Changes In Plaque Morphology Research Articles

Quantitative imaging biomarkers of coronary plaque morphology: insights from EVAPORATE.

Residual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result. EVAPORATE randomized the patients to IPE 4 g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2 mm3 vs. an increase of 41 mm3, p = 0.008), widening at 18 months (6 mm3 vs. 58 mm3 increase, p = 0.015) were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p < 0.01 (sustained at 18 months), generalizing well to a validation cohort. Plaques in the IPE-treated patients acquired more characteristics of stability. Reliable assessment using histologically validated analysis of individual response is possible at 9 months, with sustained stabilization at 18 months, providing a quantitative basis to elucidate drug mechanism and assess individual patient response.

Impact of Intensive Low-Density Lipoprotein Cholesterol-Lowering Therapy on Coronary Artery Plaques in Acute Coronary Syndrome

Acute coronary syndrome (ACS) is associated with a high incidence of unstable plaques beyond the culprit lesion, leading to early recurrence of cardiovascular events. Coronary computed tomography angiography (CCTA) can be used to noninvasively observe plaques throughout the coronary arteries. To evaluate the impact of intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy on quantitative changes in coronary plaque, assessed using CCTA in a study population with ACS. In total, 81 consecutive patients with ACS who underwent CCTA at discharge and at 1-year follow-up from April 2018 to March 2020 were analyzed. The patients were divided into 2 groups: those who achieved LDL-C <70 mg/100 ml and those who did not. Changes in plaque morphology within and between the 2 groups were compared using CCTA. A total of 198 vessels were analyzed. The calcified plaque volume was significantly increased in the LDL-C <70 group (65.8 ± 80.1 mm3 to 73.6 ± 83.7 mm3, p=0.007), whereas no significant change was observed in the LDL-C ≥70 group (106.9 ± 161.7 mm3 to 105.7 ± 137.5 mm3, p=0.552). Percent change in low-attenuation plaque volume in the LDL <70 group was significantly lower than in the LDL-C ≥70 group (17.2 ± 90.9% vs 84.4 ± 162.6%, p=0.020). Receiver operating characteristic curve analysis demonstrated that the target LDL-C level for low-attenuation plaque volume regression was 64 mg/100 ml. In conclusion, noninvasive CCTA demonstrated that intensive LDL-C lowering in high-risk patients with ACS could potentially lead to plaque stabilization.

Transient increase in atherosclerotic plaque macrophage content following Streptococcus pneumoniae pneumonia in ApoE-deficient mice.

Despite epidemiological associations between community acquired pneumonia (CAP) and myocardial infarction, mechanisms that modify cardiovascular disease during CAP are not well defined. In particular, largely due to a lack of relevant experimental models, the effect of pneumonia on atherosclerotic plaques is unclear. We describe the development of a murine model of the commonest cause of CAP, Streptococcus pneumoniae pneumonia, on a background of established atherosclerosis. We go on to use our model to investigate the effects of pneumococcal pneumonia on atherosclerosis. C57BL/6J and ApoE-/- mice were fed a high fat diet to promote atherosclerotic plaque formation. Mice were then infected with a range of S. pneumoniae serotypes (1, 4 or 14) with the aim of establishing a model to study atherosclerotic plaque evolution after pneumonia and bacteremia. Laser capture microdissection of plaque macrophages enabled transcriptomic analysis. Intratracheal instillation of S. pneumoniae in mice fed a cholate containing diet resulted in low survival rates following infection, suggestive of increased susceptibility to severe infection. Optimization steps resulted in a final model of male ApoE-/- mice fed a Western diet then infected by intranasal instillation of serotype 4 (TIGR4) S. pneumoniae followed by antibiotic administration. This protocol resulted in high rates of bacteremia (88.9%) and survival (88.5%). Pneumonia resulted in increased aortic sinus plaque macrophage content 2 weeks post pneumonia but not at 8 weeks, and no difference in plaque burden or other plaque vulnerability markers were found at either time point. Microarray and qPCR analysis of plaque macrophages identified downregulation of two E3 ubiquitin ligases, Huwe1 and Itch, following pneumonia. Treatment with atorvastatin failed to alter plaque macrophage content or other plaque features. Without antibiotics, ApoE-/- mice fed a high fat diet were highly susceptible to mortality following S. pneumoniae infection. The major infection associated change in plaque morphology was an early increase in plaque macrophages. Our results also hint at a role for the ubiquitin proteasome system in the response to pneumococcal infection in the plaque microenvironment.

