Understanding the interplay of collagen and myocyte adaptation in cardiac volume overload: a multi-constituent growth and remodeling framework

TL;DR

This study introduces a hybrid multi-constituent growth and remodeling framework for cardiac tissue under volume overload, integrating a constrained mixture model with kinematic growth to separately quantify collagen and myocyte contributions. The authors show collagen degradation primarily softens tissue and promotes LV dilation, while myocyte hypertrophy drives eccentric remodeling; importantly, the two processes interact synergistically to accelerate progression toward diastolic dysfunction. Through an idealized left ventricle model, they demonstrate that collagen loss amplifies myocyte-driven growth, yielding larger cavity volumes and more spherical chambers than either mechanism alone. The framework provides mechanistic insight into early VO G&R and sets the stage for incorporating active stresses and biochemical signaling to capture full chemo-mechano-structural coupling across scales.

Abstract

Hearts subjected to volume overload (VO) are prone to detrimental anatomical and functional changes in response to elevated mechanical stretches, ultimately leading to heart failure. Experimental findings increasingly 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 left ventricular adaptation in both acute and chronic stages of VO. These hypotheses remain to be substantiated by comprehensive mechanistic evidence, and the contribution of each constituent to myocardial growth and remodeling (G&R) processes is yet to be quantified. In this work, we establish a hybrid G&R framework in which we integrate a mixture-based constitutive model with the kinematic growth formulation. This multi-constituent model 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 dynamics control the passive mechanical response of the myocardium, whereas myocytes predominantly impact the extent and the phenotype of eccentric hypertrophy. Importantly, collagen degradation exacerbates myocyte hypertrophy, demonstrating a synergistic interplay that accelerates left ventricular progression toward diastolic dysfunction. This work constitutes an important step towards an integrated characterization of the early compensatory stages of VO-induced cardiac G&R.

Figures (13)

• Figure 1: Kinematics of cardiac growth. A point located at $\boldsymbol{X}$ in the reference configuration $\Omega_0$ is mapped to the current configuration through the motion $\varphi(\boldsymbol{X})$ and undergoes a total deformation characterized by the deformation gradient $\boldsymbol{F}$. The total deformation is multiplicatively decomposed into the growth part $\boldsymbol{F}^g$ and the elastic part $\boldsymbol{F}^e$, such that $\boldsymbol{F} = \boldsymbol{F}^e \boldsymbol{F}^g$. Growth induces an intermediate, stress-free configuration in which the tissue expands locally without mechanical constraints, possibly creating overlaps and incompatibilities. The resulting mechanically incompatible configuration, $\Omega_\tau$, is followed by the elastic deformation $\boldsymbol{F}^e$, which restores tissue continuity and leads to the residually stressed configuration $\Omega_t$.
• Figure 2: Schematics of idealized LV model. The LV geometry is approximately represented by an ellipsoid, whose dimensions are provided (left): the endocardial (outer wall) short and long radius $\text{r}_{\text{endo,s}}$ and $\text{r}_{\text{endo,s}}$, and the epicardial (inner wall) short and long radius, $\text{r}_{\text{epi,s}}$, $\text{r}_{\text{epi,s}}$, and the wall thickness at the mid wall, $\text{t}_{mid}$ and at the apex, $t_{\text{apex}}$. Based on the geometrical parametrization, the surface boundaries are identified (middle), the endocardium $\Gamma_{0,\text{endo}}$, the epicardium $\Gamma_{0,\text{epi}}$ and the basal surface $\Gamma_{0,\text{base}}$. Lastly, the fiber orientation is retrieved by analytically computing the fiber direction $\boldsymbol{f}_0$ (right) forming an angle with respect to the tangential plane (helix angle) that varies transmurally from -41° at the epicardium to +66° at the endocardium.
• Figure 3: Collagen mass-driven local and global changes. G&R changes are quantified for each case over nineteen weeks, where week 0 corresponds to the reference no-grown configuration. On the right, tissue-level changes are represented through the evolution of the collagen partial density $\hat{\rho}_c$, the myocyte partial density $\hat{\rho}_m$, and the local stretch along the myocyte direction $\overline{\lambda}_{ff}$. Global changes reflect alteration in left ventricular cavity volume, quantified through $\Delta V_\text{cav} (\%)$, $\ \Delta V_\text{inc} (\%)$, and the SI (left).
• Figure 4: Elastic stretches. The spatial distribution of the elastic stretch along the mean fiber direction is shown at week 19, at the end of the simulated growth. Collagen mass loss yields higher elastic stretches, which increase from the LV endocardium to the LV epicardium. Globally, it induces a negligible change in LV phenotype.
• Figure 5: Biaxial properties during collagen-driven G&R. The stretch-stress behavior is plotted at the end of each growth cycle. Each curve refers to one G&R week, spanning from the baseline no-growth time (dotted line) to the end of the simulated growth corresponding to week 19. On the right, the contribution of each constituent to tensile stress is displayed at baseline and at week 19.