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Vol 79, No 10 (2021)
Review paper
Published online: 2021-10-14

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Syncope: new solutions for an old problem

Giulia Rivasi1, Andrea Ungar1, Angel Moya2, Michele Brignole3, Richard Sutton45, Artur Fedorowski56
DOI: 10.33963/KP.a2021.0138
Pubmed: 34668180
Kardiol Pol 2021;79(10):1068-1078.

Abstract

Syncope is a frequent event in the general population. Approximately 1%–2% of all emergency department admissions are due to syncope and at least one-third of all people experience fainting in their life. Although consequences of cardiac syncope are generally feared, non-cardiac syncope is much more common and may be associated with severe injuries and quality-of-life impairment, particularly in older adults. Various diagnostic and therapeutic strategies have been created and implemented over decades, leading to significant improvements in diagnostic accuracy and treatment effectiveness. In recent years, diagnosis and treatment have further evolved according to an innovative approach focused on the hemodynamic mechanism underlying syncope, based upon the assumption that knowledge of the syncope mechanism is a prerequisite for effective syncope prevention and treatment. Therefore, a new classification of syncope has been proposed, which defines two main syncope phenotypes with different predominant mechanisms: the hypotensive phenotype, where hypotension or vasodepression prevails, and the bradycardic phenotype, where cardioinhibition prevails. Identification of syncope phenotype — bradycardic or hypotensive/vasodepressive — represents the first step towards personalized management of syncope, characterized by customized interventions for prevention. The present review aims to illustrate these new developments in the diagnosis and therapy of non-cardiac syncope within a mechanism-based perspective. Diagnosis and therapy of bradycardic and hypotensive phenotypes are discussed, with a focus on recent evidence.

Keywords: reflex syncopebradycardiahypotensioncardioinhibitionvasodepressionlow blood pressure

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References

  1. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018; 39(21): 1883–1948.
    CrossRefPubMed
  2. Brignole M, Rivasi G. New insights in diagnostics and therapies in syncope: a novel approach to non-cardiac syncope. Heart. 2021; 107(11): 864–873.
    CrossRefPubMed
  3. Linzer M, Pontinen M, Gold D, et al. Impairment of physical and psychosocial function in recurrent syncope. Journal of Clinical Epidemiology. 1991; 44(10): 1037–1043.
    CrossRef
  4. van Dijk N, Sprangers MA, Colman N, et al. Clinical factors associated with quality of life in patients with transient loss of consciousness. J Cardiovasc Electrophysiol. 2006; 17(9): 998–1003.
    CrossRefPubMed
  5. Gill TM, Murphy TE, Gahbauer EA, et al. Association of injurious falls with disability outcomes and nursing home admissions in community-living older persons. Am J Epidemiol. 2013; 178(3): 418–425.
    CrossRefPubMed
  6. Vellas BJ, Wayne SJ, Romero LJ, et al. Fear of falling and restriction of mobility in elderly fallers. Age Ageing. 1997; 26(3): 189–193.
    CrossRefPubMed
  7. Gill TM, Murphy TE, Gahbauer EA, et al. The course of disability before and after a serious fall injury. JAMA Intern Med. 2013; 173(19): 1780–1786.
    CrossRefPubMed
  8. Yasa E, Ricci F, Magnusson M, et al. Cardiovascular risk after hospitalisation for unexplained syncope and orthostatic hypotension. Heart. 2018; 104(6): 487–493.
    CrossRefPubMed
  9. Rivasi G, Rafanelli M, Ungar A. Usefulness of tilt testing and carotid sinus massage for evaluating reflex syncope. Am J Cardiol. 2018; 122(3): 517–520.
    CrossRefPubMed
  10. Ungar A, Tesi F, Chisciotti VM, et al. Assessment of a structured management pathway for patients referred to the Emergency Department for syncope: results in a tertiary hospital. Europace. 2016; 18(3): 457–462.
