dic ABC Imagem Cardiovascular Arq Bras Cardiol: Imagem cardiovasc. 2675-312X Sociedade Brasileira de Cardiologia 2675-312X/20223501eabc292 10.47593/2675-312X/20223501eabc292 My Approach To My approach to diagnosis of and echocardiographic follow-up for muscular dystrophies Cirino Raphael Henrique Déa 1 Ducci Renata Dal-Prá 2 Federal University of Paraná Hospital das Clínicas Department of Clinical Medicine – Cardiology Service Curitiba PR Brazil Hospital das Clínicas of the Federal University of Paraná – Department of Clinical Medicine – Cardiology Service, Curitiba, PR, Brazil. Federal University of Paraná Hospital das Clínicas Department of Clinical Medicine – Neuromuscular Disease Service Curitiba PR Brazil Hospital das Clínicas of the Federal University of Paraná – Department of Clinical Medicine – Neuromuscular Disease Service, Curitiba, PR, Brazil Mailing Address: Raphael Henrique Déa Cirino • Rua Herculano Carlos Franco de Souza, 550, apto. 204-A, Água Verde. CEP 80240-290 – Curitiba, PR, Brazil. E-mail: rapha_cirino@yahoo.com.br

Authors’ contributions

Manuscript writing and critical review: Cirino RHD and Ducci RD.

Conflict of interest

The authors have declared that they have no conflict of interest.

 30 03 2022 2022 35 1 eabc292 13 02 2022 14 02 2022 16 02 2022 This is an open-access article distributed under the terms of the Creative Commons Attribution License Keywords: Muscular dystrophies Cardiomyopathy, dilated Echocardiography Introduction

Muscular dystrophies (MD) are a group of heterogeneous diseases genetically determined and characterized by progressive muscle atrophy and weakness. Mutations in genes encoding muscle fiber proteins lead to the development of MD. MD types vary by deficient protein, each with its natural history and characteristic clinical presentation. As with other clinical aspects, cardiac involvement is also quite variable.1 , 2

This article will review the most important aspects of the clinical-echocardiographic follow-up of MD types frequently associated with cardiomyopathies, including dystrophinopathy, limb-girdle muscular dystrophy (LGMD), myotonic dystrophy, and Emery-Dreifuss muscular dystrophy (EDMD).

 General aspects related to the clinical and echocardiographic diagnosis of MD

The clinical diagnosis of MD considers symptom progression, family history, and, in most cases, a genetic study and/or immunohistochemical analysis for its confirmation and classification ( Table 1 ).1 , 2 These patients usually present no cardiomyopathy-related symptoms and signs due to functional limitations caused by muscle weakness. In this context, echocardiography is an essential tool in MD management because, in addition to being widely available and of low cost, it assesses anatomic-functional characteristics of the heart and detects preclinical changes.3

Genetic aspects, pathogenesis and typical echocardiographic findings typical of muscular dystrophies most often associated with cardiomyopathy.
Classification Inheritance Gene Pathogenesis Non-Cardiac Clinical Manifestations Typical Echocardiographic Findings
Dystrophinopathies Duchenne Muscular Dystrophy X-linked recessive DMD Total dystrophin deficiency Delayed walking Proximal lower limb muscle weakness with onset before 5 years of age and rapid progression to walking disability (usually before 12 years of age) Proximal upper limb muscle weakness LV dilatation LV systolic dysfunction Predilection towards impairment of the LV inferolateral wall GLS reduction, especially of the basal segments of the inferior, inferolateral, anterolateral, and anterior walls
Becker Muscular Dystrophy X-linked recessive DMD Partial dystrophin deficiency Similar to DMD, but with onset around 10 years of age and slower progression
Myotonic Dystrophies Type 1 Autosomal dominant DMPK CTG repeat expansion Distal muscular weakness associated with facial muscular weakness, with eyelid ptosis and myotonic phenomenon Systemic manifestations: cataract, insulin resistance, gonadal failure and baldness. It may start at birth (congenital), in childhood or in adulthood LV systolic function Decreased GLS, especially apical longitudinal strain LV diastolic dysfunction with normal LA Mitral valve prolapse Pericardial effusion
Type 2 Autosomal dominant CNBP/ZNF9 CCTG repeat expansion Proximal muscle weakness Less intense symptoms and slower progression than in myotonic dystrophy type 1. It does not start in childhood
Limb-girdle Muscular Dystrophies Laminopathy (LGMD1) Autosomal dominant LMNA Lamin A/C deficiency Limb-girdle muscle weakness beginning in childhood through the fourth decade of life LV dilatation LV systolic and diastolic dysfunction
Sarcoglycanopathies (LGMD2C-F) Autosomal recessive SGCG SGCA SGCB SGCD Beta-sarcoglycan/gamma-sarcoglycan deficiency
Fukutinopathy (LGMD2I) Autosomal recessive FKRP Fukutin-related protein deficiency
Emery-Dreifuss Muscular Dystrophy Type 1 X-linked recessive EMD/FHL1 Emerin/FHL1 deficiency Humerus-peroneal muscle weakness associated with early prominent joint contractures (neck extension, elbow flexion and ankle flexion) with onset in childhood Predominance of biatrial dilatation over LV dilatation Atrial standstill and increased cardioembolic risk LV systolic and diastolic dysfunction
Type 2 Autosomal dominant/recessive LMNA Lamin A/C deficiency

