Author's Accepted Manuscript
People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly Jonathan R Skinner MBChB, MD, FHRS, FRACP, Colette Muir MBChB, FRACP
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)00592-5 http://dx.doi.org/10.1016/j.hrthm.2015.05.015 HRTHM6278
To appear in:
Heart Rhythm
Cite this article as: Jonathan R Skinner MBChB, MD, FHRS, FRACP, Colette Muir MBChB, FRACP, People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2015.05.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly 1,2,3
Jonathan R Skinner, MBChB, MD, FHRS, FRACP; 4
Colette Muir, MBChB, FRACP
1
Cardiac Inherited Disease Group, Auckland City Hospital, Auckland, New Zealand;
Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland,
2
New Zealand; 3
Department of Child Health, University of Auckland, Auckland, New Zealand;
Department of Developmental Paediatrics, Starship Children’s Hospital, Auckland, New Zealand
4
Corresponding author: Dr Jonathan Skinner Green Lane Paediatric and Congenital Cardiac Services Starship Children’s’ Hospital Private Bag 92024 Auckland 1142 New Zealand Ph: +64 9 3074949 Fax: +64 9 6310785 Email: [email protected] Word Count: 1645 words (1500 words including reference) References: 25 Conflicts of Interests There authors have no conflicts of interest to declare. Financial Support Dr Skinner receives salary support from Cure Kids.
Attention deficit hyperactivity disorder (ADHD) is a serious neuro-developmental disorder with major adverse outcomes. Inattentive and/or hyperactive-impulsive behaviour is associated with academic failure, poor self-esteem, poor social functioning and psychiatric comorbidities.(1, 2) Starting in childhood and often continuing into adult life, ADHD can result in life-threatening accidents, suicide, and illicit drug use.(3, 4) It also tends to be inherited,(5) and occur more frequently in socially disadvantaged families, such that affected children may be part of a particularly vulnerable family.(6) It does however respond well to treatment with stimulants, particular methylphenidate.(7) If 11% of the 50 million children aged 6-17 in the US(8) have ADHD as estimated,(9) and long QT syndrome (LQTS) has a prevalence of 1 in 2000,(10) approximately 2500 children in the US will have both LQTS and ADHD. Is it safe for these children to have methylphenidate? After the Federal Drug Administration’s recommended black box warning in 2006 of risk of cardiac arrest due to stimulants(11) an American Heart Association advisory in 2008 recommended ECG screening prior to treatment with a stimulant, with a particular emphasis on detection of a long QT interval.(12) With this background, clinicians have been nervous of treating those with LQTS with methylphenidate, particularly given the link between adrenergic stimulation and cardiac events in LQTS type 1 in childhood. Some extra concern may spill over from the fact that many other neuro-active drugs, including antipsychotics and antidepressants, have an unequivocal risk of sudden cardiac death largely through depressing the delayed rectifier potassium current (IKr).(13) However, methylphenidate and other stimulants have now been exceptionally well studied for safety. No cardiac death occurred during 42,612 person-years of stimulant use In 3-20 year olds with newly diagnosed ADHD in Florida over ten years.(14) Cardiovascular events were
rare and not associated with stimulant use in 171,126 young people 6 to 21 years old without known cardiovascular risk factors.(15) Methylphenidate does not prolong the QT interval,(16) and actually decreases QT dispersion.(17) Even in overdose (among 23 young adults) there is generally no QRS or QT prolongation and no arrhythmias.(18) Stimulants do elevate heart rate and blood pressure a little, on average in adults by 6bpm and blood pressure by 2mmHg(19) but a recent comprehensive review concludes that stimulants do not cause sudden cardiac death or serious cardiovascular problems including increased QTc, across the lifespan.(20) Yet this report concludes with the caveat that great caution is advised when considering stimulant and nonstimulant medications for patients of any age with a personal or family history of risk factors for cardiovascular disease. So the report in this journal from the Mayo clinic of a series of children with LQTS and ADHD treated with stimulants is timely.(21) It is only a small series, 15 genotype positive children with mild to moderate LQTS, none with a QTc of over 500ms and only one presenting with syncope. Nevertheless, when also treated by beta blockade, co-treatment with methylphenidate led to no adverse outcomes over 56 patient years. This pragmatic approach gives clinicians a clear option which makes sense. Alleviate the cardiac effects of stimulants; tachycardia and hypertension, with beta blockade, and simultaneously avert the theoretical risk of the co-administered stimulant to a patient with LQTS. Given their mild phenotype, most of these 15 children may have gone through their entire life without a symptom, so we should not overstate the impact of this small study alone. However, in the study mentioned above of 171,126 young people receiving methylphenidate,
