Cardiovascular Autonomic Dysfunction and its association with Aortic Stenosis

Main Article Content

Lisa Brandon Niall Connolly Mark Hensey Stephen O'Connor I Cruz-Gonzalez Rose Anne Kenny Andrew O Maree


Aortic stenosis remains the most common valvular abnormality that requires intervention and is becoming more prevalent with an ageing population. Untreated symptomatic severe aortic stenosis is associated with a mortality of 50-60% within two years. Valve replacement either surgical or transcatheter remains the only effective treatment.


The autonomic nervous system involuntarily controls many basic cardiac, respiratory, gastrointestinal and genitourinary functions and plays a central role in the regulation of heart rate and blood pressure. Cardiovascular autonomic dysfunction has shown to be a marker of increased mortality. We discuss current methods to assess autonomic function, alongside abnormalities noted in common cardiac conditions and their correlation to mortality, and review current literature available that confirms severe aortic stenosis is associated with dysregulation of cardiovascular autonomic system.

Keywords: Cardiovascular, Cardiovascular Dysfunction, Cardiovascular Autonomic Dysfunction, Aortic Stenosis

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How to Cite
BRANDON, Lisa et al. Cardiovascular Autonomic Dysfunction and its association with Aortic Stenosis. Medical Research Archives, [S.l.], v. 11, n. 1, jan. 2023. ISSN 2375-1924. Available at: <>. Date accessed: 19 july 2024. doi:
Review Articles


1. Dutta P, James JF, Kazik H, Lincoln J. Genetic and Developmental Contributors to Aortic Stenosis. Circ Res. 2021;128(9):1330-1343. doi:10.1161/CIRCRESAHA.120.317978
2. Bhatia N BSSAWN. Aortic valve disease in the older adult. J Geriatr Cardiol 2016 Dec;13(12):941-944 doi: 1011909/j.issn1671-5411201612004.
3. Goody PR, Hosen MR, Christmann D, et al. Aortic valve stenosis: From basic mechanisms to novel therapeutic targets. Arterioscler Thromb Vasc Biol. Published online April 1, 2020:885-900. doi:10.1161/ATVBAHA.119.313067
4. Akahori H, Tsujino T, Masuyama T, Ishihara M. Mechanisms of aortic stenosis. J Cardiol. 2018;71(3):215-220. doi:10.1016/j.jjcc.2017.11.007
5. Rassi AN, Pibarot P, Elmariah S. Left ventricular remodelling in aortic stenosis. Canadian Journal of Cardiology. 2014;30(9):1004-1011. doi:10.1016/j.cjca.2014.04.026
6. Pawade TA, Newby DE, Dweck MR. THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW Calcication in Aortic Stenosis The Skeleton Key. Vol 66.; 2015.
7. Zhao Y, Nicoll R, He Y hua, Henein MY. The effect of statins on valve function and calcification in aortic stenosis: A meta-analysis. Atherosclerosis. 2016;246:318-324. doi:10.1016/j.atherosclerosis.2016.01.023
8. Pawade TA, Doris MK, Bing R, et al. Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial. Circulation. 2021;143(25):2418-2427. doi:10.1161/CIRCULATIONAHA.121.053708
9. Agstam S, Agarwal T, Gupta A, Bansal S. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in aortic stenosis - Is this the light at the end of the tunnel for patients with aortic stenosis? Indian Heart J. 2021;73(2):249-252. doi:10.1016/j.ihj.2021.01.017
10. Michelena HI, Chandrasekaran K, Topilsky Y, et al. The Bicuspid Aortic Valve Condition: The Critical Role of Echocardiography and the Case for a Standard Nomenclature Consensus. Prog Cardiovasc Dis. 2018;61(5-6):404-415. doi:10.1016/j.pcad.2018.11.003
11. Liu T, Xie M, Lv Q, et al. Bicuspid aortic valve: An update in morphology, genetics, biomarker, complications, imaging diagnosis and treatment. Front Physiol. 2019;10(JAN). doi:10.3389/fphys.2018.01921
12. Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. EuroIntervention. 2022;17(14):E1126-E1196. doi:10.4244/EIJ-E-21-00009
13. Ben-Dor I, Pichard AD, Gonzalez MA, et al. Correlates and causes of death in patients with severe symptomatic aortic stenosis who are not eligible to participate in a clinical trial of transcatheter aortic valve implantation. Circulation. 2010;122(11 SUPPL. 1). doi:10.1161/CIRCULATIONAHA.109.926873
14. Marques-Alves P, Marinho AV, Teixeira R, et al. Going beyond classic echo in aortic stenosis: Left atrial mechanics, a new marker of severity. BMC Cardiovasc Disord. 2019;19(1). doi:10.1186/s12872-019-1204-2
15. Bottaro G, Zappulla P, Deste W, et al. Severe aortic valve stenosis: Symptoms, biochemical markers, and global longitudinal strain. J Cardiovasc Echogr. 2020;30(3):154. doi:10.4103/jcecho.jcecho_13_20
16. Kaden JJ et al. Systemic and local levels of fetuin-A in calcific aortic valve stenosis. International journal of molecular medicine vol 20,2 (2007): 193-7.
