Onset of Coronary Heart Disease is Associated with HCMV Infection and Increased CD14 +CD16 + Monocytes in a Population of Weifang, China.

OBJECTIVE: To investigate the relationship between human cytomegalovirus (HCMV) infection and peripheral blood CD14 +CD16 + monocytes in the pathogenesis of coronary heart disease (CHD), and to elucidate the mechanism of pathogenesis in CHD by analyzing the correlation between infection, inflammation, and CHD, to provide a basis for the prevention, evaluation, and treatment of the disease. METHODS: In total, 192 patients with CHD were divided into three groups: latent CHD, angina pectoris, and myocardial infarction. HCMV-IgM and -IgG antibodies were assessed using ELISA; CD14 +CD16 + monocytes were counted using a five-type automated hematology analyzer; mononuclear cells were assessed using fluorescence-activated cell sorting; and an automatic biochemical analyzer was used to measure the levels of triglyceride, cholesterol, high- and low-density lipoprotein cholesterols, lipoprotein, hs-CRp and Hcy. RESULTS: The positive rates of HCMV-IgM and -IgG were significantly higher in the CHD groups than in the control group. HCMV infection affects lipid metabolism to promote immune and inflammatory responses. CONCLUSION: HCMV infection has a specific correlation with the occurrence and development of CHD. The expression of CD14 +CD16 + mononuclear cells in the CHD group was increased accordingly and correlated with acute HCMV infection. Thus, HCMV antibody as well as peripheral blood CD14 +CD16 + mononuclear cells can be used to monitor the occurrence and development of CHD.

Epidemiological and clinical characteristics of 1663 hospitalized patients infected with COVID-19 in Wuhan, China: a single-center experience.

BACKGROUND: The COVID-19 outbreak in late December 2019 has quickly emerged into pandemic in 2020. We aimed to describe the epidemiology and clinical characteristics of hospitalized COVID-19 patients, and to investigate the potential risk factors for COVID-19 severity. METHOD: 1663 hospitalized patients with laboratory-confirmed diagnosed COVID-19 from Tongji Hospital between January 14, 2020, and February 28, 2020 were included in the present study. Demographic information, exposure history, medical history, comorbidities, signs and symptoms, chest computed tomography (CT) scanning, severity of COVID-19 and laboratory findings on admission were collected from electronic medical records. Multivariable logistic regression was used to explore the association between potential risk factors with COVID-19 severity. RESULTS: In the present study, the majority (79%) of 1663 COVID-19 patients were aged over 50 years old. A total of 2.8% were medical staff, and an exposure history of Huanan seafood market was document in 0.7%, and 7.4% were family infection. Fever (85.8%), cough (36.0%), fatigue (23.6%) and chest tightness (11.9%) were the most common symptoms in COVID-19 patients. As of February 28, 2020, of the 1663 patients included in this study, 26.0% were discharged, 10.2% were died, and 63.8% remained hospitalized. More than 1/3 of the patients had at least one comorbidity. Most (99.8%) patients had abnormal results Chest CT, and the most common manifestations of chest CT were local patchy shadowing (70.7%) and ground-glass opacity (44.8%). On admission, lymphocytopenia was present in 51.1% of the patients, mononucleosis in 26.6%, and erythrocytopenia in 61.3%. Most of the patients had increased levels of C-reactive protein (80.4%) and D-dimer (64.4%). Compared with non-severe patients, severe patients had more obvious abnormal laboratory results related to inflammation, coagulation disorders, liver and kidney damage (all P < 0.05). Older age (OR = 2.37, 95% CI: 1.47-3.83), leukocytosis (OR = 2.37, 95% CI: 1.47-3.83), and increased creatine kinase (OR = 2.37, 95% CI: 1.47-3.83) on admission were significantly associated with COVID-19 severity. CONCLUSION: Timely medical treatment and clear diagnosis after the onset might be beneficial to control the condition of COVID-19. Severe patients were more likely to be to be elder, and tended to have higher proportion of comorbidities and more prominent laboratory abnormalities. Older age, leukocytosis, and increased creatine kinase might help clinicians to identify severe patients with COVID-19.

Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris.

