Effective testosterone treatment reduces incidence of atrial fibrillation

Effective testosterone treatment reduces incidence of atrial fibrillation

Sharma, R., et al., Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc, 2017. 6(5)

While the effect of testosterone treatment on heart disease 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 heart disease 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 - an irregular and often rapid heart rate that can increase risk of stroke, heart failure and other heart-related complications - in testosterone deficient men with documented low testosterone levels.1

Key Points

  • Atrial fibrillation is the most common form of abnormal heart rhythm, 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 form of abnormal heart rhythm, 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, several 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 excessively high doses of synthetic androgens in combination with excessively high doses of 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 optimal 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% reduced risk of atrial fibrillation than group 2 (23 939 patients, median age 65 years) and a 21% 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.

Table 1: Reduction in Risk of Atrial Fibrillation Effective vs. Ineffective Testosterone Therapy
vergrößern Data from Sharma, R., et al., Normalization of Testosterone Levels After Testosterone Replacement 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 blood clots in the legs or lungs.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 combination of cardiovascular events that included heart attack, coronary revascularization (bypass surgery), angina (chest pain caused by reduced blood flow to the heart), stroke, mini-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 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 (optimal) levels of testosterone might reduce risk of atrial fibrillation development remain to be established and are likely multifactorial. Data suggest that testosterone prevents heart rhythm abnormalities.8

Inflammation seems to contribute to the development 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 high testosterone levels are associated with a lower level of inflammatory markers, and that testosterone treatment decreases levels of these inflammatory markers.19-21 Thus, the anti-inflammatory effect of testosterone, combined with its heart rhythm protective action, likely contributes to the observed reduced incidence of atrial fibrillation.

A report of two patient cases suggested that testosterone could be used as an atrial fibrillation treatment in aging men 22, which is supported by the study presented here.

References:

1. Sharma, R., et al., Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Associated With Decreased Incidence of Atrial Fibrillation. J Am Heart Assoc, 2017. 6(5).
2. 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.
3. 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.
4. 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.
5. Heeringa, J., et al., Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J, 2006. 27(8): p. 949-53.
6. Lai, J., et al., Reduced testosterone levels in males with lone atrial fibrillation. Clin Cardiol, 2009. 32(1): p. 43-6.
7. Liu, T., et al., Androgens and atrial fibrillation: friends or foes? Int J Cardiol, 2010. 145(2): p. 365-7.
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10. Sullivan, M.L., C.M. Martinez, and E.J. Gallagher, Atrial fibrillation and anabolic steroids. J Emerg Med, 1999. 17(5): p. 851-7.
11. Lau, D.H., et al., Atrial fibrillation and anabolic steroid abuse. Int J Cardiol, 2007. 117(2): p. e86-7.
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13. 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.
14. Sharma, R., et al., Association Between Testosterone Replacement 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.
15. 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.
16. Kourliouros, A., et al., Current concepts in the pathogenesis of atrial fibrillation. Am Heart J, 2009. 157(2): p. 243-52.
17. 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.
18. 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.
19. 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.
20. Kupelian, V., et al., Association of sex hormones and C-reactive protein levels in men. Clin Endocrinol (Oxf), 2010. 72(4): p. 527-33.
21. 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.
22. 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.

G.COM.GM.MH.08.2017.0458
Last updated: 2017
G.GM.MH.04.2015.0334