Obesity and hypertension

Endocrinol Metab Clin N Am 32 (2003) 823–854

Obesity and hypertension Fadi El-Atat, MDa, Ashish Aneja, MDb, Samy Mcfarlane, MDc, James Sowers, MDc,* a Division of Cardiovascular Diseases, Department of Medicine, State University of New York–Health Science Center and Veteran Affairs Hospital, 450 Clarkson Avenue, Brooklyn, NY 11201, USA b Department of Medicine, State University of New York–Health Science Center and Veteran Affairs Hospital, 450 Clarkson Avenue, Brooklyn, NY 11201, USA c Division of Endocrinology, Hypertension, and Diabetes, Department of Medicine, State University of New York–Health Science Center and Veteran Affairs Hospital, 450 Clarkson Avenue, Box 1250, Brooklyn, NY 11201, USA

An ‘‘epidemic’’ of obesity is increasingly being recognized in much of the industrialized world, with devastating economic, medical, and surgical health burdens on humanity [1–4]. Obesity, predominantly central-pattern obesity, triggers a plethora of maladaptive cardiovascular, renal, metabolic, prothrombotic, and inflammatory responses, some of which form the cardiometabolic syndrome. These responses, individually and interdependently, lead to a substantial increase in cardiovascular disease (CVD) morbidity and mortality, including hypertension, coronary heart disease, congestive heart failure, sudden cardiac death, stroke, and end-stage renal disease (ESRD) [1–31]. This article concentrates on hypertension as a sequela of obesity or what recently has been referred to as ‘‘obesity hypertension.’’ Epidemiologic studies have revealed a strong relation between obesity and hypertension. Data from the National Health and Nutrition Examination Survey (NHANES; Fig. 1) show a remarkable and linear relationship between rise in body mass index (BMI) and systolic (SBP), diastolic (DBP), and pulse pressures in the US population. In regression models corrected for age-related rise in blood pressure, a gain in BMI of 1.7 kg/m2 for men and 1.25 kg/m2 for women or an increase in waist circumference of 4.5 cm for men and 2.5 cm for women corresponds to an increase in SBP of 1 mm Hg [10]. Obesity alone possibly accounts for 78% and 65% of essential hypertension in men and women, respectively, according to data from the Framingham cohort [1,3,7]. Animal experiments and human studies have confirmed this causation and have provided insight into the mechanisms * Corresponding author. E-mail address: [email protected] (J. Sowers). 0889-8529/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8529(03)00070-7

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Fig. 1. Age-adjusted SBP and DBP from the NHANES II and III by NHANES III quintile of BMI. (Source: Centers for Disease Control and Prevention, National Centers for Health Statistics.)

involved [1,2,7,12,19–28]. Among others, hyperinsulinemia, hyperleptinemia, hypercortisolemia, renal dysfunction, altered vascular structure and function, enhanced sympathetic and renin-angiotensin system activity, and blunted natriuretic peptide activity stand out as major contributory mechanisms to obesity hypertension [1–5,10,12–15]. Epidemiology The prevalence of obesity is increasing rapidly in developing and industrialized countries [1–4]. As many as 61% of Americans were either overweight or obese according to data from the 1999 census, and the total economic costs incurred because of obesity were 117 billion dollars in the year 2000 [1,3–6]. The prevalence of the cardiometabolic syndrome has been estimated at 22%. This prevalence increases with age and varies according to ethnicity. Mexican Americans have the highest age-adjusted prevalence (31.9%) [4]. Among African Americans and Mexican Americans, the prevalence was higher in women than in men (57% and 26% higher prevalence, respectively) [1,3,4,8,9]. Definitions Body mass index Overweight is defined as a BMI greater than 251. Obesity is defined as a BMI more than 30, and morbidly obese people have BMIs greater than 35 [4]. 1

(m2).

BMI is calculated by body weight (kg) divided by height (m2), or weight (kg)/height

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Central obesity The distribution of weight gain is important. A predominantly central pattern of weight gain as measured by a waist-to-hip ratio (WHR) is considered more ominous from cardiovascular and glycemic standpoints insofar as it confers a far higher risk than is dictated by BMI measurements alone. Central obesity is often referred to as abdominal obesity, or upper body, male-type, android, and visceral obesity, versus female-type, or gynoid, obesity with preferential fat accumulation in the gluteal and femoral distribution [1,3,4,11]. Abdominal obesity is diagnosed clinically by a WHR that is greater than 0.95 in men and greater than 0.85 in women. Although clinical measures are considered acceptable in the diagnosis of true central obesity, better imaging techniques may be required for accurate description. Metabolic syndrome A constellation of findings, variously referred to as the ‘‘cardiometabolic syndrome,’’ ‘‘deadly quartet,’’ ‘‘insulin resistance syndrome,’’ and ‘‘syndrome X,’’ is now an established and strong risk factor for premature and severe CVD. The metabolic syndrome is defined by guidelines from the National Cholesterol Education Program Adult Treatment Panel III (ATP III). These guidelines suggest that the clinical identification of the metabolic syndrome be based on the presence of any three of the following: 1. Abdominal obesity, defined as a waist circumference in men greater than 102 cm (40 in) and greater than 88 cm (35 in) in women; the ATP III noted that some men with lesser waist circumference (94–102 cm) may develop insulin resistance because of genetic factors. 2. Triglyceride levels of 150 mg/dL or more (1.7 mmol/L). 3. High-density lipoprotein (HDL) cholesterol levels less than 40 mg/dL (1 mmol/L) in men and less than 50 mg/dL (1.3 mmol/L) in women. 4. Blood pressure levels of 130/85 mm Hg or higher. 5. Fasting glucose levels of 110 mg/dL or greater (6.1 mmol/L). The World Health Organization proposed a different definition for the metabolic syndrome. A diagnosis of the metabolic syndrome required the presence of either hyperinsulinemia or a fasting plasma glucose level of 110 mg/dL or greater (6.1 mmol/L) and an additional two characteristics from the following: 1. Abdominal obesity, defined as a WHR greater than 0.90, a BMI of 30 kg/m2 or greater, or a waist girth of 94 cm or more (37 in). 2. Dyslipidemia, defined as serum triglyceride levels of 150 mg/dL or more (1.7 mmol/L) or HDL cholesterol levels less than 35 mg/dL (0.9 mmol/L). 3. Blood pressure of 140/90 mm Hg or higher or the administration of antihypertensive drugs.

