Estimation of metabolic syndrome heritability in three large populations including full pedigree and genomic information.

Metabolic syndrome is a complex human disorder characterized by a cluster of conditions (increased blood pressure, hyperglycemia, excessive body fat around the waist, and abnormal cholesterol or triglyceride levels). Any of these conditions increases the risk of serious disorders such as diabetes or cardiovascular disease. Currently, the degree of genetic regulation of this syndrome is under debate and partially unknown. The principal aim of this study was to estimate the genetic component and the common environmental effects in different populations using full pedigree and genomic information. We used three large populations (Gubbio, ARIC, and Ogliastra cohorts) to estimate the heritability of metabolic syndrome. Due to both pedigree and genotyped data, different approaches were applied to summarize relatedness conditions. Linear mixed models (LLM) using average information restricted maximum likelihood (AIREML) algorithm were applied to partition the variances and estimate heritability (h2) and common sib-household effect (c2). Globally, results obtained from pedigree information showed a significant heritability (h2: 0.286 and 0.271 in Gubbio and Ogliastra, respectively), whereas a lower, but still significant heritability was found using SNPs data ([Formula: see text]: 0.167 and 0.254 in ARIC and Ogliastra). The remaining heritability between h2 and [Formula: see text] ranged between 0.031 and 0.237. Finally, the common environmental c2 in Gubbio and Ogliastra were also significant accounting for about 11% of the phenotypic variance. Availability of different kinds of populations and data helped us to better understand what happened when heritability of metabolic syndrome is estimated and account for different possible confounding. Furthermore, the opportunity of comparing different results provided more precise and less biased estimation of heritability.

Early varicocelectomy by percutaneous scleroembolization improves seminiferous tubules spermatozoa release in the adolescent phase of testicular growth.

Varicocele is a rather common andrological condition in adolescents, which can adversely affect testicular growth and seminal parameters, leading to infertility in about 20% of adults. The aim of this study was to investigate if treating varicocele before the age of 18 is a beneficial option to improve testicular hypotrophy and seminal parameters and if minimally invasive techniques could be an appropriate treatment choice for adolescent varicocele associated with spermatic vein reflux. A percutaneous scleroembolization was performed in sixty-four consecutive young patients (13-19 years old) with left varicocele, preceded by a fluoroscopy. In thirty-four of them, semen samples were also collected. We examined semen samples and testicles dimensions before and after percutaneous varicocelectomy, compared to a nonoperated control group, with a six-month follow-up. Total sperm count and sperm morphology were significantly increased in the intervention group. Left testicular volume significantly increased in both groups, while only correction of varicocele improved spermatozoa release per unit of testis volume. We conclude that early varicocelectomy by percutaneous scleroembolization significantly ameliorates seminiferous tubules activity in the critical adolescent phase of testicular growth. It is suggested that adolescents should be; offered varicocele repair as soon as possible in order to improve reproductive potential.

Flaccid penile acceleration as a marker of cardiovascular risk in men without classical risk factors.

INTRODUCTION: Conventional cardiovascular (CV) risk factors identify only half of subjects with incident major adverse CV events (MACE). Hence new markers are needed in high CV risk subjects, as those with erectile dysfunction (ED). A role for dynamic peak systolic velocity (D-PSV) at penile color Doppler ultrasound (PCDU) has been suggested, but it is operator dependent and time consuming. Flaccid penile acceleration (FPA) is a PCDU parameter that reflects PSV, the systolic rise time (SRT), and end diastolic velocity (EDV), arithmetically defined as (PSV-EDV)/SRT. AIM: The study aims to verify, in a large series of ED patients, whether FPA has a role in predicting MACE. METHODS: A selected series of 1,903 patients (aged 54.6 ± 11.7) with a suspected organic component for ED was retrospectively studied from January 2000 until July 2012. A subset of this sample (n = 622) was enrolled in a longitudinal study that ended in December 2007. MAIN OUTCOME MEASURES: Several clinical, biochemical, and instrumental (PCDU) parameters were studied. RESULTS: Decreased FPA levels were associated with worse metabolic profile and sexual symptoms. In addition, FPA was positively associated with both total and calculated free testosterone. In the longitudinal study, unadjusted incidence of MACE was significantly associated with lower baseline FPA. When FPA was introduced in a multivariate model, along with D-PSV, after adjusting for age and Chronic Disease Score, lower FPA, but not D-PSV, was associated with incident MACE in lower--risk-i.e., younger (HR = 0.48 [0.23-0.99]), nonhypertensive (HR = 0.59 [0.38-0.92]), nonobese (HR = 0.68 [0.49-0.96]), or nondiabetic (HR = 0.67 [0.49-0.96] subjects; all P < 0.05--but not in higher-risk ones. FPA demonstrated a threshold effect in predicting MACE at a value <1.17 m/s(2) which showed a threefold increase in incidence of MACE in apparently lower-risk individuals. CONCLUSIONS: FPA is an easily obtained PCDU parameter and capable of identifying adverse metabolic and CV profiles, particularly in apparently lower-risk individuals with ED.

