CMV & other infections cause heart disease

Cytomegalovirus

Cytomegalovirus antigen within human arterial smooth muscle cells. JL Melnick, BL Petrie, GR Dreesman, J Burek, CH McCollum, ME DeBakey. Lancet 1983 Sep 17;2(8351):644-647.More than 25% of plaque and biopsy samples contained CMV antigens.

Cytomegalovirus and atherosclerosis (letter). MS Smith, PC Venter, JL de Wet. S Afr Med J 1984 May 19;65(20):793. No abstract.

Herpesviridae in the endothelial and smooth muscle cells of the proximal aorta in arteriosclerotic patients. F Gyorkey, JL Melnick, GA Guinn, P Gyorkey, ME DeBakey. Exp Mol Pathol 1984 Jun;40(3):328-339.

High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. E Adam, JL Melnick, JL Probtsfield, BL Petrie, J Burek, KR Bailey, CH McCollum, ME DeBakey. Lancet 1987 Aug 8;2(8554):291-293. "The prevalence of CMV antibodies was higher in the surgical group than in the control group (90% and 74%, respectively), and a significantly greater percentage (p less than 0.001) of surgical cases than controls had high titres of CMV antibodies (57% and 26%, respectively)."

The presence of cytomegalovirus nucleic acids in arterial walls of atherosclerotic and nonatherosclerotic patients. MG Hendrix, PH Dormans, P Kitslaar, F Bosman, CA Bruggeman. Am J Pathol 1989 May;134(5):1151-1157.

High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. MG Hendrix, MM Salimans, CP van Boven, CA Bruggeman. Am J Pathol 1990 Jan;136(1):23-28. "By PCR 90% of the samples obtained from atherosclerotic patients were shown to contain viral nucleic acids as compared to 53% of patients with maximally grade I atherosclerosis, thus substantiating a role for this virus in the pathogenesis of atherosclerosis."

Warner-Lambert/Parke-Davis Award Lecture. Viral pathogenesis of atherosclerosis. Impact of molecular mimicry and viral genes. DP Hajjar. Am J Pathol 1991 Dec;139(6):1195-1211. Review.

Possible role of cytomegalovirus in the pathogenesis of inflammatory aortic diseases: a preliminary report. S Tanaka, Y Toh, R Mori, K Komori, K Okadome, K Sugimachi. J Vasc Surg 1992 Aug;16(2):274-279.

Cytomegalovirus and atherosclerosis. JL Melnick, E Adam, ME DeBakey. Eur Heart J 1993 Dec;14 Suppl K:30-38. Review, including the known role of avian herpesviruses in atherosclerosis in chickens; and accelerated atherosclerosis in immunosuppressed heart transplant patients.

Cytomegalovirus DNA in arterial walls of patients with atherosclerosis. JL Melnick, C Hu, J Burek, E Adam, ME DeBakey. J Med Virol 1994 Feb;42(2):170-174. Evidence of CMV infection was found in 90% of surgical samples from 135 patients.

Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. E Speir, R Modali, ES Huang, MB Leon, F Shawi, T Finkel, SE Epstein. Science 1994 Jul 15;265(5170):391-394. 23/60 (38%) of lesions accumulated high levels of p53, "and this correlated with the presence of human cytomegalovirus (HCMV) in the lesions." HCMV protein IE84 bound to and inactivated p53.

Cytomegalovirus and atherosclerosis. JL Melnick, E Adam, ME DeBakey. Bioessays 1995 Oct;17(10):899-903. Review.

[Detection of human cytomegalovirus DNA in vascular plaques of atherosclerosis by in situ hybridization] S Chen, W Li, Y Yang. Zhonghua Yi Xue Za Zhi 1995 Oct;75(10):592-3, 638. CMV DNA was found in 13/32 atherosclerosis specimens versus 1/15 normal specimens.

Cytomegalovirus and atherosclerosis. JL Melnick, E Adam, ME DeBakey. Arch Immunol Ther Exp (Warsz) 1996;44(5-6):297-302. Review.

Cytomegalovirus infection, lipoprotein(a), and hypercoagulability: an atherogenic link? FJ Nieto, P Sorlie, GW Comstock, K Wu, E Adam, JL Melnick, M Szklo. Arterioscler Thromb Vasc Biol 1997 Sep;17(9):1780-1785. "CMV virus might have procoagulant properties."

Cytomegalovirus infection and atherosclerosis. E Adam, JL Melnick, ME DeBakey. Cent Eur J Public Health 1997 Sep;5(3):99-106. Review.

Cytomegalovirus genome and the immediate-early antigen in cells of different layers of human aorta. SYu Pampou, SN Gnedoy, VB Bystrevskaya, VN Smirnov, EI Chazov, JL Melnick, ME DeBakey. Virchows Arch 2000 Jun;436(6):539-552.

Host response to cytomegalovirus infection as a determinant of susceptibility to coronary artery disease. Zhu J et al. Circulation 2000 Nov 14;102:2491-2496. In men, CMV infection is linked to coronary artery disease via elevation of C-reactive protein levels. In women, "CMV positivity was independently predictive of CAD, a relationship that was highly significant (odds ratio, 41.8; 95% CI, 4.12 to 423.74; P = 0.002). However, the association between elevated CRP levels and CAD was not as strong in women as it was in men. It therefore seems that men, more consistently than women, mount an inflammatory response to CMV infection and that this response appears to predispose to CAD." "We found that although there was no influence of immunoresponse patterns on disease susceptibility in men, susceptibility to CMV-related CAD was limited to women with a humoral immune response to CMV infection.... These differences could not be explained by subgroup-related differences in age, smoking, diabetes, hypercholesterolemia, and hypertension (all P > 0.1)."

Cytomegalovirus seropositivity and C-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. JB Muhlstein, BD Home, JF Carlquist, TE Madsen, TL Bair, RR Pearson, JL Anderson. Circulation 2000 Oct 17;102(16):1917-1923. CRP and CMV at baseline predicted death during approximately 2.7 year followup (HR=2.4, P=0.001; HR=1.9, P<0.05).

Discordant cellular and humoral immune responses to cytomegalovirus infection in healthy blood donors: existence of a T(h)1-type dominant response. J Zhu, GM Shearer, FM Marincola, JE Norman, D Rott, JP Zou, SE Epstein. Int Immunol 2001 Jun;13(6):785-790. "Whether these different patterns predict susceptibility or resistance to CMV-induced disease remains to be determined." But it looks like a sure bet.

Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. S Blankenberg, HJ Rupprecht, C Bickel, C Espinola-Klein, G Rippin, G Hafner, M Ossendorf, K Steinhagen, J Meyer. Circulation 2001 Jun 19;103(24):2915-2921. "CONCLUSIONS: [C]MV seropositivity in patients with an inflammatory response is independently associated with future cardiac mortality, whereas this association is lost in patients who do not demonstrate an inflammatory response. These data support the hypothesis that the atherosclerotic effects of CMV are mediated through an underlying inflammatory response."

Molecular-based strategies for assessment of CMV infection and disease in immunosuppressed transplant patients. A Kulkarni, D Westmoreland, JD Fox. Clin Microbiol Infect 2001 Apr;7(4):179-186. News re Kulkarni: Molecular tests for cytomegalovirus do not always agree. M Pownall. PSL Group Doctors Guide 2001 Jun 21.

Cytomegalovirus seropositivity and c-reactive protein have independent and combined predictive value for mortality in patients with angiographically demonstrated coronary artery disease. B Freedman. Circulation 2001 Jul 31;104(5):E20-E21. No abstract.

Further evidence against the implication of active cytomegalovirus infection in vascular atherosclerotic diseases. MC Borgia, C Mandolini, C Barresi, G Battisti, F Carletti, MR Capobianchi. Atherosclerosis 2001 Aug;157(2):457-462. "These findings confirm previous evidence from the increased exposure to CMV infections in patients with atheromatous lesions."

(News) Heart disease risk increased by immune response to CMV. Medscape Wire Nov. 14, 2001; re Zhu et al. Circulation 2001 Nov 14. In men CMV was related to heart disease through higher levels of C-reactive protein; in women, high levels of antibodies to the virus were the most related to coronary artery disease.

Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. H Zhu, JP Cong, D Yu, WA Bresnahan, TE Shenk. Proc Natl Acad Sci USA 2002 Feb 26;[epub ahead of print]. And: Antiviral activity seen with COX-2 inhibitors. Medscape - Reuters Health 2002 Feb 26.

Human cytomegalovirus seropositivity is associated with impaired vascular function. C Grahame-Clarke, NN Chan, D Andrew, GL Ridgway, DJ Betteridge, V Emery, HM Colhoun, P Vallance. Circulation 2003 Aug 12;108(6):678-683. "Individuals who were seropositive for CMV had reduced responses to bradykinin (P=0.005) and glyceryl trinitrate (P=0.006). The reduced response to bradykinin remained significant (P=0.045) after adjusting for the response to glyceryl trinitrate and was independent of conventional risk factors. Positive serology for the other organisms did not have an independent effect on reactivity. There was a weaker association between CMV and coronary artery calcification (P=0.09). Positive serology for each of the other pathogens did not affect reactivity, but there was a relation between total pathogen burden and impaired vascular reactivity. No significant differences were found between diabetics and nondiabetics." [Note that 82% of the subjects were from non-manual classes, and may have been infected later in life than those in manual classes.]

Anti-cytomegalovirus (CMV) IgG antibody titer in patients with risk factors to atherosclerosis. A Blum, A Peleg, M Weinberg. Clin Exp Med 2003 Nov;3(3):157-160. "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."

Are the high levels of cytomegalovirus antibodies a determinant in the development of coronary artery disease? NK Eryol, H Kilic, A Gul I Ozdogru, T Inanc, A Dogan, R Topsakal, E Basar. Int Heart J 2005 Mar;46(2):205-209. "Fifty-six patients had normal coronary arteries and 123 patients had CAD. Six patients did not have anti-CMV antibodies and 87 of the 173 seropositive patients had high levels of anti-CMV antibodies (> or = 8 U/mL). High CMV seropositivity (> or = 8 U/mL) was a significant CAD determinant even after adjustment for traditional CAD risk factors (odds ratio [OR] = 2.1 P = 0.04, respectively)."

Unusual CD4+CD28null T Lymphocytes and Recurrence of Acute Coronary Events. G Liuzzo, LM Biasucci, G Trotta, S Brugaletta, M Pinnelli, G Digianuario, V Rizzello, AG Rebuzzi, C Rumi, A Maseri, F Crea. J Am Coll Cardiol 2007; 50:1450-1458. "CD4+CD28null T-cell frequency was an independent predictor of future acute coronary events (odds ratio 3.01, 95% confidence interval 1.1 to 8.25; p = 0.023)."

CMV and Immunity

Occult herpes family viruses may increase mortality in critically ill surgical patients. CH Cook, JK Yenchar, TO Kraner, EA Davies, RM Ferguson. Am J Surg 1998 Oct;176(4):357-360. "Twenty eligible patients had positive viral cultures during the study period, and 85% of these patients developed subsequent bacterial and/or fungal infections. Mortality was significantly higher following viral infection than in chronic SICU patients (65% vs 35%, P <0.006). Patients with thrombocytopenia complicating their viral infection had significantly higher mortality than those without thrombocytopenia (92% vs 25%, P <0.004). CONCLUSIONS: At least 14% of critically ill surgical patients have occult infection or reactivation of herpes family viruses. These viruses have known immunosuppressive effects, which may predispose chronic SICU patients to subsequent bacterial and fungal infection, and subsequent organ system failure and death."

Expansions of peripheral blood CD8 T-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the Swedish NONA immune study. A Wikby, B Johansson, J Olsson, S Lofgren, BO Nilsson, F Ferguson. Exp Gerontol 2002 Jan 3;37(2-3):445-453. "Results from a previous longitudinal study, the Swedish OCTO-Immune study, indicated that the combination of higher CD8 peripheral blood lymphocytes (PBLs), decreased CD4 PBLs, and poor proliferative response to mitogenic stimulation in very old humans were associated with an increased 2 year mortality.... As in the OCTO study, the NONA-Immune data indicated that the changes are associated significantly with seropositive responses to CMV."