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Alterations in renal function and structure leading to obesity-related hypertension Renal hemodynamic changes A high-fat diet consistently causes increases in sodium reabsorption by the kidneys (Fig. 2). Weight loss causes promotion of urinary sodium excretion (Fig. 3), however, demonstrating the direct link between BMI and sodium retention [32–47]. Obesity is associated with activation of the reninangiotension system (RAS) [1,2,4–6,38], increased sympathetic nervous system (SNS) activity [1–3,10,12,13,34], and hyperinsulinemia [1,3,12], all of which may contribute to sodium reabsorption and associated fluid retention and may therefore contribute to renal obesity hypertension [1–3,5,10,13,19,32–47]. A compensatory lowered renal vascular resistance, elevated kidney plasma flow, increased glomerular filtration rate, and the higher blood pressure associated with obesity are important in overcoming increased sodium reabsorption. Neurohumoral factors like angiotensin II (Ang II), the sympathetic system, and cytokines, whether individually or

Fig. 2. Effects of 5 weeks of a high-fat diet on cumulative sodium balance, sodium reabsorption, and glomerular filtration rate. (Adapted from Hall JE, Brands MW, Dixon WN, Smith MJ Jr. Obesity-induced hypertension: renal function and systemic hemodynamics. Hypertension 1993;22:292–9; with permission.)

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Fig. 3. Steady-state relation between mean arterial pressure and urinary sodium excretion for nonobese adolescents (n = 18), obese adolescents (n = 60), and obese adolescents after weight loss (n = 36). (Adapted from Rocchini AP, Key J, Bordie D, et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989;321:580–5; with permission.)

synergistically, are involved in these compensatory mechanisms. There is an inappropriately small natriuretic response to a saline load and mean arterial pressure (MAP) or intraglomerular pressure, which is often referred to as ‘‘impaired pressure natriuresis’’ (see Fig. 3) [13,19,25,32,42–45]. These adaptive changes increase glomerular wall stress and, especially in the presence of other risk factors such as hyperlipidemia and hyperglycemia, may provoke glomerulosclerosis, proteinuria, microalbuminuria, and loss of nephron function in the ‘‘obese’’ kidney, even before structural microscopic changes are evident. The combination of these potentially nephrotoxic mechanisms, including hyperfiltration and hypertension, may initiate and perpetuate renal damage. Furthermore, the early glomerular hyperfiltration in obesity is often as great as observed in uncontrolled type 1 diabetes. Renal structural changes Altered intrarenal physical forces also are believed to play a role in sodium retention, mainly by slowing down the tubular flow rate [1,3,5,11– 13,35,38,42,46–58]. Observations from obese animals and humans have shown an increase in renal weight attributable to the endothelial cell proliferation, intrarenal lipid, and hyalouronate deposition in the matrix and inner medulla [5,13,42,55–57]. These depositions in the tightly encapsulated kidney lead to distortion of the intrarenal mechanical forces. The interstitial fluid hydrostatic pressure is elevated to 19 mm Hg in obese dogs compared with only 9 to 10 mm Hg in lean dogs. This increase in pressure

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and volume causes parenchymal prolapse and urine outflow obstruction, resulting in slow intrarenal flow and increased reabsorption [59,60]. Of particular importance is the increased sodium reabsorption in the loop of Henle, which leads to a feedback-mediated renal vascular dilation, elevation of glomerular filtration rate (GFR), and stimulation of RAS despite the volume expansion overcoming the increased tubular reabsorption and maintaining sodium balance [13,35]. Persistent glomerular hyperfiltration in combination with glucose intolerance, hyperlipidemia, and hypertension, however, will cause glomerulosclerosis and renal failure. The structural changes occurring in the human kidney as a consequence of obesity have been demonstrated in a large-scale retrospective study, which incorporated 6800 renal biopsies. Obesity was associated with a peculiar obesity-related glomerulopathy, defined as focal segmental glomerulosclerosis associated with enlargement of the glomerulus itself [3,51,53]. The mean BMI in these patients was 41.7. Compared with the idiopathic variety, obesity-associated focal segmental glomerulosclerosis had lower rates of nephrotic syndrome, fewer lesions of segmental sclerosis, and a greater glomerular size. The disease course in this population was dictated largely by the presence of comorbid conditions, such as hypertension and dyslipidemia. A recent study of the German World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease (WHO-MONICA) (study population, in Augsberg, also showed a steady increase in the presence of microalbuminuria, an early marker of renal vascular damage with quintiles of WHR. In this study, the odds ratio for the development of microalbuminuria for individuals with central obesity was not very different from that for patients with hypertension [3,50,52]. Thus, over time, obesity by itself may perpetuate hypertension by these structural damages. The parallel increase in the prevalence of obesity and ESRD (Fig. 4), in addition to the close association between obesity and type 2 diabetes and hypertension, which are the two major risks of ESRD, has led to speculation that obesity may account for at least half of the ESRD in the United States [3]. In summary, persistent obesity causes renal injury and functional nephron loss, contributing to elevated blood pressure, which in turn leads to further renal injury, thereby setting off a vicious circle of events leading to further elevated blood pressure and renal injury. It is difficult to dissociate the ‘‘cause’’ from ‘‘effect’’ in this circle, because the overall burden of obesity may be strongly time dependent (Fig. 5) [3].

Role of sympathetic nervous system, biochemical, neurochemical, and hormonal mediators Sympathetic nervous system Several mechanisms and mediators may cause the genesis of adrenergic overactivity in obese individuals [1–3,5,10,12,14,15,21,25,33,34,61–71].

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Fig. 4. Estimated prevalence of cardiovascular risk factors as assessed by the NHANES I, II, and III incidence of ESRD reported by the US Renal Data Systems surveys.

