Lyme neuroborreliosis with antibodies in cerebrospinal fluid but not in serum.

BACKGROUND AND PURPOSE: To diagnose Lyme neuroborreliosis (LNB), cerebrospinal fluid (CSF) is tested for pleocytosis and intrathecal antibody production. The Dutch guideline for Lyme borreliosis indicates a lumbar puncture in the case of positive Borrelia serology or a strong clinical suspicion of LNB. This suggests that LNB might be underdiagnosed in patients with negative Borrelia serology and/or a minor clinical suspicion. The objective was to assess how often negative Borrelia serology occurs in the case of LNB. METHOD: A retrospective study was performed among patients with LNB visiting Gelre Hospitals between January 2007 and December 2020. Electronic medical records of patients with pleocytosis were reviewed to identify patients with LNB. Data were collected from medical records. RESULTS: Included were 127 patients with LNB, 58 of whom were children. In 67 patients Borrelia antibodies were present in both serum and CSF. In 53 of 67 patients there was intrathecal antibody production. In 28 patients there was intrathecal antibody production but serum antibodies were absent. Of patients with positive serology 77% had antibodies in CSF versus 83% of patients with negative serology (p = 0.435). Of patients with positive serology 61% had intrathecal antibody production versus 78% of patients with negative serology (p = 0.073). CONCLUSIONS: Twenty-eight LNB patients had intrathecal antibody production but no antibodies in serum. In this specific patient population, positive serum serology was not associated with antibodies in CSF nor with intrathecal antibody production. In Lyme endemic areas, in patients with symptoms suggestive for LNB, there is a need to lower the threshold for a lumbar puncture.

Coping strategies and quality of life in patients with chronic symptoms visiting a Lyme Center in a Dutch teaching hospital.

INTRODUCTION: Little is known on coping strategies in patients with chronic symptoms suspected of Lyme borreliosis (LB). Different coping strategies might influence quality of life (QoL). We assessed coping strategies and QoL in patients with chronic symptoms suspected of LB. METHODS: Adult patients referred to the Lyme Center Apeldoorn were included (November 2019-April 2021). Participants completed the RAND-36 to assess QoL and the Utrecht Coping List to assess coping strategies. Patient data were extracted from medical records. Patients were categorized based on clinical LB and serology. Linear regression analyses were conducted to examine an association between coping strategies and QoL subscales. RESULTS: Included were 201 patients. Patients suspected of LB had a different coping profile and lower QoL compared to the reference population. Patients with negative serology and no clinical LB scored lowest on all QoL subscales. In multivariate analyses, correcting for age, gender, comorbidity, and patient category, a negative association was found between passive coping and the QoL subscales physical functioning (ß(SE) = - 1.1(0.5)), social functioning (ß(SE) = - 3.3(0.5)), role limitations (emotional) (ß(SE) = - 5.5(0.8)), mental health (ß(SE) = - 3.7(0.3)), vitality (ß(SE) = - 2.3(0.3)), pain (ß(SE) = - 2.3(0.5)), and general health (ß(SE) = - 2.7(0.3)). A negative association was also found between palliative coping and the QoL subscale role limitations (physical) (ß(SE) = - 1.8(0.6)) and between expressing emotions and mental health (ß(SE) = - 1.3(0.6)). A positive association was found between active coping and the QoL subscales mental health (ß(SE) = 1.0(0.3)) and role limitations (emotional) (ß(SE) = 1.9(0.8)). CONCLUSION: In patients suspected of LB, dysfunctional coping strategies were associated with worse quality of life. There is a need for interventions that can guide patients with chronic symptoms suspected of LB towards more active coping and increase QoL.

Unspecified Strokes: Time Trends, Determinants, and Long-Term Prognosis in the General Population.

