Lipoprotein-associated phospholipase A2 (LpPLA2) levels are associated with stroke, though whether this extends to all populations and stroke subtypes is unknown.
Serum samples from stroke-free community participants in the Northern Manhattan Study were assayed for LpPLA2 mass and activity. Participants were followed annually for stroke. Cox-proportional-hazard models were fitted to estimate hazard-ratios and 95% confidence intervals (HR, 95% CI) for the association of LpPLA2 levels with ischemic stroke (IS), after adjusting for demographic and medical risk factors.
Serum samples were available in 1946 participants, of whom 151 (7.8%) experienced a first IS during median follow-up 11 years. Mean age was 69 (SD 10), 35.6% were men, 20% non-Hispanic Whites, 22% non-Hispanic Blacks, and 55% Hispanics. LpPLA2 mass and activity levels were not associated with overall IS risk.
LpPLA2 mass but not activity levels were associated with strokes due to large artery atherosclerosis (LAA; adjusted HR per SD 1.55, 95% CI 1.17–2.04). There was a dose-response relationship with LAA (compared to first quartile, 2nd quartile HR = 1.43, 95% CI 0.23–8.64; 3rd quartile HR = 4.47, 95% CI 0.93–21.54; 4th quartile HR = 5.07, 95% CI 1.07–24.06). The associations between LpPLA2-mass and LAA-stroke risk differed by race-ethnicity (p = 0.01); LpPLA2-mass was associated with increased risk of LAA among non-Hispanic Whites (adjusted HR per SD 1.44, 95% CI 0.98–2.11), but not other race-ethnic groups.
LpPLA2-mass levels were associated with risk of atherosclerotic stroke among non-Hispanic White participants, but not in other race-ethnic groups in the cohort. Further study is needed to confirm these race-ethnic differences and the reasons for them.
Elevated lipoprotein(a) [Lp(a)] is associated with ischemic stroke (IS) among Whites, but data is sparse for non-White populations.
Using a population-based case-control study design with subjects from the Northern Manhattan Stroke Study, we assessed whether Lp(a) levels were independently associated with IS risk among Whites, Blacks and Hispanics.
Design and Setting
Lp(a) levels were measured in 317 IS cases (mean age 69 ± 13 years; 56% women; 16% Whites, 31% Blacks and 52% Hispanics) and 413 community-based controls, matched by age, race/ethnicity and gender. In-person assessments included demographics, socioeconomic status, presence of vascular risk factors and fasting lipid levels. Logistic regression was used to determine the independent association of Lp(a) and IS. Stratified analyses investigated gender and race/ethnic differences.
Mean Lp(a) levels were greater among cases than controls (46.3 ± 41.0 vs. 38.9 ± 38.2 mg/dl; p < 0.01). After adjusting for stroke risk factors (hypertension, diabetes mellitus, coronary artery disease, cigarette smoking), lipid levels, and socioeconomic status, Lp(a) levels ≥30 mg/dl were independently associated with an increased stroke risk in the overall cohort (adjusted odds ratio, OR, 1.8, 95% confidence interval, CI, 1.20–2.6; p = 0.004). There was a significant linear dose-response relationship between Lp(a) levels and IS risk. The association between IS risk and Lp(a) ≥30 mg/dl was more pronounced among men (adjusted OR 2.0, 95% CI 1.1–3.5; p = 0.02) and among Blacks (adjusted OR 2.7, 95% CI 1.2–6.2; p = 0.02).
Elevated Lp(a) levels were significantly and independently associated with increased stroke risk, suggesting that Lp(a) is a risk factor for IS across White, Black and Hispanic race/ethnic groups.
Lipoprotein(a); Northern Manhattan Stroke Study; Ischemic stroke
Background and Purpose
Cardiac mortality after stroke is common, and small studies have suggested an association of short-term cardiac mortality with insular location of cerebral infarction. Few population-based studies with long-term follow-up have evaluated the effect of stroke location on the long-term risk of cardiac death or myocardial infarction (MI) after first ischemic stroke. We sought to determine the association between stroke location and cardiac death or MI in a multiethnic community-based cohort.
