Antonio Barbato

Do statins reduce blood pressure?: a meta-analysis of randomized, controlled trials.

A meta-analysis was performed of the effect of 3hydroxy3methylglutaryl-coenzyme A reductase inhibitors (statins) on blood pressure in humans including the randomized, controlled trials of statin therapy (20 trials and 828 patients) in which concomitant antihypertensive treatment (if any) remained unchanged throughout the study. A total of 291 and 272 patients were given a statin or placebo, respectively, in parallel group trials, whereas 265 took part in crossover trials receiving a statin and placebo (or probucol, in 1 trial). Systolic blood pressure was significantly lower in patients on statin than in those on placebo or control hypolipidemic drug (mean difference: −1.9 mm Hg; 95% CI: −3.8 to −0.1). The effect was greater when the analysis was restricted to studies with a baseline systolic blood pressure >130 mm Hg (&Dgr; systolic blood pressure: −4.0; 95% CI: −5.8 to −2.2 mm Hg). There was a trend for lower diastolic blood pressure in patients receiving statin therapy compared with control: −0.9 mm Hg (95% CI: −2.0 to 0.2) overall and −1.2 mm Hg (95% CI: −2.6 to 0.1) in studies with a baseline diastolic blood pressure >80 mm Hg. In general, the higher the baseline blood pressure, the greater the effect of statins on blood pressure (P=0.066 for systolic blood pressure and P=0.023 for diastolic blood pressure). The blood pressure response to statins was unrelated to age, changes in serum cholesterol, or length of the trial. In conclusion, statin therapy has a relatively small but statistically significant and clinically meaningful effect on blood pressure.

Genetic Variation in the Renin–Angiotensin System and Abdominal Adiposity in Men: The Olivetti Prospective Heart Study

