The endothelin system may play a role in the pathogenesis of vasovagal syncope (VVS) because it is implicated in blood pressure regulation. We hypothesized that endothelin-related genetic polymorphisms might modulate susceptibility to VVS. This study aimed to evaluate the possible influence of endothelin-1 (EDN1) and endothelin receptor A (EDNRA) gene variants on the occurrence of tilt-induced VVS and autonomic nervous system activity during the head-up tilt test (HUT). Results were expressed as mean +/- SEM. In 254 patients with recurrent syncope (age 45.33+/-1.22 years, 94 males, 160 females), heart rate variability (HRV) was measured during HUT. EDN1 rs5370 G>T and EDNRA rs5333 T>C gene polymorphisms were assessed using high-resolution melting analysis. There was no statistically significant association between polymorphisms EDN1 rs5370 and EDNRA rs5333 and positivity of HUT or hemodynamic types of VVS. Patients with GT or TT genotypes at the rs5370 locus of the EDN1 had significantly higher values of high-frequency (HF) and the standard deviation of the average NN intervals at the time of the syncope, and they tended to have lower low-frequency (LF) and LF/HF ratio when compared to homozygotes (GG). No statistically significant differences were found in HRV parameters concerning the EDNRA rs5333 genotypes. Our findings suggest the potential role of EDN1 rs5370 variants in regulating autonomic nervous activity and pathogenesis of VVS.

4th Department of Internal Medicine Medical Faculty of University of P J Safarik Kosice Slovak Republic

Zobrazit více v PubMed

Sheldon RS, Sandhu RK. The search for the genes of vasovagal syncope. Front Cardiovasc Med. 2019;6:175. doi: 10.3389/fcvm.2019.00175. PubMed DOI PMC

Klein KM, Berkovic SF. Genetics of vasovagal syncope. Auton Neurosci. 2014;184:60–5. doi: 10.1016/j.autneu.2014.03.008. PubMed DOI

Mitro P, Habalova V, Evin L, Muller E, Simurda M, Slaba E, Murin P, Valocik G. Gene polymorphism of the adenosine A2a receptor in patients with vasovagal syncope. Pacing Clin Electrophysiol. 2016;39:330–37. doi: 10.1111/pace.12806. PubMed DOI

Márquez MF, Hernández-Pacheco G, Hermosillo AG, Gómez JR, Cárdenas M, Vargas-Alarcón G. The Arg389Gly beta1-adrenergic receptor gene polymorphism and susceptibility to faint during head-up tilt test. Europace. 2007;9:585–589. doi: 10.1093/europace/eum059. PubMed DOI

Lelonek M, Pietrucha T, Matyjaszczyk M, Goch JH. Genetic insight into syncopal tilted population with severe clinical presentation. Auton Neurosci. 2009;147:97–100. doi: 10.1016/j.autneu.2009.01.011. PubMed DOI

Agapitov AV, Haynes WG. Role of endothelin in cardiovascular disease. JRAAS. 2002;3:1–15. doi: 10.3317/jraas.2002.001. PubMed DOI

Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ. Endothelin Pharmacol Rev. 2016;68:357–418. doi: 10.1124/pr.115.011833. PubMed DOI PMC

Sorrentino S, Forleo C, Iacoviello M, Guida P, D’andria V, Favale S. Endothelin system polymorphisms in tilt test-induced vasovagal syncope. Clin Auton Res. 2009;19:347–354. doi: 10.1007/s10286-009-0008-3. PubMed DOI

Brignole M, Menozzi C, Del Rosso A, Costa S, Gaggioli G, Bottoni N, Bartoli P, Sutton R. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Vasovagal Syncope International Study. Europace. 2000;2:66–76. doi: 10.1053/eupc.1999.0064. PubMed DOI

Torabi P, Ricci F, Hamrefors V, Melander O, Sutton R, Benditt DG, Fedorowski A. Impact of cardiovascular neurohormones on onset of vasovagal syncope by head-up tilt. J Am Heart Assoc. 2019;8:e012559. doi: 10.1161/JAHA.119.012559. PubMed DOI PMC

Kaufmann H, Oribe E, Oliver JA. Plasma endothelin during upright tilt: Relevance for orthostatic hypotension? Lancet. 1991;338:1542–1545. doi: 10.1016/0140-6736(91)92370-H. PubMed DOI

Magerkurth C, Riedel A, Braune S. Permanent increase in endothelin serum levels in vasovagal syncope. Clin Auton Res. 2005;15:299–301. doi: 10.1007/s10286-005-0291-6. PubMed DOI

Nilsson D, Sutton R, Melander O, Fedorowski A. Spontaneous vs nitroglycerininduced vasovagal reflex on head-up tilt: are there neuroendocrine differences? Heart Rhythm. 2016;13:1674–1678. doi: 10.1016/j.hrthm.2016.03.018. PubMed DOI

Fedorowski A, Burri P, Struck J, Juul-Möller S, Melander O. Novel cardiovascular biomarkers in unexplained syncopal attacks: The SYSTEMA cohort. J Intern Med. 2013;273:359–367. doi: 10.1111/joim.12043. PubMed DOI

