Role of sympathetic overactivity in the pathophysiology of the

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					Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004

Role of sympathetic overactivity in the
pathophysiology of the metabolic syndrome
Brent M. Egan, MD; Stevo Julius, MD, ScD
Medical University of South Carolina, SC (B. M. Egan) - University of Michigan - Ann Arbor, Mich (S. Julius) - USA

The global obesity epidemic is driving metabolic                                         n this review, the role of the autonomic nervous
(insulin-resistance) syndrome–related health problems,
including an approximately 3- to 4-fold increased
coronary heart disease risk. Autonomic dysfunction, ie,
increased sympathetic drive and reduced vagal tone,
                                                                                   I     system, especially the adrenergic component, in
                                                                                         the pathophysiology and complications of the
                                                                                         metabolic syndrome will be examined. The metab-
                                                                                   olic syndrome is a term that denotes a constellation
                                                                                   of cardiovascular risk factors related to insulin resist-
may participate in the pathogenesis and complications                              ance and obesity with a centripetal fat pattern. While
of the metabolic syndrome—comprising higher blood                                  the insulin resistance syndrome has worn many previ-
pressure (BP), more active renin-angiotensin system,                               ous labels over the past three decades, metabolic
insulin resistance, faster heart rates, excess cardiovas-                          syndrome gained preeminence after publication and
cular disease, including sudden death—and possibly                                 revision of the World Health Organization’s Expert
                                                                                   Committee Report on the diagnosis and classification
aggravate the tendency to weight gain and obesity.                                 of diabetes mellitus in 1999 and the National Choles-
Components of the metabolic syndrome that may en-                                  terol Education Program (NCEP) Adult Treatment
hance sympathetic drive include alterations of insulin,                            Panel–III (ATP III) guidelines in the USA in 2001.1-3
leptin, nonesterified fatty acids (NEFAs), cytokines,                              While the definitions provided by these two working
triiodothyronine, eicosanoids, sleep apnea, nitric oxide,                          groups present some differences, both predict a signif-
endorphins, and neuropeptide Y (NPY). Of note, high                                icantly greatly risk of developing diabetes in those not
plasma fatty acids are an independent risk factor for                              yet afflicted as well as an excess of coronary heart dis-
                                                                                   ease and total cardiovascular disease.4-6 The metabolic
hypertension and sudden death. In short-term human                                 syndrome already affects a substantial proportion of
studies, fatty acids can raise BP, heart rate, and                                 adults in virtually every society with access to excess
  1 -adrenoceptor vasoreactivity, while reducing barore-                           of calories, labor-saving devices, and passive leisure
flex sensitivity, endothelium-dependent vasodilatation,                            time activities. The syndrome is poised to become pan-
and vascular compliance. Efforts to further identify                               demic as the worldwide race to obesity runs unchecked
the mechanisms and consequences of sympathetic
dysfunction in the metabolic syndrome may provide                                      SELECTED ABBREVIATIONS AND ACRONYMS
insights for therapeutic advances to ameliorate the
excess cardiovascular risk and adverse outcomes.                                     ATP III       Adult Treatment Panel–III
                                                                                     BMI           body mass index
                                                                                     CHD           coronary heart disease
                                                                                     CVD           cardiovascular disease
Keywords: metabolic syndrome; insulin resistance; sympathetic dysfunction;           MSNA          muscle sympathetic nerve activity
hypertension; renin-angiotensin system; cardiovascular disease; coronary             NEFA          nonesterified fatty acid
heart disease; heart rate; treatment
Address for correspondence: Brent M. Egan, Professor of Medicine                     NHANES III    Third National Health And Nutrition
and Pharmacology, Medical University of South Carolina, General Internal                             Examination Survey
Medicine Hypertension Section, 96 Jonathan Lucas Street, CSB 826,
PO Box 250623, Charleston, SC 29425, USA                                             NPY           neuropeptide Y
(e-mail:                                                            PPS           Paris Prospective Study
Dialogues Cardiovasc Med. 2004;9:143-157

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

           WHO Definition (fasting hyperinsulinemia or                                ATP III Definition
           impaired glucoregulation and >2 other factors)                             (≥3 of 5 risk factors)
           • Either (a) fasting insulin in the upper quartile for                     • Waist circumference:
               nondiabetics                                                              – >102 cm (40 inches) for men
                                                                                         – >88 cm (35 inches) for women
           • or (b) fasting plasma glucose ≥5.6 mmol/L or
               110 mg/dL and ≥2 of the following:                                     • Blood pressure:
               – Blood pressure ≥140 systolic and/or                                      – ≥130 mm Hg systolic and/or
                    >90 mm Hg diastolic                                                   – ≥85 mm Hg diastolic
               – Dyslipidemia: triglycerides ≥1.7 mmol/L                              • Fasting glucose:
                    (150 mg/dL) or HDL <35 (0.9 mmol/L) for men                           – ≥110 mg/dL or 6.1 mmol/L
                    or <39 mg/dL (1.0 mmol/L) for women                               • Triglycerides:
               – Central obesity: WHR >0.90 for men or >0.85                              – >150 mg/dL or 1.69 mmol/L
                    for women and/or BMI >30 mg/m2                                    • HDL-cholesterol:
               – Microalbuminuria (≥20 mg/min or                                         – <40 mg/dL (1.04 mmol/L) in men
                    albumin/creatinine ≥30 mg/g)                                         – <50 mg/dL (1.29 mmol/L) in women

