The impact of testosterone levels on J-wave patterns observed in healthy Turkish males

Abstract

Objectives: Early-repolarization (ER) and Brugada-type-ECG-patterns (BTEP) have recently been grouped under a common terminology called “J-wave patterns” (JWP) and have been associated with an increased risk of sudden-cardiac-death. Scarce data is present about the male dominance in JWP and the probable effects of gonadal hormones on cardiac ion-channel functions. We sought to evaluate the relationship of testosterone-levels and the presence of JWP in healthy Turkish-males.

Methods: One hundred eighty-five healthy male volunteers between ≥18 to ≤50 years old without any cardiac disorders were evaluated. ECG, blood biochemistry and total testosterone levels were obtained together with thorough physical examination. Subjects with complete-bundle-branch-block, non-sinus-rhythms and any abnormality on cardiac examination were excluded from the study. BTEP was searched according to the EHRA/HRS 2016 Consensus Conference on V1-V3. ER on ECG was defined as J-point elevation of ≥ 0.1 mV in ≥ 2 leads in the inferior (II, III, aVF) (Inferior ER), lateral (DI, aVL, V4-6) (Lateral ER) or both (Inferolateral ER).

Results: A total of 179 subjects (mean age 34.9 ± 7.9 years) were included in our analyses. Three BTEP (1.7%) and 45 ER (26%) were detected. 22 were lateral (49%), 13 inferior (29%) and 10 were (22%) inferolateral ER. JWP (+) subjects (n = 48, 27%) were demonstrating significantly lower basal heart rates (73.9 ± 11bpm vs 68.4 ± 10.3 bpm, p = 0.001) and longer PR intervals (153.9 ± 20.3 ms vs 163.3 ± 21.6 ms, p = 0.01). JWP (+) subjects had significantly higher testosterone levels compared with the ones without (485.5 ± 128.3 ng/dl vs 559.3 ± 167.7, p < 0.001). In the subgroup analyses, BTEP and inferior/inferolateral ER patterns were significantly associated with higher testosterone levels compared with the JWP (-) population, while testosterone levels of subjects with lateral ER was not significantly higher. Electrolytes and blood chemistry values were non-significant between JWP + and - subjects. In the ROC analysis, the cut-off value for predicting the presence of a JWP on ECG was 629 ng/dl with a sensitivity of 44% and specificity of 86% [AUC = 0.66 (95% CI: 0.56-0.75), p = 0.001]. In multivariate analysis, total testosterone level > 629 ng/dl was significantly predicting a JWP on ECG, even outperforming age and hs-CRP levels with an OR of 4.57 (95% CI 1.910-10.9, p = 0.001).

Conclusions: Testosterone might be associated with the male predominance observed in the JWP. More malignant inferior/inferolateral ER seems to be mainly associated with the high testosterone levels in Turkish male population. This finding might be attributed to the previously demonstrated effects of testosterone on cardiac ion-channel functions, especially outward-K channels. 

Keywords

• electrocardiogram
• j wave pattern
• male
• testosterone

References

1. 1. Barnes AR, Katz LN, Levine SA, Pardee HEB, White PD, Wilson FN. The standardization of electrocardiographic nomenclature. J Am Med Assoc 1943;121:1347-9.
2. 2. Osborn JJ. Experimental hypothermia: respiratory and blood pH changes in relation to cardiac function. Am J Physiol Content 1953;175:389-98.
3. 3. Myers GB, Klein HA. Normal variations in multiple precordial leads. Am Heart J 1947;34:785-808.
4. 4. Goldman MJ. RS-T segment elevation in mid- and left precordial leads as a normal variant. Am Heart J 1953;46:817-20.
5. 5. Klatsky AL, Oehm R, Cooper RA, Udaltsova N, Armstrong MA. The early repolarization normal variant electrocardiogram: correlates and consequences. Am J Med 2003;115:171-77.
6. 6. Haïssaguerre M, Derval N, Sacher F, Jesel L, Deisenhofer I, de Roy L, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008;358:2016-23.
7. 7. Nam G-B, Kim Y-H, AntC zelevitch. Augmentation of J waves and electrical storms in patients with early repolarization. N Engl J Med 2008;358:2078-9.
8. 8. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, et al. Long-term outcome associated with early repolarization on electrocardiography. N Engl J Med 2009;361:2529-37.