17. Yalta K, Palabiyik O, Gurdogan M, Gurlertop Y. Serum copeptin might improve risk stratification and management of aortic valve stenosis: a review of pathophysiological insights and practical implications. Ther Adv Cardiovasc Dis. 2019;13:1-11. doi:10.1177/1753944719826420
18. Gharacholou SM, Karon BL, Shub C, Pellikka PA. Aortic valve sclerosis and clinical outcomes: Moving toward a definition. American Journal of Medicine. 2011;124(2):103-110. doi:10.1016/j.amjmed.2010.10.012
19. Owens DS, Katz R, Takasu J, Kronmal R, Budoff MJ, O’Brien KD. Incidence and Progression of Aortic Valve Calcium in the Multi-Ethnic Study of Atherosclerosis (MESA). American Journal of Cardiology. 2010;105(5):701-708. doi:10.1016/j.amjcard.2009.10.071
20. Palmiero P, Maiello M, Passantino A, Wasson S, Reddy HK. Aortic valve sclerosis: Is it a cardiovascular risk factor or a cardiac disease marker? Echocardiography. 2007;24(3):217-221. doi:10.1111/j.1540-8175.2007.00379.x
21. Karemaker JM. An introduction into autonomic nervous function. Physiol Meas. 2017;38(5):R89-R118. doi:10.1088/1361-6579/aa6782
22. Wink J, van Delft R, Notenboom RGE, et al. Human adult cardiac autonomic innervation: Controversies in anatomical knowledge and relevance for cardiac neuromodulation. Autonomic Neuroscience. 2020;227:102674. doi:10.1016/j.autneu.2020.102674
23. Stiles GL, Lefkowitz RJ. Cardiac Adrenergic Receptors. Annu Rev Med. 1984;35(1):149-164. doi:10.1146/
24. Ajijola OA, Vaseghi M, Zhou W, et al. Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle. American Journal of Physiology-Heart and Circulatory Physiology. 2013;304(4):H579-H588. doi:10.1152/ajpheart.00754.2012
25. Jamali HK, Waqar F, Gerson MC. Cardiac autonomic innervation. Journal of Nuclear Cardiology. 2017;24(5):1558-1570. doi:10.1007/s12350-016-0725-7
26. Wang HJ, Wang W, Cornish KG, Rozanski GJ, Zucker IH. Cardiac Sympathetic Afferent Denervation Attenuates Cardiac Remodeling and Improves Cardiovascular Dysfunction in Rats With Heart Failure. Hypertension. 2014;64(4):745-755. doi:10.1161/HYPERTENSIONAHA.114.03699
27. Goldberger JJ, Arora R, Buckley U, Shivkumar K. Autonomic Nervous System Dysfunction: JACC Focus Seminar. J Am Coll Cardiol. 2019;73(10):1189-1206. doi:10.1016/j.jacc.2018.12.064
28. Ulphani JS, Cain JH, Inderyas F, et al. Quantitative analysis of parasympathetic innervation of the porcine heart. Heart Rhythm. 2010;7(8):1113-1119. doi:10.1016/j.hrthm.2010.03.043
29. Henning R. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001;49(1):27-37. doi:10.1016/S0008-6363(00)00229-7
30. Armour JA, Murphy DA, Yuan BX, MacDonald S, Hopkins DA. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat Rec. 1997;247(2):289-298. doi:10.1002/(SICI)1097-0185(199702)247:2<289::AID-AR15>3.0.CO;2-L
31. Armour JA. Cardiac neuronal hierarchy in health and disease. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2004;287(2):R262-R271. doi:10.1152/ajpregu.00183.2004
32. Kougias P et al. Arterial baroreceptors in the management of systemic hypertension. Medical science monitor : international medical journal of experimental and clinical research vol 16,1 (2010): RA1-8.
33. Cody RJ. The sympathetic nervous system and the renin-angiotensin-aldosterone system in cardiovascular disease. The American journal of cardiology vol 80,9B (1997): 9J-14J doi:101016/s0002-9149(97)00832-1.
34. Jimenez-Ruiz A, Racosta JM, Kimpinski K, Hilz MJ, Sposato LA. Cardiovascular autonomic dysfunction after stroke. Neurological Sciences. 2021;42(5):1751-1758. doi:10.1007/s10072-021-05128-y
35. Rodrigues B, Lira FS, Consolim-Colombo FM, et al. Role of Exercise Training on Autonomic Changes and Inflammatory Profile Induced by Myocardial Infarction. Mediators Inflamm. 2014;2014:1-11. doi:10.1155/2014/702473
36. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114(11):1815-1826. doi:10.1161/CIRCRESAHA.114.302589
37. Fukuda K, Kanazawa H, Aizawa Y, Ardell JL, Shivkumar K. Cardiac Innervation and Sudden Cardiac Death. Circ Res. 2015;116(12):2005-2019. doi:10.1161/CIRCRESAHA.116.304679
38. Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. BMJ. 1982;285(6346):916-918. doi:10.1136/bmj.285.6346.916
39. Armstrong R, Wheen P, Brandon L, Maree A, Kenny RA. Heart rate: control mechanisms, pathophysiology and assessment of the neurocardiac system in health and disease. QJM: An International Journal of Medicine. Published online January 24, 2021. doi:10.1093/qjmed/hcab016
40. McCrory C, Berkman LF, Nolan H, O’Leary N, Foley M, Kenny RA. Speed of Heart Rate Recovery in Response to Orthostatic Challenge. Circ Res. 2016;119(5):666-675. doi:10.1161/CIRCRESAHA.116.308577
41. la Rovere MT et al. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet (London, England) vol 351,9101 (1998): 478-84 doi:101016/s0140-6736(97)11144-8.
42. Nakajo M et al. Iodine-131 metaiodobenzylguanidine intra- and extravesicular accumulation in the rat heart. Journal of nuclear medicine : official publication, Society of Nuclear Medicine vol 27,1 (1986): 84-9.
43. Raffel DM and DMW. Development of mIBG as a Cardiac Innervation Imaging Agent. JACC Cardiovascular imaging vol 3,1 (2010): 111-6 doi:101016/j.jcmg200909015.
44. Sisson JC et al. Metaiodobenzylguanidine as an index of the adrenergic nervous system integrity and function. Journal of nuclear medicine : official publication, Society of Nuclear Medicine vol 28,10 (1987): 1620-4.
45. Roveda F, Middlekauff HR, Rondon MUPB, et al. The effects of exercise training on sympathetic neural activation in advanced heart failure: A randomized controlled trial. J Am Coll Cardiol. 2003;42(5):854-860. doi:10.1016/S0735-1097(03)00831-3
46. Kuniyoshi RR, Martinelli M, Negrão CE, et al. Effects of cardiac resynchronization therapy on muscle sympathetic nerve activity. PACE - Pacing and Clinical Electrophysiology. 2014;37(1):11-18. doi:10.1111/pace.12254
47. Esler M, Jennings G, Korner P, et al. Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension. 1988;11(1):3-20. doi:10.1161/01.HYP.11.1.3
48. Ziegler D, Dannehl K, Mühlen H, Spüler M, Gries FA. Prevalence of Cardiovascular Autonomic Dysfunction Assessed by Spectral Analysis, Vector Analysis, and Standard Tests of Heart Rate Variation and Blood Pressure Responses at Various Stages of Diabetic Neuropathy. Diabetic Medicine. 1992;9(9):806-814. doi:10.1111/j.1464-5491.1992.tb01898.x
49. Kennedy WR, Navarro X, Sutherland DER. Neuropathy profile of diabetic patients in a pancreas transplantation program. Neurology. 1995;45(4):773-780. doi:10.1212/WNL.45.4.773
50. Chen HS, Hwu CM, Kuo BI, et al. Abnormal Cardiovascular Re¯ex Tests Are Predictors of Mortality in Type 2 Diabetes Mellitus. Vol 18.; 2001.
