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.—McCarthy, C. G., Webb, R. C. The toll of the gridiron: damage-associated molecular patterns and hypertension in American football.

American football (referred to hereinafter as football) is one of the most popular sports in the United States. Its popularity is related to the intense, fast-paced, and combative nature of the game (1, 2). Despite its popularity, it is well known that participation in football has inherent risks associated with its physical and aggressive aspects. Trauma to the musculoskeletal system (e.g., sprains, strains, fractures, and contusions) is the most common injury among football participants (3). Recent evidence has revealed an alarming association of football participation with the risk of cardiovascular disease and the development of high blood pressure (4–7). Along with football’s emerging association with chronic traumatic encephalopathy (CTE) and neurodegeneration (8–10), the risk of acute and chronic disease paints a disturbing picture for football participants and their quality of life in the future.

FOOTBALL PARTICIPATION IS ASSOCIATED WITH AN ELEVATION IN ARTERIAL BLOOD PRESSURE

Hypertension is defined as chronically elevated systemic blood pressure (systolic/diastolic ≥140/90 mm Hg). Approximately 1 in 3 U.S. adults has hypertension; only half of those have their high blood pressure under control (11), and hypertension is an ominous predictor of the development of cardiovascular diseases (12). Elevated blood pressure, in the prehypertensive (systolic/diastolic = 120/80–139/89 mm Hg) and hypertensive ranges, have regularly been observed in active National Football League (NFL) players compared with that of age-equivalent men in the general population (4–6). Furthermore, linemen, in particular, have increased prevalence of elevated blood pressure compared with that of players in nonlineman positions (4–6). Recently, Weiner et al. (7) observed that participation in National Collegiate Athletic Association football is associated with significant increases in intraseason systolic and diastolic blood pressure. Among the measured characteristics, playing the lineman position, intraseason weight gain, and family history of hypertension were the strongest independent predictors of postseason high blood pressure. These increases in blood pressure caused by participation in football also have the disturbing effect of contributing to end-organ maladaptation. Weiner et al. specifically correlated increases in blood pressure with concentric left ventricular hypertrophy and change in left ventricular mass. Similarly, Kim et al. (13) observed that a single season of collegiate football participation led to an elevation in central aortic pulse pressure and pulse wave velocity, indicating increased arterial stiffness. Although these investigations revealed an association between increased blood pressure and deleterious cardiovascular remodeling with participation in football, it has also been observed that incidences of prehypertension are not increased over multiple football seasons. In a retrospective cohort of collegiate athletes, Karpinos et al. (14) observed that hypertension and prehypertension were common among them and that they were more likely to have hypertension than were male athletes from other sports. However, the incidence of prehypertension or hypertension did not change significantly from the first year to the final year of collegiate competition. Therefore, although football players have increased blood pressure compared to both male nonfootball athletes and men in the general population, and football participation increases blood pressure within a season, these factors do not have a cumulative effect on the incidence of hypertension in the long term. It is plausible that blood pressure returns to normal during the off-season and, for that reason, there is no growing incidence of hypertension among football players. Nonetheless, this notion should not diminish concern about hypertension, even the acute form, in terms of end-organ damage and prolonged risk of cardiovascular disease and does not change the fact that hypertensive football players are likely to benefit from increased surveillance of resting blood pressure coupled with blood pressure–lowering therapies (e.g., dietary interventions, lifestyle modifications, and pharmacological agents).

POTENTIAL MECHANISMS FOR THE ELEVATED BLOOD PRESSURE IN FOOTBALL PLAYERS

Excess weight, especially when associated with increased visceral adiposity, is a major contributor to hypertension, accounting for 65–78% of the risk of human essential hypertension (15, 16). Thus, a logical explanation for the increased prevalence of hypertension among football players is excess body weight. Increased visceral fat is evident in many NFL players, and a greater percentage of body fat and body weight in NFL linemen has been reported for several decades (17). Harp et al. (18) made the striking observation that 97% of NFL players were overweight [body mass index (BMI) ≥ 25 kg/m²], 56% were obese (BMI ≥ 30 kg/m²), and 29% were class II obese (BMI ≥ 35 kg/m²). Although BMI is an easy and economical measurement of body composition and has epidemiologic value, interpretation of what it means in strength athletes has not been precisely determined (19). In other words, caution should be applied when using BMI as a measure of body size, because it does not discriminate fat from lean tissue—an especially confounding factor when assessing muscular athletes, such as football linemen.

