IJE Advance Access originally published online on October 24, 2008
International Journal of Epidemiology 2009 38(1):253-261; doi:10.1093/ije/dyn215
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Adipocytokines and risk of stroke in older people: a nested case–control study
1 Division of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Scotland, UK.
2 Robertson Centre for Biostatistics, University of Glasgow, Scotland, UK.
3 Department of Vascular Biochemistry, Faculty of Medicine, University of Glasgow, Scotland, UK.
4 Section of Gerontology and Geriatrics, Department of General Internal Medicine, Leiden University Medical Centre, The Netherlands.
5 Department of Cardiology, Leiden University Medical Centre, The Netherlands.
* Corresponding author. Academic Section of Geriatric Medicine, 3rd Floor Queen Elizabeth Building, Glasgow Royal Infirmary, Glasgow G31 2ER, Scotland, UK. E-mail: d.j.stott{at}clinmed.gla.ac.uk
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Abstract |
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Background Inflammation may play an important role in atherothrombosis and in promoting cerebral damage after stroke. We hypothesized that plasma adipocytokine concentrations would be associated with risk of stroke in older people.
Methods Nested case–control study from the Prospective Study of Pravastatin in the Elderly (PROSPER). Subjects were aged 70–82 years and followed up for a mean of 3.2 years: 266 incident stroke cases (179 confirmed as ischaemic) were compared with 532 controls matched for age, gender and treatment allocation (pravastatin or placebo). Adipocytokines [adiponectin, interleukin- (IL-)18 and tumour necrosis factor (TNF)
] were measured on stored baseline plasma samples.
Results Elevated plasma adiponectin was associated with lower risk of ischaemic stroke on univariate analysis: odds ratio (OR) 0.78 per 1 SD increase (95% CI 0.62–0.97). There were no associations of IL-18 or TNF with risk for ischaemic or total strokes. In multivariate models the independent predictors of ischaemic stroke were prior cerebrovascular accident (OR 2.68, 95% CI 1.60–4.50), any alcohol use (1.98, 1.33–2.94), triglycerides (1.40, 1.11–1.77), Barthel score (0.75, 0.58–0.96) and known diabetes (1.72, 1.04–2.83); adiponectin, IL-18 and TNF did not contribute. A similar pattern of risk was seen for total stroke.
Conclusions Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL-18 and TNF are unlikely to play any important part. These adipocytokines do not have clinical predictive utility; history of prior cerebrovascular accident, known diabetes mellitus, prior disability and higher alcohol intake explain much of the stroke risk.
Keywords Stroke, inflammation, adiponectin, tumour necrosis factor
, interleukin-18, case–control study, agedAccepted 3 September 2008
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Introduction |
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Inflammation plays an important role in atherothrombosis,1 and potentially also in promoting cerebral ischaemia following arterial occlusion.2 Circulating ‘downstream’ inflammatory markers such as C-reactive protein (CRP)3–5 and fibrinogen6 have been associated with increased risk of stroke as well as coronary heart disease (CHD); however, whether these associations are cause, consequence or due to confounding is uncertain. Furthermore, there is limited data from prospective cohort studies on the association of other circulating cytokines such as interleukin- (IL-)18 and tumour necrosis factor (TNF)
7 or the adipokine, adiponectin,8 with incident stroke. In terms of mechanisms of disease, these cytokines act ‘upstream’ of more established biomarkers such as CRP and fibrinogen. Adiponectin has apparent anti-inflammatory and anti-atherogenic properties. It is mainly secreted by adipocytes9 and low levels are strongly associated with increased risk of type-2 diabetes mellitus. Low levels have also been associated with increased mortality after ischaemic stroke.10 IL-18 is a potent proinflammatory cytokine with potential atherogenic properties. Particularly high levels of IL-18 messenger ribonucleic acid are found in unstable carotid plaque,11 and circulating IL-18 may be increased after ischaemic stroke.12 TNF is one of the most prominent inflammatory mediators and central in starting off the inflammatory reactions of the innate immune system. Elevated levels of TNF are associated with increased risk of recurrent myocardial infarction.13 Levels may also be increased after acute stroke.14,15 However, data examining the association of circulating adiponectin, IL-18 or TNF with incident total or ischaemic stroke are sparse.
