Current Hypertension Reviews - Volume 6, Issue 2, 2010

Obesity, hypertension, obesity-related hypertension, metabolic syndrome and type 2 diabetes have increased dramatically in prevalence and now pose a significant burden on health and health budgets. Indeed, several large cohort longitudinal studies such as the National Health and Nutrition Examination Survey (NHANES), the Behavioural Risk Factor Surveillance System (BRFSS) have found that obesity, diabetes and hypertension have increased in the United States in the past decade, and have demonstrated very close associations between the prevalence of obesity and the incidence of hypertension and diabetes. In addition, obesity, hypertension and diabetes mellitus are stated as risk factors for cardiovascular events. For example, the Framingham Heart study demonstrated higher cardiovascular and all-cause mortality in diabetic subjects compared to nondiabetic patients. Furthermore, the National Heart Foundation Risk Factor Prevalence Survey in Australia showed that central obesity plus smoking could predict future coronary heart disease and cardiovascular disease death. It is widely recognized that heightened sympathetic nerve activity, insulin resistance (or hyperinsulinemia), stimulated renin-angiotensin- aldosterone system (RAAS), adiponectin and leptin in some way relate to obesity, hypertension, and metabolic syndrome. Indeed, many investigators have indicated that insulin resistance may play a major role in obesity, hypertension, and obesity-related hypertension. On the other hand, some investigators have reported that heightened sympathetic nerve activity may be a prime mover for obesity, hypertension, obesity-related hypertension, and insulin resistance (metabolic syndrome). Furthermore, there are a number of studies that have examined the relationships between RAAS and insulin resistance in obesity, hypertension and diabetes. Most investigations, however, emphasize the close linkage between insulin resistance, heightened sympathetic nerve activity and stimulated RAAS. Further, recent investigations demonstrated that adiponectin and leptin play important roles in the pathogenesis and development of obesity, hypertension, and metabolic syndrome. However, the precise relationships between heightened sympathetic nerve activity, stimulated RAAS, insulin resistance and other hormonal mechanisms in obesity, hypertension and metabolic syndrome remain uncertain. With the development of tools to examine genetic polymorphisms, studies have demonstrated that genetic polymorphisms of the β2- and β3-adrenoceptor gene have also been associated with insulin resistance, obesity, hypertension, and diabetes in many epidemiological studies. Thus, the genetic polymorphism might be another factor responsible for the close relationships between insulin resistance and heightened sympathetic nerve activity. Similarly, angiotensin-converting enzyme (ACE) polymorphisms, angiotensin II type 1 and type 2 receptors polymorphisms, and leptin receptor polymorphisms are closely related to obesity, hypertension and diabetes. These genetic investigations also support the close interactions between these conditions and sympathetic nervous system, the RAAS, and leptin. The purpose of this special issue is to provide a synthesis of the current findings on obesity, hypertension and the metabolic syndrome with a special focus on the mechanisms of onset. A better understanding of the relationships of genetic background with sympathetic nervous system activity, insulin resistance and RAAS to the cause of obesity-rerlated illness may assist in the management of obesity-related illness. Further, clarification of the pathogenesis and mechanisms of obesity-related illness may lead to the prevention of obesity and result in the reduction of cardiovascular risks. Each chapter in this issue was written by one of the experts in the area. The editor hopes that this issue will help obese patients suffering from hypertension and diabetes to prevent their more serious cardiovascular risk and help medical practitioners who are treating those patients, and finally prevent the global health issue.

Overweight and obesity is a growing “world-wide epidemic problem” as many as, because two-thirds of the adult population and a growing number of children are overweight. The prevalence of diabetes mellitus, especially type 2 diabetes mellitus, metabolic syndrome and hypertension are significantly increased with the prevalence of obesity. Many patients are both diabetic and hypertensive as well as being obese. Obesity, hypertension and diabetes are involved in the six leading causes of death in the United States. Obesity, hypertension, and diabetes (metabolic syndrome) are high risk factors for subsequent cardiovascular and renal complications. Sympathetic nervous activation and insulin resistance frequently observed in obesity may play major roles in cardiovascular and renal complications in patients with hypertension, diabetes, and obesity. The purpose of this article is to provide a synthesis of the current findings from epidemiological surveys on the relationships of obesity, hypertension and diabetes mellitus and the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, hypertension, diabetes mellitus and metabolic syndrome. A better understanding of the close linkage of obesity with hypertension and diabetes may help with the clinical treatment of obesity, and may lead to reductions in cardiovascular and renal risk.

