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Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a risk factor for atrial fibrillation and a marker of cardiac function used in detection of heart failure. Few studies evaluated the role of NT-proBNP as risk factor for stroke. Hypothesis: Given the link between cardiac dysfunction and stroke, NT-proBNP is a candidate marker of stroke risk. Our aim was to evaluate the association of NT-proBNP with stroke outcomes and to determine the predictive value beyond a panel of established risk factors for stroke. Methods: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project we analysed data of 43,815 participants (48.3% men; mean age 52 yr) free of cardiovascular disease from 6 prospective population-based cohorts across Europe with a maximum follow-up of 22 years. All NT-proBNP measurements were performed on frozen samples in the central BiomarCaRE laboratory. The endpoints considered were validated fatal and non-fatal stroke. Results: We observed 565 stroke events (78 fatal) in men and 290 (54) in women. Growing quartiles of NT-proBNP were associated with increasing risk of stroke (Table; multivariable cox regression analysis adjusted for the base model: age, centre, smoking, BMI, diabetes, hypertension medication, systolic and diastolic blood pressure, total and HDL cholesterol), both in men (p for trend Conclusions: In European individuals free of cardiovascular disease, levels of NT-proBNP in the top quartile (>87.7 pg/mL) are associated with a doubled risk of stroke. However, the addition of NT-proBNP to variables of established risk score poorly improves prediction of stroke disease.

Aims. To explore the magnitude of educational-class inequalities in ischemic stroke incidence in European populations, and to assess to what extent they can be explained by major risk factors. Methods. The MORGAM study comprised 45 cohorts from Nordic Countries (Finland, Denmark, Sweden), UK (Northern Ireland, Scotland), Central EU (France, Germany, Northern Italy) and East EU (Lithuania, Poland) and Russia. Only cohorts with both fatal and non-fatal ischemic strokes during follow-up (median 12 years, IQR 10-19 years) were included. Baseline data were collected adhering to MONICA-like procedures. Stroke subtype was attributed based on hospital records and death codes. We derived 3 educational classes from population-, sex- and birth year-specific tertiles of years of schooling. We used Poisson regression models to estimate the age-adjusted difference in event rates between the bottom and the top educational classes distribution (Slope Index of Inequality, SII) and the proportion of events to be redistributed to achieve equality in event rates among educational classes (Relative Concentration Index, RCI). We estimated the pooled age- and risk factors-adjusted hazard ratios for bottom to top education (Relative Index of Inequality, RII) from sex-specific Cox models with a dummy variable for each population . We also tested the hypothesis of homogeneity of inequalities across populations by adding population*education interaction terms. The contribution of risk factors to RII was measured by: (lnRII[RFadj]- lnRII[AGEadj]) / lnRII[AGEadj] Results. The cohorts included 66,052 CVD-free subjects aged 35-64 years (37,181 men) at baseline. In men, the age-adjusted inequalities in ischemic stroke rates (SIIs) were 125 events per 100,000 person-years in the Nordic Countries, 156 in the UK and 178 in Central EU; the RCIs were 6%, 13% and 21%, respectively. In women, an inverse gradient (higher rates among more educated subjects) was present in Northern Sweden; in the remaining populations, the SII (RCI) ranged between 4 (1%) in Northern Italy and 278 (23%) events in Germany. Age-adjusted pooled RIIs for bottom to top education were 1.7 (95%CI: 1.4-2.1) in men and 1.5 (1.2-1.9) in women, with some variability across populations (homogeneity test p-value=0.06 in men and 0.07 in women) and gender groups. Together, total- and HDL-cholesterol, systolic blood pressure, anti-hypertensive treatment, smoking and diabetes explained 26% of hazard excess in men, and 40% in women. Main contributors were smoking (13%) and systolic blood pressure (9%) in men; and systolic blood pressure (13%), HDL-cholesterol (12%) and smoking (11%) in women. Conclusions. Less educated men and women had a higher ischemic stroke incidence risk in most European populations; in men, such inequalities followed a clear North-South geographic gradient. Traditional risk factors accounted for a minor part of risk excess in men.

