Introduction: The mechanical stability of an atheroma fibrous cap (FC) is a crucial factor for the risk of heart attack or stroke in asymptomatic vulnerable plaques. Common determinants of plaque vulnerability are the cap thickness and the presence of micro-calcifications (µCalcs). Higher local stresses have been linked to thin caps(<65µm) and, more recently, our lab demonstrated how µCalcs can potentially initiate cap rupture [1-3]. When combined, these two factors can compromise to a greater extent the stability of the plaque. On this basis, we quantitatively analyzed both individual and combined effects of key determinants of plaque rupture using a tissue damage model on idealized atherosclerotic arteries. Our results were then tested against a diseased human coronary sample.
Methods: We performed 28 finite element simulations on three-dimensional idealized atherosclerotic arteries and a human coronary sample. The idealized models present 10% lumen narrowing and 1.25 remodeling index (RI)(Fig.1A). The FC thickness values that we considered were of 50, 100, 150 and 200µm. The human coronary presents a RI=1.31, with 31% lumen occlusion and a 140µm-thick cap(Fig.1B). The human model is based on 6.7μm high-resolution microcomputed tomography (HR-μCT) images. The µCalc has a diameter of 15µm and each artery was expanded up to a systolic pressure of 120mmHg. Layer-specific material properties were de-fined by the HGO model coupled with the hyperelastic failure description proposed by Volokh et al. [4] to repli-cate the rupture of the FC. We considered a max. princi-pal stress for rupture of 545kPa[5]. The lipid core and the µCalc were considered as elastic materials (Ecore = 5kPa, νcore = 0.49; EµCalc= 18,000 kPa, νµCalc=0.3). To obtain a detailed analysis of the cap stresses and rupture progres-sion, a sub-modeling approach was implemented using ABAQUS (Dassault Systemes, v.2019) (Fig. 1).
Results: We investigated the quantitative effect of cap thickness and µCalc by simulating tissue failure and de-riving a vulnerability index (VI) for each risk factor. The VI coefficient was defined as the peak cap stress (PCS) normalized by the threshold stress for rupture (545kPa). The relationship between the risk factors and VI was de-termined by deriving the Pearson’s correlation coefficient (PCC) followed by one-tailed t-test (SPSS, IBM, v.25). The null hypothesis was rejected if p<0.05.
The presence of the µCalc is the factor that manifests the greater impact on cap stability, leading to at least a 2.5-fold increase in VI and tissue rupture regardless of cap thickness (Fig.2A,B). One µCalc in the cap is the first predictor of vulnerability, with PCCµCalc=0.59 and pµCalc=0.001. Our results also confirm the substantial in-fluence of cap thickness, with an exponential increase in stresses as the cap becomes thinner. The 50µm cap is the only phenotype that ruptures without µCalc (Fig2A).
The human sample exhibits PCS levels that are close to the idealized case with 150µm cap and it doesn’t rupture in the absence of the µCalc (PCShuman=233kPa, PCSideal= 252kPa). Conversely, the phenotypes with the µCalc showed an increase in VI of about 2.5 and reached rup-ture under the same blood pressure regime.
Conclusions: Our results clearly show the multifactorial nature of plaque vulnerability and the significance of micro-calcifications on the cap mechanical stability. The presence of a μCalc strongly amplifies the stresses in the surrounding tissue, and it can provoke tissue failure even in thick caps that would otherwise be classified as stable. Clearly, plaque phenotypes with a thin cap and μCalcs in the tissue represent the most vulnerable condition. Finally, these observations are well validated by the case of the human atherosclerotic segment, which closely compares to its corresponding idealized model. The novel imple-mentation of the tissue damage description and the defi-nition of a vulnerability index allow one to quantitatively analyze the individual and combined contribution of key determinants of cap rupture, which precedes the for-mation of a thrombus and myocardial infarction.
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The effect of size and proximity of micro-beads on the rupture threshold of atheroma cap laboratory models
Introduction
The mechanical vulnerability of the atherosclerotic cap is a crucial risk factor in asymptomatic fibroatheromas. Our research group demonstrated using numerical modeling that microcalcifications (µCalcs) located in the fibrous cap can multiply the tissue background stress by a factor 2-7[1-3]. We showed how this effect depends on the size and the ratio of the gap between particles pairs (h) and their diameter (D) along the tensile axis. In this context, we studied the impact of micro-beads of varying diameters and concentration on the rupture of human fibroatheroma laboratory models.
Methods
We created silicone-based (DowsilEE-3200, Dow Corning) dumbbell-shaped models (80%-scaled ASTM D412-C) of arterial tissues. Samples were divided into three groups: (1) without μBeads (control, n=12), (2) with μBeads of varying diameter (D=30,50,100μm) at a constant concentration of 1% weight (n=36), (3) with μBeads of constant diameter (D=50μm) at different concentrations (3% and 5% weight) (n=24). Before testing, samples were scanned under Micro-CT, at a resolution of 4µm. Images were then reconstructed in NRecon (SkySCan, v.2014) and structural parameters obtained in CTan (SkyScan, v.2014). These data were used to calculate the number of beads and their respective h/D ratio in a custom-made MATLAB script. We tested the samples using a custom-made micro material testing system equipped with real-time control and acquisition software (LabVIEW, v. 2018, NI). The reaction force and displacement were measured by the system and images of the sample were recorded by a high-resolution camera. The true stress and strain profiles of each sample were obtained by means of Digital Image Correlation (DIC).
Results
Samples with and without μBeads exhibited a distinct hyperelastic behaviour typical of arterial tissues (Fig1).
Comparison of the mean ultimate stress (UTS) between groups was performed by one-way ANOVA test followed by post-hoc pairwise comparison. Regardless of the group, the presence of μBeads determined a statistically significant reduction in UTS (Fig2). Increasing the μBeads concentration was also positively correlated with lower stresses at rupture as more clusters formed resulting in lower values of h/D (Table1).
Discussions
Our results clearly capture the influence of μBeads on the rupture threshold of a vascular tissue mimicking material. In fact, samples with μBeads exhibit levels of UTS that are around two times lower than the control group. This effect appears to be dependent on the μBeads proximity, as lower h/D correlates with higher UTS reductions. On the other hand, the effect of particle size is not apparent for the diameters considered in this study. The plausible explanation for the observed change in rupture threshold is the increase in stress concentration around spherical μBeads, which we have previously shown in analytical and numerical studies [1-3]. Our experimental observations support our previous studies suggesting that μCalcs located within the fibroatheroma cap may be responsible for significantly increasing the risk of cap rupture that precedes myocardial infarction and sudden death.
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- NSF-PAR ID:
- 10389222
- Date Published:
- Journal Name:
- 27th Congress of the European Society of Biomechanics
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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