Lipid-rich Necrotic Core Size Research Articles

Mechanical wall stress and wall shear stress are associated with atherosclerosis development in non-calcified coronary segments

Atherosclerotic plaque onset and progression are known to be affected by local biomechanical factors. While the role of wall shear stress (WSS) has been studied, the impact of another biomechanical factor, namely mechanical wall stress (MWS), remains poorly understood. In this study, we investigated the association of MWS, independently and combined with WSS, towards atherosclerosis in coronary arteries. Thirty-four human coronary arteries were analyzed using near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) at baseline and after 12 months. Baseline WSS and MWS were calculated using computational models, and wall thickness (ΔWT) and lipid-rich necrotic core size (ΔLRNC) change were measured in non-calcified coronary segments. The arteries were further divided into 1.5 mm/45° sectors and categorized as plaque-free or plaque sectors. For each category, associations between biomechanical factors (WSS & MWS) and changes in coronary wall (ΔWT & ΔLRNC) were studied using linear mixed models. In plaque-free sectors, higher MWS (p< 0.001) was associated with greater vessel wall growth. Plaque sectors demonstrated wall thickness reduction over time, likely due to medical therapy, where higher levels of WSS and WMS, individually and combined, (p< 0.05) were associated with a greater reduction. Sectors with low MWS combined with high WSS demonstrated the highest LRNC increase (p<0.01). In this study, we investigated the association of the (largely-overlooked) biomechanical factor MWS with coronary atherosclerosis, individually and combined with WSS. Our results demonstrated that both MWS and WSS significantly correlate with atherosclerotic plaque initiation and development.

MR imaging of vulnerable carotid plaque.

Current risk stratification for stroke is still based upon percentage of carotid stenosis, despite this measure providing minimal patient-specific information on the actual risk of stroke for both symptomatic individuals without significant carotid artery stenosis as well as asymptomatic carotid stenosis patients. A continuously growing body of literature suggests that the identification and quantification of certain carotid plaque characteristics, including lipid-rich necrotic core (LRNC), thin/ruptured fibrous cap (FC), and intraplaque hemorrhage (IPH), provide a superior means of predicting future stroke. These characteristics are identifiable via magnetic resonance imaging (MRI), with most features detectable using commercially available coils and sequences utilized in routine clinical practice in as little as 4 minutes. The presence of LRNC, a thin/ruptured FC, and IPH is associated with increased risk of future stroke or TIA. Plaques with greater than 40% LRNC with a thin overlying FC are prone to rupture. LRNC is T2 hypointense and lacks enhancement on contrast enhanced T1 weighted images. Increasing LRNC size is associated with the development of new ulceration, FC rupture, increasing plaque burden, as well as fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome (ACS), and symptom-driven revascularization, allowing for MR biomarkers of carotid plaque vulnerability to be utilized for systemic athero-thrombotic risk and not just stroke/TIA. LRNC typically shrinks with appropriate statin therapy, with PCSK9 inhibitors possibly playing a role in patients with inadequate response. Carotid plaques with IPH represent a more advanced stage of atherosclerotic disease. IPH is detectable with field strengths of both 3.0 T and 1.5 T and will demonstrate high signal on all T1 weighted imaging sequences. The presence of IPH increases the risk of future stroke in both symptomatic and asymptomatic patients, with multivariate analysis identifying IPH as a predictor of stroke, independent of percent stenosis, with no statistical difference in men vs. women, demonstrating that simple carotid stenosis measurements and traditional risk factor analysis may be inadequate in identifying patients at the highest risk for adverse cerebrovascular events. In the evaluation for recurrent stroke in recently symptomatic patients with >50% carotid stenosis, the estimated annual stroke risk is 23.2% in IPH+ patients and only 0.6% in IPH- patients, calling into question the current risk-benefit assessment for CEA. Additionally, a recent meta-analysis suggests that IPH+ plaque in patients with symptomatic <50% stenosis may be the etiology of embolic strokes previously labeled as "embolic stroke of undetermined source" (ESUS). There are no prospective drug trials testing the ability of any lipid-lowering therapies to decrease IPH and/or total plaque volume (TPV). Given the continuously increasing evidence of IPH as a significant predictor of carotid plaque progression and future adverse vascular events, trials aimed at targeted therapy for IPH represents a significant need.

Quantitative Analysis of Lipid-Rich Necrotic Core in Carotid Atherosclerotic Plaques by In Vivo Magnetic Resonance Imaging and Clinical Outcomes.

