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Obesity, Diabetes, and Hypertension
Abstract
Obesity, the so-called killer of the 21st century, is a serious and pervading health problem in the industrialized world and
developing countries. Its prevalence is on the rise, and its cost to health systems is astounding. The risk of death from
all causes rises as body mass index (BMI) increases for both men and women in all age groups (1). For example, a 20-yr-old Caucasian male with a BMI greater than 45 kg/m2 is estimated to lose 13 yr of his life owing to obesity—a 17% reduction in life expectancy assuming a life expectancy of
78 yr (2).
Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension. We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events. In this post hoc analysis, we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients.
After stratification according to center, sex, and presence or absence of previous cardiovascular complications, 4695 patients (age, > or =60 years) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were randomly assigned to receive active treatment or placebo. Active treatment consisted of nitrendipine (10 to 40 mg per day) with the possible addition or substitution of enalapril (5 to 20 mg per day) or hydrochlorothiazide (12.5 to 25 mg per day) or both, titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg. In the control group, matching placebo tablets were administered similarly.
At randomization, 492 patients (10.5 percent) had diabetes. After a median follow-up of two years, the systolic and diastolic blood pressures in the placebo and active-treatment groups differed by 8.6 and 3.9 mm Hg, respectively, among the diabetic patients. Among the 4203 patients without diabetes, systolic and diastolic pressures differed by 10.3 and 4.5 mm Hg, respectively, in the two groups. After adjustment for possible confounders, active treatment was found to have reduced overall mortality by 55 percent (from 45.1 deaths per 1000 patients to 26.4 deaths per 1000 patients), mortality from cardiovascular disease by 76 percent, all cardiovascular events combined by 69 percent, fatal and nonfatal strokes by 73 percent, and all cardiac events combined by 63 percent in the group of patients with diabetes. Among the nondiabetic patients, active treatment decreased all cardiovascular events combined by 26 percent and fatal and nonfatal strokes by 38 percent. In the group of patients receiving active treatment, reductions in overall mortality, mortality from cardiovascular disease, and all cardiovascular events were significantly larger among the diabetic patients than among the nondiabetic patients (P=0.04, P=0.02, and P=0.01, respectively).
Nitrendipine-based antihypertensive therapy is particularly beneficial in older patients with diabetes and isolated systolic hypertension. Thus, our findings do not support the hypothesis that the use of long-acting calcium-channel blockers may be harmful in diabetic patients.
We measured arterio-venous differences in concentrations of tu- mor necrosis factor-a (TNFa) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects (22 women and 17 men; median age, 36 yr (interquartile range, 26 - 48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6 -50.7%)). A subgroup of 8 subjects had arterio- venous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high car- bohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed (arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36 -9.62 pg/mL); P , 0.001), but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r 5 0.48; P , 0.01) and percent body fat (Spearman's r 5 0.49; P , 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800 - 1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNFa (across adipose tissue: arterial, 1.83 pg/mL (range, 1.36 -2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44 -2.53 pg/mL); P 5 NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74 -2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69 -1.70 pg/mL); P 5 NS). Al- though both IL-6 and TNFa are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNFa is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically. (J Clin Endocrinol Metab 82: 4196 - 4200, 1997)
Summary Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes. Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy. Findings The study was stopped 6 months early (after 4·5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0·0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0·027). After adjustment for the changes in systolic (2·4 mm Hg) and diastolic (1·0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0·0004). Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.
Objective:
Diabetes is the fifth leading cause of death by disease in the U.S. Diabetes also contributes to higher rates of morbidity-people with diabetes are at higher risk for heart disease, blindness, kidney failure, extremity amputations, and other chronic conditions. The objectives of this study were 1). to estimate the direct medical and indirect productivity-related costs attributable to diabetes and 2). to calculate and compare the total and per capita medical expenditures for people with and without diabetes.
Research design and methods:
Medical expenditures were estimated for the U.S. population with and without diabetes in 2002 by sex, age, race/ethnicity, type of medical condition, and health care setting. Health care use and total health care expenditures attributable to diabetes were estimated using etiological fractions, calculated based on national health care survey data. The value of lost productivity attributable to diabetes was also estimated based on estimates of lost workdays, restricted activity days, prevalence of permanent disability, and mortality attributable to diabetes. RESULTS-Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at 132 billion US dollars. Direct medical expenditures alone totaled 91.8 billion US dollars and comprised 23.2 billion US dollars for diabetes care, 24.6 billion US dollars for chronic complications attributable to diabetes, and 44.1 billion US dollars for excess prevalence of general medical conditions. Inpatient days (43.9%), nursing home care (15.1%), and office visits (10.9%) constituted the major expenditure groups by service settings. In addition, 51.8% of direct medical expenditures were incurred by people >65 years old. Attributable indirect expenditures resulting from lost workdays, restricted activity days, mortality, and permanent disability due to diabetes totaled 39.8 billion US dollars. U.S. health expenditures for the health care components included in the study totaled 865 billion US dollars, of which 160 billion US dollars was incurred by people with diabetes. Per capita medical expenditures totaled 13243 US dollars for people with diabetes and 2560 US dollars for people without diabetes. When adjusting for differences in age, sex, and race/ethnicity between the population with and without diabetes, people with diabetes had medical expenditures that were approximately 2.4 times higher than expenditures that would be incurred by the same group in the absence of diabetes.
Conclusions:
The estimated 132 billion US dollars cost likely underestimates the true burden of diabetes because it omits intangibles, such as pain and suffering, care provided by nonpaid caregivers, and several areas of health care spending where people with diabetes probably use services at higher rates than people without diabetes (e.g., dental care, optometry care, and the use of licensed dietitians). In addition, the cost estimate excludes undiagnosed cases of diabetes. Health care spending in 2002 for people with diabetes is more than double what spending would be without diabetes. Diabetes imposes a substantial cost burden to society and, in particular, to those individuals with diabetes and their families. Eliminating or reducing the health problems caused by diabetes through factors such as better access to preventive care, more widespread diagnosis, more intensive disease management, and the advent of new medical technologies could significantly improve the quality of life for people with diabetes and their families while at the same time potentially reducing national expenditures for health care services and increasing productivity in the U.S. economy.
Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.
To examine potential mechanisms for the blood pressure-lowering action of the thiazolidinedione compound, pioglitazone (PIO), we studied the effects of the drug on blood pressure and insulin action in vivo and on vascular tissue in vitro. In vivo, PIO lowered blood pressure in fructose-fed and chow-fed rats to an extent that could not be explained by alterations in fasting plasma insulin or free magnesium concentrations or by alterations in whole-body insulin sensitivity. In vitro, PIO caused significant blunting of the contractile responses of aortic rings to NE, arginine vasopressin (AVP), and potassium chloride; the blunting of responses to NE was maintained after removal of the endothelium. To assess the potential importance of extracellular calcium to the vasodepressor effect of PIO, we measured contractile responses to NE in the absence of calcium, and then after acute restoration of calcium in the presence of NE. PIO had no effect on the contractile response in the absence of calcium. By contrast, PIO blunted by 42% the contractile response that occurred when the extracellular calcium supply was acutely restored in the presence of NE, suggesting that the blunting was mediated by blockade of calcium uptake by vascular smooth muscle. Such an effect was confirmed in cultured a7r5 vascular smooth muscle cells, which exhibited a brisk increase in intracellular calcium in response to AVP that was blocked by PIO in a dose-dependent fashion. Our data indicate that PIO has a direct vascular effect that appears to be mediated at least in part by inhibition of agonist-mediated calcium uptake by vascular smooth muscle. The direct vascular effect may contribute to the blood pressure-lowering actions of PIO in vivo, because that effect could not be explained by alterations in whole-body insulin sensitivity.
A previous study reported the increased expression of the cytokine TNF in the adipose tissue of genetically obese rodents. To examine this paradigm in humans, we studied TNF expression in lean, obese, and reduced-obese human subjects. TNF mRNA was demonstrated in human adipocytes and adipose tissue by Northern blotting and PCR. TNF protein was quantitated by Western blotting and ELISA in both adipose tissue and the medium surrounding adipose tissue. Using quantitative reverse transcriptase PCR (RT-PCR), TNF mRNA levels were examined in the adipose tissue of 39 nondiabetic subjects, spanning a broad range of body mass index (BMI). There was a significant increase in adipose TNF mRNA levels with increasing adiposity. There was a significant correlation between TNF mRNA and percent body fat (r = 0.46, P < 0.05, n = 23). TNF mRNA tended to decrease in very obese subjects, but when subjects with a BMI > 45 kg/m2 were excluded, there was a significant correlation between TNF mRNA and BMI (r = 0.37, P < 0.05, n = 32). In addition, there was a significant decrease in adipose TNF with weight loss. In 11 obese subjects who lost between 14 and 66 kg (mean 34.7 kg, or 26.6% of initial weight), TNF mRNA levels decreased to 58% of initial levels after weight loss (P < 0.005), and TNF protein decreased to 46% of initial levels (P < 0.02). TNF is known to inhibit LPL activity. When fasting adipose LPL activity was measured in these subjects, there was a significant inverse relationship between TNF expression and LPL activity (r = -0.39, P < 0.02, n = 39). With weight loss, LPL activity increased to 411% of initial levels. However, the magnitude of the increase in LPL did not correlate with the decrease in TNF. Thus, TNF is expressed in human adipocytes. TNF is elevated in most obese subjects and is decreased by weight loss. In addition, there is an inverse relationship between TNF and LPL expression. These data suggest that endogenous TNF expression in adipose tissue may help limit obesity in some subjects, perhaps by increasing insulin resistance and decreasing LPL.
To determine the effects of metformin on blood pressure, left ventricular mass, and some metabolic and endocrine parameters in nondiabetic, obese, hypertensive women.
Twelve obese, nondiabetic, hypertensive women received 850 mg metformin 2 times/day for 12 wk and placebo for another 12 wk, according to a double-blind, cross-over, randomized design. All patients were hospitalized 4 times, i.e., before randomization and after each treatment (metformin or placebo), to conduct metabolic and cardiovascular investigations (oral glucose tolerance test, euglycemic clamp associated with indirect calorimetry, and echocardiography).
Fasting glucose, HbA1c, fasting and glucose-stimulated insulin, blood pressure and left ventricular mass, cholesterol, triglycerides, and fibrinogen decreased significantly after metformin treatment, whereas high-density lipoprotein cholesterol increased. The improvement in glucose metabolism resulted from increased sensitivity to insulin.
These findings suggest that metformin treatment in obese, nondiabetic, hypertensive women produces a more favorable cardiovascular risk profile.
To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.
Leptin is a peptide hormone produced by adipose tissue which acts centrally to decrease appetite and increase energy expenditure. Although leptin increases norepinephrine turnover in thermogenic tissues, the effects of leptin on directly measured sympathetic nerve activity to thermogenic and other tissues are not known. We examined the effects of intravenous leptin and vehicle on sympathetic nerve activity to brown adipose tissue, kidney, hindlimb, and adrenal gland in anesthetized Sprague-Dawley rats. Intravenous infusion of mouse leptin over 3 h (total dose 10-1,000 microg/kg) increased plasma concentrations of immunoreactive murine leptin up to 50-fold. Leptin slowly increased sympathetic nerve activity to brown adipose tissue (+286+/-64% at 1,000 microg/kg; P = 0.002). Surprisingly, leptin infusion also produced gradual increases in renal sympathetic nerve activity (+228+/-63% at 1,000 microg/kg; P = 0.0008). The effect of leptin on sympathetic nerve activity was dose dependent, with a threshold dose of 100 microg/kg. Leptin also increased sympathetic nerve activity to the hindlimb (+287+/-60%) and adrenal gland (388+/-171%). Despite the increase in overall sympathetic nerve activity, leptin did not increase arterial pressure or heart rate. Leptin did not change plasma glucose and insulin concentrations. Infusion of vehicle did not alter sympathetic nerve activity. Obese Zucker rats, known to possess a mutation in the gene for the leptin receptor, were resistant to the sympathoexcitatory effects of leptin, despite higher achieved plasma leptin concentrations. These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic.
