Published online before print October 19, 2006, doi: 10.1161/01.STR.0000249056.24657.8b
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(Stroke. 2006;37:2898.)
© 2006 American Heart Association, Inc.
Original Contributions |
Metabolic Risk Factors for Stroke and Transient Ischemic Attacks in Middle-Aged Men
A Community-Based Study With Long-Term Follow-Up
From Department of Public Health and Caring Sciences (B.W., J.S., J.Á., B.V., B.Z.) and Medical Sciences (A.T., L.L), Uppsala University, Uppsala, Sweden; AstraZeneca R&P, Mölndal (L.L.), Sweden.
Correspondence to Dr Bernice Wiberg, Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala Science Park, SE-751 85 Uppsala, Sweden. E-mail bernice.wiberg{at}akademiska.se
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Abstract |
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Background and Purpose— The impact of lipometabolic and glucometabolic disturbances on stroke incidence remains to be characterized in detail. We investigated relations of a comprehensive panel of baseline lipometabolic and glucometabolic variables to incident fatal and nonfatal stroke or transient ischemic attack (TIA), and stroke subtypes.
Methods— A community-based prospective study of 2313 middle-aged men invited to a health survey at age 50.
Results— During a follow-up of up to 32 years, 421 developed stroke or TIA. In Cox proportional hazards analyses adjusting for treatment with cardiovascular drugs at baseline, 1-standard deviation increases in body mass index, systolic and diastolic blood pressures, serum proinsulin, and lipoprotein(a) were associated with 11 to 35% increased risk for subsequent stroke/TIA. Electrocardiographic left ventricular hypertrophy and smoking were also associated with a higher risk for stroke/TIA. Essentially the same variables were related to brain infarction/TIA. Higher proportions of palmitic (16:0), palmitoleic (16:1), and oleic acid (18:1) in cholesterol esters were associated with an increased risk, whereas a higher proportion of linoleic acid (18:2 n-6) was protective against stroke/TIA. Further adjusting all models also for hypertension, diabetes, the metabolic syndrome, serum cholesterol, atrial fibrillation, cardiovascular disease, smoking, and physical activity, essentially the same pattern was observed.
Conclusions— Indices of an unhealthy dietary fat intake and a high serum lipoprotein (a) level predicted fatal and nonfatal stroke/TIA independently of established risk factors in a community-based sample of middle-aged men followed for 32 years.
Key Words: fatty acids • lipoproteins • risk factors • stroke
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Introduction |
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The relations of lipometabolic characteristics to subsequent stroke incidence remain controversial. Studies of dietary fat quality as a predictor of stroke incidence have shown a borderline protective effect of long-chain n-3 fatty acids.1,2 A protective effect of fruit and vegetable intake has been demonstrated in some,3,4 but not all,5 studies. A case-control study of serum fatty acids demonstrated a protective effect of linoleic acid (18:2 n-6) and an adverse effect of saturated fatty acids for subsequent stroke.6 The importance of serum fatty acid patterns for future stroke has not previously been investigated in a prospective setting.
The serum lipoprotein (a), Lp(a), level was demonstrated to predict stroke in elderly people in a large longitudinal7 and in a case-control study,8 and a weak relation of apolipoprotein (apo)A-1 and apoB levels to stroke incidence was observed in another study.9 These observations warrant confirmation in other populations.
Insulin resistance is common in stroke/transient ischemic attack (TIA) patients.10 A relation between proinsulin levels and stroke has previously been reported in a case-control study,11 but longitudinal studies of detailed glucometabolic predictors of stroke are lacking.
We hypothesized that an unhealthy dietary fat intake, lipid dysregulation, and insulin resistance contribute to increased risk for fatal and nonfatal stroke/TIA, independently of established risk factors. Accordingly, we investigated relations of baseline lipometabolic and glucometabolic variables to incident stroke/TIA and subgroups of brain infarction (BI), TIA, and intracerebral hemorrhage (ICH) in a sample of middle-aged men followed-up for 32 years.
