Coronary artery disease (CAD) occurs at an earlier age in South Asians compared with other ethnic groups. Infection and inflammation show a positive association with the disease.
To investigate the association of infection and inflammatory markers with premature CAD in the Indian Atherosclerosis Research Study population.
Antibody titres for Chlamydia pneumoniae, cytomegalovirus (CMV), Helicobacter pylori, herpes simplex virus and levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen and secretory phospholipase A2, were measured in 866 individuals (433 CAD patients and matched controls). All individuals were followed-up for recurrent cardiac events for four years. ANOVA was used to study the association of infection and inflammation with CAD.
The present study found that the 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.
Pathogen burden, especially CMV infection in combination with inflammatory markers, is a significant predictor of CAD risk in the young Indian population.
Coronary artery disease; C-reactive protein; Cytomegalovirus; Inflammatory markers; Pathogen burden
We examined the cross-sectional relationships of subclinical atherosclerosis – expressed by carotid intimal–medial thickness and coronary calcification – with antibodies to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex virus, hepatitis A virus, and pathogen burden (number of positive pathogens). A random sample of 1056 individuals chosen from 5030 Multi-Ethnic Study of Atherosclerosis cohort participants were included. After multiple adjustment, no associations were found between atherosclerosis measures and either individual pathogens or pathogen burden. Interactions with inflammatory and endothelial function markers, demographic factors, BMI, high-density lipoprotein, diabetes, and smoking were also explored. The only interaction that was large, qualitative, statistically significant (P < 0.05) and in the expected direction was that between hepatitis A virus and soluble intercellular adhesion molecule-1 with regard to Agatston calcium score: the difference between hepatitis A virus-positive and hepatitis A virus-negative participants was −86 units in participants with soluble intercellular adhesion molecule-1 below the median, and +162 units in those with soluble intercellular adhesion molecule-1 equal or above the median. However, given the number of interactions that were explored, these results must be interpreted cautiously.
Findings from the present analyses do not provide support for an infectious etiology for subclinical atherosclerosis. However, the study’s limitations, which include its cross-sectional design and insufficient statistical power, suggest that inferences from its findings should be made cautiously.
atherosclerosis; infections; pathogens
Prospective studies have identified chronic inflammation as a risk factor for type 2 diabetes. However, it is not known whether infection by specific pathogens or having a greater “pathogen burden” is associated with diabetes. The aim of this study was to examine the cross-sectional relation of seropositivity to five pathogens (C. pneumoniae, cytomegalovirus, H. pylori, hepatitis A virus, herpes simplex virus) and prevalent diabetes.
Baseline data from a random sample of MultiEthnic Study of Atherosclerosis (MESA) participants (n=1,000; age: 45-84) were used. Diabetes was defined by ADA 2003 criteria, and “pathogen burden” by the number of pathogens (0–5) for which an individual was seropositive. Logistic regression was used to test differences in diabetes prevalence by seropositivity. Linear regression was used to explore associations between pathogen seropositivity and the inflammation markers CRP, IL-6, and fibrinogen.
Diabetes prevalence was 12.7%, while seropositivity for C. pnuemoniae was 76%, cytomegalovirus 77%, H. pylori 45%, hepatitis A 58%, and herpes simplex virus 85%. 72% were seropositive for ≥3 pathogens. In crude analyses, the prevalence of diabetes was higher among those with a pathogen burden ≥3, and with seropositivity to cytomegalovirus, H. pylori, hepatitis A, and herpes simplex virus. After adjustment for demographic covariates (particularly race) all associations became nonsignificant. Pathogen seropositivity was also not related to inflammation marker levels.
Following demographic adjustments, no associations were observed between infection by several pathogens and diabetes status, suggesting no etiologic role for them in the occurrence of diabetes.
diabetes; infection; pathogen; seropositivity
The biologic mechanisms linking socioeconomic position and psychosocial factors to cardiovascular disease (CVD) are not well understood. Immune response to persistent pathogens may be one of these mechanisms.
