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Sympathetic activation in congestive heart failure: an updated overview

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Abstract

Conclusive evidence demonstrates that the sympathetic nervous system activation is a hallmark of congestive heart failure. This has been shown via a variety of biochemical, neurophysiological, and neuroimaging approaches for studying human sympathetic neural function. The sympathetic activation appears to be an early phenomenon in the clinical course of the disease, closely related to its severity and potentiated by the concomitant presence of other comorbidities, such as obesity, diabetes mellitus, metabolic syndrome, hypertension, and renal failure. The adrenergic overdrive in heart failure is associated with other sympathetic abnormalities, such as the downregulation of beta-adrenergic adrenoreceptors at cardiac level, and exerts unfavorable consequences on the cardiovascular system. These include the endothelial dysfunction, the development of left ventricular hypertrophy, the atherosclerosis development, as well as the generation of atrial and ventricular arrhythmias, and, at very extreme levels of sympathetic activation, the occurrence of microscopic myocardial necrosis. Given the close direct independent relationships detected in heart failure between sympathetic activation and mortality, the adrenergic overdrive has become a target of neuromodulatory therapeutic interventions, which include non-pharmacological, pharmacological, and device-based interventions. For some of these approaches (specifically bilateral renal nerves ablation and carotid baroreceptor stimulation), additional studies are needed to better define their impact on the clinical course of the disease.

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References

  1. Willis T (1664-1964) The anatomy of the brain and nerves, 3rd edn. Feindel W (ed). McGill University Press, Montreal

  2. Heymans CJF, Folkow B (1982) Vasomotor control and regulation of blood pressure. In: Fishman AP, Richards DW (eds) Circulation of the blood. Men and Ideas. American Physiological Society, Bethesda, pp 407–486

    Google Scholar 

  3. Von Euler US (1946) A specific sympathetic ergone in adrenergic nerve fibres (sympathin) and its relation to adrenaline and noradrenaline. Acta Physiol Scand 12:73–97

    Google Scholar 

  4. Von Euler US, Hellner S, Purkhold A (1954) Excretion of noradrenaline in the urine in hypertension. Scand J Clin Lab Invest 6:54–59

    Google Scholar 

  5. Grassi G, Esler M (1999) How to assess sympathetic activity in humans. J Hypertens 17:719–734

    CAS  PubMed  Google Scholar 

  6. Goldstein DS, Chang PC, Eisenhofer G, Miletich R, Finn R, BacherJ (1990) Positron emission tomographic imaging of cardiac sympathetic innervation and function. Circulation 81:1606–1621

  7. Hagbarth KE, Vallbo AB (1968) Pulse and respiratory grouping of sympathetic impulses in human muscle nerves. Acta Physiol Scand 74:96–106

    CAS  PubMed  Google Scholar 

  8. Wallin BG, Delius W, Hagbarth KE (1973) Comparison of sympathetic nerve activity in normotensive and hypertensive subjects. Circ Res 33:9–21

    CAS  PubMed  Google Scholar 

  9. Grassi G, Colombo M, Seravalle G, Spaziani D, Mancia G (1998) Dissociation between muscle and skin sympathetic nerve activity in essential hypertension, obesity, and congestive heart failure. Hypertension 31:64–67

    CAS  PubMed  Google Scholar 

  10. Grassi G, Seravalle G, Quarti-Trevano F, Dell’Oro R, Bolla G, Mancia G (2003) Effects of hypertension and obesity on the sympathetic activation of heart failure patients. Hypertension 42:873–877

    CAS  PubMed  Google Scholar 

  11. Grassi G, Seravalle G, Cattaneo BM, Lanfranchi A, Vailati S, Giannattasio C, Del Bo A, Sala C, Bolla GB, Pozzi M, Mancia G (1995) Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 92:3206–3211

    CAS  PubMed  Google Scholar 

  12. Macefield V, Wallin BG, Vallbo AB (1994) The discharge behaviour of single vasoconstrictor motoneurones in human muscle nerves. J Physiol Lond 481:799–809

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lambert E, Straznicky N, Schlaich MP, Dawood T, Hotchkin E, Esler MD, Lambert GW (2007) Differing patterns of sympathoexcitation in normal weight and obesity-related hypertension. Hypertension 50:862–868

