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.
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."
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 / PubMedThe 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 / PubMedHigh 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 / PubMedWarner-Lambert/Parke-Davis Award Lecture. Viral pathogenesis
of
atherosclerosis. Impact of molecular mimicry and viral genes. DP
Hajjar. Am J Pathol 1991 Dec;139(6):1195-1211. Review.
Possible role of cytomegalovirus in the pathogenesis of inflammatory aortic diseases: a preliminary report. S Tanaka, Y Toh, R Mori, K Komori, K Okadome, K Sugimachi. J Vasc Surg 1992 Aug;16(2):274-279.
Tanaka - J Vasc Surg 1992 abstract / PubMedCytomegalovirus 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 / PubMedCytomegalovirus 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 / PubMedPotential 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 / PubMedCytomegalovirus 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 / PubMedCytomegalovirus 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 / PubMedCytomegalovirus infection, lipoprotein(a), and hypercoagulability: an atherogenic link? FJ Nieto, P Sorlie, GW Comstock, K Wu, E Adam, JL Melnick, M Szklo. Arterioscler Thromb Vasc Biol 1997 Sep;17(9):1780-1785. "CMV virus might have procoagulant properties."
Nieto / Arterioscler Thromb Vasc Biol 1997 full articleCytomegalovirus 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 / PubMedCytomegalovirus 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.
Pampou - Virchows Arch 2000 abstract / PubMedHost 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 articleCytomegalovirus 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 articleDiscordant 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 articleCytomegalovirus 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 articleMolecular-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 / PubMedCytomegalovirus 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 / PubMedFurther 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 articleHuman cytomegalovirus seropositivity is associated with
impaired
vascular function. C Grahame-Clarke, NN Chan, D Andrew, GL Ridgway, DJ
Betteridge, V Emery, HM Colhoun, P Vallance. Circulation 2003 Aug
12;108(6):678-683. "Individuals who were seropositive for CMV had
reduced responses to bradykinin (P=0.005) and glyceryl trinitrate
(P=0.006). The reduced response to bradykinin remained significant
(P=0.045) after adjusting for the response to glyceryl trinitrate and
was independent of conventional risk factors. Positive serology for the
other organisms did not have an independent effect on reactivity. There
was a weaker association between CMV and coronary artery calcification
(P=0.09). Positive serology for each of the other pathogens did not
affect reactivity, but there was a relation between total pathogen
burden and impaired vascular reactivity. No significant differences
were found between diabetics and nondiabetics." [Note that 82% of the
subjects were from non-manual classes, and may have been infected later
in life than those in manual classes.]
Anti-cytomegalovirus (CMV) IgG antibody titer in patients with
risk
factors to atherosclerosis. A Blum, A Peleg, M Weinberg. Clin Exp Med
2003 Nov;3(3):157-160. "One Hundred and twentysix patients had high
anti-CMV antibody titers (>/=1:800) compared with none in the
control group. Although 80 patients (90%) in the control group were
seropositive, none had anti-CMV IgG antibody titers higher than 1:400.
The statistical difference between the patients and the control group
was highly significant ( p<0.0001). An immunological response
against CMV (expressed as an anti-CMV IgG antibody titer) could be a
marker of a long-standing immunological reaction causing an
inflammatory response that eventually would cause advanced clinical
atherosclerosis. We suggest that anti-CMV antibody titer should be used
as an early predictor of atherosclerosis. Our findings support the
infectious theory and an association between CMV infection and
atherosclerosis at an early stage, maybe even years before clinical
events occur."
Are the high levels of cytomegalovirus antibodies a
determinant in
the development of coronary artery disease? NK Eryol, H Kilic, A Gul I
Ozdogru, T Inanc, A Dogan, R Topsakal, E Basar. Int Heart J 2005
Mar;46(2):205-209. "Fifty-six patients had normal coronary arteries and
123 patients had CAD. Six patients did not have anti-CMV antibodies and
87 of the 173 seropositive patients had high levels of anti-CMV
antibodies (> or = 8 U/mL). High CMV seropositivity (> or
= 8
U/mL) was a significant CAD determinant even after adjustment for
traditional CAD risk factors (odds ratio [OR] = 2.1 P = 0.04,
respectively)."
