Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart Study

BACKGROUND: Several recent studies have suggested that calcium antagonist drugs, which are widely used for the treatment of hypertension, are associated with increased risk of cardiovascular disease. These studies have cast doubts on the long-term safety of calcium antagonists. OBJECTIVE: To examine the association of calcium antagonist use with mortality in subjects with hypertension followed up in the Framingham Heart Study. SUBJECTS AND METHODS: We stratified 3539 subjects (mean+/-SD age, 64+/-13 years) from the Framingham Heart Study who had hypertension at routine clinic examinations, according to the use of calcium antagonists and presence of coronary heart disease at the baseline examination. At each follow-up examination (every 2-4 years), subjects were reclassified with regard to the use of calcium antagonists. The end point of the study was all-cause mortality. Hazard ratios and 95% confidence intervals associated with the use of calcium antagonists were obtained using Cox proportional hazards regression models. RESULTS: There were 970 deaths during follow-up. Hazard ratios for mortality associated with the use of calcium antagonists were 0.93 (95% confidence interval, 0.72-1.21; P=.59) for subjects with hypertension without coronary heart disease, and 0.92 (95% confidence interval, 0.69-1.24; P=.58) for those with coronary heart disease at baseline. All models were adjusted for age, sex, current smoking, systolic and diastolic blood pressure, use of beta-blockers, and use of other antihypertensive medications. CONCLUSIONS: In this cohort of 3539 subjects with hypertension there were no differences in mortality among subjects with hypertension using a calcium antagonist compared with those who were not. Results were similar among subjects with hypertension with and without coronary heart disease. The results of ongoing long-term, randomized clinical trials will provide more definitive data on the safety of calcium antagonists.     

Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham Heart Study

Few studies of the GH axis and bone have focused specifically on elderly people. The objective of this study was to determine the association between insulin-like growth factor I (IGF-I) and bone mineral density (BMD) in 425 women and 257 men aged 72-94 who participated in the Framingham Osteoporosis Study component of the Framingham Heart Study in 1992-1993. Serum IGF-I level was determined by RIA. BMD at three femoral sites and the lumbar spine was determined by dual x-ray absorptiometry, and at the radius by single-photon absorptiometry. IGF-I level was positively associated with BMD at all five sites (Ward's area, femoral neck, trochanter, radius, and lumbar spine) in women after adjustment for weight loss and other factors (P < or = 0.01) and protein intake in a subset of participants (0.006 < P < 0.07). A threshold effect of higher BMD was evident at each of the 3 femoral sites and the spine (P < 0.03) but not at the radius for women in the highest quintile of IGF-I (> or = 179 g/liter) vs. those in the lowest four quintiles. IGF-I was not significantly associated with BMD in men. These results indicate that higher IGF-I levels are associated with greater BMD in very old women, and suggest that future clinical trials employing GH may have a role in the development of treatments for older women with osteoporosis.     

Body fat and skeletal muscle mass in relation to physical disability in very old men and women of the Framingham Heart Study

BACKGROUND: Low muscle mass has been assumed to be associated with disability, but no studies confirming this association have been published. High body weight and high body mass index, both rough indicators of body fatness, have been shown to increase the risk for disability; however, the specific role of body fatness has not been studied. METHODS: The relations of skeletal muscle mass and percent body fat with self-reported physical disability were studied in 753 men and women aged 72 to 95 years. Cross-sectional data from biennial examination 22 (1992-1993) of the Framingham Heart Study were used. Body composition was assessed by dual-energy x-ray absorptiometry. Disability was scored as any versus none on a 9-item questionnaire. RESULTS: Total body and lower extremity muscle mass were not associated with disability in either men or women. However, a strong positive association between percent body fat and disability was observed. The odds ratio for disability in those in the highest tertile of body fatness was 2.69 (95% confidence interval 1.45-5.00) for women and 3.08 (1.22-7.81) for men compared to those in the lowest tertile. The increased risk could not be explained by age, education, physical activity, smoking, alcohol use, estrogen use (women only), muscle mass, and health status. Analyses restricting disability to mobility items gave similar results. CONCLUSIONS: In contrast to current assumptions, low skeletal muscle mass was not associated with self-reported physical disability. Persons with a high percent body fat had high levels of disability. Because it cannot be ruled out that persons with low skeletal muscle mass dropped out earlier in the study, prospective studies are needed to further assess the relationship between body composition and physical disability.     

