High prevalence of human cytomegalovirus in carotid atherosclerotic plaques obtained from Russian patients undergoing carotid endarterectomy (original) (raw)
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Archives of Medical Science - Atherosclerotic Diseases
Introduction: The most common etiologic factor of coronary artery disease (CAD), carotid artery disease, and peripheral artery disease is atherosclerosis. In our study, we aimed to show the effect of cytomegalovirus (CMV), which can occur almost everywhere in the human body, on triggering the chronic inflammatory process in the pathophysiology of atherosclerosis, and its presence and impact in the plaques leading to carotid artery stenosis. Material and methods: Thirty-six patients, who underwent carotid endarterectomy at the Department of Cardiovascular Surgery, Istanbul University Istanbul Medical Faculty between April 2017 and April 2018, were included in this study upon their consent. Patients with additional immunosuppressive conditions were not included in the study. Unilateral atheromatous plaque was preferred for patients undergoing bilateral carotid endarterectomy and all risk factors (DM, HT, hyperlipidemia, etc.) were evaluated together for all patients. Results: When the relationship between CMV (DNA) presence in samples taken from patients' plaques and sex, age and comorbidities was examined, CMV (DNA) positivity (45.8%) was significantly higher in DM patients than non-DM patients (8.3%) (p = 0.024). Likewise, CMV(DNA) positivity (40%) was significantly higher in HT patients than in non-HT patients (25%) (p = 0.008). CMV(DNA) positivity (63%) was significantly higher in patients with bilateral carotid artery stenosis than patients without bilateral carotid artery stenosis (0%) (p < 0.001). Conclusions: It has not yet been clarified whether CMV is a primary trigger for atherosclerosis on the vascular wall, or whether it presents incidentally due to its affinity. When CMV (DNA) positivity was examined according to the presence of bilateral carotid artery stenosis in our study, CMV (DNA) positivity was found to be significantly higher in patients with bilateral carotid artery stenosis (63.16%).
Experimental and clinical cardiology
Human cytomegalovirus (HCMV) has been suggested by several studies as an infectious agent that may induce or accelerate the progression of atherosclerosis in humans. In the present study, the main objective was to analyze the presence of HCMV-DNA in atherosclerotic plaques obtained from surgical procedures and, then, correlate risk factors for the development of atherosclerosis, such as diabetes mellitus, hypertension, myocardial infarction, smoking, age and gender. Combinations, or associations, of these risk factors were also evaluated. A total of fifty seven atherosclerotic plaque samples were analyzed using the Nested-PCR technique for HCMV-DNA detection. HCMV-DNA was detected in 17/57 patients (29.82%). In the present study, was not detected high HCMV prevalence in atherosclerotic plaques. The relationship between smoking and the presence of HCMV in the specimens was found to be statistically significant (p≤0.0364).
Human cytomegalovirus infection and atherothrombosis
Journal of Thrombosis and Thrombolysis, 2012
Vascular endothelium, as a key regulator of hemostasis, mediates vascular dilatation, prevents platelet adhesion, and inhibits thrombin generation. Endothelial dysfunction caused by acute or chronic inflammation, such as in atherosclerosis, creates a proinflammatory environment which supports leukocyte transmigration toward inflammatory sites, and at the same time promotes coagulation, thrombin generation, and fibrin deposition in an attempt to close the wound. Life-long persistent infection with human cytomegalovirus (HCMV) has been associated with atherosclerosis. In vivo studies have revealed that HCMV infection of the vessel wall affects various cells including monocytes/macrophages, smooth muscle cells (SMCs) and endothelial cells (ECs). HCMV-infected SMCs within vascular lesions display enhanced proliferation and impaired apoptosis, which contribute to intimamedia thickening, plaque formation and restenosis. Monocytes play a central role in the process of viral dissemination, whereas ECs may represent a viral reservoir, maintaining persistent infection in HCMV-infected atherosclerotic patients following the primary infection. Persistent infection leads to dysfunction of ECs and activates proinflammatory signaling involving nuclear factor jB, specificity protein 1, and phosphatidylinositol 3-kinase, as well as expression of platelet-derived growth factor receptor. Activation of these pathways promotes enhanced proliferation and migration of monocytes and SMCs into the intima of the vascular wall as well as lipid accumulation and expansion of the atherosclerotic lesion. Moreover, HCMV infection induces enhanced expression of endothelial adhesion molecules and modifies the proteolytic balance in monocytes and macrophages. As a consequence, infected endothelium recruits naive monocytes from the blood stream, and the concomitant interaction between infected ECs and monocytes enables virus transfer to migrating monocytes. Endothelial damage promotes thrombin generation linking inflammation and coagulation. HCMV, in turn, enhances the thrombin generation. The virus carries on its surface the molecular machinery necessary to initiate thrombin generation, and in addition, may interact with the prothrombinase protein complex thereby facilitating thrombin generation. Thus, infection of endothelium may significantly increase the production of thrombin. This might not only contribute to thrombosis in patients with atherosclerosis, but might also induce thrombin-dependent proinflammatory cell activation. This review summarizes the existing evidence on the role of HCMV in vascular inflammation.