Excess body weight is associated with an increased prevalence of metabolic syndrome. A cluster of risk factors including dyslipidemia, hyperglycemia, visceral obesity, and hypertension (20) and obesity-induced hypertension are often associated with dyslipidemia (15). Therefore, another possibility for the increased prevalence of hypertension among football players is cardiometabolic risk factors. Selden et al. (4) reported an increased prevalence among NFL players of impaired fasting glucose (≥100 mg/dl) and a BMI classified as obese (BMI ≥ 30 kg/m²), compared with men in the general population. However, the players were similar to the general population in prevalence of hypertriglyceridemia, enlarged waist circumference, and low levels of high-density lipoprotein–cholesterol (HDL-C). Similarly, Tucker et al. (5) observed that the larger BMI in their study group of NFL players was associated with elevated blood pressure, as well as increased low-density lipoprotein–cholesterol (LDL-C) and triglycerides and decreased HDL-C compared with the general population. However, the players had a lower prevalence of impaired fasting glucose and a similar prevalence of dyslipidemia (total cholesterol, LDL-C, HDL-C, and triglycerides). On the contrary, Allen et al. (6) reported on a sample of NFL players who had LDL-C, HDL-C, total cholesterol, triglycerides, and fasting glucose all within normal ranges. However, the linemen in this investigation had lower HDL-C and higher triglycerides when compared with levels in nonlinemen. Finally, Weiner et al. (7) observed that their sample of collegiate football linemen had a significant postseason increase in body weight, BMI, and body surface area, compared with preseason measurements.

Overall these data suggest an association between excess body weight and cardiometabolic risk factors, with hypertension and cardiovascular remodeling in football players, especially in linemen. However, not all the increases in blood pressure can be attributed solely to these factors. Therefore, labeling excess body weight as the only culprit is still premature and does not acknowledge the complexity and multifactorial nature of the pathogenesis of hypertension. It is possible that repeated hits in football cause spikes in sympathetic activity that could also cause long-term elevation in blood pressure. Moreover, uncontrolled inflammation from either the high prevalence of injuries (3) or tissue trauma (21, 22) could contribute to the hypertension in football players. More than likely, it is a combination of these mechanisms that synergizes with the excess body weight and associated cardiometabolic risk factors to cause hypertension (Fig. 1).

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.

DAMAGE ACTIVATES THE INNATE IMMUNE SYSTEM

It is known that chronic inflammation caused by uncontrolled immune system activation contributes to the development of chronic disease, including cardiovascular disease and hypertension (23). However, the precise mechanisms that mediate this sterile (or noninfectious) inflammation are only beginning to emerge. Innate immune system recognition and response to damage-associated molecular patterns (DAMPs) is becoming an increasingly accepted mechanism. DAMPs are endogenous molecules that are normally compartmentalized within cellular membranes and shielded from components of the immune system. However, when a cell has its plasma membrane ruptured or dies, these endogenous molecules freely diffuse. The immune system senses these molecules as a danger and elicits a response (24). Although short-term inflammation is necessary to facilitate clearance of the danger and mediate tissue repair, inappropriate or chronic activation of the immune system negates its evolutionarily conserved salutary effects (25).

The intensity and duration of strenuous exercise cause skeletal muscle damage, attributable to both metabolic and mechanical factors (26). The damage is reflected in increased circulating levels of skeletal muscle enzymes or proteins that are normally necessary for function. Creatine kinase, lactate dehydrogenase, aldolase, myoglobin, troponin, aspartate aminotransferase, and carbonic anhydrase (CA)-III are frequently used markers of muscle injury (26), and creatine kinase has consistently been found to be elevated as a result of football participation (27–29). However, these skeletal muscle enzymes and proteins would not be the only molecules released as a result of damage. Tissue injury theoretically would enable the nonselective release of all intracellular molecules. Therefore, although the skeletal muscle proteins cited above have not yet been characterized as activators of the immune system, muscle damage caused by strenuous exercise does not preclude the release of molecules that have been identified as immunogenic (i.e., DAMPs).

DAMPs can be either passively released into the extracellular environment as a result of cell death or damaged extracellular matrix or actively secreted into the extracellular environment or exposed on cell surfaces (e.g., neoantigens) as a result of cellular stress. Because of the varied nature of DAMPs, in their release and mechanism of immune system activation, these molecules have been broadly classified into 5 groups. For more information on the emerging classifications of DAMPs, we refer the interested reader to a review (30). Specific DAMPs include high-mobility group box 1 (HMGB1) protein, mitochondrial DNA (mtDNA), heat-shock proteins, uric acid, altered matrix proteins, S100 proteins, and a broader group of modified biologic molecules, including oxidized LDL-C and advanced glycation end products (23).

