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Purpose\ud Leptin is associated with cardiovascular risk factors (e.g. hypertension, insulin resistance, kidney disease and excess body weight). Experimental studies showed that leptin might affect serum uric acid, by modulation of the uric acid excretion. However, there are few observational data on the relationship between leptin and uric acid in the general population. Therefore, the aim of the present study was to evaluate the relationship between leptin and uric acid and its excretion in a large middle-aged male general population.\ud \ud Methods\ud A sample of 930 adult male individuals (mean age: 52 years) without therapy for high uric acid was included in the analysis (the Olivetti Heart Study).\ud \ud Results\ud Uric acid was significantly and positively associated with blood pressure, BMI, waist circumference, insulin resistance, C-reactive protein and leptin (p

BACKGROUND: Because high circulating plasma leptin is associated with many features of the metabolic syndrome (MS), such as abdominal obesity, insulin resistance and high blood pressure (BP), we analysed the ability of plasma leptin concentration to predict the risk of developing MS in a prospective investigation of adult male participants of the Olivetti Heart Study (OHS). METHODS AND RESULTS: Three hundred and sixty out of 907 men participating in the 1994-95 and 2002-04 OHS examinations (mean age at baseline 50.4 years, range 25-73 years) were free of MS at first visit according to NCEP-ATP III criteria (modified for the lack of high-density lipoprotein cholesterol measurement at baseline). During an average follow-up period of 8 years, there were 52 incident cases of MS (14.5%) due, in particular, to a rise in the prevalence of high BP (+42.4%), abdominal obesity (+16.4%) and impaired fasting glucose (IFG, +6.1%). In multivariate analyses, a one standard deviation difference in baseline plasma leptin concentration was associated with a 1.58-fold greater risk of developing MS (95% confidence interval = 1.10-2.30, P = 0.016) accounting for age, waist circumference, homeostatic assessment model index, smoking, alcohol consumption and physical activity. In particular, plasma leptin was positively associated with the risk of developing high BP (0.006) and IFG (0.014), after adjustment for confounders. CONCLUSION: In this sample of an adult male population free of MS at baseline, circulating plasma leptin was a significant predictor of the risk of MS and, in particular, of its high BP and IFG components, independently of potential confounders.

This analysis compares the performance of 7 different diagnostic criteria of metabolic syndrome (MS) with regard to the prevalence of the syndrome, the characteristics of subjects with a positive diagnosis, and the ability to correctly identify individuals at high calculated cardiovascular (CV) risk or with signs of systemic inflammation or early organ damage. The diagnostic criteria proposed by the World Health Organization (1998); European Group for the Study of Insulin Resistance (EGIR) (1999); Adult Treatment Panel III (ATP III) (2001); American Association of Clinical Endocrinologists (AACE) (2003); ATP III (2004); International Diabetes Federation (IDF) (2005); and American Heart Association/National Heart, Lung, and Blood Institute (2005) were applied to the population of 933 men aged 59.5 years (range, 33-81 years) attending the 2002-2004 examination of the Olivetti Heart Study. Standardized measurements were available for body mass index, waist circumference, blood pressure, fasting serum total and high-density lipoprotein cholesterol, triglyceride, glucose, insulin, high-sensitivity C-reactive protein, and microalbuminuria. Insulin resistance was estimated by the homeostasis model assessment index; and CV risk, by the Prospective Cardiovascular Munster algorithm. The MS prevalence ranged from 8.6% (AACE) to 44.5% (IDF). Among MS-positive subjects, insulin resistance ranged from 94.8% (EGIR) to 49.2% (IDF), whereas type 2 diabetes mellitus (excluded by EGIR and AACE criteria) rated 59.9% by World Health Organization and 22% to 24% by ATP III, IDF, or American Heart Association/National Heart, Lung, and Blood Institute. By most criteria, MS-positive subjects had greater calculated CV risk than MS-negative subjects; but in general, the ability to correctly identify individuals at high CV risk was dampened by limited sensitivity (maximum 60%). Lowering the cutoff for abdominal adiposity (waist circumference