We analyzed cross-sectional data from the Multi-Ethnic Study of Atherosclerosis (N=999) composed of adults age 45–84. Log-binomial regression and ordinal logistic regression models were used to examine associations of socioeconomic factors and psychosocial factors with pathogen burden and immune response among those infected. Pathogen burden was assessed based on seroprevalence of Helicobacter pylori, cytomegalovirus, herpes simplex virus-1, and Chlamydia pneumoniae and antibody levels were used to characterize high immune response to all four pathogens.
Low education was a strong and significant independent predictor of higher pathogen burden after adjustment for covariates (adjusted odds ratio (OR) 95% confidence interval (CI) 1.37, 1.19–1.57). Among subjects seropositive for all four pathogens, low education and a higher level of chronic psychosocial stress showed a positive association with higher antibody response, although associations were no longer significant in models with all covariates included (OR = 1.64, 95%CI 0.82–3.31 for lowest vs. highest educational category and OR= 1.29, 95%CI 0.96–1.73 for a one level increase in chronic stress).
Pathogen burden and heightened immune response may represent a biological pathway by which low socioeconomic position and chronic stress are related to increased rates of cardiovascular disease.
Infection; inflammation; epidemiology; cardiovascular diseases
Antibodies against infectious pathogens provide information on past or present exposure to infectious agents. While host genetic factors are known to affect the immune response, the influence of genetic factors on antibody levels to common infectious agents is largely unknown. Here we test whether antibody levels for 13 common infections are significantly heritable.
IgG antibodies to Chlamydophila pneumoniae, Helicobacter pylori, Toxoplasma gondii, adenovirus 36 (Ad36), hepatitis A virus, influenza A and B, cytomegalovirus, Epstein-Barr virus, herpes simplex virus (HSV)-1 and −2, human herpesvirus-6, and varicella zoster virus were determined for 1,227 Mexican Americans. Both quantitative and dichotomous (seropositive/seronegative) traits were analyzed. Influences of genetic and shared environmental factors were estimated using variance components pedigree analysis, and sharing of underlying genetic factors among traits was investigated using bivariate analyses.
Serological phenotypes were significantly heritable for most pathogens (h2 = 0.17–0.39), except for Ad36 and HSV-2. Shared environment was significant for several pathogens (c2 = 0.10–0.32). The underlying genetic etiology appears to be largely different for most pathogens.
Our results demonstrate, for the first time for many of these pathogens, that individual genetic differences of the human host contribute substantially to antibody levels to many common infectious agents, providing impetus for the identification of underlying genetic variants, which may be of clinical importance.
Pathogen; Infection; Antibody; Serology; Genetics; Heritability; Mexican Americans
Inflammation increases with age and is associated with many chronic diseases that are prevalent among older adults. Persistent pathogens such as latent herpesviruses and chronic bacterial infections can act as a source of inflammation. Herpesviruses, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV), establish latent infections following primary infection and reactivate when the cellular immune system is compromised. EBV and CMV replication can induce proinflammatory cytokine production and thus could influence systemic inflammation. The present study addressed relationships among EBV and CMV antibody titers, and levels of C-reactive protein (CRP) and interleukin-6 (IL-6) in a sample of 222 community dwelling older adults (meanage= 64.1 ± 14.1 years). Participants were divided into two groups based on whether they were EBV seropositive and CMV seronegative (EBV+CMV−), or EBV and CMV seropositive (EBV+CMV+). Among individuals who were EBV+CMV−, EBV antibody titers were not associated with either CRP or IL-6 levels. However, among those who were EBV+CMV+, higher EBV antibody titers were related to elevated levels of CRP and IL-6 in those individuals with higher CMV antibody titers; there was no relationship between EBV antibody titers and CRP or IL-6 levels in those participants with lower CMV antibody titers. These data suggest that the combination of latent EBV and CMV reactivation (indexed by antibody titers) may boost CRP and IL-6 production. Thus, reactivation of multiple herpesviruses may drive inflammation and could contribute to poorer health among older adults.
cytomegalovirus (CMV); Epstein-Barr virus (EBV); C-reactive protein (CRP); interleukin-6 (IL-6); aging; latent reactivation; immunosenescence
Persistent pathogens have been proposed as risk factors for stroke; however, the evidence remains inconclusive. Mexican Americans have an increased risk of stroke especially at younger ages, as well as a higher prevalence of infections caused by several persistent pathogens.
