The overall goal of this project is to understand how complications of sickle cell disease affect pulmonary pulsatile hemodynamics and right ventricular function. Sickle cell disease is one of the most common heritable monogenetic disease in the world. Pulmonary hypertension as emerged as a leading cause of morbidity and mortality among patients with sickle cell disease. The mechanisms by which pulmonary hypertension develops in patients with sickle cell disease remains unclear. Multiple pathways have been proposed including increased red blood cell stiffness, hyperviscosity, hypoxemia, hemolysis, reperfusion injury and pulmonary embolism. However, the mechanical mechanisms and resulting hemodynamic changes, by which pulmonary hypertension develops in patients with sickle cell disease has not been explored in depth. The investigation of pulmonary pulsatile hemodynamics in pulmonary hypertension alone, has revealed that changes in arterial stiffness affect right ventricular afterload, and have been shown to better predict mortality in these patients. While patients with sickle cell disease have been shown to have increased arterial stiffness systemically, the stiffness of either the proximal or distal pulmonary arteries has not been explored in depth. The first two aims proposed will focus on how changing red blood cell stiffness, hypoxemia and hyperviscosity contribute to changes in pulmonary pulsatile hemodynamics.
The third aim will measure changes in both right ventricular afterload, including changes in pulmonary arterial stiffness, and right ventricular function in mice with pulmonary hypertension associated with sickle cell disease. This project would be the first to investigate pulmonary pulsatile hemodynamics, right ventricular function, and ventricular-vascular interactions in the context of pulmonary hypertension associated with sickle cell disease. Our results will lend valuable insight into how sickle cell disease affects pulmonary pulsatile hemodynamics and contributes to the high rates of mortality in patients with pulmonary hypertension and sickle cell disease.

Public Health Relevance

Sickle cell disease is one of the most comment heritable monogenetic diseases in the world, and the development of pulmonary hypertension associated with sickle cell disease is a major cause of mortality. This project will study how complications o sickle cell disease including hypoxemia, hyperviscosity, increased red blood cell stiffness, and pulmonary embolism change pulmonary pulsatile hemodynamics and right ventricular function, which ultimately lead to pulmonary hypertension. This project will advance mechanical and hemodynamic understanding of how sickle cell disease affects the pulmonary vasculature, as the methods and approach in this project have never been utilized to study the right ventricle and pulmonary vasculature in sickle cell disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL128088-03
Application #
9305128
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chang, Henry
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Schreier, David A; Forouzan, Omid; Hacker, Timothy A et al. (2016) Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure. J Biomech Eng 138:021012