Biomechanical Assessment of Macro-Calcification in Human Carotid Atherosclerosis and Its Impact on Smooth Muscle Cell Phenotype.

Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing feature of late-stage human lesions, associated with a reacquisition of more differentiated properties of plaque smooth muscle cells (SMCs) and extracellular matrix (ECM) remodeling. Here, we hypothesized that biomechanical forces related to macro-calcification within plaques influence SMC phenotype and contribute to plaque stabilization. We generated a finite element modeling (FEM) pipeline to assess plaque tissue stretch based on image analysis of preoperative computed tomography angiography (CTA) of carotid atherosclerotic plaques to visualize calcification and soft tissues (lipids and extracellular matrix) within the lesions. Biomechanical stretch was significantly reduced in tissues in close proximity to macro calcification, while increased levels were observed within distant soft tissues. Applying this data to an in vitro stretch model on primary vascular SMCs revealed upregulation of typical markers for differentiated SMCs and contractility under low stretch conditions but also impeded SMC alignment. In contrast, high stretch conditions in combination with calcifying conditions induced SMC apoptosis. Our findings suggest that the load bearing capacities of macro calcifications influence SMC differentiation and survival and contribute to atherosclerotic plaque stabilization.

Patient-specific biomechanical analysis of atherosclerotic plaques enabled by histologically validated tissue characterization from computed tomography angiography: A case study.

BACKGROUND: Rupture of unstable atherosclerotic plaques with a large lipid-rich necrotic core and a thin fibrous cap cause myocardial infarction and stroke. Yet it has not been possible to assess this for individual patients. Clinical guidelines still rely on use of luminal narrowing, a poor indicator but one that persists for lack of effective means to do better. We present a case study demonstrating the assessment of biomechanical indices pertaining to plaque rupture risk non-invasively for individual patients enabled by histologically validated tissue characterization. METHODS: Routinely acquired clinical images of plaques were analyzed to characterize vascular wall tissues using software validated by histology (ElucidVivo, Elucid Bioimaging Inc.). Based on the tissue distribution, wall stress and strain were then calculated at spatial locations with varied fibrous cap thicknesses at diastolic, mean and systolic blood pressures. RESULTS: The von Mises stress of 152 [131, 172] kPa and the equivalent strain of 0.10 [0.08, 0.12] were calculated where the fibrous cap thickness was smallest (560 µm) (95% CI in brackets). The stress at this location was at a level predictive of plaque failure. Stress and strain at locations with larger cap thicknesses were calculated to be lower, demonstrating a clinically relevant range of risk levels. CONCLUSION: Patient specific tissue characterization can identify distributions of stress and strain in a clinically relevant range. This capability may be used to identify high-risk lesions and personalize treatment decisions for individual patients with cardiovascular disease and improve prevention of myocardial infarction and stroke.