Obesity, hypertension, obesity-related hypertension and the metabolic syndrome are growing health problems. Importantly, while frequently associated, not all obese subjects have hypertension. It is widely recognized that heightened sympathetic nerve activity and insulin resistance (or hyperinsulinemia) relate to obesity, hypertension and the metabolic syndrome. However, the precise relationships between heightened sympathetic nerve activity and insulin resistance in obesity and hypertension remain uncertain. Many investigators have indicated that insulin resistance may play a major role in obesity, hypertension, and obesity-related hypertension, and heightened sympathetic nerve activity accompanies insulin resistance. On the other hand, some investigators have reported in a series of longitudinal studies that heightened sympathetic nerve activity may be a prime mover for obesity, hypertension, and obesity-related hypertension, and insulin resistance may play an ancillary role. Blunted sympathetic nerve responses to insulin stimulation was observed during oral glucose loading only in insulin resistant subjects, obese subjects or hypertensive subjects, suggesting that the relationships between insulin resistance and sympathetic nerve activity might be different due to the stage of obesity, hypertension, or severity of insulin resistance. Both hypotheses emphasize the close linkage between insulin resistance and heightened sympathetic nerve activity; however, which is the prime mover for obesity or hypertension remains unknown. The purpose of this review is to provide the current findings on the relationships between sympathetic nerve activity and insulin resistance in obesity, hypertension, and the metabolic syndrome.

Obesity, hypertension and obesity-related hypertension are growing health problems. Hypertension is an important risk factor for cardiovascular disease (CVD), particularly in patients with obesity, diabetes, and metabolic disease. Obese subjects are frequently associated with hypertension, diabetes mellitus, metabolic disease, and end-organ damage (i.e. end-stage renal damage). An integrated cardiovascular risk management approach is being adopted: aggressive blood pressure (BP) control is important in patients with high CVD risk, and well-tolerated antihypertensive agents with protective benefits beyond BP lowering are advantageous. The identification and management of these CVD risk factors is an important part of the overall management of hypertensive patients. Because patients in these special populations such as subjects with obesity or metabolic syndrome are more predisposed to target organ damage, stringent targets for blood pressure control have been set in clinical guidelines, however clinical trial and real-life evidence suggest that these targets are difficult to achieve. The first line of treatment of obesity and metabolic syndrome associated with obesity are weight loss with a lifestyle modification such as low caloric diet and exercise (see the previous chapter) or gastric band/gastric bypass surgery or bariatric surgery. Recently, anti-obesity drugs (Orlistat, Sibutramine) have been developed, but the precise effects on blood pressure and neurohormonal parameters have not been fully clarified. In addition, leptin administration (pegylated recombinant leptin; PEG-OB) as theoretical treatment for obesity has been examined in overweight or obese human and in animal models. Central leptin gene therapy was also examined in animal models. However, the anti-obesity effects of leptin administration were controversial. Recently, many clinical and epidemiological studies have shown that angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) are highly efficacious, persistent, well-tolerated antihypertensive agents, with additional benefits in obesity-related hypertension, cardiovascular pathogenesis, end-organ damage, and in metabolic syndrome. For example, the Irbesartan/HCTZ combination therapy Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial has shown comparable antihypertensive efficacy and tolerability regardless of BMI or diabetes status. Another observation is emerging that Telmisartan, in addition to blocking the angiotensin II type 1 receptor, activates the peroxisome proliferator-activated receptor (PPAR)-gamma, a well-known target for treatment of the metabolic syndrome and diabetes. This clinical evidence perhaps argues against this, with the The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) showing no benefit for Telmisartan compared with Ramipril, in prevention of new diabetes development. Another antihypertensive drug class with favourable properties are the centrally acting Imidazolin, Moxonidine, and Rilmenidine, which inhibit sympathetic overflow from the brain. Obesity-related hypertension has sympathetic nervous system activation as the primary pathophysiology, cruicial in the pathogenesis of the blood pressure elevation. The purpose of this article is to provide the current findings on pharmacological antihypertensive treatments in obesity, obesity-related hypertension and metabolic syndrome, including anti-obesity pharmacological treatments.

Several recent clinical trials show that blocking agents of the renin-angiotensin-aldosterone system (RAAS) reduce cardiovascular events in patients with metabolic syndrome based on insulin resistance and obesity, especially accumulated visceral fat. Our laboratory has focused on the relationship between the vascular RAAS and the action of insulin on the vasculature. We first revealed that the addition of insulin to cultured vascular smooth muscle cells (VSMC) markedly increases angiotensinogen and angiotensin II (Ang II) expression and production. Insulin addition also induces VSMC growth that is inhibited by the blockade of the RAAS by either ACEI or ARB which suggests a role for the RAAS in insulin-mediated growth. Insulin has a quite different effect on cultured vascular endothelial cells (EC) as it reduces angiotensinogen and renin expression. However, insulin added to EC induces a marked activation of ACE and the activated ACE promotes the conversion of Ang I to Ang II and cell growth under conditions of high insulin concentration. Ang II induces the progression of atherosclerosis through the production of oxidative stress that blocks insulin signaling and accelerates atherosclerosis. In this paper, we attempt to clarify the relationship between insulin resistance, the RAAS, and oxidative stress in vascular tissues to mimic in vivo conditions found in patients with metabolic syndrome and obesity-related hypertension.