    CAS  PubMed  Google Scholar 

  14. Seals DR, Esler MD (2000) Topical review: human ageing and the sympathoadrenal system. J Physiol (London) 528:407–417

    CAS  Google Scholar 

  15. Macefield VG, Rundqvist B, Bergmann-Sverrisdottir Y, Wallin BG, Elam M (1999) Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with heart failure. Circulation 100:1708–1713

    CAS  PubMed  Google Scholar 

  16. Vaddadi GL, Esler MD, Socratous F, Schlaich MP, Chopra R, Eikelis N, Lambert G, Trauer T, Lambert E (2011) Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes. Circ Arrhythm Electrophysiol:711–718

  17. Esler M, Jennings G, Lambert G, Meredith I, Horne M, Eisenhofer G (1990) Overflow of catecholamine neurotransmitters to the circulation: source, fate and functions. Physiol Rev 70:963–985

    CAS  PubMed  Google Scholar 

  18. Hasking G, Esler M, Jennings G, Burton D, Johns J, Korner P (1986) Norepinephrine spillover to plasma in congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73:615–621

    CAS  PubMed  Google Scholar 

  19. Adanich R, El Hunjut M, Alkhawam H, Kosmas CE, Madanich A, Vittorio TJ (2016) A perspective on sympathetic renal denervation in chronic congestive heart failure. Heart Fail Rev 21:1–10

    Google Scholar 

  20. Afari ME, Syed W, Tsao L (2018) Implantable devices for heart failure monitoring and therapy. Heart Fail Rev 23:935–944

    PubMed  Google Scholar 

  21. Kingwell BA, Thompsom JH, Kaye DM, Mc Pherson GA, Jennings GL, Esler MD (1994) Heart rate spectral analysis, cardiac norepinephrine spillover and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation 90:234–240

    CAS  PubMed  Google Scholar 

  22. Allman KC, Wieland DM, Muzik O, Degrado TR, Wolfe ER, Schwaiger M (1993) Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans. J Am Coll Cardiol 22:368–375

    CAS  PubMed  Google Scholar 

  23. Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702

    CAS  PubMed  Google Scholar 

  24. Eisenhofer G, Friberg P, Rundqvist B, Quyyumi AA, Lambert G, Kaye DM, Kopin IJ, Goldstein DS, Esler MD (1996) Cardiac sympathetic nerve function in congestive heart failure. Circulation 93:1667–1676

    CAS  PubMed  Google Scholar 

  25. Goldstein DS, Holmes C, Stuhlmuller JE, Lenders GW, Kopin IJ (1997) 6-[18F] fluorodopamine positron emission tomography (PET) scanning in the assessment of cardiac sympathoneuronal function. Clin Auton Res 7:17–29

    CAS  PubMed  Google Scholar 

  26. Chidsey CA, Braunwald E, Morrow GA (1965) Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Am J Med 39:442–451

    CAS  PubMed  Google Scholar 

  27. Chidsey CA, Braunwald E, Morrow GA, Mason DT (1963) Myocardial norepinephrine concentration in man: effects of reserpine and of congestive heart failure. N Engl J Med 269:653–658

    CAS  PubMed  Google Scholar 

  28. Esler MD, Kaye D (2000) Measurement of sympathetic nervous system activity in heart failure. The role of norepinephrine kinetics. Heart Fail Rev 5:15–25

    Google Scholar 

  29. Thomas JA, Marks BH (1978) Plasma norepinephrine in congestive heart failure. Am J Cardiol 41:233–243

    CAS  PubMed  Google Scholar 

  30. Grassi G, D’Arrigo G, Pisano A, Bolignano D, Mallamaci F, Dell’Oro R, Quarti-Trevano F, Seravalle G, Mancia G, Zoccali C (2019) Sympathetic neural overdrive in congestive heart failure and its correlates: systematic reviews and meta-analysis. J Hypertens 37:1746–1756

    CAS  PubMed  Google Scholar 

  31. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL (1986) Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 73:913–919

    PubMed  Google Scholar 

  32. Grassi G, Seravalle G, Bertinieri G, Turri C, Stella ML, Scopelliti F, Mancia G (2001) Sympathetic and reflex abnormalities in heart failure secondary to ischaemic or idiopathic dilated cardiomiopathy. Clin Sci 101:141–146

    CAS  Google Scholar 

  33. Grassi G, Seravalle G, Dell’Oro R, Facchini A, Ilardo V, Mancia G (2004) Sympathetic and baroreflex function in hypertensive or heart failure patients with ventricular arrhythmias. J Hypertens 22:1747–1753

    CAS  PubMed  Google Scholar 

  34. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzales-Juanatey JR, Hariola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope M, Ruschitzka F, Rutten FH, van der Meer P (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur Heart J 37:2129–2200

    PubMed  Google Scholar 

  35. Seravalle G, Quarti-Trevano F, Dell’Oro R, Gronda E, Spaziani D, Facchetti R, Cuspidi C, Mancia G, Grassi G (2019) Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction. J Hypertens 37:443–448

    CAS  PubMed  Google Scholar 

  36. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sagerman WS, Liuie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 307:205–211

    CAS  PubMed  Google Scholar 

  37. Nakata T, Hashimoto A, Sugawara H (2013) Cardiac metaiodobenzylguanidine imaging and heart failure. Curr Heart Fail Rep 10:359–364

    CAS  PubMed  Google Scholar 

  38. Morris MJ, Cox HS, Lambert GW, Kaye DM, Jennings GL, Meredith IT, Esler MD (1997) Region-specific plasma NPY concentrations and overflows at rest and during sympathetic activation in man. Hypertension 29:137–143

    CAS  PubMed  Google Scholar 

  39. Brunner-La Rocca HP, Esler MD, Jennings GL, Kaye DM (2001) Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure. Eur Heart J 22:1136–1143

    CAS  PubMed  Google Scholar 

  40. Zucher IH, Liu JL (2000) Angiotensin II-nitric oxide interactions in the control of sympathetic outflow in heart failure. Heart Fail Rev 5:27–43

    Google Scholar 

  41. Singh RB, Hristova K, Fedacko J, El-Killary G, Cornelissen G (2019) Chronic heart failure. A disease of the brain. Heart Fail Rev 24:301–330

    PubMed  Google Scholar 

  42. Eckberg DL, Drabinsky M, Braunwald E (1971) Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 285:877–883

    CAS  PubMed  Google Scholar 

  43. Floras JS (2009) Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J Am Coll Cardiol 54:375–385

    CAS  PubMed  Google Scholar 

  44. Shivkumar K, Ajijola OA, Anand I, Armour JA, Chen PS, Elser MD, De Ferrari GM, Fishbein MC, Goldberger JJ, Harper RM, Joyner MJ, Khalsa SS, Kumar R, Lane R, Mahajan A, Po S, Schwartz PJ, Somers VK, Valderrabano M, Vaseghi M, Zipes DP (2016) Clinical neurocardiology - defining the value of neuroscience-based cardiovascular therapeutics. J Physiol 594:3911–3954

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Cohn J, Levine T, Olivari MT, Garberg V, Tura D, Francis GS, Simon AB, Rector T (1984) Plasma norepinephrine as a guide to prognosis in patients with congestive heart failure. N Engl J Med 311:819–823

    CAS  PubMed  Google Scholar 

  46. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD (1995) Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 26:1257–1263

    CAS  PubMed  Google Scholar 

  47. Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FC, Tripepi G, Bonanno G, Rapisarda F, Fatuzzo P, Seminara G, Cataliotti A, Malatino LS (2002) Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation 105:1354–1359

    CAS  PubMed  Google Scholar 

  48. Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trobetta IC, Roveda F, De Matos LN, Braga AM, Middelekauff HR, Negrao CE (2009) Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol 135:302.307

    Google Scholar 

  49. Petersson M, Friberg P, Eisenhofer G, Lambert G, Rundqvist B (2005) Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure. Eur Heart J 26:906–913

    PubMed  Google Scholar 

  50. DiBona GF, Kopp UC (1997) Neural control of renal function. Physiol Rev 77:75–197

    CAS  PubMed  Google Scholar 

  51. Martins T, Vitorino M, Moreira-Goncalves D, Amado F, Duarte JA, Ferreira R (2014) Recent insights on the molecular mechanisms and therapeutic approaches for cardiac cachexia. Clin Biochem 47:8–15

    CAS  PubMed  Google Scholar 

  52. Horwich TB, Fonarow GL, Clark AL (2018) Obesity and obesity paradox in heart failure. Prog Cardiovasc Dis 61:151–156

    PubMed  Google Scholar 

  53. Esler MD, Lambert G, Schlaich M, Dixon J, Ika Sari C, Lambert E (2018) The obesity paradox in hypertension: is this due to the sympathetic nervous system activation in obesity-hypertension taking a benign form? Hypertension 71:22–33

    CAS  PubMed  Google Scholar 

  54. Van Bilsen M, Patel HC, Bauersachs J, Böhm M, Borggrefe M, Brutsaert D, Coats AJS, de Boer RA, de Keulenaer GW, Filippatos GS, Floras J, Grassi G, Jankowska EA, Kornet L, Lunde IG, Maack C, Mahfoud F, Pollesello P, Ponikowski P, Ruschitzka F, Sabbah HN, Schultz HD, Seferovic P, Slart RHJA, Taggart P, Tocchetti CG, Van Laake LW, Zannad F, Heymans S, Lyon AR (2017) The autonomic nervous system as a therapeutic target in heart failure: a scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 19:1361–1378

    PubMed  Google Scholar 

  55. Correale M, Monaco I, Tricarico L, Bottigliero D, Sicuranza M, Del Forno B, Godeas G, Teri A, Maiorano A, Perulli R, Centola A, De Bonis M, Di Biase M, Brunetti ND (2019) Advanced heart failure: non pharmacological approach. Heart Fail Rev 24:779–791

    PubMed  Google Scholar 

  56. Jafri SM (2004) The effects of beta-blockers on morbidity and mortality in heart failure. Heart Fail Rev 9:115–121

    CAS  PubMed  Google Scholar 

  57. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004

    Google Scholar 

  58. Devgun J, Jobanputra VB, Arustamyan M, Chait R, Ghumman W (2018) Devices and interventions for the prevention of the adverse outcome of tachycardia on heart failure. Heart Fail Rev 23:507–516

    CAS  PubMed  Google Scholar 

  59. Hopper I, Gronda E, Hoppe UC, Rundqvist B, Marwick TH, Shetty S, Hayward C, Lambert T, Hering D, Esler M, Schlaich M, Walton A, Airoldi F, Brandt MC, Cohen SA, Reiters P, Krum H (2017) Sympathetic responses and outcomes following renal denervation in patients with chronic heart failure: 12-month outcomes from the Symplicity HF feasibility study. J Card Fail 23:702–707

    PubMed  Google Scholar 

  60. Gronda E, Seravalle G, Brambilla G, Costantino G, Casini A, Alsheraei A, Lovett EG, Mancia G, Grassi G (2014) Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function and cardiac haemodynamics in heart failure. A proof-of-concept study. Eur J Heart Fail 16:977–983

    PubMed  PubMed Central  Google Scholar 

  61. Abraham WT, Zile MR, Weaver FA, Butter C, Ducharme A, Halbach M, Lovett EG, Muller-Ehmsen J, Scahfer J, Senni M, Swarup V, Wachter R, Little WC (2015) Baroreflex activation therapy for the treatment of heart failure with a preserved ejection fraction. J Am Coll Cardiol Heart Fail 3:487–496

    Google Scholar 

  62. Tsioufis C, Iliakis P, Kasiakogias A, Kostantinidis D, Lovic D, Petras D, Doumas M, Tsiamis E, Papademetriou V, Tousoulis D (2017) Non pharmacological modulation of the autonomic nervous system for heart failure treatment: where do we stand? Curr Vasc Pharmacol 16:30–43

    PubMed  Google Scholar 

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  1. Clinica Medica, Department of Medicine and Surgery, University of Milano-Bicocca, Via Pergolesi 33, 20052, Monza, Italy

    Guido Grassi & Fosca Quarti-Trevano

  2. Baker IDI Heart and Diabetes Institute, Melbourne, Australia

    Murray D. Esler

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  1. Guido Grassi
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  2. Fosca Quarti-Trevano
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  3. Murray D. Esler
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Grassi, G., Quarti-Trevano, F. & Esler, M.D. Sympathetic activation in congestive heart failure: an updated overview. Heart Fail Rev 26, 173–182 (2021). https://doi.org/10.1007/s10741-019-09901-2

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