Untreated HIV infection and large and small artery elasticity.

BACKGROUND: Untreated HIV infection may increase risk for cardiovascular disease, and arterial elasticity is a marker of cardiovascular risk and early disease. METHODS: HIV-infected participants not taking antiretroviral therapy (n=32) were compared with HIV-negative controls (n=30). Large and small artery elasticity (LAE and SAE) were estimated via analysis of radial pulse waveforms. Differences in LAE and SAE by HIV status were compared using analysis of covariance, with and without adjustment for Framingham risk (model 1); covariates that differed between groups [smoking, injection drug use, hepatitis C, and high-density lipoprotein cholesterol (HDLc); model 2]; or age, sex, race/ethnicity, smoking, injection frug use, hepatitis C, HDLc, and non-HDLc (model 3). RESULTS: HIV infection was associated with impaired LAE (-2.55 mL/mm Hg x 10; P=0.02) and SAE (-1.50 mL/mm Hg x 100; P=0.02). Associations with traditional risk factors were often stronger for SAE than LAE, including with Framingham score (per 1% higher; SAE -0.18, P=0.01; LAE -0.19, P=0.13). Fasting lipid levels were not significantly associated with LAE and SAE. After adjustment, differences between HIV-infected and HIV-uninfected participants were similar in model 1 (-2.36 for LAE, P=0.04; -1.31 for SAE, P=0.04), model 2 (-2.67 for LAE, P=0.02; -1.13 for SAE, P=0.07) and model 3 (-2.91 for LAE, P=0.02; -1.34 for SAE, P=0.03). CD4 count and HIV RNA level were not associated with LAE and SAE among HIV-infected participants. CONCLUSIONS: Untreated HIV infection is associated with impaired arterial elasticity, of both the large and small vasculature, after controlling for additional risk factors. Pulse waveform analysis is a noninvasive technique to assess cardiovascular disease risk that should be evaluated in larger studies of HIV-infected persons.

HCV infection facilitates asymptomatic carotid atherosclerosis: preliminary report of HCV RNA localization in human carotid plaques.

BACKGROUND: Clinical and experimental evidence suggests that hepatitis C virus (HCV) infection shows peculiar characteristics that strongly support a role in the development of atherosclerosis. We aimed to investigate whether (a) HCV infection can facilitate asymptomatic carotid lesions and (b) the presence of HCV RNA sequences can be shown in plaque tissues. METHODS: The status of carotid arteries, studied as intima-media thickness (IMT) in carotid bifurcation and prevalence and severity of plaques in internal carotid artery, was investigated by high-resolution B-mode ultrasonography in 31 HCV seropositive (HCV+) and in 120 age-matched HCV seronegative (HCV-) subjects evaluated for cardiovascular risk factors. The atherosclerotic risk profile, inflammation markers and main liver function tests were also studied in all patients. HCV RNA sequences were investigated by highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) in plaque tissues and serum of 2 HCV+ patients who underwent carotid revascularization. RESULTS: Genomic and antigenomic HCV RNA strands were evidenced within both the carotid plaque tissues examined. The prevalence of an IMT > 1 mm, but not the prevalence and severity of internal carotid plaques, was significantly higher (P < 0.001) in HCV+ than in HCV patients. The atherosclerotic risk profile for traditional and inflammatory factors did not differ between the HCV+ and HCV- groups. Main liver function tests did not differ between the two groups. HCV positivity was significantly associated with >1 mm IMT (P < 0.01) according to univariate analysis, and this association remained significant in multivariate regression analysis. CONCLUSIONS: The novel finding of HCV RNA sequences within carotid plaques suggests a local pro-atherogenetic action of the virus inside the plaque. On the whole our data strongly support that HCV infection facilitates the occurrence of carotid atherosclerotic lesions.

Enterovirus in arteriosclerosis: a pilot study.