Notable among these are the following: hyperinsulinemia; renal afferent nerves, which in turn are stimulated by increased intrarenal pressures and subsequent activation of renal mechanoreceptors; plasma free fatty acids (FFAs); Ang II; elevated leptin levels; potentiation of central chemoreceptor sensitivity; and impaired baroreflex sensitivity. There are several reasons to believe that activation of the SNS may contribute to the obesity-hypertension syndrome. Obese subjects have elevated sympathetic activity, measured directly and indirectly [1,33,34,61, 62,64]. An obesogenic diet has been found to increase baseline plasma norepinephrine levels, to amplify the SNS response to stimuli, such as handgrip and upright posture, and to increase catecholamine turnover in peripheral tissues. In addition to elevated renal sympathetic activity, muscle sympathetic activity also has been found to be elevated in obese hypertensive subjects when measured with microneurographic methods [1,65]. Weight loss, however, reduces sympathetic activity, which further supports the aforementioned hypothesis. Pima Indians do not demonstrate a markedly increased sympathetic tone when obese and also do not become hypertensive to the same degree as other groups [1,65]. Also, use of medications that abolish or diminish the central sympathetic drive causes a greater blood pressure reduction in obese compared with lean individuals [1,12,21,25, 67,70]. In dogs fed a high-calorie diet, a combined blockade of a and b receptors lowered blood pressure more significantly in obese versus lean dogs. Clonidine, which blocks central a2 receptors and thereby reduces the central sympathetic drive, markedly blunts hypertension in dogs fed a high-calorie diet. Similar results have been observed in humans. To further support the hypothesis, sympathetic denervation of the kidneys has a significant negative effect on renal sodium retention and thereby on obesity hypertension as shown in Fig. 6 [12,67]. In dogs fed a high-fat diet, renal nerves seem to be important for sodium retention and hypertension

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Fig. 5. Mechanisms responsible for progressive renal failure in obesity hypertension. Structural and functional alterations in the kidneys collaborate, resulting in activation of the SNS and the RAAS, leading to fluid retention. Once ESRD develops, it perpetuates hypertension.

(Fig. 6). In dogs with denervated kidneys, sodium retention was markedly attenuated, thereby leading to a lower blood pressure. It therefore seems that renal nerves play a pivotal role in salt retention, impaired pressure natriuresis, and hypertension. Insulin In the recent past, hyperinsulinemia was considered the key factor governing obesity-induced hypertension. Obese subjects have markedly elevated insulin levels, which are required to maintain glucose and fatty acid metabolism, and are often resistant to the actions of insulin on peripheral tissues [1,3,32,34,72,73]. This resistance to insulin is not universal to all tissues, and some tissues retain their sensitivity to its effects, otherwise referred to as ‘‘selective insulin resistance’’ [13,74]. Studies in the acute setting suggest that insulin may contribute to sodium retention and sympathetic activity and therefore may contribute to hypertension [32,74–79]. On further investigation, however, elevated insulin levels in both the acute and chronic

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Fig. 6. Effects of 5 weeks of a high-fat diet on MAP and cumulative sodium balance in dogs with innervated kidneys (control) and bilaterally denervated kidneys (denervated). (From Kassab S, Kato T, Wilkins C, Chen R, Hall JE, Granger JP. Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension 1995;25:893–7; with permission.)

setting have not been found to have an effect on salt excretion, sympathetic activity, and blood pressure in humans and dogs [1,13,72,80,81]. Furthermore, infusions of insulin in subjects to raise insulin levels to match those found in obese subjects actually lower blood pressure, suggesting a dominant depressor effect for insulin. Even in obese dogs that are resistant to the metabolic effects of insulin, it did not have a pressor effect. A central (central nervous system) infusion of insulin also did not demonstrate a change in blood pressure in dogs [1]. In rats, however, hyperinsulinemia does elevate blood pressure. The underlying mechanisms are believed to be mediated by a complex interaction between insulin, the renin angiotensin aldosterone system (RAAS), and thromboxane (TXA2) activity. This hypothesis was further tested when a blockade of RAAS or TXA2 abolished the blood pressure rise [82,83]. It therefore seems that the initial enthusiasm generated by these rodent studies in hyperinsulinemia may not be extrapolated to humans. Role of cortisol The hypothalamic-pituitary-adrenal axis in obese subjects also may cause sodium retention and hypertension. The abnormalities associated with the metabolic syndrome are similar to that seen in Cushing’s syndrome [12,84].

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In addition, cardiovascular and metabolic consequences of obesity are more ominous in persons with visceral obesity [12,85]. This finding inspired researchers to speculate on the role of hypercortisolemia in the genesis of obesity hypertension. Furthermore, restriction fragment length polymorphism of the glucocorticoid receptor gene leads to abdominal obesity, insulin resistance, and hypertension [12,86]. Free fatty acids High FFA levels are believed to raise blood pressure by increasing sympathetic activity or by enhancing sympathetic vascular responses [1,3, 87,88]. Individuals with visceral obesity deliver an FFA load to the liver, which in turn activates hepatic afferent pathways that may lead to sympathetic activation. Obese individuals’ FFA levels are approximately twofold higher than in lean individuals. Also, an acute rise in FFA levels caused by lipid infusion increases vascular reactivity to a-adrenergic agonists. It may also enhance reflex vasoconstrictor responses in the peripheral circulation. Infusions of oleic acid into the portal or systemic circulation in rats increased their blood pressure and heart rates. These effects were abolished by adrenergic blockade. Portal vein infusion caused a greater blood pressure rise than systemic infusions, however, emphasizing the potential role of afferent pathways in the liver. In humans, high rates of intralipid and heparin infusion caused a small (4 mm Hg) increase in mean blood pressure [1,89]. Long-term effects of FFAs on blood pressure are less clear and warrant further investigation [1,90]. In dogs, infusion of long-chain fatty acids had no effect on blood pressure, in contrast to rats who demonstrated a rise in blood pressure and heart rate. Neither cerebral (by way of the vertebral artery) nor systemic infusion of long-chain fatty acids in dogs has a significant effect on arterial pressure, renal function, or hemodynamic responses. At present, therefore, the relationship between elevated FFA levels and hypertension is tenuous at best and merits further investigation. Leptin Leptin is a 167 amino acid peptide that has been gaining much attention as a mediator of obesity hypertension (Fig. 7) [1–3,5,92–122]. It is secreted by white adipocytes. Leptin levels correlate well with the amount of adipose tissue present in the body [1,3,5,93]. Levels of 5 to 15 lg/mL are noted in lean individuals and are elevated in most obese subjects [5,93]. Leptin crosses the blood-brain barrier to the central nervous system by means of a saturable transport-mediated endocytosis, where it binds to its receptors (Ob-R) in the lateral and medial regions of the hypothalamus [1,3,5]. The Ob-Rb is full-length receptor with a transmembrane domain and a long intracellular carboxyl-terminal tail. The Ob-Ra, Ob-Rc, and Ob-Rd are prematurely terminated receptor proteins with short intracellular tails.

