Pediatric pulmonary arterial hypertension (PAH) is a degenerative disease that can ultimately lead to right heart failure. Lately, proposed clinical techniques for assessing disease progression and risk stratification have utilized the relative safety of, and abundant information available in, Cardiac MR (CMR) images. These techniques allow for direct functional and morphological measurements, and can be used to perform patient-specific computational simulations that can predict the biomechanical state of the heart under different scenarios. Tagged MRI is a relatively new technique that can also reveal strain and local ventricular twisting. This project will combine MR imaging (with and without tissue tagging) and computational modeling in pediatric PH patients, and tissue gene expression in rats, to completely phenotype right ventricular dysfunction in pediatric pulmonary hypertension and improve our understanding of the biomechanical/biochemical progression of the disease. Right ventricular (RV) dysfunction is commonly attributed to pressure or volume overload, but direct contribution of the left ventricle (LV) is usually overlooked. However, multiple previous studies have shown that the RV is relying on the mechanical energy transfer from LV contraction for up to 80% of its pumping performance. The initial dysfunction of a single ventricle can trigger a remodeling response in the neighboring ventricle, which would further contribute to the dysfunction of the former. Therefore, changes to LV twisting-rate seen in PAH is likely both the cause and effect of ultimate RV dysfunction. The objective of this study is to: (1) provide definitive evidence that LV torsion-rate is decreased in pediatric PAH, which is associated with a decrease in RV contractility; (2) investigate, using computational modeling, if restoring LV torsion- rate would improve RV function and consequently establish LV torsion-rate as the biomechanical cause for declining RV function; and (3) identify differentially expressed genes in the blood and myocardium of a PH rat model. The successful completion of these objectives will: (1) lead to novel prognostic markers and a better understanding of the cardio-pulmonary pathophysiology associated with PAH; (2) provide career development training for animal modeling, genomic analysis, and bioinformatics; and (3) generate preliminary data for a future NIH R01 application to study the link between functional RV-LV decompensation and changes in gene expression.

Public Health Relevance

Pediatric pulmonary arterial hypertension (PAH) is a progressive disease with a high mortality rate. Routine clinical evaluation is limited by the invasive nature of right heart catheterization, which focuses on the pulmonary vasculature and right ventricular pressure as a measure of disease progress. This project will investigate the impact of left ventricular torsion-rate on RV pressure generation and mechanical stress. This work will identify the biomechanical cause of declining RV function during PAH and underlying changes in gene expression that could be impacting ventricular contraction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Quantitative Research Career Development Award (K25)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Wang, Wayne C
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University of Colorado Denver
Biomedical Engineering
Schools of Medicine
United States
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