Cardiovascular prevention, despite its apparent simplicity (eat healthy foods, exercise regularly, avoid smoking…), is fraught with complexities and challenges, even for the informed and competent cardiovascular specialist. One of the greatest yet subtle hurdles in this field is the translational gap between proof of association and proof of intervention. In other words, something (or its lack thereof) may be associated, even meaningfully, with a set of relevant outcomes. Yet, it may often be the case that simply providing (or avoiding) such something may not yield the desired benefits.
This scenario may become even more complicated when we face predictors of substantial inherent complexities, such as sex hormones.(1) Indeed, we know that physiology of testosterone, in men as well as women, is multifaceted. For instance, circadian rhythms imply that a single measurement cannot inform on average values. Similarly, effects may vary substantially depending on the target tissue, as well as capability to enter subcellular structures (Figure 1). This is why the jury is still out on the actual role of testosterone in cardiovascular disease in general, and prevention in particular, even if its beneficial role for the treatment of erectile dysfunction are undisputed, and similar to those of phosphodiesterase-type 5 inhibitors.(1-3) For instance, we know that testosterone supplementation may prove of benefit in men with muscle weakness and low blood levels of testosterone, but its safety, in particularly on the long-term, remains unclear.(2)
The importance of framing accurately the role of testosterone in primary and secondary prevention is clearly embodied by two articles published in the European Journal of Preventive Cardiology.(4-5) In particular, Zeller et al highlighted the significant association between blood testosterone levels and long-term risk of atrial fibrillation and stroke.(4) This work confirms prior research efforts and expands their implications on the complex interplay between cardiac function, gonadal physiology, cerebrovascular events, and cognitive function.(4,6-7) Notably, Zeller and colleagues do not shy from highlighting the two-face impact of blood levels of testosterone on risk, with this molecule being positively associated with risk (i.e. detrimental) in women, and inversely associated (i.e. protective) in men.(4)
Focusing on secondary prevention, Gencer et al report on the predictive role of admission blood levels of testosterone among men admitted for acute coronary syndromes.(5) Specifically, lower testosterone levels were associated with adverse outcomes, thus confirming the inverse relationship already reported among males by Zeller and colleagues.
Evidently, the next step will be the careful design and conduct of a large and pragmatic randomised trial suitable for quantifying the risk-benefit profile of long-term testosterone supplementation, with substantial precision and external validity.(8)
Figure: Diverse impact of testosterone on several body targets, and highlights of its role on prognosis in patients with acute coronary syndromes (ACS) and for risk-prediction of stroke and atrial fibrillation (AF).