Obesity Is Strongly Associated With Low Testosterone and Reduced Penis Growth During Development.

CONTEXT: Growth of male genitalia represents an important marker of sexual development. Testicle size is the primary measure and little is known regards penile length changes during puberty. OBJECTIVE: This work aims to assess penis growth and testosterone levels in obese vs normal-weight children and adolescents, to evaluate a possible influence of obesity on genital development in boys, and to establish a new method for measuring penis length that allows comparison of normal-weight and overweight boys. METHODS: We assessed anthropometric and genital development in 1130 boys from birth to age 20 years. Testosterone levels were also measured. A new method for penile length measurement was employed to minimize errors when comparing obese and nonobese children. Penis length was measured with a gentle, painless, straight positioning on a centimetric ruler without stretching, which is doable from the first years of life until the end of adolescence. RESULTS: Penis length and testosterone are strongly related in children during puberty. Penile length growth is significantly decreased (by about 10%) in obese boys when compared to normal-weight boys, with concomitantly reduced testosterone levels, across puberal phases. CONCLUSION: Childhood obesity represents an important determinant of lower testosterone level and reduced penis development. A new method should be employed to improve penis measurement in normal-weight and overweight/obese boys. The possible significance of these observations for adult genital development and reproductive potential will require large longitudinal studies.

Twenty-year cardiovascular and all-cause mortality trends and changes in cardiovascular risk factors in Gubbio, Italy: the role of blood pressure changes.

AIMS: In an observational population study that lasted 20 years, the relationships between mortality trends and changes in cardiovascular risk factor levels were examined. METHODS AND RESULTS: In the town of Gubbio, in central Italy, population surveys for measurement of cardiovascular risk factors were performed 20 years apart. In a subset of the initial cohort (1927 men and 2333 women), mortality data were collected for 20 years. Cardiovascular risk factor levels were compared in individuals in the same age range (20-79 years) examined at the initial survey (1927 men and 2333 women) and at the final survey (1761 men and 2055 women). Age-adjusted rates significantly declined, by 28% among men and 51% among women, for all causes of death, and by 50% among men and 71% among women for cardiovascular disease deaths. Declines were observed in the levels of systolic blood pressure, serum cholesterol, resting heart rate, smoking habits, BMI, plasma glucose (the latter two only in women) and the estimated cardiovascular risk, together with increases in serum high-density lipoprotein cholesterol and in the proportion of treated and controlled hypertensive patients. CONCLUSION: Although similar but less impressive changes were recorded in Italy at large, the existence of the observational study in Gubbio might have motivated the general population and the medical profession towards actions promoting general health.

The association between varicocele, premature ejaculation and prostatitis symptoms: possible mechanisms.

