Virginia Genelhu

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.

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.

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.

Sodium and Hypertension Still a Controversy in 1986

SummaryInterpopulation studies support the hypothesis of a causal relationship between sodium consumption and arterial hypertension. However, although this association has been contradicted by intrapopulation studies, the correlation between sodium and hypertension appears to be genetically determined, as there are both sodium-sensitive and sodium-resistant individuals.Sodium is essential for the maintenance of extracellular and plasma volume equilibrium. It is controlled metabolically by the interaction of several biological systems such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, and the kallikrein-kinin and prostaglandin systems. Thus, sodium has a definite role in the mechanism involved in the pathophysiology of the predominantly volume-dependent forms of arterial hypertension.Recently, different structural substances with natriuretic effects have been identified. Natriuretic hormone is a non-peptide substance which inhibits the Na,K-ATPase in response to extracellular volume increase. This hormone acts on the renal tubular cells reducing sodium reabsorption, and at an arteriolar level elevating peripheral resistance by increasing smooth muscle tension. Mammalian atria contain various precursors of biologically active peptides, with potent natriuretic and diuretic effects. They are released in response to volume loading and atrial stretch. Although some data suggest an important role for these natriuretic substances in fluid volume and blood pressure control, their place in physiology and in abnormal clinical states should be more definitively clarified in the next few years.RésuméLes études interpopulations renforcent l’hypothèse d’une relation causale entre la consommation de sodium et l’hypertension artérielle. Cette corrélation est contredite par les études intrapopulations, elle semble toutefois génétiquement déterminée puis qu’il existe à la fois des individus sodium-sensibles et des individus sodium-résistants.Le sodium est essentiel au maintien de l’équilibre des volumes extracellulaire et plasmatique. Il est métaboliquement contrôlé par l’interaction de plusiers systèmes biologiques tels que le système aldostérone-rénine-angiotensine, le système nerveux autonome, les systèmes prostaglandines et kallikréine-kinines. Ainsi, le sodium joue un rôle précis dans le mécanisme qui intervient dans la physiopathologie des hypertensions artérielles essentiellement volume-dépendantes.Récemment, on a identifié différentes substances natriurétiques. L’hormone natriurétique est une substance non peptidique qui inhibe la Na, K-A TPase en réponse à une augmentation du volume extracellulaire. Cette hormone agit sur les cellules tubulaires rénales provoquant une diminution de la réabsorption du sodium et au niveau artériolaire, élevant les résistances périphériques par augmentation de la contraction des muscles lisses. L’oreillette des mammifères contient divers précurseurs des peptides biologiquement actifs, qui majorent les effets natriurétique et diurétique. Ils sont libérés en réponse à un accroissement des volumes et à une distension auriculaires. Un certain nombre de données suggère que ces substances natriurétiques tiennent un rôle important dans le contrôle des volumes liquidiens et de la pression sanguine. Cependant, leur rôle exact dans la physiologie et les états cliniques pathologiques devraient être plus clairement précisé dans les prochaines années.ZusammenfassungBevölkerungsstudien stützen die Hypothese einer kausalen Beziehung zwischen Natriumverbrauch und arterieller Hypertonie. Wenn auch dieser Assoziation in Bevölkerungsstudien widersprochen wurde, scheint jedoch die Korrelation zwischen Natrium und Hypertonie genetisch bestimmt zu sein, da es sowohl Natrium-sensitive als auch Natrium-resistente Personen gibt.Natrium ist für die Aufrechterhaltung des Gleichgewichts von extrazellulärem und Plasma-Volumen erforderlich. Es wird metabolisch durch die Interaktion verschiedener biologischer Systeme, wie das Renin-Angiotensin-Aldosteron-System, das sympathische Nervensystem sowie das Kalikrein-Kinin und das Prostaglandin-System kontrolliert. Damit besitzt das Natrium eine definitive Rolle bei dem Mechanismus, der an der Pathophysiologie der vornehmlich Volumenabhängigen Formen der arteriellen Hypertonie beteiligt ist.Kürzlich wurden verschiedene strukturelle Substanzen mit natriuretischen Effekten identifiziert. Das natriuretische Hormon ist eine nicht peptidartige Substanz, die die Na, K-A TPase in Reaktion auf einen Anstieg des extrazellulären Volumens hemmt. Dies Hormon wirkt auf die Zellen der Nierentubuli, indem es die Natriumresorption reduziert und auf Höhe der Arteriolen den peripheren Widerstand durch Erhöhung des Tonus der glatten Muskulatur erhöht. Der Herzvorhof von Säugetieren enthält verschiedene Vorstufen von biologisch-aktiven Peptiden mit potenten natriuretischen und diuretischen Effekten. Sie werden als Reaktion auf eine Volumenüberladung und Dehnung des Vorhofs freigesetzt. Wenn auch einige Daten eine wichtige Rolle für diese natriuretische Substanzen bei der Kontrolle des Flüssigkeitsvolumens und Blutdrucks