Background and aim: Poor sleep quality has been found associated with increasing risk of cardiovascular diseases. We aim to estimate the long-term risk of first cardiovascular (CVD) event (coronary or ischemic stroke) in subjects with sleep disturbances in North-Italian cohorts. Methods: Four independent population-based cohorts were enrolled between 1986 and 1994 from the Brianza population (Northern Italy). At baseline LDL-, HDL-cholesterol, systolic blood pressure, diabetes and cigarette smoking were ascertained through standardized MONICA procedures. The study sample comprises 3047 men and 3097 women, aged 25 to 75 years and CVD-free at baseline, who were followed-up for incidence of first coronary and ischemic stroke events (fatal and non-fatal; MONICA validated). Sleep disturbances were assessed with the Jenkins Sleep Questionnaire, investigating sleep disturbances (4 items) in the last month, and then categorized in three classes: none-some (reference), moderate, severe/extreme. Age and CVD risk factors adjusted HRs for first CVD, coronary or ischemic stroke event were estimated in the overall sample, in men and women, from separate Cox models. Results: In a median 15 years of follow-up 437 first CVD events occurred (305 coronary and ischemic stroke). When adjusting for LDL- and HDL-cholesterol, systolic blood pressure, diabetes and cigarette smoking, the risk of first CVD events was higher in subjects with severe sleep disorders compared with none-some (HR=1.84; 95%CI:1.19-2.84). Gender-stratification confirms the association both in men and women, but only in men resulted statistically significant (HR=2.34; 95%CI:1.34-4.08). The association was prominent for ischemic strokes (HR=2.10; 95%CI:1.11-3.97) and less clear for coronary events. These associations resulted higher when the follow-up was shortened to 10 years. Conclusions: In this population of middle-aged CVD-free subjects from Northern Italy, severe sleep disturbances were associated with first CVD events. The risk was higher in men and when ischemic strokes were considered only.

Background: The number of elderly persons with cardiovascular disease (CVD) is rapidly increasing, mainly due to worldwide aging population. All CVD risk scores consider age as risk factor but most of them assume that the etiological role of other established risk factors is similar at all ages. This analyses aimed to assess the predictive role of cardiovascular risk factors in elderly persons. Methods: We considered 10,979 men and 16,533 women aged 35-74 years from cohorts in North, Centre and South of Italy with 10 years median follow-up time for fatal and non fatal coronary and cerebrovascular events (819 in men and 467 in women) validated according to MONICA criteria. In all cohorts risk factors were assessed by using standardized procedures. Two age groups were defined: adult 35-54 years of age (6,353 men and 10,358 women) and elderly 55-74 years (4,626 men and 6,175 men). Cox models were implemented including age, systolic blood pressure (SBP), total (TC) and HDL cholesterol (HDL-C), smoking, diabetes (DM - fasting blood glucose >=126 mg/dl or under glucose treatment) and hypertension treatment (HT). For continuous variables, hazard ratios (HR) were reported at 1 standard deviation higher level and for dichotomized variables, yes vs no. Results: For adult men SBP resulted having a stronger impact on CVD risk than for elderly even if not statistically significant: adult HR 1.32, 95% confidence interval 1.18-1.48, vs elderly HR 1.25, 1.15-1.36; similar results for TC (HR 1.47 vs 1.25), smoking (HR 1.91, vs 1.52), DM (HR 1.76 vs 1.56), HT (HR 2.30 vs 1.25). HDL-C resulted not significantly associated with CVD risk in elderly men. Among adult women a stronger impact was found than in elderly for SBP (HR 1.59 vs 1.26), HDL-C (0.65 vs 0.84), smoking (2.43 vs 1.99), and HT (2.34 vs 1.45); the opposite for TC (1.19 vs 1.27). DM resulted not significantly associated with CVD risk in adult women. Age resulted having a stronger impact in elderly persons both in men and women (HR 1.22, 1.07-1.39, vs 1.44, 1.29-1.61; 1.45, 1.17-1.80, vs 1.63, 1.42-1.86 respectively). Conclusions: SBP and HT resulted having a pronounced lower impact on CVD risk in elderly than in adult as well as HDL-C for men; age shows a stronger impact in elderly than in adult. Further analyses are recommended to study the reliability of risk scores based on age-specific risk models, evaluating the introduction of different risk factors and considering survival probability derived from data in elderly population.

