Plaque Stability In Patients Research Articles

Correlation analysis of carotid adipose tissue density and plaque stability in patients with carotid artery stenosis

Objective: To investigate the correlation between perivascular fat density (PFD) and plaque stability in patients with carotid artery stenosis. Methods: Clinical data of 110 patients with carotid artery stenosis treated at Drum Tower Hospital, Nanjing University Medical School from January 2018 to December 2022 were retrospectively collected. Based on pathological results of carotid plaque specimens obtained from carotid endarterectomy (CEA), patients were categorized into stable plaque group (n=51) and vulnerable plaque group (n=59). All patients underwent preoperative carotid CT angiography (CTA) to measure PFD at the narrowest carotid artery. Preoperative levels of interleukin-6 (IL-6) and other hematological parameters were collected. Multivariable logistic regression analysis was used to identify factors associated with plaque stability in carotid artery stenosis patients. Area under the curve (AUC) of receiver operating characteristic (ROC) was performed to evaluate the predictive value of PFD for plaque stability. Results: The stable plaque group consisted of 43 males and 8 females with a mean age of (67.6±9.0) years, while the vulnerable plaque group comprised 48 males and 11 females with a mean age of (69.3±9.0) years. The proportions of smokers were 31.4% (16/51) and 50.8% (30/59) in the stable and vulnerable plaque groups, respectively. The proportions of patients with diabetes were 33.3% (17/51) and 52.5% (31/59), respectively. IL-6 levels were 3.46(2.67, 5.34) and 4.51(3.62, 5.51) ng/L in the stable and vulnerable groups, respectively. Mean PFD values were (-69.04±5.35) and (-63.24±6.08) HU, respectively, with maximum PFD values of (-62.90±6.98) and (-56.93±5.90) HU, respectively. The differences were statistically significant (all P<0.05). Multivariable logistic regression analysis showed that increased mean PFD (OR=1.167, 95%CI: 1.029-1.324, P=0.016) and elevated IL-6 levels (OR=1.489, 95%CI: 1.151-1.926, P=0.002) were associated with vulnerability of carotid artery plaques. ROC curve analysis results showed that a cut-off value of -65.5 HU, the AUC for predicting plaque stability based on the mean PFD was 0.756 (95%CI: 0.667-0.844, P<0.001), with sensitivity of 64.4% and specificity of 74.5%. Conclusion: Increased mean PFD at the narrowest carotid artery is associated with vulnerability of plaques in patients with carotid artery stenosis.

Early and short-term use of proprotein convertase anti-subtilisin-kexin type 9 inhibitors on coronary plaque stability in acute coronary syndrome.

Proprotein convertase anti-subtilisin-kexin type 9 inhibitors (PCSK9Is) improve plaque volume and composition and reduce major adverse coronary events in chronic coronary artery disease. We evaluated the effects of the short-term use of PCSK9Is on coronary plaque stability in patients with acute coronary syndrome (ACS) using optical coherence tomography (OCT). This is a multicentre, open-label randomized controlled trial. The enrolled 80 subjects met the inclusion criteria. Of these, 52 patients (age 60 ± 11 years, 38 men, 14 women) with ST-elevated ACS had undergone successful primary percutaneous coronary intervention with LDL-cholesterol (LDL-C) levels > 70 mg/dL while receiving high-intensity statins. Participants were randomly assigned to the PCSK9I group (evolocumab 420 mg for 3 months, n = 29) or the standard of care (SoC) group (n = 23). Optical coherence tomography was performed at baseline (BL) and 3 and 9 months after randomization to assess lipid-rich plaques in non-culprit lesions. The change in the minimum fibrous cap thickness (MFCT) from BL to 9 months was the primary endpoint. The percentage change in LDL-C levels from BL to 3 months was significantly greater in the PCSK9I group (-67.8 ± 21.5% in the PCSK9I group vs. -16.3 ± 21.8% in the SoC group; P < 0.0001), and the difference between the two groups disappeared from BL to 9 months (-20.0 ± 37.8% in the PCSK9I group vs. -6.7 ± 34.2% in the SoC group; P = 0.20). The changes in MFCT from BL to 9 months were significantly greater in the PCSK9I group, even after PCSK9I discontinuation {100 μm [interquartile range (IQR): 45-180 μm] vs. 50 μm [IQR: 0-110 μm]; P = 0.032}. Combination treatment with PCSK9Is and statins resulted in more marked plaque stabilization after ACS than SoC alone, and this effect persisted for 6 months after PCSK9I discontinuation. Adage-Joto study, UMIN ID No. 26516.