Acute blood pressure elevations with caffeine in men with borderline systemic hypertension

It has been shown that the problem of nosocomial infections is different in each specialist hospital division, and it is important to be aware of the local situation and to identify the specific problems. In order to set up an effective prevention programme and in the setting of a general system of control of nosocomial infection, we studied the incidence of infections and correlated the pathogenic organisms appearing during hospitalization in patients admitted to our Pneumology Division and Intermediate Intensive Care Unit over a period of 12 months. A nosocomial infections incidence of 13% was observed and 75% of these were respiratory, 21% urinary and 4% other infections. Seventy two percent of pathogenic agents were Gram-negative bacilli and 28% Gram-positive cocci. The site-specific rates of infections observed are related to intrinsic (host dependent) and extrinsic (non-host-dependent) risk factors that have not been exhaustively evaluated in the present study. However, the data so far collected will allow us to redirect the resources used in the control of nosocomial infections by targeting efforts at the surveillance of better defined groups of patients and by achieving data more suitable for comparisons between hospitals.     

Muscle mass and fat mass in relation to bone mineral density in very old men and women: the Framingham Heart Study

Aim of the study was investigate the cross-sectional relationship between body composition and bone mineral density (BMD) in very old men and women. The study sample consisted of 504 women and 285 men, aged 72-93 yr, participating in examination 22 (1992-1993) of the Framingham Heart Study. Total body BMD, regional BMD, and soft-tissue body composition was measured by dual-energy X-ray absorptiometry. Both muscle mass and percentage body fat were positively associated with total body BMD in women. After adjustment for age, physical activity, smoking status, estrogen use, and thiazide use, BMD increased with increasing tertile of muscle mass (p = 0.007) and with increasing tertile of percentage body fat (p = 0.0001) in women. In men muscle mass, not percentage body fat, was positively associated with BMD. After adjustment for potential confounders, BMD remained associated with muscle mass only (p = 0.02). These results were similar for leg BMD and arm BMD. The study suggests that the influence of muscle and fat mass on bone mineral density is different between very old men and women.     

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene associated with macroangiopathy and blood pressure in patients with non-insulin-dependent diabetes mellitus

In the search for new risk factors for diabetic macroangiopathy the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene was studied in 237 consecutive patients (125 men and 112 women) with non-insulin-dependent diabetes. The female population showed an excess of ischemic electrocardiographic changes or definite myocardial infarctions in the patients homozygous for the deletion [D/D; odds ratio (OR) 2.8; 95% confidence interval (CI) 1.4-5.3] and in the insertion/deletion heterozygotes (I/D; OR 1.8; CI 1.1-3.1) compared with the patients homozygous for the insertion (I/I). In the total series coronary heart disease, cerebrovascular disease, and claudication were more often observed in the patients with I/D (OR 1.5; CI 1.0-2.2) or the D/D genotype patients (OR 1.7; CI 1.1-2.6) than in those with the genotype I/I. The systolic blood pressure was lower in patients with genotype I/I (138 +/- 19 mmHg) than in those with the genotype I/D (149 +/- 22 mmHg) or D/D (150 +/- 21 mmHg; P < 0.02). The prevalence of hypertension and the median urinary albumin excretion rate also tended to be lowest in the I/I genotype patients. Multiple logistic analysis revealed that in women the angiotensin-converting enzyme D/D genotype is independently associated with coronary heart disease. Our findings suggest that variation at the angiotensin-converting enzyme gene locus is one of the factors involved in the predisposition of diabetic patients to the development of arterial disease and hypertension.     

