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Cited by 60Blood Pressure and Hypertension StudiesCardiovascular Function and Risk FactorsDiabetes, Cardiovascular Risks, and Lipoproteins

Obesity Paradox in Hypertension: Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form?

Open access
Esler, Murray, Lambert, Gavin, Schlaich, Markus, Dixon, John, Sari, Carolina Ika, Lambert, Elisabeth·2018·Hypertension
DOI 10.1161/hypertensionaha.117.09790
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Abstract

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AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that the obesity paradox in hypertension may be explained by differing sympathetic nervous system activation phenotypes: normal-weight essential hypertension has a more toxic cardiac sympathetic profile, whereas obesity-hypertension largely lacks these cardiac abnormalities despite shared renal sympathetic activation. It argues this neural difference may outweigh metabolic risk in obesity-hypertension and has implications for antihypertensive drug choice.

Key findings

  • In cited hypertension cohorts, overweight/obese patients had lower mortality or cardiovascular events than normal-weight patients: Barrett-Connor and Khaw’s 1727 men aged 50 to 79 years, and INVEST’s 22 576 hypertensive patients with coronary artery disease, in whom class I obese patients had the lowest rate of primary outcome and death.
  • Sympathetic activation is not uniform: normal-weight essential hypertension shows cardiac sympathetic activation, increased single-fiber firing rate with salvos, impaired neuronal norepinephrine reuptake (cardiac tritiated norepinephrine extraction 65% vs 81% in controls, P<0.03; tritiated DHPG 992 vs 4588 dpm/min, P<0.01), and sympathetic nerve epinephrine corelease (outward flux averaging 2 ng/min, 5% to 15% of accompanying neuronal norepinephrine release). Obesity-hypertension lacks these: cardiac sympathetic activity is normal or low, single fibers are recruited at a normal firing rate without salvos, reuptake is normal, and epinephrine corelease is absent.
  • Both lean and obese essential hypertension share renal sympathetic activation: renal norepinephrine spillover is doubled in milder essential hypertension and trebled in resistant hypertension; renal denervation lowers blood pressure similarly across BMI.
  • The authors hypothesize that the toxic sympathetic phenotype cluster in normal-weight hypertension may explain the obesity paradox, and suggest antiadrenergic antihypertensive drugs may be preferred in normal-weight hypertension while diuretics may be preferred in obesity-hypertension.

Methods

  • Narrative review and hypothesis paper, not a new primary study; it synthesizes the authors’ prior work and cited literature.
  • Data source: over 3 decades of catecholamine isotope dilution and sympathetic nerve recording methodologies in untreated lean and obese patients with essential hypertension, plus cited trials and cohorts.
  • Main analysis: qualitative synthesis of organ-specific norepinephrine spillover, clinical microneurography single-fiber firing, cardiac norepinephrine reuptake, and epinephrine cotransmission to contrast sympathetic phenotypes.

Limitations

  • Stated in the paper: metabolic and other potential mechanisms “have not been tested for”; causality “can only be inferred”; epinephrine cotransmission is “probable but not proven” and its toxicity “has not been directly proven”; CNS origins of the phenotypes “remain largely obscure”; some mechanisms have not been directly tested in human hypertension.
  • Evident from the text: this is a narrative review without systematic search, formal quality assessment, or meta-analysis; it relies on selected prior studies and the authors’ database and presents no new outcome data to directly test the proposed mechanism.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/hypertensionaha.117.09790

Cites

117 of 117 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 80 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The outward epinephrine flux averaged 2 ng/min in normal-weight essential hypertension, equivalent to 5% to 15% of the accompanying neuronal norepinephrine release.

    “This outward epinephrine flux, measurable by isotope dilution analogous to the measurement of norepinephrine spillover, averaged 2 ng/min in normal-weight essential hypertension, 41 equivalent to 5% to 15% of the accompanying neuronal norepinephrine release.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] source

      Not checked in the free run.

    • The authors state this as an assumption: The epinephrine is coreleased from cardiac sympathetic nerves along with norepinephrine.
  • Findingreasoning

    There is a remarkable disparity in sympathetic nervous system biology between normal-weight hypertension and obesity-hypertension.