Occult herpes family viral infections are endemic in critically ill surgical patients. CH Cook, LC Martin, JK Yenchar, MC Lahm, B McGuinness, EA Davies, RM Ferguson. Crit Care Med 2003 Jul;31(7):1923-1929. "The prevalence (95% confidence interval) of positive respiratory cultures for herpes simplex or CMV was 35% (22-49%); 15% (5-25%) cultured positive for CMV, 23% (11-35%) cultured positive for herpes simplex virus, and one patient's respiratory secretions culturing positive for both CMV and herpes simplex virus. The prevalence of CMV viremia was only 5.8% (1-10%). CMV+ patients had longer hospital admissions, intensive care unit admissions, and periods of ventilator dependence than CMV- patients, despite having comparable severity of illness scores. CMV+ patients also had significantly higher numbers of blood transfusions, prevalence of steroid exposure, and prevalence of hepatic dysfunction, and all were immunoglobulin G positive at the beginning of the study. In contrast, herpes simplex virus-positive patients had lengths of hospital admissions, lengths of intensive care unit admissions, and periods of ventilator dependence comparable with patients without viral infections (p >.05)."

Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. P Trzonkowski, J Myśliwska, E Szmit, J Wieckiewicz, K Lukaszuk, LB Brydak, M Machała, A Myśliwski. Vaccine 2003 Sep 8;21(25-26):3826-3836. "Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known to be associated with CMV carrier status) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol."

Expansion of peripheral CD8+ T cells in patients with coronary artery disease: relation to cytomegalovirus infection. L Jonasson, A Tompa, A Wikby. J Intern Med 2003 Nov;254(5):472-478. 43 patients with angina and angiographically verified CAD, versus 69 clinically healthy controls. "An expansion of CD8+ T cells expressing CD57 but lacking CD28 was seen in the patient group. The numbers of CD8+ CD57+ and CD8+ CD28-T-cell subsets were independently related to CMV seropositivity (P<0.001) but also to CAD per se (P<0.05). Serum concentrations of C-reactive protein (CRP) and soluble interleukin-2 receptor (sIL-2R) were elevated in the patients but not related to CMV or CD8+ T-cell subsets."

Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MT Vossen, AT Rowshani, PM Wertheim-van Dillen, RA van Lier, IJ ten Berge. J Immunol 2004 Aug 1;173(3):1834-1841. "In this study, we show that in primary CMV infections, CD4(+)CD28(-) T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4(+)CD28(-) T cells. In line with this, we found these cells only in CMV-infected persons [emphasis added]. CD4(+)CD28(-) cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4(+)CD28(-) cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4(+)CD28(-) cells only produced IFN-gamma after stimulation with CMV-Ag, whereas CD4(+)CD28(+) cells also produced IFN-gamma in response to varicella-zoster virus and purified protein derivative. Thus, CD4(+)CD28(-) T cells emerge as a consequence of CMV infection."

Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. R Vescovini, A Telera, FF Fagnoni, C Biasini, MC Medici, P Valcavi, P di Pede, G Lucchini, L Zanlari, G Passeri, F Zanni, C Chezzi, C Franceschi, P Sansoni. Exp Gerontol 2004 Aug;39(8):1233-1243. In nonagenarians and centenarians, "The frequency and absolute number of CD8+ T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8+ CD28+ cells. By contrast, CMV infection was characterized by highly variable numbers of CD8+ T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8+ T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8+ lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases."

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004 Dec 15;173(12):7481-7489. "CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status."

Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. G Almanzar, S Schwaiger, B Jenewein, M Keller, D Herndler-Brandstetter, R Wurzner, D Schonitzer, B Grubeck-Loebenstein. J Virol 2005 Mar;79(6):3675-3683. "CD8+ T cells were analyzed in young, middle-aged, and elderly clinically healthy persons with a positive or negative CMV antibody serology. Numbers and functional properties of CMVpp65(495-503)-specific CD8+ T cells were also studied. We demonstrate that aging as well as CMV infection lead to a decrease in the size of the naive CD8+ T-cell pool but to an increase in the number of CD8+ effector T cells, which produce gamma interferon but lack substantial growth potential. The size of the CD8+ memory T-cell population, which grows well and produces interleukin-2 (IL-2) and IL-4, also increases with aging, but this increase is missing in CMV carriers. Life-long latent CMV infection seems thus to diminish the size of the naive and the early memory T-cell pool and to drive a Th1 polarization within the immune system. This can lead to a reduced diversity of CD8 responses and to chronic inflammatory processes which may be the basis of severe health problems in elderly persons."

Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. HN Schmaltz, LP Fried, QL Xue, J Walston, SX Leng, RD Semba. J Am Geriatr Soc 2005 May;53(5):747-754. 724 women. "Frailty status was based on previously validated criteria: unintentional weight loss, weak grip strength, exhaustion, slow walking speed, and low level of activity.... Eighty-seven percent of women were CMV seropositive, an indication of chronic infection. CMV was associated with prevalent frailty, adjusting for age, smoking history, elevated body mass index, diabetes mellitus, and congestive heart failure (CMV frail adjusted odds ratio (AOR)=3.2, P=.03; CMV prefrail AOR=1.5, P=.18). IL-6 interacted with CMV, significantly increasing the magnitude of this association (CMV positive and low IL-6 frail AOR=1.5, P=.53; CMV positive and high IL-6 frail AOR=20.3, P=.007; CMV positive and low IL-6 prefrail AOR=0.9, P=.73; CMV positive and high IL-6 prefrail AOR=5.5, P=.001)."

Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. JM Fletcher, M Vukmanovic-Stejic, PJ Dunne, KE Birch, JE Cook, SE Jackson, M Salmon, MH Rustin, AN Akbar. J Immunol 2005 Dec 15;175(12):8218-8225. "We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors."

Interleukin 12 induces T-cell recruitment into the atherosclerotic plaque. X Zhang, A Niessner, T Nakajima, W Ma-Krupa, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circ Res 2006 Mar 3;98(4):524-531. "(CD4+)CD28- T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation." In human atheroma-SCID mouse chimeras, "Exposure of nonstimulated (CD4+)CD28- T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, (CD4+)CD28- T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions."

The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. A Wikby, BO Nilsson, R Forsey, J Thompson, J Strindhall, S Lofgren, J Ernerudh, G Pawelec, F Ferguson, B Johansson. Mech Ageing Dev 2006 Aug;127(8):695-704. "IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells."

Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MH Heemskerk, IJ ten Berge, RA van Lier. Blood 2006 Nov 1;108(9):3121-3127. "In the acute response, CMV-specific CD4+ T cells are highly activated and proliferating, have a CD45RA+CD45R0+CD28+CD27+ phenotype, and produce IFN after stimulation with CMV antigen in vitro. Late after primary infection, CMV-specific CD4+ T cells have returned to a resting stage, and the percentage of IFN-producing CMV-specific CD4+ T cells is considerably lower than during the acute infection. Moreover, a considerable number of CMV-specific CD4+ T cells have progressed toward a further differentiated phenotype, characterized by the loss of both CD27 and CD28 and the acquisition of cytolytic molecules such as perforin and granzyme B (grB). CD4+CD28– grB+ T cells appear to be characteristic for CMV infection because they emerge after primary CMV infection and can be found only in CMV-seropositive individuals. Consequently, proliferation and cytokine production by CD4+CD28– T cells can be induced by CMV but not by other viral antigens."

Massive Load of Functional Effector CD4+ and CD8+ T Cells against Cytomegalovirus in Very Old Subjects. R Vescovini, C Biasini, FF Fagnoni, AR Telera, L Zanlari, M Pedrazzoni, L Bucci, D Monti, MC Medici, C Chezzi, C Franceschi, and P Sansoni. J Immunol 2007;179: 4283-4291. "Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN- induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN- in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases."

Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. WW Lee, ZZ Yang, G Li, CM Weyand, JJ Goronzy. J Immunol 2007 Aug 15;179(4):2609-2615. Expression of CD70 was the most striking difference between CD4(+)CD28(-) and CD4(+)CD28(+) T cells; and "CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation."

CMV & social class

The prevalence of CMV infection varies with social class: "In developed countries, 10% to 15% of children are infected with CMV by early adolescence; this varies by socioeconomic class, with greater seroprevalence correlating with lower income and homosexual adolescents and men. From late adolescence to adulthood, seroprevalence of CMV in the United States increases from 15% to 50%." (From: Treatment of cytomegalovirus (CMV) retinitis in the era of highly active anti-retroviral therapy. DF Martin. Medscape HIV/AIDS Clinical Management 1999 Aug 30;4.)

Cytomegalovirus seroprevalence among women of childbearing age during a 10-year period. GS Marshall, GG Stout. Am J Perinatol 2005 Oct;22(7):371-376. "Overall, 58% of 2992 women were seropositive. After stratification by socioeconomic status (SES), nonwhite race was strongly associated with seropositivity (odds ratio, 3.0; 95% confidence interval [CI], 2.5 to 3.8), and after stratification by race, lower SES also was associated (odds ratio, 2.0; 95% CI, 1.7 to 2.3). There were no trends in seroprevalence over time in any demographic group.... Seropositivity ranged from 40% among older, white primigravidas of upper SES to 89% among older, nonwhite, multigravid women of lower SES."

Seroprevalence of Cytomegalovirus Infection in the United States, 1988–1994. SAS Staras, SC Dollard, KW Radford, WD Flanders, RF Pass, MJ Cannon. Clin Infect Dis 2006;43:1143-1151. Based on age-specific CMV seroprevalences from the Third National Health and Nutrition Examination Survey (NHANES III). "CMV seroprevalence increased gradually with age, from 36.3% in 6–11-year-olds to 90.8% in those aged 80 years. CMV seroprevalence differed by race and/or ethnicity as follows: 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans."

Incidence of cytomegalovirus infection among the general population and pregnant women in the United States. FA Colugnati, SA Staras, SC Dollard, MJ Cannon. BMC Infect Dis 2007 Jul 2;7:71. Based on age-specific CMV seroprevalences from the Third National Health and Nutrition Examination Survey (NHANES III). "The average age of CMV infection was 28.6 years. Force of infection was significantly higher among non-Hispanic Blacks (5.7) and Mexican Americans (5.1) than among non-Hispanic Whites (1.4). Force of infection was significantly higher in the low household income group (3.5) than in the middle (2.1) and upper (1.5) household income groups."

Strain differences in CMV infection

Quantification of replication of clinical cytomegalovirus isolates in cultured endothelial cells and fibroblasts by a focus expansion assay. C Sinzger, J Knapp, B Plachter, K Schmidt, G Jahn. J Virol Methods 1997 Jan;63(1-2):103-112. "Remarkable differences in the cytopathogenicity of these isolates in fibroblasts as well as in endothelial cells were found."

Glycoprotein B genotype correlates with cell tropism in vivo of human cytomegalovirus infection. U Meyer-Konig, C Vogelberg, A Bongarts, D Kampa, R Delbruck, G Wolff-Vorbeck, G Kirste, M Haberland, FT Hufert, D von Laer. J Med Virol 1998 May;55(1):75-81. The strain that did not infect T lymphocytes was less harmful in bone marrow transplant patients.

Two clinical isolates and the Toledo strain of cytomegalovirus contain endothelial cell tropic variants that are not present in the AD169, Towne, or Davis strains. LP MacCormac, JE Grundy. J Med Virol 1999 Mar;57(3):298-307. Some strains infect fibroblasts but not endothelial cells.

Efficient lytic infection of human arterial endothelial cells by human cytomegalovirus strains. M Kahl, D Siegel-Axel, S Stenglein, G Jahn, C Sinzger. J Virol 2000 Aug;74(16):7628-7635. Differences in the type of cells each strain infects are more important than differences in the pathogenicity of the strain.

Tropism of human cytomegalovirus for endothelial cells is determined by a post-entry step dependent on efficient translocation to the nucleus. C Sinzger, M Kahl, K Laib, K Klingel, P Rieger, B Plachter, G Jahn. J Gen Virol 2000 Dec;81(1412): 3021-3035. "With nonendotheliotropic strains, the content of viral DNA in the cell nucleus was 100-1000-fold lower in EC when compared to endotheliotropic strains." In contrast, all CMV strains are efficient in fibroblasts.

gpUL73 (gN) genomic variants of human cytomegalovirus isolates are clustered into four distinct genotypes. S Pignatelli, P Dal Monte, MP Landini. J Gen Virol 2001 Nov;82(Pt 11):2777-2784. "Clinical isolates of human cytomegalovirus (HCMV) show differences in tissue tropism, severity of clinical manifestations and ability to establish persistent of latent infections..."

