Victoria E. Young

Carotid-artery imaging in the diagnosis and management of patients at risk of stroke

Carotid atherosclerotic disease is one of the major preventable causes of ischaemic strokes. In clinical practice, decision making with regard to carotid endarterectomy or stenting is still primarily based on the extent of luminal stenosis. In most centres worldwide, luminal stenosis is now mainly assessed with non-invasive techniques, such as Doppler ultrasound, magnetic resonance angiography, and CT angiography, either alone or in combination. Although intra-arterial digital subtraction angiography remains the historical gold standard, it has now mostly been replaced by these non-invasive techniques. Moreover, in addition to luminal stenosis, certain morphological features of carotid plaques, such as large lipid cores, intraplaque haemorrhage, or thin or ruptured fibrous caps, are increasingly believed to be associated with heightened risk of stroke. In this Review, we discuss current state-of-the-art non-invasive diagnostic imaging strategies for luminal stenosis and describe the most promising novel imaging techniques, such as high-resolution MRI and CT combined with PET imaging, which can be used to characterise vulnerable carotid-plaque features in vivo.

Iron Oxide Particles for Atheroma Imaging

The selection of patients for vascular interventions has been solely based on luminal stenosis and symptomatology. However, histological data from both the coronary and carotid vasculature suggest that other plaque features such as inflammation may be more important in predicting future thromboembolic events. Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans. It has reached the stage of development to have been recently used in an interventional drug study to not only assess inflammatory progression but also select patients at high risk. This article reviews the basic science behind the use of USPIO contrast agents in atheroma MR imaging, experimental work in animals, and how this has led to the emergence of this promising targeted imaging platform for assessment of high risk carotid atherosclerosis in humans.

Utility of high resolution MR imaging to assess carotid plaque morphology: A comparison of acute symptomatic, recently symptomatic and asymptomatic patients with carotid artery disease

OBJECTIVES Compare carotid plaque morphology of acute symptomatic, recently symptomatic and asymptomatic patients (groups 1, 2 and 3 respectively) with carotid artery disease using high resolution magnetic resonance imaging (MRI), to identify high-risk plaque characteristics best associated with risk of recurrent thrombo-embolic events. METHODS 60 patients underwent multi-contrast imaging of their internal carotid arteries. Different plaque components were manually delineated on acquired axial images to assess the difference in prevalence of plaque hemorrhage, fibrous cap (FC) rupture and FC thickness among the three groups. RESULTS 55% acute symptomatic patients had plaque hemorrhage vs. 35% for recently symptomatic group and 5% for asymptomatic group (p-value: group 1 vs. 3: 0.001, group 2 vs. 3: 0.04). Type 1 hemorrhage was more common in acute symptomatic patients than recently symptomatic patients (40% vs. 5%, p=0.01). Type 2 hemorrhage was more common in recently symptomatic vs. acute symptomatic patients (15% vs. 30%). FC rupture was observed in 50% of patients in group 1 vs. 35% of group 2 patients (p=0.02) but none in group 3. The mean minimum FC thickness was same in acute and recently symptomatic groups (600+/-200microm), compared to 800+/-200microm for asymptomatic patients (p-value: 0.03 and 0.007 respectively). Good correlation was present among the three MR readers (intra-class correlation coefficient=0.71). CONCLUSION High resolution MRI can differentiate plaque components associated with increased risk of thrombo-embolic events.

Association between Biomechanical Structural Stresses of Atherosclerotic Carotid Plaques and Subsequent Ischaemic Cerebrovascular Events – A Longitudinal in Vivo Magnetic Resonance Imaging-based Finite element Study

BACKGROUND High-resolution magnetic resonance (MR) imaging has been used for MR imaging-based structural stress analysis of atherosclerotic plaques. The biomechanical stress profile of stable plaques has been observed to differ from that of unstable plaques; however, the role that structural stresses play in determining plaque vulnerability remains speculative. METHODS A total of 61 patients with previous history of symptomatic carotid artery disease underwent carotid plaque MR imaging. Plaque components of the index artery such as fibrous tissue, lipid content and plaque haemorrhage (PH) were delineated and used for finite element analysis-based maximum structural stress (M-C Stress) quantification. These patients were followed up for 2 years. The clinical end point was occurrence of an ischaemic cerebrovascular event. The association of the time to the clinical end point with plaque morphology and M-C Stress was analysed. RESULTS During a median follow-up duration of 514 days, 20% of patients (n = 12) experienced an ischaemic event in the territory of the index carotid artery. Cox regression analysis indicated that M-C Stress (hazard ratio (HR): 12.98 (95% confidence interval (CI): 1.32-26.67, p = 0.02), fibrous cap (FC) disruption (HR: 7.39 (95% CI: 1.61-33.82), p = 0.009) and PH (HR: 5.85 (95% CI: 1.27-26.77), p = 0.02) are associated with the development of subsequent cerebrovascular events. Plaques associated with future events had higher M-C Stress than those which had remained asymptomatic (median (interquartile range, IQR): 330 kPa (229-494) vs. 254 kPa (166-290), p = 0.04). CONCLUSIONS High biomechanical structural stresses, in addition to FC rupture and PH, are associated with subsequent cerebrovascular events.