BackgroundThe aim of this study was to explore the accuracy of in vivo magnetic resonance imaging (MRI) in the quantitative evaluation of lipid-rich necrotic core (LRNC) in carotid atherosclerotic plaques compared with histopathology, and to assess the association of LRNC size with cerebral ischemia symptoms.Material/MethodsThirty patients were enrolled and 19 patients (16 men and 3 women) were analyzed. All the patients were submitted to MRI on a Siemens Avanto (1.5-Tesla) device before carotid endarterectomy (CEA). The scanning protocol included three-dimensional time of flight (3D TOF), T1-weighted image (T1WI), T2-weighted image (T2WI), turbo spin-echo T2-weighted (T2-TSE), and contrast-enhanced T1-weighted image. MRI images were reviewed for quantitative measurements of LRNC areas. LRNC specimens were collected for histology. Percentages of LRNC area to total vessel area were assessed to determine the association of MRI with histological findings.ResultsThere were 151 pairs of matched MRI and pathological sections. LRNC area percentages (LRNC area/vessel area) measured by MRI and histology were 20.6±9.0% and 18.7±9.5%, respectively (r=0.69, p<0.001). Twelve out of 19 patients had symptoms (S-group; 3 had recent stroke, 3 had a recent stroke and a history of transient ischemic attack (TIA), and 6 had TIA); the remaining 7 subjects showed no symptoms (NS-group). LRNC area percentages in the S- and NS-groups were 22.2±5.8% and 12.6±10.7%, respectively (p<0.05).ConclusionsMRI can quantitatively measure LRNC in carotid atherosclerotic plaques, and may be useful in predicting the rupture risk of plaques. These findings provide a basis for imaging use in individualized treatment plan.

Biomarkers of plaque instability.

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.

Abstract W P31: Are Current Lipid Profile Measurements Reliable for Monitoring Carotid Plaque??

Objective: To test the hypothesis that lipid indices have a role in monitoring lipid-rich necrotic core (LRNC) burden and to see if this varies with statin exposure. METHODS: Cohort of 73 symptomatic carotid stenosis patients were identified with MR angiogram imaging to assess their carotid LRNC percentage determined by 2 independent radiologists and corresponding lipid profiles . Patients were further stratified into two groups as statin naïve (&lt; 30 day exposure to statin) and term statin group (&gt; 1 month exposure to statin).Simple linear regression was performed between with the dependent variable of LRNC size and independent variables of LDL: HDL ratio, TG :HDL ratio and HDL alone. RESULTS: Of 73 patients with LRNC percentage reported 26 were statin naive and 47 were term statin users. Overall LDL:HDL, TG:HDL-C and HDL-C were associated (r,P){moderately(0.37, 0.049)}, {weakly(0.23,0.049)}, {Moderately (-0.30 ,0.01)} LRNC size respectively. Patients with statin naive status, LDL:HDL, TG:HDL-C and HDL-C were associated (r,P){strongly (0.6,0.001)},{not(0.37,0.06)},{Strongly(-0.45,0.02)} with LRNC size respectively. After Stratifying with statin status (Term Statin), LDL:HDL, TG:HDL-C and HDL-C were not associated (r,P) {0.18,0.2),(0.17,0.2),(-0.24,0.1)} with LRNC size respectively. Furthermore, longer duration of statin exposure did not reveal a greater reduction in the size of necrotic core (r=-0.004, P=0.96)(see figure). Conclusions: Lipid indices correlate better with carotid plaque morphology in statin naïve patients. After starting statin the same indices correlate poorly with LRNC. Poorly controlled hyperlipidemia is a riskfactor for atherosclerosis, but lack of correlation between LRNC size and lipid levels after patients have been placed on statin therapy suggests the individual patient response to clearing LRNC with statin therapy is heterogenous. Persistent large LRNC with statin may improve lipid but, not the future risk of stroke.

Inhibitory Effects of Vinpocetine on the Progression of Atherosclerosis Are Mediated by Akt/NF-κB Dependent Mechanisms in apoE-/- Mice

BackgroundRecent studies have found additional roles for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE-/- mice and explore the underlying anti-atherogenic mechanisms in macrophages.Methodology/Principal FindingsVinpocetine markedly decreased atherosclerotic lesion size in apoE-/- mice measured by oil red O. Masson’s trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated inflammation. In vitro experiments exhibited a significant decrease in monocyte adhesion treated with vinpocetine. Further, active TNF-α, IL-6, monocyte chemoattractant protein-1and matrix metalloproteinase-9 expression induced by ox-LDL were attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine inhibited the enhanced Akt, IKKα/β, IκBα phosphorylation and NF-κB activity induced by ox-LDL, and the inhibition of NF-κB activity was partly caused by Akt dephosphorylation. However, knockdown of PDE1B did not affect Akt, IKKα/β and IκBα phosphorylation.ConclusionsThese results suggest that vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhesion, oxidative stress and inflammatory response, which are mediated by Akt/NF-κB dependent pathway but independent of PDE1 blockade in macrophages.

