Calcification & Fibrous Tissue Characteristics in Atherosclerotic Plaques

Abstract

Atherosclerotic plaque rupture is the main cause of acute myocardial infarction and stroke, the two leading causes of death worldwide. Rupture of plaque tissue is a mechanical event, where plaque stress or strain locally exceeds its strength. Biomechanical studies agree with histopathological findings that a large lipid pool and thin fibrous cap overlying the lipid pool increase the likelihood of rupture, by showing increased plaque stresses for these geometries. Another plaque morphological feature that is frequently encountered is calcification. However, its role in the vulnerability of plaques to rupture is not fully understood, and biomechanical modeling studies do not agree on the effect of calcifications on plaque stress. These studies used isotropic material properties for the anisotropic and collagen rich plaque tissue, and generally focused on the effect of calcification on lumen stress or cap stress. However, histopathological findings revealed tissue damage at the interface between calcification and surrounding tissue.

This study investigated stresses and strains at the interface between calcification and fibrous tissue, how these stresses and strains are influenced by local anisotropy of the fibrous tissue and how geometric features of the calcification are related to these metrics. A morphometric study was conducted first, to investigate and categorize different patterns of fiber alignment around the calcifications, and to measure the calcification geometric features including its location in the plaque, its shape and its size. Biomechanical models including the local anisotropic material properties were constructed next, based on the observations and measurements made in the morphometric analysis. Stress and strain metrics were investigated at the calcification boundary, and subsequently related to fiber patterns and calcification geometric features.

Hundred forty five calcifications were segmented and measured in the morphometric analysis, and surrounding fiber alignments were studied. The analysis revealed that four main fiber patterns in the fibrous tissue surrounding calcifications exist: the Attached pattern, Pushed Aside pattern, Encircling pattern and Random pattern. Collagen fibers are attached to the calcification in the Attached pattern, are pushed aside by the calcification in the second pattern, encircle the calcification in the third pattern, and show a disorganized alignment in the Random pattern. The Attached pattern was the most prevalent fiber pattern, and its corresponding calcifications had larger aspect ratios and were on average larger than the other three fiber patterns. Large peak stresses and strains at the calcification boundary were identified in the biomechanical models for the Attached pattern and Pushed Aside pattern, while these metrics showed generally lower peak values for the Encircling pattern and Random pattern. Peak values for all stress and strain metrics were attained at the tip of the calcifications. Multivariate analysis showed that stresses and strains are related to the calcification geometric features; calcification interface stress and strain increased if the calcification was closer to the lumen, had a larger length/width ratio and was larger in size.

Histopathological examination of plaques evidenced damage at the interface between calcification and fibrous tissue, potentially caused by an adverse mechanical state at this boundary. Most studies focused on stresses at the lumen or in the cap however, and this study for the first time specifically investigated stresses and strains at the calcification boundary while simultaneously introducing local fibrous tissue anisotropy in the computational models. Results show that peak stresses and strains can develop at this boundary, which will remain undiscovered if isotropic materials are used. This study was also the first to extensively analyze calcification geometric features and surrounding fiber alignment in relation to these interface stresses and strains. Peak values were found to be dependent on these features and fiber alignment patterns, indicating a relation between these characteristics and mechanical stability of the plaque. The findings of this study further increase the clinical relevance of finite element modeling in rupture risk prediction by showing previously undiscovered peak stress and strain values for interfaces and geometric configurations which already were deemed to be destabilizing in clinical and histopathological studies.