       Table I. Clinical criteria defining the metabolic syndrome.1-3
       Abbreviations: ATP III, Adult Treatment Panel–III; BMI, body mass index; HDL, high-density lipoprotein; WHR, waist-to-hip ratio.

in a global population that is aging.7 The health and                         metabolic syndrome are also linked with high levels of
economic toll taken by the metabolic syndrome is very                         inflammatory risk markers/factors, such as interleukins,
high and has the potential to produce a level of devas-                       tumor necrosis factor–α (TNFα), and C-reactive pro-
tation exceeding that of major armed conflict. Evidence                       tein (CRP),9 and defects in fibrinolysis, such as elevat-
implicates a fundamental role for the autonomic nerv-                         ed plasminogen activator inhibitor–1 (PAI-1)10 and a
ous system in the pathogenesis and complications of                           greater magnitude of oxidative stress.11,12 Other evi-
the metabolic syndrome. This review summarizes that                           dence indicates the metabolic syndrome is associated
evidence and attempts to provide a foundation for in-                         with microalbuminuria,13 abnormalities in autonomic
forming and guiding rationale efforts to more effec-                          cardiovascular regulation, and activation of one or more
tively prevent and treat the growing global epidemic                          components of the renin-angiotensin-aldosterone axis.
of metabolic syndrome–related health and economic                             The autonomic nervous system appears to play an in-
problems.                                                                     tegral role in multiple facets of the metabolic syndrome,
                                                                              including its pathophysiology and complications.14
                                                                              WHO Definition
The metabolic syndrome as defined by The World                                The WHO criteria for the metabolic syndrome were
Health Organization (WHO) and ATP III definitions of                          applied to eight different European cohorts, and the
the metabolic syndrome, while similar, are not identical.                     prevalence of the syndrome determined for men and
The two definitions are summarized in Table I.1-3                             women 40 to 55 years of age and for those older than
                                                                              55 years.2 The prevalence for each of these age and
                 Associated risk factors                                      gender subgroups is summarized in Table II.

In addition to the clinical criteria used to define the
metabolic syndrome, the syndrome is associated with                                                     Men                    Women
postprandial hyperinsulinemia and resistance to in-                                                 <55 y  >55 y            <55 y  >55 y
sulin’s glucose- and fatty acid–lowering actions, greater                        Prevalence, %       23%         41%         13%           26%
density, and numbers of low-density lipoprotein (LDL)-
                                                                                 Risk factors,
cholesterol particles,8 decreased levels of the cardio-                                            1.7±1.2 2.1±1.2          1.0±1.1 1.6±1.2
protective high-density lipoprotein (HDL)-cholesterol,
and skewing of the residual HDL particles toward                              Table II. Metabolic syndrome prevalence by WHO criteria in
smaller and less beneficial fractions. Obesity and the                        8 European studies.2

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

NCEP definition
The ATP III criteria for diagnosis of the metabolic syn-                                                            Metabolic syndrome
drome when applied to the Third National Health and                                                                   prevalence, %
Nutrition Examination Survey (NHANES III) in the US                           Category            BMI, kg/m2           Men        Women
in 1988 to 1994 generated an age-adjusted estimated
prevalence of 23.7% or ≈47 000 000 adults.15 Although                         Normal weight           <25.0             4.6%         6.2%
body mass index (BMI, kg/m2) is not a criterion used                          Overweight           25.0 - 29.9        22.4%        28.1%
by the ATP III to define the metabolic syndrome, it is,                       Obese                    >30            59.6%        50.0%
nevertheless, very strongly related to BMI in both men
and women, as summarized in Table III. 16                                  Table III. Estimated prevalence of the metabolic syndrome using the
                                                                           ATP III definition among normal weight, overweight, and obese men
Future trends in prevalence                                                and women in NHANES III.16
The metabolic syndrome is at epidemic proportions           Abbreviations: ATP III, Adult Treatment Panel–III; BMI, body mass index;
                                                            NHANES III, Third National Health And Nutrition Examination Survey.
and likely to become endemic in the next several years
given the rapid increase in the prevalence of
obesity magnified by two powerful demograph-                       Diabetes                                Heart
ic trends.                                        10-Year risk                      Hypertension                        Stroke
                                                                    mellitus                             disease