The Northern Manhattan Study is a population-based study designed to determine stroke incidence, risk factors, and prognosis in a multiethnic urban population. First ischemic stroke patients age 40 or older were prospectively followed up for cardiac death defined as fatal MI, fatal congestive heart failure, or sudden death/arrhythmia and for nonfatal MI. Primary brain anatomic site was determined by consensus of research neurologists. Hazard ratios (HRs) and 95% CIs were calculated by Cox proportional-hazards models and adjusted for vascular risk factors (age, sex, history of coronary disease, hypertension, diabetes, cholesterol, and smoking), stroke severity, infarct size, and stroke etiology.
The study population consisted of 655 patients whose mean age was 69.7 ± 12.7 years; 44.6% were men and 51.3% were Hispanic. During a median follow-up of 4.0 years, 44 patients (6.7%) had fatal cardiac events. Of these, fatal MI occurred in 38.6%, fatal congestive heart failure in 18.2%, and sudden death in 43.2%. In multivariate models, clinical diagnosis of left parietal lobe infarction was associated with cardiac death (adjusted HR = 4.45; 95% CI, 1.83 to 10.83) and cardiac death or MI (adjusted HR = 3.30; 95% CI, 1.45 to 7.51). When analysis of anatomic location was restricted to neuroimaging (computed tomography, magnetic resonance imaging, or both [n = 447]), left parietal lobe infarction was associated with cardiac death (adjusted HR = 3.37; 95% CI, 1.26 to 8.97), and both left (adjusted HR = 3.49; 95% CI, 1.38 to 8.80) and right (adjusted HR = 3.13; 95% CI, 1.04 to 9.45) parietal lobe infarctions were associated with cardiac death or MI. We did not find an association between frontal, temporal, or insular stroke and fatal cardiac events, although the number of purely insular strokes was small.
Parietal lobe infarction is an independent predictor of long-term cardiac death or MI in this population. Further studies are needed to confirm whether parietal lobe infarction is an independent predictor of cardiac events and death. Surveillance for cardiac disease and implementation of cardioprotective therapies may reduce cardiac mortality in patients with parietal stroke.
acute stroke; cardiac arrhythmia; epidemiology; sudden death
Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic white and black people who often have a greater prevalence of vascular risk factors and are at elevated risk of dementia. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free race/ethnically diverse community-based sample from Northern Manhattan.
We used mixed effects models to measure the effect of IL-6 on change in performance on the Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors.
There were 1224 participants with IL-6 levels (median 1.5 pg/mL, interquartile range (IQR) 0.83 – 2.57 pg/mL) and TICS-m data available (mean=31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person- and a median 3.0 years of follow-up (IQR 1.1 – 4.0). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (β= −0.17 points per year, p=0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (P for interaction <0.001). There was no interaction by race-ethnicity, vascular risk factors, C-reactive protein (CRP), APOE4 allele status, or the metabolic syndrome among non-diabetics.
Interleukin 6 associated with cognitive decline among older participants in this race/ethnically diverse sample independent of other vascular risk factors and CRP.
cognitive decline; cohort studies; Interleukin-6; inflammation
Previous research in our cohort showed a delayed decline in functional status after first ischemic stroke. We compared the long-term trajectory of functional status before and after ischemic stroke.
The Northern Manhattan Study contains a prospective, population-based study of stroke-free individuals >40 years of age, followed for a median 11 years. The Barthel index (BI), a commonly used measure of activities of daily living, was assessed annually. Generalized estimating equations were used to assess functional decline over time before and beginning 6 months after stroke. Follow-up was censored at the time of recurrent stroke.
Among 3298 participants, 210 had an ischemic stroke during follow-up and had post-stroke BI assessed. Mean age (+standard deviation) was 77+9 years, 38% were male, 52% were Hispanic, 37% had diabetes, and 31% had coronary artery disease. There was no difference in rate of functional decline over time before and after stroke (p=0.51), with a decline of 0.96 BI points per year before stroke (p<.0001) and 1.24 after stroke (p=0.001). However, when stratified by insurance status, among those with Medicaid or no insurance, in a fully adjusted model, there was a difference in slope before and after stroke (p=0.04), with a decline of 0.58 BI points per year before stroke (p=0.02) and 1.94 after stroke (p=0.001).
In this large, prospective, population-based study with long-term follow-up, there was a significantly steeper decline in functional status after ischemic stroke compared to before stroke among those with Medicaid or no insurance, after adjusting for confounders.
