Vascular collagen accumulation & mechanical mechanisms in pulmonary hypertension

描述（由申请人提供）：肺血管重塑是肺动脉高压的结果，可导致右心室衰竭。然而，重塑导致心室衰竭的机制尚不清楚。以前的传统观点认为，小动脉肌化导致管腔直径减小和心室稳定工作增加，但最近的证据挑战了这一观点。我们的首要假设是肺血管胶原蛋白的积累是增加搏动性心室工作，这严重损害功能，并通过动脉硬化。在体循环中，动脉硬化已被认为是心血管死亡率的独立危险因素。动脉硬化对右心室功能的影响是该领域的一个主要知识空白。在这里，我们试图测试特定的假设，即肺动脉高压时血管胶原蛋白的积累（1）增加肺动脉硬度，（2）增加肺动脉脉搏波反射，（3）损害右心室功能。此外，我们试图表明，恢复期间恢复正常的动脉、血液动力学和心室功能取决于胶原蛋白的降解，并且防止血管胶原蛋白积聚（使用新型抗纤维化治疗剂）可防止进展。我们将测试我们的假设与国家的最先进的生物力学和血液动力学实验野生型和基因工程小鼠。我们还将在临床试点研究中探索这些终点的临床相关性。我们的具体目标是：1.通过测量离体肺动脉和肺血管网的压力-直径来确定血管胶原积聚在肺动脉硬化中的作用。2.通过测量离体、通气和灌注肺的脉动压力-流量，确定血管胶原积聚在肺动脉波反射中的作用。3.通过活体小鼠右心室原位压力-容积测量，确定血管胶原积聚在右心室功能中的作用。4.检测肺动脉高压患者的肺血管血流动力学和右心室功能，重点关注胶原过度积聚的患者。该项目的成功完成将对肺动脉高压的进展、治疗和恢复产生重要的见解。此外，这些研究将回答有关肺动脉高压继发于肺血管重构的右心室功能障碍的机械机制的关键问题。

DESCRIPTION (provided by applicant): 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.