Background
Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.
Methods
18 790 patients, from 26 countries, aged 50–80 years (mean 61·5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure ⩽90 mm Hg, 6264 to ⩽85 mm Hg, and 6262 to ⩽80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.
Findings
Diastolic blood pressure was reduced by 20·3 mm Hg, 22·3 mm Hg, and 24·3 mm Hg, in the ⩽90 mm Hg, ⩽85 mm Hg, and ⩽80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82·6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86·5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group ⩽80 mm Hg compared with target group ⩽90 mm Hg (p for trend=0·005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0·03) and all myocardial infarction by 36% (p=0·002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0·001).
Interpretation
Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82·6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.
Obesity in children and adolescents is associated with significant health problems in the pediatric age group, and it is important early risk factor for a great deal of adult morbidity and mortality. Metabolic syndrome (visceral adiposity, impaired glucose tolerance, diabetes mellitus type 2, insulin resistance, dyslipidemia, high blood pressure), was a huge problem in obese adults, until now. In the recent reports metabolic syndrome was found in 24 to 51% of overweight youths. Therefore, it is very important to recognize children at-risk for developing metabolic syndrome, and to begin with therapy at time, in purpose to prevent late complications.
Purpose: Physical activity has been associated with reduced blood pressure in observational epidemiologic studies and individual clinical trials. This meta-analysis of randomized, controlled trials was conducted to determine the effect of aerobic exercise on blood pressure. Data Sources: English-language articles published before September 2001. Study Selection: 54 randomized, controlled trials (2419 participants) whose intervention and control groups differed only in aerobic exercise. Data Extraction: Using a standardized protocol and data extraction form, three of the investigators independently abstracted data on study design, sample size, participant characteristics, type of intervention, follow-up duration, and treatment outcomes. Data Synthesis: In a random-effects model, data from each trial were pooled and weighted by the inverse of the total variance. Aerobic exercise was associated with a significant reduction in mean systolic and diastolic blood pressure (-3.84 mm Hg [95% Cl, -4.97 to -2.72 mm Hg] and -2.58 mm Hg [CI, -3.35 to -1.81 mm Hg], respectively). A reduction in blood pressure was associated with aerobic exercise in hypertensive participants and normotensive participants and in overweight participants and normal-weight participants. Conclusions: Aerobic exercise reduces blood pressure in both hypertensive and normotensive persons. An increase in aerobic physical activity should be considered an important component of lifestyle modification for prevention and treatment of high blood pressure.
In population surveys, blood pressure and plasma insulin concentration are related variables, but the association is confounded by age and obesity. Whether insulin resistance is independently associated with higher blood pressure in normal subjects is debated. We analyzed the database of the European Group for the Study of Insulin Resistance, made UP of nondiabetic men and women from 20 centers, in whom insulin sensitivity was measured by the euglycemic insulin clamp. After excluding subjects aged ≤70 years, those with severe obesity (body mass index [BMI] >40 kg · m-2), and those with abnormal blood pressure values (≤140/90 mm Hg), 333 cases (ages 18 to 70 years; BMI, 18.4 to 39.8 kg · m-2) were available for analysis. In univariate analysis, both systolic and diastolic blood pressures were inversely related to insulin sensitivity, with r values of 0.18 (P<.005) and 0.34 (P<.0001), respectively. In a multivariate model simultaneously accounting for sex, age, BMI, and fasting insulin, systolic and diastolic blood pressures were still inversely related to insulin sensitivity (partial r, 0.15 and 0.19; P<.01 for both). In this model, age was positively related to blood pressure levels independently of insulin sensitivity, whereas BMI was not. The predicted impact on blood pressure of a decrease in insulin sensitivity of 10 μmol · min-1 · kg-1 was +1.4 mm Hg, similar to that associated with a 10-year difference in age. Although insulin levels and insulin action were reciprocally interrelated, diastolic blood pressure varied as a simultaneous function of both. In normotensive, nondiabetic Europeans, insulin sensitivity and age are significant, mutually independent correlates of blood pressure, whereas body mass is not. The relation of blood pressure to both insulin action and circulating insulin levels is compatible with distinct influences on blood pressure by insulin resistance and compensatory hyperinsulinemia.
Background: Weight loss appears to be an effective method for primary prevention of hypertension. However, the long-term effects of weight loss on blood pressure have not been extensively studied. Objective: To present detailed results from the weight loss arm of Trials of Hypertension Prevention (TOHP) II. Design: Multicenter, randomized clinical trial testing the efficacy of lifestyle interventions for reducing blood pressure over 3 to 4 years. Participants in TOHP II were randomly assigned to one of four groups. This report focuses only on participants assigned to the weight loss (n = 595) and usual care control (n = 596) groups. Patients: Men and women 30 to 54 years of age who had nonmedicated diastolic blood pressure of 83 to 89 mm Hg and systolic blood pressure less than 140 mm Hg and were 110% to 165% of their ideal body weight at baseline. Intervention: The weight loss intervention included a 3-year program of group meetings and individual counseling focused on dietary change, physical activity, and social support. Measurements: Weight and blood pressure data were collected every 6 months by staff who were blinded to treatment assignment Results: Mean weight change from baseline in the intervention group was -4.4 kg at 6 months, -2.0 kg at 18 months, and -0.2 kg at 36 months. Mean weight change in the control group at the same time points was 0.1, 0.7, and 1.8 kg. Blood pressure was significantly lower in the intervention group than in the control group at 6, 18, and 36 months. The risk ratio for hypertension in the intervention group was 0.58 (95% Cl, 0.36 to 0.94) at 6 months, 0.78 (Cl, 0.62 to 1.00) at 18 months, and 0.81 (Cl, 0.70 to 0.95) at 36 months. In subgroup analyses, intervention participants who lost at least 4.5 kg at 6 months and maintained this weight reduction for the next 30 months had the greatest reduction in blood pressure and a relative risk for hypertension of 0.35 (Cl, 0.20 to 0.59). Conclusions: Clinically significant long-term reductions in blood pressure and reduced risk for hypertension can be achieved with even modest weight loss.
