Atherosclerosis is a serious chronic disease of elastic and large muscular arteries. It is the cause of many clinical cardiovascular conditions, such as coronary artery disease, myocardial infarction, cerebral vascular disease, stroke, and peripheral vascular disease [1,2]. Atherosclerosis is characterized by an atheroma, often referred to as a fibroinflammatory lipid plaque [3]. It has been described by histopathology studies in both human autopsy and surgical specimens [4,5], and in numerous experimental animal models of atherosclerosis [6]. The atheroma forms as a stable plaque in the intima/upper media of the artery wall and then may undergo phenotypic changes resulting in a destabilized plaque that may cause serious complications due to occlusive acute thrombosis.

The classical thinking on the pathogenesis of the human atheroma involves an interplay between the contents and hemodynamic forces in the vascular lumen and the artery wall itself. The focus has been on lipids, the endothelium, macrophages and other immune cells, and vascular smooth muscle cells (SMCs). Important observations by N. Anitschkow linking cholesterol to atherosclerosis and by R. Virchow linking immune cells to the pathogenesis of atherosclerosis, as described by Mayerl et al. [7], set the stage for several hypotheses and concepts being proposed by the mid 20th century. These classical concepts include the thrombo-atherosclerotic hypothesis [8], response to injury hypothesis [9,10], lipid hypothesis [11], and the response to retention hypothesis of early atherogenesis [12]. These may be grouped under an “inside-out” paradigm in which the atheromas are initiated in the intima and inner media and progressively lead to the formation of the necrotic core and fibrous cap. Challenging this thinking is an alternative approach, but not exclusive to the above theories. The “outside-in” paradigm focuses on the contributions of the adventitia [13] and perivascular adipose tissue (PVAT) [14] to the initiation, progression, and complications of plaques [15], [16], [17]. For example, pigs fed a high fat diet developed neovascularization to expand the vasa vasorum in the outer artery wall prior to endothelial dysfunction and intimal thickening [18].

Capturing the progression from stable to unstable plaque has been challenging and is the focus of this review. Currently, there are no non-invasive technologies in humans to allow for detailed examination of a particular lesion as it develops over time from a pre-atheroma to a stable atheroma and then to an unstable atheroma. The approaches to examine human plaque tissue continues to be histopathology and autopsy studies, and more recently, intravascular imaging techniques including intravascular ultra-sonography (IVUS) [19,20], optical coherence tomography (OCT) [21], and near-infrared spectroscopy [22]. The use of hybrid IVUS/OCT catheter systems offer improved capabilities to assess the structure of the coronary artery [23]. Coronary computed tomography angiography has shown promise as a non-invasive imaging technology that identifies plaque morphology and limited composition although spatial and temporal resolution needs improvement, and radiation exposure remains an issue [24].

Most studies involving lesion progression are designed to evaluate tissue or images at fixed time points at vascular locations that are consistently prone to lesion formation and often associated with disturbed shear stress. It is therefore assumed that the more advanced lesions are a progression of less advanced lesions found at the same location. These snapshots in time are designed to deduce what has occurred between sampled time points at the cell and molecular level. This brings up an important issue since some early lesions do not develop into advanced lesions and lesions seem to progress at their own rate by slow growth with or without acute events such as plaque hemorrhage and fibrous cap rupture. Since there is no experimental model that has all the characteristics of the human lesion, the tendency is for these models to be designed to study specific components, processes and events that are thought to be important in pathogenesis. Thus, it is still very difficult to trace the sequence of events throughout the lifetime of an atherosclerotic plaque to understand when to intervene therapeutically to reduce plaque burden in humans and to predict, detect, and prevent the conversion of a stable plaque to an unstable plaque. Studies in this review are discussed through the lens of a simplified two-step paradigm. First, the formation of a stable atheroma and second, the conversion of a stable atheroma to an unstable one as the atheroma takes on different phenotypes that lead to acute coronary syndromes (ACS) and cerebrovascular strokes.