Effective testosterone treatment reduces incidence of atrial fibrillation
August 2017
Sharma, R., et al., Normalization of Testosterone Levels After Testosterone Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc, 2017. 6(5)
While the effect of testosterone treatment on cardiovascular health is a topic of ongoing debate, a growing body of evidence is refuting the widespread belief that testosterone treatment supposedly is harmful in terms of cardiovascular risk.
Here we report the results of a study, published in the Journal of the American Heart Association, which investigated the effect of testosterone treatment on the incidence of atrial fibrillation in hypogonadal men with documented low testosterone levels.1
KEY POINTS
- Atrial fibrillation is the most common cardiac arrhythmia worldwide, causing significant morbidity, mortality, and financial burden, especially in older men.
- Effective testosterone treatment that achieves large enough elevations in testosterone levels reduces the incidence of atrial fibrillation by up to 21%.
- Ineffective testosterone treatment, which does not achieve large enough elevations in testosterone levels, does not confer benefits.
What is known about testosterone and atrial fibrillation?
Atrial fibrillation is the most common cardiac arrhythmia worldwide, causing significant morbidity, mortality, and financial burden.2-4 The burden of atrial fibrillation increases with age and is higher in men than in women.5 Although the causes this sex difference are still unclear, one preclinical and several small clinical studies have suggested that testosterone deficiency may play a role in the development of atrial fibrillation.6-9
In contrast, it is also documented that anabolic steroid use, which involves supraphysiological doses of synthetic androgens in combination with supraphysiological doses testosterone, is associated with an increased risk of atrial fibrillation.10-12
To date, no study has examined the effect of testosterone therapy, which increases testosterone levels from deficient to physiological levels, on new incidence of atrial fibrillation in hypogonadal men.
What this study adds
The study published in the Journal of the American Heart Association compared the incidence of atrial fibrillation among patients who did not receive testosterone therapy, those who received testosterone therapy that resulted in normalization of total testosterone levels (effective testosterone treatment), and those who received testosterone therapy but that did not result in normal testosterone levels (ineffective testosterone treatment).
Subjects were 76,639 veterans with low total testosterone levels who had received medical care during the period of 1999 to 2014. They were divided into 3 groups.
Group 1: Effective testosterone treatment (resulting in normalization of testosterone levels)
Group 2: Ineffective testosterone treatment (not achieving sufficient elevation of testosterone levels)
Group 3: No testosterone treatment.
This study design allowed for evaluation of the impact of non-treatment as well as the impact of effective vs. ineffective testosterone therapy on atrial fibrillation incidence.
Results showed that Group 1 (40,856 patients, median age 66 years) had a significant 10% (hazard ratio 0.90, P=0.0255) reduced risk of atrial fibrillation than group 2 (23,939 patients, median age 65 years) and a 21% (hazard ratio 0.79, P=0.0001) reduced risk of atrial fibrillation than group 3 (11,853 patients, median age 67 years). There was no significant difference between groups 2 and 3 in incidence of atrial fibrillation. Table 1 shows the reduction in risk of atrial fibrillation in men receiving effective vs. ineffective testosterone treatment, compared to non-treated hypogonadal men. Note that the risk reduction in the ineffective treatment group was not significant, meaning that it could have been caused by chance rather than a true treatment effect.
Table 1: Reduction in risk of atrial fibrillation in men receiving effective vs. ineffective testosterone treatment, compared to non-treated hypogonadal men.
Data from Sharma, R., et al., Normalization of Testosterone Levels After Testosterone Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc, 2017. 6(5)
These novel results suggest that effective testosterone treatment that achieves normalization of testosterone levels - in other words, a high enough increase in testosterone levels - significantly decreases the incidence of atrial fibrillation.
Commentary
Importance of adherence and achievement of effective (therapeutic) testosterone levels
This study is the first and largest to evaluate the association between testosterone treatment and the incidence of atrial fibrillation. It confirms previous reports that low testosterone levels are associated with increased incidence of atrial fibrillation. The largest and significant decrease in the incidence of atrial fibrillation was seen in the group receiving effective testosterone treatment. This underscores the importance of adherence to testosterone treatment in order to realize clinical benefits, which require achievement of a high enough elevation in testosterone levels.
The importance of providing effective testosterone treatment (achieving normalization of testosterone levels) was highlighted in a previous study which showed that it results in major and significant reduction of heart attack, stroke and all-cause mortality by 18%, 30% and 47%, respectively, compared to ineffective testosterone treatment (not achieving normalization of testosterone levels).13 We covered this study in a previous editorial “Adherence to testosterone therapy - short term treatment is not sufficient for achievement of maximal benefits”.
Safety
Contrary to what is commonly feared, testosterone treatment that effectively increases testosterone levels does not increase the risk of deep venous thrombosis or pulmonary embolism.14 The cardiovascular safety of testosterone treatment was recently confirmed in a new study published in the Journal of the American Medical Association (JAMA). This study investigated the association between testosterone treatment and cardiovascular outcomes in men with testosterone deficiency.15 The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction, coronary revascularization, unstable angina, stroke, transient ischemic attack, and sudden cardiac death.