INTRODUCTION: In the absence of neuroimaging, a stroke is typically labelled as unspecified. While the majority of clinic-based stroke research focuses on hemorrhagic or ischemic stroke, in the general population, a substantial proportion of strokes remains unspecified. OBJECTIVE: To investigate time trends in the occurrence and determinants of unspecified strokes and differences in patient characteristics and survival compared to ischemic or hemorrhagic stroke. METHODS: We included 1,546 participants from the population-based Rotterdam Study who suffered a first-ever stroke during follow-up (1990-2016). We calculated the proportion of unspecified strokes per year and compared their characteristics between 3 time periods (1990-1999, 2000-2009, and 2010-2016) using a chi-square test, and furthermore investigated differences between unspecified, ischemic, and hemorrhagic stroke in patient characteristics and survival using age- and sex-adjusted survival curves. RESULTS: The occurrence of unspecified stroke among all strokes decreased from 75% in 1990 to 16% in 2016. Compared to the first time period (1991-1999), diagnosis of unspecified strokes was more often done by nursing home physicians (13 vs. 40%) and unspecified stroke patients had more often dementia (30 vs. 43%) in the last time period (2010-2016). Compared to patients with ischemic or hemorrhagic stroke, patients with unspecified stroke were on average older (84.3 vs. 78.5 years) and had more often physical impairments and dementia. Furthermore, patients with unspecified stroke had a lower survival probability up to 10 years after stroke than those with ischemic stroke. CONCLUSIONS: The proportion of unspecified strokes decreased drastically from 75 to 16% in the last decades. Patients who do not undergo neuroimaging and therefore are classified as unspecified stroke represent an older, more frail patient group that suffers more often from multimorbidities and poor long-term prognosis than those who do undergo neuroimaging and are thus classified as ischemic or hemorrhagic stroke.

Separate prediction of intracerebral hemorrhage and ischemic stroke.

OBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS). METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots. RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort. CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual's stroke risk.

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Insulin resistance and the risk of stroke and stroke subtypes in the nondiabetic elderly.

Insulin resistance, which plays a key role in the development of diabetes mellitus, is a putative modifiable risk factor for stroke. The aim of this study was to investigate if markers of insulin resistance were associated with risk of stroke in the general elderly population. This study was part of the large population-based Rotterdam Study and included 5,234 participants who were aged 55 years or older and stroke free and diabetes free at baseline (1997-2001). Fasting insulin levels and homeostasis model assessment for insulin resistance were used as markers for insulin resistance. Cox regression was used to determine associations between insulin resistance markers and stroke risk, adjusted for age, sex, and potential confounders. During 42,806 person-years of follow-up (median: 8.6 years), 366 first-ever strokes occurred, of which 225 were cerebral infarctions, 42 were intracerebral hemorrhages, and 99 were unspecified strokes. Fasting insulin levels were not associated with risk of any stroke, cerebral infarction, or intracerebral hemorrhage. Homeostasis model assessment for insulin resistance, which almost perfectly correlated with fasting insulin levels, was also not associated with risk of stroke or stroke subtypes. In conclusion, in this population-based cohort study among nondiabetic elderly, insulin resistance markers were not associated with risk of stroke or any of its subtypes.

Assessment of cerebral small vessel disease predicts individual stroke risk.

BACKGROUND: Despite several known risk factors it is still difficult to foresee who will develop a stroke and who will not. Vascular brain damage, visualised with MRI, reflects how the brain tolerates the effects of vascular risk factors and may therefore be relevant in predicting individual stroke risk. OBJECTIVE: To examine whether the presence of small vessel disease on brain MRI could improve the prediction of stroke beyond the classic stroke risk factors from the 1991 Framingham Stroke Risk Function. METHODS: 1007 community-dwelling elderly people, free of stroke at baseline were included in the study. Small vessel disease--that is, the presence of silent brain infarcts (SBI) and white matter lesions (WML), was scored on MRI scans obtained in 1995-6. 10-Year stroke risk prediction was assessed by the C statistic and by reclassification adding SBI and WML to a risk model including the classic stroke risk factors. RESULTS: During 10-years of follow-up 99 strokes occurred. Individual stroke risk prediction significantly improved from 0.73 (95% CI 0.67 to 0.78) to 0.75 (0.69 to 0.80) in men and from 0.69 (0.64 to 0.75) to 0.77 (0.71 to 0.82) in women after inclusion of SBI and periventricular WML to the stroke risk factors. Reclassification occurred mainly in the intermediate stroke risk group (men 26%; women 61% reclassified). CONCLUSIONS: Assessment of small vessel disease with MRI beyond the classic stroke risk factors improved the prediction of subsequent stroke, especially in women with an intermediate stroke risk. These findings support the use of MRI as a possible tool for better identifying people at high risk of stroke.