Findings Using data from the Sacramento Area Latino Study on Aging (n = 1621), the authors used discrete-time regression to examine associations between stroke risk and (1) immunoglobulin G antibody levels to Helicobacter pylori (H. pylori), Cytomegalovirus, Varicella Zoster Virus, Toxoplasma gondii and Herpes simplex virus 1, and (2) concurrent exposure to several pathogens (pathogen burden), defined as: (a) summed sero-positivity, (b) number of pathogens eliciting high antibody levels, and (c) average antibody level. Models were adjusted for socio-demographics and stroke risk factors. Antibody levels to H. pylori predicted incident stroke in fully adjusted models (Odds Ratio: 1.58; 95% Confidence Interval: 1.09, 2.28). No significant associations were found between stroke risk and antibody levels to the other four pathogens. No associations were found for pathogen burden and incident stroke in fully adjusted models.
Our results suggest that exposure to H. pylori may be a stroke risk factor in Mexican Americans and may contribute to ethnic differences in stroke risk given the increased prevalence of exposure to H. pylori in this population. Future studies are needed to confirm this association.
To date, there has been no convincing evidence for an association between Chlamydia pneumoniae or Helicobacter pylori and ectasia. In this case-control study, we have investigated the association of H. pylori and C. pneumoniae seropositivity with ectasia, severe coronary atherosclerosis, and normal vessels, which were so classified by coronary angiography. We have also evaluated the influence of these infections on inflammatory markers such as high-sensitive C-reactive protein (hsCRP) and interleukin 6 (IL-6).
Of the 796 patients undergoing coronary angiography for suspected ischemic heart disease, 244 patients were recruited. Of these, 91 had normal vessels, 88 had 3 or more obstructed vessels, and 65 had ectatic vessels without atherosclerosis. Eighty-seven atherosclerotic patients (98.9%) were positive for C. pneumoniae IgG, as were 64 ectatic patients (98.5%) and 76 controls (83.5%) (P < 0.001). Forty-two atherosclerotic patients (47.7%) were positive for C. pneumoniae IgM, as were 43 ectatic patients (66.2%) and 43 controls (47.3%) (P = 0.036). Seventy-two atherosclerotic patients (81.8%) were positive for H. pylori IgA, as were 26 ectatic patients (40.0%) and 44 controls (48.4%) (P < 0.001). High-sensitive CRP levels were significantly higher in ectatic patients (5.639 mg/L) than in controls (4.390 mg/L) (P = 0.032), and IL-6 levels were significantly higher in atherosclerotic patients (33.92 U/L) than in controls (14.01 U/L) (P < 0.001). Interleukin-6 levels were higher in H. pylori seropositive patients, and hsCRP levels were higher in C. pneumoniae seropositive patients, when compared with seronegatives.
We suggest that, as in atherosclerosis, C. pneumoniae infection is related to ectasia, with raised CRP levels.
Atherosclerosis; bacterial infections/complications; biological markers; C-reactive protein; chlamydia infections/complications; Chlamydia pneumoniae; Cardiovascular diseases/etiology; dilatation, pathologic/etiology; helicobacter infections/complications; Helicobacter pylori; inflammation; interleukin-6
PRO-- PCOS is associated with low-grade systemic inflammation as evidenced by elevation of multiple markers of inflammation such as C-reactive protein, interleukin-18, monocyte chemoattractant protein-1 and white blood count as well as endothelial dysfunction and increased oxidative stress.