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Fig. 7. A summary of the interactions through which leptin is believed to contribute to hypertension. AGRP, agouti-related peptide; a-MSH, a-melanocyte stimulating hormone; EDRF, endothelium derived relaxing factor; MCH, melanin-concentrating hormone; NPY, neuropeptide Y.

The Ob-Re lacks the transmembrane domain and therefore it may function as a soluble receptor to bind and inactivate the circulating leptin [5]. This binding triggers a series of reactions and neuropeptide pathways, which serve to regulate energy balance by reducing appetite and increasing energy expenditure by means of stimulation of the adrenergic system. Genetic studies in mice and humans have shown that leptin acts as a feedback inhibitor of food intake and regulates body weight. Mice that lack the ability to synthesize leptin (eg,, ob/ob mice) or that have mutations of the leptin receptor (eg, db/db mice) develop extreme obesity [3,121]. Mutations of the leptin gene in humans result in extreme obesity but are very rare and do not contribute significantly to the obesity epidemic [3,121]. The role of minor differences in the production and sensitivity to leptin and its contribution to obesity is less well understood. Women typically have higher leptin levels than do men [3,122], but these differences may not be accountable by fat mass alone. The effect of ethnicity on leptin levels is even less well understood. Blacks may have higher leptin concentrations than whites, even when adjusted for fat volume [3]. Also, differences in sensitivity to leptin levels may differ by gender and ethnicity and needs further study.

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Fig. 8. Effect of bilateral carotid artery infustion of leptin at 0.1 lg/kg/min (5 days) and 1.0 lg/ kg/min (7 days) on MAP, heart rate, and daily food intake in conscious, normal SpragueDawley rats. (Adapted from Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension 1998;31:409–14; with permission.)

Several rodent studies have indicated that intravenous and intracerebroventricular infusion of leptin increases sympathetic activity in kidneys, adrenal glands, and brown adipose tissue after 2 to 3 hours of infusion (Fig. 8) [1,3,95,96]. Leptin infusion in rodents causes mild acute blood pressure elevation, whereas long-term infusions cause a more significant and sustained rise in contrast to FFA administration [1,3,95,96]. Failure of blood pressure to rise significantly in the acute scenario may be explained by a concomitant stimulation of nitric oxide (NO) synthesis, which in turn counteracts its pressor effects [1,98]. An alternative explanation is that leptin’s sympathetic effect on peripheral vasoconstriction is probably not potent enough to produce significant blood pressure elevation, whereas the main leptin pressor effect is by means of the sympathetic system, which causes avid renal salt retention and hence hypertension [1]. The rise in blood pressure with leptin infusion is slow in onset and occurs despite a reduction in food intake that accompanies it that would tend to reduce blood pressure [1]. Moreover, the hypertensive effects of leptin are amplified when NO synthesis is blocked [1,3], as in obese subjects who invariably develop endothelial dysfunction.

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Transgenic mice that overexpress leptin have elevated blood pressure comparable to that produced by leptin infusions [3,91,105]. Importantly, these chronic blood pressure elevations are abolished completely by a- and b-adrenergic blockade [1,3,108,119]. In addition, obese mice that are leptin deficient and obese rats with a leptin receptor mutation usually have no elevation in blood pressures compared with lean control mice. This finding suggests that hyperleptinemia with normally functioning leptin receptors are crucial for leptin-induced hypertension [3]. Another important concept that has gained ground is the presence of selective ‘‘leptin resistance’’ [1,3,5,109]. Obese humans continue to overeat despite elevated circulating leptin levels, which indicates a failure of feedback mechanisms on satiety. Yet, they still develop hypertension, indicating that the effect of leptin on the sympathetic system is intact. Attractive as this hypothesis may sound, it has only been tested in rodents [3,120]. The complexity of the relationship between adiposity, leptin, and long-term blood pressure control is further illustrated by the fact that lower body obesity causes greater increases in leptin than does visceral obesity, even though visceral obesity is more closely associated with hypertension [1]. Role of neuropeptide Y, melanocortin-4 receptors, and other neurochemicals in mediating effects of leptin The negative effect of leptin on the formation of neuropeptide Y (NPY) in the hypothalamus was believed to be the primary mediator causing appetite suppression [1,99]. NPY injections into the thalamus reproduce all features of hypoleptinemia, such as obesity, excessive eating behavior, and decreased brown adipose tissue heat production [1,99]. The ob/ob phenotype in ob/ob mice seems to be mediated, in part, by increased NPY because ob/ob mice in which NPY expression has been knocked out (NPY
/NPY
) are substantially less obese than ob/ob mice with normal NPY expression. Obesity in these mice is severe even in the absence of NPY expression, however, and they respond normally to the satiety effects of leptin, indicating that leptin must also act on other targets to induce satiety. The administration of NPY into the vagal nucleus of the tractus solitarius or the caudal ventrolateral medulla causes a reduction in blood pressure [1,100]. Because hyperleptinemia causes a reduction in brain NPY levels, it is possible that the hypertensive effects of leptin may be mediated by a reduction in the NPY levels. At present, there is little evidence on the putative role of reduced central levels of NPY in mediating the effects of leptin on sympathetic activity and arterial pressure. The proopiomelanocortin (POMC) pathway may interact with leptin to stimulate sympathetic activity and regulate energy balance [1,101,105,123– 129]. In addition, melanocortin-4 receptors (MC4-R) may play an important role in feeding mechanisms [1,2,102]. Although the central administration of MC4-R agonists decreases feeding, deletion of the MC4-R induces obesity

