Obese Hypertensive Individuals Research Articles

Relation of obesity to circulating B-type natriuretic peptide concentrations in blacks: the Jackson Heart Study.

Lower plasma B-type natriuretic peptide (BNP) concentrations in obese individuals ("natriuretic handicap") may play a role in the pathogenesis of obesity-related hypertension. Whether this phenomenon may contribute to hypertension in blacks is unknown. We tested the hypothesis that body mass index is inversely related to BNP concentrations in blacks. We examined the relation of plasma BNP to body mass index in 3742 Jackson Heart Study participants (mean age, 55 ± 13; 62% women) without heart failure using multivariable linear and logistic regression, adjusting for clinical and echocardiographic covariates. The multivariable-adjusted mean BNP was higher for lean participants compared with obese participants in both normotensive (P<0.0001) and hypertensive (P<0.0012) groups. In sex-specific analyses, the adjusted mean BNP was higher in lean hypertensive individuals compared with obese hypertensive individuals for both men (20.5 versus 10.9 pg/mL, respectively; P=0.0009) and women (20.0 versus 13.8 pg/mL; P=0.011). The differences between lean and obese participants were more pronounced in normotensive participants (men, 9.0 versus 4.4 pg/mL; P<0.0001; women, 12.8 versus 8.4 pg/mL; P=0.0005). For both hypertensive and normotensive individuals in the pooled sample, multivariable-adjusted BNP was significantly related to both continuous body mass index (P<0.05 and P<0.0001, respectively) and categorical body mass index (P for trend <0.006 and <0.0001, respectively). Our cross-sectional study of a large community-based sample of blacks demonstrates that higher body mass index is associated with lower circulating BNP concentrations, thereby extending the concept of a natriuretic handicap in obese individuals observed in non-Hispanic whites to this high-risk population.

Sex differences in obesity-related changes in left ventricular morphology: the Strong Heart Study

It is unclear whether there are sex differences in the relations of left ventricular mass to body composition and fat distribution in nonobese or obese hypertensive and nonhypertensive individuals and whether the obesity-related increase in left ventricular mass is similar in men and women. We examined sex differences in the relations between left ventricular mass and both body composition and fat distribution, in the presence or absence of obesity in 1068 men and 1851 women (65%) of the Strong Heart Study cohort, without prevalent cardiovascular disease or severe chronic kidney disease. Fat-free mass (FFM) and adipose mass were estimated by bioelectric impedance analysis and fat distribution by waist-to-hip ratio (WHR). Adipose mass was significantly higher in women than in men for any weight category (P < 0.0001). After adjusting for age, hypertension, systolic blood pressure (BP) and diabetes, both left ventricular mass/height (LVMi) and left ventricular mass (LVM)/FFM were greater in obese women than obese men (P < 0.0001). Relative wall thickness was also greater in women than in men (P < 0.0001). LVM was independently related to Doppler-stroke volume, FFM and systolic BP in both sexes, with WHR and adipose mass contributing to variance of LVM in women but not in men (both P < 0.03). Obesity influences left ventricular geometry substantially more in women than in men, possibly due to biological factors specifically associated with female adiposity.

Angiotensin receptor blocker/diuretic combination preserves insulin responses in obese hypertensives.

Thiazide diuretics can impair glucose metabolism and increase new-onset diabetes. Adding an angiotensin receptor blocker to diuretics may protect against these metabolic effects; however, the mechanism of this protection is unclear. To explore potential mechanisms, a 16-week multicenter trial was conducted to ascertain the relative glucose metabolism effects of combined hydrochlorothiazide and angiotensin receptor blocker (valsartan) therapy compared with hydrochlorothiazide and calcium channel blocker (amlodipine) treatment in 412 centrally obese hypertensive individuals (BMI = 35 +/- 7 kg/m, seated BP = 159 +/- 8/94 +/- 8 mmHg, and mean age 56 years). Individuals were randomized to valsartan/hydrochlorothiazide, with force-titration to 320/25 mg or hydrochlorothiazide, with titration to hydrochlorothiazide 25 mg and amlodipine 10 mg, respectively. Changes from baseline to week 16 in fasting and 2-h postprandial glucose and insulin levels after an oral glucose load were measured. At week 16, clinic blood pressure reductions were similar (P > 0.05) in both groups. Fasting and 2-h glucose levels increased (P < 0.05) with the amlodipine combination but not with the valsartan combination. In concert with these glucose responses, postprandial insulin increases from baseline were substantially greater with valsartan than with amlodipine plus hydrochlorothiazide group (P = 0.001). The glucose responses were inversely related to insulin responses at the study conclusion. The novel observation of this investigation was that the combination of valsartan and hydrochlorothiazide was associated with greater glucose-stimulated insulin secretory and lesser glycemic excursion responses than the amlodipine combination group. Thus, this data suggests that adding an angiotensin receptor blocker attenuates the negative effects of thiazides on pancreatic beta-cell glucose-induced insulin secretion.

