Thirty-Minute Office Blood Pressure Monitoring in Primary Care.

PURPOSE: Automated office blood pressure monitoring during 30 minutes (OBP30) may reduce overtreatment of patients with white-coat hypertension in primary health care. OBP30 results approximate those of ambulatory blood pressure monitoring, but OBP30 is much more convenient. In this study, we compared OBP30 with routine office blood pressure (OBP) readings for different indications in primary care and evaluated how OBP30 influenced the medication prescribing of family physicians. METHODS: All consecutive patients who underwent OBP30 for medical reasons over a 6-month period in a single primary health care center in the Netherlands were enrolled. We compared patients' OBP30 results with their last preceding routine OBP reading, and we asked their physicians why they ordered OBP30, how they treated their patients, and how they would have treated their patients without it. RESULTS: We enrolled 201 patients (mean age 68.6 years, 56.7% women). The mean systolic OBP30 was 22.8 mm Hg lower than the mean systolic OBP (95% CI, 19.8-26.1 mm Hg). The mean diastolic OBP30 was 11.6 mm Hg lower than the mean diastolic OBP (95% CI, 10.2-13.1 mm Hg). Considerable differences between OBP and OBP30 existed in patients with and without suspected white-coat hypertension, and differences were larger in individuals aged 70 years or older. Based on OBP alone, physicians said they would have started or intensified medication therapy in 79.1% of the studied cases (95% CI, 73.6%-84.6%). In fact, with the results of OBP30 available, physicians started or intensified medication therapy in 24.9% of cases (95% CI, 18.9%-30.9%). CONCLUSIONS: OBP30 yields considerably lower blood pressure readings than OBP in all studied patient groups. OBP30 is a promising technique to reduce overtreatment of white-coat hypertension in primary health care.

Anxiety and the Risk of Stroke: The Rotterdam Study.

BACKGROUND AND PURPOSE: It is unclear whether anxiety is a risk factor for stroke. We assessed the association between anxiety and the risk of incident stroke. METHODS: This population-based cohort study was based on 2 rounds of the Rotterdam Study. Each round was taken separately as baseline. In 1993 to 1995, anxiety symptoms were measured using the Hospital Anxiety and Depression Scale-Anxiety (HADS-A). In 2002 to 2004, anxiety disorders were assessed using the Munich version of the Composite International Diagnostic Interview. Participants were followed up for incident stroke until January 2012. RESULTS: In the sample undergoing HADS-A (N=2625; mean age at baseline, 68.4 years), 332 strokes occurred during 32 720 years of follow-up. HADS-A score was not associated with the risk of stroke during complete follow-up (adjusted hazard ratio, 1.02; 95% confidence interval, 0.74-1.43; for HADS-A≥8 compared with HADS-A <8), although we did find an increased risk after a shorter follow-up of 3 years (adjusted hazard ratio, 2.68; 95% confidence interval, 1.33-5.41). In the sample undergoing the Munich version of the Composite International Diagnostic Interview (N=8662; mean age at baseline, 66.1 years), 340 strokes occurred during 48 703 years of follow-up. Participants with any anxiety disorder had no higher risk of stroke than participants without anxiety disorder (adjusted hazard ratio, 0.95; 95% confidence interval, 0.64-1.43). We also did not observe an increased risk of stroke for the different subtypes of anxiety. CONCLUSIONS: Anxiety disorders were not associated with stroke in our general population study. Anxiety symptoms were only related to stroke in the short term, which needs further exploration.

Role of Prestroke Vascular Pathology in Long-Term Prognosis After Stroke: The Rotterdam Study.