Genes of the renin-angiotensin–aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme ( ACE ), M235T of angiotensinogen ( AGT ), A1166C of angiotensin II type-1 receptor ( AT1R ), and C-344T of aldosterone synthase ( CYP11B2 ). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M ( AGT ), A ( AT1R ), and C ( CYP11B2 ) in the presence of the D allele of ACE (DD/ID) showed lower FE-Li (20.0%±5.9% versus 25.0%±7.5%; P =0.004; mean± s D), FE-UA (6.3%±2.0% versus 8.2%±2.7%; P =0.001), and FE-Na (0.96%±0.41% versus 1.22%±0.61%; P =0.004) as compared with all other allelic combinations (n=890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.

METHODS: The association of the Trp64Arg polymorphism of the beta3-adrenoceptor (beta3-AR) gene with high blood pressure, central adiposity and other features of the metabolic syndrome was investigated in a large unselected sample of a white male working population in Southern Italy (n = 979). RESULTS: In the whole population, subjects heterozygous for the Trp64Arg mutation (11.2%) were not different from the homozygous Trp64Trp for any of the variables investigated. However, upon stratification for age, among men in the upper tertile of age (> 53 years), the Trp64Arg genotype was associated with higher waist: hip ratio (0.992 +/- 0.021 versus 0.982 +/- 0.037, P< 0.05), serum uric acid (6.34 +/- 1.50 versus 5.75 +/- 1.30 micromol/l, P < 0.05) and systolic blood pressure (144.3 +/- 19.4 versus 136.9 +/- 18.9 mmHg, P< 0.05) compared with the wild-type homozygotes. Accordingly, in the same age group, the carriers of Trp64Arg genotype were more often in the upper tertile of abdominal adiposity (69.7 versus 43.7%, P< 0.02) and serum uric acid (56.3 versus 34.8%, P < 0.02) and were more often hypertensive (68.6 versus 57.6%, P< 0.058) than the Trp64Trp homozygotes. No such differences were observed in younger age groups. No association was found with fasting serum insulin and the homeostasis model assessment (HOMA) index of insulin resistance. Furthermore, in a subgroup of 457 men for whom retrospective 20-year follow-up data were available, the variant genotype was associated with a higher probability of developing overweight (44.7 versus 27.0%, P < 0.05) and a trend to higher blood pressure (52.6 versus 38.4%, P = 0.09) over 20 years. CONCLUSION: We conclude that the Trp64Arg variant of the beta3-AR receptor predicts a greater tendency to develop abdominal adiposity and high blood pressure with advancing age.

A higher prevalence of hypertension has been associated with the G -->A/GT (Gly40Ser) polymorphism of the glucagon receptor gene (GCGR) in two population studies. As the mutated receptor is less responsive to glucagon, it has been speculated that the increased susceptibility to hypertension is due to deprivation of the recognized natriuretic effect of the hormone. To test this hypothesis we determined the frequency of the polymorphic variant and evaluated the segmental renal sodium handling by the clearances of uric acid and of exogenous lithium in the Olivetti Heart Study participants (n = 971). The polymorphic variant was present only in heterozygous form in 37 individuals (3.8%). After controlling for age and body mass index, the carriers of the variant were twice more likely to be hypertensive and almost three times more likely to be on antihypertensive treatment at the time of examination. Compared to participants carrying the wild type, those carrying the Gly40Ser allele had higher serum uric acid and lower fractional excretion of uric acid and exogenous lithium, independently of age, body mass, and current pharmacological treatment. We conclude that the Gly40Ser polymorphism of the GCGR gene is associated with higher risk of hypertension and with enhanced proximal tubular sodium reabsorption, a factor possibly contributing to hypertension in this group.

