Phase I clinical studies are experiments in which a new drug is administered to humans to determine the maximum dose that causes toxicity with a target probability. Phase I dose-finding is often formulated as a quantile estimation problem. For studies with a biological endpoint, it is common to define toxicity by dichotomizing the continuous biomarker expression. In this article, we propose a novel variant of the Robbins–Monro stochastic approximation that utilizes the continuous measurements for quantile estimation. The Robbins–Monro method has seldom seen clinical applications, because it does not perform well for quantile estimation with binary data and it works with a continuum of doses that are generally not available in practice. To address these issues, we formulate the dose-finding problem as root-finding for the mean of a continuous variable, for which the stochastic approximation procedure is efficient. To accommodate the use of discrete doses, we introduce the idea of virtual observation that is defined on a continuous dosage range. Our proposed method inherits the convergence properties of the stochastic approximation algorithm and its computational simplicity. Simulations based on real trial data show that our proposed method improves accuracy compared with the continual re-assessment method and produces results robust to model misspecification.
Continual re-assessment method; Dichotomized data; Discrete barrier; Heteroscedasticity; Robust estimation; Semiparametric mean-variance relationship
High-sensitivity C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) are hypothesized to be biomarkers of systemic inflammation and risk of myocardial infarction (MI) and stroke. Little is known, however, about the stability of these markers over time, and in particular, about the effects of acute vascular events on these marker levels.
Serum samples were collected at 4 annual intervals in 52 stroke-free participants from the Northern Manhattan Study (NOMAS), and assayed for hsCRP and Lp-PLA2 mass and activitylevels using standard techniques. Log transformation of levels was performed as needed to stabilize the variance. Stability of marker levels over time was assessed using random effects models unadjusted and adjusted for demographics and other risk factors. In addition, samples from 37 initially stroke-free participants with stroke (n=17) or MI (n=20) were available for measurement before and after the vascular event (median 5 days, range 2–40 days). Levels before and after events were compared using non-parametric tests.
HsCRP and Lp-PLA2 activity levels were stable over time, while Lp-PLA2 mass levels decreased on average 5% per year (p=0.0015). Using accepted thresholds to define risk categories of Lp-PLA2 mass, there was no significant change over time. HsCRP increased after stroke (from median 2.2 mg/L pre-stroke to 6.5 mg/L post-stroke; p=0.0067) and MI (from median 2.5 mg/L pre-MI to 13.5 mg/L post-MI; p<0.0001). Lp-PLA2 mass and activity levels both decreased significantly after stroke and MI (for Lp-PLA2 mass, from median 210.0 ng/mL to 169.4 ng/mL post-stroke, p=0.0348, and from median 233.0 ng/mL to 153.9 post-MI, p<0.0001).
Lp-PLA2 mass levels decrease modestly, while hsCRP and Lp-PLA2 activity appear stable over time. Acutely after stroke and MI, hsCRP increases, while Lp-PLA2 mass and activity levels decrease. These changes imply that measurements made soon after stroke and MI are not reflective of pre-stroke levels, and may be less reliable for long-term risk stratification.
C-reactive protein; Biomarker; Inflammation; Ischemic-Stroke; Myocardial Infarction
Race/ethnic differences in carotid arterial function and structure exist among those with cerebrovascular disease, but whether differences persist among healthy populations is unknown. Our objective was to investigate differences in carotid artery diameter and stiffness between race/ethnic groups, and examine whether these race/ethnic differences were age-dependent.
Carotid diameters were assessed by B-mode ultrasound among 1536 participants from the Northern Manhattan Study (NOMAS), and carotid stiffness metrics were calculated. We used multivariable linear regression models to determine the relationship between race/ethnicity and both carotid arterial stiffness and carotid diastolic diameter.