Context Angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and angiotensin II receptor type I (AT2R1) are expressed in adipose tissue, but their role in obesity is unknown. Common polymorphisms involve the ACE gene on chromosome 17 (ACE I/D), the AGT gene on chromosome 1, and the AT2R1 receptor gene on chromosome 3. Contribution Among 959 adult Italian men, DD homozygosity in the ACE gene was associated with overweight (odds ratio, 1.82 [95% CI, 1.16 to 2.87]) and abdominal obesity (odds ratio, 1.76 [CI, 1.06 to 2.90]) compared with the genotypes I/D and II. It was also associated with increases in weight over 20 years. Polymorphisms of AGT and AT2R1 were unrelated to measures of body size. Implications These results suggest that the reninangiotensin system plays a role in the development of obesity. The Editors Human obesity is caused by the interaction of genetic predisposition and many environmental and lifestyle factors (1). Although the chromosomal location of a few putative major genes for human obesity has been identified (2-5), the presence of a greater number of minor genes involved in the process of adipogenesis or in the regulation of adipocyte metabolism probably engenders susceptibility to obesity (6). Polymorphism in several obesity candidate genes has been the subject of intensive investigation, but little attention has been paid to the genes encoding for components of the reninangiotensin system. The products of these genes (angiotensinogen [AGT], angiotensin-converting enzyme [ACE], and angiotensin II type 1 [AT2R1] and type II [AT2R2] receptors) are expressed in the adipose tissue in animal models as well as in humans (7-10). Recent experimental studies suggest that adipose tissue in the reninangiotensin system plays a role in adipocyte growth and differentiation through angiotensin II (11, 12). In addition, epidemiologic studies have reported associations between AGT plasma levels (13, 14), plasma renin activity (15, 16), plasma ACE activity (17), and body mass index (BMI). We investigated the relationship of overweight, obesity, and body fat distribution to three common polymorphisms of the reninangiotensin system: intron 16 of the ACE gene on chromosome 17 (18), the M235T polymorphism of the AGT gene in exon 2 on chromosome 1 (19), and the A-to-C polymorphism in the 3-untranslated region at nucleotide 1166 of the AT2R1 gene on chromosome 3 (20). Because the reninangiotensin system plays a fundamental role in blood pressure regulation and in vascular and cardiac modifications, these polymorphisms have been studied with regard to hypertension and cardiovascular disease. Associations have been reported between the AGT M235T and the AT2R1 A1166C variants and hypertension (19-24), as well as among ACE I/D polymorphism, insulin sensitivity (25-27), and the risk for coronary heart and cerebrovascular disease (28, 29). In adult men who attended the 19941995 follow-up examination of the Olivetti Prospective Heart Study, we examined associations between these polymorphic variants and overweight or obesity, body fat distribution, and related metabolic and hemodynamic variables. We also reported longitudinal findings for a subset of participants who were first examined in 1975 and had been followed for 20 years. Methods Study Sample and Procedures We used the DNA bank and the database of the Olivetti Prospective Heart Study, an epidemiologic investigation of cardiovascular risk factors in men working at the Olivetti factories in southern Italy. The procedures of the Olivetti Prospective Heart Study, which began in 1975, have been described in detail elsewhere (30). Between May 1994 and December 1995, we examined 1075 men 25 to 75 years of age. The participants were seen in the morning, after fasting, in a quiet room at the medical center of the Olivetti factories in Pozzuoli and Marcianise, suburbs of Naples, Italy. We obtained anthropometric measurements, performed blood tests, and administered a fixed-sequence questionnaire that assessed demographic information and medical history. Genotyping of the three polymorphisms of the reninangiotensin system was possible in 959 participants. A group of 457 men seen at the 19941995 follow-up visit of the Olivetti Prospective Heart Study had also been examined in 1975; of these, 143 reported being under dietary restriction for various reasons at follow-up examination. Since the Olivetti Prospective Heart Study aims to evaluate spontaneous changes in body mass and blood pressure, this subgroup was excluded from the main analysis. The local ethics committee approved the study protocol, and participants gave informed consent. Anthropometric Measurements Body weight and height were measured on a standard beam-balance scale with an attached ruler. Body weight was measured to the nearest 0.1 kg, and height was measured to the nearest 1 cm; participants wore light indoor clothing and no shoes. Body mass index was calculated as weight in kilograms divided by the square of the height in meters. At the 19941995 examination, but not at the 1975 examination, waist and arm circumferences were also measured. Waist circumference was measured at the umbilicus level as participants stood erect with abdomens relaxed, arms at their sides, and feet together. After the acromion was marked with each participants arm flexed at a 90-degree angle, arm circumference was measured at the midpoint between the acromion and the olecranon with the arm relaxed and hanging just away from the side of the body. The measurements were obtained to the nearest 0.1 cm with a flexible plastic measuring tape. Overweight was defined as a BMI greater than or equal to 27 kg/m2, obesity was defined as a BMI greater than or equal to 30 kg/m2, and abdominal adiposity was defined as a waist circumference greater than 1.00 m. Blood Pressure Measurement Blood pressure was measured after the participant had been sitting upright for at least 10 minutes. Systolic and diastolic (phase V) blood pressure was measured three 2 minutes apart with a random-zero sphygmomanometer (Gelman Hawksley Ltd., Sussex, United Kingdom). The first reading for each type of pressure was discarded, and the average of the second two readings was recorded. Hypertension was defined as a systolic blood pressure 140 mm Hg or greater, a diastolic blood pressure 90 mm Hg or greater, or both, or as current use of antihypertensive drugs. Biochemical Assays After blood pressure was measured, a fasting venous blood sample was taken in the seated position without stasis. The blood specimens were immediately subjected to centrifugation and stored at 70 C until analyzed. Glucose levels were measured by using an automated method (Cobas-Mira, Roche, Italy), and serum insulin concentration was measured by using radioimmunoassay (Insuline Lisophase, Technogenetics, Milan, Italy). Insulin resistance was estimated by homeostasis model assessment using the following formula, as described by Matthews and colleagues (31): fasting serum insulin level (U/mL) fasting serum glucose level (mmol/L)/22.5. Gene Polymorphisms in the ReninAngiotensin System Genomic DNA was isolated from leukocytes with a nonenzymatic, salting-out procedure (32). The ACE I/D polymorphism in intron 16 was typed by using the method of Rigat and associates (33). To address the possibility of mistyping ID heterozygotes as DD homozygotes because of the preferential amplification of the smaller D allele, all samples typed as DD homozygotes were subjected to a second, independent polymerase chain reaction with a primer pair that permits amplification only in the presence of the I allele; this was done by using the method described by Lindpaintner and coworkers (34). The T235 allele of the ATG gene was detected by using the method of Russ and colleagues (35), and the A1166C polymorphism of the AT2R1 gene was tested as described elsewhere (36). Allelic frequencies were estimated by using gene counting, and genotype distribution was tested for HardyWeinberg equilibrium by using chi-square analysis. Statistical Analysis Analysis of variance was used to evaluate differences in quantitative variables according to genotype; analysis of covariance was performed to account for confounders. A nonparametric test (KruskalWallis) was used for variables that were not normally distributed. The interaction between the effects of gene polymorphism and age on the anthropometric indexes and blood pressure was tested by using multiple linear regression analysis. The association of categorical variables with gene polymorphisms was tested by using logistic regression analysis and is expressed as odds ratios and 95% CIs. Results are expressed as the mean SD or as the mean SE, as specified. Two-sided P values and 95% CIs were used to test the statistical significance of between-group differences. Statistical analysis was performed by using SPSS statistical software, version 10.0 (SPSS, Inc., Chicago, Illinois). Role of the Funding Source The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Table 1 summarizes the main characteristics of the participants of the Olivetti Prospective Heart Study at the 19941995 examination. Nine hundred fifty-nine participants were tested for ACE, AGT, and AT2R1 polymorphism. For the ACE I/D polymorphism, 40% (n = 385) had the DD genotype, 45% (n = 431) had the ID genotype, and 15% (n = 143) had the II genotype. For the AGT polymorphism, 31% (n = 297) had the M235M genotype, 48% (n = 460) had the M235T genotype, and 21% (n = 202) had the T235T genotype. For the AT2R1 polymorphism, 54% (n = 518) had the A1166A genotype, 39% (n = 377) had the A1166C genotype, and 7% (n = 64) had the C1166C genotype. All three polymorphisms were in HardyWeinberg equilibrium, showing that the study sample excluded selection pressure for the genotypes under investigation. Table 1. Characteristics of

