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Cited by 616Blood Pressure and Hypertension StudiesHeart Rate Variability and Autonomic ControlCardiovascular Syncope and Autonomic Disorders

The Sympathetic Nervous System Alterations in Human Hypertension

Open access
Grassi, Guido, Mark, Allyn, Esler, Murray·2015·Circulation Research
DOI 10.1161/circresaha.116.303604PMC PMC4367954
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Abstract

Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that sympathetic nervous system activation contributes to the development, maintenance, and complications of human hypertension, with distinct neuroadrenergic patterns in obesity-related and renal hypertension. It critically evaluates methods for assessing human sympathetic activity and device-based sympathetic deactivation, concluding that renal denervation remains promising but was undermined by incomplete and often untested denervation, notably in SYMPLICITY HTN-3.

Key findings

  • Direct measures—muscle sympathetic nerve traffic and regional norepinephrine spillover—show sympathetic activation in early and established hypertension, including skeletal muscle, kidney, and heart, but the activation is not uniform; for example, it does not extend to skin sympathetic activity, and elderly hypertensives do not always show increased renal norepinephrine spillover.
  • Obesity-related hypertension has a distinct sympathetic profile: cardiac norepinephrine spillover is lower in obese normotensive and hypertensive patients than in lean counterparts; renal norepinephrine spillover is elevated in obese subjects but is not higher in obese hypertensive vs obese normotensive subjects, whereas lean hypertensives have higher renal norepinephrine spillover than lean normotensives. Pharmacologic studies show an exaggerated sympathetic contribution to blood pressure in obesity, with ganglionic blockade producing a fall in blood pressure in obese hypertensives double that in obese normotensives.
  • Renal sympathetic nerves are central to hypertension pathogenesis; chronic kidney disease and end-stage renal disease show sympathetic activation, with end-stage renal disease having the highest systemic sympathetic activation, equal to or exceeding New York Heart Association class IV cardiac failure, reversed by bilateral nephrectomy but not by renal transplantation.
  • Device-based therapies: the Rheos carotid baroreceptor stimulator trial implanted 265 patients randomized 2:1 to immediate stimulation (n=181) or deferred stimulation (n=84), but the primary efficacy endpoint was not reached at 6 months; renal denervation trials showed office systolic blood pressure falling on average by 20–30 mm Hg, durable beyond 3 years, yet SYMPLICITY HTN-1 achieved on average only 47% renal denervation (sometimes <25%), and SYMPLICITY HTN-3 failed its primary efficacy endpoint, with 74% of patients lacking even one fully circumferential renal artery energy application.

Methods

  • Narrative review of human studies assessing sympathetic cardiovascular function, including heart rate, power spectral analysis, plasma norepinephrine, radiolabeled norepinephrine spillover, microneurography, and sympathetic neuroimaging.
  • The review draws mainly on studies using regional norepinephrine spillover and direct microneurographic recordings, and discusses clinical trials of carotid baroreceptor stimulation and catheter-based renal denervation, including SYMPLICITY HTN-1, HTN-2, HTN-3, and the Rheos trial.
  • No systematic search strategy, meta-analysis, or new primary data collection is described; the synthesis is expert narrative.

Limitations

  • The paper states limitations of sympathetic assessment methods: heart rate is nonspecific and not a reliable marker of regional sympathetic activity; plasma norepinephrine has poor sensitivity and reproducibility and cannot represent “overall” sympathetic activity; microneurography cannot directly assess kidney or heart sympathetic activity; norepinephrine spillover requires radiolabeled norepinephrine and catheterization; neuroimaging is costly and static.
  • The paper states limitations of renal denervation research: denervation was almost never tested in clinical trials, achieved denervation is often incomplete and non-uniform, SYMPLICITY HTN-3 failed its primary endpoint with inadequate energy delivery, and patient preselection remains problematic until denervation effectiveness and hypertension pathophysiology can be discriminated.
  • Evident from the text: as a review, it provides no new experimental data, and its conclusions depend on selected literature; the paper also notes that human mechanistic evidence for obesity-associated sympathetic activation and hypertension remains inconclusive, partly due to lack of safe, reversible leptin antagonists.

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

Integrity signals

Registry

Crossref · 10.1161/circresaha.116.303604

Cites

127 of 127 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 204 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Subsequent studies employing microneurography or measurements of norepinephrine spillover in young adults with borderline or established hypertension have demonstrated marked sympathetic activation.

    “Subsequent studies employing microneurography or measurements of norepinephrine spillover in young adults with borderline or established hypertension have also demonstrated marked sympathetic activation28,32,33.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Esler M Jennings G Korner P Willett I Dudley F Hasking G Anderson W Lambert G The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover Hypertension 1988 11 3 20 2828236 source

      Not checked in the free run.

    • cites [32] Anderson EA Sinkey CA Lawton WJ Mark AL Elevated sympathetic nerve activity in borderline hypertensive humans: evidence from direct intraneural recordings Hypertension 1988 14 1277 1283 2759678

      Not checked in the free run.

    • cites [33] Floras JS Hara K Sympathoneural and haemodynamic characteristics of young subjects with mild essential hypertension J Hypertens 1993 11 647 655 8397244 source

      Not checked in the free run.

  • Premisecitation

    Young subjects with hyperkinetic borderline hypertension had increased heart rate frequently associated with an elevation in plasma norepinephrine.

    “In classic studies by Julius et al31, young subjects with hyperkinetic borderline hypertension, had increased heart rate which was frequently associated with an elevation in plasma norepinephrine.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Julius S Krause L Schork NJ Majia AD Jones KA van der Ven C Johnson EH Sekkarie MA Kjieldsen SE Petrin J Hyperkinetic borderline hypertension in Tecumseh, Michigan J Hypertens 1991 9 77 84 1848264 source

      Not checked in the free run.

  • Interpretationreasoning

    Although there are exceptions, the weight of evidence suggests that in the early stages of hypertension, particularly in young patients, there is marked adrenergic overdrive.

    “Although there are several exception34,35, the weight of evidence suggest that in the early stages of hypertension, particularly in young patients, there is marked adrenergic overdrive, a finding that supports the hypothesis that sympathetic overactivity occurs in the clinical phases of essential hypertension.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Rea RF Hamdan M Baroreflex control of muscle sympathetic nerve activity in borderline hypertension Circulation 1990 82 856 862 2394007 source

      Not checked in the free run.

    • cites [35] Schobel HP Heusser K Schmieder RE Veelken R Fischer T Luft FC Evidence against elevated sympathetic vasoconstrictor activity in borderline hypertension. J Am Soc Neprol 1998 9 1581 1587 9727365 source

      Not checked in the free run.