9. 9. Haruta D, Matsuo K, Tsuneto A, Ichimaru S, Hida A, Sera N, et al. Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram. Circulation 2011;123:2931-7.
10. 10. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada Syndrome: Report of the Second Consensus Conference. Circulation 2005;111:659-70.
11. 11. Kamakura S, Ohe T, Nakazawa K, Aizawa Y, Shimizu A, Horie M, et al. Long-term prognosis of probands with Brugada-pattern ST-elevation in leads V1-V3. Circ Arrhythm Electrophysiol 2009;2:495-503.
12. 12. Antzelevitch C. J wave syndromes: molecular and cellular mechanisms. J Electrocardiol 2013;46:510-8.
13. 13. Macfarlane PW, Antzelevitch C, Haissaguerre M, Huikuri H V., Potse M, Rosso R, et al. The early repolarization pattern: a consensus paper. J Am Coll Cardiol 2015;66:470-7.
14. 14. Bozkurt A, Yas D, Seydaoglu G, Acartürk E. Frequency of Brugada-type ECG pattern (Brugada sign) in southern Turkey. Int Heart J 2006;47:541-7.
15. 15. Hünük B, Kepez A, Erdoğan O. The prevalence of early repolarization variant in Turkish male subjects: a clinical single center study. Turk Kardiyol Dern Ars 2012;40:409-13.
16. 16. Rollin A, Maury P, Bongard V, Sacher F, Delay M, Duparc A, et al. Prevalence, prognosis, and identification of the malignant form of early repolarization pattern in a population-based study. Am J Cardiol 2012;110:1302-08.
17. 17. Di Diego JM, Antzelevitch C. Inferolateral J-wave syndromes: A reflection of abnormal repolarization, depolarization, or both? Heart Rhythm 2018. doi:10.1016/j.hrthm.2018.11.020.
18. 18. Antzelevitch C, Yan G-X, Ackerman MJ, Borggrefe M, Corrado D, Guo J, et al. J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge. Europace 2017;19:665-94.
19. 19. Benito B, Sarkozy A, Mont L, Henkens S, Berruezo A, Tamborero D, et al. Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol 2008;52:1567-73.
20. 20. James AF, Choisy SCM, Hancox JC. Recent advances in understanding sex differences in cardiac repolarization. Prog Biophys Mol Biol 2007;94:265-319.
21. 21. Shimizu W, Matsuo K, Kokubo Y, Satomi K, Kurita T, Noda T, et al. Sex hormone and gender difference--role of testosterone on male predominance in Brugada syndrome. J Cardiovasc Electrophysiol 2007;18:415-21.
22. 22. Patton KK, Ellinor PT, Ezekowitz M, Kowey P, Lubitz SA, Perez M, et al. Electrocardiographic early repolarization. Circulation 2016;133:1520-9.
23. 23. Nakagawa M, Ooie T, Ou B, Ichinose M, Takahashi N, Hara M, et al. Gender differences in autonomic modulation of ventricular repolarization in humans. J Cardiovasc Electrophysiol 2005;16:278-84.
24. 24. Stramba-Badiale M, Spagnolo D, Bosi G, Schwartz PJ. Are gender differences in QTc present at birth? MISNES Investigators. Multicenter Italian Study on neonatal electrocardiography and sudden infant death syndrome. Am J Cardiol 1995;75:1277-8.
25. 25. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol 1992;8:690-5.
26. 26. Pecori-Giraldi F, Toja PM, Filippini B, Michailidis J, Scacchi M, Stramba-Badiale M, et al. Increased prevalence of prolonged QT interval in males with primary or secondary hypogonadism: a pilot study. Int J Androl 2010;33:e132-8.
27. 27. Bidoggia H, Maciel JP, Capalozza N, Mosca S, Blaksley EJ, Valverde E, et al. Sex differences on the electrocardiographic pattern of cardiac repolarization: possible role of testosterone. Am Heart J 2000;140:678-83.
28. 28. Nakagawa M, Ooie T, Takahashi N, Taniguchi Y, Anan F, Yonemochi H, et al. Influence of menstrual cycle on QT interval dynamics. Pacing Clin Electrophysiol 2006;29:607-13.
29. 29. Di Diego JM, Cordeiro JM, Goodrow RJ, Fish JM, Zygmunt AC, Pérez GJ, et al. Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation 2002;106:2004-11.
30. 30. Ezaki K, Nakagawa M, Taniguchi Y, Nagano Y, Teshima Y, Yufu K, et al. Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone. Circ J 2010;74:2448-54.
31. 31. Nakagawa M, Takahashi N, Watanabe M, Ichinose M, Nobe S, Yonemochi H, et al. Gender differences in ventricular repolarization: terminal T wave interval was shorter in women than in men. Pacing Clin Electrophysiol 2003;26:59-64.
32. 32. Yang P-C, Kurokawa J, Furukawa T, Clancy CE. Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study. PLoS Comput Biol 2010;6:e1000658.
33. 33. Bai C-X, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 2005;112:1701-10.
34. 34. Asada K, Kurokawa J, Furukawa T. Redox- and calmodulin-dependent S-nitrosylation of the KCNQ1 channel. J Biol Chem 2009;284:6014-20.
35. 35. Kurokawa J, Furukawa T. Non-genomic action of sex steroid hormones and cardiac repolarization. Biol Pharm Bull 2013;36:8-12.
36. 36. Juhani-Junttila M, Tikkanen JT, Porthan K, Oikarinen L, Jula A, Kenttä T, et al. Relationship between testosterone level and early repolarization on 12-lead electrocardiograms in men. JACC 2013;62:1633-4.
37. 37. Hussein AA, Gottdiener JS, Bartz TM, Sotoodehnia N, DeFilippi C, See V, et al. Inflammation and sudden cardiac death in a community-based population of older adults: The Cardiovascular Health Study. Heart Rhythm 2013;10:1425-32.
38. 38. Yang G, Liu J, Wang Y, Du Y, Ma A, Wang T. Lack of influence of sex hormones on Brugada syndrome-associated mutant Nav1.5 sodium channel. J Electrocardiol 2019;52:82-7.