Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men,but protective in women

Abstract

Background

Atrial fibrillation is the most common serious abnormal heart rhythm, and a frequent cause of ischaemic stroke. Recent experimental studies, mainly in orchiectomised rats, report a relationship between sex hormones and atrial electrophysiology and electroanatomy. We aimed to evaluate whether low testosterone levels are predictive for atrial fibrillation and/or ischaemic stroke in men and women.

Design and methods

The serum total testosterone levels were measured at baseline in a population cohort of 7892 subjects (3876 male, 4016 female), aged 25–74 years, using a commercially available immunoassay. The main outcome measure was atrial fibrillation or ischaemic stroke, whichever came first.

Results

During a median follow-up of 13.8 years, a total of 629 subjects (8.0%) suffered from incident atrial fibrillation (n = 426) and/or ischemic stroke (n = 276). Cox regression analyses, adjusted for age (used as time-scale), geographical region, total cholesterol (log), high-density lipoprotein-cholesterol (log), hypertension medication, known diabetes, smoking status, waist-hip-ratio, and time of blood drawn, documented differential predictive value of low sex-specific testosterone levels for atrial fibrillation and/or ischaemic stroke, in men and in women: Increasing levels were associated with lower risk in men (hazard ratio per one nmol/l increase 0.98 (95% confidence interval 0.93–1.00); p = 0.049). On the other hand, increasing testosterone levels were associated with higher risk in women (hazard ratio per one nmol/l increase 1.17 (95% confidence interval 1.02–1.36); p = 0.031).

Conclusion

Our study indicates that low testosterone levels are associated with increased risk of future atrial fibrillation and/or ischaemic stroke in men, while they are protective in women.

Keywords

Testosterone atrial fibrillation stroke prognosis women

Get full access to this article

View all access options for this article.

References

Hylek

Phillips

et al.

Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 285: 2370–2375.

Gorenek

Pelliccia

Benjamin

et al.

European Heart Rhythm Association (EHRA)/European Association of Cardiovascular Prevention and Rehabilitation (EACPR) position paper on how to prevent atrial fibrillation endorsed by the Heart Rhythm Society (HRS) and Asia Pacific Heart Rhythm Society (APHRS). Eur J Prev Cardiol 2017; 24: 4–40.

Wattigney

Mensah

Croft

. Increased atrial fibrillation mortality: United States, 1980–1998. Am J Epidemiol 2002; 155: 819–826.

Wang

Larson

Levy

et al.

Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: The Framingham Heart Study. Circulation 2003; 107: 2920–2925.

Coyne

Paramore

Grandy

et al.

Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health 2006; 9: 348–356.

Ringborg

Nieuwlaat

Lindgren

et al.

Costs of atrial fibrillation in five European countries: Results from the Euro Heart Survey on atrial fibrillation. Europace 2008; 10: 403–411.

Frost

Vestergaard

Mosekilde

et al.

Trends in incidence and mortality in the hospital diagnosis of atrial fibrillation or flutter in Denmark, 1980–1999. Int J Cardiol 2005; 103: 78–84.

Wolf

Mitchell

Baker

et al.

Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998; 158: 229–234.

Wolf

Dawber

Thomas

Jr et al.

Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study. Neurology 1978; 28: 973–977.

10.

Ruigomez

Johansson

Wallander

et al.

Risk of cardiovascular and cerebrovascular events after atrial fibrillation diagnosis. Int J Cardiol 2009; 136: 186–192.

11.

Chamberlain

Agarwal

Folsom

et al.

A clinical risk score for atrial fibrillation in a biracial prospective cohort (from the Atherosclerosis Risk in Communities (ARIC) study). Am J Cardiol 2011; 107: 85–91.

12.

Tsuneda

Yamashita

Kato

et al.

Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. J Cardiovasc Electrophysiol 2009; 20: 1055–1060.

13.

Gimeno

Webb

. Sex hormone studies. The effects on the cellular membrane potentials and contractility of isolated rat atrium. Calif Med 1963; 98: 67–69.

14.