Sex differences in anatomic measures of interhemispheric connectivity: correlations with cognition in women but not men

BACKGROUND: Pediatric urologists tend to use one-stage procedures for the repair of hypospadias. As there are various types of hypospadias, we cannot repair this disease with a single modality. It is difficult to estimate the exact length of the neourethra in cases of severe hypospadias before surgery. METHODS: After a circumferential incision is made about the coronal sulcus and the chordee is completely released, the distance between the glans tip and the retreated native meatus is measured to determine the length of the neourethra. Urethroplasty with the method of Transverse Preputial Island Flap (TPIF) is selected when the distance ranges from 3 to 4 cm, while urethroplasty using with modified OUPF IV (Koyanagi) is selected in cases of more than 4 cm. RESULTS: We performed surgery on 14 hypospadiac patients with chordee between April 1996 and April 1997. Eight patients underwent urethroplasty using the TPIF method and 6 underwent urethroplasty with the method of the modified OUPF IV. With the TPIF methods, 7 to 8 patients underwent repair successfully and one experienced urethrocutaneous fistula, while 5 of 6 treated by the modified OUPF IV method has successful repairs and meatal stenosis occurred in one patient. CONCLUSION: Even if we encounter severe hypospadias, we can treat these patients with one stage repair alternatively. A relatively high success rate was obtained with both methods to repair severe hypospadias.     

Evidence for genetic linkage between the ure and trh genes in Vibrio parahaemolyticus

BACKGROUND: Many factors have been demonstrated to influence flexure of rigid contact lenses, but the contributions of surface tension and eyelid forces to flexure are not well understood. METHODS: We placed lenses on a model eye consisting of a polymethyl methacrylate (PMMA) base which could be flexed, and measured resultant flexure with a videokeratoscope. We varied the base toricity, sequence of measurement, and lens base curve. The effects of evaporation of the postlens fluid were also observed. RESULTS: Clinically significant flexure (> 0.50 D) occurred when two conditions were met: (1) the volume of the postlens space would increase if the lens unflexed, and (2) there was a paucity of fluid available to fill that space. Flexure was minimal (< or = 0.50 D) when ample fluid was present. CONCLUSION: Surface tension forces serve more to maintain rather than create rigid lens flexure. Our model helps to explain why steep-fitting lenses flex more and leads to several predictions for flexure, which appear generally to be obeyed.     

Inverse relation of dietary protein markers with blood pressure. Findings for 10,020 men and women in the INTERSALT Study. INTERSALT Cooperative Research Group. INTERnational study of SALT and blood pressure

BACKGROUND: The purpose of this study was to assess relations to blood pressure (BP) in individuals of markers of dietary protein in their 24-hour urine collections. METHODS AND RESULTS: INTERSALT (INTERnational study of SALT and blood pressure) was a cross-sectional study of 10020 men and women aged 20 to 59 years in 52 population-based samples in 32 countries worldwide, with quality-controlled standardized procedures and assessment of multiple possible confounders. Three measurements of dietary protein in 24-hour urine of each individual participant were studied: total nitrogen and urea as indexes of total protein intake, and sulfate as an index of sulfur-containing dietary amino acids. Repeat examination was performed in a random 8% of participants to assess reliability and to correct for regression-dilution bias. Significant independent inverse relationships were found between BP (systolic and diastolic) and both 24-hour urinary total nitrogen and urea nitrogen, with adjustment for age, sex, alcohol intake, body mass, and 24-hour urinary sodium, potassium, calcium, and magnesium. With adjustment for regression-dilution bias, it was estimated that systolic and diastolic BP were on average 3.0 and 2.5 mm Hg lower, respectively, for persons with dietary total protein intake 30% above the overall mean than for those whose dietary protein intake was 30% below the overall mean (12.94 versus 6.96 g/d urinary total nitrogen, equivalent to 81 versus 44 g/d dietary protein, respectively). For the association of these markers with diastolic BP, results were similar for younger (20- to 39-year-old) and older (40- to 59-year-old) persons and for women and men. For their relation to systolic BP, regression coefficients were larger both for those aged 40 to 59 years than for those aged 20 to 39 years and for women than for men. Nonsignificant inverse relations were recorded for urinary sulfate and BP. CONCLUSIONS: These INTERSALT findings lend support to the hypothesis that higher dietary protein intake has favorable influences on BP.     