BACKGROUND: Various pathogens have been suspected to play a role in the initiation or amplification of the atherosclerotic lesions. Both experimental and epidemiological arguments plead for a possible role of enterovirus in this process. OBJECTIVE: To determine the prevalence of enterovirus genome in atherosclerotic plaques, in comparison with Chlamydia pneumoniae, human cytomegalovirus (hCMV) and herpes simplex virus. STUDY DESIGN: Pilot study on 18 patients who underwent artery resection. Five artery samples were tested for each patient and each pathogen by using PCR techniques whose sensitivity was evaluated for this kind of specimen. The quality of the extraction step was assessed by amplification of a fragment of the human aldolase A gene. RESULTS: The genome of at least one infectious agent was detected in artery samples from 7 of the 18 patients (38.9%). In all cases, only one of the five aliquots was found positive; a confirmation was done by sequencing the PCR product. With regards to enterovirus, four patients (22.2%) were detected positive (one of them being also positive for hCMV). CONCLUSIONS: These results suggest that small amounts of enterovirus genome are commonly found in lesions of patients with advanced arteriosclerosis. Further studies are needed to evaluate the clinical significance of this association.

A study of arteriosclerosis in healthy subjects with HBV and HCV infection.

BACKGROUND: It is unclear whether infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) affects arteriosclerosis. We performed a cross-sectional study to clarify the effect of HBV and HCV infection on arteriosclerosis. METHODS: The study subjects were 1806 healthy individuals who visited Shimane Environment and Health Public Corporation for routine medical check-ups. Serum levels of total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, and blood glucose were investigated in all subjects. The degree of arteriosclerosis was assessed using systolic blood pressure, the bilateral ankle brachial index (ABI), the heart-carotid pulse wave velocity (HCPWV), and the heart-ankle PWV (HAPWV). These cardiovascular parameters were compared between control subjects and subjects with HBV and HCV infection, using analysis of covariance to adjust for confounding factors (sex, age, body mass index, and smoking and drinking). RESULTS: Of the 1806 subjects, 39 and 31 were diagnosed as positive for HBV and HCV infection, respectively. The remaining 1736 were considered to be the controls. Adjusted serum lipid levels in the subjects with HBV and those with HCV infection tended to be lower than those in the control subjects. Adjusted arteriosclerotic parameters in the subjects with HBV and HCV infection were similar to those in the control subjects, even after adjusting for serum lipid levels. CONCLUSIONS: Infection with HBV or HCV does not influence the severity of arteriosclerosis in healthy subjects.

Serum and peripheral blood mononuclear cells infectious burden: correlation to inflammation and atherosclerosis in haemodialysis patients.

BACKGROUND: Infectious agents may be implicated in the inflammatory atherosclerotic process. Not only specific microorganisms but also the infectious burden, defined as the number of pathogens to which a patient is exposed, has been associated with atherosclerosis. In the present study, the infectious burden, determined directly (by identification of viable pathogens in peripheral blood mononuclear cells (PBMC)) and indirectly (by serum antibodies detection) is correlated to the inflammatory and atherosclerotic status in haemodialysis (HD) patients, a population at high risk for cardiovascular disease. METHODS: The viable forms of four microorganisms (Chlamydia pneumoniae, herpes virus 1 and 2 and cytomegalovirus) were identified in patients PBMC by cell cultures and subsequent polymerase chain reaction. Serum IgG against the above pathogens and Helicobacter pylori were also determined. Inflammation was assessed by measurement of C-reactive protein (CRP), serum amyloid A (SAA), three pro- and one anti-inflammatory cytokines and four adhesion molecules. Atherosclerosis was defined by a scoring system using medical history data. RESULTS: The number of viable pathogens identified in PBMC in the 122 HD patients included in the study were zero in 22.1% of them, one in 33.6%, two in 43.4% and three in one patient. The number of IgG antibodies determined was one in 6.6% of patients, two in 32%, three in 48.4% and four in 13.1%. Seropositivity was not significantly different between patients with or without the respective viable pathogen identified in PBMC. Atherosclerosis was present in 40.2% of patients, and CRP, SAA and interleukin-6 were all increased in these patients. Neither inflammatory indexes nor atherosclerosis were significantly different in patients with a higher number of viable pathogens detected in PBMC or in those with a higher antibodies number. CONCLUSIONS: The direct infectious burden determination (the number of viable pathogens in PBMC) does not coincide with the serum (by IgG detection) infectious burden. Although inflammation correlates to atherosclerosis, neither PBMC nor the serum infectious burden is associated with these two entities in the inflamed and atherosclerotic HD patients.