International epidemiology of intracerebral hemorrhage.

Intracerebral hemorrhage is the second most common subtype of stroke. In recent decades our understanding of intracerebral hemorrhage has improved. New risk factors have been identified; more knowledge has been obtained on previously known risk factors; and new imaging techniques allow for in vivo assessment of preclinical markers of intracerebral hemorrhage. In this review the latest developments in research on intracerebral hemorrhage are highlighted from an epidemiologic point of view. Special focus is on frequency, etiologic factors and pre-clinical markers of intracerebral hemorrhage.

Trends in stroke incidence rates and stroke risk factors in Rotterdam, the Netherlands from 1990 to 2008.

Stroke incidence rates have decreased in developed countries over the past 40 years, but trends vary across populations. We investigated whether age-and-sex-specific stroke incidence rates and associated risk factors as well as preventive medication use have changed in Rotterdam in the Netherlands during the last two decades. The study was part of the Rotterdam Study, a large population-based cohort study among elderly people. Participants were 10,994 men and women aged 55-94 years who were stroke-free at baseline. Trends were calculated by comparing the 1990 subcohort (n=7516; baseline 1990-1993) with the 2000 subcohort (n=2883; baseline 2000-2001). Poisson regression was used to calculate incidence rates and incidence rate ratios in age-and-sex-specific strata. We further compared the prevalence of stroke risk factors and preventive medication use in the two subcohorts. In the 1990 subcohort 467 strokes occurred during 45,428 person years; in the 2000 subcohort 115 strokes occurred in 18,356 person years. Comparing the subcohorts, incidence rates decreased by 34% in men, but remained unchanged in women. Blood pressure levels increased between 1990 and 2000, whereas the proportion of current cigarette smokers decreased in men, but not in women. There was a strong increase in medication use for treatment of stroke risk factors across all age categories in both sexes. Our findings suggest that in Rotterdam between 1990 and 2008 stroke incidence rates have decreased in men but not in women.

Serum lipid levels and the risk of intracerebral hemorrhage: the Rotterdam Study.

OBJECTIVE: Low serum total cholesterol levels are associated with an increased risk of symptomatic intracerebral hemorrhage and with presence of asymptomatic cerebral microbleeds. The relative contribution of lipid fractions to these associations is unclear and requires investigation. We determined whether serum HDL-cholesterol, LDL-cholesterol, and triglycerides are associated with risk of intracerebral hemorrhage and presence of cerebral microbleeds. METHODS AND RESULTS: Nine thousand sixty-eight stroke-free community-dwelling persons aged ≥55 were followed from baseline (1990-2001) up to January 1, 2009, of whom 85 suffered from intracerebral hemorrhage during follow-up. Brain MRI was carried out in 789 healthy participants, of whom 162 had cerebral microbleeds. Triglycerides were strongly and inversely associated with intracerebral hemorrhage, independently of HDL-cholesterol, LDL-cholesterol, and potential confounders [hazard ratio for highest versus lowest quartile: 0.20 (0.06-0.69)]. Triglycerides were also associated with deep or infratentorial microbleeds [odds ratio for highest versus lowest quartile: 0.37 (0.14-0.96)], but not with strictly lobar microbleeds. No associations were found for HDL-cholesterol or LDL-cholesterol. CONCLUSIONS: Low serum triglyceride levels were associated with an increased risk of intracerebral hemorrhage and with the presence of deep or infratentorial cerebral microbleeds. This provides novel insights into the role of lipid fractions, particularly triglycerides, in the etiology of intracerebral hemorrhage.