Arterial hypertension is frequently associated with serum lipid abnormalities. Lipid metabolism can also be affected by antihypertensive treatment, possibly via an interference with lipoprotein lipase (LPL) activity. The aims of this study were to investigate the metabolic and hemodynamic factors that can interfere with plasma postheparin LPL activity in a sample of 13 patients with mild, uncomplicated arterial hypertension. The effects of vasodilator administration (prazosin and hydralazine) alone or in combination with a beta-blocker (propranolol) were also studied. A direct correlation between serum insulin levels and LPL activity was found during placebo treatment. This was confirmed by multiple regression analysis, which also showed a positive correlation of LPL activity with aortic flow velocity and plasma adrenaline (F significance = 0.0007, R2 = .905). Serum insulin was also directly correlated with cholesterol in high-density lipoproteins (HDLs) and in the HDL2 subfraction. A significant decrease in LPL activity was observed during the addition of propranolol to vasodilators as compared with vasodilators alone. A positive correlation was found between LPL and adrenaline changes induced by the combined treatment. These data suggest that LPL may play a role in the pathophysiologic connections between insulin action, the adrenergic nervous system (ANS), and lipid metabolism.

BACKGROUND: The renin-angiotensin system is involved in adipocyte growth and differentiation and possibly in adipose tissue metabolism. OBJECTIVE: To investigate the association of polymorphism in the angiotensin-converting enzyme (ACE) I/D gene, angiotensinogen M235T gene, and angiotensin II type 1 receptor A1166C gene with body mass index, body fat pattern, and obesity-associated hypertension. DESIGN: Cross-sectional longitudinal study. SETTING: The Olivetti factories in Marcianise and Pozzuoli, suburbs of Naples, Italy. PARTICIPANTS: 959 adult men, 25 to 75 years of age. MEASUREMENTS: Renin-angiotensin system polymorphism, anthropometric indexes, blood pressure, and serum glucose and insulin levels. RESULTS: No association was detected between angiotensinogen or angiotensin II type 1 receptor gene polymorphism and anthropometric indexes or blood pressure. For ACE I/D polymorphism, significant age-genotype interaction was detected on cross-sectional observation; the relation of body mass index, waist circumference, and diastolic blood pressure to age was significantly greater in persons with the DD genotype than in those with the ID or II genotype. Overweight and abdominal adiposity were more common in men with the DD genotype, particularly among older participants (51.1% vs. 36.5% and 33.1% vs. 22.0%, respectively). Odds ratios were 1.82 (95% CI, 1.16 to 2.87) for overweight and 1.76 (CI, 1.06 to 2.90) for abdominal adiposity. Among 314 untreated men first examined 20 years earlier, those with the DD genotype had greater age-adjusted weight gain (1.45 kg [CI, 0.12 to 2.78 kg]) and change in diastolic blood pressure (2.83 mm Hg [CI, 0.39 to 5.28 mm Hg]). The relative risk for overweight was 2.34 (CI, 1.32 to 4.15) among participants with the DD genotype versus those with the ID or II genotype. CONCLUSIONS: The ACE I/D polymorphism was a significant predictor of overweight and abdominal adiposity in men. DD homozygosity was associated with larger increases in body weight and blood pressure in aging persons, as well as with higher incidence of overweight.

A significant and positive association between red blood cell sodium lithium countertransport (Na-Li CT) and blood pressure has been found in numerous studies. However, the majority of the studies presented to date are cross-sectional in nature and limited information exists on the longitudinal association between Na-Li CT and blood pressure. The present study analyzes the longitudinal association between Na-Li CT and blood pressure in 124 men participants in the Olivetti Heart Study and normotensives at the baseline examination. The Na-Li CT measured at the 12 year follow-up examination was analyzed in regard to the blood pressure changes over time during the 12 year follow-up. Na-Li CT (measured at follow-up examination) was positively related to changes over time in systolic pressure (r = 0.16) and diastolic pressure (r = 0.07) and changes in body mass index (r = 0.18). When blood pressure changes over time were analyzed by tertiles of Na-Li CT, the highest tertile group exhibited on the average significantly higher increases in systolic blood pressure compared with participants of the lowest tertile of the Na-Li CT distribution. This difference remained statistically significant after adjusting for the changes in weight observed during the 12 years follow-up. These findings indicate that the Na-Li CT distribution is related to blood pressure changes over time. However, the usefulness of Na-Li CT as a predictor of incidence of hypertension remains to be established. Am J Hypertens 1996;9:1132–1135