Systemic inflammation is linked to cardiovascular risk, but the influence of persistent pathogens, which are conventionally dichotomously categorized, on circulating levels of inflammatory markers is not clear. Antibody levels of pathogens have not been examined in relation to inflammation.
Using data from a subsample of the Multi-Ethnic Study of Atherosclerosis, we examined circulating levels of interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen in relation to five common persistent pathogens: cytomegalovirus, herpes simplex virus-1, Hepatitis A virus, Helicobacter pylori and Chlamydia pneumoniae. We tested the hypothesis that the number of seropositive pathogens (based on conventional cut-off points) would not be as sensitive a marker of inflammation as immune response measured by antibody levels to pathogens.
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).
High antibody response to pathogens was a more consistent marker of inflammatory outcomes compared to seropositivity alone and high antibody response to multiple pathogens was a stronger marker compared to any single pathogen.
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
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
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
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
We assessed associations of herpes simplex virus types 1 and 2 (HSV-1 and -2), cytomegalovirus (CMV), and human herpesvirus 8 (HHV-8) infection with subclinical coronary atherosclerosis in 291 HIV-infected men in the Multicenter AIDS Cohort Study. Coronary artery calcium (CAC) was measured by non-contrast coronary CT imaging. Markers for herpesviruses infection were measured in frozen specimens collected 10-12 years prior to case identification. Multivariable logistic regression models and ordinal logistic regression models were performed. HSV-2 seropositivity was associated with coronary atherosclerosis (adjusted odds ratio [AOR] =4.12, 95% confidence interval [CI] =1.58-10.85) after adjustment for age, race/ethnicity, cardiovascular risk factors, and HIV infection related factors. Infection with a greater number of herpesviruses was associated with elevated CAC levels (AOR=1.58, 95% CI=1.06-2.36). Our findings suggest HSV-2 may be a risk factor for subclinical coronary atherosclerosis in HIV-infected men. Infection with multiple herpesviruses may contribute to the increased burden of atherosclerosis.
herpesvirus; HSV-2; atherosclerosis; HIV-1/AIDS; risk factors
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.
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
Human immunodeficiency virus (HIV) infection continues to be a major health problem for society. Intravenous drug users are the second largest risk group for HIV infection. The disease primarily affects immunologic functioning. This study examined the inherent immunologic dysfunction by measuring the seroprevalence of infection against pathogens often associated with HIV infection. Additionally, chi square analysis was used to compare intravenous drug users with a non-drug-using control group to see if any difference existed in the prevalence of antinuclear antibody, rheumatoid factor, abnormal titer of antibody to Toxoplasma gondii, cytomegalovirus, and herpes simplex virus (types 1 and 2). The intravenous drug users had a significantly greater level of antibody titers for antinuclear antibody and Toxoplasma gondii than did controls. Abnormal serologic results were not significantly associated with HIV seropositivity. The findings of this study suggest that intravenous drug users experience a greater prevalence of alteration in serologic markers unrelated to HIV exposure.
To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI.
Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11).
In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.
Testing of patients who are deemed to be at high risk for TORCH pathogens, e.g., pregnant women, their fetuses, neonates, and acquired immunodeficiency syndrome (AIDS) patients, is important so that specific treatment can be initiated. This study included 1,857 such patients between 2005 and 2008. Logistic regression was used to evaluate factors associated with Toxoplasma gondii seropositivity. Among 823 women of childbearing age, 35.1% and 5.2% tested positive for T. gondii IgG and IgM, respectively. Three infants ≤ 6 months of age (0.8% of 353) were congenitally infected. Factors associated with T. gondii IgG seropositivity included older age, East Mediterranean or African nationality, positive cytomegalovirus (CMV) and herpes simplex virus (HSV)-1 serostatus, and negative rubella IgG results. The decreasing prevalence of IgM antibodies between 2005 and 2008 suggested that exposure to T. gondii from food or environmental sources declined over this period in Qatar. Population-based studies of newborns would be helpful to accurately estimate incidence of congenital toxoplasmosis.