Effect of Ayurveda-based Dietary Modification and Panchakarma Therapy on Plaque Stabilization in patients with coronary artery disease – A Prospective Study

Abstract Background: Lifestyle modification, particularly diet modification, has a significant impact on coronary artery disease (CAD) progression. Ayurveda, traditional Indian medical literature, provides a guide to a balanced lifestyle with detailed dietary instructions. Objective: This study was designed to evaluate the effect of the Ayurveda-based diet kit on components of atheroma plaque: calcified and soft plaque, individually. Methods: This prospective, single-arm, multicenter study was conducted in January 2021–December 2021. Patients were assessed for demographic and clinical characteristics and underwent routine 128-slice multi-detector coronary computed tomography angiography with plaque volumetric analysis for CAD diagnosis and to reflect the extent of plaque deposition at the time of recruitment (baseline) and posttherapy. Patients were prescribed appropriate Panchakarma therapy and a high protein, low carbohydrate diet plan provided with the reverse diet kit that is known to have a high oxidative radical absorption capacity (64,000 units per day). Results: Out of 280 known CAD patients, 246 patients (mean ± standard deviation: 57.63 ± 9.82 years) completed the study. The mean weight and body mass index significantly decreased poststudy intervention. The mean total cholesterol, mean serum triglycerides, and the mean low-density lipoprotein were noted to be significantly and substantially lowered. The fibrotic plaque volume, the fibrofatty plaque volume, and the overall soft plaque volume were also significantly lowered. The mean total atheroma volume (baseline: 541.33 mm3 vs. end of study: 469.57 mm3) was found to be significantly lowered. Conclusion: This study provides an objective world evidence of the effect of Ayurveda-based diet as assessed by the currently available high-end diagnostic tools.

Frequency, predictors and clinical outcomes of AMI patients with triple regression of coronary atherosclerosis: A sub-analysis of the PACMAN AMI trial

Abstract Background Recent studies have shown that coronary artery disease regression is not limited to atheroma reduction but also includes plaque stabilization in patients treated with high-intensity lipid-lowering therapy. The frequency and characteristics of patients who simultaneously show atheroma volume reduction and plaque stabilization defined as reduction in plaque lipid content and increase in fibrous cap thickness (i.e., triple regression) are unknown. Purpose This study sought to determine the percentage and determinants of both plaque volume reduction and plaque stabilization in patients with acute myocardial infarction (MI) and treated wiTh alirocumab or placebo added to high-intensity statin therapy. Methods The PACMAN-AMI trial employed serial intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography to compare the effects of alirocumab vs. placebo (1:1) in 265 patients (537 non–infarct-related coronary arteries) receiving high-intensity statin therapy. Triple regression was defined by the combined presence of reduction in percent atheroma volume (PAV), reduction in maximum lipid core burden index (maxLCBI4mm) and increase in minimal fibrous cap thickness (FCT). Clinical outcomes of patients with or without triple regression were assessed at one year follow-up. Results Overall, 199 (75.1%) patients showed PAV reduction, 180 (67.7%) maxLCBI4mm reduction and 172 (77.6%) minimal FCT increase, with a total of 84 (31.7%) patients having triple regression (40.8% in the alirocumab group vs. 23.0% in the placebo group, p=0.002). The percentage of patients with triple regression was similar among the groups with PAV reduction, maxLCBI4mm reduction or minimal FCT thickening (42%, 51% or 49%, respectively, p=0.30). Similar baseline clinical features and a higher reduction in low-density lipoprotein cholesterol (LDL-C, -27.1 [37.7 to -16.6] mg/dl, p&amp;lt;0.001) and apolipoprotein B levels (-18.5 [-26.0 to -11.0] p&amp;lt;0.001) were observed patienst with vs. without triple regression. A higher reduction in PAV (-1.54 [-2.14 to -0.95] %, p&amp;lt;0.001), maxLCBI4mm (-111.24 [-140.46 to -82.02], p&amp;lt;0.001) and a higher increase in minimal FCT (56.39 [38.67 to 74.11] µm, p&amp;lt;0.001) were found in patients with triple regression. At multivariable analysis, factors independently associated with triple regression included higher baseline maxLCBI4mm (1.03, 1.01 to 1.06, p=0.013) and alirocumab treatment (2.83, 1.57 to 5.16, p=0.001). The composite clinical endpoint of death, MI and ischemia-driven revascularization occurred less frequently in patients with versus without triple regression (8.3% vs 18.2%, p=0.042). Conclusions Triple regression occurred among one third of acute AMI patients receiving high-intensity lipid lowering therapy. Alirocumab treatment and higher baseline lipid accumulation were independent predictors of triple regression. Triple regression was associated with a reduced rate of adverse cardiovascular events.