CNBP/ZNF9: Cellular Nucleic Acid-binding Protein/Zinc Finger Protein 9; CTG: Cytosine-Thymine-Guanine; DMD: Duchenne Muscular Dystrophy; DMPK: Myotonic Dystrophy Protein Kinase; FHL1: Four And A Half LIM Domains 1; FKRP: Fukutin Related Protein LGMD: Limb-girdle Muscular Dystrophy; GLS: Global longitudinal strain; CNS: Central Nervous System.

Due to the development of new specific therapies, the increased survival of patients with some types of MD has made cardiological complications the leading cause of morbidity and mortality. For this reason, the early detection of cardiac changes and the introduction of cardiomyopathy-directed therapy have become essential.3 , 4

 Dystrophinopathy cardiac presentation and echocardiographic findings

Duchenne MD (DMD) is the most common neuromuscular disease in children and reflects the most severe spectrum of dystrophinopathies, which also include Becker MD and asymptomatic female carriers of the DMD gene mutation4 . Clinical cardiological presentations are characterized by dilated cardiomyopathy (DCM) and its complications and can occur in any spectrum of dystrophinopathy without a correlation with peripheral muscle involvement severity.4 , 5

In recent years, the role of echocardiography in assessing dystrophinopathies has been questioned, as some studies demonstrated the superiority of cardiac magnetic resonance imaging (cMRI).6 Despite this, and considering the limitations inherent to cMRI, echocardiography remains valuable in the routine evaluation of these patients for being widely available, being of low cost, and presenting no severe adverse effects.7 , 8 Studies comparing echocardiography with cMRI show that left ventricular (LV) fractional shortening6 , 9 and LV ejection fraction (LVEF) by the area-length method6 are the echocardiographic parameters used to assess LV systolic function that best correlate with cMRI.

Typical echocardiographic findings are LV dilation and systolic dysfunction, which define the DCM phenotype ( Figure 1 ).4 , 5 Characteristic dystrophinopathy changes include segmental contractility changes with a predilection for LV inferolateral wall involvement.4 , 5 Myocardial strain evaluated by speckle tracking also shows changes versus healthy individuals, with reduced global longitudinal (GLS) ( Figures 2 and 3 ),4 , 7 , 10 , 11 global circumferential,7 , 11 and global radial strains, especially the basal segments of the inferior, inferolateral, anterolateral and anterior walls.7 , 11 One study also demonstrated reduced three-dimensional myocardial strain in the longitudinal, circumferential, or radial axis.12 A recent meta-analysis determined that GLS, the most studied and most reliable echocardiographic parameter for the early detection of LV systolic dysfunction,13 can be reduced in up to to 50% of DMD patients with a normal LVEF.8 As for LV diastolic dysfunction, DMD patients present lower septal and lateral e’ waves values and higher E/e' ratios than controls11 but do not meet echocardiographic criteria for significant LV diastolic dysfunction. The functions of the right chambers are usually preserved.7

Dilated cardiomyopathy phenotype in a 15-year-old ambulatory patient with Becker muscular dystrophy. Left ventricular (LV) longitudinal strain analysis in apical four- (A), two- (B), and three-chamber (C) views, and LV global longitudinal strain (D) of a patient with Duchenne muscular dystrophy with a normal LV ejection fraction and a reduced global longitudinal strain (-17%). Global longitudinal strain (GLS) study of three Duchenne muscular dystrophy patients: (1) Male 10-year-old patient, symptom onset 5 years previous, ambulatory, preserved left ventricular (LV) systolic function, LV ejection fraction (LVEF) of 65%, and GLS of -20%; (2) male 12-year-old patient, symptom onset 10 years previous, wheelchair user, early LV systolic dysfunction, LVEF of 58%, and GLS of -14%; and (3) male 17-year-old patient, symptom onset 15 years prior, wheelchair user, overt LV systolic dysfunction, LVEF of 34%, and GLS of -14%.

