Chlamydia pneumoniae and Helicobacter pylori can cause persistent infections of the respiratory and gastrointestinal tract, respectively. It has been suggested that persistent infection of arteries with these bacteria can contribute to the development of atherosclerosis. The aims of this study were to determine the presence of C. pneumoniae and H. pylori DNA in atherosclerotic plaque samples by PCR and to evaluate the correlation between clinical status and DNA positivity of these bacteria. Eighty-five consecutive patients (mean age, 59 ± 10; 75 male, 10 female) undergoing coronary artery bypass grafting, carotid endarterectomy, and surgery of the abdominal aorta for atherosclerotic obstructive lesions were included in the study. Forty-six endarterectomy specimens from the atherosclerotic lesions and 39 specimens from healthy regions of the ascending aorta, which were accepted as the control group, were excised. The presence of microorganism DNA in endarterectomy specimens was assessed by PCR. C. pneumoniae DNA was found in 12 (26%) of 46 endarterectomy specimens and none of the healthy vascular-wall specimens (P < 0.001), while H. pylori DNA was found in 17 (37%) of 46 endarterectomy specimens and none of the controls (P < 0.001). Either C. pneumoniae or H. pylori DNA was positive in 23 (50%) of 46 patients and none of the controls (P < 0.001). Six of the atherosclerotic lesions showed coexistence of both of the microorganism DNAs. The presence of C. pneumoniae and H. pylori DNA in a considerable number of atherosclerotic plaques but their absence in healthy vascular wall supports the idea that they may have a role in the development of atherosclerosis, especially in countries where infection is prevalent and where conventional risk factors fail to explain the high prevalence of atherosclerotic vascular disease.
Fractalkine (CX3CL1, FKN) is expressed in the inflamed vascular wall and absence of FKN reduces atherogenesis. Whether FKN is expressed throughout all stages of atherosclerotic disease and whether it directly contributes to monocyte recruitment to atherosclerotic lesions is not known. We collected human atherosclerotic plaque material and blood samples from patients with carotid artery disease undergoing endarterectomy. Plaques were analyzed by immunohistochemistry and qPCR. We found that FKN is expressed at all stages of atherosclerotic lesion formation, and that the number of FKN-expressing cells positively correlates with the number of CX3CR1-positive cells in human carotid artery plaques. In the circulation, soluble FKN levels are significantly elevated in the presence of high-grade (sub-occlusive) stenosis. To determine the role of the FKN-CX3CR1 axis for monocyte adhesion in vivo we then performed intravital videofluorescence microscopy of the carotid artery in ApoE−/− mice. Notably, FKN-CX3CR1 interactions are critical for recruitment of circulating monocytes to the injured atherosclerotic vascular wall. Thus, this chemokine dyad could represent an attractive target for anti-atherosclerotic strategies.
We examined the cross-sectional relationships of subclinical atherosclerosis – expressed by carotid intimal–medial thickness and coronary calcification – with antibodies to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex virus, hepatitis A virus, and pathogen burden (number of positive pathogens). A random sample of 1056 individuals chosen from 5030 Multi-Ethnic Study of Atherosclerosis cohort participants were included. After multiple adjustment, no associations were found between atherosclerosis measures and either individual pathogens or pathogen burden. Interactions with inflammatory and endothelial function markers, demographic factors, BMI, high-density lipoprotein, diabetes, and smoking were also explored. The only interaction that was large, qualitative, statistically significant (P < 0.05) and in the expected direction was that between hepatitis A virus and soluble intercellular adhesion molecule-1 with regard to Agatston calcium score: the difference between hepatitis A virus-positive and hepatitis A virus-negative participants was −86 units in participants with soluble intercellular adhesion molecule-1 below the median, and +162 units in those with soluble intercellular adhesion molecule-1 equal or above the median. However, given the number of interactions that were explored, these results must be interpreted cautiously.