Epithelial Na+ Channel (ENaC), Hormones, and Hypertension

This minireview examines both the basic science and clinical observations over the past 20 years to show how and why overstimulation of the amiloride-sensitive epithelial Na(+) channel (ENaC) expressed by epithelial principal cells of the renal collecting duct may be responsible for a large portion of hypertension in modern society. This idea is based on the finding that, in Liddle syndrome, a mutation of the beta- and/or gamma-subunits of ENaC produces an activated ion channel, in turn resulting in severe hypertension that is resistant to most forms of conventional antihypertensive therapy. ENaC can also be stimulated to conduct sodium by two hormones: aldosterone and insulin. These hormones are both often elevated in obese individuals with therapy-resistant hypertension. Thus, overstimulation of ENaC by metabolic abnormalities in obese individuals may be a likely cause of the hypertension that accompanies obesity. The molecular mechanisms underlying both Liddle syndrome and obesity-related hypertension are different (i.e. genetic and hormonal, respectively), but both have the same end result, namely increased ENaC activity.

Neutrophil Infiltration and Systemic Vascular Inflammation in Obese Women

Obesity has become epidemic worldwide and is especially pronounced in women of reproductive age, which is important because obesity is a major risk factor for preeclampsia and chronic hypertension. We hypothesized that vascular inflammation is critical to the pathophysiology of hypertension in obese individuals because obesity and hypertensive disorders share common features related to inflammation. To study this, we collected subcutaneous fat biopsies from normal weight, overweight, and obese women and stained the tissues for CD66b, a neutrophil marker, and for activated nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) as markers of inflammation. We found that the number of neutrophils per vessel and the percentage and intensity of vessel staining for CD66b, NF-kappaB and COX-2 were greatest in obese women and least in normal weight women, and that neutrophil infiltration and vascular inflammation significantly correlated with body mass index (BMI) and blood pressure. These data may help explain the relationship between obesity and hypertensive disorders.

Candidate gene microarray analysis in peripheral blood cells for studying hypertension/obesity.

The gene expression of 182 cardiovascular candidate genes was measured in high quality groups of individuals (n = 20) by microarrays to determine whether a subset of genes would discriminate obese and hypertensive individuals, in spite of the existence of a close link between these two cardiovascular risk factors. The results were validated on the 20 subjects used for microarray analysis and on 62 additional individuals by real-time PCR. The first analysis, where patient groups were compared with healthy subjects, revealed 15 out of 182 genes that differed in hypertensive, obese or obesity-related hypertensive individuals. These genes were ALOX5, APOA2, SELL, RGS2, CD14, FPR1, CAMP, DEFA3, DEFA4, CBS, CHRM1, ICAM1, NR1H2, SCNN1B and TGFB1. A second analysis was carried out in which patient groups were compared with each other, demonstrating FPR1 and DEFA3 as being significant genes discriminating patient groups. Furthermore, an analysis stratified by sex revealed that, with the exception of DEFA3, there are no other common genes between men and women. We were able to indentify a number of interesting genes that distinguish patient and healthy subject groups as well as patient groups between them. In addition, it seems that gender plays an important role, at least for some of the genes we tested. These findings may have important implications in the screening and etiology of hypertension or obesity, and could further help to focus on these specific mRNAs as antisense therapy targets.

Secondary Hypertension: Obesity and the Metabolic Syndrome

The epidemic of obesity in the United States and around the world is intensifying in severity and scope and has been implicated as an underlying mechanism in systemic hypertension. Obese hypertensive individuals characteristically exhibit volume congestion, relative elevation in heart rate, and high cardiac output with concomitant activation of the renin-angiotensin-aldosterone system. When the metabolic syndrome is present, insulin resistance and hyperinsulinemia may contribute to hypertension through diverse mechanisms. Blood pressure can be lowered when weight control measures are successful, using, for example, caloric restriction, aerobic exercise, weight loss drugs, or bariatric surgery. A major clinical challenge resides in converting short-term weight reduction into a sustained benefit. Pharmacotherapy for the obese hypertensive patient may require multiple agents, with an optimal regimen consisting of inhibitors of the renin-angiotensin-aldosterone system, thiazide diuretics, beta-blockers, and calcium channel blockers if needed to attain contemporary blood pressure treatment goals.