Epidemiology; Disability; Rehabilitation
Recent studies have suggested poor quality and diminished quantity of sleep may be independently linked to vascular events, though prospective and multiethnic studies are limited. This study aimed to explore the relationship between daytime sleepiness and the risk of ischemic stroke and vascular events in an elderly, multi-ethnic prospective cohort.
Methods and Results
As part of the Northern Manhattan Study, the Epworth Sleepiness Scale (ESS) was collected during the 2004 annual follow-up. Daytime sleepiness was trichotomized using previously reported cut points of “no dozing,” “some dozing,” and “significant dozing”. Subjects were followed annually for a mean of 5.1 years. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for stroke, MI and death outcomes. We obtained the ESS on 2088 community residents. The mean age was 73.5 ± 9.3 yrs; 64% were women; 17% white, 20% black, 60% Hispanic, and 3% other. Over 44% of the cohort reported no daytime dozing, 47% reported “some dozing” and 9% “significant daytime dozing.” Compared to those reporting no daytime dozing, individuals reporting significant dozing had an increased risk of ischemic stroke [HR=2.74 (95% CI 1.38-5.43)], all 6 stroke [3.00 (1.57-5.73)], the combination of ischemic stroke, MI and vascular death [2.38 (1.50-3.78)], and all vascular events [2.48 (1.57-3.91)], after adjusting for medical comorbidities.
Daytime sleepiness is an independent risk factor for stroke and other vascular events. These findings suggest the importance of screening for sleep problems at the primary care level.
Ischemic Stroke; Sleep; Epidemiology; Vascular Disease; race/ethnicity
Prior studies have reported that Hispanics have lower cardiovascular disease (CVD) mortality despite a higher burden of risk factors. We examined whether Hispanic ethnicity was associated with a lower risk of nonfatal myocardial infarction (MI) coronary death (CD) and vascular death.
A total of 2671 participants in the Northern Manhattan Study without clinical CVD were prospectively evaluated. Cox models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association of race–ethnicity with nonfatal MI, CD, and vascular death after adjusting for demographic and CVD risk factors.
Mean age was 68.8 (10.4) years; 52.8% were Hispanic (88% Caribbean-Hispanic). Hispanics were more likely to have hypertension (73.1% vs. 62.2%, p < .001) and diabetes (22.0% vs. 13.3%, p < .001), and less likely to perform any physical activity (50.1% vs. 69.2%, p < .001) compared to non-Hispanic whites (NHW). During a mean 10 years of follow-up there were 154 nonfatal MIs, 186 CD, and 386 vascular deaths. In fully adjusted models, Hispanics had a lower risk of CD (adjusted HR = 0.36, 95% CI: 0.21–0.60), and vascular death (adjusted HR = 0.62, 95% CI: 0.43–0.89), but not nonfatal MI (adjusted HR = 0.95, 95% CI: 0.56–1.60) when compared to NHW.
We found a “Hispanic paradox” for coronary and vascular deaths, but not nonfatal MI.
Hispanic; Paradox; Mortality; Cardiovascular Disease
Background and Purpose
Diabetes increases stroke risk, but whether diabetes status immediately prior to stroke improves prediction, and whether duration is important, are less clear. We hypothesized that diabetes duration independently predicts ischemic stroke.
Among 3,298 stroke-free participants in the Northern Manhattan Study (NOMAS), baseline diabetes and age at diagnosis were determined. Incident diabetes was assessed annually (median=9 years). Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals (HR, 95% CI) for incident ischemic stroke using baseline diabetes, diabetes as a time-dependent covariate, and duration of diabetes as a time-varying covariate; models were adjusted for demographic and cardiovascular risk factors.
Mean age was 69±10 years (52% Hispanic, 21% white, and 24% black); 22% were diabetic at baseline and 10% developed diabetes. There were 244 ischemic strokes, and both baseline diabetes (HR 2.5, 95% CI 1.9-3.3) and diabetes considered as a time-dependent covariate (HR 2.4, 95% CI 1.8-3.2) were similarly associated with stroke risk. Duration of diabetes was associated with ischemic stroke (adjusted HR=1.03 per year with diabetes, 95% CI=1.02-1.04). Compared to non-diabetic participants, those with diabetes for 0-5 years (adjusted HR=1.7, 95% CI=1.1-2.7), 5-10 years (adjusted HR=1.8, 95% CI=1.1-3.0), and ≥10 years (adjusted HR=3.2, 95% CI=2.4-4.5) were at increased risk.