up to 1 in 2000 may by coincidence have also had undiscovered LQTS, that’s 85 children. No cardiac events occurred even without beta blockers. Is it possible that methylphenidate will actually reduce risk in LQTS? We think it might. After all, one end of the spectrum of ADHD is the hyperactive, impulsive “tantrum” end. Extreme peaks of heart rate are to be expected in the child and also in the family confronting it. Such peaks prolong the QT interval post exercise in LQTS, and may lead to syncope or cardiac arrest. (22, 23) A mild increase in the resting heart rate brought on by methylphenidate may be a small price to pay to remove the peaks in heart rate due to improved temper and behaviour. Furthermore, a beneficial response to stimulants may result in improved adherence to beta blockers and recommended life-style modifications. In some centres, fear of poor adherence to beta blocker therapy in vulnerable families may play a greater part than at the Mayo Clinic. The authors mention that a left cardiac sympathectomy might be an option in this group. Although there is emerging evidence that exercise and healthy diet can improve symptoms of ADHD,(24, 25) stimulant medication remains the first line treatment for ADHD in school age children and adolescents,(7) and there is distinct lack of evidence that they should be avoided in LQTS. Children and youth with LQTS who also suffer with ADHD deserve the best available treatment. We don’t know yet if stimulants are safe in the most severe forms of LQTS, and clinical long QT registries should remain vigilant. However, stimulants may even be beneficial in risk reduction in this group for the reasons explained above. For now, with a sense of some relief, we endorse the sensible approach presented by Rohatgi et al in children with LQTS with a mild or moderate phenotype; that of the co-administration of stimulants with beta blockers, along with regular cardiological review to assure long term adherence.
Acknowledgements The authors gratefully acknowledge Charlene Nell, Team Support Administrator, Green Lane Cardiovascular Research Unit, for excellent secretarial assistance and for preparing the manuscript.
References 1.
Barbaresi WJ, Colligan RC, Weaver AL, Voigt RG, Killian JM, Katusic SK. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. Pediatrics 2013;131:637-644.
2.
Harpin V, Mazzone L, Raynaud JP, Kahle J, Hodgkins P. Long-Term Outcomes of ADHD: A Systematic Review of Self-Esteem and Social Function. J Atten Disord 2013; Epub ahead of print.
3.
Lee SS, Humphreys KL, Flory K, Liu R, Glass K. Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review. Clinical psychology review. 2011;31:328341.
4.
Lange H, Buse J, Bender S, Siegert J, Knopf H, Roessner V. Accident proneness in children and adolescents affected by ADHD and the impact of medication. J Atten Disord 2014; Epub ahead of print.
5.
Schachar R. Genetics of attention deficit hyperactivity disorder (ADHD): Recent Updates and future prospects. Curr Dev Disord Rep 2014;1:41–49
6.
Russell G, Ford T, Rosenberg R, Kelly S. The association of attention deficit hyperactivity disorder with socioeconomic disadvantage: alternative explanations and evidence. J Child Psychol Psychiatry. 2014;55:436-445.
7.
Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement and Management, Wolraich M, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128:1007-1022.
8.
U.S. Census Bureau, Current Population Reports. Forum on Child and Family Statistics. U.S. Department of Education, National Center for Education Statistics (NCES). http://www.childstats.gov/americaschildren/tables/pop1.asp - accessed 5 May 2015.
9.
Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, et al. Trends in the parent-report of health care provider-diagnosed and medicated attentiondeficit/hyperactivity disorder: United States, 2003-2011. J Am Acad Child Adolesc Psychiatry. 2014;53:34-46 e2.
10. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761-1767. 11. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354(14):14451448. 12. Vetter VL, Elia J, Erickson C, Berger S, Blum N, Uzark K, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117:2407-2423. 13. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5:97-104.
14. Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A. Cardiac safety of central nervous system stimulants in children and adolescents with attentiondeficit/hyperactivity disorder. Pediatrics. 2007;120:e1494-501. 15. Olfson M, Huang C, Gerhard T, Winterstein AG, Crystal S, Allison PD, et al. Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:147-156. 16. Negrao BL, Crafford D, Viljoen M. The effect of sympathomimetic medication on cardiovascular functioning of children with attention-deficit/hyperactivity disorder. Cardiovasc J Afr. 2009;20:296-299. 17. Ilgenli TF, Congologlu A, Ozturk C, Turkbay T, Akpinar O, Kilicaslan F. Acute effect of methylphenidate on QT interval duration and dispersion in children with attention deficit hyperactivity disorder. Adv Ther. 2007;24:182-188. 18. Hill SL, El-Khayat RH, Sandilands EA, Thomas SH. Electrocardiographic effects of methylphenidate overdose. Clin Toxicol (Phila). 2010;48:342-346. 19. Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol. 2013;23:534-541. 20. Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs. 2013;27:15-30. 21. Rohatgi RK, Bos,M., Ackerman,M.J. Stimulant Therapy in Children with Attention Deficit Hyperactivity Disorder and Concomitant Long QT Syndrome: a Safe Combination? Heart Rhythm. 2015. 22. Swan H, Toivonen L, Viitasalo M. Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Eur Heart J. 1998;19:508-513.
23. Ali RH, Zareba W, Moss AJ, Schwartz PJ, Benhorin J, Vincent GM, et al. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol. 2000;85:457-461. 24. Silva AP, Prado SO, Scardovelli TA, Boschi SR, Campos LC, Frere AF. Measurement of the effect of physical exercise on the concentration of individuals with ADHD. PLoS One. 2015;10:e0122119. 25. Ghanizadeh A, Haddad B. The effect of dietary education on ADHD, a randomized controlled clinical trial. Ann Gen Psychiatry. 2015;14:12.
People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly Jonathan R Skinner MBChB, MD, FHRS, FRACP, Colette Muir MBChB, FRACP
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(15)00592-5 http://dx.doi.org/10.1016/j.hrthm.2015.05.015 HRTHM6278
To appear in:
Heart Rhythm
Cite this article as: Jonathan R Skinner MBChB, MD, FHRS, FRACP, Colette Muir MBChB, FRACP, People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly, Heart Rhythm, http://dx.doi.org/ 10.1016/j.hrthm.2015.05.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
People with long QT syndrome who have attention deficit hyperactivity disorder deserve to be treated properly 1,2,3
Jonathan R Skinner, MBChB, MD, FHRS, FRACP; 4
Colette Muir, MBChB, FRACP
1
Cardiac Inherited Disease Group, Auckland City Hospital, Auckland, New Zealand;
Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland,
2
New Zealand; 3
Department of Child Health, University of Auckland, Auckland, New Zealand;
Department of Developmental Paediatrics, Starship Children’s Hospital, Auckland, New Zealand
4
Corresponding author: Dr Jonathan Skinner Green Lane Paediatric and Congenital Cardiac Services Starship Children’s’ Hospital Private Bag 92024 Auckland 1142 New Zealand Ph: +64 9 3074949 Fax: +64 9 6310785 Email: [email protected] Word Count: 1645 words (1500 words including reference) References: 25 Conflicts of Interests There authors have no conflicts of interest to declare. Financial Support Dr Skinner receives salary support from Cure Kids.
