To review current information, the National Heart, Lung, and Blood Institute, National Institutes of Health convened a workshop to review the clinical manifestations of HbAS, discuss exercise-related sudden death reports in HbAS, and examine the public health, societal, and ethical implications of policies regarding HbAS. The goal of the workshop was to identify potential research questions to address gaps in knowledge. During sessions devoted to discussion of reports of sudden death in individuals with HbAS, three major questions and the potential role for screening were addressed.
- Exercise-Related Death
- Is HbAS an independent risk factor for sudden death in young athletes?
- What are the etiologies of sudden death?
- Is sudden death preventable in individuals with HbAS?
- Can screening for HbAS prevent or mitigate-associated morbidity or mortality?
Sudden death in athletes
From a definition perspective, exercise-related sudden death in all athletes is generally viewed as an irreversible and terminal dependence upon life support implemented within 1 hr of the onset of symptoms. The causes of sudden death have been described as cardiac (myocardial, anatomic, electrical, and combined disease), pulmonary, neurologic (brain stem injury and vagal reactions), metabolic (rhabdomyolysis and malignant hyperthermia), endocrine, hemorrhagic, and thrombotic. For cardiac or idiopathic sudden death, the US National Registry of Sudden Death in Athletes [9
] reports 115 cases per year and the 36th Bethesda Conference on Eligibility Recommendations for Competitive Athletes with Cardiovascular Abnormalities estimated a prevalence of 1 in 33,000–50,000 with a male predominance of 5:1 to 9:1 [10
]. The number of reported cases increased by about 6% per year with 0.3% of the deaths attributed to HbAS. Of the cardiovascular deaths, 82% were reported as exertional; 2.4% of the deaths were attributed to heat stroke. The most common cardiac etiology was hypertrophic cardiomyopathy (HCM) (36%) followed by coronary artery anomalies (17%). The average age of those affected was 18 ± 5 years and 89% were reported to be male. Hypertrophic cardiomyopathy, inherited as an autosomal dominant trait, has been attributed to mutations in genes that encode for sarcomere proteins [11
]. Thirteen genes account for ~50% of HCM cases. HCM is disproportionately present in African American athletes. Of the relevant electrical diseases, the long QT Syndrome is the most important. Inherited in either autosomal or dominant fashion, 13 genes have been described that are involved in the timely execution of the cardiac action potential [12
]. The utility of ECG screening for athletes continues to be debated and provides some parallels for the current discussions of screening for HbAS [13
]. Issues of cost, test sensitivity and specificity, resource utilization and difficulty of program implementation are central to this discussion [14
Performance of black athletes
Review of the historical athletic participation of individuals from ancestral populations with higher prevalence of HbAS (e.g. athletes of African ancestry, self identified as black or African American), adds perspective. In the 1936 Olympics, 18 black athletes won 14 medals, 25% of those won by US athletes, and dominated the track and field events. In the 1968 Olympics, nearly 19% of the athletes were black and ~1% (11/1,265) had HbAS. There were no clinically detected adverse events at Mexico City’s high altitude (7,350 feet above sea level). Black athletes continue to participate in the National Football League (NFL) (60% of players are black), the National Basketball Association (NBA) (over 80% of players are black), and in college athletics (34% of football players and 45% of male and 33% of female basketball players are black). Many U.S. black athletes compete at high altitude in Denver, Colorado (5,280 feet above sea level), experiencing frequent exposures to reduced oxygen tension, with rare reports of adverse events, although one NFL player with HbAS suffered splenic complications.
Conditions favoring sickling
Acute, intense exercise has multiple effects that could potentially trigger sickling of HbS containing erythrocytes. These effects include a decrease in plasma volume and pH and increases in sympathetic outflow, oxidative stress, heat production, microvascular perfusion, tissue hypoxia, and release of inflammatory mediators. These detrimental effects are balanced by the benefits of chronic physical training which include a reduced resting heart rate and blood pressure, improved autonomic system balance, increased maximal myocardial oxygen uptake, improved endothelial function and vascular compliance, metabolic and neuromuscular modifications, and training-specific muscle adaptations [15
The potential roles of skeletal muscle function in exercise
Skeletal muscle function is fundamental to exercise and is affected by mechanical, metabolic, hormonal, and neuronal stressors. The consequences of these stressors depend on the degree of loading, the number of contractions, and the thresholds of protective mechanisms for stress-induced damage. The threshold is affected by fiber type, number and oxidative content of mitochondria, energy reserves, speed and strength of fiber contraction, and fiber size. The major types of muscle fibers are Type I (slow twitch), Type IIa (fast twitch), and Type IId (x) (fast twitch). Slow twitch fibers have higher aerobic capacity, myoglobin content, and fatigue resistance, whereas fast twitch fibers have higher glycolytic capacity, glycogen content, and sarcoplasmic reticulum (SR) development. Contraction speeds are slower for the fast twitch fibers compared with the slow twitch fibers. The three types of fibers are further distinguished by different myosin heavy chains.