  • Premisecitation

    Microneurographic studies almost universally show that sympathetic nerve traffic is potentiated in established hypertension in middle age and in elderly as well as young patients.

    “As far as the second issue is concerned, microneurographic studies almost universally shown that sympathetic nerve traffic is potentiated in established hypertension in middle age and in elderly as well as young patients38–46.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [38] Grassi G Cattaneo BM Seravalle G Lanfranchi A Mancia G Baroreflex control of sympathetic nerve activity in essential and secondary hypertension Hypertension 1998 81 68 72 9449393 source

      Not checked in the free run.

    • cites [39] Grassi G Seravalle G Bertinieri G Turri C Dell'Oro R Stella ML Mancia G Sympathetic and reflex alterations in systo-diastolic and systolic hypertension of the elderly J Hypertens 2000 18 587 593 10826562 source

      Not checked in the free run.

    • cites [40] Greenwood JP Scott EM Stoker JB Mary DASG Hypertensive left ventricular hypertrophy: relationship to peripheral sympathetic drive J Am Coll Cardiol 2001 38 1711 1717 11704385 source

      Not checked in the free run.

    • cites [41] Smith PA Graham LN Mackintosh AF Stoker JB Mary DA Sympathetic neural mechanisms in white-coat hypertension J Am Coll Cardiol 2002 40 126 133 12103266 source

      Not checked in the free run.

    • cites [42] Schlaich MP Kaye DM Lambert E Sommerville M Socratous F Esler MD Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy Circulation 2003 108 560 565 12847071 source

      Not checked in the free run.

    • cites [43] Smith PA Graham LN Mackintosh AF Stoker JB Mary DA Relationship between central sympathetic activity and stages of human hypertension Am J Hypertens 2004 17 217 222 15001194 source

      Not checked in the free run.

    • cites [44] Burns J Sivananthan MU Ball SG Mackintosh AF Mary DASG Greenwood JP Relationship between central sympathetic drive and magnetic resonance imaging-determined left ventricular mass in essential hypertension Circulation 2007 115 1999 2005 17389264 PMC3925820 source

      Not checked in the free run.

    • cites [45] Grassi G Seravalle G Quarti-Trevano F Dell'Oro R Arenare F Spaziani D Mancia G Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction Hypertension 2009 53 205 209 19124679 source

      Not checked in the free run.

    • cites [46] Mancia G Grassi G The autonomic nervous system and hypertension Circ Res 2014 114 1804 1814 24855203 source

      Not checked in the free run.

  • Interpretationcitation

    In the early stages of hypertension or in young hypertensives, the sympathetic nervous system is activated.

    “Studies examining indirect and direct markers of sympathetic function have provided compelling evidence in the early stages of hypertension or in young hypertensives, the sympathetic nervous system is activated.”
    Quote in the paperSubstantial claim
  • May combine two claims. 63
  • Classified as probably not a substantial claim. 7
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Power spectral analysis of heart rate has significant limitations as a quantitative and specific indicator of cardiac sympathetic as opposed to parasympathetic activity, and its insight does not extend beyond sympathetic control of heart rate.

    “Despite this appeal, the method has significant limitations, particularly as a quantitative and specific indicator of cardiac sympathetic as opposed to parasympathetic activity, and its insight does not extend beyond sympathetic control of heart rate26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Eckberg DL Sympathovagal balance. A critical appraisal Circulation 1997 96 3224 3232 9386196 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    There is no such thing as 'overall' or 'generalized' sympathetic nerve activity or tone, and no single method can provide an overall assessment of the sympathetic nervous system.

    “As a result of these complexities, there is no such thing as “overall” or “generalized” sympathetic nerve activity or tone, and one cannot obtain an overall assessment of the sympathetic nervous system with any single method.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Grassi G Esler M How to assess sympathetic activity in humans J Hypertens 1999 17 719 734 10459867 source

      Not checked in the free run.

    • cites [23] Grassi G Vailati S Bertinieri G Seravalle G Stella ML Dell’Oro R Mancia G Heart rate as marker of sympathetic activity J Hypertens 1998 16 1635 1639 9856364 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Measurements of regional norepinephrine spillover to kidney and heart and direct microneurographic recordings of central neural sympathetic traffic to skeletal muscle circulation represent the gold standards for evaluating the sympathetic nervous system in humans today.

    “In summary, measurements of regional norepinephrine spillover to kidney and heart and direct microneurographic recordings of central neural sympathetic traffic to the skeletal muscle circulation represent the gold standards for evaluating the sympathetic nervous system in humans today.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In normotensive obese humans, there are marked increases in renal norepinephrine spillover but decreases in cardiac norepinephrine spillover despite the frequent presence of elevated heart rate.

    “As mentioned later, an example of this advantage is the evidence that in normotensive obese humans, there are marked increases in renal norepinephrine spillover, but decreases in cardiac norepinephrine spillover despite the frequent presence of elevated heart rate30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Vaz M Jennings G Turner A Cox H Lambert G Esler M Regional sympathetic nervous system activity and oxygen consumption in obese normotensive subjects Circulation 1997 96 3423 3429 9396437 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Heart rate cannot be taken as either a marker of cardiac sympathetic adrenergic activity or a reliable indicator of sympathetic activity to other regional circulations.

    “These and other studies24,25 indicate that despite the ease of measurement, heart rate cannot be taken as either a marker of cardiac sympathetic adrenergic activity or a reliable indicator of sympathetic activity to other regional circulations.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Grassi G Seravalle G Calhoun DA Bolla GB Giannattasio C Marabini M Del Bo A Mancia G Mechanisms responsible for sympathetic activation by cigarette smoking in humans Circulation 1994 90 248 253 8026005 source

      Not checked in the free run.

    • cites [25] Anderson EA Hoffman RP Balon TW Sinkey CA Mark AL Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans J Clin Invest 1991 87 2246 2252 2040704 PMC296986 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Measurement of plasma norepinephrine has limited sensitivity and reproducibility as an index of sympathetic activity.

    “However, the sensitivity and reproducibility of the measurements are far from optimal22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Grassi G Esler M How to assess sympathetic activity in humans J Hypertens 1999 17 719 734 10459867 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Measurement of plasma norepinephrine (or any other single measurement) cannot be taken as a sensitive or specific marker of overall sympathetic activity and may miss alterations in sympathetic activity in various regions or levels.

