Emílio Antonio Francischetti

Obesity-hypertension : an ongoing pandemic

Considerable evidence has suggested that excessive weight gain is the most common cause of arterial hypertension. This association has been observed in several populations, in different regions of the world. Obesity–hypertension, a term that underscores the link between these two deleterious conditions, is an important public health challenge, because of its high frequency and concomitant risk of cardiovascular and kidney diseases. The obesity–hypertension pandemic imposes a considerable economic burden on societies, directly reflecting on healthcare system costs. Increased renal sodium reabsorption and blood volume expansion are central features in the development of obesity–hypertension. Overweight is also associated with increased sympathetic activity. Leptin, a protein expressed in and secreted by adipocytes, is the main factor linking obesity, increased sympathetic nervous system activity and hypertension. The renin–angiotensin–aldosterone system has also been causally implicated in obesity–hypertension, because angiotensinogen is expressed in and secreted by adipose tissue. Hypoadiponectinemia, high circulating levels of free fatty acids and increased vascular production of endothelin‐1 (ET‐1) have been reported as potential mechanisms for obesity–hypertension. Lifestyle changes are effective in obesity–hypertension control, though pharmacological treatment is frequently necessary. Despite the consistency of the mechanistic approach in explaining the causal relation between hypertension and obesity, there is yet no evidence that one class of drug is superior to the others in controlling obesity–hypertension. In this review, we present the current knowledge and research in obesity–hypertension, exploring the epidemiologic evidence of the association, its probable pathophysiological mechanisms and treatment issues.

Effects of Greater-than-5% Weight Reduction on Hemodynamic, Metabolic and Neuroendocrine Profiles of Grade I Obese Subjects

OBJECTIVE To evaluate the effects of a greater-than-5% weight reduction in hemodynamic, metabolic, and neuroendocrine profiles of grade I obese subjects. METHODS Observational study with 47 grade I obese subjects, with mean age of 33 years who received monthly orientation regarding diet, physical exercises, and eating behavior for four months. Blood pressure using the auscultatory method and pulse rate were assessed monthly, whereas the following variables (and respective methods) were measured at the beginning and at the end of the study: total cholesterol, triglycerides, HDL-cholesterol (enzymatic method), LDL-cholesterol (Friedewald formula), blood glucose (hexokinase method), leptin, adiponectin, renin, aldosterone, insulin (radioimmunoassay) and insulin-resistance index (HOMA). RESULTS After adjustment for other variables, significant reductions of 6 mmHg in diastolic blood pressure, 7 pg/ml in renin, 13 mg/dl in total cholesterol and 12 mg/dl in LDL-cholesterol were observed in the greater-than-5% weight reduction group. Also, a tendency to a higher increase in adiponectin levels by the end of the study, as well as a three-fold higher reduction in blood glucose, insulin, and HOMA levels, and a six-fold higher reduction in leptin levels were observed in this group. CONCLUSION Non-pharmacological measures that promote a greater-than-5% weight reduction produce hemodynamic, metabolic, and neuroendocrine effects that improve the cardiovascular risk of obese subjects.

Skin capillary density and microvascular reactivity in obese subjects with and without metabolic syndrome.

Obesity is associated with increased cardiovascular morbidity and mortality. We hypothesized that microvascular function may be impaired in obese subjects with metabolic syndrome (OB-MetSnd) compared to obese subjects without MetSnd (OB) and healthy subjects (HS). In this cross-sectional study, we evaluated skin capillary density (SCD) in OB-MetSnd (n=20, 12 women, BMI=36.5±1.1kg/m(2)), OB (n=25, 16 women, BMI=34.5±0.7kg/m(2)), and HS (n=30, 22 women, BMI=22.8±0.3kg/m(2)) groups. SCD was evaluated by intravital video-microscopy at rest and after post-occlusive reactive hyperemia (PORH) and venous congestion (VC). OB-MetSnd subjects exhibited significant differences in the values of MetSnd components and in leptin and HOMA-IR levels compared to OB and HS individuals. There were no differences in SCD among groups in resting conditions. The OB-MetSnd group failed to show a significant increase in the number of recruited capillaries during PORH and VC compared to the SCD evaluated at rest. A negative correlation of SCD with waist circumference, BMI, blood pressure, and HOMA-IR was observed after PORH and VC. When obese subjects were analyzed according to their HOMA-IR quartiles, a significant decrease in SCD was observed during POHR (P=0.02). Our findings showed that obese subjects have structural and functional alterations in skin microcirculation that are proportional to the increase in the degree of global and central obesity. In addition, in OB-MetSnd subjects, the cutaneous capillaries at rest are already maximally recruited, indicating an absence of functional capillary reserve. This may be related to the insulin resistance observed in OB-MetSnd individuals.

