Complex Atherosclerotic Plaques Research Articles

Abstract 14353: Deficiency of Protein Kinase Cδ Revamps Atherosclerotic Plaque Complexity by Halting Inflammasome Activation and Intensifying Mitochondrial Function

Introduction: Plaque complexities substantially contribute to acute coronary syndrome. Inflammation and cell death in macrophages play a vital role in the formation of vulnerable plaques. Previous study had shown that protein kinase Cδ (PKCδ) is involved in the initiation and progression of atherosclerosis. However, the role of PKCδ on plaque stability remains unclear. Hypothesis: PKCδ regulates macrophage inflammation and cell death, leading to the formation of vulnerable plaques. Methods: The PKC family gene expressions in human atheroma plaques and nearby macroscopically intact tissues were analyzed from the gene expression omnibus data sets GSE43292. Two main mice models, including Ldlr -/- / PKCδ -/- mice and Ldlr -/- mice lethally irradiated and bone marrow transplanted (BMT) with either PKCδ -/- or wild type (WT), were applied to evaluate the impact of macrophages PKCδ on atherosclerosis. Blood, aorta, and aortic sinus were collected. The effects and underlying molecular mechanisms of PKCδ on inflammasome activation, pyroptosis, and mitochondrial function were explored using bone marrow-derived macrophage (BMDM) from PKCδ -/- and WT mice. Results: The gene expression of PKCδ significantly increases in human atheroma plaques, which is correlated with the expression of NLRP3 inflammasome. The deletion of PKCδ reduces plasma lipid profile and atherosclerosis in Ldlr -/- mice. Moreover, the deletion of PKCδ attenuates necrotic core formation, in both double knockout and BMT models. The RNA-seq analysis revealed that pyroptosis and mitochondrial oxidative phosphorylation (OXPHOS) are the potential mechanisms in PKCδ-regulated atherosclerosis. Additionally, knockout of PKCδ reduces expressions of LPS/IFNγ-induced TNFα, IL-6, and NLRP3 inflammasome in BMDM. Finally, the deficiency of PKCδ increases mitochondrial OXPHOS in BMDM, suggesting a potential role for PKCδ in the regulation of cellular metabolism and inflammation. Conclusions: Our findings indicate a crucial role for PKCδ in the development of complex atherosclerotic plaques, as it promotes inflammation, pyroptosis, and mitochondrial dysfunction. Targeting PKCδ could potentially be a therapeutic strategy for the treatment of atherosclerosis.

Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis.

Atherosclerosis is the root cause of major cardiovascular diseases (CVD) such as myocardial infarction and stroke. ADP-ribosylation factor 6 (Arf6) is a ubiquitously expressed GTPase known to be involved in inflammation, vascular permeability and is sensitive to changes in shear stress. Here, using atheroprone, ApoE-/- mice, with a single allele deletion of Arf6 (HET) or wildtype Arf6 (WT), we demonstrate that reduction in Arf6 attenuates atherosclerotic plaque burden and severity. We found that plaque burden in the descending aorta was lower in HET compared to WT mice (p˂0.001) after the consumption of an atherogenic Paigen diet for 5 weeks. Likewise, luminal occlusion, necrotic core size, plaque grade, elastic lamina breaks, and matrix deposition were lower in the aortic root atheromas of HET compared to WT mice (all p≤0.05). We also induced advanced human-like complex atherosclerotic plaque in the left carotid artery using partial carotid ligation surgery and found that atheroma area, plaque grade, intimal necrosis, intraplaque hemorrhage, thrombosis, and calcification were lower in HET compared to WT mice (all p≤0.04). Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p≤0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p≤0.001) but independent of changes in circulating lipids (all p≥0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.