Altered renal sodium handling in men with abdominal adiposity: a link to hypertension.

Objectives Central adiposity, insulin resistance and hypertension are clearly interrelated but the mechanisms underlying this association have not been thoroughly elucidated. As renal sodium handling plays a central role in salt-sensitive forms of hypertension, we investigated the relation of renal tubular sodium handling to abdominal adiposity, blood pressure and insulin sensitivity. Design Population-based study. Participants Five hundred and fifty-five untreated Olivetti male workers, aged 25–75 years. Setting Olivetti factory medical centers in Pozzuoli and Marcianise (Naples, Italy) Main outcome measures Anthropometric indices, serum insulin, homeostatic model assessment index of insulin sensitivity, blood pressure, fractional excretions of uric acid and exogenous lithium (as markers of renal tubular sodium handling). Results In univariate analysis, measures of central adiposity (i.e. sagittal abdominal diameter and umbilical circumference) were directly correlated with serum insulin (P < 0.001) and blood pressure levels (P < 0.001) and inversely associated with the fractional excretions of uric acid and lithium (P = 0.01–0.001). In multiple linear regression analysis, the same anthropometric indices but not the measures of peripheral adiposity (arm circumference and tricipital skinfold thickness), were significant predictors of the fractional excretion of uric acid and lithium, independently of age, blood pressure and serum insulin levels (P = 0.01–0.001). Conclusions Abdominal adiposity was associated with altered renal tubular sodium handling apart from insulin resistance and high blood pressure. The data indicate that men with prevalent abdominal adiposity have an enhanced rate of tubular sodium reabsorption, mainly at proximal sites. These findings provide a possible mechanistic link between central adiposity and salt-dependent hypertension.

Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study.