CON-- The evidence in support of the presence of chronic inflammatory state in the majority of women with PCOS is incontrovertible. It is apparent that PCOS is associated with a significant elevation of multiple markers of inflammation including CRP, IL-18, MCP-1, and white blood count. Furthermore, PCOS is associated with other derangements associated with inflammation such as increased oxidative stress and endothelial dysfunction. While the etiology of systemic inflammation in PCOS remains unclear, recent data raise the intriguing possibility of a link between PCOS, inflammation and chronic low grade infectious agents such as Chlamydia pneumoniae, Helicobacter pylori and pathogens inducing periodontal inflammation.
Social support is associated with cardiovascular disease mortality, however the physiologic mechanisms underlying this relationship remains unspecified. This study evaluated the association of social support with inflammatory markers associated with cardiovascular risk: C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen. We evaluated two competing models of the support-inflammation relationship: first, that low social support is directly associated with inflammation, and second, that high support acts to buffer the effect of stress on inflammation. Using data from the baseline interview of the Multi-Ethnic Study of Atherosclerosis (N = 6,814, 53% female, age 45–84 years) we assessed the independent and interacting associations of social support and stress with inflammation. Social support was measured by the Emotional Social Support Index. Stressors in multiple domains (work, family, finances, interpersonal) were assessed. Serum CRP, IL-6, and fibrinogen were analyzed from fasting samples using high-sensitivity assays. Multivariate linear regression, including models stratified by gender and age group (45 – 64 and 65 – 84 years), was used to assess the direct and buffering relationships between social support, stress, and inflammation. In bivariate analyses low social support was associated with higher levels of all three markers. In adjusted models, low support was associated with higher lnCRP (B: 0.15, 95% CI: 0.01, 0.30) among men but not women. High social support buffered the relationship between stress and CRP among middle-aged women only (P for interaction 0.042). Overall, social support was only modestly associated with inflammation in this relatively healthy sample, and these relationships varied by age and gender.
social support; inflammation; aging; gender differences
Recent publications have suggested that infective pathogens might play an important role in the pathogenesis of atherosclerosis. This review focuses on these microorganisms in the process of atherosclerosis. The results of in vitro studies, animal studies, tissue studies, and serological studies will be summarised, followed by an overall conclusion concerning the strength of the association of the microorganism with the pathogenesis of atherosclerosis. The role of the bacteria Chlamydia pneumoniae and Helicobacter pylori, and the viruses human immunodeficiency virus, coxsackie B virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and measles virus will be discussed.
Key Words: atherosclerosis • Chlamydia pneumoniae • Helicobacter pylori
That infections with certain pathogens, by initiating an inflammatory response, may contribute to the development of atherosclerosis is suggested by clinical and experimental evidence.
To analyse atherosclerotic plaques of the carotid artery, samples of apparently healthy greater saphenous veins and circulating leucocytes from the same individual patients for the presence of Helicobacter pylori and Mycoplasma pneumoniae.
Samples from 36 patients undergoing carotid endarterectomy for symptomatic carotid artery stenosis were analysed by polymerase chain reaction for the presence of DNA specific for H pylori and M pneumoniae. IgG antibody titres against H pylori and M pneumoniae and plasma levels of soluble E‐selectin, soluble intercellular adhesion molecule‐1 and soluble vascular cell adhesion molecule‐1 were determined.
M pneumoniae‐specific DNA was detected in the atherosclerotic plaques of 13 of 36 (36.1%) patients, in the saphenous veins of 9 of 36 (25%) patients and in the leucocytes of 27 of 36 (75%) patients. No salient association was observed between the presence of M pneumoniae‐specific DNA in leucocytes and atherosclerotic plaques or veins. A marked correlation between the presence of M pneumoniae in the respective specimens and the studied inflammatory markers or the presence of anti‐M pneumoniae antibodies was not observed. H pylori‐specific DNA could not be detected in the specimens tested.
The absence of H pylori and the random distribution of M pneumoniae in tissue samples obtained from patients with symptomatic carotid artery stenosis do not support a role for these pathogens in the development of atherosclerosis due to a direct interaction of the bacteria with the vasculature.