We hypothesized that a proinflammatory profile of adipocytokines (reduced adiponectin and increased IL-18 and TNF) creates a pro-atherosclerotic,16 and prothrombotic environment,17 contributing to the aetiology of stroke in older people. We also hypothesized that these adipocytokines have clinical predictive utility, over and above traditional cardiovascular risk factors. The research questions were as follows; are reduced levels of adiponectin and increased plasma levels of IL-18 and TNF associated with increased risk of total and ischaemic stroke? If associations are found are these independent of traditional risk factors and of ‘downstream’ markers of activation of the inflammation cascade, including CRP and fibrinogen?
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Methods |
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This was a nested case–control study; 266 patients with incident stroke were compared with 532 controls from the PROSPER cohort.18 Matching variables included age (within 5 years), gender (in part to overcome gender differences in adiponectin) and treatment allocated (pravastatin or placebo). The PROSPER study was a randomized placebo-controlled trial of pravastatin in 5804 subjects (2520 in Scotland, 2184 Ireland and 1100 The Netherlands) aged 70–82 years, with vascular risk factors or known vascular disease.19 The follow-up from the randomized controlled phase of the trial was completed by May 2002. The trial showed that 3.2 years of lipid-lowering treatment with pravastatin 40 mg in elderly subjects reduced the risk of myocardial infarction but had no significant effect on stroke.18
A blinded endpoints committee reviewed and adjudicated all incident vascular endpoints, including all possible strokes. Stroke was defined as: (i) rapid onset of focal neurological deficit lasting 
24 h, (ii) focal neurological deficit mode of onset uncertain but with no plausible evidence of alternative (non-stroke) cause or (iii) rapid onset of global neurological deficit (e.g. coma) lasting 24 h with no other plausible non-stroke cause. Strokes were categorized as ischaemic or haemorrhagic on the basis of neuroimaging (computed tomography or magnetic resonance imaging) or post-mortem. Where no neuroimaging or post-mortem was available strokes were categorized as ‘unclassified’. Of the 266 incident strokes in PROSPER 179 (67%) were infarcts, 18 (7%) primary intracerebral haemorrhages and 69 (26%) undefined.
Assays of adiponectin, IL-18 and TNF were performed on 0.3 ml stored EDTA plasma from a fasting venous blood sample taken at study baseline, using conventional (adiponectin, IL-18) and high-sensitivity (TNF) ELISAs (R&D Systems, Oxford, UK). The intra-assay co-efficients of variation for these assays were <7%, 5.6% and 8.4%, respectively.
A priori power calculations were performed for all stroke and confirmed ischaemic stroke. For adiponectin, with a mean of 8.46 µg/ml and a SD of 4.5 (SAPHIR study20), we estimated 85% power to detect a 15% difference between cases and controls for total stroke. For IL-18, with a geometric mean of 160 pg/ml and a SD of 32 (MONICA Augsberg region21), we estimated 91% power to detect a 5% difference between cases and controls for total stroke. For TNF, with a mean of 3.23 and a SD of 1.33 (based on a cohort study in an older population22), we estimated 89% power to detect a 10% difference between cases and controls for total stroke. For ischaemic strokes (n = 179), we estimated 80% power to detect differences between the cases and controls of 14% for adiponectin, 6% for IL-18 and 11% for TNF. The order of magnitude that we had power to detect is similar to that observed for CRP, with a 9% increase in those who have recurrent stroke, compared with those who do not.23
Data were analysed using the SAS version 9.1 software package (SAS Institute Inc., Cary, NC, USA). Baseline variables were summarized as mean (SD) for continuous variables and as number (%) for categorical variables. Where necessary (e.g. for CRP and IL-6) continuous variables were transformed logarithmically to give a near-normal distribution of data for parametric analysis. Statistical analyses included calculation of the univariate conditional logistic regression odds ratio (OR) for baseline characteristics, for both total stroke and for ischaemic stroke compared with controls. The OR for continuous variables was calculated for a 1 SD (taken from the control group) increase. To assess the independent prognostic value of adiponectin, IL-18 and TNF, multivariate conditional logistic regression models were fitted. The models included known risk factors such as history of vascular disease and CRP, and were carried out for both total stroke and for ischaemic stroke compared with controls.
