Influence of Distal Resistance and Proximal Stiffness on Hemodynamics and RV Afterload in Progression and Treatments of Pulmonary Hypertension: A Computational Study with Validation Using Animal Models
We develop a simple computational model based on measurements from a hypoxic neonatal calf model of pulmonary hypertension (PH) to investigate the interplay between vascular and ventricular measures in the setting of progressive PH. Model parameters were obtained directly from in vivo and ex vivo measurements of neonatal calves. Seventeen sets of model-predicted impedance and mean pulmonary arterial pressure (mPAP) show good agreement with the animal measurements, thereby validating the model. Next, we considered a predictive model in which three parameters, PVR, elastic modulus (EM), and arterial thickness, were varied singly from one simulation to the next to study their individual roles in PH progression. Finally, we used the model to predict the individual impacts of clinical (vasodilatory) and theoretical (compliance increasing) PH treatments on improving pulmonary hemodynamics. Our model (1) displayed excellent patient-specific agreement with measured global pulmonary parameters; (2) quantified relationships between PVR and mean pressure and PVS and pulse pressure, as well as studiying the right ventricular (RV) afterload, which could be measured as a hydraulic load calculated from spectral analysis of pulmonary artery pressure and flow waves; (3) qualitatively confirmed the derangement of vascular wall shear stress in progressive PH; and (4) established that decreasing proximal vascular stiffness through a theoretical treatment of reversing proximal vascular remodeling could decrease RV afterload. 1. Introduction Pulmonary hypertension (PH) is associated with a progressive increase of pulmonary vascular resistance (PVR) and sustained elevation of mean pulmonary artery pressure (mPAP), which together contribute to the right heart dysfunction. However, recent studies showed that mPAP apparently does not correlate with either the severity of symptoms or survival. Although many recent developments employing clinical and experimental measurements have investigated symptoms [1–4] to further elucidate the roles of pulmonary arterial mechanics and hemodynamics, the individual relative importance of the components of PVR, pulmonary vascular stiffness (PVS), geometry and cardiac function are unclear in disease progression. In addition, while current PH treatment focuses on distal vasodilation, it is unknown whether or not other treatment targets might beneficially impact right ventricular function, and as a result improve of PH treatment. Clinical and traditional scientific studies of PH focus on changes in the distal circulation. For example, the distal
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