Mean participant age was 70 ± 9 years (Hispanics=68 ± 8, blacks=72 ± 9, and whites=74 ± 9, p<0.0001). Mean DDIAM was 6.2 ± 1.0mm (Hispanics=6.2 ± 0.9mm, blacks=6.3 ± 1.0mm, and whites=6.3 ± 1.0mm, p<0.005) and mean STIFF was 8.7 ± 6.3 (Hispanics=8.5 ± 5.7, blacks=9.2 ± 6.2 and whites=8.9 ± 6.9, p<0.02). In a model that adjusted for sociodemographics and vascular risk factors including hypertension, diabetes, dislipidemia, renal function, physical acticity and a history of known coronary artery diseases; age was positively associated with greater DDIAM in Hispanics (p<0.0001) but not among blacks or whites. Older age was associated with greater stiffness among Hispanics (p<0.0001) and blacks (p<0.003), but not among whites.
We found race/ethnic differences in the association between age and arterial stiffness and diameter, including age-dependent arterial dilation observed in Hispanics that was not observed among blacks or whites.
arterial stiffness; atherosclerosis; diastolic diameter; carotid artery; race/ethnicity; carotid ultrasound
Basic and clinical research provide evidence that inflammatory mechanisms play a central role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Inflammatory biomarkers such as high-sensitivity C-reactive protein (hsCRP) have been identified as predictors of first stroke and prognosis after stroke. The value of hsCRP and other markers may depend on the characteristics of the study population; their utility may be less among populations with high vascular risk. A recent randomized clinical trial suggests that the use of rosuvastatin therapy in otherwise healthy patients with hsCRP > 2 mg/dl can reduce the risk of a first stroke by 50%. The prognostic role of hsCRP among patients after a stroke, however, is less clear, and other biomarkers, including lipoprotein-associated phospholipase A2, may provide complementary information about risk of stroke recurrence. Infections, moreover, may contribute to inflammation and stroke risk. While no single infectious organism is likely to be identified as the direct cause of atherosclerosis, summary measures of multiple chronic infectious exposures, or “infectious burden,” have been associated with risk of stroke and atherosclerosis affecting carotid arteries. Acute infections have also been found to serve as stroke triggers in epidemiological studies. Recommendations to vaccinate patients with cardiovascular disease against influenza represent the first specific anti-infective strategy to be employed in vascular prophylaxis. Further studies are needed to determine the role of treatment of inflammation and infection in stroke prevention.
atherosclerosis; inflammation; infection; infectious burden; statins; stroke; cerebral thrombosis; risk factors
Background and Purpose
The Framingham coronary heart disease (CHD) risk score (FRS) estimates 10-year risk of myocardial infarction (MI) and CHD death. Since preventive approaches to CHD and stroke are similar, a composite outcome may be more appropriate. We compared 10-year risk of 1) MI or CHD death, and 2) stroke, MI, or CHD death, among individuals free of vascular disease.
The Northern Manhattan Study contains a prospective, population-based study of stroke- and CHD-free individuals ≥40 years of age, followed for a median of 10 years for vascular events. FRS was calculated for each individual, and for each category of predicted risk, Kaplan-Meier observed 10-year cumulative probabilities were calculated for 1) MI or CHD death and 2) stroke, MI, or CHD death. The cumulative probability of (1) was subtracted from (2), and 95% confidence intervals (CI) for the difference were obtained with 1000 bootstrap samples. Using stratified analyses by race-ethnicity, we compared risk differences between race-ethnic groups.
Among 2613 participants (53% Hispanic, 25% non-Hispanic black and 20% non-Hispanic white), observed 10-year risk of MI or CHD death was 14.20%. With stroke in the outcome, observed risk was 21.98% (absolute risk difference 7.78%, 95% CI 5.86-9.75%). The absolute risk difference among blacks was significantly larger than among whites (p=0.01).
In this multi-ethnic urban population, adding stroke to the risk stratification outcome cluster resulted in a 55% relative increase in estimated risk, and crossing of the absolute risk threshold (>20% over 10 years) considered for preventive treatments such as statins.
Epidemiology; Stroke Management; Risk Factors
Background and Purpose
Elevated blood pressure (BP) is a risk factor for stroke and dementia, but the effect of BP, and change in BP over time, on WMHV is not fully understood. Few studies have included Hispanics, who are at greater risk of stroke and dementia than non-Hispanic whites. We examined BP in relation to white matter hyperintensity volume (WMHV) in a stroke-free cohort.
