Pulmonary arterial hypertension (PAH) is a chronic disease with a high mortality rate mainly related to progressive right ventricular (RV) failure. In patients who deteriorate despite optimal medical therapy, lung transplantation remains the only therapeutic option. However, because of shortage of organ donors, many patients die on the waiting list. RV Assist Devices (RVADs) could reduce hospitalizations for RV failure and bring patient to transplantation. To date, the experience on RVAD in these patients is poor. Simulators with computational models have been pivotal in the development of left ventricular assist devices but haven't allowed the evolution of RVAD. In fact, to date the available models don't overcome the pathophysiological problems of PH, having the following limitations: not calibrated on human data; focus only on RV passive mechanics ignoring active mechanics; don't take into account interventricular interaction, neither coronary circulation nor the ventilator mechanics and don't couple together systemic and pulmonary circulatory systems. Our center has been collaborating in the last years with the National Research Council (CNR) Institute of Clinical physiology, leading to the development of a simulator computational model, CARDIOSIM©.
Our aim is to bring this simulator platform from a TRL 6 to 8, developing a new, robust and innovative computational software able to simulate pathophysiologic behaviors in advanced PAH and to provide important information to improve RVAD development in the near future. The projects will consist of 3 phases: 1)algorithm implementation; 2)data collection of right heart catheterization at rest and after exercise, cardiac magnetic resonance and cardiopulmonary test from a derivation cohort from our center in Policlinico Umberto I using them to train the simulator; 3) software validation using data of the cohorts from Arizona College of Medicine and Ohio centers State University Wexner Medical Center.
Pulmonary arterial hypertension (PAH) is a hemodynamic condition defined as an increase in mean pulmonary arterial pressure (PAPm) >25 mmHg at rest, with a wedge pressure 3 Wood units, assessed by righ-heart catheterization (RHC), in the absence of other causes of pre-capillary PH. Despite current therapies have improved, the long-term mortality remains high with a median survival of 7 years. Right ventricular (RV) dysfunction is the leading cause of hospitalizations and death. In patients with severe PAH and inadequate response to optimal treatments, lung transplantation (LT) is the only therapeutic option but is limited by the current shortage of organ donors availability and the long waiting-list. Only about 200 LT procedures are performed yearly worldwide in patients with PAH. In patients with RV heart failure on the waiting list for LT, mechanical support should be considered as a bridge to transplantation. RV Assist Devices (RVADs) may have potential benefits in terms of RV unloading and assisting systolic function. In contrast with left ventricular assist devices (LVADs), experience with RVADs in PAH patients is poor. Simulators with computational models have been pivotal in the development of LVADs, but haven't allowed the evolution of RVAD.To date the available models have the following limitations: not calibrated on human data, focus only on RV passive mechanics, don't take into account interventricular interaction neither coronary circulation nor the ventilator mechanics and don't couple together both systemic and pulmonary circulatory systems. Our center has been collaborating in the last years with the National Research Council (CNR) Institute of Clinical physiology, developing a simulator computational model (CARDIOSIM©). It has a modular structure consisting of 7 different general sections, which can be assembled to reproduce different patho-physiological conditions. Many circulatory districts derived from complex numerical models are implemented within the platform. Cardiocirculatory assistances as LVAD, RVAD, IABP, BiVAD, BiV pacing, thoracic artificial lung, extracorporeal membrane oxygenation are developed in the CARDIOSIM© library. Moreover, the platform allows to simulate the effects induced on hemodynamic and energic variables by mechanical ventilator assistance (MVA)(1-3). CARDIOSIM© has been tested in the last decade in a multicenter collaboration among Sapienza University/Policlinico Umberto I, Giovanni XIII-Bergamo Hospital, Royal Brompton Hospital, Royal Brompton & Harefield NHS Foundation Trust-London, NIH-Bethesda-USA to study the interplay between hemodynamic variables and ventricular energetics in advanced LH failure. Our aim is to implement the CARDIOSIM© software with the ventilatory mechanics and interventricular interaction in advanced PAH patients. The project will consist of 3 phases: 1)algorithm implementation; 2) data collection of the derivation cohort including PAH patients from our center to train the completed software; 3)validation of the model using data of PAH patients from the University of Arizona College of Medicine (Prof. F. Rischard) and the Ohio State University Wexner Medical Center (Prof. Benza R.L.). Technology readiness levels (TRLs) are a method for estimating the maturity of technologies and are classified from 1 to 9. The aim of our project is to move the CARDIOSIM© software from TRL 6 (Technology demonstrated in relevant environment-industrially relevant environment in the case of key enabling technologies) to 8 (System complete and qualified). CARDIOSIM© software will therefore be able to overcome the above limits of currently available simulators: 1-being calibrated on human data from PAH patients;2-analyzing both active and passive ventricular mechanics;3-analyzing interventricular and interatrial interaction;4-coupling systemic and pulmonary circulation together;5-analyzing ventilatory mechanics and coronary circulation. Our results will lead to the development of a new, robust and innovative computational software able to simulate pathophysiologic behaviors in advanced PAH and provide important information to improve RVAD development in the near future.
References:
1)C. De Lazzari et al. Interactive simulator for e-learning environments: a teaching software for health care professionals. BioMedical Engineering OnLine 2014
2)C. De Lazzari et al. Interaction between the septum and the left (right) ventricular free wall in order to evaluate the effects on coronary blood flow: numerical simulation. Computer Methods in Biomechanics and Biomedical Engineering, 15 (12), 2012, p. 1359-1368
3)C. De Lazzari et al. A desktop computer model of the circulatory system for heart assistance simulation: effect of an LVAD on energetic relationships inside the left ventricle, Medical Engineering & Physics, 16(2), 1994 p. 97-103