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Sickle Cell Trait Associated With Sudden Death in Competitive Athletes
Sickle Cell Trait Associated With Sudden Death in Competitive Athletes Kevin M. Harris, MDa, Tammy S. Haas, RNa, E. Randy Eichner, MDb, and Barry J. Maron, MDa,* Sickle cell trait (SCT; hemoglobin AS) occurs in 8% of African Americans and although typically benign has been associated with sudden death in military recruits during intense physical activity. However, the role of SCT in the deaths of trained athletes is less well documented or acknowledged. The 31-year United States Sudden Death in Athletes Registry was interrogated to determine the frequency, epidemiology, and clinical profile of SCT-related death in a large population of competitive athletes. Of 2,462 athlete deaths, 23 (0.9% overall, 3.3% of African Americans) occurred in association with SCT: ages 12 to 22 years, 21 male (91%), and all African Americans. SCT diagnosis was made by solubility testing (n ⴝ 13) and/or hemoglobin electrophoresis (n ⴝ 16). Most victims competed in college (n ⴝ 17) and in football (n ⴝ 19). Of 271 African American football deaths in the registry, 7% (1 in 14) were known to be associated with SCT. Each athlete experienced distinctive noninstantaneous collapse with gradual deterioration over several minutes associated with vigorous or exhaustive physical exertion, usually during conditioning drills (n ⴝ 22) and typically early in the training season. Ambient temperatures were >80°F in 20 patients (87%), with most events in southern or border states during the summer and autumn (n ⴝ 17 [74%]). In conclusion, SCT can be associated with largely unpredictable sudden collapse and death and apparent predilection for African American college football players during conditioning. Understanding the risks, mechanisms, and event triggers of SCT may allow lifesaving alterations in training methods to be implemented. © 2012 Published by Elsevier Inc. (Am J Cardiol 2012;110:1185–1188)
Sickle cell trait (SCT), in which a normal hemoglobin gene and an abnormal mutated -globin sickle gene are inherited, occurs in 8% of African Americans in the United States.1 Although typically a benign condition, SCT has nevertheless been occasionally associated with sudden collapse and death or other life-threatening events.2–5 One study 25 years ago associated SCT with deaths in basic military training recruits during vigorous exercise.2 Recently, anecdotal reports have raised concern that SCT could be responsible for the sudden deaths of young athletes during training,5 underscored by the National Collegiate Athletic Association’s decision to adopt mandatory SCT screening for Division I athletes.6 In addition, preventive training modification guidelines and precautions for SCT-affected athletes are now recommended by the National Collegiate Athletic Association and the National Athletic Trainers’ Association.7,8 Although there is increasing interest in potential risks posed by SCT in trained athletes,9,10 most available data are anecdotal and derived from case reports. Systematic reporting of the epidemiology, prevalence, and clinical presentation of deaths associated with SCT in large athlete populations is lacking. We interrogated the unique, long-standing United States Sudden Death in Athletes Registry11–14 for SCT-assoa
The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation at Abbott-Northwestern Hospital, Minneapolis, Minnesota; and bUniversity of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Manuscript received March 30, 2012; revised manuscript received and accepted June 2, 2012. *Corresponding author: Tel: 612-863-3996; fax: 612-863-3875. E-mail address: [email protected] (B.J. Maron). 0002-9149/12/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2012.06.004
ciated events, to investigate this rapidly emerging medical issue. Methods The registry is a forensic database instituted at the Minneapolis Heart Institute Foundation for the purpose of prospectively and retrospectively assembling data on the deaths of young athletes participating in organized competitive sports.11–14 Over a 31-year period (1980 to 2010), 2,462 such sudden deaths (and survivors of cardiac arrest) have been tabulated. The registry population was identified by targeted searches using a variety of sources at the time each of these strategies became available during the duration of the study, including LexisNexis archival database. Athletes were included in the registry if 2 criteria were met: (1) participation in organized team or individual sports requiring regular competition, and placing a premium on excellence and achievement, and (2) sudden death at ⱕ39 years of age.11 A systematic tracking process was established to assemble detailed information on each case, including the complete autopsy report and pertinent clinical and demographic information. Data are expressed as mean ⫾ SD. Proportions were compared using chi-square or Fisher’s exact tests. Continuous variables were compared using unpaired Student’s t tests or Mann-Whitney rank-sum tests. Results There were 2,462 athlete deaths recorded in the registry as of December 2010. Ages ranged from 8 to 39 years www.ajconline.org
