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. 132 patients with atherosclerosis after blood-vessel surgery. More than 25% of plaque and biopsy samples contained CMV antigens.

Melnick - Lancet 1983 abstract / PubMed

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. Electron microscopy of biopsies of 60 patients with atherosclerosis undergoing cardiovascular surgery. "Virions of the Herpesviridae family were observed in ten of the patients. They were detected in occasional smooth muscle and rare endothelial cells."

Gyorkey - Exp Mol Pathol 1984 abstract / PubMed

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)."

Adam - Lancet 1987 abstract / PubMed

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.

Hendrix - Am J Pathol 1989 abstract / PubMed

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."

Hendrix - Am J Pathol 1990 abstract / PubMed

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.

Hajjar - Am J Pathol 1991 full article / UCSF (pdf, 17 pp)
Hajjar - Am J Pathol 1991 full article / PubMed Central

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 DNA was present in seven (88%) of eight lesions of inflammatory aortic diseases with periaortic fibrosis, five of six inflammatory aneurysms, and all of two aortic occlusive lesions with inflammation. Cytomegalovirus DNA was detected in 20 (61%) of 33 atherosclerotic aneurysms, whereas it was detected in only five (31%) of 16 autopsy samples that showed neither inflammation nor atherosclerosis."

Tanaka - J Vasc Surg 1992 abstract / PubMed

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.

Melnick - Eur Heart J 1993 abstract / PubMed

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.

Melnick - J Med Virol 1994 abstract / PubMed

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.

Speir - Science 1994 abstract / PubMed

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

Melnick - Bioessays 1995 abstract / PubMed

[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.

Chen - Zhonghua Yi Xue Za Zhi 1995 abstract / PubMed

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

Melnick - Arch Immunol Ther Exp (Warsz) 1996 abstract / PubMed

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. 300 adult residents in Washington County, Md., of the Atherosclerosis Risk in Communities Study. " In the longitudinal analyses, CMV titers in 1974 were directly associated with 1987 through 1989 plasma levels of von Willebrand factor, factor VIII, and protein C and negatively associated with activated partial thromboplastin time. In the cross-sectional analyses, CMV titers were directly related to antithrombin III and fibrinogen levels. When the association between CMV antibodies and atherosclerosis was examined in stratified analyses, a significant association was restricted to individuals with high levels of lipoprotein(a) and fibrinogen. These results are compatible with previous evidence suggesting that CMV virus might have procoagulant properties."

Nieto / Arterioscler Thromb Vasc Biol 1997 full article

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

Adam - Cent Eur J Public Health 1997 abstract / PubMed

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. Comment. "The observations of viral antigens and nucleic acid sequences in arterial smooth muscle cells suggest that latent CMV infection of the arterial wall may be common in patients with atherosclerosis. The seroepidemiologic studies suggest that a periodically activated latent infection is present in patients with atherosclerosis. Important are the observations that in immunosuppressed heart transplant patients infected with CMV, atherosclerosis is prone to develop in the transplanted heart."

Pampou - Virchows Arch 2000 abstract / PubMed

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. "The subset of CD4(+)CD28(null) T cells was expanded in patients with UA and infrequent in patients with stable angina (median frequencies: 10.8% versus 1.5%, P<0.001). CD4(+)CD28(null) T cells included a large monoclonal population, with 59 clonotypes isolated from 20 UA patients. T-cell clonotypes from different UA patients used antigen receptors with similar sequences. T-cell receptor sequences derived from monoclonal T-cell populations were detected in the culprit but not in the nonculprit lesion of a patient with fatal myocardial infarction."

Liuzzo - Circulation 2000 full article / PubMed Central

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)."

Zhu / Circulation 2000 full article

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).

Muhlstein / Circulation 2000 full article
Muhlstein - Circulation 2000 abstract / PubMed

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.

Zhu / Int Immunol 2001 full article
Zhu - Int Immunol 2001 abstract / PubMed

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. 989 patients. "Increasing titers of CMV correlated with the elevation of IL-6 levels (P<0.001) after adjustment for possible confounders. All patients were followed up for a median of 3.1 years (maximum 4.3 years). During follow-up, 96 patients died, 70 of cardiac disease. Overall, CMV seropositivity was not related to cardiac mortality after adjustment for confounding variables (P=0.19). In contrast, in patients with elevated IL-6 levels (≥11.9 pg/mL, median level), CMV seropositivity was independently associated with a 3.2-fold (95% CI 1.4 to 7.3, P=0.007) increase in risk of future cardiac death, whereas in individuals without IL-6 elevation, previous CMV infection had no effect on cardiac mortality."

Blankenberg / Circulation 2001 full article
Blankenberg - Circulation 2001 abstract / PubMed

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.

Kulkarni - Clin Microbiol Infect 2001 abstract / PubMed
Kulkarni / PSL Group Doctors Guide 2001 news

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.

Freedman - Circulation 2001 abstract / PubMed

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."

Borgia - Atherosclerosis 2001 abstract / PubMed

(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.

Medscape News 2001 re Zhu et al.

Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. H Zhu, JP Cong, D Yu, WA Bresnahan, TE Shenk. Proc Natl Acad Sci USA 2002 Mar 19;99(6):3932-3937.

Zhu / PNAS 2002 full article
Zhu - PNAS 2002 abstract / PubMed

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.]

Grahame-Clarke / Circulation 2003 full article

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."

Blum - Clin Exp Med 2003 abstract / PubMed

Heat-shock protein 60-reactive CD4+CD28null T cells in patients with acute coronary syndromes. B Zal, JC Kaski, G Arno, JP Akiyu, Q Xu, D Cole, M Whelan, N Russell, JA Madrigal, IA Dodi, C Baboonian. Circulation 2004 Mar 16;109(10):1230-1235. Twenty-one patients with ACS and 12 with chronic stable angina. "CD4+CD28null cells from 12 of 21 patients with ACS reacted with hHSP60. No response was detected to HCMV, C pneumoniae, or ox-LDL. Incubation of the cells with anti-MHC class II and anti-CD4 antibodies but not anti-class I antibodies blocked antigen presentation, confirming recognition of the hHSP60 to be via the MHC class II pathway. Patients with CSA had low numbers of CD4+CD28null cells. These cells were nonreactive to any of the antigens used. Circulating CD4+CD28null cells were present in 5 of the 9 healthy controls. None reacted with hHSP60."

Zal / Circulation 2004 full article

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)."

Eryol - Int Heart J 2005 abstract / PubMed

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)." [These CD4+CD28- T-cells are a specific marker of CMV infection.]

Liuzzo - J Am Coll Cardiol 2007 abstract / PubMed

High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage. CA Bolovan-Fritts, RN Trout, SA Spector. Blood 2007 Sep 15;110(6):1857-63. "[D]onors with high frequencies of antigen-specific T cells to CMV (high responders) induce higher levels of activation-associated chemokines such as fractalkine, RANTES (regulated on activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1beta, together with cell-adhesion markers in endothelial cells compared with donors with low levels of CMV-specific T cells (low responders). High-responder cultures had higher levels of leukocyte recruitment and adherence to the endothelial monolayers associated with progressive damage and loss of the endothelial cells. These processes that led to endothelial destruction only required viral antigen and did not require infectious virus."

Bolovan-Fritts - Blood 2007 abstract / PubMed
Bolovan-Fritts - Blood 2007 full article / PubMed Central

CD4+ CD28 null T cells in coronary artery disease: when helpers become killers. IE Dumitriu, ET Araguás, C Baboonian, JC Kaski. Cardiovasc Res 2009 Jan 1;81(1):11-19. REVIEW.

Dumitriu - Cardiovasc Res 2009 abstract / PubMed
Dumitriu / Cardiovasc Res 2009 full article

Neopterin, CD4+CD28- lymphocytes and the extent and severity of coronary artery disease. HF Alber, C Duftner, M Wanitschek, J Dörler, M Schirmer, A Suessenbacher, M Frick, W Dichtl, O Pachinger, F Weidinger. Int J Cardiol 2009 Jun 12;135(1):27-35. Graded coronary angiograms of 30 patients with stable angina pectoris. "More extensive CAD was associated with increased neopterin levels (8.3 +/- 3.3 vs. 5.5 +/- 1.2 nmol/L, p < 0.001) and increased CD3+CD4+CD28- cells (3.1 +/- 1.6 vs. 2.0 +/- 1.2%, p < 0.05). A high Gensini severity score was associated with increased neopterin levels (7.8 +/- 2.7 vs. 6.3 +/- 1.7 nmol/L, p < 0.05), but not with CD3+CD4+CD28- cells. Neopterin correlated with both the extent (r = 0.59, p < 0.001) and the Gensini score (r = 0.57, p < 0.003)."