Findings from the present analyses do not provide support for an infectious etiology for subclinical atherosclerosis. However, the study’s limitations, which include its cross-sectional design and insufficient statistical power, suggest that inferences from its findings should be made cautiously.
atherosclerosis; infections; pathogens
Chronic infection known to be a predisposing factor for the development of atherosclerosis. Several studies have found a possible role of Helicobacter pylori in the pathogenesis of atherosclerosis. The aim of this study was to investigate the presence of H. pylori in atherosclerotic plaques in iliac arteries in 25 end stage renal disease (ESRD) patients undergoing kidney transplantation. Esophagogastroduodenoscopy was performed in all patients before transplantation. Biopsy specimens obtained from gastric antrum were sent for pathologic evaluation. Gastric H. pylori infection was confirmed by microscopic assessment and rapid urease test. Arterial specimens were obtained from iliac arteries during kidney transplantation. Presence of H. pylori DNA in atherosclerotic plaques and healthy vessel samples was evaluated by the polymerase chain reaction (PCR). The mean age of patients was 44.1 ± 22.6 years. Risk factors in patients with atherosclerosis were hypertension (68%), diabetes mellitus (20%), hyperlipidemia (20%), positive family history (16%). Atherosclerotic plaques were found in 21 (84%) patients. PCR analysis did not detect H. pylori in any case. There was a significant relationship of atherosclerosis with hypertension (P = 0.006) but not with diabetes mellitus and hyperlipidemia (P = 0.5). There was no significant relationship between atherosclerosis and gastric H. pylori infection (P = 0.6). This study revealed no association between the presence of H. pylori as a pathogen of vessel walls and atherosclerosis in ESRD.
Atherosclerosis; end stage renal disease; helicobacter pylori; kidney transplantation
Chlamydia pneumoniae is a ubiquitous pathogen that causes acute respiratory disease. The spectrum of C. pneumoniae infection has been extended to atherosclerosis and its clinical manifestations. Seroepidemiologic studies have associated C. pneumoniae antibody with coronary artery disease, myocardial infarction, carotid artery disease, and cerebrovascular disease. The association of C. pneumoniae with atherosclerosis is corroborated by the presence of the organism in atherosclerotic lesions throughout the arterial tree and the near absence of the organism in healthy arterial tissue. C. pneumoniae has also been isolated from coronary and carotid atheromatous plaques. To determine whether chronic infection plays a role in initiation or progression of disease, intervention studies in humans have been initiated, and animal models of C. pneumoniae infection have been developed. This review summarizes the evidence for the association and potential role of C. pneumoniae in cardiovascular disease.
The features of carotid atherosclerosis in ketosis-onset diabetes have not been investigated. Our aim was to evaluate the prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed Chinese diabetic patients with ketosis but without islet-associated autoantibodies.
In total, 423 newly diagnosed Chinese patients with diabetes including 208 ketosis-onset diabetics without islet-associated autoantibodies, 215 non-ketotic type 2 diabetics and 79 control subjects without diabetes were studied. Carotid atherosclerosis was defined as the presence of atherosclerotic plaques in any of the carotid vessel segments. Carotid intima-media thickness (CIMT), carotid atherosclerotic plaque formation and stenosis were assessed and compared among the three groups based on Doppler ultrasound examination. The clinical features of carotid atherosclerotic lesions were analysed, and the risk factors associated with carotid atherosclerosis were evaluated using binary logistic regression in patients with diabetes.
The prevalence of carotid atherosclerosis was significantly higher in the ketosis-onset diabetic group (30.80%) than in the control group (15.2%, p=0.020) after adjusting for age- and sex-related differences, but no significant difference was observed in comparison to the non-ketotic diabetic group (35.8%, p=0.487). The mean CIMT of the ketosis-onset diabetics (0.70±0.20 mm) was markedly higher than that of the control subjects (0.57±0.08 mm, p<0.001), but no significant difference was found compared with the non-ketotic type 2 diabetics (0.73±0.19 mm, p=0.582) after controlling for differences in age and sex. In both the ketosis-onset and the non-ketotic diabetes, the prevalence of carotid atherosclerosis was markedly increased with age (both p<0.001) after controlling for sex, but no sex difference was observed (p=0.479 and p=0.707, respectively) after controlling for age. In the ketosis-onset diabetics, the presence of carotid atherosclerosis was significantly associated with age, hypertension, low-density lipoprotein cholesterol and mean CIMT.
