Association of stroke risk biomarkers with stroke symptoms: the Reasons for Geographic and Racial Differences in Stroke cohort.

Essentials Stroke symptom history predicts future stroke and may indicate prior unrecognized stroke. We studied associations of stroke symptoms with stroke risk biomarkers. Several stroke risk biomarkers were independently associated with stroke symptom history. Findings support a hypothesis that stroke symptoms may represent unrecognized stroke. SUMMARY: Background History of stroke symptoms in the absence of prior diagnosed stroke or transient ischemic attack (TIA) is associated with future stroke risk, as are biomarkers of inflammation, cardiac function and hemostasis. Objective To better elucidate the pathobiology of stroke symptoms, we studied associations of these biomarkers with history of stroke symptoms. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30 239 black and white Americans age 45 years and older in 2003-7. In cross-sectional analyses in a random sample of 960 participants without prior stroke or TIA, levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), fibrinogen, factor VIII (FVIII), factor XI (FXI), C-reactive protein (CRP) and D-dimer were studied in relation to self-reported history of six sudden onset stroke symptoms. Results There were 190 participants with at least one stroke symptom and 770 without. Adjusting for age, race, sex and stroke risk factors, NT-proBNP, FXI, CRP and D-dimer in the top vs. bottom quartile were associated with prevalent stroke symptoms with odds ratios 2.69 (95% confidence interval [CI], 1.45-4.98), 1.65 (95% CI, 1.00-2.73), 2.21 (95% CI, 1.32-3.71) and 2.14 (95% CI, 1.22-3.75), respectively. Conclusions Strong associations of stroke risk biomarkers with stroke symptoms in persons without a clinical history of cerebrovascular disease support a hypothesis that some of these stroke symptoms represent unrecognized cerebrovascular disease. Future work is needed to determine whether these biomarkers identify persons with stroke symptoms who have a particularly high stroke risk.

Racial and geographic differences in fish consumption: the REGARDS study.

BACKGROUND: Omega-3 fatty acids from fish have been shown to have favorable effects on platelet aggregation, blood pressure, lipid profile, endothelial function, and ischemic stroke risk, but there are limited data on racial and geographic differences in fish consumption. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) is a national cohort study that recruited 30,239 participants age ≥45 years with oversampling from the southeastern Stroke Belt and Buckle and African Americans (AAs). Centralized phone interviewers obtained medical histories and in-home examiners measured weight and height. Dietary data for this cross-sectional analysis were collected using the self-administered Block98 Food Frequency Questionnaire (FFQ). Adequate intake of nonfried fish was defined as consumption of ≥2 servings per week based on American Heart Association guidelines. After excluding the top and bottom 1% of total energy intake and individuals who did not answer 85% or more of questions on the FFQ, the analysis included 21,675 participants. RESULTS: Only 5,022 (23%) participants consumed ≥2 servings per week of nonfried fish. In multivariable analysis, factors associated with inadequate intake of nonfried fish included living in the Stroke Belt (vs non-Belt) (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.77-0.90) and living in the Stroke Buckle (vs non-Belt) (OR 0.89, 95% CI 0.81-0.98); factors associated with ≥2 servings per week of fried fish included being AA (vs white) (OR 3.59, 95% CI 3.19-4.04), living in the Stroke Belt (vs non-Belt) (OR 1.32, 95% CI 1.17-1.50), and living in the Stroke Buckle (vs non-Belt) (OR 1.17, 95% CI 1.00-1.36). CONCLUSIONS: Differential consumption of fish may contribute to the racial and geographic disparities in stroke.

Decline in US stroke mortality: an analysis of temporal patterns by sex, race, and geographic region.

BACKGROUND AND PURPOSE: Although stroke mortality rates have declined rapidly over the past 30 years, the decline has slowed to a plateau. Here, we assess whether the race-sex-region groups have participated equally in this decline and whether there are groups in which stroke mortality rates are still declining, and we predict how these rates will eventually differ. METHODS: Data on stroke mortality in the United States between 1968 and 1996 were analyzed in a 3-step procedure: (1) we calculated "crude" age-adjusted stroke mortality rates by race, sex, and county; (2) we "smoothed" the rates across counties and years; and (3) we fit a model to describe the temporal pattern. From this model we calculated the percent decline in stroke mortality, the anticipated additional decline (thereby identifying regions that will continue to decline), and the anticipated eventual stroke mortality rates. RESULTS: Maps by race-sex-region group describe the above parameters. White men have experienced the largest decline in stroke mortality, and black men have seen the smallest. Generally, stroke mortality appears to still be slowly declining for blacks but not for whites. Geographic differences in stroke mortality are predicted to persist. CONCLUSIONS: The analysis suggests that the Deep South (Alabama and Mississippi) will fall from the stroke belt and be replaced by other regions (notably Oregon, Washington, and Arkansas). New York City and southern Florida had low stroke mortality rates in 1968, have experienced large declines, and continue to experience declines, resulting in even larger relative heterogeneity of stroke mortality rates. The reasons for these differences in the pattern of the decline in stroke mortality are not understood.

Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design.

Elevated plasma levels of homocyst(e)ine [H(e)] are surprisingly common and strongly associated with endothelial dysfunction and a marked increase in vascular risk. Treatment with a combination of folic acid, pyridoxine (vitamin B6) and cobalamin (vitamin B12) reduces plasma H(e) levels in most cases, restores endothelial function, and regresses carotid plaque, but there is no evidence that such treatment will reduce clinical events. The Vitamin Intervention for Stroke Prevention (VISP) study is a double-masked, randomized, multicenter clinical trial designed to determine if, in addition to best medical/surgical management, high-dose folic acid, vitamin B6, and vitamin B12 supplements will reduce recurrent stroke compared to lower doses of these vitamins. Patients at least 35 years old with a nondisabling ischemic stroke within 120 days, and screening plasma H(e) > the 25th percentile of benchmark population data are eligible. Secondary endpoints are myocardial infarction or fatal coronary heart disease. This paper describes the design and rationale of the study.

Ethnic disparities in stroke: the scope of the problem.

An excess stroke mortality rate among African Americans is well known and should be considered a national crisis. This excess persists today despite dramatic declines in stroke mortality between 1970 and 1990 for both White and African-American men and women. Only a portion of this excess stroke mortality among African Americans can be explained by the higher prevalence of hypertension and diabetes in African Americans, and by the lower average socioeconomic status (SES) among African Americans. The majority of the excess burden of stroke mortality is borne by relatively young (ages 35-64) African Americans and by African Americans living in the Southeastern United States. While overall stroke mortality rates have been rapidly declining for both African Americans and Whites, the magnitude of the relative increased risk of dying from a stroke among African Americans, as compared to Whites, has remained largely unchanged. As such, efforts to reduce ethnic disparities in stroke mortality have been unsuccessful.

Effect of contralateral occlusion on long-term efficacy of endarterectomy in the asymptomatic carotid atherosclerosis study (ACAS). ACAS Investigators.

BACKGROUND AND PURPOSE: The Asymptomatic Carotid Atherosclerosis Study (ACAS) established the effectiveness of prophylactic carotid endarterectomy, for patients in good health who had stenosis >/=60%, if conducted by surgeons with a surgical morbidity and mortality of <3%. This secondary analysis was performed to determine whether the presence of contralateral cervical carotid occlusion alters the efficacy of asymptomatic ipsilateral carotid endarterectomy. METHODS: One hundred sixty-three participants who had a baseline contralateral occlusion documented by Doppler ultrasound (77 medical, 86 surgical) were compared with 1485 participants with a patent contralateral carotid artery (748 medical, 737 surgical) for the risk of a combined end point of perioperative (30-day) death or stroke or long-term (5-year) ipsilateral stroke. RESULTS: For those without contralateral occlusion, surgery was associated with a 6.7% absolute reduction in the 5-year risk (95% CI, 2.1% to 11.4%), while for those with a contralateral occlusion, surgery was associated with a 2.0% absolute increase in risk (95% CI, -9.3% to 5.2%), which was a statistically significant difference in the effect of surgery (P:=0.047). This difference is primarily attributable to low long-term risk for medically managed patients with contralateral occlusion. CONCLUSIONS: While this post hoc analysis should be interpreted with caution, the findings suggest that endarterectomy in asymptomatic subjects with contralateral occlusion provides no long-term benefit (and may be harmful) in preventing stroke and death. These findings were a result of the benign course of medically treated subjects.

Low mini-mental status predicts mortality in asymptomatic carotid arterial stenosis. Asymptomatic Carotid Atherosclerosis Study investigators.

OBJECTIVE: To determine whether carotid endarterectomy is superior to best medical therapy in preserving cognition, and whether low Mini-Mental State Examination (MMSE) scores predict TIA, stroke, myocardial infarction, or death. METHODS: Subjects participating in the Asymptomatic Carotid Atherosclerosis Study were administered the MMSE at periodic intervals. Group means were calculated at randomization, 1 and 3 months later, and every 6 months thereafter. The group means were compared by treatment and over time. A proportional hazard regression model incorporating postrandomization MMSE score as a predictor variable was used to estimate risk of death, stroke, or other outcome events. RESULTS: There was no intergroup difference in mean MMSE score during 5 years of observation. For individual patients, the relationship between a low postrandomization score on the MMSE and increased risk of death was significant (p

Race, socioeconomic status, and cause-specific mortality.