    “Consequently, measurement of plasma norepinephrine (or any other single measurement) cannot be taken as a sensitive or specific marker of overall sympathetic activity and may miss alterations in sympathetic activity in various regions or levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Circulating norepinephrine levels are only a minor fraction of the amount secreted from sympathetic nerve terminals, so plasma norepinephrine values may not reflect sympathetic neural drive and secretion.

    “First, circulating norepinephrine levels are only a minor fraction of the amount secreted from sympathetic nerve terminals27. As a result, plasma norepinephrine values may not reflect sympathetic neural drive and secrection of the neurotransmitter27,28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Esler M Jennings G Lambert G Meredith I Horne M Eisenhofer G Overflow of catecholamine neurotransmitters to the circulation: source, fate and functions Physiol Rev 1990 70 963 985 1977182 source

      Not checked in the free run.

    • cites [28] Esler M Jennings G Korner P Willett I Dudley F Hasking G Anderson W Lambert G The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover Hypertension 1988 11 3 20 2828236 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Measurement of regional norepinephrine spillover to kidney and heart is the distinctive strength of the norepinephrine isotope dilution method; no other method currently available provides direct quantitative measurement of sympathetic adrenergic drive to the kidney or heart in humans.

    “Measurement of regional norepinephrine spillover to kidney and heart is the distinctive strength of this method. No other method currently available provides direct quantitative measurement of sympathetic adrenergic drive to the kidney or heart in humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In healthy humans there are good relationships between microneurographic data collected in the peroneal nerve and the cardiac or renal neural network, but this may not pertain in pathologic states.

    “In healthy humans there are good relationships between the microneurographic data collected in the peroneal nerve and the ones characterizing the cardiac or the renal neural network, but this may not pertain in pathologic states22,.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Grassi G Esler M How to assess sympathetic activity in humans J Hypertens 1999 17 719 734 10459867 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The norepinephrine isotope dilution method permits precise quantification of the net release of norepinephrine from sympathetic nerves and the amount of norepinephrine undergoing clearance from the bloodstream.

    “This method permits precise quantification of the “net” release of the adrenergic neurotransmitter from sympathetic nerves and the amount of norepinephrine undergoing “clearance” from the bloodstream27,28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Esler M Jennings G Lambert G Meredith I Horne M Eisenhofer G Overflow of catecholamine neurotransmitters to the circulation: source, fate and functions Physiol Rev 1990 70 963 985 1977182 source

      Not checked in the free run.

    • cites [28] Esler M Jennings G Korner P Willett I Dudley F Hasking G Anderson W Lambert G The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover Hypertension 1988 11 3 20 2828236 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because of limited methodology, there is much less information about sympathetic activity to the splanchnic circulation in humans.

    “Because of limited methodology, there is much less information about sympathetic activity to the splanchnic circulation in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The sympathetic nervous system contributes to the development and maintenance of hypertension and to end organ damage.

    “This evidence supports the concept that the sympathetic nervous system contributes to the development and maintenance of hypertension and to end organ damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Neuroadrenergic factors may contribute to the maintenance and progression as well as the development of the hypertensive state.

    “This finding suggests that neuroadrenergic factors may contribute to the maintenance and progression as well as the development of the hypertensive state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Studies of elderly hypertensives have not always documented an increase in renal norepinephrine spillover, in contrast to the finding of increased sympathetic nerve traffic to skeletal muscle circulation.

    “Interestingly, studies of elderly hypertensives have not always documented an increase in renal norepinephrine spillover in contrast to the finding of increased sympathetic nerve traffic to the skeletal muscle circulation22,28,39,47.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [22] Grassi G Esler M How to assess sympathetic activity in humans J Hypertens 1999 17 719 734 10459867 source

      Not checked in the free run.

    • cites [28] Esler M Jennings G Korner P Willett I Dudley F Hasking G Anderson W Lambert G The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover Hypertension 1988 11 3 20 2828236 source

      Not checked in the free run.

    • cites [39] Grassi G Seravalle G Bertinieri G Turri C Dell'Oro R Stella ML Mancia G Sympathetic and reflex alterations in systo-diastolic and systolic hypertension of the elderly J Hypertens 2000 18 587 593 10826562 source

      Not checked in the free run.

    • cites [47] Esler M Lambert G Jennings G Regional norepinephrine turnover in human hypertension Clin Exp Hypertens 1989 11 Suppl 1 75 89 2743607 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In obese hypertensive humans, there is enhanced muscle sympathetic nerve activity, but the neurophysiologic basis of this increase is different in obese vs lean hypertensive subjects.

    “In obese hypertensive humans, there is enhanced muscle sympathetic nerve activity, but the neurophysiologic basis of this increase is different in obese vs lean hypertensive subjects67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Lambert E Straznicky N Schlaich M Esler M Dawood T Hotchkin E Lambert G Differing pattern of sympathoexcitation in normal-weight and obesity-related hypertension Hypertension 2007 50 862 8628 17909120 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cardiac norepinephrine spillover is decreased in obese normotensives and is only marginally increased in obese hypertensives.

    “First, cardiac norepinephrine spillover is decreased in obese normotensives and is only marginally increased in obese hypertensives59,60–61.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [59] Vaz M Jennings G Turner A Cox H Lambert G Esler M Regional sympathetic nervous system activity and oxygen consumption in obese normotensive subjects Circulation 1997 96 3423 3429 9396437 source

      Not checked in the free run.

    • cites [60] Rumantir MS Vaz M Jennings GL Collier G Kaye DM Seals DR Wiesner GH Brunner-LaRocca HP Esler MD Neural mechanisms in human obesity-related hypertension J Hypertens 1999 17 1125 1133 10466468 source

      Not checked in the free run.

    • cites [61] Esler M Straznicky N Eikelis N Masuo K Lambert G Lambert E Mechanisms of sympathetic activation in obesity-related Hypertension Hypertension 2006 48 787 796 17000932 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Sympathetic overactivity in human hypertension is not uniform or universal; it does not extend to skin sympathetic activity.

    “The sympathetic overactivity is not, however, uniform or universal. It does not, for example, extend to skin sympathetic activity57.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Grassi G Colombo M Seravalle G Spaziani G Mancia G Dissociation between muscle and skin sympathetic nerve activity in essential hypertension, obesity and congestive heart failure Hypertension 1998 31 84 87 9449392 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While obesity and essential hypertension are both characterized by sympathetic overactivity, there are features of the altered sympathetic nervous system in human obesity and obesity-associated hypertension that are distinct from those in essential hypertension.