Abstract 13392: 3D TEE Aids in Assessment of Embolic Stroke Due to Aortic Atherosclerotic Plaque

Case Presentation: A 69-year-old right-handed man presented with new left-sided weakness and recurrent ischemic strokes. His had history of coronary artery disease, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease stage 3, obstructive sleep apnea and obesity. Plasma low-density lipoprotein was 127 mg/dL. Brain MRI showed diffusion restriction in the left caudate head, left corona radiata, left anterior lentiform nucleus, and left periventricular white matter from acute to subacute infarction. CT angiogram showed diffuse atheromatous disease in the anterior and posterior circulation, bilateral mild cervical internal carotid artery stenosis, and calcifications in the aortic arch ( Figure 1 ). Transthoracic echocardiogram (TTE) showed mild generalized left ventricular hypokinesis (ejection fraction 45%) without thrombus. Transesophageal echocardiogram (TEE) showed complex mobile atherosclerotic plaques in the aortic arch ( Figure 2 ) after which Apixaban & Clopidogrel were started and statins increased. At 1-year follow-up there was no recurrent stroke. Discussion: This case highlights the role of 3D TEE in the detection of complex aortic arch atherosclerotic plaque with mobile components as the etiology of recurrent embolic stroke. 2D TTE & TEE and CT chest were unable to show mobile components in the aortic arch plaque. Many patients identified as having “cryptogenic stroke” after 2D TTE & TEE may in fact have mobile aortic arch plaques which can only be delineated by 3D TEE, thus reducing the need for further workup and expediting appropriate treatment.

Факторы, предрасполагающие к прогрессированию атеросклероза каротидных артерий у пациентов с артериальной гипертензией

The aim of the research. To study clinical and genetic factors predisposing to progression of carotid artery atherosclerosis among the Shor people based on a 5-year dynamic follow-up of hypertensive patients. Material and methods. A prospective clinical and epidemiological study of the indigenous population of the Mountain Shoria was carried out including patients with arterial hypertension (367 subjects). The dynamics of the intima-media complex thickness and atherosclerotic plaque thickness was assessed 5 years later by repeat ultrasound examination of carotid arteries. Polymorphisms of ACE (I/D, rs 4340), AGT (c.803T>C, rs699), AGTR1 (A1166C, rs5186), ADRB1 (c.145A>G, Ser49Gly, rs1801252), ADRA2B (I/D, rs28365031), MTHFR (C677T, rs1801133) and eNOS (VNTR 4b/4a) genes were tested using polymerase chain reaction. Results. The 5-year observation of the indigenous population of the Mountain Shoria has shown that such factors as the age (p=0.011) and the course of arterial hypertension (3rd-degree AH, duration of the disease for over 10 years, failure to achieve the target level of arterial pressure during treatment) play a significant role in the frequent unfavourable dynamics of the intima-media complex thickness. Th e study has also established association between the development of the atherosclerotic process in carotid arteries and smoking (OR=1.52), abdominal obesity (OR=2.87) and impaired glucose tolerance (OR=2.94). The increased level of low-density lipoprotein cholesterol also determines the negative dynamics as manifested by the growth of the atherosclerotic plaque in brachiocephalic arteries (OR=1.93). A high risk of atherosclerosis in the Shor cohort is associated with carriership of the prognostically unfavourable D alleles of the ACE gene (OR=8.29), C of the AGTR1 gene (OR=7.04) and T of the MTHFR gene (OR=3.25). Conclusion. The 5-year prospective observation of the small indigenous population of the Shors has revealed certain clinical and genetic factors for patients with arterial hypertension that are associated with the carotid artery atherosclerosis. The polymorphism of certain candidate genes is an important strategic biomarker that can be used in the future for early diagnostics of diseases associated with atherosclerosis.

The Role of Traditional Risk Factors and Inflammation Activity in Atherosclerosis Development in Psoriatic Arthritis Patients

