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 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 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 6 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% 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.
Keywords: Stroke, risk factors, biomarkers, epidemiology, cerebrovascular disease
Stroke symptom history can be ascertained using self-report questionnaires in persons without a history of cerebrovascular disease. Stroke symptoms, as defined by such questionnaires, are common among people without a clinical history of stroke or transient ischemic attack (TIA), present in 18% of adults ≥45 years of age in one study [1]. Moreover, presence of stroke symptoms, ascertained with these questionnaires, is associated with increased risk of future stroke and mortality [2-6]. These findings underscore the importance of evaluating reasons why stroke symptoms are associated with stroke risk. A prior study demonstrated that six individual stroke symptoms on such self-report tools are not uniformly associated with stroke risk factors, emphasizing the importance of further inquiry on the underlying causes of these symptoms [7].
In recent years several promising biomarkers have been reported in association with stroke risk and mortality. These include inflammation biomarkers such as C-reactive protein (CRP)[8, 9] and fibrinogen[10, 11], cardiac function biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) [12-15], and markers of hemostasis, such as the procoagulant factors[11, 16] and D-dimer [17]. Study of associations of these biomarkers with self-reported stroke symptoms could provide insight into whether stroke symptoms represent silent cerebrovascular disease.
We hypothesized that, among those without history of stroke or TIA, NT-proBNP and biomarkers of inflammation and hemostasis would be higher among individuals with a history of stroke symptoms compared to those without such history, and that observed associations would be independent of other stroke risk factors.
Methods
Subjects
Between 2003 and 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 adults ≥45 years old, 42% black and 58% white, 45% men and 55% women, from the contiguous United States to study reasons for geographic and black-white disparities in stroke mortality [18]. The study was approved by institutional review boards of participating centers, and detailed study methods have been published [1, 18]. Participants were recruited from commercially available lists (Genesys, Inc) by a mailing followed by a phone call. For verbally consenting participants, a telephone interview was conducted to collect demographics, risk factors, and medical history. Trained professionals then visited participants’ homes to collect written consent, fasting morning blood and urine samples, blood pressure and other physical measurements, medication inventory, and an electrocardiogram (ECG).
Blood was collected in standardized fashion with phlebotomy and sample processing methods previously described [19]. Blood was kept on ice and centrifuged, with serum or plasma separated within 120 minutes of phlebotomy. Samples were shipped overnight on gel ice packs to the University of Vermont Laboratory for Clinical Biochemistry Research. Samples were recentrifuged at 4°C for 30,000 g-minutes, and stored at −80°C.
For this study we used data from a cohort random sample of 1099 participants stratified for age, sex, and race who were selected for a prior case-cohort study [13]. Strata were used to ensure sufficient representation of high-risk groups to achieve 50% black, 50% white; 50% women, 50% men; and age groups 45-54 (20%), 55-64 (20%), 65-74 (25%), 75-84 (25%), and ≥85 (10%) years. Participants with self-reported history of stroke (n=82) or transient ischemic attack (n=57) were excluded from analysis, leaving 960 participants for analysis.
Study Definitions
Stroke symptoms were defined as positive response to any of these 6 questions from the Questionnaire for Verifying Stroke-Free Status [20]: sudden onset of any of unilateral painless weakness, unilateral numbness or dead feeling, painless loss of vision unilaterally or bilaterally, hemifield vision loss, loss of ability to understand what people were saying, or loss of ability to express oneself verbally or in writing [21]. Prebaseline stroke or TIA was defined by self-report elicited using the questions, “Were you ever told by a physician that you had a stroke?” and “Were you ever told by a physician that you had a mini-stroke or TIA, also known as a transient ischemic attack?”
Age, race, sex, and current smoking were determined by self-report. Hypertension was defined as self-reported use of blood pressure lowering medications or blood pressure ≥140/90 mmHg. Diabetes was defined as fasting glucose ≥126 mg/dL (or nonfasting glucose ≥200 mg/dL) or self-reported medication use for glucose control. Dyslipidemia was defined as triglycerides ≥240 mg/dL, low-density lipoprotein ≥160 mg/dL or high-density lipoprotein ≤40 mg/dL. Left ventricular hypertrophy (LVH) was classified by ECG [22]. Atrial fibrillation was defined as self-report or ECG evidence. History of heart disease was defined as self-reported pre-baseline myocardial infarction (MI), coronary artery bypass surgery, coronary angioplasty/stenting, or evidence of MI on ECG.