Effects of magnesium on blood pressure and intracellular ion levels of Brazilian hypertensive patients

Fifteen patients with uncomplicated mild to moderate primary hypertension (7 males, 8 females, age range 36-65 years) were submitted to a double blind randomized crossover study, receiving MgO 3 times a day at a daily dose of 1.0 g (600 mg/day of magnesium) and placebo for a period of 6 weeks. This was to test the effects of oral magnesium supplementation on blood pressure and sodium, potassium, calcium and magnesium intraerythrocyte concentrations. Concomitantly, plasma renin activity and serum aldosterone was also measured. Oral magnesium reduced significantly the systolic (delta = -7.6 mmHg, P < 0.05); diastolic (delta = -3.8 mmHg, P < 0.01) and mean blood pressure (delta = -5.9 mmHg, P < 0.01). After magnesium supplementation intraerythrocyte sodium concentration was reduced (delta = -0.55 mEq/l per cell, P < 0.01) and intraerythrocyte magnesium concentration was increased (delta = 1.20 mg/dl per cell, P < 0.01). The diminution of the blood pressure correlated positively with the reduction in intraerythrocyte sodium (r = 0.66, P < 0.01) after magnesium. However, our results have shown that the blood pressure response to oral magnesium was not homogeneous. Forty percent of our patients had their blood pressure effectively controlled (more than 10 mmHg reduction in mean blood pressure), being the hypotensive effect more evident in patients with recent hypertension and in those where the reduction in intraerythrocyte sodium was significantly greater than in the non-responder individuals. Intraerythrocyte potassium and calcium, serum aldosterone, plasma renin activity and urinary sodium excretion were maintained unchanged after magnesium supplementation. These data showed that oral magnesium supplementation may reduce the blood pressure, which can be partially explained by the decrease in intracellular sodium and augment in intracellular magnesium.

Renal functional reserve in obesity hypertension.

The capacity to increase glomerular filtration rate in response to an acute oral protein load is known as the renal functional reserve; the loss of such capacity is used as a marker of hyperfiltration. This physiological response in obese hypertensives is not yet fully understood. We aimed to study the interdependent effects of obesity and hypertension on renal reserve, taking into account renal kallikrein and nitric oxide in the modulation of that parameter. Fourteen obese hypertensives (mean age, 50.5 ± 0.9 years) and nine lean hypertensives (mean age, 50.6 ± 2.7 years) were evaluated. Renal haemodynamics and the levels of serum nitric oxide and urinary kallikrein were assessed at baseline and after a protein load (1 g/kg of body weight). An increase in the following parameters was observed when comparing obese and lean hypertensives: basal glomerular filtration rate; renal plasma flow; and urinary kallikrein and nitric oxide levels (129.2 ± 2.9 vs. 101.4 ± 3.4 ml/min/1.73 m2; 587.5 ± 18.2 vs. 502.8 ± 16.7 ml/min/1.73 m2; 0.120 ± 0.02 vs. 0.113 ± 0.02 mU/ml; 23.2 ± 0.8 vs. 19.5 ± 1.2 mmol/ml, respectively). The renal reserve was lower in obese hypertensives when compared with that of lean hypertensives (4.1 ± 0.5 vs. 11.8 ± 0.8 ml/min, p < 0.005). After a protein load, contrasting with the lean group, inability to elevate the nitric oxide serum levels and a lower increase in urinary kallikrein were observed in the obese group. These data suggest that obese hypertensives lose renal reserve earlier in the evolution to renal dysfunction. This may be due to the defective modulation of renal vasodilatation mechanisms by renal kallikrein and nitric oxide production.

Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy

AIM To evaluate the effects of combined treatment of an ACE inhibitor and an angiotensin II receptor antagonist on parameters related to the progression of renal disease in type 2 diabetic patients. METHODS 20 hypertensive type 2 diabetic patients with non-nephrotic proteinuria (0.5 - 3.0 g/day) and estimated creatinine clearance > or = 40 ml/min/1.73m2 were randomly assigned to be treated with perindopril 8 mg/day (Per), irbesartan 300 mg/day (Irb) or a combination of both with the same doses (Per + Irb). Each treatment phase lasting 16 weeks was preceded by a four-week washout period. Diuretics, clonidine and hydralazine were used as supplementary drugs for blood pressure control. Patients were evaluated at baseline and at the end of each treatment phase. RESULTS 15 (3M/12F) patients completed all the phases. Use of Per, Irb and Per + Irb led to a reduction in 24-hour mean blood pressure of 6 mmHg, 4 mmHg and 4 mmHg, respectively. Changes in glomerular filtration rate were not significant at any phase. Renal plasma flow was significantly more elevated with Irb than Per. Treatment with both Irb and Per + Irb induced similar plasma renin elevation, but treatment with Per did not, suggesting escape. Plasma aldosterone was reduced only by treatment with Per + Irb (-36%, p < 0.02). Reduction in proteinuria during Per + Irb (-33%) was not significantly different from Per (-34%) or Irb (-22%). Urinary transforming growth factor beta1 (TGF-beta1) excretion was significantly reduced with both Irb (-24%, p < 0.05) and Per + Irb (-36%, p < 0.05) but not with Per (-11%, p = 0.60). CONCLUSION Only combined therapy with irbesartan plus perindopril concurrently reduces plasma aldosterone, proteinuria and urinary TGF-beta1.

Not all obese subjects of multiethnic origin are at similar risk for developing hypertension and type 2 diabetes

BACKGROUND Whether insulin resistance and not obesity per se is the major contributor to clinical outcomes associated with obesity has not been fully established. This study evaluated in a group of obese Brazilians of multiethnic origin to what extent the prevalence of hypertension and other cardiometabolic risk factors varies as a function of the degree of insulin sensitivity. METHODS The study involved 118 individuals (mean age of 44+/-12 years; BMI=38.6+/-7.9 kg/m(2)) without evidence of diabetes or cardiovascular disease. Insulin resistance was assessed by HOMA-IR index, which was used to stratify patients into tertiles. RESULTS The mean HOMA-IR in tertile 1, the most insulin-sensitive group, was 2.7+/-0.8 and in tertile 3, the most insulin-resistant group, 9.1+/-2.4 (P<0.001). Mean arterial pressure showed a linear and significant variation across the HOMA-IR tertiles 1, 2, and 3 (94.3+/-11.7; 98.7+/-11.4; 105.0+/-12.4 mm Hg), as did fasting plasma glucose (93.6+/-12.1; 98.1+/-12.7; 100.0+/-11.0 mg/dL), uric acid (4.7+/-1.4; 5.9+/-1.9; 6.3+/-1.4 mg/dL), HDL-cholesterol (48.1+/-11.6; 46.5+/-10.5; 42.2+/-8.0 mg/dL), and plasma adiponectin (7.8+/-3.3; 7.0+/-2.8; 6.3+/-6.5 microg/mL), respectively. The results indicated that 27.5% of our patients had dysglicemia, 28.2% had hypertriglyceridemia, and 30.7% had arterial hypertension in the most insulin-sensitive tertile, when compared with 51%, 53.8% and 79.4%, respectively, in the most insulin-resistant tertile. A stepwise regression analysis showed that only HOMA-IR and age independently affected the risk for increased systolic blood pressure. CONCLUSION In conclusion, our findings have shown that the risk of developing essential hypertension, type 2 diabetes, and cardiovascular disease is accentuated in obese individuals who are also more insulin resistant.