Purpose. The study was aimed to investigate the frequency of diabetes mellitus type 2 in patients infected with chronic hepatitis C virus and its association with cirrhosis. Patients and Methods. This prospective case series was conducted at Section of Gastroenterology and Hepatology, Isra University Hospital, Hyderabad, over a period of 4 months from June 2009 to October 2009. Hepatitis C virus seropositive patients who were older than 18 years, diabetic or nondiabetic, were included. Basic demographic data collected by questionnaire and laboratory investigations including fasting blood glucose levels, serum cholesterol, and liver function tests were done. A logistic regression model was used to explore the association between diabetic and nondiabetic HCV seropositives and type 2 diabetes mellitus with cirrhosis. Results. A total of 361 patients with hepatitis C were analyzed; the prevalence of type 2 diabetes mellitus in HCV patients was 31.5%. Out of the total number of the participants, 58.4% (n = 211) were cirrhotics, while 41.6% (n = 150) were noncirrhotic HCV seropositives. In multivariate analysis, cirrhotic patients appeared significantly more likely (P = 0.01) to be diabetic as compared with noncirrhotic patients (OR = 2.005, 95% CI: 1.15, 3.43). Conclusion. Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients, and there is a statistically significant association of cirrhosis observed with type 2 diabetes mellitus.
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
OBJECTIVE—The prevalence of type 2 diabetes among Hispanic and Asian Americans is increasing. These groups are largely comprised of immigrants who may be undergoing behavioral and lifestyle changes associated with development of diabetes. We studied the association between acculturation and diabetes in a population sample of 708 Mexican-origin Hispanics, 547 non–Mexican-origin Hispanics, and 737 Chinese participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
RESEARCH DESIGN AND METHODS—Diabetes was defined as fasting glucose ≥126 mg/dl and/or use of antidiabetic medications. An acculturation score was calculated for all participants using nativity, years living in the U.S., and language spoken at home. The score ranged from 0 to 5 (0 = least acculturated and 5 = most acculturated). Relative risk regression was used to estimate the association between acculturation and diabetes.
RESULTS—For non–Mexican-origin Hispanics, the prevalence of diabetes was positively associated with acculturation score, after adjustment for sociodemographics. The prevalence of diabetes was significantly higher among the most acculturated versus the least acculturated non–Mexican-origin Hispanics (prevalence ratio 2.49 [95% CI 1.14−5.44]); the higher the acculturation score is, the higher the prevalence of diabetes (P for trend 0.059). This relationship between acculturation and diabetes was partly attenuated after adjustment for BMI or diet. Diabetes prevalence was not related to acculturation among Chinese or Mexican-origin Hispanics.
CONCLUSIONS—Among non–Mexican-origin Hispanics in MESA, greater acculturation is associated with higher diabetes prevalence. The relation is at least partly mediated by BMI and diet. Acculturation is a factor that should be considered when predictors of diabetes in racial/ethnic groups are examined.
Optimism and pessimism are associated with cardiovascular disease mortality and progression, however the biological mechanism remains unclear. This study investigates the association between optimism/pessimism and concentrations of seven inflammation and hemostasis markers.
This cross-sectional study used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a study of 6814 persons aged 45–84 with no history of clinical cardiovascular disease. The Life-Orientation Test—Revised (LOT-R) was used to measure dispositional optimism and pessimism. Regression analyses were used to estimate associations of optimism and pessimism with interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, homocysteine, factor VIII, D-dimer, and plasmin-antiplasmin, before and after adjustment for sociodemographics, depression, cynicism, health behaviors, BMI, hypertension, and diabetes.