    “When these components of sympathetic activation are considered, there is a remarkable disparity in sympathetic nervous system biology between normal-weight hypertension and obesity-hypertension (Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    In normal-weight essential hypertension, the epinephrine-specific radioactivity in arterial plasma falls in passage through the heart because of the outward flux of epinephrine into coronary sinus blood.

    “The epinephrine-specific radioactivity (ratio of tritiated epinephrine concentration/patient's own epinephrine concentration) in arterial plasma in normal-weight essential hypertension falls in passage through the heart because of the outward flux of epinephrine into coronary sinus blood.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The epinephrine is coreleased from cardiac sympathetic nerves along with norepinephrine.
  • Findingcitation

    Essential hypertensive patients, lean and obese, both share activation of the sympathetic outflow to the kidneys.

    “In contrast, essential hypertensive patients, lean and obese, both share an activation of the sympathetic outflow to the kidneys.24”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] source

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  • Findingcitation

    Multiunit sympathetic nerve firing is similarly increased in both lean and obese hypertensive patients.

    “That multiunit sympathetic nerve firing is similarly increased in both lean and obese hypertensive patients is well known.31,32”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] source

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    • cites [32] source

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  • May combine two claims. 16
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingcitation

    Activation of the sympathetic outflow to the heart is present in normal-weight essential hypertension only; in obesity-hypertension, cardiac sympathetic activation is absent.

    “Activation of the sympathetic outflow to the heart is present in normal-weight essential hypertension only (Figure 1).24 In obesity-hypertension, cardiac sympathetic activation is absent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] source

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  • May combine two claims.

    Findingcitation

    Neuronal uptake of norepinephrine is impaired substantially in lean hypertensive patients, but not reduced at all in obesity-hypertension.

    “Neuronal uptake of norepinephrine is impaired substantially in lean hypertensive patients, but not reduced at all in obesity-hypertension. 36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] source

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  • May combine two claims.

    Findingcitation

    In normal-weight essential hypertension, total spillover of norepinephrine to plasma, a measure of global sympathetic activity, is increased and higher than in obesity-hypertension.

    “In normal-weight essential hypertension, the total spillover of norepinephrine to plasma, measured by isotope dilution, a measure of global sympathetic activity, is increased 24 and higher than in obesityhypertension.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] source

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  • May combine two claims.

    Findingcitation

    In lean hypertensive patients, the increase in sympathetic activity evident in multiunit burst number and size is because of an increase in the firing rate of individual single fibers and to the common presence of firing salvos, multiple firings in a single cardiac cycle.

    “In lean hypertensive patients, the increase in sympathetic activity evident in multiunit burst number and size is because of an increase in the firing rate of individual single fibers, and to the common presence of firing salvos, multiple firings in a single cardiac cycle 31 (Figure 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] source

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  • May combine two claims.

    Findingnone given

    In obesity-hypertension, single-fiber firing salvos are infrequent, and the single-fiber firing rate is normal.

    “Conversely, in obesity-hypertension, single-fiber firing salvos are infrequent, and the single-fiber firing rate is normal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Molecular analyses of sympathetic nerves of hypertensive patients accessed by subcutaneous vein biopsy disclose the presence of the epinephrine-synthesizing enzyme phenylethanolamine-N-methyltransferase, suggesting that epinephrine is synthesized in situ in the nerves.

    “Molecular analyses of sympathetic nerves of hypertensive patients accessed by subcutaneous vein biopsy disclose the presence of the epinephrine-synthesizing enzyme phenylethanolamine-N-methyltransferase, 70 suggesting that epinephrine is synthesized in situ in the nerves.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] source

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  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Cardiac sympathetic excitation is confined to normal-weight essential hypertension.

    “Cardiac sympathetic excitation is confined to normal-weight essential hypertension.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Cardiac failure, depressive illness, panic disorder, postural tachycardia syndrome, and aging share with normal-weight essential hypertension, to differing degrees, the possession of the sympathetic activation phenotypes; obesity-hypertension has none.

    “Cardiac failure, depressive illness, panic disorder, postural tachycardia syndrome, and aging share with normal-weight essential hypertension, to differing degrees, the possession of the sympathetic activation phenotypes.Obesityhypertension has none (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Extraction of tritiated norepinephrine from plasma in cardiac transit was reduced in normal-weight essential hypertension compared with healthy controls, and generation of tritiated DHPG was less.