INTRODUCTION: No study has ever systematically evaluated the impact of varicocele on sexual function. AIM: Two cross-sectional studies were performed in patients attending an andrology unit either for male sexual dysfunction (study 1) or couple infertility (study 2). In study 1, we evaluated the impact of varicocele on sexual function. In study 2, we retrospectively evaluated a possible association between varicocele and prostatitis signs and symptoms. METHODS: Study 1 refers to a consecutive series of 2,448 (mean age 52.0 +/- 12.9 years) subjects. Study 2 consists of a consecutive series of 139 male subjects (mean age 37.3 +/- 6.3). MAIN OUTCOME MEASURES: In study 1, varicocele was clinically classified into three grades according to Dubin criteria. Different hormonal parameters were also evaluated. All the patients of study 2 underwent simultaneous scrotal and transrectal color-Doppler ultrasonography (CDU) along with seminal characteristics and interleukin-8, a surrogate marker of prostatitis. RESULTS: After adjusting for age, subjects with severe varicocele (N = 284, 11.6%; Dubin grade 2 and 3) showed a reduction of testicular volume (P < 0.01), higher luteinizing hormone (LH) (P < 0.05), follicle stimulating hormone (FSH) (P < 0.0001) and prolactin (P < 0.05) levels, and also an enlarged or tender prostate at digito-rectal examination (P < 0.05). Premature ejaculation was the only sexual symptoms significantly associated with varicocele (29.2% vs. 24.9% in subjects with or without varicocele, respectively; P < 0.05). In study 2, subjects with severe echographic-defined varicocele (basal venous reflux increasing or not after Valsalva's maneuver; N = 28, 20.1%) showed CDU features of prostatitis and higher seminal inteleukin-8 levels. The presence of any degree of varicocele (N = 40, 28.8%) was also associated with prostatitis symptoms, as measured by the National Institutes of Health Chronic Prostatitis Symptom Index scoring (P < 0.05), and in particular with the pain domain (P < 0.05). CONCLUSIONS: In conclusion, signs and symptoms of prostatitis are more common in varicocele patients, who more often complain of premature ejaculation.

Definition of kidney dysfunction as a cardiovascular risk factor: use of urinary albumin excretion and estimated glomerular filtration rate.

BACKGROUND: Urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) have been used separately to provide information about cardiovascular risk. We analyzed whether UAE and eGFR used together provide complementary information. METHODS: We analyzed UAE, eGFR, cardiovascular risk factors, and incidence of cardiovascular disease in 1665 men and women of the Gubbio Population Study (aged 45-64 years). We designated UAE in the highest decile as high (>or= 18.6 microg/min in men and >or= 15.7 microg/min in women) and eGFR in the lowest decile as low (<64.20 mL/min/1.73 m(2) in men and <57.90 mL/min/1.73 m(2) in women). RESULTS: Kidney dysfunction defined using both markers was more frequent than using 1 marker (UAE alone or eGFR alone) (P< .001) because high UAE and low eGFR clustered in different individuals and were weakly associated with each other (P= .12). The hazard ratio (HR) for incident cardiovascular disease was elevated for both markers, independently of each other (HR for high UAE, 2.15; 95% confidence interval [CI], 1.33-3.49; HR for low eGFR, 2.14; 95% CI, 1.32-3.48). Kidney dysfunction defined by both markers predicted cardiovascular disease independently of sex, age, hypertension, hypercholesterolemia, smoking, diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, and obesity (HR, 1.50; 95% CI, 1.05-2.14). The discriminant power of dysfunction defined by both markers was statistically significant (area under the receiver operating characteristic curve, 0.569 [P= .02]) and slightly higher than what was found with 1 marker of diabetes mellitus, prior cardiovascular disease, left ventricular hypertrophy, and obesity. CONCLUSIONS: High UAE and low eGFR provide complementary information in defining kidney dysfunction because they cluster in different individuals. Concomitant evaluation of both markers should be considered to adequately assess kidney dysfunction and cardiovascular risk.

Myoinositol and D-Chiro Inositol in Improving Insulin Resistance in Obese Male Children: Preliminary Data.

Myoinositol and D-chiro inositol, which are inositol isomers, have been shown to possess insulin-mimetic properties and to improve insulin resistance, especially in women with polycystic ovary syndrome. However, it has not been determined if this relationship exists also in children. Based on these previous findings, we hypothesized that inositol could be effective in improving insulin sensitivity in children with insulin resistance. To evaluate this hypothesis, we administered both inositol formulations before carrying out an oral glucose tolerance test (OGTT) in a group of obese insulin-resistant male children with high basal insulin levels and compared the values obtained with an OGTT previously conducted without inositol, in the same group, with unchanged BMI. Our results confirm that myoinositol and D-chiro inositol acutely reduce insulin increase after glucose intake mainly in children with high basal insulin level.

