Pulmonary vascular remodeling is a consequence of pulmonary hypertension that can lead to right ventricular failure. However, the mechanisms by which remodeling causes ventricular failure are unknown. Previous conventional thinking was that arteriolar muscularization led to reduced lumen diameters and increased steady ventricular work, but recent evidence has challenged that view. Our overarching hypothesis is that pulmonary vascular collagen accumulation is responsible for increased pulsatile ventricular work, which severely impairs function, and does so via arterial stiffening. In the systemic circulation, arterial stiffening has been recognized as an independent risk factor for cardiovascular mortality. The impact of arterial stiffening on right ventricular function represents a major knowledge gap in the field. Here, we seek to test the specific hypotheses that vascular collagen accumulation in response to pulmonary hypertension (1) increases pulmonary arterial stiffness, (2) increases pulmonary arterial pulse wave reflections, and (3) impairs right ventricular function. Furthermore, we seek to show that the return to normal arterial, hemodynamic and ventricular function during recovery is dependent on the degradation of collagen and that preventing vascular collagen accumulation (with a novel anti-fibrotic treatment agent) prevents progression. We will test our hypotheses with state-of-the-art biomechanical and hemodynamic experiments on wild type and genetically-engineered mice. We will also explore the clinical correlates of these endpoints in a clinical pilot study.
Our specific aims are: 1. To determine the role of vascular collagen accumulation in pulmonary arterial stiffening - via pressure- diameter measurements in isolated pulmonary arteries and the pulmonary vascular network. 2. To determine the role of vascular collagen accumulation in pulmonary arterial wave reflections - via pulsatile pressure-flow measurements in isolated, ventilated and perfused lungs. 3. To determine the role of vascular collagen accumulation in right ventricular function - via pressure- volume measurements in the right ventricle of live mice in situ. 4. To examine the pulmonary vascular hemodynamics and right ventricular function of patients with pulmonary hypertension, focusing on those with excessive collagen accumulation. The successful completion of this project will yield important insights into the progression of, treatment for and recovery from pulmonary hypertension. Furthermore, these studies will answer critical questions regarding the mechanical mechanisms of right ventricular dysfunction secondary to pulmonary vascular remodeling in pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086939-04
Application #
7870490
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Moore, Timothy M
Project Start
2007-06-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$356,969
Indirect Cost
Name
University of Wisconsin Madison
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Cheng, Tik-Chee; Philip, Jennifer L; Tabima, Diana M et al. (2018) Multiscale structure-function relationships in right ventricular failure due to pressure overload. Am J Physiol Heart Circ Physiol 315:H699-H708
Goss, Kara N; Beshish, Arij G; Barton, Gregory P et al. (2018) Early Pulmonary Vascular Disease in Young Adults Born Preterm. Am J Respir Crit Care Med :
Philip, Jennifer L; Chesler, Naomi C (2018) Know Your Limitations: Assumptions in the Single-Beat Method for Estimating Right Ventricular-Pulmonary Vascular Coupling. Am J Respir Crit Care Med 198:707-709
Qureshi, M Umar; Colebank, Mitchel J; Schreier, David A et al. (2018) Characteristic impedance: frequency or time domain approach? Physiol Meas 39:014004
Pewowaruk, Ryan J; Philip, Jennifer L; Tewari, Shivendra G et al. (2018) Multiscale Computational Analysis of Right Ventricular Mechanoenergetics. J Biomech Eng 140:
Wang, Zhijie; Patel, Jitandrakumar R; Schreier, David A et al. (2018) Organ-level right ventricular dysfunction with preserved Frank-Starling mechanism in a mouse model of pulmonary arterial hypertension. J Appl Physiol (1985) 124:1244-1253
Golob, Mark J; Massoudi, Dawiyat; Tabima, Diana M et al. (2018) Cardiovascular function and structure are preserved despite induced ablation of BMP1-related proteinases. Cell Mol Bioeng 11:225-266
Philip, Jennifer L; Pewowaruk, Ryan J; Chen, Claire S et al. (2018) Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions. Front Physiol 9:731
Golob, Mark J; Tabima, Diana M; Wolf, Gregory D et al. (2017) Pulmonary arterial strain- and remodeling-induced stiffening are differentiated in a chronic model of pulmonary hypertension. J Biomech 55:92-98
Wang, Zhijie; Schreier, David A; Abid, Hinnah et al. (2017) Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension. J Appl Physiol (1985) 122:253-263

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