Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease, even with modern therapies. The cause of death is typically right ventricular failure. Recently, increased stiffness of the large pulmonary arteries was identified as a powerful predictor of mortality in PAH. Increased stiffness of the small arteries may also contribute to disease progression. The effects of proximal and distal arterial stiffening on a patient's exercise capacity and ability to benefit from exercise are unknown. We hypothesize that proximal arterial stiffening is responsible for right ventricular dysfunction via inefficient hemodynamic interactions. We also hypothesize that distal arterial stiffening limits exercise capacity. The goals of this study are to quantify right ventricular-pulmonary vascular interactions in different types of PAH, to determine the temporal changes in these interactions with PAH progression and to quantify the effects of exercise on right ventricular function. We have a particular interest in the subpopulation of PAH with systemic sclerosis (SSc) because we anticipate that this group has worse arterial stiffening than other groups, and consequently more inefficient right ventricular-pulmonary vascular interactions, which account for their worse prognosis.
Our aims are:
Aim 1. To quantify the relationships between pulmonary arterial stiffness, right ventricular function and the efficiency of ventricular-vascular interactions in patients with PAH.
Aim 2. To quantify the effects of exercise on pulmonary arterial stiffness, pulmonary vascular resistance, right ventricular function and the efficiency of ventricular-vascular interactions in patients with PAH.
Aim 3. To investigate the progression of loss of efficiency of ventricular-vascular interactions in canine models of IPAH and CTEPH. The clinical and scientific communities investigating PAH were recently charged with studying the cardiopulmonary system more comprehensively, especially in subpopulation of PAH with SSc. Our goals are to investigate the hemodynamic mechanisms of right ventricular-pulmonary vascular interactions in PAH, differences among PAH subtypes and the effects of exercise on ventricular and vascular function and interactions in PAH. Importantly, our results may lead to a novel "physiomarker" of disease that could enable clinicians to better identify PAH patients who are at risk for ventricular-vascular dysfunction and determine who will likely benefit from exercise training. 1

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a poorly understood disease of the arteries of the lung that ultimately leads to heart failure. The benefits of exercise in current clinical management of PAH are highly controversial, largely because its effects on heart function are unknown. We propose to measure the impact of exercise on blood flow and heart function to improve our understanding of this disease, identify patients who are likely to benefit from exercise, and develop novel predictors of disease progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105598-02
Application #
8317371
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Moore, Timothy M
Project Start
2011-09-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$607,371
Indirect Cost
$152,284
Name
University of Wisconsin Madison
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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