Alber - Int J Cardiol 2009 abstract / PubMed

Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. I Spyridopoulos, J Hoffmann, A Aicher, TH Brümmendorf, HW Doerr, AM Zeiher, S Dimmeler. Circulation 2009 Oct 6;120(14):1364-13672. 14 young and 13 older healthy male volunteers, and 25 age-matched patients. "TL [telomere length] was approximately 0.5 kilobases (kb) shorter in leukocytes from patients with CHD than in their age-matched control subjects. This difference was identical for CD34+ peripheral blood stem cells and progenitor cells, monocytes, granulocytes, B lymphocytes, and CD4+ T cells, including their memory and naďve subpopulations. Surprisingly, only in cytotoxic CD8+ T lymphocytes, we found a substantially increased TL deficit of 1.0 kb in CHD patients as opposed to control subjects. Further analysis revealed that TL shortening was particularly pronounced in CD8+CD28(-) T cells obtained from cytomegalovirus-seropositive CHD patients, whereas such a difference was not observed in healthy cytomegalovirus-positive as opposed to cytomegalovirus-negative control subjects. Finally, TL shortening of CD8+CD45(RA+) T cells was correlated with the decrease in left ventricular function in CHD patients (r=0.629, P=0.001)."

Spyridopoulos / Circulation 2009 full article (pdf, 28 pp)

Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. ET Roberts, MN Haan, JB Dowd, AE Aiello. Am J Epidemiol 2010 Aug 15;172(4):363-371. 1,468 of 1,789 participants inthe Sacramento Area Latino Study on Aging, aged 60-101 years in California during 1998-2008. "For individuals with CMV IgG antibody titers in the highest quartile compared with lower quartiles, fully adjusted models showed that all-cause mortality was 1.43 times (95% confidence interval: 1.14, 1.79) higher over 9 years. In fully adjusted models, the hazard of CVD mortality was also elevated (hazard ratio = 1.35, 95% confidence interval: 1.01, 1.80). A composite measure of tumor necrosis factor and interleukin-6 mediated a substantial proportion of the association between CMV and all-cause (18.9%, P < 0.001) and CVD (29.0%, P = 0.02) mortality."

Roberts - Am J Epidemiol 2010 abstract / PubMed

Association between HLA-DRB1, HLA-DRQB1 alleles, and CD4(+)CD28(null) T cells in a Chinese population with coronary heart disease. W Sun, Y Cui, L Zhen, L Huang. Mol Biol Rep 2011 Mar;38(3):1675-1679. "The HLA-DRB1*01 (RR = 4.705, P < 0.005) and DRB1*04 (RR = 3.554, P < 0.005) alleles showed the strongest association with CHD in the Chinese population, and increased numbers of CD4(+)CD28(null) T cells were found in association with HLA-DRB1*04 (17.1%) and DRB*01 (12.9%), while decreased numbers of CD4(+)CD28(null) T cells were present in subjects with DRB1*15 (0.8%)."

Sun - Mol Biol Rep 2011 abstract / PubMed

Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. S Giubilato, G Liuzzo, S Brugaletta, D Pitocco, F Graziani, C Smaldone, RA Montone, V Pazzano, D Pedicino, LM Biasucci, G Ghirlanda, F Crea. Eur Heart J 2011 May;32(10):1214-1226. 166 acute coronary syndrome patients with or without DM (ACS/DM+, n= 51 and ACS/DM-, n= 115), and 60 healthy controls. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4(+)CD28(null)T-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1-48) vs. ACS/DM- (3.9%, 0.2-35), cDM (3.1%, 0.3-22.4), and controls (1.5%, 0.1-9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4(+)CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4(+)CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4(+)CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4(+)CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4(+)CD28(null)T-cells ≥4% and highest in those without DM and CD4(+)CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features."

Giubilato - Eur Heart J 2011 abstract / PubMed

Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. S Li, J Zhu, W Zhang, Y Chen, K Zhang, LM Popescu, X Ma, WB Lau, R Rong, X Yu, B Wang, Y Li, C Xiao, M Zhang, S Wang, L Yu, AF Chen, X Yang, J Cai. Circulation 2011 Jul 12;124(2):175-184. "Using microarray-based miRNA expression profiling, we compared the miRNA expressions in plasma samples from 13 hypertensive patients and 5 healthy control subjects. Twenty-seven miRNAs were found to be differentially expressed. The expressions of selected miRNAs (miR-296-5p, let-7e, and a human cytomegalovirus [HCMV]-encoded miRNA, hcmv-miR-UL112) were validated independently in plasma samples from 24 hypertensive patients and 22 control subjects. The absolute expression levels of hcmv-miR-UL112, miR-296-5p, and let-7e were further determined in 127 patients and 67 control subjects (fold changes are 2.5, 0.5, and 1.7 respectively; all P<0.0001). Additionally, we demonstrated that interferon regulatory factor 1 is a direct target of hcmv-miR-UL112. Increased HCMV seropositivity and quantitative titers were found in the hypertension group compared with the control group (52.7% versus 30.9%, P=0.0005; 1870 versus 54 copies per 1 mL plasma, P<0.0001). Seropositivity, log-transformed copies of HCMV, and hcmv-miR-UL112 were independently associated with an increased risk of hypertension (odds ratio, 2.48; 95% confidence interval, 1.48 to 4.15; P=0.0005; odds ratio, 1.97; 95% confidence interval, 1.58 to 2.46; P<0.0001; and odds ratio, 2.55; 95% confidence interval, 1.98 to 3.27; P<0.0001, respectively)."

Li - Circulation 2011 abstract / PubMed

Role of herpes simplex virus-1, cytomegalovirus and Epstein-Barr virus in atherosclerosis. A Al-Ghamdi. Pak J Pharm Sci 2012 Jan;25(1):89-97. Seventy five patients (20 with acute coronary artery disease, 20 with chronic coronary artery disease, 20 with cerebral stroke and 15 with peripheral arterial disease, and 15 healthy controls). "Individuals who had CMV-specific IgG were more liable to have vascular disease compared to those without (OR=4.10, CI= 1.07-15.75). The levels of CMV- and EBV-specific IgG antibodies were significantly (P<0.01 and < 0.05 respectively) elevated among patients with atherosclerotic vascular diseases when compared to those of the controls. There was no significant correlation between the levels of virus-specific IgG and lipid profile or hsCRP."

Al-Ghamdi - Pak J Pharm Sci 2012 abstract / PubMed

High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome. IE Dumitriu, P Baruah, CJ Finlayson, IM Loftus, RF Antunes, P Lim, N Bunce, JC Kaski. Circ Res 2012 Mar 16;110(6):857-869. "Patients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4(+)CD28(null) T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function... Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4(+)CD28(null) T cells compared to classical CD4(+)CD28(+) T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4(+)CD28(null) T cells constituted an important proportion of CD4(+) T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4(+)CD28(null) T cells to produce interferon-γ and tumor necrosis factor-α and release perforin."

Dumitriu / Circ Res 2012 full article

Cytomegalovirus localization in atherosclerotic plaques is associated with acute coronary syndromes: report of 105 patients. M Izadi, M Fazel, SH Saadat, MH Nasseri, M Ghasemi, H Dabiri, RS Aryan, AA Esfahani, A Ahmadi, D Kazemi-Saleh, MH Kalantar-Motamed, S Taheri. Methodist Debakey Cardiovasc J 2012 Apr-Jun;8(2):42-46. "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)."

Izadi - Methodist Debakey Cardiovasc J 2012 / PubMed Central

Cytomegalovirus infection and coronary heart disease risk: a meta-analysis. YN Ji, L An, P Zhan, XH Chen. Mol Biol Rep 2012 Jun;39(6):6537-6546. "Ultimately, 55 studies, involving 9,000 cases and 8,608 controls from six prospective studies (all with a nested case-control design) and 49 retrospective case-control studies were included. Overall, people exposed to CMV infection had an odds ratio (OR) of 1.67 (95% CI, 1.56-1.79) for CHD risk, relative to those not exposed. CMV infection was clearly identified as a risk factor for CHD in both prospective studies (OR, 1.31; 95% CI, 1.132-1.517) and retrospective studies (OR, 1.79; 95% CI, 1.659-1.939), and in both Asian group (OR, 2.69; 95% CI, 2.304-3.144) and non-Asian group (OR, 1.48; 95% CI, 1.371-1.600). Interestingly, in the subgroup analyses by detection methods of CMV, the increased risk (OR, 8.121) was greater among studies using polymerase chain reaction than the risk (OR, 1.561) among studies using enzyme-linked immunosorbent assay."

Ji - Mol Biol Rep 2012 abstract / PubMed

Human cytomegalovirus neutralising antibodies and increased risk of coronary artery disease in Indian population. LA Mundkur, H Shivanandan, S Hebbagudi, V Endrész, M Varma, V Rao, E Gonczol, VV Kakkar. Heart 2012 Jul;98(13):982-987. 391 consecutive CAD patients and 391 controls, and 91 patients reporting recurrent cardiac events during a 4-year follow-up and 91 controls. "High CMV-NA titres showed a positive association with CAD occurrence (OR 2.24, 95% CI 1.31 to 3.85, p=0.003) and recurrent cardiac events in CAD patients (OR 4.65, 95% CI 1.21 to 17.86, p=0.025) compared with total CMV antibodies (OR 1.67, 95% CI 1.04 to 2.69, p=0.034, and 2.70, 1.04 to 7.02, p=0.040, respectively). Patients with higher quartile of CMV-NA titres and sPLA2 levels had an adjusted OR of 7.82 (95% CI 1.87 to 32.65, 0.005) for recurrent cardiac events compared with those with the lowest quartiles for both markers."