Higher scores on the LOT-R (positive disposition) were related to lower concentrations of IL-6 (p=0.001), fibrinogen (p<0.001) and homocysteine (p=0.031). Associations were stronger for the pessimism subscale. After adjustment for demographics, the percentage differences in inflammatory markers corresponding to a 2-standard deviation increase in pessimism were 6.01% (p=0.001) for IL-6; 10.31% (p=0.001) for CRP; 2.47% (p<0.0001) for fibrinogen, and 1.36% (p=0.07) for homocysteine. Associations were attenuated but significant after adjustment for sociodemographics, depression, cynical distrust, and behaviors. Further adjustment for hypertension, BMI and diabetes reduced associations for CRP and IL-6. Pessimism remained associated with a 1.36% (p=0.02) increase in fibrinogen in the fully adjusted model. Factor VIII, D-dimer and plasmin-antiplasmin were not associated with the LOT-R or subscales.
Pessimism is related to higher levels of inflammation. Health behaviors, BMI, hypertension and diabetes appear to play a mediating role.
Psychosocial factors; inflammation; coagulation; epidemiology; risk factors
Several models for estimating risk of incident diabetes in US adults are available. The authors aimed to determine the discriminative ability and calibration of published diabetes risk prediction models in a contemporary multiethnic cohort. Participants in the Multi-Ethnic Study of Atherosclerosis without diabetes at baseline (2000–2002; n = 5,329) were followed for a median of 4.75 years. The predicted risk of diabetes was calculated using published models from the Framingham Offspring Study, the Atherosclerosis Risk in Communities (ARIC) Study, and the San Antonio Heart Study. The mean age of participants was 61.6 years (standard deviation, 10.2); 29.3% were obese, 53.1% had hypertension, 34.9% had a family history of diabetes, 27.5% had high triglyceride levels, 33.8% had low high density lipoprotein cholesterol levels, and 15.3% had impaired fasting glucose. There were 446 incident cases of diabetes (fasting glucose level ≥126 mg/dL or initiation of antidiabetes medication use) diagnosed during follow-up. C statistics were 0.78, 0.84, and 0.83 for the Framingham, ARIC, and San Antonio risk prediction models, respectively. There were significant differences between observed and predicted diabetes risks (Hosmer-Lemeshow goodness-of-fit chi-squared test for each model: P < 0.001). The recalibrated and best-fit models achieved sufficient goodness of fit (each P > 0.10). The Framingham, ARIC, and San Antonio models maintained high discriminative ability but required recalibration in a modern, multiethnic US cohort.
cohort studies; diabetes mellitus; models, statistical; risk; validation studies as topic
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 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
Recent studies have implicated the human cytomegalovirus (HCMV) as a possible pathogen for causing hypertension. We aimed to study the association between HCMV infection and hypertension in the United States National Health and Nutrition Examination Survey (NHANES).
We analyzed data on 2979 men and 3324 women in the NHANES 1999–2002. We included participants aged 16–49 years who had valid data on HCMV infection and hypertension.
Of the participants, 54.7% had serologic evidence of HCMV infection and 17.5% had hypertension. There were ethnic differences in the prevalence of HCMV infection (P<0.001) and hypertension (P<0.001). The prevalence of both increased with age (P<0.001). Before adjustment, HCMV seropositivity was significantly associated with hypertension in women (OR = 1.63, 95% CI = 1.25–2.13, P = 0.001) but not in men. After adjustment for race/ethnicity, the association between HCMV seropositivity and hypertension in women remained significant (OR = 1.55, 95% CI = 1.20–2.02, P = 0.002). Further adjustment for body mass index, diabetes status and hypercholesterolemia attenuated the association (OR = 1.44, 95% CI = 1.10–1.90, P = 0.010). However, after adjusting for age, the association was no longer significant (OR = 1.24, 95% CI = 0.91–1.67, P = 0.162).
In this nationally representative population-based survey, HCMV seropositivity is associated with hypertension in women in the NHANES population. This association is largely explained by the association of hypertension with age and the increase in past exposure to HCMV with age.