Local hospital Ethics Committees in Scotland, Ireland and the Netherlands approved the PROSPER study including the biobank and laboratory analyses.
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Results |
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Baseline clinical characteristics of the 266 patients with all incident strokes compared with 532 age- and sex-matched controls are presented in Table 1. Prior history of stroke (OR 2.48, 95% CI 1.62–3.79), myocardial infarction (OR 1.54, 1.02–2.32) and diabetes mellitus (OR 1.59, 1.05–2.41) were associated with increased risk of stroke, as were lower cognitive function (Mini-Mental State Examination; OR 0.84, 0.73–0.97) reduced speed of information processing (STROOP; OR 1.16, 1.00–1.34), lower Instrumental Activities of Daily Living score (OR 0.86, 0.76–0.97) and reduced Barthel index (OR 0.83, 0.75–0.93) at baseline. Similar associations were seen for the subgroup of subjects with ischaemic stroke compared with controls. Prior history of stroke (OR 2.30, 1.42–3.74) and diabetes mellitus (OR 1.91, 1.22–3.01) were associated with increased risk, as were lower cognitive function (Mini-Mental State Examination; OR 0.83, 0.70–0.97), reduced speed of information processing (STROOP test; OR 1.23, 1.04–1.45) and reduced Barthel index (OR 0.83, 0.73–0.94) at baseline.
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Comparing all subjects with incident stroke with non-stroke subjects there were no differences in baseline TNF
(OR 0.91, 0.76–1.10) or IL-18 (OR 1.06, 0.92–1.22), with a trend for reduced adiponectin in patients with incident stroke (OR 0.86, 0.72–1.03) (Table 2). There were also no apparent differences between all stroke cases and controls in CRP or IL-6. Fasting glucose level was increased in those with incident stroke (OR 1.18, 1.04–1.34).
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Restricting analysis to only the predefined incident ischaemic stroke cases, baseline plasma adiponectin was lower in the cases (mean 6.07 µg/ml) compared with controls (6.99 µg/ml) (Table 2). However, restricting analysis to those with ischaemic stroke did not reveal any trends for increased IL-18 or TNF
among the case population compared with controls.
We analysed separately results of laboratory variables for the subgroups of patients on placebo and for those on pravastatin. There were no convincing differences between patients allocated to placebo vs those allocated pravastatin, however, there was a trend for IL-6 to be higher in those with incident stroke who were allocated to placebo (OR 1.15, 0.93–1.42) and no such trend was observed for those allocated to pravastatin (OR 0.88, 0.68–1.14). There was also a trend for TNF to be lower in incident stroke cases whom were allocated pravastatin (OR 0.71, 0.44–1.13) when no such trend was observed for those allocated placebo (OR 1.04, 0.83–1.31).
Table 3 illustrates associations of adiponectin, IL-18 and TNF with risk of total or ischaemic stroke using conditional logistic regression with all three biomarkers in a multivariate model also adjusting for log CRP, log IL-6 and fibrinogen. As expected from previous comparisons, neither IL-18 nor TNF showed any associations with stroke risk. Adiponectin levels were inversely associated with ischaemic stroke risk, such that 1 SD increase in adiponectin levels was associated with a multivariate OR of 0.79 (95% CI 0.63–0.99).