Mundkur - Heart 2012 abstract / PubMed

Pathogen burden, cytomegalovirus infection and inflammatory markers in the risk of premature coronary artery disease in individuals of Indian origin. LA Mundkur, VS Rao, S Hebbagudi, J Shanker, H Shivanandan, RK Nagaraj, VV Kakkar. Exp Clin Cardiol 2012 Summer;17(2):63-68. 433 cases, 433 controls, 4-year follow-up. "odds of CAD occurrence was 2.42 (95% CI 1.26 to 4.64; P<0.008), with all four infections and increased in the presence of hsCRP (OR 4.67 [95% CI 1.43 to 15.25]); P=0.011). Only anti-CMV antibody levels were a significant risk factor for CAD occurrence (OR 2.23 [95% CI 1.20 to 4.15]; P=0.011) and recurrent cardiac events (OR 1.94 [95% CI 0.85 to 4.45]; P=0.015). Mean values of the inflammatory biomarkers IL-6 (P=0.035), fibrinogen (P=0.014), hsCRP (P=0.010) and secretory phospholipase A2 (P=0.002) increased with CMV antibody levels. Incorporating hsCRP and IL-6 in the risk prediction models significantly increased the OR to 2.56 (95% CI 1.16 to 5.63; P=0.019) with a c statistic of 0.826."

Mundkur - Exp Clin Cardiol 2012 full article / PubMed

Higher Immunoglobulin G antibody levels against Cytomegalovirus are associated with incident ischaemic heart disease in the population based EPIC-Norfolk cohort. E Gkrania-Klotsas, C Langenberg, SJ Sharp, R Luben, KT Khaw, NJ Wareham. J Infect Dis 2012 Dec;206(12):1897-903. 1,356 first-time ischaemic heart disease events during approximately 12 years. "After adjustment for classical ischaemic heart disease risk factors, belonging to the highest antibody group compared to seronegativity was associated with an increased risk of incident ischaemic heart disease (HR 1.22 (95% CI 1.05, 1.42)). After additionally adjusting for measures of social class, inflammation and possible confounders this association was unchanged (HR 1.21 (95% CI 1.04, 1.41))."

Gkrania-Klotsas - J Infect Dis 2012 abstract / PubMed

Seropositivity and higher IgG antibody levels against Cytomegalovirus are associated with mortality in the population based EPIC-Norfolk cohort. E Gkrania-Klotsas, C Langenberg, SJ Sharp, R Luben, KT Khaw, NJ Wareham. Clin Infect Dis 2013 May;56(10):1421-1427. 2,514 deaths / 13,090 participants. "Cytomegalovirus seropositivity (prevalence 59%) was associated with increased all-cause mortality (age and sex adjusted hazard ratio (HR) 1.16 (95% CI 1.07, 1.26)), similarly in men and women (p-interaction=0.52). The association persisted after additionally adjusting for measures of socioeconomic status and possible confounders. Cause-specific analyses suggested increased mortality from cardiovascular disease (HR (95% CI) 1.06 (0.91, 1.24)), cancer (HR (95% CI) 1.13 (0.98, 1.31)) and other causes (HR (95% CI) 1.23 (1.04, 1.47)) all appeared to contribute to the overall associations."

Gkrania-Klotsas - Clin Infect Dis 2013 abstract / PubMed

Cytomegalovirus infection is associated with increased mortality in the older population. G Sawa, A Pachnio, B Kaul, K Morgan, F Huppert, C Brayne, P Moss; The Medical Research Council Cognitive Function Ageing Study. Aging Cell 2013 Jun;12(3):381-387. Cohort of 511 >65y followed 18 years. "The mean age of the participants was 74 years of which 70% were CMV seropositive. CMV was strongly linked to socio-economic status, and CMV infection increased the annual mortality rate by 42% (Hazard ratio = 1.42, 95% CI=1.11-1.76 after adjusting for age, sex and baseline socio-economic and health variables) corresponding to 3.7 years lower life expectancy from age 65. Infection was associated with a near doubling of cardiovascular deaths whereas there was no increase in mortality from other causes."

Sawa - Aging Cell 2013 abstract / PubMed

Decreased Naive and Increased Memory CD4(+) T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis. NC Olson, MF Doyle, NS Jenny, SA Huber, BM Psaty, RA Kronmal, RP Tracy. PLoS One 2013 Aug 23;8(8):e71498. 6,814 asymptomatic men and women. "European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = -0.02 (-0.004, -0.03)]... These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4(+) T cells, and with innate immunity (inflammation), in atherosclerosis..."

Olson - PLoS One 2013 full article / PubMed Central
Olson / PLoS One 2013 full article

The probable role of cytomegalovirus in acute myocardial infarction. M Izadi, MM Zamani, N Sabetkish, H Abolhassani, SH Saadat, S Taheri, H Dabiri. Jundishapur J Microbiol 2014 Mar;7(3):e9253. Autopsy of 26 males and 34 females. "PCR test results were negative for C. pneumoniae and H. pylori in all cadavers of both groups. Nine cadavers from the acute myocardial infarction group and one from the non- acute myocardial infarction group showed positive PCR results for Cytomegaloviruses (30% and 3.33%, respectively). There was a significant difference between the two groups regarding Cytomegaloviruses positivity in coronary artery plaques (P < 0.01, odd ratio: 12.42, 95% CI: 10.46 to 15.73)."

Izadi - Jundishapur J Microbiol 2014 full article / PubMed Central

A novel CMV-induced regulatory type T-cell subset increases in older life and links virus-specific immunity to vascular pathology. N Terrazzini, M Bajwa, S Vita, E Cheek, D Thomas, N Seddiki, H Smith, F Kern. J Infect Dis 2014 May;209(9):1382-1392. "CMV-specific iTregs recognized the same antigens as conventional CD4 T-cells and were significantly more frequent at older ages. They suppressed antigen-specific and non-specific proliferation and in large part expressed Foxp3. Frequencies of CMV-specific iTregs and CD8 T-cells (summated response) were significantly associated with diastolic and mean arterial pressures. Confounders including age, BMI, smoking, antihypertensive medication use, or CRP levels did not explain these observations."

Terrazzini - J Infect Dis 2014 abstract / PubMed

Myocardial Ischemia and Reperfusion Leads to Transient CD8 Immune Deficiency and Accelerated Immunosenescence in CMV-Seropositive Patients. J Hoffmann, E Shmeleva, SE Boag, K Fiser, A Bagnall, S Murali, I Dimmick, H Pircher, C Martin-Ruiz, M Egred, B Keavney, T von Zglinicki, R Das, S Todryk, I Spyridopoulos. Circ Res 2015 Jan 2;116(1):87-98. 34 followed longitudinally and 54 studied cross-sectionally. "CMV-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 min of reperfusion compared with CMV-seronegative patients (-192 vs. -63 cells/µl; p=0.008), correlating with the expression of programmed cell death-1 (PD-1) before PPCI (r=0.8; p=0.0002). A significant proportion of TEMRA cells remained depleted for at least 3 months in CMV-seropositive patients. Using high-throughput 13-parameter flow cytometry and HLA class I CMV-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and CMV-specific CD8+ cells in CMV-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic CMV-seropositive post-MI patients was associated with signs of terminal differentiation including an increase in KLRG1 and shorter telomere length in CD8+ T cells (2225 bp vs. 3397 bp; p<0.001)."

Hoffmann - Circ Res 2015 full article / PubMed Central

Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4⁺CD28null T cells resistant to apoptosis in acute coronary syndrome. E Kovalcsik, RF Antunes, P Baruah, JC Kaski, IE Dumitriu. Circulation 2015 Feb 24;131(8):709-720. "The number of CD4(+)CD28(null) (CD28(null)) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28(null) T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis... We found that CD28(null) T cells in ACS were resistant to apoptosis induction via Fas-ligation or ceramide. This was attributable to a dramatic reduction in proapoptotic molecules Bim, Bax, and Fas in CD28(null) T cells, whereas antiapoptotic molecules Bcl-2 and Bcl-xL were similar in CD28(null) and CD28(+) T cells. We also show that Bim is phosphorylated in CD28(null) T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28(null) T cells in ACS."

Kovalcsik - Circulation 2015 abstract / PubMed

Cytomegalovirus infection and atherosclerosis in candidate of coronary artery bypass graft. H Heybar, SM Alavi, M Farashahi Nejad, M Latifi. Jundishapur J Microbiol 2015 Mar 21;8(3):e15476. 55 bypass patients, 55 other surgery patients. "CMV-DNA was present in 8 (14.5%) of the cases and 2 (4%) of the controls. CMV-DNA was associated with higher risk of atherosclerosis (OR: 7.7, 95% CI = 1.1-51.4, P = 0.03). Of the total normal aortic samples (55 in cases and 55 in controls), there was no individual with simultaneous positive CMV-DNA among aortic atherosclerotic and normal tissue samples."

Heybar - Jundishapur J Microbiol 2015 full article / PubMed Central

Unpacking the 'black box' of total pathogen burden: is number or type of pathogens most predictive of all-cause mortality in the United States? AM Simanek, JB Dowd, A Zajacova, AE Aiello. Epidemiol Infect 2015 Sep;143(12):2624-2634. 6522 subjects from NHANES III, tested for CMV, HSV-1, HSV-2 and H. pylori. "We did not observe a statistically significant graded relationship between total pathogen burden level and all-cause mortality. Furthermore, compared to those seronegative for all four pathogens, the greatest statistically significant rate of all-cause mortality was for those CMV+/HSV-2+ (hazard ratio 1·95, 95% confidence interval 1·13-3·35) adjusting for age, gender, race/ethnicity, education level, body mass index (kg/m2) and smoking status."

