Original Article
33
Cardiac Function in Types II and III Spinal Muscular Atrophy: Should We Change Standards of Care?
1 Department of Paediatric Neurology, Catholic University, Rome, Italy 2 Department of Laboratory Medicine, Unit of Molecular Medicine,
Bambino Gesù Hospital, Rome, Italy
Address for correspondence Eugenio Mercuri, MD, Department of Paediatric Neurology Catholic University Largo Agostino Gemelli, 00168 Rome, Italy (e-mail: [email protected]).
3 Department of Neurosciences, Psychiatry and Anaesthesiology,
University of Messina, Messina, Italy 4 Department of Myopathology and Neuroimmunolgy, Pediatric
Neurology and Neuroradiology Units, Neurological Institute C. Besta, Milan, Italy 5 Department of Neurosciences and Psychiatry and Anaesthesiology, University of Padoa, Padoa, Italy 6 Neuromuscular Center, S.G. Battista Hospital, University of Turin, Turin, Italy 7 Department of Experimental Medicine, Cardiomiology and Medical Genetics, Second University of Naples, Naples, Italy 8 Developmental Neurology Unit, Neurological Institute C. Besta, Milan, Italy 9 Medical Genetics Institute, Catholic University, Rome, Italy Neuropediatrics 2015;46:33–36.
Abstract
Keywords
► SMA ► cardiac function ► standard of care
received August 8, 2014 accepted after revision September 20, 2014 published online December 24, 2014
Objective In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. Patients and Methods We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2–74 years). Of them, 82 also had echocardiography. Results None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. Conclusions Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care.
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1395348. ISSN 0174-304X.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Flaviana Bianco1 Marika Pane1 Adele D’Amico2 Sonia Messina3 Angelica Bibiana Delogu1 Gianni Soraru5 Maria Carmela Pera1 Tiziana Mongini6 Luisa Politano7 Giovanni Baranello8 Gianluca Vita3 Francesco Danilo Tiziano9 Lucia Morandi4 Enrico Bertini2 Eugenio Mercuri1
Cardiac Function in Types II and III SMA
Bianco et al.
Introduction
Patients and Methods
The spinal muscular atrophies (SMA) can be classified into three forms according to time of onset and course of the disease: the most severe form (type I) or Werdnig–Hoffmann disease, the intermediate form (type II), and the mild form (type III) or Kugelberg–Welander disease. In the last few years, there has been increasing evidence of a possible cardiac involvement in the SMA patients. After the report that heart can be involved in Kugelberg–Welander syndrome in 1971, cardiac and/or autonomic complications have been described in several SMA patients. Recent reviews of the literature1,2 have reported 23 cases of type I SMA with congenital heart defects such as atrial septal defect (ASD) or ventricular septal defect (VSD). The presence of ASD or VSD was highly correlated with the number of survival motor neuron 2 (SMN2) copies, ranging from 75% in patients with only one copy of SMN2, to 6% in those with two copies, and 0% in those with three copies.2 In another study, 15 of 63 patients affected by type I SMA (24%) had severe, symptomatic bradycardia suggesting a possible concomitant autonomic dysfunction.3,4 Clinical observations of autonomic dysfunction were mirrored by similar evidence in animal models showing bradyarrhythmia with progressive heart block and reduced ventricular depolarization efficiency in the SMNΔ7 SMA mouse model.5 Cardiac involvement in the more severe forms of SMA has also been suggested by a study investigating heart involvement at different developmental stages starting from embryos in a severe model (SMN /, SMN2 þ/þ) with a survival of 4 to 5 days and in the SMAΔ7 model.6 The study reported that the more severe model had more obvious signs of remodeling, such as the width of the interventricular septum and of the left ventricular wall and interstitial fibrosis. Cardiac signs, mainly consisting in rhythm disturbances have however also been reported in the milder form of SMA (type III). A recent review reported 12 previously published cases of SMA III with alteration of heart rate, including atrial fibrillation, atrial standstill, atrial flutter, and atrioventricular block.7 Other cases of heart rate abnormalities have also been reported with occasional cases of dilated cardiomyopathy.7,8 In contrast, a recent study performing echocardiography in types II and III SMA confirmed that only 2 of the 37 patients examined (5.4%), both above the age of 60 years, had minimal signs of dilated cardiomyopathy, without systolic dysfunction.9 Altogether, these findings raise the question whether heart rate should be routinely investigated in types II and III SMA patients. While routine cardiac examinations are part of standards of care in Duchenne muscular dystrophy or other muscular dystrophies,10 there is no suggestion of routine cardiac assessments in the recent standards of care guidelines for types II and III SMA.11–13 The aim of this study was to assess possible cardiac abnormalities in children and adults with types II and III SMA by performing 24-hour electrocardiography (ECG) and echocardiography.