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Table 1 Deaths associated with sickle cell trait in 23 competitive athletes Patient
Age (years)/Gender
Sport
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
12/M 14/F 15/M 15/M 15/M 18/M 18/M 18/M 18/M 19/M 19/M 19/M 19/M 20/F 20/M 20/M 20/M 20/M 21/M 21/M 21/M 21/M 22/M
FB BB FB FB TR FB FB FB FB FB FB FB FB BB FB FB FB FB BB FB FB FB FB
Level JHS HS HS HS HS C C HS C C C C C C C C C C C C C C C
State
SCT Solubility Test
Hemoglobin Electrophoresis*
Rhabdomyolysis
Ohio Texas Florida Texas Florida Tennessee Florida California Ohio Texas Arkansas Missouri Florida Texas Mississippi Georgia North Carolina Indiana Florida New Mexico Mississippi Arizona North Carolina
⫹ NA ⫹ ⫹ ⫹ NA ⫹ ⫹ NA ⫹ NA NA ⫹ NA ⫹ ⫹ ⫹ NA NA ⫹ NA ⫹ NA
NA ⫹ ⫹ NA NA ⫹ NA NA ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ NA ⫹ ⫹ ⫹ ⫹ ⫹ NA ⫹
⫹ 0 0 0 0 NA 0 0 ⫹ ⫹ ⫹ 0 ⫹ 0 0 ⫹ 0 ⫹ 0 ⫹ ⫹ ⫹ ⫹
BB ⫽ basketball; C ⫽ college; F ⫽ female; FB ⫽ football; HS ⫽ high school; JHS ⫽ junior high school; M ⫽ male; NA ⫽ no information available; TR ⫽ track (sprinter); ⫹ ⫽ present; 0 ⫽ absent. * Usually defined as bands present for hemoglobin A and S, with hemoglobin S 35% to 45%.
(mean 18.7 ⫾ 6); 1,459 patients were white (59%), 34 (1.4%) Asian, and 699 (28%) African American. The most common causes of death were blunt trauma (n ⫽ 476), commotio cordis (n ⫽ 98), and a variety of cardiovascular diseases (n ⫽ 1,396). The latter were most frequently hypertrophic cardiomyopathy (n ⫽ 375) and congenital coronary artery anomalies of wrong sinus origin (n ⫽ 131). Notably, 23 of the deaths (0.9%) were in athletes with SCT, documented by testing during life or at autopsy; each of these athletes was African American (Table 1). Ages ranged from 12 to 22 years (mean 18.6 ⫾ 2.6); 21 (91%) were male. At the time of their deaths, these athletes were competing in organized college (n ⫽ 17), high school (n ⫽ 5), or junior high school (n ⫽ 1) sports. The 23 athletes with SCT-related death represent 3.3% of 699 African American athletes in the registry. SCT diagnosis was made by solubility testing alone (n ⫽ 7, including 3 by newborn or university screening), hemoglobin electrophoresis alone (n ⫽ 10, 5 antemortem), or both (n ⫽ 6). All athletes died under similar distinctive circumstances: noninstantaneous collapse with gradual but rapid deterioration (i.e., dyspnea, fatigue, weakness, and muscle cramping) over an estimated 10 to 45 minutes, associated with exertional rhabdomyolysis in 11. Each event occurred during vigorous or exhaustive maximal physical exertion, usually during training and conditioning (n ⫽ 22), or competition (n ⫽ 1), and often after brief sustained effort such as repetitive short-distance sprints or endurance running. SCT events were most common early in the conditioning season and in 6 cases were documented on the first day of practice. Notably, SCT-deaths occurred predominately in football players (n ⫽ 19 of 23 [83%]), constituting 2.6% of all 723
deaths occurring in that sport and 7.0% of deaths in the 271 African American football players (i.e., 1 of 14). Other SCT-deaths occurred in basketball (n ⫽ 3) and track sprinting (n ⫽ 1). SCT deaths were similar to other cardiovascular deaths in the registry with respect to age (mean 18.6 ⫾ 2.6 vs 17.6 ⫾ 5.0 years, p ⫽ 0.092) and gender (91% vs 88% male, p ⫽ 1.00) but were more common in African Americans (100% vs 37%, p ⬍0.001). Deaths were most frequent in the summer and early autumn months of June to October (17 of 23 [74%]). Twenty of the 23 deaths (87%) occurred in southern or border states, most commonly Florida (n ⫽ 5), Texas (n ⫽ 4), Mississippi, North Carolina, and Ohio (n ⫽ 2 each). Potential associated triggers for SCT collapse were environmental temperature (ⱖ80°F) in 20 (87%) and high altitude in 2 (Albuquerque, New Mexico, and Tucson, Arizona), as well as maximum intensity of exercise. Four of the 23 athletes had associated structural cardiac abnormalities identified at autopsy: 2 with tunneled coronary arteries (1 left anterior descending and 1 right coronary), 1 with redundant mitral valve and features consistent with hypertrophic cardiomyopathy, and 1 with 80% right coronary artery narrowing by atherosclerosis. Heart weights ranged from 225 to 640 g (mean 423); 5 were ⬎500 g. Largely on the basis of the circumstances of collapse, these features are unlikely to be the primary or a major cause of death. Discussion From our forensic-based registry study, we have assembled the first sizable series of competitive athletes (n ⫽ 23) in whom SCT was associated with otherwise unexplained