It is known that patients with autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus) have early atherosclerosis development which might lead to the life threatening complications and death. Epidemiology studies demonstrated the risk of myocardial infarction, cardiovascular death is increased in patients with psoriatic arthritis (PsA), which also can be explained by premature atherosclerosis development but its risk factors (RF) remain unclear.The objective: defining relationship of traditional RF for cardiovascular diseases (CVD) with the activity of the inflammatory process and atherosclerosis in patients with PsA.Materials and methods. The study included 42 patients with PsA and 20 patients with skin psoriasis (PS) who did not have atherosclerotic CVD, diabetes, chronic kidney disease and other serious diseases and did not take statins. The control group consisted of 20 healthy persons who had no signs of rheumatic, infectious and other inflammatory diseases. All enrolled patients underwent complete physical examinations, evaluation of disease activity (DAS28, PASI indexes); laboratory investigations included full blood count and ESR, CRP, plasma lipids and uric acid level. Ultrasound of carotid arteries was performed to evaluate the surrogate atherosclerosis markers – intima-media complex thickness (IMT) and atherosclerotic plaques (AP).Results. It was determined that in patients with PsA, the severity of the atherosclerotic process is more prominent compared to patients with PS (the traditional RF profiles were the same).Сonclusion. The highest level of C-reactive protein, fibrinogen, uric acid, thicker intima-media complex was found in PsA group, which may indicate a pathogenetic association of additional RF with the development of a more aggressive atherosclerotic process.

P1942A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signaling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity

Abstract A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signalling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity Objectives We aimed to investigate interleukin (IL)-1 generation and the regulatory role of inflammasome in human advanced atherosclerosis. Background IL-1β is key contributor to the inflammatory process associated with atherosclerosis and its complications. Recent studies suggested that IL-1β blockade reduces the burden of inflammation and recurrence of cardiovascular events. Yet, other cytokines in IL-1 family and the regulation of IL-1 generation in patients with atherosclerosis remains poorly understood. Methods and results A focused transcriptomic analysis in human atherosclerotic specimens discovered that human atherosclerotic plaques host a broad reservoir of inflammasome components, characterised by expression of canonical inflammasome gene NLRP6, NLRP12, NLRC4, NLRP3 and non-canonical inflammasome gene caspase 4 significantly elevated in the symptomatic plaques versus the asymptomatic plaques. Upregulation of NLRP3 inflammasome expression in plaque validated by immunohistochemistry staining suggested it as a distinctive characteristic of plaque vulnerability and complexity. Functional studies on atherosclerotic explants obtained from patients undergoing carotid endarterectomy revealed constitutive generation of IL-1β accompanied by secretion of comparable levels of IL-1α from the majority of the plaques, while IL-18 and IL-33 generation from some of the plaques. Stimulation of the plaques with inflammasome activators showed an inducible generation of both IL-1α and IL-1β, not IL-18 or IL-33, mediated by specific canonical and non-canonical inflammasome pathways. Analysis on the medication records of these patients indicated that plaques from patients with suboptimally controlled hyperlipidemia, imaging signs for plaque instability and inadequate statins therapy possessed higher recruitable production of IL-1β, suggesting the conventional atherogenic factor in regulation of inflammasome immunity and disease activity. Mechanistic studies on tissue and cells isolated from atheromatous plaques demonstrate that generation of mature IL-1β is via a mechanism controlled by NLRP3 and the effector caspase-1. Conclusions The study supports a profound canonical and non-canonical inflammasomes mediated plaque IL-1α/β generation, via a key mechanism by NLRP3 and caspase-1. The results provide biological insights into the clinical merit of high-intensity cholesterol lowering and anti-IL-1 signalling-directed therapies in high-risk patients with atherosclerosis. Acknowledgement/Funding KI-Mayo collaboration project, the Swedish Research Council, the Swedish Heart-Lung Foundation, European Union FP7 projects, the NIH

P3109Coronary vulnerable plaque development is promoted by multidirectional wall shear stress

