Relative energy deficiency in sport (RED-S) refers to a syndrome characterized by a state of energy deficiency in athletes. It encompasses impairments in metabolism, menstruation, bone health, cardiovascular (CV) health, immunity, and protein synthesis.

The term RED-S has been in existence since 2014 and was conceptualized by the International Olympic Committee as an update to the previously existing terminology, Female Athlete Triad.¹ The Female Athlete Triad originally included the entities of disordered eating, amenorrhea and osteoporosis.² Low energy availability (EA) was later incorporated as an essential, underpinning component of the triad.³

Low EA arises from a mismatch between energy intake (EI) and exercise energy expenditure (EEE) during exercise. The resulting caloric deficit leads to impaired functioning of organ systems necessary for maintaining optimal health.

EA is calculated by subtracting the EEE or energy cost of exercise from the EI relative to the fat free mass (FFM).¹

Studies of female athletes have found a value of less than 30 kcal/kg/FFM to be the threshold for low EA with lower, less well defined cut points observed in the male demographic.^3-5 Low EA is a frequently encountered predicament facing athletes who participate in endurance or aesthetic sports or sports with weight categories, with prevalence rates ranging from 22 -53%.^6-8

Potential CV Consequences of RED-S

Athletes with RED-S may be referred to the sports cardiologist for evaluation of a perceived decline in performance, bradyarrhythmias, and/or autonomic dysfunction. It is imperative that sports cardiologists have a heightened level of suspicion for RED-S in such athletes who are participating in the sporting disciplines described above and be familiar with the potential CV findings and consequences of this syndrome.

Endothelial Dysfunction

The association between impaired flow mediated vasodilation (FMD) and endothelial dysfunction and coronary artery disease (CAD) have been well documented in the medical literature.⁹ Studies show that amenorrheic athletes have significantly lower FMD values in comparison to their oligomenorrheic and eumenorrheic counterparts therefore predisposing them to early onset CAD.^10,11

Hyperlipidemia

Amenorrheic athletes develop unfavorable elevations in total cholesterol, low density lipoprotein and apolipoprotein (B) levels which are related to their hypoestrogenic state.¹¹ Longitudinal studies are required to elucidate whether this translates to increased CV morbidity and mortality.

Dysautonomia

Exercising females with functional amenorrhea are sensitive to orthostatic stress and have lower systolic blood pressures compared to eumenorrheic exercising women.¹² They rely on an augmented sympathetic vasoconstrictor response for blood pressure support rather than activation of the renin angiotensin aldosterone pathway.¹² The attenuated renin angiotensin aldosterone response is believed to be the consequence of estrogen deficiency and possibly low triiodothyronine levels.¹²

Bradycardia

Highly trained athletes can have resting heart rates as low as 30 beats per minute. Distinguishing healthy athletes from those with disordered eating such as anorexia nervosa (AN), where bradycardia is commonly encountered, can pose a challenge. Bradycardia in athletes stems from an increased parasympathetic tone as well as electrical remodeling of the sinoatrial node while bradycardia in AN is due to cardiac vagal hyperactivity.^13-15 Findings such as significant pauses, heart rates less than 30 beats per minute or chronotropic incompetence on maximal effort exercise stress testing can serve as potential clues for coexisting AN in athletes.

QT Prolongation

Interestingly, this is an inconsistent finding in studies of patients with eating disorders.^15,16 Plausible explanations for this include the sole use of Bazett's correction formula, small sample sizes, electrolyte disturbances and concurrent use of QT prolonging medications.¹⁶ QT prolongation has not been studied in athletes with RED-S.

QT Dispersion

This denotes the difference between the longest and shortest QT intervals on the electrocardiogram (ECG) and reflects heterogeneity in ventricular repolarization. It is considered a marker of ventricular arrhythmias and sudden death. In anorexic women, QT dispersion is thought to be related to histological abnormalities of the cardiac myocytes and diminished left ventricular (LV) mass.^15,17 Data on LV mass in athletes with AN are unavailable to date. Since QT dispersion is not found in healthy athletes, it can be used to risk stratify athletes with eating disorders.

Mitral Valve Prolapse

Mitral valve prolapse (MVP) is frequently observed in the AN cohort and is postulated to be due to a loss of LV mass.¹⁸ The prevalence of MVP has not been studied in athletic AN patients. In a study of professional ballet dancers, the prevalence of MVP was 48%, with ponderal index serving as the best predictor of MVP.¹⁹ Extrapolating from this data, one may predict a higher prevalence of MVP and subsequently a greater predilection for arrhythmias amongst athletes with RED-S.

Pericardial Effusion

It has been theorized that AN associated myocardial atrophy and reduction in pericardial fat leads to an increase in pericardial space with subsequent development of pericardial effusion.¹⁸ There are no data pertaining to pericardial effusion in athletes with AN.

CV Performance

Studies of male athletes showed an increased or unchanged maximal oxygen consumption (VO₂max) following a 2-4 week period of low EA exposure.^20,21 Cardiopulmonary exercise test (CPET) data beyond this time frame is not available however a decline in endurance performance will ultimately develop in prolonged low EA states.²²

Risk Assessment

The RED-S Clinical Assessment Tool (RED-S CAT™) assists in the clinical evaluation and management of athletes with suspected RED-S and categorizes athletes into low, moderate and high risk levels.²³ Severe ECG abnormalities and AN are deemed high risk features.²³ Such patients are not allowed to train or participate in sport and must submit to a written treatment contract. A multidisciplinary team approach is employed which includes treatment by a physician, dietitian, psychotherapist, and physiologist.