    CrossRefPubMed
  11. Brignole M, Ungar A, Casagranda I, et al. Prospective multicentre systematic guideline-based management of patients referred to the Syncope Units of general hospitals. Europace. 2010; 12(1): 109–118.
    CrossRefPubMed
  12. Brignole M, Rivasi G, Sutton R, et al. Low-blood pressure phenotype underpins the tendency to reflex syncope. J Hypertens. 2021; 39(7): 1319–1325.
    CrossRefPubMed
  13. Stewart JM, Medow MS, Sutton R, et al. Mechanisms of vasovagal syncope in the young: reduced systemic vascular resistance versus reduced cardiac output. J Am Heart Assoc. 2017; 6(1).
    CrossRefPubMed
  14. Nilsson D, Sutton R, Tas W, et al. Orthostatic changes in hemodynamics and cardiovascular biomarkers in dysautonomic patients. PLoS One. 2015; 10(6): e0128962.
    CrossRefPubMed
  15. Kohno R, Detloff BLS, Chen LY, et al. Greater early epinephrine rise with head-up posture: A marker of increased syncope susceptibility in vasovagal fainters. J Cardiovasc Electrophysiol. 2019; 30(3): 289–296.
    CrossRefPubMed
  16. Torabi P, Ricci F, Hamrefors V, et al. Impact of cardiovascular neurohormones on onset of vasovagal syncope induced by head-up tilt. J Am Heart Assoc. 2019; 8(12): e012559.
    CrossRefPubMed
  17. Lindenberger M, Fedorowski A, Melander O, et al. Cardiovascular biomarkers and echocardiographic findings at rest and during graded hypovolemic stress in women with recurrent vasovagal syncope. J Cardiovasc Electrophysiol. 2019; 30(12): 2936–2943.
    CrossRefPubMed
  18. Fedorowski A, Burri P, Struck J, et al. Novel cardiovascular biomarkers in unexplained syncopal attacks: the SYSTEMA cohort. J Intern Med. 2013; 273(4): 359–367.
    CrossRefPubMed
  19. Fedorowski A, Rivasi G, Torabi P, et al. Underlying hemodynamic differences are associated with responses to tilt testing. Sci Rep. 2021; 11(1): 17894.
    CrossRefPubMed
  20. Wieling W, Jardine DL, de Lange FJ, et al. Cardiac output and vasodilation in the vasovagal response: An analysis of the classic papers. Heart Rhythm. 2016; 13(3): 798–805.
    CrossRefPubMed
  21. van Dijk JG, Ghariq M, Kerkhof FI, et al. Novel methods for quantification of vasodepression and cardioinhibition during tilt-induced vasovagal syncope. Circ Res. 2020; 127(5): e126–e138.
    CrossRefPubMed
  22. Rivasi G, Torabi P, Secco G, et al. Age-related tilt test responses in patients with suspected reflex syncope. Europace. 2021; 23(7): 1100–1105.
    CrossRefPubMed
  23. Monahan KD. Effect of aging on baroreflex function in humans. Am J Physiol Regul Integr Comp Physiol. 2007; 293(1): R3–RR12.
    CrossRefPubMed
  24. Pfeifer M, Weinberg C, Cook D, et al. Differential changes of autonomic nervous system function with age in man. The American Journal of Medicine. 1983; 75(2): 249–258.
    CrossRef
  25. Sutton R, Brignole M. Twenty-eight years of research permit reinterpretation of tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J. 2014; 35(33): 2211–2212.
    CrossRefPubMed
  26. Brignole M, Moya A, Menozzi C, et al. Proposed electrocardiographic classification of spontaneous syncope documented by an implantable loop recorder. Europace. 2005; 7(1): 14–18.
    CrossRefPubMed
  27. Freeman R, Abuzinadah AR, Gibbons C, et al. Orthostatic hypotension: JACC state-of-the-art review. J Am Coll Cardiol. 2018; 72(11): 1294–1309.
