Cardiac Allograft Vasculopathy (CAV) is one of the major manifestations of chronic rejection following heart transplantation (HTx). It is a progressive form of coronary artery disease (CAD), characterized by concentric and diffuse intimal thickening, leading to significant lumen narrowing and graft failure. CAV arises from the interplay of i) immunological processes, such as infiltration of lymphocytes (LYMs) and macrophages (MPs), and ii) non-immunological factors like disturbed hemodynamics. Today, its underlying mechanisms remain poorly understood. Current diagnostic methods rely on invasive procedures and remain limited in their ability to detect the disease at an early stage. Thus, effective treatments are scarce, with re-transplantation remaining the only viable long-term solution, although challenging to access after a first rejection.