Risk Factors for Ischemic Stroke Subtypes
The Atherosclerosis Risk in Communities Study
Background and Purpose— To evaluate risk factors for ischemic stroke by its subtypes may contribute to more effective prevention of ischemic stroke, but few prospective studies have characterized risk factors for specific subtypes of ischemic stroke.
Methods— Between 1987 and 1989, 14 448 men and women aged 45 to 64 years and free of clinical stroke took part in the first examination of the Atherosclerosis Risk in Communities study. The incidence of stroke was ascertained from hospital surveillance records.
Results— During an average follow-up of 13.4-years, 531 incident ischemic strokes occurred (105 lacunar, 326 nonlacunar, and 100 cardioembolic). Blacks had a 3-fold higher multivariate-adjusted risk ratio of lacunar stroke compared with whites. No racial difference in nonlacunar or cardioembolic strokes was found after adjusting for prevalent risk factors. In addition to traditional risk factors, nontraditional risk factors, such as waist-to-hip ratio, history of coronary heart disease, left ventricular hypertrophy, lipoprotein(a), and von Willebrand factor, were associated with increased risk for nonlacunar stroke, whereas lacunar stroke was related to only 1 nontraditional risk factor, white blood cell count. The population-attributable fraction (PAF) for hypertension was ≈35% for all ischemic stroke subtypes. The respective PAFs for diabetes and current smoking were 26.3% and 22.0% for lacunar versus 11.3% and 11.4% for nonlacunar stroke. The PAF for elevated von Willebrand factor was greater than that for current smoking for cardioembolic stroke.
Conclusions— The impact of traditional and nontraditional risk factors other than hypertension on the incidence of ischemic stroke varied according to its subtype.
Epidemiological studies have identified several risk factors for ischemic stroke, including hypertension, smoking, diabetes mellitus, and hemostatic factors.1 However, few prospective studies have characterized risk factors for specific subtypes of ischemic stroke.2–4 Because the pathogenesis, prognosis, and treatment differ among subtypes, evaluating risk factors for individual subtypes may contribute to more effective primary and secondary prevention of ischemic stroke.
A prospective study of 4736 older US, predominantly white, women and men showed that current smoking and a history of diabetes were independently associated with increased risk of lacunar stroke but not atherosclerotic or embolic stroke,2 whereas another prospective study in US women reported that a history of diabetes was associated with all ischemic stroke subtypes.4 A prospective study of 1621 Japanese men and women observed significant positive associations of current smoking and glucose intolerance with lacunar stroke incidence in women but not in men.3 Previous studies have examined the relations between traditional risk factors and stroke subtypes, but none has assessed the associations of nontraditional risk factors, such as hemostatic factors and lipoprotein(a) [Lp(a)], with ischemic stroke subtypes.
The Atherosclerosis Risk in Communities (ARIC) study reported that blacks had a 2.4-fold higher age-adjusted relative risk of stroke incidence compared with whites,5 which could be partially explained by a higher prevalence of stroke risk factors such as hypertension, diabetes, and current smoking among blacks than among whites.6 This higher prevalence of stroke risk factors among blacks may contribute to a predominance of a particular stroke subtype among blacks.
To examine the relation of traditional and nontraditional risk factors with the incidence of ischemic stroke subtypes, we used data from follow-up on men and women in the ARIC study.
The ARIC sample included 15 792 men and women aged 45 to 64 years between 1987 and 1989 in 4 US communities: Forsyth County, NC; Jackson, Miss; 8 northwestern suburbs of Minneapolis, Minn; and Washington County, Md.7
We excluded participants in Forsyth County who were not white or black (n=21) and participants in Minneapolis and Washington County who were not white (n=82). We then excluded participants with a history of stroke or transient ischemic attack (TIA) at baseline (n=282) and participants with missing data for risk factors (n=919) at baseline. The remaining 14 488 participants (2285 black women, 1391 black men, 5745 white women, and 5067 white men) were followed up to determine the incidence of stroke through 2002. The study protocol was approved by the institutional review boards of the collaborating institutions, and informed, written consent was obtained from each participant.