Laboratory Methods
We previously reported that the studied biomarkers were accurately measured using REGARDS sample processing methods [19]. D-dimer was measured on the STAR automated coagulation analyzer, using an immuno-turbidometric assay (Liatest D-DI; Diagnostica Stago, Parsippany, NJ) with coefficient of variation (CV) ranging from 5-14% at different levels. Factors VIII and XI antigen were determined using enzyme linked immunosorbent assays (Enzyme Research Laboratories, South Bend, IN) with CVs 4-7%. Fibrinogen antigen and CRP were measured using the BNII nephelometer (N Antiserum to Human Fibrinogen, N High-sensitivity CRP ; Seimens Healthcare Diagnostics, Deerfield, IL) with CVs 3 -5% and 2.1-5.7%., respectively. NT-proBNP was measured by electrochemiluminescent immunoassay using the Roche Elecsys 2010 analyzer (Roche Diagnostics Indianopolis, IN; CV <5%).
Statistical Methods
Sample weights, using inverse probability weighting, from the cohort sample were applied to all analyses to report results reflecting the entire REGARDS cohort with stroke symptoms (n=4,990) and controls (n=21,469). NT-proBNP, Factor VIII, Factor XI, CRP and D-dimer were log-transformed when necessary to correct for their skewed distributions.
Logistic regression was used to calculate the odds ratio of presence of any stroke symptom by quartiles of each biomarker, using the first quartile as the reference group. We also calculated the odds ratio of stroke symptoms per SD increment of each biomarker. Model 1 was adjusted for age, sex and race. Model 2 was further adjusted for Framingham stroke risk factors (history of heart disease, atrial fibrillation, diabetes, hypertension medication use, current smoking, systolic blood pressure, LVH by ECG), statin use and regular aspirin use. Interactions terms for each biomarker with race and sex were tested with a p value to denote significance of <0.10.
We used two strategies to study associations of biomarkers with individual stroke symptoms. Logistic regression models following the above method were undertaken for each stroke symptom. In addition, because there were relatively low numbers of participants with some stroke symptoms, we used linear regression to examine each individual stroke symptom as a predictor of each biomarker as the outcome, expressed as the level divided by the SD to yield standardized regression coefficients for the association of each stroke symptom with a 1 SD higher level of each biomarker. To minimize the impact of false positive findings due to multiple testing we only performed multivariable analysis for Model 2 if, in Model 1, a p-value <0.10 was observed for the association of a biomarker with a stroke symptom.
Results
Among 960 included participants, 190 (20%) reported a history of any individual stroke symptom, and 770 (80%) without a history of stroke symptoms were considered controls. Participants with stroke symptoms were older, more likely to be black and more likely to have a history of heart disease than controls (Table 1). Those with stroke symptoms also had higher levels of all biomarkers than controls, although this difference was small for fibrinogen and factor VIII (Table 1).
Table 1.
Demographic, Health Characteristics, and Biomarker Concentrations by Stroke Symptom Presence
| Characteristic (mean (SD) or frequency | Controls (n=770) | Any Stroke Symptom (n=190) |
|---|---|---|
| Demographic and Health Characteristics | ||
| Age (SD) | 64.3 (9.3) | 65.5 (9.3) |
| Sex, female (%) | 55 | 57 |
| Race, black (%) | 38 | 50 |
| Current smoking, % | 13 | 17 |
| Body-mass index (SD) | 29.2 (5.7) | 29.6 (6.5) |
| Diabetes, % | 21 | 28 |
| Hypertension, % | 54 | 60 |
| Dyslipidemia, % | 60 | 62 |
| Atrial fibrillation, % | 8 | 12 |
| Left ventricular hypertrophy, % | 7 | 9 |
| History of heart disease % | 14 | 23 |
| Systolic blood pressure (SD) | 127 (16) | 129 (20) |
| Biomarkers | ||
| NT-proBNP, pg/mL (SD) | 146 (676) | 226 (441) |
| Fibrinogen, mg/dL (SD) | 388 (99) | 403 (104) |
| Factor VIII, % (SD) | 119 (42) | 121 (41) |
| Factor XI, % (SD) | 106 (25) | 112 (27) |
| D-dimer, μg/mL (SD) | 0.61 (0.86) | 0.70 (0.65) |
| CRP, mg/L (SD) | 4.1 (7.05) | 4.9 (6.37) |
NT-proBNP, N-terminal pro-B-type natriuretic peptide; CRP, C-reactive protein
The most common stroke symptom was sudden unilateral numbness (n=77), followed by sudden painless unilateral weakness (n=66), sudden loss of vision in one or both eyes (n=51), sudden loss of ability to communicate verbally or in writing (n=40), sudden hemifield vision loss (n=33), and sudden loss of ability to understand people (n=32).