51. Rathmann W, Ziegler D, Jahnke M, Haastert B, Cries FA. Mortality in Diabetic Patients with Cardiovascular Autonomic Neuropathy. Diabetic Medicine. 1993;10(9):820-824. doi:10.1111/j.1464-5491.1993.tb00173.x
52. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: A clinical perspective. Diabetes Care. 2010;33(2):434-441. doi:10.2337/dc09-1294
53. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998 Apr;41(4):416-23 doi: 101007/s001250050924.
54. McAlister FA. Meta-analysis: β-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure. Ann Intern Med. 2009;150(11):784. doi:10.7326/0003-4819-150-11-200906020-00006
55. Florea VG, Cohn JN. The autonomic nervous system and heart failure. Circ Res. 2014;114(11):1815-1826. doi:10.1161/CIRCRESAHA.114.302589
56. Patel HC, Rosen SD, Lindsay A, Hayward C, Lyon AR, di Mario C. Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management. Int J Cardiol. 2013;170(2):107-117. doi:10.1016/j.ijcard.2013.10.058
57. Packer M, Coats AJS, Fowler MB, et al. Effect of Carvedilol on Survival in Severe Chronic Heart Failure. New England Journal of Medicine. 2001;344(22):1651-1658. doi:10.1056/NEJM200105313442201
58. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet (London, England) vol 353,9146 (1999): 9-13.
59. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet (London, England) vol 353,9169 (1999): 2001-7.
60. Pitt B et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The New England journal of medicine vol 348,14 (2003): 1309-21 doi:101056/NEJMoa030207.
61. Pitt B, Zannad F, Remme WJ, et al. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. New England Journal of Medicine. 1999;341(10):709-717. doi:10.1056/NEJM199909023411001
62. Effects of Enalapril on Mortality in Severe Congestive Heart Failure. New England Journal of Medicine. 1987;316(23):1429-1435. doi:10.1056/NEJM198706043162301
63. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. The Lancet. 2010;376(9744):875-885. doi:10.1016/S0140-6736(10)61198-1
64. Akinseye OA, Ralston WF, Johnson KC, Ketron LL, Womack CR, Ibebuogu UN. Renal Sympathetic Denervation: A Comprehensive Review. Curr Probl Cardiol. 2021;46(3). doi:10.1016/j.cpcardiol.2020.100598
65. Bhatt DL, Kandzari DE, O’Neill WW, et al. A Controlled Trial of Renal Denervation for Resistant Hypertension. New England Journal of Medicine. 2014;370(15):1393-1401. doi:10.1056/NEJMoa1402670
66. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex Activation Therapy Lowers Blood Pressure in Patients With Resistant Hypertension. J Am Coll Cardiol. 2011;58(7):765-773. doi:10.1016/j.jacc.2011.06.008
67. Hoppe UC, Brandt MC, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: Results from the Barostim neo trial. Journal of the American Society of Hypertension. 2012;6(4):270-276. doi:10.1016/j.jash.2012.04.004
68. Zile MR, Lindenfeld J, Weaver FA, et al. Baroreflex Activation Therapy in Patients With Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2020;76(1):1-13. doi:10.1016/j.jacc.2020.05.015
69. Pinnell J, Turner S, Howell S. Cardiac muscle physiology. Continuing Education in Anaesthesia, Critical Care and Pain. 2007;7(3):85-88. doi:10.1093/bjaceaccp/mkm013
70. José A. Nicolás-Ávila LPCPMC and AH. Macrophages, Metabolism and Heterophagy in the Heart. Circulation Research 2022;130:418–431,
71. Azarov JE, Demidova MM, Koul S, van der Pals J, Erlinge D, Platonov PG. Progressive increase of the Tpeak-Tend interval is associated with ischaemia-induced ventricular fibrillation in a porcine myocardial infarction model. EP Europace. 2018;20(5):880-886. doi:10.1093/europace/eux104
72. Opthof T, Coronel R, Vermeulen JT, Verberne HJ, van Capelle FJL, Janse MJ. Dispersion of refractoriness in normal and ischaemic canine ventricle: effects of sympathetic stimulation. Cardiovasc Res. 1993;27(11):1954-1960. doi:10.1093/cvr/27.11.1954
73. Priori SG, Mantica M, Schwartz PJ. Delayed afterdepolarizations elicited in vivo by left stellate ganglion stimulation. Circulation. 1988;78(1):178-185. doi:10.1161/01.CIR.78.1.178