Electrocardiography and transthoracic echocardiography are recommended at diagnosis, every two years before 10 years of age, and annually thereafter. Thus, cMRI should always be considered, especially in older patients with poorer echocardiographic image quality, and many clinicians advocate annual cMRI, especially in patients who already have dystrophinopathy-related cardiomyopathy.4 , 6

 Cardiac presentation and echocardiographic findings in myotonic dystrophy

Myotonic dystrophies are the most common hereditary MD in adults, being characterized by multisystem involvement.14 , 15 The most characteristic cardiac presentation is arrhythmia, including conduction disorders, atrial and ventricular tachyarrhythmias, sudden cardiac death, and less frequently DCM.14 , 16 These complications are more common in type 1 than in type 2,1 , 15 , 17 accounting for about 30% of deaths in myotonic dystrophy type 1 patients.14

Echocardiographic changes vary and may include LV dilation, systolic dysfunction, and excessive trabeculation; LV hypertrophy and diastolic dysfunction; and mitral valve prolapse.14 Mitral, aortic, and tricuspid valve sclerosis may also be observed in addition to pericardial effusion.14 , 15 The prevalence of LV systolic dysfunction is 13.8% in type 1 myotonic dystrophy.14 , 15 LV systolic dysfunction presence and severity help in the decision to implant intracardiac devices, such as a pacemaker and implantable cardioverter-defibrillator as they are predictors of conduction disorders and severe tachyarrhythmias.14 LV GLS is the most reliable parameter for the early detection of systolic dysfunction, with a reduced apical longitudinal strain being the most characteristic finding.19

Due to the scarcity of symptoms, the high prevalence of subclinical electrocardiographic and echocardiographic changes and the worse prognosis due to these changes, we recommend assessment at the time of diagnosis followed by an annual routine assessment with ECG, 24-hour Holter monitoring, and transthoracic echocardiography and consider early primary prevention with the implantation of intracardiac devices such as a pacemaker and implantable cardioverter-defibrillator.17 , 19

 Cardiac presentation and echocardiographic findings in LGMD

LGMD is a group of diseases characterized by pelvic and scapular girdle atrophy and weakness.1 , 16 , 17 Those most frequently associated with cardiomyopathy are laminopathy (LGMD1B), sarcoglycanopathy (LGMD2C-F), and fukutinopathy (LGMD2I).1 , 17 , 20 Cardiac clinical presentations resemble those of other MD, including DCM, cardiac arrhythmias, and sudden cardiac death.1 , 17

DCM is the most characteristic echocardiographic pattern, featuring LV dilation and systolic and diastolic dysfunction,20 with an LVEF < 50% occurring in about 80%, 50%, and 39–45% of patients with LGMD2E (beta-sarcoglycanopathy), LGMD2C (gamma-sarcoglycanopathy), and LGMD2I, respectively.17 , 21 , 22 , 23

Recommendations about the frequency of echocardiographic assessment in LGMD are based on expert consensus.17 In our practice, we perform ECG and transthoracic echocardiography at diagnosis and annually thereafter. More studies are needed to investigate the benefits of myocardial strain and other recent echocardiographic techniques in LGMD.

 Cardiac presentation and echocardiographic findings in EDMD

EDMD is a rare disease characterized by a high frequency of cardiac involvement that usually presents as supraventricular and ventricular arrhythmias, conduction disorders, chamber dilation, and systolic dysfunction.1 , 2 , 16 , 24 , 25

The most common echocardiographic findings in EDMD patients characterize the DCM phenotype and include LV dilatation and systolic dysfunction, LV diastolic dysfunction, and bi-atrial enlargement. Atrial standstill and an increased risk of embolic phenomena may also occur.16 Marchel et al . demonstrated that up to 41% of EDMD patients (median age, 43 years) had LV dilation and 32% had an LVEF lower than 50%. Atrial enlargement is present in more than 2/3 of cases and predominates over ventricular dilation. Echocardiographic changes are similar in EDMD types 1 and 2 despite LMNA gene mutations being more frequently associated with DCM, heart failure and sudden cardiac death, regardless of the presence of peripheral skeletal muscle involvement.24

The frequency of echocardiographic assessment is not well established, but in our clinical practice, we recommend ECG, 24-hour Holter monitoring, and transthoracic echocardiography at diagnosis and annually thereafter. The literature is scarce on the use of new echocardiographic techniques such as myocardial strain in EDMD. Due to the high risk of conduction disorders, ventricular arrhythmias, and sudden cardiac death associated with EDMD, cardiac screening of first-degree relatives and asymptomatic carriers should be performed routinely. For the same reason, an implantable cardioverter-defibrillator should be considered for primary prevention in EDMD type 2.17