Abdominal Obesity Is Associated With Potassium Depletion and Changes in Glucose Homeostasis During Diuretic Therapy

The activation of the renin-angiotensin system (RAS) is an important mechanism that contributes to hypertension in obese individuals. Thiazide diuretics also activate the RAS in response to volume contraction and can lead to a decrease in serum potassium values and glucose metabolism abnormalities. To evaluate the impact of abdominal obesity on potassium depletion and glucose homeostasis in hypertensive patients receiving thiazide therapy, the authors studied 329 hypertensive patients without known diabetes or impaired renal function. Patients were stratified into 2 major groups according to whether they used thiazide diuretic therapy, and each group was further divided in 2 subgroups according to the presence of abdominal obesity. The authors demonstrated that obese patients receiving diuretic therapy had lower plasma potassium levels and higher glucose values compared with nonobese patients receiving diuretic therapy. In conclusion, abdominal obesity predisposes to potassium depletion during diuretic therapy in association with effects on glucose homeostasis.

Hypoadiponectinemia is associated with blood pressure increase in obese insulin-resistant individuals

Adiponectin is a major adipocytokine and has been considered as an independent risk factor for arterial hypertension. Most studies on the subject have been restricted to biracial (white-black) and Asian groups. The present report examined whether adiponectin affects blood pressure in a sample of untreated obese Brazilians of multiethnic origin. Fasting plasma adiponectin and serum insulin were determined by radioimmunoassay. Insulin resistance was estimated by homeostatic model assessment of insulin resistance (HOMA-IR). Blood pressure was recorded using Dinamap 1846 (Critikon, Tampa, FL). Adiponectin was significantly lower in obese hypertensive individuals than in obese normotensive ones. Blood pressure, insulin, and HOMA-IR were significantly higher in obese hypertensive than in obese normotensive individuals. Plasma adiponectin was negatively associated with waist-to-hip ratio, blood pressure, insulin, and HOMA-IR. The comparison of obese individuals who markedly differed in their HOMA-IR (> vs ≤2.71) showed that the association of adiponectin and blood pressure remained significant only in obese insulin-resistant individuals, whose adiponectin showed a positive association with high-density lipoprotein cholesterol. Stepwise regression analysis revealed that HOMA-IR, adiponectin, body mass index, and age independently affected the risk for increased systolic blood pressure, with HOMA-IR the strongest of them all. Finally, when patients were stratified into tertiles of HOMA-IR and further classified according to the 50th percentile of adiponectin (≤ vs >6. 5 μg/mL), a 3 × 2 analysis of variance showed an independent contribution of adiponectin in the variation of mean arterial pressure. These results support the notion that HOMA-IR and adiponectin independently predict blood pressure variation in obese insulin-resistant Brazilians.

Adaptation of Vasomotor Function of Human Coronary Arterioles to the Simultaneous Presence of Obesity and Hypertension

We hypothesized that simultaneous presence of obesity and hypertension activates adaptive vascular mechanisms affecting dilations of human coronary arterioles. Agonist-induced dilations were assessed in isolated pressurized coronary arterioles from patients (n=38) who underwent cardiac surgery. Among normotensives we found that dilations to bradykinin (BK) and the NO-donor, sodium-nitroprusside (SNP) were reduced in obese subjects (BK, 10(-7) mol/L, lean: 90+/-4%, obese: 64+/-7%; SNP, 10(-6) mol/L, lean: 89+/-7%, obese: 76+/-5%). However, among hypertensives, both BK- and SNP-induced dilations were significantly enhanced in obese patients, when compared with lean individuals (BK, lean: 71+/-7%, obese: 85+/-3%; SNP, lean: 60+/-6%, obese: 83+/-2%). Correspondingly, in hypertensive patients, but not in those of normotensives, a positive correlation was found between body mass index (BMI) and BK-induced (P=0.036, r=0.46), and also SNP-evoked (P=0.031, r=0.44) coronary dilations. Moreover, in additional 55 hypertensive patients flow-mediated (FMD) and nitroglycerin (NTG)-induced dilations of the brachial artery were assessed. In obese hypertensive individuals, FMD- and NTG-induced dilations were greater (FMD: 6.2+/-0.7%, NTG: 17.2+/-0.9%), than in lean hypertensive patients (FMD: 3.7+/-0.6%, NTG: 13.6+/-1.1%). Correspondingly, FMD- and NTG-induced dilations were positively correlated with BMI (P=0.020, r=0.31 and P=0.033, r=0.29, respectively). These findings are the first to suggest that obesity may lead to activation of adaptive vascular mechanisms to enhance the dilator function of coronary and peripheral arterial vessels in hypertensive patients.