    “These studies have demonstrated that while obesity and essential hypertension are both characterized by sympathetic overactivity, there are features of the altered sympathetic nervous system in human obesity and obesity-associated hypertension that are distinct from those in essential hypertension.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Insulin-induced increases in skeletal muscle blood flow play an important role in glucose delivery and uptake, and impaired insulin-induced vasodilation in skeletal muscle contributes importantly to reduced glucose uptake in skeletal muscle and to insulin resistance.

    “Laakso et al83 introduced the concept that insulin-induced increases in skeletal muscle blood flow play an important role in glucose delivery and uptake, i.e. impaired insulin-induced vasodilation in skeletal muscle contributes importantly to reduced glucose uptake in skeletal muscle and to insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Laakso M Edelman SV Brechtel G Baron AD Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: a novel mechanism for insulin resistance J Clin Invest 1990 85 1844 1852 2189893 PMC296649 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Heightened sympathetic activity may be a necessary but not sufficient cause for the development of hypertension in obesity.

    “An additional explanation may be that heightened sympathetic activity is a necessary but not sufficient cause for the development of hypertension in obesity61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Esler M Straznicky N Eikelis N Masuo K Lambert G Lambert E Mechanisms of sympathetic activation in obesity-related Hypertension Hypertension 2006 48 787 796 17000932

      Not checked in the free run.

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

    Premisecitation

    The sympathoexcitatory response to obesity is triggered by hyperinsulinemia, and the sympathetic activation in turn increases vascular resistance.

    “Landsberg62 proposed that the sympathoexcitatory response to obesity is triggered by hyperinsulinemia and that the sympathetic activation in turn increases vascular resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Landsberg L Diet, obesity, and hypertension: an hypothesis involving insulin, the sympathetic nervous system and adaptive thermogenesis Q J Med 1986 61 1081 1090 3310065 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    After ganglionic blockade, blood pressure was normalized in obese normotensives, while in obese hypertensives it decreased but did not completely normalize, indicating that factors other than the sympathetic nervous system contribute to obesity-associated hypertension.

    “Third, after ganglionic blockade, blood pressure was normalized in the obese normotensives. Blood pressure also decreased in the obese hypertensives but it did not completely indicating that factors other than the sympathetic nervous system contribute to obesity-associated hypertension.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Shibao C Gamboa A Diedrich A Ertl AC Chen KY Byrne DW Farley G Paranjape SY Davis SN Biaggioni I Autonomic contribution to blood pressure and metabolism in obesity Hypertension 2007 49 27 33 17116758 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The fall in blood pressure with ganglionic blockade in obese hypertensives was double that in obese normotensives, consistent with an important role for the sympathetic nervous system in maintaining blood pressure in obese hypertensives.

    “Second, the fall in blood pressure with ganglionic blockade in the obese hypertensives was double that in the obese normotensives, consistent with an important role for the sympathetic nervous system in maintaining blood pressure in obese hypertensives.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Shibao C Gamboa A Diedrich A Ertl AC Chen KY Byrne DW Farley G Paranjape SY Davis SN Biaggioni I Autonomic contribution to blood pressure and metabolism in obesity Hypertension 2007 49 27 33 17116758 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationcitation

    The sympathetic contribution to blood pressure is greater in hypertensive vs normotensive obese humans.

    “This study supports an exaggerated sympathetic contribution to blood pressure in both normotensive and hypertensive obese humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Muscle sympathetic nerve activity is higher in hypertensive vs normotensive obese subjects, but renal norepinephrine spillover is not different in hypertensive vs normotensive obese subjects.

    “Muscle sympathetic nerve activity is higher in hypertensive vs normotensive obese subjects, but renal norepinephrine spillover is not different in hypertensive vs normotensive obese subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Increased sympathetic vasoconstriction decreases glucose uptake in skeletal muscle and thereby promotes insulin resistance and compensatory hyperinsulinemia.

    “In turn, increased sympathetic vasoconstriction decreases glucose uptake in skeletal muscle and thereby promotes insulin resistance and compensatory hyperinsulinemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The sympathetic nervous system promotes insulin resistance in skeletal muscle through hemodynamic mechanisms, and the interaction of insulin, the sympathetic nervous system and insulin sensitivity is a two-way street.

    “These studies advanced the concept that the sympathetic nervous system promotes insulin resistance in skeletal muscle through hemodynamic mechanisms and that the interaction of insulin, the sympathetic nervous system and insulin sensitivity is a two way street88.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Julius S Jamerson K Sympathetics, insulin resistance and coronary risk in hypertension: the ‘chicken and egg’ question J Hypertens 1994 12 494 502 7930548 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A bolus injection of leptin in healthy lean men produces an acute increase in muscle sympathetic nerve activity but blood pressure does not increase.

    “Machleidt et al93 demonstrated that a bolus injection of leptin in healthy lean men produced an acute increase in muscle sympathetic nerve activity but blood pressure did not increase.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Machleidt F Simon P Krapalis AF Hallschmid M Lehnert H Sayk F Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans J Clin Endocrinol Metab 2013 98 E491 E496 23393176 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ganglionic blockade improves insulin-glucose metabolism in obese insulin resistant subjects with elevated baseline muscle sympathetic nerve activity but not in obese insulin sensitive subjects.

    “Recently, Gamboa et al87 expanded on this discovery by demonstrating that ganglionic blockade improved insulin-glucose metabolism in obese insulin resistant subjects with elevated baseline muscle sympathetic nerve activity but not in obese insulin sensitive subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Gamboa A Okamoto LE Arnold AC Figueroa RA Diedrich A Raj SR Paranjape SY Farley G Abumrad N Biaggioni I Autonomic blockade improves insulin sensitivity in obese subjects Hypertension 2014 64 867 874 25001269 PMC4162826 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The renal sympathetic nerves, through their multiple influences on tubular processing of sodium, on renin secretion and on renal vascular resistance, with activation of the renal sympathetic outflow in essential hypertension as the driver, are pivotal in hypertension pathogenesis.

    “The renal sympathetic nerves, through their multiple influences on tubular processing of sodium, on renin secretion and on renal vascular resistance94,95, with activation of the renal sympathetic outflow in essential hypertension as the driver, are pivotal in hypertension pathogenesis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] DiBona GF The functions of the renal nerves Rev Physiol Biochem Pharmacol 1982 94 75 181

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95] DiBona GF Kopp UC Neural control of renal function Physiol Rev 1997 77 75 197 9016301 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Obesity-associated hypertension in humans is characterized by sympathetic overactivity, but there are features of the sympathetic nervous system in obesity that are distinct from those in lean hypertensives.