Age-related macular degeneration and the risk of stroke: the Rotterdam study.

BACKGROUND AND PURPOSE: Age-related macular degeneration (AMD) and stroke are both frequent diseases in the elderly. A link between AMD and stroke has been suggested, because both disorders have many risk factors in common. The aim of this study was to investigate the association between AMD and stroke and the subtypes cerebral infarction and intracerebral hemorrhage in the general elderly population. METHODS: This study was part of the population-based Rotterdam Study and included 6207 participants aged ≥ 55 years who were stroke-free at baseline (1990 to 1993). Signs of AMD were assessed on fundus photographs at baseline and at regular follow-up examinations and were categorized in 5 stages (0 to 4) representing an increasing severity. Late AMD (Stage 4) was subdivided into dry and wet AMD. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed using time-dependent Cox regression models adjusted for age, sex, and potential confounders. RESULTS: During a median follow-up of 13.6 years, 726 participants developed a stroke (397 cerebral infarction, 59 intracerebral hemorrhage, 270 unspecified). Late AMD was associated with an increased risk of any stroke (hazard ratio, 1.56; 95% CI, 1.08 to 2.26) due to a strong association with intracerebral hemorrhage (hazard ratio, 6.11; 95% CI, 2.34 to 15.98). In contrast, late AMD was not associated with cerebral infarction. Earlier AMD stages were not associated with risk of stroke or any of its subtypes. CONCLUSIONS: We found that late AMD is strongly associated with intracerebral hemorrhage, but not with cerebral infarction, in the general elderly population.

Burden of atherosclerosis improves the prediction of coronary heart disease but not cerebrovascular events: the Rotterdam Study.

AIMS: Since atherosclerosis is a systemic process, risk prediction would benefit from targeting multiple components of cardiovascular disease simultaneously. To this end, it is useful to examine the predictive value of non-invasive measures of atherosclerosis in various vascular beds for both coronary heart disease (CHD) and cerebrovascular disease. METHODS AND RESULTS: Between September 2003 and February 2006, 2153 asymptomatic participants (69.6±6.6 years) from the Rotterdam Study underwent a multi-detector computed tomography scan. During a median follow-up of 3.5 years, 58 CHD events (myocardial infarction and CHD death) and 52 cerebrovascular events (TIA and stroke) occurred. Participants were classified into low (<5%), intermediate (5-10%), and high (>10%) 5-year risk categories based on a refitted Framingham risk model. The model was extended by coronary, aortic arch, or carotid calcium and reclassification percentages were calculated. For the outcome CHD, the C-statistic improved from 0.693 for the Framingham refitted model to 0.743, 0.740, and 0.749 by addition of coronary, aortic arch, and carotid calcium, respectively. Reclassification was most substantial in the intermediate risk group where addition of coronary calcium reclassified 56% of persons [net reclassification improvement (NRI): 15%; P<0.01)]. Adding aortic arch calcium led to a reclassification of 32% of persons (NRI: 8%; P=0.01) and adding carotid calcium reclassified 51% (NRI: 9%; P=0.02). In contrast, calcification in any of the three vascular beds did not improve cerebrovascular risk prediction. CONCLUSION: Coronary, aortic arch, and carotid artery calcification significantly improved risk prediction of CHD but not of cerebrovascular events.

Transient ischemic attack and incident depression.