Effect of a High-Fiber Diet vs a Fiber-Supplemented Diet on C-Reactive Protein Level

Diets high in fiber are associated with lower levels of inflammatory markers. This study examined the reduction in inflammation from a diet supplemented with fiber compared with a diet naturally high in fiber. Randomized crossover intervention trial of 2 diets, a high-fiber (30-g/d) Dietary Approaches to Stop Hypertension (DASH) diet or fiber-supplemented diet (30 g/d), after a baseline (regular) diet period of 3 weeks. There were 35 participants (18 lean normotensive and 17 obese hypertensive individuals) aged 18 to 49 years. The study included 28 women and 7 men; 16 (46%) were black, the remainder white. The mean (SD) fiber intake on baseline diets was 11.9 (0.3) g/d; on the high-fiber DASH diet, 27.7 (0.6) g/d; and on the supplemented diet, 26.3 (0.4) g/d. Overall, the mean C-reactive protein (CRP) level changed from 4.4 to 3.8 mg/L (-13.7%; P = .046) in the high-fiber DASH diet group and to 3.6 mg/L (-18.1%) in the fiber-supplemented diet group (P = .03). However, CRP levels decreased in the 18 lean normotensive participants in either intervention diet group (2.0 mg/L [baseline] vs 1.4 mg/L [high-fiber DASH] vs 1.2 mg/L [supplemented]); P<.05) but did not change significantly (7.1 mg/L [baseline] vs 6.2 mg/L [high-fiber DASH] vs 6.5 mg/L [supplemented]; P>.05) in obese hypertensive participants. Neither age nor race influenced the response of CRP levels to the diets. No evidence of a crossover effect was detected. The results demonstrate that fiber intake of about 30 g/d) from a diet naturally rich in fiber or from a supplement can reduce levels of CRP. Further research is needed to more clearly elucidate the differential effect seen in lean vs obese individuals and whether modification of dietary fiber may be helpful in modulating inflammation and its consequent cardiovascular consequences.

From big fat cells to high blood pressure: a pathway to obesity-associated hypertension

The environment created by modern industrialized societies has caused an unprecedented rise in the prevalence of obesity and obesity-related disorders, including hypertension. Mechanisms that underlie the development of hypertension in obese individuals are not very well understood; they are thought to involve activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system, and oxidative stress. Recent research suggests that obesity-associated hypertension may be causally related to the accumulation of 'dysfunctional' adipose tissue characterized by the presence of 'large' lipid-laden adipocytes. Excess energy-intake leads to an expansion of adipose tissue, a hallmark of obesity. But morphology of the expanded adipose tissue differs across individuals, including the size of adipocytes. The presence of 'large' rather than 'small' adipocytes is associated with functional and structural abnormalities of adipose tissue. These include increased production of bioactive molecules, such as leptin, angiotensinogen, pro-inflammatory cytokines, and reactive oxygen species; insufficient capacity to accommodate excess energy-intake leading to ectopic fat storage in tissues and in turn insulin resistance and hyperinsulinemia; and augmented macrophage infiltration enhancing the production of pro-inflammatory cytokines and reactive oxygen species. Such a 'dysfunctional' adipose tissue may, in turn, induce activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system and oxidative stress and, hence, promote the development of obesity-associated hypertension.