Association of carotid atherosclerotic plaque features with acute ischemic stroke: A magnetic resonance imaging study

It remains unclear whether direct vessel wall imaging can identify carotid high-risk lesions in symptomatic subjects and whether carotid plaque characteristics are more effective indicators for cerebral infarct severity than stenosis. This study sought to determine the associations of carotid plaque characteristics by MR imaging with stenosis and acute cerebral infarct (ACI) sizes on diffusion weighted imaging (DWI). One hundred and fourteen symptomatic patients underwent carotid and brain MRI. ACI volume was determined from symptomatic internal carotid artery territory on DWI images. Ipsilateral carotid plaque morphological and compositional characteristics, and stenosis were also determined. The relationships between carotid plaque characteristics, stenosis and ACIs size were then evaluated. In carotid arteries with 30-49% stenosis, 86.7% and 26.7% were found to have lipid-rich necrotic core (LRNC) and intraplaque hemorrhage, respectively. Furthermore, 45.8% of carotid arteries with 0-29% stenosis developed LRNCs. Carotid morphological measurements, such as % wall volume, and the LRNC size were significantly associated with ipsilateral ACIs volume before and after adjustment for significant demographic factors (age and LDL) or stenosis in patients with carotid plaque (all p<0.05). A substantial number of high-risk plaques characterized by vessel wall imaging exist in carotid arteries with lower grade stenosis. In addition, carotid plaque characteristics, particularly the % wall volume and LRNC size, are independently associated with cerebral infarction as measured by DWI lesions. Our findings indicate that characterizing atherosclerotic plaque by MR vessel wall imaging might be useful for stratification of plaque risk and infarction severity.

ASSA13-03-13 Inhibitory Effects of Vinpocetine on the Progression of Atherosclerosis Are Mediated by Akt/NF-kB Dependent Mechanisms

<h3>Objective</h3> Recent studies have found additional role for vinpocetine, a potent phosphodiesterase type I inhibitor, in anti-proliferation and anti-inflammation of vascular smooth muscle cells and cancer cells via different mechanisms. In this study, we attempted to investigate whether vinpocetine protected against atherosclerotic development in apoE^-/- mice and explore the underlying anti-atherogenic mechanisms in macrophages. <h3>Methods and Results</h3> Vinpocetine markedly decreased atherosclerotic lesion size in apoE^-/- mice measured by oil red O. Masson’s trichrome staining and immunohistochemical analyses revealed that vinpocetine significantly increased the thickness of fibrous cap, reduced the size of lipid-rich necrotic core and attenuated the expression of TNF-alpha and matrix metalloproteinase-9 (MMP-9) within plaque area. <i>In vitro</i> experiments exhibited a significant decrease in monocyte adhension treated with vinpocetine. In parallel with few changes in ox-LDL uptake and foam cell formation, the expression levels of scavenger receptor A and CD 36 were not altered after treatment with vinpocetine. Further, active TNF-alpha, IL-6, monocyte chemoattractant protein-1 and MMP-9 expression induced by ox-LDL was attenuated by vinpocetine in a dose-dependent manner. Similarly, ox-LDL-induced reactive oxygen species were significantly repressed by vinpocetine. Both western blot and luciferase activity assay showed that vinpocetine restored the enhanced Akt, IKK-alpha/beta, IkappaB-alpha phosphorylation and NF-kappaB activity induced by ox-LDL. Cotreatment with LY294002, a specific Akt inhibitor, augmented the inhibitory effects of vinpocetine on IKK-alpha/beta and IkappaB-alpha phosphorylation, suggesting that inhibition of NF-kappaB activity was partly caused by Akt dephosphorylation. Knockdown of PDE1B resulted in an increase of intracellular cGMP contents, however, did not affect Akt, IKK-alpha/beta and IkappaB-alpha phosphorylation. <h3>Conclusions</h3> Vinpocetine exerts anti-atherogenic effects through inhibition of monocyte adhension, oxidative stress and inflammatory response, which are mediated by Akt/NF-kappaB dependent pathway but independent of PDE1 blockade in macrophages.

