Decoding the Risk: Heart Rate Variability as a Powerful Predictor of Sudden Cardiac Death in Chronic Hemodialysis Patients—A 36-Month Prospective Study

Authors

  • Petar Avramovski Department of Internal Medicine, “St. Kliment Ohridski” – University, Bitola https://orcid.org/0000-0003-2816-3365
  • Maja Avramovska Department of Obstetrics and Gynecology, “St. Kliment Ohridski” – University, Bitola, Clinical Hospital “D-r Trifun Panovski” – Bitola, Bitola
  • Zorica Nikleski Medico - Legal Department, MedAssess, Sydney, New South Wales
  • Liljana Todorovska Department of Nuclear Medicine, Clinical Hospital “D-r Trifun Panovski” – Bitola, Bitola
  • Kosta Sotiroski Department of Statistics, “St. Kliment Ohridski – Bitola”, Faculty of Economics – Prilep, Prilep
  • Vesna Siklovska Department of Radiology, Clinical Hospital “D-r Trifun Panovski” – Bitola, Bitola
  • Irena Trajcevska Department of Radiology, Clinical Hospital “D-r Trifun Panovski” – Bitola, Bitola
  • Saso Vasilevski Department of Radiology, Clinical Hospital “D-r Trifun Panovski” – Bitola, Bitola

DOI:

https://doi.org/10.18502/dmj.v8i2.19005

Keywords:

heart rhythm variability, standard deviation of normal-to-normal intervals, sudden cardiac death, chronic hemodialysis patients, Holter electrocardiography

Abstract

Introduction: This study aimed to estimate the impact of the C-reactive protein (CRP), serum albumin, lipids, and heart rate variability (HRV) on sudden cardiac death (SCD) in chronic hemodialysis patients (CHPs) to derive the strongest predictor for SCD.

Methods: In this prospective study, 90 CHPs, average age 59.2 ± 11.4 years, were observed over a three-year follow-up period to detect SCD. HRV, with a focus on standard deviation of normal-to-normal intervals (SDNN), was measured using a 12- channel ECG. Peripheral blood samples were obtained from all participants, followed by routine blood tests: urea, creatinine, lipid status, hemoglobin, hs-CRP, albumin, and calcium - phosphorus product.

Key Findings: The mean SDNN was 107.97 ± 24.51 ms. Among CHPs, SDNN was significantly lower in deceased patients (79.20 ± 14.84 ms) compared to survivors (106.91 ± 23.09 ms, P = 0.0097). The mean survival time for SCD was 34.8 ± 5.3 months. Cox regression coefficients b (-0.1146, 0.1224, 0.0781, and 0.0934), hazard ratio (HR) (0.8917, 1.1303, 1.0812, and 1.0979), and p-value (0.042, 0.203, 0.680 and 0.378) for SDNN, hs-CRP, albumin and hemodialysis (HD) duration, respectively, showed strongest predictive impact for SCD of HRV (SDNN) covariate, with hazard rate rising by 1.12145 (12.45%) for every single unit decrease of SDNN. Receiver operating characteristics (ROC) analyses for SDNN were as follows: area under the curve (AUC) = 0.835 (P < 0.001), with a cut-off value of ≤84 ms (sensitivity 80.0%, specificity = 83.53%). AUC results for covariate albumin (AUC = 0.542, P = 0.766), CRP (AUC = 682, P = 0.204), and HD duration (AUC = 0.558, P = 0.717) did not reach significance in predicting the risk for SCD.

Conclusion: HRV proved to be a robust and independent predictor of sudden SCD in CHPs, with HR increasing by 11.48% for each unit decrease in SDNN (ms). In contrast, hs-CRP, serum albumin, lipids, and HD did not demonstrate a statistically significant effect on SCD risk prediction in CHPs.

References

[1] Herzog CA, Asinger RW, Berger AK, Charytan DM, Díez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011 Sep;80(6):572–586. DOI: https://doi.org/10.1038/ki.2011.223

[2] Wang AY, Lam CW, Chan IH, Wang M, Lui SF, Sanderson JE. Sudden cardiac death in end-stage renal disease patients: A 5-year prospective analysis. Hypertension. 2010 Aug;56(2):210–216. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.110.151167

[3] Annual US. Data Report. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006.

