Vascular collagen accumulation & mechanical mechanisms in pulmonary hypertension

肺血管重构是肺动脉高压的结果，可导致右肺 心力衰竭。然而，重塑导致心力衰竭的机制尚不清楚。 以前的传统想法是动脉肌化导致管腔直径减小和 稳定的心室功增加，但最近的证据挑战了这一观点。我们最重要的是 假设肺血管胶原堆积是搏动性室性心动过速增加的原因 工作，这严重损害了功能，并通过动脉硬化来做到这一点。在体循环中，动脉 强直已被认为是心血管死亡的独立危险因素。网络的影响 动脉硬化对右室功能的影响是该领域的一大知识空白。在这里，我们寻求 为了验证血管胶原堆积对肺动脉高压的反应的特定假说 (1)增加肺动脉僵硬，(2)增加肺动脉脉搏波反射，以及(3) 会损害右心功能。此外，我们试图证明，恢复正常的动脉， 恢复期间的血流动力学和心功能依赖于胶原的降解，而且 防止血管胶原堆积(使用一种新型的抗纤维化治疗药物)可防止病情恶化。 我们将用最先进的生物力学和血液动力学实验来验证我们的假说。 以及基因工程小鼠。我们还将在临床试验中探索这些终点的临床相关性。 先导研究。我们的具体目标是： 1.通过压力测定血管胶原沉积在肺动脉硬化中的作用 离体肺动脉和肺血管网的直径测量。 2.确定血管胶原沉积在肺动脉波反射中的作用-通过 离体肺、通气肺和灌流肺的脉动压力-流量测量。 3.确定血管胶原堆积在右室功能中的作用-通过压力- 活体小鼠右心室的原位体积测量。 4.检测慢性阻塞性肺疾病患者的肺血管血流动力学和右心功能 肺动脉高压，集中在那些胶原过度积聚的人。 这个项目的成功完成将对治疗的进展产生重要的见解 以及从肺动脉高压中恢复。此外，这些研究将回答关键问题 关于肺血管继发右心功能不全的力学机制 肺动脉高压的重塑。

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 aimsare: 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.