Simanek - Epidemiol Infect 2015 abstract / PubMed

CD4+CD28null T cells in acute coronary syndrome: lower with ST-elevation myocardial infarction. NM Sayed, SM Abdel-Rahman, I Esmat, W Nammas. Scand Cardiovasc J 2015 Dec;49(6):325-330. 55 patients, 16 controls. "Mean CD4 + CD28null T cell percentage was 5.9 ± 3.8% in the study cohort versus 0.8 ± 0.7% in controls (p < 0.001). Mean CD4 + CD28null T cell percentage was higher in patients presenting with non-ST-segment-elevation acute coronary syndrome versus those presenting with STEMI: 7.3 ± 4.1% versus 4.6 ± 3.1%, respectively (p = 0.008). Multivariable regression analysis identified the category of acute coronary syndrome as the only variable independently associated with CD4 + CD28null T cell percentage (p = 0.007)."

Sayed - Scand Cardiovasc J 2015 abstract / PubMed

Lymphocyte subpopulations in myocardial infarction: a comparison between peripheral and intracoronary blood. N Lluberas, N Trías, A Brugnini, R Mila, G Vignolo, P Trujillo, A Durán, S Grille, R Lluberas, D Lens. Springerplus 2015 Dec 1;4:744. 33 patients with myocardial infarction. "CD4(+)CD28null T-lymphocytes were significantly increased in IC compared to PB (3.7 vs. 2.9 %, p < 0.0001). Moreover, patients with more than 6 h of evolution of STEMI exhibited higher levels of CD4(+)CD28null T-cells suggesting that this subset may be associated with more intense myocardial damage. The rare NK subpopulation CD3(-)CD16(+)CD56(-) was also increased in IC samples (5.6 vs. 3.9 %, p = 0.006). CD4(+)CD28null T-cells and CD3(-)CD16(+)CD56(-) NK subpopulations were also associated with higher CK levels."

Lluberas - Springerplus 2015 full article / PubMed Central

High Human Cytomegalovirus IgG Level is Associated with Increased Incidence of Diabetic Atherosclerosis in Type 2 Diabetes Mellitus Patients. J Zhang, YY Liu, HL Sun, S Li, HR Xiong, ZQ Yang, GD Xiang, XJ Jiang. Med Sci Monit 2015 Dec 30;21:4102-4110. 222 hospitalized T2DM patients. "Binary logistic regression demonstrated that the highest quartile of HCMV IgG concentration (>500 U/ml) was correlated with the incidence of diabetic atherosclerosis (OR: 8.0, 95%CI: 2.3-27.2), and that titer >127U/ml of HCMV IgG is an independent predictor for the development of diabetic atherosclerosis in T2DM patients (OR: 4.6, 95%CI: 1.9-11.3) after adjustment for all potential confounding factors."

Zhang - Med Sci Monit 2015 full article / PubMed Central
Zhang / Med Sci Monit 2015 full article landing page

Obesity, Metabolic Health, and History of Cytomegalovirus Infection in the General Population. M Hamer, GD Batty, M Kivimäki. J Clin Endocrinol Metab 2016 Apr;101(4):1680-1685. 9,517 men and women. "CMV was associated with an increased prevalence of cardiovascular diseases (odds ratio=1.67; 1.07 - 2.60) independently of obesity, metabolic risk factors, and other covariates."

Hamer - J Clin Endocrinol Metab 2016 abstract / PubMed

Cytomegalovirus in Plasma of Acute Coronary Syndrome Patients. EA Nikitskaya, JC Grivel, EV Maryukhnich, AM Lebedeva, OI Ivanova, PP Savvinova, AV Shpektor, LB Margolis, EY Vasilieva. Acta Naturae 2016 Apr-Jun;8(2):102-107. 97 CAD patients and 53 healthy subjects. "We demonstrated that the number of plasma CMV genome copies in ACS patients was significantly higher than that in healthy subjects (p = 0.01). The CMV genome copy number was correlated with the plasma CRP level (p = 0.002). These findings indicate a potential relationship between CMV activation and atherosclerosis exacerbation that, in turn, leads to the development of unstable angina and acute myocardial infarction."

Nikitskaya - Acta Naturae 2016 abstract / PubMed Central

Cytomegalovirus-Productive Infection Is Associated With Acute Coronary Syndrome. E Nikitskaya, A Lebedeva, O Ivanova, E Maryukhnich, A Shpektor, JC Grivel, L Margolis L, E Vasilieva. J Am Heart Assoc 2016 Aug 20;5(8):e003759. 71 patients with acute coronary syndrome, 26 patients with stable coronary artery disease, and 53 healthy volunteers and in atherosclerotic plaques of 22 patients with peripheral artery disease. "HHV‐5 (cytomegalovirus [CMV]) was the only HHV with a level that was higher in acute coronary syndrome patients than in the control group and that correlated with the level of high‐sensitivity C‐reactive protein. The numbers of effector memory T cells positively correlated with the numbers of CMV genome copies in carotid arteries plaques, whereas the numbers of central memory T cells negatively correlated with CMV copy numbers."

Nikitskaya / J Am Heart Assoc 2016 full article

CMV, Immunity & Social Class

CMV Impairs Immunity

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."

Sinzger - J Virol Methods 1997 abstract / PubMed

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.

Meyer-Konig - J Med Virol 1998 abstract / PubMed

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.

MacCormac - J Med Virol 1999 abstract / PubMed

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.

Kahl / J Virol 2000 full article

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.

Sinzger / J Gen Virol 2000 full article

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..."

Pignatelli / J Gen Virol 2001 full article
Pignatelli - J Gen Virol 2001 abstract / PubMed

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.

Cicin-Sain / J Virology 2005 abstract

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."

Lengerova / J Clin Microbiol 2007 abstract

Mechanisms of CMV causing heart disease

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.

Liuzzo / Circulation 2000 full article

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."

Vallejo / J Immunol 2000 full article

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."

Nakajima / Circulation 2002 full article

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. 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.]

Nakajima / Circ Res 2003 full article

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.]

Gerli / Circulation 2004 full article

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."

Rahbar & Soderberg-Naucler / J Virology 2005 abstract

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 are specific to CMV infection, van Leeuwen, J Immunol 2004.]

Zhang - Circ Res 2006 abstract / PubMed

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."

Regoes / Proc Biol Sci 2006 full article
Regoes - Proc Biol Sci 2006 full article / PubMed Central

Human cytomegalovirus-induced reduction of extracellular matrix proteins in vascular smooth muscle cell cultures: a pathomechanism in vasculopathies? B Reinhardt, M Winkler, P Schaarschmidt, R Pretsch, S Zhou, B Vaida, A Schmid-Kotsas, D Michel, P Walther, M Bachem, T Mertens. J Gen Virol 2006 Oct;87(Pt 10):2849-2858. "Quantitative immunoassays showed a significant reduction of soluble collagen type I and fibronectin proteins in supernatants of both cell types. This was shown to be a direct effect of HCMV infection and not due to a response to interferons released from infected cells, since neutralization of alpha and beta interferon activity could not block virus-induced downregulation of matrix proteins. As the amount of ECM depends on both synthesis and degradation, we also assessed the influence of HCMV on the activity of matrix metalloproteinases (MMP). Interestingly, a significant difference in virus-induced matrix degradation could be shown between the two cell types. HCMV upregulated MMP-2 protein and activity in SMC but not in HFF."

Reinhardt / J Gen Virol 2006 full article

High T-cell response to human cytomegalovirus induces chemokine-mediated endothelial cell damage. CA Bolovan-Fritts, RN Trout, SA Spector. Blood 2007 Sep 15;110(6):1857-1863. "In this work, we report that donors with high frequencies of antigen-specific T cells to CMV (high responders) induce higher levels of activation-associated chemokines such as fractalkine, RANTES (regulated on activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1beta, together with cell-adhesion markers in endothelial cells compared with donors with low levels of CMV-specific T cells (low responders). High-responder cultures had higher levels of leukocyte recruitment and adherence to the endothelial monolayers associated with progressive damage and loss of the endothelial cells. These processes that led to endothelial destruction only required viral antigen and did not require infectious virus."

Bolovan-Fritts / Blood 2007 full article
Bolovan-Fritts - Blood 2007 full article / PubMrd Central

C-Reactive Protein Mediates the Effect of Apolipoprotein E on Cytomegalovirus Infection. AE Aiello, HO Nguyen, MN Haan. J Infect Dis 2008 Jan 1;197(1):34-41. "CMV antibody and CRP levels varied significantly by APOE genotype. The association between CRP and CMV antibody was strengthened in the presence of ε4. In contrast, this effect was not observed in HSV-1. We found that APOE-4 carriers had significantly lower levels of CRP yet significantly higher levels of CMV antibodies, suggesting a mediating pathway."