On the nonlinear relationship between wall shear stress topology and multi-directionality in coronary atherosclerosis

Background and ObjectiveIn this paper we investigate twelve multi-directional/topological wall shear stress (WSS) derived metrics and their relationships with the formation of coronary plaques in both computational fluid dynamics (CFD) and dynamic fluid-structure interaction (FSI) frameworks. While low WSS is one of the most established biomechanical markers associated with coronary atherosclerosis progression, alone it is limited. Multi-directional and topological WSS derived metrics have been shown to be important in atherosclerosis related mechanotransduction and near-wall transport processes. However, the relationships between these twelve WSS metrics and the influence of both FSI simulations and coronary dynamics is understudied. MethodsWe first investigate the relationships between these twelve WSS derived metrics, stenosis percentage and lesion length through a parametric, transient CFD study. Secondly, we extend the parametric study to FSI, both with and without the addition of coronary dynamics, and assess their correlations. Finally, we present the case of a patient who underwent invasive coronary angiography and optical coherence tomography imaging at two time points 18 months apart. Associations between each of the twelve WSS derived metrics in CFD, static FSI and dynamic FSI simulations were assessed against areas of positive/negative vessel remodelling, and changes in plaque morphology. Results22–32% stenosis was the threshold beyond which adverse multi-directional/topological WSS results. Each metric produced a different relationship with changing stenoses and lesion length. Transient haemodynamics was impacted by coronary dynamics, with the topological shear variation index suppressed by up to 94%. These changes appear more critical at smaller stenosis levels, suggesting coronary dynamics could play a role in the earlier stages of atherosclerosis development. In the patient case, both dynamics and FSI vs CFD changes altered associations with measured changes in plaque morphology. An appendix of the linear fits between the various FSI- and CFD-based simulations is provided to assist in scaling CFD-based results to resemble the compliant walled characteristics of FSI more accurately. ConclusionsThese results highlight the potential for coronary dynamics to alter multi-directional/topological WSS metrics which could impact associations with changes in coronary atherosclerosis over time. These results warrant further investigation in a wider range of morphological settings and longitudinal cohort studies in the future.

Pitavastatin: Coronary Atherosclerotic Plaques Changes and Cardiovascular Prevention

Stains remain the first therapeutic approach in patients with dyslipidemia to control plasma lipids levels and cardiovascular risk. Multiple clinical trials have demonstrated the benefits of statins in reducing major cardiovascular adverse events in primary and secondary prevention. Moreover, in patients with coronary artery disease, statins decrease coronary atherosclerotic plaque volume and composition, inducing atheroma stabilization. Pitavastatin, is a new-generation lipophilic statin, indicated for the treatment of dyslipidemia and prevention of cardiovascular diseases. The purpose of this review, the first at our knowledge on this topic, is to summarize and examine the current knowledge about the effectiveness of pitavastatin in patients with coronary artery disease. The available data suggest that pitavastatin significantly, lowers the rate of adverse cardiovascular events, in patients at a high risk of atherosclerotic disease, with stable angina pectoris or with acute coronary syndrome. Moreover intravascular ultrasound have shown that pitavastatin induces favorable changes in plaque morphology, increasing the fibrous cap thickness, and decreasing both plaque and lipid volume indexes. Globally the efficacy of pitavastatin is greater or similar to other statins.

Plaque Longitudinal Heterogeneity in Morphology, Property, and Mechanobiology

Background and Purpose: The hemodynamic environment of an atherosclerotic plaque varies along the longitudinal direction. Investigating the changes in plaque morphology and its biomechanical environment along the longitudinal direction and their correlations will enhance our understanding of plaque progression and arterial remodeling. Methods: Six male patients with carotid stenosis >70% were recruited. Multisequence high-resolution MRI was performed at the carotid bifurcation. Carotid endarterectomy was performed following MRI, and the plaque tissue was collected for histological and mechanical testing. Patient-specific biomechanical modeling and simulations were conducted to calculate the mechanical stresses (wall shear stress [WSS] and von Mises stress [VMS]). Changes in plaque cross-sectional morphology, WSS, and VMS as well as their correlations were evaluated. Results: Positive correlations were found between % stenosis and % inflammation (MA) (p = 0.019), % lipid area and % MA (p = 0.026), and % calcification area and VMS (p = 0.007). Negative correlations were found between VMS and % stenosis (p = 0.028) and VMS and average WSS (p = 0.034). Moreover, the peak stresses and neovessels were found to be in the shoulder regions. High-stress concentrations were found in the interface regions of the calcification and surrounding tissue, thereby increasing plaque vulnerability. Conclusions: Correlations between the morphology and stresses suggest that arterial remodeling is a dynamic interaction between mechanical environment and plaque progression resulting in plaque heterogeneity. Our finding indicates that plaque heterogeneity is associated with plaque progression and can be combined with mechanical stresses for identifying high-risk plaques.