Inherited chromosomally integrated human herpesvirus-6 (iciHHV-6) results in the germ-line transmission of the HHV-6 genome. Every somatic cell of iciHHV-6+ individuals contains the HHV-6 genome integrated in the telomere of chromosomes. Whether having iciHHV-6 predisposes humans to diseases remains undefined. DNA from 19,597 participants between 40 and 69 years of age were analyzed by quantitative PCR (qPCR) for the presence of iciHHV-6. Telomere lengths were determined by qPCR. Medical records, hematological, biochemical, and anthropometric measurements and telomere lengths were compared between iciHHV-6+ and iciHHV-6- subjects. The prevalence of iciHHV-6 was 0.58%. Two-way ANOVA with a Holm-Bonferroni correction was used to determine the effects of iciHHV6, sex, and their interaction on continuous outcomes. Two-way logistic regression with a Holm-Bonferroni correction was used to determine the effects of iciHHV6, sex, and their interaction on disease prevalence. Of 50 diseases monitored, a single one, angina pectoris, is significantly elevated (3.3×) in iciHHV-6+ individuals relative to iciHHV-6- subjects (P = 0.017; 95% CI, 1.73-6.35). When adjusted for potential confounding factors (age, body mass index, percent body fat, and systolic blood pressure), the prevalence of angina remained three times greater in iciHHV-6+ subjects (P = 0.015; 95%CI, 1.23-7.15). Analyses of telomere lengths between iciHHV-6- without angina, iciHHV-6- with angina, and iciHHV-6+ with angina indicate that iciHHV-6+ with angina have shorter telomeres than age-matched iciHHV-6- subjects (P = 0.006). Our study represents, to our knowledge, the first large-scale analysis of disease association with iciHHV-6. Our results are consistent with iciHHV-6 representing a risk factor for the development of angina.

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.

Impact of intimal pathogen burden in acute coronary syndromes--correlation with inflammation, thrombosis, and autoimmunity.

BACKGROUND: Increasing evidence supports a link between serological evidence of pathogen burden (PB) and the risk for future cardiovascular events. Our study evaluates the intimal presence of 4 pathogens in atheroma, clinically associated with acute coronary syndromes (ACS) and stable angina (SA), and the effect on the expression of intimal C-reactive protein (CRP), tissue factor (TF) and human heat-shock protein 60 (hHSP60). METHODS: Coronary atherectomy specimens retrieved from 60 primary lesions of patients with ACS (n=35) or SA (n=25) were assessed immunohistochemically for the presence of Chlamydia pneumoniae (Cpn), Helicobacter pylori (HP), Cytomegalovirus (CMV) and Epstein­Barr Virus (EBV) and for the expression of CRP, TF, and hHSP60. RESULTS: Analysis 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. CONCLUSIONS: Our data demonstrate the impact of PB in plaque instability and suggest local proinflammatory, prothrombotic, and proimmunogenic effects.

Active cytomegalovirus replication in patients with coronary disease.

OBJECTIVES: To study the prevalence of active cytomegalovirus (CMV) infection in patients with stable and unstable conditions of coronary artery disease (CAD). DESIGN: Forty patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 clinically healthy controls were included. Monocytes were isolated from peripheral blood and CMV-RNA expression was determined by a nested RT-PCR assay. CMV IgM and IgG antibodies, interleukin-(IL)-6, IL-10 and CRP were measured in serum. RESULTS: The prevalence of active CMV infection was significantly higher in patients with ACS (15%) and in patients with SA (10%) compared with controls (2%) (p<0.001). The presence of an active CMV infection was associated with increased serum concentrations of IL-6. CONCLUSIONS: Active CMV infection was found to a larger extent in CAD patients than in healthy controls. The data indicate that CAD patients are more susceptible to reactivation of CMV and put new focus on the role of CMV in atherosclerosis.

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.

Serologic markers for cytomegalovirus in acute coronary syndromes.