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Methods |
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Study Sample
All men born 1920 to 1924 and residing in Uppsala County were invited to a health survey at age 50 (in 1970 to 73), in which 2322 of 2841 invited men participated (82%). The aim was to identify subjects at risk for cardiovascular disease (Uppsala Longitudinal Study of Adult Men, www.pubcare.uu.se/ulsam). In the present study, 9 subjects were excluded because of a history of stroke or TIA before the baseline examination. All subjects gave written consent and the Ethics Committee of Uppsala University approved the study.
Baseline Examinations
These examinations have previously been described in detail.12 Participants underwent an interview including smoking status, a medical questionnaire and a physical examination. Body mass index (BMI) was calculated as weight (in kg) divided by height (in meters) squared. Blood pressures were measured after 10 minutes rest with the subject in the supine position. Blood samples were drawn in the morning after an overnight fast. A standard 12-lead ECG was classified for atrial flutter/fibrillation and left ventricular hypertrophy (LVH) defined as high-amplitude R-waves together with left ventricular strain pattern.13 We identified persons with the metabolic syndrome using a slightly modified National Cholesterol Education Program definition (BMI used instead of waist circumference).14 We defined diabetes according to the 1997 American Diabetes Association criteria.15
Lipometabolic Variables
Total cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured, and low-density lipoprotein cholesterol was calculated using Friedenwald’s formula. Lp(a) and apoB were determined by a 2-site immunoradiometric assay and apoA-1 by a competitive radio immunoassay using commercial kits (Pharmacia, Uppsala, Sweden). The cholesterol ester (CE) proportions of fatty acids (14:0 to 22:6 n-3) were determined by gas chromatography.16 To facilitate interpretation of the CE fatty acid pattern, factor analysis was performed using all analyzed CE fatty acids. Principal components were determined, and only the first principal component was retained (eigen value 4.0) as a marker for the main variation in the fatty acid spectrum. Loadings (eigenvectors) of individual fatty acids on the fatty acid principal component (FAPC) are presented in supplemental Table I (available online at http://stroke.ahajournals.org). The interpretation of fatty acid principal components in the present cohort has recently been described in detail.17
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Glucometabolic Variables
Fasting concentrations of intact proinsulin and 32 to 33 split proinsulin were analyzed using a 2-site immunometric assay technique,18 and specific insulin by the Access Immunoassay System (Sanofi Pasteur Diagnostics). Because of a freezer failure, concentrations of intact and 32 to 33 split proinsulin and specific insulin were only analyzed in baseline plasma samples from 1306 subjects.
Follow-Up
The subjects were followed-up from the baseline investigation at age 50 (in 1970 to 1973) until December 31, 2002. The subjects had a median follow-up time of 29.3 years (range 0.04 to 32.7), contributing to 57769 person years at risk (PYAR).
End Points
End Points were defined using the Swedish Hospital Discharge Record (SHDR) and Cause-of Death Registries (CDR). The end points investigated in the present study were in order of priority: (1) fatal or nonfatal stroke or TIA (ICD-9 codes 430 to 32 and 434 to 36, ICD-10 codes I60-I64, I66 and G45); (2) fatal or nonfatal BI or TIA (ICD-9 codes 434 to 35, ICD-10 codes I63, I66 and G45); and (3) fatal or nonfatal intracerebral hemorrhage (ICD-9 codes 431 to 32, ICD-10 codes I61–62).
Some participants have experienced >1 of these end points during the follow-up period and can appear in more than one category. Only the first occurrence of the end point studied in a particular model merited censoring (Figure 1).
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Statistical Analyses
Distributions were tested for normality by Shapiro-Wilk W test, and logarithmic transformation was performed when W <0.95. The prognostic value of 1 SD increase in the continuous variables, or transfer from one level to another of the dichotomous variables, was investigated with Cox proportional hazard ratios. We also investigated incidence rate of the end points by quartiles of the independent variables to assess possible nonlinear relationships. Two sets of models were investigated: one adjusting for treatment with antihypertensive, antidiabetic, and lipid-lowering drugs, and the other adjusting additionally for hypertension, diabetes, the metabolic syndrome, serum cholesterol, smoking, and physical activity. Nelson-Aalen curves were used to confirm proportionality of hazards. The statistical power to detect hazard ratios of 1.5 and 1.3 was 99.6% and 80.1%, respectively, assuming equally sized groups. Two-tailed 95% confidence intervals and probability values were given, with P<0.05 regarded as significant. The statistical software packages Stata 6.0 (Stata Corp) was used.