    CrossRefPubMed
  28. Fedorowski A, van Wijnen VK, Wieling W. Delayed orthostatic hypotension and vasovagal syncope: a diagnostic dilemma. Clin Auton Res. 2017; 27(4): 289–291.
    CrossRefPubMed
  29. WHO Expert Committee on Arterial Hypertension & World Health Organization. Arterial hypertension: report of a WHO expert committee [‎meeting held in Geneva from 13 to 21 March 1978]; 1978‎: 7–56.
  30. Owens PE, Lyons SP, O'Brien ET. Arterial hypotension: prevalence of low blood pressure in the general population using ambulatory blood pressure monitoring. J Hum Hypertens. 2000; 14(4): 243–247.
    CrossRefPubMed
  31. Pemberton J. Does constitutional hypotension exist? BMJ. 1989; 298(6674): 660–662.
    CrossRefPubMed
  32. Jacob G, Barbic F, Glago M, et al. Cardiovascular autonomic profile in women with constitutional hypotension. J Hypertens. 2018; 36(10): 2068–2076.
    CrossRefPubMed
  33. De Buyzere M, Clement DL, Duprez D. Chronic low blood pressure: a review . Cardiovasc Drugs Ther. 1998; 12(1): 29–35.
    CrossRefPubMed
  34. Sim JJ, Zhou H, Bhandari S, et al. Low systolic blood pressure from treatment and association with serious falls/syncope. Am J Prev Med. 2018; 55(4): 488–496.
    CrossRefPubMed
  35. Sink KM, Evans GW, Shorr RI, et al. Syncope, hypotension, and falls in the treatment of hypertension: results from the randomized clinical systolic blood pressure intervention trial. J Am Geriatr Soc. 2018; 66(4): 679–686.
    CrossRefPubMed
  36. Rivasi G, Rafanelli M, Mossello E, et al. Drug-Related orthostatic hypotension: beyond anti-hypertensive medications. Drugs Aging. 2020; 37(10): 725–738.
    CrossRefPubMed
  37. Rivasi G, Brignole M, Rafanelli M, et al. Blood pressure management in hypertensive patients with syncope: how to balance hypotensive and cardiovascular risk. J Hypertens. 2020; 38(12): 2356–2362.
    CrossRefPubMed
  38. Scuteri A, Modestino A, Frattari A, et al. Occurrence of hypotension in older participants. Which 24-hour ABPM parameter better correlate with? J Gerontol A Biol Sci Med Sci. 2012; 67(7): 804–810.
    CrossRefPubMed
  39. Ceccofiglio A, Mussi C, Rafanelli M, et al. Increasing prevalence of orthostatic hypotension as a cause of syncope with advancing age and multimorbidity. J Am Med Dir Assoc. 2019; 20(5): 586–588.
    CrossRefPubMed
  40. Ungar A, Mussi C, Ceccofiglio A, et al. Etiology of syncope and unexplained falls in elderly adults with dementia: Syncope and Dementia (SYD) study. J Am Geriatr Soc. 2016; 64(8): 1567–1573.
    CrossRefPubMed
  41. Liang Y, Fratiglioni L, Wang R, et al. Effects of biological age on the associations of blood pressure with cardiovascular and non-cardiovascular mortality in old age: A population-based study. Int J Cardiol. 2016; 220: 508–513.
    CrossRefPubMed
  42. Rivasi G, Tortù V, D'Andria MF, et al. Hypertension management in frail older adults: a gap in evidence. J Hypertens. 2021; 39(3): 400–407.
    CrossRefPubMed
  43. Stergiou GS, Palatini P, Parati G, et al. 2021 European Society of Hypertension practice guidelines for office and out-of-office blood pressure measurement. J Hypertens. 2021; 39(7): 1293–1302.
    CrossRefPubMed
  44. Ishikawa J, Ishikawa Y, Edmondson D, et al. Age and the difference between awake ambulatory blood pressure and office blood pressure: a meta-analysis. Blood Press Monit. 2011; 16(4): 159–167.