Is the effect of atorvastatin 60 mg on stabilization of lipid-rich plaque equivalent to that of rosuvastatin 10 mg? A serial optical coherence tomography combined with intravascular ultrasound imaging.

This study aimed to compare the effect of atorvastatin 60 (AT60) mg to that of rosuvastatin 10 (RT10) mg on the morphological changes in lipid-rich plaques (LRPs) and plaque volume, using serial optical coherence tomography (OCT) and intravascular ultrasound imaging (IVUS). Intensive lipid lowering therapy by statin provides more clinical benefit compared to that of moderate lipid lowering therapy. Fifty patients who underwent OCT and IVUS at baseline, 6, and 12 months were grouped by statin therapy into the AT60 mg (n = 27) and RT10 mg (n = 23) groups. The relationships between absolute and percentage changes in biomarkers and fibrous cap thickness (FCT) during follow-up were investigated using a simple regression analysis. At 6 months, the mean low-density lipoprotein cholesterol level reduced from 113.5 to 65.5 mg/dl (AT60 mg group) and 100.2 to 72.2 mg/dl (RT10 mg groups). A continuous increase in FCT from baseline to 12 months was observed in both groups (p < .001, p < .001, respectively). Mean lipid arc significantly decreased in both AT60 mg (189.0 ± 55.9°, 170.9 ± 60.2°, 155.6 ± 50.6°, p < .001) and RT10 mg (160.0 ± 45.6°, 151.2 ± 48.5°, 141.1 ± 52.9°, p = .010) groups. Plaque burden did not change significantly in both groups. Lipid-lowering therapy effect with AT60 mg was equivalent to that of RT10 mg in terms of change in plaque morphology. AT60 mg showed more intensive low-density lipid cholesterol level reduction compared to RT10 mg while RT10 mg was effective in increasing the high-density lipid cholesterol level. Both statin therapies could effectively stabilize LRPs.

Abstract 15245: Cd34+ Progenitor Cells in the Progression of Cardiac Allograft Vasculopathy

Introduction: CD34+ progenitor cells play a role in vascular repair and plaque stability. However, their role in cardiac allograft vasculopathy (CAV), vessel remodeling, and changes in plaque morphology is incompletely understood. Hypothesis: We hypothesized that decreased levels of baseline CD34+ progenitor cells would be associated with Intravascular Ultrasound (IVUS)-defined vulnerable plaque characteristics and CAV progression. Methods: In heart transplant patients undergoing annual IVUS, CD34+ cells were counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. Gray-scale and virtual-histology IVUS were used to evaluate vessel size, plaque burden, and plaque composition (fibrous, fibrofatty, necrotic core, calcific). Positive remodeling was defined as expansion of external elastic membrane area on follow-up. Patients were divided into two groups by the median of the change (Δ) in necrotic core volume over the subsequent 3 years. Results: A total of 55 patients (mean age 52±15 years, 65% males) were included. Median time after transplant was 4.2 years at baseline. Average vessel area at baseline and three years were 15.8±4.6 and 15.3±5.4 mm, respectively (p=0.32). Twenty-four patients (44%) who showed positive remodeling at follow-up, compared to those who did not, had lower levels of baseline CD34+ progenitor cells (absolute count per 100,000 counts, 980 [690, 1460]) vs. 665 [438, 1015], p=0.02) (Fig. 1A). Patients with greater than median (&gt;1.96 mm3) Δnecrotic core volume, as compared to those with below median Δ, also had lower baseline CD34+ cells (705 [483, 998] vs. 1180 [660, 1620] per 100,000 counts, p=0.04) (Fig. 1B). Conclusions: Lower levels of CD34+ progenitor cells are associated with long-term positive coronary vascular remodeling and increased plaque necrotic core volume in patients who underwent allograft heart transplant. This study supports the notion that circulating CD34+ progenitor cells play a role in CAV.