Objective The mechanisms underlying high blood pressure in the framework of metabolic syndrome (MS) are not clarified: we thus analyzed the relationship of MS and its components to renal tubular sodium handling among participants of the Olivetti Heart Study, an epidemiological investigation of a representative sample of adult white male population in southern Italy. Methods Proximal (FPRNa) and distal (FDRNa) fractional sodium reabsorption were estimated by the clearance of exogenous lithium in 702 participants aged 25–75 years examined in 1994–1995. Blood pressure and relevant anthropometric and biochemical variables were also measured. The diagnosis of MS was based on modified National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria. Results FPRNa, but not FDRNa, was directly associated with body mass index (BMI), waist circumference, diastolic pressure, serum triglyceride and uric acid, independently of age and of antihypertensive treatment. After adjustment for age, FPRNa, but not FDRNa, was significantly greater in individuals with MS, as compared to those without [77.6% (95% confidence interval = 76.7–80.1) versus 74.4% (73.7–75.1), P < 0.001]. A similar difference was observed after the exclusion of participants on current antihypertensive treatment (P = 0.018). In untreated individuals, a significant interaction was observed between obesity and insulin resistance as related to FPRNa (P = 0.002): the highest age-adjusted levels of FPRNa were detected in obese hypertensive and obese insulin-resistant participants. Conclusion In this sample of an adult male population, MS was associated with an increased rate of FPRNa. This finding is relevant to the pathophysiology of MS and possibly to the prevention of its cardiovascular and renal consequences.

Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pressure : Interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study

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 μmol/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.

Circulating leptin levels predict the development of metabolic syndrome in middle-aged men: an 8-year follow-up study.

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.

Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population

Background The aldosterone synthase gene (CYP1B2) locus is a candidate region involved in the development of hypertension. Objective To study the relationship between the C-344T CYP1B2 polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. Design Population-based, cross-sectional study of 1313 middle-aged men and women (456 white, 441 of African origin and 416 South Asian). Anthropometry, blood pressure, biochemistry, questionnaire data and timed urine collections were taken with standardized techniques. All were genotyped for the C-344T CYP11B2 polymorphism. Results The frequency of the C allele was significantly lower in people of African origin (0.21) than in white (0.46) and South Asian (0.43) (P < 0.001). After adjustment for age, sex and ethnicity the TT genotype was associated with 14% higher plasma aldosterone levels, 3.7 mmHg higher systolic and 2.1 mmHg higher diastolic blood pressure than CC (P for linear trend < 0.05). No significant interactions with age, sex, ethnicity, body mass index (BMI) and fractional excretion of sodium were found in the associations between genotype and both blood pressure and aldosterone levels. In a sub-sample of participants in which plasma renin activity was measured (n = 457), a significant excess of T alleles was found in those with a raised (⩾ 750) aldosterone-to-renin ratio (ARR). Conclusion In this multi-ethnic population, the C-344T CYP1B2 polymorphism is associated with blood pressure, plasma aldosterone levels and ARR. Although significant differences in allele frequencies were found between groups, ethnicity does not explain the results.

Relationships between salt sensitivity of blood pressure and sympathetic nervous system activity: a short review of evidence.

Experimental and clinical studies provided evidence in favor of complex relationships between sympathetic nervous system activity and salt-sensitivity of blood pressure. Genetic and acquired metabolic alterations associated with a tendency to retain salt and water may generate salt-sensitivity of blood pressure and shift the pressure-natriuresis curve to the right, promoting an increase in blood pressure. Sympathetic activation is a factor contributing to this result. Chronic high dietary salt intake is followed by a derangement in mechanisms of central sympathetic inhibition and then by an enhanced peripheral sympathetic tone. This, in turn, may generate salt-sensitivity of blood pressure by affecting renal hemodynamics, tubular sodium and water handling. Insulin resistance and sodium and water retention are prompted by high-fat (as well as high carbohydrate) diets, and by an increase in body fat mass. Also, aging is a condition of impaired interactions of the above factors. A gain in weight due to reduced physical activity, not followed by a parallel decrease in calorie intake, brings to a fall in insulin sensitivity. In many cases, the natural age-related decline of renal function is associated with a reduced physical exercise, hyperinsulinemia and sodium retention; sympathetic nervous system activity is enhanced and causes an increase in blood pressure.

Diagnostic criteria for metabolic syndrome: a comparative analysis in an unselected sample of adult male population

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 <94 cm by IDF) did not improve the performance in this regard but identified a larger number of individuals with microalbuminuria (56%) and elevated C-reactive protein (53%).

Hypertension, diabetes and cardiovascular risk in ethnic minorities in the UK

Mortality from coronary heart disease (CHD), stroke and end-stage renal failure (ESRF) is high in South Asian (Indo-Asian) migrants in the UK. This is associated with a high prevalence of diabetes ...