    CrossRefPubMed
  45. Vallelonga F, Romagnolo A, Merola A, et al. Detection of orthostatic hypotension with ambulatory blood pressure monitoring in parkinson's disease. Hypertens Res. 2019; 42(10): 1552–1560.
    CrossRefPubMed
  46. Stuebner E, Vichayanrat E, Low DA, et al. Twenty-four hour non-invasive ambulatory blood pressure and heart rate monitoring in Parkinson's disease. Front Neurol. 2013; 4: 49.
    CrossRefPubMed
  47. Alquadan KF, Singhania G, Koratala A, et al. Office orthostatic blood pressure measurements and ambulatory blood pressure monitoring in the prediction of autonomic dysfunction. Clin Hypertens. 2017; 23: 3.
    CrossRefPubMed
  48. Giulia Rivasi, Antonella Groppelli, Michele Brignole, Davide Soranna, Antonella Zambon, Grzegorz Bilo, Martino Pengo, Bashaaer Sharad, Viktor Hamrefors, Martina Rafanelli, Giuseppe Dario Testa, Richard Sutton, Andrea Ungar, Artur Fedorowski GP Ambulatory blood pressure monitoring: a new diagnostic approach for detection of hypotension in reflex syncope. 2021(SynABPM 1 study): Submitted.
  49. Conroy SP, Harrison JK, Van Der Wardt V, et al. Ambulatory blood pressure monitoring in older people with dementia: a systematic review of tolerability. Age Ageing. 2016; 45(4): 456–462.
    CrossRefPubMed
  50. Sutton R, Fedorowski A, Olshansky B, et al. Tilt testing remains a valuable asset. Eur Heart J. 2021; 42(17): 1654–1660.
    CrossRefPubMed
  51. Torabi P, Ricci F, Hamrefors V, et al. Classical and delayed orthostatic hypotension in patients with unexplained syncope and severe orthostatic intolerance. Front Cardiovasc Med. 2020; 7: 21.
    CrossRefPubMed
  52. Brignole M, Kessisoglu F, Croci F, et al. Complementary effectiveness of carotid sinus massage and tilt testing for the diagnosis of reflex syncope in patients older than 40 years: a cohort study. Europace. 2020; 22(11): 1737–1741.
    CrossRefPubMed
  53. Sutton R. Reflex Atrioventricular Block. Front Cardiovasc Med. 2020; 7: 48.
    CrossRefPubMed
  54. Brignole M, Deharo JC, Menozzi C, et al. The benefit of pacemaker therapy in patients with neurally mediated syncope and documented asystole: a meta-analysis of implantable loop recorder studies. Europace. 2018; 20(8): 1362–1366.
    CrossRefPubMed
  55. Moya A, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with isolated syncope and in patients with tilt-positive syncope. Circulation. 2001; 104(11): 1261–1267.
    CrossRefPubMed
  56. Deharo JC, Guieu R, Mechulan A, et al. Syncope without prodromes in patients with normal heart and normal electrocardiogram: a distinct entity. J Am Coll Cardiol. 2013; 62(12): 1075–1080.
    CrossRefPubMed
  57. Brignole M, Guieu R, Tomaino M, et al. Mechanism of syncope without prodromes with normal heart and normal electrocardiogram. Heart Rhythm. 2017; 14(2): 234–239.
    CrossRefPubMed
  58. Joulia F, Coulange M, Lemaitre F, et al. Plasma adenosine release is associated with bradycardia and transient loss of consciousness during experimental breath-hold diving. Int J Cardiol. 2013; 168(5): e138–e141.
    CrossRefPubMed
  59. Solari D, Tesi F, Unterhuber M, et al. Stop vasodepressor drugs in reflex syncope: a randomised controlled trial. Heart. 2017; 103(6): 449–455.