Attention deficit hyperactivity disorder (ADHD) is a serious neuro-developmental disorder with major adverse outcomes. Inattentive and/or hyperactive-impulsive behaviour is associated with academic failure, poor self-esteem, poor social functioning and psychiatric comorbidities.(1, 2) Starting in childhood and often continuing into adult life, ADHD can result in life-threatening accidents, suicide, and illicit drug use.(3, 4) It also tends to be inherited,(5) and occur more frequently in socially disadvantaged families, such that affected children may be part of a particularly vulnerable family.(6) It does however respond well to treatment with stimulants, particular methylphenidate.(7) If 11% of the 50 million children aged 6-17 in the US(8) have ADHD as estimated,(9) and long QT syndrome (LQTS) has a prevalence of 1 in 2000,(10) approximately 2500 children in the US will have both LQTS and ADHD. Is it safe for these children to have methylphenidate? After the Federal Drug Administration’s recommended black box warning in 2006 of risk of cardiac arrest due to stimulants(11) an American Heart Association advisory in 2008 recommended ECG screening prior to treatment with a stimulant, with a particular emphasis on detection of a long QT interval.(12) With this background, clinicians have been nervous of treating those with LQTS with methylphenidate, particularly given the link between adrenergic stimulation and cardiac events in LQTS type 1 in childhood. Some extra concern may spill over from the fact that many other neuro-active drugs, including antipsychotics and antidepressants, have an unequivocal risk of sudden cardiac death largely through depressing the delayed rectifier potassium current (IKr).(13) However, methylphenidate and other stimulants have now been exceptionally well studied for safety. No cardiac death occurred during 42,612 person-years of stimulant use In 3-20 year olds with newly diagnosed ADHD in Florida over ten years.(14) Cardiovascular events were
rare and not associated with stimulant use in 171,126 young people 6 to 21 years old without known cardiovascular risk factors.(15) Methylphenidate does not prolong the QT interval,(16) and actually decreases QT dispersion.(17) Even in overdose (among 23 young adults) there is generally no QRS or QT prolongation and no arrhythmias.(18) Stimulants do elevate heart rate and blood pressure a little, on average in adults by 6bpm and blood pressure by 2mmHg(19) but a recent comprehensive review concludes that stimulants do not cause sudden cardiac death or serious cardiovascular problems including increased QTc, across the lifespan.(20) Yet this report concludes with the caveat that great caution is advised when considering stimulant and nonstimulant medications for patients of any age with a personal or family history of risk factors for cardiovascular disease. So the report in this journal from the Mayo clinic of a series of children with LQTS and ADHD treated with stimulants is timely.(21) It is only a small series, 15 genotype positive children with mild to moderate LQTS, none with a QTc of over 500ms and only one presenting with syncope. Nevertheless, when also treated by beta blockade, co-treatment with methylphenidate led to no adverse outcomes over 56 patient years. This pragmatic approach gives clinicians a clear option which makes sense. Alleviate the cardiac effects of stimulants; tachycardia and hypertension, with beta blockade, and simultaneously avert the theoretical risk of the co-administered stimulant to a patient with LQTS. Given their mild phenotype, most of these 15 children may have gone through their entire life without a symptom, so we should not overstate the impact of this small study alone. However, in the study mentioned above of 171,126 young people receiving methylphenidate,
up to 1 in 2000 may by coincidence have also had undiscovered LQTS, that’s 85 children. No cardiac events occurred even without beta blockers. Is it possible that methylphenidate will actually reduce risk in LQTS? We think it might. After all, one end of the spectrum of ADHD is the hyperactive, impulsive “tantrum” end. Extreme peaks of heart rate are to be expected in the child and also in the family confronting it. Such peaks prolong the QT interval post exercise in LQTS, and may lead to syncope or cardiac arrest. (22, 23) A mild increase in the resting heart rate brought on by methylphenidate may be a small price to pay to remove the peaks in heart rate due to improved temper and behaviour. Furthermore, a beneficial response to stimulants may result in improved adherence to beta blockers and recommended life-style modifications. In some centres, fear of poor adherence to beta blocker therapy in vulnerable families may play a greater part than at the Mayo Clinic. The authors mention that a left cardiac sympathectomy might be an option in this group. Although there is emerging evidence that exercise and healthy diet can improve symptoms of ADHD,(24, 25) stimulant medication remains the first line treatment for ADHD in school age children and adolescents,(7) and there is distinct lack of evidence that they should be avoided in LQTS. Children and youth with LQTS who also suffer with ADHD deserve the best available treatment. We don’t know yet if stimulants are safe in the most severe forms of LQTS, and clinical long QT registries should remain vigilant. However, stimulants may even be beneficial in risk reduction in this group for the reasons explained above. For now, with a sense of some relief, we endorse the sensible approach presented by Rohatgi et al in children with LQTS with a mild or moderate phenotype; that of the co-administration of stimulants with beta blockers, along with regular cardiological review to assure long term adherence.
Acknowledgements The authors gratefully acknowledge Charlene Nell, Team Support Administrator, Green Lane Cardiovascular Research Unit, for excellent secretarial assistance and for preparing the manuscript.