Background: The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago, but are less clear in those with mildly to moderately elevated blood pressure. Objective: To assess whether candesartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events, cognitive decline and dementia. Design: Prospective, double-blind, randomized, parallel-group study conducted in 1997–2002. Setting and participants: The study was of 4964 patients aged 70–89 years, with systolic blood pressure 160–179 mmHg, and/or diastolic blood pressure 90–99 mmHg, and a Mini Mental State Examination (MMSE) test score ≥ 24. A total of 527 centres in 15 countries participated in the study. Intervention: Patients were assigned randomly to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive therapy added as needed. As a consequence, active antihypertensive therapy was extensively used in the control group (84% of patients). Mean follow-up was 3.7 years. Main outcome measures: The primary outcome measure was major cardiovascular events, a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction. Secondary outcome measures included cardiovascular death, non-fatal and fatal stroke and myocardial infarction, cognitive function measured by the MMSE and dementia. Results: Blood pressure fell by 21.7/10.8 mmHg in the candesartan group and by 18.5/9.2 mmHg in the control group. A first major cardiovascular event occurred in 242 candesartan patients and in 268 control patients; risk reduction with candesartan was 10.9% [95% confidence interval (CI), −6.0 to 25.1, P = 0.19]. Candesartan-based treatment reduced non-fatal stroke by 27.8% (95% CI, 1.3 to 47.2, P = 0.04), and all stroke by 23.6% (95% CI, −0.7 to 42.1, P = 0.056). There were no significant differences in myocardial infarction and cardiovascular mortality. Mean MMSE score fell from 28.5 to 28.0 in the candesartan group and from 28.5 to 27.9 in the control group (P = 0.20). The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups. Conclusions: In elderly hypertensive patients, a slightly more effective blood pressure reduction during candesartan-based therapy, compared with control therapy, was associated with a modest, statistically non-significant, reduction in major cardiovascular events and with a marked reduction in non-fatal stroke. Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions. Both treatment regimens were generally well tolerated.
Background— Inflammation plays a pivotal role in atherosclerosis. In addition to being a risk marker for cardiovascular disease, much recent data suggest that C-reactive protein (CRP) promotes atherogenesis via effects on monocytes and endothelial cells. The metabolic syndrome is associated with significantly elevated levels of CRP. Plasminogen activator inhibitor-1 (PAI-1), a marker of atherothrombosis, is also elevated in the metabolic syndrome and in diabetes, and endothelial cells are the major source of PAI-1. However, there are no studies examining the effect of CRP on PAI-1 in human aortic endothelial cells (HAECs).
Methods and Results— Incubation of HAECs with CRP results in a time- and dose-dependent increase in secreted PAI-1 antigen, PAI-1 activity, intracellular PAI-1 protein, and PAI-1 mRNA. CRP stabilizes PAI-1 mRNA. Inhibitors of endothelial NO synthase, blocking antibodies to interleukin-6 and an endothelin-1 receptor blocker, fail to attenuate the effect of CRP on PAI-1. CRP additionally increased PAI-1 under hyperglycemic conditions.
Conclusions— This study makes the novel observation that CRP induces PAI-1 expression and activity in HAECs and thus has implications for both the metabolic syndrome and atherothrombosis. (Circulation. 2003;107:398-404.)
Received November 14, 2002; revision received December 3, 2002; accepted December 4, 2002.
Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo.Background
The fibrinolytic system plays an important role in degrading fibrin-rich thrombi and in vascular and tissue remodeling. Elevated levels of plasminogen activator inhibitor-1 (PAI-1) can reduce the efficiency of the endogenous fibrinolytic system. Angiotensin (Ang) has been shown to regulate PAI-1 expression via the Ang type 1 (AT1) receptor in some tissues and via the AT4 receptor in cultured endothelium. The purpose of this study was to examine the tissue-specific pattern of PAI-1 expression in response to infusion of Ang II in vivo.Methods
Adult male Sprague-Dawley rats (N = 5 in each group) were treated with four hours of intravenous infusions of Ang II or vehicle control while mean arterial pressure (MAP) was monitored: group 1, 600 ng/kg/min Ang II; group 2, Ang II + 10 mg/kg of the AT1 receptor antagonist (AT1RA) L158-809 q2 hour; group 3, Ang II + 0.01 to 0.1 mg/kg hydralazine as required to maintain normal blood pressure; and group 4, saline-infused controls. After infusion, tissue was harvested for Northern blotting, immunohistochemical analysis, and in situ hybridization.ResultsIn group 1, Ang II infusion increased MAP from 105 ± 8 to 160 ± 9 mm Hg (mean ± SE, P < 0.01). Ang II induced increased expression of PAI-1 mRNA in all tissues examined from 5.1-fold in the heart, 9.7-fold in the kidney, 10.0-fold in the aorta, and up to 30.0-fold in the liver (all P < 0.01 vs. control). While both AT1RA (group 3) and hydralazine (group 4) prevented Ang II-induced elevation in blood pressure, the Ang II-dependent expression of PAI-1 mRNA was reduced by only AT1 receptor blockade.Conclusions
We conclude that in the rat, PAI-1 is induced in a variety of tissues by Ang II directly through the AT1 receptor, independent of its effects on blood pressure.