Men who had been prescribed testosterone treatment (given by injection, orally, or gel/cream) were found to have a 33% reduced incidence (hazard ratio 0.67) of cardiovascular end points during a follow-up period of up to 6.6 years, compared to men who had never been prescribed testosterone treatment.15 It was concluded that testosterone treatment is not associated with an increased risk of cardiovascular outcomes. In opposition to popular belief, during long-term follow-up the risk of cardiovascular events is lower in testosterone-treated men.15 These findings support both the safety and efficacy of testosterone therapy in testosterone deficient men.
Protective mechanisms of testosterone
The exact mechanisms by which therapeutic (normal) levels of testosterone might reduce risk of atrial fibrillation development remain to be established and are likely multifactorial. Data suggest that testosterone has anti-arrhythmogenic properties.8
Inflammation has been implicated in the pathogenesis of atrial fibrillation 16,17, and inflammatory markers - including tumor necrosis factor α, interleukin 6, interleukin 2, and C-reactive protein – are elevated in patients with atrial fibrillation.18 Several studies have shown that endogenous testosterone levels are inversely associated with inflammatory markers, and that testosterone treatment decreases levels of tumor necrosis factor α, interleukin 6, C-reactive protein, and other proinflammatory cytokines.19-21 Thus, the anti-inflammatory and anti-arrhythmogenic effects of testosterone likely contribute to the observed reduced incidence of atrial fibrillation.
A report of two case studies suggested that testosterone could be used as an atrial fibrillation treatment in aging men 22, which is supported by the study presented here.
Recommendations
References
- Sharma, R., et al., Normalization of Testosterone Levels After Testosterone Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc, 2017. 6(5). Return to content
- Lip, G.Y.H., C.M. Brechin, and D.A. Lane, The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest, 2012. 142(6): p. 1489-1498. Return to content
- Go, A.S., 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(18): p. 2370-5. Return to content
- Benjamin, E.J., et al., Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation, 2017. 135(10): p. e146-e603. Return to content
- Heeringa, J., et al., Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J, 2006. 27(8): p. 949-53. Return to content
- Lai, J., et al., Reduced testosterone levels in males with lone atrial fibrillation. Clin Cardiol, 2009. 32(1): p. 43-6. Return to content
- Liu, T., et al., Androgens and atrial fibrillation: friends or foes? Int J Cardiol, 2010. 145(2): p. 365-7. Return to content
- Tsuneda, T., et al., Deficiency of testosterone associates with the substrate of atrial fibrillation in the rat model. J Cardiovasc Electrophysiol, 2009. 20(9): p. 1055-60. Return to content
- Magnani, J.W., et al., Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Circ Arrhythm Electrophysiol, 2014. 7(2): p. 307-12. Return to content
- Sullivan, M.L., C.M. Martinez, and E.J. Gallagher, Atrial fibrillation and anabolic steroids. J Emerg Med, 1999. 17(5): p. 851-7. Return to content
- Lau, D.H., et al., Atrial fibrillation and anabolic steroid abuse. Int J Cardiol, 2007. 117(2): p. e86-7. Return to content
- Akcakoyun, M., et al., Long-term anabolic androgenic steroid use is associated with increased atrial electromechanical delay in male bodybuilders. Biomed Res Int, 2014. 2014: p. 451520. Return to content
- Sharma, R., et al., Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J, 2015. 36(40): p. 2706-15. Return to content
- Sharma, R., et al., Association Between Testosterone Therapy and the Incidence of DVT and Pulmonary Embolism: A Retrospective Cohort Study of the Veterans Administration Database. Chest, 2016. 150(3): p. 563-71. Return to content
- Cheetham, T.C., et al., Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med, 2017. 177(4): p. 491-499. Return to content
- Kourliouros, A., et al., Current concepts in the pathogenesis of atrial fibrillation. Am Heart J, 2009. 157(2): p. 243-52. Return to content
- Joseph, P., et al., Atrial fibrillation is associated with hematopoietic tissue activation and arterial inflammation. Int J Cardiovasc Imaging, 2016. 32(1): p. 113-9. Return to content
- Henningsen, K.M., et al., Prognostic impact of hs-CRP and IL-6 in patients with persistent atrial fibrillation treated with electrical cardioversion. Scand J Clin Lab Invest, 2009. 69(3): p. 425-32. Return to content
- Bobjer, J., et al., Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. PLoS One, 2013. 8(4): p. e61466. Return to content
- Kupelian, V., et al., Association of sex hormones and C-reactive protein levels in men. Clin Endocrinol (Oxf), 2010. 72(4): p. 527-33. Return to content
- Malkin, C.J., et al., The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab, 2004. 89(7): p. 3313-8. Return to content
- Eby, G., Testosterone as an atrial fibrillation treatment and stroke preventative in aging men: case histories and hypothesis. Med Hypotheses, 2010. 75(2): p. 269-70. Return to content
