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

Abstract

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.

Pulmonary hypertension in children

“…Total right ventricular afterload can be measured as pulmonary vascular input impedance and consists of a dynamic component (compliance / stiffness) and a static component (resistance). [79][80][81] In children, pulsatile components of right ventricular afterload, represented by pulmonary arterial capacitance and pulmonary stroke volume index, provide important prognostic information to conventional static hemodynamic parameters. 82,83 RV stroke work (RVSW), the product of mean pulmonary artery pressure and stroke volume, integrates contractility, afterload and ventricular-vascular coupling.…”

Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep

“…Proximal PA stiffness plays an important role in disease progression in adults with PH and is an independent predictor of morbidity and mortality in other diseases and postnatal models of PH (20,23,25). However, previous studies of the distal vasculature suggest that arterial collagen content is not altered in experimental PPHN (4, 5).…”

“…Although PPHN is associated with altered vascular tone and vasoreactivity, smooth muscle cell hyperplasia, and reduced arterial density, past studies of PPHN have largely focused on the contribution of small pulmonary arteries (PA) to high PVR (9,29). More recently, proximal PA stiffness has been shown to be an important prognostic in the progression of disease in models of postnatal pulmonary hypertension (PH) (25). However, the proximal elastic PA has received little study in the developing lung or in experimental models of PPHN.…”

Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy

“…PVR measures the resistance to flow and clinically describes the degree of vasoconstriction or angiogenic development of the distal vasculature. More recently, proximal PA stiffness has increasing interest as an important indicator of disease progression (20,32,35,36). Proximal PA stiffness through extracellular matrix (ECM) remodeling increases impedance that increase RV afterload (9,14).…”

“…Proximal PA stiffness through extracellular matrix (ECM) remodeling increases impedance that increase RV afterload (9,14). Both PVR and impedance components contribute to the pathogenesis and RV dysfunction in PH (35) but are poorly understood in the setting of BPD. Furthermore, neonatal complications of BPD have been clinically associated with global RV structural and functional differences in adult life (21), motivating the need to understand RV-PA function in the neonate.…”