Duration of diabetes is independently associated with ischemic stroke risk adjusting for risk factors. The risk increases 3% each year, and triples with diabetes ≥10 years.
Diabetes mellitus; ischemic stroke; epidemiology; risk factors
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
Risk modification through behavior change is critical for primary and secondary stroke prevention. Theories of health behavior identify perceived risk as an important component to facilitate behavior change; however, little is known about perceived risk of vascular events among stroke survivors.
The SWIFT (Stroke Warning Information and Faster Treatment) study includes a prospective population-based ethnically diverse cohort of ischemic stroke and transient ischemic attack survivors. We investigate the baseline relationship between demographics, health beliefs, and knowledge on risk perception. Regression models examined predictors of inaccurate perception.
Only 20% accurately estimated risk, 10% of the participants underestimated risk, and 70% of the 817 study participants significantly overestimated their risk for a recurrent stroke. The mean perceived likelihood of recurrent ischemic stroke in the next 10 years was 51 ± 7%. We found no significant differences by race-ethnicity with regard to accurate estimation of risk. Inaccurate estimation of risk was associated with attitudes and beliefs [worry (p < 0.04), fatalism (p < 0.07)] and memory problems (p < 0.01), but not history or knowledge of vascular risk factors.
This paper provides a unique perspective on how factors such as belief systems influence risk perception in a diverse population at high stroke risk. There is a need for future research on how risk perception can inform primary and secondary stroke prevention.
Copyright © 2011 S. Karger AG, Basel
Risk perception; Stroke knowledge; Health beliefs
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
Serum levels of the soluble Receptor for Advanced Glycation End-products (sRAGE) have been associated with risk of cardiovascular disease. We hypothesized that sRAGE levels are associated with subclinical cerebrovascular disease in an ethnically diverse population.
Clinically stroke-free participants in the multi-ethnic Northern Manhattan Study (NOMAS) underwent brain MRI to quantify subclinical brain infarcts (SBI) and white matter hyperintensity volume (WMHV) (n=1102). Serum levels of sRAGE were measured by ELISA. Logistic and multiple linear regression were employed to estimate associations of sRAGE with SBI and WMHV, after adjusting for demographics and vascular risk factors.
Median sRAGE levels were significantly lower in Hispanics (891.9 pg/ml; n=708) and non-Hispanic blacks (757.4 pg/ml; n=197) than in non-Hispanic whites (1120.5 pg/ml; n=170), and these differences remained after adjusting for other risk factors. Interactions were observed by race-ethnicity between sRAGE levels and MRI measurements, including for SBI in Hispanics (p=0.04) and WMHV among blacks (p=0.03). In Hispanics, increasing sRAGE levels were associated with a lower odds of SBI, with those in the upper sRAGE quartile displaying a 50% lower odds of SBI after adjusting for sociodemographic and vascular risk factors (p=0.05). Among blacks, those in the upper quartile of sRAGE had a similarly reduced increased risk of SBI (p=0.06) and greater WMHV (p=0.04).
Compared to whites, Hispanics and blacks have significantly lower sRAGE levels, and these levels were associated with more subclinical brain disease. Taken together, these findings suggest sRAGE levels may be significantly influence by ethnicity. Further studies of sRAGE and stroke risk, particularly in minorities, are warranted.
RAGE (receptor for advanced glycation end products); biological marker; Hispanics; white matter hyperintensities; subclinical infarct; MRI
To explore race-ethnic differences in the relationship between plasma lipid components and risk of incident myocardial infarction (MI).
As part of the Northern Manhattan Study, 2738 community residents without cardiovascular disease were prospectively evaluated. Baseline fasting blood samples were collected and lipid panel components were analyzed as continuous and categorical variables. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for incident MI after adjusting for demographic and cardiovascular risk factors.
