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Background Body-mass index (BMI) and diabetes have increased worldwide, whereas global average blood pressure and cholesterol have decreased or remained unchanged in the past three decades. We quantified how much of the effects of BMI on coronary heart disease and stroke are mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors. Methods We pooled data from 97 prospective cohort studies that collectively enrolled 1·8 million participants between 1948 and 2005, and that included 57 161 coronary heart disease and 31 093 stroke events. For each cohort we excluded participants who were younger than 18 years, had a BMI of lower than 20 kg/m2, or who had a history of coronary heart disease or stroke. We estimated the hazard ratio (HR) of BMI on coronary heart disease and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose. We pooled HRs with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators. Findings The HR for each 5 kg/m2 higher BMI was 1·27 (95% CI 1·23-1·31) for coronary heart disease and 1·18 (1·14-1·22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors reduced the HRs to 1·15 (1·12-1·18) for coronary heart disease and 1·04 (1·01-1·08) for stroke, suggesting that 46% (95% CI 42-50) of the excess risk of BMI for coronary heart disease and 76% (65-91) for stroke is mediated by these factors. Blood pressure was the most important mediator, accounting for 31% (28-35) of the excess risk for coronary heart disease and 65% (56-75) for stroke. The percentage excess risks mediated by these three mediators did not differ significantly between Asian and western cohorts (North America, western Europe, Australia, and New Zealand). Both overweight (BMI ≥25 to

STUDY OBJECTIVE: To evaluate the relation of body mass index (BMI) to short-term mortality in a large Italian population sample. DESIGN: Within the Italian RIFLE pooling project, BMI was measured in 47 population samples made of 32,741 men and 30,305 women ages 20-69 years (young 20-44, mature 45-69). Data on mortality were collected for the next six years. MAIN OUTCOME MEASURES: Age adjusted death rates in quintile classes of BMI and Cox proportional hazards models with six year all causes mortality as end point, BMI as covariate and age, smoking, systolic blood pressure as possible confounders were computed. Multivariate analysis was tested in all subjects and after the exclusion of smokers, early (first two years) deaths, and both categories. RESULTS: The univariate analysis failed to demonstrate in all cases a U or inverse J shaped relation. The Cox coefficients for the linear and quadratic terms of BMI proved significant for both young and mature women. The minimum of the curve was located at 27.0 (24.0, 30.0, 95% confidence limits, CL) and 31.8 (25.5, 38.2, 95% CL) units of BMI, for young and mature women respectively. Similar findings were obtained even when exclusion were performed. No relation was found for young men while for mature adult men only the model for all subjects retained significant curvilinear relation (minimum 29.3; 22.4, 36.2, 95% CL). CONCLUSION: These uncommon high values of BMI carrying the minimum risk of death seems to be in contrast with weight guidelines. A confirmation of these findings in other population groups might induce the consideration of changes in the suggested healthy values of BMI.

Individual studies of stroke have not clearly answered two questions: on the relation, if any, between total blood cholesterol and stroke ; and on how the strength of the relation between diastolic blood pressure and stroke varies with age. The associations of blood cholesterol and diastolic blood pressure with subsequent stroke rates were investigated by review of 45 prospective observational cohorts involving 450 000 individuals with 5-30 years of follow-up (mean 16 years, total 7·3 million person-years of observation), during which 13 397 participants were recorded as having had a stroke. Most of these were fatal strokes in studies that recorded only mortality and not incidence, but about one- quarter were from studies that recorded both fatal and non-fatal strokes. After standardisation for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary heart disease, or ethnicity (Asian or non-Asian). However, because the types of the strokes were not centrally available, the lack of any overall relation might conceal a positive association with ischaemic stroke together with a negative association with haemorrhagic stroke. When the highest and the lowest of the six blood pressure categories were compared, the difference in usual diastolic blood pressure was 27 mm Hg (102 vs 75 mm Hg), and there was a fivefold difference in stroke risk. This fivefold difference was seen both in those with a pre-existing history of coronary heart disease and in those without it. The proportional difference in stroke risk, however, was more extreme in middle than in old age. Among those aged