The prevalence and risk of carotid atherosclerosis were significantly higher in the ketosis-onset diabetics than in the control subjects but similar to that in the non-ketotic type 2 diabetics. The characteristics of carotid atherosclerotic lesions in the ketosis-onset diabetics resembled those in the non-ketotic type 2 diabetics. Our findings support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes.
Ketosis-prone diabetes; Type 2 diabetes; Atherosclerosis; Carotid arteries; Epidemiology
Despite extensive efforts to confirm a direct association between Chlamydia pneumoniae and atherosclerosis, different laboratories continue to report a large variability in detection rates. In this study, we analyzed multiple sections from atherosclerotic carotid arteries from 10 endartectomy patients to determine the location of C. pneumoniae DNA and the number of sections of the plaque required for analysis to obtain a 95% confidence of detecting the bacterium. A sensitive nested PCR assay detected C. pneumoniae DNA in all patients at one or more locations within the plaque. On average, 42% (ranging from 5 to 91%) of the sections from any single patient had C. pneumoniae DNA present. A patchy distribution of C. pneumoniae in the atherosclerotic lesions was observed, with no area of the carotid having significantly more C. pneumoniae DNA present. If a single random 30-μm-thick section was tested, there was only a 35.6 to 41.6% (95% confidence interval) chance of detecting C. pneumoniae DNA in a patient with carotid artery disease. A minimum of 15 sections would therefore be required to obtain a 95% chance of detecting all true positives. The low concentration and patchy distribution of C. pneumoniae DNA in atherosclerotic plaque appear to be among the reasons for inconsistency between laboratories in the results reported.
To analyse histological composition and progression of carotid plaque.
Thirty-one patients (22 males, mean age 68.03 ± 7.3 years) admitted for carotid endarterectomy for extracranial high-grade internal carotid artery stenosis (≥ 70% luminal narrowing) were enrolled. The patients were divided into 2 groups according to symptomatology (group I, 17 symptomatic patients; and group II, 14 asymptomatic patients). A histological analysis and inflammatory cell quantification of each excised carotid plaque was made. Nine carotid arteries were removed from human cadavers that were not preselected for carotid artery disease. These specimens were used as a control tissue without any macroscopic signs of atherosclerotic plaques.
Fifty eight percent of all carotid plaques were classified as complex plaque with possible surface defect, hemorrhage or thrombus. The inflammatory cells concentration did not differ between the two groups. All specimens from human cadavers were classified as preatheroma with extracellular lipid pools.
Asymptomatic and symptomatic patients could have the same histological components on their carotid plaques. Fibrotic and calcific plaques could become vulnerable as complex plaques with surface defect, hemorrhage and thrombus could remain silent. Asymptomatic carotid stenosis should be followed close with no invasive diagnostic methods and clinical evaluation.
The association of Chlamydia pneumoniae with atherosclerosis is controversial. We investigated the presence of C. pneumoniae and other Chlamydia spp. in atheromatous carotid artery tissue.
Forty elective carotid endarterectomy patients were recruited (27 males, mean age 65 and 13 females mean age 68), 4 had bilateral carotid endarterectomies (n= 44 endarterectomy specimens). Control specimens were taken from macroscopically normal carotid artery adjacent to the atheromatous lesions (internal controls), except in 8 cases where normal carotid arteries from post mortem (external controls) were used. Three case-control pairs were excluded when the HLA DRB gene failed to amplify from the DNA. Genus specific primers to the major outer membrane protein (MOMP) gene were used in a nested polymerase chain reaction (nPCR) in 41 atheromatous carotid specimens and paired controls. PCR inhibition was monitored by spiking with target C. trachomatis. Atheroma severity was graded histologically. Plasma samples were tested by microimmunofluorescence (MIF) for antibodies to C. pneumoniae, C. trachomatis and C. psittaci and the corresponding white cells were tested for Chlamydia spp. by nPCR.
C. pneumoniae was not detected in any carotid specimen. Twenty-five of 38 (66%) plasma specimens were positive for C. pneumoniae IgG, 2/38 (5%) for C. trachomatis IgG and 1/38 (3%) for C. psittaci IgG.
