ESC Heart Fail. 2021 Sep 07; doi: 10.1002/ehf2.13580. Epub 2021 Sep 07.

Sympathetic activation in heart failure with reduced and mildly reduced ejection fraction: the role of aetiology.

ESC heart failure

Réka Urbancsek, Zoltán Csanádi, Ildikó Noémi Forgács, Tímea Bianka Papp, Judit Boczán, Judit Barta, Csaba Jenei, László Nagy, László Rudas

PMID: 34492735 DOI: 10.1002/ehf2.13580

Abstract

AIM: While sympathetic overactivity in heart failure (HF) with reduced ejection fraction (HFrEF; EF < 40%) is well-documented, it is ill-defined in patients with mildly reduced EF (HFmrEF; EF 40-49%). Furthermore, the significance of ischaemic versus non-ischaemic aetiology in sympathetic activation is also unclear and has yet to be studied in HF. Our goal was to compare muscle sympathetic nerve activity (MSNA) in HFmrEF and HFrEF patients and in healthy subjects, as well as to elucidate the influence of the underlying disease.

METHODS AND RESULTS: Twenty-three HFrEF (age 58 ± 10 years), 33 HFmrEF patients (age 61 ± 10 years), including 11 subjects with non-ischaemic cardiomyopathy in each HF groups and 10 healthy controls (age 55 ± 10 years), were studied. MSNA-detected by peroneal microneurography, continuous arterial pressure, and ECG-was recorded. MSNA frequency (burst/min) and incidence (burst/100 cycles) were calculated. Association with the patients' characteristics were assessed, and aetiology-based comparisons were performed. Burst frequency demonstrated a significant stepwise increase in both HFmrEF (41 ± 11 burst/min) and HFrEF (58 ± 17 burst/min, P < 0.001) patients as compared with controls (27 ± 9; P < 0.001 for both HF groups). Similarly, burst incidences were 66 ± 17, 82 ± 15, and 36 ± 10 burst/100 cycles in HFmrEF, HFrEF patients, and in healthy controls, respectively (P < 0.001 for all). Burst frequencies in HF patients showed significant correlation with NT-proBNP levels, and significant inverse correlations with the subjects' mean RR intervals, stroke volumes, pulse pressures, and EF.

CONCLUSIONS: Muscle sympathetic nerve activity parameters indicated significant sympathetic activation in both HFmrEF and HFrEF patients as compared with healthy controls with no difference in relation to ischaemic versus non-ischaemic aetiology.

© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Keywords: Baroreflex; Ejection fraction; Heart failure; Muscle sympathetic nerve activity