The risks of obesity, including hypertension,         18.5-21.9                  1.0                1.0                1.0           1.0
diabetes, and an excess of cardiovascular and         22.0-24.9                  1.8                1.5                1.1           1.1
renal diseases, were well described 80 years          25.0-29.9                  5.6                2.4                1.7           1.3
ago.17 Subsequent studies showed that obe-            30-34.9                  18.2                 3.8                2.2           2.1
sity, especially when linked with a truncal or
                                                      >35.0                    41.2                 4.2                2.4           2.5
abdominal fat distribution, is associated with
hypertension, faster heart rates, hyperinsu-
                                                   Table IV. Relative risk for diabetes, hypertension, heart disease, and stroke over the next
linemia, and insulin resistance with related       decade among men initially free of disease stratified by baseline BMI.21
abnormalities of carbohydrate and lipid met-
abolism.8,14,18 Moreover, the syndrome is associated              In view of the strong relationships between obesity,
with premature cardiovascular morbidity and mortality,            the metabolic syndrome (Table II), and the develop-
with an excess of sudden deaths.7,8 Despite the recent            ment of cardiovascular risk factors and events, over the
explosion of information about the health risks of ex-            next decade among overweight and obese adults with-
cess body weight, the epidemic of overweight (BMI 25              out risk or disease (Table IV), the magnitude of metab-
to 30 kg/m2) and obesity (BMI >30) continues to ex-               olic syndrome and related health problems is posi-
pand at unprecedented rates.                                      tioned to escalate dramatically in the years ahead. If we
                                                                  now look at future age trends, the median age of pop-
The estimated age-adjusted prevalence of obesity, ie,             ulations in most of the developed world is increasing
BMI >30 kg/m2, among US adults increased from 22.9%               rapidly as birth rates decline.24 The prevalence of the
in 1988 to 1994 to 30.5% in 1999 to 2000.   19 The preva-         metabolic syndrome is highly age-dependent in the USA
lence of overweight (BMI >25 kg/m2) increased between             and Europe (Table II). In the USA, for example, among
these two NHANES surveys from 55.9% to 64.5%. More                adults 20 to 29 years of age, ≈7% met the ATP III criteria
recent self-reported information from a random tele-              for the metabolic syndrome.10 The prevalence of the
phone survey of adult Americans suggests the preva-               metabolic syndrome rose to 40% or more among adults
lence of obesity increased further in 2001 from self-             aged 60 years and older. In view of these facts, the ab-
reports in 2000.20 Epidemiological data indicate that             solute number of adults with the metabolic syndrome
obesity in subjects free of cardiovascular risk and dis-          is likely to rise in the future as a consequence of aging
ease at baseline is associated with impressive increases          populations throughout most developed countries.
in relative risk for these adverse outcomes during the
ensuing decade, especially in men.21 Moreover, the                                Clinical significance: impact
obesity epidemic has metastasized to affect young                            on CHD, CVD, and total mortality
adults and children not only in economically developed
countries, but also several emerging economies world-             The clinical significance of the metabolic syndrome
wide.7 In fact, on a relative basis, the obesity epidemic         is not defined by its prevalence, but by its impact on
is growing faster in these newer targets.22,23                    health and health care costs. The metabolic syndrome

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

                                                                                   attributed to obesity are generated by the association
   Mortality           WHO definition               ATP definition*                with diabetes, hypertension, and heart disease, ie,
                                                                                   metabolic syndrome–related health risks and events.27
   CHD                    2.9 (1.2-6.8)               4.2 (1.6-10.8)

   CVD                    2.6 (1.4-5.1)               2.5 (1.1-5.8)                Given the prevalence, future trends, clinical impact,
                                                                                   and economic significance of the metabolic syndrome,
   All cause              1.9 (1.2-3.0)               2.0 (1.1-3.6)                this disorder constitutes a major health problem of
   *102 cm waist circumference for men.                                            potentially escalating proportions. Efforts to further
                                                                                   identify the mechanisms and consequences of sym-
Table V. The metabolic syndrome and mortality from CHD, CVD, and                   pathetic dysfunction in the metabolic syndrome may
all causes.* 5 ATP, Adult Treatment Panel.
                                                                                   provide insights for therapeutic advances to amelio-
*Data indicate relative risk ratios and 95% confidence intervals for indi-         rate the excess cardiovascular risk and adverse out-
viduals with the metabolic syndrome adjusted for age, examination year,
LDL-cholesterol, cigarette smoking, and family history of coronary heart
                                                                                   comes. We will now explore the literature, which ad-
disease (model 2).8                                                                dresses the interrelationships between the sympathetic
                                                                                   nervous system, obesity, and the metabolic syndrome.
as defined by both WHO and ATP III in Table I is asso-
ciated with significantly greater risk for mortality from                                     OVERWEIGHT, OBESITY,
coronary heart disease (CHD), overall cardiovascular                                          AND INSULIN DYNAMICS
disease (CVD), and all causes.5,6 When the WHO and                                                 AND ACTION
ATP III criteria for the metabolic syndrome were ap-
plied to a population of 1209 Finnish men followed                                 Body weight (BMI) and insulin dynamics and action
from their enrollment in 1984 to 1989 until 1998, an                               are closely linked.1 For example, among Italians, hyper-
impressively positive relationship was found with mor-                             insulinemia and insulin resistance affect only ≈10%
tality from CHD, CVD, and all causes (Table V).5                                   of individuals with BMIs <25 kg/m2, but 60% or more
                                                                                   of individuals with BMI ≥35 kg/m2.28 In some ethnic
                       Economic impact                                             groups, eg, Asians and African-Americans, significant
                                                                                   risk for insulin resistance and various facets of the
The costs of obesity in the USA alone, estimated at be-                            metabolic syndrome begins at BMI values well below
tween $46 to $68 billion in 1990, rose to ≈$99 billion                             25 kg/m2.29,30
in 1995 and have likely exceeded that level on an an-
nualized basis.25 While obesity accelerates degenera-                              In this review, an attempt is made to synthesize infor-
tive joint disease and increases cancers of the breast,                            mation from the community to the bench and bed-
uterus, prostate, and colon,26 much of the excess costs                            side to further elucidate the pathogenesis underlying
                                                                                   sympathetic activation (Table VI) and the cardiovascu-
                                                                                   lar and metabolic consequences of that activation
       • Hyperleptinemia                                                           (Table VII) among individuals with the insulin resist-
       • Hyperinsulinemia                                                          ance syndrome. Evidence suggests both that abnor-
                                                                                   malities in neurogenic regulation are driven in part
       • Visceral obesity
                                                                                   by various facets of the syndrome and that increased
       • Sleep apnea                                                               sympathetic drive can contribute to dimensions of the
       • Elevated nonesterified fatty acids (NEFAs)                                metabolic syndrome and associated end-organ com-
       • Disturbances in nitric oxide                                              plications. Consequently, a better understanding on the
                                                                                   causes and consequences of sympathetic overactivity
       • Suppressed anger
                                                                                   in the metabolic syndrome may enhance efforts to
       • Altered eicosanoid metabolism                                             more effectively prevent and manage this condition and
       • Increased cytokines                                                       related complications.
       • High levels of active T3
                                                                                             SYMPATHETIC FUNCTION
    Table VI. Factors that may contribute to sympathetic activation                               IN OBESITY
    in obesity.*
                                                                                   Obesity is not an entirely homogeneous disorder. In
    *Based on the literature review, the factors that are more likely to
    activate the sympathetic nervous system in obesity are listed first,           both animals and man, evidence for underactivity and
    whereas those that are less likely (speculative) are listed last.              overactivity of the sympathetic nervous system has