We were unable to show an association between the presence of Chlamydia spp. and atheroma in carotid arteries in the presence of a high seroprevalence of C. pneumoniae antibodies in Northern Ireland.
Atherosclerotic carotid artery disease poses a grave threat to cerebral circulation, leading to a stroke with its devastating sequelae, if left untreated. Carotid endarterectomy has a proven track record with compelling evidence in stroke prevention.
a) To confirm that carotid endarterectomy (CEA) is safe and effective in preventing stroke at both short and long term. b) to demonstrate long term patency of internal carotid artery when arteriotomy repair is performed using autologous saphenous vein patch.
Materials and Methods:
During ten years, from September 1997 to February 2008, thirty nine patients who underwent consecutive carotid endarterectomy at our institute, form the basis of this report. Their age ranged from thirty to seventy eight years, with a mean age of 56. There were four women in this cohort. Thirty seven patients were symptomatic with >70% stenosis and two were asymptomatic with >80% stenosis, incidentally detected. Imaging included Duplex scan and MRA for carotid territory and brain, and non-invasive cardiac assessment. Co-morbidities included smoking, hypertension, diabetes, and coronary artery disease. Carotid Endarterectomy was performed under general anaesthesia, using carotid shunt and vein patch arteriotomy repair.
All the patients made satisfactory recovery, without major adverse cerebral events in this series. Morbidities included Transient Ischemic Attack (TIA) in two, needing only medications in one, and carotid stenting in the other. Minor morbidities included neck hematoma in two and transient hypoglossal paresis in three patients. Yearly follow-up included duplex scan assessment for all the patients. Two patients died of contralateral stroke, two of myocardial events and two were lost to follow up. Thirty three patients are well and free of the disease during the follow up of three to 120 months.
Carotid endarterectomy provided near total freedom from adverse cerebral events and its catastrophic sequelae, leading to excellent outcome, both short as well as long term.
Carotid artery; stenosis; stroke; carotid endarterectomy
The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multi-ethnic cohort.
Antibody titers to five common infectious microorganisms (i.e. Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants, and a weighted index of infectious burden (IB) was calculated based on Cox models previously derived from for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness (MCPT). Weighted least squares regression was used to measure the association between IB and MCPT after adjusting for other risk factors.
Serological results for all five infectious organisms were available in 861 participants with MCPT measurements available (mean age 67.2+/−9.6 yrs). Each individual infection was associated with stroke risk after adjusting for other risk factors. The IB index (n=861) had a mean of 1.00 ± standard deviation 0.35, median 1.08. Plaque was present in 52% of participants (mean 0.90+/−1.04 mm). IB was associated with MCPT (adjusted increase in MCPT 0.09 mm, 95% confidence interval 0.03–0.15 mm, per standard deviation increase of IB).
A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multi-ethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.
Chlamydia pneumoniae is a respiratory pathogen that has been associated with chronic inflammatory diseases such as asthma and atherosclerosis. Recent isolation of C. pneumoniae from human carotid and coronary atheromas provides additional support for a role of this organism in atherogenesis. We characterized the coronary strain C. pneumoniae A-03 by sequence analysis of the major outer membrane protein gene (omp1). In addition, the in vitro activities of A-03 and three respiratory strains of C. pneumoniae (BAL-16, TW-183, and T-2634) were examined in infected human umbilical vein endothelial cells (HUVEC) by analysis of the production of interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and soluble intercellular cell adhesion molecule 1 (sICAM-1). Sequence analysis of omp1 of C. pneumoniae A-03, compared to prototype strains TW-183 and AR-39, revealed five nucleotide changes resulting in nonsynonymous codons. Of interest was a nonconservative amino acid substitution (Ser to Pro) in position 61 of variable segment 1. In vitro, the extent of MCP-1, IL-8, and sICAM-1 production was dependent on the C. pneumoniae strain examined at low multiplicities of infection following 24 h of incubation. Strain A-03 displayed the lowest stimulatory activity in infected HUVEC, while T-2634 induced the highest levels of MCP-1, IL-8, and sICAM-1 among all strains examined. Heat-inactivated C. pneumoniae failed to stimulate production of these proteins by all strains tested. In contrast, only partial inhibition was observed by UV-inactivated organisms. Results from this study demonstrate that unlike prototype respiratory strains of C. pneumoniae, the coronary strain A-03 displays divergence in the omp1 gene. In addition, the stimulation of chemokines and adhesion molecules involved in the recruitment of leukocytes to sites of inflammation by C. pneumoniae may be important in the pathogenesis of diseases associated with this organism, including atherosclerosis.