Aiello - J Infect Dis 2008 abstract / PubMed

Differential pathways govern CD4+ CD28- T cell proinflammatory and effector responses in patients with coronary artery disease. B Zal, JC Kaski, JP Akiyu, D Cole, G Arno, J Poloniecki, A Madrigal, A Dodi, C Baboonian. J Immunol 2008 Oct 15;181(8):5233-5241. 536 T cell clones from 12 patients patients with coronary artery disease and 3 healthy volunteers. "KIR2DS2 specifically interacted with MHC class I-presenting human heat shock protein 60 (hHSP60) inducing cytotoxicity. Further investigations revealed the novel finding that hHSP60 stimulation of TCR alone could not induce a cytotoxic response, and that this response was specific and KIR dependent. Analysis of CD4(+)CD28(-)2DS2(+) clones (n = 162) showed that not all were hHSP60 cytotoxic; albeit, their prevalence correlated with coronary disease status (p = 0.017). A higher proportion of clones responded to hHSP60 by IFN-gamma compared with perforin (p = 0.008)."

Zal - J Immunol 2008 abstract / PubMed

Infection by Human Cytomegalovirus Alters the MMP-9/TIMP-1 Balance in Human Macrophages. K Strĺĺt, R de Klark, S Gredmark, P Eriksson, C Söderberg-Nauclér. J Virol 2009 Jan;83(2):830-835. "Since matrix metalloproteinases (MMPs) have been implicated in atherosclerosis and plaque rupture, we investigated the effect of HCMV infection on MMP expression in human macrophages... HCMV infection reduced MMP-9 mRNA, protein, and activity levels but increased TIMP-1 mRNA and protein levels. Furthermore, a decrease in MMP-12, MMP-14, TIMP-2, and TIMP-3 mRNA levels could be detected. The MMP-9 and TIMP-1 mRNA alterations required viral replication. MMP-9 mRNA expression was affected by an immediate-early or early viral gene product, whereas TIMP-1 mRNA expression was affected by late viral gene products. We conclude that HCMV infection specifically alters the MMP-9/TIMP-1 balance in human macrophages, which in turn reduces MMP-9 activity in infected cells. Since MMP-9 prevents atherosclerotic plaque development in mice, these results suggest that HCMV may contribute to atherogenesis through specific effects on MMP-9 activity."

Strĺĺt / J Virol 2009 abstract

Differential Ligand Binding to a Human Cytomegalovirus Chemokine Receptor Determines Cell Type–Specific Motility. J Vomaske, RM Melnychuk, PP Smith, J Powell, L Hall, V DeFilippis, K Früh, M Smit, DD Schlaepfer, JA Nelson, DN Streblow. PLoS Pathog 2009;5(2):e1000304. "Our finding that Fractalkine causes migration of US28-expressing macrophages suggests a further role for US28 in the development of vascular disease. US28 has been shown to be expressed in HCMV-infected peripheral blood mononuclear cells. Foam cells found in atherosclerotic lesions originate as circulating monocytes and chemokines play an important role in the deposition of monocytes in lesions. In particular, Fractalkine expression is known to be important for the development of atherosclerosis in mouse models of heart disease via recruitment of macrophages into atherosclerotic plaques."

Vomaske / PLoS Pathog 2009 full article

Persistent pathogens linking socioeconomic position and cardiovascular disease in the US. AM Simanek, JB Dowd, AE Aiello. Int J Epidemiol 2009 Jun;38(3):775-87. NHANES subjects >/=45 years old. Socioeconomic position "was associated with CMV, HSV-1 and seropositivity to both pathogens. CMV seropositivity was associated with cardiovascular disease history even after adjusting for confounders as well as SEP. The odds of reporting a history of cardiovascular disease for those with less than a high school education compared with those with more than a high school education decreased by 7.7% after adjusting for CMV (Sobel mediation test for CMV, P = 0.0006)." "Approximately 87.9% (N = 6811/7752) of those tested for CMV and 86.2% (N = 3499/4059) tested for HSV-1 were seropositive (data not shown). Of those tested for both CMV and HSV-1, 77.1% were seropositive to both pathogens, 19.0% were seropositive to one of the pathogens and 4.0% were seronegative to both." 40% of cardiovascular disease prevalence was attributable to CMV seropositivity.

Simanek / Int J Epidemiol 2009 full article

Commentary: Understanding the pathophysiology of poverty. FJ Nieto. Int J Epidemiol 2009 Jun;38(3):787-790. "Surprisingly, even though a majority of subjects with clinical CVD has at least one of the well-established risk factors, in relative terms, only a small fraction of CVD incidence (15−40%) appears to be explained by the conventional risk factors... [T]he most striking finding of Simanek et al.'s study is that the relatively modest OR of CVD associated with CMV infection translates into an estimate of the population attributable risk or attributable fraction of CVD of ∼ 40%... What is striking about this 40% attributable fraction estimate is the implication that eliminating CMV infection would prevent as many CVD cases as the complete removal of smoking and almost twice as many as the elimination of either hypercholesterolaemia or hypertension from the population."

Nieto / Int J Epidemiol 2009 full article

Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility. G Chan, MT Nogalski, AD Yurochko. Proc Natl Acad Sci USA 2009 Dec 29;106(52):22369-22374. "Based on our studies, we suggest that during primary infection, newly infected peripheral monocytes acquire a motile phenotype that promotes exit of the infected cell from the circulating blood into multiple organ tissue despite the absence of a chemotactic gradient. Once in the surrounding tissue, differentiation into HCMV replication-competent macrophages occurs, resulting in viral spread and lifelong persistence in the organs that serve as portals of viral exit."

Chan - Proc Natl Acad Sci USA 2009 full article / PubMed Central

Cytomegalovirus-induced effector T cells cause endothelial cell damage. PJ van de Berg, SL Yong, EB Remmerswaal, RA van Lier, IJ ten Berge. Clin Vaccine Immunol 2012 May;19(5):772-779. We investigated whether CMV-induced immune responses could lead to endothelial damage in humans. We found that terminally differentiated effector CD4(+) and CD8(+) T cells, formed during primary CMV infection and maintained throughout latency, express high levels of CX3CR1 and CXCR3. The ligands of these receptors, fractalkine and IP-10, respectively, are expressed by activated endothelial cells. Peripheral blood mononuclear cells (PBMC) stimulated with CMV antigen produced soluble factors that stimulated endothelial cells to produce both chemokines. Finally, effector cells migrated in a fractalkine- and IP-10-dependent fashion to activated endothelial cells and induced apoptosis in endothelial cells that were stimulated by supernatant from CMV-activated PBMC."

van de Berg - Clin Vaccine Immunol 2012 full article / PubMed Central
van de Berg / Clin Vaccine Immunol 2012 full article

Supra-additive expression of interleukin-6, interleukin-8 and basic fibroblast growth factor in vascular smooth muscle cells following coinfection with Chlamydia pneumoniae and cytomegalovirus as a novel link between infection and atherosclerosis. D Prochnau, E Straube, HR Figulla, J Rödel. Can J Infect Dis Med Microbiol 2012 Summer;23(2):e26-30. "[E]xpression of IL-6, IL-8, RANTES and bFGF was stimulated in a dose- and time-dependent fashion in C pneumoniae and also in HCMV-infected cultures. In contrast, the expression of PDGF-AA was only stimulated following HCMV infection. Coinfection with C pneumoniae and HCMV resulted in a supra-additive stimulation of IL-6 (30% increased expression, P≤0.05) at 48 h, IL-8 (137% increased expression, P≤0.001) at 24 h and bFGF (209% increased expression, P≤0.01) at 48 h following infection."

Prochnau - Can J Infect Dis Med Microbiol 2012 full article / PubMed Central

Infection of Vascular Endothelial Cells with Human Cytomegalovirus Under Fluid Shear Stress Reveals Preferential Entry and Spread of Virus in Flow Conditions Simulating Atheroprone Regions of the Artery. JB Durose, J Li, S Chien, DH Spector. J Virol 2012 Dec;86(24):13745-13755. "[T]he distribution of atherosclerotic plaques within the vasculature is preferentially located at branch points and curves where blood flow is disturbed and shear stress is low... We found that endothelial cells cultured under low shear stress, which simulates the flow condition of atheroprone regions in vivo, are more permissive to HCMV infection than cells experiencing high shear stress or static conditions. Cells exposed to low shear show increased entry of HCMV compared to cells exposed to high shear or static conditions. Viral structural gene expression, viral titers, and viral spread are also enhanced in endothelial cells exposed to low shear."

Durose - J Virol 2012 abstract / PubMed

Presence of cytomegalovirus DNA in leucocytes is associated with increased oxidative stress and subclinical atherosclerosis in healthy adults. YL Lee, CE Liu, WL Cho, CL Kuo, WL Cheng, CS Huang, CS Liu. Biomarkers 2014 Mar;19(2):109-113. "The CMV DNA positive subjects had a higher mean mtDNAΔCT and greater IMT than subjects in the control group."

Lee - Biomarkers 2014 abstract / PubMed

Human Cytomegalovirus-Platelet Interaction Triggers Toll-Like Receptor 2-Dependent Proinflammatory and Proangiogenic Responses. A Assinger, J Kral, KC Yaiw, W Schrottmaier, E Kurzejamska, Y Wang, AA Mohammad, P Religa, A Rahbar, G Schabbauer, LM Butler, C Söderberg-Naucler. Arterioscler Thromb Vasc Biol 2014 Apr;34(4):801-809. "We studied the effects of HCMV-platelet interactions in blood from healthy donors using the purified clinical HCMV isolate VR1814. We demonstrated that HCMV bound to a Toll-like receptor (TLR) 2-positive platelet subpopulation, which resulted in signal transduction, degranulation, and release of proinflammatory CD40L and interleukin-1β and proangiogenic vascular endothelial-derived growth factor..."