The mean age was 68.8±10.4 years; 36.7% men, 19.9% non-Hispanic white, 24.9% non-Hispanic black, and 52.8% Hispanic (over 80% from the Caribbean). Hispanics had lower mean HDL-C, and higher TG/HDL-C. During a mean 8.9 years of follow-up there were 163 incident MIs. In the whole cohort all lipid profile components were associated with risk of MI in the expected directions. However, HDL-C (adjusted HR per 10 mg/dl increase 0.93, 95%CI 0.76–1.12) and TG/HDL-C>2 (adjusted HR 0.89, 95%CI 0.51–1.55) were not predictive of MI among Hispanics, but were predictive among non-Hispanic blacks and whites. TG/HDL-C per unit increase was associated with an 8% higher risk of MI among Hispanics (adjusted HR 1.08, 95%CI 1.04–1.12).
In Hispanics, low HDL-C and TG/HDL-C>2 were not associated with MI risk. Our data suggests that a different TG/HDL ratio cutoff may be needed among Hispanics to predict MI risk.
Physical inactivity is an important and modifiable cardiovascular disease risk factor. Little is known about the social determinants of physical inactivity in older, urban-dwelling populations.
We collected socio-demographic and medical risk factor information and physical activity questionnaires in the Northern Manhattan Study. Logistic regression models were constructed to examine whether measures of social isolation, race-ethnicity, and sex were associated with physical inactivity.
Physical inactivity was present in 40.5% of the cohort. In multivariable models adjusted for medical comorbidities, Hispanic race-ethnicity (compared to non-Hispanic white) was associated with higher odds of physical inactivity (OR 2.18, 95% CI 1.78, 2.67), while women were more likely to be inactive than men (OR 1.33, 95% CI 1.15, 1.54). Having Medicaid/being uninsured (OR 1.20, 95% CI 1.02, 1.42), and having fewer than 3 friends (1.41, 95% CI 1.15, 1.72) were also associated with physical inactivity.
Physical inactivity is common, particularly in Hispanics, women, and those who are socially isolated. Public health interventions aimed at increasing physical activity in these more sedentary groups are required.
Depression is highly prevalent after stroke, and may influence recovery. We aimed to determine whether depressed mood acutely after stroke predicts subsequent disability and mortality.
As part of the Northern Manhattan Stroke Study, a population-based incident stroke case follow-up study performed in a multiethnic urban population, participants were asked about depressed mood within 7–10 days after stroke. Participants were followed every 6 months the first 2 years, and yearly thereafter for 5 years, for death and disability measured by the Barthel Index (BI). We fitted polytomous logistic regression models using canonical link to examine the association between depressed mood after stroke and disability, comparing moderate (BI 60–95) and severe (BI < 60) disability to no disability (BI ≥ 95). Cox-proportional hazards models were created to examine the association between depressed mood and mortality.
A question about depressed mood within 7–10 days after stroke was asked in 340 of 655 ischemic stroke patients enrolled, and 139 reported that they felt depressed. In multivariate analyses controlling for socio-demographic factors, stroke severity, and medical conditions, depressed mood was associated with a greater odds of severe disability compared to no disability at one (OR 2.91, 95% CI 1.07–7.91) and two years (OR 3.72, 95% CI 1.29–10.71) after stroke. Depressed mood was not associated with all cause mortality or vascular death.
Depressed mood after stroke is associated with disability but not mortality after stroke. Early screening and intervention for mood disorders after stroke may improve outcomes and requires further research.
Presence of informal social networks has been associated with favorable health and behaviors, but whether different types of social networks impact on different health outcomes remains largely unknown. We examined the associations of different social network types (marital dyad, household, friendship, and informal community networks) with acute stroke preparedness behavior. We hypothesized that marital dyad best matched the required tasks and is the most effective network type for this behavior.
We collected in-person interview and medical record data for 1,077 adults diagnosed with stroke and transient ischemic attack. We used logistic regression analyses to examine the association of each social network with arrival at the emergency department (ED) within 3 h of stroke symptoms.
Adjusting for age, race-ethnicity, education, gender, transportation type to ED and vascular diagnosis, being married or living with a partner was significantly associated with early arrival at the ED (odds ratio = 2.0, 95% confidence interval: 1.2–3.1), but no significant univariate or multivariate associations were observed for household, friendship, and community networks.
The marital/partnership dyad is the most influential type of social network for stroke preparedness behavior.