Abstract Aim Wall shear stress (WSS) has been widely associated with plaque development and destabilization. However, the multidirectionality of WSS, induced by the pulsatile nature of blood flow in combination with the arterial geometry, is rarely taken into account. The purpose of this study was to investigate the influence and predictive value of five (multidirectional) WSS parameters for coronary plaque progression and composition. Methods Familial hypercholesterolemic pigs (n=10, castrated male, 3 years old) were put on a high-fat diet and underwent imaging (near infrared spectroscopy-intravascular ultrasound (NIRS-IVUS), optical coherence tomography (OCT) and CT) of the three main coronary arteries at baseline and 10/12 months follow-up. IVUS-based lumen contours were combined with the centerline of artery as extracted from CT to obtain a 3D reconstruction of the coronary artery. Local flow velocity measurements were combined with the 3D-geometry of the coronary arterial lumen to calculate five multidirectional WSS parameters including: time average wall shear stress (TAWSS), oscilatory shear index (OSI), relative residence time (RRT), trans wall shear stress (TransWSS), cross flow index (CFI). For the analysis, arteries were divided into 3mm/45° sectors (n=3627). Per vessel each segment was classified as low, mid or high for each WSS metric based on the average value in the sector. Changes in wall thickness (WT) and plaque composition were assessed with NIRS-IVUS and OCT, and histology and related to the local (multidirectional) WSS. Results Half of the pigs developed lumen intruding, complex, lipid-rich plaques. In these pigs, coronary segments exposed to low baseline levels of TAWSS exhibited a significantly larger plaque growth per month compared to regions with either mid or high TAWSS (p<0.05, see figure). Furthermore, plaque growth correlated positively with the multidirectional WSS metrics OSI, RRT and CFI, with high multidirectionality resulting in the largest plaque growth (see figure). The positive predictive values (PPV) of the WSS metrics for plaque presence (WT>0.5mm) at follow up were 50% (low TAWSS), 48% (high OSI), 49% (high RRT), 47% (high CFI) and 43% (high transWSS). The PPVs for the presence of a fibroatheroma observed with histology were 61% (low TAWSS), 58% (high OSI), 61% (high RRT), 59% (high CFI) and 49% (high transWSS). Plaque growth vs. multidirectional WSS Conclusions This study shows that both low and multidirectional WSS promote the development of large and complex coronary atherosclerotic plaques with vulnerable characteristics. The high predictive values for fibrous cap atheroma development demonstrate the potential of multidirectional WSS metrics as a predictive clinical marker for vulnerable disease. Acknowledgement/Funding ERC- starter grant (grant agreement 310457)

Finite element analysis for fatigue behaviour of a self-expanding Nitinol peripheral stent under physiological biomechanical conditions

Self-expanding Nitinol stents are increasingly used to treat femoropopliteal artery (FPA) occlusions, but the risk of stent fatigue failure exists due to complex artery deformation during daily activities. Finite element analysis (FEA) has been widely applied to study the stent fatigue behaviours, but physiological deformation and atherosclerotic plaque were not considered simultaneously in previous studies. In this work, to show the necessity and feasibility of considering both factors in evaluation of the stent fatigue behaviours, a comprehensive FEA framework considering both factors is established, and an easy loading method for the complex boundary condition is proposed. Four comparative simulations are successfully conducted, and the stent fatigue behaviours are analysed based on the distributions and maximum values of the self-defined mean and alternating strains. Results show that both the physiological deformation and atherosclerotic plaque significantly contribute to the stent fatigue life. The case with the complex boundary condition and atherosclerotic plaque is the most critical of the four cases, and the minimum safety factor is 0.62. In conclusion, it is necessary to consider both physiological deformation and atherosclerotic plaque in the evaluation of stent fatigue behaviours, and ignoring any of them would lead to overestimation of the stent fatigue life. The work in this paper offers a solid foundation for accurate evaluation of the stent fatigue lifetime in patient-specific surgery plans via FEA.

THE VERIFICATION OF SUBCLINICAL CAROTID ATHEROSCLEROSIS IN THE RISK STRATIFICATION AT PRIMARY CARDIOVASCULAR PROPHYLAXIS

In this review of literature present duplex scanning technology as modern noninvasive information technique of subclinical carotid atherosclerosis verification. The article gives assessment and description of intima-media complex thicknesses and atherosclerotic plaques in patients risk stratification within the scope of primary cardiovascular prophylaxis.