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The independent predictors of ischaemic stroke in the case–control study are shown in a stepwise addition multivariable model (Table 4). Independent predictors included previous cerebrovascular accident (multivariate OR 2.68, 95% CI 1.60–4.5), any alcohol use (OR 1.98, 1.33–2.94), triglycerides (OR 1.40, 1.11–1.77), Barthel score (OR 0.75, 0.58–0.96) and history of diabetes (OR 1.72, 1.04–2.83). A similar pattern of risk was seen for incident total stroke, with previous cerebrovascular accident, alcohol and Barthel score persisting as independent risk factors, as well as blood glucose and smoking. Therefore, no inflammatory cytokines or indicators of adiposity (in Tables 1 and 2) were independently associated with risk of ischaemic or all-stroke in this elderly population. When added into the multivariable model for total stroke the adiponectin multivariate OR = 0.967 (0.930–1.005, P = 0.085), TNF
OR = 0.988 (0.928–1.052, P = 0.711) and IL-18 OR = 1.000 (1.000–1.001, P = 0.323). When added into the multivariable model for ischaemic stroke the adiponectin OR = 0.963 (0.917–1.011, P = 0.127), TNF OR = 1.002 (0.937–1.072, P = 0.949) and IL-18 OR = 1.001 (1.000–1.002, P = 0.259).
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Discussion |
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To our knowledge, this is the largest study to date examining associations of adiponectin, IL-18 or TNF
with the risk of incident stroke in a population comprising both those without and those with prior history of clinical ischaemic events. Although adiponectin was associated with risk for ischaemic stroke in older subjects, independent of other measures of inflammation, the strength of association was relatively modest. Adiponectin is an insulin-sensitizing anti-inflammatory and anti-atherogenic cytokine mainly secreted by adipocytes. Levels are reduced in obesity and diabetes mellitus.9 The effects of ageing on adiponectin levels are uncertain, with variable results from cross-sectional studies; some report an increase in older people,24,25 others a reduction26 and some no change.25 However, centenarians have high levels,27 and it has therefore been suggested that increased levels of adiponectin may promote healthy ageing. Part of the confusion in the literature may relate to complexities in interpreting benefits from higher levels of adiponectin vs pathological increases as in heart failure.28 Adiponectin is inversely related to CRP and other cytokines, in line with its putative anti-inflammatory actions, although the correlations that we found between adiponectin and other markers of inflammation were very weak (Table 5). Lower levels were originally associated with increased risk of acute myocardial infarction, but a recent meta-analysis of data from prospective studies of generally middle-aged populations has questioned this.29 In contrast low levels have been shown to independently predict increased mortality after ischaemic stroke; long-term (5 years) survivors had an adiponectin level of 7.3 compared with 4.1 µg/ml for those who died during follow-up.9,10 However, our data are in line with recent findings in another nested case–control study where adiponectin was associated with risk in univariable models, but not after adjusting for confounders.8
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IL-18 and TNF
were not predictive of incidence of either total or ischaemic stroke in this older cohort.11,12 Moderate associations of IL-18 with risk of myocardial infarction and with outcome in patients with ischaemic heart disease have been demonstrated in previous studies30,31 although more complete adjustment models from more recent data may question this.32,33 A haplotype of the IL-18 gene that is associated with lower IL-18 levels may be associated with reduced cardiovascular risk in middle-aged men with coronary artery disease.34 However, our data suggest IL-18 is not an important aetiological factor for total or ischaemic stroke in older people, in line with a recent study that found IL-18 was not associated with increased risk of stroke recurrence.7
TNF is one of the most prominent inflammatory mediators. Levels increase with ageing, and may contribute to the high prevalence of insulin resistance in older people.35 Elevated levels of TNF are associated with increased risk of first myocardial infarction in healthy elderly people,36 recurrent myocardial infarction13 and levels may also be increased after acute stroke.14,15 However, little is known about the predictive value of circulating TNF for incident stroke. The Health ABC study found no significant association of TNF with risk of stroke, but was underpowered with only 60 incident stroke cases.36 Our data with larger number of incident events appear to verify this observation.