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Results |
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Baseline characteristics are described in Tables 1 and 2
. During follow-up, 421 cases of a first hospitalization for stroke/TIA occurred (incidence rate 7.29/1000 PYAR). A first BI/TIA was experienced by 308 men and 86 experienced a first ICH (incidence rates 5.27 and 1.44//1000 PYAR, respectively; Figure 1). During follow-up, 1068 men died. Stroke was the cause in 73 cases and other cardiovascular reasons in 424 cases. Four hundred ninety-six men experienced a fatal or nonfatal myocardial infarction (8.8/1000 PYAR) and 282 developed heart failure (4.8/1000 PYAR).
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In Cox proportional hazards models adjusting for treatment with antihypertensive, antidiabetic and lipid-lowering drugs (Table 3), systolic and diastolic blood pressures, ECG-LVH, proinsulin, and Lp(a) were related to both the stroke/TIA and the BI/TIA outcomes. BMI and smoking were associated with a significantly elevated risk for stroke/TIA, but not for BI/TIA. Diastolic blood pressure, ECG-LVH, and smoking were significant predictors of ICH.
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Higher proportions of palmitic (16:0), palmitoleic (16:1), and oleic acid (18:1) were associated with an increased risk for stroke/TIA and BI/TIA, whereas a higher proportion of linoleic acid (18:2 n-6) was protective against stroke/TIA and BI/TIA (Table 4). A 1-SD increment in the FAPC was related to a 17% increased risk for stroke/TIA, Table 4. No significant relation between serum fatty acids and subsequent ICH was observed.
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When adjusting additionally for hypertension, diabetes, the metabolic syndrome, serum cholesterol, atrial fibrillation, cardiovascular disease, smoking, and physical activity (Table 3), the significant predictors of stroke/TIA were all retained with exception for BMI and proinsulin. In these models, systolic blood pressure, ECG-LVH, and Lp(a) were related to significantly higher risk of stroke/TIA and BI/TIA. The fatty acid pattern and the FAPC followed essentially the same pattern as in the more parsimonious models (Table 4).
The longitudinal relation of linoleic acid and Lp(a) level to stroke/TIA incidence are presented in Figures 2 and 3. No apparent deviations from linearity were observed when investigating incidence rate by quartiles of the independent variables.
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Discussion |
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In this large community-based study, indices of an unhealthy dietary fat intake and a high serum Lp(a) level predicted fatal and nonfatal stroke/TIA independently of established risk factors in middle-aged men during 32 years of follow-up.
The CE–fatty acid composition is largely determined by the dietary fat quality over the past few weeks19 and may therefore be regarded as a proxy for dietary fat quality. Previous studies of the present cohort have shown a fatty acid profile indicating a high dietary intake of saturated fats and low intake of linoleic acid to be related to insulin resistance,20 and to longitudinally predict LVH21 and myocardial infarction.16 In the present study, the same pattern indicating a high dietary intake of saturated fats and low intake of linoleic acid was related to incident stroke/TIA and BI/TIA. The FAPC from the factor analysis of all CE-fatty acids had high positive loadings by shorter saturated fatty acids and a high negative loading by linoleic acid. The FAPC may therefore be perceived as a marker for dietary saturated versus unsaturated fat. The FAPC, integrating information on all CE–fatty acids, was an independent predictor of stroke/TIA supporting the picture of an unhealthy dietary fat intake playing a role as a stroke/TIA risk factor. Our observations confirm and extend those from 2 case-control studies.6,22 Nevertheless, intervention trials have not been unanimously able to confirm significant reductions in cardiovascular mortality or morbidity or carotid artery disease when the diet was markedly enriched in linoleic or fish long-chain fatty acids.23,24 Favorable relations of linolenic acid to some surrogate cardiovascular end points have been observed. 