Studies about associations of infections with herpes viruses and other pathogens, such as Chlamydia pneumoniae (CP) and Helicobacter pylori (HP) with cardiovascular disease (CVD), diabetes mellitus (DM), frailty and/or mortality are conflicting. Since high levels of antibodies against these pathogens occur in the elderly, the role of these pathogens in morbidity and mortality of vulnerable elderly was explored.
Blood samples of 295 community dwelling psycho-geriatric patients were tested for IgG antibodies to herpes simplex virus type 1 and 2, varicella zoster virus, Epstein Barr virus (EBV), cytomegalovirus (CMV), human herpes virus type 6 (HHV6), CP and HP. Frailty was defined with an easy-to-use previously described frailty risk score. Relative risks (RR) with 95% confidence intervals were calculated to evaluate associations between CVD, DM, frailty and pathogens. Pathogens as a predictor for subsequent mortality were tested using Kaplan Meier analyses and Cox proportional hazard models. The mean age was 78 (SD: 6.7) years, 20% died, 44% were defined as frail, 20% had DM and 49% had CVD. Presence of CMV antibody titers was associated with frailty, as shown by using both qualitative and quantitative tests, RR ratio 1.4 (95% CI: 1.003-2.16) and RR ratio 1.5 (95% CI: 1.06-2.30), respectively. High IgG antibody titers of HHV6 and EBV were associated with DM, RR ratio 3.3 (95% CI: 1.57-6.49). None of the single or combined pathogens were significantly associated with mortality and/or CVD.
Prior CMV infection is associated with frailty, which could be in line with the concept that CMV might have an important role in immunosenescence, while high IgG titers of HHV6 and EBV are associated with DM. No association between a high pathogen burden and morbidity and/or mortality could be demonstrated.
Herpes viruses; Cytomegalovirus; Frailty; Diabetes mellitus; Morbidity; Mortality
Chronic low-grade systemic inflammation is a key component in atherogenesis. Decreased heart rate variability (HRV), a strong predictor of cardiovascular events, has been associated with elevations in circulating levels of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen in apparently healthy individuals. We investigated whether decreased HRV is associated with inflammatory markers in patients with coronary heart disease (CHD).
We studied the relationship between HRV and CRP, IL-6, and fibrinogen in 862 outpatients with CHD. All participants provided fasting blood samples and underwent 24-h ambulatory monitoring to assess time-domain measures of HRV (MeanNN, SDNN, SDANN, and RMSSD). Regression analyses were adjusted for age, sex, ethnicity, body mass index, smoking, diabetes, beta blocker use, and cardiopulmonary history.
MeanNN, SDNN, and SDANN were significantly and inversely associated with CRP and IL-6 levels in age-adjusted models and after adjustment for all covariates (p ≤ 0.02). MeanNN, SDNN, and SDANN were also inversely associated with fibrinogen levels in age-adjusted models (p < 0.03), but not significantly so in multivariable-adjusted models. Reduced vagal modulation of heart rate (RMSSD) was not significantly associated with any inflammatory measures.
Reduced cardiac autonomic control is associated with increased systemic inflammation in patients with stable CHD. This relationship was largely independent of important covariates.
Autonomic nervous system; Biomarkers; Cardiac autonomic function; Cardiovascular disease; Heart rate variability; Inflammation
Inflammation plays a pivotal role in all stages of atherosclerosis. Numerous inflammatory, lipid, and cytokines markers have been associated with coronary artery disease (CAD) risk but data directly comparing their predictive value are limited. Studies were carried to elucidate the role of high-sensitivity C-reactive protein (hsCRP), other inflammatory as well as lipid markers and their associations. Among 1021 subjects, comprising 774 CAD affected members from Indian Atherosclerosis Research Study (IARS), plasma hsCRP levels showed strong correlation with inflammatory markers, namely, IL6 (r = .373; P = <.0001), sPLA2 (r = .544; P = <.0001) as also with fibrinogen (r = .579; P = <.0001). Levels of hsCRP were higher among subjects affected by CAD who suffered a repeat coronary event as compared to those who remained event free and subjects in the top quartile of hsCRP (>3.58 mg/L) were found to have a fourfold higher risk. In conclusion, hsCRP appears to be an independent predictor of recurrent CAD events in Asian Indian population.