The Gubbio Study is an Italian population study measuring risk factors for and incidence of major cardiovascular diseases. This analysis investigates the association of serum uric acid with the incidence of coronary and cardiovascular events.A population sample of 2469 men and women aged 35-74 years, free from major cardiovascular diseases and in whom serum uric acid was measured in 1983 along with other standard risk factors, were followed up for 6 years and the incidence of coronary heart disease (CHD) and all cardiovascular atherosclerotic (CVD) events, both fatal and non-fatal, was computed. Proportional hazards models were used for the prediction of these events.In six years 61 CHD hard criteria, 109 CHD any criterion and 149 CVD events were recorded. Age-adjusted rates per 1000 of the 3 event categories were computed in sex-specific quintiles (Q) of serum uric acid with 428 +/- 76 (Q5) and 198 +/- 42 (Q1) micromol/l, respectively. Although higher rates were seen in Q5 as compared to Q1 for all three first event categories considered (relative risks 6.2, 3.6 and 3.7, respectively), a statistically significant trend was seen only for CVD all criteria (t = 3.63, p0.036). These trends were borderline significant for CHD any criterion (t = 2.92, p0.06) and not significant for CHD hard criteria (t = 2.23, p0.11). In multivariate models, adjusted for 8 other risk factors, serum uric acid showed a statistically significant contribution to predict CVD incidence [relative risk (RR) for 92 micromol/l difference of 1.24 with 95% confidence intervals (CI) 1.05-1.45], whereas the statistical contribution to predict CHD any criterion (RR = 1.19 with CI 0.98-1.45) and CHD hard criteria (RR = 1.20 with CI 0.93-1.55) was not significant. Diuretic treatment and blood urea, as further confounders, were positively and significantly related to event incidence (RR ranging from 1.21 to 2.00) but serum uric acid maintained its independent and statistically significant role in the prediction of CVD events (RR = 1.18 with CI 1.00-1.39). Presence of specific treatments to lower serum uric acid levels (in 1.13% of the population), tested as final confounders, was not statistically contributory.Increased serum uric acid levels are independently and significantly associated with risk of CVD events in the 6-year follow-up of the Gubbio Study. Longer follow-up is needed before the contributory role of serum uric acid can be properly assessed to explain CHD incidence.

The Italian Committee for Drugs has recently modified "Appendix 13" to a recent Italian regulation related to reimbursement of hypolipidemic agents for primary or secondary prevention of heart diseases. There is some confusion in concepts, terminology and phrasing, also dealing with disease definition, which need comment. Moreover, "Appendix 13" suggests to estimate risk based on charts derived from the Framingham experience, which are inappropriate when applied to Italy. Finally, "Appendix 13" is not clear as to how categorize high risk individuals. There has been a growing interest in estimating coronary risk since 1994, probably as the result of primary and, secondary intervention trials with statins used to lower blood cholesterol levels. On the other hand, European guidelines have been published, accompanied by risk charts (derived from the Framingham study) helping to index individuals who may benefit from treatment of coronary risk factors. At least thirteen such or similar instruments have been produced worldwide (and three of these in Italy) to estimate coronary risk. In Italy, there are other instruments in preparation. Data are reviewed wherefrom it is possible to conclude that it is inadequate, since substantially erroneous, to use risk functions to estimate absolute coronary risk when these are derived from largely different populations as to those in which practical applications are looked for.

The authors aimed to quantify the effects of current systolic blood pressure (SBP) and serum total cholesterol on the risk of mortality in comparison with SBP or serum cholesterol 25 years previously, taking measurement error into account. The authors reanalyzed 35-year follow-up data on mortality due to coronary heart disease and stroke among subjects aged 65 years or more from nine cohorts of the Seven Countries Study. The two-step method of Tsiatis et al. (J Am Stat Assoc 1995;90:27-37) was used to adjust for regression dilution bias, and results were compared with those obtained using more commonly applied methods of adjustment for regression dilution bias. It was found that the commonly used univariate adjustment for regression dilution bias overestimates the effects of both SBP and cholesterol compared with multivariate methods. Also, the two-step method makes better use of the information available, resulting in smaller confidence intervals. Results comparing recent and past exposure indicated that past SBP is more important than recent SBP in terms of its effect on coronary heart disease mortality, while both recent and past values seem to be important for effects of cholesterol on coronary heart disease mortality and effects of SBP on stroke mortality. Associations between serum cholesterol concentration and risk of stroke mortality are weak.

