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Untangling the mechanisms of pulmonary hypertension-induced right ventricular stiffening in a large animal model.
Kakaletsis, Sotirios; Malinowski, Marcin; Mathur, Mrudang; Sugerman, Gabriella P; Lucy, Jeff J; Snider, Caleb; Jazwiec, Tomasz; Bersi, Matthew; Timek, Tomasz A; Rausch, Manuel K.
Afiliação
  • Kakaletsis S; Department of Aerospace Engineering & Engineering Mechanics, The University of Texas at Austin, Austin, TX.
  • Malinowski M; Division of Cardiothoracic Surgery, Spectrum Health, Grand Rapids, MI.
  • Mathur M; Department of Cardiac Surgery, Medical University of Silesia, Katowice, Poland.
  • Sugerman GP; Department of Mechanical Engineering, The University of Texas at Austin, TX.
  • Lucy JJ; Department of Biomedical Engineering, The University of Texas at Austin, TX.
  • Snider C; Center for Advanced Brain Imaging Research, Rutgers University, New Brunswick, NJ.
  • Jazwiec T; Department of Mechanical Engineering & Materials Science, Washington University at St. Louis, St. Louis, MO.
  • Bersi M; Division of Cardiothoracic Surgery, Spectrum Health, Grand Rapids, MI.
  • Timek TA; Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Medical University of Silesia in Katowice, Silesian Centre for Heart Diseases, Zabrze, Poland.
  • Rausch MK; Department of Mechanical Engineering & Materials Science, Washington University at St. Louis, St. Louis, MO.
bioRxiv ; 2023 Apr 06.
Article em En | MEDLINE | ID: mdl-37066294
ABSTRACT

Background:

Pulmonary arterial hypertension (PHT) is a devastating disease with low survival rates. In PHT, chronic pressure overload leads to right ventricle (RV) remodeling and stiffening; thus, impeding diastolic filling and ventricular function. Multiple mechanisms 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 as well as imaging, experimental, and computational approaches to untangle these mechanisms.

Methods:

We induced PHT in eight 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. All findings were compared to 12 control animals. Finally, we used computational modeling to disentangle the relative importance of each stiffening mechanism.

Results:

First, we found that the RVs of PHT animals thickened most at the base and the free wall. Additionally, we found that PHT induced excessive collagen synthesis and microstructural disorganization, consistent with increased expression of fibrotic genes. We also found that the myocardium itself stiffened significantly. Importantly, myocardial stiffening correlated significantly with excess collagen synthesis. Finally, our model of normalized RV pressure-volume relationships predicted that myocardial stiffness contributes to RV stiffening significantly more than other mechanisms.

Conclusions:

In summary, we found that PHT induces wall thickening, microstructural disorganization, and myocardial stiffening. These remodeling mechanisms were both spatially and directionally dependent. Using modeling, we show that myocardial stiffness is the primary contributor to RV stiffening. Thus, myocardial stiffening may be an important predictor for PHT progression. Given the significant correlation between myocardial stiffness and collagen synthesis, collagen-sensitive imaging modalities may be useful for non-invasively estimating myocardial stiffness and predicting PHT outcomes.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article