Unusual CD4+CD28null T Lymphocytes and Recurrence of Acute
Coronary
Events. G Liuzzo, LM Biasucci, G Trotta, S Brugaletta, M
Pinnelli, G Digianuario, V Rizzello, AG Rebuzzi, C Rumi, A Maseri, F
Crea. J Am Coll Cardiol 2007; 50:1450-1458. "CD4+CD28null
T-cell
frequency was an independent predictor of future acute coronary events
(odds ratio 3.01, 95% confidence interval 1.1 to 8.25; p = 0.023)."
[These CD4+CD28- T-cells are a specific marker of CMV infection.]
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."
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.
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)."
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 naïve 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)."
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."
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)."
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%)."
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."
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)."
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 CentralCytomegalovirus 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."
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."
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 / PubMedHigher 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 / PubMedCytomegalovirus infection is associated with increased mortality in the older population. G Savva, A Pachnio, B Kaul, K Morgan, F Huppert, C Brayne, P Moss; The Medical Research Council Cognitive Function Ageing Study. Aging Cell 2013 Feb 26 [Epub ahead of print]. 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."
Savva - Aging Cell 2013 abstract / PubMedSeropositivity 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 Feb 26 [Epub ahead of print]. 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 / PubMedQuantification 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 / PubMedGlycoprotein 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 / PubMedTwo 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 / PubMedEfficient 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 articleTropism 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 articlegpUL73 (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 articleFrequent 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 abstractFailure 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."
Monoclonal T-cell proliferation and plaque instability in
acute
coronary syndromes. G Liuzzo, JJ Goronzy, H Yang, SL Kopecky, DR
Holmes, RL Frye, CM Weyand. Circulation 2000 Jun 27;101(25):2883-2888.
34 patients with stable angina and 34 with unstable angina.
"CD4+CD28null T cells were infrequent in our cohort of 34 SA patients,
with a median frequency of 1.5%. Their frequency was increased 10-fold
in our cohort of 34 UA patients (median 10.8%, P<0.001)... An
average of 3 T-cell clones was seen in UA patients (range 0 to 11)...
Individual T-cell clones differed in size, with large clones reaching
5% and small clones accounting for 0.5% of the circulating CD4+ T-cell
pool... CD4+CD28null T-cell clonotypes are accumulated in lesions with
plaque rupture, suggesting that they are involved in the events leading
to plaque instability, rupture, superimposed thrombosis, and induction
of acute ischemia." CD4+CD28null T-cells also secrete large amounts of
IFN-γ, a potent stimulator of macrophages.
Clonality and longevity of CD4+CD28null T cells are associated
with
defects in apoptotic pathways. AN Vallejo, M Schirmer, CM Weyand, JJ
Goronzy. J Immunol 2000 Dec 1;165(11):6301-6307. "CD4(+)CD28(null) T
cells are oligoclonal lymphocytes rarely found in healthy individuals
younger than 40 yr, but are found in high frequencies in elderly
individuals and in patients with chronic inflammatory diseases.
Contrary to paradigm, they are functionally active and persist over
many years... the present studies unequivocally show dysregulation of
apoptotic pathways in CD4(+)CD28(null) T cells that favor their clonal
outgrowth and maintenance in vivo."
T-cell-mediated lysis of endothelial cells in acute coronary
syndromes. T Nakajima, S Schulte, KJ Warrington, SL Kopecky, RL Frye,
JJ Goronzy, CM Weyand. Circulation 2002 Feb 5;105(5):570-575. 24
patients with stable angina, 22 with unstable angina, and 20 controls.
"Gene profiling identified perforin, CD161, and members of the
killer-cell immunoglobulin-like receptors as being differentially
expressed in CD4+CD28null T cells, a T-cell subset that preferentially
infiltrates unstable plaque. Frequencies
of CD161+ and perforin-expressing CD4 T cells in peripheral blood were
significantly increased in patients with unstable angina (UA).