Impact of Body Mass Index on Markers of Left Ventricular Thickness and Mass Calculation: Results of a Pilot Analysis

Specific correlations between body mass index (BMI) and left ventricular (LV) thickness have been conflicting. Accordingly, we investigated if a particular correlation exists between BMI and echocardiographic markers of ventricular function. A total of 122 patients, referred for routine transthoracic echocardiography, were included in this prospective pilot study using a 3:1 randomization approach. Patient demographics were obtained using a questionnaire. Group I consisted of 80 obese (BMI was >30 kg/m2), Group II of 16 overweight (BMI between 26 and 29 kg/m2), and Group III of 26 normal BMI (BMI < 25 kg/m2) individuals. No difference was found in left ventricular wall thickness, LV end-systolic cavity dimension, fractional shortening (FS), or pulmonary artery systolic pressure (PASP) among the groups. However, mean LV end-diastolic cavity dimension was greater in Group I (5.0 +/- 0.9 cm) than Group II (4.6 +/- 0.8 cm) or Group III (4.4 +/- 0.9 cm; P < 0.006). LV mass indexed to height(2.7) was also significantly larger in Group I (61 +/- 21) when compared to Group III (48 +/- 19; P < 0.001). Finally, left atrial diameter (4.3 +/- 0.7 cm) was also larger (3.8 +/- 0.6 and 3.6 +/- 0.7, respectively; P < 0.00001). We found no correlation between BMI and LV wall thickness, FS, or PASP despite the high prevalence of diabetes and hypertension in obese individuals. However, obese individuals had an increased LV end-diastolic cavity dimension, LV mass/height(2.7), and left atrial diameter. These findings could represent early markers in the sequence of cardiac events occurring with obesity. A larger prospective study is needed to further define the sequence of cardiac abnormalities occurring with increasing BMI.

Hypertensive therapy: Part I.

If the incidence of hypertension in the population could be reduced through lifestyle modification, much of the morbidity and mortality associated with coronary heart disease, renal disease, and stroke might be prevented.1–3 Randomized, controlled trials have shown that lifestyle modification can lower blood pressure (BP) in both hypertensive and high-risk normotensive (now called prehypertensive ) persons and can prevent hypertension in the latter group. Accordingly, lifestyle modification is recommended for all persons (Table 1), either alone or in conjunction with pharmacological therapy (Table 21–34). View this table: TABLE 1. Lifestyle Modifications to Manage Hypertension *† View this table: TABLE 2. Guidelines for Treatment of Hypertension Based on Compelling Indications for Individual Drug Classes ### Weight Loss and Maintenance of Normal Body Weight Weight loss is the most effective of all nonpharmacological measures to prevent and treat hypertension.35 This effect is independent of sodium restriction and is seen in both obese and nonobese hypertensive individuals. Clinical trial evidence suggests that weight loss interventions produce BP benefits that persist even after cessation of active therapy.3,36 Body mass index (BMI) should be maintained between 18.5 and 24.9 kg/m2. Because sustained weight reduction is extremely difficult to achieve, emphasis should be placed on prevention of weight gain, particularly in younger individuals with prehypertension and in families with a high prevalence of hypertension. ### Increased Physical Activity At least 30 minutes of moderately intense physical activity, such as brisk walking, swimming, bicycling, or yard work, carried out at least 3 times per week (preferably once per day) can lower BP in both normotensive and hypertensive individuals. Studies suggest that such moderate activity may lower systolic BP (SBP) by 4 to 9 mm Hg.37,38 Additional benefits of regular physical activity include weight loss, enhanced sense of well-being, improved functional health status, and reduced risk of cardiovascular disease (CVD) and mortality from all causes. Accordingly, regular aerobic physical activity …

Obesity, sleep apnea, and hypertension.

Obesity has a high and rising prevalence and represents a major public health problem. Obstructive sleep apnea (OSA) is also common, affecting an estimated 15 million Americans, with a prevalence that is probably also rising as a consequence of increasing obesity. Epidemiologic data support a link between obesity and hypertension as well as between OSA and hypertension. For example, untreated OSA predisposes to an increased risk of new hypertension, and treatment of OSA lowers blood pressure, even during the daytime. Possible mechanisms whereby OSA may contribute to hypertension in obese individuals include sympathetic activation, hyperleptinemia, insulin resistance, elevated angiotensin II and aldosterone levels, oxidative and inflammatory stress, endothelial dysfunction, impaired baroreflex function, and perhaps by effects on renal function. The coexistence of OSA and obesity may have more widespread implications for cardiovascular control and dysfunction in obese individuals and may contribute to some of the clustering of abnormalities broadly defined as the metabolic syndrome. From the clinical and therapeutic perspectives, the presence of resistant hypertension and the absence of a nocturnal decrease in blood pressure in obese individuals should prompt the clinician to consider the diagnosis of OSA, especially if clinical symptoms suggestive of OSA (such as poor sleep quality, witnessed apnea, excessive daytime somnolence, and so forth) are also present.