Enhanced Na-Li countertransport: a marker of inherited susceptibility to type 2 diabetes.

UNLABELLED: Introduction The association between type 2 diabetes and hypertension has long been described, but the mechanisms remain unclear. Na-Li countertransport (Na-Li CT) activity is viewed as a marker of inherited pre-disposition to hypertension, especially if associated with other metabolic abnormalities. Aim To evaluate whether enhanced Na-Li CT activity is a predictor of type 2 diabetes. METHODS: Study participants were 2167 men and women, 30-70 years. Na-Li CT activity, glucose, HDL cholesterol, blood pressure, height, and weight were measured. Six years incidence of diabetes (WHO) was assessed. RESULTS: Baseline Na-Li CT activity was significantly higher for people who developed diabetes at follow-up (n = 101) than for those who remained non-diabetic (364 +/- 184 vs 300 +/- 150 micromol/l RBC/h, P < 0.001). This finding was confirmed after correction for obesity, hypertension, and blood glucose. Six years' incidence of diabetes increased across tertiles of baseline Na-Li CT activity--from 2 to 7%--with a significant linear trend (P < 0.001). In multivariate analyses Na-Li CT is a significant predictor of diabetes independent of age, BMI, HDL cholesterol, hypertension, and plasma glucose; based on exponentiation of the regression coefficient Na-Li CT higher by 154 micromol (i.e. 1 SD of the population mean) was associated with a 36% greater risk of incident diabetes. CONCLUSIONS: Prospective data from the present study show for the first time enhanced Na-Li CT activity is a significant predictor of development of diabetes in adults, thus suggesting that it could be viewed as a pre-clinical, possibly genetic, marker of inherited susceptibility to type 2 diabetes.

Indexation criteria of ventricular mass and predictive role of blood pressure and body composition.

BACKGROUND: There is no definite consensus on which indexation of left ventricular mass (LVM) should be used to better identify left ventricular hypertrophy (LVH). Left ventricular mass has been adjusted to height, to height2.7(h2.7) and to body surface area (BSA). The aims of the present study were to evaluate the prevalence of LVH according to different indexations and different cut-offs and to identify the most useful indexation of LVM to detect hypertension-related LVH. METHODS: Echocardiographic LVH was defined as LVM to h2.7, LVM to BSA, LVM to height, LVM values in the upper 5th percentile of our gender-related LVM distribution, using different partition values suggested in previous population-based studies. RESULTS: Prevalence of LVH in the general population was 32% using the less restrictive criterion (LVH 49.2/46.7 g/m2.7), 15% with the criterion of LVH 116/104 g/m2, and 3.8% with the most restrictive one (LVH 134/110 g/m2). Prevalence of LVH in hypertensive subjects was almost twice than in normotensive subjects with all criteria. Only 20 subjects out of the 707 evaluated were found to have LVH with all six criteria. In multiple regression analysis SBP was independently associated with nonindexed LVM and was indexed to both BSA and h2.7. On the other hand, fat-free mass was a powerful predictor of nonindexed LVM or of LVM to BSA, whereas body mass index was the strongest predictor of LVM to h2.7. CONCLUSIONS: The indexation of LVM to BSA, possibly with the cut-off of LVH 116/104, is probably the best criterion for identifying blood pressure-related LVH.

Antihypertensive treatment is not a risk factor for major cardiovascular events in the Gubbio residential cohort study.

