Vascular collagen accumulation & mechanical mechanisms in pulmonary hypertension

描述(由申请人提供)：肺血管重塑是可导致右心衰竭的肺动脉高压的结果。然而，重塑导致心力衰竭的机制尚不清楚。以前的传统观点认为微动脉肌化可以减少管腔直径，增加稳定的心室功，但最近的证据对这一观点提出了质疑。我们的主要假设是，肺血管胶原堆积是导致搏动性室功增加的原因，这严重损害了功能，并通过动脉硬化实现了这一点。在体循环中，动脉硬化已被认为是心血管死亡的独立危险因素。动脉硬化对右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堆积(1)增加了肺动脉僵硬，(2)增加了肺动脉脉搏波反射，(3)损害了右心功能。此外，我们试图证明，在恢复过程中恢复正常的动脉、血流动力学和心室功能依赖于胶原的降解，防止血管胶原堆积(使用新的抗纤维化治疗药物)可以防止进展。我们将在野生型和转基因小鼠身上用最先进的生物力学和血液动力学实验来验证我们的假设。我们还将在一项临床先导研究中探索这些终点的临床相关性。我们的具体目标是：1.通过对离体肺动脉和肺血管网的压力-直径测量，确定血管胶原堆积在肺动脉硬化中的作用。2.通过对离体肺、通气肺和灌流肺的脉动压力-流量测量，确定血管胶原沉积在肺动脉波反射中的作用。3.通过对在体小鼠右室压力-容量的测量，探讨血管胶原沉积在右室功能中的作用。4.检测肺动脉高压患者的肺血管血流动力学和右心功能，重点观察胶原过度积聚患者的肺血管血流动力学和右室功能。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室功能障碍的关键问题。

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.