Development Of High-risk Plaques Research Articles

Significance of Intra-plaque Hemorrhage for the Development of High-Risk Vulnerable Plaque: Current Understanding from Basic to Clinical Points of View.

Acute coronary syndromes due to atherosclerotic coronary artery disease are a leading cause of morbidity and mortality worldwide. Intra-plaque hemorrhage (IPH), caused by disruption of intra-plaque leaky microvessels, is one of the major contributors of plaque progression, causing a sudden increase in plaque volume and eventually plaque destabilization. IPH and its healing processes are highly complex biological events that involve interactions between multiple types of cells in the plaque, including erythrocyte, macrophages, vascular endothelial cells and vascular smooth muscle cells. Recent investigations have unveiled detailed molecular mechanisms by which IPH leads the development of high-risk "vulnerable" plaque. Current advances in clinical diagnostic imaging modalities, such as magnetic resonance image and intra-coronary optical coherence tomography, increasingly allow us to identify IPH in vivo. To date, retrospective and prospective clinical trials have revealed the significance of IPH as detected by various imaging modalities as a reliable prognostic indicator of high-risk plaque. In this review article, we discuss recent advances in our understanding for the significance of IPH on the development of high-risk plaque from basic to clinical points of view.

Carotid Artery Tortuosity and Internal Carotid Artery Plaque Composition.

Little is known about the association between carotid artery tortuosity and internal carotid artery atherosclerosis. This study sought to evaluate the associations between various types of arterial tortuosity and vulnerable plaque components on magnetic resonance angiography (MRA). Aretrospective review was completed of 102patients who had undergone MRA neck imaging, with intraplaque hemorrhage (IPH) present in one or both cervical internal carotid arteries (ICA). Each ICA was assessed for two categories of tortuosity: variant arterial pathway(s) (retrojugular and/or retropharyngeal) and abnormal curvature (kinks, loops, and/or coils). All ICA plaques were assessed for the presence or absence of intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), ulceration, and enhancement, as well as the volume of IPH and degree of luminal stenosis. The mean age of included patients was 73.5years (SD = 9.0 years) and 88 (86.3%) subjects were male. The left carotid plaque was significantly more likely to have IPH (68.6% vs. 47.1%; p = 0.02). The left ICA was more likely to have aretrojugular course (22% vs. 9.9%; p = 0.002) and any variant arterial course (26.5% versus 14.67%, p = 0.01). On the right there was an association between the presence of aLRNC and retropharyngeal and/or retrojugular arterial pathway (p = 0.03). On the left there was an association between the presence of any abnormal arterial curvature and IPH volume (p = 0.03). Neither association met the adjusted statistical threshold after Bonferroni correction, with alpha set at 0.0028. ICA tortuosity is not associated with carotid artery plaque composition, and likely does not play arole in the development of high-risk plaques.

P126 THE DANGEROUS LINK BETWEEN ECTOPIC ADIPOSITY AND HIGH RISK ATHEROSCLEROSIS: A PARADIGMATIC CASE OF STEMI

Abstract Nowadays CCTA has become the first line diagnostic tool in the clinical management of CAD thanks to its outstanding performance in assessing both the degree of stenosis and coronary plaques features, with crucial prognostic implications. Furthermore, CTCA allows an accurate quantification of epicardial fat, which has been shown to be a metabolic active tissue that by means of inflammatory mediators influences the development of high risk plaques and atrial fibrillation. A 70–years–old man underwent primary PCI for an acute STEMI. He was a former smoker with a history of obesity, hypertension, hypercholesterolemia and type II diabetes, without previous major cardiovascular events or significant comorbidities. The coronary angiography revealed diffuse coronary artery ectasia and a thrombotic total occlusion of the proximal portion of the RCA. After intravenous antiplatelet agent administration, balloon angioplasty was performed and three drug eluting stents were implanted. Furthermore, since the coronary angiography showed a calcific contour travelling parallel to the RCA course, in order to rule out a thrombosed coronary pseudoaneurysm, a CTCA was performed. CTCA unexpectedly revealed an enormous fibro–fatty plaque surrounded by a calcific shell in the RCA ostium–proximal segment, with the stents located at one border of the plaque, well expanded inside the vessel lumen. The post–procedural hospital stay was marked by new onset Atrial Fibrillation, unresponsive to pharmacological cardioversion. In contrast with coronary invasive angiography, CT was able to detect a very high plaque burden and a salient ubiquitary epicardial fat volume. In addition, at the site of the culprit lesion, CT showed huge plaque volume with an extreme eccentrically positive vessel remodeling, large low attenuation areas and spotty calcifications, all features known to predict adverse coronary events. This case shows how the combination of metabolic syndrome and ectopic fat accumulation fosters a milieu conducive for high risk atherosclerosis and its clinical complications.