As shown in table 2, in Model 1 NT-proBNP, CRP, and D-dimer in the top versus bottom quartile were each associated with history of any stroke symptom with ORs 1.99 to 3.06. The SD increments of these biomarkers and higher factor XI (on the log scale where appropriate) were also significantly associated with prevalence of any stroke symptom with ORs of 1.21 to 1.54. The upper 3 quartiles of CRP and NT-pro-BNP were all associated with increased odds of stroke symptoms. In Model 2, the ORs for biomarkers were little changed; the highest quartile of NT-proBNP, CRP and D-dimer remained strongly associated with a history of any stroke symptom, as was the highest quartile of FXI. In Model 2, SD increments of NT-proBNP, FXI and CRP also remained significantly associated with a history of any stroke symptom, while the association of D-dimer persisted but lost statistical significance. Fibrinogen and FVIII were not associated with a history of stroke symptoms in the minimally or fully adjusted model. There were no significant interactions by race or sex for any of the biomarkers.
Table 2.
Odds Ratio of Any Stroke Symptom by Biomarker Quartiles and per SD Increment of Each Biomarker
| Odds Ratio of Any Stroke Symptom by Biomarker Quartiles (reference group is Quartile 1)* | Odds Ratio of Any Stroke Symptom per SD Higher Biomarker | |||
|---|---|---|---|---|
| Quartile 2 | Quartile 3 | Quartile 4 | ||
| Cardiac Function | ||||
| NT-proBNP, pg/mL | ||||
| Model 1 | 1.87 (1.08, 3.23) | 1.77 (1.01, 3.10) | 3.06 (1.76, 5.34) | 1.54 (1.31, 1.80) |
| Model 2 | 1.75 (0.96, 3.17) | 1.48 (0.79, 2.77) | 2.69 (1.45, 4.98) | 1.50 (1.26, 1.80) |
| Inflammation | ||||
| Fibrinogen, mg/dL | ||||
| Model 1 | 0.87 (0.54, 1.41) | 0.96 (0.59, 1.55) | 1.24 (0.79, 1.94) | 1.11 (0.93, 1.31) |
| Model 2 | 0.82 (0.48, 1.40) | 0.81 (0.48, 1.36) | 1.15 (0.71, 1.87) | 1.05 (0.87, 1.26) |
| CRP, mg/L | ||||
| Model 1 | 2.10 (1.27, 3.46) | 1.82 (1.10, 3.00) | 2.32 (1.43, 3.74) | 1.21 (1.04, 1.40) |
| Model 2 | 1.91 (1.10, 3.30) | 1.55 (0.90, 2.68) | 2.16 (1.28, 3.67) | 1.20 (1.02, 1.42) |
| Coagulation | ||||
| FVIII, % | ||||
| Model 1 | 1.04 (0.64, 1.70) | 0.99 (0.62, 1.59) | 1.14 (0.71, 1.81) | 1.03 (0.88, 1.20) |
| Model 2 | 1.01 (0.59, 1.73) | 0.85 (0.51, 1.43) | 0.94 (0.57, 1.55) | 0.93 (0.79, 1.09) |
| FXI, % | ||||
| Model 1 | 0.90 (0.55, 1.43) | 1.45 (0.92, 2.29) | 1.57 (0.99, 2.47) | 1.26 (1.07, 1.47) |
| Model 2 | 0.94 (0.56, 1.57) | 1.52 (0.92, 2.53) | 1.59 (0.96, 2.65) | 1.24 (1.04, 1.47) |
| D-dimer, μg/mL | ||||
| Model 1 | 1.80 (1.06, 3.04) | 1.27 (0.74, 2.16) | 1.99 (1.20, 3.29) | 1.21 (1.02, 1.42) |
| Model 2 | 2.21 (1.23, 3.96) | 1.58 (0.86, 2.90) | 2.23 (1.26, 3.95) | 1.18 (0.98, 1.41) |
Model 1 Adjusted for age, race and sex.