YKL-40 has been demonstrated to be related to atherosclerosis, but its role in predicting plaque status and the outcome of carotid atherosclerosis (CAS) caused by CagA-positive helicobacter pylori remains unclear. This study was aimed to investigate the role of YKL-40 in predicting the outcome of carotid atherosclerosis with CagA-positive Helicobacter pylori infection.
The serum concentrations of YKL-40, C-reaction protein in 310 patients undergoing color Duplex assessment of carotid atherosclerosis were recorded and divided into 3 groups according to the infectious statuses of helicobacter pylori. We also examined serum YKL-40, C-reaction protein and the plaque morphology in animal model of carotid atherosclerosis with different types of helicobacter pylori infection.
Overexpression of YKL-40 was only found in carotid atherosclerosis group with CagA-positive helicobacter pylori infection; C-reaction protein failed to distinguish different infectious statuses of helicobacter pylori infection. In patients with CagA-positive helicobacter pylori infection, elevated YKL-40 expression was accompanied by more severe clinical symptoms. We also confirmed similar findings in rabbit model of carotid atherosclerosis with CagA-positive helicobacter pylori infection. We found that in 7 rabbits treated with anti-helicobacter pylori therapy, the serum YKL-40 level decreased and the plaque became more stable.
Our findings suggested that increased serum YKL-40 level indicates plaque instability and more severe clinical symptoms of carotid atherosclerosis with CagA-positive helicobacter pylori infection. Compared with C-reaction protein, YKL-40 seems to be a more specific predictor of plaque status and outcome of carotid atherosclerosis with CagA-positive helicobacter pylori infection.
Objective: To observe the difference of androgen and inflammatory cytokines level in atherosclerosis and analyse their relations. Method: Both carotid arteries and arteries of lower extremity were subjected to ultrasonic examination by Doppler’s method. Those with much atheromatous plaque formation were ranged into case group, and those with normal result formed control group. Total, free testosterone and estradiol were assayed by radioimmunoassay. C reactive protein (CRP) was assayed by nepheloturbidity. Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Interleukin-18 (IL-18), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were assayed by ELISA. The mean difference between two groups and the correlation between free testosterone and cytokines were analysed. Results: Free testosterone was (6.337±3.371) pg/L in case group and (11.375±4.733) pg/L in control group, P<0.01. No differences were found in total testosterone and estradiol. CRP was (27.294±10.238) mg/L in case group and (12.843±6.318) mg/L in control group, P<0.01. IL-6 was (41.700±31.385) pg/L in case group and (25.396±20.772) pg/L in control group, P<0.05. IL-8 was (89.249±58.357) pg/L in case group and (67.873±31.227) pg/L in control group, P<0.05. sICAM-1 was (470.491±134.078) pg/L in case group and (368.487±97.183) pg/L in control group, P<0.01. sVCAM-1 was (537.808±213.172) pg/L in case group and (457.275±157.273) pg/L in control group, P<0.05. There were no differences in TNF-α, IL-10 and IL-18. Correlation analysis showed that FT (free testosterone) had negative correlation with CRP, IL-6 and sICAM-1. Among them FT had well correlation with CRP, correlation index was −0.678. Conclusion: Free testosterone was in negative correlation with atherosclerosis in old-age male. Free testosterone may have the role of anti-atherosclerosis, and this effect was not achieved by its transformation to estradiol. Low free testosterone level was followed by increased level of inflammatory cytokines. Low free testosterones coexist with inflammation and they both affect the process of atherosclerosis in old-age male.
Atherosclerosis; Old-age male; Androgen; Free testosterone; Inflammatory cytokine
We investigated the relationship between acute coronary ischemia and the presence of Helicobacter pylori DNA in aortic regions that were absent macroscopic atheromatous plaques.