BACKGROUND AND OBJECTIVES: Demonstration of antihypertensive beneficial role in population settings is difficult. Relationships of antihypertensive treatment, blood pressure control, risk factors and cardiovascular outcomes were investigated in the Gubbio study. MATERIAL AND METHODS: Among 2248 cardiovascular disease-free men and women aged 35-74 years, individuals were classified as nonhypertensive, controlled hypertensive, uncontrolled hypertensive and untreated hypertensive based on cut-off limits of 140/90  mmHg for SBP/DBP and/or the use of antihypertensive drugs. End-point was the first major coronary, cerebrovascular or peripheral hard event [cardiovascular disease (CVD)] during a 15-year average. Univariate and multivariate analyses were run. RESULTS: Nonhypertensive individuals were about 10 years younger and had lower risk factor levels than the other categories. The relative risk (and 95% confidence interval) for CVD versus nonhypertension was 1.78 (1.02-3.10) for controlled hypertension, 3.76 (2.79-5.06) for uncontrolled hypertension and 3.30 (2.59-4.21) for untreated hypertension (UTH). After adjusting for covariates, such as sex, age, achieved blood pressure and other risk factors, the CVD risk of controlled hypertension was practically equal to that of nonhypertension, and remained unchanged even when blood pressure was excluded from the model (1.03, 0.58-1.82). The higher cardiovascular risk of uncontrolled hypertension and UTH was reduced after adjusting for covariates, but remained significantly higher than in nonhypertension, with no significant differences between uncontrolled hypertension and UTH. CONCLUSIONS: A higher level of baseline risk is not due to treatment per se, the risk being similar in uncontrolled hypertension and UTH. Adjustment for risk factors reduces the risk only in controlled hypertension, suggesting that there may be structural alterations scarcely reversible by antihypertensive treatment.

The relationship of waist circumference to blood pressure: the Olivetti Heart Study.

BACKGROUND: The association between overweight, high blood pressure (BP), and insulin resistance is well established, but the role of body fat distribution in this association has yet to be fully elucidated. The aim of this study was to investigate the role of central adiposity in the association between overweight, high BP, and insulin resistance. METHODS: A total of 1,079 men participated in the follow-up of the Olivetti Heart Study from 1994 to 1995. The present analysis includes 768 men, after the exclusion of 184 participants on pharmacological treatment for hypertension. In 65 men fasting blood glucose was >7 mmol/L; in 48, age was below or above 2 standard deviations from the mean of the population; and in 14 the data set was incomplete. Anthropometric indices of adiposity, metabolic variables (including fasting serum insulin and homeostasis model assessment [HOMA] index of insulin sensitivity), and BP were measured. RESULTS: In univariate analysis, waist circumference was the anthropometric index that best correlated with BP (P < .001). In multiple regression analysis, waist circumference remained the strongest independent predictor of BP after adjustment for confounders. Significant increase of systolic (P value for trend analysis < .001) and diastolic (P < .001) pressure, heart rate (P = .003), fasting and postload serum insulin (P < .001), and HOMA index of insulin sensitivity (P < .001) were observed across age-adjusted quintiles of waist circumference. Greater degrees of central adiposity were associated with higher prevalence of elevated BP values and insulin resistance (P value < .001, chi2 for linear trend). CONCLUSIONS: In middle-aged men, a central distribution of body fat is associated with increased BP, independently of body mass index and insulin resistance, thus suggesting a key role of central adiposity in the full expression of the "metabolic syndrome."

Increased carotid artery intima-media thickness is associated with a novel mutation of low-density lipoprotein receptor independently of major cardiovascular risk factors.

The current study sought to investigate the role of low-density lipoprotein receptor (LDLr) mutations in assessing the risk profile of familial hypercholesterolemia (FH) patients, independently of major cardiovascular risk factors. FH due to LDLr mutations is associated with premature atherosclerosis. The variable clinical severity of the disease in heterozygotes has been related to cholesterol levels and the coexistence of other cardiovascular risk factors, but the independent role of different LDLr mutations is still unclear. cDNA of LDL gene was sequenced in 102 patients with clinical features of heterozygous FH. Carotid artery intima-media thickness (IMT) was measured by B-mode ultrasound imaging in all patients. Sixteen different mutations (5 never described) were found in 82 patients (49 families; mean age, 39 years; 53% women). One of the newly described mutations, the 2312-3 C-->A, was found in 24 patients (13 families). The mean of maximum thicknesses was significantly higher in the 2312-3 C-->A group than in patients with other LDLr mutations (P=.004 after adjustment for major cardiovascular risk factors). Similar results (P=.001) were obtained in the adjusted comparisons of probands only, and of the patients with similar baseline cholesterol (P=.002). This study indicates that the identification of an LDLr mutation can help to assess the risk profile of FH patients independently of the major cardiovascular risk factors.