The study includes two cohorts in whom cardiac assessments were available for review. The first cohort includes 78 type II and 30 type III SMA patients (age range, 2–74 years) from four centers (Rome Catholic University and Rome Ospedale Bambino Gesù, Milan, and Messina) in whom 24-hour ECG were performed as part of our policy at the time of starting treatment with albuterol. Following our previous observations that albuterol can provide an increase in muscle function14,15 all patients in our centers older than 3 years are routinely offered albuterol and undergo 24-hour ECG before starting treatment. This protocol was approved by the Ethic Committee of each center. A total of 33 consecutive patients of this cohort also had echocardiography that was routinely performed for a short period. This cohort included patients with different levels of functional abilities ranging from the weak type II, that is, those who were able to sit unsupported only for a few minutes and had limited functional abilities, to the strong type III. The second cohort includes 49 adult patients (age range, 19–56 years) from six centers (Milan, Padua, Turin, Messina, Rome Catholic University, and Naples) enrolled in a prospective study aimed at establishing the effect of albuterol on SMN transcript.16,17 As part of this study, all the patients were asked to perform 24-hour ECG, and echocardiogram at baseline and during the study. Only the assessments performed at baseline are reported in this study. This protocol was also approved by the Ethic Committee of each center.
Neuropediatrics
Vol. 46
No. 1/2015
24-Hour Electrocardiography Holter monitoring was performed using two-channel Oxford Medilog MR-4500 tape recorders (leads monitored CM1 and CM5; Oxford-Medilog of America, Incorporated, Boston, Massachusetts, United States). All patients were asked to record all activities performed during the recording. Holter tapes were analyzed by an experienced cardiologist using excel 2.0 Oxford Medilog system (Oxford Instruments, Abingdon, UK). Results of Holter monitoring were assessed in children, adolescents, and adults according to age-specific– published reference data in each center.18,19 Mean heart rate values outside the age-specific reference data, or couplets, triplets, runs, ventricular tachycardia or pause > 2.5 seconds were classified as abnormal.
Echocardiography Two-dimensional/Doppler echocardiograms were performed to investigate whether any morphological and/or functional abnormality could be detected in these patients. Echocardiographic data, collected by five different centers, were obtained in accordance with standard recommendations of the American Society of Echocardiography. All the centers used modern digital echocardiographic equipment with appropriate transducers to define the cardiac structures. Echocardiographic study included complete morphological assessment, evaluation of cardiac chamber dimensions, and functional parameters. In pediatric population, all the echo measurements were normalized for body surface area from
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
34
height and weight, and compared with published data from normal–control patients.20,21 Ejection fraction was measured for each patient and considered abnormal if below 2 standard deviations. Special attention was also paid to detect possible congenital heart defects.
Results 24-Hour Electrocardiography This was normal in the 108 patients in the first cohort including both children and adults, and in the 49 adult patients in the second cohort. All had values within the age-specific reference data, with mean heart rate between 66 and 114 beats/min (mean, 89.9; SD,11.96). None had signs of bradycardia or of any other sign of an arrhythmia.