Black, African men had significantly more Type IIa fibers (49 vs. 42%) and fewer Type I fibers (33 vs. 41%) than Caucasian men [16
]. The muscle activities of glycolytic pathway enzymes were 40 to 76% higher in black than Caucasian men and the average creatine kinase nearly twice as high. Obese black women have been reported to have a higher percentage of Type IIb fibers and a lower percentage of Type I fibers than Caucasian women [17
A study of young, military recruits with Exertional Heat Illness (EHI) in Taiwan found that 24 of 37 with EHI developed rhabdomyolysis and that the percentage of Type II fibers was 66% in controls, 75.5% in individuals with EHI alone, and 81% in those with EHI and rhabdomyolysis [18
Other genetic factors influencing muscle function
Rapid rises in cytoplasmic calcium are required for skeletal muscle contraction. The increases in calcium are the result of calcium release through type I ryanodine receptors (RYR1
). Analysis of RYR1
is used as a screening test for susceptibility to Malignant Hyperthermia. A possible relation between malignant hyperthermia, EHI, and rhabdomyolysis has been proposed. Small clinical series have suggested a relationship between RYR1
variants and Malignant Hyperthermia and coexistent HbAS [19
]. Other potential genetic factors contributing to sudden death in African Americans include polymorphisms in the cardiac sodium channel gene, SCN5A
Y1102, associated with increased risk of sudden death and ventricular arrhythmias in black adults [20
Lessons from the military experience
Individuals with HbAS could be at increased risk for EHI due to the polymerization of sickle hemoglobin in an exercise induced hypoxic, dehydrated, acidotic, hyperthermic environment. Agonal hypoxia causes extensive sickling in these individuals and may not have a causal role. There is no evidence that antemortem sickling can be differentiated from postmortem sickling in HbAS carriers who die suddenly. To study this on a population basis, all natural deaths among ~2 million Armed Forces Recruits were reviewed from 1977 to 1981. The prevalence of HbAS was estimated based on the number of African American recruits (8%) plus 0.08% of the recruits from other races. Fewer than 10% of the sudden death cases were tested for hyperthermia or rhabdomyolysis. The calculated number of African American HbAS recruits had a 30-fold increased relative risk of exercise-related death compared with those without hemoglobin S (P < 10−6).
Excess mortality related to exercise has been investigated in military recruits and may help evaluate interventions to reduce the risk for participation in college level athletics [21
]. Half of the cases of military recruit deaths had fatal EHI with exertional rhabdomyolysis, heat stroke, and/or acute renal failure although requirements for life support were delayed. The other half suffered idiopathic sudden death in cardio-pulmonary arrest. About 1 out of 15 to 1 out of 30 of these cases were found to have acute EHI as the cause of sudden death; however, only 3% were screened for EHI. The spectrum of clinical presentations described in military recruits included collapse, rapid progression of muscle pain, slowly developing painful muscle(s), and hyperthermia.
In response to these findings, an interventional program was devised when the Wet Bulb Temperature Index increased. The program included limiting exercise intensity, reducing work/rest ratios, ordering observed water consumption and use of light clothing in hot weather conditions if possible. Both Test and Control groups used prompt evaluation and triage of any recruit with early signs of EHI including failure to keep up with group activities, determination of field rectal temperature, cooling, rehydration, and rapid transport to medical facilities. The intervention reduced deaths in both the HbAS cohort (relative risk for death = 0.06 [P
< 0.0001]) and the HbAA groups compared with those not receiving the intervention. Both idiopathic and EHI deaths were prevented by the intervention [22
In a small cohort of military recruits, presumptive alpha-thalassemia was an additional factor reducing risk for exercise-related death. The lower HbS concentration in the cells of those with HbAS-alpha thalassemia may theoretically have reduced HbS polymerization.