The contractile wall of the caput epididymidis in men affected by congenital or postinflammatory obstructive azoospermia.

The transport and storage of spermatozoa in the epididymis depend on the contractile activity of its tubular wall. It is not known what differences exist in the contractile wall of the human epididymis in cases of obstructive azoospermia. The contractile wall in the tubules of the caput epididymidis was analyzed by light microscopy and transmission electron microscopy in 10 azoospermic men, 5 with a bilateral congenital absence of vas deferens (CBAVD) and 5 with a bilateral postinflammatory congestive obstruction of the epididymis. Five specimens from the same region of the caput epididymidis, obtained from fertile men who had undergone an orchidectomy because of testicular cancer, served as controls. No differences were observed between congenital and congestive obstructions. The contractile wall in caput tubules proximal to the obstructed level was strongly thickened when compared with controls (62.98 +/- 5.84 micro; 80.82 +/- 7.72 micro vs 19.59 +/- 2.23 micro, respectively, for congestive and congenital obstructions vs controls; P <.0001 vs controls), and the spindle-shaped myoid cells, which formed the contractile wall in normal cases, were replaced by large smooth muscle cells (SMCs) that showed features of coexisting contractile and secretory functions. The former included crowded cytoplasmic bundles of thin myofilaments (5-6 nm in diameter) converging to a large number of dense bodies, numerous micropinocytotic vesicles of the plasma membrane, and a continuous cell basement membrane. The presence of a developed rough endoplasmic reticulum and a Golgi complex, associated with the accumulation of thick layers of pericellular basement membrane-like material and ground substance, was indicative of a secretory phenotype of SMCs. The increased mechanical forces on the epididymal wall upstream from the obstruction might eventually activate the differentiation of myoid cells into SMCs, leading to an altered physiology of the contractile wall that could have possible clinical relevance in the case of microsurgical epididymovasostomy.

Red blood cell count in short-term prediction of cardiovascular disease incidence in the Gubbio population study.

OBJECTIVE: The Gubbio Study is an Italian population study measuring risk factors and incidence for major cardiovascular diseases. This analysis investigates the association between red blood cell (RBC) count, after preliminarily taking into account haematocrit, and incidence of coronary and cardiovascular events. METHODS: A population sample of 2,469 men and women aged 35-74 years, free from major cardiovascular diseases and in whom RBC count and haematocrit were measured in 1983 along with other standard risk factors, were followed up for 6 years and incidence was estimated for both fatal and non-fatal coronary heart disease (CHD) and all cardiovascular atherosclerotic (CVD) events. Proportional hazards models were solved for the prediction of these events. RESULTS: In six years 61 CHD hard criteria, 109 CHD any criterion and 149 CVD events were recorded. Preliminarily, both haematocrit and RBC count, two highly correlated variables, were studied to predict CVD events; however, haematocrit did not contribute multivariately, in the overall population and separately in men and women. Age-adjusted rates per 1,000 of the 3 event categories were computed in sex-specific RBC count quintiles (Q) and a difference was observed between Q5 and Q1 (with 5.21 +/- 0.31 and 4.18 +/- 0.23 x 10(6) per microl, respectively) for CHD any criterion (p < 0.07) and CVD (p < 0.05). P on trends was < 0.05 for both end-points. In multivariate models, adjusted for 7 other risk factors, RBC count contributed a weak statistical significance to predict CVD incidence [relative risk (RR) for a 0.5 x 10(6) per microl difference 1.23 with 95% confidence intervals (CI) 1.00- 1.51], whereas its contribution to predict CHD any criterion (RR = 1.19 with CI 0.93- 1.51) and CHD hard criteria (RR = 1.15 with Cl 0.83-1.58) was not statistically significant. Inclusion of blood glucose and presence of diuretics (11.33% of the population) as possible confounders had no major effect although the latter were, as expected, a significant risk factor (RR = 1.90 with Cl 1.28-2.82) which further diluted the CVD predictive role of RBC count (RR = 1.22 with CI 0.99- 1.50). CONCLUSIONS: Increased RBC count is independently (yet weakly) 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 RBC count can be properly assessed to explain CHD incidence.

The risk functions incorporated in Riscard 2002: a software for the prediction of cardiovascular risk in the general population based on Italian data.

