Ascending thoracic aortic aneurysms (ATAA) are a potentially life-threating dilatation of the aortic section from the aortic root up to the aortic arch. Surgical intervention is advised when the risk of rupture of the aneurysm outweighs risks related to the procedure. In today’s clinical practice, the diameter of the aneurysm is considered as decision metric, yet it has been proven to be ineffective, which has severe consequences. Therefore, this project aims to deepen the understanding of the multiscale biomechanics underlying ATAA and how it relates to measurable functional parameters, such as the volumetric distensibility of the aneurysm. To achieve this, a biofidelic 3-layer (cell-tissue-aorta) multiscale digital twin of the ascending aorta will be developed. This digital twin will include models of vascular smooth muscle cell (dys)functions which play a crucial role in the initiation and progression of ATAA. The integration of this type of cellular models with finite element models has, to our knowledge, never been attempted before. The digital twin will be gradually built up, and validated in different stages to ensure its credibility. Finally, the developed digital twin will be exploited to gain profound insights into ATAA progression and potential new decision criteria for surgery based on their relation to the risk of rupture. This novel approach will advance the field of vascular mechanics as well as boost the progression of in silico medicine in general.