    CrossRefPubMed
  60. Bress AP, Kramer H, Khatib R, et al. Potential Deaths Averted and Serious Adverse Events Incurred From Adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) Intensive Blood Pressure Regimen in the United States: Projections From NHANES (National Health and Nutrition Examination Survey). Circulation. 2017; 135(17): 1617–1628.
    CrossRefPubMed
  61. van der Wardt V, Harrison JK, Welsh T, et al. Withdrawal of antihypertensive medication: a systematic review. J Hypertens. 2017; 35(9): 1742–1749.
    CrossRefPubMed
  62. Verhaeverbeke I, Mets T. Drug-induced orthostatic hypotension in the elderly: avoiding its onset. Drug Saf. 1997; 17(2): 105–118.
    CrossRefPubMed
  63. Duschek S, Heiss H, Buechner B, et al. Hemodynamic determinants of chronic hypotension and their modification through vasopressor application. J Physiol Sci. 2009; 59(2): 105–112.
    CrossRefPubMed
  64. Izcovich A, González Malla C, Manzotti M, et al. Midodrine for orthostatic hypotension and recurrent reflex syncope: A systematic review. Neurology. 2014; 83(13): 1170–1177.
    CrossRefPubMed
  65. Eschlböck S, Wenning G, Fanciulli A. Evidence-based treatment of neurogenic orthostatic hypotension and related symptoms. J Neural Transm (Vienna). 2017; 124(12): 1567–1605.
    CrossRefPubMed
  66. Sheldon R, Faris P, Tang A, et al. Midodrine for the prevention of vasovagal syncope: a randomized clinical trial. Ann Intern Med. 2021 [Epub ahead of print].
    CrossRefPubMed
  67. Sheldon R, Raj SR, Rose MS, et al. POST 2 Investigators. Fludrocortisone for the prevention of Vasovagal syncope: a randomized, placebo-controlled trial. J Am Coll Cardiol. 2016; 68(1): 1–9.
    CrossRefPubMed
  68. Hakamäki T, Rajala T, Lehtonen A. Ambulatory 24-hour blood pressure recordings in patients with Parkinson's disease with or without fludrocortisone. Int J Clin Pharmacol Ther. 1998; 36(7): 367–369.
    PubMed
  69. van Lieshout JJ, ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure. Clin Auton Res. 2000; 10(1): 35–42.
    CrossRefPubMed
  70. Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014; 83(4): 328–335.
    CrossRefPubMed
  71. Hauser RA, Isaacson S, Lisk JP, et al. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B). Mov Disord. 2015; 30(5): 646–654.
    CrossRefPubMed
  72. Keating GM. Droxidopa: a review of its use in symptomatic neurogenic orthostatic hypotension. Drugs. 2015; 75(2): 197–206.
    CrossRefPubMed
  73. Sheldon RS, Lei L, Guzman JC, et al. A proof of principle study of atomoxetine for the prevention of vasovagal syncope: the Prevention of Syncope Trial VI. Europace. 2019; 21(11): 1733–1741.
    CrossRefPubMed
  74. Sheldon RS, Ritchie D, McRae M, et al. Norepinephrine transport inhibition for treatment of vasovagal syncope. J Cardiovasc Electrophysiol. 2013; 24(7): 799–803.
    CrossRefPubMed
  75. Tajdini M, Aminorroaya A, Tavolinejad H, et al. Atomoxetine as an adjunct to nonpharmacological treatments for preventing vasovagal attacks in patients with recurrent vasovagal syncope: A pilot randomized-controlled trial. Int J Cardiol Heart Vasc. 2021; 34: 100789.
    CrossRefPubMed
  76. Baron-Esquivias G, Morillo CA, Moya-Mitjans A, et al. Dual-Chamber pacing with closed loop stimulation in recurrent reflex vasovagal syncope: the SPAIN study. J Am Coll Cardiol. 2017; 70(14): 1720–1728.
    CrossRefPubMed
  77. Brignole M, Russo V, Arabia F, et al. Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. Eur Heart J. 2021; 42(5): 508–516.