The Northern Manhattan Study includes 1,290 stroke-free participants who had brain MRI. We examined baseline systolic (SBP) and diastolic (DBP) BP, and changes in BP from baseline to MRI, and WMHV.
There were 1,281 participants with brain MRI and two BP measurements (mean age 64, SD=8, range 40–94). Baseline DBP was associated with greater WMHV (p<0.0001) independent of sociodemographic and vascular risk factors. Each 10 mm Hg above the mean baseline DBP (83 ± 11 mm Hg) was associated with a 1.17% greater WMHV. Over seven years average follow up, participantswith an increase >5 mm Hg DBP from baseline to MRI had 1.21% greater WMHV relative to those whose BP did not increase (p = 0.02). The association between baseline DBP and WMHV was strongest for blacks compared to Hispanics and whites (interaction p=0.04).
Baseline DBP and longitudinal increases in DBP were independently associated with a greater WMHV, and the association between DBP and WMHV was greatest among blacks.
The most common cause of arterial ischemic stroke (AIS) in a previously healthy child is a large vessel cerebral arteriopathy. Varicella zoster virus is an established etiology, and recent data implicate a non-specific effect of additional common viral infections on cerebral vessels. The Vascular effects of Infection in Pediatric Stroke (VIPS) study is a multicenter cohort study that will test the hypotheses that (1) infection can lead to childhood AIS by causing vascular injury, and (2) the resultant arteriopathy, and inflammatory markers, predict recurrent stroke.
We are prospectively enrolling 480 children (aged 1 month through 18 years) with AIS and collecting (1) extensive infectious histories (through parental interview), (2) blood and serum samples (and CSF, when clinically obtained), and (3) clinically obtained but standardized brain and cerebrovascular imaging studies. Imaging studies are being centrally reviewed and adjudicated. Centralized laboratory assays will include serologies (acute and convalescent) and molecular assays for herpes viruses, and levels of inflammatory markers. Subjects are followed prospectively for recurrent ischemic events for the duration of the study (minimum of 1 year). We are banking biological specimens (including DNA) for future studies of specific infectious agents and mediators of inflammation relevant to thrombosis and vascular injury.
In a cross-sectional analysis, we will use logistic regression techniques to measure the association between markers of infection (from the clinical history and laboratory assays) and cerebral arteriopathy. In a prospective cohort analysis, we will use survival analysis techniques to determine whether cerebral arteriopathy and inflammatory markers predict recurrent stroke.
VIPS will shed light on the vascular effects of infection in childhood stroke. Because arteriopathy is likely the major predictor of recurrent stroke in children, a better understanding of the vascular injury pathway is critical for the development of rational strategies for secondary stroke prevention in children.
Left atrial (LA) maximum volume (LAVmax) is an indicator of left ventricular (LV) diastolic function. However, LAVmax is also influenced by systolic events, whereas the LA minimum volume (LAVmin) is directly exposed to LV pressure. The authors hypothesised that LAVmin may be a better correlate of LV diastolic function than LAVmax.
357 participants from a community-based cohort study.
LA volumes and reservoir function, measured as total LA emptying volume (LAEV) and LA emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography. LV diastolic function was assessed by trans-mitral early (E) and late (A) Doppler velocities and mitral early diastolic velocity by tissue-Doppler (e′). LV systolic function was assessed by LV ejection fraction (LVEF) and global longitudinal strain (GLS) by speckle-tracking.
LAVmin significantly increased with worsening diastolic dysfunction (p<0.001), whereas the increase in LAVmax was less pronounced (p=0.07). LAEV and LAEF decreased with worsening diastolic dysfunction (both p<0.001). In linear regressions, LAVmin and LAVmax were significant predictors of E/e′, with higher parameter estimates for LAVmin. In multivariate models, LAVmin resulted strongly associated with E/e′ (β=0.45, p<0.001), whereas LAVmax was not (β=− 0.16, p=0.08). LA reservoir function was better associated with GLS than LVEF. In multivariate analyses, GLS was significantly associated with LAVmax (β=− 0.15, p=0.002), LAEV (β=−0.37, p<0.001) and LAEF (β=−0.28, p<0.001) but not with LAVmin.