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in rats. The a-melanocyte-stimulating hormone (a-MSH), which is derived from the breakdown of POMC, may be the endogenous ligand for the MC4R. The expression of POMC in the arcuate nucleus may be increased by leptin, and this effect could be part of a feedback pathway for control of appetite and sympathetic activity. Increasing leptin, associated with obesity, would stimulate arcuate POMC expression and a-MSH, which would then act elsewhere in the hypothalamus on MC4-R-expressing neurons, causing decreased food intake and increased sympathetic activity [1,103]. There are other factors that may influence the MC4-R pathway, including the agoutirelated peptide, which acts as an antagonist on this receptor [1,2,102]. Yellow agouti mice, which have ectopic overexpression of the agouti peptide, are obese and hyperleptinemic because of antagonism of the hypothalamic melanocortin system by the excess agouti protein. Treatment of rodents with an MC4-R antagonist completely abolishes the increased renal sympathetic activity associated with short-term intracerebroventricular (ICV) leptin infusion in rats [1,104]. MC4-R blockade does not prevent leptin-induced stimulation of sympathetic activity in brown adipose tissue (BAT), however. This finding suggests that the thermogenic effects of leptin in BAT are not mediated through the MC4-R, whereas the short-term effect of leptin to enhance renal sympathetic activity seems to depend on an intact MC4-R. These paradoxic effects of MC4-R blockade on BAT and renal sympathetic activity also suggest that leptin may activate the sympathetic nervous system through complex central pathways. The orexins and melanin-concentrating hormone, which regulate appetite and energy homeostasis, are mediators that have been discovered recently [1,99]. Short-term experiments involving intracerebroventricular injections of orexins, increased renal sympathetic activity, heart rate, and arterial pressure in rats, and thereby blood pressure [106]. The control mechanisms for orexin release are opposite of those of leptin in that expression of the orexins usually increases with starvation and decreases with increased energy intake [107]. Therefore, orexin levels are reduced in situations in which leptin is increased (eg, obesity) and therefore probably do not mediate the hypertensive effects of leptin. The importance of orexins and other neurochemical pathways in the hypothalamus in modulating the chronic effects of leptin on sympathetic activity, thermogenesis, and arterial pressure are largely unexplored. Role of adipose tissue and systemic renin-angiotensin aldosterone system Systemic renin-angiotensin aldosterone system The RAAS seems to be activated in obesity despite a state of volume expansion and sodium retention. Elevated serum aldosterone levels have been reported in obese individuals [32,131–133], and it is postulated that a yet unidentified factor (possibly a fatty acid) derived from adipose tissue causes the release of a hepatic factor that in turn steps up aldosterone synthesis [133,134]. There are reports that suggest that a relationship between

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Fig. 9. Correlation between plasma angiotensin (AGT) and plasma leptin levels. Correlation between plasma levels of AGT and leptin in young, healthy, normotensive male subjects (n = 81; r = 0.39, P \ 0.01). These data suggest a relationship between fat mass and AGT plasma levels that may be explained by AGT secretion from adipocytes. Plasma AGT was converted to Ang I, which was then measured by radioimmunoassay. (Adapted from Schorr U, Blaschke K, Turan S, Distler A, Sharma AM. Relationship between angiotensinogen, leptin and blood pressure levels in young normotensive men. J Hypertens 1998;16:1475–80; with permission.)

plasma angiotensin (Ang II) levels, plasma renin activity (PRA), and plasma angiotensin-converting enzyme (ACE) with BMI exists in humans [130,132,135–141]. Sharma et al [15] reported a relationship between plasma leptin and angiotensin levels and leptin and PRA (Fig. 9). Because plasma leptin levels correlate with the adipose tissue mass [142], it is fair to speculate that adipose tissue may directly contribute to the circulating angiotensin. Sharma et al [15] also noted that a positive family history of hypertension predicts a relationship between plasma angiotensin and blood pressure, suggesting a role for genetic factors in angiotensin-related blood pressure response. The effect of weight loss on RAAS also has been investigated. On a shortterm scale, Tuck et al [33] studied the effect of weight loss on RAAS and blood pressure in 25 obese patients placed on a 12-week weight-reducing diet; sodium intake was either medium or low. There were significant reductions in PRA, aldosterone, and MAP.The reduction in PRA but not in aldosterone correlated with weight loss in both sodium-intake groups. MAP fell significantly and to the same degree in both groups, correlating with weight loss throughout the study and with PRA from the fourth through twelfth weeks. These results suggest that weight loss is accompanied by reductions in PRA and aldosterone, and that PRA reductions may contribute to the decline in blood pressure.

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Despite evidence in favor of a stimulated RAAS in obesity, the role of genetic factors remains under investigation. In addition, there is little information on the long-term effect weight loss has on the RAAS and largerscale studies are needed to investigate the short-term effect. Renin-angiotensin aldosterone system in adipose tissue It is becoming increasingly evident that adipose tissue possesses a local RAS, which plays an important role in adipose tissue function. Recent studies suggest that adipose tissue angiotensinogen mRNA expression is higher in abdominal than in subcutaneous adipose tissue, and therefore may be associated with increased cardiovascular risk. Fat cells possess the capability to synthesize all components of the RAAS. They apparently also express angiotensin receptors, which makes them a target for the paracrine-produced Ang II [143]. Experiments in angiotensinogen-knockout (AGT-knockout) mice that exhibit low blood pressure, have hypotrophic fat cells with reduced fatty acid synthase activity, and demonstrate abnormal diet-induced weight gain suggest that local Ang II may be a growth factor for fat cells [144]. It has been suggested from studies in these animals that adipose tissue RAS may govern blood pressure. Massiera et al [144] expressed the AGT gene in adipose tissue of AGT-knockout mice, creating a transgenic-knockout mouse model in which production of angiotensin is limited to adipose tissue. In these animals, systemic levels of angiotensin increased to 20% of wild-type levels, demonstrating that angiotensin produced in fat cells can enter the circulation. In addition, blood pressure and sodium homeostasis were restored in the transgenic animals, lending further credence to the theory that an increased fat cell mass may result in higher circulating angiotensin levels, a finding confirmed in obese individuals [15]. There is more evidence supporting the role of adipose tissue in the causation of hypertension. A transgenic mouse that overexpresses the cortisol-forming enzyme 11b-hydroxysteroid-dehydrogenase-1 develops obesity hypertension and all features of the metabolic syndrome [145]. This model also was found to overexpress angiotensin in adipose tissue and had elevated serum angiotensin levels. In addition, obese hypertensive women have been found to overexpress genes encoding renin, ACE, and Ang II type 1 receptor in subcutaneous abdominal fat cells [146]. Although expression of the AGT gene is lower in obese individuals, the high Ang II levels in circulation may be derived of the huge fat cell mass, resulting in hypertension. It also has recently been reported that mutations in the deletion/deletion (D/D) phenotype of the ACE gene may be associated with obesity hypertension in white men. Role of natriuretic peptide system The natriuretic peptide system consists of the atrial natriuretic peptide (ANP), the brain natriuretic peptide, and the C-type natriuretic peptide, each