    “Obesity-associated hypertension in humans is characterized by sympathetic overactivity, but there are features of the sympathetic nervous system in obesity that are distinct from those in lean hypertensives.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The genetic neurobiologic basis of obesity can critically influence the sympathetic and blood pressure response to obesity, and hypothalamic melanocortin-4 receptors contribute to regulation of sympathetic activity and blood pressure in obese humans.

    “These data support the concept, discussed above, that the genetic neurobiologic basis of obesity can critically influence the sympathetic and blood pressure response to obesity78, and demonstrate that hypothalamic melanocortin-4 receptors contribute to regulation of sympathetic activity and blood pressure in obese humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Mark AL Correia M Morgan DA Shaffer RA Haynes WG State-of-the-art-lecture: obesity induced hypertension: new concepts from emerging biology of obesity Hypertension 1999 33 537 541 9931161 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rodents with loss of function mutations in hypothalamic melanocortin-4 receptors are obese but lack sympathetic activation and obesity-associated hypertension.

    “Rodents with loss of function mutations in the hypothalamic melanocortin-4 receptors are obese but lack sympathetic activation and obesity-associated hypertension74,75.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Rahmouni K Obesity-associated hypertension. Recent progress in deciphering the pathogenesis Hypertension 2014 64 215 221 24821943 PMC4184930 source

      Not checked in the free run.

    • cites [75] Hall JE da Silva AA do Carmo JM Dubinion J Hamza S Munusamy S Smith G Stec DE Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins J Biol Chem 2010 285 17271 17276 20348094 PMC2878489 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stimulation of hypothalamic melanocortin-4 receptors increases sympathetic activity and blood pressure.

    “In addition to inhibiting appetite and increasing metabolism, stimulation of hypothalamic melanocortin-4 receptors increases sympathetic activity and blood pressure74,75.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Rahmouni K Obesity-associated hypertension. Recent progress in deciphering the pathogenesis Hypertension 2014 64 215 221 24821943 PMC4184930 source

      Not checked in the free run.

    • cites [75] Hall JE da Silva AA do Carmo JM Dubinion J Hamza S Munusamy S Smith G Stec DE Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins J Biol Chem 2010 285 17271 17276 20348094 PMC2878489 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The sympathetic neural outflow is commonly activated also to the heart and skeletal muscle vasculature, but renal sympathetic activation is central to hypertension pathogenesis.

    “The sympathetic neural outflow is commonly activated also to the heart, shown with selective cardiac norepinephrine spillover measurements28, and to the skeletal muscle vasculature, demonstrated with microneurographic nerve traffic recording32,33,38–46, but it is the renal sympathetic activation which is central to hypertension pathogenesis96–97.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [28] Esler M Jennings G Korner P Willett I Dudley F Hasking G Anderson W Lambert G The assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover Hypertension 1988 11 3 20 2828236 source

      Not checked in the free run.

    • cites [32] Anderson EA Sinkey CA Lawton WJ Mark AL Elevated sympathetic nerve activity in borderline hypertensive humans: evidence from direct intraneural recordings Hypertension 1988 14 1277 1283 2759678

      Not checked in the free run.

    • cites [33] Floras JS Hara K Sympathoneural and haemodynamic characteristics of young subjects with mild essential hypertension J Hypertens 1993 11 647 655 8397244 source

      Not checked in the free run.

    • cites [38] Grassi G Cattaneo BM Seravalle G Lanfranchi A Mancia G Baroreflex control of sympathetic nerve activity in essential and secondary hypertension Hypertension 1998 81 68 72 9449393 source

      Not checked in the free run.

    • cites [39] Grassi G Seravalle G Bertinieri G Turri C Dell'Oro R Stella ML Mancia G Sympathetic and reflex alterations in systo-diastolic and systolic hypertension of the elderly J Hypertens 2000 18 587 593 10826562 source

      Not checked in the free run.

    • cites [40] Greenwood JP Scott EM Stoker JB Mary DASG Hypertensive left ventricular hypertrophy: relationship to peripheral sympathetic drive J Am Coll Cardiol 2001 38 1711 1717 11704385 source

      Not checked in the free run.

    • cites [41] Smith PA Graham LN Mackintosh AF Stoker JB Mary DA Sympathetic neural mechanisms in white-coat hypertension J Am Coll Cardiol 2002 40 126 133 12103266 source

      Not checked in the free run.

    • cites [42] Schlaich MP Kaye DM Lambert E Sommerville M Socratous F Esler MD Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy Circulation 2003 108 560 565 12847071 source

      Not checked in the free run.

    • cites [43] Smith PA Graham LN Mackintosh AF Stoker JB Mary DA Relationship between central sympathetic activity and stages of human hypertension Am J Hypertens 2004 17 217 222 15001194 source

      Not checked in the free run.

    • cites [44] Burns J Sivananthan MU Ball SG Mackintosh AF Mary DASG Greenwood JP Relationship between central sympathetic drive and magnetic resonance imaging-determined left ventricular mass in essential hypertension Circulation 2007 115 1999 2005 17389264 PMC3925820 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Nociceptive sensory nerves of the kidneys detect renal injury, project to the central nervous system, and contribute to the systemic sympathetic nervous system activation of severe essential hypertension, renal hypertension and end-stage renal disease.

    “Beyond that, nociceptive sensory nerves of the kidneys which detect renal injury, through projection to the central nervous system, contribute to the systemic sympathetic nervous system activation of severe essential hypertension, renal hypertension and end-stage renal disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pressure-sensitive receptors in the renal pelvis are sympathoinhibitory and important in mediating reno-renal reflexes.

    “The second are pressure-sensitive receptors in the renal pelvis; these are sympathoinhibitory and important in mediating reno-renal reflexes95.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] DiBona GF Kopp UC Neural control of renal function Physiol Rev 1997 77 75 197 9016301 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Renal sympathetic denervation shifts the renal pressure-natriuresis curve to the left, promoting urinary sodium excretion and lowering blood pressure.

    “Renal sympathetic denervation shifts the renal pressure-natriuresis curve to the left, promoting urinary sodium excretion and lowering of blood pressure94–98.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [94] DiBona GF The functions of the renal nerves Rev Physiol Biochem Pharmacol 1982 94 75 181

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95] DiBona GF Kopp UC Neural control of renal function Physiol Rev 1997 77 75 197 9016301 source

      Not checked in the free run.

    • cites [96] DiBona GF Esler M Translational medicine: the antihypertensive effect of renal denervation Am J Physiol Regul Integr Comp Physiol 2012 298 R245 R253 19955493 source

      Not checked in the free run.