Echocardiography Echocardiography, performed in 33 in the first cohort and in all 49 patients in the second cohort, showed no signs of congenital cardiac defects with the exception of 1 patient in the first cohort who had a history of ventricular septal defects. None had obvious signs of dilated cardiomyopathy or other abnormalities. Ejection fraction was between 58 and 79% (mean, 64.14; SD, 5.2), all within normal values of the reference data.21 None had cardiac symptoms with the exception of two adult patients in the second cohort who had hypertension requiring treatment.
Bianco et al.
patients types II and III patients scanned had signs of congenital heart defect, often found in type I SMA.4 Therefore, our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings confirm recent suggestions that patients with the milder forms of SMA have a lower chance of developing involvement of other organs, such as heart and liver, recently reported in type I SMA.6 The wide age and functional range of the patients included in the study also suggested that cardiac disturbances are unlikely to occur even in older or weaker patients. This is probably also because of the fact that weaker patients have limited functional abilities and put a relative stress on the heart. Because of the retrospective nature of the study, we cannot exclude that a prospective assessment with a more specific protocol and a control group would have allowed to detect differences with age-matched peers. However, our results were enough to exclude obvious signs of cardiac impairment requiring treatment. This study also provides for the first time 24-hour ECG and echocardiograms in a large cohort of type II patients. Further prospective and more detailed studies in this cohort may help to identify minor cardiac signs or more subtle differences with control groups. Detecting minor cardiac signs may become important if the new therapeutic strategies that are being proposed, will improve functional abilities and increase the stress on the heart.
Conclusions Discussion The cardiological findings previously reported in patients with SMA can be broadly subdivided in the following two big groups: congenital heart defects and alteration of heart rate. The congenital hearts defects have only been described in patients with the severe form of SMA (type I or Werdnig– Hoffmann disease). In contrast, heart rate abnormalities such as atrial fibrillation, A-V block, atrial flutter, etc. have been described not only in type I but also in the milder form of SMA (type III). Type II patients appear to be spared but the available data are limited to only one study reporting normal standard ECG in 37 patients with types II and III SMA.9 To detect possible obvious signs of autonomic dysfunction, we retrospectively reviewed 24-hour ECG in a large number of types II and III SMA patients of ages ranging from 2 to 74 years. None of the 157 patients included in this study had signs of bradycardia, atrial fibrillation, or of the other previously reported rhythm disturbances, regardless of the age at examination or of the type of SMA. A 24-hour ECG was normal in all, including patients at the weaker end of the spectrum of type II, that is, those who were able to sit unsupported only for a few minutes and had limited functional abilities, with inability to lift the hands at shoulder level or to roll. The results of the echocardiography study, available only in the second cohort and in a proportion of the first cohort confirmed previous findings that dilated cardiomyopathy are not frequent in SMA. With one exception, none of the 82
Our findings indicate that there is no need to modify the existing standards of care suggesting a more accurate cardiac surveillance in type II and type III patients as it is unlikely that these patients will develop obvious clinical, ECG, or echocardiographic signs of cardiomyopathy.
Acknowledgments The authors thank Dr. Antonella Spinelli, Dr. Vincenzo Giglio, and the staff of UILDM, Rome, for performing some of the echocardiograms reported in the article.
References 1 Menke LA, Poll-The BT, Clur SA, et al. Congenital heart defects in
2
3
4 5
spinal muscular atrophy type I: a clinical report of two siblings and a review of the literature. Am J Med Genet A 2008;146A(6): 740–744 Rudnik-Schöneborn S, Heller R, Berg C, et al. Congenital heart disease is a feature of severe infantile spinal muscular atrophy. J Med Genet 2008;45(10):635–638 Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E. Long-term survival in Werdnig-Hoffmann disease. Am J Phys Med Rehabil 2007;86(5):339–345, quiz 346–348, 379 Bach JR. Medical considerations of long-term survival of WerdnigHoffmann disease. Am J Phys Med Rehabil 2007;86(5):349–355 Heier CR, Satta R, Lutz C, DiDonato CJ. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet 2010;19(20):3906–3918
Neuropediatrics
Vol. 46
No. 1/2015
35
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Cardiac Function in Types II and III SMA
Cardiac Function in Types II and III SMA
Bianco et al.