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encoded by a separate gene [147]. These peptides are synthesized predominantly in the heart, brain, and kidneys. They work by means of specific receptors, namely natriuretic peptide receptor A (NPr-A), NPr-B, and NPrC [148,149]. The natriuretic peptides have salutary effects on plasma volume, renal sodium handling, and blood pressure and cause a reduction in the sympathetic tone in the peripheral vasculature. They dampen baroreceptor function and lower the activation threshold of vagal efferents, thereby suppressing reflex tachycardia and vasoconstriction resulting from decreased extracellular volume. Transgenic mice that overexpress the ANP gene have lower blood pressure, whereas animals with an inactivated ANP gene are prone to develop salt-sensitive hypertension [150,151]. Therefore, the natriuretic peptides have a protective role on the development of hypertension because of their natriuretic and vasodilator effects and because of their inhibitory effect on the SNS and the RAAS. The NPr-C receptor is overexpressed in adipose tissue in obese individuals and may consequently adversely affect the systemic activity and actions of the natriuretic peptides, leading to sodium retention and hypertension. It has been reported that ANP plasma levels were lower in obese hypertensive subjects than in obese normotensive subjects [152]. These obese hypertensive subjects also demonstrated a stronger response to exogenously administered ANP, as measured by blood pressure reduction, natriuresis, and increases in urine cyclic guanosine monophosphate excretion [153]. These effects were pronounced after these subjects had been on a low-calorie diet for a span of time, rather than at baseline. The ANP response to a salt load was found to be suppressed in obese individuals compared with a potent ANP elevation in lean individuals. Concomitantly, PRA and aldosterone also were suppressed in obese individuals when given a saline challenge [71]. Obese rats that were subjected to a 40% weight loss by caloric restriction demonstrated a significant increase in circulating ANP levels and a strong decrease in PRA [154]. A recent study reported an association between a promoter variant at position
55 in the NPr-C gene, a higher blood pressure, and lower ANP plasma levels in obese hypertensive subjects [155]. Further studies are needed to understand the role of this finding and its possible contribution to blood pressure elevation.

Cardiovascular system changes Vascular adaptations An alteration in Ca2þ ions at the cellular and molecular level seems to be important in regulating vascular smooth muscle tone. These may be deregulated in obese individuals, resulting in abnormal vascular responsiveness [156]. Insulin works as a vasodilator by inhibiting voltage-gated Ca2þ influx and also stimulates glucose transport and phosphorylation of glucose to glucose-6-phosphate, which further activates Ca2þ ATPase

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transcription and increases cellular Ca2þ efflux. These actions result in a net decrease in intracellular Ca2þ and, therefore, decreased vascular resistance. These effects are blunted in obesity because of insulin resistance, leading to increased vascular resistance [157]. Resnick et al [158] discovered that increased abdominal visceral fat, decreased intracellular magnesium, and advanced age were closely associated with reduced aortic distensibility. In this study, MRI was used to evaluate the aorta of normal and hypertensive subjects. Jacobs et al [159] studied the effect of weight reduction on peripheral vascular resistance, reflected by forearm vascular resistance and MAP in obese persons. Weight loss resulted in a clearly significant decrease in peripheral vascular resistance and MAP. Cardiac adaptations Obesity is a major cause of type 1 diabetes, hypertension, and hyperlipidemia. These disorders individually and synergistically increase the cardiovascular risk as shown in the Prospective Cardiovascular Munster Study (PROCAM; Fig. 10) [3]. Lean hypertensive individuals tend to have a concentric left ventricular hypertrophy in response to sustained hypertension. The predominant pattern of cardiac hypertrophy noted in obese hypertensive persons is

Fig. 10. Interaction among cardiovascular risk factors in the PROCAM study. The incidence of myocardial infarction is shown in a group of 2574 men with no risk factors, hypertension only, diabetes only, hypertension and diabetes, or hypertension plus diabetes and hyperlipidemia. (Adapted from Assmann G. Schulte H. The Prospective Cardiovascular Munster Study (PROCAM): prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary artery disease. Am Heart J 1988;1116:1713–24; with permission.)

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eccentric, however. With concentric hypertrophy, cardiac dilatation is a late and terminal event [160,161]. Also, heart failure is more common in obese individuals, even if corrected for the presence of hypertension [162]. The presence of both obesity and hypertension in the same patient results in a mixed pattern of cardiac hypertrophy caused by an elevation in both cardiac preload and afterload [163]. Obesity results in increased preload because of an expanded vascular volume and the high afterload can be accounted for by the presence of hypertension and sympathetic system activation [160]. After adjustment for established risk factors, there is an increase in the risk of heart failure of 5% for men and 7% for women for each increment of 1 unit in BMI. Compared with individuals with a normal BMI, obese individuals have twice the risk of heart failure after adjustment for comorbid risk factors. Autopsy data from the Mayo Clinic reveal that the average cardiac mass is 467 g in obese hypertensive individuals, compared with 367 g in obese individuals without heart disease and 272 g in nonobese hypertensive individuals [164]. Because left ventricular hypertrophy by itself is a major risk factor for sudden death and death from progressive cardiac decompensation, it may in part explain the increased incidence of cardiovascular morbidity and mortality in obese individuals [165,166]. The myocardium in obese individuals shows the presence of mononuclear cell infiltration in and around the sinoatrial node, with fat deposition all along the conduction system [167]. Lipomatous hypertrophy of the interatrial septum also has been noted in obesity [167]. All these changes make the myocardium in obese hypertensive individuals an ideal substrate for cardiac arrhythmia and sudden death (Fig. 11) [168].

