1. Untangling the mechanisms of pulmonary arterial hypertension-induced right ventricular stiffening in a large animal model.
- Author
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Kakaletsis S, Malinowski M, Snider JC, Mathur M, Sugerman GP, Luci JJ, Kostelnik CJ, Jazwiec T, Bersi MR, Timek TA, and Rausch MK
- Subjects
- Humans, Animals, Sheep, Heart Ventricles pathology, Pulmonary Artery metabolism, Pulmonary Artery pathology, Collagen metabolism, Disease Models, Animal, Pulmonary Arterial Hypertension metabolism, Pulmonary Arterial Hypertension pathology, Hypertension, Pulmonary diagnostic imaging, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary pathology
- Abstract
Pulmonary hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) stiffening; thus, impeding diastolic filling. Multiple mechanisms may contribute to RV stiffening, including wall thickening, microstructural disorganization, and myocardial stiffening. The relative importance of each mechanism is unclear. Our objective is to use a large animal model to untangle these mechanisms. Thus, we induced pulmonary arterial hypertension (PAH) in sheep via pulmonary artery banding. After eight weeks, the hearts underwent anatomic and diffusion tensor MRI to characterize wall thickening and microstructural disorganization. Additionally, myocardial samples underwent histological and gene expression analyses to quantify compositional changes and mechanical testing to quantify myocardial stiffening. Finally, we used finite element modeling to disentangle the relative importance of each stiffening mechanism. We found that the RVs of PAH animals thickened most at the base and the free wall and that PAH induced excessive collagen synthesis, increased cardiomyocyte cross-sectional area, and led to microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with collagen synthesis. Finally, our computational models predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms. Thus, myocardial stiffening may be the most important predictor for PAH progression. Given the correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for estimating myocardial stiffness and predicting PAH outcomes. STATEMENT OF SIGNIFICANCE: Ventricular stiffening is a significant contributor to pulmonary hypertension-induced right heart failure. However, the mechanisms that lead to ventricular stiffening are not fully understood. The novelty of our work lies in answering this question through the use of a large animal model in combination with spatially- and directionally sensitive experimental techniques. We find that myocardial stiffness is the primary mechanism that leads to ventricular stiffening. Clinically, this knowledge may be used to improve diagnostic, prognostic, and therapeutic strategies for patients with pulmonary hypertension., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Rausch has a speaking agreement with Edwards Lifesciences., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
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