Background Numerous studies have documented a strong inverse association between cardiovascular disease and socioeconomic position (SEP). Several infections are associated with both cardiovascular disease and SEP; hence infection may form an important link between SEP and cardiovascular disease. This study examines whether seropositivity to cytomegalovirus (CMV), to herpes simplex virus type-1 (HSV-1), and/or to both pathogens mediates the relationship between SEP and cardiovascular disease history in a nationally representative sample of the United States.
Methods We conducted a cross-sectional study of subjects ≥45 years of age, who were tested for seropositivity to CMV, HSV-1 or both pathogens and assessed for cardiovascular disease history in the National Health and Nutrition Examination Survey III. Cardiovascular disease history was defined as history of stroke, heart attack and/or congestive heart failure and SEP as education level.
Results SEP was associated with CMV, HSV-1 and seropositivity to both pathogens. CMV seropositivity was associated with cardiovascular disease history even after adjusting for confounders as well as SEP. The odds of reporting a history of cardiovascular disease for those with less than a high school education compared with those with more than a high school education decreased by 7.7% after adjusting for CMV (Sobel mediation test for CMV, P = 0.0006). In contrast, neither seropositivity to HSV-1 nor to both pathogens was associated with cardiovascular disease history after adjusting for SEP.
Conclusions Persistent pathogens such as CMV infection may explain a portion of the relationship between SEP and cardiovascular disease in the United States. Further studies examining additional pathogens and sociobiological mechanisms are warranted.
SEP; CMV; HSV-1; co-infection; cardiovascular disease; mediation
Microvascular disease is a major pathogenic factor for chronic kidney disease (CKD) in persons with diabetes, but the role of microvascular disease in the development of CKD in the general population is unclear. The aim of this study is to examine whether microvascular disease precedes the development of CKD stage 3 in participants of the Multi-Ethnic Study of Atherosclerosis (MESA).
Population-based cohort study.
Setting & Participants
MESA is a prospective cohort study of adults aged 45-84 years living in 6 US communities; 4,594 adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 when they underwent retinal photography (visit 2: in 2002-2004) were examined.
Retinal microvascular caliber measured from fundus photographs.
Incident CKD stage 3 (ie, eGFR <60 mL/min/1.73 m2) at 2 subsequent follow-up examinations (visit 3 in 2004-2005, and visit 4 in 2005-2007) and an annual eGFR decrease >1 mL/min/1.73 m2 computed using the CKD Epidemiology Collaboration (CKD-EPI) equation.
After a median follow-up of 4.8 years, there were 232 incident CKD stage 3 cases. Overall, retinal microvascular caliber was not associated with incident CKD stage 3. However, in race-stratified analysis, narrower arterioles in whites was associated with a higher risk of developing CKD stage 3 after adjusting for age, sex, blood pressure, diabetes, and other factors (HR, 1.78; 95% CI, 1.01-3.15; P = 0.04, lowest vs highest arteriolar caliber tertile). This association was seen even in whites without hypertension and diabetes (HR, 2.95; 95% CI, 1.10-7.98; P = 0.03). Retinal arteriolar caliber was not associated with incident CKD stage 3 in African Americans, Chinese, or Hispanics.
Analyses were based on a single eGFR measurement, and retinal microvascular caliber and eGFR measurements were not ascertained concurrently.
Microvascular changes as manifest in the eye may contribute to the development of CKD stage 3 in whites.
Microvascular changes; retinal microvascular caliber; chronic kidney disease
To describe the prevalence and risk factors of diabetic retinopathy in a multi-ethnic US population of whites, blacks, hispanics, and chinese.
Cross-sectional study of 778 individuals from ages 45 to 85 years with diabetes, participating in the Multi-Ethnic Study of Atherosclerosis (MESA).