References 1.
Barbaresi WJ, Colligan RC, Weaver AL, Voigt RG, Killian JM, Katusic SK. Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. Pediatrics 2013;131:637-644.
2.
Harpin V, Mazzone L, Raynaud JP, Kahle J, Hodgkins P. Long-Term Outcomes of ADHD: A Systematic Review of Self-Esteem and Social Function. J Atten Disord 2013; Epub ahead of print.
3.
Lee SS, Humphreys KL, Flory K, Liu R, Glass K. Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review. Clinical psychology review. 2011;31:328341.
4.
Lange H, Buse J, Bender S, Siegert J, Knopf H, Roessner V. Accident proneness in children and adolescents affected by ADHD and the impact of medication. J Atten Disord 2014; Epub ahead of print.
5.
Schachar R. Genetics of attention deficit hyperactivity disorder (ADHD): Recent Updates and future prospects. Curr Dev Disord Rep 2014;1:41–49
6.
Russell G, Ford T, Rosenberg R, Kelly S. The association of attention deficit hyperactivity disorder with socioeconomic disadvantage: alternative explanations and evidence. J Child Psychol Psychiatry. 2014;55:436-445.
7.
Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement and Management, Wolraich M, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128:1007-1022.
8.
U.S. Census Bureau, Current Population Reports. Forum on Child and Family Statistics. U.S. Department of Education, National Center for Education Statistics (NCES). http://www.childstats.gov/americaschildren/tables/pop1.asp - accessed 5 May 2015.
9.
Visser SN, Danielson ML, Bitsko RH, Holbrook JR, Kogan MD, Ghandour RM, et al. Trends in the parent-report of health care provider-diagnosed and medicated attentiondeficit/hyperactivity disorder: United States, 2003-2011. J Am Acad Child Adolesc Psychiatry. 2014;53:34-46 e2.
10. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761-1767. 11. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354(14):14451448. 12. Vetter VL, Elia J, Erickson C, Berger S, Blum N, Uzark K, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117:2407-2423. 13. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5:97-104.
14. Winterstein AG, Gerhard T, Shuster J, Johnson M, Zito JM, Saidi A. Cardiac safety of central nervous system stimulants in children and adolescents with attentiondeficit/hyperactivity disorder. Pediatrics. 2007;120:e1494-501. 15. Olfson M, Huang C, Gerhard T, Winterstein AG, Crystal S, Allison PD, et al. Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:147-156. 16. Negrao BL, Crafford D, Viljoen M. The effect of sympathomimetic medication on cardiovascular functioning of children with attention-deficit/hyperactivity disorder. Cardiovasc J Afr. 2009;20:296-299. 17. Ilgenli TF, Congologlu A, Ozturk C, Turkbay T, Akpinar O, Kilicaslan F. Acute effect of methylphenidate on QT interval duration and dispersion in children with attention deficit hyperactivity disorder. Adv Ther. 2007;24:182-188. 18. Hill SL, El-Khayat RH, Sandilands EA, Thomas SH. Electrocardiographic effects of methylphenidate overdose. Clin Toxicol (Phila). 2010;48:342-346. 19. Mick E, McManus DD, Goldberg RJ. Meta-analysis of increased heart rate and blood pressure associated with CNS stimulant treatment of ADHD in adults. Eur Neuropsychopharmacol. 2013;23:534-541. 20. Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs. 2013;27:15-30. 21. Rohatgi RK, Bos,M., Ackerman,M.J. Stimulant Therapy in Children with Attention Deficit Hyperactivity Disorder and Concomitant Long QT Syndrome: a Safe Combination? Heart Rhythm. 2015. 22. Swan H, Toivonen L, Viitasalo M. Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Eur Heart J. 1998;19:508-513.
23. Ali RH, Zareba W, Moss AJ, Schwartz PJ, Benhorin J, Vincent GM, et al. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol. 2000;85:457-461. 24. Silva AP, Prado SO, Scardovelli TA, Boschi SR, Campos LC, Frere AF. Measurement of the effect of physical exercise on the concentration of individuals with ADHD. PLoS One. 2015;10:e0122119. 25. Ghanizadeh A, Haddad B. The effect of dietary education on ADHD, a randomized controlled clinical trial. Ann Gen Psychiatry. 2015;14:12.