BACKGROUND AND PURPOSE: Mortality after stroke remains high for years, mostly because of cardiovascular causes. Given that cardiovascular pathology plays an important role in causing the initial stroke, such prestroke pathology might also influence the prognosis after stroke. Within the population-based Rotterdam Study, we examined the proportion of deaths after stroke that are attributable to pre-existent cardiovascular risk factors before stroke (the population attributable risk). METHODS: We examined 1237 patients with first-ever stroke and 4928 stroke-free participants (between 1990 and 2012), matched on age, sex, examination round, and stroke date (index date). Cardiovascular risk factors measured on ≈4 years before index date were used as determinants. Participants were continuously followed up for mortality (≈6 years) after the index date. We calculated separate and combined population attributable risk of hypertension, total cholesterol, high-density lipoprotein-cholesterol, body mass index, diabetes mellitus, smoking, transient ischemic attack, and atrial fibrillation. RESULTS: Nine hundred and nineteen patients with stroke and 2654 stroke-free participants died. The combined population attributable risk in patients with stroke was 27% (95% confidence interval, 14%-45%) and in stroke-free participants was 19% (95% confidence interval, 12%-29%). Population attributable risks of diabetes mellitus, smoking, and atrial fibrillation were higher in patients with stroke than in the reference group because of a higher prevalence of risk factors. In addition, people with atrial fibrillation and stroke had a higher hazard ratio for death than those with only atrial fibrillation. CONCLUSIONS: One quarter of deaths after stroke could theoretically be prevented with rigorous cardiovascular prevention and treatment, but this should preferably start before stroke occurrence. In addition, research into factors explaining the remaining deaths needs to be encouraged.

Subjective memory complaints and the risk of stroke.

BACKGROUND AND PURPOSE: Persons with cognitive impairment, as assessed by cognitive tests, are at a higher risk of stroke. Subjective memory complaints might be an earlier marker for stroke, especially in persons with higher education. Their cognitive reserve might mask their cognitive impairment during cognitive testing. In a population-based setting, we investigated the association between subjective memory complaints and stroke. We simultaneously investigated the association between Mini-Mental State Examination and stroke. We also assessed whether these associations varied with educational level. METHODS: 9152 participants from the Rotterdam Study (baseline 1990-1993 or 2000-2001) completed the subjective memory complaints questionnaire and underwent Mini-Mental State Examination assessment. Subsequently, the entire cohort was followed for incident stroke until 2012. We used Cox proportional hazard models to estimate the associations between subjective memory complaints and Mini-Mental State Examination, with stroke. RESULTS: During a follow-up of 111 593 person years, 1134 strokes were identified, of which 663 were ischemic and 99 hemorrhagic. In the fully adjusted model, presence of subjective memory complaints was independently associated with a higher risk of stroke (hazard ratio, 1.20; 95% confidence interval, 1.04-1.39), but a higher Mini-Mental State Examination was not (hazard ratio per point increase, 0.99; 95% confidence interval, 0.95-1.02). The association between subjective memory complaints and risk of stroke was modified by educational level, with a higher risk of stroke in persons with a higher level of education (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). CONCLUSIONS: Subjective memory complaints might be an early indicator of stroke risk, especially in highly educated individuals.

The potential for prevention of dementia across two decades: the prospective, population-based Rotterdam Study.

BACKGROUND: Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades. METHODS: We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors. RESULTS: During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05-0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06-0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07-0.62) in the original cohort and 0.33 (95 % CI, 0.07-0.77) in the extended cohort. CONCLUSIONS: A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades.

Modifiable etiological factors and the burden of stroke from the Rotterdam study: a population-based cohort study.

BACKGROUND: Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke. METHODS AND FINDINGS: This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged ≥55 y and free from stroke at baseline (1990-1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population. The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41-0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41-0.68) for ischemic stroke and 0.70 (95% CI 0.45-0.87) for hemorrhagic stroke. The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population. CONCLUSIONS: About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors. Please see later in the article for the Editors' Summary.

[Musculoskeletal injections during the GP residency; deliberations of GP residents on the administration of musculoskeletal injections]. / Musculoskeletale injecties in de huisartsopleiding.