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

been documented.31 On balance, the literature strongly                                Evidence of sympathetic activation
suggests sympathetic hyperfunction in a substantial                                   with obesity and insulin resistance
subset of obese individuals. Several studies provide                                         from animal studies
clues on the pathogenesis and consequences of sym-
pathetic overactivity in obesity.                                               Evidence for both sympathetic hypofunction and hy-
                                                                                perfunction has been documented in animal models
In at least a substantial subset of obese subjects, sym-                        of obesity.31 In fact, sympathetic underactivity appears
pathetic drive is increased at key target organs in obe-                        to underlie the lower metabolic rates that contribute
sity, including the kidney, skeletal muscle, and periph-                        to obesity in some rodents.45 Conversely, in healthy
eral vasculature.32-34 There is less evidence for increased                     animals, obesity induced by overfeeding is associated
                                                                                with sympathetic activation and hypertension.39,46
                                                                                Sympathetic activation is an early abnormality induced
   • Sodium retention                                                           by overfeeding and reversed with weight loss. Feeding-
   • Increased cardiac output                                                   induced sympathetic changes appear to precede and
   • Increased heart rate                                                       perhaps drive alterations in renin-angiotensin system
                                                                                activity.39,42 In at least some of these models, hyper-
   • Inappropriately high vascular resistance
                                                                                tension is prevented or reversed by centrally acting
   • Secondary activation of the renin-angiotensin system                       α2-adrenoceptor agonists or combined α1- and β-adren-
   • Elevated blood pressure                                                    ergic receptor antagonists.39-41
   • Enhanced oxygen consumption limiting weight
      gain (short term)                                                         Observations from animal research have also helped
   • β-Adrenergic receptor downregulation and                                   to elucidate the potential mechanisms by which obe-
       weight gain                                                              sity and insulin resistance activate the sympathetic
                                                                                nervous system and contribute to cardiovascular risk
   • Defects in regulation of heart rate variability
                                                                                and disease. While these experiments have provided
   • Sudden death                                                               important insights, the results indicate that the rela-
   • Insulin resistance                                                         tionship between obesity, insulin resistance, and sym-
   • Increased nonesterified fatty acids (NEFAs)                                pathetic function is complex and modified by genetic
                                                                                and environmental factors.47
   • Non–insulin-dependent or type 2 diabetes
   • Dyslipidemia                                                               In normotensive rats, high sucrose diets, even without
   • Vascular remodeling and other target-organ changes                         weight gain, induce insulin resistance and hypertension
   • Downregulation of β-adrenergic receptors.                                  that is blunted by central sympatholytics acting as
                                                                                agonists at α2-adrenoceptors.48 In both rats and dogs,
   • Congestive heart failure
                                                                                hypertension induced by high sucrose or high fat diets
Table VII. Potential effects of sympathetic activation in the metabolic
                                                                                is abrogated by clonidine, whereas the hyperinsuline-
syndrome.                                                                       mia is variably affected.39,48

sympathetic drive to the heart, especially in obese                                   Evidence of sympathetic activation
normotensive humans.32 Nevertheless, disturbances                                     with obesity and insulin resistance
of autonomic control of heart rate variability, which                                        from human studies
include decreased vagal tone, either with or without
increased sympathetic tone, are very well document-                             Plasma and urine catecholamines, systemic and region-
ed.35,36 Sympathetic activation at the various target                           al norepinephrine turnover, and direct sympathetic
sites appears to play an important pathophysiological                           nerve recording, or microneurography, have been used
role in obesity-associated insulin resistance,37,38 hy-                         to measure sympathetic drive in humans. Each of these
pertension,39-41 activation of the renin-angiotensin                            methods has yielded evidence for sympathetic hyper-
system,42-44 and sudden death.35                                                function among individuals with obesity and the metab-
                                                                                olic syndrome.
We will now examine the evidence from various animal
and human studies documenting that the sympathetic                              Plasma catecholamines
nervous system is activated with obesity and insulin                            Several studies have identified elevated plasma cate-
resistance.                                                                     cholamines in obese human subjects, particularly those

