Pulmonary hypertension (PH) is a complex disorder associated with elevated pulmonary arterial pressure. Unlike systemic hypertension, PH is difficult to detect in routine physical examinations and the current gold standard for diagnosing PH is through invasive right heart catheterization. Unlike in systemic hypertension, for which patients have effective pharmacological management of blood pressure for decades, PH prognosis remains poor with 15% mortality within 1 year on modern therapy. Challenges in early detection of PH, as well as structural differences in the cardio-pulmonary system (e.g., thinner ventricular wall, more distributed compliance and larger number of peripheral vessels) may explain the stark differences in clinical outcomes between systemic hypertension and PH. Our current understanding of PH has largely been obtained through animal models, clinical studies and computational modeling. However, surgical banding or chronic hypoxia animal models do not fully reproduce the etiology of human PH. Invasive clinical measurements of pulmonary vascular resistance (PVR), stiffness and ventricular elastance provide limited insight into disease progression. Computational models have been developed to study growth and remodeling (G&R) in the ventricles and hemodynamics in PH. However, these models are incomplete: ventricular G&R models lack coupling with evolving pulmonary hemodynamics, whereas pulmonary hemodynamic models have not included ventricular-arterial coupling. Given that the interactions between RV and the pulmonary vasculature are a key determinant of the clinical course of PH, specifically, the transition from compensated to decompensated remodeling, we submit that there is a pressing need to develop a multi-scale (MS) computational model that can couple the short term (e.g. hemodynamics) and long-term G&R interactions between the RV and the pulmonary circulation. In this project, we propose to develop a multi-scale, multi-physics computational model of the cardio-pulmonary circulation and calibrate it using longitudinal data acquired on cohorts of pediatric pulmonary hypertension and control (e.g., cardiac transplant) subjects. The model will be the first of its kind because it will be able to describe the bi-directional interactions between evolving ventricular and vascular biomechanics and hemodynamics using human pulmonary hypertension data.

Public Health Relevance

Pulmonary hypertension (PH) is a complex disorder associated with elevated pulmonary arterial pressure. Unlike in systemic hypertension, for which patients have effective pharmacological management of blood pressure for decades, PH prognosis remains poor with 15% mortality within 1 year on modern therapy. Animal models and invasive clinical assessment have yielded limited insight into disease progression. We submit that there is a pressing need to develop a multi-scale (MS) computational model that can couple the short term (e.g. hemodynamics) and long-term tissue growth & remodeling interactions between the RV and the pulmonary circulation in PH subjects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL135842-04
Application #
9905410
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Natarajan, Aruna R
Project Start
2017-03-15
Project End
2021-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zambrano, Byron A; McLean, Nathan A; Zhao, Xiaodan et al. (2018) Image-based computational assessment of vascular wall mechanics and hemodynamics in pulmonary arterial hypertension patients. J Biomech 68:84-92
Shavik, Sheikh Mohammad; Jiang, Zhenxiang; Baek, Seungik et al. (2018) High Spatial Resolution Multi-Organ Finite Element Modeling of Ventricular-Arterial Coupling. Front Physiol 9:119