Collagen and myocyte interplay in cardiac volume overload: a multi-constituent growth and remodeling framework

Hearts subjected to volume overload (VO) are prone to detrimental anatomical and functional changes in response to elevated mechanical loading, ultimately leading to heart failure. Experimental findings now emphasize that organ-scale changes following VO cannot be explained by myocyte growth alone, as traditionally proposed in the literature. Collagen degradation, in particular, has been associated with VO and assumed to play a central role in both its acute and chronic stages. This hypothesis, however, remains to be substantiated by comprehensive mechanistic evidence, and each constituent contribution to myocardial growth and remodeling (G&R) processes is yet to be quantified. In this work, we present a multi-constituent G&R framework that integrates a mixture-based constitutive model within the kinematic growth formulation. This framework enables us to mechanistically assess the relative contributions of collagen and myocyte changes to alterations in tissue properties, ventricular dimensions, and growth phenotype. Our numerical results confirm that collagen remodeling affects the passive mechanical response of the myocardium, whereas myocytes predominantly influence the extent and phenotype of VO-induced growth. Importantly, collagen degradation exacerbates myocyte hypertrophy, revealing a synergistic interplay that accelerates the left ventricular eccentric growth and thereby promotes systolic dysfunction. This work constitutes an important step towards an integrated characterization of the early compensatory stages of VO-induced cardiac G&R.

💡 Research Summary

The paper addresses a critical gap in the modeling of cardiac volume overload (VO) by moving beyond the traditional focus on myocyte hypertrophy to incorporate the concurrent remodeling of the extracellular matrix, specifically collagen. The authors develop a multi‑constituent growth and remodeling (G&R) framework that couples a kinematic growth formulation with a constrained mixture (CM) theory. In this framework, the total deformation gradient F is multiplicatively decomposed into an elastic part (F_e) and a growth part (F_g). Each tissue constituent—collagen and myocytes—is assigned its own growth tensor (F_g^i), mass (m_i), volume (V_i), and density (ρ_i), allowing independent tracking of volume adaptation (VA) and density adaptation (DA). VA represents changes in constituent volume at roughly constant density (e.g., collagen loss leading to reduced volume), while DA captures changes in density at constant volume (e.g., myocyte protein accumulation).

The constitutive model splits the Helmholtz free energy ψ into a volumetric term ψ_vol(J_e) and an isochoric term ψ̄( C̄ ). The volumetric term enforces near‑incompressibility through a quadratic penalty (μ/2)(J_e − 1)^2, reflecting the high water content of cardiac tissue. The isochoric part incorporates anisotropic fiber reinforcement, similar to the Holzapfel‑Gasser‑Ogden formulation, and depends on the structural tensor N = n⊗n. Growth evolution laws are driven by mechanical stimuli (e.g., fiber stretch) and can be extended to include biochemical signals.

Numerical simulations are performed on an idealized left‑ventricular geometry under three scenarios: (C) collagen‑only remodeling, (M) myocyte‑only growth, and (C+M) combined remodeling. In the collagen‑only case, loss of collagen mass reduces passive stiffness but produces minimal changes in ventricular volume. In the myocyte‑only case, increased myocyte mass drives substantial eccentric dilation, altering the ventricular shape without markedly affecting passive stiffness. The combined case reveals a synergistic interaction: collagen degradation amplifies myocyte hypertrophy, accelerating eccentric growth and leading to pronounced systolic dysfunction. These results align with experimental observations that early collagen loss precedes and facilitates myocyte elongation and ventricular dilation.

Key contributions of the work include: (1) a rigorous separation of constituent‑specific VA and DA, enabling quantitative dissection of how collagen and myocytes each influence cardiac mechanics; (2) integration of mixture theory with kinematic growth, thereby capturing density‑driven changes in tissue stiffness that traditional growth models neglect; (3) identification of a mechanistic pathway whereby collagen degradation synergistically enhances myocyte hypertrophy, offering a novel explanation for the rapid transition from compensation to decompensation in VO; and (4) provision of a computational platform that can be extended to evaluate therapeutic strategies aimed at preserving collagen integrity or modulating myocyte growth. The framework thus represents a significant step toward a unified, multiscale understanding of early cardiac adaptation to volume overload and sets the stage for future investigations into targeted interventions for VO‑induced heart failure.