LAVmin is a better correlate of LV diastolic function than LAVmax. The impact of LV longitudinal systolic function on LA reservoir function might explain the weaker relation between LAVmax and LV diastolic function.
Background and Purpose
Little is known about acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with short-term risk of stroke.
The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days prior to incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years prior to stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios and 95% confidence intervals (OR, 95% CI) were calculated using conditional logistic regression. Confirmatory analyses assessed hazard ratios (HR) of stroke from Cox regression models with hospitalization for infection as a time-varying exposure.
During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days prior to stroke, OR=3.4 (95% CI 1.8–6.5). The point estimates of risks were higher when examining shorter intervals: for 30 days, OR= 7.3 (95% CI 1.9–40.9), and 14 days, OR=8.0 (95% CI 1.7–77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted HR=2.4 (95% CI 1.6–3.4).
Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.
Epidemiology; Cerebral Infarction; Infectious Diseases
The safety of intravenous thrombolysis (IVT) in patients with acute ischemic stroke over age 80 is unclear. We hypothesized that patients over age 80 can be safely treated with IVT.
Admission and discharge data were collected on all patients at a single tertiary care center presenting within 12 hours of onset. Collected data included treatment with IVT, demographics, pre-treatment National Institutes of Health Stroke Scale (NIHSS) score, length of stay (LOS), mortality and discharge disposition. Analyses were restricted to patients over age 80, and the primary outcome was in-hospital mortality. Logistic regression was used to examine whether IVT was associated with mortality.
Between 1/1/05 and 6/30/10, 112 patients over age 80 presented within 3 hours of ischemic stroke onset, and 31 received IVT. There were 15 deaths. In multi-variable models adjusted for age, sex, race-ethnicity and NIHSS, treatment with IVT compared to no treatment, was not associated with in-hospital death (adjusted OR 1.2, 95% confidence interval 0.3 – 4.3).
Treating ischemic stroke patients over 80 with IVT was not associated with an increase in mortality in an urban tertiary care center.
The meanings of several target neuropsychological variables, including measures of executive functioning, were examined using contextual analysis across a sample of English-speakers and a sample of Spanish-speakers. Results of the contextual analysis, which examined the contributions of the latent constructs of memory, psychomotor speed, visual spatial ability, and knowledge and comprehension, to the target neuropsychological variables indicate that each of the target variables likely reflects the unique contribution of several reference abilities. These findings provide evidence that the neuropsychological variables are multi-dimensional. The patterns of relations were similar across the samples of English and Spanish speakers.
contextual analysis; executive functioning; memory; psychomotor speed; structural equation modeling; race; ethnicity; vascular cognitive impairment
To examine the association between a Mediterranean-style diet (MeDi) and brain MRI white matter hyperintensities (WMH). The MeDi has previously been associated with a reduced risk of cardiovascular morbidity, possibly including stroke. A greater understanding of modifiable risk factors for small vessel damage may facilitate the prevention of stroke and cognitive decline.
A cross-sectional analysis within a longitudinal population-based cohort study. A semi-quantitative food frequency questionnaire was administered and a score (range 0-9) was calculated to reflect increasing similarity to the MeDi pattern.
The Northern Manhattan Study.
1,091 participants, of which 966 had dietary information (mean age 72, 59% women, 65% Hispanic, 16% White, 17% Black).
Main outcome measures
WMH volume was measured by quantitative brain MRI. Linear regression models were constructed to examine the relation between the MeDi score and the log-transformed WMH volume as a proportion of total cranial volume, controlling for sociodemographic and vascular risk factors.
On the MeDi scale, 12% scored 0-2, 16 scored 3, 23% scored 4, 23% scored 5, 26% scored 6-9. Each 1-point increase in MeDi score was associated with a lower log WMH volume (β=-0.04, p=0.02). The only MeDi score component that was an independent predictor of WMH volume was the ratio of monounsaturated to saturated fat (β=-0.20, p=0.001).