Model 2 Adjusted for age, race, sex, history of heart disease, atrial fibrillation, diabetes mellitus, antihypertensive medication use, current smoking, systolic blood pressure, LVH, lipid lowering medication use and regular aspirin use.
Quartile cutpoints (25th, 50th, 75th percentile) and SD values: NT-proBNP (31, 61, 121 pg/ml and 1.11*), Fibrinogen (334, 384, 446 and 99 mg/dL), FVIII (90, 109, 137% and 0.33*), FXI (90, 103, 122% and 0.25*), CRP (0.9, 2.1, 4.7 mg/dL and 1.1*), D-dimer (0.23, 0.39, 0.71 pg/ml and 0.85*) *=Log-transformed
Table 3 shows the ORs of individual stroke symptoms by biomarker levels. Due to low numbers of participants with some individual stroke symptoms, analysis was limited to 3 of the 6 stroke symptoms: sudden onset of unilateral numbness, painless unilateral weakness and painless vision loss in one or both eyes. Similar to analyses in table 2, there was little confounding by stroke risk factors. In Model 2, the top quartile of CRP was associated with a 2.39-fold increased odds of unilateral numbness (95% CI 1.08, 5.26) and a 4.77-fold increased odds of painless vision loss (95% CI 1.92-11.83), but CRP was not significantly associated with unilateral weakness (OR 1.60 (95% CI 0.70-3.68). Conversely, the top quartile of D-dimer was associated with increased odds of unilateral weakness (OR 3.87, CI 95% 1.55-9.64). Higher D-dimer was associated with over twice the odds of unilateral numbness or vision loss but these odds ratios were not statistically significant. There was no association of NT-proBNP, fibrinogen, FVIII or factor XI quartiles with unilateral numbness, vision loss or unilateral weakness in fully adjusted models. Considering SD increments of all the biomarkers (on log scale where appropriate), the only positive association in adjusted models was for CRP and painless loss of vision (OR 1.38; 95% CI 1.09-1.75).
Table 3.
Odds Ratio of Individual Stroke Symptoms by Biomarkers in the Fourth versus First Quartile
| Individual Stroke Symptoms |
|||
|---|---|---|---|
| Biomarker | Unilateral numbness (n=77) | Unilateral painless weakness (n=66) | Painless loss of vision in one or both eyes (n=51) |
| Cardiac Function | |||
| NT-proBNP, pg/mL | |||
| Model 1 | 1.36 (0.66, 2.82) | 1.54 (0.66, 3.57) | 1.22 (0.51, 2.91) |
| Model 2 | 1.52 (0.66, 3.48) | 0.95 (0.36, 2.50) | 1.23 (0.49, 3.09) |
| Inflammation | |||
| Fibrinogen, mg/dL | |||
| Model 1 | 0.79 (0.43, 1.42) | 1.41 (0.72, 2.75) | 1.19 (0.57, 2.49) |
| Model 2 | 0.72 (0.37, 1.39) | 1.06 (0.51, 2.20) | 1.23 (0.53, 2.83) |
| CRP, mg/L | |||
| Model 1 | 2.42 (1.18, 4.96) | 1.77 (0.82, 3.81) | 4.39 (1.88, 10.23) |
| Model 2 | 2.45 (1.09, 5.51) | 1.53 (0.66, 3.56) | 4.83 (1.91, 12.19) |
| Coagulation | |||
| FXI, % | |||
| Model 1 | 1.19 (0.62, 2.30) | 1.97 (0.88, 4.39) | 1.16 (0.54, 2.49) |
| Model 2 | 1.18 (0.56, 2.48) | 1.77 (0.76, 4.15) | 1.19 (0.47, 3.00) |
| D-dimer, μg/mL | |||
| Model 1 | 1.93 (0.98, 3.82) | 2.94 (1.31, 6.59) | 2.57 (0.96, 6.89) |
| Model 2 | 2.11 (0.99, 4.52) | 3.74 (1.48, 9.43) | 2.27 (0.82, 6.28) |
Model 1 Adjusted for age, race and sex.