PURPOSE: Life expectancy for black Americans is five to eight years less than for Whites. The socioeconomic status (SES) of Blacks is also less than for Whites, and SES is associated with early mortality. This paper estimates the proportion of the racial difference in mortality attributable to SES by specific causes of death. METHODS: Data on 453,384 individuals in the National Longitudinal Mortality Study were used to estimate the hazard ratio associated with black race, with and without adjustment for income and education (measures of SES), in 38 strata defined by cause of death and age. RESULTS: For women, SES accounted for much (37-67%) of the black excess mortality for accidents, ischemic heart disease (ages 35-54), diabetes, and homicide; but not for hypertension, infections, and stomach cancers (11-17%). For men, SES accounted for much of the excess risk (30-55%) for accidents, lung cancer, stomach cancer, stroke, and homicide; but not for prostate cancer, pulmonary diseases, hypertension, and cardiomyopathy (0-17%). CONCLUSIONS: These results confirm those specific causes of death likely to underlie the overall excess mortality of Blacks, and identify those causes where SES may play a large role.

Transcription activation at the Escherichia coli melAB promoter: the role of MelR and the cyclic AMP receptor protein.

MelR is a melibiose-triggered transcription activator that belongs to the AraC family of transcription factors. Using purified Escherichia coli RNA polymerase and a cloned DNA fragment carrying the entire melibiose operon intergenic region, we have demonstrated in vitro open complex formation and activation of transcription initiation at the melAB promoter. This activation is dependent on MelR and melibiose. These studies also show that the cyclic AMP receptor protein (CRP) interacts with the melAB promoter and increases MelR-dependent transcription activation. DNAase I footprinting has been exploited to investigate the location of MelR-and CRP-binding sites at the melAB promoter. We showed previously that MelR binds to two identical 18 bp target sequences centred at position -100.5 (Site 1) and position -62.5 (Site 2). In this work, we show that MelR additionally binds to two other related 18 bp sequences: Site 1', centred at position -120.5, located immediately upstream of Site 1, and Site R, at position -238.5, which overlaps the transcription start site of the divergent melR promoter. MelR can bind to Site 1', Site 1, Site 2 and Site R, in both the absence and the presence of melibiose. However, in the presence of melibiose, MelR also binds to a fifth site (Site 2', centred at position -42.5) located immediately downstream of Site 2, and overlapping the -35 region of the melAB promoter. Additionally, although CRP is unable to bind to the melAB promoter in the absence of MelR, in the presence of MelR, it binds to a site located between MelR binding Site 1 and Site 2. Thus, tandem-bound MelR recruits CRP to the MelR. We propose that expression from the melAB promoter has an absolute requirement for MelR binding to Site 2'. Optimal expression of the melAB promoter requires Sites 1', Site 1, Site 2 and Site 2'; CRP acts as a 'bridge' between MelR bound at Sites 1' and 1 and at Sites 2 and 2', increasing expression from the melAB promoter. In support of this model, we show that improvement of the base sequence of Site 2' removes the requirement for Site 1' and Site 1, and short circuits the effects of CRP.

Evaluation of social status as a contributing factor to the stroke belt region of the United States.

BACKGROUND AND PURPOSE: The southeastern United States has stroke mortality rates above the national average. The causes for this excess mortality are unknown; however, lower socioeconomic status (SES) is a risk factor for stroke, and the lower SES in the Southeast is a potential cause. In this report we assess the proportion of the excess stroke mortality attributable to SES. METHODS: The more than 400,000 participants in the National Longitudinal Mortality Study were categorized into three regions: the coastal plain region of North Carolina, South Carolina, and Georgia ("stroke buckle"); the remainder of these states plus five other southern states ("stroke belt"); and the remainder of the United States. The stroke mortality rates were calculated with and without adjustment for SES, and the proportion of the excess mortality attributable to SES was estimated. RESULTS: In persons between the ages of 35 and 54 years, stroke mortality in the stroke buckle is estimated to be more than twice that of the rest of the nation and 1.7 times greater for ages 55 to 74 years. For persons in the stroke belt, the stroke mortality was 1.3 times greater than that in the rest of the nation for the ages of 35 to 54 and 55 to 74 years. Less than 16% of this excess stroke morality was attributable to SES. CONCLUSIONS: SES does not appear to be a major contributor to the excess mortality in the southeastern United States. Of additional concern is the stroke buckle region, which was shown to have stroke mortality rates substantially greater than those in the traditionally recognized stroke belt.