References

1. Lam CSP, Solomon SD. The middle child in heart failure: heart failure with mid-range ejection fraction (40-50%). Eur J Heart Fail 2014; 16: 1049-1055. - PubMed
2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P. 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 Cardi-ology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129-2200. - PubMed
3. Koh AS, Tay WT, Teng THK, Vedin O, Benson L, Dahlstrom U, Savarese G, Lam CS, Lund LH. A comprehensive population-based characterization of heart failure with mid-range ejection fraction. Eur J Heart Fail 2017; 19: 1624-1634. - PubMed
4. Savarese G, Orsini N, Hage C, Dahlström U, Vedin O, Rosano GM, Lund LH. Associations with and prognostic and discriminatory role of N-Terminal pro-B-type natriuretic peptide in heart failure with preserved versus mid-range versus reduced ejection fraction. J Cardiac Fail 2018; 24: 365-374. - PubMed
5. Webb J, Draper J, Fovargue L, Sieniewicz B, Gould J, Claridge S, Barton C, Smith S, Tondel K, Rajani R, Kapetanakis S. Is heart failure with mid range ejection fraction (HfmrEF) a distinct clinical entity or an overlap group? Int J Cardiol Heart Vasc 2018; 21: 1-6. - PubMed
6. Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 1971; 285: 877-883. - PubMed
7. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlöf G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986; 73: 913-919. - PubMed
8. Ferguson DS, Berg WJ, Sanders JS. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. J Am Coll Cardiol 1990; 16: 1125-1134. - PubMed
9. Ferguson DS, Berg WJ, Roach PJ, Oren RM, Merk A. Effects of heart failure on baroreflex control of sympathetic neural activity. Am J Cardiol 1992; 69: 523-531. - PubMed
10. Floras JS. Sympathetic nervous system activation in human heart failure. J Am Coll Cardiol 2009; 54: 375-395. - PubMed
11. Barretto ACP, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, Roveda F, de Matos LN, Braga AM, Middlekauff HR, Negrão CE. Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Intern J Cardiol 2009; 135: 302-307. - PubMed
12. Grassi G, Seravalle G, Cattaneo BM, Lanfranchi A, Vailati S, Giannattasio C, Del Bo A, Sala C, Bolla GB, Pozzi M, Mancia G. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 1995; 92: 3206-3211. - PubMed
13. Rundquist B, Elam M, Bergmann-Sverrisdottir Y, Eisenhoffer G, Friberg P. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation 1997; 95: 169-175. - PubMed
14. 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. - PubMed
15. Verloop WL, Beeftink MMA, Santema BT, Bots ML, Blankestijn PJ, Cramer MJ, Doevendans PA, Voskuil M. A systematic review concerning the relation between the sympathetic nervous system and heart failure with preserved ejection fraction. Plos One; doi: 10.1371/journal.pone.0117332. Published online 6 Feb 2015. - PubMed
16. Toschi-Dias E, Rondon MUPB, Cogliati C, Paolocci N, Tobaldini E, Montano N. Contribution of autonomic reflexes to the hyperadrenergic state in heart failure. Front Neurosci; doi: 10.3389/fnins.2017.00162. Published online 30 Mar 2017. - PubMed
17. Seravalle G, Quarti-Trevano F, Dell'Oro R, Gronda E, Spaziani D, Facchetti R, Cuspidi C, Mancia G, Grassi G. Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction. J Hyperterns. 2019; 37: 443-448. - PubMed
18. Notarius CF, Spaak J, Morris BL, Floras JS. Comparison of muscle sympathetic activity in ischemic and nonischemic heart failure. J Card Fail 2007; 13: 470-475. - PubMed
19. Grassi G, Seravalle G, Bertineri G, Turri C, Stella ML, Scopelliti F, Mancia G. Sympathetic and reflex abnormalities in heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Clin Sci 2001; 101: 121-146. - PubMed
20. Chioncel O, Lainscak M, Seferovic PM, Anker SD, Crespo Leiro MG, Harjola VP, Parissis J, Laroche C, Piepoli MF, Fonseca C, Mebazaa A. Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry. Eur J Heart Fail 2017; 19: 1574-1585. - PubMed
21. Penttilä J, Snapir A, Kentala E, Koskenvuo J, Posti J, Scheinin M, Scheinin H, Kuusela T. Estimation of cardiac output in a pharmacological trial using a simple method based on arterial blood pressure signal waveform: a comparison with pulmonary thermodilution and echocardiographic methods. Eur J Clin Pharmacol 2006; 62: 401-407. - PubMed
22. Fagius J, Wallin BG. Sympathetic reflex latencies and conduction velocities in normal man. J Neurol Sci 1980; 47: 433-448. - PubMed
23. Faggiano P, D'Aloia A, Gualeni A, Brentana L, Dei CL. The 6 minute walking test in chronic heart failure: indications, interpretation and limitations from a review of the literature. Eur J Heart Fail 2004; 6: 687-691. - PubMed
24. Swedberg K, Cleland J, Dargie H, Drexler H, Follath F, Komajda M, Tavazzi L, Smiseth OA, Gavazzi A, Haverich A, Hoes A, Jaarsma T, Korewicki J, Lévy S, Linde C, Lopez-Sendon JL, Nieminen MS, Piérard L, Remme WJ. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005). The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26: 2472-2473. - PubMed
25. Urbancsek R, Forgács IN, Papp TB, Boczán J, Barta J, Édes I, Csanádi Z, Rudas L. Cardiovagal and sympathetic baroreflex regulation in heart failure. Orv Hetil 2021; 162: 91-98. - PubMed
26. Rudas L, Crossman AA, Morillo CA, Halliwill JR, Tahvanainen KU, Kuusela TA, Eckberg DL. Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol 1999; 276: H1691-H1698. - PubMed
27. Floras JS, Ponikowski P. The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 2015; 36: 1974-1982. - PubMed
28. Grassi G, D'Arrigo G, Pisano A, Bolignano D, Mallamaci F, Dell'Oro R, Quarti-Trevano F, Seravalle G, Mancia G, Zoccali C. Sympathetic neural overdrive in congestive heart failure and its correlates: systematic reviews and meta-analysis. J Hypertens 2019; 37: 1746-1756. - PubMed
29. Teng-Hwa KT, Wan TT, Dahlstrom U, Benson L, Lam CSP, Lund LH. Different relationship between pulse pressure and mortality in heart failure with reduced, mid-range and preserved ejection fraction. Intern J Cardiol 2018; 254: 203-209. - PubMed

Publication Types

• Journal Article

Grant support

• GINOP-2.3.2-15-2016-00043/Development of Therapeutic Dosies Forms Thematic Programme of the University of Debrecen
• NKFIH-1150-6/2019/Ministry of Innovation and Technology in Hungary