BACKGROUND: The purpose of this analysis was to produce risk functions for the prediction of cardiovascular diseases based on Italian epidemiological data and suitable for the use in a PC program dedicated to the estimate of risk. METHODS: Three studies were used for the purpose: the Italian Rural Areas of the Seven Countries Study, the Gubbio Population Study and the ECCIS study, for a total of 9771 men and women aged 35 to 74 years and followed for a period lasting 5 to 6 years. The risk factors used for the prediction of cardiovascular events were sex, age, body mass index (derived from height and weight), mean blood pressure (derived from systolic and diastolic blood pressures), non-HDL cholesterol (derived from total and HDL cholesterol), HDL cholesterol, diabetes (yes-no), heart rate, and daily cigarette consumption. The endpoints were the first major coronary event, the first major cerebrovascular event, and the first major cardiovascular event (either one between the previous two plus major peripheral artery diseases). The model employed for the analysis was the accelerated failure time model. RESULTS: Having excluded those already presenting with a cardiovascular disease and those with missing values, a total of 9089 subjects were included in the models. In a period lasting 5 or 6 years, a total of 211 coronary, 64 cerebrovascular and 269 cardiovascular events occurred and were considered for analysis. Coefficients from the coronary model suggested a significant association of all risk factors except body mass index and diabetes (marginal significance). Coefficients from the cerebrovascular model suggested a significant association limited to age and mean blood pressure. Coefficients from the cardiovascular model suggested a significant association of all risk factors except body mass index. The discrimination between cases and non-cases was satisfactory with proportions of 37.0, 52.3 and 37.8% of observed cases in decile 10 of the distribution of the estimated risk for the three endpoints respectively. CONCLUSIONS: The three models were used as a mathematical core for the construction of a PC software for the prediction of major cardiovascular events in Italy.

Cohort profile: The Gubbio Population Study.

The Gubbio Study is a prospective epidemiological study on the population residing in the city of Gubbio, Italy. Original objectives of the study were the control of hypertension and the role of cellular electrolyte handling in hypertension. Other objectives were added during the 30-year activity of the study. The original target cohort consists of individuals aged ≥5 years residing within the medieval walls of the city. To complete family genealogies, individuals residing outside the city were also included. Three active screenings (exams) were conducted. A total of 5376 individuals (response rate 92%) participated in Exam 1 which was performed in 1983-86. Follow-up exams were completed between 1989-92 and 2001-2007. Data categories included demographics, personal and family medical history, lifestyle habits, education, type of work, anthropometry, blood pressure, pulse rate, blood biochemistry, urine biochemistry and special investigations on cellular electrolyte handling. Electrocardiogram, echocardiogram, 24-h ambulatory blood pressure and uroflowmetry were performed in selected subgroups defined by age and/or sex. Data about hospitalizations, mortality and causes of death were collected starting from completion of Exam 1. The study shared the data with other studies.

Typical and atypical coronary heart disease deaths and their different relationships with risk factors. The Gubbio residential cohort study.

OBJECTIVES: The Seven Countries Study showed that fatal coronary heart disease (CHD) with only chronic heart failure, arrhythmia or blocks (atypical CHD, A-CHD) may represent a distinct disease as compared to fatal CHD cases with angina pectoris, acute myocardial infarction (AMI) or sudden death (typical CHD, T-CHD). We aimed at validating this, using identical diagnostic criteria, in a separate residential cohort first examined in 1983-85 in Gubbio, central Italy. MATERIAL AND METHODS: Forced Cox's models were run to assess 9 classic risk factors and their 20-year predictivity of A-CHD versus T-CHD, in the entire cohort or separately for men and women. RESULTS: There were 3229 subjects aged 30-79 years. Entry mean age was slightly higher in women than men although age at death was lower in men than in women for both T-CHD (71.99 ± 11.38 versus 81.20 ± 9.35 years, p<0.0001) and A-CHD (80.22 ± 9.44 versus 84.98 ± 8.13 years, p<0.0001). T-CHDs were predicted by male gender, age, continued smoke, systolic blood pressure (SBP), blood glucose, total and HDL-cholesterol (protective). A-CHDs were predicted by age, continued smoke, SBP, body mass index and blood glucose but neither total nor HDL-cholesterol or gender was significant. In the entire cohort and in men there were predictive differences of T-CHD versus A-CHD fatalities only in relation to age (p<0.01), SBP (p<0.05) and total cholesterol (p<0.01). CONCLUSION: As age, SBP and total cholesterol had a different predictive role of T-CHD versus A-CHD fatalities also in the Gubbio cohort, the possibility is reinforced that a different etiology exists between these entities.