CD161 appeared on CD4+CD28null T cells after stimulation, suggesting
spontaneous activation of circulating CD4 T cells in UA.
Perforin-expressing CD4+ T-cell clones from patients with UA exhibited
cytotoxic activity against human umbilical vein endothelial cells
(HUVECs) in redirected cytotoxicity assays after T-cell receptor
triggering and also after stimulation of major histocompatibility
complex class I–recognizing killer-cell immunoglobulin-like receptors.
HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by
the paralyzing effect of pretreating CD4+CD28null T cells with
strontium. Incubation
of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a
dose-dependent fashion." This causes erosion or rupture
of the
atherosclerotic plaque, followed by thrombosis. "We have demonstrated
that plaque-infiltrating T lymphocytes include a subset of functionally
distinct CD4 T cells that lack CD28 expression. CD4+CD28null clonotypes
can be isolated from culprit lesions but not from stable plaque. These
T cells are capable of releasing large amounts of interferon (IFN)- and
are the dominant population of IFN-–producing cells in peripheral blood
of patients with unstable angina (UA). One of their functions seems to
be the activation of monocytes and macrophages. Monocytes from patients
with UA display a molecular fingerprint of ongoing IFN- stimulation...
In the present study, we show that CD4+CD28null T cells from patients
with UA have killer-cell functions and can cause target-cell death
through the release of the pore-forming enzyme perforin. Endothelial
cells are susceptible to this T-cell–mediated injury. In the presence
of C-reactive protein (CRP), at concentrations frequently found in
patients at risk for coronary events, susceptibility of endothelial
cells to T-cell–mediated cytotoxicity was increased, suggesting that
CRP sensitized endothelial cells to cytolysis."
De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes. T Nakajima, O Goek, X Zhang, SL Kopecky, RL Frye, JJ Goronzy, CM Weyand. Circ Res 2003 Jul 25;93(2):106-113. "Patients with ACS can be distinguished from age-matched healthy controls and patients with stable angina by the increased frequency of a subset of CD4+ T cells that are oligoclonally expanded in the peripheral blood and have lost the expression of the costimulatory molecule CD28.12 Data on the relationship between plaque-infiltrating T cells and these oligoclonally expanded CD4+CD28null T cells are limited. However, phenotypic and T-cell receptor sequence analysis in the patients who have been studied indicate that these T cells accumulate in culprit lesions and are not present in stable lesions (authors’ unpublished data, 2003). CD4+CD28null T cells are functionally distinct from classic CD4+ helper T cells. Besides their ability to release large amounts of interferon (IFN)-, CD4+CD28null T cells express perforin and granzyme B.11 On triggering of the T-cell receptor, they lyse target cells, including endothelial cells. It is possible, therefore, that these T cells directly contribute to plaque instability." [(CD4+)CD28- T cells were specific to CMV infection, van Leeuwen, J Immunol 2004.]
Nakajima / Circ Res 2003 full articleHydroxymethyl-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 articleCD4+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 articleHuman cytomegalovirus infection of endothelial cells triggers
platelet adhesion and aggregation. A. Rahbar, C. Soderberg-Naucler. J
Virology 2005 Feb;79(4):2211-2220. "The increased thrombogenicity was
dependent on active virus replication and could be inhibited by
foscarnet and gancyclovir; these results suggest that a late viral gene
may be mediating this phenomenon, which may contribute to vascular
catastrophes in patients with atherosclerotic disease."