Abstract 11734: Allopurinol &amp; Plaque Stabilization in Patients With Acute Coronary Syndrome: A Randomized Clinical Trial

Background: Allopurinol, a xanthine inhibitor that lowers uric acid (UA) concentration, has been proven to reduce inflammation and oxidative stress in patients with cardiovascular disease. However, it is unknown whether these beneficial effects translate into favorable plaque modification in acute coronary syndromes (ACS). Aims: This study aimed to investigate whether allopurinol therapy could improve plaque stabilization in ACS patients using coronary computed tomography angiography (CCTA). Methods: This was a prospective, single-center, randomized, double-blind clinical trial began in March 2019 (clinical trial.gov identifier NCT03745729). A total of 162 acute coronary syndromes (ACS) patients aged 18-80 years with a blood level of high-sensitivity C-reactive protein (hsCRP) &gt; 2 mg/L were included. The subjects were randomly assigned in a 1:1 ratio to receive either allopurinol sustained-release capsules (at a dose of 0.25 g once daily) or placebo for 12 months. The primary efficacy endpoint was the change in low-attenuation plaque volume (LAPV) from baseline to the 12-month follow-up. Results: Among 162 patients, 54 in allopurinol group and 51 in placebo group completed the study. There were no significant differences between the allopurinol and placebo groups in terms of baseline data for age (58.5±10.2 years vs. 56.8±10.0 years, P=0.392) and sex (male/female, 40/14 vs. 40/11, P=0.600). The median follow-up duration was 14 months in both groups. Compared with placebo, allopurinol therapy did not significantly alter LAPV (-13.4±3.7% vs. -17.8±3.6%, P=0.390), intermediate attenuation plaque volume (-16.1±3.0% vs. -16.2±2.9%, P=0.992), dense calcified plaque volume (12.2±13.7% vs. 9.7±13.0%, P=0.894), total atheroma volume (-15.2±3.2% vs. -16.4±3.1%, P=0.785), remodeling index (2.0±3.9% vs. 5.4±3.8%, P=0.536) or hsCRP levels (-73.6 [17.9-91.6] % vs. -81.2 [47.7-95.4] %, P=0.286). Conclusions: Our findings suggest, for the first time, that allopurinol therapy does not improve atherosclerotic plaque instability or inflammation in ACS.

High dietary inflammatory index is associated with decreased plaque stability in patients with coronary heart disease

Coronary plaque stability is a key pathological mechanism of coronary heart disease (CHD). Inflammation is recognized as a key factor of coronary plaque stability. The dietary inflammatory index (DII) is calculated from 21 dietary nutrients to predict the inflammation potential of an individual's diet. We hypothesized that high DII may be associated with decreased coronary plaque stability in CHD patients; therefore, this study aimed to evaluate the association between DII and plaque stability in patients with CHD. This cross-sectional study included 314 patients with CHD. DII was calculated based on food frequency questionnaires. Plaque stability was measured with optical coherence tomography. The DII ranged from –1.41 to 3.04. After adjusting for confounding factors, higher DII scores were associated with unstable plaque characteristics including thin-capped fibroatheroma (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.78–7.29), macrophage infiltration (OR, 2.16; 95% CI, 1.01–4.61), and plaque rupture (OR, 3.55; 95% CI, 1.73–7.29). Mediation analyses revealed that DII was important mediator of the relationship between plaque stability and food intake including soybeans and nuts, fish and shrimp, eggs (P < .05). The present study confirmed that higher DII is significantly associated with decreased plaque stability in CHD patients, suggesting an important protective role of anti-inflammatory diets in the pathogenesis of CHD.

NOX4 mRNA correlates with plaque stability in patients with carotid artery stenosis

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis.