Assinger - Arterioscler Thromb Vasc Biol 2014 abstract / PubMed

Human cytomegalovirus infection impairs endothelial cell chemotaxis by disturbing VEGF signaling and actin-polymerization. B Reinhardt, R Godfrey, G Fellbrich, H Frank, A Lüske, T Mertens, J Waltenberger. Cardiovasc Res 2014 Nov 1;104(2):315-325. "We identified two HCMV-induced mechanisms explaining the reduction of chemotaxis: First, a nonambiguous reduction of VEGFR-2 protein was observed, due to decreased transcription. This protein down-modulation could not be inhibited by Ganciclovir. The remaining VEGFR-2 expressed on infected HCAEC were able to stimulate cell activation. Second, HCMV-infection influences actin-polymerization in HCAEC as shown by FACS analysis: Actin-polymerization was significantly reduced to 53% and 51% (p<0.05) compared to non-infected HCAEC at 24 h and 72 h p.i., respectively."

Reinhardt - Cardiovasc Res 2014 abstract / PubMed

Senescent profile of angiogenic T cells from systemic lupus erythematosus patients. P López, J Rodríguez-Carrio, A Martínez-Zapico, L Caminal-Montero, A Suarez. J Leukoc Biol 2016 Mar;99(3):405-412. 84 lupus patients and 46 healthy controls, plus 48 rheumatoid arthritis patients and 72 "with traditional cardiovascular risk factors" as disease controls. "CD4+CD28null cells were notably increased in the systemic lupus erythematosus patients and disease controls compared with healthy controls. In contrast, angiogenic T cells were only reduced in the disease controls (those with rheumatoid arthritis or traditional cardiovascular risk factors). Nevertheless, an anomalous presence of CD28null-angiogenic T cells, with cytotoxic and senescent characteristics, was noted in systemic lupus erythematosus patients in association with anti-dsDNA titer, anti-SSA/Ro antibodies and circulating TNF-α, IL-8, IFN-α, and B lymphocyte stimulator amounts. This subset was also detected in those with traditional cardiovascular risk factors but not in the rheumatoid arthritis patients. In contrast, CD28+-angiogenic T cells were reduced in the systemic lupus erythematosus patients with cardiovascular disorders. In conclusion, CD28 expression must be used to redefine the angiogenic T cell population, because in pathologic conditions, a senescent CD28null-angiogenic T cell subset with inflammatory, rather than protective, effects could be present."

López - J Leukoc Biol 2016 abstract / PubMed

Cytomegalovirus Infection Leads to Development of High Frequencies of Cytotoxic Virus-Specific CD4+ T Cells Targeted to Vascular Endothelium. A Pachnio, M Ciaurriz, J Begum, N Lal, J Zuo, A Beggs, P Moss. PLoS Pathog. 2016 Sep 8;12(9):e1005832. 73 CMV-seropositive donors. "CMV-specific CD4+ T cells can be detected in several stages of differentiation and reveals progression through a dual CD45RA+CD45RO+ stage prior to loss of CD45RA expression and attainment of CCR7+CD45RO+ central memory phenotype. Further differentiation led to downregulation of CCR7 followed by a sequential loss of CD27 and CD28 expression. Indeed, 64% of cells exhibited a predominant CD27-CD28- profile whereas 22% (12/55) displayed a largely CD27-CD28+ profile. CD57 expression is a predominant feature of CMV-specific T cells and was observed almost exclusively on CD27-CD28- cells, with minor expression on the CD27-CD28+ population. A final stage of differentiation, in a minority of cells, was the re-expression of CD45RA which coincided with complete loss of CD45RO expression."

Pachnio / PLoS Pathog 2016 full article

Effect on CMV of drugs used to prevent heart disease

Aspirin attenuates cytomegalovirus infectivity and gene expression mediated by cyclooxygenase-2 in coronary artery smooth muscle cells. E Speir, ZX Yu, VJ Ferrans, ES Huang, SE Epstein. Circ Res 1998 Jul 27;83(2):210-216. "We found that CMV induces ROS, at least partly, through a cyclooxygenase-2 (COX-2)-dependent pathway. Moreover, the viral immediate-early (IE) gene products, IE72 and IE84, have the capacity to transactivate the COX-2 promoter. Aspirin and indomethacin, both cyclooxygenase inhibitors as well as direct ROS scavengers, reduce CMV-induced ROS, probably through both of these activities. Sodium salicylate also has antiviral effects as the result of its potent antioxidant properties. Furthermore, by reducing ROS, aspirin and sodium salicylate inhibit CMV-induced NFkappaB activation, the ability of IE72 to transactivate its promoter, CMV IE gene expression after infection of SMCs, and CMV replication in SMCs. This is the first time aspirin has been shown to have antiviral effects."

Speir / Circ Res 1998 full article

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."

Potena / Circulation 2004 full article

Prolonged activation of NF-kappaB by human cytomegalovirus promotes efficient viral replication and late gene expression. IB DeMeritt, JP Podduturi, AM Tilley, MT Nogalski, AD Yurochko. Virology 2006 Mar 1;346(1):15-31. "To confirm that fluorescence intensity was an accurate measurement of HCMV replication in our system, dot blot analyses were performed on untreated cells, or cells pre-treated with aspirin, MG-132, or the drug solvent DMSO for one hour prior to infection with GFP-HCMV. Total cellular DNA was harvested at 72 hpi and dot blot analysis was performed using an HCMV-specific 32P-labeled probe (Figure 1C). Compared to untreated cells or cells treated with DMSO alone, viral replication was inhibited in cells treated with aspirin or MG-132 prior to infection, suggesting that HCMV genomic replication is regulated in a positive manner by NF-κB."

DeMeritt - Virology 2006 full article / PubMed Central
DeMeritt - Virology 2006 full article / Science Direct

Rosuvastatin induces apoptosis in CD4(+)CD28 (null) T cells in patients with acute coronary syndromes. A Link, S Selejan, L Hewera, F Walter, G Nickenig, M Böhm. Clin Res Cardiol 2011 Feb;100(2):147-158. "Patients with troponin-positive ACS (n = 35) without cholesterol lowering drugs were randomised to placebo (n = 17) or rosuvastatin 20 mg (n = 18) once daily for 6 weeks. CD4(+)CD28(null) T cell abundance (>1%) was distributed equally among the two groups at entry (n = 10 per group). Within 72 h rosuvastatin treatment significantly reduced mean CD4(+)CD28(null) T cell numbers (37 × 10⁶/L vs. placebo 122 × 10⁶/L, n = 20, P = 0.041), IFN-γ production (62.6 vs. 101.5%, P = 0.049) and increased apoptosis of these T cells (63.4 vs. 12.3%, P < 0.001). The intrinsic mitochondria-dependent pathway measured by the anti-apoptotic protein expression of B cell lymphoma 2 (BCL-2) was significantly down-regulated (mean fluorescence intensity 16.08 vs. placebo 43.34, P < 0.001)."

Link - Clin Res Cardiol 2011 abstract / PubMed

Statins demonstrate a broad anti-cytomegalovirus activity in vitro in ganciclovir-susceptible and resistant strains. N Ponroy, A Taveira, NJ Mueller, AL Millard. J Med Virol 2015 Jan;87(1):141-153. "Whereas atorva-, fluva-, and simvastatin showed comparable EC50 and EC90 within a low micromolar range in HAEC, pravastatin exhibited only limited effects. In metabolite rescue experiments, mevalonate almost completely abrogated the anti-CMV activity of all statins, whereas cholesterol failed to counteract the effects. Geranylgeranyl-pyrophosphate partially reversed the anti-CMV activity of most statins, suggesting an involvement of the non-sterol isoprenoid arm of the mevalonate pathway as the mode-of-action. The accumulation of immediate early viral antigens was blocked after 1 dpi onwards, and early and late antigen expression was completely abolished in HAEC. The antiviral activity of statins was comparable to ganciclovir and was retained in a ganciclovir-resistant HCMV strain."

Ponroy - J Med Virol 2015 abstract / PubMed

Type I interferon counteracts antiviral effects of statins in the context of gammaherpesvirus infection. PT Lange, EJ Darrah, EP Vonderhaar, WP Mboko, MM Rekow, SB Patel, DJ Sidjanin, VL Tarakanova. J Virol 2016 Jan 6;90(7):3342-3354. "Specifically, reduced availability of intermediates required for protein prenylation was responsible for decreased gammaherpesvirus replication in statin-treated primary macrophages. We also demonstrate that statin treatment of a chronically infected host attenuates gammaherpesvirus latency in a route of infection-specific manner. Unexpectedly, we found that the antiviral effects of statins are counteracted by type I IFN."

Lange - J Virol 2016 abstract / PubMed

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)."

Smits - Clin Transpl 2003 abstract / PubMed

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."

Fateh-Moghadam - Transplantation 2003 abstract / PubMed

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."

