Left Ventricular Geometry, Tissue Composition, and Residual Stress in High Fat Diet Dahl-Salt Sensitive Rats

Abstract

Background

Hypertension drives myocardial remodeling, leading to changes in structure, composition and mechanical behavior, including residual stress, which are linked to heart disease progression in a gender-specific manner. Emerging therapies are also targeting constituent-specific pathological features. All previous studies, however, have characterized remodeling in the intact tissue, rather than isolated tissue constituents, and did not include sex as a biological variable.

Objective

In this study we first identified the contribution of collagen fiber network and myocytes to the myocardial residual stress/strain in Dahl-Salt sensitive rats fed with high fat diet. Then, we quantified the effect of hypertension on the remodeling of the left ventricle (LV), as well as the existence of sex-specific remodeling features.

Methods

We performed mechanical tests (opening angle, ring-test) and histological analysis on isolated constituents and intact tissue of the LV. Based on the measurements from the tests, we performed a stress analysis to evaluate the residual stress distribution. Statistical analysis was performed to identify the effects of constituent isolation, elevated blood pressure, and sex of the animal on the experimental measurements and modeling results.

Results

Hypertension leads to reduced residual stress/strain in the intact tissue, isolated collagen fibers, and isolated myocytes in male and female rats. Collagen remains the largest contributor to myocardial residual stress in both normotensive and hypertensive animals. We identified sex-differences in both hypertensive and normotensive animals.

Conclusions

We observed both constituent- and sex-specific remodeling features in the LV of an animal model of hypertension.

Appendices

Appendix 1

In order to calculate the stress distribution across the wall given by equation (4), we used each sample’s individual geometry from the open configuration (R_i, R_o, Φ), along with their pooled material properties (c_c, k_c, c_m, k_m) and constituent area fractions (ϕ_c, ϕ_m). It should be noted that when using equation (3) for intact tissue, ϕ_c and ϕ_m were equal to their experimental values. For each sample, the inner and outer radii and axial stretch of the closed, load-free configuration (ρ_i, ρ_o, Λ_z) were estimated by using the deformation gradient in equation (5) and allowing the closed configuration to reach radial and axial equilibrium (using the lsqnonlin function on Matlab)—i.e.,

$$ \underset{\rho_i}{\overset{\rho_o}{\int }}\frac{1}{\rho}\left({t}_{\theta \theta}-{t}_{\rho \rho}\right) d\rho =0, $$

$$ \underset{\rho_i}{\overset{\rho_o}{\int }}\rho \left[2{t}_{zz}-\left({t}_{\theta \theta}+{t}_{\rho \rho}\right)\right] d\rho =0. $$

Additionally, an assumption of incompressibility was made for equation (5), resulting in a third equation used to solve for the unknown geometry:

$$ {\rho}_o=\sqrt{\rho_i^2+\frac{1}{\Lambda_z}\frac{2\pi }{2\pi -\Phi}\left({R}_o^2-{R}_i^2\right)} $$

Finally, for each sample, we had individual geometry measurements (R_i, R_o, Φ, ρ_i, ρ_o, Λ_z), pooled material properties from their breed and sex (c_c, k_c, c_m, k_m) and collagen and myocytes area fractions (ϕ_c, ϕ_m) for the intact tissue, measured for each breed, sex, and diet (i.e. HFD or CD). Using all of this information, we were able to calculate the radial, circumferential, and axial stresses for each group as functions of their non-dimensional radii.

Appendix 2

Fig. 9

Transmural residual stretch distribution for one representative sample. Radial stretch (solid line), circumferential stretch (dashed line), and axial stretch (dashed dotted line). For each sample, after evaluating the principal stretches distribution, as shown, we identified values of interest to compare across groups. Specifically, we calculated the minimum and maximum values of the radial and circumferential stretches. Note: while the axial stretch assumes in most cases values close to 1, no plain strain assumption was made