Gene polymorphism in tissue epidermal growth factor receptor (EGFR) influences clinical and histological vulnerability of carotid plaques

IntroductionDifferent models have been proposed for the prediction of the risk/benefit ratio of surgery in patients with carotid atheromasic disease, mainly based on clinical patients’ characteristics and risk factors, but no definite biological markers predictive of plaque instability and disease evolution have emerged so far, able to help the surgeon in the choice and timing of treatment. The main purpose of the present study was to assess the role of the polymorphism for genes commonly implicated in cell proliferation and neoangiogenesis in the clinical and histopathological carotid plaque vulnerability. Materials and methodsWe retrospectively studied 29 consecutive patients who underwent carotid endarterectomy in 6 months. All histological variables were collected, as well as patients’ cardiovascular risk factors, clinical presentation, and brain computed tomography (CT) for the presence of ischemic lesions. Next-Generation Sequencing (NGS) was performed on 10-µm FFPE sections by means of a multi-gene panel used for sequencing 343 amplicons in 28 genes. ResultsAmong the gene variants observed, the polymorphism p.(Gln787=) in the EGFR gene was inversely correlated with intraplaque hemorrhage (p = 0.014), but also with the presence of ischemic brain lesions at CT (p = 0.001). Also p.(Gly105=) polymorphism in the IDH1 gene was inversely correlated with the presence of ischemic brain lesions (p = 0.038). ConclusionsThe variant p.(Gln787=) in the EGFR gene seems to play a role in plaque stability in patients with carotid atheromasic disease, on both histopathological and clinical grounds, probably acting on plaque matrix remodeling. This can open new scenarios on the pre-surgical management of these patients.

Low-dose colchicine after MI reduced a composite ischemic cardiovascular outcome vs placebo.

ACP Journal Club21 April 2020Low-dose colchicine after MI reduced a composite ischemic cardiovascular outcome vs placeboRichard G. Bach, MDRichard G. Bach, MDWashington University School of Medicine, St. Louis, Missouri, USA (R.G.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ202004210-039 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationTardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381:2497-2505. https://pubmed.ncbi.nlm.nih.gov/31733140Clinical Impact RatingsGIM/FP/GP: Cardiology: References1 Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97. [PMID: 26039521] Google Scholar2 Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61:404-10. [PMID: 23265346] Google Scholar3 Deftereos S, Giannopoulos G, Angelidis C, et al. Anti-Inflammatory treatment with colchicine in acute myocardial infarction: a pilot study. Circulation. 2015;132:1395-403. [PMID: 26265659] Google Scholar4 Vaidya K, Arnott C, Martínez GJ, et al. Colchicine therapy and plaque stabilization in patients with acute coronary syndrome: a CT coronary angiography study. JACC Cardiovasc Imaging. 2018;11:305-16. [PMID: 29055633] Google Scholar5 Verma S, Eikelboom JW, Nidorf SM, et al. Colchicine in cardiac disease: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2015;15:96. [PMID: 26318871] Google Scholar Author, Article, and Disclosure InformationAffiliations: Washington University School of Medicine, St. Louis, Missouri, USA (R.G.B.)Disclosures: The commentator has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-3041.This article was published at Annals.org on 7 April 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 21 April 2020Volume 172, Issue 8Page: JC39KeywordsAcute coronary syndromeAnginaColchicineCoronary arteriesCoronary revascularizationHospitalizationsMyocardial infarctionStable coronary artery diseaseStrokeTreatment guidelines ePublished: 21 April 2020 Issue Published: 21 April 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

High-density lipoprotein cholesterol as a therapeutic target for residual risk in patients with acute coronary syndrome.

ObjectiveThe current guideline recommends lowering low-density lipoprotein cholesterol (LDL-C) for the primary management of dyslipidemia in patients at high-risk of cardiovascular events. Patients who have achieved LDL-C levels below the recommended targets may still experience cardiovascular events, suggesting additional therapeutic targets beyond LDL-C. The aim of this study was to investigate whether high-density lipoprotein cholesterol (HDL-C) levels had an impact on plaque stabilization in patients with acute coronary syndrome (ACS).MethodsThis study consisted of 90 ACS patients with untreated dyslipidemia. In optical coherence tomography (OCT) analysis, a plaque with fibrous cap thickness ≦160 μm was defined as a high-risk plaque. We registered one high-risk plaque per one patient by baseline OCT imaging, and then administrated high-intensity statin. Based on the follow-up OCT results, patients whose registered plaque was no longer high-risk plaque were classified into a responder group and the remains into a non-responder group.ResultsNo differences were observed in the baseline LDL-C and HDL-C levels between the two groups. Reduction of LDL-C levels (δ LDL-C: −53 ± 21 mg/dL vs. −42 ± 29 mg/dL, p = 0.036) and increase of HDL-C levels (δ HDL-C: 2.5 ± 5.9 mg/dL vs. −0.3 ± 6.7 mg/dL, p = 0.039) were greater in the responder group. On multivariate logistic regression analysis, δ LDL-C levels (OR: 0.956, 95% CI: 0.921–0.993; p = 0.020) and δ HDL-C levels (OR: 1.143; 95% CI: 1.005–1.300, p = 0.041) were independent contributors for plaque stabilization.ConclusionsIncrease of HDL-C levels is associated with plaque stabilization in patients with ACS. HDL-C could be a therapeutic target for residual risk management.