[4] Jha VK. Sudden cardiac death and chronic kidney disease. APIK Journal of Internal Medicine. 2023;11(1):7–13. DOI: https://doi.org/10.4103/ajim.ajim_114_21

[5] Pun PH, Middleton JP. Sudden cardiac death in hemodialysis patients: A comprehensive care approach to reduce risk. Blood Purif. 2012;33(1-3):183–189. DOI: https://doi.org/10.1159/000334154

[6] Kaur J, Young BE, Fadel PJ. Sympathetic overactivity in chronic kidney disease: Consequences and mechanisms. Int J Mol Sci. 2017 Aug;18(8):16–82. DOI: https://doi.org/10.3390/ijms18081682

[7] Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert EA, Straznicky N, et al. Sympathetic activation in chronic renal failure. J Am Soc Nephrol. 2009 May;20(5):933–939. DOI: https://doi.org/10.1681/ASN.2008040402

[8] Fukuta H, Hayano J, Ishihara S, Sakata S, Mukai S, Ohte N, et al. Prognostic value of heart rate variability in patients with end-stage renal disease on chronic haemodialysis. Nephrol Dial Transplant. 2003 Feb;18(2):318–325. DOI: https://doi.org/10.1093/ndt/18.2.318

[9] Parekh RS, Plantinga LC, Kao WH, Meoni LA, Jaar BG, Fink NE, et al. The association of sudden cardiac death with inflammation and other traditional risk factors. Kidney Int. 2008 Nov;74(10):1335–1342. DOI: https://doi.org/10.1038/ki.2008.449

[10] Shaffer F, Ginsberg JP. An overview of heart rate variability metrics and norms. Front Public Health. 2017 Sep;5:258. DOI: https://doi.org/10.3389/fpubh.2017.00258

[11] Faitatzidou D, Dipla K, Theodorakopoulou MP, Koutlas A, Tsitouridis A, Dimitriadis C, et al. Heart rate variability at rest and in response to stress: Comparative study between hemodialysis and peritoneal dialysis patients. Exp Biol Med (Maywood). 2023 Oct;248(20):1745–1753. DOI: https://doi.org/10.1177/15353702231198081

[12] Hernesniemi JA, Pukkila T, Molkkari M, Nikus K, Lyytikainen L, Viik J, et al. Prediction of sudden cardiac death with ultra-short-term heart rate fluctuations. JACC Clin Electrophysiol. 2024;10(9):2010–2020. DOI: https://doi.org/10.1016/j.jacep.2024.04.018

[13] Kida N, Tsubakihara Y, Kida H, Ageta S, Arai M, Hamada Y, et al. Usefulness of measurement of heart rate variability by Holter ECG in hemodialysis patients. BMC Nephrol. 2017 Jan;18(1):8. DOI: https://doi.org/10.1186/s12882-016-0423-3

[14] Tfelt-Hansen J, Garcia R, Albert C, Merino J, Krahn A, Marijon E, et al. Risk stratification of sudden cardiac death: A review. Europace. 2023 Aug;25(8):8–19. DOI: https://doi.org/10.1093/europace/euad203

[15] Avramovski P, Avramovska M, Sotiroski K, Sikole A. Acute-phase proteins as promoters of abdominal aortic calcification in chronic dialysis patients. Saudi J Kidney Dis Transpl. 2019;30(2):376–386. DOI: https://doi.org/10.4103/1319-2442.256845

[16] Shehab AM, MacFadyen RJ, McLaren M, Tavendale R, Belch JJ, Struthers AD. Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: A pilot study. Heart. 2004 Nov;90(11):1263–1268. DOI: https://doi.org/10.1136/hrt.2003.028399

[17] Choudhury D, Tuncel M, Levi M. Disorders of lipid metabolism and chronic kidney disease in the elderly. Semin Nephrol. 2009 Nov;29(6):610–620. DOI: https://doi.org/10.1016/j.semnephrol.2009.07.006

[18] Kovesdy CP, Kalantar-Zadeh K. Review article: Biomarkers of outcomes in advanced chronic kidney disease. Nephrology (Carlton). 2009;14(4):408–415. DOI: https://doi.org/10.1111/j.1440-1797.2009.01119.x

[19] Mann DL, Zipes DP, Libby P, Bonow RO. Braunwald’s heart disease: A textbook of cardiovascular medicine, single volume. Tenth edition. Philadelphia, PA: Elsevier; 2014.

[20] Herzog CA, Mangrum JM, Passman R. Sudden cardiac death and dialysis patients. Semin Dial. 2008;21(4):300–307. DOI: https://doi.org/10.1111/j.1525-139X.2008.00455.x

[21] Stein PK. Assessing heart rate variability from real-world Holter reports. Card Electrophysiol Rev. 2002 Sep;6(3):239–244.