Valutazione della esposizione agli esteri fosforici dei lavoratori agricoli mediante la determinazione dei composti alchilfosfati nelle urine come stima della c.d. Dose interna globale

Background and aims: Forty-year all-cause mortality and its association with entry risk factor levels are reported for men enrolled in the Italian Rural Areas of the Seven Countries Study of Cardiovascular Diseases. Methods: Forty-eight potential risk factors were measured in 1712 men aged 40-59 at entry examination in 1960. Mortality data were collected during 40 years of follow-up. The relationship of entry risk factor levels with all-cause mortality was studied by univariate and multivariate approaches. Results: Overall death rate was 83.7%. The main causes of death were cardiovascular diseases, followed by cancer and others. The 48 risk factors were tested with univariate and multivariate approaches. In the final model, 15 risk factors were strongly and significantly related to all-cause mortality and survival. They were age, father and mother history of premature mortality, cigarette smoking, job-related physical activity (protective), body mass index (BMI) (in an inverse J-shaped fashion), mid-arm circumference (protective), mean blood pressure, forced respiratory volume in 314 seconds (protective), serum cholesterol, corneal arcus, xanthelasma, presence of cardiovascular diseases, cancer and diabetes at entry examination, Conclusions: During a 40-year period 15 mainly cardiovascular risk factors were highly predictive of all-cause mortality and survival in middle-aged men. (c) 2006, Editrice Kurtis.

ACKGROUND AND AIMS: Time trends in major cardiovascular risk factors are described in cohorts of middle-aged men followed for 35 years in 9 European cohorts of Finland, The Netherlands, Italy, Serbia and Greece. METHODS: Men aged 40 to 59 years at entry in the early 1960s were repeatedly re-examined 3 to 5 times over the last 35 years. Systolic blood pressure, serum cholesterol, body weight and body mass index were considered for analysis, including study of aging (35 years of follow-up) and of generation effects (10 years for men aged 50-59 in the period 1960-1970 and separately 10 years for men aged 75-84 years in the period 1985-1995). RESULTS: For the aging effect, average systolic blood pressure increased approximately 15 mmHg over 25 years maintaining a steady state thereafter, the largest increases being found in Serbia and Greece. Average serum cholesterol varied between approximately 4.5 in Serbia and 6.5 mmo/L in Finland in about 1960. Twenty-five years later, the average level was about 6 mmol/L in all five countries and decreased slightly thereafter. Average body weight and body mass index increased in all countries for 25 years and levelled off thereafter. For the generation effect, average systolic blood pressure decreased in all countries, with the exception of men aged 50-59 in Serbia and men aged 75-84 in The Netherlands. Average serum cholesterol uniformly increased in men aged 50-59 for the younger age-class and slightly decreased in men aged 75-84. Average body weight and body mass index increased systematically in all countries and in both age groups. CONCLUSIONS: Major changes were the great increases in average systolic blood pressure and serum cholesterol level in Serbia and in systolic blood pressure level in Greece between 1960 and 1985, and the large decrease in average serum cholesterol in Finland between 1970 and 1995. Average body weight and body mass index showed universal increases in both middle-aged and older men after 1960.

The present article reviews the epidemiological and statistical bases of the multivariate prediction of cardiovascular events and its transformation into practical tools for primary prediction. The problems with the use of tools derived from studies conducted in populations that are different from those in which the estimate is being made are documented. A description is made of a number of predictive tools produced in the past and recently included in risk manuals, charts and computer programs and their main characteristics are outlined. The problems in the origin, structure and use of the chart suggested by the Task Force of three European Scientific Societies, including the marked overestimate of the risk when this tool is applied to Italian data, are reviewed in detail. The need to use predictive tools derived from Italian population studies is stressed. Comments are made on the difficult choice between the use of the absolute and relative risks for the identification of high-risk subjects to be treated on an individual basis for primary prevention of major cardiovascular diseases.