The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multi-ethnic cohort.
Antibody titers to five common infectious microorganisms (i.e. Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants, and a weighted index of infectious burden (IB) was calculated based on Cox models previously derived from for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness (MCPT). Weighted least squares regression was used to measure the association between IB and MCPT after adjusting for other risk factors.
Serological results for all five infectious organisms were available in 861 participants with MCPT measurements available (mean age 67.2+/−9.6 yrs). Each individual infection was associated with stroke risk after adjusting for other risk factors. The IB index (n=861) had a mean of 1.00 ± standard deviation 0.35, median 1.08. Plaque was present in 52% of participants (mean 0.90+/−1.04 mm). IB was associated with MCPT (adjusted increase in MCPT 0.09 mm, 95% confidence interval 0.03–0.15 mm, per standard deviation increase of IB).
A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multi-ethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.
The pathophysiological mechanisms that underlie health disparities by socioeconomic status and race/ethnicity are poorly understood. Promising new research suggests that the burden of persistent infection may influence adult disease risk and mortality. This article examines how multiple persistent infections cluster within individuals and how this clustering varies by socioeconomic position and race/ethnicity in U.S. adults.
We analyze data from the National Health and Nutrition Examination Survey III (N = 19,275) for adults aged 17–90 years. The clustering of infections within individuals is studied using tetrachoric correlations. Multiple indicator multiple cause models are used to analyze the infection burden construct as measured by seropositivity to Helicobacter pylori, cytomegalovirus, herpes simplex virus-1, and hepatitis B, focusing on the burden's distribution by socioeconomic position and race/ethnicity. The results are corroborated using ordered logistic regression for a commonly used count index of individual infections.
Seroprevalence of individual persistent infections is positively correlated, suggesting common factors related to exposure or susceptibility. Education, income, and race/ethnicity are strong and significant independent predictors of infection burden in U.S. adults in all models.
The disproportionate burden of persistent infections among disadvantaged groups across all ages may be one biologic pathway by which low socioeconomic position is related to increased rates of morbidity and mortality in the United States.
Socioeconomic; Race; Ethnic; United states; Adults; Infection; Biomarkers
The presence of antibodies to rubella, cytomegalovirus and Toxoplasma gondii was determined at birth and at 6 months of age in a group of 147 infants with cord serum IgM levels ≥ 19.0 mg/dl and in 92 control infants. Maternal syphilis serology was determined in both groups as well. No significant differences in the prevalence or levels of antibodies to these pathogens were found between the two groups which might have led to the diagnosis of unsuspected intrauterine infection. Persistence of antibodies to 6 months of age was similar in the two groups, indicating that this is not a useful index of intrauterine infection.
Analysis of the results yielded the following data on the prevalence of antibodies to the pathogens studied: rubella virus, 90 and 75% seropositivity at birth and 6 months respectively; cytomegalovirus, 65 and 35%; and Toxoplasma gondii, 33% seropositivity at birth.
Inflammation and pulse wave velocity (PWV) are a potential risk factor and marker, respectively, for atherosclerosis in the primary prevention setting. Atherosclerosis is now generally accepted to be an inflammatory disorder of the arterial wall, and the high-sensitivity C-reactive protein (hs-CRP) level has been reported to be a strong predictor of cardiovascular events. High-sensitivity-CRP is associated with two factors related to inflammation: (1) the local production of CRP by atheromatous tissue or coronary artery smooth muscle cells and (2) adipose tissue as a potent source of inflammatory cytokines. Based on studies in North America and Europe, hs-CRP has been established as a cardiovascular risk factor and a cut-off value has been recommended. However, Japanese have lower hs-CRP values than their Western counterparts, partly because Japanese have a lower body mass index (BMI), which correlates positively to hs-CRP, and partly because lifestyle and genetic factors can affect hs-CRP values. Therefore, a cut-off value needs to be established by cohort studies for the Japanese population. Carotid-femoral PWV is most commonly measured by applanation tonometry, particularly in Europe, but this method is critically dependent upon the accurate placing of transducers over the arteries and is both time-consuming and complex. A novel device has been recently developed in Japan that measures brachial-ankle PWV (baPWV) using a volume-rendering method. Brachian-ankle PWV is a suitable screening method because of its technical simplicity and shorter measurement time. It is associated not only with conventional cardiovascular risk factors but also with new risk factors, such as inflammation, γ-glutamyltransferase, chronic kidney disease, and psychosocial factors. However, a suitable cut-off value has yet to be established.