[22] Vlad S, Ciupa RV. International Conference on Advancements of Medicine and Health Care through Technology: 5th–7th June 2014, Cluj-Napoca, Romania: Meditech 2014. Cham: Springer, (2014). DOI: https://doi.org/10.1007/978-3-319-07653-9

[23] Ye Y, Liu H, Chen Y, Zhang Y, Li S, Hu W, et al. Hemoglobin targets for the anemia in patients with dialysis-dependent chronic kidney disease: A meta-analysis of randomized, controlled trials. Ren Fail. 2018 Nov;40(1):671–679. DOI: https://doi.org/10.1080/0886022X.2018.1532909

[24] Krane V, Heinrich F, Meesmann M, Olschewski M, Lilienthal J, Angermann C, et al.; German Diabetes and Dialysis Study Investigators. Electrocardiography and outcome in patients with diabetes mellitus on maintenance hemodialysis. Clin J Am Soc Nephrol. 2009 Feb;4(2):394–400. DOI: https://doi.org/10.2215/CJN.02020408

[25] Nishimura M, Tokoro T, Nishida M, Hashimoto T, Kobayashi H, Yamazaki S, et al. Sympathetic overactivity and sudden cardiac death among hemodialysis patients with left ventricular hypertrophy. Int J Cardiol. 2010 Jun;142(1):80–86. DOI: https://doi.org/10.1016/j.ijcard.2008.12.104

[26] Oikawa K, Ishihara R, Maeda T, Yamaguchi K, Koike A, Kawaguchi H, et al. Prognostic value of heart rate variability in patients with renal failure on hemodialysis. Int J Cardiol. 2009 Jan;131(3):370–377. DOI: https://doi.org/10.1016/j.ijcard.2007.10.033

[27] Gatzoulis KA, Arsenos P, Trachanas K, Dilaveris P, Antoniou C, Tsiachris D, et al. Signal-averaged electrocardiography: past, present, and future. J Arrhythm. 2018 May;34(3):222–229. DOI: https://doi.org/10.1002/joa3.12062

[28] Johansson M, Gao SA, Friberg P, Annerstedt M, Bergstrom G, Carlstrom J, et al. Reduced baroreflex effectiveness index in hypertensive patients with chronic renal failure. Am J Hypertens. 2005;18(7):995–1016. DOI: https://doi.org/10.1016/j.amjhyper.2005.02.002

[29] Waks JW, Tereshchenko LG, Parekh RS. Electrocardiographic predictors of mortality and sudden cardiac death in patients with end stage renal disease on hemodialysis. J Electrocardiol. 2016;49(6):848– 854. DOI: https://doi.org/10.1016/j.jelectrocard.2016.07.020

[30] Drawz PE, Babineau DC, Brecklin C, He J, Kallem RR, Soliman EZ, et al.; CRIC Study Investigators. Heart rate variability is a predictor of mortality in chronic kidney disease: A report from the CRIC Study. Am J Nephrol. 2013;38(6):517–528. DOI: https://doi.org/10.1159/000357200

[31] Benichou T, Pereira B, Mermillod M, Tauveron I, Pfabigan D, Maqdasy S, et al. Heart rate variability in type 2 diabetes mellitus: A systematic review and meta-analysis. PLoS One. 2018 Apr;13(4):e0195166. DOI: https://doi.org/10.1371/journal.pone.0195166

[32] Yalım Z, Demir ME, Yalım SA, Alp Ç. Investigation of heart rate variability and heart rate turbulence in chronic hypotensive hemodialysis patients. Int Urol Nephrol. 2020 Apr;52(4):775–782. DOI: https://doi.org/10.1007/s11255-020-02429-7

[33] Rastović M, Srdić-Galić B, Barak O, Stokić E, Polovina S. Aging, heart rate variability and metabolic impact of obesity. Acta Clin Croat. 2019 Sep;58(3):430–438. DOI: https://doi.org/10.20471/acc.2019.58.03.05

[34] Reardon M, Malik M. Changes in heart rate variability with age. Pacing Clin Electrophysiol. 1996;19(11 Pt 2):1863–1866. DOI: https://doi.org/10.1111/j.1540-8159.1996.tb03241.x

[35] Thio CH, van Roon AM, Lefrandt JD, Gansevoort RT, Snieder H. Heart rate variability and its relation to chronic kidney disease: Results from the PREVEND study. Psychosom Med. 2018 Apr;80(3):307–316. DOI: https://doi.org/10.1097/PSY.0000000000000556

[36] Gui-Ling X, Jing-Hua W, Yan Z, Hui X, Jing-Hui S, Si-Rui Y. Association of high blood pressure with heart rate variability in children. Iran J Pediatr. 2013 Feb;23(1):37–44.