Journal of Vascular Surgery, 1999
Background: Although the association between inflammation and atherosclerosis is well established, the biologic events that trigger the local inflammatory response within plaque are not fully understood. Cytotoxic free radicals and infectious agents, both of which are associated with an inflammatory response, have previously been implicated in the initiation and progression of atherosclerosis. In this study, we analyzed carotid plaque for evidence of oxidative vascular injury by determining the presence and distribution of inducible nitric oxide synthase (iNOS) expression and nitrotyrosine formation and for evidence of infection with cytomegalovirus. Methods: Carotid plaque from 51 patients who underwent endarterectomy for either primary (n = 37) or recurrent (n = 14) stenosis were examined histologically (hematoxylineosin staining and Masson's trichrome staining) and with immunohistochemistry with specific antibodies to α-smooth muscle actin, macrophages (CD68), T-lymphocytes (CD3), and T-cell activation (human leukocyte antigen-DR). Twenty-eight specimens from patients with primary (n = 15) and recurrent (n = 13) stenosis were examined for the presence of iNOS and nitrotyrosine with immunohistochemistry and in situ hybridization (iNOS). Twenty-three additional specimens (22 primary, and 1 recurrent) were analyzed with antibodies to p53, cytomegalovirus, and the polymerase chain reaction (cytomegalovirus, n = 8). Results: Primary atherosclerotic lesions were either complex heterogenous cellular plaques (n = 29) or relatively acellular fibrous plaques (n = 8). Ten of 14 recurrent plaques were either complex or fibrous lesions, and the remaining four were typical of myointimal thickening. CD68-positive staining cells were detected in all specimens regardless of their structural morphology. CD3-positive cells were interspersed between macrophages in all heterogeneous cellular plaques and only infrequently noted in fibrous plaques. iNOS and nitrotyrosine immunoreactivity were detected in macrophages and smooth muscle cells in all complex and fibrous plaques and in two of four myointimal plaques. The presence of iNOS and nitrotyrosine in plaque correlated with the existence of symptoms in 80% of primary and 62% of recurrent lesions. Cytomegalovirus was detected in only two of 23 carotid specimens (9%). Conclusion: The association between ischemic cerebrovascular symptoms and iNOS and nitrotyrosine immunoreactivity in complex primary and recurrent carotid plaque and the infrequent occurrence of cytomegalovirus in primary carotid lesions suggests that ongoing free radical oxidative damage rather than viral infection may contribute to plaque instability in patients with complex and fibrous carotid plaques. (J Vasc Surg 1999;30:36-50.)
Atherosclerosis, 2001
The possible contribution of cytomegalovirus (CMV) to pathogenetic events associated with atherosclerotic lesion establishment and progression is still controversial. We evaluated the possibility that active ongoing CMV infection could be correlated to evolution of unstable atheromatous lesion, by analyzing patients suffering from unstable angina (n = 61), acute myocardial infarction (n=43), stable angina (n= 26) and peripheral arteriopathy (n = 22) as compared to healthy subjects (n =30). Particularly, we assessed: past exposure to CMV by evaluating anti-CMV IgG antibodies; ongoing CMV infection by evaluating anti-CMV IgM antibodies and circulating interleukin (IL)-8 in serum; and CMV DNAemia in peripheral blood mononuclear cells (PBMC). Mean IgG values were significantly increased in patients from all groups, as compared to healthy subjects. CMV-specific IgM, as well as CMV DNAemia, were undetectable in both controls and patients. Circulating IL-8, significantly elevated in a group of individuals experiencing active CMV infection, was not significantly higher in cardiovascular disease patients, as compared to control subjects. These findings confirm previous evidence from the increased exposure to CMV infection in patients with atheromatous lesions. However, they provide further evidence against a direct implication of active systemic CMV infection in the pathogenesis of cardiovascular diseases, particularly those involving plaque instability.