Miscellaneous/Sickle Cell Trait and Sudden Death
sudden and unexpected collapse and death. These athletes constituted 0.9% of our large registry of almost 2,500 sudden deaths, with a predominance in college football players. The outcomes in these athletes can most reasonably be linked to the presence of SCT and its unpredictable consequences,15 particularly with no reasonable alternative explanation or disease to explain demise. Clinical profiles in the 23 SCT athletes were similar and distinctive. Cardiovascular collapse followed several minutes of gradual clinical worsening with dyspnea, fatigue, and weakness (sometimes permitting verbalization) during and after vigorous or exhaustive physical activity, often early in the workout season.5,16 Such scenarios differ distinctly from sudden death occurring from ventricular tachyarrhythmias due to structural cardiovascular diseases (e.g., hypertrophic cardiomyopathy, ion channelopathies) in which collapse is virtually instantaneous. Although the pathophysiology and determinants of SCT events are not fully understood, it is likely that cardiovascular collapse occurs under conditions that increase risk for exertional sickling of red blood cells, including heat stress, dehydration, illness, and altitude.1–3,17,18 It is reasonable to hypothesize that a cascade of events ensues with intramuscular and microvascular sickling leading to vascular occlusion, endothelial damage, and impaired blood flow to muscles, which promotes ischemic rhabdomyolysis and disseminated intravascular coagulation. Rhabdomyolysis leads to hyperkalemia and acidosis, which in the setting of hypoxia adversely affects cardiac function and lowers the threshold for a lethal cardiac arrhythmia.1,3,17–21 Indeed, although rhabdomyolysis was present in almost 50% of our SCT athletes, we found only 5 other athletes in the registry in whom rhabdomyolysis was the sole cause of death, all of whom were unassociated with SCT. Each was white, 17 to 28 years old, and died during running sports (exclusive of football). However, the finding of widespread sickling in the heart and other organs at autopsy does not represent unequivocal evidence for this mechanism of death because of the obstacle in distinguishing histologic postmortem sickling (which can be caused by the diminished oxygen environment after death) from antemortem sickling.1,4 This unavoidable limitation contributes to the debate over the pathogenesis of SCT and its relation to sudden death. Notably, the epidemiology and pathophysiology of SCT events have vital implications and provide clues that can enhance prevention with targeted measures and tailored precautions during training. For example, SCT events showed a clear predilection for male athletes during football practice and were often associated with brief bursts of sustained maximal exertion. These considerations have led to specific recommendations for athletes with known SCT: gradual conditioning at the beginning of the season, attention to modifying pace and providing periods of rest during conditioning drills, adequate hydration, and a high index of caution for immediate cessation of physical activity with muscle cramping, fatigue, and excessive dyspnea. Collapse with SCT is a medical emergency requiring the administration of oxygen, intravenous hydration, and cooling to protect against rhabdomyolysis. Although cardiac arrest is a possible sequela, and an external defibrillator should be in place,1,5,7 its effectiveness in this setting is unpredictable.22
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There has been some skepticism and substantial emotion surrounding the legitimacy of SCT as a causative factor for cardiovascular sudden death. However, our data support the principle that SCT may well be primarily linked to such uncommon events with vigorous exercise in young physically active individuals, often associated with elevated environmental temperatures as a trigger. SCT should be included among the myriad of nontraumatic risks of sports participation.9 –13 However, in this analysis we were unable to document the overall association of SCT and sudden death in the registry or to show that such events are more (or less) common compared to athletes without SCT. This is an unavoidable limitation, because laboratory-based SCT diagnoses were not available to the registry for all athletes, given confidentiality restrictions. However, it is particularly notable that 7% of 271 African American football players in the registry died of SCT, which approximates the 8% of African American football players who would be estimated to carry the trait in this population.15 Controversy surrounding SCT screening in athlete populations is a complex and sometimes polarizing ethical and legal