A Mediterranean-style diet was associated with a lower WMH burden, a marker of small vessel damage in the brain. However, white matter hyperintensities are etiologically heterogenous and can include neurodegeneration. Replication by other population-based studies is needed.
Social isolation is associated with progression of cardiovascular disease with the most socially isolated patients being at increased risk. Increased left ventricular mass is a predictor of cardiovascular morbidity and mortality. It is not yet clear whether social isolation is a determinant of increased left ventricular mass.
We performed a cross-sectional study of Northern Manhattan Study participants who were free of clinical cardiovascular disease, had obtained transthoracic echocardiograms (n=2021) and a baseline questionnaire on social habits. Social isolation was defined as the lack of friendship networks (knowing fewer than 3 people well enough to visit within their homes). Echocardiographic left ventricular mass was indexed to height2.7, analyzed as a continuous variable and compared between exposure groups.
The prevalence of social isolation was 13.5%. The average left ventricular mass was significantly higher (50.2 gm/m2.7) in those who were, as compared to those who were not (47.6 gm/m2.7), socially isolated (p<0.05). Higher prevalence of social isolation was found among those less educated, uninsured or unemployed.There were no significant race-ethnic differences in the prevalence of social isolation. In multivariate analysis, there was a trend toward an association between social isolation and increased left ventricular mass in the total cohort (p=0.09). Among Hispanics, social isolation was significantly associated with greater left ventricular mass. Hispanics who were socially isolated averaged 3.9 gm/ht2.7 higher left ventricular mass compared to those not socially isolated (p=0.002). This relationship was not present among non-Hispanic blacks or whites.
In this urban tri-ethnic cohort, social isolation was prevalent and associated with indices of low socioeconomic status. Hispanics who were socially isolated had a greater risk for increased left ventricular mass.
social isolation; left ventricular mass; Hispanics; psychosocial factors
The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989–2007) in 3,754 community-dwelling US adults aged 65–100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥30 kg/m2) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25–29.9 kg/m2) was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.
aging; body composition; body size; coronary disease; stroke
3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are among the most prescribed medications in the United States. Statins act on the rate-limiting step in cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate) and are effective in treating dyslipidemia. However, statins decrease other downstream products of the mevalonate pathway, and it is via these pathways that statins may affect inflammation, nitric oxide synthesis, the coagulation cascade, and other processes. Through these pleiotropic effects, statins may have an effect on neurologic diseases, including ischemic and hemorrhagic stroke, Alzheimer disease, Parkinson disease, and multiple sclerosis. This article reviews the basic biochemistry of statins as it relates to these pleiotropic effects, the potential role of statins in several neurologic disorders, and the results of clinical trials performed for several of these conditions.
The metabolic syndrome (MetS) is a risk factor for diabetes, stroke, myocardial infarction, and increased mortality, and has been associated with cognition in some populations. We hypothesized that MetS would be associated with lower Mini-Mental State Examination (MMSE) scores in a multi-ethnic population, and that MetS is a better predictor of cognition than its individual components or diabetes.
We conducted a cross-sectional analysis among 3,150 stroke-free participants. MetS was defined by the modified National Cholesterol Education Program guidelines-Adult Treatment Panel III (NCEP-ATPIII) criteria. Linear regression and polytomous logistic regression estimated the association between MMSE score and MetS, its individual components, diabetes, and inflammatory biomarkers.
MetS was inversely associated with MMSE score (unadjusted β = −0.67; 95% CI −0.92, −0.41). Adjusting for potential confounders, MetS was associated with lower MMSE score (adjusted β = −0.24; 95% CI −0.47, −0.01), but its individual components and diabetes were not. Those with MetS were more likely to have an MMSE score of <18 than a score of ≥24 (adjusted OR = 1.94; 95% CI 1.26, 3.01). There was an interaction between MetS and race-ethnicity, such that MetS was associated with lower MMSE score among non-Hispanic whites and Hispanics but not non-Hispanic blacks.
MetS was associated with lower cognition in a multi-ethnic population. Further studies of the effect of MetS on cognition are warranted, and should account for demographic differences.