Obesity increases cardiovascular morbidity and mortality in part by inducing hypertension. One factor linking excess fat mass to cardiovascular diseases may be the sympathetic cardiovascular actions of leptin. Initial studies of leptin showed it regulates appetite and enhances energy expenditure by activating sympathetic nerve activity (SNA) to thermogenic brown adipose tissue. Further study, however, demonstrated leptin also causes sympathetic excitation to the kidney that, in turn, increases arterial pressure. In animal studies, elevating circulating leptin levels increased arterial pressure. Moreover, mice with diet-induced obesity have a preserved arterial pressure response to leptin despite the resistance to the metabolic action of leptin and these mice have elevated baseline arterial pressure. Conversely, severely obese, but leptin-deficient, mice and humans display low sympathetic tone and decreased blood pressure. Together, these findings demonstrate that leptin plays a physiological role in maintaining sympathetic tone and blood pressure, and further suggest that hyperleptinemia may contribute to the elevated blood pressure associated with obesity. Consistent with this selectivity in leptin resistance, mounting evidence suggests that the sympathetic nervous system subserving different tissues is differentially controlled by leptin. For instance, different molecular signaling mechanisms are engaged by the leptin receptor to control the regional sympathetic nerve activity. Understanding the mechanisms by which leptin controls the sympathetic nervous system will provide insight into the cardiovascular complications of obesity.

Visceral fat accumulation has been shown to play crucial roles in the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia, and hypertension, and the so-called metabolic syndrome. Obese patients, particularly those with visceral fat accumulation, have reduced plasma levels of adiponectin, the most abundant and adipose-specific adipocytokine. A series of clinical and experimental studies has reported a link between adiponectin and obesity, the metabolic syndrome, and hypertension. Adiponectin has been recognized as a key molecule in obesity as well as in the metabolic syndrome, and a potentially promising target for the prevention and treatment of the metabolic syndrome and other diseases. This mediator may represent a novel target for the prevention and treatment of visceral obesity, the metabolic syndrome, and hypertension. This review focuses on the roles of adiponectin in the development of these diseases.

Obesity, hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension and diabetes mellitus. Human obesity, hypertension and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the β-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to obesity. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, obesity, hypertension and metabolic syndrome have not been fully clarified. A few studies regarding the relationships between sympathetic nervous activity and adrenoceptor polymorphisms in the same studies have been reported. Masuo et al. have observed in a series of studies in a Japanese male cohort that: 1) β2-adrenoceptor polymorphisms are associated with heightened sympathetic nerve activity, and predict the future onset of obesity and hypertension in nonobese individuals, 2) β2-adrenoceptor polymorphisms accompanied by heightened sympathetic nerve activity and abdominal obesity, predict weight loss resistance during a weight loss program, and also predict rebound weight gain, 3) β2-adrenoceptor polymorphisms are linked to blunted leptin-mediated sympathetic nerve activation, leptin-resistance and resultant obesity, 4) β2-adrenoceptor polymorphisms are related to insulin-resistance, in both nonobese and obese normotensive individuals, and 5) β3-adrenoceptor polymorphism is directly linked to obesity and hypertension, but only in obese individuals. These suggest that β2- and β3-adrenoceptor polymorphisms accompanying heightened sympathetic nerve activity play a major role in the onset and the maintenance of obesity, hypertension and insulin resistance. This article provides the current topics involving the influence of the sympathetic nervous system and β2- and β3-adrenoceptor polymorphisms in obesity, hypertension and metabolic syndrome (type 2 diabetes).

Obesity is a chronic problem affecting an increasing number of people worldwide and is now recognized as a global epidemic. Various factors involved in the complex genetic-environmental interactions that cause obesity will promote long-term positive energy balance. A cluster of environmental factors, including high energy intakes in the diet, low energy expenditure, and disturbed substrate oxidation, favour the increase and unfavourable distribution of fat mass. Obesity is a major risk factor for hypertension, cardiovascular disease development and diabetes mellitus, and represents a growing worldwide health problem. Several epidemiological studies have shown a high prevalence of cardiovascular complications and mortality in obesity and metabolic syndrome, type-2 diabetes or hypertension. For at “risk populations” predisposed to target organ damage, stringent targets for blood pressure control, dyslipidaemia, and glycaemia have been set in clinical guidelines, however clinical trial and real-life evidence suggest that these targets are difficult to achieve and sustain. The first line treatment for obesity, and obesity related conditions is weight loss. Life-style modification including low caloric diet, reducing sedentary behaviour and increasing exercise form the basis of all therapy, with more severe obesity pharmacotherapy or bariatric (weight loss) surgery may be indicated. Maintaining weight loss is often the greatest challenge. We review the effect of weight loss, using life-style modifications or bariatric surgery in obese subjects, on obesity-related hypertension, the metabolic syndrome, and some of the putative neurohormonal changes that drive obesity related disease.

This review describes the interactions between the renin-angiotensin and the sympathetic nervous system. Secondly, conditions and disease states particularly characterized by hyperactivity of the renin-angiotensin and/or the sympathetic nervous system will be discussed and finally evidence on the effects on the sympathetic nervous system of agents that inhibit the renin-angiotensin system and the significance of these findings in our understanding of the pathogenesis of sympathetic hyperactivity are summarized.