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Background and Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce cardiovascular events, but their effects on atherosclerotic plaque remain elusive. Using serial magnetic resonance imaging (MRI), we studied changes in carotid plaque lipid content and neovasculature under PCSK9 inhibition with alirocumab., Methods: Among patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl but ineligible for high-dose statin therapy, those with lipid core on carotid MRI were identified to receive alirocumab 150 mg every 2 weeks. Follow-up MRI was performed at 3, 6, and 12 months after treatment. Pre- and post-contrast MRI were acquired to measure percent lipid core volume (% lipid core). Dynamic contrast-enhanced MRI was acquired to measure the extravasation rate of gadolinium contrast (K trans ), a marker of plaque neovasculature., Results: Of 31 patients enrolled, 27 completed the study (mean age: 69 ± 9; male: 67%). From 9.8% at baseline, % lipid core was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months (p = 0.014 for trend), which was accompanied by a progressive increase in % fibrous tissue (p = 0.009) but not % calcification (p = 0.35). K trans was not reduced until 12 months (from 0.069 ± 0.019 min -1 to 0.058 ± 0.020 min -1 ; p = 0.029). Lumen and wall areas did not change significantly during the study period., Conclusions: Regression in plaque composition and neovasculature were observed under PCSK9 inhibition on carotid MRI, which provides unique insight into the biological process of plaque stabilization with disease-modifying therapies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Prospective studies have shown a strong association between carotid intraplaque hemorrhage (IPH), detected by magnetic resonance imaging (MRI), and cerebrovascular ischemic events. However, IPH is also observed in a substantial number of asymptomatic patients. We hypothesized that there are differences in the characteristics of IPH+ plaques associated with recent symptoms, compared to IPH+ plaques not associated with recent symptoms., Methods: Patients with recent (≤2 weeks) anterior circulation ischemic events were scanned using a standardized multisequence protocol. Those showing IPH bilaterally were included and analyzed for differences in T1/T2 signals, plaque morphology, and coexisting plaque characteristics between the ipsilateral symptomatic and contralateral asymptomatic sides., Results: Thirty-one subjects (67 ± 9 years, 97% males) with bilateral IPH were studied. Despite comparable luminal stenosis (53 ± 42% vs. 53 ± 39%, p = 0.99), T1 signal of IPH measured as signal-intensity-ratio compared to muscle was stronger (SIR IPH-to-muscle : 5.8 ± 2.4 vs. 4.7 ± 1.8, p = 0.004) and tended to be more extensively distributed (IPH volume: 150 ± 199 vs. 88 ± 106 mm 3 , p = 0.071) on the symptomatic side. IPH+ plaques on the symptomatic side were longer (24 ± 6 vs. 21 ± 7 mm, p = 0.026) and associated with larger necrotic core volume (406 ± 354 vs. 291 ± 293 mm 3 , p = 0.039) than those on the asymptomatic side., Conclusions: In recently symptomatic patients with bilateral carotid IPH, the symptomatic side showed stronger T1 signals, larger necrotic cores, and longer plaque length than the asymptomatic side. Serial studies on the temporal relationship between these imaging features and clinical events will eventually establish their diagnostic and prognostic value beyond the mere presence of IPH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Plaque fissuring, a phenomenon morphologically distinct from the classical rupture of a thinned fibrous cap, has not been well characterized in carotid atherosclerosis. The aim of this study was to establish the prevalence of plaque fissures in advanced carotid plaques with an otherwise intact luminal surface, and to determine whether they might be a source of intraplaque hemorrhage (IPH)., Methods: We evaluated 244 surgically intact, 'en bloc' embedded, serially sectioned carotid endarterectomy specimens and included only those plaques with a grossly intact luminal surface., Results: Among the 67 plaques with grossly intact luminal surface, cap fissure was present in 39 (58%) plaques. A total of 60 individual fissures were present, and longitudinally mean fissure length was 1.3 mm. Most fissures were found distal to the bifurcation (63%), proximal to the stenosis (88%), and in the posterior (opposite the flow divider) or lateral quadrants (80%). 36% of the fissures remained in the superficial third of the plaque. 52% extended from the lumen surface to the middle third of the plaque and 12% reached the outer third of the plaque on cross section. Fissures often occurred between two tissue planes and were connected to IPH (fresh: 63%; any type: 92%) and calcifications (43%). No correlation was found with patient characteristics such as symptom status, carotid stenosis, hypertension, diabetes, smoking and medications (statins or antiplatelet agents)., Conclusions: Plaque fissures are common in advanced carotid plaques with an otherwise grossly intact luminal surface and are associated with fresh intraplaque hemorrhage. As they occur on the interface between plaque components with different mechanical properties, further biomechanical studies are needed to unravel the underlying failure mechanisms., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

The purpose of this in vivo MRI study was to quantify changes in atherosclerotic plaque morphology prospectively and to identify factors that may alter the rate of progression in plaque burden. Sixty-eight asymptomatic subjects with >or=50% stenosis, underwent serial carotid MRI examinations over an 18-month period. Clinical risk factors for atherosclerosis, and medications were documented prospectively. The wall and total vessel areas, matched across time-points, were measured from cross-sectional images. The normalized wall index (NWI=wall area/total vessel area), as a marker of disease severity, was documented at baseline and at 18 months. Multiple regression analysis was used to correlate risk factors and morphological features of the plaque with the rate of progression/regression. On average, the wall area increased by 2.2% per year (P=0.001). Multiple regression analysis demonstrated that statin therapy (P=0.01) and a normalized wall index >0.64 (P=0.001) were associated with a significantly reduced rate of progression in mean wall area. All other documented risk factors were not significantly associated with changes in wall area. Findings from this study suggest that increased normalized wall index and the use of statin therapy are associated with reduced rates of plaque progression amongst individuals with advanced, asymptomatic carotid atherosclerosis.

Aim: The purpose of the study was to assess whether ex vivo measures of low-density lipoprotein (LDL) oxidation improved prediction of carotid artery disease (CAAD) case-control status compared to standard lipid and smoking measures., Methods: One hundred and forty cases with a high degree of carotid artery stenosis aged 40-83 years and an equal number of controls without stenosis or other vascular disease were matched by censored age within 2 years. Matched logistic regression evaluated the significance of copper-induced oxidative measures with and without covariates. The relationship of LDL oxidation measures with statin use and current smoking was also evaluated., Results: Logistic regression demonstrated a significant effect of the three correlated measures of oxidative susceptibility (lag time, oxidation rate and maximal rate of oxidation) separately on disease prediction (all p<0.05). These oxidative measures remained significant predictors of case-control status when other cardiovascular disease predictors (age; LDL-C, HDL-C and ApoAI levels; current smoking, ever smoking and pack-years smoked) were jointly considered. This relationship was not attributable to the effects of statin use on LDL oxidation., Conclusions: Ex vivo measures of oxidation improved the prediction of carotid artery disease status, suggesting that this is an important determinant of atherosclerotic risk in this older population.