Methods for blood processing in the ARIC study have been described.8 Participants were asked to fast for 12 hours before their morning clinic appointments. Lp(a) was measured as total protein component [apolipoprotein(a) plus apolipoprotein B] with a double-antibody ELISA technique for apolipoprotein(a) detection. Plasma fibrinogen and von Willebrand factor (vWF) antigen were measured by the thrombin time titration method and ELISA, respectively. Serum glucose was measured by a hexokinase/glucose 6-phosphate dehydrogenase method. Body mass index (BMI) was calculated as weight (kg)/height (m)2. The ratio of waist (umbilical level) to hip (maximum buttocks) circumference (WHR) was calculated as a measure of fat distribution. A 12-lead electrocardiogram (ECG) tracing was obtained, and left ventricular hypertrophy (LVH) was determined by Cornell voltage criteria.9 We defined prevalent coronary heart disease (CHD) and stroke at baseline as a self-reported history of a physician-diagnosed heart attack, prior myocardial infarction by ECG, prior cardiovascular surgery, prior coronary angioplasty, or prior stroke or TIA identified by a standardized interview.10
End Point Determination
For the present study, we included stroke events7 occurring between ARIC visit 1 and December 31, 2002. TIAs were not ascertained. All participants were contacted annually by phone, and all hospitalizations and deaths in the previous year were identified. We also surveyed lists of discharges from local hospitals and death certificates from state vital statistics offices for potential cerebrovascular events. Abstractors recorded signs and symptoms and photocopied neuroimaging (CT or MRI) and other diagnostic reports if the list of discharge diagnoses included a cerebrovascular disease code (International Classification of Diseases, Ninth Revision, code 430 to 438), if a cerebrovascular condition or procedure was mentioned in the discharge summary, or if a cerebrovascular finding was noted on a CT or MRI report. Of the stroke-eligible hospitalizations, 84% had at least 1 CT scan, 27% had an MRI of the head, 15% had a cerebral angiogram, and 6% had undergone lumbar puncture.5 Each eligible case was classified by computer algorithm and by an expert reviewer, according to criteria adapted from the National Survey of Stroke.11 Details on quality assurance for ascertainment and classification of stroke are described elsewhere.5 Qualifying strokes were further classified into definite or probable hospitalized ischemic (cardioembolic or thrombotic) or hemorrhagic stroke on the basis of neuroimaging studies and autopsy, when available.
A stroke was classified as ischemic when a brain CT or MRI revealed acute infarction or showed no evidence of hemorrhage. All definite ischemic strokes were further classified as either lacunar or nonlacunar on the basis of the recorded neuroimaging results. A stroke was classified as lacunar when 2 criteria were met: (1) typical location of the infarct (basal ganglia, brain stem, thalamus, internal capsule, or cerebral white matter) and (2) infarct size of ≤2 cm or unstated size. Definite or probable cardioembolic stroke required the same criteria as ischemic infarction, plus either (1) autopsy evidence of an infarcted area in the brain and a source of possible cerebral emboli in a vessel or the presence of an embolus in the brain or (2) medical record evidence of a possible source of embolus, such as moderate or greater valvular heart disease, atrial fibrillation, cardiac or arterial procedure, or intracardiac thrombus.
Differences among stroke groups in age-, sex-, and race-adjusted mean values or prevalences of potential risk factors at baseline were tested by ANCOVA for continuous variables and logistic regression for dichotomous variables. Time at risk (time to event or time to censoring) was calculated from the date of the baseline examination to the earliest of the following: date of hospital admission for incident ischemic stroke, date of death, date of last follow-up contact, or December 31, 2002.
Age-, sex-, and race-adjusted and multivariate-adjusted rate ratios (RRs) and 95% CIs of stroke incidence in relation to the baseline variables were computed by Cox proportional-hazards regression. Continuous variables, except for Lp(a), were converted to standardized z scores, making the RRs interpretable an increment in risk for each standard deviation increase in the continuous variable. Because the distribution of Lp(a) values was skewed, the RR for the ≥80th percentile of Lp(a) level relative to the <80th percentile was calculated. To estimate the impact of potential risk factors on the incidence of stroke subtypes, we calculated the population-attributable fraction (PAF) as P×[(adjusted RR−1)/adjusted RR], where P is the proportion of cases with the risk factor. The formula of Greenland12 was used for the calculation of 95% CIs. For PAF calculation, continuous variables were divided into fifths, and the RRs of the highest fifth, with the other fifths used as the reference, were calculated.
Among the 14 488 men and women followed up for an average of 13.4 years, 531 incident ischemic strokes occurred, including 105 lacunar, 326 nonlacunar, and 100 cardioembolic strokes. The number of cases (incidence rate per 1000 person-years) for blacks and whites were 65 (1.38) and 40 (0.27) for lacunar, 114 (2.41) and 212 (1.44) for nonlacunar, and 39 (0.83) and 61 (0.42) for cardioembolic strokes, respectively.
Blacks were more likely than whites to experience an ischemic stroke (Table 1). Mean values of BMI, WHR, systolic blood pressure (SBP), fibrinogen, vWF, and white blood cell count (WBC) and the prevalences of current smoking, hypertension, and diabetes were higher among subjects with any subtype of ischemic stroke than among subjects without ischemic stroke. The prevalences of past CHD and LVH were higher among subjects with nonlacunar stroke and cardioembolic stroke than among subjects without ischemic stroke. Subjects with cardioembolic stroke had higher mean values of vWF compared with subjects with lacunar and nonlacunar stroke.