O'Neal

Nazarian

Alonso

et al.

Sex hormones and the risk of atrial fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA). Endocrine 2017; 58: 91–96.

15.

Chan

O'Malley

. Mechanism of action of the sex steroid hormones (first of three parts). N Engl J Med 1976; 294: 1322–1328.

16.

Wang

et al.

Endogenous sex hormone levels and coronary heart disease risk in postmenopausal women: A meta-analysis of prospective studies. Eur J Prev Cardiol 2017; 24: 600–611.

17.

Zeller

Hughes

Tuovinen

et al.

BiomarCaRE: Rationale and design of the European BiomarCaRE project including 300,000 participants from 13 European countries. Eur J Epidemiol 2014; 29: 777–790.

18.

Borodulin

Vartiainen

Peltonen

et al.

Forty-year trends in cardiovascular risk factors in Finland. Eur J Public Health 2015; 25: 539–546.

19.

Pajunen

Koukkunen

Ketonen

et al.

The validity of the Finnish Hospital Discharge Register and Causes of Death Register data on coronary heart disease. Eur J Cardiovasc Prev Rehabil 2005; 12: 132–127.

20.

Sund

. Quality of the Finnish Hospital Discharge Register: A systematic review. Scand J Public Health 2012; 40: 505–515.

21.

Inker

Schmid

Tighiouart

et al.

CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012; 367: 20–29.

22.

Van Buuren

Groothuis-Oudshoorn

. MICE: Multivariate imputation by chained equations in R. J Stat Softw 2011; 45: 1–67.

23.

Anderson

Kappelle

Eliasziw

et al.

Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke 2002; 33: 1963–1967.

24.

Sanna

Diener

Passman

et al.

CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370: 2478–2486.

25.

Lin

Wolf

Kelly-Hayes

et al.

Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27: 1760–1764.

26.

Jorgensen

Nakayama

Reith

et al.

Acute stroke with atrial fibrillation. The Copenhagen Stroke Study. Stroke 1996; 27: 1765–1769.

27.

Kistler

Sanders

Fynn

et al.

Electrophysiologic and electroanatomic changes in the human atrium associated with age. J Am Coll Cardiol 2004; 44: 109–116.

28.

Scragg

Jones

Channer

et al.

Testosterone is a potent inhibitor of L-type Ca(2+) channels. Biochem Biophys Res Commun 2004; 318: 503–506.

29.

Vest

Wehrens

Reiken

et al.

Defective ryanodine receptor regulation during atrial fibrillation. Circulation 2005; 111: 2025–2032.

30.

Ohkusa

Ueyama

Yamada

et al.

Alterations in cardiac sarcoplasmic reticulum Ca2 + regulatory proteins in the atrial tissue of patients with chronic atrial fibrillation. J Am Coll Cardiol 1999; 34: 255–263.

31.

Lai

Lin

et al.

Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca(2+)-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: An insight into the mechanism of atrial electrical remodeling. J Am Coll Cardiol 1999; 33: 1231–1237.

32.

Grosman

Rosales

Fabre

et al.

Association between testosterone levels and the metabolic syndrome in adult men. Aging Male 2014; 17: 161–165.

33.

Schneider

Kirschner

Berkowitz

et al.

Increased estrogen production in obese men. J Clin Endocrinol Metab 1979; 48: 633–638.

34.

Kley

Deselaers

Peerenboom

et al.

Enhanced conversion of androstenedione to estrogens in obese males. J Clin Endocrinol Metab 1980; 51: 1128–1132.

35.

Isidori

Caprio

Strollo

et al.

Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 1999; 84: 3673–3680.

36.

Tena-Sempere

. Leptin inhibits testosterone secretion from adult rat testis in vitro. J Endocrinol 1999; 161: 211–218.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.09 MB

Low testosterone levels are predictive for incident atrial fibrillation and ischaemic stroke in men,but protective in women – results from the FINRISK study

Abstract

Background

Design and methods

Results

Conclusion

Keywords

Get full access to this article

References

Supplementary Material