Arterial stiffness; Atherosclerosis; C-reactive protein; Inflammation; Pulse wave velocity
Levels of acute phase reactants are impacted by age. To what extent cardiovascular risk associated with aging is due to an increase in the inflammatory burden is not known. We assessed the relationship with age of inflammatory markers, representing a) systemic (C-reactive protein [CRP], fibrinogen and serum amyloid-A [SAA]) and b) vascular (lipoprotein-associated phospholipase A2 [Lp-PLA2] and pentraxin-3 [PTX-3]) inflammation.
Methods and Results
We determined Lp-PLA2 mass and activity, CRP, fibrinogen, SAA, and PTX-3 levels and other CVD risk factors in 336 Caucasians and 224 African Americans. Levels of systemic inflammatory markers increased significantly with age in both ethnic groups (P<0.05 for all), while trend patterns of vascular inflammatory markers did not change significantly with age for either group. In multivariate regression models adjusting for confounding variables, age remained independently associated with a composite z-score for systemic, but not vascular inflammation (β=0.250, P<0.001 and (β=0.276, P<0.001, for Caucasians and African Americans respectively).
We report an increase in the systemic, but not vascular, inflammatory burden over age. Levels of both categories of inflammatory markers over age were similar across ethnicity after adjustment for confounders. Our results underscore the importance of age in evaluating inflammatory markers to assess cardiovascular risk.
Inflammation; aging; cardiovascular disease; epidemiology
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
Atherosclerosis; Calcium; Inflammation; Population
Background—Helicobacter pylori is a
human pathogen that colonises the gastric mucosa and causes permanent
Aims—To assess the symptoms of H
pylori infection in an adult unselected population.
Subjects—A random sample of 3589 adult Danes who
were examined in 1982 and 1987 (n=2987).
Methods—Abdominal symptoms within the preceding
year were recorded at both attendances. Circulating IgG antibodies
against H pylori in serum samples drawn in 1982 were
measured by using in-house indirect enzyme linked immunosorbent assays (ELISA).
Results—People with increased levels of IgG
antibodies to H pylori were more likely than uninfected
individuals to report heartburn (odds ratio (OR) = 1.26, 95%
confidence interval (CI) 1.03-1.54) and abdominal pain characterised
by daily length (OR= 1.33, 95% CI 0.92-1.91), nocturnal occurrence
(OR = 1.62, 95% CI 1.19-2.19), spring aggravation (OR = 1.68, 95% CI
0.70-4.05), and no relation to meals (OR = 0.62, 95% CI 0.43-0.91)
or stress (OR = 0.69, 95% CI 0.50-0.95). The inclusion of people with
increased levels of IgG antibodies to H pylori, but
without upper dyspepsia, at study entry significantly increased the
likelihood of reporting upper dyspepsia at follow up (OR = 1.71, 95%
CI 1.24-2.36). People with epigastric pain and increased levels of IgM
antibodies to H pylori only indicative of acute H
pylori infection were more likely to report nocturnal pain,
heartburn, nausea, and vomiting.
Conclusions—H pylori infection may
precede the development of dyspepsia and is associated with a variety
of gastrointestinal symptoms in people with no history of peptic ulcer disease.
epidemiology; Helicobacter pylori;
non-ulcer dyspepsia; symptomatology; upper dyspepsia
Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.
