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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.