vermuten lassen, sollte ihre Bedeutung in der Physiologie und abnormen klinischen Zuständen in den nächsten paar Jahren definitiv geklärt werden.ResumenLos estudios interpoblación confirman la relación causal entre consumo de sodio e hipertensión arterial. Aunque esta asociación ha sido negada por otros estudios intrapoblación, la cor-relación entre sodio e hipertensión parece estar determinada genéticamente al haber individuos sodiosensibles y sodiorresistentes.El sodio es esencial para el mantenimiento del equilibrio del volumen extracelular y el plasmatico, controlado metabólicamente por la interaccion de varios sistemas biológicos, tales como el de renina-angiotensina-aldosterona, el sistema nervioso simpâtico y los sistemas calicreína-cinina y prostaglandina. Así pues, el sodio desempeña una función bien definida en el mecanismo fisiopatológico de las formas de hipertensión arterial, en su mayor parte dependientes del volumen.Recientemente se han identificado diferentes sustancias estructurales con efectos natriuréticos. La hormona natriurética es una sustancia no peptídica que inhibe la Na, K-A TPasa en respuesta al aumento de volumen extracelular. Esta hormona actúa sobre las células tubulares rénales reduciendo la reabsorción de sodio y elevando la resistencia periférica en las asteriolas por aumento de la tension del músculo liso. Las aurículas de mamífero contienen diversos precursores de péptidos biológicamente activos con potentes efectos natriuréticos y diuréticos, que se liberan en respuesta a la carga de volumen y a la dilatación auricular. Aunque algunos datos parecen confirmar la importancia de estas sustancias natriuréticas en el control del volumen líquido y de la presión arterial, su función en fisiología y en los estados clínicos anómalos debera determinarse con mayor precisión en el futuro.ResumoEstudos interpopulacionais sustentam a hipótese de que o consumo de sódio tem relação causal com a hipertensão arterial. Entretanto, embora os estudos intrapopulacionais tenham contradito uma tal associação, a correlação entre o sódio e hipertensão parece ser genéticamente determinada, uma vez que há indivíduos sensíveis e indivíduos resistentes ao sódio.O sódio é essencial para a manutenção do equiliíbrio do volume plasmático e extracelular. Ele é controlado metabolicamente pela interação de diversos sistemas biológicos, tais como o sistema renina-angiotensina-aldosterona, o sistema nervoso simpático e os sistemas calicreínaquinina e prostaglandina. Assim sendo, o sódio tem papel definido no mecanismo implicado na fisiopatologia das formas de hipertensão arterial predominantemente dependentes do volume.Recentemente, identificou-se diversas substâncias estruturais com efeitos natriuréticos. O hormônio natriurético é uma substância não-peptídica que inibe a Na-K-A TPase como reação a um aumento do volume extracelular. Este hormônio a tua nas células tubulares renais, reduzindo a reabsorção do sódio, e, num nível arteriolar, elevando a resistência periférica por meio de um aumento da tensão de músculo liso. Os átrios de mamíferos contêm diversos precursores de peptídeos biologicamente ativos, dotados de poderosos efeitos natriuréticos e diuréticos. Eles são liberados em reação ao aumento do volume e ao estiramento dos átrios. Embora alguns dados surgiram que estas substâncias natriuréticas tenham um papel importante no controle do volume de fluido e da pressão sanguínea, o seu desempenho nafisiologia e nos estados clínicos anormals deveria ser esclarecido de forma mais definida nos próximos anos.RiassuntoGli studi tra popolazioni confermano l’ipotesi di un rapporto causale ira consumo di sodio e ipertensione arteriosa. Tuttavia, sebbene questo rapporto sia stato smentito da studi intrapopolazione, la correlazione tra sodio e ipertensione appare geneticamente determinata, poichè vi sono sia individui sodio—sensibili che sodio-resistenti. Il sodio è essenziale per il mantenimento dell’equilibrio del volume plasmatico ed extracellulare. È controllato metabolicamente dall’inter azione di diversi sistemi biologici, come il sistema renina—angiotensina—aldosterone, il sistema nervoso simpatico e i sistemi callicreina—chinina e prostaglandinico. Pertanto il sodio ha un ruolo preciso nei meccanismi fisiopatologici delle forme di ipertensione arteriosa di tipo prevalentemente volume—dipendente. Recentemente sono state identificate differenti sostanze con effetti natriuretici. Vormone natriuretico è una sostanza non peptidica che inibisce la Na, K—ATPasi in risposta ad aumenti del volume extracellulare. Questo ormone agisce sulle cellule dei tubuli renali riducendo il riassorbimento di sodio e a livello arteriolare aumentando la tensione della muscolatura liscia. Gli atri dei mammiferi contengono vari precursori di peptidi biologicamente attivi, co

Hypoadiponectinemia is associated with prehypertension in obese individuals of multiethnic origin.

Considering that prehypertension is associated with an increase in cardiovascular risk, hypoadiponectinemia seems to be a predictor of hypertension.

Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH) Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH), endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide) were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD) and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity.