Atherogenesis is now appreciated as a multifactorial process in which the arterial wall interacts with a number of systemic and local factors. The disturbed flow conditions at carotid bifurcation make the carotid bulb a predilection site of extracranial carotid artery for atherosclerosis. Nonetheless, more extensive disease, detectable by improved imaging approaches, is not uncommon, particularly in the common carotid artery. Individual variations in the geometry of carotid bulb and the unknown extent of outward remodeling make it difficult to discern the true plaque burden by angiography or similar techniques.

The accumulation of extracellular lipids and cell debris, the migration and proliferation of smooth muscle cells, and extracellular matrix production are recognized processes in the formation of plaques with well-developed necrotic core(s) and an overlying fibrous cap, or fibroatheroma as described by Virmani et al. in coronary atherosclerosis [6]. Structural changes are paralleled by the recruitment and activation of immune cells that respond to local insult and modulate the inflammatory process. A variety of immune cells including monocytes, lymphocytes, and, more recently, granulocytes have been shown to play a role in the pathogenesis and prognosis of atherosclerosis. Furthermore, it has been suggested through dedicated experimental and human autopsy studies that immune cells can be highly adaptive in response to microenvironmental signals. In accord, functionally indistinct monocytes may differentiate into polarized macrophage subpopulations in the atherogenic milieu, taking on heterogeneous biological functions that may stabilize or destabilize the plaque [7]. Therefore, the biological complexity of plaque inflammation has placed a higher demand on molecular imaging by emphasizing the activities rather than the mere presence of immune cells. Another morphological change that initiates early in the disease process is plaque neovascularization, resulting from the penetration of the medial layer (i.e., tunica media) by hyperplastic vasa vasorum (i.e., the nutritional microvasculature present in large- and medium-sized arteries, with the physiological function of supplying oxygen and nutrients to the outer portion of the medial layer). Initially considered as a compensatory mechanism to alleviate arterial wall hypoxia as wall thickness increases, accumulating evidence from recent studies suggests that plaque neovascularization has an active role in atherothrombosis by contributing to the development, progression, and destabilization of atherosclerotic plaques. Leaky microvessels may facilitate the entry of inflammatory cells as well as plasma proteins. Furthermore, it is thought that episodic ruptures of plaque microvessels are likely the origin of intraplaque hemorrhage, a common finding in advanced human lesions. Improvements in research approaches, for both histopathology and imaging, have recently enabled a better appreciation of the prominent role of intraplaque hemorrhage in atherogenesis as well as the pathophysiology of clinical manifestations. However, mechanistic insights about intraplaque hemorrhage are still limited at this moment, as the phenomenon is rarely seen in prevailing animal models.

To date, much of the understanding of carotid atherosclerotic plaque morphology is based on histopathological examination of carotid endarterectomy specimens, which do not cover the full spectrum of lesion severity as compared to human autopsy. The peripheral sections of advanced carotid specimens are presumed to give a glimpse of early or intermediate lesions, which frequently show proteoglycan accumulation, lipid retention, or early stage necrotic cores. Based on these observations, it appears sensible to describe carotid plaque morphology with nomenclature proposed for classifying coronary atherosclerosis. Yet caution should be exercised when making an analogy for a specific feature with regards to its role in pathogenesis and prognosis, given the distinct differences in vessel diameter and flow conditions between coronary circulation and extracranial carotid circulation.

Few studies have attempted to compare plaque morphologies between coronary and carotid atherosclerosis, yet notable differences seem to be present. The fibrous cap overlying necrotic core(s) is at risk of rupture in both coronary and carotid lesions. The high mechanical forces in the carotid circulation may render the fibrous cap of carotid atherosclerosis more vulnerable to rupture, as it has been reported that ruptured carotid plaques have much thicker fibrous cap and fewer macrophage infiltration than ruptured coronary plaques [8]. Thrombotic activity typically ensues, yet the high flow velocity is likely a limiting factor for the propagation of mural thrombus and the healing of fibrous cap rupture. In line with the hypothesis, ulceration is reported more frequently in carotid atherosclerosis than in coronary atherosclerosis, whereas total thrombotic occlusion of carotid stenosis is not as common as in coronary atherosclerosis. Fibrous cap erosion and calcified nodules are the other two types of surface disruption reported in the coronary artery, which may be accountable for over a third of atherothrombotic events in coronary atherosclerosis [6]. However, in the carotid artery, plaque rupture is predominant, while plaque erosion does not seem to be a major cause for atherothrombosis [9]. Although calcified nodules are more frequently seen in carotid atherosclerosis in comparison to coronary atherosclerosis, its role in atherothrombosis in the carotid artery has yet to be determined.