6 Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL.
16 Tiziano FD, Lomastro R, Pinto AM, et al. Salbutamol increases
Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet 2010;19(20):4059–4071 Takahashi N, Shimada T, Ishibashi Y, et al. Cardiac involvement in Kugelberg-Welander disease: a case report and review. Am J Med Sci 2006;332(6):354–356 Elkohen M, Vaksmann G, Elkohen MR, Francart C, Foucher C, Rey C. Cardiac involvement in Kugelberg-Welander disease. A prospective study of 8 cases [in French]. Arch Mal Coeur Vaiss 1996;89(5): 611–617 Palladino A, Passamano L, Taglia A, et al. Cardiac involvement in patients with spinal muscular atrophies. Acta Myol 2011;30(3): 175–178 Bushby K, Finkel R, Birnkrant DJ, et al; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9(1): 77–93 Wang CH, Finkel RS, Bertini ES, et al; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007;22(8):1027–1049 Wang CH, Lunn MR. Spinal muscular atrophy: advances in research and consensus on care of patients. Curr Treat Options Neurol 2008; 10(6):420–428 Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol 2012;11(5): 443–452 Kinali M, Mercuri E, Main M, et al. Pilot trial of albuterol in spinal muscular atrophy. Neurology 2002;59(4):609–610 Pane M, Staccioli S, Messina S, et al. Daily salbutamol in young patients with SMA type II. Neuromuscul Disord 2008;18(7):536–540
survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design. J Med Genet 2010;47(12):856–858 Tiziano FD, Lomastro R, Di Pietro L, et al. Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study. Eur J Hum Genet 2013;21(6):630–636 Kadish AH, Buxton AE, Kennedy HL, et al. ACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiography. A report of the ACC/AHA/ACP-ASIM Task Force on Clinical Competence (ACC/AHA Committee to Develop a Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography). J Am Coll Cardiol 2001;38(7): 2091–2100 Southall DP, Johnston F, Shinebourne EA, Johnston PG. 24-hour electrocardiographic study of heart rate and rhythm patterns in population of healthy children. Br Heart J 1981;45(3):281–291 Quiñones MA, Douglas PS, Foster E, et al; American College of Cardiology; American Heart Association; American College of Physicians-American Society of Internal Medicine; American Society of Echocardiography; Society of Cardiovascular Anesthesiologists; Society of Pediatric Echocardiography. ACC/AHA clinical competence statement on echocardiography: a report of the American College of Cardiology/American Heart Association/ American College of Physicians-American Society of Internal Medicine Task Force on Clinical Competence. J Am Coll Cardiol 2003;41(4):687–708 Kampmann C, Wiethoff CM, Wenzel A, et al. Normal values of M mode echocardiographic measurements of more than 2000 healthy infants and children in central Europe. Heart 2000; 83(6):667–672
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33
Cardiac Function in Types II and III Spinal Muscular Atrophy: Should We Change Standards of Care?
1 Department of Paediatric Neurology, Catholic University, Rome, Italy 2 Department of Laboratory Medicine, Unit of Molecular Medicine,
Bambino Gesù Hospital, Rome, Italy
Address for correspondence Eugenio Mercuri, MD, Department of Paediatric Neurology Catholic University Largo Agostino Gemelli, 00168 Rome, Italy (e-mail: [email protected]).