Comorbid cardiovascular system disorders in patients with cryoglobulinaemia

Aim. To study a possible association between cryoglobulinemia and cardiovascular and peripheral vascular disease in patients with symptomatic cryoglobulinemic vasculitis and rheumatoid arthritis patients with elevated cryoglobulins. Methods. Analysis of the coexistent cardiovascular system diseases prevalence, heart and carotid arteries echocardiography data of 32 patients with cryoglobulinemic vasculitis, and 129 patients with rheumatoid arthritis depending on the fact of high cryoglobulins titers in the blood plasma compared to 32 healthy volunteers in the control group was conducted. Cryoglobulins isolation from the blood was performed using the A.E. Kalovidoris method in N.A. Konstantinova modification. Results. In patients with cryoglobulinemic vasculitis and rheumatoid arthritis with asymptomatic cryoglobulinemia a high frequency of hypertension prevalence (46.8 and 34.4%, respectively), ischemic heart disease (15.6 and 7.9%), congestive heart failure (9.4 and 10.5%), chronic venous insufficiency (53.1 and 23.7%) and postthrombophlebetic syndrome (28.1 and 18.4%) was observed. When analyzing ultrasound data in patients with cryoglobulinemic vasculitis and rheumatoid arthritis it has been found that the cryoglobulinemia is accompanied by left ventricular myocardial geometry violation (in 81.3 and 65.7% respectively versus 12.5% of patients in the control group), myocardial diastolic dysfunction (71 9 and 65.7% versus 15.6%), an increase in the proportion of patients with the «intima-media» complex thickening (78.1 and 36.8% versus 31.2%) and atherosclerotic plaques (34.4 and 13, 2% versus 6.2%) in the carotid arteries. Conclusion. Cryoglobulinemia can be considered as adjuvant risk factor for cardiovascular disease in patients with rheumatism.

A robust fully automatic lumen segmentation method for in vivo intracoronary optical coherence tomography

Introduction: Intravascular optical coherence tomography (IVOCT) is an in-vivo imaging modality based on the introduction of a catheter in a blood vessel for viewing its inner wall using electromagnetic radiation. One of the most developed automatic applications for this modality is the lumen area segmentation, however on the evaluation of these methods, the slices inside bifurcation regions, or with the presence of complex atherosclerotic plaques and dissections are usually discarded. This paper describes a fully-automatic method for computing the lumen area in IVOCT images where the set of slices includes complex atherosclerotic plaques and dissections. Methods The proposed lumen segmentation method is divided into two steps: preprocessing, including the removal of artifacts and the second step comprises a lumen detection using morphological operations. In addition, it is proposed an approach to delimit the lumen area for slices inside bifurcation region, considering only the main branch. Results Evaluation of the automatic lumen segmentation used manual segmentations as a reference, it was performed on 1328 human IVOCT images, presenting a mean difference in lumen area and Dice metrics of 0.19 mm2 and 97% for slices outside the bifurcation, 1.2 mm2 and 88% in the regions with bifurcation without automatic contour correction and 0.52 mm2 and 90% inside bifurcation region with automatic contour correction. Conclusion This present study shows a robust lumen segmentation method for vessel cross-sections with dissections and complex plaque and bifurcation avoiding the exclusion of such regions from the dataset analysis.

Oxidative theory of atherosclerosis and antioxidants.

Atherosclerosis is a multifactorial process that begins early in infancy and affects all the humans. Early steps of atherogenesis and the evolution towards complex atherosclerotic plaques are briefly described. After a brief history of the 'Lipid theory of atherosclerosis', we report the most prominent discoveries on lipoproteins, their receptors and metabolism, and their role in atherogenesis. The main focus is the 'oxidative theory of atherosclerosis', with emphasis on free radicals and reactive oxygen species, lipid peroxidation and LDL oxidation, biological properties of oxidized LDL and their potential role in atherogenesis. Then, we report the properties of antioxidants and antioxidant systems and their effects invitro, on cultured cells, in animal models and in humans. The surprising discrepancy between the efficacy of antioxidants invitro and in animal models of atherosclerosis and the lack of protective effect against cardiovascular events and death in epidemiological study and clinical trials are discussed. In contrast, epidemiological studies seem to indicate that the Mediterranean diet may protect (in part) against atherosclerosis complications (myocardial infarction and cardiovascular death).

Activation of sterol regulatory element binding protein and NLRP3 inflammasome in atherosclerotic lesion development in diabetic pigs.