Effect of a high-calcium energy-reduced diet on abdominal obesity and cardiometabolic risk factors in obese Brazilian subjects

Background:  Clinical trials designed to examine the effects of calcium supplementation on abdominal obesity have had ambiguous results.

Selective imidazoline agonist moxonidine in obese hypertensive patients

Obesity is the major risk factor for the development of hypertension. This association accentuates the risk of cardiovascular disease, as it is frequently accompanied by the components of the metabolic syndrome. This randomised open parallel study evaluated the chronic effects of moxonidine – a selective imidazoline receptor agonist – on blood pressure, plasma catecholamines, leptin, insulin and components of the metabolic syndrome in obese hypertensives. Amlodipine was used as the control drug. Our results showed that moxonidine and amlodipine significantly reduced blood pressure when measured using the oscillometric method and 24‐hour blood pressure monitoring. Moxonidine therapy decreased systolic blood pressure from 160.4 ± 2.4 to 142.1 ± 3.3 mmHg (p < 0.005) and diastolic blood pressure from 102.4 ± 1.3 to 89.7 ± 1.6 mmHg (p < 0.005) after 24 weeks of treatment. Moxonidine administration reduced the supine arterial plasma levels of adrenaline from 63.2 ± 6.6 to 49.0 ± 6.7 pg/ml (p < 0.005), the supine arterial plasma levels of noradrenaline from 187.9 ± 10.7 to 149.7 ± 13.2 pg/ml (p < 0.01) and the orthostatic venous plasma levels of noradrenaline from 258.6 ± 25.0 to 190.3 ± 16.4 pg/ml (p = 0.03). Those variables were not changed by amlodipine. The plasma levels of leptin and insulin 120 min after a glucose load decreased after moxonidine administration from 27.2 ± 3.5 to 22.6 ± 2.9 pg/ml (p < 0.05) and from 139.7 ± 31.2 to 76.0 ± 15.2 U/ml (p < 0.05), respectively. Amlodipine, however, did not modify those variables. This study showed a comparable reduction in blood pressure with both antihypertensive drugs. Moxonidine decreased sympathetic nervous activity, improved insulin resistance and reduced the plasma levels of leptin.

Treatment of hypertension in individuals with the cardiometabolic syndrome: role of an angiotensin II receptor blocker, telmisartan

Arterial hypertension is a global public health problem owing to its high prevalence and association with increased risk for cerebral, cardiac and renal events. Hypertension frequently clusters with other cardiometabolic risk factors, such as dysglycemia, low levels of high-density lipoprotein cholesterol and high triglyceride levels. These, along with other factors such as central obesity, increased inflammation, endothelial dysfunction and thrombosis, are components of the metabolic syndrome. All guidelines recommend that the first-line therapy in metabolic syndrome should be based on lifestyle modification, consisting of diet and moderate exercise for at least 30 min/day. Concerning drug treatment of hypertension associated with other cardiometabolic risk factors, many results of head-to-head studies have demonstrated a reduction in new-onset Type 2 diabetes in hypertensive patients treated with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, when compared with conventional antihypertensive therapy. The explanations of the different actions of both these drugs include several mechanisms related to pancreatic insulin release and insulin sensitivity improvement. Another mechanism by which the inhibition of the renin–angiotensin system may improve insulin sensitivity is through the partial peroxisome proliferator-activated receptor-γ agonism of telmisartan. For that reason, telmisartan has been considered by some experts to be an antihypertensive agent that is particularly useful in the treatment of hypertension associated with cardiometabolic risk factors. The impact of the promising metabolic action exhibited by telmisartan on the outcome of hypertensive patients aggregating other cardiometabolic risk factors waits for adequately randomized and powered clinical trials.