debate.4,6,23 Screening proponents emphasize the potential for prevention of death by prospective recognition of SCT-affected individuals. Others regard SCT testing as potentially discriminatory practice used for selective targeting, and an infringement on individual privacy and liberty. Nevertheless, in 2010, the National Collegiate Athletic Association mandated SCT screening for all Division I student athletes as part of a legal settlement concerning an athlete death due to SCT.6 Recently, hematologists rejected mandatory SCT screening, instead recommending universal training interventions.24 We take neither side of this controversy and have confined ourselves to reporting a substantial series of athlete deaths associated with (and apparently due to) SCT. Our data also underscore the unpredictability of SCT events. With an 8% prevalence in African Americans, we would expect that thousands of individuals with SCT have competed safely during vigorous and competitive sports, but only a small fraction appear susceptible to catastrophe from this genetic defect, which has been generally regarded as benign. This observation raises the possibility of a SCT subset at particular risk because of currently undefined and unpredictable genetic, physiological, or environmental factors. Acknowledgment: We appreciate the statistical assistance of Ross F. Garberich, MSc, of the Minneapolis Heart Institute Foundation. 1. Tsaras G, Owusu-Ansah A, Boateng FO, Amaoteng-Adjepong Y. Complications associated with sickle-cell trait: a brief narrative review. Am J Med 2009;122:507–512. 2. Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med 1987;317:781–787. 3. Jones SR, Binder RA, Donowho EM. Sudden death in sickle-cell trait. N Engl J Med 1970;282:323–325. 4. Mitchell BL. Sickle cell trait and sudden death— bringing it home. J Natl Med Assoc 2007;99:300 –305. 5. Eichner ER. Sickle cell trait in sports. Curr Sports Med Rep 2010;9: 347–351.
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6. Bonham VL, Dover GJ, Brody LC. Screening student athletes for sickle cell trait—a social and clinical experiment. N Engl J Med 2010;363:997–999. 7. National Athletic Trainers’ Association. The National Athletic Trainers’ Association (NATA) releases “Sickle Cell Trait and the Athlete” consensus statement. Available at: http://www.nata.org/NR062107. Accessed April 17, 2012. 8. Klossner D. 2009-10 NCAA sports medicine handbook. Available at: http://www.ncaapublications.com/productdownloads/MD10.pdf. Accessed May 3, 2011. 9. Thompson PD. The cardiovascular complications of vigorous physical activity. Arch Intern Med 1996;156:2297–2302. 10. Van Camp SP, Bloor CM, Mueller FO, Cantu RC, Olson HG. Nontraumatic sports death in high school and college athletes. Med Sci Sports Exerc 1995;27:641– 647. 11. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the U.S. 1980-2006. Circulation 2009;119:1085–1092. 12. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes: clinical, demographic and pathologic profiles. JAMA 1996;276:199 –204. 13. Maron BJ. Sudden death in young athletes. N Engl J Med 2003;349: 1065–1075. 14. Maron BJ, Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;41:974–980. 15. Harmon KG, Drezner JA, Klossner D, Asif IM. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. Br J Sports Med 2012;46:325–330.
16. Rosenthal MA, Parker DJ. Collapse of a young athlete. Ann Emerg Med 1992;21:1493–1498. 17. Loosemore M, Walsh SB, Morris E, Stewart G, Porter JB, Montgomery H. Sudden exertional death in sickle cell trait. Br J Sports Med 2012;46:312–314. 18. Rodgers GP. Sickle-cell trait and physical training: evidence for improved fitness. Arch Intern Med 1988;148:1019 –1020. 19. Ramirez A, Hartley LH, Rhodes D, et al. Morphological feature of red blood cells in subjects with sickle cell trait: changes during exercise. Arch Intern Med 1976;136:1064 –1066. 20. Martin TW, Weisman IM, Zeballos RJ, Stephenson SR. Exercise and hypoxia increase sickling in venous blood from an exercising limb in individuals with sickle cell trait. Am J Med 1989;87:48 –56. 21. Phillips M, Robinowitz M, Higgins JR, Boran KJ, Reed T, Virmani R. Sudden cardiac death in Air Force recruits. A 20-year review. JAMA 1986;256:2696 –2699. 22. Soar J, Perkins GD, Abbas G, Alfonzo A, Barelli A, Bierens JJ, Brugger H, Deakin CD, Dunning J, Georgiou M, Handley AJ, Lockey DJ, Paal P, Sandroni C, Thies KC, Zideman DA, Nolan JP. European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. Resuscitation 2010;81:1400 –1433. 23. Steinberg MH. In the clinic: sickle cell disease. Ann Intern Med 2011;155:ITC31–ITC315. 24. American Society of Hematology. ASH policy opposes mandatory sickle cell trait screening for athletic participation, recommends universal training interventions & additional research. Available at: http:// www.hematology.org/news/2012/7703.aspx. Accessed April 17, 2012.
