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.

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)."

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. S Blankenberg, HJ Rupprecht, C Bickel, C Espinola-Klein, G Rippin, G Hafner, M Ossendorf, K Steinhagen, J Meyer. Circulation 2001 Jun 19;103(24):2915-2921. 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."

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

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

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

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

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

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

Anti-cytomegalovirus (CMV) IgG antibody titer in patients with risk factors to atherosclerosis. A Blum, A Peleg, M Weinberg. Clin Exp Med 2003 Nov;3(3):157-160. "One Hundred and twentysix patients had high anti-CMV antibody titers (>/=1:800) compared with none in the control group. Although 80 patients (90%) in the control group were seropositive, none had anti-CMV IgG antibody titers higher than 1:400. The statistical difference between the patients and the control group was highly significant ( p<0.0001). An immunological response against CMV (expressed as an anti-CMV IgG antibody titer) could be a marker of a long-standing immunological reaction causing an inflammatory response that eventually would cause advanced clinical atherosclerosis. We suggest that anti-CMV antibody titer should be used as an early predictor of atherosclerosis. Our findings support the infectious theory and an association between CMV infection and atherosclerosis at an early stage, maybe even years before clinical events occur."

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

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

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."

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."

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))."

Cytomegalovirus 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."

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 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."

CMV, Immunity & Social Class

Strain differences in CMV infection

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

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

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

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

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

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

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

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

Mechanisms

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

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

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

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

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

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

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

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

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

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."

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."

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."

CMV and heart transplants

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

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

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

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."

Dental Infections

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

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

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

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

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

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

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

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

Periodontal 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)."

Multiple infections

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

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

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

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

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

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

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

Chlamydia pneumoniae and cytomegalovirus seropositivity, inflammatory markers, and the risk of myocardial infarction at a young age. M Gattone, L Iacoviello, M Colombo, AD Casteinuovo, F Soffiantino, A Gramoni, D Picco, M Benedetta, P Giannuzzi. Am Heart J 2001 Oct;142(4):633-640. "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."

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

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

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

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

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

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)."

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

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."

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)."

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)."

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."

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).

Interactions between infections

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

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

Animal studies

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

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

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."

See Also:

cast 03-24-13