http://repub.eur.nl/res/aut/19894/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/21425/ 2010-11-01T00:00:00Z Patients with heart failure used to have an increased risk of stroke, but this may have changed with current treatment regimens. We assessed the association between heart failure and the risk of stroke in a population-based cohort that was followed since 1990. The study uses the cohort of the Rotterdam Study and is based on 7,546 participants who at baseline (1990-1993) were aged 55 years or over and free from stroke. The associations between heart failure and risk of stroke were assessed using time-dependent Cox proportional hazards models, adjusted for cardiovascular risk factors (smoking, diabetes mellitus, BMI, ankle brachial index, blood pressure, atrial fibrillation, myocardial infarction and relevant medication). At baseline, 233 participants had heart failure. During an average follow-up time of 9.7 years, 1,014 persons developed heart failure, and 827 strokes (470 ischemic, 75 hemorrhagic, 282 unclassified) occurred. The risk of ischemic stroke was more than five-fold increased in the first month after diagnosis of heart failure (age and sex adjusted HR 5.79, 95% CI 2.15-15.62), but attenuated over time (age and sex adjusted HR 3.50 [95% CI 1.96-6.25] after 1-6 months and 0.83 [95% CI 0.53-1.29] after 0.5-6 years). Additional adjustment for cardiovascular risk factors only marginally attenuated these risks. In conclusion, the risk of ischemic stroke is strongly increased shortly after the diagnosis of heart failure but returns to normal within 6 months after onset of heart failure. http://repub.eur.nl/res/pub/22447/ 2009-09-01T00:00:00Z 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. http://repub.eur.nl/res/pub/16532/ 2009-04-23T00:00:00Z 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<5×10-8). 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. http://repub.eur.nl/res/pub/30269/ 2008-12-01T00:00:00Z Background: Information on incidence of stroke is important for developing and maintaining public health strategies in primary and secondary prevention. Nationwide data on the incidence of stroke are scarce and absent for the Netherlands. Methods: New cases of first stroke and stroke subtypes in the Dutch population in 2000 were identified through linkage of national registers and included hospitalized patients for first stroke and out-of-hospital deaths from first stroke. The number of non-fatal, non-hospitalized stroke patients was estimated based on data from the Rotterdam study, a population based cohort. Results: We identified 26 556 patients with a first stroke (20 798 hospitalized patients, 5758 out-of-hospital deaths). The number of non-fatal, non-hospitalized first stroke patients was estimated to be 12 255. Extrapolation of the data to the total Dutch population led to an overall estimate of approximately 41 000 patients with a first stroke. Stroke incidence increased with age and was higher in men than in women, except in the lowest (< 45 years) and highest age group (> 85 years). Conclusions: The present study provides for the first time incidence estimates of first stroke (hospitalized patients, out-of hospital deaths and non-fatal, non-hospitalized patients) based upon virtually the entire Dutch population. http://repub.eur.nl/res/pub/29117/ 2008-11-01T00:00:00Z http://repub.eur.nl/res/pub/29244/ 2008-09-01T00:00:00Z Background: Previous studies that have assessed whether the presence of depressive symptoms predisposes to stroke in the general elderly population have been contradictory. Moreover, they did not distinguish between men and women and did not perform psychiatric workups in those with depressive symptoms. This study examines the association between depressive symptoms, depressive disorder and the risk of stroke in the general population. Methods: This prospective population based cohort study included 4424 participants from the third Rotterdam Study Survey (1997-1999) who, at that time, were ≥61 years of age and free from stroke. Depressive symptoms were assessed using the Centre for Epidemiological Studies Depression Scale (CESD) and considered present if the CESD score was ≥16. Participants with depressive symptoms had a diagnostic interview for depressive disorder. Follow-up was complete until 1 January 2005. Data were analysed using Cox proportional hazards models with adjustment