Computational modeling of cardiac growth and remodeling in pressure overloaded hearts—Linking microstructure to organ phenotype

Abstract

Cardiac growth and remodeling (G&R) refers to structural changes in myocardial tissue in response to chronic alterations in loading conditions. One such condition is pressure overload where elevated wall stresses stimulate the growth in cardiomyocyte thickness, associated with a phenotype of concentric hypertrophy at the organ scale, and promote fibrosis. The initial hypertrophic response can be considered adaptive and beneficial by favoring myocyte survival, but over time if pressure overload conditions persist, maladaptive mechanisms favoring cell death and fibrosis start to dominate, ultimately mediating the transition towards an overt heart failure phenotype. The underlying mechanisms linking biological factors at the myocyte level to biomechanical factors at the systemic and organ level remain poorly understood. Computational models of G&R show high promise as a unique framework for providing a quantitative link between myocardial stresses and strains at the organ scale to biological regulatory processes at the cellular level which govern the hypertrophic response. However, microstructurally motivated, rigorously validated computational models of G&R are still in their infancy.This article provides an overview of the current state-of-the-art of computational models to study cardiac G&R. The microstructure and mechanosensing/mechanotransduction within cells of the myocardium is discussed and quantitative data from previous experimental and clinical studies is summarized. We conclude with a discussion of major challenges and possible directions of future research that can advance the current state of cardiac G&R computational modeling. Statement of SignificanceThe mechanistic links between organ-scale biomechanics and biological factors at the cellular size scale remain poorly understood as these are largely elusive to investigations using experimental methodology alone. Computational G&R models show high promise to establish quantitative links which allow more mechanistic insight into adaptation mechanisms and may be used as a tool for stratifying the state and predict the progression of disease in the clinic. This review provides a comprehensive overview of research in this domain including a summary of experimental data. Thus, this study may serve as a basis for the further development of more advanced G&R models which are suitable for making clinical predictions on disease progression or for testing hypotheses on pathogenic mechanisms using in-silico models.

Biomechanics of Human Fetal Hearts with Critical Aortic Stenosis

“…Much work has been done for adult FE modelling for pressure overloaded hearts, 37 including modelling of growth and remodelling. 39 Such work can be very useful if applied to the fetal heart, potentially predicting morphological changes subsequent to disease biomechanics.…”

Precision medicine in human heart modeling

“…It some cases, however, it can become non-compensatory and initiate negative feedback mechanisms ( Grossman 1980 ). The underlying structural response to cardiac growth and remodeling manifests itself in two major patterns: eccentric hypertrophy associated with myocyte lengthening caused by a chronic overload in volume and concentric hypertrophy associated with myocyte thickening caused by a chronic overload in pressure ( Niestrawska et al 2020 ). In both cases, these mechanisms lead to pathological structural alterations that compromise the heart’s electrical and mechanical function ( Sahli Costabal et al 2017 ).…”

Fluid–structure interaction in a fully coupled three-dimensional mitral–atrium–pulmonary model

“…Longterm disease progression such as the material property adaptation for the LA wall, the MV and the pulmonary vessel, and geometrical changes including LA dilation and wall thickening are not included, since these are chronic effects as the result of the volume and pressure overloading (Cameli et al 2017;Messika-Zeitoun et al 2007). A further extension of the current work is to incorporate tissue growth and remodelling process into our three-dimensional LA-MV model (Niestrawska et al 2020;Gao et al 2017b) following the volumetric growth framework (Rodriguez et al 1994) or the agent-based approach (Zhuan et al 2019).…”