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

with elevated blood pressure.49 Moreover, weight loss               modestly elevated, on average, in obese hypertensives.32
was associated with a relatively rapid reduction of                 The studies of norepinephrine kinetics suggest that
plasma norepinephrine, which correlated with the de-                regional differences in sympathetic function exist be-
cline of blood pressure that accompanies negative calo-             tween obesity, hypertension, and their combination.
rie balance.42 Studies have demonstrated that plasma
norepinephrine is elevated in obese children with high              Muscle sympathetic nerve activity (MSNA)
blood pressure and predicts the decline of blood pres-              MSNA is higher in obese normotensive and obese
sure that occurs with salt restriction.50 These data sug-           hypertensive subjects than in lean normotensive con-
gested that sympathetic overactivity contributes to                 trols33 and may be explained by central differences in
sodium retention and blood pressure elevation in                    autonomic regulation.55 Grassi and colleagues showed
obese children, an impression that is consistent with               that weight loss in obese normotensives reduced
evidence from studies of regional norepinephrine                    MSNA, lowered plasma norepinephrine, and improved
turnover in obese adults.32                                         deficits in baroreflex sensitivity and whole-body glu-
                                                                    cose disposal.56
Regional norepinephrine kinetic studies
Esler and colleagues, using regional norepinephrine                 The changes in MSNA and glucose disposal may be
kinetics, identified increased sympathetic activity to              linked. An elegant regional hemodynamic study by
the heart and kidneys in hypertensive patients.32,51 The            Jamerson and colleagues, demonstrated an inverse
sympathetic activation likely plays a key role in the               relationship between vascular α-adrenergic tone and
pathogenesis of hypertension in these individuals.                  insulin-mediated glucose disposal.38 Thus, it is tempt-
While the pathogenesis of sympathetic activation has                ing to speculate that the increased MSNA in obese
not been fully elucidated, studies in hypertensive pa-              normotensives enhances α-adrenergic vasoconstric-
tients identified increased norepinephrine turnover in              tion and contributes to impaired insulin-mediated
the brain, which may underlie the increased sympathet-              glucose disposal. While vasoconstriction from any
ic drive to the heart and kidneys.51 These observations             cause has been implicated in insulin resistance,57 the
are consistent with research by Julius and colleagues               effects of α-adrenergic vasoconstriction on glucose
indicating a central neurogenic basis for hyperkinetic              disposal appear more adverse than a similar vasocon-
borderline hypertension characterized by faster heart               striction induced by angiotensin II.38 Conversely, the
rates and higher cardiac outputs with a transition                  marked reduction in MSNA with weight loss in obese
phase to the more typical high-resistance, normal car-              normotensives could have reduced their α-adrenergic
diac output phase of sustained hypertension.52,53                   vasoconstriction and improved insulin-mediated
                                                                    glucose disposal.
Using regional norepinephrine turnover, increased sym-
pathetic drive to the kidney was identified in obese                While it is challenging to separate the effects of caloric
normotensive and obese hypertensive subjects.32 Since               restriction from those of weight loss on MSNA in obese
the kidney is of fundamental importance in blood pres-              subjects, it appears that significant weight loss and
sure control,54 the implications of sympathetic over-               not just reduced calorie intake is necessary. For exam-
activity in obese normotensive subjects is difficult to             ple, after 3 days of semistarvation diets in obese wom-
interpret. Obesity is associated with relative (to height)          en, MSNA was not changed. However, measurements
volume expansion, and renal sympathetic overactivity                obtained by Andersson and colleagues when the wom-
may participate in maintaining volume expansion at                  en lost 7% of their initial weight showed a significant
a given (normal) blood pressure level in the presence               decline in MSNA.58
of the renal vasodilation that occurs in obesity. How-
ever, if the sympathetic activity results in greater sodi-          MSNA is reportedly higher in men than in women. In
um retention and volume expansion than can be bal-                  studies to assess these gender differences, Jones and
anced by the natriuretic effects of renal vasodilation,             coworkers analyzed the relationship of body fat to
then a higher arterial pressure would be required to                MSNA in men and women.59 They found that MSNA
maintain sodium-volume homeostasis, resulting in                    was more strongly correlated to central than peripheral
hypertension.                                                       body fat. Several studies demonstrate that the central,
                                                                    or male, fat pattern is associated with greater degrees
Based on studies using norepinephrine turnover, sym-                of hyperinsulinemia, insulin resistance, hypertension,
pathetic drive to the heart does not appear to be ele-              diabetes, and CHD than the peripheral or gynoid fat
vated in obese normotensives and appears to be only                 pattern characteristically seen in women.18,60 The largest