Sex Differences in Compositional Plaque Volume Progression in Patients With Coronary Artery Disease

ObjectivesThis study sought to explore sex-based differences in total and compositional plaque volume (PV) progression. BackgroundIt is unclear whether sex has an impact on PV progression in patients with coronary artery disease (CAD). MethodsThe study analyzed a prospective multinational registry of consecutive patients with suspected CAD who underwent 2 or more clinically indicated coronary computed tomography angiography (CTA) at ≥2-year intervals. Total and compositional PV at baseline and follow-up were quantitatively analyzed and normalized using the analyzed total vessel length. Multivariate linear regression models were constructed. ResultsOf the 1,255 patients included (median coronary CTA interval 3.8 years), 543 were women and 712 were men. Women were older (62 ± 9 years of age vs. 59 ± 9 years of age; p < 0.001) and had higher total cholesterol levels (195 ± 41 mg/dl vs. 187 ± 39 mg/dl; p = 0.002). Prevalence of hypertension, diabetes, and family history of CAD were not different (all p > 0.05). At baseline, men possessed greater total PV (31.3 mm3 [interquartile range (IQR): 0 to 121.8 mm3] vs. 56.7 mm3 [IQR: 6.8 to 152.1 mm3] p = 0.005), and there was an approximately 9-year delay in women in developing total PV than in men. The prevalence of high-risk plaques was greater in men than women (31% vs. 20%; p < 0.001). In multivariate analysis, after adjusting for age, clinical risk factors, medication use, and total PV at baseline, despite similar total PV progression rates, female sex was associated with greater calcified PV progression (β = 2.83; p = 0.004) but slower noncalcified PV progression (β = –3.39; p = 0.008) and less development of high-risk plaques (β = –0.18; p = 0.049) than in men. ConclusionsThe compositional PV progression differed according to sex, suggesting that comprehensive plaque evaluation may contribute to further refining of risk stratification according to sex. (NCT02803411).

P4389Effect of cigarette smoking on carotid artery atherosclerosis: a community-based cohort study

Abstract Background Cigarette smoking is closely associated with the development of cardiovascular diseases (CVD), and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend smoking bans.On the other hand, the relationship between cigarette smoking and subclinical atherosclerosis has not been fully studied. Carotid intima-media thickness (cIMT) is commonly used as a subclinical atherosclerosis marker, and a carotid plaque feature is also known to be an important predictor of cardiovascular diseases. Purpose We sought to clarify the association between cigarette smoking and subclinical atherosclerosis by evaluating carotid plaque including cIMT and carotid plaque features in general population. Methods and results Among 1,209 participants with no prior coronary artery disease who received a medical check-up with cardiovascular examination at our institution, 450 participants (37.2%) were smokers (including both past and current smokers). We defined carotid plaque as cIMT ≥1.1 mm and high-risk plaque as carotid plaque with hypoechoic dominant and/or plaque ulceration. The value of cIMT and the rate of carotid plaque were not different between smokers and never smokers (Figure A &amp; B). However, the rate of carotid high-risk plaque was significantly higher in participants with smokers than those with never smokers (29.7%, vs 23.5%, p=0.011) (Figure C). Even after adjustment with covariates including age, gender and traditional cardiovascular risk factors, cigarette smoking was independently associated with high-risk plaque formation (odds ratio 1.384, 95% CI 1.020–1.877; p=0.037). According to the subgroup analysis classified by age, cigarette smoking was associated with not only the development of high-risk plaque but also the increased value of cIMT in the subgroup over 60 years old, whereas only the rate of high-risk plaque was higher in smokers than never smokers in the subgroup under 60 years old. Carotid plaque and smoking Conclusion The development of high-risk carotid artery plaque may precede thickening of cIMT in cigarette smokers, suggesting that the novel insight for the pathological mechanism underlying cardiovascular events and cigarette smoking.