    • cites [97] Esler M Lambert E Schlaich M Point:Counterpoint. Chronic activation of the sympathetic nervous system is the dominant contributor to systemic hypertension J Appl Physiol 2010 109 1996 1998 20185633 source

      Not checked in the free run.

    • cites [98] Roman RJ Cowley AW Characterisation of a new model for the study of pressure natriuresis in the rat Am J Physiol Renal Physiol 1985 248 F190 F198 3970209 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sympathetic activation is present in the early phases of renal disease, in the absence of uremia, being seen in patients with nephrotic syndrome and with autosomal dominant polycystic kidney disease despite normal renal function, and increases with disease progression.

    “Sympathetic activation is present in the early phases of renal disease, in the absence of uremia, being seen in patients with nephrotic syndrome and with autosomal dominant polycystic kidney disease despite normal renal function, and increases with disease progression103.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Campese VM Kogosov E Renal afferent denervation prevents hypertension in rats with chronic renal failure Hypertension 1995 25 878 882 7721447 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The plasma concentration of norepinephrine predicts the incidence of cardiovascular events, and survival, in patients with end-stage renal disease.

    “A striking observation is that of Zoccali and colleagues, who demonstrated the plasma concentration of norepinephrine to predict the incidence of cardiovascular events, and survival, in patients with end-stage renal disease10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Zoccali C Mallamaci F Parlongo S Cutrupi S Benedetto FA Tripepi G Bonanno G Rapisarda F Fatuzzo P Seminara G Cataliotti A Stancanelli B Malatino LS Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease Circulation 2002 105 1354 1359 11901048 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The sympathetic activation of end-stage renal disease, and commonly also the hypertension, is not reversed by successful renal transplantation, but is reversed by bilateral removal of the diseased native kidneys.

    “The sympathetic activation of end-stage renal disease, and commonly also the hypertension, is not reversed by successful renal transplantation49, but is reversed by bilateral removal of the diseased native kidneys48, the surgery removing the influence of the afferent renal nerves.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Hausberg M Kosch M Harmelink P Barenbrock M Hohage H Kisters K Dietl KH Rahn KH Sympathetic nerve activity in end-stage renal disease Circulation 2002 106 1974 1979 12370222 source

      Not checked in the free run.

    • cites [48] Converse RL Jr Jacobsen TN Toto RD Jost CM Cosentino F Fouad-Tarazi F Victor RG Sympathetic overactivity in patients with chronic renal failure N Engl J Med 1992 327 1912 1918 1454086 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Surgical sympathectomy in experimental hypertension abolishes the hypertension, or prevents its development.

    “Surgical sympathectomy in experimental hypertension abolishes the hypertension, or prevents its development94–95.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] DiBona GF The functions of the renal nerves Rev Physiol Biochem Pharmacol 1982 94 75 181

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95] DiBona GF Kopp UC Neural control of renal function Physiol Rev 1997 77 75 197 9016301 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    High sympathetic activity in the heart is arrhythmogenic, providing a partial explanation for the very high rate of sudden death in chronic renal failure.

    “High sympathetic activity in the heart is arrhythmogenic, providing a partial explanation for the very high rate of sudden death in chronic renal failure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Sympathetic nervous system activation in renal hypertension and end-stage renal disease contributes to the blood pressure elevation, to kidney disease progression and to cardiovascular complications and clinical outcomes.

    “Sympathetic nervous system activation in renal hypertension and end-stage renal disease contributes to the blood pressure elevation, to kidney disease progression and to cardiovascular complications and clinical outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sympathetic activation aggravates existing hypertension, proteinuria, interstitial fibrosis and glomerulosclerosis.

    “Sympathetic activation aggravates existing hypertension, proteinuria, interstitial fibrosis and glomerulosclerosis104.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Adamczak M Zeier M Dikow R Ritz E Kidney and hypertension Kidney Int. Suppl 2002 61 S62 S67 11982815 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Three facts provided the knowledge base for the development of catheter-based renal denervation for treatment of essential hypertension: the presence of an activated renal sympathetic outflow in hypertensive patients, the blood-pressure lowering effect of surgical renal denervation in experimental models of hypertension, and the anatomy of the postganglionic renal sympathetic nerves in theirpassag

    “Three facts provided the knowledge base for the development of catheter-based renal denervation for treatment of essential hypertension: 1) the presence of an activated renal sympathetic outflow in hypertensive patients, 2) the blood-pressure lowering effect of surgical renal denervation in experimental models of hypertension, and 3) the anatomy of the postganglionic renal sympathetic nerves in”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [94] DiBona GF The functions of the renal nerves Rev Physiol Biochem Pharmacol 1982 94 75 181

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [95] DiBona GF Kopp UC Neural control of renal function Physiol Rev 1997 77 75 197 9016301 source

      Not checked in the free run.

    • cites [96] DiBona GF Esler M Translational medicine: the antihypertensive effect of renal denervation Am J Physiol Regul Integr Comp Physiol 2012 298 R245 R253 19955493 source

      Not checked in the free run.

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

    Premisenone given

    These new therapies were developed on the well established premise that activation of the sympathetic nervous system commonly initiates and sustains the blood pressure elevation in essential hypertension.

    “These new therapies were developed on the well established premise that activation of the sympathetic nervous system commonly initiates and sustains the blood pressure elevation in essential hypertension.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    In a large-scale, double-blind study, the Rheos device was implanted in 265 patients who were subsequently randomised (2:1) to immediate baroreceptor stimulation for the first 6 months (n=181), or deferred stimulation after 6 months (n=84).

    “In a large-scale, double-blind study, the Rheos device was implanted in 265 patients who were subsequently randomised (2:1) to immediate baroreceptor stimulation for the first 6 months (n=181), or deferred stimulation after 6 months (n=84)117.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Bisognano JD Bakris G Nadim MK Sanchez L Kroon AA Schafer J De Leeuw PW Sica DA Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension J Am Coll Cardiol 2011 58 765 773 21816315 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At 6 months, blood pressure fell in the group receiving immediate treatment, but the primary efficacy endpoint was not reached, partly because blood pressure likewise decreased in many control subjects.

    “At 6 months, blood pressure fell in the group receiving immediate treatment, but the primary efficacy endpoint was not reached, partly because blood pressure likewise decreased in many control subjects117.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Bisognano JD Bakris G Nadim MK Sanchez L Kroon AA Schafer J De Leeuw PW Sica DA Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension J Am Coll Cardiol 2011 58 765 773 21816315 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ganglionic blocking drugs, discovered by Paton and Zaimis, ended the period of surgical sympathectomy for hypertension and ushered in the era of antiadrenergic drugs.