The study group (Group 1) consisted of 42 patients who underwent coronary artery bypass grafting. Biopsy samples were obtained from 2 different locations: from regions of the aorta that were free (macroscopically) of atheromatous plaque (Group 1A), and from the internal mammary artery (Group 1B). The control group (Group 2) of 10 patients who had no atherosclerotic vascular disease provided aortic tissue samples for comparison. The real-time polymerase chain reaction method was used to detect H. pylori DNA in all biopsy samples.
Eleven of 42 aortic tissue samples (26%) in Group 1A were positive for H. pylori DNA. Neither biopsies from the left internal mammary arteries of those patients nor biopsies from the aortas of the control group (Group 2) were positive for H. pylori DNA. There was a statistically significant difference between 1A and 1B in terms of H. pylori positivity (P=0.001). In Group 1 as a whole, acute coronary ischemia was more prevalent in the H. pylori-positive patients than in the H. pylori-negative patients (P=0.001).
To our knowledge, this is the 1st study to investigate the detection of H. pylori DNA in aortic biopsy samples that are macroscopically free of atheromatous plaque. Such detection in patients who have atherosclerotic coronary artery disease could be an important indication of the role of microorganisms in the pathogenesis of atherosclerosis.
Aorta; arteriosclerosis/etiology; Helicobacter infections/complications; Helicobacter pylori/pathogenicity; polymerase chain reaction; prospective studies; real-time PCR; mammary arteries; muscle, smooth, vascular
The management of atherosclerotic carotid occlusive disease for stroke prevention has entered a time of dramatic change. Improvements in medical management have begun to challenge traditional interventional approaches to asymptomatic carotid stenosis. Simultaneously, carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CE). Finally, multiple factors beyond degree of stenosis and symptom status now mitigate clinical decision making. These factors include brain perfusion, plaque morphology, and patency of intracranial collaterals (circle of Willis). With all of these changes, it seems prudent to review the role of carotid duplex ultrasonography in the management of atherosclerotic carotid occlusive disease for stroke prevention. Carotid duplex ultrasonography (CDU) for initial and serial imaging of the carotid bifurcation remains an essential component in the management of carotid bifurcation disease. However, correlative axial imaging modalities (computer tomographic angiography (CTA) and contrast-enhanced magnetic resonance angiography (CE-MRA)) increasingly aid in the assessment of individual stroke risk and are important in treatment decisions. The purpose of this paper is twofold: (1) to discuss foundations and advances in CDU and (2) to evaluate the current role of CDU, in light of other imaging modalities, in the clinical management of carotid atherosclerosis.
For about 50 years, angiography represented the only imaging method for studying carotid arteries in order to detect the presence of pathological stenosis due to atherosclerotic plaque. Recently, thanks to the use of non-invasive methods, physicians are able to study and quantify the presence of carotid atherosclerosis in vivo. These procedures have enabled the introduction of new concepts: (1) the degree of carotid stenosis is approximate to the volume and extension of carotid plaque; and (2) a set of parameters, easily identifiable by computed tomography angiography, magnetic resonance angiogram and ultra-sound echo-color Doppler, are closely linked to the development of ischemic symptoms and can significantly increase the risk of stroke regardless of the degree of stenosis. In light of these findings, vulnerable plaques should be identified early, and the role of Digital Subtraction Angiography which is a purely technical luminal technique should be determined.
Carotid arteries; Computed tomography angiography; Digital Subtraction Angiography
Carotid artery stenting (CAS) is currently a standard procedure to treat severe carotid artery stenosis. This procedure causes mechanical plaque rupture, potentially releasing soluble factors into the circulating blood. The purpose of this study is to clarify whether inflammation factors are released from an atherosclerotic plaque after CAS and whether local release of inflammation factors is associated with periprocedural new ischemic lesions. The study consisted of 35 patients with 40 severely stenotic carotid arteries who underwent CAS. Blood samples were obtained from the aorta before the procedure and from the carotid plaque site just after the procedure. Blood levels of interleukin-6 (IL-6), interleukin-18, matrix metalloproteinase (MMP)-2, and tissue inhibitor of MMP-1 were determined. Diffusion-weighted magnetic resonance imaging was performed before and after the procedure. Among inflammatory markers, IL-6 levels markedly increased at the plaque site in comparison to those at the aorta (P<0.001). The IL-6 levels in the local samples were significantly higher in symptomatic lesions than those in asymptomatic lesions. More importantly, higher local IL-6 levels were associated with the appearance of new ischemic lesions (P=0.003). The association remained significant (P=0.030) after controlling for potential risk factors for CAS. Association of local IL-6 levels and periprocedural new ischemic lesions suggests that massive release from the plaque and entry into the cerebral circulation of IL-6 might be one of important factors on periprocedural complications related to CAS.