Retinal photographs were obtained with a 45° nonmydriatic digital fundus camera. Presence and severity of diabetic retinopathy were graded at a central reading center on the basis of a modification of the Airlie House classification system. All participants underwent a standardized interview, examination, and laboratory investigations.
In this population with diabetes, the prevalence of any retinopathy was 33.2% and macular edema 9.0%. The prevalence of any diabetic retinopathy and macular edema was significantly higher in blacks (36.7% and 11.1%) and hispanics (37.4% and 10.7%) than in whites (24.8% and 2.7%) and chinese (25.7% and 8.9%) (P = .01 and P = .007, comparing racial/ethnic differences for retinopathy and macular edema, respectively). Significant independent predictors of any retinopathy were longer duration of diabetes, higher fasting serum glucose, use of diabetic oral medication or insulin, and greater waist-hip ratio. Race was not an independent predictor of any retinopathy.
This study provides contemporary data on the prevalence of and risk factors for diabetic retinopathy among whites, blacks, hispanics, and chinese participating in the MESA.
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.
Chronic infections could be contributing to the socioeconomic gradient in chronic diseases. Although chronic infections have been associated with increased levels of inflammatory cytokines and cardiovascular disease, there is limited evidence on how infections affect risk of diabetes.
RESEARCH DESIGN AND METHODS
We examined the association between serological evidence of chronic viral and bacterial infections and incident diabetes in a prospective cohort of Latino elderly. We analyzed data on 782 individuals aged >60 years and diabetes-free in 1998–1999, whose blood was tested for antibodies to herpes simplex virus 1, varicella virus, cytomegalovirus, Helicobacter pylori, and Toxoplasma gondii and who were followed until June 2008. We used Cox proportional hazards regression to estimate the relative incidence rate of diabetes by serostatus, with adjustment for age, sex, education, cardiovascular disease, smoking, and cholesterol levels.
Individuals seropositive for herpes simplex virus 1, varicella virus, cytomegalovirus, and T. gondii did not show an increased rate of diabetes, whereas those who were seropositive for H. pylori at enrollment were 2.7 times more likely at any given time to develop diabetes than seronegative individuals (hazard ratio 2.69 [95% CI 1.10–6.60]). Controlling for insulin resistance, C-reactive protein and interleukin-6 did not attenuate the effect of H. pylori infection.
We demonstrated for the first time that H. pylori infection leads to an increased rate of incident diabetes in a prospective cohort study. Our findings implicate a potential role for antibiotic and gastrointestinal treatment in preventing diabetes.
Genetic variants associated with fasting glucose in European ancestry populations are increasingly well understood. However, the nature of the associations between these SNPs and fasting glucose in other racial and ethnic groups is unclear. We sought to examine regions previously identified to be associated with fasting glucose in Caucasian GWAS across multiple ethnicities in the Multi-Ethnic Study of Atherosclerosis (MESA). Non-diabetic MESA participants with fasting glucose measured at the baseline exam and with GWAS genotyping were included; 2349 Caucasians, 664 individuals of Chinese descent, 1366 African Americans, and 1171 Hispanics. Genotype data was generated from the Affymetrix 6.0 array and imputation in IMPUTE. Fasting glucose was regressed on SNP dosage data in each ethnic group adjusting for age, gender, MESA study center, and ethnic-specific principal components. SNPs from the three gene regions with the strongest associations to fasting glucose in previous Caucasian GWAS (MTNR1B / GCK / G6PC2) were examined in depth. There was limited power to replicate associations in other ethnic groups due to smaller allele frequencies and limited sample size; SNP associations may also have differed across ethnic groups due to differing LD patterns with causal variants. rs10830963 in MTNR1B and rs4607517 in GCK demonstrated consistent magnitude and direction of association with fasting glucose across ethnic groups, although the associations were often not nominally significant. In conclusion, certain SNPs in MTNR1B and GCK demonstrate consistent effects across four racial and ethnic groups, narrowing the putative region for these causal variants.
GWAS; fasting glucose; SNP