Current smoking, SBP, hypertension status, taking antihypertensive medication, diabetes, lower education level, lower HDL cholesterol, fibrinogen, vWF, and WBC appeared to be significant risk factors for all ischemic stroke subtypes (Table 2). BMI, WHR, a history of CHD, and LVH were additional risk factors for nonlacunar and cardioembolic stroke but not lacunar stroke. Heavy drinking, total cholesterol, and Lp(a) were associated with increased risk of nonlacunar stroke but not lacunar or cardioembolic stroke.
Multivariate analysis showed that age, current smoking, SBP, and diabetes mellitus were independent risk factors for all ischemic stroke subtypes (Table 3). Blacks had a 3-fold higher multivariate-adjusted RR of lacunar stroke compared with whites, whereas there was no racial difference for nonlacunar and cardioembolic strokes: the adjusted RRs were 2.98 (95% CI, 1.87 to 4.76) for lacunar stroke, 1.09 (95% CI, 0.82 to 1.43) for nonlacunar stroke, and 1.07 (95% CI, 0.65 to 1.76) for cardioembolic stroke. LVH and vWF were independent risk factors for both nonlacunar and cardioembolic stroke; WHR, a history of CHD, and Lp(a) were independent risk factors for nonlacunar stroke only; WBC was an independent risk factor for both lacunar and cardioembolic stroke; and education level and HDL cholesterol were independent risk factors for lacunar stroke only.
Table 4 presents multivariate-adjusted PAFs and 95% CIs for stroke subtypes. The PAF for hypertension was ≈35% for all ischemic stroke subtypes. The PAFs for diabetes and current smoking were 26.3% (95% CI, 20.0 to 30.4) and 22.0% (95% CI, 11.9 to 29.0) for lacunar stroke versus 11.3% (95% CI, 7.0 to 14.7) and 11.4% (95% CI, 5.5 to 16.1) for nonlacunar stroke. For nonlacunar stroke, the PAFs for WHR, Lp(a), and vWF were similar to those for diabetes and current smoking. For cardioembolic stroke, the PAF for elevated vWF of 19.5% (95% CI, 8.8 to 26.5) was greater than that for current smoking [16.4% (95% CI, 5.6 to 23.4)].
This prospective study found that whereas hypertension was the most powerful predictor for all ischemic stroke subtypes, the estimated impact of traditional and nontraditional risk factors on the incidence of ischemic stroke varied according to subtype. Diabetes and current smoking were important predictors of lacunar and nonlacunar ischemic stroke subtypes, with RRs and PAFs of diabetes and current smoking somewhat higher for lacunar than nonlacunar stroke, which is consistent with previous reports.2,3 Regarding nontraditional risk factors, higher WHR and Lp(a) levels were significantly related to increased nonlacunar stroke incidence, and vWF was particularly associated with cardioembolic stroke. These results suggest that the etiologic relation of risk factors with ischemic stroke varies by subtype.
Blacks had a 3-fold higher multivariate-adjusted RR of lacunar stroke compared with whites, which is higher than a 1.4-fold higher adjusted RR for total ischemic stroke previously reported by ARIC5 and the 1.3-fold higher adjusted RR in this study. Recently, 2 population-based studies reported a higher incidence of total ischemic stroke among blacks compared with whites, although the blacks’ excess burden of ischemic stroke was not uniformly distributed across all ischemic stroke subtypes.13,14 These studies, however, did not compare multivariate-adjusted incident rates of ischemic stroke subtypes between blacks and whites. The present study provides further evidence that whereas blacks have 2- to 2.4-fold higher age- and sex-adjusted RRs of incidence of nonlacunar and embolic strokes, they may have no excess risk of nonlacunar and cardioembolic strokes after adjusting for traditional and nontraditional risk factors. Thus, the high incidence of nonlacunar and cardioembolic strokes among blacks compared with whites in ARIC appears to be explained by the high prevalence of risk factors such as current smoking, hypertension, diabetes, LVH, Lp(a), and vWF among blacks.4,15,16 On the other hand, the excess risk in blacks for lacunar stroke remained significant after adjustment for traditional and nontraditional risk factors. Further research on risk factors and genetic determinants of stroke is needed to understand this ethnic difference.