Interleukin 12 induces T-cell recruitment into the
atherosclerotic
plaque. X Zhang, A Niessner, T Nakajima, W Ma-Krupa, SL Kopecky, RL
Frye, JJ Goronzy, CM Weyand. Circ Res 2006 Mar 3;98(4):524-531. "Here
we report that (CD4+)CD28- T cells, either isolated from the plaque
tissue or from the blood of patients with acute coronary syndrome
(ACS), spontaneously express interleukin (IL)-12 receptors, even in the
absence of antigenic stimulation. (CD4+)CD28- IL-12R+ cells responded
to IL-12 stimulation with the upregulation of the chemokine receptor
CCR5 and the C-type lectin receptor CD161, both implicated in
regulating tissue homing of effector T cells. IL-12 treatment of
(CD4+)CD28- T cells enhanced their chemotaxis and transendothelial
migration toward the chemokine CCL5. In vivo relevance for the role of
IL-12 in regulating the recruitment of (CD4+)CD28- T cells into the
atheroma was examined in human atheroma-SCID mouse chimeras. Exposure
of nonstimulated (CD4+)CD28- T cells to IL-12 was sufficient to amplify
T-cell accumulation within the inflamed plaque, and coadministration of
anti-CCR5 antibodies blocked T-cell recruitment into the plaque. Thus,
(CD4+)CD28- T cells functionally resemble NK cells, which have
proinflammatory activity even in the unprimed state and respond to any
IL-12-inducing host infection with a shift in tissue trafficking and
accrual in inflammatory lesions." [(CD4+)CD28- T cells were specific to
CMV infection, van
Leeuwen, J
Immunol 2004.]
Modelling cytomegalovirus replication patterns in the human
host:
factors important for pathogenesis. RR Regoes, EF Bowen, AV Cope, D
Gor, AF Hassan-Walker, HG Prentice, MA Johnson, P Sweny, AK Burroughs,
PD Griffiths, S Bonhoeffer, VC Emery. Proc Biol Sci 2006 Aug
7;273(1596):1961-1967. "We use a statistical model that allows all
viral load data sampled during infection to be analysed, and have
applied it to four immunocompromised groups exhibiting five distinct
cytomegalovirus-related diseases. The results show that for all
diseases, peaks
in viral load contribute less to disease progression than phases of low
virus load with equal amount of viral turnover.
The
model
accurately predicted the time of disease onset for fever,
gastrointestinal disease and pneumonitis but not for hepatitis and
retinitis, implying that other factors may be involved in the pathology
of these diseases."
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 articleHigh 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."
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."
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)."
Infection by Human Cytomegalovirus Alters the MMP-9/TIMP-1
Balance
in Human Macrophages. K Strååt, 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."
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."
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."
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 / PubMedThree-year survival rates for all consecutive heart-only and
lung-only transplants performed in Eurotransplant, 1997-1999. JM Smits,
J Vanhaecke, A Haverich, E de Vries, M Smith, E Rutgrink, A Ramsoebhag,
A Hop, G Persijn, G Laufer. Clin Transpl 2003;:89-100. In heart
transplants, "Survival was significantly associated with the CMV
serologic status of the donor and recipient; the 3-year survival rates
were: D+/R+, 71%; D+/R-, 69%; D- R-, 76%; and D-/R+, 76% (p=0.04)." In
lung transplants, "A donor CMV+ and recipient CMV- match was a risk
factor for long-term mortality, with 3-year survival rates of 56% for
D+/R+, 55% for D+/R-, 71% for D-/R- and 62% for D-/R+ transplants
(p=0.046)."
Cytomegalovirus infection status predicts progression of
heart-transplant vasculopathy. S Fateh-Moghadam, W Bocksch, R Wessely,
G Jager, R Hetzer, M Gawaz. Transplantation 2003 Nov
27;76(10):1470-1474. In 103 consecutive heart-transplant recipients
followed for one year, "The HCMV-positive group showed more advanced,
calcified lesions (64.7% vs. 27.5%, P=0.002), and the maximal plaque
thickness was significantly different from the HCMV IgG/IgM-negative
group (median [quartile] 1.36 [0.85, 1.88] vs. 1.05 [0.58, 1.34],
P=0.02)... In addition, HCMV PCR positivity even increases the risk
for accelerated TVP (P=0.017) and, consecutively, transplant failure."