Comparison of lipid‐rich necrotic core size in symptomatic and asymptomatic carotid atherosclerotic plaque: Initial results

To investigate the potential difference in the size of the lipid-rich necrotic core (LRNC) in carotid plaques of symptomatic patients versus asymptomatic patients. Pathological studies established that a large LRNC is an important feature of vulnerable atherosclerotic plaque. Previously, we have demonstrated a high correlation between semiquantitative analysis of the LRNC size in T1-weighted (w) turbo field echo (TFE) MR images and histology. Thirty-seven patients with carotid stenosis >70% with (n = 26) or without (n = 11) symptoms were included. Three independent MR readers quantified the amount of LRNC with a T1w TFE pulse sequence. The relative amount of LRNC (LRNC score) was defined as sum of cross-sectional area percentages LRNC per carotid plaque. Interreader agreement for the three MR readers was good, with an intraclass correlation coefficient (ICC, 95% confidence interval [CI]) of 0.72 (0.57-0.83). All three MR readers on average found a larger LRNC in the symptomatic group of patients, although this was not statistically significant. The mean LRNC score was 116 +/- 129 and 59 +/- 62 for symptomatic and asymptomatic patients, respectively (P = 0.13). Symptomatic patients showed wide ranges in LRNC scores (0-424), while the range was much lower in the asymptomatic group (0-170). Single-sequence T1w TFE may be a promising technique to study atherosclerotic plaque at risk of stroke. Larger studies are warranted to confirm these promising results.

Intra‐ and interreader reproducibility of magnetic resonance imaging for quantifying the lipid‐rich necrotic core is improved with gadolinium contrast enhancement

To test the hypothesis that intra- and interreader reproducibility for measuring the lipid-rich necrotic core (LR-NC) size is significantly improved with gadolinium (Gd) contrast-enhanced magnetic resonance imaging (CEMRI) compared to non-CEMRI. Thirty-seven individuals with >50% carotid artery stenosis underwent carotid MRI at 1.5T (pre- and postcontrast T1-weighted (T1W), T2-weighted (T2W), proton density-weighted (PDW), and three-dimensional time-of-flight (TOF) sequences). Two independent readers measured the mean area of the LR-NC from the precontrast images only, followed by a second measurement using the additional postcontrast images. One reader repeated the measurements after an interval of five months. Intra- and interreader reproducibility was analyzed by means of the intraclass correlation coefficient (ICC), coefficient of variation (CV), and standard deviation (SD). The CV decreased from 33.7% to 8.8% for intrareader measurements of the LR-NC, and from 33.5% to 17.6% for interreader measurements. The SD was significantly smaller with CEMRI than with non-CEMRI (P = 0.003 and P = 0.006, respectively). The ICC increased from 0.94 to 0.99 and from 0.85 to 0.93 for the intra- and interreader measurements, respectively. Reader reproducibility for in vivo MRI quantification of LR-NC size is significantly improved by the addition of Gd contrast in individuals with >50% carotid stenosis.

In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque

Previous studies with contrast-enhanced magnetic resonance imaging (CEMRI) have shown that the fibrous cap (FC) in atherosclerotic carotid plaques enhances with gadolinium-based contrast agents. Conversely, the lipid-rich necrotic core (LR-NC), lacking both vasculature and matrix, shows no or only slight enhancement. The goal of this study was to assess whether CEMRI can be used to accurately measure the dimensions of the intact FC and LR-NC. Twenty-one patients scheduled for carotid endarterectomy were imaged with a 1.5-T scanner. Precontrast images and CEMRI were obtained. One hundred eight locations with an intact FC were matched between MRI and the excised histology specimens. Quantitative measurements of FC length along the lumen circumference, FC area, and LR-NC area were collected from CEMRI images and histology sections. Blinded comparison of corresponding MR images and histology slices showed moderate to good correlation for length (r=0.73, P<0.001) and area (r=0.80, P<0.001) of the intact FC. The mean percentage LR-NC areas (LR-NC area/wall area) measured by CEMRI and histology were 30.1% and 32.7%, respectively, and were strongly correlated across locations (r=0.87, P<0.001). In vivo high-resolution CEMRI is capable of quantitatively measuring the dimensions of the intact FC and LR-NC. These new parameters may be useful to evaluate plaque vulnerability and provide continuous variables for characterizing the intact FC and LR-NC in progression and regression studies.