Conclusion

It is crucial for the sports cardiologist to be familiar with RED-S and its CV consequences and appreciate the interplay between specific cardiac findings and risk stratification of the athlete. Further research geared towards cardiac imaging findings and long term CV outcomes specific to this athletic population is warranted. This not only will ensure a greater understanding of the CV consequences of RED-S but can also provide additional risk stratification measures that can potentially guide return to play decision making.

References

1. Mountjoy M, Sundgot-Borgen J, Burke L, et al. The IOC consensus statement: beyond the female athlete triad—relative energy deficiency in sport (RED-S). Br J Sports Med 2014;48:491-97.
2. Yeager KK, Agostini R, Nattiv A, Drinkwater B. The female athlete triad: disordered eating, amenorrhea, osteoporosis. Med Sci Sports Exerc 1993;25-775-77.
3. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP. American College of Sports Medicine position stand. The Female Athlete Triad. Med Sci Sports Exerc 2007;39:1867-82.
4. Lane AR, Hackney AC, Smith-Ryan AE, Kucera K, Register-Mihalik JK, Ondrak K. Energy availability and RED-S risk factors in competitive, non-elite male endurance athletes. Transl Med Exerc Prescr 2021;1:25-32.
5. Jurov I, Keay N, Rauter S. Reducing energy availability in male endurance athletes: a randomized trial with a three-step energy reduction. J Int Soc Sports Nutr 2022;19:179-95.
6. Civil R, Lamb A, Loosmore D, et al. Assessment of dietary intake, energy status, and factors associated with RED-S in vocational female ballet students. Front Nutr 2019;5:136.
7. Braun H, von Andrian-Werburg J, Schänzer W, Thevis M. Nutrition status of young elite female German football players. Pediatr Exerc Sci 2018;30:157-67.
8. Heikura IA, Uusitalo ALT, Stellingwerff T, Bergland D, Mero AA, Burke LM. Low energy availability is difficult to assess but outcomes have large impact on bone injury rates in elite distance athletes. Int J Sport Nutr Exerc Metab 2018;28:403-11.
9. Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995;26:1235-41.
10. Hoch AZ, Dempsey RL, Carrera GF, et al. Is there an association between athletic amenorrhea and endothelial cell dysfunction? Med Sci Sports Exerc 2003;35:377-83.
11. Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL. Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid profile. J Clin Edocrinol Metab 2005;90:1354-59.
12. O'Donnell E, Goodman J, Mak S, et al. Discordant orthostatic reflex renin-angiotensin and sympathoneural responses in premenopausal exercising-hypoestrogenic women. Hypertension 2015;65:1089-95.
13. D'Souza A, Bucchi A, Johnsen AB, et al. Exercise training reduces resting heart rate via downregulation of the funny channel HCN4. Nat Commun 2014;5:3775.
14. Carter JB, Banister EW, Blaber AP. Effect of endurance exercise on autonomic control of heart rate. Sports Med 2003;33:33-46.
15. Olivares JL, Vázquez M, Fleta J, Moreno LA, Pérez-González JM, Bueno M. Cardiac findings in adolescents with anorexia nervosa at diagnosis and after weight restoration. Eur J Pediatr 2005;164:383-86.
16. Janzen ML, Malhi N, Laksman ZWM, Puyat J, Krahn AD, Hawkins NM. The QT interval in anorexia nervosa: a meta-analysis. JACC Clin Electrophysiol 2018;4:839-41.
17. Galetta F, Franzoni F, Cupisti A, Belliti D, Prattichizzo F, Rolla M. QT interval dispersion in young women with anorexia nervosa. J Pediatr 2002;140:456-60.
18. Smythe J, Colebourn C, Prisco L, Petrinic T, Leeson P. Cardiac abnormalities identified with echocardiography in anorexia nervosa: systematic review and meta-analysis. Br J Psychiatry 2021;219:477-86.
19. Cohen JL, Austin SM, Segal KR, Millman AE, Kim CS. Echocardiographic mitral valve prolapse in ballet dancers: a function of leanness. Am Heart J 1987;113:341-44.
20. Stenqvist TB, Torstveit MK, Faber J, Melin AK. Impact of a 4-week intensified endurance training intervention on markers of relative energy deficiency in sport (RED-S) and performance among well-trained male cyclists. Front Endocrinol (Lausanne) 2020;11:512365.
21. Jurov I, Keay N, Spudić D, Rauter S. Inducing low energy availability in trained endurance male athletes results in poorer explosive power. Eur J Appl Physiol 2022;122:503-13.
22. Vanheest JL, Rodgers CD, Mahoney CE, De Souza MJ. Ovarian suppression impairs sport performance in junior elite female swimmers. Med Sci Sports Exerc 2014;46:156-66.
23. Mountjoy M, Sundgot-Borgen J, Burke L, et al. RED-S CAT. Relative Energy Deficiency in Sport (RED-S) Clinical Assessment Tool (CAT). Br J Sports Med 2015;49:421-23.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Pericardial Disease, Sports and Exercise Cardiology, Implantable Devices

Keywords: Sports, Relative Energy Deficiency in Sport, Athletes, Female, Hyperlipidemias, Primary Dysautonomias, Bradycardia, Mitral Valve Prolapse, Pericardial Effusion, Risk Assessment, Risk, Risk Factors, Health Expenditures, Return to Sport

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