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A computational growth and remodeling framework for adaptive and maladaptive pulmonary arterial hemodynamics

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Abstract

Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step toward predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.

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All data and code from this work are available on request.

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Funding

The authors appreciate funding support from the Parker B. Francis Fellowship program for this work. This work was also supported in part by the Stanford Maternal and Child Health Research Institute through the Pilot Award Program and a grant from the National Heart, Lung and Blood Institute (1T32HL098049).

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Authors and Affiliations

  1. Department of Pediatrics (Cardiology), Stanford University, Stanford, CA, 94305, USA

    Jason M. Szafron, Weiguang Yang, Jeffrey A. Feinstein, Marlene Rabinovitch & Alison L. Marsden

  2. Cardiovascular Institute, Stanford University, Palo Alto, CA, 94305, USA

    Jason M. Szafron, Jeffrey A. Feinstein, Marlene Rabinovitch & Alison L. Marsden

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  1. Jason M. Szafron
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  2. Weiguang Yang
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Contributions

JMS performed the simulations and data analysis with guidance from WY and ALM. JMS, MR, and ALS conceptualized the study design. JAF and MR provided clinical context for the results and discussion. JMS, WY, and ALS wrote the main manuscript text. All authors reviewed and edited the text.

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Correspondence to Alison L. Marsden.

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Szafron, J.M., Yang, W., Feinstein, J.A. et al. A computational growth and remodeling framework for adaptive and maladaptive pulmonary arterial hemodynamics. Biomech Model Mechanobiol 22, 1935–1951 (2023). https://doi.org/10.1007/s10237-023-01744-z

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