Cognitive performance; Cognitive impairment; Vascular dementia; Vascular cognitive impairment; Cerebrovascular disorders; Metabolic syndrome
Background and Purpose
Few studies have examined the early effects of statins on carotid artery elasticity, a potential surrogate marker of cardiovascular risk. This study examined the short-term effects of atorvastatin 80 mg daily on carotid elasticity measured by high resolution B-mode ultrasound.
The study included 40 stroke-free and statin-naïve subjects over age 45 (mean age 70±7 years; 55% men; 64% Caribbean-Hispanic). Outcome measures included carotid stiffness indices at 14 and 30 days after initiation of treatment. The systolic (SD) and diastolic (DD) diameters of the right common carotid artery were averaged from multiple B-mode imaging frames. Absolute and relative changes of Strain [(SD-DD)/DD], Stiffness (β) [ln (systolic/diastolic blood pressure)/strain] and distensibility (1/β adjusted for wall thickness) from baseline were compared by the repeated measures t-test and considered significant at α of 0.05.
Baseline mean stiffness was 0.08 (95% CI: 0.06–0.10). It significantly decreased at Day 30 to 0.05 (CI: 0.04–0.06; p<0.01). Mean baseline distensibility was 15.25 [CI: 13.18–17.32], increasing significantly at Day 30 to 17.23 [CI: 14.01–20.45, p<0.05]. An improvement in distensibility of ≥ 10% from baseline was observed in 29 (73%) subjects. Changes in stiffness and distensibility were maximal among subjects with baseline low-density lipoprotein (LDL) levels <130 mg/dL.
Short-term treatment with high-dose atorvastatin was associated with improvement in the carotid elasticity metrics. Carotid artery elasticity measured by B-mode ultrasound is a simple non-invasive measure of arterial wall function and may be a useful surrogate endpoint in clinical trials targeting individuals at increased risk for atherosclerosis.
statins; carotid arteries; elasticity; carotid ultrasound
Prior studies suggest that the causes of calcific aortic valve (AV) disease involve chronic inflammation, lipoprotein levels, and calcium metabolism, all of which may differ among race-ethnic groups. We sought to determine whether AV thickness differs by race-ethnicity in a large multi-ethnic population-based cohort.
The Northern Manhattan Study (NOMAS) includes stroke-free community-based Hispanic (57%), non-Hispanic black (22%), and non-Hispanic white (21%) participants. The relation between AV thickness on transthoracic echocardiography and clinical risk factors for atherosclerosis was evaluated among 2085 participants using polytomous logistic regression models. AV thickness was graded in three categories (normal, mild, and moderate/severe) based on leaflet thickening and calcification.
Mild AV thickness was present in 44.4% and moderate/severe thickness in 5.7% of the cohort, with the lowest frequency of moderate/severe thickness seen particularly among Hispanic females. In multivariate models adjusting for age, sex, race-ethnicity, body mass index, hypertension, coronary artery disease, blood glucose, and high-density lipoprotein cholesterol, Hispanics had significantly less moderate/severe AV thickness (odds ratio (OR) 0.43, 95% confidence interval (95% CI) 0.25 to 0.73) than non-Hispanic whites. Men were almost 2-fold as likely to have moderate/severe AV thickness compared to women (OR 1.96, 95% CI 1.24 to 3.10).
In this large multi-ethnic population-based cohort, there were ethnic differences in the degree of AV thickness. Hispanic ethnicity was strongly protective against AV thickness. This effect was not related to traditional risk factors, suggesting that unmeasured factors related to Hispanic ethnicity and AV thickness may be responsible.
Common infections may be associated with stroke risk, though no single infection is likely a major independent predictor.
To determine the association between a composite measure of serologies to common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, Herpes Simplex Virus 1 and 2) and stroke risk in a prospective cohort study.
Prospective cohort followed longitudinally for median 8 years.
Randomly selected stroke-free participants from a multiethnic urban community.
Northern Manhattan Study (NOMAS).
Main Outcome measure
Incident stroke and other vascular events.