Proinflammatory and prothrombotic changes Adipose tissue is a source of inflammatory cytokines and hormones Central adipose tissue is currently recognized as a rich milieu and source of inflammatory cytokines, such as tumor necrosis factor a (TNF-a), interleukin 6 (IL-6), and C-reactive protein (CRP), and plasminogen activator inhibitor (PAI-1). As such, obesity has been suggested to be a low-grade inflammatory condition increasingly important in the causation and progression of hypertension and atherosclerosis [3,4,169,170]. It is believed that the central adipocyte synthesizes TNF-a, which in turn stimulates IL-6, considered a major regulator in the production of acute phase reactants, such as CRP, PAI-1, and fibrinogen, from the hepatocyte [4]. It is possible that the relationship between obesity and vascular disease depends, in part, on the increased production and release of these inflammatory mediators from adipose tissue. A direct cause-and-effect relationship, however, has not been clearly established. It is not known, for example, whether long-term treatment with aspirin or other nonsteroidal anti-inflammatory drugs reduces the level of inflammatory cytokines and CVD in obese patients.

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Fig. 11. A summary of the mechanisms by which obesity leads to cardiovascular morbidity and mortality. HF, heart failure; HR, heart rate; LVH, left ventricular hypertrophy; NAP, natriuretic peptide; PVR, peripheral vascular resistance; RAAS, renin-angiotensin aldosterone system; ", increase.

Hypercoagulation and increased risk of thrombosis in obesity Increased risk for thrombosis may contribute to a higher incidence of heart disease and stroke in obesity. Obesity is associated with polycythemia, and there is epidemiologic evidence that hypercoagulation and impaired fibrinolysis activity is related to BMI or WHR. For example, obese subjects have higher levels of factor VII antigen, fibrinogen, plasminogen, and PAI-1 activity, all of which have been suggested to increase the risk for CVD [3,171–173]. The increased flux of FFAs in obesity may promote thrombosis by increasing protein C, PAI-1, or platelet aggregation. Adipose tissue production of leptin or inflammatory mediators also has been suggested as an important factor in causing increased thrombosis [174], but these aspects of the relationship between obesity and CVD are poorly understood and require additional study. Thrifty gene hypothesis Although most scientists see obesity as a disease, and currently as an epidemic, others emphasize the evolutionary aspect of obesity. The pressure of survival and evolution could have caused the natural selection of ‘‘thrifty genes’’ and a propensity for obesity in times of plenty in populations that

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have fought repeated famine and deprivation for ages [175]. Humans worldwide historically never had plentiful and unrestricted access to food until the improved technology of the last half-century. This development coincides with increased incidence and prevalence of obesity, emphasizing the effect of evolutionary processes. The development of fatty tissue is necessary for survival of species that do not have ready and sustained access to food. Animals that live in water have the luxury of surplus and immediately available food and do not need adipose tissue stores. Oysters, for example, merely open their shells and filter the abundance of surrounding nutrients in seawater. Oysters rarely become obese because they live with their food supply, which obviates the need to store energy. In contrast, humans have developed the ability to store fat for periods of food deprivation. Thus, those who defend the ‘‘thrifty gene hypothesis’’ regard obesity as an adaptation mechanism in the survival-of-the-fittest world.

Genetics The fact that all obese people do not develop hypertension underscores the importance of the role that genetic mechanisms may play in the genesis of obesity hypertension [1,3,16–18]. The Pima Indians, for example, have a high burden of obesity but do not have correspondingly high rates of hypertension until diabetic nephropathy develops. African American women also have a lower risk of hypertension for the same degree of weight gain than do white women. In addition, genetics often determines the distribution of excess body fat in populations of different ethnic and racial groups and may thus influence the cardiovascular risk in these populations [4].

Management Physical exercise Increased physical activity is perhaps the most widely quoted, and the most poorly complied with, strategy in weight reduction. It requires considerable time, thought, and effort on the part of both the patient and the therapist. Physical activity is essential for long-term weight control. It is the best predictor of maintenance of weight loss. Furthermore, even in the absence of weight loss, increased physical activity is associated with other desirable outcomes. Studies suggest that, in overweight and obese persons, physical activity is independently associated with the redistribution of adiposity away from the abdomen. It is important not to set inappropriately ambitious physical activity goals, because they increase the likelihood of abandonment of the exercise program. In addition, high levels of aerobic physical activity at a fitness center are not needed to obtain health benefits. Several studies have compared the impact of lifestyle activity versus physical