3 Department of Neurosciences, Psychiatry and Anaesthesiology,
University of Messina, Messina, Italy 4 Department of Myopathology and Neuroimmunolgy, Pediatric
Neurology and Neuroradiology Units, Neurological Institute C. Besta, Milan, Italy 5 Department of Neurosciences and Psychiatry and Anaesthesiology, University of Padoa, Padoa, Italy 6 Neuromuscular Center, S.G. Battista Hospital, University of Turin, Turin, Italy 7 Department of Experimental Medicine, Cardiomiology and Medical Genetics, Second University of Naples, Naples, Italy 8 Developmental Neurology Unit, Neurological Institute C. Besta, Milan, Italy 9 Medical Genetics Institute, Catholic University, Rome, Italy Neuropediatrics 2015;46:33–36.
Abstract
Keywords
► SMA ► cardiac function ► standard of care
received August 8, 2014 accepted after revision September 20, 2014 published online December 24, 2014
Objective In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. Patients and Methods We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2–74 years). Of them, 82 also had echocardiography. Results None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. Conclusions Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care.
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1395348. ISSN 0174-304X.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Flaviana Bianco1 Marika Pane1 Adele D’Amico2 Sonia Messina3 Angelica Bibiana Delogu1 Gianni Soraru5 Maria Carmela Pera1 Tiziana Mongini6 Luisa Politano7 Giovanni Baranello8 Gianluca Vita3 Francesco Danilo Tiziano9 Lucia Morandi4 Enrico Bertini2 Eugenio Mercuri1
Cardiac Function in Types II and III SMA
Bianco et al.
Introduction
Patients and Methods
The spinal muscular atrophies (SMA) can be classified into three forms according to time of onset and course of the disease: the most severe form (type I) or Werdnig–Hoffmann disease, the intermediate form (type II), and the mild form (type III) or Kugelberg–Welander disease. In the last few years, there has been increasing evidence of a possible cardiac involvement in the SMA patients. After the report that heart can be involved in Kugelberg–Welander syndrome in 1971, cardiac and/or autonomic complications have been described in several SMA patients. Recent reviews of the literature1,2 have reported 23 cases of type I SMA with congenital heart defects such as atrial septal defect (ASD) or ventricular septal defect (VSD). The presence of ASD or VSD was highly correlated with the number of survival motor neuron 2 (SMN2) copies, ranging from 75% in patients with only one copy of SMN2, to 6% in those with two copies, and 0% in those with three copies.2 In another study, 15 of 63 patients affected by type I SMA (24%) had severe, symptomatic bradycardia suggesting a possible concomitant autonomic dysfunction.3,4 Clinical observations of autonomic dysfunction were mirrored by similar evidence in animal models showing bradyarrhythmia with progressive heart block and reduced ventricular depolarization efficiency in the SMNΔ7 SMA mouse model.5 Cardiac involvement in the more severe forms of SMA has also been suggested by a study investigating heart involvement at different developmental stages starting from embryos in a severe model (SMN /, SMN2 þ/þ) with a survival of 4 to 5 days and in the SMAΔ7 model.6 The study reported that the more severe model had more obvious signs of remodeling, such as the width of the interventricular septum and of the left ventricular wall and interstitial fibrosis. Cardiac signs, mainly consisting in rhythm disturbances have however also been reported in the milder form of SMA (type III). A recent review reported 12 previously published cases of SMA III with alteration of heart rate, including atrial fibrillation, atrial standstill, atrial flutter, and atrioventricular block.7 Other cases of heart rate abnormalities have also been reported with occasional cases of dilated cardiomyopathy.7,8 In contrast, a recent study performing echocardiography in types II and III SMA confirmed that only 2 of the 37 patients examined (5.4%), both above the age of 60 years, had minimal signs of dilated cardiomyopathy, without systolic dysfunction.9 Altogether, these findings raise the question whether heart rate should be routinely investigated in types II and III SMA patients. While routine cardiac examinations are part of standards of care in Duchenne muscular dystrophy or other muscular dystrophies,10 there is no suggestion of routine cardiac assessments in the recent standards of care guidelines for types II and III SMA.11–13 The aim of this study was to assess possible cardiac abnormalities in children and adults with types II and III SMA by performing 24-hour electrocardiography (ECG) and echocardiography.