BACKGROUND AND PURPOSE: Depression after stroke is common. Like stroke, transient ischemic attack (TIA) is a manifestation of long-term atherosclerotic damage to the brain. However, the risk of depression developing after a TIA is uncertain. We studied whether TIA increases the risk of incident late-life depression. METHODS: A cohort study of 5095 inhabitants of Rotterdam, the Netherlands, was performed between 1993 and 2005. Participants were aged 56 years or older and free of depression at baseline. TIA and depression were identified through regular standardized examinations and continuous monitoring of medical records. We estimated hazard ratios (HR) with time-varying Cox regression analyses, adjusting for sociodemographic and health-related factors. RESULTS: During follow-up, 407 depressive syndromes occurred, of which 103 met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM) for depressive disorders. TIA was significantly associated with the risk of incident depressive syndromes (HR, 1.68; 95% CI, 1.12-2.51) and DSM-defined depressive disorders (HR, 2.42; 95% CI, 1.26-4.67). The risk of depressive syndromes increased with the number of TIA a person had experienced (HR, 1.45; 95% CI, 1.17-1.81), as did the risk of depressive disorders (HR, 1.63; 95% CI, 1.18-2.24). In persons without a history of depression at baseline, we found an almost 3-fold increased risk of DSM-defined depressive disorders (HR, 2.91; 95% CI, 0.96-8.81). CONCLUSIONS: TIA was independently associated with an increased risk of incident depression. Our finding suggests that symptomatic cerebrovascular disease increases the vulnerability to late-life depression.

Retinal vascular calibers and the risk of intracerebral hemorrhage and cerebral infarction: the Rotterdam Study.

BACKGROUND AND PURPOSE: Narrower retinal arteriolar calibers and wider venular calibers are associated with cardiovascular disease, including cerebral infarction. We investigated the association between retinal vascular calibers and the long-term risk for stroke and its subtypes with particular focus on intracerebral hemorrhage. METHODS: We included 5518 participants (aged ≥ 55 years) from the prospective population-based Rotterdam Study who were stroke-free at baseline (1990-1993) and of whom digital retinal images were available. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally for potential confounders. Arteriolar and venular calibers were entered both separately and simultaneously in the models. RESULTS: During an average follow-up of 11.5 years, 623 participants developed a first-ever stroke (50 hemorrhagic, 361 ischemic, 212 unspecified). Larger venular caliber was independently associated with an increased risk for stroke (hazard ratio [HR] per SD increase: 1.20; 95% confidence interval [CI]: 1.09 to 1.33), cerebral infarction (HR: 1.28; 95% CI: 1.13 to 1.46), and intracerebral hemorrhage (HR: 1.53; 95% CI: 1.09 to 2.15). Much weaker, only borderline significant associations were found between arteriolar caliber and risk for stroke (HR per SD decrease: 1.12; 95% CI: 0.99 to 1.23), cerebral infarction (HR: 1.12; 95% CI, 0.98 to 1.27), and intracerebral hemorrhage (HR: 1.25; 95% CI: 0.87 to 1.79). Retinal vascular calibers were strongly associated with lobar hemorrhages and oral anticoagulant-related hemorrhages. CONCLUSIONS: Larger retinal venular caliber is associated with an increased risk for stroke in the general population and, in particular, with an increased risk for intracerebral hemorrhage.

High von Willebrand factor levels increase the risk of stroke: the Rotterdam study.

BACKGROUND AND PURPOSE: Many studies have investigated the role of plasma von Willebrand factor level in coronary heart disease, but few have investigated its role in stroke. The aim of this study was to determine if von Willebrand factor levels are associated with the risk of stroke. METHODS: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥55 years. We included 6 250 participants who were free from stroke at baseline (1997 to 2001) and for whom blood samples were available. Follow-up for incident stroke was complete up to January 1, 2005. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally with models adjusted for other potential confounders including ABO blood group. A subgroup analysis was performed in participants without atrial fibrillation. Effect modification by sex was tested on a multiplicative and on an additive scale. RESULTS: During an average follow-up time of 5.0 years, 290 first-ever strokes occurred, of which 197 were classified as ischemic. The risk of stroke increased with increasing von Willebrand factor levels (age- and sex-adjusted hazard ratios per SD increase in von Willebrand factor level: 1.12 [95% CI, 1.01 to 1.25] for stroke, 1.13 [95% CI, 0.99 to 1.29] for ischemic stroke). Adjustments for additional confounders slightly attenuated the association. The association was also present in subjects without atrial fibrillation and did not differ between sexes. CONCLUSIONS: High von Willebrand factor levels are associated with stroke risk in the general population.

