The possible role of human cytomegalovirus (HCMV) in the origin of atherosclerosis
Introduction
More than half of the population of developed countries is dying as a result of cardiovascular disease or stroke, primarily, although not exclusively, related to atherosclerosis. While the major life-threatening effects are produced by atherosclerotic lesions in the coronary arteries leading to myocardial infraction or carotid arteries leading to stroke, the same lesions can be found in the iliac-femoral bed, producing claudication and non-healing leg ulcers, or in the renal arteries (producing hypertension), and in the aorta.
Atherosclerosis results from the response of elastic and muscular arteries to the stresses of turbulence, stretch and in an environmental and genetic makeup of the individual. Injury of the normal endothelium by physical, biochemical or biological factors leads to changes in the surface characteristics and/or function of this tissue layer. This is followed by the adhesion of platelets and of monocytes/macrophages and the migration of the latter into subendothelium, where they imbibe lipid (primarily cholesteryl ester droplets) creating so called ‘foam cells’ (Andĕl et al., 1997).
Although many well-known causes (both genetic and environmental) of atherogenesis have been published, many authors also refer to the possible role of pathogen infection in this process (Stites and Terr, 1991, Danesh et al., 1997). The mechanism of action of these pathogens in atherogenesis could be based on direct endothelium damage (atherosclerosis development succeeds the primer arterial wall attack), on the overproduction of growth factors based on the alteration of metabolism of infected cells (Alcami et al., 1991), on the expression of specific adhesive molecules and perhaps also on the C-reactive protein (CRP) activity (which level increase upon infection) (Stites and Terr, 1991, Andĕl et al., 1997).
Human herpesviruses causing persistent or latent infections are the most suspected pathogen from this point of view. They are widespread in human population and the primer infection generally occurs in early childhood. For instance in the US the prevalence of human cytomegalovirus (HCMV) is about 10–15% in adolescents, it rises to more than 50% by the age 35 and exceeds 70% in those older than 65 (Grattan et al., 1989, Melnick et al., 1996). Also Epstein–Barr virus (EBV) infections occurs in more than 90% of the adult population and the antibodies against human herpesvirus 6 (HHV6) were presented in more than 60% of the adult population (The et al., 1992, Straus, 1993).
After initial, usually asymptomatic infection the herpesviruses can remain latent, periodically reactivated, in otherwise healthy individuals mostly without evident consequences. Clinical, serological and epidemiological data has been used to formulate a concept of etiological relation between chronic persistent EBV infection and atherosclerosis (Krylov and Kupchinski, 1990).
HCMV is also one of the most important pathogens in patients after organ transplantation in which an active infection, often complicated with other opportunistic infections, may lead to interstitial pneumonia with bad prognosis (Wolff et al., 1996). It seems to be also implicated in the graft arteriosclerosis and chronic rejection after heart transplantation (Lautenschlager et al., 1997). Possibly it also can affect the process of myocarditis, imitating graft rejection, and can also affect the process of rejection by induction of antigen changes or by direct heart tissue damage (Jäkel et al., 1992).
Higher frequency of concominant EBV and HCMV infection was observed in atherosclerotic patients when using serological methods (Musiani et al., 1990, Kupchinski, 1993, Kupchinski and Krylov, 1993, Robertson et al., 1995). The clinical importance of HHV6 remains to be resolved. Primary infection can sometimes be demonstrated in children as an exanthema subitum and, in immunosuppressed patients, can cause pneumonia (Herbein et al., 1996).
The presented work is focused on the possible effect of HCMV, EBV and HHV6 on the initiation of IHD. In order to enlarge our knowledge about the role of herpesviruses in the origin of IHD the presence of DNA in these three herpesviruses in aortic and venous walls as well as in peripheral blood samples of both IHD patients and a coronarographically negative control group was tested by the use of polymerase chain reaction (PCR). Genetic tests were accompanied by tests of sera for the presence of anti-virus antibodies of IgM and IgG types for all experimental groups.
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Positive controls
For the preparation of positive controls, the following virus-infected cell cultures were used: human embryonic lung fibroblasts (HEL) infected by HCMV strain AD169, HEL infected by HHV6, EBV containing P3HR1 and Raji cell cultures. All the tissue cultures and strains were kindly provided by Dr Roubalová, Nat. Lab. for Herpesviruses, SZU Praha, CZ. To the PCR 2 μl of each cell suspension were added without any isolation.
Subjects and specimens
There are three groups of patients used in the study:
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Group 1: 244 IHD
Results
In order to prove the presence of genomic DNA of three human herpesviruses (HCMV, EBV, and HHV6) in aortic or venous walls and determine possible associations between virus infection and atherosclerosis development, three groups of subjects were tested. For viral DNA presence in the aortic walls 244 IHD patients were examined (Group 1). For the viral DNA presence in aortic and venous wall as well as in peripheral blood 85 IHD patients were tested (Group 2). As a negative control, the group of
Discussion
Atherosclerosis can develop after initial damage of arterial wall. HCMV, which is able to infect arterial wall endothelium and cause smooth muscle cell proliferation, seems to be one of the possible causes of such damage. Moreover, it is known that HCMV can alter cell metabolism and perhaps induce transformation of cell surface antigens of infected tissues (Melnick et al., 1990, Andĕl et al., 1997).
The support for the hypothesis of HCMV origin of atherosclerosis is available mostly from
References (30)
- et al.
Chronic infections and coronary heart disease: is there a link?
Lancet
(1997) - et al.
Persistent cytomegalovirus in liver allografts with chronic rejestion
Hepatology
(1997) - et al.
Cytomegalovirus antigen within human arterial smooth muscle cells
Lancet
(1983) - et al.
Culture characterization and viral infection of aortic smooth muscle cells from Japanese quail susceptible to atherosclerosis
Exp. Mol. Pathol.
(1994) - et al.
Cytomegalovirus infection induces vascular injury in the rat
Atherosclerosis
(1992) - et al.
Possible role of cytomegalovirus in the pathogenesis of inflamatory aortic diseases
J. Vasc. Surg.
(1992) - et al.
Induction of an endothelial cell growth factor by human cytomegalovirus infection of fibroblasts
J. Gen. Virol.
(1991) - et al.
Pathogenesis of atherosclerosis: from metabolic changes to persistent infection with aspects of cummulating disease
Praktický lékar
(1997) - et al.
The possible role of CMV in atherogenesis
Prog. Med. Virol.
(1991) - et al.
Impaired arterial reactivity following cytomegalovirus infection in the immunosupressed rat
Br. J. Pharmacol.
(1996)
Cytomegalovirus is asociated with cardiac allograft rejection and atherosclerosis
JAMA
The presence of cytomegalovirus nucleic acids in arterial wals of atherosclerotic and non-atherosclerotic patients
Am. J. Pathol.
Longitudial study of human herpesvirus 6 infection in organ transplantant recipients
Clin. Infect. Dis.
Rejection, herpesvirus infection, and Ki-67 expression in endomyocardial biopsy specimens from heart transplant recipients
Path. Res. Pract.
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