Acute stroke; Emergency department admission; Ischemic attack; Social networks; Stroke symptoms
Background and Purpose
Inflammatory biomarkers, including lipoprotein-associated phospholipase A2 (Lp-PLA2), myeloperoxidase (MPO), and high-sensitivity C-reactive protein (hsCRP) are associated with ischemic stroke risk. White matter hyperintensities (WMH) seen on brain MRI scans are associated with vascular risk factors and an increased risk of incident stroke, but their relation to inflammatory biomarkers is unclear.
The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, black, and white participants with quantitative measurement of WMH volume (WMHV) and inflammatory biomarkers. We measured the association between Lp-PLA2, MPO, and hsCRP levels and log-transformed WMHV after adjusting for sociodemographic and vascular risk factors.
HsCRP (median 2.42 mg/L; IQR 1.04,5.19), Lp-PLA2 (median 220.97 ng/mL; IQR 185.77,268.05), and MPO (median 15.14 ng/mL; IQR12.32,19.69) levels were available in 527 NOMAS participants with WMHV data but no subclinical infarcts. Those with hsCRP in the upper quartile (Q4>4.92 mg/L) or >3 mg/L, Lp-PLA2 in Q4 (≥264.9 ng/mL), or MPO levels in Q3 (15.04-19.39 ng/mL) or Q4 (>19.39 ng/mL) each had greater WMHV adjusting for sociodemographic and vascular risk factors. Adjusting for all biomarkers simultaneously, WMHV was 1.3 fold greater for Lp-PLA2 levels in Q4 compared to Q1 (β=0.28, P=0.008) and 1.25 fold greater for MPO levels above the median compared to below (β=0.22, P=0.02), but hsCRP was not associated with WMHV.
Relative elevations of the inflammatory markers Lp-PLA2 and MPO were associated with a greater burden of WMH independent of hsCRP.
Lipoprotein-associated phospholipase A2; Myeloperoxidase; C-reactive protein; leukoaraiosis; white matter disease
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 improve global vascular risk prediction with behavioral and anthropometric factors.
Few cardiovascular risk models are designed to predict the global vascular risk of MI, stroke, or vascular death in multi-ethnic individuals, and existing schemes do not fully include behavioral risk factors.
A randomly-derived, population-based, prospective cohort of 2737 community participants free of stroke and coronary artery disease were followed annually for a median of 9.0 years in the Northern Manhattan Study (mean age 69 years; 63.2% women; 52.7% Hispanic, 24.9% African-American, 19.9% white). A global vascular risk score (GVRS) predictive of stroke, myocardial infarction, or vascular death was developed by adding variables to the traditional Framingham cardiovascular variables based on the likelihood ratio criterion. Model utility was assessed through receiver operating characteristics, calibration, and effect on reclassification of subjects.
Variables which significantly added to the traditional Framingham profile included waist circumference, alcohol consumption, and physical activity. Continuous measures for blood pressure and fasting blood sugar were used instead of hypertension and diabetes. Ten -year event-free probabilities were 0.95 for the first quartile of GVRS, 0.89 for the second quartile, 0.79 for the third quartile, and 0.56 for the fourth quartile. The addition of behavioral factors in our model improved prediction of 10 -year event rates compared to a model restricted to the traditional variables.
A global vascular risk score that combines both traditional, behavioral, and anthropometric risk factors, uses continuous variables for physiological parameters, and is applicable to non-white subjects could improve primary prevention strategies.
Cardiovascular Disease; Cerebrovascular Disease; Prevention; Risk Factors; Epidemiology
Arterial Stiffness, an intermediate pre-clinical marker of atherosclerosis, has been associated with an increased risk of stroke and cardiovascular disease (CVD). The metabolic syndrome and its components are established CVD risk factors and may also increase arterial stiffness, but data on this potential relationship is limited. The goal of this study was to determine the association between the metabolic syndrome (MetSyn) and carotid artery stiffness (STIFF) in an elderly multi-ethnic cohort.
STIFF was assessed by carotid ultrasound as part of the Northern Manhattan Study (NOMAS), a prospective population-based cohort of stroke-free individuals. STIFF was calculated as [ln(systolicBP/diastolicBP)/Strain], where Strain was [(Systolic Diameter Diastolic Diameter)/Diastolic Diameter]. MetSyn was defined by the National Cholesterol Education Program: Adult Treatment Panel III (NCEP ATP III) criteria. LogSTIFF was analyzed as the dependent variable in linear regression models, adjusting for demographics, education, current smoking, presence of carotid plaque and intima-media thickness.
