Background: The diagnostic ability of computer-based methods for cardiovascular system (CVS) monitoring offers significant clinical potential. This research tests the clinical applicability of a newly improved computer-based method for the proof of concept case of tracking changes in important hemodynamic indices due to the influence acute pulmonary embolism (APE). Methods: Hemodynamic measurements from a porcine model of APE were used to validate the method. Of these measurements, only those that are clinically available or inferable were used in to identify pig-specific computer models of the CVS, including the aortic and pulmonary artery pressure, stroke volume, heart rate, global end diastolic volume, and mitral and tricuspid valve closure times. Changes in the computer-derived parameters were analyzed and compared with experimental metrics and clinical indices to assess the clinical applicability of the technique and its ability to track the disease state. Results: The subject-specific computer models accurately captured the increase in pulmonary resistance (Rpul), the main cardiovascular consequence of APE, in all five pigs trials, which related well (R² = 0.81) with the experimentally derived pulmonary vascular resistance. An increase in right ventricular contractility was identified, as expected, consistent with known reflex responses to APE. Furthermore, the modeled right ventricular expansion index (the ratio of right to left ventricular end diastolic volumes) closely followed the trends seen in the measured data (R² = 0.92) used for validation, with sharp increases seen in the metric for the two pigs in a near-death state. These results show that the pig-specific models are capable of tracking disease-dependent changes in pulmonary resistance (afterload), right ventricular contractility (inotropy), and ventricular loading (preload) during induced APE. Continuous, accurate estimation of these fundamental metrics of cardiovascular status can help to assist clinicians with diagnosis, monitoring, and therapy-based decisions in an intensive care environment. Furthermore, because the method only uses measurements already available in the ICU, it can be implemented with no added risk to the patient and little extra cost. Conclusions: This computer-based monitoring method shows potential for real-time, continuous diagnosis and monitoring of acute CVS dysfunction in critically ill patients.