BackgroundAberrantly elevated sterol regulatory element binding protein (SREBP), the lipogenic transcription factor, contributes to the development of fatty liver and insulin resistance in animals. Our recent studies have discovered that AMP-activated protein kinase (AMPK) phosphorylates SREBP at Ser-327 and inhibits its activity, represses SREBP-dependent lipogenesis, and thereby ameliorates hepatic steatosis and atherosclerosis in insulin-resistant LDLR−/− mice. Chronic inflammation and activation of NLRP3 inflammasome have been implicated in atherosclerosis and fatty liver disease. However, whether SREBP is involved in vascular lipid accumulation and inflammation in atherosclerosis remains largely unknown.Principal FindingsThe preclinical study with aortic pouch biopsy specimens from humans with atherosclerosis and diabetes shows intense immunostaining for SREBP-1 and the inflammatory marker VCAM-1 in atherosclerotic plaques. The cleavage processing of SREBP-1 and -2 and expression of their target genes are increased in the well-established porcine model of diabetes and atherosclerosis, which develops human-like, complex atherosclerotic plaques. Immunostaining analysis indicates an elevation in SREBP-1 that is primarily localized in endothelial cells and in infiltrated macrophages within fatty streaks, fibrous caps with necrotic cores, and cholesterol crystals in advanced lesions. Moreover, concomitant suppression of NAD-dependent deacetylase SIRT1 and AMPK is observed in atherosclerotic pigs, which leads to the proteolytic activation of SREBP-1 by diminishing the deacetylation and Ser-372 phosphorylation of SREBP-1. Aberrantly elevated NLRP3 inflammasome markers are evidenced by increased expression of inflammasome components including NLPR3, ASC, and IL-1β. The increase in SREBP-1 activity and IL-1β production in lesions is associated with vascular inflammation and endothelial dysfunction in atherosclerotic pig aorta, as demonstrated by the induction of NF-κB, VCAM-1, iNOS, and COX-2, as well as by the repression of eNOS.ConclusionsThese translational studies provide in vivo evidence that the dysregulation of SIRT1-AMPK-SREBP and stimulation of NLRP3 inflammasome may contribute to vascular lipid deposition and inflammation in atherosclerosis.

Thromboembolism or Atherothromboembolism in Atrial Fibrillation?

Atrial fibrillation (AF) is associated with increased morbidity, mortality, and ischemic stroke,1 and these ischemic strokes are almost always severe.2 Thrombus formation in the left atrium with ensuing embolism in the cerebral circulation is deemed to be the cause.2 Article see p 1168 According to the Virchow’s triad, hypercoagulability, endothelial dysfunction, and venous stasis should be prerequisite for thrombus formation in the left atrium.3 Several markers of clotting and platelet activation have been detected in AF patients, including high-plasma levels of the prothrombin fragment F1+2, a marker of thrombin generation, and P-selectin, a marker of clotting activation.3 The existence of a prothrombotic state may predispose to vascular disease. In a prospective study performed in 231 AF patients, we showed that plasma levels of CD40L, a marker of platelet activation, was associated with and predicted vascular outcomes, such as ischemic stroke and myocardial infarction (MI), during a follow-up period of 2 years.4 Endothelial dysfunction has been documented by measuring von Willebrand factor, which has been found to be elevated in AF patients and associated with poor vascular outcomes.5 The rate of endothelial damage seems temporarily related to AF duration because the highest levels have been observed in patients with permanent compared with those with paroxysmal or persistent AF.5 Venous stasis is the third component; it is supposed to be related not only to arrhythmia but also to AF-induced atrium remodeling, which could further lower contractility via several mechanisms, including low Ca2+ mobilization and impaired myosin phosphorylation.3 Furthermore, AF-related remodeling of left atrium may have a negative impact on the cardiac circulation as it is associated with downregulation of atrial NO, a molecule with vasodilator and antiaggregating properties.6 It is still unclear, however, whether remodeling-related venous stasis per se is actually …

Cellular and molecular players in the atherosclerotic plaque progression

Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low-level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed.