Change in atherosclerosis progression in HIV-infected patients: ANRS Aquitaine Cohort, 1999-2004.

This study reported the changes in carotid intima-media thickness (IMT) during a 36-month period in 233 HIV-infected patients. Median IMT increased in the first 12 months and then decreased by month 36. The prevalence of treatment with lipid-lowering agents and protease inhibitor-free highly active antiretroviral therapy regimens increased, whereas smoking prevalence decreased. The progression of atherosclerosis in HIV-infected patients can be controlled. The impact of individual measures to reduce the cardiovascular risk should be evaluated further.

Viral load of the human immunodeficiency virus could be an independent risk factor for endothelial dysfunction.

BACKGROUND: Recent reports of myocardial infarction in young persons infected with human immunodeficiency virus (HIV) who are receiving protease inhibitor therapy have raised concerns about premature coronary artery disease in this population. However, endothelial dysfunction, hypercoagulability, hypertriglyceridemia, and abnormal coronary artery pathology have been observed in association with HIV infection prior to the availability of protease inhibitor therapy. HYPOTHESIS: The study was undertaken to determine the association between endothelial function, viral load, CD4+ count, and other well-established risk factors for atherosclerosis. METHODS: This prospective, case-controlled study compared viral (HIV) load and the CD4+ T-lymphocyte count and endothelial function in 24 HIV-positive carriers. Brachial artery diameter, HIV viral load, and CD4 count were measured. RESULTS: We found that viral load correlated inversely with endothelial function; the higher the viral load, the worse the endothelial dysfunction (p < 0.005). CONCLUSION: High viral load appears to be associated with endothelial dysfunction in patients with HIV. This preliminary observation supports the infectious theory that viruses may play an important role in the pathogenesis of atherosclerosis.

Cytomegalovirus aggravates intimal hyperplasia in rats by stimulating smooth muscle cell proliferation.

Epidemiological and animal studies suggest a role for cytomegalovirus (CMV) in restenosis. Previously, we demonstrated that proliferating smooth muscle cells (SMCs) in the injured arterial wall are particularly susceptible to CMV-induced effects. Therefore, we hypothesised that, depending on the time point of infection after vascular injury, CMV infection may affect cell proliferation either in the media or in the neointima, thereby aggravating the process of restenosis. In the present study, we focused on the individual layers of the arterial wall by evaluating, besides the neointima-to-media ratio, the medial and neointimal area and cellularity in the rat femoral artery. Vascular injury was photochemically induced in rat femoral arteries. Immediately or 14 days thereafter, rats were infected with rat CMV (RCMV) or mock infected. The presence of RCMV in the vascular wall was determined at 3, 5, 14 and 35 days after infection by quantitative real-time PCR. When rats were infected immediately after injury, a significant increase was seen only in the medial but not in the neointimal cross-sectional area. On the other hand, when rats were infected 14 days after the initial injury, a significant increase was only seen in the neointimal area, thereby confirming our hypothesis that RCMV infection primary affects proliferating SMCs. As the mean number of SMCs per microm2 in both cell layers was unchanged despite an increase in cross-sectional area, this implies that RCMV stimulated SMC proliferation. Furthermore, these vascular effects were observed without the virus being abundantly present in the vascular wall, suggesting that inflammatory and immune-mediated responses to RCMV infection are more important in aggravating the response to vascular injury than the virus itself.

Induction of endothelial cell damage by hCMV molecular mimicry.