Ultrasound Assessment of the Relation Between Local Hemodynamic Parameters and Plaque Morphology

Mechanical factors, especially wall shear stress (WSS) and circumferential strain (CS), play an important role in the progression and rupture of atherosclerotic plaques. Previous studies have shown that the temporal phase angle between WSS and CS, referred to as the stress phase angle (SPA) may be a biomarker for plaque development and vulnerability. Since the SPA is influenced by the severity and length of the stenosis, a multifactorial relationship between local hemodynamic variables and plaque morphology can be hypothesized. However, due to ethical restrictions and the difficulty of developing animal models, there is little experimental data to support such a hypothesis about the biomarker function of SPA. In this study, a novel non-invasive ultrasound-based method for investigating the relationship between local hemodynamics and plaque morphology is developed and investigated in-vitro and in-vivo with an apolipoprotein deficient mouse model. In the in-vitro experiments, using polyvinyl alcohol cryogel (PVA-c) phantoms, we have observed that the SPA becomes more negative and the wall shear rate (WSR) rises, as the severity of the stenosis increases. Conversely, SPA becomes more positive and WSR falls with increasing plaque length. These changes in plaque morphology have little effect on CS. The in-vivo experiments show that, as the severity of the plaque increases, the SPA becomes more negative and WSR tends to more positive values; whereas, the CS drops. We conclude that these local hemodynamic parameters such as SPA, WSR and CS, as suggested by others, can be regarded as prognostic markers for the assessment of plaque vulnerability.

Coronary artery plaque growth: A two-way coupled shear stress-driven model.

Atherosclerosis in coronary arteries can lead to plaque growth, stenosis formation, and blockage of the blood flow supplying the heart tissue. Several studies have shown that hemodynamics play an important role in the growth of coronary artery plaques. Specifically, low wall shear stress (WSS) appears to be the leading hemodynamic parameter promoting atherosclerotic plaque growth, which in turn influences the blood flow and WSS distribution. Therefore, a two-way coupled interaction exists between WSS and atherosclerosis growth. In this work, a computational framework was developed to study the coupling between WSS and plaque growth in coronary arteries. Computational fluid dynamics (CFD) was used to quantify WSS distribution. Surface mesh nodes were moved in the inward normal direction according to a growth model based on WSS. After each growth stage, the geometry was updated and the CFD simulation repeated to find updated WSS values for the next growth stage. One hundred twenty growth stages were simulated in an idealized tube and an image-based left anterior descending artery. An automated framework was developed using open-source software to couple CFD simulations with growth. Changes in plaque morphology and hemodynamic patterns during different growth stages are presented. The results show larger plaque growth towards the downstream segment of the plaque, agreeing with the reported clinical observations. The developed framework could be used to establish hemodynamic-driven growth models and study the interaction between these processes.

Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation.

Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease. Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule. Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108±2.3 nm, a surface charge of -15.4±14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6±9.79 %) compared with untreated mice (30.2±13.34 %) and rapamycin alone (26.8±9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa-treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554±363.9, P=9.95122×10-6). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa-treated mice. We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.

Qualitative and quantitative evaluation of dynamic changes in non-culprit coronary atherosclerotic lesion morphology: a longitudinal OCT study.

There is limited in vivo evidence regarding the temporal evolution of non-culprit coronary plaque morphology. We aimed to evaluate changes in non-culprit plaque morphology over time by optical coherence tomography (OCT). Seventy-two (72) patients with 257 non-culprit segments with serial OCT studies were analysed. Non-culprit 5 mm-long coronary segments from the same imaged region were matched between baseline and follow-up. OCT plaque characterisation including automated attenuation analysis was performed, and changes over a median follow-up of 6.2 months were evaluated. On segment level, lumen area decreased from baseline to follow-up, whereas fibrous cap thickness increased. Similarly, plaque attenuation indices at follow-up were significantly decreased. Minimal cap thickness per patient did not change. In 68.5% of segments, plaque morphology did not change. Favourable change was observed in 18.4% of segments and unfavourable in 12.9%. There were no robust clinical predictors of change in plaque morphology. Attenuation analysis supported the qualitative characterisation, showing significantly different attenuation between different plaque types. In non-culprit coronary segments of patients with coronary artery disease under standard medical therapy, segment-level but not patient-level minimum fibrous cap thickness increases over time, with observations of both favourable and unfavourable changes in individual segments.

