Abstract
BackgroundThe role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV–pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children.MethodsBalanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method.ResultsLV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH.ConclusionsThe PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.
Highlights
Pulmonary arterial hypertension (PAH) is a condition characterized by an occlusive pulmonary vasculopathy that leads to increased afterload on the right ventricle (RV) and a progressive decline in ventricular function, which left untreated results in eventual right ventricular (RV) failure and death [1, 2]
Historically pulmonary arterial hypertension (PAH) has been treated with RV function solely in mind [4], our recent research has shown altered left ventricular (LV) mechanics with reduction in LV torsion and LV circumferential strain in pediatric PAH populations, which is associated with impaired RV contractility and function [5, 6]
One patient was diagnosed as PAH due to a connective tissue disease, one patient had hereditary PAH, three had PAH due to congenital heart disease, and 13 of the PAH patients were diagnosed as idiopathic PAH. 66% of the PAH group and 65% of the control group were female
Summary
Pulmonary arterial hypertension (PAH) is a condition characterized by an occlusive pulmonary vasculopathy that leads to increased afterload on the right ventricle (RV) and a progressive decline in ventricular function, which left untreated results in eventual RV failure and death [1, 2]. A study on patients with a systemic-loaded RV demonstrated that LV mechanical dysfunction in ventricular strain and twisting had a significant effect on RV mechanics [8], and others have shown prognostic value in reduced LV and RV myocardial strain for prediction of adverse outcome in both adults [9] and children [10]. These studies are strongly indicative of the LV’s influence on RV function, yet they do not investigate altered ventricular mechanical interdependence longitudinally in PAH, nor explore potential therapeutic interventions. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children
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