Aims: We assess the external validation, on a “new” set of subjects, of the CAMUNI 20-year risk score, developed in a northern Italian population. Although an external validation analysis is recommended before adopting a score in clinical practice, it is rarely performed in long-term prediction equations as it requires similar long-term follow-up procedures in different cohort studies. Methods: The CAMUNI risk score was developed to estimate the 20-year risk of first coronary or ischemic stroke event, fatal or non-fatal, in 5247 (2574 men) 35-69 subjects free of CVD at baseline enrolled in late 1980s-early 1990s in Brianza, northern Italy (derivation set). The score is based on two gender-specific Cox models, including age, total- and HDL-cholesterol, systolic blood pressure, anti-hypertensive treatment, cigarette smoking and diabetes. As validation set, we considered 5307 (2418 men) subjects enrolled in the Rome area in the same time span (MATISS Study). Both the derivation and the validation cohorts shared the same procedures for baseline risk assessment and follow-up procedures, including MONICA definition of acute events. We evaluated the performance of the CAMUNI score in the validation set; the Framingham CVD risk score was used for comparison. The absolute predicted risk from both scores was re-calibrated to the 20-year risk observed in the validation set. We report the calibration slope as a measure of calibration; a value different from 1 is suggestive of a different strength in predictor effects. The Area Under the ROC-curve (AUC) measured the discrimination ability; the AUC in the validation set was compared to the value in the derivation set, corrected for over-optimism. Results: The 20-year Kaplan-Meier risk of event was 16.1% (derivation set; 315 events) and 13.2% (validation set; 238 events) in men, and 6.1% (123 events) and 5.6% (119 events) in women. The calibration slope for the CAMUNI score did not significantly differ from 1 in men (1.1; 95% confidence interval 0.9; 1.2) nor in women (1.0; 0.8;1.2). The Framingham score performed equally well in men (1.1; 0.9; 1.2) but worse in women (1.3; 1.1;1.6). In the derivation set, the over-optimism corrected AUC for the CAMUNI model was 0.737 (men) and 0.801 (women); the corresponding figures in the validation set were 0.732 (95% CI: 0.727-0.738) in men, and 0.801 (0.794-0.808) in women. The Framingham score performed less well in men (0.722; 0.717-0.727) and in women (0.705; 0.699-0.711). Conclusions: Based on these preliminary results, the CAMUNI 20-year risk score seems to be appropriate for long-term risk prediction in Italy and, more generally, in low-incidence populations.

Aims. Recent US guidelines advocate the introduction of lifetime or long-term absolute risk prediction for primary prevention of cardiovascular events, especially for young people and women. Therefore, long-term prediction models might be specially beneficial in population considered at low incidence. We aim to develop a 20-year absolute risk prediction equation in a Northern Italy population. Methods. Four independent population-based cohorts were enrolled between 1986 and 1994 from the Brianza population (Northern Italy), adopting standardized MONICA procedures. The study sample comprises n=2574 men and 2673 women, aged 35 to 69 years and free of CVD at baseline. Participants were followed-up for incidence of first coronary and ischemic stroke events (fatal and non-fatal; all MONICA validated) for a median time of 15 years (IQ range: 12-20) and up to the end of 2008. We compared several gender-specific Cox Proportional Hazards models: the basic one includes age, total cholesterol, HDL-cholesterol, systolic blood pressure, anti-hypertensive treatment, cigarette smoking and diabetes. Candidates to model addition were diastolic blood pressure, triglycerides, BMI, family history of CHD, and education. Model calibration was tested using the Grønnesby-Bogan goodness-of-fit statistic. The Area Under the ROC-Curve (AUC) was a measure of discrimination, corrected for over-optimism via bootstrapping. Changes in discrimination (Δ-AUC) and reclassification (Net Reclassification Improvement, NRI) defined the improvement from the basic model due to an additional risk factor. Intermediate risk was defined as 20-year risk between 10% and 40%. Results. We observed n=286 events in men (incidence rate 7.7 per 1000 person-years) and n=108 in women (2.6 per 1000 person-years). All risk factors included in the basic model were predictive of first cardiovascular event in both genders; discrimination was 0.725 and 0.802 in men and women, respectively. Average specificity in the top risk quintile (cut-off value: 23% in men and 8.5% in women) was similar in men and women (85% vs. 83%), while sensitivity was higher in women (63% vs. 46%). All the models were well-calibrated (p-values >0.05). The addition of a positive family history of CHD in men (Hazard Ratio: 1.6; 95%CI 1.2-2.1) and of diastolic blood pressure in women (HR: 1.4 for 11 mmHg increase; 1.1-1.8) significantly improved discrimination (Δ-AUC=0.01; 95%CI 0.002-0.02 [men] and Δ-AUC=0.005; 95%CI 0.0001-0.01 [women]) and reclassification of subjects at intermediate risk (NRI=8.4%;1.7%-19.1% [men]; and NRI=11.7%; -3.2%-33.5% [women]). Conclusions. Traditional risk factors are predictive of cardiovascular events after 20 years, with good discrimination. The addition of family history of CHD may contribute to model improvement, at least among men; the role of diastolic blood pressure in women should be carefully evaluated.