Abstract 338: Statin Therapy is Associated with Decreased Plaque Instability in Symptomatic Carotid Atherosclerotic Plaque: a Clinicopathological Analysis

Background: Statin therapy has been shown to deplete atherosclerotic plaque instability in human carotid arteries by various imaging modalities or in animal models by pathological analysis. However, whether statin therapy attenuates plaque instability in human carotid plaque has not been fully described in a pathological analysis. The aim of this study was to analyze pathologically the possible relationships between statin therapy and plaque stability in patients undergoing carotid endarterectomy (CEA). Methods: Among consecutive 79 patients with advanced carotid artery stenosis (&gt;70%) between May 2015 and February 2017, 66 patients without statin therapy (group 1) and 13 patients with statin therapy (group 2) were analyzed. The specimens were stained with hematoxylin/eosin and elastica-Masson. Immunohistochemistry was performed, using an endothelial specific antibody to CD31, CD34 and PDGFRβ. Results: Plaques from group 2 had significantly less plaque rupture (P=0.009), lumen thrombus (P=0.009), inflammatory cells (P=0.008), intraplaque hemorrhage (P=0.030) and intraplaque microvessels (P&lt;0.001), compared with those from group 1. Among stroke patients with infarct size &gt;1.0 cm 3 in MRI, the mean infarct volume in group 2 (4.2 ± 2.5 cm 3 ) was significantly smaller than that in group 1 (8.2 ± 7.1 cm 3 , p = 0.031). There was no significant difference in the mean concentration of low-density lipoprotein cholesterol between group 1 and group 2 (121 ± 32 mg/dl vs. 105 ± 37 mg/dl, P=0.118). Conclusions: This clinicopathological analysis of carotid atherosclerotic plaque suggests that statin therapy is associated with decreased plaque instability, which might result in smaller infarct volume in stroke patients undergoing CEA. This plaque stability might be derived from pleiotropic effect beyond lipid lowering of statin therapy.

Colchicine Therapy and Plaque Stabilization in Patients With Acute Coronary Syndrome: A CT Coronary Angiography Study

ObjectivesThe authors sought to evaluate the plaque-modifying effects of low-dose colchicine therapy plus optimal medical therapy (OMT) in patients post-acute coronary syndrome (ACS), as assessed by coronary computed tomography angiography (coronary CTA). BackgroundColchicine therapy has been postulated to have beneficial anti-inflammatory effects in patients with ACS, translating into reduction in future adverse cardiovascular events. However, whether favorable plaque modification underpins this is yet unproven. MethodsIn this prospective nonrandomized observational study of 80 patients with recent ACS (<1 month), patients received either 0.5 mg/day colchicine plus OMT or OMT alone and were followed for 1 year. Our primary outcome was change in low attenuation plaque volume (LAPV), a marker of plaque instability on coronary CTA and robust predictor of adverse cardiovascular events. Secondary outcomes were changes in other coronary CTA measures and in high-sensitivity C-reactive protein (hsCRP). ResultsMean duration of follow-up was 12.6 months; mean age was 57.4 years. Colchicine therapy significantly reduced LAPV (mean 15.9 mm3 [−40.9%] vs. 6.6 mm3 [−17.0%]; p = 0.008) and hsCRP (mean 1.10 mg/l [−37.3%] vs. 0.38 mg/l [−14.6%]; p < 0.001) versus controls. Reductions in total atheroma volume (mean 42.3 mm3 vs. 26.4 mm3; p = 0.28) and low-density lipoprotein levels (mean 0.44 mmol/l vs. 0.49 mmol/l; p = 0.21) were comparable in both groups. With multivariate linear regression, colchicine therapy remained significantly associated with greater reduction in LAPV (p = 0.039) and hsCRP (p = 0.004). There was also a significant linear association (p < 0.001) and strong positive correlation (r = 0.578) between change in LAPV and hsCRP. ConclusionsOur findings suggest, for the first time, that low-dose colchicine therapy favorably modifies coronary plaque, independent of high-dose statin intensification therapy and substantial low-density lipoprotein reduction. The improvements in plaque morphology are likely driven by the anti-inflammatory properties of colchicine, as demonstrated by reductions in hsCRP, rather than changes in lipoproteins. Colchicine may be beneficial as an additional secondary prevention agent in patients post-ACS if validated in future studies.