Objective.-To compare six antihypertensive interventions for the treatment of mild hypertension. Design.-Randomized, double-blind, placebo-controlled clinical trial. Setting.-Four hypertension screening and treatment centers in the United States. Participants.-Hypertensive men and women, aged 45 to 69 years, with diastolic blood pressure less than 100 mm Hg. Intervention.-Sustained nutritional-hygienic advice to all participants to reduce weight, dietary sodium intake, and alcohol intake, and increase physical activity. Participants were randomly allocated to take (1) placebo (n=234); (2) chlorthalidone (n=136); (3) acebutolol (n=132); (4) doxazosin mesylate (n=134); (5) amlodipine maleate (n=131); or (6) enalapril maleate (n=135). Main Outcome Measures.-Blood pressure, quality of life, side effects, blood lipid levels and analysis of other serum components, echocardiographic and electrocardiographic changes, and incidence of cardiovascular events over an average of 4.4 years of follow-up. Results.-Blood pressure reductions were sizable in all six groups, and were significantly greater for participants assigned to drug treatment than placebo (-15.9 vs -9.1 mm Hg for systolic blood pressure and -12.3 vs -8.6 mm Hg for diastolic blood pressure; P<.0001). After 4 years, 59% of participants assigned to placebo and 72% of participants given drug treatment continued on their initial medication as mono-therapy. A smaller percentage of participants assigned to the drug-treatment groups died or experienced a major nonfatal cardiovascular event than those assigned to the placebo group (5.1 % vs 7.3%; P=.21). After including other clinical events, the percentage of participants affected was 11.1 % for those in the drug-treatment groups and 16.2% for those in the placebo group (P=.03). Incidence rates of most resting electrocardiographic abnormalities were lower and quality of life was improved more for those assigned to drug-treatment groups rather than the placebo group. Differences among the five drug treatments did not consistently favor one group in terms of regression of left ventricular mass, blood lipid levels, and other outcome measures. Conclusions.-As an initial regimen, drug treatment in combination with nutritional-hygienic intervention was more effective in preventing cardiovascular and other clinical events than was nutritional-hygienic treatment alone. Drug-treatment group differences were minimal. Pending results from large-scale clinical trials to evaluate drug treatments for their effect on cardiovascular clinical events, these findings support the recommendations of the new fifth Joint National Committee report regarding treatment choices for people with stage 1 (''mild'') hypertension.
Objective: Abdominal obesity has a key role in the pathogenesis of prevalent and serious diseases and has been shown to be associated with an altered hypothalamic-pituitary-adrenal (HPA) axis function, which is regulated by endocrine feedback mediated via hippocampal glucocorticoid receptors (GR).
Research Methods and Procedures: We examined the HPA axis function by repeated salivary samples for the assessment of cortisol, as well as other endocrine, anthropometric, metabolic, and circulatory variables in middle-aged Swedish men (n = 284). With the restriction enzyme BclI, variants of the GR gene (GRL) locus were identified and two alleles with fragment lengths of 4.5 and 2.3 kilobases (kb) were detected.
Results: The observed frequencies were 40.1% for the 2.3- and 2.3-kb, 46.2% for the 4.5- and 2.3-kb, and 13.7% for the 4.5- and 4.5-kb genotypes. The larger allele (4.5 and 4.5 kb) was associated with elevated body mass index (BMI; p < 0.001), waist-to-hip circumference ratio (p = 0.015), abdominal sagittal diameter (p = 0.002), leptin (p < 0.001), and systolic blood pressure (borderline, p = 0.058). The 4.5- and 4.5-kb allele was associated with leptin after adjustment for BMI. Moreover, salivary cortisol values, particularly after stimulation by a standardized lunch (p = 0.040 to 0.086), were elevated in the men with the larger allele.
Discussion: These results indicate that there is an association between a deficient GR function, defined as a poor feedback regulation of the HPA axis activity, and a polymorphic restriction site at the GR gene locus. An abnormal control of HPA axis function due to genetic alterations may contribute to the pathogenesis of abdominal obesity.
LR: 20061115; JID: 7501160; 0 (Antilipemic Agents); 0 (Cholesterol, HDL); 0 (Cholesterol, LDL); 57-88-5 (Cholesterol); CIN: JAMA. 2001 Nov 21;286(19):2401; author reply 2401-2. PMID: 11712930; CIN: JAMA. 2001 Nov 21;286(19):2400-1; author reply 2401-2. PMID: 11712929; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712928; CIN: JAMA. 2001 Nov 21;286(19):2400; author reply 2401-2. PMID: 11712927; CIN: JAMA. 2001 May 16;285(19):2508-9. PMID: 11368705; CIN: JAMA. 2003 Apr 16;289(15):1928; author reply 1929. PMID: 12697793; CIN: JAMA. 2001 Aug 1;286(5):533-5. PMID: 11476650; CIN: JAMA. 2001 Nov 21;286(19):2401-2. PMID: 11712931; ppublish
Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension. Taken together, our findings suggest that overexpression of 1 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.
Thiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma is expressed predominantly in adipose tissue, yet a major site of TZD-responsive glucose disposal is skeletal muscle. Potential explanations for this paradox are discussed in this review.
Adverse treatment effects were assessed in 840 elderly hypertensive patients randomly assigned to active treatment (a combination of triamterene and hydrochlorothiazide) or placebo; methyldopa was added to the regimen in one third of the treated patients. Symptoms of dry mouth, nasal stuffiness, and diarrhea were reported by significantly more treated patients than placebo control subjects. More patients receiving diuretics plus methyldopa than diuretics alone reported dry mouth and diarrhea. Significantly more treated patients than control subjects showed evidence of a high serum creatinine level, mild hypokalemia, and gout. More treated patients tended to have diabetes. The benefits of treatment outweighed these adverse treatment effects.
Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.
A common mechanism which may be involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of insulin at the cellular level. Observations from a number of laboratories suggest that impaired cellular response to insulin rather than hyperinsulinemia predisposes to increased vascular smooth muscle tone (the hallmark of hypertension in the diabetic state). This review presents some of the data which suggest that there is a relationship between impaired cellular action of insulin, altered cellular calcium metabolism and the development of hypertension.
