Physical Activity Level Is Not a Determinant of Autonomic Nervous System Activity and Clinical Severity in Children/Adolescents With Sickle Cell Anemia: A Pilot Study Keyne Charlot, PhD, 1,2,3 Berenike Moeckesch, MSc, 1,2,3 St ephane Jumet, MSc, 2 Marc Romana, PhD, 1,3 Xavier Waltz, PhD, 1,2,3 Lydia Divialle-Doumdo, MD, 4 Marie-Dominique Hardy-Dessources, PhD, 1,3 Marie Petras, MD, 4 Benoı ˆt Tressi eres, MSc, 5 Aur elien Pichon, PhD, 6 Vanessa Tarer, PhD, 4 Olivier Hue, PhD, 2 Maryse Etienne-Julan, MD, PhD, 4 Sophie Antoine-Jonville, PhD, 2 and Philippe Connes, PhD 1,3,7,8 * INTRODUCTION The identification of physiological and/or biological markers that could help in predicting the occurrence of acute complica- tions in cardiovascular diseases, as well as in the general population, is an important medical challenge. In that way, it is now well accepted that altered autonomic nervous system (ANS) activity is a powerful and independent predictor of an adverse prognosis in patients with heart disease and several other disorders.[1] Using heart rate variability (HRV) analyses, several studies investigated the autonomic nervous system (ANS) activity in sickle cell anemia (SCA).[2] Autonomic imbalance caused by parasympathetic withdrawal at rest[3–5] and impaired autonomic reactivity during different challenges[6–8] have been reported in this population and the degree of impairment has been associated with the clinical severity.[4,9,10] For instance, adults with SCA at high risk for vaso-occlusive crises (VOC) and acute chest syndrome (ACS) have lower ANS activity than those with a mild clinical phenotype.[4,10] In healthy individuals, free-living physical activity energy expenditure (PAEE) is positively associated with ANS activity and especially parasympathetic nervous system (PNS) activity.[11–13] Regular physical activity increases PNS activity, which protects individuals from the development of cardiovascular diseases,[14] while inactivity causes ANS activity imbalance which may promote the development of cardiovascular disorders and inflammatory syndromes.[15,16] Strenuous exercise must clearly be avoided in SCA since it may trigger severe vaso-occlusive like complications. [17] However, recent experiments conducted in a murine model of SCA (SAD mice) suggest that spontaneous and regular physical activity could be beneficial on the clinical course of this disease. [18–20] No study investigated the associations between regular physical activity, ANS activity, and clinical severity in patients with SCA. We hypothesized that low levels of physical activity would be associated with exacerbated ANS dysfunction and poor health status in patients with SCA. To answer this question, we investigated HRVand PAEE in a group of 22 children with SCA regularly followed since birth at the Sickle Cell Center of Guadeloupe. Background. Autonomic nervous system (ANS) activity has been suggested to modulate the clinical severity of sickle cell anemia (SCA) by increasing the risk for vaso-occlusive events. Regular physical activity (PA) is known to improve ANS activity and health status in several cardiovascular and metabolic diseases. Whether regular PA improves the health status of SCA patients remains unknown. Procedure. Twenty-two patients with SCA and 15 healthy (AA) children/adolescents participated to the study. Heart rate variability was measured in supine position and after a tilt-test to quantify the ANS activity. PA energy expenditure (PAEE) was assessed with questionnaire. Results. 1) PAEE was lower in SCA compared to AA (190  152 vs. 432  277 kcald 1 , respectively, P < 0.01), 2) overall ANS activity was lower in SCA compared to AA, 3) parasympathetic withdrawal was observed in SCA with aging, 4) ANS reactivity was slightly impaired in SCA compared to AA (reduction in HFnu: 38  27 vs. 58  14%, respectively, P < 0.05), 5) ANS indices, PAEE, and rates of clinical events were not correlated. Conclusion. Both the level of PA and ANS activity are reduced in SCA compared to AA children/adolescents, particularly in those older than 15 years. Neither PAEE, nor ANS activity seem to influence the clinical severity of children/adolescents with SCA. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. Key words: acute chest syndrome; heart rate variability; physical activity energy expenditure; sickle cell disease; vaso-occlusive crises Abbreviations: ACS, acute chest syndrome; ANS, autonomic nervous system; HF, high-frequencies in ms 2 ; HFnu, high-frequencies in normalized units; HRV, heart rate variability; LF, low-frequencies; PAEE, physical activity energy expenditure; PNS, parasympathetic nervous system; REE, resting energy expenditure; RRI, R-R interval; SCA, sickle cell anemia; SNS, sympathetic nervous system; TEE, total energy expenditure; TP, total power; VOC, vaso-occlusive crisis 1 UMR Inserm U1134, French West Indies and Guiana University, Pointe- a-Pitre, Guadeloupe, France; 2 Laboratory ACTES (EA 3596), Department of Physiology, French West Indies and Guiana University, Pointe- a-Pitre, Guadeloupe, France; 3 Laboratoire d’Excellence du Globule Rouge (LABEX GR-Ex) PRES Sorbonne, Paris, France; 4 Sickle Cell Center, Academic Hospital of Pointe- a-Pitre, Pointe-  a-Pitre, Guadeloupe, France; 5 Centre Investigation Clinique Antilles Guyane 1424 Inserm, Academic Hospital of Pointe- a-Pitre, Pointe-  a-Pitre, Guadeloupe, France; 6 Laboratory MOVE, EA6314, University of Poitiers, Poitiers, France; 7 Institut Universitaire de France (IUF), Paris, France; 8 Laboratory CRIS EA647, Section Vascular Biology and Red Blood Cell, University of Lyon, Lyon, France Sophie Antoine-Jonville and Philippe Connes contributed equally to this work. Conflict of interest: Nothing to declare.  Correspondence to: Philippe Connes, UMR Inserm U1134, French West Indies and Guiana University, Pointe- a-Pitre, Guadeloupe, France. E-mail: pconnes@yahoo.fr Received 19 March 2015; Accepted 28 April 2015  C 2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25604 (wileyonlinelibrary.com). Pediatr Blood Cancer 2015;62:1962–1967 Published online 19 May 2015 in Wiley Online Library 2015;62:1962–1967.