Sickle cell trait (SCT), in which a normal hemoglobin gene and an abnormal mutated -globin sickle gene are inherited, occurs in 8% of African Americans in the United States.1 Although typically a benign condition, SCT has nevertheless been occasionally associated with sudden collapse and death or other life-threatening events.2–5 One study 25 years ago associated SCT with deaths in basic military training recruits during vigorous exercise.2 Recently, anecdotal reports have raised concern that SCT could be responsible for the sudden deaths of young athletes during training,5 underscored by the National Collegiate Athletic Association’s decision to adopt mandatory SCT screening for Division I athletes.6 In addition, preventive training modification guidelines and precautions for SCT-affected athletes are now recommended by the National Collegiate Athletic Association and the National Athletic Trainers’ Association.7,8 Although there is increasing interest in potential risks posed by SCT in trained athletes,9,10 most available data are anecdotal and derived from case reports. Systematic reporting of the epidemiology, prevalence, and clinical presentation of deaths associated with SCT in large athlete populations is lacking. We interrogated the unique, long-standing United States Sudden Death in Athletes Registry11–14 for SCT-assoa
The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation at Abbott-Northwestern Hospital, Minneapolis, Minnesota; and bUniversity of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Manuscript received March 30, 2012; revised manuscript received and accepted June 2, 2012. *Corresponding author: Tel: 612-863-3996; fax: 612-863-3875. E-mail address: [email protected] (B.J. Maron). 0002-9149/12/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2012.06.004
ciated events, to investigate this rapidly emerging medical issue. Methods The registry is a forensic database instituted at the Minneapolis Heart Institute Foundation for the purpose of prospectively and retrospectively assembling data on the deaths of young athletes participating in organized competitive sports.11–14 Over a 31-year period (1980 to 2010), 2,462 such sudden deaths (and survivors of cardiac arrest) have been tabulated. The registry population was identified by targeted searches using a variety of sources at the time each of these strategies became available during the duration of the study, including LexisNexis archival database. Athletes were included in the registry if 2 criteria were met: (1) participation in organized team or individual sports requiring regular competition, and placing a premium on excellence and achievement, and (2) sudden death at ⱕ39 years of age.11 A systematic tracking process was established to assemble detailed information on each case, including the complete autopsy report and pertinent clinical and demographic information. Data are expressed as mean ⫾ SD. Proportions were compared using chi-square or Fisher’s exact tests. Continuous variables were compared using unpaired Student’s t tests or Mann-Whitney rank-sum tests. Results There were 2,462 athlete deaths recorded in the registry as of December 2010. Ages ranged from 8 to 39 years www.ajconline.org
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Table 1 Deaths associated with sickle cell trait in 23 competitive athletes Patient
Age (years)/Gender
Sport
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
12/M 14/F 15/M 15/M 15/M 18/M 18/M 18/M 18/M 19/M 19/M 19/M 19/M 20/F 20/M 20/M 20/M 20/M 21/M 21/M 21/M 21/M 22/M
FB BB FB FB TR FB FB FB FB FB FB FB FB BB FB FB FB FB BB FB FB FB FB
Level JHS HS HS HS HS C C HS C C C C C C C C C C C C C C C
State
SCT Solubility Test
Hemoglobin Electrophoresis*
Rhabdomyolysis
Ohio Texas Florida Texas Florida Tennessee Florida California Ohio Texas Arkansas Missouri Florida Texas Mississippi Georgia North Carolina Indiana Florida New Mexico Mississippi Arizona North Carolina
⫹ NA ⫹ ⫹ ⫹ NA ⫹ ⫹ NA ⫹ NA NA ⫹ NA ⫹ ⫹ ⫹ NA NA ⫹ NA ⫹ NA
NA ⫹ ⫹ NA NA ⫹ NA NA ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ NA ⫹ ⫹ ⫹ ⫹ ⫹ NA ⫹
⫹ 0 0 0 0 NA 0 0 ⫹ ⫹ ⫹ 0 ⫹ 0 0 ⫹ 0 ⫹ 0 ⫹ ⫹ ⫹ ⫹
BB ⫽ basketball; C ⫽ college; F ⫽ female; FB ⫽ football; HS ⫽ high school; JHS ⫽ junior high school; M ⫽ male; NA ⫽ no information available; TR ⫽ track (sprinter); ⫹ ⫽ present; 0 ⫽ absent. * Usually defined as bands present for hemoglobin A and S, with hemoglobin S 35% to 45%.
(mean 18.7 ⫾ 6); 1,459 patients were white (59%), 34 (1.4%) Asian, and 699 (28%) African American. The most common causes of death were blunt trauma (n ⫽ 476), commotio cordis (n ⫽ 98), and a variety of cardiovascular diseases (n ⫽ 1,396). The latter were most frequently hypertrophic cardiomyopathy (n ⫽ 375) and congenital coronary artery anomalies of wrong sinus origin (n ⫽ 131). Notably, 23 of the deaths (0.9%) were in athletes with SCT, documented by testing during life or at autopsy; each of these athletes was African American (Table 1). Ages ranged from 12 to 22 years (mean 18.6 ⫾ 2.6); 21 (91%) were male. At the time of their deaths, these athletes were competing in organized college (n ⫽ 17), high school (n ⫽ 5), or junior high school (n ⫽ 1) sports. The 23 athletes with SCT-related death represent 3.3% of 699 African American athletes in the registry. SCT diagnosis was made by solubility testing alone (n ⫽ 7, including 3 by newborn or university screening), hemoglobin electrophoresis alone (n ⫽ 10, 5 antemortem), or both (n ⫽ 6). All athletes died under similar distinctive circumstances: noninstantaneous collapse with gradual but rapid deterioration (i.e., dyspnea, fatigue, weakness, and muscle cramping) over an estimated 10 to 45 minutes, associated with exertional rhabdomyolysis in 11. Each event occurred during vigorous or exhaustive maximal physical exertion, usually during training and conditioning (n ⫽ 22), or competition (n ⫽ 1), and often after brief sustained effort such as repetitive short-distance sprints or endurance running. SCT events were most common early in the conditioning season and in 6 cases were documented on the first day of practice. Notably, SCT-deaths occurred predominately in football players (n ⫽ 19 of 23 [83%]), constituting 2.6% of all 723
deaths occurring in that sport and 7.0% of deaths in the 271 African American football players (i.e., 1 of 14). Other SCT-deaths occurred in basketball (n ⫽ 3) and track sprinting (n ⫽ 1). SCT deaths were similar to other cardiovascular deaths in the registry with respect to age (mean 18.6 ⫾ 2.6 vs 17.6 ⫾ 5.0 years, p ⫽ 0.092) and gender (91% vs 88% male, p ⫽ 1.00) but were more common in African Americans (100% vs 37%, p ⬍0.001). Deaths were most frequent in the summer and early autumn months of June to October (17 of 23 [74%]). Twenty of the 23 deaths (87%) occurred in southern or border states, most commonly Florida (n ⫽ 5), Texas (n ⫽ 4), Mississippi, North Carolina, and Ohio (n ⫽ 2 each). Potential associated triggers for SCT collapse were environmental temperature (ⱖ80°F) in 20 (87%) and high altitude in 2 (Albuquerque, New Mexico, and Tucson, Arizona), as well as maximum intensity of exercise. Four of the 23 athletes had associated structural cardiac abnormalities identified at autopsy: 2 with tunneled coronary arteries (1 left anterior descending and 1 right coronary), 1 with redundant mitral valve and features consistent with hypertrophic cardiomyopathy, and 1 with 80% right coronary artery narrowing by atherosclerosis. Heart weights ranged from 225 to 640 g (mean 423); 5 were ⬎500 g. Largely on the basis of the circumstances of collapse, these features are unlikely to be the primary or a major cause of death. Discussion From our forensic-based registry study, we have assembled the first sizable series of competitive athletes (n ⫽ 23) in whom SCT was associated with otherwise unexplained
Miscellaneous/Sickle Cell Trait and Sudden Death
sudden and unexpected collapse and death. These athletes constituted 0.9% of our large registry of almost 2,500 sudden deaths, with a predominance in college football players. The outcomes in these athletes can most reasonably be linked to the presence of SCT and its unpredictable consequences,15 particularly with no reasonable alternative explanation or disease to explain demise. Clinical profiles in the 23 SCT athletes were similar and distinctive. Cardiovascular collapse followed several minutes of gradual clinical worsening with dyspnea, fatigue, and weakness (sometimes permitting verbalization) during and after vigorous or exhaustive physical activity, often early in the workout season.5,16 Such scenarios differ distinctly from sudden death occurring from ventricular tachyarrhythmias due to structural cardiovascular diseases (e.g., hypertrophic cardiomyopathy, ion channelopathies) in which collapse is virtually instantaneous. Although the pathophysiology and determinants of SCT events are not fully understood, it is likely that cardiovascular collapse occurs under conditions that increase risk for exertional sickling of red blood cells, including heat stress, dehydration, illness, and altitude.1–3,17,18 It is reasonable to hypothesize that a cascade of events ensues with intramuscular and microvascular sickling leading to vascular occlusion, endothelial damage, and impaired blood flow to muscles, which promotes ischemic rhabdomyolysis and disseminated intravascular coagulation. Rhabdomyolysis leads to hyperkalemia and acidosis, which in the setting of hypoxia adversely affects