Circulation Research “In This Issue” Anthology

Circulation Research “In This Issue” Anthology

Cytochrome P450 Genetic Variants and Their Metabolite Levels Associated with Plaque Stability in Patients with Ischemic Stroke.

Cytochrome P450s (CYP450) enzymes regulate inflammation and atherosclerosis and can affect carotid plaque stability in patients with ischemic stroke (IS). This study aimed to investigate the association of CYP450 genetic variants with CYP plasma metabolite levels and plaque stability in patients with IS. Eleven single nucleotide polymorphisms (SNPs) of CYP genes and their plasma metabolite [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] levels were measured in 396 patients with IS who underwent high-resolution B-mode ultrasound carotid plaque detection and were stratified into the following groups: non-carotid plaque and carotid plaque groups. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP). Among the 396 patients with IS, 294 cases (74%) had plaques. The frequency of rs17110453CC, rs751141 GG, and rs9333025 GG genotypes was significantly higher in patients with plaque than those without plaque. The CC, GG, GG, and GG genotypes of rs17110453, rs776746, rs751141, and rs9333025 polymorphisms were independently associated with ELP (OR, 2.62 [1.34-5.26]; OR, 1.89 [1.16-3.58]; OR, 3.12 [1.27-7.13]; and OR, 2.06 [1.34-6.33], respectively). These polymorphisms were also associated with CYP plasma metabolite levels. Patients with ELP have also shown significantly higher levels of 20-HETE and DiHETEs, but lower levels of EETs. Our data demonstrates that CYP450 SNPs are associated with plasma CYP450 metabolite levels and echolucent plaques, indicating that these SNPs may be potential markers for plaque instability.

TCT-313 DNA repair activity determines atherosclerotic plaque stability in patients with stable coronary artery disease

Despite advances in therapeutic strategies, atherosclerotic coronary artery disease (CAD) remains the commonest worldwide cause of morbidity and mortality. DNA damage and repair have been identified as important in atherogenesis. DNA ligase is crucial in single/double stranded DNA break repair by