carotid artery stenting; complications; embolism; inflammation; interleukins
Stroke is a major cause of disability and mortality, and a major cause of stroke is carotid artery stenosis. This stenosis is caused by carotid atherosclerotic plaques, the prevention and management of which are the key to avoiding many resultant strokes. The plaque can either embolize to a cerebral artery or build up in a carotid artery, ultimately resulting in thrombosis and total occlusion. Noninvasive testing can now make the diagnosis of carotid stenosis. Medical management with plaque stabilization and platelet inhibition plays a key role in stroke prevention. Carotid endarterectomy and invasive carotid angioplasty stenting are also important for lesions with extensive progression, and patients with a very high overall risk may especially benefit from the latter procedure. A medical-surgical team approach is now greatly contributing to the avoidance of stroke and its devastation.
Carotid artery disease; Endarterectomy; Stenting; Stroke
Carotid atherosclerotic plaques represent both stable and unstable atheromatous lesions. Atherosclerotic plaques that are prone to rupture owing to their intrinsic composition such as a large lipid core, thin fibrous cap and intraplaque hemorrhage are associated with subsequent thromboembolic ischemic events. At least 15–20% of all ischemic strokes are attributable to carotid artery atherosclerosis. Characterization of plaques may enhance the understanding of natural history and ultimately the treatment of atherosclerotic disease. MRI of carotid plaque and embolic signals during transcranial Doppler have identified features beyond luminal stenosis that are predictive of future transient ischemic attacks and stroke. The value of specific therapies to prevent stroke in symptomatic and asymptomatic patients with severe carotid artery stenosis are the subject of current research and analysis of recently published clinical trials that are discussed in this article.
carotid atherosclerosis; carotid endarterectomy; diagnostic studies; medical therapy; stenting; stroke
Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy.
Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470.
1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2·76, 95% CI 1·17–6·51; p=0·021; HR for non-disabling stroke 3·00, 1·10–8·36; p=0·031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1·18, 0·40–3·55; p=0·76; HR for disabling or fatal stroke 1·41, 0·38–5·26; p=0·607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2·98, 1·29–6·93; p=0·011; HR for non-disabling stroke 6·34, 1·45–27·71; p=0·014), but there was no risk difference in patients with an ARWMC score of less than 7.
The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions.
Medical Research Council, the Stroke Association, Sanofi-Synthélabo, the European Union Research Framework Programme 5.
Objective: To investigate the association between Chlamydia pneumoniae and matrix metalloproteinase-9 (MMP-9) in atherosclerotic plaques.
Design: 31 coronary atherosclerotic plaque specimens were studied by immunohistochemistry, polymerase chain reaction (PCR), and reverse transcription PCR for the presence of C pneumoniae antigen and genomic DNA, and of MMP-9 protein and transcripts.
Results: Immunohistochemical analysis identified a strong association between the presence of C pneumoniae antigen and production of MMP-9 in coronary atherosclerotic plaques (p = 0.001). Furthermore, analysis of the intralesional amount of C pneumoniae and MMP-9 indicated an increased number of cells positive for MMP-9 in arterial sections that had increased C pneumoniae positivity (p < 0.05).
Conclusions: This study provides evidence of an association between expression of MMP-9 and the intravascular presence of C pneumoniae and may suggest a potential pathological mechanism whereby C pneumoniae may contribute to the progression of coronary atherosclerosis.
atherosclerosis; Chlamydia pneumoniae; immunohistochemistry; matrix metalloproteinase; polymerase chain reaction
Risk assessment based on plaque vulnerability would be valuable in the management of asymptomatic carotid stenosis. The purpose of this study was to compare plaque morphology in symptomatic and asymptomatic patients with significant extracranial carotid artery stenosis using MDCT angiography.