In this study, the impact of baseline hypertension on the incidence of ischemic stroke did not vary according to ischemic stroke subtype, but we could not evaluate whether uncontrolled hypertension over time affected the results. Many previous studies have shown that patients with lacunar stroke tended to have a higher prevalence of hypertension compared with nonlacunar stroke.17 More than half of these previous studies, however, included hypertension in their definition of ischemic stroke subtypes.17 For instance, the Trial of Org 10172 in Acute Stroke Treatment (TOAST), the most commonly used classification for stroke subtypes, uses a history of diabetes mellitus and hypertension in its lacunar stroke definition.18 This could lead to bias when assessing differences in risk factor profiles among ischemic stroke subtypes. In this study, we defined ischemic stroke subtypes with a risk factor–free classification to avoid classification bias. A recent systematic review reported that the apparent excess of hypertension in lacunar stroke compared with nonlacunar stroke was confined to studies that included hypertension or other risk factors in their definitions of ischemic stroke subtypes.17
On the other hand, the estimated impact of several traditional and nontraditional risk factors other than hypertension on the incidence of ischemic stroke varied according to subtype. The PAFs of diabetes and current smoking were almost twice as great for lacunar as for nonlacunar stroke. Although the cause of this distinction between lacunar and nonlacunar stroke cannot be inferred from our data, arteriosclerosis of the small, penetrating arterioles of the cerebral basal ganglia and reduced fibrinolytic activity caused by continued high blood glucose may play a role in the development of lacunar stroke.19 Impaired endogenous fibrinolysis and reduced blood flow in the brain attributable to vasoconstriction by smoking are also associated with the development of lacunar stroke.20
In addition to traditional risk factors, nontraditional risk factors, such as WHR, a history of CHD, LVH, Lp(a), vWF, and WBC, were associated with increased risk for nonlacunar stroke, whereas lacunar stroke was related only to 1 of the nontraditional risk factors evaluated. Because these latter risk factors for nonlacunar stroke also have been associated with incident CHD,21 the etiological risk factor profile for CHD may be closer to that for nonlacunar stroke than for lacunar stroke. Furthermore, the present study adds to existing evidence that increased vWF may raise the risk of nonlacunar and cardioembolic stroke, especially cardioembolic stroke, but not lacunar stroke.
The strength of the present study is that we analyzed risk factors for ischemic stroke subtypes from population-based data, including both blacks and whites, with a relatively large numbers of events in a prospective study. Although a number of cross-sectional and case-control studies have reported differences in risk factors for ischemic stroke subtypes, corresponding population-based prospective studies are scarce. Furthermore, previous prospective studies of risk factors for ischemic stroke subtypes have had several methodological limitations. One of 3 previous prospective studies was hospital based, and all participants had hypertension.2 The numbers of ischemic stroke events were relatively small,2,3 and, in 1, self-reports were used to evaluate risk factors.4 Therefore, our results may have greater validity than previous studies.
Potential limitations of this study warrant consideration. Although neuroimaging reports and clinical features were used to classify ischemic stroke cases into subtypes, some cases may have been misclassified.5 This may have led to an overestimate or underestimate of the impact of various risk factors by stroke subtype. Our subtype classification was made by a review of medical records and neuroimaging reports, rather than direct examination of patients or images. The physicians who treated the patients were not blinded to their patients’ risk factors and may have been biased in their recording of subtype information. This could have exaggerated some RRs or led to apparent differences in RRs and PAFs by subtype. Another weakness of this study is that we did not have adequate numbers to conduct sex-specific analyses; associations of ischemic stroke with some risk factors such as HDL cholesterol and Lp(a) may differ by sex.22 In this study, LVH was determined by ECG criteria, which may have led to an underestimate of the impact of LVH because ECG LVH is insensitive, compared with LVH assessed by cardiac ultrasonography. Furthermore, we analyzed the associations between risk factors and ischemic stroke subtypes from a single assessment at baseline, which may have misclassified the habitual risk factor profiles of some individuals. The number of incident strokes differed among stroke subtypes, potentially decreasing the precision for lacunar and cardioembolic strokes. For example, some embolic strokes attributable to cryptogenic sources of emboli such as aortic arch atheroma might be classified into nonlacunar but not cardioembolic stroke. This may have led to an underestimate of the associations of risk factors with nonlacunar stroke. Finally, we calculated the PAFs from the proportion of cases in the highest fifth of continuous variables (eg, WHR, HDL cholesterol, vWF, and WBC) relative to the other fifths. This dichotomization of continuous variables may have led to an underestimate of their impact on stroke subtypes.
In conclusion, although we cannot verify that all risk factor associations we observed are causal, the estimated impact of traditional and nontraditional risk factors other than hypertension on the incidence of ischemic stroke was shown to vary by subtype. Although blacks had a greater rate of all ischemic stroke subtypes than did whites, the excess risk for nonlacunar and cardioembolic strokes was no longer apparent after accounting for traditional and nontraditional risk factors. Further research on other risk factors and genetic determinants may lead to better understanding and prevention of ischemic stroke, especially lacunar stroke among blacks.
The authors thank William Baker for technical assistance, as well as the staff and participants in the ARIC Study for their important contributions.
Sources of Funding
The ARIC Study was funded by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022.
- Received April 4, 2006.
- Revision received June 27, 2006.
- Accepted July 11, 2006.
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