OBJECTIVE: Musculoskeletal injections can alleviate pain in certain problems of the musculoskeletal system. A significant part of general practitioners (GPs) does not feel competent to administer these injections while it is also known that medical residents of several specialties lack confidence in surgical and other technical skills. However, it is not known whether GP residents feel competent in these skills at the end of their residency and which factors are associated with this self-assessed competence. METHOD: To find out how GP residents think about musculoskeletal injections, twenty Dutch GP residents were interviewed in their final year using semi-structured interview techniques. These interviews were analyzed using template analysis. RESULTS: GP residents often experience a certain reluctance in the administration of musculoskeletal injections even though they mostly find that these injections do belong in primary care. The most named barriers are a low self-assessed competence and fear of septic arthritis, while other factors relate to the resident (confidence, coping style, and views on the specialty), the supervisor (their attitude), the patient (their situation and preferences), the injection (feasibility and estimated effectiveness) and the practice organization (office hours). CONCLUSION: GP residents consider many factors in their decision to administer musculoskeletal injections, most importantly their own competence and a fear of complications. Medical departments can help their residents through education on the decision-making process and the risks of certain interventions and provide opportunities to improve specific technical skills.

Genomewide association studies of stroke.

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Variation in the estrogen receptor alpha gene and risk of stroke: the Rotterdam Study.

BACKGROUND AND PURPOSE: Variations in the -397T>C (rs2234693) and -351A>G (rs9340799) single nucleotide polymorphisms of the estrogen alpha receptor (ESR1) gene were found to be strongly associated with risk of ischemic heart disease, although not all studies could replicate this finding. One study also reported an association with stroke. We assessed whether variations in the ESR1 gene are associated with the risk of stroke in the general population. METHODS: This prospective population-based study was based on 6229 Rotterdam Study participants who at baseline (1990-1993) were aged 55 years or older, free from stroke, and had assessment of the ESR1 rs2234693 and rs9340799 single nucleotide polymorphisms. Follow-up for incident stroke was complete until January 1, 2005. Data were analyzed with Cox proportional hazards models for men and women separately with adjustment for age. RESULTS: During an average follow-up time of 10.1 years, 659 strokes occurred, of which 386 were ischemic. Three common haplotypes were identified: -397T/-351A (carried by 78% of all participants), -397C/-351G (carried by 57%), and -397C/-351A (carried by 22%). Although we had at least 89% power to detect a relative risk of 1.5 (alpha=0.05) in all subgroups, we did not find any association between ESR1 haplotype carriership and risk of stroke and ischemic stroke. CONCLUSIONS: We have not been able to replicate the previously reported association between variations in the ESR1 gene and risk of stroke.

Prestroke cognitive performance, incident stroke, and risk of dementia: the Rotterdam Study.

BACKGROUND AND PURPOSE: Several studies indicate that stroke increases the risk of dementia. Most of these studies lacked the ability to take accurately assessed prestroke cognitive function into account. Whether the effects of stroke merely unravel an ongoing underlying dementing process or in fact cause the dementia has implications for the prevention of dementia in persons with cerebrovascular disease. We explored in a prospective cohort study whether stroke occurrence was related to a higher risk of subsequent dementia and whether this association was dependent on prestroke slope of cognitive function. METHODS: Cox proportional hazard models were used to relate incident stroke as a time-varying exposure with the risk of dementia in 6724 participants of the Rotterdam Study without dementia or stroke at baseline (49,361 person years of follow-up). Subsequently Cox proportional hazard models were performed to assess whether this association was dependent on slope of prestroke cognitive performance and other risk factors for cognitive decline. RESULTS: Independent of both level and the rate of change of prestroke cognitive performance and other risk factors for cognitive decline, incident stroke was associated with a more than doubled risk of subsequent dementia (hazard ratio, 2.1; 95% CI, 1.55 to 2.81). CONCLUSIONS: Prestroke cognitive function is not a major determinant of the effect of stroke on the risk of poststroke dementia.

Variation in fibrinogen FGG and FGA genes and risk of stroke: the Rotterdam Study.