cardiac function and lowers the threshold for a lethal cardiac arrhythmia.1,3,17–21 Indeed, although rhabdomyolysis was present in almost 50% of our SCT athletes, we found only 5 other athletes in the registry in whom rhabdomyolysis was the sole cause of death, all of whom were unassociated with SCT. Each was white, 17 to 28 years old, and died during running sports (exclusive of football). However, the finding of widespread sickling in the heart and other organs at autopsy does not represent unequivocal evidence for this mechanism of death because of the obstacle in distinguishing histologic postmortem sickling (which can be caused by the diminished oxygen environment after death) from antemortem sickling.1,4 This unavoidable limitation contributes to the debate over the pathogenesis of SCT and its relation to sudden death. Notably, the epidemiology and pathophysiology of SCT events have vital implications and provide clues that can enhance prevention with targeted measures and tailored precautions during training. For example, SCT events showed a clear predilection for male athletes during football practice and were often associated with brief bursts of sustained maximal exertion. These considerations have led to specific recommendations for athletes with known SCT: gradual conditioning at the beginning of the season, attention to modifying pace and providing periods of rest during conditioning drills, adequate hydration, and a high index of caution for immediate cessation of physical activity with muscle cramping, fatigue, and excessive dyspnea. Collapse with SCT is a medical emergency requiring the administration of oxygen, intravenous hydration, and cooling to protect against rhabdomyolysis. Although cardiac arrest is a possible sequela, and an external defibrillator should be in place,1,5,7 its effectiveness in this setting is unpredictable.22
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There has been some skepticism and substantial emotion surrounding the legitimacy of SCT as a causative factor for cardiovascular sudden death. However, our data support the principle that SCT may well be primarily linked to such uncommon events with vigorous exercise in young physically active individuals, often associated with elevated environmental temperatures as a trigger. SCT should be included among the myriad of nontraumatic risks of sports participation.9 –13 However, in this analysis we were unable to document the overall association of SCT and sudden death in the registry or to show that such events are more (or less) common compared to athletes without SCT. This is an unavoidable limitation, because laboratory-based SCT diagnoses were not available to the registry for all athletes, given confidentiality restrictions. However, it is particularly notable that 7% of 271 African American football players in the registry died of SCT, which approximates the 8% of African American football players who would be estimated to carry the trait in this population.15 Controversy surrounding SCT screening in athlete populations is a complex and sometimes polarizing ethical and legal debate.4,6,23 Screening proponents emphasize the potential for prevention of death by prospective recognition of SCT-affected individuals. Others regard SCT testing as potentially discriminatory practice used for selective targeting, and an infringement on individual privacy and liberty. Nevertheless, in 2010, the National Collegiate Athletic Association mandated SCT screening for all Division I student athletes as part of a legal settlement concerning an athlete death due to SCT.6 Recently, hematologists rejected mandatory SCT screening, instead recommending universal training interventions.24 We take neither side of this controversy and have confined ourselves to reporting a substantial series of athlete deaths associated with (and apparently due to) SCT. Our data also underscore the unpredictability of SCT events. With an 8% prevalence in African Americans, we would expect that thousands of individuals with SCT have competed safely during vigorous and competitive sports, but only a small fraction appear susceptible to catastrophe from this genetic defect, which has been generally regarded as benign. This observation raises the possibility of a SCT subset at particular risk because of currently undefined and unpredictable genetic, physiological, or environmental factors. Acknowledgment: We appreciate the statistical assistance of Ross F. Garberich, MSc, of the Minneapolis Heart Institute Foundation. 1. Tsaras G, Owusu-Ansah A, Boateng FO, Amaoteng-Adjepong Y. Complications associated with sickle-cell trait: a brief narrative review. Am J Med 2009;122:507–512. 2. Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med 1987;317:781–787. 3. Jones SR, Binder RA, Donowho EM. Sudden death in sickle-cell trait. N Engl J Med 1970;282:323–325. 4. Mitchell BL. Sickle cell trait and sudden death— bringing it home. J Natl Med Assoc 2007;99:300 –305. 5. Eichner ER. Sickle cell trait in sports. Curr Sports Med Rep 2010;9: 347–351.