Because considerable important information has been published since our previous review, this update concentrates on new findings with regard to cardiovascular and renal risk factors contributing to the striking morbidity and mortality of these coexisting diseases. For example, a large body of investigative data has recently emerged suggesting or delineating a pathogenic role for hyperglycemic-related glycosylation and oxidation of lipoproteins and vascular and renal tissues. Great strides have recently been made in the understanding of platelet, coagulation, lipoprotein, and endothelial abnormalities in the pathogenesis of cardiovascular and renal disease associated with diabetes mellitus and hypertension. Major progress has been made in clarifying the pathophysiology of glomerulosclerosis and other processes involved in the progression of diabetic nephropathy. Furthermore, accumulating data surveyed in this review address new and promising pharmacological interventions that specifically address these pathophysiological mechanisms.
Recent studies from this laboratory have demonstrated that angiotensin II (Ang II) stimulates the expression of plasminogen activator inhibitor 1 (PAI-1) in cultured endothelial cells. This response does not appear to be mediated via an interaction with either the AT1 or the AT2 receptor subtype. Since a novel angiotensin receptor has been identified in a variety of tissues that specifically binds the hexapeptide Ang IV (Ang II, [3-8]), we therefore examined the effects of Ang IV on the expression of PAI-1 mRNA in bovine aortic endothelial cells. Ang IV stimulated dose- and time-dependent increases in the expression of PAI-1 mRNA. The effect of Ang IV (10 nM) was not inhibited by Dup 753 (1.0 microM), a highly specific antagonist of the AT1 receptor, or by PD123177 (1.0 microM), a highly specific antagonist of the AT2 receptor. In contrast, the AT4 receptor antagonist, WSU1291 (1.0 microM), effectively prevented PAI-1 expression. Although larger forms of angiotensin (i.e., Ang I, Ang II, and Ang III) are capable of inducing PAI-1 expression, this property is lost in the presence of converting enzyme or aminopeptidase inhibitors. These results indicate that the hexapeptide Ang IV is the form of angiotensin that stimulates endothelial expression of PAI-1. This effect appears to be mediated via the stimulation of an endothelial receptor that is specific for Ang IV.
The role of endothelin ETB receptors in mediating vasoconstriction in humans is unclear. As yet, there have been no in vivo studies in resistance vessels, and in vitro data have been contradictory. We therefore investigated the function of ETB receptors in vivo in human forearm resistance and hand capacitance vessels using endothelin-1 as a nonselective agonist at ETA and ETB receptors and endothelin-3 and sarafotoxin S6c as selective agonists at the ETB receptor.
A series of single-blind studies were performed, each in six healthy men. Brachial artery infusion of endothelin-1 and endothelin-3 caused slow-onset dose-dependent forearm vasoconstriction. Although endothelin-3 caused significantly less forearm vasoconstriction than endothelin-1 at low doses, vasoconstriction was similar to the two isopeptides at the highest dose (60 pmol/min). Endothelin-3 caused transient forearm vasodilatation at this dose, whereas endothelin-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to endothelin-1 (P = .04). Dorsal hand vein infusion of sarafotoxin S6c caused local venoconstriction that was also less than that to endothelin-1 (P = .002).
Selective ETB receptor agonists cause constriction of forearm resistance and hand capacitance vessels in vivo in humans, suggesting that both ETA and ETB receptors mediate vasoconstriction. Hence, antagonists at both ETA and ETB receptors, or inhibitors of the generation of endothelin-1, may be necessary to completely prevent vasoconstriction to endogenously generated endothelin-1.
Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An
induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity
and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats
caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for
TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.
In several studies hypertension has been shown to be associated with an increased incidence of non-insulin-dependent diabetes mellitus (NIDDM). This may be due to hypertension itself or to the deleterious effects of some antihypertensive agents on glucose tolerance and insulin sensitivity.
We examined the 3.5-year incidence of diabetes mellitus in relation to hypertension and antihypertensive medication in a population-based study of elderly subjects (n = 805) aged 65-74 years in Kuopio, Finland.
Of the subjects studied, 60% had hypertension at baseline and 50% of the hypertensive subjects were on drug therapy at baseline. Hypertensive subjects had a significantly higher incidence of NIDDM than non-hypertensive subjects. However, after adjustment for age, body mass index, waist: hip ratio, sex, and fasting glucose and insulin levels, the increased risk of NIDDM in hypertensive subjects was no longer statistically significant. Subjects with high blood pressure (> or = 160/95 mmHg) at the baseline examination who were not taking beta-blockers or diuretic medication had a 1.56-fold increased risk of developing NIDDM, whereas subjects with hypertension who were taking those agents had a 1.88-fold risk of developing NIDDM compared with subjects with normal blood pressure. The risk of developing NIDDM was accompanied by elevated fasting insulin levels. After adjustment for age, sex, body mass index, waist:hip ratio, and fasting glucose and insulin levels, hypertensive subjects taking diuretics or beta-blockers, or both, still had a 1.56-fold increased risk of developing NIDDM relative to normotensive subjects. Hypertensive subjects taking diuretics or beta-blockers, or both, had a significantly higher incidence of NIDDM than hypertensive subjects not on pharmacological therapy. However, after adjustment for 2-h glucose and insulin concentrations, the incidence of NIDDM did not differ between the hypertensive subjects.
The data presented suggest that the increased risk of NIDDM in hypertensive subjects taking beta-blockers or diuretics, or both, is explained at least partly by metabolic disturbances related to drug therapy.