for relevant confounders. Results: Men with depressive symptoms (n = 73) were at increased risk of stroke (adjusted hazard ratio (HR) 2.17; 95% CI 1.11 to 4.23) and ischaemic stroke (adjusted HR 3.21; 95% CI 1.62 to 6.38). These associations were at least partly attributable to men who reported depressive symptoms but who did not fulfil Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnostic criteria for depressive disorder (n = 32): they had a very high risk of stroke (adjusted HR 2.70; 95% CI 1.15 to 6.33) and ischaemic stroke (adjusted HR 4.01; 95% CI 1.68 to 9.57). In women there was no association between presence of depressive symptoms and risk of stroke. Conclusions: Presence of depressive symptoms is a strong risk factor for stroke in men but not in women. http://repub.eur.nl/res/pub/32339/ 2008-08-01T00:00:00Z 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. http://repub.eur.nl/res/pub/32510/ 2008-06-09T00:00:00Z Background: In clinical trials, cyclooxygenase (COX)-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) were associated with an increased risk of thromboembolic events. We studied the association between NSAID use and risk of stroke in the prospective, population-based Rotterdam Study. Methods: We followed 7636 persons free of stroke at baseline (1991-1993) for incident stroke until September 2004. Data on all filled prescriptions came from pharmacy records. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of stroke for time-dependent current use, compared with never use, of NSAIDs grouped according to COX selectivity (COX-1 selective, nonselective, and COX-2 selective) and individual NSAIDs. Results: At baseline, the mean age of the study sample was 70.2 years, and 61.3% were female. During 70 063 person-years of follow-up (mean, 9.2 years), 807 persons developed a stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified). Current users of nonselective (HR, 1.72; 95% confidence interval [CI], 1.22-2.44) and COX-2-selective (HR, 2.75; 95% CI, 1.28-5.95) NSAIDs had a greater risk of stroke, but not users of COX-1-selective NSAIDs (HR, 1.10; 95% CI, 0.41-2.97). Hazard ratios (95% CIs) for ischemic stroke were 1.68 (1.05-2.69) for nonselective and 4.54 (2.06-9.98) for COX-2-selective NSAIDs. For individual NSAIDs, current use of the nonselective naproxen (HR, 2.63; 95% CI, 1.47-4.72) and the COX-2-selective rofecoxib (HR, 3.38; 95% CI, 1.48-7.74) was associated with a greater risk of stroke. Hazard ratios (95% CIs) for diclofenac (1.60 [1.00-2.57]), ibuprofen (1.47 [0.73-3.00]), and celecoxib (3.79 [0.52-27.6]) were greater than 1.00 but were not statistically significant. Conclusions: In the general population, we found a greater risk of stroke with current use of nonselective and COX-2-selective NSAIDs. The risk of stroke was not limited to the use of COX-2-selective NSAIDs. http://repub.eur.nl/res/pub/22436/ 2008-06-01T00:00:00Z BACKGROUND: In clinical trials, cyclooxygenase (COX)-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) were associated with an increased risk of thromboembolic events. We studied the association between NSAID use and risk of stroke in the prospective, population-based Rotterdam Study. METHODS: We followed 7636 persons free of stroke at baseline (1991-1993) for incident stroke until September 2004. Data on all filled prescriptions came from pharmacy records. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of stroke for time-dependent current use, compared with never use, of NSAIDs grouped according to COX selectivity (COX-1 selective, nonselective, and COX-2 selective) and individual NSAIDs. RESULTS: At baseline, the mean age of the study sample was 70.2 years, and 61.3% were female. During 70 063 person-years of follow-up (mean, 9.2 years), 807 persons developed a stroke (460 ischemic, 74 hemorrhagic, and 273 unspecified). Current users of nonselective (HR, 1.72; 95% confidence interval [CI], 1.22-2.44) and COX-2-selective (HR, 2.75; 95% CI, 1.28-5.95) NSAIDs had a greater risk of stroke, but not users of COX-1-selective NSAIDs (HR, 1.10; 95% CI, 0.41-2.97). Hazard ratios (95% CIs) for ischemic stroke were 1.68 (1.05-2.69) for nonselective and 4.54 (2.06-9.98) for COX-2-selective NSAIDs. For individual NSAIDs, current use of the nonselective naproxen (HR, 2.63; 95% CI, 1.47-4.72) and the COX-2-selective rofecoxib (HR, 3.38; 95% CI, 1.48-7.74) was associated with a greater risk