Frequent occult infection with cytomegalovirus in cardiac
transplant
recipients despite antiviral prophylaxis. L Potena, CTJ Holweg, ML
Vana, L Bashyam, J Rajamani, AL McCormick, JP Cooke, HA Valantine, ES
Mocarski. J Clin Microbiol 2007 Jun;45(6):1804-1810. Heart transplant
patients who were CMV-positive more often had high levels of infection
than CMV-negative transplant patients who received hearts from
CMV-positive donors. "Therefore, active systemic CMV infection
involving leukocytes is common in heart transplant recipients receiving
prophylaxis to reduce acute disease. Infection of the transplanted
organ is rare, suggesting that chronic vascular disease attributed to
CMV may be driven by the consequences of systemic infection."
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."
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."
Streptococci from the mouth which enter the bloodstream during dental work have long been known to cause endocarditis. And, "early immunization experiments with oral streptococcal organisms (especially s mutans for vaccination against caries) resulted in the production of autoimmune antivascular and anticardiac cross-reactive immunoglobulins. Recently, landmark studies by Herzberg et al have identified the cross-reactive immunodeterminants responsible. S sanguis contains an outer membrane associated protein... which is identical to the platelet-interactive domain of Type I and Type II collagens. This bacterial protein thus presents or 'mimics' the normal platelet receptor that initiates thrombus formation. Type III collagen is in the wall and basement membrane of vessels and is normally covered with endothelial cells, which serves to mask these platelet binding receptor sequences from circulating blood cells. Trauma or other noxious stimuli which expose these receptors and thereby provide an important signal to initiate hemostasis or thrombosis. Herzberg et al also report that Porphyromonas gingivalis (a gram-negative periodontal pathogen) has properties similar to S sanguis. Taken together, these findings suggest that oral organisms may serve as a thromboembolic trigger." (Dental infections and atherosclerosis. JD Beck, J Pankow, HA Tyroler, S Offenbacher. Am Heart J 1999;138:S528-S533.)
Beck - Am Heart J 1999 abstract / PubMed"Patients who experience acute MI are nearly three times more likely to have periodontitis than healthy persons, according to data presented here Monday at the American Heart Association's Scientific Sessions." (Re: E Deliagyris et al. Reuters Medical News via Medscape, 2000 Nov 14.)
Deliagyris spin doctors his study for the masses. In the news report on Gannett / NBC WGRZ Channel 2, Buffalo, New York, Deliagyris claimed "'We know a lot of risk factors for heart attacks, including high blood pressure, high cholesterol, diabetes, and cigarette smoking, but all those combined only explain about two-thirds of heart attacks,' Deliagyris said. 'Since about a third of people who suffer heart attacks don't have those risk factors, there's a wide search going on for other conditions that may contribute to increased risk."
This is the official lie of the anti-smoking establishment. The deceit is in pretending that the supposed risk factors, particularly smoking, "explain" any cases at all; and pretending that it's only those few cases that aren't thus "explained" which would be involved. IN FACT, it is the health establishment's conspiracy to ignore the confounding role of infection that is the cause of the supposed "smoking risk."
Periodontal infections and cardiovascular disease -- how strong is the association? GC Armitage. Oral Dis 2000 Nov;6(6):335-350. Review.
Armitage - Oral Dis 2000 abstract / PubMedGum disease may nourish other maladies. Richard a. Marini, New York Times Syndicate 2001 Oct 17.
Marini, 2001 / Dr. Rajiv KhoslaSystemic release of endotoxins induced by gentle mastication: association with periodontitis severity. SO Geerts, M Nys, MP De, J Charpentier, A Albert, V Legrand, EH Rompen. J Periodontol 2002 Jan;73(1):73-78. "This finding suggests that a diseased periodontium can be a major and underestimated source of chronic, or even permanent, release of bacterial pro-inflammatory components into the bloodstream." (News re Geerts et al.: Infected gums leak toxins into bloodstream. By Melissa Schorr. Reuters Health Information - Medscape 2002 Feb. 8.)
