Abstract: It is generally agreed that biomechanical stresses play important roles in advanced atherosclerotic plaque progression and rupture. This paper aims to perform a pilot study to access the influences of blood perfusion, blood pressure, histology and material properties of plaques on the levels of blood flow stress (FSS) and plaque structural stress (PSS), and meanwhile to access the intervention of enhanced external counterpulsation (EECP), a kind of clinical non-invasive assisted circulation therapy. A method combining in vivo measurements performed in a porcine model and 3D fluid-structure interaction (FSI) numerical simulation was adopted. Results showed that, when the stenotic degree was fixed to 50%, FSS level of the plaque depended mainly on blood perfusion, while PWS level was mainly determined by both blood pressure and fibrous cap (FC) length. Only when FC was thin enough, plaque material properties had significant influence on PSS. A thinnest FC together with a softest lipid pool led to the peak critical plaque wall stress (3D CPWS) of 257.72 kPa (normal physiological state) and 300.20 kPa (EECP state). Note that changes in FC length or lipid pool material property only induced the variation of 3D CPWS significantly, we suggested that 3D CPWS was a stress-based factor that might play a much more important role during plaque progression than max WSS (MWSS) or global max plaque stress (GMPWS). Moreover, EECP treatment significantly increased the levels of both FSS and PWS, whether it would intervene the progression and remodeling of advanced plaque, and should be brought the attention in its clinical applications might need more detailed evaluations.