The innate immune system is the body’s early warning system, which rapidly detects danger and damage, allowing time for the adaptive immune system to mount an antigen-specific response (25). Important components of the innate immune system that are responsible for recognizing and responding to DAMPs are sentinel pattern-recognition receptors (PRRs). PRRs recognize evolutionarily conserved motifs; therefore, distinct molecular patterns that range from pathogens to DAMPs can activate specific PRRs and unique proinflammatory pathways (24). They are expressed on immune and nonimmune cells of various tissues, including the cardiovascular system (23, 31). Until recently, there has been limited knowledge of the role of PRRs in the pathogenesis of cardiovascular diseases (31), including hypertension (23). As a result, various components of the PRRs, and in particular TLRs, are becoming a significant research focus in the field of hypertension (32, 33).

HYPOTHESIS

We have compelling evidence that DAMPs released from injured or dying cells in damaged muscles play a mechanistic role in hypertension (32). Circulating HMGB1 and mtDNA are increased in hypertension [McCarthy et al. (32) and unpublished observations]. These DAMPs activate the innate immune response via Toll-like receptor (TLR)4 and -9, respectively, and we have extensive preliminary data demonstrating that activation of these receptors causes endothelial dysfunction and hypertension (32, 33). Our central hypothesis is that musculoskeletal injury in football players and trauma from repeated hits, particularly in linemen, leads to elevated circulating HMGB1 and mtDNA, which activates TLRs in endothelial cells, leading to impaired endothelium-dependent vasodilation, increased vascular tone, and hypertension.

That linemen are particularly vulnerable to within-season elevations in blood pressure is intriguing. It is plausible that meeting the physical demands of the position is more strenuous and causes more damage than meeting those of other football positions. In general, the lineman position is played by the heaviest individuals on the team (17). Therefore, when the 2 sets of linemen (offense and defense) engage at the onset of each play, considerable amounts of mass are accelerated to generate forces equivalent to a 30 mph car crash (34), and the encounter is repeated for close to 130 plays per game (35). In contrast, most nonlinemen perform short sprints and rapid movements, and although these players sustain hits during some plays, the nature of their positions does not expose them repeatedly. Off-the-field stressors could also predispose lineman to increases in blood pressure. For example, they often undertake nutritional regimens and resistance training aimed at increasing (lean) mass. Therefore, it is possible that these differences in both on- and off-field activities contribute to the differences between linemen and nonlinemen in musculoskeletal trauma, circulating DAMPs, and blood pressure. Moreover, the predisposition of linemen in particular to hypertension suggests that it is lineman-specific actions that contribute to elevated blood pressure, as behavior such as doping with anabolic steroids and ingesting over-the-counter stimulants and anti-inflammatory drugs would not be isolated to players of one particular position.

The importance of the endothelium in our hypothesis stems from the fact that it is the interface between the blood and the vascular wall. Even thought it is only a thin monolayer, the endothelium is a dynamic organ sensitive to blood-borne chemical signals, such as DAMPs, and to physical forces exerted by the flowing blood. These signals contribute collectively to the degree of vascular tone, cell adhesion, platelet aggregation, vascular smooth muscle phenotype, and vessel wall inflammation. One form of endothelial dysfunction is the abnormal secretion of vasoactive substances that cause either diminished relaxation or increased contraction of the arteries. Such endothelium-dependent increases in vascular tone can be caused by the decreased production and bioavailability of NO, exacerbated formation of cytokines and reactive oxygen species (ROS), and the release of vasoconstrictor metabolites of arachidonic acid (AA) (e.g., thromboxane A₂) (36) (Fig. 2). Our group has observed that TLR4 (33) and -9 (32) can impart vascular dysfunction through endothelium-dependent mechanisms, as described above. Therefore, if football players, linemen in particular, have increased circulating DAMPs from chronic musculoskeletal trauma, it is possible that the hypertension observed in these players is caused by the deleterious actions of DAMPs on endothelial function and vascular tone.

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.