Williford NN, Chapleau MW, Olshansky B. Neurohormones in vasovagal syncope: Are they important? J Am Heart Assoc. 2019;8:e013129. doi: 10.1161/JAHA.119.013129. PubMed DOI PMC

Hamrefors V, Nilsson D, Melander O, Sutton R, Fedorowski A. Low adrenomedullin and endothelin-1 predict cardioinhibitory response during vasovagal reflex in adults over 40 years of age. Circ Arrhythm Electrophysiol. 2017;10:1–3. doi: 10.1161/CIRCEP.117.005585. PubMed DOI

Agapitov AV, Haynes WG. Role of endothelin in cardiovascular disease. JRAAS. 2002;3:1–15. doi: 10.3317/jraas.2002.001. PubMed DOI

Brunner F, Brás-Silva C, Cerdeira AS, Leite-Moreira AF. Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. Pharmacol Ther. 2006;111:508–531. doi: 10.1016/j.pharmthera.2005.11.001. PubMed DOI

Stow LR, Jacobs ME, Wingo CS, Cain BD. Endothelin-1 gene regulation. FASEB J. 2011;25:16–28. doi: 10.1096/fj.10-161612. PubMed DOI PMC

Ahmed M, Rghigh A. Polymorphism in endothelin-1 gene: An overview. Curr Clin Pharmacol. 2016;11:191–210. doi: 10.2174/1574884711666160701000900. PubMed DOI

Li J, Yin W, Liu M-S, Mao L-J, Wang X-H. Potential correlation between EDN1 gene polymorphisms with preeclampsia. Eur Rev Med Pharmacol Sci. 2020;24:1602–1608. doi: 10.26355/eurrev_202002_20334. PubMed DOI

Dhawan I, Choudhury M, Hote MP, Gupta A, Malhotra P, Mani KV. Is endothelin gene polymorphism associated with postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting? Ann Card Anaesth. 2017;20:341–347. doi: 10.4103/aca.ACA_264_16. PubMed DOI PMC

Tousoulis D, Toli E, Miliou A, Antoniades C, Kampoli AM, Hatzis G, Labrini Kormali L, Metaxa S, Papaoikonomou S, Tsiamis E, Stefanadis C. The impact of G5665T polymorphism of endothelin-1 gene, on endothelin-1 levels and left ventricular function in ischemic heart disease. Int J Cardiol. 2013;168:1568–1569. doi: 10.1016/j.ijcard.2013.01.188. PubMed DOI

Aydin AF, Vural P, Dogru-Abbasoglu S, Çil E. The endothelin 1 and endothelin receptor A gene polymorphisms increase the risk of developing papillary thyroid cancer. Mol Biol Rep. 2019;46:199–205. doi: 10.1007/s11033-018-4461-8. PubMed DOI

Barden AE, Herbison CE, Beilin LJ, Michael CA, Walters BN, Van Bockxmeer FM. Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J Hypertens. 2001;19:1775–1782. doi: 10.1097/00004872-200110000-00011. PubMed DOI

Popowski K, Sperker B, Kroemer HK, John U, Laule M, Stangl K, Cascorbi I. Functional significance of a hereditary adenine insertion variant in the 5′-UTR of the endothelin-1 gene. Pharmacogenetics. 2003;13:445–451. doi: 10.1097/00008571-200308000-00002. PubMed DOI

Tanaka C, Kamide K, Takiuchi S, Kawano Y, Miyata T. Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene. Hypertens Res. 2004;27:367–37. doi: 10.1291/hypres.27.367. PubMed DOI

Jin JJ, Nakura J, Wu Z, Yamamoto M, Abe M, Tabara Y, Yamamoto Y, Igase M, Kohara K, Miki T. Association of endothelin-1 gene variant with hypertension. Hypertension. 2003;41:163–167. doi: 10.1161/01.HYP.0000043680.75107.CF. PubMed DOI

Schiffrin EL. Role of enfothelin-1 in hypertentsion and vascular disease. Am J Hypertens. 2001;14:83S–89S. doi: 10.1016/S0895-7061(01)02074-X. PubMed DOI

Dubovyk YI, Oleshko TV, Ataman AV. Positive association between EDN1 rs5370 (Lys198Asn) polymorphism and large artery stroke in a Ukrainian population. Dis Markers. 2018;2018:1695782. doi: 10.1155/2018/1695782. PubMed DOI PMC

Kuwaki T, Koshiya N, Takanashi H, Takahashi H, Terui N, Kumada M. Modulatory effects of endothelin-1 on central cardiovascular control in rats. Japan J Physiol. 1990;40:827–841. doi: 10.2170/jjphysiol.40.827. PubMed DOI

Eroglu E, Kocyigit I, Lindholm B. The endothelin system as target for therapeutic interventions in cardiovascular and renal disease. Clin Chim Acta. 2020;506:92–106. doi: 10.1016/j.cca.2020.03.008. PubMed DOI