Model 2 Adjusted for age, race, sex, history of heart disease, atrial fibrillation, diabetes mellitus, antihypertensive medication use, current smoking, systolic blood pressure, LVH, lipid lowering medication use and regular aspirin use
Similar to the logistic regression results in table 3, in linear regression analysis of associations of stroke symptoms with biomarker levels, shown in Table 4, higher CRP was also associated with painless vision loss, and D-dimer and FXI were associated with unilateral painless weakness in Models 1 and 2. Conversely to the results in table 3, in Model 2, NT-proBNP was associated with multiple stroke symptoms, including painless vision loss, hemifield vision loss, and loss of ability to understand others. Fibrinogen was associated with loss of ability to communicate, however this association was attenuated in Model 2.
Table 4.
Standardized Regression Coefficients for Individual Stroke Symptoms and Biomarkers
| Unilateral Numbness (n=77) | Unilateral Painless Weakness (n=66) | Hemifield Vision Loss (n=33) | Painless Loss of Vision in One or Both Eyes (n=51) | Loss of Ability to Understand (n=32) | Loss of Ability to Communicate (n=40) | |
|---|---|---|---|---|---|---|
| Cardiac Function | ||||||
| NT-proBNP | ||||||
| Model 1 | 0.13 | 0.21* | 0.44† | 0.28† | 0.26* | 0.11 |
| Model 2‡ | - | 0.06 (−0.18-0.30) | 0.35 (0.02-0.67) | 0.25 (−0.03-0.52) | 0.28 (−0.04-0.60) | - |
| Inflammation | ||||||
| Fibrinogen | ||||||
| Model 1 | −0.04 | 0.15 | −0.03 | 0.15 | −0.14 | 0.22* |
| Model 2 | - | - | - | - | - | 0.14 (−0.08-0.36) |
| CRP | ||||||
| Model 1 | 0.14 | 0.00 | 0.09 | 0.28† | −0.23 | −0.09 |
| Model 2 | - | - | - | 0.32 (0.09-0.56) | - | - |
| Coagulation | ||||||
| FXI | ||||||
| Model 1 | 0.16 | 0.30† | 0.08 | 0.07 | 0.12 | 0.12 |
| Model 2 | - | 0.24 (−0.02-0.54) | - | - | - | - |
| D-dimer | ||||||
| Model 1 | 0.11 | 0.21* | 0.14 | 0.04 | −0.01 | 0.00 |
| Model 2 | - | 0.21 (−0.04-0.47) | - | - | - | - |
Model 1 Adjusted for age, race and sex.
Model 2. 95% CI is shown in parentheses. Adjusted for age, race, sex, history of heart disease, atrial fibrillation, diabetes mellitus, antihypertensive medication use, current smoking, systolic blood pressure, LVH, lipid lowering medication use and regular aspirin use.
p value ≤0.10
p value ≤0.05
Model 2 analysis was only performed if the p value for model 1 was <0.10.
Discussion
In this national cohort of US black and white adults, higher levels of the stroke risk biomarkers NT-proBNP, CRP, factor XI and D-dimer were each associated with increased odds of prevalent stroke symptoms in participants without prior stroke or TIA. Associations were strongest for NT-proBNP and CRP. Analysis of biomarker associations with individual stroke symptoms was somewhat limited by power, however distinct patterns of associations did emerge for the 3 more common stroke symptoms. Strong associations were seen between CRP and painless vision loss in one or both eyes as well as between D-dimer and unilateral painless weakness. The robust association between NT-proBNP and history of any stroke symptom appeared to be due to its association with multiple individual stroke symptoms rather than a more specific pattern.