Frequent coinfection of cells explains functional in vivo complementation between cytomegalovirus variants in the multiply infected host. L Cicin-Sain, J Podlech, M Messerle, MJ Reddehase, UH Koszinowski. J Virology 2005 Aug;79(15):9492-9502. "[C]oinfection of host cells is more frequent than statistically predicted and that this coinfection alters virus fitness," resulting in increased pathogenicity to the host.

Failure of Real-Time PCR Diagnostics Caused by Nucleotide Variability within Exon 4 of the Human Cytomegalovirus (CMV) Major Immediate Early (MIE) Gene. M Lengerova, Z Racil, P Volfova, J Lochmanova, J Berkovcova, D Dvorakova, J Vorlicek, J Mayer. J Clin Microbiol 2007 Mar;45(3):1042-1044. "Here we report how variability in the human cytomegalovirus genome sequence may seriously affect the outcome of its molecular diagnosis. A real-time quantitative PCR assay targeting the major immediate-early gene failed to detect the viral load in some, but not all, clinical samples from hematooncological patients. By amplification and sequencing the DNA across the regions targeted by this assay we found a number of nucleotide substitutions which accounted for decreased primer/probe binding. This decreased the sensitivity of the assay up to 1000 fold."

Mechanisms

Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. G Liuzzo, JJ Goronzy, H Yang, SL Kopecky, DR Holmes, RL Frye, CM Weyand. Circulation 2000 Jun 27;101(25):2883-2888. 34 patients with stable angina and 34 with unstable angina. "CD4+CD28null T cells were infrequent in our cohort of 34 SA patients, with a median frequency of 1.5%. Their frequency was increased 10-fold in our cohort of 34 UA patients (median 10.8%, P<0.001).... An average of 3 T-cell clones was seen in UA patients (range 0 to 11)... Individual T-cell clones differed in size, with large clones reaching 5% and small clones accounting for 0.5% of the circulating CD4+ T-cell pool.... CD4+CD28null T-cell clonotypes are accumulated in lesions with plaque rupture, suggesting that they are involved in the events leading to plaque instability, rupture, superimposed thrombosis, and induction of acute ischemia." CD4+CD28null T-cells also secrete large amounts of IFN-γ, a potent stimulator of macrophages.

Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. AN Vallejo, M Schirmer, CM Weyand, JJ Goronzy. J Immunol 2000 Dec 1;165(11):6301-6307. "CD4(+)CD28(null) T cells are oligoclonal lymphocytes rarely found in healthy individuals younger than 40 yr, but are found in high frequencies in elderly individuals and in patients with chronic inflammatory diseases. Contrary to paradigm, they are functionally active and persist over many years... the present studies unequivocally show dysregulation of apoptotic pathways in CD4(+)CD28(null) T cells that favor their clonal outgrowth and maintenance in vivo."

T-cell-mediated lysis of endothelial cells in acute coronary syndromes. T Nakajima, S Schulte, KJ Warrington, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circulation 2002 Feb 5;105(5):570-575. 24 patients with stable angina, 22 with unstable angina, and 20 controls. "Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4+CD28null T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161+ and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4+CD28null T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4+ T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I–recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4+CD28null T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion." This causes erosion or rupture of the atherosclerotic plaque, followed by thrombosis. "We have demonstrated that plaque-infiltrating T lymphocytes include a subset of functionally distinct CD4 T cells that lack CD28 expression. CD4+CD28null clonotypes can be isolated from culprit lesions but not from stable plaque. These T cells are capable of releasing large amounts of interferon (IFN)- and are the dominant population of IFN-–producing cells in peripheral blood of patients with unstable angina (UA). One of their functions seems to be the activation of monocytes and macrophages. Monocytes from patients with UA display a molecular fingerprint of ongoing IFN- stimulation... In the present study, we show that CD4+CD28null T cells from patients with UA have killer-cell functions and can cause target-cell death through the release of the pore-forming enzyme perforin. Endothelial cells are susceptible to this T-cell–mediated injury. In the presence of C-reactive protein (CRP), at concentrations frequently found in patients at risk for coronary events, susceptibility of endothelial cells to T-cell–mediated cytotoxicity was increased, suggesting that CRP sensitized endothelial cells to cytolysis."

De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes. T Nakajima, O Goek, X Zhang, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circ Res 2003 Jul 25;93(2):106-113. "Patients with ACS can be distinguished from age-matched healthy controls and patients with stable angina by the increased frequency of a subset of CD4+ T cells that are oligoclonally expanded in the peripheral blood and have lost the expression of the costimulatory molecule CD28.12 Data on the relationship between plaque-infiltrating T cells and these oligoclonally expanded CD4+CD28null T cells are limited. However, phenotypic and T-cell receptor sequence analysis in the patients who have been studied indicate that these T cells accumulate in culprit lesions and are not present in stable lesions (authors’ unpublished data, 2003). CD4+CD28null T cells are functionally distinct from classic CD4+ helper T cells. Besides their ability to release large amounts of interferon (IFN)-, CD4+CD28null T cells express perforin and granzyme B.11 On triggering of the T-cell receptor, they lyse target cells, including endothelial cells. It is possible, therefore, that these T cells directly contribute to plaque instability." [(CD4+)CD28- T cells were specific to CMV infection, van Leeuwen, J Immunol 2004.]

Hydroxymethyl-glutaryl coenzyme a reductase inhibition limits cytomegalovirus infection in human endothelial cells. L Potena, G Frascaroli, F Grigioni, T Lazzarotto, G Magnani, L Tomasi, F Coccolo, L Gabrielli, C Magelli, MP Landini, A Branzi. Circulation 2004 Feb 3;109(4):532-536. Fluvastatin inhibited CMV replication in n human umbilical vein endothelial cells. "CMV DNA concentration was consistently lower in supernatants from fluvastatin-treated cells than in infected controls, and viral particle concentration was up to 30 times lower," with a dose-response effect. "[I]n vivo studies suggest that production of IE antigens is sufficient to initiate the atherosclerotic process by inducing inflammatory cytokine production, monocyte adhesion, and uptake of LDL in endothelial cells... The concentrations of fluvastatin used in the experiment have been demonstrated not to affect cell viability and were consistent with the in vivo blood concentrations observed during therapy in humans."