Relation Between the Incidence, Location, and Extent of Thoracic Aortic Atherosclerosis Detected by Transesophageal Echocardiography and the Extent of Coronary Artery Disease by Angiography

Atherosclerotic lesions in the thoracic aorta detected by transesophageal echocardiography (TEE) have been correlated with coronary artery disease (CAD). We determined whether simple or complex aortic plaques seen on transesophageal echocardiogram correlated with extent, location, and severity of CAD. The study population consisted of 188 patients who underwent TEE and coronary angiography. Atherosclerotic plaques seen on transesophageal echocardiogram were defined as (1) complex plaques in the presence of protruding atheroma ≥4-mm thickness, mobile debris, or plaque ulceration or (2) simple plaques in the absence of findings consistent with complex plaques. Extent of CAD was grouped into 4 groups according to number of coronary vessels with ≥70% stenosis. Numbers of patients with CAD with 0-, 1-, 2-, and 3-vessel disease were 99, 31, 28, and 30 respectively. Compared to patients without CAD, patients with CAD (n = 89) had a significantly greater prevalence of aortic atherosclerotic plaques irrespective of degree of plaque complexity or location (p <0.05). Multivariate analysis found that hypertension (odds ratio 3.0, 95% confidence interval 1.3 to 7.0, p = 0.013), diabetes mellitus (odds ratio 2.4, 95% confidence interval 1.1 to 4.9, p = 0.022), and aortic plaque (odds ratio 3.8, 95% confidence interval 1.8 to 8.2, p = 0.001) were significantly associated with CAD. There was a significant relation between simple and complex aortic plaques with increasing severity of CAD (p <0.001). Multivariate logistic regression analysis showed that complex plaque in the descending aorta (odds ratio 5.4, 95% confidence interval 1.8 to 16.4, p = 0.003) was the strongest predictor of CAD. In conclusion, simple and complex thoracic atherosclerotic plaques detected by TEE are associated with increasing severity of CAD. Complex plaque in the descending aorta was the strongest association with presence of CAD.

Imaging of coronary atherosclerosis: intravascular ultrasound

Atherosclerosis is the main cause of coronary heart disease, which is today the leading cause of death worldwide and will continue to be the first in the world in 2030. In the formation of atherosclerotic coronary lesions, a critical primary step is the accumulation and oxidation of low-density lipoprotein (LDL) particles. Oxidized-LDL favours leucocyte recruitment and their activation, as well as cell death. This leads to generation of complex atherosclerotic plaques. These plaques have a high content of necrotic core, a thin inflamed fibrous cap (intense accumulation of macrophages) and scarce presence of smooth muscle cells (i.e. thin-capped fibroatheroma). At early stages of the formation of the atheroma, the remodelling of the vessel wall usually prevents plaque from encroaching on the lumen, thereby masking the presence of atheroma on angiography. In contrast, greyscale intravascular ultrasound can fully assess the extension of the disease axially and longitudinally. This intravascular imaging technique has played a vital role in advancing our understanding of the pathophysiology of coronary artery disease, and in the development of novel cardiovascular drugs and device therapies. This intravascular imaging technology and its clinical and research applications are discussed in more detail below.