In This Issue

HomeCirculation ResearchVol. 116, No. 5In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published27 Feb 2015https://doi.org/10.1161/RES.0000000000000050Circulation Research. 2015;116:763Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis (p 789)Sortilin protein drives cholesterol uptake in macrophages and promotes atherosclerosis, report Patel et al.Download figureDownload PowerPointA characteristic feature of atherosclerosis is the formation of foam cells that arise from cholesterol-loaded macrophages. But exactly how macrophages take up cholesterol from transporter proteins such as low-density lipoprotein (LDL) is unclear, especially since the deletion of known macrophage lipoprotein receptors in mice does not prevent foam cell formation. Patel and colleagues thus turned their attention to a protein called sortilin. This protein mediates hepatic LDL uptake and, through genome-wide association studies, has been linked with coronary artery disease. The function of sortilin in macrophages, however, was unknown. The team found that atherosclerosis-prone mice lacking sortilin—either in all cells or just macrophages—showed a significant reduction in the number of atherolsclerotic lesions compared to mice with normal levels of the protein. They also discovered that sortilin-lacking macrophages exhibited a reduction in LDL uptake, while macrophages that over-expressed sortilin actually increased their LDL uptake. These results suggest that preventing the sortilin-driven uptake of LDL in macrophages might reduce foam cell formation and thus be a novel strategy for treating, and perhaps even preventing, atherosclerosis in the future.Transcriptional reversion of cardiomyocyte fate during mammalian cardiac regeneration (p 804)O’Meara et al describe the transcriptional signature of mammalian heart regeneration.Download figureDownload PowerPointThe adult mammalian heart has a limited capacity for regeneration. In contrast, neonatal mice, within the first week of life, can completely repair their hearts after injury. During this regeneration, neonatal heart cells lose their sarcomeric structures, adopt a less-differentiated state, and reenter the cell cycle. If this same regenerative process could be recapitulated in the adult hearts, full recovery from myocardial injury might be possible. Hence to understand the mechanism underlying the regenerative capacity of the neonatal heart, O’Meara and colleagues examined changes in the global gene expression profiles of the neonatal heart after injury and during regeneration. They also studied the expression profiles of normal neonatal and adult cardiomyocytes, mouse embryonic stem cells during differentiation into cardiomyocytes, and adult cardiomyocytes induced to de-differentiate. After cross-referencing these data, the team identified a reference panel of genes involved in the differentiation and regeneration of a normal heart. They found that injury to the neonatal heart essentially reversed the differentiation process such that seven days post-injury the genes encoding sarcomeric proteins were reduced, while the expression of cell cycle genes was elevated. The team highlighted IL-13, STAT3 and STAT6 as regulators of cell cycle re-entry, but their results provide a large number of additional candidates that could be examined in future regeneration studies.Effects of DNA damage in smooth muscle cells in atherosclerosis (p 816)DNA damage promotes atherosclerotic plaque instability report Gray et al.Download figureDownload PowerPointDNA damage occurs in the vascular smooth muscle cells (VSMCs) of atherosclerotic plaques and it becomes more pervasive with disease progression. But whether such damage is a cause or consequence of the condition is unclear. It is known that DNA damage reduces cell proliferation—because cells stop cycling to repair the DNA, and this could arguably slow down plaque growth. If, however, the damage is severe, senescence and apoptosis can occur, which induces proinflammatory cytokine production and immune cell recruitment, thus exacerbating plaque growth. To better define the relationship between plaque growth and DNA damage, Gray and colleagues studied the effects of accelerating or inhibiting DNA repair in human VSMC from normal aorta and atherosclerotic plaques. As expected, they found that VSMCs from plaques had significantly higher levels of DNA damage as well as increased activation of DNA repair pathways. By accelerating this repair in a mouse model of atherosclerosis, they found that while plaque size remained the same, there was an increase in the stability of the fibrous caps of the plaques. Inhibiting repair, on the other hand, promoted plaque instability. Because unstable plaques are associated with a greater risk of myocardial infarction and stroke, preventing DNA damage, or promoting DNA repair could be a novel therapeutic strategy for enhancing plaque stability in patients with atherosclerotic disease. Previous Back to top Next FiguresReferencesRelatedDetails February 27, 2015Vol 116, Issue 5 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000050 Originally publishedFebruary 27, 2015 PDF download Advertisement

Relationship between lysophosphatidic acid and matrix metalloproteinase-9 plasma concentrations and carotid atheromatous plaque stability in patients with cerebral infarction

To investigate the correlation between plasma lysophosphatidic acid (LPA), matrix metalloproteinase (MMP)-9 and carotid atheromatous plaque stability in patients with cerebral infarction. Patients with cerebral infarction underwent carotid artery duplex ultrasonography and transcranial Doppler monitoring for detection of microemboli. Patients were stratified by plaque type (no plaque, intima thickening, unstable plaque, stable plaque) and presence or absence of micoremboli. Plasma LPA and MMP-9 were quantified. LPA and MMP-9 concentrations were significantly higher and microemboli positivity was significantly more common in patients with unstable plaque (n = 21) than the other three groups (intima thickening, n = 16; stable plaque n = 41; no plaque; n = 12). There was a significant positive correlation between LPA and MMP-9 concentrations. Plasma LPA and MMP-9 concentrations may be useful biomarkers in the clinical identification and prediction of unstable plaque, and in guiding treatment.

The additional effect of Eicosapentanoic acid on coronary plaque stability in stable angina patients with statin use by Optical Coherence Tomography analysis