Morphological and pathological features of carotid atherosclerosis have been shown to be associated with downstream neurological ischemic events. Despite the longtime focus of clinical imaging on luminal stenosis, chronic stenosis or occlusion from carotid atherosclerosis rarely leads to ischemic stroke and is therefore not considered the pathological substrate of ischemic stroke. In a study of 269 carotid plaques obtained en bloc from surgical endarterectomy (96 ischemic stroke, 91 transient ischemic attack, 82 asymptomatic), Spagnoli et al. observed a high prevalence of fresh mural thrombus constituted of platelets or fibrin on plaque surface, which was associated with either plaque rupture (90.1 %) or erosion (9.9 %) in patients with stroke [9]. Furthermore, fresh thrombus was more frequently observed when carotid endarterectomy was performed closer to symptom onset. With carotid plaques collected from participants of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS) trials (71 symptomatic, 170 asymptomatic), Fisher et al. noted that thrombus was associated with plaque ulceration, both of which were more prevalent in symptomatic patients than in asymptomatic patients [10]. Another study by Redgrave et al. examined 570 consecutive symptomatic carotid plaques and demonstrated a continued post-event decline of plaque vulnerability features including cap rupture and plaque inflammation [11]. These studies have provided important insights onto the pathogenesis of ischemic events associated with carotid atherosclerosis. A typical plaque responsible for a recent ischemic stroke can be described as one with active thrombosis on the luminal surface, triggered by plaque rupture and exposure of thrombogenic materials to the flowing blood. Subsequently, acute plaque rupture and thrombosis may lead to artery-to-artery embolism or thrombotic occlusion, which is in line with clinical observations.

Mechanisms of plaque rupture are not yet fully understood. In the study by Redgrave et al. [11], two morphological features demonstrated independent association with cap rupture – intraplaque hemorrhage and inflammatory cell infiltration of fibrous cap. Other studies based on data from coronary atherosclerosis have suggested that fibrous cap thickness and necrotic core size are good discriminators of plaques at risk for rupture from those that are stable [12]. Of note, the degree of stenosis could fit in here as one of the risk factors for plaque rupture, considering the increased mechanical forces associated with local narrowing. Some of these risk factors may have a more dynamic natural course, such as cap inflammation. It is plausible that in vivo characterization of major risk factors of cap rupture may enable accurate estimation of the short-term or long-term risk of neurological ischemic events in patients with carotid atherosclerosis.

In contrast to luminal imaging using bright blood MR angiography, vessel wall visualization and the identification of components of atherosclerosis require suppression of signal from intraluminal blood. Thus, MRI sequences commonly referred to as black-blood MRI are essential for vessel wall imaging. Normal extracranial carotids have thin pulsating walls and are often situated in deep tissue planes in patients with a large neck. Carotid bifurcation, the most frequent site of carotid atherosclerosis, has a complex flow pattern with recirculating flow. Thus, complete flow suppression in carotid bifurcation requires special consideration of the flow conditions at carotid bifurcation.

In addition to blood suppression, considerations of spatial resolution, signal-to-noise ratio (SNR), motion suppression, etc., are also important to obtaining diagnostic quality vessel wall images. Atherosclerotic plaque components are small but complicated structures that require high spatial resolution for identification and quantification. Of note, the requirement of high spatial resolution must be achieved with good SNR within a clinically acceptable scan time. Another reason to avoid long scan times is to reduce motion artifacts. Due to the unique location of carotid arteries, patient swallowing has been one of the major causes for degraded image quality of carotid MRI, whereas it will be less of a problem if the scanning time is short.

Contrast-to-noise ratio (CNR) is equally important in order to characterize vessel wall pathology. Delineation of the lumen requires good CNR with adequate blood suppression, while delineation of the outer wall requires good fat suppression. This allows plaque boundaries to be clearly identified and disease burden to be accurately estimated. Furthermore, MRI sequences with special contrast mechanisms are required for identification of various plaque components such as calcification, lipid-rich necrotic core, intraplaque hemorrhage, etc. Indeed, a unique advantage of MR plaque imaging is to employ more than one contrast weightings to help differentiate various atherosclerotic components.

Thus, carotid vessel wall imaging places special technical constraints on field strength, coils, and pulse sequences, which are required for accurate identification of pathology. Carotid MRI protocols need to consider all these aspects while being tailored for each study. This section outlines the established carotid MRI sequences and emerging trends in carotid atherosclerosis imaging.