    “The extraction of tritiated norepinephrine from plasma in cardiac transit was reduced in normal-weight essential hypertension (EH) compared with healthy controls (NS), and the generation of tritiated DHPG was less.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form?

    The relation of BMI to mortality is J shaped, this relationship is not dictated by smoking, and the best (lowest mortality) weight for height increases with age.

    “Andres reported that the relation of BMI to mortality was J shaped, this relationship not being dictated by smoking, and that the best (lowest mortality) weight for height increases with age.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Andres 1

      Not checked in the free run.

    • cites Build study, 2

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Whole-body DEXA scans demonstrate a clear relationship of BMI to fat mass and fat-free mass.

    “Despite these considerations, whole-body DEXA (dual-energy X-ray absorptiometry) scans demonstrate a clear relationship of BMI to fat mass and fat-free mass.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] source

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisenone given
    § Is This Because Sympathetic Activation in Obesity-Hypertension Takes a Benign Form?

    No ready explanation of the Obesity Paradox is available.

    “Beyond the general premise that it might be helpful to have ample energy reserves available in the form of adipose depots in contexts like these, a not unreasonable proposition, no ready explanation of the Obesity Paradox is available.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Applying extensive exclusions to the analysis of weight and mortality data is a flawed process.

    “Flegal et al 16 have emphasized that applying extensive exclusions to the analysis of weight and mortality data is a flawed process.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

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  • May combine two claims.

    Premisecitation

    In the index study of 1727 men aged 50 to 79 years, age-adjusted all-cause and ischemic heart disease mortality was reduced in overweight and obese men, and this finding remained when those with a history of cigarette smoking were excluded.

    “In this index study on 1727 men aged 50 to 79 years, age-adjusted all-cause and ischemic heart disease mortality was reduced in overweight and obese men, a finding which remained when those with a history of cigarette smoking were excluded.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With the coexistence of impaired norepinephrine reuptake with firing salvos in normal-weight essential hypertension and in depressive illness and panic disorder, there is evidence of cardiac risk, even in panic disorder.

    “Conversely, with the coexistence of impaired norepinephrine reuptake with firing salvos in normal-weight essential hypertension 31,[33][34][35][36] and in depressive illness 42,51,79 and panic disorder, 51,79,80 there is evidence of cardiac risk, 84 even in panic disorder.[85][86][87]”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [31] source

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    • cites [42] source

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    • cites [51] source

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    • cites [79] source

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    • cites [80] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Epinephrine has higher affinity for β-adrenoceptors than norepinephrine, so a potential for cardiac arrhythmia generation exists.

    “But of interest is the high affinity of epinephrine for β-adrenoceptors, higher than for norepinephrine, so a potential for cardiac arrhythmia generation exists.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    There is evidence of greater blood pressure lowering with antiadrenergic antihypertensive drugs in patients with obesity-hypertension.

    “One view is that in patients with obesity-hypertension, antiadrenergic antihypertensive drugs should be preferentially used; there is evidence of greater blood pressure lowering in them.105”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fissuring or rupture of an atherosclerotic plaque commonly is the immediate antecedent to activation of the thrombosis cascade.

    “The fissuring or rupture of an atherosclerotic plaque commonly is the immediate antecedent to the activation of the thrombosis cascade.99”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] source

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  • May combine two claims.

    Interpretationcitation

    Nerve firing salvos are most likely generated in sympathetic ganglia and are probably represented in multiple regional sympathetic outflows, including the outflow to skeletal muscle vasculature and to the heart.

    “The phenomenon of nerve firing salvos, because it is most likely generated in sympathetic ganglia, 52 is probably represented in multiple regional sympathetic outflows, including in the outflow to skeletal muscle vasculature where it can be measured, and to the heart where it can be inferred.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The presence of multiple firing salvos in the human heart is probable, because patients who have nerve firing salvos recorded at microneurography have, in parallel, the highest levels of cardiac norepinephrine spillover.

    “Direct recording from the human cardiac sympathetic nerves is not possible, but the presence there of multiple firing salvos is probable, as patients who have nerve firing salvos recorded at microneurography have, in parallel, the highest levels of cardiac norepinephrine spillover.51”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ongoing systemic sympathetic activation has long been thought to be noxious in heart failure and renal failure.

    “Ongoing systemic sympathetic activation has long been thought to be noxious, in heart failure 18,19 and renal failure.113”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] source

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    • cites [19] source

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    • cites [113] source

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  • May combine two claims.

    Premisecitation

    A diet producing negative energy balance, with accompanying weight loss, reduces sympathetic activity and lowers blood pressure.

    “A diet producing negative energy balance, with accompanying weight loss, reduces sympathetic activity and lowers blood pressure.111,112”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [111] source

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    • cites [112] source

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  • Classified as probably not a substantial claim.

    Interpretationnone given

    Evaluation of sympathetic activation has usually been imprecise, involving global, generic tests such as plasma norepinephrine measurements.

    “But it has not been possible to take this idea further, to the investigation of less extreme cases, because the evaluation of sympathetic activation has usually been imprecise, involving global, generic tests such as plasma norepinephrine measurements.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aging increases sympathetic activity, evident in higher multiunit sympathetic nerve firing measured by microneurography and in higher cardiac norepinephrine spillover, both at rest and during mental stress.

    “Aging does increase sympathetic activity, evident in higher multiunit sympathetic nerve firing measured by microneurography 77 and in higher cardiac norepinephrine spillover, both at rest and during mental stress.90”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [77] source

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    • cites [90] source

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24 of 24

  • The authors state this as an assumption.

    The existence of an Obesity Paradox in hypertension is taken as given.

    “I take the existence of an Obesity Paradox to be disputed, but a given.”

  • The authors state this as an assumption.

    The epinephrine is coreleased from cardiac sympathetic nerves along with norepinephrine.

    “The assumption, probable but not proven here, is that the epinephrine is coreleased from cardiac sympathetic nerves along with norepinephrine.”

  • The paper relies on this without support.

    Volume expansion is common in obesity-hypertension.

    “in contrast with obesity-hypertension, in whom volume expansion is common.”

  • The paper relies on this without support.

    Metabolic risk is commonly present in obesity-hypertension.

    “The thesis is that this risk must outrank the metabolic risk commonly present in obesity-hypertension.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Renal sympathetic nerve activity, assessed by kidney noradrenaline spillover, is higher in individuals with obesity than in those who are non-obese and normotensive.

    “RSNA, assessed by kidney noradrenaline spillover, is also higher in individuals with obesity than in those who are non-obese and normotensive152,154.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [154]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cardiac epinephrine release in heart failure is described as both neural and nonneural

    Minor

    The text says reference 39 demonstrated release from sympathetic nerves, but the cited reference's title describes evidence for nonneural release. Those descriptions assign opposing sources to the same reported finding.

1 of 1

Cites

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Cited by

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Related

Authors
Esler, M., Lambert, G., Schlaich, M., Dixon, J., Sari, C. I., & Lambert, E.
Affiliations
  • Baker Heart and Diabetes Institute (AU)
  • From the Baker Heart and Diabetes Institute, Melbourne, Australia (M.E., J.D., C.I.S.); Swinburne University of Technology, Melbourne, Australia (G.L., E.L.); and School of Medicine, Royal Perth Hospital Unit, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Perth (M.S.).
ORCID
Venue
Hypertension
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-01
Volume
71
Issue
1
Pages
22-33
ISSN
  • 0194-911X (ISSN-L)
  • 1524-4563
DOI
10.1161/hypertensionaha.117.09790
OpenAlex
W2770121686
Semantic Scholar
5b84cbb3f471e879e70742f2e63f94a7a41cdbd8
Cited by
60
References
117
Citations by year
2026: 1 · 2025: 1 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 10 · 2020: 6 · 2019: 9 · 2018: 8
FWCI
0.89
Type
journal article
Language
en
Open access
Locations
  • Hypertension (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
  • Swinburne figshare (Swinburne University of Technology) (submittedVersion)
Funders
  • Australian Government
  • Swinburne University of Technology
  • State Government of Victoria
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
obesity paradox, obesity, cardiovascular risk
MeSH terms
Humans, Hypertension, Mortality, Obesity, Sympathetic Nervous System, Comorbidity, Body Mass Index

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