CD4+CD28- T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. R Gerli, G Schillaci, A Giordano, EB Bocci, O Bistoni, G Vaudo, S Marchesi, M Pirro, F Ragni, Y Shoenfeld, E Mannarino. Circulation 2004 Jun 8;109(22):2744-2748. 87 RA and 33 control subjects who also underwent evaluation of carotid artery intima-media thickness (IMT) and endothelial function. All were non-smokers. "Patients had higher IMT and lower FMV [flow-mediated vasodilation] compared with control subjects. The frequency of CD4+CD28null cells was significantly higher in patients than in control subjects. Twenty patients with persistent expansion of circulating CD4+CD28null cells had more marked increase of carotid artery IMT and stronger decrease of brachial artery FMV. Blockade of tumor necrosis factor-alpha led to a partial reappearance of the CD28 molecule on the CD4+ cell surface." [(CD4+)CD28- T cells were specific to CMV infection, van Leeuwen, J Immunol 2004.]

Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation. A. Rahbar, C. Soderberg-Naucler. J Virology 2005 Feb;79(4):2211-2220. "The increased thrombogenicity was dependent on active virus replication and could be inhibited by foscarnet and gancyclovir; these results suggest that a late viral gene may be mediating this phenomenon, which may contribute to vascular catastrophes in patients with atherosclerotic disease."

Interleukin 12 induces T-cell recruitment into the atherosclerotic plaque. X Zhang, A Niessner, T Nakajima, W Ma-Krupa, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circ Res 2006 Mar 3;98(4):524-531. "Here we report that (CD4+)CD28- T cells, either isolated from the plaque tissue or from the blood of patients with acute coronary syndrome (ACS), spontaneously express interleukin (IL)-12 receptors, even in the absence of antigenic stimulation. (CD4+)CD28- IL-12R+ cells responded to IL-12 stimulation with the upregulation of the chemokine receptor CCR5 and the C-type lectin receptor CD161, both implicated in regulating tissue homing of effector T cells. IL-12 treatment of (CD4+)CD28- T cells enhanced their chemotaxis and transendothelial migration toward the chemokine CCL5. In vivo relevance for the role of IL-12 in regulating the recruitment of (CD4+)CD28- T cells into the atheroma was examined in human atheroma-SCID mouse chimeras. Exposure of nonstimulated (CD4+)CD28- T cells to IL-12 was sufficient to amplify T-cell accumulation within the inflamed plaque, and coadministration of anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus, (CD4+)CD28- T cells functionally resemble NK cells, which have proinflammatory activity even in the unprimed state and respond to any IL-12-inducing host infection with a shift in tissue trafficking and accrual in inflammatory lesions." [(CD4+)CD28- T cells were specific to CMV infection, van Leeuwen, J Immunol 2004.]

Modelling cytomegalovirus replication patterns in the human host: factors important for pathogenesis. RR Regoes, EF Bowen, AV Cope, D Gor, AF Hassan-Walker, HG Prentice, MA Johnson, P Sweny, AK Burroughs, PD Griffiths, S Bonhoeffer, VC Emery. Proc Biol Sci 2006 Aug 7;273(1596):1961-1967. "We use a statistical model that allows all viral load data sampled during infection to be analysed, and have applied it to four immunocompromised groups exhibiting five distinct cytomegalovirus-related diseases. The results show that for all diseases, peaks in viral load contribute less to disease progression than phases of low virus load with equal amount of viral turnover. The model accurately predicted the time of disease onset for fever, gastrointestinal disease and pneumonitis but not for hepatitis and retinitis, implying that other factors may be involved in the pathology of these diseases."

CMV and heart transplants

Three-year survival rates for all consecutive heart-only and lung-only transplants performed in Eurotransplant, 1997-1999. JM Smits, J Vanhaecke, A Haverich, E de Vries, M Smith, E Rutgrink, A Ramsoebhag, A Hop, G Persijn, G Laufer. Clin Transpl 2003;:89-100. In heart transplants, "Survival was significantly associated with the CMV serologic status of the donor and recipient; the 3-year survival rates were: D+/R+, 71%; D+/R-, 69%; D- R-, 76%; and D-/R+, 76% (p=0.04)." In lung transplants, "A donor CMV+ and recipient CMV- match was a risk factor for long-term mortality, with 3-year survival rates of 56% for D+/R+, 55% for D+/R-, 71% for D-/R- and 62% for D-/R+ transplants (p=0.046)."

Cytomegalovirus infection status predicts progression of heart-transplant vasculopathy. S Fateh-Moghadam, W Bocksch, R Wessely, G Jager, R Hetzer, M Gawaz. Transplantation 2003 Nov 27;76(10):1470-1474. In 103 consecutive heart-transplant recipients followed for one year, "The HCMV-positive group showed more advanced, calcified lesions (64.7% vs. 27.5%, P=0.002), and the maximal plaque thickness was significantly different from the HCMV IgG/IgM-negative group (median [quartile] 1.36 [0.85, 1.88] vs. 1.05 [0.58, 1.34], P=0.02).... In addition, HCMV PCR positivity even increases the risk for accelerated TVP (P=0.017) and, consecutively, transplant failure."

Frequent occult infection with cytomegalovirus in cardiac transplant recipients despite antiviral prophylaxis. L Potena, CTJ Holweg, ML Vana, L Bashyam, J Rajamani, AL McCormick, JP Cooke, HA Valantine, ES Mocarski. J Clin Microbiol 2007 Jun;45(6):1804-1810. Heart transplant patients who were CMV-positive more often had high levels of infection than CMV-negative transplant patients who received hearts from CMV-positive donors. "Therefore, active systemic CMV infection involving leukocytes is common in heart transplant recipients receiving prophylaxis to reduce acute disease. Infection of the transplanted organ is rare, suggesting that chronic vascular disease attributed to CMV may be driven by the consequences of systemic infection."

Dental infections

Streptococci from the mouth which enter the bloodstream during dental work have long been known to cause endocarditis. And, "early immunization experiments with oral streptococcal organisms (especially s mutans for vaccination against caries) resulted in the production of autoimmune antivascular and anticardiac cross-reactive immunoglobulins. Recently, landmark studies by Herzberg et al have identified the cross-reactive immunodeterminants responsible. S sanguis contains an outer membrane associated protein... which is identical to the platelet-interactive domain of Type I and Type II collagens. This bacterial protein thus presents or 'mimics' the normal platelet receptor that initiates thrombus formation. Type III collagen is in the wall and basement membrane of vessels and is normally covered with endothelial cells, which serves to mask these platelet binding receptor sequences from circulating blood cells. Trauma or other noxious stimuli which expose these receptors and thereby provide an important signal to initiate hemostasis or thrombosis. Herzberg et al also report that Porphyromonas gingivalis (a gram-negative periodontal pathogen) has properties similar to S sanguis. Taken together, these findings suggest that oral organisms may serve as a thromboembolic trigger." (Dental infections and atherosclerosis. JD Beck, J Pankow, HA Tyroler, S Offenbacher. Am Heart J 1999;138:S528-S533.)