Ultrasmall Superparamagnetic Iron Oxide-enhanced Magnetic Resonance Imaging of Abdominal Aortic Aneurysms–A Feasibility Study

OBJECTIVES Abdominal aortic aneurysms (AAAs), being predominantly atherosclerotic in nature, have underlying inflammatory activity. As it is well established that ultrasmall superparamagnetic iron oxide (USPIO) particles accumulate in the macrophages within atheromatous lesions, USPIO-enhanced magnetic resonance (MR) imaging can be potentially effective in the quantification of the associated inflammatory processes. METHODS A total of 14 patients underwent USPIO-enhanced MR imaging using a 1.5T-MR system. Quantitative T(2)* and T(2) relaxation time data were acquired before and 36 h after UPSIO infusion at identical AAA locations. The pre- and post-USPIO-infusion relaxation times (T(2)(∗) and T(2)) were quantified and the correlation between pre- and post-USPIO infusion T(2)* and T(2) values was investigated. RESULTS There was a significant difference between pre- and post-infusion T(2)* and T(2) values (both respective p-values = 0.005). A significant correlation between T(2)* and T(2) values post-USPIO infusion was observed (r = 0.90, p < 0.001), which indicates USPIO uptake by the aortic wall. CONCLUSIONS Aortic wall inflammation using USPIO-enhanced MR imaging is feasible. Use of quantitative T(2) and T(2)* pulse sequences provides a quantitative method for assessing USPIO uptake by the aortic wall.

The mechanical triggers of plaque rupture: shear stress vs pressure gradient

The aim of this study was to evaluate the mechanical triggers that may cause plaque rupture. Wall shear stress (WSS) and pressure gradient are the direct mechanical forces acting on the plaque in a stenotic artery. Their influence on plaque stability is thought to be controversial. This study used a physiologically realistic, pulsatile flow, two-dimensional, cine phase-contrast MRI sequence in a patient with a 70% carotid stenosis. Instead of considering the full patient-specific carotid bifurcation derived from MRI, only the plaque region has been modelled by means of the idealised flow model. WSS reached a local maximum just distal to the stenosis followed by a negative local minimum. A pressure drop across the stenosis was found which varied significantly during systole and diastole. The ratio of the relative importance of WSS and pressure was assessed and was found to be less than 0.07% for all time phases, even at the throat of the stenosis. In conclusion, although the local high WSS at the stenosis may damage the endothelium and fissure plaque, the magnitude of WSS is small compared with the overall loading on plaque. Therefore, pressure may be the main mechanical trigger for plaque rupture and risk stratification using stress analysis of plaque stability may only need to consider the pressure effect.

Finite element analysis of vulnerable atherosclerotic plaques: a comparison of mechanical stresses within carotid plaques of acute and recently symptomatic patients with carotid artery disease

Objectives There is considerable evidence that patients with carotid artery stenosis treated immediately after the ischaemic cerebrovascular event have a better clinical outcome than those who have delayed treatment. Biomechanical assessment of carotid plaques using high-resolution MRI can help examine the relationship between the timing of carotid plaque symptomology and maximum simulated plaque stress concentration. Methods Fifty patients underwent high-resolution multisequence in vivo MRI of their carotid arteries. Patients with acute symptoms (n=25) underwent MRI within 72 h of the onset of ischaemic cerebrovascular symptoms, whereas recently symptomatic patients (n=25) underwent MRI from 2 to 6 weeks after the onset of symptoms. Stress analysis was performed based on the geometry derived from in vivo MRI of the symptomatic carotid artery at the point of maximum stenosis. The peak stresses within the plaques of the two groups were compared. Results Patient demographics were comparable for both groups. All the patients in the recently symptomatic group had severe carotid stenosis in contrast to patients with acute symptoms who had predominantly mild to moderate carotid stenosis. The simulated maximum stresses in patients with acute symptoms was significantly higher than in recently symptomatic patients (median (IQR): 313×104 dynes/cm2 (295 to 382) vs 252×104 dynes/cm2 (236 to 311), p=0.02). Conclusions Patients have extremely unstable, high-risk plaques, with high stresses, immediately after an acute cerebrovascular event, even at lower degrees of carotid stenoses. Biomechanical stress analysis may help us refine our risk-stratification criteria for the management of patients with carotid artery disease in future.