Acta Microbiologica et Immunologica Hungarica, 2006
The aim of our study was to investigate the combination of Chlamydophila pneumoniae and human cytomegalovirus (HCMV) as a pathogenic factor in atherosclerosis. Accordingly, we tested by means of PCR and immunohistochemistry the presence of these pathogens in the same atherosclerotic carotid specimen. The histology of the samples and the patients' antibodies against these pathogens were evaluated. Further, we examined the impact of C. pneumoniae and HCMV infection on the gene expression of the human monocytic cell line U937. Six of the 22 samples contained only C. pneumoniae, 4 contained only HCMV, 7 contained both C. pneumoniae DNA and/or antigens of both pathogens, and 5 samples were negative. No correlation was found between the presence of these microbes and either the cellular structure of the plaques, or the serostatus of the patients. The infection of U937 cells with HCMV and especially C. pneumoniae induced inflammation and atherosclerosis-related genes. Furthermore, the doubly-infected cells produced higher levels of the mRNA of pro-platelet basic protein and fatty acid binding protein 4. In conclusion, C. pneumoniae is often present in combination with HCMV in atherosclerotic carotid lesions. The in vitro coinfection model reveals that the doubly-infected monocytes are potent expressors of proatherosclerotic genes, suggesting that this coinfected population may accelerate the process of atherosclerosis.
2012
It has been shown that cytomegalovirus (CMV) is present in coronary atherosclerotic plaques, but the clinical relevance of this presence remains to be elucidated. In this study we sought to examine CMV infection in atherosclerosis patients defined by different methods and to identify the clinical significance of CMV replication in the atherosclerotic plaques. The study included 105 consecutive patients who were admitted to our department and underwent coronary artery bypass grafting (CABG) surgical interventions. Coronary atherosclerotic specimens as well as 53 specimens from the mamillary artery of these same patients were analyzed. Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods were used for evaluations. The CMV PCR test result was positive for 28 (26.7%) of patients with coronary artery atherosclerosis. After adjusting for other risk factors, coronary artery disease patients with a history of acute coronary syndrome were more likely to be positive for CMV PCR test (P = 0.027; odds ratio: 4.2; 95% CI: 1.18-15.0). They were also more likely to have a positive family history for cardiovascular diseases (CVD). This study confirms previous evidence about the replication of CMV virus in the atherosclerotic plaques of coronary arteries and brings clinical significance to this observation by showing a higher prevalence of acute coronary syndromes in those patients with CMV-infected plaques. Our study also suggests a familial vulnerability to CMV replication in the coronary artery walls.
Enhanced Cytomegalovirus Infection in Atherosclerotic Human Blood Vessels
The American Journal of Pathology, 2004
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. Experimental findings in animals and isolated human vascular cells, as well as some epidemiological studies in humans, support the hypothesis that human cytomegalovirus (CMV) may be a co-factor in atherosclerosis, 1-4 arterial restenosis, 5 acute arterial occlusion, 6 -8 and posttransplant coronary artery (CA) disease. 9,10 CMV might contribute to vascular disease by direct invasion of the blood vessel wall or by acting from distant sites through host-inflammatory response or perturbation of lipid metabolism. 11-13 Several investigators have reported that CMV nucleic acid is often present in walls of atherosclerotic arteries, 14 -19 implicating a role for CMV in directly initiating or advancing this disease. However, very little is known about the virus's ability to replicate within atherosclerosis-prone blood vessels, despite long-standing awareness of CMV's proclivity for replicating in and damaging small blood vessels and capillaries of persons with CMV disease. 20 Notably, rat CMV replicates in mechanically injured carotid arteries but not in healthy contralateral arteries of acutely infected rats, implying that preexisting vascular injury or inflammation can render large arteries conducive to viral replication. Endothelial cells (ECs) and smooth muscle cells (SMCs) that are isolated from human arteries and subsequently inoculated with CMV are able to support viral replication. The CMV replicative process disrupts cell-cycle control 16,24 and increases amounts or activities of procoagulant proteins, 25 reactive oxygen species, 26 -28 leukocyte adhesion molecules, 29 -32 cholesterol uptake and esterification, 33 cell motility, 34 and proinflammatory cytokines. 5,35-37 Thus, findings in isolated ECs and SMCs suggest multiple mechanisms by which CMV might promote atherogenesis and its complications.