The study includes two cohorts in whom cardiac assessments were available for review. The first cohort includes 78 type II and 30 type III SMA patients (age range, 2–74 years) from four centers (Rome Catholic University and Rome Ospedale Bambino Gesù, Milan, and Messina) in whom 24-hour ECG were performed as part of our policy at the time of starting treatment with albuterol. Following our previous observations that albuterol can provide an increase in muscle function14,15 all patients in our centers older than 3 years are routinely offered albuterol and undergo 24-hour ECG before starting treatment. This protocol was approved by the Ethic Committee of each center. A total of 33 consecutive patients of this cohort also had echocardiography that was routinely performed for a short period. This cohort included patients with different levels of functional abilities ranging from the weak type II, that is, those who were able to sit unsupported only for a few minutes and had limited functional abilities, to the strong type III. The second cohort includes 49 adult patients (age range, 19–56 years) from six centers (Milan, Padua, Turin, Messina, Rome Catholic University, and Naples) enrolled in a prospective study aimed at establishing the effect of albuterol on SMN transcript.16,17 As part of this study, all the patients were asked to perform 24-hour ECG, and echocardiogram at baseline and during the study. Only the assessments performed at baseline are reported in this study. This protocol was also approved by the Ethic Committee of each center.
Neuropediatrics
Vol. 46
No. 1/2015
24-Hour Electrocardiography Holter monitoring was performed using two-channel Oxford Medilog MR-4500 tape recorders (leads monitored CM1 and CM5; Oxford-Medilog of America, Incorporated, Boston, Massachusetts, United States). All patients were asked to record all activities performed during the recording. Holter tapes were analyzed by an experienced cardiologist using excel 2.0 Oxford Medilog system (Oxford Instruments, Abingdon, UK). Results of Holter monitoring were assessed in children, adolescents, and adults according to age-specific– published reference data in each center.18,19 Mean heart rate values outside the age-specific reference data, or couplets, triplets, runs, ventricular tachycardia or pause > 2.5 seconds were classified as abnormal.
Echocardiography Two-dimensional/Doppler echocardiograms were performed to investigate whether any morphological and/or functional abnormality could be detected in these patients. Echocardiographic data, collected by five different centers, were obtained in accordance with standard recommendations of the American Society of Echocardiography. All the centers used modern digital echocardiographic equipment with appropriate transducers to define the cardiac structures. Echocardiographic study included complete morphological assessment, evaluation of cardiac chamber dimensions, and functional parameters. In pediatric population, all the echo measurements were normalized for body surface area from
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
34
height and weight, and compared with published data from normal–control patients.20,21 Ejection fraction was measured for each patient and considered abnormal if below 2 standard deviations. Special attention was also paid to detect possible congenital heart defects.
Results 24-Hour Electrocardiography This was normal in the 108 patients in the first cohort including both children and adults, and in the 49 adult patients in the second cohort. All had values within the age-specific reference data, with mean heart rate between 66 and 114 beats/min (mean, 89.9; SD,11.96). None had signs of bradycardia or of any other sign of an arrhythmia.
Echocardiography Echocardiography, performed in 33 in the first cohort and in all 49 patients in the second cohort, showed no signs of congenital cardiac defects with the exception of 1 patient in the first cohort who had a history of ventricular septal defects. None had obvious signs of dilated cardiomyopathy or other abnormalities. Ejection fraction was between 58 and 79% (mean, 64.14; SD, 5.2), all within normal values of the reference data.21 None had cardiac symptoms with the exception of two adult patients in the second cohort who had hypertension requiring treatment.