Geerts - J Periodontol 2002 abstract / PubMedRelationship between Porphyromonas gingivalis, Epstein-Barr virus infection and reactivation in periodontitis. N Sugano, K Ikeda, M Oshikawa, H Tanaku, S Sato, K Ito. J Oral Sci 2004 Dec;46(4):203-206. P gingivalis levels were higher in saliva of EBV-positive patients, while P gingivalis stimulated EBV.
Sugano - J Oral Sci 2004 abstract / PubMedPeriodontal infections and coronary heart disease: role of
periodontal bacteria and importance of total pathogen burden in the
Coronary Event and Periodontal Disease (CORODONT) study. A Spahr, E
Klein, N Khuseyinova, C Boeckh, R Muche, M Kunze, D Rothenbacher, G
Pezeshki, A Hoffmeister, W Koenig. Arch Intern Med 2006 Mar
13;166(5):554-559. 263 CHD patients and 526 controls. "In multivariable
analyses, we found a statistically significant association between the
periodontal pathogen burden (log10 of the sum of all pathogens) (odds
ratio [OR], 1.92; 95% confidence interval [CI], 1.34-2.74;
P<.001)
or the number of A actinomycetemcomitans in periodontal pockets (log10)
(OR, 2.70; 95% CI, 1.79-4.07; P<.001) and the presence of CHD.
In
addition, a statistically significant association between an increase
in mean CPITN score by 1 and the presence of CHD (OR, 1.67; 95% CI,
1.08-2.58; P = .02) was observed."
Bacterial Profile and Burden of Periodontal Infection in
Subjects
With a Diagnosis of Acute Coronary Syndrome. S Renvert, T Pettersson, O
Ohlsson, GR Persson. J Periodontol 2006 Jul;77(7):1110-1119. In
161 surviving acute coronary patients and 161 controls, "Total oral
bacterial load was higher in the subjects with ACS (mean difference:
17.4 x 10(5); SD: 10.8; 95% confidence interval [CI]: 4.2 to 17.4; P
<0.001), and significant for 26 of 40 species including
Porphyromonas gingivalis, Tannerella forsythensis, and Treponema
denticola." Also: Study Supports Findings That Periodontal Bacteria May
Be Linked to Heart Disease. SOURCE: American Academy of Periodontology.
DGNews, July 19, 2006. "The amount of oral bacteria was two times
higher in the ACS group for the combination of the bacteria
streptococci species, P. gingivalis, T. forsythia and T. denticola.
Specifically, the findings suggest that T. denticola, T. forsythia and
streptococci species are bacteria in a shared infectious etiology for
periodontitis and ACS."
Detection of cariogenic Streptococcus mutans in extirpated
heart
valve and atheromatous plaque specimens. K Nakano, H Inaba, R Nomura, H
Nemoto, M Takeda, H Yoshioka, H Matsue, T Takahashi, K Taniguchi, A
Amano, T Ooshima. J Clin Microbiol 2006 Sep;44(9):3313-3317. 35 heart
valve and 27 atheromatous plaque clinical specimens, as well as 32
dental plaque specimens from the same subjects, analyzed by PCR.
"Streptococcus mutans was frequently detected in the heart valve (69%)
and atheromatous plaque (74%) specimens, while other bacterial species,
including those related to periodontitis, were detected with much lower
frequencies."
Evaluation of the incidence of periodontitis-associated
bacteria in
the atherosclerotic plaque of coronary blood vessels. M Zaremba, R
Górska, P Suwalski, J Kowalski. J Periodontol 2007
Feb;78(2):322-327. "In 13 of 20 patients, the pathogens most frequently
found in severe chronic periodontitis were also found in coronary
vessels. In 10 cases, those species of bacteria were also present in
atherosclerotic plaque. The most frequently identified bacteria were
Porphyromonas gingivalis and Treponema denticola."