Aims. The 10-year absolute risk of cardiovascular events, a current standard for treatment indication in CVD primary prevention, has been recently shown to inadequately estimate the risk in young subjects and women, even in presence of a cluster of risk factors. We aim to compare a 10- and a 20-year absolute risk of CVD prediction models in a low incidence population. Methods. Four independent population-based cohorts were enrolled between 1986 and 1994 in Northern Italy, adopting standardized MONICA procedures. N=2574 men and n=2673 women, 35-69 years old and free of CVD at baseline, were followed-up to ascertain the first coronary or ischemic stroke event (fatal and non-fatal; all MONICA validated) for a median time of 15 years (IQ range: 12-20) and up to the end of 2008. The 10- and the 20-year absolute risk (AR) of event were estimated from gender-specific Cox models including age, total cholesterol, HDL-cholesterol, systolic blood pressure, anti-hypertensive treatment, cigarette smoking and diabetes. Model discrimination at year 10 and 20, defined as the Area Under the ROC Curve, as well as sensitivity and specificity in the top quintile, were estimated taking censoring into account; the AUC was adjusted for over-optimism via bootstrapping. We assessed the Net Reclassification Improvement (NRI) for the 20-year risk model compared to the 10-year risk model re-calibrated to the Kaplan-Meier estimate of 20-year survival. We report NRI in young men and women as well as in subjects with AR(10)240 mg/dl; HDL-cholesterol 160 mmHg; smoking; diabetes). Results. The Kaplan-Meier estimates of AR(10) and AR(20) were 7.1% and 14.0% in men; and 2.2% and 5.3% in women. After 20 years from measurement, major risk factors were still predictive of CV events; although in comparison to the 10-year model the hazard ratio for total cholesterol in men fell from 1.40 to 1.34; and for HDL-cholesterol in women reduced from 0.64 to 0.71, both calculated for 1 SD increase. In the top risk quintile, the 20-year model had higher specificity (85% vs. 82% in men; 83% vs. 81% in women) and lower sensitivity (46% vs. 50% in men; 63% vs. 69% in women) than the 10-year model; the overall discrimination was similar (0.725 vs. 0.732 [men], and 0.802 vs. 0.813 [women]). NRI in young subjects was 10.5% in men (15.4% in cases) and 5% in women. Six per cent of men and 15% of women had 2 or more major risk factors but an AR(10) Conclusions. In our low-incidence population, long-term prediction of first major ischemic cardiovascular event is more suitable to identify high CVD risk in young men and in women with a cluster of risk factors, overcoming the limits of the 10-year model. Preventive strategies based on long-term absolute risk should be evaluated.

Aims: Although socioeconomic status is a recognized independent risk factor for CVD mortality, the recommended European risk prediction equation for primary prevention does not consider it; an approach criticized by previous results in the UK and US. We aim to assess whether the SCORE project equation adequately estimates the risk in different educational classes, across several European populations. Methods: We considered 47 prospective population-based surveys from Nordic Countries (Finland, Denmark, Sweden), UK (Belfast and Scotland), Central Europe (France, Germany and Italy) and East Europe (Lithuania, Poland) and Russia. Baseline data collection and mortality follow-up (median time 10 years) adhered to standardized MONICA-like procedures. Three educational classes were derived from population-, sex- and birth year-specific tertiles of years of schooling. The individual SCORE risk was computed from age, total cholesterol, systolic blood pressure and smoking; the risk was recalibrated to the average observed risk in each population. We estimated age- and traditional risk factors-adjusted hazard ratios (HR) for 10 year CVD mortality (highest education as the reference), from Cox models. Moreover, the observed number of fatal CVD events by educational class was compared to the expected number, as estimated by the recalibrated SCORE function. Results: The cohorts summed-up 39,215 men and 29,240 women 40 to 64 years old and free from CVD event at baseline. Education was associated with CVD mortality in men (pooled age-adjusted HR for low vs high education: 1.6, 95% CI 1.4–1.9); the hazard ratios ranged from 1.3 (95%CI: 0.9–1.8) in Central Europe to 2.1 (1.6–2.7) in East Europe and Russia. The association attenuated after adjustment for SCORE risk factors and HDL-cholesterol. Among women, the association was significant in Nordic Countries only (age-adjusted HR for low vas high education: 1.7, 95% CI 1.1–2.6), but it was no more significant after adjustment for multiple risk factors. The original SCORE equation overestimated the risk at a population level, both in men and in women, except in East Europe and Russia. After recalibration, the SCORE equation overestimated the risk among the more educated men by 20% to 50% (in Central Europe, East Europe and Russia, respectively), but underestimated it in the less educated men by 7% to 23% (in Central Europe, East Europe and Russia, respectively). Conclusions: Our results, based on a well-harmonized study comprising several European populations, suggest the need to include country-specific socioeconomic status in the risk estimation equations.