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

sexual dimorphism in body fat distribution is present                    Potential mechanisms contributing to
in younger adults and decreases as women gain weight                       sympathetic activation in obesity
with a centripetal fat distribution as they age.61 Fur-
thermore, overweight is more strongly related to hyper-             The literature implicates several factors in the sympa-
tension in men than in women <45 years old.62 These                 thetic activation that occurs with obesity. Since obesity
findings relating MSNA to body fat pattern, in view of              is a heterogeneous condition, the relative contribution
the literature noted, raise the possibility that greater            of these factors may vary based upon other modifying
sympathetic activation among individuals with abdom-                biological factors, both genetic and environmental.
inal obesity contributes to their propensity to insulin             Evidence will now be examined for several factors
resistance, hypertension, and diabetes.                             that may increase sympathetic activity in obesity. This
                                                                    list is not intended to be exclusionary, and other fac-
Obesity and hypertension have separate and addition-                tors may participate.
al effects on MSNA. In studies by Grassi and colleagues,
MSNA was significantly and similarly elevated by ≈40%               The possibility that a primary increase in sympathetic
to 50% in both lean hypertensive and obese normo-                   tone might in some individuals play a primary role in
tensive subjects than in lean normotensive volunteers.55            the development of the metabolic syndrome obesity is
In obese hypertensive subjects, MSNA was nearly                     supported by the observations in the Osaka study.66
double the level observed in lean normotensive volun-               The authors followed normal volunteers for a period
teers, suggesting that the effects of obesity and hyper-            of 10 years. An elevated plasma norepinephrine at the
tension on MSNA were approximately additive. These                  baseline predicted future higher BP readings, gain of
investigators showed that reflex alterations of MSNA                weight, and higher insulin values. Whereas the mech-
evoked by blood pressure changes were impaired in                   anism whereby the sympathetic vasoconstriction could
obese normotensive patients compared with both lean                 cause higher insulin values has been demonstrated,38
normotensives and lean hypertensives. The defects in                the processes by which a primary increase in sympa-
baroreflex-mediated changes of MSNA were greater in                 thetic tone could lead to increased weight are less well
obese hypertensive than obese normotensive subjects.                understood. We recently reviewed the literature that
These findings indicate that obesity is associated with             supports the concept that enhanced sympathetic tone
increased MSNA as well as impaired regulation of                    downregulates β-adrenergic receptors, which in turn,
MSNA by arterial baroreceptors. The abnormalities of                could decrease a person’s ability to dissipate calories.67
MSNA in obesity are amplified by concomitant hyper-                 β-Adrenergic receptors are known to mediate the in-
tension.55                                                          creased thermogenic response to food and the basal
                                                                    metabolic rate. The possible primacy of sympathetic
Spectral analysis                                                   overactivity is further supported by the study of Neutel
Obese patients are more susceptible to ventricular                  and colleagues68 in which normotensive children of
arrhythmias and sudden death than lean individuals.63               hypertensive parents exhibited higher plasma nor-
Faster heart rates are a powerful predictor of sudden               epinephrine values and mild dyslipidemia.68 Finally, as
death, especially in men.64 Autonomic abnormalities                 noted earlier, studies in dogs support the crucial im-
play an important role in the faster heart rates observed           portance of sympathetic overactivity in the genesis of
in some hypertensive patients.32,33 Of note, both sym-              insulin resistance.39 When they were fed a diet of boiled
pathetic and parasympathetic abnormalities of heart                 lard, dogs developed the metabolic syndrome of over-
rate control are greater in women with upper body                   weight, insulin resistance, and high blood pressure.
(abdominal), and especially visceral adiposity, than in             The authors then treated the animals with clonidine
women with lower body obesity.65 Moreover, weight                   to decrease the sympathetic tone emanating form the
loss resulting from caloric restriction improved cardiac            central nervous system, which prevented (reversed)
parasympathetic tone at night and reduced the ratio                 the hypertension.39
of sympathetic/parasympathetic cardiac tone during
the day without changes of resting heart rate.65 While              Insulin
this review is focused on the sympathetic nervous sys-              An extensive literature in animals and man indicates
tem, obesity is also associated with abnormalities of               that elevations of plasma insulin, even within the phys-
parasympathetic function that may have clinically im-               iological range, activate the sympathetic nervous sys-
portant consequences. Many of the autonomic abnor-                  tem. In fact, theories linking hyperinsulinemia and
malities associated with obesity appear to improve                  insulin resistance to hypertension are based on the
with weight loss.                                                   premise that potential pressor actions of insulin are

