to arrive at an analytical description of cardiac output in the closed hydraulic loop of the entire circulatory system on the basis of the properties of the major system components. We developed the framework of analysis of ventriculo-arterial coupling by characterizing both the ventricle and arterial system in terms of the end-systolic pressure vs. stroke volume (Pes-SV) relationships. This approach, motivated by the load-insensitivity of ventricular end-systolic pressure-volume relationship (ESPVR), yielded stroke volume as the intersection between the ventricular Pes-SV relationship and arterial Pes-SV relationship. The theoretical outcome was validated by comparing the stroke volume predicted as a result of interaction between a given ventricular ESPVR and a set of arterial impedances against those SVs actually measured by imposing the same arterial impedance on the isolated canine ventricles. Furthermore, because of the mathematical simplicity of this approach, it enabled us to describe cardiac output in the closed circulatory loop with a small set of analytical equations. We conclude that the proposed framework is useful in analyzing the ventriculo-arterial coupling and various mechanisms which affect cardiac output in the closed circulatory loop.