"Patients who experience acute MI are nearly three times more likely to have periodontitis than healthy persons, according to data presented here Monday at the American Heart Association's Scientific Sessions." (Re: E Deliagyris et al. Reuters Medical News via Medscape, 2000 Nov 14.)

Deliagyris spin doctors his study for the masses. In the news report on Gannett / NBC WGRZ Channel 2, Buffalo, New York, Deliagyris claimed "'We know a lot of risk factors for heart attacks, including high blood pressure, high cholesterol, diabetes, and cigarette smoking, but all those combined only explain about two-thirds of heart attacks,' Deliagyris said. 'Since about a third of people who suffer heart attacks don't have those risk factors, there's a wide search going on for other conditions that may contribute to increased risk."

This is the official lie of the anti-smoking establishment. The deceit is in pretending that the supposed risk factors, particularly smoking, "explain" any cases at all; and pretending that it's only those few cases that aren't thus "explained" which would be involved. IN FACT, it is the health establishment's conspiracy to ignore the confounding role of infection that is the cause of the supposed "smoking risk."

Periodontal infections and cardiovascular disease -- how strong is the association? GC Armitage. Oral Dis 2000 Nov;6(6):335-350. Review.

Gum disease may nourish other maladies. Richard a. Marini, New York Times Syndicate 2001 Oct 17.

Systemic release of endotoxins induced by gentle mastication: association with periodontitis severity. SO Geerts, M Nys, MP De, J Charpentier, A Albert, V Legrand, EH Rompen. J Periodontol 2002 Jan;73(1):73-78. "This finding suggests that a diseased periodontium can be a major and underestimated source of chronic, or even permanent, release of bacterial pro-inflammatory components into the bloodstream." (News re Geerts et al.: Infected gums leak toxins into bloodstream. By Melissa Schorr. Reuters Health Information - Medscape 2002 Feb. 8.)

Relationship between Porphyromonas gingivalis, Epstein-Barr virus infection and reactivation in periodontitis. N Sugano, K Ikeda, M Oshikawa, H Tanaku, S Sato, K Ito. J Oral Sci 2004 Dec;46(4):203-206. P gingivalis levels were higher in saliva of EBV-positive patients, while P gingivalis stimulated EBV.

Bacterial Profile and Burden of Periodontal Infection in Subjects With a Diagnosis of Acute Coronary Syndrome. S Renvert, T Pettersson, O Ohlsson, GR Persson. J Periodontol 2006 Jul;77(7):1110-1119. In 161 surviving acute coronary patients and 161 controls, "Total oral bacterial load was higher in the subjects with ACS (mean difference: 17.4 x 10(5); SD: 10.8; 95% confidence interval [CI]: 4.2 to 17.4; P <0.001), and significant for 26 of 40 species including Porphyromonas gingivalis, Tannerella forsythensis, and Treponema denticola." Also: Study Supports Findings That Periodontal Bacteria May Be Linked to Heart Disease. SOURCE: American Academy of Periodontology. DGNews, July 19, 2006. "The amount of oral bacteria was two times higher in the ACS group for the combination of the bacteria streptococci species, P. gingivalis, T. forsythia and T. denticola. Specifically, the findings suggest that T. denticola, T. forsythia and streptococci species are bacteria in a shared infectious etiology for periodontitis and ACS."

Treatment of periodontitis and endothelial function. MS Tonetti, F D'Aiuto, L Nibali, A Donald, C Storry, M Parkar, J Suvan, AD Hingorani, P Vallance, John Deanfield. New Engl J Med 2007 Mar 1;356(9):911-920. A randomized clinical trial of 120 patients with severe periodontal disease, assigned to community-based periodontal care (59 patients) or intensive periodontal treatment (61). Endothelial function, as assessed by measurement of the diameter of the brachial artery during flow (flow-mediated dilatation), and inflammatory biomarkers and markers of coagulation and endothelial activation were evaluated before treatment and 1, 7, 30, 60, and 180 days after treatment. "Conclusions Intensive periodontal treatment resulted in acute, short-term systemic inflammation and endothelial dysfunction. However, 6 months after therapy, the benefits in oral health were associated with improvement in endothelial function."

Multiple infections

Herpesviridae in the coronary arteries and aorta of young trauma victims. HM Yamashiroya, L Ghosh, R Yang, AL Robertson Jr. Am J Pathol 1988 Jan;130(1):71-79. "The histologic findings indicate that HSV and CMV are associated with areas showing early or advanced atheromatous changes in the coronary arteries and with lesion-free as well as lesion areas in the thoracic aorta."

In: Multiple infections in carotid atherosclerotic plaques (B Chiu. Am Heart J 1999;138:S534-S536), 33 carotid atherectomy specimens were investigated for five potential pathogens by immunostaining. 63.6% were positive for C pneumoniae; 42% were positive for cytomegalovirus; 42% were positive for Porphyromonas gingivalis, a major dental pathogen; 12% were positive for Streptococcus sanguis, another dental pathogen; and 9% were positive for herpes simplex virus-1. 30% had one, 24% had two, 21% had three, and 6% had four organisms, localized mainly in macrophages in the plaque.

Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease in older adults: the cardiovascular health study. DS Siscovick et al. Circulation 2000 Nov 7;102(19):2335-2340.

Previous exposure to Chlamydia pneumoniae, Helicobacter pylori and other infections in Canadian patients with ischemic heart disease. M Smieja, L Cronin, M Levine, CH Goldsmith, S Yusuf, JB Mahony. Can J Cardiol 2001 Mar;17(3):270-276.

Frequency of occurrence of cytomegalovirus and Chlamydia pneumoniae in lymphocytes of atherosclerotic patients. AA al-Amro, AA al-Jafari, MR al-Fagih, M Tajeldin, HB Qavi. Cent Eur J Public Health 2001 May;9(2):106-108. "These results demonstrate that atherosclerotic patients are more frequently infected with CMV or C-pneumoniae or both."

Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. HJ Rupprecht, S Blankenberg, C Bickel, G Rippin, G Hafner, W Prellwitz, W Schlumberger, J Meyer, AutoGene Investigators. Circulation 2001 Jul 3;104(1):25-31. "Patients seropositive to >5 pathogens compared to those seropositive to <4 pathogens had a 5.1 (1.4 to 18.3) higher risk of future cardiac death. This result was mainly driven by the pathogen burden of seropositivities to Herpesviridae (P<0.0001)."

Seroprevalence of antibodies to microorganisms known to cause arterial and myocardial damage in patients with or without coronary stenosis. C Stollberger, G Molzer, J Finsterer. Clin Diagn Lab Immunol 2001 Sep;8(5):997-1002. In 112 angiography patients, 92% of patients with CAD were H pylori positive versus 68% of those without CAD.

Chlamydia pneumoniae and cytomegalovirus seropositivity, inflammatory markers, and the risk of myocardial infarction at a young age. M Gattone, L Iacoviello, M Colombo, AD Casteinuovo, F Soffiantino, A Gramoni, D Picco, M Benedetta, P Giannuzzi. Am Heart J 2001 Oct;142(4):633-640. "The combination of both infections is associated with an enhanced inflammatory response and a markedly increased risk of premature MI."

Impact of infectious burden on extent and long-term prognosis of atherosclerosis. C Espinola-Klein, HJ Rupprecht, S Blankenberg, C Bickel, H Kopp, G Rippin, A Victor, G Hafner, W Schlumberger, J Meyer. Circulation 2002 Jan 1;105(1):15-21. "We showed a significant association between infectious burden and the extent of atherosclerosis. Moreover, the risk for future death was increased by the number of infectious pathogens, especially in patients with advanced atherosclerosis." And: Pathogen exposure level tied to extent of atherosclerosis, adverse outcome risk. Medscape - Reuters Health 2002 Jan 3.

Lack of association of Helicobacter pylori infection with coronary artery disease and frequency of acute myocardial infarction or death. J Zhu, AA Quyyumi, JB Muhlestein, FJ Nieto, BD Horne, A Zalles-Ganley, JL Anderson, SE Epstein. Am J Cardiol 2002 Jan 15;89(2):155-158. This study found that "CAD prevalence significantly increased stepwise depending on H. pylori seropositivity and elevated CRP levels, " but that "Significance was lost after adjustment for traditional risk factors. Further analysis revealed that age was the critical confounder." [However, dismissing elevated CRP as merely an effect of age means overlooking a possibly treatable condition -cast.]

Effect of treatment for Chlamydia pneumoniae and Helicobacter pylori on markers of inflammation and cardiac events in patients with acute coronary syndromes: South Thames Trial of Antibiotics in Myocardial Infarction and Unstable Angina (STAMINA). AF Stone, MA Mendall, JC Kaski, TM Edger, P Risley, J Poloniecki, AJ Camm, TC Northfield. Circulation 2002 Sep 3;106(10):1219-1223. Antibiotics improve outcome in acute coronary syndromes. L Barclay, Medscape Medical News 2002 Aug 20.

The association of seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus with risk of cardiovascular disease: a prospective study. AW Haider, PW Wilson, MG Larson, JC Evans, EL Michelson, PA Wolf, CJ O'Donnell, D Levy. J Am Coll Cardiol 2002 Oct 16;40(8):1408-1413. Like their friends at the National Cancer Institute who can't find Epstein-Barr virus in EBV-related cancers, the Framingham gang finds low rates of infection and no risk from them.

Enterovirus, mycoplasma and other infections as predictors for myocardial infarction. A Reunanen, M Roivainen, M Kleemola, P Saikku, M Leinonen, T Hovi, P Knekt, A Leino, A Aromaa. J Intern Med 2002 Nov;252(5):421-429. "Men without reported baseline heart disease, but not those with heart disease, showing the highest quartile of antibodies to enterovirus and mycoplasma or increased levels of immune complex-bound antibodies to chlamydia had a significantly higher risk of coronary events than men with lower level of antibodies."

Interactions between infections

Chlamydia pneumoniae-induced transactivation of the major immediate early promoter of cytomegalovirus: potential synergy of infectious agents in the pathogenesis of atherosclerosis. C Wanishsawad, YF Zhou, SE Epstein. J Infect Dis 2000 Feb;181(2):787-790). "The results of this investigation show that 2 infectious agents linked to the development of atherosclerosis, CMV and C. pneumoniae, have the capacity to interact in a host. Because of the interaction, infection with one pathogen has the capacity to increase gene expression of the other...."

"These results also extend the concept generated by previous studies in which we showed that the 'aggregate pathogen burden' contributes to increased risk of coronary artery disease. The aggregate pathogen burden not only predicted risk of coronary artery disease but also was directly related to C-reactive protein levels, a marker of inflammation and a predictor of subsequent cardiovascular events. The current findings therefore suggest that multiple pathogens may contribute to the atherogenic process, not only by the direct interactions between the specific pathogen and the host but also by interactions among pathogens, whereby the presence of one may augment the activity of the other. Such pathogenic interactions may lead to synergistic effects on the atherogenic process."

Animal studies

Cytomegalovirus infection increases development of atherosclerosis in Apolipoprotein-E knockout mice. E Hsich, YF Zhou, B Paigen, TM Johnson, MS Burnett, SE Epstein. Atherosclerosis 2001 May;156(1):23-28.

Pathogen-Accelerated Atherosclerosis Occurs Early after Exposure and Can Be Prevented via Immunization. T. Miyamoto, H. Yumoto, Y. Takahashi, M. Davey, F.C. Gibson III, C.A. Genco. Infect. Immun. 2006;74 1376-1380. "Animals challenged with P. gingivalis presented with increased macrophage infiltration, innate immune marker expression, and atheroma without elevated systemic inflammatory mediators. We conclude that localized up-regulation of innate immune markers early after infection, rather than systemic inflammation, contributes to pathogen-accelerated atherosclerosis. " The analyses of most human studies of infection and heart disease are based upon looking for correlations between elevated systemic inflammatory markers and disease; also, their subjects are older people. Those studies would therefore underestimate the relationship.

See Also:

cast 03-08-08