Factors that influence the risk of hypertension in obese individuals.

Obesity, which has reached epidemic prevalence, is now recognized as an independent risk factor for increasing blood pressure. The complex mechanisms of obesity-related hypertension are unclear, but several studies have provided evidence of a hypertensive shift in pressure natriuresis. Excess sympathetic outflow to the kidneys and changes in renal structure and function may both affect the renal pressure relationship. Other factors that may contribute to altered natriuresis include hyperinsulinemia, hyperleptinemia and activation of the renin-angiotensin system. Disruption of the renal alpha2 adrenoceptors or leptin receptor implicated in natriuresis control may also be an additive risk for the increase in tubular reabsorption in obesity hypertension. Recent advances have highlighted the importance of two adipocyte-derived hormones - leptin and angiotensinogen - in obesity hypertension. Leptin has direct central effects that increase sympathetic outflow to the kidney and the new concept of selective leptin resistance, suggests the maintenance of leptin-induced sympathetic activation in obesity, despite resistance to leptin metabolic effects. On the other hand, a recent study showed that angiotensinogen produced in the adipocyte is also relevant to blood pressure control. The article reviews the factors implicated in the disruption of blood pressure control in obesity. Further investigation on the time course of the disease would reveal the relative importance of each of the factors that influence the risk of hypertension in obese individuals.

Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster.

To determine whether raised concentrations of non-esterified fatty acids (NEFAs) may contribute to the cardiovascular risk factor cluster by increasing oxidative stress in vivo. Plasma and urine F2-isoprostanes, biomarkers of oxidative stress, were measured after an overnight fast and during a 4 h infusion of Intralipid and heparin to increase NEFAs in 10 obese hypertensive patients with and 12 healthy normotensive individuals without evidence of insulin resistance. A time-control group of nine healthy normotensive individuals received saline and heparin. Plasma F2-isoprostanes increased more in obese hypertensive individuals than in lean normotensive individuals after 2 h (14.9 +/- 2.8 ng/ml compared with 4.6 +/- 2.8 ng/ml; P < 0.05) but not after 4 h (10.3 +/- 2.5 ng/ml compared with 8.1 +/- 4.1 ng/ml; NS) of the Intralipid and heparin infusion. When obese and lean individuals were combined, plasma (+9.1 +/- 2.5 ng/ml; P < 0.05) and urine (+0.7 +/- 0.3 ng/mg creatinine; P < 0.05) F2-isoprostanes increased by about 20% after 4 h of Intralipid and heparin, whereas plasma F2-isoprostanes decreased by approximately 20% (-9.7 +/- 4.5 ng/ml; P < 0.05) after 4 h of saline and heparin. When individuals from both infusions were combined, the correlation between changes in plasma NEFAs and F2-isoprostanes after 4 h persisted after controlling for changes in triglyceride concentrations (partial r = 0.49; P < 0.01), whereas the correlation between changes in triglycerides and F2-isoprostanes did not persist after controlling for changes in NEFA concentrations (partial r = 0.33, NS). The findings indicate that an acute increase in plasma lipids increases the concentration of F2-isoprostanes, biomarkers of oxidative stress, especially in obese hypertensive individuals. The observations raise the possibility that increased concentrations of NEFAs contribute to the cardiovascular risk factor cluster through oxidative-stress-sensitive mechanisms.

Choice of drug treatment for obesity-related hypertension: where is the evidence?

Hypertension and obesity are common medical conditions independently associated with increased cardiovascular risk. Many large epidemiological studies have demonstrated associations between body mass index and blood pressure, and there is evidence to suggest that obesity is a causal factor in the development of hypertension in obese individuals. Consequently, all hypertension management guidelines consider weight reduction as a first step in the management of increased blood pressure in obese individuals. Weight reduction may be achieved by behaviour modification, diet and exercise, or by the use of anti-obesity medications. However, the long-term outcomes of weight management programmes for obesity are generally poor, and most hypertensive patients will require antihypertensive drug treatment. Some classes of antihypertensive agents may have potentially unwanted effects on some of the metabolic and haemodynamic abnormalities that link obesity and hypertension, yet most hypertension guidelines fail to provide specific advice on the pharmacological management of obese patients. This may be because there are currently no studies examining the efficacy of specific antihypertensive agents in reducing mortality in obese hypertensive patients. This paper reviews the theoretical reasons for the differential use of the major classes of antihypertensive agents in the pharmacological management of obesity-related hypertension and also considers the potential role of anti-obesity agents.