Haplotypes of the fibrinogen gamma and alpha (FGG and FGA) genes are associated with the structure of the fibrin network and may therefore influence the risk of stroke. We investigated the relationship between common variation in these genes with ischemic and haemorrhagic stroke. The study was based on 6,275 participants of the prospective population-based Rotterdam Study who at baseline (1990-1993) were aged 55 years or over, free from stroke, and had successful assessment of at least one FGG or FGA single nucleotide polymorphisms (SNP). Common haplotypes were estimated using seven tagging SNPs across a 30 kb region containing the FGG and FGA genes. Follow-up for incident stroke was complete until January 1, 2005. Associations between constructed haplotypes and risk of stroke were estimated with an age- and sex-adjusted logistic regression model. We observed 668 strokes, of which 393 were ischemic and 62 haemorrhagic, during a median follow-up time of 10.1 years. FGG + FGA haplotype 3 (H3) was associated with an increased risk of ischemic stroke (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.09-1.69) and the risk estimate for hemorrhagic stroke was 0.71 (95% CI 0.46-1.09) compared to the most frequent H1. The FGG and FGA genes were not associated with stroke or its subtypes when analyzed separately. In conclusion, risk of ischemic stroke was higher in FGG + FGA H3 than in H1. The results suggested that an opposite association may exist for haemorrhagic stroke.

High serum C-reactive protein level is not an independent predictor for stroke: the Rotterdam Study.

BACKGROUND: Current guidelines recommend the assessment of C-reactive protein (CRP) levels with a high-sensitivity assay in cardiovascular risk prediction. Recent studies have put forward that although elevated CRP is a risk factor for cardiovascular disease, it is not helpful in the prediction of cardiovascular disease risk. We studied the importance of CRP as a risk factor and as a risk predictor of future stroke. METHODS AND RESULTS: The present study was based on 6430 participants of the Rotterdam Study who at baseline (1990-1993) were > or = 55 years of age, were stroke free, and had blood taken. Strokes were classified as hemorrhagic, ischemic, or unspecified. Ischemic strokes were further subclassified. Whether stroke risk varied with baseline CRP serum levels was assessed with Cox proportional hazards models. Whether CRP was helpful in the prediction of individual stroke risk was assessed with receiver operating characteristic curves and by comparing the distribution of strokes between predicted risk strata. During an average of 8.2 years of follow-up, 498 first-ever strokes occurred. High CRP levels were significantly associated with risk of any stroke (age- and sex-adjusted hazard ratio per SD, 1.14; 95% confidence interval, 1.04 to 1.24) and risk of ischemic stroke (age- and sex-adjusted hazard ratio per SD, 1.17; 95% confidence interval, 1.04 to 1.32). Taking CRP levels into account did not improve the individual stroke risk prediction, however, regardless of whether it was based on the Framingham stroke risk score or on age and sex only. CONCLUSIONS: Although CRP levels are associated with stroke risk, their use in the assessment of individual stroke risk seems limited.

Decreased glomerular filtration rate is a risk factor for hemorrhagic but not for ischemic stroke: the Rotterdam Study.

BACKGROUND AND PURPOSE: Persons with early stages of chronic kidney disease, defined by a decreased glomerular filtration rate (GFR), have an increased risk of cardiovascular disease. It is unclear whether decreased GFR is a risk factor for stroke. We assessed the association between GFR and stroke in a prospective population-based cohort study. METHODS: The study was based on 4937 participants of the Rotterdam Study who at baseline (1990 to 1993) were aged 55 years or over, free from stroke, and had serum creatinine assessment. GFR was estimated with the Cockcroft-Gault equation. Follow-up for incident cerebrovascular disease was complete until January 1, 2005. Data were analyzed with Cox proportional hazards models with adjustment for relevant confounders and results were expressed as hazard ratios with 95% CIs. RESULTS: During an average follow-up of 10.2 years, 586 strokes (338 ischemic, 44 hemorrhagic, and 204 unspecified strokes) occurred. We found no association between GFR and risk of overall stroke or risk of ischemic stroke. In contrast, with decreasing GFR, the risk of hemorrhagic stroke strongly increased; the age- and sex-adjusted hazard ratio for hemorrhagic stroke was 4.10 (95% CI, 1.25 to 13.42) for lowest versus highest quartile of GFR, and there was a clear and highly significant dose-effect relationship. Adjustment for other vascular risk factors only slightly attenuated this association. CONCLUSIONS: Decreased GFR is a strong risk factor for hemorrhagic, but not ischemic stroke.

Transcranial Doppler hemodynamic parameters and risk of stroke: the Rotterdam study.

BACKGROUND AND PURPOSE: We explored the association between transcranial Doppler hemodynamic parameters and the risk of stroke in the general population. METHODS: At baseline, we assessed mean flow velocity, peak systolic flow velocity, end diastolic flow velocity, and vasomotor reactivity with transcranial Doppler in 2022 Rotterdam Study participants aged 61 years and over in both middle cerebral arteries. All participants, who at baseline were free from previous stroke, were subsequently followed for occurrence of stroke (average follow-up time 5.1 years). We calculated hazard ratios for the association between hemodynamic parameters and risk of stroke using Cox proportional hazards models with adjustment for age, sex, systolic blood pressure, antihypertensive drug use, diabetes mellitus, ever smoking, current smoking, carotid intima media thickness, and carotid distensibility. RESULTS: Risk of stroke (n=122) and ischemic stroke (n=89) increased with increasing middle cerebral artery flow velocity; when comparing the tertile with highest velocity to the tertile with lowest velocity, the hazard ratio was 1.74 (95% CI: 1.09 to 2.77) for the association between mean flow velocity and stroke, 1.63 (95% CI: 1.03 to 2.58) for end diastolic flow velocity and stroke, and 1.33 (95% CI: 0.86 to 2.08) for peak systolic flow velocity and stroke. These estimates increased 10% to 26% when only ischemic strokes were included. The side of highest flow velocity was not associated with the side of stroke. We found no associations between vasomotor reactivity and risk of stroke. CONCLUSIONS: Risk of stroke increased strongly with increasing middle cerebral artery flow velocity as measured with transcranial Doppler in the general population.

Incidence and prognosis of transient neurological attacks.

CONTEXT: Transient neurological attacks (TNAs) are attacks with temporary (<24 hours) neurological symptoms. These symptoms can be focal, nonfocal, or a mixture of both. The prognostic significance of TNAs with focal symptoms (better known as transient ischemic attacks [TIAs]) is well understood. Conversely, hardly anything is known about the prognostic significance of TNAs with nonfocal or mixed symptoms. OBJECTIVE: To study the incidence and prognosis of focal TNAs (or TIAs), nonfocal TNAs, and mixed TNAs. DESIGN, SETTING, AND PARTICIPANTS: The study population comprised 6062 community-dwelling Rotterdam Study participants who were aged 55 years or older and free from stroke, myocardial infarction, and dementia at baseline (1990-1993). They were followed up for events until January 1, 2005. We analyzed the associations between incident TNAs and subsequent adverse events with age- and sex-adjusted Cox regression models. MAIN OUTCOME MEASURES: Stroke, ischemic heart disease, or dementia. RESULTS: During 60 535 person-years, 548 participants developed TNA (282 focal, 228 nonfocal, and 38 mixed). The incidence rate per 1000 person-years was 4.7 (95% confidence interval [CI], 4.1-5.2) for focal TNA, 3.8 (95% CI, 3.3-4.3) for nonfocal TNA, and 0.6 (95% CI, 0.4-0.9) for mixed TNA. Participants with focal TNA were at higher risk of subsequent stroke than participants without TNA (n = 46 vs 540; hazard ratio [HR], 2.14; 95% confidence interval [CI]; 1.57-2.91) but had an equal risk of ischemic heart disease and dementia. Nonfocal TNA patients were at higher risk of stroke (27 vs 540; HR, 1.56; 95% CI, 1.08-2.28) and dementia (30 vs 552; HR, 1.59; 95% CI, 1.11-2.26) than participants without TNA. Mixed TNA patients were at higher risk of stroke (6 vs 540; HR, 2.48; 95% CI, 1.11-5.56), ischemic heart disease (8 vs 779; HR, 2.26; 95% CI, 1.07-4.78), vascular death (8 vs 594; HR, 2.54; 95% CI, 1.31-4.91), and dementia (7 vs 552; HR, 3.46; 95% CI, 1.72-6.98) than participants without TNA. CONCLUSION: Patients who experience nonfocal TNAs, and especially those with mixed TNAs, have a higher risk of major vascular diseases and dementia than persons without TNA.

Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study.

BACKGROUND AND PURPOSE: The role of uric acid as a risk factor for myocardial infarction is controversial, and little is known about its role as a risk factor for stroke. Recent evidence suggests that uric acid may be an important causal agent in cardiovascular disease, for example, by inducing renal disease and hence hypertension. We investigated the association between serum uric acid and coronary heart disease and stroke in a large prospective population-based study. METHODS: The study was based on 4385 participants of the Rotterdam Study who, at baseline (1990 to 1993), were > or =55 years of age, free from stroke and coronary heart disease, and had blood taken. Follow-up for incident stroke and myocardial infarction was complete until January 1, 2002. Data were analyzed with Cox proportional hazards models with adjustment for relevant confounders. RESULTS: Average follow-up was 8.4 years. High serum uric acid levels were associated with risk of myocardial infarction and stroke; age- and sex-adjusted hazard ratios (95% CIs) for highest versus lowest quintile of uric acid were 1.68 (1.24 to 2.27) for cardiovascular disease (515 cases), 1.87 (1.12 to 3.13) for myocardial infarction (194 cases), 1.57 (1.11 to 2.22) for stroke (381 cases), 1.77 (1.10 to 2.83) for ischemic stroke (205 cases), and 1.68 (0.68 to 4.15) for hemorrhagic stroke (46 cases). Adjustment for other vascular risk factors only slightly attenuated these associations. Associations were stronger in persons without hypertension than in those with hypertension. CONCLUSIONS: Uric acid is a strong risk factor for myocardial infarction and stroke.

Alpha-adducin polymorphism, atherosclerosis, and cardiovascular and cerebrovascular risk.

BACKGROUND AND PURPOSE: Carriers of the 460Trp allele of the alpha-adducin gene (ADD1) show higher rates of sodium reabsorption compared with homozygous carriers of the Gly460 allele and were found to have an increased risk of hypertension and cardiovascular disease. We studied the association between the Gly460Trp polymorphism and atherosclerosis, cardiovascular disease, and cerebrovascular disease. METHODS: Intima-media thickness of the common carotid artery, as well as incident stroke and myocardial infarction, were studied within 6471 subjects of the Rotterdam Study. Within 1018 subjects of the Rotterdam Scan Study, prevalent silent brain infarcts and cerebral white matter lesions were studied. Subjects were grouped into 460Trp carriers (variant carriers) and homozygous carriers of the Gly460 allele (reference). RESULTS: Intima-media thickness of the common carotid artery was 0.80 mm in variant carriers compared with 0.79 mm in the reference group (P=0.04). Variant carriers had an increased risk of any stroke (hazard ratio [HR], 1.22; 95% CI, 1.02 to 1.45), ischemic stroke (HR, 1.29; 95% CI, 1.02 to 1.63), hemorrhagic stroke (HR, 1.07; 95% CI, 0.59 to 1.92), and of myocardial infarction (HR, 1.33; 95% CI, 1.05 to 1.69). For any ischemic stroke, there was a significant interaction between the Gly460Trp polymorphism and hypertension. Variant carriers more often had a silent brain infarct (odds ratio, 1.36; 95% CI, 0.98 to 1.88) and had more subcortical white matter lesions than the reference group (1.45 vs1.24 mL; P=0.22). CONCLUSIONS: The Gly460Trp polymorphism is associated with atherosclerosis, cardiovascular disease, and cerebrovascular disease, especially in hypertensive subjects.

TGF-beta 1 polymorphisms and risk of myocardial infarction and stroke: the Rotterdam Study.

BACKGROUND AND PURPOSE: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cardiovascular and cerebrovascular complications. Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine with a central role in inflammation. Little is known of the relation of variations within the gene and risk of cardiovascular and cerebrovascular disease. We therefore investigated 5 polymorphisms in the TGF-beta1 gene (-800 G/A, -509 C/T, codon 10 Leu/Pro, codon 25 Arg/Pro, and codon 263 Thr/Ile) in relation to the risk of myocardial infarction and stroke in a population-based study. METHODS: Participants (N=6456) of the Rotterdam Study were included in the current study. Analyses of the relations of genotypes with the risk of myocardial infarction and stroke were performed according to Cox proportional-hazards methods. All analyses were adjusted for age, sex, conventional cardiovascular risk factors, and medical history. RESULTS: We found no association with the risk of myocardial infarction. A significantly increased risk of stroke was found, associated with the T allele of the -509 C/T polymorphism (relative risk, 1.26; (95% CI, 1.06 to 1.49) and the Pro variant of the codon 10 polymorphism (relative risk, 1.24; 95% CI, 1.04 to 1.48). CONCLUSIONS: No association between the TGF-beta1 polymorphisms and myocardial infarction was observed; however, the -509 C/T and codon 10 Leu/Pro polymorphisms were associated with the risk of stroke.

Plasma homocysteine is a risk factor for recurrent vascular events in young patients with an ischaemic stroke or TIA.

OBJECTIVES: Young patients with an ischaemic stroke or transient ischaemic attack (TIA) often have no vascular risk factors. Hyper-homocysteinaemia is an established risk factor for stroke in elderly patients but it is uncertain whether it is also important for the prognosis of young ischaemic stroke and TIA patients. We examined the possible effect of the plasma homocysteine level on the risk of recurrent vascular events in patients between 18 and 45 years of age. METHODS: The study population consisted of 161 consecutive patients with a recent cerebral infarction or TIA. Data on the primary event and the homocysteine level were collected retrospectively from hospital records. General practitioners and patients were contacted by telephone to record vascular events and the type of medication used during the follow-up period. Vascular events included cerebral infarction, TIA, pulmonary embolism, venous thrombosis, myocardial infarction and peripheral arterial disease. RESULTS: A Kaplan- Meier curve showed a dose effect relationship between event-free survival time and tertiles of the homocysteine level (Log rank statistic 5.91; p=0.05). The Cox hazard ratio, after adjustment for homocysteine lowering treatment, was 1.7 (95 % CI, 1.1 to 2.8) for any vascular outcome event, 1.9 (95% CI, 1.1 to 3.0) for arterial outcome events and 1.8 (95 % CI, 1.1 to 2.9) for cerebral outcome events. CONCLUSIONS: In spite of our small number of outcome events we found a significant association at the 95% confidence level between homocysteine level and the risk of recurrent vascular events in young patients with an ischaemic stroke or TIA. The association is of the same magnitude as in elderly people.

Subclinical cardiac dysfunction increases the risk of stroke and dementia: the Rotterdam Study.

OBJECTIVE: To investigate the association between cardiac function and the risk of stroke and dementia in elderly free of clinical cardiac disease. Additionally, we investigated the relation between cardiac function and MRI markers of subclinical cerebrovascular disease. METHODS: This study was conducted within the population-based Rotterdam Study. A total of 3,291 participants (60.8% female, age-range 58-98 years) free of coronary heart disease, heart failure, atrial fibrillation, stroke, and dementia underwent echocardiography in 2002-2005 to measure cardiac function. Follow-up finished in 2012. In 2005-2006, a random subset of 577 stroke-free people without dementia underwent brain MRI on which infarcts and white matter lesion volume were assessed. RESULTS: During 21,785 person-years of follow-up, 164 people had a stroke and during 19,462 person-years of follow-up, 208 people developed dementia. Measures of better diastolic function, such as higher E/A ratio, were associated with a lower risk of stroke (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.69; 0.98) and dementia (HR 0.82; 95% CI 0.70; 0.96). Better systolic function, measured as higher fractional shortening, was only associated with a lower risk of stroke (HR 0.84; 95% CI 0.72; 0.98). Better diastolic function was related to a lower prevalence of silent infarcts on MRI, especially lacunar infarcts. CONCLUSIONS: In elderly free of clinical cardiac disease, worse diastolic function is associated with clinical stroke, dementia, and silent infarcts on MRI, whereas worse systolic function is related only to clinical stroke. These findings can form the basis for future research on the utility of cardiac function as potential intervention target for prevention of neurologic diseases.