PERSPECTIVES

Regular physical activity and fitness are associated with lower mortality and a wide array of health benefits (37). Therefore, the increased prevalence of hypertension in football players seems paradoxical. It could mean that football does not fit within the recommendations of physical activity for health and disease prevention (38) and that football players are predisposed to unique cardiovascular risks factors as a result of participation and necessary lifestyle choices, or a combination of these. A more general explanation could be that it is a manifestation of competitive sports. Hypertension is the most common cardiovascular complication observed in competitive athletes (39). Therefore, competitive sports and recreational fitness, from which most of the research on the benefits of exercise is derived, must be viewed as mutually exclusive entities. For example, the physiologic and psychologic demands of competition and training are unique to the competitive athlete and generally cannot be replicated recreationally, because recreational athletes do not participate in arenas where winning and physical prowess are rewarded with prestige, championships, and money. As a result, competitive athletes regularly push themselves to their maximum capacity over long periods, often at the expense of other lifestyle considerations. Indeed, this is generally the case for professional and collegiate football players.

To the best of our knowledge, competitive swimmers are the only athletic group that has had systemic DAMPs measured (40). In that study, the increase in DAMPs in this group was attributed to both intensive training and exposure to by-products of chlorination, but, unfortunately, blood pressure was not reported. As the BMI of the swimmers in this investigation was normal (∼21 kg/m²), we infer that the presence of DAMPs among athletes is not due to excess body weight alone; other factors associated with training and competition contribute to their presence. The observation that swimmers have increased DAMPs is somewhat surprising, because it is generally assumed that endurance athletes have heightened endogenous defenses against chronic disease as a result of exercise-induced adaptations (41). However, it should also be noted that prolonged exertion, such as marathon running and ultraendurance events, have been associated with markers of damage and negative cardiovascular events (42), including exercise-induced hypertension (43–45). In contrast, weightlifting, may be more comparable to football in terms of duration and intensity, and it is a noncontact activity that football players frequently engage in. Weightlifting alone does not cause long-term elevation in blood pressure (46–49), in contrast to sumo wrestling (50) and soccer (51), both of which are contact sports. Although knowing whether DAMPs are increased as a result of participation in different sports is of interest, it would be more valuable to clarify the point at which the damage associated with physical activities overwhelms the presumed benefits and contributes to the development of chronic disease.

Furthermore, although our hypothesis is focused on hypertension, it could also have implications for the development of CTE and neurodegeneration in retired football players. CTE represents the cumulative long-term neurologic consequences of repetitive concussive and subconcussive blows to the brain and generally manifests clinically as dementia-like syndromes and depression. The association between CTE and football has been well established in the peer-reviewed literature (8–10) and the mainstream media (34), and the NFL is currently involved in a long-running legal battle with former players as a result of misdiagnosis and mismanagement of concussions. There are several ways by which our hypothesis could be extended to the pathogenesis of CTE. For example, it is currently unknown whether DAMPs and TLRs contribute to CTE; however, it is known that the DAMPs HMGB1 and mtDNA contribute to the neuroinflammation associated with traumatic brain injury (52, 53). Therefore, it is plausible that DAMPs and TLRs contribute to concussion-related CTE. Furthermore, could intraseasonal hypertension during a football player’s career predispose him to subsequent CTE? Although it has been determined that the incidence of hypertension does not increase over the course of a playing career (14), could the acute intraseason hypertension induce maladaptations in vital end organs (7, 13) that contribute to chronic disease later in life? Collectively, we hypothesize that DAMPs are novel mediators not only in football-induced hypertension, but also in other football-related conditions that are defined by chronic inflammation.

CONCLUSIONS

The current literature paints a disturbing picture for football players. Participation in the sport predispose these individuals to the risk of both musculoskeletal trauma (3) and elevations in blood pressure (4–7). These acute risks, coupled with the chronic risks of CTE (8–10) and cardiovascular disease in retired players (54–58), suggest that health strategies should be explored to prevent and treat the dangerous and damaging effects of football participation. Our hypothesis represents a novel mechanism by which DAMPs and TLRs contribute to chronic inflammation and hypertension in football players (Fig. 3). Although this hypothesis addresses the acute development of hypertension in football players, it could also have important implications for the development of chronic disease and for the quality of the football player’s life upon retirement from the game.

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.

Glossary

AA

arachidonic acid

BMI

body mass index

CTE

chronic traumatic encephalopathy

DAMP

damage-associated molecular pattern

HDL-C

high-density lipoprotein–cholesterol

HMGB1

high-mobility group box 1 protein

LDL-C

low-density lipoprotein–cholesterol

mtDNA

mitochondrial DNA

NFL

National Football League

PRR

pattern recognition receptor

ROS

reactive oxygen species

TLR

Toll-like receptor

TxA₂

thromboxane A₂