Prior REGARDS reports demonstrated the clinical importance of a history of stroke symptoms as defined here [1, 3-5]. We are not aware of other studies examining stroke biomarker levels in relation to history of stroke symptoms. Prior studies showed an association between NT-proBNP and CRP with MRI-defined silent brain infarcts [23, 24]. Silent stroke is common in middle and older age [25-27], and is strongly associated with future stroke and mortality [28, 29]. Using similar stroke symptoms to the present study, Windham et al. demonstrated an association of stroke symptoms with silent brain infarction and clinical stroke [5]. These studies, taken together with the current findings, suggest that a history of stroke symptoms represents unrecognized cerebrovascular disease, and the biomarker associations observed here support that hypothesis.
Previous studies reported associations between the studied biomarkers and future stroke risk, with NT-proBNP having the most robust relationship [8-17]. In this analysis most of these biomarkers were also associated with a history of stroke symptoms, except FVIII and fibrinogen. A possible explanation for this discrepancy is that factor VIII and fibrinogen relate more closely to more severe strokes that are more likely to come to medical attention.
The associations of NT-proBNP, CRP, D-dimer and FXI with a history of stroke symptoms supports our present understanding of the involvement of heart disease, inflammation, and thrombosis in stroke pathophysiology. Furthermore, our analysis of individual stroke symptoms showed patterns of association with specific biomarkers suggesting each symptom may have a unique risk factor profile. For example, an inverse relationship between FVIII and loss of ability to communicate might indicate small brain hemorrhage in association with lower factor VIII. The variable patterns of association that emerged in our present study agree with prior studies demonstrating non-uniformity in associations between stroke symptoms and stroke risk factors [1, 7].
Strengths of this study include the use of a national general population sample of black and white adults with objectively measured risk factors. There are also limitations to consider. Prior validation studies of the Questionnaire for Verifying Stroke-Free Status demonstrated high sensitivity but modest specificity in detecting stroke; positive answers to the questions may be caused by conditions unrelated to cerebrovascular disease[21]. For example, weakness or numbness may be due to recent surgery; higher D-dimer or CRP might be expected in such cases. We believe the impact of this is small since participants might be less likely to undertake their REGARDS enrollment in-home visit right after acute illness. Another limitation is low power for associations of biomarkers with individual stroke symptoms due to relatively few participants with some symptoms. We used linear regression analysis to try to overcome this, and associations were mostly consistent with the logistic regression analysis, supporting the validity of the associations found for rarer stroke symptoms only in the linear regression, including hemifield vision loss, loss of ability to understand and loss of speech or ability to write. Finally, REGARDS does not have brain imaging to confirm that stroke symptoms represent cerebrovascular disease and confirm that biomarker changes with stroke symptoms are clinically important.
In conclusion, we report associations of NT-proBNP, CRP, FXI, and D-dimer with presence of a history of stroke symptoms, and with some individual symptoms. In the right clinical context, elevated levels of these biomarkers may suggest undiagnosed cerebrovascular disease. Future work is needed to determine whether these biomarkers identify persons with a history of stroke symptoms who are at particularly high stroke risk.
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.
Acknowledgements
The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org.
This research project is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. Additional funding was from K08HL096841 (to N. A. Zakai) and T32HL007594 (to K. S. Alexander) from the National Heart, Lung and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.
Footnotes
Addendum
K. K. Landry contributed to the concept and design, interpretation of data and drafting the paper. K. S. Alexander contributed to the analysis of data and revision of the intellectual content/paper. N. A. Zakai contributed to the concept and design, interpretation of data, and revision of the intellectual content/paper. S. E. Judd contributed to the concept and design, analysis of data, and revision of the intellectual content/paper. D. O. Kleindorfer contributed to the concept and design, interpretation of data, and revision of the intellectual content/paper. V. J. Howard contributed to the concept and design, interpretation of data, and revision of the intellectual content/paper. G. Howard contributed to the concept and design, interpretation of data, and revision of the intellectual content/paper. M. Cushman contributed to the concept and design, interpretation of data, and drafting of the paper. All authors gave final approval of the paper.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interests.
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