Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease, even with modern therapies. The cause of death is typically right ventricular (RV) failure. Narrowing of the small, distal pulmonary arteries is know to cause PAH. Recently, increased stiffness of the large, proximal pulmonary arteries (PAs) was identified as a powerful predictor of mortality in PAH. However, the impact of distal and proximal PA remodeling on the critical transition from a healthy RV to a failing RV remains a major knowledge gap. Over the initial funding period (2008-2012), we focused on the vascular impact of the mechanically important protein collagen on proximal arterial stiffening, pulmonary hemodynamics and subsequent changes in RV function with hypoxia-induced pulmonary hypertension (HPH). Here we extend the work in three important ways. First, we employ novel methods to generate not only RV dysfunction but also RV failure, which has been a limitation of mouse PH models until recently. Second, we designed a novel experimental approach to uncouple and therefore distinguish the effects of proximal PA stiffening from distal PA narrowing, which are tightly coupled clinically but may impair RV function through independent mechanisms. Third, we investigate the role of RV collagen content and cross-linking in RV dysfunction and the transition to failure.
Our aims are:
Aim 1. To demonstrate the dependence of adaptive RV hypertrophy (thickened but not failing RV) on distal PA narrowing and independence from proximal PA stiffening in mild/moderate PAH, because we hypothesize that increases in mean pulmonary arterial pressure due to distal PA narrowing are necessary and sufficient to cause adaptive RV hypertrophy in mild to moderate PAH.
Aim 2. To demonstrate the dependence of maladaptive RV remodeling (failing RV) on the combination of distal PA narrowing and proximal PA stiffening in severe PAH, because we hypothesize that increases in mean pulmonary arterial pressure are necessary but not sufficient to cause maladaptive RV remodeling in severe PAH;we hypothesize that increases in pulse pressure induced by proximal PA stiffening are also necessary.
Aim 3. To investigate the relationship between RV function and RV fibrosis because we hypothesize that a more fibrotic RV is more impaired by distal PA narrowing and proximal PA stiffening than a less fibrotic RV. The clinical and scientific communities investigating PAH were recently charged with improving our understanding of the dependence of RV function on pulmonary vascular changes. Our goals are to investigate critical mechanobiological changes in proximal and distal PAs as well as the RV itself that drive the transition from a hypertrophied, functional RV to a failing RV during PAH progression, with a particular emphasis on the role of collagen, which in the future may impact treatment options for this rapidly fatal disease.
The most serious clinical consequence of pulmonary hypertension is right heart failure. However, much research is focused on an intermediate step in disease progression - pulmonary arterial remodeling. In this work we focus on the end effect of the disease - right heart failure - and seek to link its development with specific mechanical changes in the arteries of the lung and the heart tissue itself. Our work focuses specifically on the role of particular mechanically important protein, collagen, in large arterial stiffening, smal artery narrowing, and right heart failure. Our work will shed light on the factors that promote the critical transition from a strong heart muscle to a weak heart muscle in pulmonary hypertension progression.
|Barker, Alex J; Roldán-Alzate, Alejandro; Entezari, Pegah et al. (2015) Four-dimensional flow assessment of pulmonary artery flow and wall shear stress in adult pulmonary arterial hypertension: results from two institutions. Magn Reson Med 73:1904-13|
|Liu, Aiping; Schreier, David; Tian, Lian et al. (2014) Direct and indirect protection of right ventricular function by estrogen in an experimental model of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 307:H273-83|
|Golob, Mark; Moss, Richard L; Chesler, Naomi C (2014) Cardiac tissue structure, properties, and performance: a materials science perspective. Ann Biomed Eng 42:2003-13|
|Schreier, David A; Hacker, Timothy A; Hunter, Kendall et al. (2014) Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia. J Appl Physiol (1985) 117:833-9|
|Roldán-Alzate, Alejandro; Frydrychowicz, Alex; Johnson, Kevin M et al. (2014) Non-invasive assessment of cardiac function and pulmonary vascular resistance in an canine model of acute thromboembolic pulmonary hypertension using 4D flow cardiovascular magnetic resonance. J Cardiovasc Magn Reson 16:23|
|Vanderpool, Rebecca R; El-Bizri, Nesrine; Rabinovitch, Marlene et al. (2013) Patchy deletion of Bmpr1a potentiates proximal pulmonary artery remodeling in mice exposed to chronic hypoxia. Biomech Model Mechanobiol 12:33-42|
|Wang, Zhijie; Chesler, Naomi C (2013) Pulmonary vascular mechanics: important contributors to the increased right ventricular afterload of pulmonary hypertension. Exp Physiol 98:1267-73|
|Wang, Zhijie; Kristianto, Jasmin; Yen Ooi, Chen et al. (2013) Blood pressure, artery size, and artery compliance parallel bone size and strength in mice with differing ece1 expression. J Biomech Eng 135:61003-9|
|Wang, Zhijie; Lakes, Roderic S; Eickhoff, Jens C et al. (2013) Effects of collagen deposition on passive and active mechanical properties of large pulmonary arteries in hypoxic pulmonary hypertension. Biomech Model Mechanobiol 12:1115-25|
|Schreier, David; Hacker, Timothy; Song, Gouqing et al. (2013) The role of collagen synthesis in ventricular and vascular adaptation to hypoxic pulmonary hypertension. J Biomech Eng 135:021018|
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