P6165Sex differences in compositional plaque volume progression in patients with stable coronary artery disease: observations from a serial CCTA registry

Abstract Background It is unclear whether sex impacts the plaque volume (PV) progression in patients with stable coronary artery disease (CAD). Purpose To explore whether the total and compositional PV progression rate differ according to sex. Methods We performed a prospective multinational registry of consecutive patients who underwent serial CCTA at ≥2-year interval. Total and compositional PV at baseline and follow-up were quantitatively analysed and normalized using the analysed total vessel length. Multivariate linear regression models were constructed for each women and men. Results Of the 1,255 patients included (median CT interval 3.8 years), 543 were women and 712 were men. Women were older (62±9 years vs. 59±9 years, p&lt;0.001) and had higher total cholesterol level (195±41mg/dL vs. 187±39mg/dL, p=0.002). Prevalence of hypertension, diabetes, and family history of CAD were not different (all p&gt;0.05). At baseline, men possessed greater total PV (131.5±230.5mm3 vs. 97.7±193.6mm3, p=0.005) and a higher prevalence of high-risk plaques (HRP) than women (31% vs. 20%, p&lt;0.001). Annual total PV progression rate was greater in men, driven by the greater non-calcified PV progression (TABLE). In multivariate analysis (TABLE), although total PV progression rate was not different, women were associated with greater calcified PV progression (β=2.83, p=0.004) but slower non-calcified PV progression (β=-3.39, p=0.008) and less development of HRP (β=-0.18, p=0.049) than men. CCTA findings according to sex Univariate analysis Female Sex in Multivariable Analysis Women (n=543) Men (n=712) P β SE P Agatston CACS, /year 0.44±0.7 0.4±0.7 0.332 0.106 0.04 0.006 Total PVnormalized, mm3/year 14.7±23.4 17.8±26.2 0.026 -0.56 1.33 0.677 Calcified PVnormalized, mm3/year 10.5±21.5 10.0±19.1 0.670 2.83 0.98 0.004 Non-calcified PVnormalized, mm3/year 4.2±17.3 7.8±21.2 0.001 -3.39 1.28 0.008 Development of high-risk plaque*, n (%) 86 (15.8) 139 (19.5) 0.092 -0.18 0.09 0.049 In linear multivariate regression analysis adjusted with age, race, HTN, DM, family history, smoking, LDL, statin, anti-platelets, beta-blockers, and PV at baseline, women were associated with greater calcified PV progression and slower non-calcified PV progression. (High-risk plaque was defined as ≥2 of low-attenuation plaque, spotty calcification, and positive remodelling.) Conclusion In this large CCTA cohort, we found that the compositional PV progression differs according to sex. These findings, which are hypothesis generating, suggest that comprehensive plaque evaluation may contribute to further refine risk stratification according to sex. Acknowledgement/Funding This work was supported by the National Research Foundation of Korea funded by the Ministry of Science and ICT (Grant No. 2012027176).

PM2.5 concentration in the ambient air is a risk factor for the development of high-risk coronary plaques.

We aimed to investigate whether long-term exposure to particulate matter with an aerodynamic diameter <2.5 μm (PM2.5) in the ambient air is related to the development or growth of coronary plaques. This study involved 364 residents of Seoul, Korea, who underwent serial coronary computed tomographic angiography (CCTA) at an interval of ≥2 years. Each participant's average concentration of residential PM2.5 between the two CCTAs was calculated. Primary endpoint was the development of high-risk plaque (HRP), defined as a plaque with low attenuation, spotty calcium, and positive remodelling. Secondary endpoints were the volume increase of total plaque and its component volume. Among those without HRP at baseline (n = 341), 20 patients developed HRP at follow-up CCTA, the residential PM2.5 concentration of which was significantly higher than those without HRP at follow-up (25.8 ± 2.0 vs. 25.0 ± 1.7 μg/m3 for patients with newly developed HRP vs. patients without HRP at follow-up; P = 0.047). An increase in PM2.5 concentration was associated with increased incidence of HRP at follow-up [adjusted hazard ratio (aHR) 1.62, 95% confidence interval (CI) 1.22-2.15, P < 0.001]. In a secondary analysis, the PM2.5 concentration was associated with an increased risk of the formation of either fibrofatty or necrotic core component in newly developed plaques (aHR 1.41, 95% CI 1.23-1.61, P < 0.001), and with a higher risk of total plaque volume progression in the pre-existing plaques (aHR 1.14, 95% CI 1.05-1.23, P = 0.002). Exposure to higher concentration of PM2.5 in the ambient air is significantly associated with the development of high-risk coronary plaques.