Cholesterol Embolization Syndrome

Cholesterol embolization syndrome refers to embolization of the contents of an atherosclerotic plaque (primarily cholesterol crystals) from a proximal large-caliber artery to distal small to medium arteries causing end-organ damage by mechanical plugging and an inflammatory response. Synonyms used in the medical literature include atheromatous embolization, cholesterol crystal embolization, and atheroembolism. Cholesterol embolization syndrome should be distinguished from the related and much more common syndrome of arterio-arterial thromboembolism in which fragments of a thrombus that forms atop an atheromatous plaque in the aorta or a large artery travel distally and occlude medium to large arteries.1 Cholesterol embolization syndrome is generally characterized by a multitude of small emboli (showers of microemboli) occurring over time. This is in contrast to arterio-arterial thromboembolism, which is usually characterized by an abrupt release of 1 or a few large emboli, leading to severe ischemia of target organs. Cholesterol embolization syndrome has a variety of clinical presentations. Cholesterol emboli originating in the descending thoracic and abdominal aorta may lead to renal failure, gut ischemia, and emboli to the skeletal muscles and the skin. Dermatologic manifestations (most commonly livedo reticularis and blue toe syndrome) are usually confined to the lower extremities but may extend to the abdomen and the chest. Cholesterol emboli originating in the ascending aorta may in addition cause neurological damage that is typically diffuse and due to small infarcts. Cholesterol embolization syndrome is also characterized by a nonspecific acute inflammatory response leading to constitutional symptoms (such as fever and malaise) and abnormalities in laboratory tests (such as hypereosinophilia and elevated erythrocyte sedimentation rate). These manifestations will be discussed in detail later in the text. Danish physician Fenger and his colleagues appear to have provided the first description of atheroembolism in the Danish medical brochure Ugeskrift for Laeger (Doctors’ Weekly).2 In 1844, they …

Prevalence and Clinical Implication of Complex Atherosclerotic Plaque in the Descending Thoracic Aorta of Japanese Patients Assessed by Transesophageal Echocardiography

Aging and westernization of lifestyle has accelerated the prevalence and severity of atherosclerotic cardiovascular diseases in the Japanese population. The aim of this study was to examine the prevalence of complex plaque formation in the descending thoracic aorta (DTA) as assessed by real-time 3-dimensional transesophageal echocardiography (3DTEE) and its relation to clinical factors. A prospective analysis of atherosclerotic plaque in the DTA of 350 consecutive patients who were clinically indicated for real-time 3DTEE was performed. Systematic assessment of the DTA plaques was performed using a biplane mode from the aorta at the level of the stomach to the aortic arch. When a large plaque (>4mm) was identified, detailed 3-dimensional (D) observations were performed using a 3D zoom mode. Complex plaque was defined as either mobile or an ulcer-like pouch in the DTA. Complex plaques were detected in 51 patients (15%), who were more advanced in age and had a higher prevalence of chronic kidney disease. A multivariate analysis revealed that the presence of complex plaque was an independent predictor of renal impairment. The prevalence of complex plaque was not low in the this Japanese study population. A close association between complex plaque and renal dysfunction raises the possibility that complex plaque in the DTA is a potential cause of renal dysfunction.

Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow

In addition to cholesterol-lowering properties, statins exhibit lipid-independent immunomodulatory, anti-inflammatory actions. However, high concentrations are typically required to induce these effects in vitro, raising questions concerning therapeutic relevance. We present evidence that endothelial cell sensitivity to statins depends upon shear stress. Using heme oxygenase-1 expression as a model, we demonstrate differential heme oxygenase-1 induction by atorvastatin in atheroresistant compared with atheroprone sites of the murine aorta. In vitro, exposure of human endothelial cells to laminar shear stress significantly reduced the statin concentration required to induce heme oxygenase-1 and protect against H(2)O(2)-mediated injury. Synergy was observed between laminar shear stress and atorvastatin, resulting in optimal expression of heme oxygenase-1 and resistance to oxidative stress, a response inhibited by heme oxygenase-1 small interfering RNA. Moreover, treatment of laminar shear stress-exposed endothelial cells resulted in a significant fall in intracellular cholesterol. Mechanistically, synergy required Akt phosphorylation, activation of Kruppel-like factor 2, NF-E2-related factor-2 (Nrf2), increased nitric-oxide synthase activity, and enhanced HO-1 mRNA stability. In contrast, heme oxygenase-1 induction by atorvastatin in endothelial cells exposed to oscillatory flow was markedly attenuated. We have identified a novel relationship between laminar shear stress and statins, demonstrating that atorvastatin-mediated heme oxygenase-1-dependent antioxidant effects are laminar shear stress-dependent, proving the principle that biomechanical signaling contributes significantly to endothelial responsiveness to pharmacological agents. Our findings suggest statin pleiotropy may be suboptimal at disturbed flow atherosusceptible sites, emphasizing the need for more specific therapeutic agents, such as those targeting Kruppel-like factor 2 or Nrf2.