Molecular mimicry between infectious agents and normal human host cell components is one of the mechanisms responsible for autoimmunity. Among infectious agents, some viruses represent ideal candidates for their ability to infect human cells, where they are harbored for the duration of the life of the host in a latent state. Human cytomegalovirus (hCMV) infection has been implicated in the pathogenesis of vascular damage in systemic sclerosis (SSc) and atherosclerosis. Based on recent data describing a cause and effect relationship between hCMV and endothelial cell damage in SSc and atherosclerosis, we propose that the immune response to particular hCMV proteins might result in autoaggression through a mechanism of molecular mimicry of normally expressed endothelial cell surface molecules.

Roles of an IkappaB kinase-related pathway in human cytomegalovirus-infected vascular smooth muscle cells: a molecular link in pathogen-induced proatherosclerotic conditions.

Viral and bacterial pathogens have long been suspected to affect atherogenesis directly. However, mechanisms linking innate immunity to chronic inflammatory diseases such as atherosclerosis are still poorly defined. Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with human cytomegalovirus (HCMV) leads to activation of the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector of the cellular innate immune response. We demonstrate that part of the HCMV inflammatory response is most likely mediated via this novel kinase because the canonical IKK complex was only poorly activated upon infection of HAOSMC. An increase in TBK1 phosphotransferase activity led to a strong activation of the interferon regulatory factor (IRF)-3 transcription factor as measured by its C-terminal phosphorylation, dimerization, and DNA binding activity. In addition to TBK1, HAOSMC also express another IKK-related kinase isoform, IKKepsilon, albeit at a lower level. Nevertheless, both isoforms were required for full activation of IRF-3 by HCMV. The transcripts of proatherosclerotic genes Ccl5 (encoding for the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted)) and Cxcl10 (encoding for the chemokine IP-10 (interferon-gamma-inducible protein 10)) were induced in an IRF-3-dependent manner after HCMV infection of smooth muscle cells. In addition, cytokine arrays analysis showed that RANTES and IP-10 were the predominant chemokines present in the supernatant of HCMV-infected HAOSMC. Activation of the TBK1/IRF-3 pathway was independent of epidermal growth factor receptor and pertussis toxin-sensitive G protein-coupled receptor activation. Our results thus add additional molecular clues to a possible role of HCMV as a modulator of atherogenesis through the induction of a proinflammatory response that is, in part, dependent of an IKK-related kinase pathway.

Detection of herpes simplex virus, cytomegalovirus and Epstein-Barr virus DNA in atherosclerotic plaques and in unaffected bypass grafts.

BACKGROUND: Herpes virus infections are suspected to be involved in the pathogenesis of atherosclerosis. OBJECTIVE AND METHOD: Viral DNA of herpes simplex virus (HSV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was analyzed by real-time PCR on 48 biopsies from atherosclerotic plaques extracted by end-arterectomy (46 coronary arteries, 2 carotid arteries), and in tissue from non-atherosclerosis vessels from the same patient as controls (23 internal mammary arteries, 43 saphenous veins). RESULTS: HSV-1 DNA was detected significantly more frequently in plaques (35%) than in control veins (9%, P = 0.006). However, the frequency of HSV-1 DNA detection in the internal mammary artery grafts was as high as in plaques (22%, P = 0.28). CMV and EBV DNA were exclusively found in plaques but not in controls, with 10% for CMV (P = 0.06 versus veins, P = 0.17 versus graft arteries) and 2% for EBV (P = 1.0), respectively. HSV-2 was neither detected in plaques nor in controls. Herpes viral DNA was significantly associated only with arterial hypertension but not with other classical risk factors (P = 0.02), in accordance with the hypothesis that herpes viral infection may alter the vessel wall. CONCLUSION: We conclude that herpes viral infections may have a role in atherosclerosis and that the presence of herpes viral DNA in the grafts used for bypass surgery might constitute a potential risk for atherosclerosis or restenosis.

[The presence of Chlamydophila pneumoniae, Helicobacter pylori and cytomegalovirus in human atherosclerosis detected by molecular and serological methods]. / Aterosklerozda Chlamydophila pneumoniae, Helicobacter pylori ve cytomegalovirus varliginin moleküler ve serolojik yöntemlerle arastirilmasi.