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

maintained, eg, sympathetic activation and renal sodi-              metabolic syndrome and less responsive to suppres-
um retention, while potential depressor effects are                 sion by insulin.73,74 Elevated fatty acids are strongly
reduced, eg, vasodilation—a debate which exceeds the                implicated in the abnormalities of glucose and lipid
scope of this review.                                               metabolism accompanying insulin resistance.75,76 Until
                                                                    the past decade, abnormalities in NEFA metabolism
A series of experiments by investigators at the Univer-             were not linked to sympathetic activation and cardio-
sity of Iowa demonstrated that euglycemic hyperinsu-                vascular regulation.
linemia raises MSNA similarly in healthy younger and
older subjects and individuals with borderline hyper-               In minipigs, a rise in plasma NEFAs evoked by infusion
tension.69,70 Despite differences in insulin action and             of Intralipid, a source of triglycerides, and heparin,
peripheral vasodilation, blood pressure does not in-                which activates lipoprotein lipase and accelerates the
crease during the short term in any of these groups. In             hydrolysis of fatty acids from triglycerides, induces
other studies, MSNA correlated most strongly with BMI               vasoconstriction and raises blood pressure.77 In nor-
(N=37, r =0.67, P <0.001) and total body fat (r =0.64,              motensive rats, infusion of oleate into the portal vein
P <0.001) and less strongly with plasma insulin (r =0.34,           induces sympathetic activation and blood pressure ele-
P <0.04).71 These data suggest that hyperinsulinemia                vation. The oleate-induced pressor response is blocked
may account for only a comparatively small portion of               by α1-adrenoceptor antagonists.78 In dogs, unlike rats,
the sympathetic activation observed in obesity. More-               infusion of oleate did not induce sympathetic activa-
over, in contrast to reports by other investigators, this           tion or a pressor response.79
group observed that obese subjects were resistant to
insulin’s effect to increase MSNA, but equally respon-              In humans, doubling of plasma NEFAs during an infu-
sive to other stimuli that raise MSNA. Collectively, the            sion of Intralipid and heparin increases blood pressure
evidence suggests that insulin contributes to, but prob-            by ≈10 to 14/6–8 mm Hg over the course of 4 hours.80
ably does not fully explain, the sympathetic activation             Despite the rise in blood pressure, heart rate increases
that occurs with obesity.                                           by ≈8 beats/minute, which is consistent with neuro-
                                                                    genic activation. In other studies, the infusion of Intra-
Leptin                                                              lipid and heparin also impairs endothelium-dependent
Several studies document that leptin induces sympa-                 vasodilation and augments α1-adrenoceptor–mediated
thetic activation in animals and humans. Leptin, like               pressor reactivity.81,82 These two effects may be linked,
insulin, has some actions that are potentially pressor              since nitric oxide appears to attenuate α-adrenergic
and other effects that are depressor.47 For example,                vasoconstriction.83 One or more of these actions of
leptin acts directly on the kidney to enhance renal sodi-           NEFAs may underlie the independent association of
um excretion and vascular nitric oxide production,                  plasma NEFA as a predictor of future hypertension in
which could lower blood pressure. Leptin also increas-              the Paris Prospective Study (PPS).84
es sympathetic drive to the kidney, adrenals, and heart,
which could raise blood pressure. While short-term                  An elevation of plasma fatty acids in humans also
infusions of leptin in animals typically do not raise               acutely impairs baroreflex sensitivity,85 while enhancing
blood pressure, longer-term infusions of leptin are                 sympathetic and impairing parasympathetic control
pressor. Whereas the short-term infusions of leptin are             of heart rate variability.86 Since less heart rate variabili-
natriuretic, sodium retention emerges with decreases                ty is associated with higher mortality rates, these ob-
in renal blood flow and increases of renal vascular re-             servations may provide a potential mechanism linking
sistance during prolonged infusions. This and other                 elevated fatty acids to sudden death in the PPS.87
evidence implicates leptin in some models of obesity-
associated hypertension. While both insulin and lep-                Cytokines
tin can activate the sympathetic nervous system, the                The link between cytokines and sympathetic activation
regional patterns of sympathetic activation with these              in obesity is speculative. Adipocytes produce several
two peptides are different. Moreover, in humans, MSNA               different inflammatory cytokines in proportion to their
appears to be more closely related to plasma leptin                 volume. Obesity is associated with an increase in sev-
than insulin in multivariate analysis.72                            eral of these proinflammatory signaling peptides.88
                                                                    Patients with congestive heart failure and those with
Nonesterified fatty acids                                           sleep apnea have increased cytokines and sympathetic
Plasma nonesterified fatty acids (NEFAs) or free fatty              activation, which implies an association, while not es-
acids are, on balance, elevated in subjects with the                tablishing a causal link.89,90

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Sympathetic overactivity and metabolic syndrome - Egan and Julius

Triiodothyronin                                                     acting peripherally enhances sympathetic function.104
The ratio of active-to-reverse triiodothyronine (T3) is             As with endorphins, several NPY receptor subtypes
linked to caloric intake, especially carbohydrate. The              exist to mediate the various tissue-specific effects. While
ratio of active-to-reverse T3 rises rapidly with overfeed-          peripheral NPY levels appear normal in obesity, alter-
ing and falls with fasting.91 Similarly, overfeeding is             ation in central levels and/or peripheral and central
associated with increases, and caloric deprivation with             actions of NPY could also contribute to defects in au-
decreases in measures of sympathetic activity, as dis-              tonomic drive and tone.
cussed previously. While these associations raise the
possibility of a causal connection, the evidence linking            Sleep apnea
excess thyroid hormone (T4) to sympathetic activation               Sleep apnea, unlike the previously cited factors that
is variable, with some data suggesting that sympathetic             may contribute to neurogenic activation in obesity, is
drive is inhibited by hyperthyroidism. Further studies              a medical condition and not a peptide- or lipid-signal-
may be useful to determine if the effects of T4 and T3              ing molecule. Sleep apnea is an obesity-associated
on autonomic function are similar.                                  condition that is both common and often unrecognized.
                                                                    Sleep apnea may affect as many as 50% of hyperten-
Eicosanoids                                                         sive patients.90,105 Sleep apnea is associated with mul-
Adipose tissue produces several peptide- and lipid-                 tiple changes, including severe insulin resistance, hy-
signaling molecules, which may be increased among                   perleptinemia, hypercytokinemia, and sympathetic
obese individuals.92 Eicosanoid products modulate                   activation.106 Thus, several factors already discussed
autonomic activity 93 in a clinically significant manner.94         may contribute to adrenergic activation in patients with
Thus, abnormalities of eicosanoid metabolism in obe-                sleep apnea. In addition, hypoxemia, by activating pe-
sity could potentially contribute to defects in sympa-              ripheral chemoreceptors and/or central effectors, eg, C1
thetic activation and related downstream effects.                   or catecholamine-containing neurons in the medulla,
                                                                    may play a major role in the sympathetic activation
Nitric oxide                                                        that occurs in sleep apnea.107 Imidazolines, like cloni-
Ntiric oxide is a neurotransmitter and local autacoid               dine, suppress sympathetic activation by effects on
that modulates sympathetic activation centrally and                 C1 neurons.108 Thus, activation of these receptors by
neurogenic vasoconstriction peripherally.95,96 Of inter-            hypoxia could potentially contribute to neurogenic
est, leptin increases nitric oxide and increases sympa-             hypertension in obese patients with sleep apnea.
thetic drive.47 Inhibition of nitric oxide during exoge-
nous infusion of leptin significantly enhances the
increase in sympathetic drive, especially to the heart.97
                                                                    Obesity is a growing worldwide epidemic. Metabolic
Endorphins                                                          syndrome–related health problems are closely related
Central endorphins can modulate sympathetic nervous                 to this anthropometric change. With minimal efforts at
system activity, appetite, and glucocorticoid (hypotha-             hyperbole, the global epidemic is poised to escalate
lamic-pituitary-adrenal axis) function.98-100 Endorphins            into a pandemic in the years ahead. The clinical epi-
also appear to mediate the sympatholytic effects of                 demiological significance of the syndrome is highlight-
central α2 / imidazole receptor agonists.101 In short-              ed by its association with a 2- to 4-fold increase in
term studies in human volunteers, opioid antagonists,               risk for coronary heart disease, total cardiovascular dis-
eg, naloxone, are potent modulators of sympathetic                  ease, and all-cause mortality. The rapidly growing bur-
activity.102 The effects of endorphins/opioids on sym-              den of obesity together with a population that is be-
pathetic function are variable, depending upon the                  coming older and made up of an increasing proportion
specific site of action and the subtype of receptor acti-           of high-risk ethnic minorities raises the importance of
vated.103 The evidence suggests that abnormalities of               effective strategies for the primary prevention of the
endorphins could contribute to disturbances in energy               metabolic syndrome. Obesity is associated with multi-
intake relative to expenditure, the hypothalamic-pitu-              ple health risks that impact the structure and function
itary-adrenal axis, and autonomic function described                of virtually every organ system. Obesity is a heteroge-
in obesity.                                                         neous condition modulated by a variety of genetic,
                                                                    developmental, and environmental factors. The litera-
Neuropeptide Y                                                      ture indicates that the sympathetic nervous system is
Neuropeptide Y (NPY) acting at the hypothalamus re-                 activated in a substantial subset of obese individuals
duces appetite and sympathetic outflow, whereas NPY                 and appears to play an important role in the insulin