Bianco et al.
patients types II and III patients scanned had signs of congenital heart defect, often found in type I SMA.4 Therefore, our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings confirm recent suggestions that patients with the milder forms of SMA have a lower chance of developing involvement of other organs, such as heart and liver, recently reported in type I SMA.6 The wide age and functional range of the patients included in the study also suggested that cardiac disturbances are unlikely to occur even in older or weaker patients. This is probably also because of the fact that weaker patients have limited functional abilities and put a relative stress on the heart. Because of the retrospective nature of the study, we cannot exclude that a prospective assessment with a more specific protocol and a control group would have allowed to detect differences with age-matched peers. However, our results were enough to exclude obvious signs of cardiac impairment requiring treatment. This study also provides for the first time 24-hour ECG and echocardiograms in a large cohort of type II patients. Further prospective and more detailed studies in this cohort may help to identify minor cardiac signs or more subtle differences with control groups. Detecting minor cardiac signs may become important if the new therapeutic strategies that are being proposed, will improve functional abilities and increase the stress on the heart.
Conclusions Discussion The cardiological findings previously reported in patients with SMA can be broadly subdivided in the following two big groups: congenital heart defects and alteration of heart rate. The congenital hearts defects have only been described in patients with the severe form of SMA (type I or Werdnig– Hoffmann disease). In contrast, heart rate abnormalities such as atrial fibrillation, A-V block, atrial flutter, etc. have been described not only in type I but also in the milder form of SMA (type III). Type II patients appear to be spared but the available data are limited to only one study reporting normal standard ECG in 37 patients with types II and III SMA.9 To detect possible obvious signs of autonomic dysfunction, we retrospectively reviewed 24-hour ECG in a large number of types II and III SMA patients of ages ranging from 2 to 74 years. None of the 157 patients included in this study had signs of bradycardia, atrial fibrillation, or of the other previously reported rhythm disturbances, regardless of the age at examination or of the type of SMA. A 24-hour ECG was normal in all, including patients at the weaker end of the spectrum of type II, that is, those who were able to sit unsupported only for a few minutes and had limited functional abilities, with inability to lift the hands at shoulder level or to roll. The results of the echocardiography study, available only in the second cohort and in a proportion of the first cohort confirmed previous findings that dilated cardiomyopathy are not frequent in SMA. With one exception, none of the 82
Our findings indicate that there is no need to modify the existing standards of care suggesting a more accurate cardiac surveillance in type II and type III patients as it is unlikely that these patients will develop obvious clinical, ECG, or echocardiographic signs of cardiomyopathy.
Acknowledgments The authors thank Dr. Antonella Spinelli, Dr. Vincenzo Giglio, and the staff of UILDM, Rome, for performing some of the echocardiograms reported in the article.
References 1 Menke LA, Poll-The BT, Clur SA, et al. Congenital heart defects in
2
3
4 5
spinal muscular atrophy type I: a clinical report of two siblings and a review of the literature. Am J Med Genet A 2008;146A(6): 740–744 Rudnik-Schöneborn S, Heller R, Berg C, et al. Congenital heart disease is a feature of severe infantile spinal muscular atrophy. J Med Genet 2008;45(10):635–638 Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E. Long-term survival in Werdnig-Hoffmann disease. Am J Phys Med Rehabil 2007;86(5):339–345, quiz 346–348, 379 Bach JR. Medical considerations of long-term survival of WerdnigHoffmann disease. Am J Phys Med Rehabil 2007;86(5):349–355 Heier CR, Satta R, Lutz C, DiDonato CJ. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet 2010;19(20):3906–3918
Neuropediatrics
Vol. 46
No. 1/2015
35
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Cardiac Function in Types II and III SMA
Cardiac Function in Types II and III SMA
Bianco et al.
6 Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL.
16 Tiziano FD, Lomastro R, Pinto AM, et al. Salbutamol increases
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