Epidemiologic assessment of the role of blood pressure in stroke: the Framingham Study. 1970

Control of hypertension, labile or fixed, systolic or diastolic, at any age, in either sex appears to be central to prevention of atherothrombotic brain infarction (ABI). Prospectively, hypertension proved the most common and potent precursor of ABI's. Its contribution was direct and could not be attributed to factors related both to stroke and hypertension. Asymptomatic, causal "hypertension" was associated with a risk of ABI about four times that of normotensives. The probability of occurrence of an ABI was predicted no better with both blood pressure measurements or the mean arterial pressure than with systolic alone. Since there was no diminishing impact of systolic pressure with advancing age, the concept that systolic elevations are, even in the aged, innocuous is premature. Comparing normotensives and hypertensives in each sex, women did not tolerate hypertension better than men.     

Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels in young white males

BACKGROUND: The renin-angiotensin system regulates blood pressure through its effects on vascular tone, renal hemodynamics, and renal sodium and fluid balance. METHODS AND RESULTS: Using data from a large population-based sample of 1488 siblings having a mean age of 14.8 years and belonging to the youngest generation of 583 randomly ascertained three-generation pedigrees from Rochester, Minn, we carried out variance components-based linkage analyses to evaluate the contribution of variation in four renin-angiotensin system gene regions (angiotensinogen, renin, angiotensin I-converting enzyme, and angiotensin II receptor type 1) to interindividual variation in systolic, diastolic, and mean arterial pressure. We rejected the null hypothesis that allelic variation in the region of the angiotensin-converting enzyme (ACE) gene does not contribute to interindividual blood pressure variability. After conditioning on measured covariates, variation in this region accounted for 0%, 13% (P=0.04), and 16% (P=0.04) of the interindividual variance in systolic, diastolic, and mean arterial pressures, respectively. These estimates were even greater in a subset of subjects with a positive family history of hypertension (0%, 29% [P=0.005], and 32% [P<0.005], respectively). In sex-specific analyses, genetic variation in the region of the ACE gene significantly influenced interindividual blood pressure variation in males (37% for SBP [P=0.03], 38% for DBP [P=0.04], and 53% for MAP [P<0.005]) but not in females. CONCLUSIONS: Although it is possible that variation in a gene near the ACE gene may explain the observed results, knowledge about the physiological involvement of ACE in blood pressure regulation supports the proposition that the ACE gene itself influences blood pressure variability in a sex-specific manner.     

Chymase gene locus is not associated with myocardial infarction and is not linked to heart size or blood pressure

The chymase gene is said to be important for the generation of angiotensin II in the heart and therefore is a candidate gene for heart disease. However, we were unable to find an association between allelic variants of the chymase gene and acute myocardial infarction or linkage between the chymase gene locus and heart size.     

Physical activity and risk of breast cancer in the Framingham Heart Study

The authors analyzed data from the Framingham Heart Study to evaluate the association between physical activity and breast cancer risk. Physical activity was ascertained by a physician-administered questionnaire from 2,321 women at the fourth biennial examination conducted in 1954-1956. Breast cancers were identified by self-report, surveillance of admissions to Framingham Union Hospital, and review of death records; all but one were histologically confirmed. During 28 years of follow-up, 117 breast cancer cases were diagnosed among the 2,307 women with data on physical activity and reproductive history (a potential confounder). Analysis was performed using Cox proportional hazards models with age as the underlying time variable. Models were adjusted for age at physical activity assessment, menopausal status, age at first pregnancy, parity, education, occupation, and alcohol ingestion. We observed a gradient of increasing risk of breast cancer with increasing physical activity (trend p = 0.06). The relative risk for women in the highest versus lowest activity quartile was 1.6 (95% confidence interval 0.9-3.0; p = 0.13). Although both moderate-to-heavy leisure and occupational activities were associated with an increased risk, the association was marginally significant only for leisure activity (p = 0.06). Our findings do not support a protective effect of physical activity during adulthood for breast cancer, but suggest an increased risk among more active women.     