Repeated Measurements of Serum Concentrations of TNF-alpha, Interleukin-6, and Interleukin-10 in the Evaluation of Internal Carotid Artery Stenosis Progression

Long-term trends in serum concentrations of IL-6 and IL-10 in patients with ICA stenosis helps predict stenosis progression and unfavorable changes in plaque morphology.

Intracoronary Imaging, Cholesterol Efflux, and Transcriptomics after Intensive Statin Treatment in Diabetes

Residual atherothrombotic risk remains higher in patients with versus without diabetes mellitus (DM) despite statin therapy. The underlying mechanisms are unclear. This is a retrospective post-hoc analysis of the YELLOW II trial, comparing patients with and without DM (non-DM) who received rosuvastatin 40 mg for 8–12 weeks and underwent intracoronary multimodality imaging of an obstructive nonculprit lesion, before and after therapy. In addition, blood samples were drawn to assess cholesterol efflux capacity (CEC) and changes in gene expression in peripheral blood mononuclear cells (PBMC). There was a significant reduction in low density lipoprotein-cholesterol (LDL-C), an increase in CEC and beneficial changes in plaque morphology including increase in fibrous cap thickness and decrease in the prevalence of thin cap fibro-atheroma by optical coherence tomography in DM and non-DM patients. While differential gene expression analysis did not demonstrate differences in PBMC transcriptome between the two groups on the single-gene level, weighted gene coexpression network analysis revealed two modules of coexpressed genes associated with DM, Collagen Module and Platelet Module, related to collagen catabolism and platelet function respectively. Bayesian network analysis revealed key driver genes within these modules. These transcriptomic findings might provide potential mechanisms responsible for the higher cardiovascular risk in DM patients.

Repeated measurements of serum concentrations of TNF-alpha, interleukin-6 and interleukin-10 in the evaluation of internal carotid artery stenosis progression

Background and aimsThe inflammatory process (with TNFα, interleukin-6 and interleukin-10 involvement) plays a key role in the development, progression and destabilization of atherosclerotic plaques. The aim of this study was to assess the importance of double-checked measurements of TNFα, interleukin-6 (IL-6) and interleukin-10 (Il-10) serum levels in patients with internal carotid artery (ICA) stenosis to determine the dynamics of changes in the stenosis degree and in the ultrasound plaque morphology. MethodsThe study included 65 patients with ICA stenosis. Ultrasound of the carotid arteries was performed during qualification and every 3 months to identify any progression of stenosis degree and dynamics of changes in plaque morphology.Serum concentrations of TNF-alpha, IL-6 and IL-10 were measured during qualification and at month 6 of the study. Calculations considered cytokine concentrations and their indices determined as relative differences of cytokine levels assessed in the first and in second tests. ResultsPatients with increasing degree of ICA stenosis had higher indices of IL-6 and IL-10 than patients without any increase in the stenosis degree. In patients with unfavorable dynamics of changes in plaque morphology, significantly higher levels of interleukin-6 were found in the second test; these patients had higher indices of IL-6 and IL-10 than patients with favorable dynamics of atherosclerotic plaque morphology on ultrasound. ConclusionsLong-term trends in serum concentrations of IL-6 and IL-10 in patients with ICA stenosis allow to predict the progression of the degree of stenosis and the unfavorable change of atherosclerotic plaque morphology.

Intracoronary Imaging, Cholesterol Efflux, and Transcriptomes After Intensive Statin Treatment: The YELLOW II Study