    “Ganglionic blocking drugs, discovered by Paton and Zaimis113, ended the period of surgical sympathectomy for hypertension, and ushered in the era of antiadrenergic drugs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Paton WDM Zaimis EJ Paralysis of autonomic ganglia by methonium salts Brit J Pharmacol 1951 6 155 168 PMC1509185 14821313

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with chronic renal failure, moxonidine minimizes progression of renal disease compared with nitrendipine, an effect not explained by the small falls in blood pressure.

    “and in another study in patients with chronic renal failure106, to minimize progression of renal disease compared with a comparator drug, nitrendipine, an effect not explained by the small falls in blood pressure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Vonend O Marsalek P Russ H Wulkow R Oberhauser V Rump LC Moxonidine treatment of hypertensive patients with advanced renal failure J Hypertens 2003 21 1709 1717 12923404 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The degree of renal denervation achieved in the SYMPLICITY HTN-1 trial was less than expected (on average 47%), but did seem to be sufficient, in that the antihypertensive response was very adequate.

    “The degree of renal denervation achieved in the SYMPLICITY HTN-1 trial was less than expected (on average 47%)20, but did seem to be sufficient, in that the antihypertensive response was very adequate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Krum H Schlaich M Whitbourn R Sobotka PA Sadowski J Bartus K Kapelak B Walton A Sievert H Thambar S Abraham WT Esler M Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study Lancet 2009 373 1275 1281 19332353 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In experimental models of hypertension, activation of central baroreflex pathways by continuous electrical stimulation of the nerves of the carotid sinus baroreceptors reduces sympathetic outflow from the central nervous system and lowers blood pressure.

    “In experimental models of hypertension, activation of central baroreflex pathways by continuous electrical stimulation of the nerves of the carotid sinus baroreceptors reduces sympathetic outflow from the central nervous system and lowers blood pressure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Only two small pilot studies have been conducted, both uncontrolled but successful, in renal hypertension and in end-stage renal disease.

    “To this point only two small pilot studies have been conducted, both uncontrolled but successful, in renal hypertension, and in end-stage renal disease107–108.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] Hering D Mahfoud F Walton AS Krum H Lambert GW Lambert EA Sobotka P Bohm M Cremers B Esler MD Schlaich MP Renal denervation in moderate to severe CKD J Am Soc Nephrol 2012 23 1250 1257 22595301 PMC3380649 source

      Not checked in the free run.

    • cites [108] Schlaich MP Bart B Hering D Walton A Marusic P Mahfoud F Bohm M Lambert EA Krum H Sobotka P Schmieder RE Ika-Sara C Eikelis N Straznicky N Lambert GW Esler MD Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease Int J Cardiology 2013 168 2214 2220 23453868 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The blood pressure reduction after renal denervation is durable, persisting beyond 3 years, with no evidence that renal nerve regeneration occurs to cancel out blood pressure lowering.

    “The blood pressure reduction is durable, persisting beyond 3 years, with no evidence that renal nerve regeneration occurs, to cancel out blood pressure lowering.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    In studies of surgical renal denervation in experimental hypertension, good experimental design demands that the effectiveness of denervation is always confirmed, typically by documenting 90-95% reduction in the kidney content of norepinephrine.

    “This contrasts with the studies of surgical renal denervation in experimental hypertension, where good experimental design demands that the effectiveness of denervation is always confirmed, typically by documenting 90–95% reduction in the kidney content of norepinephrine.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Two device-based therapies targeting the sympathetic nervous system were developed: the surgically implanted barostimulator device and catheter-based renal denervation.

    “This was the development of two device-based therapies targeting the sympathetic nervous system, the surgically implanted barostimulator device117 and catheter-based renal denervation20,118.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [117] Bisognano JD Bakris G Nadim MK Sanchez L Kroon AA Schafer J De Leeuw PW Sica DA Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension J Am Coll Cardiol 2011 58 765 773 21816315 source

      Not checked in the free run.

    • cites [20] Krum H Schlaich M Whitbourn R Sobotka PA Sadowski J Bartus K Kapelak B Walton A Sievert H Thambar S Abraham WT Esler M Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study Lancet 2009 373 1275 1281 19332353 source

      Not checked in the free run.

    • cites [118] Symplicity HTN-2 Investigators Renal sympathetic denervationin patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial Lancet 2010 376 1903 1309 21093036 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SYMPLICITY HTN-3 was five times larger than the first two SYMPLICITY renal denervation trials and incorporated a blinded sham design.

    “Five times larger than the first two SYMPLICITY renal denervation trials, and incorporating a blinded sham design”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Bhatt D Kandzari D O’Neill D’Agostino R Flack J Katzen B Leon M Liu M Mauri L Negoita M Cohen SA Oparil S Rocha-Singh K Towsend RR Bakris GL SYMPLICITY HTN-3 Investigators A controlled trial of renal denervation for resistant hypertension New Engl J Med 2014 370 1393 1401 24678939 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In SYMPLICITY HTN-3, energy delivery was not preferentially to the distal renal artery, where it should have been, but was more typically to the proximal renal artery.

    “Energy delivery was not preferentially to the distal renal artery, where it should have been, but inexplicably was more typically to the proximal renal artery”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kandzari D, presented on behalf of the SYMPLICITY HTN-3 Investigators. EuroPCR 2014, Paris, France

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Subsequent analyses in Melbourne confirm that denervation is often very incomplete, and surprisingly non-uniform from patient to patient.

    “Subsequent analyses in Melbourne confirm that denervation is often very incomplete, and surprisingly non-uniform from patient to patient (Figure 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Achieved denervation can be less than 25%, no doubt inadequate for a full therapeutic effect.

    “Achieved denervation can be less than 25%, no doubt inadequate for a full therapeutic effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    Measurement of regional norepinephrine spillover is well established as a valid test for sympathetic denervation, having been applied for two decades in the diagnosis of pure autonomic failure.

    “Measurement of regional norepinephrine spillover is well established as a valid test for sympathetic denervation, having been applied for two decades in the diagnosis of pure autonomic failure124, a disorder characterized by spontaneous degeneration of postganglionic sympathetic nerve fibers, and denervation of the heart, kidneys and other organs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Meredith IT Esler MD Cox HS Lambert GW Jennings GL Eisenhofer G Biochemical evidence of sympathetic denervation of the heart in pure autonomic failure Clin Auton Res 1991 1 187 194 1822251 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Surgical sympathectomy for the treatment of hypertension, applied in the years 1935-1960, was demonstrably of value in lowering blood pressure and prolonging life in patients with severe and malignant hypertension, but at the cost of disabling side effects.

    “Surgical sympathectomy for the treatment of hypertension, applied in the years 1935–1960112 took many forms, with the various surgeries being demonstrably of value in lowering blood pressure and prolonging life in patients with severe and malignant hypertension, but at the cost of disabling side effects, most notably postural and postprandial hypotension and syncope, and sexual dysfunction.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Smithwick RH Thompson JE Splanchnicectomy for essential hypertension; results in 1,266 cases J Am Med Ass 1953 152 1501 1504 13061307

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After emerging from the kidneys, the afferent nerves travel rostrally at some distance from the renal arteries, but converge on the arteries near their origin from the aorta.

    “after emerging from the kidneys, the afferent nerves travel rostrally at some distance from the renal arteries, but converge on the arteries near their origin from the aorta120.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Sakakura K Ladich E Cheng Q Otsuka F Yahagi K Kolodgie F Joner M Virmani R Anatomical distribution of human renal sympathetic nerves: Pathological study J Am Coll Cardiol 2014 64 635 643 25125292

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In studies where denervation was not tested, the commonly attributed reason for renal denervation to fail to lower blood pressure-that sympathetic activity was not increased-has no authenticity; failure to denervate is the ever-present confounder.

    “The commonly attributed reason for renal denervation to fail to lower blood pressure, that in such patients sympathetic activity was not increased, has no authenticity in studies where denervation was not tested; failure to denervate is the ever-present confounder.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In all but one trial of renal denervation, denervation was not tested.

  • May combine two claims.

    Interpretationreasoning

    Renal denervation is incomplete and non-uniform between patients.

    “As renal denervation is incomplete and non-uniform between patients”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Effective nerve ablation requires fully circumferential renal artery application of energy bilaterally.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    Renal denervation is invariably antihypertensive in four mammalian species (rats, dogs, rabbits, pigs).

    “Why should renal denervation, in four mammalian species (rats, dogs, rabbits pigs) invariably be antihypertensive95–96”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] DiBona GF Kopp UC Neural control of renal function Physiol Rev 1997 77 75 197 9016301 source

      Not checked in the free run.

    • cites [96] DiBona GF Esler M Translational medicine: the antihypertensive effect of renal denervation Am J Physiol Regul Integr Comp Physiol 2012 298 R245 R253 19955493 source

      Not checked in the free run.

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

    Premisereasoning

    Over the past 30 years, there has been enormous progress in understanding the role and importance of the sympathetic nervous system in the pathogenesis of human hypertension and its consequences.

    “The past 30 years witnessed enormous progress in understanding the role and importance of the sympathetic nervous system in the pathogenesis of human hypertension and its consequences.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Preselection of patients will remain problematic until the influence on responder status of the two determinants-effectiveness of denervation and hypertension pathophysiology-can be discriminated.

    “Preselection of patients will remain problematic, until the influence on the responder status of the two determinants, effectiveness of denervation and hypertension pathophysiology can be discriminated.”
    Quote in the paperSubstantial claim
70 of 70

  • The paper relies on this without support.

    Sympathetic activity to the kidney is critical to the pathogenesis of hypertension.

    “Given the view that sympathetic activity to the kidney is critical to the pathogenesis of hypertension”

  • The paper relies on this without support.

    Effective nerve ablation requires fully circumferential renal artery application of energy bilaterally.

    “when it is mandatory that this be achieved bilaterally, making effective nerve ablation impossible.”

  • The paper relies on this without support.

    In all but one trial of renal denervation, denervation was not tested.

    “Failure to test for renal denervation, as an intrinsic component of all trials but one, represents the Achilles heel of the field.”
3 of 3

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 [152]

  • In contrast to skeletal muscle and kidneys, heart sympathetic nerve activity may be within the normal range, or perhaps even reduced, in patients with obesity and hypertension.

    “In contrast to skeletal muscle and kidneys, heart SNA may be within the normal range, or perhaps even reduced, in patients with obesity and hypertension152”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [152]

  • The role of the sympathetic nervous system in linking obesity with elevated blood pressure has been well documented in experimental models and in humans.

    “The role of the SNS in linking obesity with elevated BP has been well documented in experimental models and in humans121,152.”

    From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [152]

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.

  • Conflicting page ranges for the same cited trial

    Minor

    References 17 and 125 cite the same SYMPLICITY HTN-3 trial, with the same journal volume, starting page, and identifier (24678939), but give different ending pages: 1340 and 1401.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. 10.1097/01.hjh.0000084733.53355.c3 · DOI
  2. Zimmer K.Soul Made Flesh. London: The Random House (Arrow Books); 2004:188–207.
  3. van Zwieten PA. Development of antihypertensive drugs: from the bench to the clinic. , Birkenhager WH, Robertson JIS, Zanchetti A, In: Handbook of Hypertension, Hypertension in the Twentieth Century: Concepts and Achievements. Amsterdam: Elsevier; 2004:457–486.
  4. 10.1056/NEJMoa1402670 · DOI · Paper page

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Authors
Grassi, G., Mark, A., & Esler, M.
Affiliations
University of Iowa (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-03-13
Volume
116
Issue
6
Pages
976-990
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.116.303604
PMC
PMC4367954
OpenAlex
W2148827677
Semantic Scholar
fc38a9856fe5409951f47cab8a4e0bf709cf653b
Cited by
616
References
127
Citations by year
2026: 55 · 2025: 50 · 2024: 59 · 2023: 46 · 2022: 45 · 2021: 58 · 2020: 55 · 2019: 64 · 2018: 56 · 2017: 49 · 2016: 57 · 2015: 21
FWCI
44.30
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (HL-84207, P01HL084207)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
Keywords
sympathetic nervous system, hypertension, hypertension pathophysiology, heart rate, plasma norepinephrine, microneurography, norepinephrine spillover, secondary hypertension, obesity, kidney disease, carotid baroreceptor stimulation, renal nerve ablation, antihypertensive therapy
MeSH terms
Animals, Antihypertensive Agents, Clinical Trials as Topic, Diagnostic Techniques, Cardiovascular, Forecasting, Heart Rate, Humans, Hyperinsulinism, Hypertension, Hypertension, Renal, Insulin Resistance, Kidney, Kidney Diseases, Norepinephrine, Obesity, Sympathectomy, Sympathetic Nervous System, Vasoconstriction, Multicenter Studies as Topic, Sympathetic Fibers, Postganglionic, Leptin, Metabolic Syndrome, Melanocortins, Neuroimaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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