In this analysis of data from the ARIC cohort, all obesity measures were positively and similarly associated with all ischemic stroke subtypes. These associations were slightly stronger than in a previous ARIC report with fewer events and no examination of waist circumference.6
The present findings are consistent in part with the Hisayama Study, which found a positive association between BMI and lacunar stroke incidence in Japanese women.7
However, in men BMI associations were not found with any ischemic stroke subtype or for atherothrombotic or cardioembolic stroke in women. The large difference in the degree of obesity between ARIC and Hisayama studies precludes direct comparisons (mean BMIs in the Hisayama Study were 21.5 kg/m2
in men and 21.7 kg/m2
in women, compared with 27.7 kg/m2
for both genders in the ARIC Study). ARIC finding may also be consistent with a cross-sectional study that found a positive association between abdominal obesity and the prevalence of silent lacunar infarct identified by MRI in apparently healthy Japanese men and women aged 40 to59.8
found that BMI ≥ 27 kg/m2
was not associated with any ischemic stroke subtype after adjusting for age, sex, social class, hypertension, and hypercholesterolemia. Since mediating variables were included, these results are consistent with our findings from the mediation analyses. Nevertheless, further investigations in populations with various degrees of obesity that included different ethnicities and sexes, are essential to confirm the present findings.
Mediating factors together explained all the association of obesity measures with each ischemic stroke subtype, but no single mediating factor accounted totally for the associations except in the case of lacunar stroke analyses where any of hypertension, diabetes mellitus, or HDL cholesterol attenuated the significant association. Coefficients for waist circumference (HR1) changed 44% after adding systolic blood pressure and antihypertensive medication to Model I. The amount of change was 72% in the case of diabetes mellitus, and 35% for HDL cholesterol. Statistically significant associations of waist circumference with lacunar stroke incidence disappeared in all cases. Each of these variables explained some associations between waist circumference and nonlacunar thrombotic or cardioembolic stroke (changes in the coefficients from Model I ranged from 12% to 38%), but the statistical significance of the waist circumference variable remained. It was only when all these variables were entered simultaneously that the significant association was attenuated (p=0.13 for both nonlacunar thrombotic and cardioembolic stroke). Given the strong and probably causal association between obesity and hypertension, diabetes mellitus, and HDL cholesterol, obesity would be an important target for the prevention of any subtype of ischemic stroke.
However, we did not find positive associations between obesity measures and lacunar stroke incidence in subjects with hypertension. This finding may be consistent with a prospective study of hypertensive older adults aged 60 or over that did not find associations between BMI and any ischemic stroke subtype.17
We did several additional analyses in an attempt to find a possible mechanism related to the null association. However, neither additional adjustment for potential mediating variables, excluding subjects with less than five years of follow-up, nor limiting analyses to either race or sex, changed the null association in hypertensives. Other established risk factors, such as elevated systolic blood pressure, diabetes mellitus, or low HDL cholesterol, were all positively associated with lacunar stroke incidence in subjects with hypertension. Although the underlying mechanism remains unknown, it may have been due to a high incidence rate of lacunar stroke even in subjects in the lowest BMI and waist circumference quintiles among hypertensives. Other dietary or lifestyle factors may have existed in these individuals that predisposed them to lacunar stroke over the effect of obesity.18
On the other hand, confidence intervals were wide and it is possible that null finding was by chance.
There are several limitations of this study that warrant discussion. Although neuroimaging reports and clinical features were used to classify ischemic stroke cases into subtypes, some cases may have been misclassified. Subtypes were classified via a review of medical records and neuroimaging reports, rather than direct examination of patients or images. The medical record classification process did not use the obesity status or other risk factors of stroke cases, but reviewers were not blinded to such information. This might have lead to some potential biases in the associations. Further, since we used a maximum diameter of 20 mm in our study, there is the possibility of misclassification of nonlacunar thrombotic stroke into lacunar stroke; however we minimized this possibility by prioritizing neuroimaging reports that explicitly stated that the infarct was not lacunar even the image itself met the criterion. Any misclassification might have distorted the obesity and lacunar stroke association. Nevertheless, the size criterion of lacunar infarct has also been debated;19
future studies utilizing advanced imaging would be ideal. Although we did not find any effect modification by race or sex, the number of cases was limited, so we could not conduct sex- or race-specific analyses. The present sample consisted of US blacks and whites, most of which were from a single center, limiting the generalizability of our findings to other cultural or socio-economic contexts. Finally, we used regression rather than structural equation modeling to examine mediation.
A strength of the present study is that we analyzed the association of obesity measures and ischemic stroke subtypes using prospective population-based data, including both blacks and whites, with a relatively large numbers of events. There are no prior prospective studies that specifically addressed the association between obesity and ischemic stroke subtypes in detail.
In conclusion, lacunar, nonlacunar and cardioembolic stroke were all significantly positively associated with obesity measures. Although different pathophysiological mechanisms may exist relating obesity and each subtype, the prevention and control of obesity has the potential to reduce the burden of stroke in the US. Further studies are needed for other populations.