Persistant infections due to Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus are suggested to contribute to the development of atherosclerosis. In this study, the presence of these agents was investigated by polymerase chain reaction (PCR) and serological tests in atherosclerotic plaques and non-atherosclerotic vessel samples. Thirty-three specimens from the atherosclerotic plaques (lesion group), 45 specimens from the healthy left internal mammarian arteries and ascending aortas of the atherosclerotic patients (non-lesion group), and 15 specimens from the aortas of non-atherosclerotic patients as determined by angiography (control group), were included to the study. Serum samples were also collected from all study subjects for the serological investigation. PCR and ELISA were used in order to determine the nucleic acid positivity and IgG titers, respectively. C. pneumoniae and H. pylori DNA were found in 6 (18.1%) and 14 (42.4%) of the lesion group, 2 (4.4%) and 9 (20%) of the non-lesion group, respectively. CMV DNA was not found in either groups. All of the PCR results of control group were negative. C. pneumoniae IgG was found positive in one case of the lesion group (3%) and three cases of the non-lesion group (6.7%). H. pylori IgG were positive in all the subjects except for three patients who were in the non-lesion group. The presence of C. pneumoniae and H. pylori DNA in a considerable number of lesion and non-lesion groups' specimens, but absence in control group specimens supports the hypothesis that these agents have an association with atherosclerosis.

The role of viruses in cardiac allograft vasculopathy.

Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

Enhanced cytomegalovirus infection in atherosclerotic human blood vessels.

Human cytomegalovirus (CMV) is a possible co-factor in atherogenesis and vascular occlusion, but its ability to actively infect medium and large blood vessels is unclear. A vascular explant model was adapted to investigate CMV infection in human coronary artery, internal mammary artery (IMA), and saphenous vein (SV). Vascular explants were inoculated with CMV Towne or low-passage clinical isolate and examined in situ for CMV cytopathic effect and immediate-early and early antigens, as indicators of active infection. At 5 to 7 days after inoculation, we found that CMV Towne actively infected eight of eight different atherosclerotic blood vessel explants (coronary artery, n = 4; SV and IMA grafts, n = 4), whereas it only infected 2 of 14 nonatherosclerotic blood vessel explants (SV, n = 10; IMA, n = 4) (P = 0.001). The CMV clinical isolate actively infected none of six sets of nonatherosclerotic SV explants at 5 to 7 days after inoculation. The active CMV infections involved adventitial and, less frequently, intimal cells. A small subset of infected cells in atherosclerotic tissue expresses the endothelial cell marker CD31. Smooth muscle cells residing in both atherosclerotic and nonatherosclerotic blood vessels were free of active CMV infections even after all vascular tissue layers were exposed to the virus. In contrast, active CMV Towne infection was evident at 2 days after inoculation in smooth muscle cells and endothelial cells previously isolated from the SV tissues. We conclude that active CMV infection is enhanced in atherosclerotic blood vessels compared to atherosclerosis-free vascular equivalents, and this viral activity is restricted to subpopulations of intimal and adventitial cells.

[The role of infection in the pathogenesis of atherosclerosis]. / Rola zakazeniaw patogenezie miazdzycy.

Experimental models and human studies have supported a role of infection in the initiation of atherosclerosis. There are many known microorganisms who can play an important role in atherosclerosis, but especially two of them--Chlamydia pneumoniae and Cytomegalovirus are suspected to stimulate the process of atheromatosis. Until antibiotics or vaccines are useful in artery diseases prevention, therapies with proven vascular anti-inflammatory effects (diet, exercise, smoking cessation, aspirin, statins) should be optimized.

[Can we be infected with atherosclerosis?]. / Czy mozna zarazic sie miazdzyca?

