Regarding the counterintuitive finding of vigorous physical activity and increased carotid plaque vulnerability

• Vigorous activity among older adults may lead to increased carotid plaque vulnerability. • Exercise results in interleukin-6 (IL-6) release from skeletal muscle. • IL-6 leads to increased hepatic hepcidin synthesis and increased circulating hepcidin. • Hepcidin augments macrophage iron retention, resulting in proatherogenic macrophages. • Proatherogenic macrophages contribute to plaque instability. It is widely accepted that exercise is beneficial in the prevention of cardiovascular disease. However, it has recently been shown that vigorous exercise among older individuals with existing carotid atherosclerotic plaque might be linked with increased carotid plaque vulnerability. Similarly, unfavorable coronary plaque characteristics have been found among lifelong endurance athletes, who trained intensely for long periods of time. We hypothesize that increased hepcidin levels are central to how exercise at extreme levels of vigor and/or duration, particularly among individuals with existing plaque, may lead to plaque vulnerability in both the coronary and carotid vasculature. As such, extreme levels of exercise induce skeletal muscle release of the myokine, interleukin-6 (IL-6), which in turn increases hepatic hepcidin synthesis and circulating hepcidin concentration. Hepcidin, an iron regulatory hormone, downregulates ferroportin, the sole exporter of cellular iron, which results in macrophage iron retention. The resulting iron laden macrophages within atherosclerotic plaque are proatherogenic and contribute to plaque instability. This has clinical implications regarding exercise advice among individuals with existing coronary and/or carotid atherosclerosis and calls for more research in the field.