Multi-analyte profiling in human carotid atherosclerosis uncovers pro-inflammatory macrophage programming in plaques.

Molecular characterisation of vulnerable atherosclerosis is necessary for targeting functional imaging and plaque-stabilising therapeutics. Inflammation has been linked to atherogenesis and the development of high-risk plaques. We set to quantify cytokine, chemokine and matrix metalloproteinase (MMP) protein production in cells derived from carotid plaques to map the inflammatory milieu responsible for instability. Carotid endarterectomies from carefully characterised symptomatic (n=35) and asymptomatic (n=32) patients were enzymatically dissociated producing mixed cell type atheroma cell suspensions which were cultured for 24 hours. Supernatants were interrogated for 45 analytes using the Luminex 100 platform. Twenty-nine of the 45 analytes were reproducibly detectable in the majority of donors. The in vitro production of a specific network of mediators was found to be significantly higher in symptomatic than asymptomatic plaques, including: tumour necrosis factor α, interleukin (IL) 1β, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), CCL5, CCL20, CXCL9, matrix metalloproteinase (MMP)-3 and MMP-9. Ingenuity pathway analysis of differentially expressed analytes between symptomatic and asymptomatic patients identified a number of key biological pathways (p< 10(-25)). In conclusion, the carotid artery plaque culprit of ischaemic neurological symptoms is characterised by an inflammatory milieu favouring inflammatory cell recruitment and pro-inflammatory macrophage polarisation.

Abstract 512: Infiltrating CD4 Positive T cells may Support an Angiogenic Switch in Human Coronary Atheroma

Background: Pathologic angiogenesis has been implicated in the development of high-risk plaques where nascent immature leaky vessels become the primary source of intraplaque hemorrhage contributing to necrotic core expansion. The stage of lesion progression, however, favoring an angiogenic response has not been identified. Methods and Results: Multiple coronary lesions collected from 73 sudden coronary death victims at autopsy were examined. Plaque morphologies included pathologic intimal thickening (PIT), fibroatheromas whose cores were in an early stage (eFA) or late stage (lFA) of necrosis, thin-cap fibroatheromas (TCFA) and ruptures (pR). Lesions were characterized by immunostaining using specific markers directed against endothelial cells (CD31/CD34), smooth muscle cells (α-actin), macrophages (CD68), and T-lymphocytes (CD45RO, CD4). Mean intraplaque vessel densities per mm 2 between lesions with PIT and eFA increased significantly (PIT= 15.84±16.73 vs. eFA= 42.07±40.70, p=0.0054) where maximal numbers of vessels were found in pR (66.57±33.42). Overall, intraplaque vessels associated with actin 3 SMCs, were generally &lt;10%, suggesting a more immature phenotype. Increased vessel densities coincided with greater numbers of inflammatory macrophages and T-cells. Notably, T-cell numbers in areas with high intraplaque vessel densities increased approximate 3-fold between lesions with PIT and eFA (PIT= 62.62±76.50 vs. eFA= 182.33±171.54, p=0.0043) with maximal numbers displayed in TCFAs and pRs, in particular at the intimal/medial border. Populations infiltrating T cells were predominantly CD4 3 and most of these appeared to be activated (human leukocyte antigen DR positive). Conclusion: Atherosclerotic coronary arteries express a latent proangiogenic phenotype coinciding with a localized increased in activated CD4 3 T-cells and early plaque necrosis.