Validation of the ACAS TIA/stroke algorithm.

BACKGROUND AND PURPOSE: An easily administered questionnaire and algorithm classifying transient ischemic attacks (TIAs) or strokes, and also their distribution, could be invaluable for identifying endpoints in epidemiologic studies or clinical trials of prevention and therapy of cerebral ischemia. The Asymptomatic Carotid Atherosclerosis Study (ACAS) devised a symptom-based questionnaire and algorithm for detecting events in the trial. The purpose of this study was to determine sensitivity, specificity, and agreement rates of the questionnaire and algorithm against diagnoses of a panel of cerebrovascular disease authorities. METHODS: Three hundred eighty-one men and women at eight medical centers reported symptoms of stroke, TIA, or other neurologic illness. The questionnaire was administered by trained interviewers and the responses were analyzed using the algorithm. A standardized neurologic examination was performed by a neurologist. Data were submitted to two or more external reviewers. Sensitivity, specificity, and the kappa statistic (kappa) were used to evaluate the relationship between the algorithm and the external reviewers' diagnosis. RESULTS: Of the 381 reviews, 196 were diagnosed as TIA or stroke by the external panel. The algorithm's agreement with the diagnosis of TIA or stroke was 80.1%, and kappa was 0.60. Sensitivity was 87.8%, and specificity was 71.9%. CONCLUSION: While statistical agreement rates depend on the method of sample selection, the algorithm has a high agreement with an external panel of experts and is a sensitive tool for event detection. The lower specificity indicates that careful neurologic evaluation may be required to confirm or refute events identified by the screening algorithm.

An approach for the use of Doppler ultrasound as a screening tool for hemodynamically significant stenosis (despite heterogeneity of Doppler performance). A multicenter experience. Asymptomatic Carotid Atherosclerosis Study Investigators.

BACKGROUND AND PURPOSE: The Asymptomatic Carotid Atherosclerosis Study (ACAS) Doppler validation study assessed the performance of individual Doppler machines across a spectrum of laboratories. We attempted to establish a threshold specific to individual machines to predict angiographically defined hemodynamic stenosis. The reliability of these Doppler ultrasound criteria was prospectively and independently evaluated among patients screened with ultrasound in the ACAS trial. METHODS: Regression techniques were used to establish the relationship between Doppler velocity and percent stenosis by angiography for 63 specific Doppler machines. This relationship was used to establish a Doppler threshold to provide a 90% positive predictive value (PPV) of a 60% stenosis by angiography. The sensitivity of each Doppler machine to detect a 60% stenosis (at the 90% PPV threshold) was estimated. The efficacy of these Doppler thresholds was then prospectively evaluated by calculating the PPV among ACAS participants eligible by ultrasound. RESULTS: Of the 63 machines, 13 (21%) had an excellent sensitivity (80%+) at 90% PPV. In 32 devices (51%) only a marginal sensitivity (50% to 80%) could be achieved. In 9 devices (14%) the sensitivity was poor (0% to 50%), and in 9 (14%) no threshold could be established. Despite the heterogeneity of Doppler performance, the standardization program worked as designed in the ACAS trial. Of 825 surgical patients, 399 were eligible by Doppler and 395 subsequently underwent angiography. Of these, 32 (8.1%; 95% confidence interval, 5.4% to 10.8%) did not have hemodynamically significant stenosis by arteriography, a proportion nonsignificantly lower than the planned 10% by the PPV. CONCLUSIONS: The performance of Doppler ultrasound was highly variable. This suggests that Doppler performance is likely overstated in the literature, but specific devices may perform satisfactorily to detect individuals with hemodynamically significant stenosis. Because performance differs substantially among devices, local investigators are strongly urged to maintain local standardization series. With such standardization, ultrasound performance is sufficient for admission to clinical trials and as the is sufficient for admission to clinical trials and as the basis for carotid surgery. However, without quality control many ultrasound machines are not adequate to accurately predict the degree of carotid stenosis and should not be the only test to decide whether surgery is warranted.

Comparison of centralized versus "site-based" measurement of angiographic stenosis for eligibility in the asymptomatic carotid atherosclerosis study.