Purpose: Statin treatment is demonstrated to reduce cardiovascular events. However, even intensive statin treatment remains residual coronary risk. Eicosapentanoic Acid (EPA)has promising benefits for second prevention. The aim of this study is to access the additional effect of EPA on coronary plaque stability in patients with statin use by using Optical Coherence Tomography (OCT). Methods: Consecutive 14 patients who had received statin treatment before the past 6 month at baseline study with lipid-rich plaques on non-culprit lesion by OCT analysis were enrolled in this study. Of these,9 patients (10 lesions) received with EPA 1800mg/day after baseline study and 5 patients (5 lesions) with control group were assigned randomly. We measured thinnest Fibrous Cap Thickness (FCT) and the arc of lipid plaque at baseline and 9 month follow-up. Results: The change of Serum Eicosapentanoic Acid/Arachidonic acid (EPA/AA) ratio were 0.31±1.08 at baseline, 1.08±0.38 at 9 month in EPA group (p=0.0001) and 0.24±0.13, 0.26±0.16 in control group (p=0.63) respectively. Patients with both of groups had significantly thick FCT (140±48.3μm, 246±80.4μm, p=0.0004 in EPA group and 152±26.8μm, 178±19.2μm, p= 0.04, in control group), however the difference in the change of FCT was highly significant in EPA group (106±19.2μm vs. 26±9.2μm, p=0.0003).The change of the arc of lipid plaque also reduced significantly in EPA group compared to control group (-40.0±11.5° vs. -4.0±5.48°, p=0.0074). Table 1. Serum EPA/AA and OCT analysis Conclusion: Additional EPA treatment was effective on coronary plaque stabilization with increasing fibrous cap thickness and decreasing the arc of lipid plaque.

Assessment of the Genetic Effects of Polymorphisms in the Osteoprotegerin Gene, TNFRSF11B, on Serum Osteoprotegerin Levels and Carotid Plaque Vulnerability

Osteoprotegerin (OPG) is a secretory glycoprotein which belongs to the tumor necrosis factor receptor family. Various mechanisms have been suggested by which calcification might alter atherosclerotic plaque stability, but the significance of this intimal calcification is controversial. High concentrations of OPG have been associated with the presence of vascular and cardiovascular diseases. This study was designed to assess the association between gene polymorphisms of the OPG gene (TNFRSF11B), the serum OPG level, and plaque stability in patients with carotid atherosclerosis. We studied 177 patients with internal carotid artery stenosis who underwent carotid endarterectomy and also 303 controls. Carotid endarterectomy samples removed from patients were assessed by immunohistochemistry. Concentrations of OPG were measured and gene polymorphisms were examined by polymerase chain reaction and restriction enzyme analysis and were compared, initially between patients with carotid atherosclerosis and controls, and subsequently between stable and unstable carotid plaques. We found that the GG genotype of the T245G polymorphism, the CC genotype of the T950C polymorphism, and the CC genotype of the G1181C polymorphism were significantly higher in patients with carotid plaque than in controls (21.5% versus 10.9% , P<0.01; 15.8% versus 7.6%, P<0.01; and 20.3% versus 10.9%, P<0.01, respectively) and that these polymorphisms were associated with high serum OPG levels (4.02 [3.07] versus 2.94 [1.81] pmol/L; P<0.01), which were significantly higher in patients with unstable atherosclerotic plaques (5.86 [4.02] versus 3.53 [1.87] pmol/L; P<0.01). The TNFRSF11B gene polymorphisms studied are associated with high serum OPG levels and might be potential markers for plaque instability.

Soluble CD36 in Plasma Is Increased in Patients With Symptomatic Atherosclerotic Carotid Plaques and Is Related to Plaque Instability

The risk for cardiovascular events is related to the composition and stability of an atherosclerotic plaque driven by inflammation and deposition of lipids. Scavenger receptors are a family of cell surface receptors involved in lipid uptake and inflammation. Recently, we found that soluble CD36 is increased in plasma from patients with diabetes strongly correlated with insulin resistance. We tested whether soluble CD36 is a marker of plaque stability in patients with high-grade internal carotid stenoses (n=62). The patients were classified according to plaque symptomatology and plaque echogenicity on ultrasound examination. When patients were divided into 3 groups according to the latest clinical symptoms from plaques (ie, symptoms within the last 2 months [n=16], symptoms within the last 2 to 6 months [n=15], or asymptomatic [n=31]), the former group had significantly raised plasma levels of soluble CD36 as compared with the other 2 groups. In contrast, we found no differences in plasma levels of C-reactive protein, beta-thromboglobulin, lipid parameters, or HbA1C between these groups. The patients with echolucent carotid plaques (n=20) tended to have higher soluble CD36 levels in plasma compared with those with echogenic/heterogenic plaque (n=39; P=0.087). By immunohistochemistry, CD36 was localized to macrophages-rich area of intima within the atherosclerotic lesion. We propose that sCD36 may be a marker of plaque instability and symptomatic carotid atherosclerosis, possibly at least partly as a result of CD36 release to the circulation from the foam cells within the atherosclerotic lesion.