-linolenic acid has been demonstrated to lower platelet aggregation25 and to be cross-sectionally related to less carotid artery atherosclerosis,26 and administration has also been suggested as a promising target for neuroprotection after focal brain ischemia.27 In summary, the relations of fatty acid patterns to stroke incidence are to some extent still unclear.
A weak epidemiological correlation between hypercholesterolemia and increased risk for stroke has been demonstrated.28 In the present study, none of the established lipid measures, or apoA-1 and apoB were predictors of stroke/TIA.
A large longitudinal study in the elderly indicated that Lp(a) was an independent risk factor for stroke,7 as in a population-based case-control study,8 and as a predictor of combined cardiovascular events in a large cohort study.29 In the present study, we confirm those observations in a younger sample. It has been suggested that Lp(a) may participate actively in atherogenesis beyond being a marker of atherosclerosis.30 Through its low-density lipoprotein-like properties, Lp(a) may promote cholesterol deposition in the arterial wall. Moreover, because of the structural homology of its glycoprotein fraction, apo(a), Lp(a) may inhibit endothelial surface fibrinolysis by competing with plasminogen binding.31
Proinsulin showed the highest standardized hazard ratios of the glucometabolic variables in the present study. The relation of proinsulin to stroke has previously been reported in a case-control study.11 Serum proinsulin should probably be regarded as a proxy for insulin resistance, because it is unlikely that proinsulin has metabolic effects of its own in the serum level ranges observed in population samples.32 Insulin resistance, measured indirectly, has previously been demonstrated to be prevalent among stroke/TIA patients.10 Of the established risk factors for stroke that we adjusted for in the present study, 4 have repeatedly been demonstrated to play a major role in previous studies: high blood pressure, LVH, smoking, and atrial fibrillation.33–36 In our study we could again confirm that high blood pressure, ECG-LVH, and smoking increase the risk for stroke/TIA and ICH.
Strengths of the present investigation include the large community-based sample, the long follow-up, the nonexistent loss to follow-up, and the comprehensive characterization of metabolic variables. The sample is representative of the general population in Sweden regarding stroke incidence, according to data published by the Swedish National Board of Health and Welfare (http://www.sos.se/sos.se/sosmenye.htm). Because we only examined men of similar age with the same ethnic background, the results may have limited generalizability to women and to other age and ethnic groups. Another limitation is the lack of evidence regarding socioeconomic data, family history, and alcohol habits. The present cohort has been re-examined a few times since baseline and risk factors have been treated and they may therefore have been healthier during follow-up than the average man. Follow-up data concerning medication including antiplatelet therapy over time is not available. Other limitations of the study include possible misclassification of stroke, although the accuracy of the CDR and the SHDR has been shown to be high regarding the stroke diagnosis.37 Hospital discharge records were scrutinized in 50 random stroke cases showing a good correlation between registered diagnosis and the actual event. Furthermore, we do not have data concerning dietary habits and, in general, food habits have changed during the past decades. A high level of oleic acid in 1970 was a sign of high intake of fat in general, mainly from sources with high saturated fat content, whereas today when olive oil is in general use, a high intake could be related to an intake of more favorable dietary fat.
In conclusion, indices of an unhealthy dietary fat intake and a high serum Lp(a) level predicted fatal and nonfatal stroke/TIA independently of established risk factors in a study of a community-based sample of middle-aged men followed-up for 32 years. If these observations are confirmed in intervention studies, modification of food habits may play a role in the attempts to lessen stroke incidence.
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Acknowledgments |
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Sources of Funding
This study was kindly supported by grants from the Medical Faculty at Uppsala University, the Uppsala Geriatric Fund, and the Swedish Heart Lung Foundation.
Disclosures
Professor Lars Lind is employed part-time as a research consultant at the AstraZeneca. The company has no involvement in this study. All other authors report no conflict of interest.
Received April 17, 2006; revision received June 8, 2006; accepted August 14, 2006.
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