As of the date of the 2010 workshop, in collegiate football, 18 deaths related to sickling were reported in the lay press since 1974. Of the 16 cases reported during the last decade, 10 of the individuals had HbAS [24
]. Individuals with HbAS represent 3 to 4% of National Collegiate Athletic Association (NCAA) Division I football players. The NCAA attributes the deaths to an “Intensity Syndrome,” not Exertional Heat Illness. The deaths were seen as metabolic complications and are not usually sudden (within 1 hr). For each reported death, there are a total of 3–5 nonfatal events.
Studies in maximally exercising normal individuals demonstrate that hypoxemia and lactic acidosis occur within 5 min [25
]. In military recruits with HbAS, the percentage of sickled cells in venous blood increased with exercise and to a greater extent with increased altitude [26
]. However, performance was not affected. In contrast, sickling was virtually absent in arterial blood suggesting that sickling may have been reversed by exposure to oxygen tensions in the pulmonary microcirculation.
Reports from the NCAA and responses
The reported deaths in NCAA Division I athletes all occurred during conditioning, not during game play, either in sprinting or speed drills and in one case with weight lifting. Reports of the clinical presentation of events attributed to a proposed “sickling syndrome” suggest that affected individuals experience weakness but do not exhibit slowly evolving, painful muscle cramping, and do not lose consciousness. A syndrome of rhabdomyolysis is apparent in these individuals with typical laboratory findings of hyperkalemia, acidosis, elevated creatine phosphokinase, and renal failure secondary to myoglobinemia. The hypothesis that exercise-induced sickling triggers vaso-occlusion in muscle, which in turn precipitates rhabdomyolysis, has not been demonstrated empirically. Alternative explanations were proposed, such as rhabdomyolysis triggering a reinforcing cascade of events in athletes with HbAS that intensified the rhabdomyolysis syndrome, making a fatal outcome more likely. These discussions highlighted the need for further research in this area.
Altitude with concomitant hypoxia and the potential adverse influence of dietary supplements in the setting of strenuous exercise may also play a role in poor outcomes in individuals with HbAS. Anecdotal reports of college athletes suggest that sickling precedes rhabdomyolysis. A muscle biopsy study in nonathletes revealed remodeling of the microvasculature in muscles in individuals with HbAS characterized by lower capillary density, lower capillary tortuosity, and enlarged microvessels when compared with controls [27
]. In a small series, individuals with HbAS were found to have higher mean blood viscosity at rest compared with healthy controls that was normalized by hydration during exercise [28
Interventions to mitigate this symptom complex worthy of further study include taking longer breaks during practice and shortening intensity and length of practice sessions held in hot weather or high altitude. A known genetic predisposition to malignant hyperthermia might pose a genetic risk factor in conjunction with HbAS. HbAS phenotypes may be the result of interactions between conditioning status and genetic influences such as muscle fiber types and regulation of cellular calcium and sodium flux.
Interest in the potential risks of participation at college level athletics for individuals with HbAS was brought into focus in 2007 by the National Athletic Trainers’ Association (NATA) consensus statement, “HbAS and The Athlete” [29
]. NATA recommended that athletes with HbAS can participate in all sports; however, screening and simple precautions should be implemented to help prevent deaths. Although not an evidence-based review, the case for screening was determined to be “strong” by NATA [30
]. Coaches and athletes should receive education to reduce risks and to understand the response to serious complications. The Sickle Cell Disease Association of America (SCDAA) did not support the consensus statement. The NCAA recommended that member institutions test student athletes for HbAS in 2009. In April 2010, the NCAA adopted legislation that required screening of athletes. This action required that incoming Division I athletes must be tested for HbAS, show proof of a prior test, or sign a waiver releasing an institution from liability.
Potential role of pathology methods
Pathological evaluation of several individuals with delayed death, survival long enough for medical intervention, determined that all had exerted effort beyond their conditioning level and all presented with metabolic acidosis soon followed by rhabdomyolysis, renal, failure, and DIC [31
]. Individuals with sudden or rapid death who experience cardiac arrest before medical intervention should be evaluated using toxicology, pathology, and electrocardiography when feasible. Hemoglobin determination by high pressure liquid chromatography (HPLC) is the method most commonly used to diagnose HbAS at autopsy although it may be confounded by inadequate sampling or sample degradation. Histologic diagnosis has been used to identify HbAS cases with a very high degree of sensitivity and specificity even years after the time of death [31
]. Establishment of the diagnosis postmortem does not specifically address whether sickling occurred antemortem or postmortem.