Evidence for the role of Epstein Barr Virus infections in the pathogenesis of acute coronary events.

BACKGROUND: The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events. METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. 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). CONCLUSIONS/SIGNIFICANCE: These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events.

An evidence against the effect of chronic cytomegalovirus infection in unstable angina pectoris.

Recent reports have suggested that cytomegalovirus (CMV) infection may contribute to risk of cardiovascular disease. However, relationship between CMV infection and unstable angina (UA) is controversial and studies about this subject in Iran and even region are lacking. The aim of this study was to determine whether unstable angina is related to seropositivity to chronic cytomegalovirus infection. We measured serum CMV IgG levels in a case control study participants in CCU in Razi Hospital, Ahvaz, Iran, from 2004 to 2005. Blood samples were drawn during study period from 96 patients (mean age 56 years) with UA according to American Heart Association Criteria and from 96 participants free of cardiovascular disease (mean age 58 years) and stored at -20°C. Blood samples of patients were undertaken for investigating the specific anti CMV-IgG by ELISA method. Data were analyzed in SPSS 11.5 by using chi square test, odds ratios (OR) with 95% confidence intervals (CI). Ninety three percent of patients with unstable angina and 96.7% in the control group presented a positive anti CMV-IgG. Odds ratio was 0.52 with 95% CI: 0.10 to 2.42. There was no significant correlation between CMV-IgG positivity and unstable angina (P>0.05). There was also no differences in CMV-IgG positivity in clinical groups of UA (P>0.05). The relationship between seropositivity of CMV-IgG and unstable angina has been restituted by the results of this study. However, further population based cohort studies for relationship between CMV infection and coronary artery disease must be conducted.

Herpesvirus DNA (Epstein-Barr virus, herpes simplex virus, cytomegalovirus) in circulating monocytes of patients with coronary artery disease.

BACKGROUND: The underlying mechanism of the chronic inflammatory process in atherosclerosis is still unknown. As a possible trigger, several studies in recent years have suggested that different viruses and bacteria are associated with atherosclerotic diseases. METHODS: We applied polymerase chain reaction to analyse whether Epstein-Barr virus (EBV), herpes simplex virus (HSV), and cytomegalovirus (CMV) DNA could be detected in CD14 + cells from 184 patients with angiographically documented coronary artery disease (CAD) (74 patients with stable angina (SAP), 51 patients with unstable angina (UAP), and 59 patients with myocardial infarction (MI)) and from 52 healthy controls. RESULTS: In two patients (one patient with SAP, one patient with UAP) with CAD and one healthy control, DNA from CMV was found (p = 0.469). HSV DNA was detected in one patient (SAP) but not in any controls (p = 0.644). EBV DNA was found in nine patients (three patients with SAP, one patient with UAP, five patients with MI), and two controls (p = 0.752). CONCLUSION: Our data do not support the hypothesis that herpesvirus-infected monocytes are related to the incidence of human coronary atherosclerosis.

Serological markers of Chlamydia pneumoniae, cytomegalovirus and Helicobacter pylori infection in diabetic and non-diabetic patients with unstable angina pectoris.

The possible role of inflammation in coronary artery disease (CAD) is being recognised, while markers of inflammation (e.g., CRP) and infection with Chlamydia pneumoniae (C. pneumoniae), cytomegalovirus (CMV) and Helicobacter pylori (H. pylori) have been proposed as risk factors for CAD. However, these associations require further evaluation. It is a known fact that diabetic patients suffer from impaired immune response to some pathogens and a high incidence of atherosclerosis. In this case-control study we investigated serological markers of infection with C. pneumoniae, CMV, and H. pylori in a group of 140 patients with unstable angina pectoris (UA), 52 of them having type 2 diabetes mellitus, and in a matched control group. Anamnestic (IgG) and acute infection (IgA) antibodies against the above agents were tested using ELISA or indirect immunofluorescence tests. In patients with UA we found a significantly higher seroprevalence and titres of IgG antibodies against C. pneumoniae (p = 0.04) and increased titres of IgG antibodies against CMV (p = 0.007). No differences were found in IgA antibody response to these pathogens. Antibody response to H. pylori was similar in both groups tested. In diabetic patients with UA, the frequency of group-common IgG antibodies against C. pneumoniae was higher than in the non-diabetic UA patients. The other serological markers studied were comparable in the patients with or without diabetes mellitus. Our findings confirmed association of C. pneumoniae and CMV with cardiovascular heart disease. Moreover, diabetes mellitus may predispose the patients to C. pneumoniae infection. However, serological markers observed do not indicate that destabilisation of angina pectoris is associated with acute C. pneumoniae or CMV infection. No relationship was found between UA and H. pylori infection.

[Viral infection, atherosclerosis, and ischemic heart disease]. / Virusna infektsiia, ateroskleroz ta ishemichna khvoroba sertsia.

Data are submitted on significant herpes viruses- and cytomegalovirus-associated infections in patients with unstable angina, which go beyond those in essentially healthy subjects of the same age. Taking into account strong impact the viral infection exerts on immune reactions it will be noted that virus-infected subjects are much sensitive to the action of autoantigens and furthermore, that autoimmune inflammation plays its part in the development of unstable angina.

Cytomegalovirus replication is not a cause of instability in unstable angina.

BACKGROUND: Unstable angina is most frequently caused by coronary thrombosis, with or without plaque fissure, but the mechanisms underlying these events are still speculative. Since cytomegalovirus (CMV) antigens and DNA encoding CMV major immediate-early (MIE) gene have been detected in atherosclerotic arterial walls, the active replication of CMV may be responsible for plaque instability. Therefore the expression of CMV MIE gene mRNA, an early marker of viral replication, was assessed in coronary atherectomy specimens from patients with stable or unstable angina. METHODS AND RESULTS: Twenty patients with unstable angina (12 men and 8 women; mean age, 62 years; range, 44 to 89 years) and 20 patients with stable angina (16 men and 4 women; mean age, 62 years; range, 43 to 81 years) who underwent successful directional coronary atherectomy were enrolled in the study. The efficiency of mRNA extraction, transcription, and amplification from each coronary atherectomy specimen was assessed by performance of reverse transcription and thermal cycling amplification of a 548-bp human beta-actin cDNA segment. After Southern blotting and hybridization with a specific probe, all specimens but one showed a positive hybridization signal. The negative sample was excluded from the study. Reverse transcription and thermal cycling amplification of a 145-bp CMV cDNA segment of the MIE gene were then carried out. After Southern blotting and hybridization with a specific probe, none of the specimens showed a positive hybridization signal. Plasmid pACYC 184 containing the Xba I-inserted MIE gene cDNA was used as a positive control: as few as 10 molecules of the plasmid per reaction were detectable after amplification. CONCLUSIONS: Our results do not support the hypothesis that, in patients with unstable angina, replication of CMV in coronary atherosclerotic plaques is a major cause of plaque instability. These findings suggest that the research for the causes of unstable angina should be directed toward processes other than CMV replication.