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exercise and demonstrated that these two types of activity result in similar health benefits, such as control of hypertension and body fat [176,177]. From these and other observations, it is clearly inappropriate to suggest to patients that the only acceptable physical activity included in their weight loss program would be vigorous activity. Some may choose this, but those who don’t should be encouraged to start with low-impact, moderateintensity physical activity (eg, walking) of short duration, with a goal of accumulating 30 minutes of physical activity or more on most days of the week. A recent report suggests that physical activity participation for 60 minutes per day will impart increased benefits and is more likely to help maintain weight loss [178]. Behavioral modification One of the important components of any weight loss program is behavioral modification. Notable is a food log that helps identify patterns of eating and promotes self-monitoring, which are essential in producing any sustained behavioral changes [179]. Other effective behavioral strategies consist of stimulus control, meal planning, and relapse prevention. Stress and time management are other tools essential to a comprehensive weight loss program. Pharmacotherapy Antihypertensive drug treatment in obesity hypertension is not yet based on evidence from randomized controlled trials, and the treatment of obesity hypertension remains empiric [147]. No definitive guidelines exist for the management of this constellation of syndromes, and therefore only suggestions can be made based on assumed pathophysiologic mechanisms. For example, because b-blockers can potentially result in weight gain and impaired glucose tolerance, their use in uncomplicated obesity and hypertension cannot be recommended unless patients suffer from an acute coronary syndrome or their hypertension is uncontrolled in combination with multiple other agents [50,180]. The importance of adrenergic blockade in the management of this syndrome cannot be dismissed, however [181]. Masuo et al [66] recently showed that subjects who were resistant to weight lossinduced blood pressure reductions possessed a highly active SNS and would potentially benefit from adrenergic blockade. The efficacy of calcium blockers in the obese hypertensive population has been called into question based on some small-scale studies. No definitive recommendations can be made until data from large-scale randomized controlled trials become available on the subject [71,182,183]. ACE inhibitors and angiotensin-receptor blockers may be considered preferred agents for several reasons. First, they are metabolically neutral, except for the risk of hyperkalemia, which can be managed effectively with careful monitoring. Second, there is evidence from the Heart Outcomes

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Prevention Evaluation (HOPE) and Captopril Prevention Project (CAPPP) trials that ACE inhibitors can prevent or retard the development of type 2 diabetes mellitus. Third, this class of agents may be the most effective in preventing proteinuria and may retard the progression of obesity hypertension-related ESRD. Finally, this class of agents may prevent cardiac hypertrophy and progression to heart failure. Low-dose ACE inhibitors may be more effective than thiazides [184–186]. It may therefore be reasonable to recommend ACE inhibitors as first-line therapy for obesity-related hypertension. Thiazide diuretics may also be an effective class of agents for this group of patients, because they address the volume-expanded state of the obesityhypertension syndrome directly and may prevent cardiac dilatation by preload reduction. Caution must be exercised with their use in this class of patients, namely because of the risk of exacerbating dysglycemia and erectile dysfunction, which are quite prevalent in these patients. In addition, excessive diuresis may result in a state of volume contraction, triggering the activation of the SNS and the RAAS, and may result in avid renal salt and fluid retention, with exacerbation of hypertension. A combination of ACE inhibitors and low-dose thiazides may be more effective than either strategy alone in this population. There is little evidence to support these hypotheses, however. Weight loss, achieved by exercise, behavioral modification, pharmaceutic agents, or a combination of these, is the most important and effective means of reversing insulin resistance, elevated leptin levels, decreased cardiac output, and an activated SNS [93,152,157]. Despite significant initial success, however, long-term and sustained weight loss is difficult to achieve with diet and exercise alone [187]. Some recently developed pharmaceutic agents, such as orlistat and sibutramine, have shown promise in achieving significant and sustained weight loss in the range of 5% to 10%. In a recent meta-analysis that pooled data from trials using orlistat (30% of participating subjects were hypertensive), significant blood pressure reductions were noted after 1 year in subjects who lost 5% or more of their weight. The blood pressure reductions were 7 mm Hg (SBP) and 5.5 mm Hg (DBP), comparable to those achieved with antihypertensive drugs used as single agents [188]. Other cardiovascular risk factors also improved significantly in subjects who took orlistat for more than 2 years [189]. Because orlistat has no negative effect on the cardiovascular risk profile, it can be safely recommended for treating obese patients with hypertension. Another antiobesity medication, sibutramine, acts by inhibition of serotonin and norepinephrine uptake. In doing so, it enhances satiety and increases energy use [190]. A recent trial with sibutramine called the Sibutramine in Obesity Reduction and Management, or STORM, trial revealed significant and sustained weight loss comparable to that achieved with orlistat. An improvement in metabolic parameters, such as blood glucose and lipid levels, was also noted [191]. Small increases in blood

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pressure and heart rate also were noted, however, and no net blood pressure reductions could be achieved commensurate with the degree of weight loss. In another trial with sibutramine, those individuals who maintained their weight loss at 1 year had no significant changes in blood pressure and heart rate when compared with baseline parameters [192]. Therefore, sibutramine cannot be recommended for hypertensive obese patients and, if it has to be used, careful blood pressure monitoring is warranted, with use of effective antihypertensive medications. Role of surgery There is evidence from trials, such as the Swedish Obese Subjects study, that weight-reduction surgery in morbidly obese individuals who have significant comorbidities can result in improvements in metabolic parameters and also blood pressure. Surgery is an option in patients in whom all conservative measures, including pharmaceutic agents, have failed and in those who cannot tolerate drugs because of their prohibitive side-effects. There is considerable risk associated with these surgeries, and they cannot be routinely recommended [193–197]. Summary This article has discussed some of the mechanisms involved in the causal relation between obesity and hypertension. Obesity causes a constellation of maladaptive disorders that individually and synergistically contribute to hypertension, among other cardiovascular morbidities. Well-designed population-based studies are needed to assess the individual contribution of each of these disorders to the development of hypertension. In addition, because the control of obesity may eliminate 48% of the hypertension in whites and 28% in blacks, this article has offered an up-to-date on the management of this problem. It is hoped that this article will help scientists formulate a thorough understanding of obesity hypertension and form the basis for more research in this field, which has a huge impact on human life. References [1] Hall JE, Hildebrandt DA, Kuo J. Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens 2001;14:103S–15S. [2] Mark AL, Correia M, Morgan DA, et al. State-of-the-art-lecture: obesity-induced hypertension: new concepts from the emerging biology of obesity. Hypertension 1999;3:537–41. [3] Hall JE, Crook ED, Jones DW, et al. Mechanisms of obesity-associated cardiovascular and renal disease. Am J Med Sci 2002;324:127–37. [4] Castro JP, El-Atat FA, McFarlane SI, et al. Cardiometabolic syndome: pathophysiology and treatment. Curr Hypertens Rep 2003;5:393–401. [5] Zhang R, Reisin E. Obesity-hypertension: the effects on cardiovascular and renal systems. Am J Hypertens 2000;13:1308–14.

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