The toll of the gridiron: damage-associated molecular patterns and hypertension in American football

Abstract

American football has unequivocally been linked to elevations in blood pressure and hypertension, especially in linemen. However, the mechanisms of this increase cannot be attributed solely to increased body weight and associated cardiometabolic risk factors (e.g.,dyslipidemia or hyperglycemia). Therefore, understanding the etiology of football-associated hypertension is essential for improving the quality of life in this mostly young population, as well as for lowering the potential for chronic disease in the future. We propose that inflammatogenic damage-associated molecular patterns (DAMPs) released into the circulation from football-induced musculoskeletal trauma activate pattern-recognition receptors of the innate immune system-specifically, high mobility group box 1 protein (HMGB1) and mitochondrial (mt)DNA which activate Toll-like receptor (TLR)4 and -9, respectively. Previously, we observed that circulating levels of these 2 DAMPs are increased in hypertension, and activation of TLR4 and -9 causes endothelial dysfunction and hypertension. Therefore, our novel hypothesis is that musculoskeletal injury from repeated hits in football players, particularly in linemen, leads to elevated circulating HMGB1 and mtDNA to activate TLRs on endothelial cells leading to impaired endothelium-dependent vasodilation, increased vascular tone, and hypertension.

Keywords: blood pressure; inflammation; musculoskeletal trauma.

Figure 1.

The synergistic mechanisms of football-induced hypertension. Excess body weight and associated cardiometabolic factors are the most obvious mechanisms of the hypertension observed in football players. However, inflammation from trauma-derived DAMPs and spikes in sympathetic activation from hits on the playing field are additional mechanisms that are currently unexplored. It is more than likely that all these mechanisms combine to create a dangerous milieu that contributes to elevations in blood pressure in football players.

Figure 2.

Dangerous interactions of DAMPs and TLRs and their effects on the vasculature. TLR activation by DAMPs interferes with normal vascular function, such as endothelium-dependent relaxation and an appropriate degree of vascular tone. On vascular cells, TLR activation contributes to decreased production and bioavailability of NO, exacerbated formation of cytokines and ROS, and the release of vasoconstrictor metabolites of AA. Ach, acetylcholine; COX, cyclooxygenase; l-Arg, l-arginine; sGC, soluble guanylyl cyclase.

Figure 3.

A novel hypothesis that circulating DAMPs, released after musculoskeletal trauma in football players, leads to TLR activation in immune cells, endothelial cells, and vascular smooth muscle cells. Inappropriate and excessive activation of TLRs on these cells could subsequently mediate inflammation, endothelial dysfunction, and hypertension in football players exposed to high levels of muscle damage.