of stroke. Hazard ratios (95% CIs) for diclofenac (1.60 [1.00-2.57]), ibuprofen (1.47 [0.73-3.00]), and celecoxib (3.79 [0.52-27.6]) were greater than 1.00 but were not statistically significant. CONCLUSIONS: In the general population, we found a greater risk of stroke with current use of nonselective and COX-2-selective NSAIDs. The risk of stroke was not limited to the use of COX-2-selective NSAIDs. http://repub.eur.nl/res/pub/29164/ 2008-04-16T00:00:00Z http://repub.eur.nl/res/pub/22439/ 2008-04-01T00:00:00Z 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. http://repub.eur.nl/res/pub/18613/ 2008-03-19T00:00:00Z It is not easy to imagine that the essence of our being is enclosed in a single organ: the brain. In addition to its miraculous function, also the immensely delicate anatomical and chemical structure of the brain is astounding. In order to maintain its structure and function, the brain needs a constant supply of blood. If the blood flow is interrupted by the occlusion of an artery, the affected part of the brain immediately stops functioning. The brain tissue becomes irreversibly damaged within seconds and the area of irreversible brain damage expands in the course of several hours, resulting in what is called an ischemic stroke (figure 1). A hemorrhagic stroke occurs when blood leaks from an artery into the brain, which has the same detrimental effect on brain tissue as ischemia. Strokes usually take patients completely by surprise. In the normal brain, the input from all of our senses is collected, thoughts and emotions arise, and all voluntary body actions are initiated and coordinated, therefore all these functions can be affected by a stroke. For example, a patient who has a stroke may become unable to utter or understand language, become paralyzed on one side of the body, experience half-sided blindness or difficulties with swallowing, and his or her personality may change dramatically. http://repub.eur.nl/res/pub/22445/ 2008-01-01T00:00:00Z 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. http://repub.eur.nl/res/pub/22442/ 2007-12-26T00:00:00Z 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. http://repub.eur.nl/res/pub/35047/ 2007-12-26T00:00:00Z 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. http://repub.eur.nl/res/pub/22446/ 2007-12-01T00:00:00Z 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. http://repub.eur.nl/res/pub/22458/ 2007-10-01T00:00:00Z BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology. http://repub.eur.nl/res/pub/22463/ 2006-12-01T00:00:00Z 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. http://repub.eur.nl/res/pub/22465/ 2006-11-01T00:00:00Z 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. http://repub.eur.nl/res/pub/22466/ 2006-10-01T00:00:00Z 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. http://repub.eur.nl/res/pub/22470/ 2006-06-01T00:00:00Z 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. http://repub.eur.nl/res/pub/22475/ 2006-01-01T00:00:00Z BACKGROUND AND PURPOSE: Low levels of insulin-like growth factor I (IGF-I) predispose to atherosclerosis and may therefore increase the risk of stroke. Low levels have also been found to influence the outcome of cardiovascular and cerebrovascular disease. A polymorphism in the promoter region of the IGF-I gene influences IGF-I levels. Non-carriers of the 192 bp allele have lower levels of IGF-I compared with 192 bp allele carriers. We studied the IGF-I polymorphism in relation to the risk of stroke and survival after stroke. METHODS: We studied 6808 subjects of the Rotterdam Study, who were followed for the occurrence of stroke and death after stroke. Subjects were grouped according to the 192 bp allele of IGF-I into non-carriers, heterozygotes, and homozygotes. The risk of stroke and survival after stroke was studied using Cox regression analysis, adjusting for age and sex, with homozygotes for the wildtype allele as the reference. RESULTS: Non-carriers had a relative risk of 0.8 (95% CI: 0.6 to 1.0) for the occurrence of any stroke and 0.7 (95% CI: 0.5 to 1.0) for ischaemic stroke. For non-carriers, the relative risk of death after any stroke was 1.5 (95% CI: 1.0 to 2.2). After an ischaemic stroke, this relative risk was 1.5 (95% CI: 0.9 to 2.6) and after a haemorrhagic stroke 5.2 (95% CI: 1.3 to 21.5). CONCLUSIONS: Our study suggests that IGF-I is a significant determinant of survival after stroke.