Sickle Cell Disease Associated with Pulmonary Hypertension: Mechanical and Hemodynamic Consequences

与肺动脉高压相关的镰状细胞病：机械和血流动力学后果

• 批准号: 8909529
• 负责人: David A. Schreier
• 金额: $ 3.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909529
• 关键词: Adult; Affect; Animal Model; Blood; Blood Vessels; Blood Viscosity; Blood flow; Cardiac Output; Carotid Arteries; Cells; Cessation of life; Chronic; Coupling; Development; Disease; Distal; Erythrocytes; Failure; Glutaral; Goals; Heart Rate; Hemolysis; Hyperviscosity; Hypoxemia; Investigation; Lead; Lung; Lung diseases; Measures; Mechanics; Methods; Molecular; Morbidity - disease rate; Mus; Oxygen; Oxygen measurement, partial pressure, arterial; Pathway interactions; Patients; Prevalence; Published Comment; Pulmonary Embolism; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Reperfusion Injury; Reporting; Right Ventricular Function; Right ventricular structure; Risk; Secondary to; Sickle Cell; Sickle Cell Anemia; Signal Pathway; Sudden Death; Testing; Thalassemia; Time; Vascular remodeling; Vena caval structure; Ventricular; Viscosity; Wild Type Mouse; arterial stiffness; electric impedance; endothelial dysfunction; hemodynamics; in vivo; insight; mortality; mouse model; pressure; public health relevance; sickling

 DESCRIPTION (provided by applicant): 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.

 描述(由申请人提供)：本项目的总体目标是了解镰状细胞病的并发症如何影响肺搏动血流动力学和右心功能。镰状细胞病是世界上最常见的遗传性单基因疾病之一。在镰状细胞病患者中，肺动脉高压成为发病率和死亡率的主要原因。镰状细胞病患者发生肺动脉高压的机制尚不清楚。多种途径被提出，包括红细胞刚性增加、高粘滞性、低氧血症、溶血、再灌注损伤和肺栓塞。然而，镰状细胞病患者发生肺动脉高压的机械机制和由此引起的血流动力学变化尚未深入探讨。仅在肺动脉高压中对肺搏动性血流动力学的研究表明，动脉僵硬的变化影响右室后负荷，并已被证明更好地预测这些患者的死亡率。虽然镰状细胞病的患者已经被证明系统性地增加了动脉僵硬，但近端或远端肺动脉的僵硬还没有被深入研究。提出的前两个目标将集中于改变红细胞僵硬、低氧血症和高粘度如何促进肺搏动性血流动力学的变化。第三个目标将测量右室后负荷的变化，包括肺动脉僵硬的变化，以及与镰状细胞病相关的肺动脉高压小鼠右室功能的变化。该项目将首次在与镰状细胞疾病相关的肺动脉高压的背景下研究肺搏动性血流动力学、右室功能和室-血管相互作用。我们的结果将为镰状细胞病如何影响肺搏动性血流动力学以及导致肺动脉高压和镰状细胞病患者的高死亡率提供有价值的见解。