The renin-angiotensin system in obesity hypertension.

JRAAS 2001;2 (suppl 1):S114-S119 Introduction Increased intra-abdominal fat tissue is an important risk factor for hypertension. Development of hypertension in obese individuals is associated with increases in blood volume, heart rate, cardiac output, and cardiac mass. Frequently discussed pathogenic mechanisms involved in the development of ‘obesity hypertension’ include insulin resistance, increased sympathetic nervous system activity, and changes in sodium balance. Obesity-related changes in kidney function include increased renal blood flow and glomerular filtration rate, but also increased tubular sodium reabsorption, leading to a rightward shift of the pressure-natriuresis curve. Intrarenal pressure is significantly increased in obesity, probably by accumulation of intrarenal fat and extracellular matrix. Sympathetic nerve activity to the kidneys is also enhanced in obesity, with renal norepinephrine spill-over being twice that of lean individuals. One of the driving forces for sympathetic stimulation appears to be directly related to the central action of the adipose tissue-derived hormone, leptin. Bilaterally renal-denervated animals do not develop hypertension or sodium retention despite weight gain under a high-fat diet, further illustrating the role of sympathetic renal innervation in obesity-related sodium retention. The humoral control of sodium balance involves both aldosterone and atrial natriuretic peptide (ANP). As discussed below, aldosterone plasma levels are increased in obesity. Furthermore, ANP plasma levels are decreased and the ANP response to a sodium load is significantly blunted in obese subjects. Both findings can potentially contribute to obesity-associated sodium retention. Expression of the ANP clearance receptor (NPrC) gene is increased in human adipose tissue of obese hypertensive subjects, but not obese normotensive subjects. In rats, fasting selectively inhibits adipose tissue NPr-C gene expression and increases circulating ANP levels. These findings suggest that increased expression of the NPr-C receptor gene in adipose tissue may directly influence the systemic availability and thus action of natriuretic peptides in obese individuals. Furthermore, the response to exogenous ANP (blood pressure (BP) reduction and natriuresis) in obese hypertensive individuals is significantly enhanced at the end of a low-calorie diet. Thus, increased expression of NPr-C in adipose tissue may counteract the protective effects of natriuretic peptides and promote the development of obesity hypertension. Furthermore, down-regulation of the adipocyte NPr-C receptor during weight reduction or fasting might explain the natriuresis observed during the initial phase of a hypocaloric diet.

Essential hypertension : part II: treatment.

The goal of antihypertensive treatment is to reduce overall CVD risk and thus its morbidity and mortality rates. In any given patient, the decision to begin treatment is governed by the risk of CVD, which is determined by the magnitude of the BP elevation and the presence or absence of target organ disease and/or additional CVD risk factors. Recent consensus committees, including JNC VI and the World Health Organization–International Society of Hypertension (WHO-ISH) Guidelines Subcommittee, have modified traditional treatment recommendations in several important ways3,35 : (1) Criteria for initiation of treatment now take into consideration total cardiovascular risk rather than BP alone, such that treatment is now recommended for persons whose BP is in the normal range but still bear a heavy burden of CVD risk factors or established CVD. (2) Systolic BP is recognized as an important target for treatment, particularly in older persons, because it is an even more important determinant of CVD risk than diastolic BP. (3) More aggressive BP goals are recommended for hypertensive patients with comorbid conditions such as diabetes mellitus or renal insufficiency. (4) The importance of tailoring the choice of antihypertensive drug treatment to the patient’s individual profile of concomitant CVD risk factors/comorbid conditions is emphasized. (5) The role of simultaneous reduction of multiple CVD risk factors in improving prognosis in hypertensive patients is stressed. (6) Home and ambulatory BP measurement has been recommended because of its value in guiding therapy and enhancing adherence to treatment. (7) Greater reliance on evidence-based medicine (ie, results of randomized controlled trials with CVD outcomes) in making treatment decisions has been endorsed. JNC VI has arrived at an empirical classification that stratifies hypertensive patients into risk groups for therapeutic decisions (Table 4⇓). Risk group A includes patients who do not have clinical CVD, target …