74. Hirsch AT, Talsness CE, Schunkert H, Paul M, Dzau VJ. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res. 1991;69(2):475-482. doi:10.1161/01.RES.69.2.475
75. Donoghue M. Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol. 2003;35(9):1043-1053. doi:10.1016/S0022-2828(03)00177-9
76. Wu P, Vaseghi M. The autonomic nervous system and ventricular arrhythmias in myocardial infarction and heart failure. PACE - Pacing and Clinical Electrophysiology. 2020;43(2):172-180. doi:10.1111/pace.13856
77. Stavrakis S, Kulkarni K, Singh JP, Katritsis DG, Armoundas AA. Autonomic Modulation of Cardiac Arrhythmias: Methods to Assess Treatment and Outcomes. JACC Clin Electrophysiol. 2020;6(5):467-483. doi:10.1016/j.jacep.2020.02.014
78. Vaseghi M, Barwad P, Malavassi Corrales FJ, et al. Cardiac Sympathetic Denervation for Refractory Ventricular Arrhythmias. J Am Coll Cardiol. 2017;69(25):3070-3080. doi:10.1016/j.jacc.2017.04.035
79. Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human: Heart structural deterioration and compensatory mechanisms. Circulation. 2003;107(7):984-991. doi:10.1161/01.CIR.0000051865.66123.B7
80. Bull S, Loudon M, Francis JM, et al. A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis (RIAS trial). Eur Heart J Cardiovasc Imaging. 2015;16(8):834-841. doi:10.1093/ehjci/jev043
81. Zuern CS, Eick C, Rizas KD, et al. Severe autonomic failure in moderate to severe aortic stenosis: Prevalence and association with hemodynamics and biomarkers. Clinical Research in Cardiology. 2012;101(7):565-572. doi:10.1007/s00392-012-0427-3
82. Airaksinen KE et al. Impaired vagal heart rate control in aortic valve stenosis. European heart journal vol 9,10 (1988): 1126-30 doi:101093/oxfordjournals.eurheartj.a062409.
83. Jung J et al. Factors influencing heart rate variability in patients with severe aortic valve disease. Clinical cardiology vol 20,4 (1997): 341-4 doi:101002/clc4960200408Factors influencing heart rate variability in patients with severe aortic valve disease.
84. Duckheim M, Bensch C, Kittlitz L, et al. Deceleration capacity of heart rate predicts 1-year mortality of patients undergoing transcatheter aortic valve implantation. Clin Cardiol. 2017;40(10):919-924. doi:10.1002/clc.22748
85. Zuern CS, Rizas KD, Eick C, et al. Severe autonomic failure as a predictor of mortality in aortic valve stenosis. Int J Cardiol. 2014;176(3):782-787. doi:10.1016/j.ijcard.2014.07.088
86. Dumonteil N et al. Transcatheter aortic valve implantation reduces sympathetic activity and normalizes arterial spontaneous baroreflex in patients with aortic stenosis. JACC Cardiovascular interventions vol 6,11 (2013): 1195-202 doi:101016/j.jcin201306012.
87. Compostella L, Russo N, Compostella C, et al. Impact of type of intervention for aortic valve replacement on heart rate variability. Int J Cardiol. 2015;197:11-15. doi:10.1016/j.ijcard.2015.06.004
88. Kadoya Y, Zen K, Tamaki N, et al. Early effects of transcatheter aortic valve replacement on cardiac sympathetic nervous function assessed by 123I-metaiodobenzylguanidine scintigraphy in patients with severe aortic valve stenosis. Eur J Nucl Med Mol Imaging. 2020;47(7):1657-1667. doi:10.1007/s00259-019-04523-0
89. Kadoya Y, Zen K, Tamaki N, et al. Serial changes in cardiac sympathetic nervous function after transcatheter aortic valve replacement: A prospective observational study using 123I-meta-iodobenzylguanidine imaging. Journal of Nuclear Cardiology. 2022;29(5):2652-2663. doi:10.1007/s12350-021-02799-0
90. Liga R, Gimelli A, de Carlo M, Marzullo P, Pedrinelli R, Petronio AS. Cardiac sympathetic dysfunction in left ventricular hypertrophy caused by arterial hypertension and degenerative aortic stenosis. Journal of Nuclear Cardiology. 2022;29(1):337-347. doi:10.1007/s12350-020-02250-w
91. Nitta K, Fukuda Y, Susawa H, et al. Impact of Prosthesis-Patient Mismatch After Transcatheter Aortic Valve Replacement on Changes in Cardiac Sympathetic Nervous Function. Int Heart J. 2020;61(6):1188-1195. doi:10.1536/ihj.20-381