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Current Hypertension
Reviews
ISSN: 1573-4021
Current Hypertension Reviews
Volume 6, Number 2, May 2010
Contents
Current Hypertension Reviews, Hot
Topics “Obesity, Hypertension, and the Metabolic Syndrome”
Guest Editor: Kazuko Masuo
Editorial Pp. 72
Prevalence of Obesity, Hypertension, Diabetes, and Metabolic
Syndrome and Its Cardiovascular Complications Pp.
73-82
Michael L. Tuck and Dalila B. Corry
[Abstract] [Purchase
Article]
Role of Sympathetic Nerve Activity in Obesity,
Hypertension and Metabolic Syndrome Pp.
83-91
Kazuko Masuo and Murray D. Esler
[Abstract] [Purchase
Article]
Pharmacological Treatments for Obesity-Related Hypertension
Pp. 92-99
Murray D. Esler and Kazuko Masuo
[Abstract] [Purchase
Article]
Insulin Resistance and the Renin-Angiotensin-Aldosterone
System in Metabolic Syndrome and Obesity-Related Hypertension
Pp. 100-103
Kei Kamide, Hiromi Rakugi and Toshio Ogihara
[Abstract] [Purchase
Article]
Leptin-Induced Sympathetic Nerve Activation: Signaling Mechanisms
and Cardiovascular Consequences in Obesity Pp. 104-109
Kamal Rahmouni
[Abstract] [Purchase
Article]
Role of Adiponectin in Obesity, Hypertension, and
Metabolic Syndrome Pp. 110-117
Yoshio Iwashima, Takeshi Horio and Yuhei Kawano
[Abstract] [Purchase
Article]
Relationships of Beta2- and Beta3--Adrenoceptor Polymorphisms
with Obesity, Hypertension and Metabolic Syndrome
Pp. 118-129
Kazuko Masuo, Hiromi Rakugi and Toshio Ogihara
[Abstract] [Purchase
Article]
Weight Loss in Obesity and Metabolic Syndrome
Pp. 130-138
Gavin W. Lambert, Kazuko Masuo and John B. Dixon
[Abstract] [Purchase
Article]
General Articles
Reduction of Sympathetic Hyperactivity by Agents that
Inhibit the Renin Angiotensin Aldosterone System
Pp. 139-147
Laima Siddiqi and Peter J. Blankestijn
[Abstract] [Purchase
Article]
Abstracts
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Editorial: Current Hypertension Reviews, Hot
Topics “Obesity, Hypertension, and the Metabolic Syndrome”
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 non-diabetic
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.
Kazuko Masuo
Nucleus Network Ltd. and Human
Neurotransmitters Laboratory
Baker IDI Heart and Diabetes
Research Institute
75 Commercial Road
Melbourne, Victoria 3004
Australia
Tel: +61-3-8532-1111
Fax: +61-3-8532-1100
E-mail: kmasuo@bakeridi.edu.au
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Article]
Prevalence of Obesity, Hypertension, Diabetes, and
Metabolic Syndrome and Its Cardiovascular Complications
Michael L. Tuck and Dalila B. Corry
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.
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Article]
Role of Sympathetic Nerve Activity in Obesity, Hypertension
and Metabolic Syndrome
Kazuko Masuo and Murray D. Esler
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.
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Article]
Pharmacological Treatments for Obesity-Related Hypertension
Murray D. Esler and Kazuko Masuo
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 mod-ification
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.
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Article]
Insulin Resistance and the Renin-Angiotensin-Aldosterone
System in Metabolic Syndrome and Obesity-Related Hypertension
Kei Kamide, Hiromi Rakugi and Toshio Ogihara
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.
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Leptin-Induced Sympathetic Nerve Activation: Signaling Mechanisms
and Cardiovascular Consequences in Obesity
Kamal Rahmouni
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.
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Role of Adiponectin in Obesity, Hypertension, and
Metabolic Syndrome
Yoshio Iwashima, Takeshi Horio and Yuhei
Kawano
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.
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Article]
Relationships of Beta2- and Beta3--Adrenoceptor Polymorphisms
with Obesity, Hypertension and Metabolic Syndrome
Kazuko Masuo, Hiromi Rakugi and Toshio Ogihara
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).
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Weight Loss in Obesity and Metabolic Syndrome
Gavin W. Lambert, Kazuko Masuo and John
B. Dixon
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.
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Reduction of Sympathetic Hyperactivity by Agents that
Inhibit the Renin Angiotensin Aldosterone System
Laima Siddiqi and Peter J. Blankestijn
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.
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