STIFF was analyzed in 1133 NOMAS subjects (mean age 65±9 years; 61% women; 58% Hispanic, 22% Black, 20% White). The prevalence of MetSyn was 49%. The mean LogSTIFF was 2.01±0.61 among those with and 1.90±0.59 among those without MetSyn (p=0.003). MetSyn was significantly associated with increased logSTIFF in the final adjusted model (parameter estimate β=0.100, p=0.01). Among individual MetSyn components, waist circumference and elevated blood pressure were most significantly associated with a mean increase in logSTIFF (p<0.01).
MetSyn is significantly associated with increased carotid artery stiffness in a multiethnic population. Increased carotid artery stiffness may, in part, explain a high risk of stroke among individuals with the metabolic syndrome.
metabolic syndrome; arterial stiffness; atherosclerosis; elderly; race-ethnicity
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.
To determine the association between insulin resistance and risk of first ischemic stroke in a large multiethnic, stroke-free cohort without diagnosis of diabetes.
Research Design and Methods
A cohort of 1,509 non-diabetic participants from the Northern Manhattan Study (mean age 68±10 years; 64% women; 59% Hispanics) was analyzed for insulin sensitivity, expressed by the Homeostatic Model Assessment of Insulin Sensitivity (HOMA index = [fasting insulin (µU/ml]×[fasting glucose (mmol/L)] ÷ 22.5). Insulin resistance (IR) was defined by a HOMA-IR index in the top quartile (Q4). Cox proportional hazard models were used to determine the effect of HOMA-IR on the risk of incident ischemic stroke (IS), myocardial infarction (MI), vascular death, and combined outcomes (IS, MI, or vascular death).
The mean HOMA-IR was 2.3 ± 2.1, and Q4 was ≥2.8. During a mean follow-up of 8.5 years, vascular events occurred among 180 subjects; 46 had fatal or non-fatal ischemic stroke, 45 had fatal or non-fatal MI, and 121 died of vascular causes. The top quartile of the HOMA-IR vs.
Insulin resistance estimated by the homeostatic model assessment is a marker of increased risk of incident stroke among non-diabetic individuals. Our findings emphasize the need to better characterize individuals at increased risk of stroke, and the potential role for primary preventive therapies targeted at insulin resistance.
insulin resistance; incident ischemic stroke; vascular disease; cohort; prospective; population-based
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
Background and Purpose
White matter hyperintensities have been associated with increased risk of stroke, cognitive decline, and dementia. Chronic kidney disease is a risk factor for vascular disease and has been associated with inflammation and endothelial dysfunction, which have been implicated in the pathogenesis of white matter hyperintensities. Few studies have explored the relationship between chronic kidney disease and white matter hyperintensities.
The Northern Manhattan Study is a prospective, community-based cohort of which a subset of stroke-free participants underwent MRIs. MRIs were analyzed quantitatively for white matter hyperintensities volume, which was log-transformed to yield a normal distribution (log-white matter hyperintensity volume). Kidney function was modeled using serum creatinine, the Cockcroft-Gault formula for creatinine clearance, and the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate. Creatinine clearance and estimated glomerular filtration rate were trichotomized to 15 to 60 mL/min, 60 to 90 mL/min, and >90 mL/min (reference). Linear regression was used to measure the association between kidney function and log-white matter hyperintensity volume adjusting for age, gender, race–ethnicity, education, cardiac disease, diabetes, homocysteine, and hypertension.
Baseline data were available on 615 subjects (mean age 70 years, 60% women, 18% whites, 21% blacks, 62% Hispanics). In multivariate analysis, creatinine clearance 15 to 60 mL/min was associated with increased log-white matter hyperintensity volume (β 0.322; 95% CI, 0.095 to 0.550) as was estimated glomerular filtration rate 15 to 60 mL/min (β 0.322; 95% CI, 0.080 to 0.564). Serum creatinine, per 1-mg/dL increase, was also positively associated with log-white matter hyperintensity volume (β 1.479; 95% CI, 1.067 to 2.050).
The association between moderate–severe chronic kidney disease and white matter hyperintensity volume highlights the growing importance of kidney disease as a possible determinant of cerebrovascular disease and/or as a marker of microangiopathy.
chronic; kidney failure; leukoaraiosis; magnetic resonance imaging
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.
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