All five infectious serologies were available from baseline samples in 1625 participants (mean age 68.5 ± 10.1 years; 64.9% women). Cox proportional hazards models were used to estimate associations of each positive serology with stroke. Individual parameter estimates were then combined into a weighted index of infectious burden (IB) and used to calculate hazard ratios and confidence intervals (HR, 95% CI) for association with risk of stroke and other outcomes, adjusted for risk factors. Each individual infection was positively though not significantly associated with stroke risk after adjusting for other risk factors. The IB index was associated with an increased risk of all strokes (adjusted HR per standard deviation 1.39, 95% CI 1.02–1.90) after adjusting for demographics and risk factors. Results were similar after excluding those with coronary disease (adjusted HR 1.50, 95% CI 1.05–2.13) and adjusting for inflammatory biomarkers.
A quantitative weighted index of infectious burden was associated with risk of first stroke in this cohort. Future studies are needed to confirm these findings and to further define optimal measures of IB as a stroke risk factor.
To explore the relationship between lipid profile components and incident ischemic stroke in a stroke-free prospective cohort.
Population-based prospective cohort study.
Northern Manhattan, New York.
Stroke-free community residents.
As part of the Northern Manhattan Study, baseline fasting blood samples were collected on stroke-free community residents followed up for a mean of 7.5 years.
Main Outcome Measures
Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for lipid profile components and ischemic stroke after adjusting for demographic and risk factors. In secondary analyses, we used repeated lipid measures over 5 years from a 10% sample of the population to calculate the change per year of each of the lipid parameters and to impute time-dependent lipid parameters for the full cohort.
After excluding those with a history of myocardial infarction, 2940 participants were available for analysis. Baseline high-density lipoprotein cholesterol, triglyceride, and total cholesterol levels were not associated with risk of ischemic stroke. Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol levels were associated with a paradoxical reduction in risk of stroke. There was an interaction with use of cholesterol-lowering medication on follow-up, such that LDL-C level was only associated with a reduction in stroke risk among those taking medications. An LDL-C level greater than 130 mg/dL as a time-dependent covariate showed an increased risk of ischemic stroke (adjusted hazard ratio, 3.81; 95% confidence interval, 1.53–9.51).
Baseline lipid panel components were not associated with an increased stroke risk in this cohort. Treatment with cholesterol-lowering medications and changes in LDL-C level over time may have attenuated the risk in this population, and lipid measurements at several points may be a better marker of stroke risk.
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.
Epidemiological evidence suggests that infections may contribute to atherogenesis. However, with the exception of Chlamydophila pneumoniae, cultivable bacteria have not been recovered from atherosclerotic lesions. Therefore, we aimed at developing an approach to recover uncultivable bacteria from atherectomy tissues.
We cultured homogenates from atherectomy specimens from seven non-septic patients undergoing surgery for arterial obstruction either alone or together with THP-1 monocyte-like cells. We performed 16S rDNA analysis, biochemical tests, random amplification of polymorphic DNA PCR analysis, quantitative polymerase chain reaction (qPCR) and immunohistofluorescence to identify the cultivated bacteria. Wilcoxon Signed-Rank Tests were used to determine whether THP-1 treatment yielded a higher number of isolates than did the untreated controls.
We recovered more bacteria from co-cultures of atherectomy specimens with THP-1 cells than atherectomy specimens cultured alone. On average, tissue homogenates incubated with THP-1 cells vs control yielded 124 vs 22 colony-forming units (CFUs), a median of 140 vs. 7, respectively (p = 0.02). We recovered 872 isolates of limited number of species, including Propionibacterium acnes, Staphylococcus epidermidis and Streptococcus infantis and the fastidious anaerobe Porphyromonas gingivalis, and confirmed its presence in tissue using double immunofluorescence imaging. qPCR demonstrated the presence of ≥3.5 × 103 P. gingivalis genomes/g of atheromatous tissue.
These results indicate that viable previously uncultivable bacterial species are present within atheromas. Our results suggest revisiting the hypothesis that infections may have a causative role in atherosclerotic inflammation and have implications for research regarding novel diagnostics and treatments for cardiovascular disease.
atherosclerosis; monocytes; Porphyromonas gingivalis; periodontal disease; bacterial infection