Methods and Findings
We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI)) = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β = 0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].
These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.
Inflammation and inflammatory biomarkers play an important role in atherosclerosis and cardiovascular disease. Little information is available, however, on time course of serum markers of inflammation after stroke.
First ischemic stroke patients ≥40 years old had levels of high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), and fibrinogen measured in plasma samples drawn at 1, 2, 3, 7, 14, 21 and 28 days after stroke. Levels were log-transformed as needed, and parametric and non-parametric statistical tests were used to test for evidence of a trend in levels over time. Levels of hsCRP and SAA were also compared with levels in a comparable population of stroke-free participants.
Mean age of participants with repeated measures (n = 21) was 65.6 ± 11.6 years, and 13 (61.9%) were men, and 15 (71.4%) were Hispanic. Approximately 75% of patients (n = 15) had mild strokes (NIH Stroke Scale score 0–5). There was no evidence of a time trend in levels of hsCRP, SAA, or fibrinogen for any of the markers during the 28 days of follow-up. Mean log(hsCRP) was 1.67 ± 1.07 mg/L (median hsCRP 6.48 mg/L) among stroke participants and 1.00 ± 1.18 mg/L (median 2.82 mg/L) in a group of 1176 randomly selected stroke-free participants from the same community (p = 0.0252).
Levels of hsCRP are higher in stroke patients than in stroke-free subjects. Levels of inflammatory biomarkers associated with atherosclerosis, including hsCRP, appear to be stable for at least 28 days after first ischemic stroke.
Helicobacter pylori is now incriminated in the pathogenesis
To examine the importance of H. pylori infection as a
cardiovascular disease (CVD) risk factor.
Two hundred five patients (128 with H. pylori infection
[HP-seropositive] and 77 without) had a baseline assessment
for other potential CVD risk factors and were followed prospectively for 10
years (1999–2008). They were assessed on a monthly basis for the
outcomes of carotid plaque, angina pectoris, myocardial infarction, and
stroke. In the HP-seropositive group, male sex and quartile 4 for IgG
anti-H. pylori antibodies (anti-HP Ab) were correlated
with traditional CVD risk factors, stroke, myocardial infarction, and angina
At the baseline assessment, the levels of carotid intima-media thickness,
blood fibrinogen, total cholesterol, fasting plasma glucose, and uric acid
were higher in H. pylori-infected patients than in the
uninfected group. Serum HDL-cholesterol was significantly lower in the
HP-seropositive group. Men had higher levels of IgG anti-HP Ab, waist
circumference, blood pressure, uric acid, and total cholesterol than women.
Within the HP-seropositive group, individuals in quartile 4 for IgG anti-HP
Ab had higher rates of elevated fibrinogen, diabetes mellitus, low
high-density lipoprotein cholesterol, arterial hypertension, and high total
cholesterol than those in quartile 1. After adjusting for traditional CVD
risk factors, H. pylori infection was the only independent
predictor of incident carotid plaque (multivariate odds ratio
[OR] = 2.3, 95% confidence interval
[CI]: 1.2–7.2; P < 0.0001) and
incident acute stroke (multivariate OR = 3.6, 95% CI:
1.4–8.2; P < 0.0001). Within the HP-seropositive
group and after adjusting for traditional CVD risk factors, male sex was the
only independent predictor of incident angina pectoris (multivariate OR
= 3.5, 95% CI: 1.6–16; P <
0.0001), incident acute stroke (multivariate OR = 3.2, 95%
CI: 1.4–28; P < 0.0001), and acute myocardial
infarction (multivariate OR = 7.2, 95% CI: 3.1–18;
P < 0.0001).
Our study provides evidence for an association among known CVD risk factors,
carotid plaque, stroke, and H. pylori infection. Among
infected individuals, there is a significant association among severity of
HP-seropositivity, male sex, and CVD. The eradication of H.
pylori infection may therefore reduce the emerging burden of
CVD in Africa.
Helicobacter pylori; stroke; myocardial infarction; cardiovascular disease; carotid plaque; Africans