Human obesity is characterized by profound alterations in the hemodynamic and metabolic states. Whether these alterations involve sympathetic drive is controversial. In 10 young obese subjects (body mass index, 40.5 +/- 1.2 kg/m2, mean +/- SEM) with normal blood pressure and 8 age-matched lean normotensive control subjects, we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (electrocardiogram), postganglionic muscle sympathetic nerve activity (microneurography at the peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography). The measurements were performed in baseline conditions and, with the exception of plasma norepinephrine, during baroreceptor stimulation and deactivation caused by increases and reductions of blood pressure via intravenous infusions of phenylephrine and nitroprusside. Baseline blood pressure and heart rate were similar in obese and control subjects. Plasma norepinephrine was also similar in the two groups. Muscle sympathetic nerve activity, however, was 38.6 +/- 5.1 bursts per minute in obese subjects and less than half that level in control subjects (18.7 +/- 1.3 bursts per minute), the difference being highly statistically significant (P < .02). Muscle sympathetic nerve activity and heart rate were reduced during phenylephrine infusion and increased during nitroprusside infusion, but the changes were about half as great in obese subjects as in control subjects. Thus, even in the absence of any blood pressure alteration, human obesity is characterized by a marked sympathetic activation, possibly because of an impairment of reflex sympathetic restraint. This may be involved in the high rate of hypertension and cardiovascular complications seen in obesity.
The efficacy and safety of metformin in the treatment of obese, non-insulin-dependent, diabetic subjects poorly controlled by insulin after secondary failure to respond to sulphonylureas has been investigated. Fifty insulin-treated, obese diabetics participated in this prospective, randomised double-blind six-month trial. After a four-week run-in period, during which all patients were given placebo (single-blind), patients were randomly assigned to continue to receive placebo or to active treatment with metformin.
At six months, there was a relevant and significant improvement in glycaemic control in diabetics receiving the combined insulin-metformin treatment (decrease in glucose −4.1 mmol·l−1; glycosylated haemoglobin A1 decrease −1.84%). No significant changes were seen in diabetics receiving insulin and placebo. There was a significant decrease in blood lipids (trygliceride and cholesterol), an increase in HDL-cholesterol and a reduction in blood pressure in diabetics taking metformin. These postive findings were most marked in the 14 diabetics who experienced a good response to metformin (glucose profile <10 mmol·l−1), and were less marked but still significant in the remaining 13 diabetics, whose response to therapy was not so good (glucose profile >10 mmol·l−1). The fasting insulin level was significantly lower after six months of combined insulin-metformin treatment as shown by a 25% reduction in the daily dose of insulin (−21.6 U/day).
Metformin was well tolerated by all diabetics. Combining metforming with insulin in obese, insulin-treated and poorly controlled diabetics may represent a safe strategy to achieve better glycaemic control with a reduction in certain metabolic risk factors associated with the increased incidence of cardiovascular disease in diabetes mellitus.
The intravascular renin-angiotensin system is an endocrine system designed to maintain cardiovascular homeostasis in response to hypotension. Under normal conditions, angiotensinogen concentrations circulating in the plasma are rate limiting for the maximum velocity of angiotensin I formation. In the liver, the major site of circulating angiotensinogen synthesis, angiotensinogen expression is under exquisite hormonal control. We review the mechanisms by which hormones effect transcriptional control of angiotensinogen expression. Adrenal-derived glucocorticoids produce the translocation of the glucocorticoid receptor into the nucleus. It in turn binds to two glucocorticoid response elements and stimulates angiotensinogen gene transcription. Inflammation activates angiotensinogen transcription as a result of the macrophage-derived cytokines interleukin-1 and tumor necrosis factor-alpha. These cytokines change the abundance of two transcription factor families that bind a single regulatory site in the angiotensinogen promoter, the acute-phase response element. These proteins include the nuclear factor-kappaB complex and the CCAAT/enhancer binding protein family. Activation of the renin-angiotensin system, through production of angiotensin II, results in feedback stimulation of angiotensinogen synthesis (the "positive feedback loop"). We have discovered that the nuclear factor-kappaB transcription factor is regulated by angiotensin II, a finding that provides a mechanism for the transcriptional component of angiotensinogen gene synthesis in the positive feedback loop. These studies underscore the concept that induction of the angiotensinogen gene by diverse physiological stimuli is mediated through changes in the nuclear abundance of sequence-specific transcription factors. The intracellular convergence of cytokine- and angiotensin II-induced signaling pathways on the nuclear factor-kappaB transcription factor provides a point for "cross talk" between angiotensin- and cytokine-activated second messenger pathways.
To characterize natriuretic peptide receptor (NPr) gene expression in human tissues, we cloned portions of the cDNAs codifying for NPr with guanylyl cyclase activity (NPr-A and NPr-B) and without guanylyl cyclase activity (NPr-C). Total RNA was extracted from samples taken at surgery from normal human tissues. NPr-A and NPr-B cDNAs obtained from lung as well as NPr-C cDNA obtained from renal cortex were cloned, characterized, and used for comparative Northern analysis. NPr-A mRNA (approximately 4 kb) was most abundant in adipose tissue (8 patients) independently on the site of sampling, whereas it was approximately 2.5-fold and 5-fold less abundant, respectively, in kidney (either renal cortex or papilla from 3 patients) and adrenal (4 patients), known target tissues of natriuretic peptides. NPr-C mRNAs (approximately 7.7 and 6.8 kb) had a similar tissue distribution but the highest levels were found in renal tissue and only very low expression levels were found in adrenals (approximately 20-fold lower than renal cortex). The ratio of NPrA versus NPr-C mRNA levels were highest in adrenal and lowest in renal tissue. NPr-B mRNA (approximately 4 kb), which encodes the receptor for the C-type natriuretic peptide, had a different and wide tissue distribution, including expression in ileum and liver, with the highest levels in venous and prostatic tissue. These results indicate that, in humans, different patterns of NPr expression with different NPr-A/NPr-C mRNA level ratios, are present in known target tissues of natriuretic peptides. "Non-classic" target tissues, such as the adipose one, maximally expressed NPr-A and also NPr-C, suggesting that natriuretic peptides may have wider functional activities than those previously demonstrated.
To assess the effect of low-dose, diuretic-based antihypertensive treatment on major cardiovascular disease (CVD) event rates in older, non-insulin-treated diabetic patients with isolated systolic hypertension (ISH), compared with nondiabetic patients.
Double-blind, randomized, placebo-controlled trial: the Systolic Hypertension in the Elderly Program (SHEP).
Multiple clinical and support centers in the United States.