RATIONALE AND OBJECTIVES: The authors determine the reliability of centralized versus noncentralized (site-based) measurement of angiographic stenosis of patients enrolled into the multicenter, prospective, Asymptomatic Carotid Atherosclerosis Study by angiographic studies. METHODS: Percent agreements and correlations of 244 masked and prospectively interpreted angiograms were calculated for comparison of centralized and noncentralized readers measuring the percent carotid stenosis from the same angiographic studies. Univariate summary statistics for differences in percent stenoses were calculated for these readings. RESULTS: Agreement between readings were 88.5% and 91.8% with kappa statistics of 0.77 and 0.73 for > or = 60% and > or = 80% stenosis, respectively, for comparison of 33 centers to the designated central reader. Comparison between the designated central reader and a second central reader derived percent agreements of 85.0% and 86.5% with kappa statistics of 0.69 and 0.41 for > or = 60% and > or = 80% stenoses, respectively, for arteries selected from the original group. Hence, agreement was slightly better between the enrolling centers and the designated central reader than between the two central readers. CONCLUSIONS: Both centralized and noncentralized (site-based) methods of angiographic measurement of stenosis are equally reliable for large, prospective, masked, multicenter trials when quality control measures are instituted to ensure uniform application of eligibility criteria.

Surgical results: a justification of the surgeon selection process for the ACAS trial. The ACAS Investigators.

PURPOSE: The selection of surgeons to participate in a prospective randomized trial comparing the efficacy of a surgical method with medical management is critically important because it will have a direct impact on the outcome of the study and the future use of the operation. We report the success of the method used for selecting surgeons who participated in the Asymptomatic Carotid Atherosclerosis Study (ACAS) by examining the surgical morbidity and mortality rates and the outcome of the study. METHODS: A Surgical Management Committee established criteria for auditing surgeons who wished to participate in the study. The parameters included a minimum performance of at least 12 carotid endarterectomies (CEA) per year and an audit of each surgeon's last 50 consecutive CEAs with required documentation of a combined neurologic morbidity and mortality rate of <3.0% for asymptomatic patients and <5.0% for all indications including symptomatic patients. RESULTS: As of February 1991, 164 surgeons from 48 medical centers applied for ACAS participation. One hundred seventeen were approved, and their aggregate experience of 5641 operations yielded a combined neurologic morbidity and mortality rate of 2.3% for asymptomatic and symptomatic patients combined. The morbidity and mortality rate for CEA on asymptomatic patients was 1.7%. These surgeons, plus those recruited after February 1991, became investigators in the ACAS trial and were responsible for the surgical care of 825 patients who were randomized to the surgical arm. Seven hundred twenty-four patients actually underwent CEA. One patient (0.14%) died and ten patients (1.38%) had strokes within the 30-day perioperative interval, for a combined stroke or death incidence of 1.52%. The 5-year stroke event rate in the surgical group (including perioperative morbidity and mortality rates) was 5.1%. compared with 11% of patients treated medically, yielding a relative risk reduction of 53% in favor of surgery (p=0.004). CONCLUSIONS: A method for selecting surgeons for participation in the ACAS trial was successful in providing low perioperative morbidity and mortality rates. This materially influenced the outcome of the study in favor of CEA.

Role of social class in excess black stroke mortality.

BACKGROUND AND PURPOSE: It has been suggested that a substantial proportion of the excess stroke mortality among black Americans may be attributable to relatively lower socioeconomic status (SES) in this group. In this report we provide the first quantitative estimates of the proportion of excess black stroke mortality attributable to SES for a large population-based cohort. METHODS: We used data from the National Longitudinal Mortality Study for persons 45 years and older (73,400 white men, 87,528 white women, 6522 black men, and 8816 black women). Sex-specific proportional hazards model were used to estimate excess black stroke mortality with and without adjustment for education and income (measures of SES). The contribution of SES to the excess black stroke risk was estimated from the difference in regression coefficients for race in these models. RESULTS: In men, low SES was associated with increased stroke mortality (P < or = .0001) and accounted for 14% to 46% of the excess black stroke risk (P < .05). However, we could find no association between SES and stroke mortality in women, and SES did not account for a significant proportion of the excess stroke mortality in black women. CONCLUSIONS: Although SES proved to account for a statistically significant proportion of excess male black stroke mortality, overall SES explained less than one quarter of the observed excess between ages 45 and 65. In women, SES did not significantly reduce the estimated excess black stroke mortality. Although SES may be playing a role in excess black stroke mortality, a substantial proportion of the excess appears attributable to other sources, including cerebrovascular risk factors that are unrelated to SES, unmeasured lifestyle influences, social resources, and genetic factors.