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6. Bonham VL, Dover GJ, Brody LC. Screening student athletes for sickle cell trait—a social and clinical experiment. N Engl J Med 2010;363:997–999. 7. National Athletic Trainers’ Association. The National Athletic Trainers’ Association (NATA) releases “Sickle Cell Trait and the Athlete” consensus statement. Available at: http://www.nata.org/NR062107. Accessed April 17, 2012. 8. Klossner D. 2009-10 NCAA sports medicine handbook. Available at: http://www.ncaapublications.com/productdownloads/MD10.pdf. Accessed May 3, 2011. 9. Thompson PD. The cardiovascular complications of vigorous physical activity. Arch Intern Med 1996;156:2297–2302. 10. Van Camp SP, Bloor CM, Mueller FO, Cantu RC, Olson HG. Nontraumatic sports death in high school and college athletes. Med Sci Sports Exerc 1995;27:641– 647. 11. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the U.S. 1980-2006. Circulation 2009;119:1085–1092. 12. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes: clinical, demographic and pathologic profiles. JAMA 1996;276:199 –204. 13. Maron BJ. Sudden death in young athletes. N Engl J Med 2003;349: 1065–1075. 14. Maron BJ, Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;41:974–980. 15. Harmon KG, Drezner JA, Klossner D, Asif IM. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. Br J Sports Med 2012;46:325–330.
16. Rosenthal MA, Parker DJ. Collapse of a young athlete. Ann Emerg Med 1992;21:1493–1498. 17. Loosemore M, Walsh SB, Morris E, Stewart G, Porter JB, Montgomery H. Sudden exertional death in sickle cell trait. Br J Sports Med 2012;46:312–314. 18. Rodgers GP. Sickle-cell trait and physical training: evidence for improved fitness. Arch Intern Med 1988;148:1019 –1020. 19. Ramirez A, Hartley LH, Rhodes D, et al. Morphological feature of red blood cells in subjects with sickle cell trait: changes during exercise. Arch Intern Med 1976;136:1064 –1066. 20. Martin TW, Weisman IM, Zeballos RJ, Stephenson SR. Exercise and hypoxia increase sickling in venous blood from an exercising limb in individuals with sickle cell trait. Am J Med 1989;87:48 –56. 21. Phillips M, Robinowitz M, Higgins JR, Boran KJ, Reed T, Virmani R. Sudden cardiac death in Air Force recruits. A 20-year review. JAMA 1986;256:2696 –2699. 22. Soar J, Perkins GD, Abbas G, Alfonzo A, Barelli A, Bierens JJ, Brugger H, Deakin CD, Dunning J, Georgiou M, Handley AJ, Lockey DJ, Paal P, Sandroni C, Thies KC, Zideman DA, Nolan JP. European Resuscitation Council Guidelines for Resuscitation 2010 Section 8. Cardiac arrest in special circumstances: electrolyte abnormalities, poisoning, drowning, accidental hypothermia, hyperthermia, asthma, anaphylaxis, cardiac surgery, trauma, pregnancy, electrocution. Resuscitation 2010;81:1400 –1433. 23. Steinberg MH. In the clinic: sickle cell disease. Ann Intern Med 2011;155:ITC31–ITC315. 24. American Society of Hematology. ASH policy opposes mandatory sickle cell trait screening for athletic participation, recommends universal training interventions & additional research. Available at: http:// www.hematology.org/news/2012/7703.aspx. Accessed April 17, 2012.