In vivo MRI-based 3D Mechanical Stress–Strain Profiles of Carotid Plaques with Juxtaluminal Plaque Haemorrhage: An Exploratory Study for the Mechanism of Subsequent Cerebrovascular Events

OBJECTIVES Atherosclerotic plaque features, such as fibrous cap erosion, ulceration and rupture and presence of haemorrhage in carotid plaque are two important characteristics associated with subsequent cerebrovascular events and juxtaluminal haemorrhage/thrombus (JLH/T) indicates these two high-risk characteristics. This study aims to investigate the association between JLH/T and subsequent events in patients suffering from transient ischaemic attack (TIA). Three-dimensional mechanical analysis was employed to represent the critical mechanical stress (P-CStress) and stretch (P-CStretch) within the plaque. METHODS Fifty TIA patients with mild-to-moderate carotid stenosis (30-69%) underwent high-resolution magnetic resonance imaging (MRI) within 72 h of the acute event and eight were excluded from the analysis due to various reasons. A total of 21 patients were found to have JLH/T in the carotid plaque and 21 did not (N-JLH/T). During a 2-year follow-up period, 11 (52.4%) patients in the JLH/T group experienced recurrent events and none in the N-JLH/T group. Three-dimensional plaque structure was reconstructed based on the in vivo MRI for the mechanical analysis. RESULTS P-CStress of both groups was comparable (N-JLH/T: 174.45 ± 63.96 kPa vs. JLH/T: 212.60 ± 89.54 kPa; p = 0.120), but P-CStretch of JLH/T was significantly bigger than that of N-JLH/T (N-JLH/T: 1.21 ± 0.08 vs. JLH/T: 2.10 ± 0.53; p < 0.0001). Moreover, there were much bigger variations in stress and stretch of the JLH/T group during one cardiac cycle than in those of N-JLH/T group. CONCLUSIONS In vivo MRI-depicted JLH/T might be a high risk factor initiating recurrent events, as big deformation appearing around the rupture site might prevent healing and tear the haemorrhage/thrombus away from the host structure and prompt further thrombo-embolic events.

High-resolution magnetic resonance imaging-based biomechanical stress analysis of carotid atheroma: a comparison of single transient ischaemic attack, recurrent transient ischaemic attacks, non-disabling stroke and asymptomatic patient groups.

BACKGROUND Vulnerable carotid plaques are associated with cerebrovascular ischaemic events. High-resolution magnetic resonance (MR) imaging not only allows the morphological assessment of such plaques, but also provides geometrical data, which can be used for biomechanical stress analysis. We assess its utility to assess the plaque stress profiles of symptomatic (transient ischaemic attack (TIA) and non-disabling stroke) and asymptomatic patients. METHODS A total of 70 consecutive patients with confirmed underlying carotid artery disease underwent carotid MR imaging of their carotid artery in a 1.5-T MR system using a standard carotid atheroma imaging protocol. MR images were manually segmented for different plaque components and used for biomechanical stress analysis. The maximum critical stress (M-CStress) for various clinical groups was determined and compared. RESULTS M-CStress of symptomatic plaques (n = 45) was significantly higher than for asymptomatic plaques (n = 25) (median (interquartile range (IQR): 275 kPa (190-390) vs. 165 kPa (120-200), p = 0.0001)). Within the symptomatic group, no M-CStress differences were present between the TIA (n = 30) and stroke (n = 15) patients (260 kPa (190-370) vs. 295 kPa (200-510), p = 0.31). Within the TIA patient cohort, those who had presented with recurrent TIAs (n = 6) had significantly higher stresses than patients who had suffered a single episode (n = 24) (425 kPa (285-580) vs. 250 kPa (180-310), p = 0.001). CONCLUSIONS Symptomatic carotid plaques, particularly those associated with recurrent TIAs, have high biomechanical stresses. As there is pre-existing evidence to suggest that high biomechanical stresses are associated with plaque vulnerability, MR-imaging-based stress analysis has the potential to identify high-risk patients with vulnerable plaques.

Characterization of healing following atherosclerotic carotid plaque rupture in acutely symptomatic patients: an exploratory study using in vivo cardiovascular magnetic resonance

BackgroundCarotid plaque rupture, characterized by ruptured fibrous cap (FC), is associated with subsequent cerebrovascular events. However, ruptured FC may heal following stroke and convey decreased risk of future events. This study aims to characterize the healing process of ruptured FC by assessing the lumen conditions, quantified by the lumen curvature and roughness, using in vivo carotid cardiovascular magnetic resonance (CMR).MethodsPatients suffering from transient ischemic attack underwent high resolution carotid MR imaging within 72 hours of the acute cerebrovascular ischemic event. CMR imaging was repeated at 3 and 12 months in 26 patients, in whom FC rupture/erosion was observed on baseline images and subsequent cerebrovascular events were recorded during the follow-up period. Lumen curvature and roughness were quantified from carotid CMR images and changes in these values were monitored on follow-up imaging.ResultsHealing of ruptured plaque was observed in patients (23 out of 26) without any ischemic symptom recurrence as shown by the lumen surface becoming smoother during the follow-up period, characterized by decreasing maximum lumen curvature (p < 0.05), increasing minimum lumen curvature (p < 0.05) and decreasing lumen roughness (p < 0.05) during the one year follow-up period.ConclusionsCarotid plaque healing can be assessed by quantification of the lumen curvature and roughness and the incidence of recurrent cerebrovascular events may be high in plaques that do not heal with time. The assessment of plaque healing may facilitate risk stratification of recent stroke patients on the basis of CMR results.