[37] Singh JP, Larson MG, Tsuji H, Evans JC, O’Donnell CJ, Levy D. Reduced heart rate variability and new-onset hypertension: Insights into pathogenesis of hypertension: the Framingham Heart Study. Hypertension. 1998 Aug;32(2):293–297. DOI: https://doi.org/10.1161/01.HYP.32.2.293

[38] Saravanan P, Davidson NC. Risk assessment for sudden cardiac death in dialysis patients. Circ Arrhythm Electrophysiol. 2010 Oct;3(5):553–559. DOI: https://doi.org/10.1161/CIRCEP.110.937888

[39] von Känel R, Carney RM, Zhao S, Whooley MA. Heart rate variability and biomarkers of systemic inflammation in patients with stable coronary heart disease: Findings from the Heart and Soul Study. Clin Res Cardiol. 2011 Mar;100(3):241–247. DOI: https://doi.org/10.1007/s00392-010-0236-5

[40] Wu EC, Huang YT, Chang YM, Chen IL, Yang CL, Leu SC, et al. The association between nutritional markers and heart rate variability indices in patients undergoing chronic hemodialysis. J Clin Med. 2019;8(10):1700. DOI: https://doi.org/10.3390/jcm8101700

[41] Genovesi S, Valsecchi MG, Rossi E, Pogliani D, Acquistapace I, De Cristofaro V, et al. Sudden death and associated factors in a historical cohort of chronic haemodialysis patients. Nephrol Dial Transplant. 2009 Aug;24(8):2529–2536. DOI: https://doi.org/10.1093/ndt/gfp104

[42] Electrophysiology TF; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: Standards of measurement, physiological interpretation and clinical use. Circulation. 1996 Mar;93(5):1043–1065.

[43] Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998 Nov;98(21):2334–2351. DOI: https://doi.org/10.1161/01.CIR.98.21.2334

[44] Hirsch D, Lau B, Kushwaha V, Yong K. The controversies of coronary artery disease in end-stage kidney disease patients: A narrative review. Rev Cardiovasc Med. 2023 Jun;24(6):181–206. DOI: https://doi.org/10.31083/j.rcm2406181

[45] Avramovski P, Janakievska P, Sotiroski K, Zafirova-Ivanovska B, Sikole A. Aortic pulse wave velocity is a strong predictor of all—cause and cardiovascular mortality in chronic dialysis patients. Ren Fail. 2014 Mar;36(2):176–186. DOI: https://doi.org/10.3109/0886022X.2013.843359

[46] Krishnan AV, Kiernan MC. Uremic neuropathy: Clinical features and new pathophysiological insights. Muscle Nerve. 2007 Mar;35(3):273–290. DOI: https://doi.org/10.1002/mus.20713

[47] Milicević G, Lakusić N, Szirovicza L, Cerovec D, Majsec M. Different cut-off points of decreased heart rate variability for different groups of cardiac patients. J Cardiovasc Risk. 2001 Apr;8(2):93–102. DOI: https://doi.org/10.1177/174182670100800206

[48] La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ; ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet. 1998 Feb;351(9101):478–484. DOI: https://doi.org/10.1016/S0140-6736(97)11144-8

[49] Malik M, Camm AJ, Janse MJ, Julian DG, Frangin GA, Schwartz PJ. Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: A substudy of EMIAT (The European Myocardial Infarct Amiodarone Trial). J Am Coll Cardiol. 2000 Apr;35(5):1263–1275. DOI: https://doi.org/10.1016/S0735-1097(00)00571-4

[50] Malik M, Bigger JT, Camm AJ, Kleiger RE, Malliani A, Moss AJ, et al.; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Eur Heart J. 1996 Mar;17(3):354–381. DOI: https://doi.org/10.1093/oxfordjournals.eurheartj.a014868

[51] Jhen RN, Wang PC, Chang YM, Kao JL, Wu EC, Shiao CC. The clinical significance and application of heart rate variability in dialysis patients: A narrative review. Biomedicines. 2024 Jul;12(7):1547–1556. DOI: https://doi.org/10.3390/biomedicines12071547

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Published

2025-06-30

How to Cite

Avramovski, P., Avramovska, M., Nikleski, Z., Todorovska, L., Sotiroski, K., Siklovska, V., … Vasilevski, S. (2025). Decoding the Risk: Heart Rate Variability as a Powerful Predictor of Sudden Cardiac Death in Chronic Hemodialysis Patients—A 36-Month Prospective Study. Dubai Medical Journal, 8(2), 170–191. https://doi.org/10.18502/dmj.v8i2.19005