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

resistance, hypertension, tachycardia, target-organ com-
plications, and sudden death that occur earlier and                           THREE KEY QUESTIONS
more frequently in obese patients. Sympathetic activa-
tion may also induce and/or exacerbate weight gain                  One of the major aspects of the metabolic syn-
by downregulating β-adrenergic receptors.                           drome clearly is its epidemic-like prevalence, close-
                                                                    ly linked to the spiraling worldwide growth of obe-
Evidence strongly implicates leptin and hyperinsuline-              sity: this alone justifies current efforts to better
mia in the sympathetic activation that occurs in obese              understand the components of the syndrome, its
subjects. While more hypothetical, other factors, eg,               causes, its consequences, and of course to define
fatty acids, endorphins, NPY, eicosanoids, and endor-               optimal therapeutic strategies. Obviously, the scope
phins may play a role. In a more speculative mode,                  of the problem encompasses a far greater number
elevations of cytokines and increases in triiodothyro-              than the customary three key questions, and the
nine may activate or create the appearance of sympa-                Editors’ choice was a particularly tough one in this
thetic activation in obesity. Sleep apnea, which is a               case. Ivana Zavaroni, Diego Ardigò, Silvio Valtueña,
common and frequently unrecognized complication of                  and Alessandra Dei Cas, seeking to lay sound foun-
obesity, may drive sympathetic activation by several                dations for an earlier identification of subjects at
mechanisms, including hypoxia acting at C1 neurons                  risk of coronary heart disease and a more aggres-
in the medulla and by exacerbating metabolic, neuro-                sive lifestyle intervention ask: “Metabolic syn-
hormonal, and inflammatory mediators associated with                drome: what are the acknowledged markers,
visceral obesity. Behavioral factors, eg, suppressed                and how reliable are they?” We then singled out
anger and hostility, could potentially contribute to au-            hypertension among many other possible topics
tonomic changes in obese subjects.52,109                            worthy of review — we did say that we were faced
                                                                    with a difficult choice! Thus, Murray D. Esler, taking
The principal goal of this review was to examine the                a close look at the recent neurogenic explanation
causes and consequences of sympathetic activation in                for the development of hypertension in obesity,
the metabolic syndrome. It is hoped that the effort will            asks: “Metabolic syndrome and hypertension:
foster a better understanding of the factors that in-               what are the outstanding questions,” while Mar-
duce sympathetic activation and the consequences of                 celo L. G. Correia, Kamal Rahmouni, and Allyn Mark
that activation among individuals with insulin resist-              focus their scrutiny on the role of leptin, asking: “By
ance. Scientific discovery and understanding are critical           which mechanisms does leptin contribute to el-
components driving novel therapeutic interventions                  evated blood pressure?” The Editors wish that this
to reduce at least some of the devastating health and               all-too brief foray into the realm of the metabolic
economic consequences of the metabolic syndrome,                    syndrome will have whetted the reader’s appetite
and current evidence indicates several promising av-                and encouraged further investigation of the topic.
enues of inquiry.

Dialogues in Cardiovascular Medicine - Vol 9 . No. 3 . 2004
Sympathetic overactivity and metabolic syndrome - Egan and Julius

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