In addition to exploring the potential aetiological role of adipocytokines in stroke in older people, we have also examined the possible clinical utility of these biomarkers. We found that adiponectin, IL-18 and TNF were not useful predictors of incident total or ischaemic stroke. The major independent risk factors for ischaemic stroke in this elderly cohort included a history of previous stroke or transient ischaemic attack, diabetes mellitus, alcohol and triglycerides. The risks that we have observed for a previous cerebrovascular event and diabetes mellitus are similar to those previously reported in the literature.37,38 We found that alcohol intake was associated with increased risk of total and ischaemic stroke. The literature suggests that alcohol has a complex non-linear relationship with ischaemic stroke, with low or moderate intakes associated with reduced and high intake with increased risk; in contrast haemorrhagic stroke has a linear association with increasing alcohol intake.39 The relationship of triglycerides to stroke risk is controversial, with inconsistent results in different studies. It has been claimed that post-prandial levels may be a better predictor than those in the fasting state.40 Disability is a relatively novel risk factor for stroke, which is likely to be particular to older people. We found impaired activities of daily living to be associated with increased risk of incident total and ischaemic stroke. The evidence that reduced ability to perform activities of daily living is associated with increased risk of future stroke is limited. Poor scores on the physical function and mental health sections of the Short-form 36 have been associated with increased risk of stroke in older people, although this was not independent of other risk factors.41 It is plausible that older subjects with impaired ability to perform activities of daily living42 either carry an increased burden of covert ischaemic vascular disease as a contributor to their disability, or are generally less physically active, and hence they will be at increased risk of stroke.
Strengths and limitations of this study require consideration. Stroke is a complex condition to study due to the heterogeneity of the pathophysiology. This study provides detailed patient assessment including cognitive function and measures of disability, and careful and systematic follow-up of stroke, using a priori defined criteria. Categorization of stroke type as infarct or haemorrhage was possible in around three-quarters of our stroke patients. In an elderly stroke cohort it is to be expected that some are not investigated and cannot be categorized, for example with very severe and rapidly fatal strokes or other major co-morbidity. Despite this, the dataset allowed pre-specified subgroup analysis of those confirmed to have had an ischaemic stroke from neuroimaging or autopsy. In the study it was not possible to subtype ischaemic strokes. However, the proinflammatory hypothesis may be relevant for all the main causes of ischaemic stroke, including intrinsic small vessel disease (with lacunar infarction), cardioembolism or large artery disease (such as carotid stenosis). The population that we studied came from a randomized controlled trial of pravastatin, however there was no interaction between active and placebo group status for the main analysis in the present report. It is possible that pravastatin might confound any association of a pro-inflammatory state with incident stroke by damping down the inflammatory response. However, in our separate analyses of placebo and pravastatin allocated patients we found no consistent evidence to suggest any important bias from treatment allocation. Another limitation is that adipocytokines were measured only once and therefore our data do not allow adjustment for possible regression dilution bias. We did not have any reliable data source to allow us to perform an imputation to correct for this potential source of bias. Lastly, we acknowledge the results of the study may not be generalizable to all elderly patients due to the high prevalence of vascular disease in our cohort and exclusion of subjects with atrial fibrillation. However, our adiponectin results are very similar to those reported in a recent study.8
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Conclusion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionSupplementary dataFundingReferences |
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Reduced adiponectin may have a modest role in the aetiology of ischaemic stroke in older people, however IL-18 and TNF
are unlikely to play any important part. None of these adipocytokines have clinical predictive utility for total or ischaemic stroke; more easily ascertained risk factors, inclusive of history of prior cerebrovascular accident, alcohol intake and known diabetes mellitus, were the major predictors for incident stroke. Prior disability is also an important predictor of stroke in older age; it is likely this is a marker of more severe underlying vascular disease. Finally, our results suggest that more aggressive risk factor management in those with prior cerebrovascular disease or known diabetes has the potential to reduce subsequent stroke risk in older people. |
Supplementary data |
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Supplementary data are available at IJE online.
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Funding |
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Scottish Executive Health Department Biomedical and Therapeutics Committee (reference CBZ/4/530).
Conflict of interest: None declared.
KEY MESSAGES
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  R. B Schnabel and S. Blankenberg Commentary: Circulating cytokines and risk stratification of stroke incidence--will we do better in future? Int. J. Epidemiol., February 1, 2009; 38(1): 261 - 262. [Full Text] [PDF]
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