Effects of mental state on heart rate and blood pressure variability in men and women

The effect of different mental states on autonomic modulation of the cardiovascular system was assessed in healthy, normotensive men (n = 18) and women (n = 12). Heart rate variability (HRV), systolic blood pressure variability (BPV) and arterial baroreflex function were assessed during 4 tests at rest ((10 min + 5 min recovery) x 4): (1) Control (spontaneous breathing, (SB) (2) Mental distraction (SB + word puzzle) (3) Conscious control of breathing (paced at SB rate) and (4) Mental stress (SB + computer quiz). There were no significant gender differences in the responses to the interventions in terms of arterial (spontaneous) baroreflex (SPBX) control of HR, and indices of time and frequency domains of HRV and BPV, with the exception of the sympathetic indicator of HRV (low frequency power/total power; P < 0.01) which was lower in women during control and mental stress tests. Conscious control of breathing at SB did not alter HRV, BPV or SPBX in either men or women. Mental distraction and mental stress led to decreases in indices of time and frequency domains of HRV and BPV in all subjects, as well as increases in HR during distraction and in systolic BP during stress. These findings suggest that in studies of cardiovascular control: (1) Paced breathing at SB can be used for individuals with irregular breathing patterns (2) The extent of mental stress achieved is intervention-specific and for the most part, independent of gender and (3) Resting assessment of HRV, BPV and SPBX can be made by having subjects sit quietly without interventions in a controlled laboratory setting.     

The influence of cigarette smoking on the association between body weight and mortality. The Framingham Heart Study revisited

PURPOSE: To calculate for two measures of obesity, the Metropolitan Relative Weight (MRW) and body mass index (BMI), the value at which minimum mortality occurs. This was done to retest the hypothesis, in the Framingham Heart Study data, that the association between obesity and mortality can be obscured by an interaction between the measure of obesity and smoking. In the original analysis of the Framingham data it was suggested that there was a U- or J-shaped relationship between MRW and death in smokers but a linear relationship in nonsmokers. The design and setting were those of the NHLBI Framingham Heart Study. METHODS: The 5209 members of the Framingham Heart Study underwent a baseline examination in 1948-1952 (Exam 1) and they were reexamined at approximately two-year intervals over a 30-year period. The study included both men (n = 2336) and women (n = 2873) in the age range of 28 to 62 years. After excluding persons with missing baseline data, the analytic sample size was 5163. Additional analyses were conducted by deleting persons with cardiovascular disease (CVD) at baseline (n = 135), the sample used by the original paper by Garrison and colleagues, and persons who died within the first four years of follow-up (n = 62). The main outcome measures consisted of thirty-year survival through Exam 16, approximately in 1980, as influenced by MRW or BMI, age, and smoking status at baseline (Exam 1). RESULTS: We were able to show that the sample sizes of male nonsmokers were too small to test the hypothesis within age groups < 40 and 40-49 years. In men ages 50-62 there was a significant age-adjusted quadratic relationship between BMI or MRW, and risk of death. The estimated BMI at the minimum risk of death for smokers (24.5) and nonsmokers (23.8) were not statistically different. Identical results were found for MRW (minimum: smokers = 112.5, nonsmokers = 111.4). In men and women ages 28-62 there appeared to be a u- or j-shaped relationship between the 30-year crude mortality rate and MRW. After excluding persons with missing data, CVD at baseline, and persons who died within the first four years of follow-up, the age adjusted estimated BMI value at the minimum risk of death was nearly identical for men and women and for smokers and nonsmokers (Men: smokers = 22.8, nonsmokers = 22.8; Women: smokers = 22.9, nonsmokers = 23.3). Additionally, the estimates of the minimum were always below the mean. Identical results were found without deleting persons with CVD at baseline and deaths in the first four years of follow-up. Identical results were found for MRW. CONCLUSIONS: Reanalysis of the Framingham Heart Study data does not support the hypothesis that there is an interaction between smoking and measures of obesity. Moreover, the estimated BMI or MRW at the minimum risk of death was similar for men and women smokers and nonsmokers alike even after deleting prevalent cases of CVD and deaths within the first four years of follow-up.     