Potena / J Clin Microbiol 2007 abstract

Endothelial dysfunction and cytomegalovirus replication in pediatric heart transplantation. J Simmonds, M Fenton, C Dewar, E Ellins, C Storry, D Cubitt, J Deanfield, N Klein, J Halcox, M Burch. Circulation 2008 May 20;117(20):2657-2661. 50 children aged 8-17, none smokers. "Flow-mediated dilation was significantly impaired in patients with evidence of CMV replication after transplantation (6.64±1.12%, mean±SE) compared with those without (9.48±0.56%; P=0.02). This difference remained after adjustment for age, time since transplantation, and medication. Pretransplantation recipient and donor CMV status and traditional CMV risk were not associated with flow-mediated dilation."

Simmonds / Circulation 2008 full article

Cytomegalovirus Reactivation in Critically Ill Immunocompetent Patients. AP Limaye, KA. Kirby, GD. Rubenfeld, WM Leisenring, EM Bulger, MJ Neff, NS Gibran, M-L Huang, TK Santo Hayes, L Corey, M Boeckh. JAMA 2008 Jul 23/30;300(4):413-422. "The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log10 copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days." And: ICU Stays May Trigger Reactivation of CMV Infection. By Peggy Peck, Executive Editor, MedPage Today. Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine. "[W]e did not find an association between severity of illness (as assessed by the APACHE II score) and risk of CMV reactivation, thereby diminishing the likelihood that CMV reactivation was simply a surrogate marker of illness severity."

Limaye / JAMA 2008 abstract

Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation. JF Delgado, AG Reyne, S de Dios, F López-Medrano, A Jurado, RS Juan, MJ Ruiz-Cano, M Dolores Folgueira, MÁ Gómez-Sánchez, JM Aguado, C Lumbreras. J Heart Lung Transplant 2015 Aug;34(8):1112-1119. 72 / 166 (43%) patients developed CAV over median 11 years. CMV infection (HR, 2.334; 95% CI, 1.043-5.225; p < 0.0354).

Delgado - J Heart Lung Transplant 2015 abstract / PubMed

Cytomegalovirus infection and disease reduce 10-year cardiac allograft vasculopathy-free survival in heart transplant recipients. I Johansson, R Andersson, V Friman, N Selimovic, L Hanzen, S Nasic, U Nyström, V Sigurdardottir. BMC Infect Dis 2015 Dec 24;15(1):582. 226 patients. "Survival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0-7.4) compared with CMV disease (4.2 years; CI, 3.2-5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3-6.4; p = 0.013)."

Johansson - BMC Infect Dis 2015 full article / PubMed Central
Johansson - BMC Infect Dis 2015 full article

Optical coherence tomography and intravascular ultrasound evaluation of cardiac allograft vasculopathy with and without intimal neovascularization. Y Ichibori, T Ohtani, D Nakatani, K Tachibana, O Yamaguchi, K Toda, T Akasaka, N Fukushima, Y Sawa, I Komuro, JL Kotani, Y Sakata. Eur Heart J Cardiovasc Imaging 2016 Jan;17(1):51-58. 45 patients. "The risks for microchannels were donor age [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.22; P = 0.007], cytomegalovirus infection (OR 16.21; 95% CI 1.79-220.09; P = 0.012), diabetes (OR 9.5; 95% CI 1.21-116.10; P = 0.032), LDL-cholesterol (OR 1.07; 95% CI 1.01-1.13; P = 0.010), and intimal volume (OR 2.47; 95% CI 1.13-6.36; P = 0.023)."

Ichibori - J Cardiovasc Imaging 2016 abstract / PubMed

Dental Infections

Dental Infections Cause Heart Disease

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."

Yamashiroya - Am J Pathol 1988 abstract / PubMed

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.

Chiu - Am Heart J 1999 abstract / PubMed

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."

Wanishsawad - J Infect Dis 2000 abstract / PubMed

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.

Siscovick / Circulation 2000 full article
Siscovick - Circulation 2000 abstract / PubMed

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.

Smieja - Can J Cardiol 2001 abstract / PubMed

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."

al-Amro - Cent Eur J Public Health 2001 abstract / PubMed

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)."

Rupprecht / Circulation 2001 full article
Rupprecht - Circulation 2001 abstract / PubMed

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.

Stollberger / Clin Diagn Lab Immunol 2001 full article
Stollberger - Clin Diagn Lab Immunol 2001 abstract / PubMed

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. "After adjustment for coronary risk factors and socioeconomic status, the odds ratios (95% confidence intervals) for premature MI were 2.4 (1.3-4.6) for Cp infection and 2.9 (1.5-5.8) for CMV. The risk of Cp infection was greater in smokers (3.7, 1.8-7.6). When both infections were present (35% of patients vs 8% of controls, P =.001), CRP was higher (P =.01) and the risk increased by 12 times (12.5, 4-38.9) compared with that in subjects without any infection and by 5 times (4.9, 2.2-10.9) if only one was present."

Gattone - Am Heart J 2001 abstract / PubMed

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.

Espinola-Klein / Circulation 2002 full article
Espinola-Klein - Circulation 2002 abstract / PubMed

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.]

Zhu - Am J Cardiol 2002 abstract / PubMed

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.

Stone / Circulation 2002 full article
Stone - Circulation 2002 abstract / PubMed
Stone / Medscape Medical News 2002

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.

Haider - J Am Coll Cardiol 2002 abstract / PubMed

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."

Reunanen - J Intern Med 2002 abstract / PubMed

Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. M Madjid, D Vela, H Khalili-Tabrizi, SW Casscells, S Litovsky. Tex Heart Inst J 2007;34(1):11-18. Autopsies in 14 atherosclerotic patients diagnosed with an acute systemic infection and 13 controls with atherosclerosis but not infection. "5 infected patients had acute myocardial infarction with thrombosis. Macrophage density in plaques and in periadventitial fat was higher in the infected group (NS). The infected patients' adventitia had significantly more macrophages (1,577 +/- 1,872 vs 265 +/- 185 per mm(2); P=0.047). The macrophage density, similar in the control group's adventitia and plaque, was significantly greater in the infected group's adventitia than in the plaque. The adventitia and periadventitial fat of the infected group had more T cells than did samples from the control group (48.4 +/- 45.0 vs 14.1 +/- 6.3 per mm(2); P=0.002)."

Madjid - Tex Heart Inst J 2007 full article / PubMed Central

Acute infections, vaccination and prevention of cardiovascular disease. M Madjid. CMAJ 2008 Oct 7;179(8):749-750. Review.

Madjid - CMAJ 2008 full article / PubMed Central

ICAAC-IDSA: Pneumonia Linked to Acute Coronary Syndrome. By Michael Smith, North American Correspondent, MedPage Today. Oct. 27, 2008. "Patients hospitalized with bacterial pneumonia have about eight times the risk of acute coronary syndrome as those admitted for other causes, a researcher said here. The risk is highest within 15 days of admission, said Vicente Corrales-Medina, M.D., of Baylor College of Medicine in Houston. The association -- found in a retrospective case-control analysis -- is 'so striking' it suggested a causal relationship, Dr. Corrales-Medina said at the Interscience Conference on Antimicrobial Agents and Chemotherapy, held jointly with the Infectious Diseases Society of America meeting... Dr. Corrales-Medina and colleagues analyzed the records of 206 patients admitted to the Michael E. DeBakey VA Medical Center in Houston with a clinical, radiological, and bacteriological diagnosis of pneumonia from January 2000 through December 2006. Of those cases, 144 were caused by Streptococcus pneumoniae and 62 by Haemophilus influenzae, Dr. Corrales-Medina said. For a control group, the researchers identified 395 patients admitted with a diagnosis that was neither pneumonia nor acute coronary syndrome, who were matched by date and time of admission. When the two groups were compared, 22 of the pneumonia patients (10.7%) had acute coronary syndrome within 15 days of admission, compared with six (1.5%) of the controls, Dr. Corrales-Medina said. In a univariate analysis, he said, the odds ratio was 7.8, with a 95% confidence interval from 3.1 to 19.4, which was significant at P<0.001. When the researchers adjusted for possible confounding factors, the pneumonia remained a significant factor, with an odds ratio of 8.5 (and a 95% confidence interval from 3.35 to 22.23), which was again significant at P<0.001. In another analysis, the researchers looked at 36 patients who had suffered acute coronary syndrome at least once during the year before and the year after admission for pneumonia... The analysis showed the coronary syndrome tended to cluster in the "at-risk" period of 15 days after admission, he said. Specifically, 21 (58%) of the events occurred during the at-risk period, for a relative incidence ratio of 47.6, with a 95% confidence interval from 24.5 to 92.5."

ICAAC-IDSA: Pneumonia Linked to Acute Coronary Syndrome / MedPage Today 2008

Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes. VF Corrales-Medina, J Serpa, AM Rueda, TP Giordano, B Bozkurt, M Madjid, D Tweardy, DM Musher. Medicine (Baltimore) 2009 May;88(3):154-159. "In 206 pneumonia patients (144 S. pneumoniae, 62 H. influenzae) we identified 22 (10.7%) cases of ACS, which compared to 6 (1.5%) among 395 controls resulted in an odds ratio (OR) of 7.8 (95% confidence interval [CI], 3.1-19.4). With multivariate logistic regression analysis, the OR for ACS in the pneumonia group remained elevated (OR, 8.5; 95% CI, 3.4-22.2). By the self-controlled case series method, the risk of ACS remarkably increased during the first 15 days after the diagnosis of pneumonia (incidence rate ratio, 47.6; 95% CI, 24.5-92.5)."