Treatment of periodontitis and endothelial function. MS
Tonetti, F
D'Aiuto, L Nibali, A Donald, C Storry, M Parkar, J Suvan, AD
Hingorani, P Vallance, J Deanfield. New Engl J Med 2007 Mar
1;356(9):911-920. A randomized clinical trial of 120 patients with
severe periodontal disease, assigned to community-based periodontal
care (59 patients) or intensive periodontal treatment (61). Endothelial
function, as assessed by measurement of the diameter of the brachial
artery during flow (flow-mediated dilatation), and inflammatory
biomarkers and markers of coagulation and endothelial activation were
evaluated before treatment and 1, 7, 30, 60, and 180 days after
treatment. "Conclusions Intensive periodontal treatment resulted in
acute, short-term systemic inflammation and endothelial dysfunction.
However, 6 months after therapy, the benefits in oral health were
associated with improvement in endothelial function."
Correlation between atherosclerosis and periodontal putative
pathogenic bacterial infections in coronary and internal mammary
arteries. A Pucar, J Milasin, V Lekovic, M Vukadinovic, M Ristic, S
Putnik, EB Kenney. J Periodontol 2007 Apr;78(4):677-682. By PCR in 15
coronary arteries with atherosclerosis and 15 internal mammary arteries
without, each from the same patient, "Bacterial DNA was found in nine
of 15 (60%) coronary artery biopsy samples: P. gingivalis in eight
(53.33%), A. actinomycetemcomitans in four (26.67%), P. intermedia in
five (33.33%), and T. forsythensis in two (13.33%) samples; CMV was
detected in 10 (66.67%) samples, and C. pneumoniae was detected in five
(33.33%) samples. Some of the samples contained more than one type of
bacteria. Periodontal pathogens were not detected in internal mammary
artery biopsies, whereas CMV was present in seven (46.67%) samples and
C. pneumoniae was present in six (40%) samples. CONCLUSION: The absence
of putative pathogenic bacteria in internal mammary arteries, which are
known to be affected rarely by atherosclerotic changes, and their
presence in a high percentage of atherosclerotic coronary arteries
support the concept that periodontal organisms are associated with the
development and progression of atherosclerosis."
[Detection of periodontal pathogens in coronary
atherosclerotic
plaques]. LJ Zhong, YM Zhang, H Liu, P Liang, AR Murat, S Askar.
Zhonghua Kou Qiang Yi Xue Za Zhi 2008 Jan;43(1):4-7. Subgingival plaque
samples and coronary atherosclerotic plaques from 31 patients with
periodontitis at coronary artery bypass surgery. "In coronary
atherosclerotic plaques samples from the 31 patients, Porphyromonas
gingivalis (Pg, 38.7%), Actinobacillus actinomycetemcomitans (Aa, 0%),
Fusobacterium nucleatum (Fn, 22.6%), Prevotella intermedia (Pi, 12.9%),
Bacteroides forsythus (Bf, 38.7%) were detected. The concordant
presence of the same periodontal bacteria DNA in subgingival plaques
and in coronary atherosclerotic plaques in the same patient was Pg 5
(16.1%), Aa 0 (0%), Pi 2 (6.5%), Fn 4 (12.9%) and Bf 8 (25.8%)."
Periodontal infection is associated with endothelial
dysfunction in
healthy subjects and hypertensive patients. Y Higashi, C Goto, D
Jitsuiki, T Umemura, K Nishioka, T Hidaka, H Takemoto, S Nakamura, J
Soga, K Chayama, M Yoshizumi, A Taguchi. Hypertension 2008
Feb;51(2):446-453. 32 normotensive periodontal patients, 20
normotensive controls, 28 male and 10 female hypertensive patients with
periodontitis, 18 male and 6 female hypertensives without
periodontitis. "Circulating levels of C-reactive protein and
interleukin-6 were significantly higher in the periodontitis group than
in the control group. Both in healthy and hypertensive subjects,
forearm blood flow responses to acetylcholine were significantly
smaller in the periodontitis group than in the control group. Sodium
nitroprusside-stimulated vasodilation was similar in the 2 groups.
Periodontal therapy reduced serum concentrations of C-reactive protein
and interleukin-6 and augmented acetylcholine-induced vasodilation in
periodontitis patients with and without hypertension."