The relative power of linkage and association studies for the detection of genes involved in hypertension

Hypertension is a common disorder that shows a polygenic mode of inheritance. Attempts to localize genes involved in the disorder have been carried out using both linkage and association tests. The relative merit of these two approaches is reviewed with an assessment of their utility for detecting genes involved in hypertension. Power calculations were carried out following the method of Risch and Merikangas [1], assuming markers were typed across the genome. These show that, if there is a single major locus causing susceptibility, non-parametric linkage strategies using affected sibpairs may well prove very effective. However, if there are a number of genes of small effect, the sample size necessary for linkage studies will be prohibitive and a systematic search for allelic association may be more appropriate. This is due to the dramatic reduction in the excess allele sharing for genes of small effect.     

Lack of association between both insulin resistance and plasma insulin levels with blood pressure values in essential hypertension

AIM: To evaluate the role of insulin resistance and hyperinsulinaemia in the genesis of essential arterial hypertension (EAHT). SUBJECTS AND METHODS: We studied 49 patients (age 44 +/- 8 y., body mass index (BMI: 29.5 +/- 3.2 kg.m-2) with mild or moderate EAHT (systolic blood pressure: 156 +/- 13 mmHg, diastolic blood pressure: 100 +/- 6 mmHg). Patients with BMI > 27 kg.m-2 were classed as obese. Arterial pressure was measured with a mercury sphygmomanometer after the patient had been lying down for 15 min. For each patient, the results of a frequently sampled intravenous glucose tolerance test (FSIGT) were used to estimate insulin sensitivity (using the minimal model of glucose metabolism) and to characterize insulin secretion in response to intravenous glucose (area of the insulin curve above basal during the 180 min of the FSIGT test). Correlations were evaluated by means of Spearman's correlation coefficient. RESULTS: Neither fasting insulinaemia, glucose-induced insulin secretion nor insulin sensitivity correlated significantly with arterial pressure, either in the whole sample or in the obese and non-obese subsamples. CONCLUSIONS: These results suggest that neither insulin nor insulin sensitivity are important physiological regulators of arterial pressure, and lend no support to the hypothesis that insulin is related to essential arterial hypertension.     

High body fatness, but not low fat-free mass, predicts disability in older men and women: the Cardiovascular Health Study

Using data from the Cardiovascular Health Study, we studied the relation between body composition (fat mass and fat-free mass, assessed by bioelectrical impedance) and self-reported, mobility-related disability (difficulty walking or stair climbing) in 2714 women and 2095 men aged 65-100 y. In a cross-sectional analysis at baseline (1989-1990), disability was reported by 26.5% of the women and 16.9% of the men. A positive association was observed between fat mass and disability. The odds ratio for disability in the highest quintile of fat mass was 3.04 (95% CI: 2.18, 4.25) for women and 2.77 (95% CI: 1.82, 4.23) for men compared with those in the lowest quintile. Low fat-free mass was not associated with a higher prevalence of disability. In a longitudinal analysis among persons not reporting disability at baseline, 20.3% of the women and 14.8% of the men reported disability 3 y later. Fat mass at baseline was predictive of disability 3 y later, with odds ratios of 2.83 (95% CI: 1.80, 4.46) for women and 1.72 (95% CI: 1.03, 2.85) for men in the highest quintile of fat. The increased risk was not explained by age, physical activity, chronic disease, or other potential confounders. Low fat-free mass was not predictive of disability. The results showed that high body fatness is an independent predictor of mobility-related disability in older men and women. These findings suggest that high body fatness in old age should be avoided to decrease the risk of disability.     

Lack of association between the alpha-adducin locus and essential hypertension in the Japanese population

A neutral O-specific polysaccharide obtained from the lipopolysaccharide of Proteus penneri strain 26 was studied using sugar analysis and 1H and 13C NMR spectroscopy, including two-dimensional NMR techniques. The following structure of the trisaccharide repeating unit was established: -->6)-alpha-D-GlcpNAc-(1-->3)-alpha-L-QuipNAc-(1-->3)-alpha-D-Glcp NAc-(1--> where L-QuiNAc is 2-acetamido-2,6-dideoxy-L-glucose (N-acetyl-L-quinovosamine). Cross-reactivity of the Proteus penneri 26 anti-O serum with other strains of P. penneri isolated in Poland and USA and one strain of P. vulgaris is discussed.