A total of 4736 men and women aged 60 years and older at baseline with ISH (systolic blood pressure [BP], > or = 160 mm Hg; diastolic BP, <90 mm Hg) at baseline, 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients (4 additional patients not so classifiable were randomized but not included in these analyses). Diabetes mellitus defined as physician diagnosis, taking oral hypoglycemic drugs, fasting glucose level of 7.8 mmol/L or more (> or = 140 mg/dL), or any combination of these characteristics.
The active treatment group received a low dose of chlorthalidone (12.5-25.0 mg/d) with a step-up to atenolol (25.0-50.0 mg/d) or reserpine (0.05-0.10 mg/d) if needed. The placebo group received placebo and any active antihypertensive drugs prescribed by patient's private physician for persistently high BP.
The 5-year rates of major CVD events, nonfatal plus fatal stroke, nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD), major CHD events, and all-cause mortality.
The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients, with few adverse effects. For both diabetic and nondiabetic patients, all outcome rates were lower for participants randomized to the active treatment group than for those randomized to the placebo group. Thus, 5-year major CVD rate was lower by 34% for active treatment compared with placebo, both for diabetic patients (95% confidence interval [CI], 6%-54%) and nondiabetic patients (95% CI, 21%-45%). Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients (101/1000 vs 51/1000 randomized participants at the 5-year follow-up), reflecting the higher risk of diabetic patients.
Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH.
To determine the relationship between cardiovascular pathology and body fat distribution in healthy women with no ante mortem clinical evidence of cardiovascular disease.
Thirty-three female forensic autopsy cases of sudden death from violent causes.
Body height and weight, the circumferences of the waist and hip and the thicknesses of the subscapular and abdominal subcutaneous fat were measured, and Body Mass Index (BMI) and Waist-to-Hip ratio (WHR) were calculated. Omental, mesenterial and perirenal fat deposits were weighted. Heart weight was indexed to height (2.7), the degree of coronary narrowing was determined in each artery, and myocardial collagen volume fraction and myocyte cross-sectional area were measured.
The degree of coronary narrowing, heart weight in absolute terms and indexed to height (2.7), myocyte cross-sectional area and all the measures of obesity were significantly positively correlated with age. Regression of coronary narrowing on measures of obesity indicated that a quadratic model fitted the data for BMI, waist circumference and intra-abdominal fat better than a linear one. After adjusting for age, the degree of coronary narrowing was related to tertiles of BMI, waist circumference, WHR and intra-abdominal fat, the severity of the narrowing being most marked in the second tertile of BMI (24.0-31.0), waist circumference (80-96 cm) and intra-abdominal fat (500-1700 g), but in the third tertile of WHR (over 0.92). Regression on heart weight/height (2.7) on the aforementioned measures of obesity indicated a clearly linear association and heart weight indexed to height (2.7) was related to tertiles of BMI, waist circumference and WHR, and also to tertiles of intra-abdominal fat.
The results suggest that body fatness and abdominal accumulation of fat are associated with the severity of coronary atherosclerosis and myocardial hypertrophy in women with no clinical evidence of cardiovascular disease, but the relationship between coronary lesions and BMI is not linear. Both coronary lesions and myocardial hypertrophy are more advanced as the numerical value for WHR increases in women. Future autopsy studies should be directed at young women with increased WHR in order to determine their risk of developing life-threatening lesions in the atherosclerosis-prone regions of the coronary tree.
Plasminogen activator inhibitor type 1 (PAI-1) contributes to the pathogenesis of atherothrombosis. Its plasma level is strongly correlated with parameters that define the insulin resistance syndrome, in particular with BMI and visceral accumulation of body fat, suggesting that PAI-1 may be an adipose tissue-derived circulating peptide. The present study was designed to investigate PAI-1 expression by human adipose tissue and its different cellular fractions. Special interest has been paid to the amount of PAI-1 antigen produced by omental versus subcutaneous fat. PAI-1 protein detected by immunolocalization was present at the stromal and adipocyte levels. PAI-1 mRNA was detected in stromal vascular cells freshly isolated and under culture conditions. It was also detected in whole adipose tissue and adipocyte fraction under culture conditions. The mRNA signal from the adipocyte fraction was detected as early as 2 h of incubation. The increase in PAI-1 mRNA was followed by an increase in PAI-1 antigen in the conditioned medium that was suppressed by treatment with cycloheximide. Transforming growth factor-beta1 significantly increased PAI-1 antigen production by the adipocyte fraction, whereas tumor necrosis factor-alpha did not have any effect. Interestingly, after 5 h of incubation, omental tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, whereas similar production of leptin by the two territories was observed. These results strongly suggest that human adipose tissue, in particular visceral tissue, can be an important contributor to the elevated plasma PAI-1 levels observed in central obesity.
Because obesity-associated hypertension has unique hemodynamic and hormonal profiles, certain classes of antihypertensive agents may be more effective than others as monotherapy. Thus, we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week, multicenter, double-blind trial in 232 obese patients with hypertension. Patients with an office diastolic pressure between 90 and 109 mm Hg were randomized to treatment with daily doses of lisinopril (10, 20, or 40 mg), hydrochlorothiazide (12.5, 25, or 50 mg), or placebo. Mean body mass indexes were similar for all patients. At week 12, lisinopril and hydrochlorothiazide effectively lowered office diastolic (-8.3 and -7.7 versus -3.3 mm Hg, respectively; P<.005) and systolic (-9.2 and -10.0 versus -4.6 mm Hg, respectively; P<.05) pressures compared with placebo. Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo (P<.001). Significant dose-response differences were observed between treatments. Sixty percent of patients treated with lisinopril had an office diastolic pressure <90 mm Hg compared with 43% of patients treated with hydrochlorothiazide (P<.05). Responses to therapies differed with both race and age. Neither treatment significantly affected insulin or lipid profiles; however, plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril (+0.31 versus -0.21 mmol/L; P<.001). Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline. In conclusion, lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics, may have a more rapid rate of response, and may offer advantages in patients at high risk of metabolic disorders.