    CrossRefPubMed
  78. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J. 2021; 42(35): 3427–3520.
    CrossRefPubMed
  79. Rivasi G, Solari D, Rafanelli M, et al. Incidence and predictors of syncope recurrence after cardiac pacing in patients with carotid sinus syndrome. Int J Cardiol. 2018; 266: 119–123.
    CrossRefPubMed
  80. Yasa E, Ricci F, Holm H, et al. Pacing therapy in the management of unexplained syncope: a tertiary care centre prospective study. Open Heart. 2019; 6(1): e001015.
    CrossRefPubMed
  81. Brignole M, Tomaino M, Gargaro A. Vasovagal syncope with asystole: the role of cardiac pacing. Clin Auton Res. 2017; 27(4): 245–251.
    CrossRefPubMed
  82. Brignole M, Donateo P, Tomaino M, et al. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative. Circ Arrhythmia Electrophysiol. 2014; 7(1): 10–16.
    CrossRef
  83. Solari D, Maggi R, Oddone D, et al. Clinical context and outcome of carotid sinus syndrome diagnosed by means of the 'method of symptoms'. Europace. 2014; 16(6): 928–934.
    CrossRefPubMed
  84. Saal DP, Thijs RD, van Zwet EW, et al. Temporal relationship of asystole to onset of transient loss of consciousness in tilt-induced reflex syncope. JACC Clin Electrophysiol. 2017; 3(13): 1592–1598.
    CrossRefPubMed
  85. Brignole M, Iori M, Solari D, et al. Efficacy of theophylline in patients with syncope without prodromes with normal heart and normal ECG. Int J Cardiol. 2019; 289: 70–73.
    CrossRefPubMed
  86. Hu F, Zheng L, Liang E, et al. Right anterior ganglionated plexus: The primary target of cardioneuroablation? Heart Rhythm. 2019; 16(10): 1545–1551.
    CrossRefPubMed
  87. Sun W, Zheng L, Qiao Yu, et al. Catheter ablation as a treatment for vasovagal syncope: long-term outcome of endocardial autonomic modification of the left atrium. J Am Heart Assoc. 2016; 5(7).
    CrossRefPubMed
  88. Pachon JC, Pachon EI, Cunha Pachon MZ, et al. Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results. Europace. 2011; 13(9): 1231–1242.
    CrossRefPubMed
  89. Debruyne P, Rossenbacker T, Janssens L, et al. Durable physiological changes and decreased syncope burden 12 months after unifocal right-sided ablation under computed tomographic guidance in patients with neurally mediated syncope or functional sinus node dysfunction. Circ Arrhythm Electrophysiol. 2021; 14(6): e009747.
    CrossRefPubMed
  90. Calo L, Rebecchi M, Sette A, et al. Catheter ablation of right atrial ganglionated plexi to treat cardioinhibitory neurocardiogenic syncope: a long-term follow-up prospective study. J Interv Card Electrophysiol. 2021; 61(3): 499–510.
    CrossRefPubMed
  91. Aksu T, Güler TE, Bozyel S, et al. Cardioneuroablation in the treatment of neurally mediated reflex syncope: a review of the current literature. Turk Kardiyol Dern Ars. 2017; 45(1): 33–41.
    CrossRefPubMed
  92. Wieling W, Jardine DL. Cardioneuroablation for recurrent vasovagal syncope: Important questions need to be answered. Heart Rhythm. 2021 [Epub ahead of print].
    CrossRefPubMed
  93. O'Brien E, Murphy J, Tyndall A, et al. Twenty-four-hour ambulatory blood pressure in men and women aged 17 to 80 years: the Allied Irish Bank Study. J Hypertens. 1991; 9(4): 355–360.
    CrossRefPubMed
  94. Ejaz AA, Sekhon IS, Munjal S. Characteristic findings on 24-h ambulatory blood pressure monitoring in a series of patients with Parkinson's disease. Eur J Intern Med. 2006; 17(6): 417–420.
    CrossRefPubMed

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