BACKGROUND: Several studies relate cytomegalovirus (CMV) infection to the development of atherosclerosis. Its influence in triggering acute coronary syndromes (ACS) is not known. OBJECTIVES: We set out to identify a relationship between CMV infection, occurrence of ACS and prognosis. METHODS: Serologic markers (IgM and IgG) for CMV were tested prospectively at admission and at 30 days, in patients (pts) admitted to our CCU for ACS. Serologic markers for CMV were also tested in a group of pts with stable coronary artery disease admitted for elective coronary angiography. A greater than two-fold elevation of IgG titer at 30 days was defined as reactivation/reinfection. At 30 days and six months, the composite endpoint of death, myocardial (re)infarction and re-admission for unstable angina was evaluated. RESULTS: There were 60 pts with ACS in the study group (age 63 +/- 10 years, 75% male) and 31 pts in the control group (age 64 +/- 10 years, 71% male). On admission, 95% of the pts with ACS and 81% in the control group presented a positive IgG (p = 0.029). In the study group, at 30 days, the only pt with a 3-fold titer elevation had an endpoint. The percentage was 17% for the group with a > or = 2- and < 3-fold elevation and 11% in the group without reactivation (p = 0.034). At six months, 50% of the patients with a greater than 2-fold titer elevation and 15% of the remaining patients had an endpoint (p = 0.017). In the control group, at 30 days, 3 pts (10%) had a significant elevation in IgG titer, > or = 2- and < 3-fold, without endpoint. CONCLUSIONS: In pts with ACS, we found a higher prevalence of serologic markers for CMV than in pts with stable coronary disease. An elevation in IgG titer for CMV was associated with a worse outcome at 30 days and six months.

Increased incidence of cardiac complications in kidney transplant recipients with cytomegalovirus disease.

BACKGROUND: The transplant literature has not shown cytomegalovirus (CMV) disease to be a significant risk factor for posttransplant cardiac complications. A large number of nontransplant studies have, however, reported an association between coronary heart disease (CHD) and CMV disease. Pathology studies have demonstrated a high incidence of CMV in atheromatous plaques from the coronary circulation. METHODS: We performed multivariate analysis to determine if posttransplant CMV disease was a significant risk factor for cardiac complications in kidney transplant recipients. We also performed univariate analysis to determine which cardiac complications were more common in the recipients with CMV disease. RESULTS: Between January 1, 1984 and June 30, 1997, 1859 adults underwent kidney transplants at our institution. Of these, 377 developed one of the following cardiac complications posttransplant: myocardial infarction, angina, arrhythmia, congestive heart failure, and angiographic vessel occlusion. By multivariate analysis, significant risk factors for one of the above cardiac complications were recipient age >50 years [odds ratio (OR)=2.5, P=0.0001], diabetes (OR=1.99, P=0.0001), a history of cardiac disease pretransplant (OR= 1.34, P=0.04), and CMV disease (OR=1.5, P=0.01). Univariate analysis demonstrated that recipients with CMV disease had a higher overall incidence of cardiac complications. Arrhythmias, congestive heart failure, and vessel occlusion were more common in those with CMV disease. The incidence of myocardial infarction, angina, and cardiac arrest did not differ between the two groups (recipients with versus without CMV disease). CONCLUSIONS: CMV disease is associated with an increased risk of cardiac complications in kidney transplant recipients. In our series, angiographic vessel occlusion was more common in recipients with CMV disease. This interesting finding may support the theory that CMV plays some role in the pathogenesis of CHD.

Cold pressure test producing coronary spasm, coronary thrombosis and myocardial infarction in a patient with IgM antibodies against Coxsackie B virus.

Several lines of evidence have shown that viral infections are capable of causing coronary spasm and precipitating or mimicking clinical myocardial infarction. Here we report the case of a 41-year-old woman with recurrent angina who was admitted to our hospital because of ventricular tachycardia. Laboratory examination revealed positive IgM titers against Coxsackie B virus. Coronary angiography showed normal coronary arteries, but following a cold pressure test severe spasm of all coronaries with thrombotic occlusion of the second marginal branch of the circumflex artery occurred. We conclude that coronary spasm should be clinically suspected in patients with chest pain and ventricular arrhythmia in combination with IgM antibodies against Coxsackie B virus. In these patients, a cold pressure test should be avoided, and antithrombotic and antispastic therapy is recommended.

[The detection of the antibodies of human cytomegalovirus in the sera of patients with coronary heart disease].

To explore the relationship between human cytomegalovirus infection and atherosclerosis, we assayed the antibodies of human cytomegalovirus in the sera of 106 patients with coronary heart disease and 80 healthy people by indirect ELISA technique. The results showed that the positive rate of antibodies of HCMV IgG, HCMV IgM and HCMV IgA (95.3%, 12.3%, 13.2% respectively) is significantly higher than that in healthy people (85.0%, 2.5%, 3.8% respectively). Our findings indicated that HCMV infection is related to coronary heart disease. We consider that HCMV may be an etiological factor for human atherosclerosis. The periodical activation of latent HCMV may play a role in atherogenesis.

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.