Atherosclerosis is one of the most important problems of the contemporary medicine and it is the most frequent reason of deaths in Western countries. Conventional risk factors are responsible for only 50% cases of atherosclerosis. Investigations performed over last 20 years revealed new risk factors, like for example bacterial and viral infections. In recent scientific descriptions Chlamydia pneumoniae, Helicobacter pylori and viruses from Herpesviridae family (Cytomegalovirus hominis, Epstein-Barr virus, Herpesvirus hominis) are mentioned as those, which could take part in the atherogenesis. The infectious theory of atherosclerosis might be proved by the presence of maintained above pathogens in the atheromatous plaque and the existence of antibodies against bacteria and viruses in blood.

Anti-cytomegalovirus (CMV) IgG antibody titer in patients with risk factors to atherosclerosis.

Studies have demonstrated cytomegalovirus (CMV) DNA particles in restenotic lesions in atherosclerotic coronary arteries. We have shown that high (>1:800) anti-CMV IgG antibody titers in the serum are associated with active coronary disease and with post coronary angioplasty restenosis. In this study we assessed the anti-CMV antibody titer in patients with risk factors for atherosclerosis (but without documented clinical manifestations). One hundred and eighly-seven patients (men and women aged 40-80 years) that were admitted to the Department of Internal Medicine were recruited to this prospective study. All had at least one risk factor for atherosclerosis, and none had documented coronary artery disease. Fasting blood samples were drawn on admission. Risk factors included hypertension, diabetes mellitus, active smoking, hyperlipidemia, and a positive family history. Ninety-three age- and sex-matched individuals without atherosclerosis risk factors served as the control group. One Hundred and twentysix patients had high anti-CMV antibody titers (>/=1:800) compared with none in the control group. Although 80 patients (90%) in the control group were seropositive, none had anti-CMV IgG antibody titers higher than 1:400. The statistical difference between the patients and the control group was highly significant ( p<0.0001). An immunological response against CMV (expressed as an anti-CMV IgG antibody titer) could be a marker of a long-standing immunological reaction causing an inflammatory response that eventually would cause advanced clinical atherosclerosis. We suggest that anti-CMV antibody titer should be used as an early predictor of atherosclerosis. Our findings support the infectious theory and an association between CMV infection and atherosclerosis at an early stage, maybe even years before clinical events occur.

IL-6 is produced by splenocytes derived from CMV-infected mice in response to CMV antigens, and induces MCP-1 production by endothelial cells: a new mechanistic paradigm for infection-induced atherogenesis.

Atherosclerosis is an inflammatory disease. One of the candidate inflammatory triggers is infection. To further characterize the interaction between infection, cytokine induction, and atherosclerosis, we tested the hypothesis that cytomegalovirus (CMV) infection induces the pro-inflammatory cytokine interleukin-6 (IL-6), which in turn induces "pro-atherosclerotic" changes in vascular endothelial cells (ECs). ELISA was used to determine the levels of monocyte chemoattractant protein-1 (MCP-1) in the supernatant of mouse and human ECs incubated with IL-6, and IL-6 levels in supernatants of splenocytes, derived from CMV-infected and uninfected mice, stimulated with mice CMV antigens. IL-6 induced, in a dose response fashion, MCP-1 expression in human ECs: 0, 2, 10, and 50 pg/ml IL-6 increased MCP-1 levels in EC conditioned medium from 1120+/-65 to 1148+/-105, 1395+/-40, and 2119+/-130 pg/ml, respectively (P<0.001). IL-6 also induced MCP-1 expression in mouse ECs (P<0.002). Importantly, IL-6 concentration in the supernatants of splenocytes stimulated with CMV antigens rose from undetectable levels in uninfected mice to 14.9+/-5 pg/ml in the infected mice (P<0.04). These results suggest a previously unrecognized, but potentially important mechanism whereby CMV, and other pathogens, contribute to atherogenesis: T lymphocytes, clonally expanded in response to antigens presented by CMV infection, home to sites of vascular injury and locally release IL-6 when presented with either pathogen antigens that may be present in the plaque, or when they cross-react with host peptides homologous to the relevant pathogen antigens; IL-6 then triggers ECs to release MCP-1, which recruits more monocytes and T-cells into the vessel wall and thereby exacerbates local inflammation, and thus atherogenesis.