Serum uric acid and eGFR_CKDEPI differently predict long-term cardiovascular events and all causes of deaths in a residential cohort.

OBJECTIVES: Serum uric acid (SUA) and estimated glomerular filtration rate (eGFR) were separately assessed as risk factors for incident coronary hard (CHDH), cardiovascular disease (CVDH) or all-cause (ALL) deaths but never concomitantly in a residential cohort. MATERIAL AND METHODS: Men and women aged 35-74years, totaling 2888 subjects were followed 13.5-19.5years for incident CVDH, CHDH and ALL deaths. Systematic comparisons among different end-points were based on: age, gender, systolic blood pressure (SBP), total and HDL cholesterol, cigarette consumption, body mass index, blood glucose, SUA, eGFR from the Chronic Kidney Disease Prognosis Consortium (eGFR_CKDEPI) and (eGFR_CKDEPI)(2). RESULTS: Significant (p<0.00001) differences in SUA quintiles were seen for SBP, total and HDL cholesterol, body mass index and eGFR_CKDEPI whereas cigarettes and blood glucose were not statistically different. There were increasingly larger proportions of all events in SUA quintiles (0.05>p<0.0001). Among 4 major continuous variables, SUA was largely accurate (ROC>0.610) to predict all end-points whereas eGFR_CKDEPI was the worse univariate predictor. Multivariately, age, gender, SBP and cigarettes were significant predictors for all end-points. Total cholesterol was a significant predictor only for CHDH events. Blood glucose and SUA were contributors for CVDH events (RR, for 1mg/dl of SUA, 1.09, 95%CI 1.01-1.17), CVD deaths (RR 1.11, 95%CI 1.03-1.20) and ALL deaths (RR 1.08, 95%CI 1.03-1.14) whereas (eGFR_CKDEPI)(2) was for ALL deaths only (RR 1.02, 95%CI 1.00-1.04). CONCLUSION: SUA is a predictor of long-term incidence of cardiovascular events and deaths and all-cause mortality and should be considered for risk predictive purposes and instruments whereas eGFR_CKDEPI only predicts all-cause mortality by a U-shaped relation.

Heritability of blood pressure through latent curve trajectories in families from the Gubbio population study.

BACKGROUND AND OBJECTIVES: Prospective investigations on cardiovascular risk factors in populations provide a unique opportunity to dissect time-dependent quantitative complex traits, such as arterial blood pressure (BP), into their polygenic and environmental components. BP heritability analyses were carried out on 2620 patients belonging to 711 nuclear pedigrees that could be followed up throughout 25 years in the Gubbio Population Study. METHODS: Each patient's BP serial measurements were summarized into individual intercepts (expected values at baseline) and slopes (time-related changes), which were predicted through latent curve models. These models considered either age in years or waves (times from the first survey) as time axis and were linked at a family level in the heritability analyses using additive polygenic-common environment-unique error models adjusted for sex, age and clinical variables. RESULTS: The additive genetic effect explained 32-49% of the variance of SBP values at baseline, the wave-dependent analysis with nuclear pedigrees and the sibs-household matrix accounting for higher heritability values. Heritability of DBP baseline value was lower than that of SBP in analyses by age (5-15%), but fell in the same heritability range as SBP on the analysis by waves (36-37%). The BP variation over time (slope) explained by an additive genetic effect ranged from 33 to 43% and from 24 to 25% for SBP and DBP, respectively, in the analysis by age. Shared environment also exerted a significant influence, but explained a smaller portion of the variances (4-17%) for both traits. CONCLUSION: Longitudinal data from the Gubbio population show strong to moderate genetic influences on SBP and DBP baseline values and changes over time with a smaller, though significant, effect of environment.