Regarding the paradox of increased coronary atherosclerosis among highly trained athletes: Might hepcidin be the culprit?

Recent studies have shown that participants of lifelong high-intensity exercise, such as ultramarathon running, compared to individuals engaging in less intense exercise forms, have exhibited more prevalent and severe coronary atherosclerosis. This is counterintuitive to the purported benefits of exercise and this paradox eludes explanation. Interestingly, prolonged bouts of high-intensity exercise have been shown to increase hepcidin concentrations for several hours after exercise. Hepcidin, a hepatic peptide hormone and a central regulator of iron homeostasis, downregulates the expression of the only cellular iron exporter, ferroportin. As such, we posit that the repeated elevations of hepcidin over time among elite athletes lead to increases in arterial wall macrophage iron content, resulting in a proatherogenic macrophage phenotype and subsequent atherosclerosis. Mechanisms and clinical implications are discussed, and more research is suggested.