Corrales-Medina - Medicine (Baltimore) 2009 abstract / PubMed

The association between Staphylococcus aureus bacteremia and acute myocardial infarction. VF Corrales-Medina, O Fatemi, J Serpa, J Valayam, B Bozkurt, M Madjid, DM Musher. Scand J Infect Dis 2009;41(6-7):511-514. 588 patient case series. "SAB increased the risk for MI 35-fold in the 2 d after recognition of this infection (IRR = 35.3; CI 16.7-74.7)."

Corrales-Medina - Scand J Infect Dis 2009 abstract / PubMed

The influence of persistent pathogens on circulating levels of inflammatory markers: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis. A Nazmi, AV Diez-Roux, NS Jenny, MY Tsai, M Szklo, AE Aiello. BMC Public Health 2010 Nov 17;10:706. Data on C. pneumoniae, CMV, HSV, HAV and H. pylori, from a subsample of the Multi-Ethnic Study of Atherosclerosis. "High antibody response to multiple pathogens showed graded and significant associations with IL-6 (p < 0.001), CRP (p = 0.04) and fibrinogen (p = 0.001), whereas seropositive pathogen burden did not. In multiple linear regression models, high antibody response to multiple pathogens maintained a positive association only with IL-6 (4.4% per pathogen exhibiting high antibody response, 95% CI 0.0-8.9)." "Previous work has generally not differentiated between seropositivity and antibody response, but our results suggest that this may be an important distinction."

Nazmi - BMC Public Health 2010 full article / PubMed Central

Impact of intimal pathogen burden in acute coronary syndromes--correlation with inflammation, thrombosis, and autoimmunity. RP Andrié, G Bauriedel, I Tuleta, P Braun, G Nickenig, D Skowasch. Cardiovasc Pathol 2010 Nov-Dec;19(6):e205-210. Atherectomy specimens from 35 patients with acute coronary syndromes, and 25 with stable angina. "nalysis revealed eight lesions without, 22 lesions with one, 19 lesions with two, seven lesions with three, and four lesions with four pathogens. Cpn was present in 73%, HP in 31%, CMV in 16%, and EBV in 40%. Mean value of PB in ACS-lesions was significantly increased. Expressions of CRP, TF, and hHSP60 were significantly higher in ACS lesions. The number of infectious pathogens correlated significant with the expressions of CRP, TF, and hHSP60."

Andrié - Cardiovasc Pathol 2010 abstract / PubMed

Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events. PF Binkley, GE Cooke, A Lesinski, M Taylor, M Chen, B Laskowski, WJ Waldman, ME Ariza, MV Williams Jr, DA Knight, R Glaser. PLoS One 2013;8(1):e54008. Blood samples from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). "AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6 ± 2.6 pg/mL in patients with AMI vs. 3.2 ± 2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304 ± 116 pg/mL in AMI vs. 265 ± 86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p=0.008; 369 ± 183 pg/mL in AMI and positive for dUTPase vs. 249 ± 70 pg/mL in SA negative for dUTPase antibody)." dUTPase (deoxyuridine triphosphate nucleotidohydrolase) is produced following reactivation of Epstein Barr Virus (EBV).

Binkley - PLoS One 2013 full article / PubMed Central
Binkley / PLoS One 2013 full article

Other Infections

Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function. AO Brown, B Mann, G Gao, JS Hankins, J Humann, J Giardina, P Faverio, MI Restrepo, GV Halade, EM Mortensen, ML Lindsey, M Hanes, KI Happel, S Nelson, GJ Bagby, JA Lorent, P Cardinal, R Granados, A Esteban, CJ LeSaux, EI Tuomanen, CJ Orihuela. PLoS Pathog 2014 Sep 18;10(9):e1004383. "In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring... Microlesions were detected in experimentally infected mice and rhesus macaques, as well as in heart sections from humans who succumbed to invasive pneumococcal disease (IPD)."

Brown / PLoS Pathog 2014 full article

Circulating Pneumolysin Is a Potent Inducer of Cardiac Injury during Pneumococcal Infection. Y Alhamdi, DR Neill, ST Abrams, HA Malak, R Yahya, R Barrett-Jolley, G Wang, A Kadioglu, CH Toh. PLoS Pathog 2015 May 14;11(5):e1004836. "Life-threatening acute cardiac complications are more common in pneumococcal infection compared to other bacterial infections. Distinctively, these arise despite effective antibiotic therapy. Here, we describe a novel mechanism of myocardial injury, which is triggered and sustained by circulating pneumolysin (PLY)... Exposure of cultured cardiomyocytes to PLY-expressing pneumococci caused dose-dependent cardiomyocyte contractile dysfunction and death, which was exacerbated by further PLY release following antibiotic treatment. We found that high PLY doses induced extensive cardiomyocyte lysis, but more interestingly, sub-lytic PLY concentrations triggered profound calcium influx and overload with subsequent membrane depolarization and progressive reduction in intracellular calcium transient amplitude, a key determinant of contractile force."

Alhamdi / PLoS Pathog 2015 full article

Propionibacterium acnes Recovered from Atherosclerotic Human Carotid Arteries Undergoes Biofilm Dispersion and Releases Lipolytic and Proteolytic Enzymes in Response to Norepinephrine Challenge In Vitro. BB Lanter, DG Davies. Infect Immun 2015 Oct;83(10):3960-3971. "The P. acnes 16S rRNA gene was detectable in 4 of 15 carotid artery samples, and viable P. acnes was one among 10 different bacterial species recoverable in culture. Fluorescence in situ hybridization analysis of 5 additional atherosclerotic carotid arteries demonstrated biofilm bacteria within all samples, with P. acnes detectable in 4 samples. We also demonstrated that laboratory-grown cultures of P. acnes biofilms were susceptible to induction of a biofilm dispersion response when challenged with physiologically relevant levels of norepinephrine in the presence of iron-bound transferrin or with free iron."

Lanter - Infect Immun 2015 abstract / PubMed

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.

Hsich - Atherosclerosis 2001 abstract / PubMed

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.

Miyamoto / Infect Immun 2006 abstract

Cytomegalovirus infection causes an increase of arterial blood pressure. J Cheng, Q Ke, Z Jin, H Wang, O Kocher, JP Morgan, J Zhang, CS Crumpacker. PLoS Pathog 2009 May;5(5):e1000427. "Using in vivo mouse model and in vitro molecular biology analyses, we find that CMV infection alone caused a significant increase in arterial blood pressure (ABp) (p<0.01 approximately 0.05), measured by microtip catheter technique. This increase in blood pressure by mouse CMV (MCMV) was independent of atherosclerotic plaque formation in the aorta, defined by histological analyses." CMV stimulated expression of renin in mouse and human cells in an infectious dose-dependent manner.

Cheng - PLoS Pathog 2009 full article / PubMed Central
Cheng / PLoS Pathog 2009 full article

The VP1-unique region of parvovirus B19 induces myocardial injury in mice. X Nie, G Zhang, D Xu, X Sun, Z Li, X Li, X Zhang, F He, Y Li. Scand J Infect Dis 2010;42(2):121-128. "VP1u alone is sufficient to elicit pathological and ultrastructural changes in the host myocardium, and to increase the levels of the functional enzymes aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB) and alpha-hydroxybutyric acid dehydrogenase (alpha-HBDH)."

Nie - Scand J Infect Dis 2010 abstract / PubMed

Cytomegalovirus infection leads to microvascular dysfunction and exacerbates hypercholesterolemia-induced responses. MV Khoretonenko, IL Leskov, SR Jennings, AD Yurochko, KY Stokes. Am J Pathol 2010 Oct;177(4):2134-2144. Mice with murine CMV on a normal diet "exhibited impaired endothelium-dependent vasodilation versus mock-ND at 9 and 12 weeks and endothelium-independent arteriolar dysfunction by 24 weeks." A high-cholesterol diet alone "caused temporary arteriolar dysfunction and venular leukocyte and platelet recruitment, which were exaggerated and prolonged by mCMV infection."

Khoretonenko - Am J Pathol 2010 abstract / PubMed

Effect of the Kv1.3 voltage-gated potassium channel blocker PAP-1 on the initiation and progress of atherosclerosis in a rat model. X Wu, R Xu, M Cao, L Ruan, X Wang, C Zhang. Heart Vessels 2015 Jan;30(1):108-114. "CD4+CD28null T lymphocytes increase in atherosclerotic plaque, and voltage-gated potassium channel Kv1.3 blockers can suppress the function of these cells in vitro by preventing exocytosis of their cytoplasmic granules... Blockade of the Kv1.3 potassium channel via PAP-1 administration decreased perforin levels and prevented plaque formation but had no effect on the other changes seen in this AS model."

Wu - Heart Vessels 2015 abstract / PubMed

See Also:

The Surgeon General Lies That Smoking Causes Heart Disease
The Lie That Secondhand Smoke Causes Heart Disease
Chlamydia pneumoniae causes heart disease
CMV Causes Rheumatoid Arthritis
Infections in Peripheral Arterial Disease
The American Heart Association
How the Public Was Brainwashed About Heart Disease
CMV Impairs Immunity
Influenza Causes Deaths From Heart and Respiratory Disease

<= HOME

cast 09-10-16