Atherosclerosis is a chronic lipid-driven and maladaptive inflammatory disease, with an autoimmune component, whose pathogenesis involves a series of functional and structural changes that take place in the innermost layers of large- and medium-sized arteries [1,2]. The disease is histopathologically characterized by the formation of an abnormal mass, called plaque or atheroma, composed of a large core of foam cells, calcium, cholesterol esters, cellular debris, and fatty substances covered by a densely packed meshwork of collagen fibers (the fibrous cap). From a molecular point of view, determinants of atherosclerosis are numerous and very often overlap and cluster to induce and sustain vascular inflammation, oxidative stress, and senescence therefore exerting a pivotal role in the appearance and growth of the lesion [3,4]. Despite the significant advances in the medical research and clinical management, atherosclerosis remains the most common cause of premature mortality and chronic disability worldwide. Numerous studies in recent years have investigated the pathobiologic relevance of cell death within the vasculature, mainly focusing on the involvement of apoptosis in the initiation and progression of atherosclerosis and on the clinical consequences of intraplaque cell death [5], [6], [7], [8], [9]. In this regard, it has been demonstrated that apoptosis (which is almost absent in normal arteries) can occur in all cells of the plaque, such as the endothelial cells (ECs) and the smooth muscle cells (SMCs) of both the fibrous cap and the underlying media as well as in the inflammatory cells that populate the lesion [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. In contrast to apoptosis, necrotic cell death in atherosclerosis has not been well characterized in the literature, with studies describing undefined features of membrane disruption, organelles swelling and lack of chromatin condensation [20], [21]. Since these early observations in the late 1900s, there has been an apparent lack of any research article devoted to the ultrastructural characterization of cell death in atherosclerosis with only very few papers reporting data from electron microscopy (EM) and/or including EM images to support their conclusions.

Indeed, although ultrastructural criteria are still considered the best way to define a specific cell death morphotype, due to the particular skills and equipment needed, EM analysis has been largely replaced by immunohistochemical methods and molecular tecniques [22], [23], [24]. As a consequence, many ultrastructural aspects of cell death modes in human atherosclerosis remain ambiguous and understudied and the boundaries between them frequently become blurred. The present report propose a complete ultrastructural description of the way/s by which intraplaque cells can die also suggesting novel directions for future studies.