A risk chart for primary prediction of major coronary and cerebrovascular events based on Italian population data was created. Material from three Italian population studies was available: the Italian Rural Areas of the Seven Countries Study (no. 1712), the Gubbio Study (no. 3061) and the ECCIS Study (no. 4998) for a total of 9771 men and women aged 35 to 74 years and followed-up from 5 to 15 years, for a total of over 55,000 person/years. Sex, age, diabetes, cigarette smoking, systolic blood pressure and serum cholesterol were selected as risk factors, while the endpoint was established as the occurrence of the first major coronary or cerebrovascular event in 10 years. The accelerated failure time model was used as the predictive model. Two models were adopted, i.e., for relatively younger subjects (45-59 years) and for relatively older subjects (60-74 years). Both produced highly significant coefficients for each of the selected risk factors. The two models carried a satisfactory discriminating power, with 40% to more than 50% of all events located in the upper quintile of the estimated risk. Sex, age (6 classes), diabetes, cigarette smoking (4 classes), systolic blood pressure (4 classes) and serum cholesterol (5 classes) were considered for the creation of a risk map derived from multivariate models. A total of 1920 cells were filled with different colors corresponding to 6 classes of absolute risk. A similar set of cells was filled with another color scale for the estimate of the relative risk versus subjects of the same age and sex carrying Italian mean levels of risk factors. The chart is being distributed to the Italian medical profession as a practical tool to select high-risk individuals for the primary prevention of major cardiovascular diseases.

Two-hundred and fourteen patients with congestive heart failure were identified over a six-month period in the general practice of 29 GPs covering an adult population of 29,959 subjects residing in the region of Calabria, in southern Italy, with an overall prevalence of 7 per 1000. Males represented 52% of the cases and females 48%, with a median age of 75 years. On average, the condition was first diagnosed 41 months before the present examination. Patients generally had a high body mass index (28 kg/m2). Patients were classified as follows in the NYHA classification: 9.4% in class I, 45.3% in class II, 39.2% in class III, 6.1% in class IV. Hypertension, either alone or associated with ischemic heart disease (totally about 75% of cases), was the most common etiology, while COPD was the most commonly associated chronic condition. Clinical symptoms and signs were used to classify patients in a simplified version of the Boston score which was reported in 48% of cases as definite, 12% as possible, 6% as improbable and 34% as absent. A specific treatment was already ongoing in 97% of patients. The most commonly administered drugs were diuretics (83%), ACE-inhibitors (77%), and digitalis (67%). This three-drug combination (alone or with other drugs) covered 46% of patients. A comparison of four predefined typologies of treatment against the Boston score suggested that at least part of the outcome in classifying patients using this procedure was due to pathomorphosis of the syndrome induced by early pharmacological treatment.

Individual studies of stroke have not clearly answered two questions: on the relation, if any, between total blood cholesterol and stroke; and on how the strength of the relation between diastolic blood pressure and stroke varies with age. The associations of blood cholesterol and diastolic blood pressure with subsequent stroke rates were investigated by review of 45 prospective observational cohorts involving 450,000 individuals with 5-30 years of follow-up (mean 16 years, total 7.3 million person-years of observation), during which 13,397 participants were recorded as having had a stroke. Most of these were fatal strokes in studies that recorded only mortality and not incidence, but about one-quarter were from studies that recorded both fatal and non-fatal strokes. After standardization for age, there was no association between blood cholesterol and stroke except, perhaps, in those under 45 years of age when screened. This lack of association was not influenced by adjustment for sex, diastolic blood pressure, history of coronary disease, or ethnicity (Asian or non-Asian). However, because the types of the strokes were not centrally available, the lack of any overall relation might conceal a positive association with ischaemic stroke together with a negative association with haemorrhagic stroke. When the highest and the lowest of the six blood pressure categories were compared, the difference in usual diastolic blood pressure was 27 mm Hg (102 vs 75 mm Hg), and there was a fivefold difference in stroke risk. This fivefold difference was seen both in those with a pre-existing history of coronary heart disease and in those without it. The proportional difference in stroke risk, however, was more extreme in middle than in old age. Among those aged < 45, 45-64, and 65+ when screened, the differences in the relative risks of stroke (between the highest diastolic blood pressure category and a combination of the lowest two categories) were tenfold, fivefold, and twofold, respectively. However, because the absolute stroke risks are greater in old age, the absolute differences in the annual stroke rates showed an opposite pattern, being 2, 5, and 8 per thousand, respectively. This suggests that the effects of therapeutic blood pressure reductions should be assessed separately in middle age and in old age.