Antibodies to periodontal pathogens and coronary artery
calcification in type 1 diabetic and nondiabetic subjects. HM Colhoun,
JM Slaney, MB Rubens, JH Fuller, A Sheiham, MA Curtis. J Periodontal
Res 2008 Feb;43(1):103-110. 199 type 1 diabetics and 201 nondiabetics.
"Elevated antibody levels were associated with higher systolic blood
pressure (p = 0.02) and an increased odds of coronary artery
calcification in all subjects combined (odds ratio = 1.7, p = 0.047)
and in diabetic subjects examined separately (odds ratio = 2.01, p =
0.027)."
Detection of oral bacteria in cardiovascular specimens. K
Nakano, H
Nemoto, R Nomura, H Inaba, H Yoshioka, K Taniguchi, A Amano, T Ooshima.
Oral Microbiol Immunol 2009 Feb;24(1):64-68. Specimens from 203
consecutive patients (82 aortic valve, 35 mitral valve, and 86 aortic
aneurysmal wall specimens). "Streptococcus mutans was the most
frequently detected species in the cardiovascular specimens, followed
by Aggregatibacter actinomycetemcomitans. As for dental plaque
specimens from patients who underwent cardiovascular operations, most
of the tested periodontitis-related species as well as oral
streptococci were detected at high frequencies. Furthermore, the
positive rate of S. mutans in cardiovascular specimens from patients
whose dental plaque specimens were also positive for S. mutans was 78%,
which was significantly higher than any other tested species when the
same analysis was performed."
The atherogenic bacterium Porphyromonas gingivalis evades
circulating phagocytes by adhering to erythrocytes. D Belstrøm,
P Holmstrup, C Damgaard, TS Borch, MO Skjødt, K Bendtzen, CH
Nielsen. Infect Immun 2011 Apr;79(4):1559-1565. P. gingivalis fixed
complement component 3 and adhered to red blood cells, which reduced
attack by neutrophils and B cells.
Bacterial Signatures in Thrombus Aspirates of Patients with Myocardial Infarction. T Pessi, V Karhunen, PP Karjalainen, A Ylitalo, JK Airaksinen, M Niemi, M Pietila, K Lounatmaa, T Haapaniemi, T Lehtimäki, R Laaksonen, PJ Karhunen, J Mikkelsson. Circulation 2013 Mar 19;127(11):1219-1228. 101 male heart patients. "Bacterial DNA typical for endodontic infection, mainly oral viridans streptococci, was measured in 78.2% of thrombi and periodontal pathogens in 34.7%. Bacteria-like structures were detected by transmission electron microscopy in all 9/9 thrombi samples analyzed and whole bacteria in 3/9 cases. Monocyte/macrophage markers for bacteria recognition (CD14) and inflammation (CD68) were detected in thrombi (8/8) by immunohistochemistry. Among the subgroup of 30 MI patients examined by panoramic tomography, a significant association between the presence of periapical abscesses and oral viridans streptococci DNA positive thrombi was found (OR 13.2, 95% CI 2.11 - 82.5; p=0.004)."
Pessi - Circulation 2013 abstract / PubMedHerpesviridae 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 / PubMedIn: 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 / PubMedChlamydia 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 articlePrevious 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 / PubMedFrequency 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 / PubMedImpact 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 articleSeroprevalence 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 articleChlamydia 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 / PubMedImpact 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 articleLack 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 / PubMedEffect 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 articleThe 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 / PubMedEnterovirus, 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 / PubMedSystemic 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 CentralAcute infections, vaccination and prevention of cardiovascular disease. M Madjid. CMAJ 2008 Oct 7;179(8):749-750. Review.
Madjid - CMAJ 2008 full article / PubMed CentralICAAC-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."
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 / PubMedThe 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 / PubMedThe 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."
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."
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 CentralChlamydia 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 / PubMedCytomegalovirus 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 / PubMedPathogen-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.
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.
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)."
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."
cast 03-24-13