MATERIALS AND METHODS
We identified 31 patients with greater than 60% carotid artery stenosis on MDCT angiography using the criteria of the North American Symptomatic Carotid Endarterectomy Trial Collaborators. We analyzed plaque density by blinded review in Hounsfield units in the atherosclerotic plaques of 15 symptomatic and 21 asymptomatic stenotic vessels for classification as soft, intermediate, or calcified. Data were analyzed using multiple logistic regression.
Even with age, traditional cardiovascular risk factors, and treatment taken into account, we found that calcified plaques were 21 times less likely to be symptomatic than noncalcified plaques (95% confidence interval for odds ratio, 0.003, 0.749; p = 0.030). No significant predictive value was found between soft (p = 0.23) or intermediate (p = 0.18) plaque morphology for the occurrence of symptoms.
MDCT angiography may help risk-stratify patients with asymptomatic carotid artery stenosis. Extracranial carotid artery calcified plaques causing stenosis are significantly less likely to be symptomatic and thus may be more stable than noncalcified plaques. This finding may have implications for the interpretation of calcification of atherosclerotic plaque in other vascular beds.
The mechanical environment and properties of the carotid artery play an important role in the formation and progression of atherosclerosis in the carotid bifurcation. The purpose of this work was to measure and compare the range and variation of circumferential stress and tangent elastic moduli in the human common (CCA), external (ECA) and internal (ICA) carotid arteries over the cardiac cycle in vivo.
Measurements were performed in the surgically exposed proximal cervical CCA, distal ECA and distal ICA of normotensive patients (n = 16) undergoing carotid endarterectomy. All measurements were completed in vivo over the cardiac cycle in the repaired carotid bifurcation after the atherosclerotic plaque was successfully removed. B-mode Duplex ultrasonography was used for measurement of arterial diameter and wall thickness, and an angiocatheter placed in the CCA was used for concurrent measurement of blood pressure. A semi-automatic segmentation algorithm was used to track changes in arterial diameter and wall thickness in response to blood pressure. These measurements were then used to calculate the variation of circumferential (hoop) stresses, tangent elastic moduli (the slope of the stress-strain curve at specified stresses), and stress-induced stiffness of the arterial wall (stiffening in response to intraluminal blood pressure fluctuation) for each patient.
The diameter and wall thickness of the segments (CCA, ECA and ICA) of the carotid bifurcation were found to decrease and stress-induced stiffness to increase from proximal CCA to distal ECA and ICA. The circumferential stress from end-diastole (minimum pressure) to peak-systole (maximum pressure) varied nonlinearly from 25±7 to 63±23 kPa (CCA), from 22±7 to 57±19 kPa (ECA) and from 28±8 to 67±23 kPa (ICA). Tangent elastic moduli also varied nonlinearly from end-diastole to peak-systole as follows: from 0.40±0.25 to 1.50±2.05 MPa (CCA), from 0.49±0.34 to 1.14±0.52 MPa (ECA) and from 0.68±0.31 to 1.51±0.69 MPa (ICA). The stress-induced stiffness of CCA and ECA increased more than 3-fold and the stiffness of ICA increased more than 2.5-fold at peak-systole compared to end-diastole.
The in vivo mechanical behavior of the three segments of the carotid bifurcation was qualitatively similar, but quantitatively different. All three arteries – CCA, ECA and ICA – exhibited nonlinear variations of circumferential stress and tangent elastic moduli within the normal pressure range. The variability in the properties of the three segments of the carotid bifurcation indicates a need for development of carotid models that match the in vivo properties of the carotid segments. Finally, the observed nonlinear behavior of the artery points to the need for future vascular mechanical studies to evaluate the mechanical factors of the arterial wall over the entire cardiac cycle.
common carotid artery; external carotid artery; internal carotid artery; in vivo mechanical properties; circumferential stress; stiffening
Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice.This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.