Background. The relationships of body mass index and skinfold thickness to all-causes mortality during a 10-year follow-up were assessed in 8,341 men and 1,100 women ages 30–69 years from different Italian population samples. Results. Among men, both univariate and multivariate analyses showed a clear-cut parabolic (inverse J-shaped) relationship, whose left branch became less steep after the exclusion of smokers, people carrying severe diseases at entry, those who died during the first 5 years, or all of them. The minimum risk was almost always located around 28 units of body mass index, and it decreased to smaller levels of body mass index when the exclusions were adopted. The analysis of skinfold thickness showed similar but less clear-cut results. Among women, due to the limited number of fatal events, the analysis was unable to show any clear relationship of body mass index or skinfold thickness to all-causes mortality. The multivariate analysis showed a similar parabolic relationship of body mass index to all-causes mortality. The estimated multivariate risk of death broken down into five quintiles was unrelated to the mean level of body mass index for each quintile. From the multivariate model it was estimated that an excess of 10 kg in body weight (above the body mass index corresponding to the minimum risk level and everything else being equal) carries the same excess of risk produced by 5 mm Hg of systolic blood pressure or by less than 5 cigarettes smoked per day. Conclusion. These results suggest that high levels of obesity indicators are only slightly associated with an excess mortality and that overweight and obesity are health hazards only if they are accompanied by an elevation of other risk factors, mainly of blood pressure.

Sixteen cohorts of men aged 40-59 years at entry were examined with the measurement of some risk factors and then followed-up for mortality and causes of death for 25 years. These cohorts were located in the USA (1 cohort), Finland (2), the Netherlands (1), Italy (3), the former Yugoslavia (5), Greece (2), and Japan (2), and included a total of 12, 763 subjects. The differences in age- adjusted coronary heart disease (CHD) death rates were found, with extremes of 45 per 1000 in 25 years in Tanushimaru, Japan, to 288 per 1000 in 25 years in East Finland. In general, higher rates were found in the US and Northern European cohorts as compared to the Southern European and Japanese cohorts. However, during the last 10 years of follow-up large increases of CHD death rates were found in some Yugoslavian areas. Out of 5 measured entry characteristics treated as age- adjusted levels (serum cholesterol, systolic blood pressure, cigarette smoking, body mass index and physical activity at work), only serum cholesterol was significant in explaining cohort differences in CHD death rates. Over 50% of the variance in CHD death rates in 25 years was accounted for by the difference in mean serum cholesterol. This association tended to decline with increasing length of follow-up, but this was due to the great changes iri mean serum cholesterol in the two Jugoslavian cohorts of Velika Krsna and Zrenjanin. When these two cohorts were excluded the association increased with time. Changes in mean serum cholesterol between year 0 and 10 helped in explaining differences in CHD death rates from year 10 onward. It can be concluded that this study suggests that mean serum cholesterol is the major risk factor in explaining cross-cultural differences in CHD.

Nicorandil (N) increases potassium conductance in vascular smooth muscle and so induces vasodilation; N also dose-dependently reduces action potential duration (APD). However, it is unclear whether increased potassium conductance, and concomitant APD shortening, might be arrhythmogenic, particularly when myocardial ischemia (where potassium efflux is increased) concurs. Data on the anti-arrhythmic effectiveness of N have also been published: N reduced the spontaneous discharge of sino-atrial node and so reduced heart rate, both in vitro and man. On the other hand, among other vasodilators, cicletanine (C) has been reported to increase potassium conductance, an effect which was advocated to explain its antiarrhythmic potency. In the present investigation the direct myocardial effects of N were compared to those following C in 63 experiments (from 13 Guinea-pigs), using atrial strips (containing sino-atrial node) superfused in 1-compartment bath with normal Tyrode's solution. Using glass microelectrodes, standard electrophysiologic variables were recorded (APA, RMP, APD50%, Vmax) in spontaneously beating atrial tissue, either in Tyrode, dimethyl-sulfoxide (DMSO 1:100, as solvent), C 10(-5) M (in DMSO 1:100), and N 10(-3) M (in DMSO 1:100), whose respective perfusion periods (15 min) were randomized, always following 15 min of washout with Tyrode. Only N was tested in experiments of both 15 and 30 min duration.(ABSTRACT TRUNCATED AT 250 WORDS)