Carotid, aortic arch and coronary calcification are related to history of stroke: the Rotterdam Study.

OBJECTIVE: Multidetector computed tomography (MDCT), which has been mainly used to study coronary atherosclerosis, also enables non-invasive measurement of carotid and aortic atherosclerosis and might be suitable for screening in the general population. The aim of this study was to investigate the associations of carotid artery, aortic arch and coronary artery calcification as assessed by MDCT, with presence of stroke. METHODS: The study was embedded in the population-based Rotterdam Study and comprises 2521 persons (mean age 69.7±6.8 years, 48% males) that underwent an MDCT scan. History of stroke was reported by 96 persons. We used multivariable logistic regression to investigate the associations of calcification in the carotid arteries, aortic arch, and coronary arteries with presence of stroke. RESULTS: We found strong and graded associations of prevalent stroke with carotid artery (OR quartile 4 versus 1 (95% CI): 5.0 (2.2-11.0)), aortic arch (3.3 (1.5-7.4)) and coronary artery calcification (3.1 (1.3-7.3)), independent of cardiovascular risk factors. Only the association of carotid artery calcification with presence of stroke was independent of calcification in the other two vessel beds. CONCLUSION: In this population-based study, we found a strong and graded association of prevalent stroke with carotid artery, aortic arch and coronary artery calcification, independent of cardiovascular risk factors. After additional adjustment for calcification in the other vessel beds, prevalent stroke was still significantly related to carotid calcification, but no longer to aortic arch or coronary calcification.

Amino-terminal pro-B-type natriuretic peptide improves cardiovascular and cerebrovascular risk prediction in the population: the Rotterdam study.

Increased circulating amino-terminal pro-B-type natriuretic (NT-proBNP) levels are a marker of cardiac dysfunction but also associate with coronary heart disease and stroke. We aimed to investigate whether increased circulating NT-proBNP levels have additive prognostic value for first cardiovascular and cerebrovascular events beyond classic risk factors. In a community-based cohort of 5063 participants free of cardiovascular disease, aged > or =55 years, circulating NT-proBNP levels and cardiovascular risk factors were measured. Participants were followed for the occurrence of first major fatal or nonfatal cardiovascular event. A total of 420 participants developed a first cardiovascular event (108 fatal). After adjustment for classic risk factors, the hazard ratio for cardiovascular events was 2.32 (95% CI: 1.55 to 2.70) in men and 3.08 (95% CI: 1.91 to 3.74) in women for participants with NT-proBNP in the upper compared with the lowest tertile. Corresponding hazard ratios for coronary heart disease, heart failure, and ischemic stroke were 2.01 (95% CI: 1.14 to 2.59), 2.90 (95% CI: 1.33 to 4.34), and 2.06 (95% CI: 0.91 to 3.18) for men and 2.95 (95% CI: 1.30 to 4.55), 5.93 (95% CI: 2.04 to 11.2), and 2.07 (95% CI: 1.00 to 2.97) for women. Incorporation of NT-proBNP in the classic risk model significantly improved the C-statistic both in men and women and resulted in a net reclassification improvement of 9.2% (95% CI: 3.5% to 14.9%; P=0.001) in men and 13.3% (95% CI: 5.9% to 20.8%; P<0.001) in women. We conclude that, in an asymptomatic older population, NT-proBNP improves risk prediction not only of heart failure but also of cardiovascular disease in general beyond classic risk factors, resulting in a substantial reclassification of participants to a lower or higher risk category.