BackgroundDespite extensive evidence demonstrating the beneficial effects of statins on clinical outcomes, the mechanisms underlying these effects remain elusive. ObjectivesThis study assessed changes in plaque morphology using intravascular imaging, with a comprehensive evaluation of cholesterol efflux capacity (CEC) and peripheral blood mononuclear cell (PBMC) transcriptomics in patients receiving high-dose statin therapy. MethodsIn a prospective study, 85 patients with stable coronary artery disease underwent percutaneous coronary intervention for a culprit lesion, followed by intracoronary multimodality imaging, including optical coherence tomography (OCT) of an obstructive nonculprit lesion. All subjects received 40 mg of rosuvastatin daily for 8 to 12 weeks, when the nonculprit lesion was reimaged and intervention performed. Blood samples were drawn at both times to assess CEC and transcriptomic profile in PBMC. ResultsBaseline OCT minimal fibrous cap thickness (FCT) was 100.9 ± 41.7 μm, which increased to 108.6 ± 39.6 μm at follow-up, and baseline CEC was 0.81 ± 0.14, which increased at follow-up to 0.84 ± 0.14 (p = 0.003). Thin-cap fibroatheroma prevalence decreased from 20.0% to 7.1% (p = 0.003). Changes in FCT were independently associated with CEC increase by multivariate analysis (β: 0.30; p = 0.01). PBMC microarray analysis detected 117 genes that were differentially expressed at follow-up compared to baseline, including genes playing key roles in cholesterol synthesis (SQLE), regulation of fatty acids unsaturation (FADS1), cellular cholesterol uptake (LDLR), efflux (ABCA1 and ABCG1), and inflammation (DHCR24). Weighted coexpression network analysis revealed unique clusters of genes associated with favorable FCT and CEC changes. ConclusionsThe study demonstrated an independent association between fibrous cap thickening and improved CEC that may contribute to morphological changes suggesting plaque stabilization among patients taking intensive statin therapy. Furthermore, the significant perturbations in PBMC transcriptome may help determine the beneficial effects of statin on plaque stabilization. (Reduction in Coronary Yellow Plaque, Lipids and Vascular Inflammation by Aggressive Lipid Lowering [YELLOW II]; NCT01837823)

The Regression of Atherosclerosis: The Power of Multimodality Imaging

Coronary artery disease remains a leading cause of death in the Western world. It is well known that the reduction of cholesterol levels by statin therapy is associated with significant decreases in plaque burden. However, a critical question has been the ability of statin therapy to lead to lipid egress from plaque and subsequent plaque stabilization. This is crucial since lipid-rich coronary plaques are at increased risk for rupture and thrombus leading to events. We recently addressed this issue by conducting the YELLOW (reduction in yellow plaque by aggressive lipid-lowering therapy) trial. We reported that short-term intensive statin therapy reduces lipid content as assessed by near infrared spectroscopy (NIRS) in obstructive lesions. Histopathological studies suggest that the majority of acute coronary events are related to occlusive thrombus formation after disruption of a thin-cap fibroatheroma (TCFA) overlying a large necrotic lipid core. Optical coherence tomography (OCT) is an imaging modality with powerful resolution to allow for plaque characterization including the identification of TCFA. Yet, it still remains unknown as to the efficacy of high dose statin therapy for enhancing anatomic features of plaque stabilization. The YELLOW II Trial was therefore designed with the goal of combining the utilization of OCT and NIRS in the coronary arteries to extend our initial findings as well as link them to changes in plaque morphology with alterations in lipoprotein biology, HDL function and macrophage behaviour.

A rabbit model of spontaneous thrombosis induced by lipopolysaccharide.

Inflammation plays a critical role in the development of atherosclerotic plaque, and lipopolysaccharide (LPS) is a potentially important source of inflammation. The aim of this study was to develop a rabbit model of spontaneous thrombosis mimicking the pathophysiological and morphological characteristics of atherosclerotic plaque in humans. The rabbits were randomized into four groups: group A (n=10) received a normal diet; group B (n=10) received a regular diet and weekly LPS injections (1 μg/kg, Escherichia coli); group C (n=15) received a cholesterol-enriched diet before and after sustaining a balloon injury to the right common carotid artery; and group D (n=15) was treated the same as group C in addition to receiving LPS injections. The morphological characteristics of the resulting lesions were evaluated using optical coherence tomography (OCT) and histology. No significant atherosclerotic plaque was observed in groups A or B. Group D exhibited a higher incidence of spontaneous luminal thrombi than group C or B (60% vs. 20% vs. 10%, p<0.05). All of the thrombi detected with OCT were confirmed on histology. A good correlation between the fibrous cap thickness and thrombus arc was obtained on OCT and the histological evaluations. A rabbit model of LPS-induced spontaneous thrombosis was developed in which OCT was used to follow changes in plaque morphology.

A Role of RIP3-Mediated Macrophage Necrosis in Atherosclerosis Development

Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3(-/-);Ldlr(-/-) mice were no different from RIP3(+/+);Ldlr(-/-) mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe(-/-) background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3(-/-);Ldlr(-/-) and RIP3(+/+);Ldlr(-/-) mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3(-/-) mice. In vitro cellular studies showed that RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.

Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype.

BackgroundVitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.Methodology/Principal FindingsA total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.Conclusions/SignificanceVKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle.