Abstract
Several attempts have been made, by the scientific community, to develop a unifying hypothesis that explains the clinical syndrome of heart failure (HF). The currently widely accepted neurohormonal model has substituted the cardiorenal and the cardiocirculatory models, which focused on salt-water retention and low cardiac output/peripheral vasoconstriction, respectively. According to the neurohormonal model, HF with eccentric left ventricular (LV) hypertrophy (LVH) (systolic HF or HF with reduced LV ejection fraction [LVEF] or HFrEF) develops and progresses because endogenous neurohormonal systems, predominantly the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS), exhibit prolonged activation following the initial heart injury exerting deleterious hemodynamic and direct nonhemodynamic cardiovascular effects. However, there is evidence to suggest that SNS overactivity often preexists HF development due to its association with HF risk factors, is also present in HF with preserved LVEF (diastolic HF or HFpEF), and that it is linked to immune/inflammatory factors. Furthermore, SNS activity in HF may be augmented by coexisting noncardiac morbidities and modified by genetic factors and demographics. The purpose of this paper is to provide a contemporary overview of the complex associations between SNS overactivity and the development and progression of HF, summarize the underlying mechanisms, and discuss the clinical implications as they relate to therapeutic interventions mitigating SNS overactivity.
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Braunwald E (1997) Shattuck lecture–cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 337(19):1360–1369
Giannoni A, Mirizzi G, Aimo A, Emdin M, Passino C (2015) Peripheral reflex feedbacks in chronic heart failure: is it time for a direct treatment? World J Cardiol 7(12):824–828
Packer M (1995) Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure. Eur Heart J 16 Suppl F:4–6
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(5):873–877
Badrov MB, Mak S, Floras JS (2021) Cardiovascular autonomic disturbances in heart failure with preserved ejection fraction. Can J Cardiol 37(4):609–620
De Angelis E, Pecoraro M, Rusciano MR, Ciccarelli M, Popolo A (2019) Cross-talk between neurohormonal pathways and the immune system in heart failure: a review of the literature. Int J Mol Sci 20(7)
Floras JS (2016) Sympathetic nervous system in patients with sleep related breathing disorders. Curr Hypertens Rev 12(1):18–26
Bohuslavova R, Cerychova R, Papousek F, Olejnickova V, Bartos M, Gorlach A, Kolar F, Sedmera D, Semenza GL, Pavlinkova G (2019) HIF-1alpha is required for development of the sympathetic nervous system. Proc Natl Acad Sci U S A 116(27):13414–13423
Hogg K, McMurray J (2005) Neurohumoral pathways in heart failure with preserved systolic function. Prog Cardiovasc Dis 47(6):357–366
Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J (2009) The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 54(19):1747–1762
Hartupee J, Mann DL (2017) Neurohormonal activation in heart failure with reduced ejection fraction. Nat Rev Cardiol 14(1):30–38
Floras JS, Ponikowski P (2015) The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 36(30):1974–1982b
Hadaya J, Ardell JL (2020) Autonomic modulation for cardiovascular disease. Front Physiol 11:617459
Ardell JL, Foreman RD, Armour JA, Shivkumar K (2019) Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillation. JCI Insight 4(23)
Hicks MN, Mary DA, Walters GE (1987) Atrial receptor discharge in dogs with chronically induced difference in blood volume. J Physiol 393:491–497
Triposkiadis F, Butler J, Abboud FM, Armstrong PW, Adamopoulos S, Atherton JJ, Backs J, Bauersachs J, Burkhoff D, Bonow RO et al (2019) The continuous heart failure spectrum: moving beyond an ejection fraction classification. Eur Heart J 40(26):2155–2163
Triposkiadis F, Xanthopoulos A, Butler J (2020) From PARADIGM to PARAGON further evidence supporting continuous heart failure spectrum. Eur J Heart Fail 22(9):1536–1539
Floras JS (2021) The 2021 Carl Ludwig lecture. Unsympathetic autonomic regulation in heart failure: patient-inspired insights. Am J Physiol Regul Integr Comp Physiol 321(3):R338-R351
Larabee CM, Neely OC, Domingos AI (2020) Obesity: a neuroimmunometabolic perspective. Nat Rev Endocrinol 16(1):30–43
Smith MM, Minson CT (2012) Obesity and adipokines: effects on sympathetic overactivity. J Physiol 590(8):1787–1801
Lambert EA, Esler MD, Schlaich MP, Dixon J, Eikelis N, Lambert GW (2019) Obesity-Associated organ damage and sympathetic nervous activity. Hypertension 73(6):1150–1159
Grassi G, Biffi A, Seravalle G, Trevano FQ, Dell’Oro R, Corrao G, Mancia G (2019) Sympathetic neural overdrive in the obese and overweight state. Hypertension 74(2):349–358
Menendez A, Wanczyk H, Walker J, Zhou B, Santos M, Finck C (2022) Obesity and adipose tissue dysfunction: from pediatrics to adults. Genes (Basel) 13(10)
Castoldi A, Naffah de Souza C, Camara NO, Moraes-Vieira PM (2015) The macrophage switch in obesity development. Front Immunol 6:637
Pirzgalska RM, Domingos AI (2018) Macrophages in obesity. Cell Immunol 330:183–187
Russo B, Menduni M, Borboni P, Picconi F, Frontoni S (2021) Autonomic nervous system in obesity and insulin-resistance-the complex interplay between leptin and central nervous system. Int J Mol Sci 22(10)
DeLalio LJ, Sved AF, Stocker SD (2020) Sympathetic nervous system contributions to hypertension: updates and therapeutic relevance. Can J Cardiol 36(5):712–720
Fisher JP, Paton JF (2012) The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens 26(8):463–475
Grassi G, Mark A, Esler M (2015) The sympathetic nervous system alterations in human hypertension. Circ Res 116(6):976–990
Triposkiadis F, Xanthopoulos A, Butler J (2019) Cardiovascular aging and heart failure: JACC review topic of the week. J Am Coll Cardiol 74(6):804–813
Webb AJS, Werring DJ (2022) New Insights Into Cerebrovascular Pathophysiology and Hypertension. Stroke 53(4):1054–1064
Holwerda SW, Luehrs RE, DuBose L, Collins MT, Wooldridge NA, Stroud AK, Fadel PJ, Abboud FM, Pierce GL (2019) Elevated muscle sympathetic nerve activity contributes to central artery stiffness in young and middle-age/older adults. Hypertension 73(5):1025–1035
Nardone M, Floras JS, Millar PJ (2020) Sympathetic neural modulation of arterial stiffness in humans. Am J Physiol Heart Circ Physiol 319(6):H1338–H1346
Lau ES, Panah LG, Zern EK, Liu EE, Farrell R, Schoenike MW, Namasivayam M, Churchill TW, Curreri L, Malhotra R et al (2022) Arterial stiffness and vascular load in HFpEF: differences among women and men. J Card Fail 28(2):202–211
Grassi G, Seravalle G, Quarti-Trevano F, Dell’Oro R, Arenare F, Spaziani D, Mancia G (2009) Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 53(2):205–209
Verloop WL, Beeftink MM, Santema BT, Bots ML, Blankestijn PJ, Cramer MJ, Doevendans PA, Voskuil M (2015) A systematic review concerning the relation between the sympathetic nervous system and heart failure with preserved left ventricular ejection fraction. PLoS ONE 10(2):e0117332
Whelton PK, Carey RM, Mancia G, Kreutz R, Bundy JD, Williams B (2022) Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: comparisons, reflections, and recommendations. Circulation 146(11):868–877
Hirooka Y (2020) Sympathetic activation in hypertension: importance of the central nervous system. Am J Hypertens 33(10):914–926
Karakas M, Koenig W (2013) Sympathetic nervous system: a crucial player modulating residual cardiovascular risk. Circ Res 112(1):13–16
Moreira HG, Lage RL, Martinez DG, Ferreira-Santos L, Rondon M, Negrao CE, Nicolau JC (2017) Sympathetic nervous activity in patients with acute coronary syndrome: a comparative study of inflammatory biomarkers. Clin Sci (Lond) 131(9):883–895
Karlsberg RP, Penkoske PA, Cryer PE, Corr PB, Roberts R (1979) Rapid activation of the sympathetic nervous system following coronary artery occlusion: relationship to infarct size, site, and haemodynamic impact. Cardiovasc Res 13(9):523–531
Bhushan S, Kondo K, Predmore BL, Zlatopolsky M, King AL, Pearce C, Huang H, Tao YX, Condit ME, Lefer DJ (2012) Selective beta2-adrenoreceptor stimulation attenuates myocardial cell death and preserves cardiac function after ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 32(8):1865–1874
Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T et al (2012) Myocardial infarction accelerates atherosclerosis. Nature 487(7407):325–329
Kaye DM, Nanayakkara S, Wang B, Shihata W, Marques FZ, Esler M, Lambert G, Mariani J (2022) Characterization of cardiac sympathetic nervous system and inflammatory activation in HFpEF patients. JACC Basic Transl Sci 7(2):116–127
Seo M, Yamada T, Tamaki S, Watanabe T, Morita T, Furukawa Y, Kawasaki M, Kikuchi A, Kawai T, Nakamura J et al (2022) Prognostic significance of cardiac (123)I-MIBG SPECT imaging in heart failure patients with preserved ejection fraction. JACC Cardiovasc Imaging 15(4):655–668
Badrov MB, Keir DA, Tomlinson G, Notarius CF, Millar PJ, Kimmerly DS, Shoemaker JK, Keys E, Floras JS (2023) Normal and excessive muscle sympathetic nerve activity in heart failure: implications for future trials of therapeutic autonomic modulation. Eur J Heart Fail 25(2):201–210
Vergaro G, Aimo A, Prontera C, Ghionzoli N, Arzilli C, Zyw L, Taddei C, Gabutti A, Poletti R, Giannoni A et al (2019) Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction. Int J Cardiol 296:91–97
Jimenez-Marrero S, Moliner P, Rodriguez-Costoya I, Enjuanes C, Alcoberro L, Yun S, Gonzalez-Costello J, Garay A, Tajes M, Calero E et al (2020) Sympathetic activation and outcomes in chronic heart failure: does the neurohormonal hypothesis apply to mid-range and preserved ejection fraction patients? Eur J Intern Med 81:60–66
Triposkiadis F, Giamouzis G, Kitai T, Skoularigis J, Starling RC, Xanthopoulos A (2022) A holistic view of advanced heart failure. Life (Basel) 12(9)
Dunlay SM, Roger VL, Killian JM, Weston SA, Schulte PJ, Subramaniam AV, Blecker SB, Redfield MM (2021) Advanced heart failure epidemiology and outcomes: a Population-Based Study. JACC Heart Fail 9(10):722–732
Subramaniam AV, Weston SA, Killian JM, Schulte PJ, Roger VL, Redfield MM, Blecker SB, Dunlay SM (2022) Development of advanced heart failure: a population-based study. Circ Heart Fail 15(5):e009218
Diaz HS, Toledo C, Andrade DC, Marcus NJ, Del Rio R (2020) Neuroinflammation in heart failure: new insights for an old disease. J Physiol 598(1):33–59
Triposkiadis F, Giamouzis G, Parissis J, Starling RC, Boudoulas H, Skoularigis J, Butler J, Filippatos G (2016) Reframing the association and significance of co-morbidities in heart failure. Eur J Heart Fail 18(7):744–758
Roger VL (2021) Epidemiology of heart failure: a contemporary perspective. Circ Res 128(10):1421–1434
Greenlund IM, Carter JR (2022) Sympathetic neural responses to sleep disorders and insufficiencies. Am J Physiol Heart Circ Physiol 322(3):H337–H349
Mehra R, Chung MK, Olshansky B, Dobrev D, Jackson CL, Kundel V, Linz D, Redeker NS, Redline S, Sanders P et al (2022) Sleep-disordered breathing and cardiac arrhythmias in adults: mechanistic insights and clinical implications: a scientific statement from the American Heart Association. Circulation 146(9):e119–e136
Spiesshoefer J, Regmi B, Ottaviani MM, Kahles F, Giannoni A, Borrelli C, Passino C, Macefield V, Dreher M (2022) Sympathetic and vagal nerve activity in COPD: pathophysiology, presumed determinants and underappreciated therapeutic potential. Front Physiol 13:919422
van Gestel AJ, Steier J (2010) Autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD). J Thorac Dis 2(4):215–222
Ashley C, Burton D, Sverrisdottir YB, Sander M, McKenzie DK, Macefield VG (2010) Firing probability and mean firing rates of human muscle vasoconstrictor neurones are elevated during chronic asphyxia. J Physiol 588(Pt 4):701–712
Kaur J, Young BE, Fadel PJ (2017) Sympathetic overactivity in chronic kidney disease: consequences and mechanisms. Int J Mol Sci 18(8)
Grassi G, Quarti-Trevano F, Seravalle G, Arenare F, Volpe M, Furiani S, Dell’Oro R, Mancia G (2011) Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension 57(4):846–851
Klein I, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ (2001) Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol 12(11):2427–2433
Ji Y, Salavaggione OE, Wang L, Adjei AA, Eckloff B, Wieben ED, Weinshilboum RM (2005) Human phenylethanolamine N-methyltransferase pharmacogenomics: gene re-sequencing and functional genomics. J Neurochem 95(6):1766–1776
Cui J, Zhou X, Chazaro I, DeStefano AL, Manolis AJ, Baldwin CT, Gavras H (2003) Association of polymorphisms in the promoter region of the PNMT gene with essential hypertension in African Americans but not in whites. Am J Hypertens 16(10):859–863
Huang C, Zhang S, Hu K, Ma Q, Yang T (2011) Phenylethanolamine N-methyltransferase gene promoter haplotypes and risk of essential hypertension. Am J Hypertens 24(11):1222–1226
Ji Y, Snyder EM, Fridley BL, Salavaggione OE, Moon I, Batzler A, Yee VC, Schaid DJ, Joyner MJ, Johnson BD et al (2008) Human phenylethanolamine N-methyltransferase genetic polymorphisms and exercise-induced epinephrine release. Physiol Genomics 33(3):323–332
Joseph J, Liu C, Hui Q, Aragam K, Wang Z, Charest B, Huffman JE, Keaton JM, Edwards TL, Demissie S et al (2022) Genetic architecture of heart failure with preserved versus reduced ejection fraction. Nat Commun 13(1):7753
Olivotto I, Udelson JE, Pieroni M, Rapezzi C (2023) Genetic causes of heart failure with preserved ejection fraction: emerging pharmacological treatments. Eur Heart J 44(8):656–667
Maaliki D, Itani MM, Itani HA (2022) Pathophysiology and genetics of salt-sensitive hypertension. Front Physiol 13:1001434
Keir DA, Badrov MB, Tomlinson G, Notarius CF, Kimmerly DS, Millar PJ, Shoemaker JK, Floras JS (2020) Influence of Sex and age on muscle sympathetic nerve activity of healthy normotensive adults. Hypertension 76(3):997–1005
Klassen SA, Joyner MJ, Baker SE (2021) The impact of ageing and sex on sympathetic neurocirculatory regulation. Semin Cell Dev Biol 116:72–81
Xanthopoulos A, Skoularigis J, Triposkiadis F (2023) The neurohormonal overactivity syndrome in heart failure. Life (Basel) 13(1)
Kanazawa H, Fukuda K (2022) The plasticity of cardiac sympathetic nerves and its clinical implication in cardiovascular disease. Front Synaptic Neurosci 14:960606
Kumar HU, Nearing BD, Mittal S, Premchand RK, Libbus I, DiCarlo LA, Amurthur B, KenKnight BH, Anand IS, Verrier RL (2023) Autonomic regulation therapy in chronic heart failure with preserved/mildly reduced ejection fraction: ANTHEM-HFpEF study results. Int J Cardiol 381:37–44
Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ et al (2018) Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 39(1):26–35
Kober L, Thune JJ, Nielsen JC, Haarbo J, Videbaek L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE et al (2016) Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 375(13):1221–1230
Narins CR, Aktas MK, Chen AY, McNitt S, Ling FS, Younis A, Zareba W, Daubert JP, Huang DT, Rosero S et al (2022) Arrhythmic and mortality outcomes among ischemic versus nonischemic cardiomyopathy patients receiving primary ICD therapy. JACC Clin Electrophysiol 8(1):1–11
Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, Morarji K, Brown TD, Ismail NA, Dweck MR et al (2013) Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA 309(9):896–908
Vaduganathan M, Claggett BL, Chatterjee NA, Anand IS, Sweitzer NK, Fang JC, O’Meara E, Shah SJ, Hegde SM, Desai AS et al (2018) Sudden death in heart failure with preserved ejection fraction: a competing risks analysis from the TOPCAT trial. JACC Heart Fail 6(8):653–661
Florea VG, Cohn JN (2014) The autonomic nervous system and heart failure. Circ Res 114(11):1815–1826
Bencivenga L, Palaia ME, Sepe I, Gambino G, Komici K, Cannavo A, Femminella GD, Rengo G (2021) Why do we not assess sympathetic nervous system activity in heart failure management: might GRK2 serve as a new biomarker? Cells 10(2)
Pontico M, Brunotti G, Conte M, Corica F, Cosma L, De Angelis C, De Feo MS, Lazri J, Matto A, Montebello M et al (2022) The prognostic value of (123)I-mIBG SPECT cardiac imaging in heart failure patients: a systematic review. J Nucl Cardiol 29(4):1799–1809
Macefield VG, Wallin BG (2018) Physiological and pathophysiological firing properties of single postganglionic sympathetic neurons in humans. J Neurophysiol 119(3):944–956
Grassi G, Quarti-Trevano F, Esler MD (2021) Sympathetic activation in congestive heart failure: an updated overview. Heart Fail Rev 26(1):173–182
Badrov MB, Notarius CF, Keys E, Floras JS (2022) Muscle sympathetic excitatory response to dynamic 1-leg cycling in heart failure with preserved ejection fraction. JACC Case Rep 4(22):1501–1503
Goes-Santos BR, Rondon E, Fonseca GWP, Sales ARK, Santos MR, Antunes-Correa LM, Ueno-Pardi LM, Oliveira P, Trevizan PF, Mello Franco FG et al (2023) Physical capacity increase in patients with heart failure is associated with improvement in muscle sympathetic nerve activity. Int J Cardiol 378:48–54
Fraga R, Franco FG, Roveda F, de Matos LN, Braga AM, Rondon MU, Rotta DR, Brum PC, Barretto AC, Middlekauff HR et al (2007) Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol. Eur J Heart Fail 9(6–7):630–636
Notarius CF, Millar PJ, Keir DA, Murai H, Haruki N, O’Donnell E, Marzolini S, Oh P, Floras JS (2019) Training heart failure patients with reduced ejection fraction attenuates muscle sympathetic nerve activation during mild dynamic exercise. Am J Physiol Regul Integr Comp Physiol 317(4):R503–R512
Lai Y, Yu L, Jiang H (2019) Autonomic neuromodulation for preventing and treating ventricular arrhythmias. Front Physiol 10:200
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F.T and A.X. had the idea for the article, A.B., T.K., D.M., and T.A. performed the literature search and data analysis, F.T., A.B., T.K., D.M., T.A., J.S., and A.X. drafted and/or critically revised the work.
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Triposkiadis, F., Briasoulis, A., Kitai, T. et al. The sympathetic nervous system in heart failure revisited. Heart Fail Rev 29, 355–365 (2024). https://doi.org/10.1007/s10741-023-10345-y
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DOI: https://doi.org/10.1007/s10741-023-10345-y