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Evaluation of early left ventricular dysfunction in patients with Duchenne muscular dystrophy using two-dimensional speckle tracking echocardiography and tissue Doppler imaging. Pediatr Cardiol. 2018;39(8):1614-1619. doi: https://doi.org/10.1007/s00246-018-1938-0 Yu H Xia B Liu X Han C Chen W Li Z Initial application of three-dimensional speckle-tracking echocardiography to detect subclinical left ventricular dysfunction and stratify cardiomyopathy associated with Duchenne muscular dystrophy in children Int J Cardiovasc Imaging 2019 35 1 67 76 https://doi.org/10.1007/s10554-018-1436-8 12 Yu H, Xia B, Liu X, Han C, Chen W, Li Z. Initial application of three-dimensional speckle-tracking echocardiography to detect subclinical left ventricular dysfunction and stratify cardiomyopathy associated with Duchenne muscular dystrophy in children. Int J Cardiovasc Imaging. 2019;35(1):67-76. doi: https://doi.org/10.1007/s10554-018-1436-8 Song G Zhang J Wang X Zhang X Sun F Yu X Usefulness of speckle-tracking echocardiography for early detection in children with Duchenne muscular dystrophy: a meta-analysis and trial sequential analysis Cardiovasc Ultrasound 2020 18 1 26 26 https://doi.org/10.1186/s12947-020-00209-y 13 Song G, Zhang J, Wang X, Zhang X, Sun F, Yu X. Usefulness of speckle-tracking echocardiography for early detection in children with Duchenne muscular dystrophy: a meta-analysis and trial sequential analysis. Cardiovasc Ultrasound. 2020;18(1):26. doi: https://doi.org/10.1186/s12947-020-00209-y Lau JK Sy RW Corbett A Kritharides L Myotonic dystrophy and the heart: A systematic review of evaluation and management Int J Cardiol. 2015 184 600 608 https://doi.org/10.1016/j.ijcard.2015.03.069 14 Lau JK, Sy RW, Corbett A, Kritharides L. Myotonic dystrophy and the heart: A systematic review of evaluation and management. Int J Cardiol. 2015;184:600-608. doi: https://doi.org/10.1016/j.ijcard.2015.03.069 Peric S Bjelica B Aleksic K Kovacevic M Cvitan E Stojmenovic GM Heart involvement in patients with myotonic dystrophy type 2 Acta Neurol Belg 2019 119 1 77 82 https://doi.org/10.1007/s13760-018-1052-3 15 Peric S, Bjelica B, Aleksic K, Kovacevic M, Cvitan E, Stojmenovic GM, et al. Heart involvement in patients with myotonic dystrophy type 2. Acta Neurol Belg. 2019;119(1):77-82. doi: https://doi.org/10.1007/s13760-018-1052-3 Arbustini E Di Toro A Giuliani L Favalli V Narula N Grasso M Cardiac phenotypes in hereditary muscle disorders J Am Coll Cardiol 2018 72 20 2485 2506 https://doi.org/10.1016/j.jacc.2018.08.2182 16 Arbustini E, Di Toro A, Giuliani L, Favalli V, Narula N, Grasso M. Cardiac phenotypes in hereditary muscle disorders. J Am Coll Cardiol. 2018;72(20):2485-2506. doi: https://doi.org/10.1016/j.jacc.2018.08.2182 Feingold B Mahle WT Auerbach S Clemens P Domenighetti AA Jefferies JL Management of cardiac involvement associated with neuromuscular diseases: a scientific statement from the American Heart Association Circulation 2017 136 13 e200 e231 https://doi.org/10.1161/CIR.0000000000000526 17 Feingold B, Mahle WT, Auerbach S, Clemens P, Domenighetti AA, Jefferies JL, et al. Management of cardiac involvement associated with neuromuscular diseases: a scientific statement from the American Heart Association. Circulation. 2017;136(13):e200-e231. doi: https://doi.org/10.1161/CIR.0000000000000526 Russo V Sperlongano S Gallinoro E Rago A Papa AA Golino P Prevalence of left ventricular systolic dysfunction in myotonic dystrophy type 1: a systematic review J Card Fail 2020 26 10 849 856 https://doi.org/10.1016/j.cardfail.2019.07.548 18 Russo V, Sperlongano S, Gallinoro E, Rago A, Papa AA, Golino P, et al. Prevalence of left ventricular systolic dysfunction in myotonic dystrophy type 1: a systematic review. J Card Fail. 2020;26(10):849-856. doi: https://doi.org/10.1016/j.cardfail.2019.07.548 Garcia R Labarre Q Degand B Ingrand P Gal FL Bonnet B Apical left ventricular myocardial dysfunction is an early feature of cardiac involvement in myotonic dystrophy type 1 Echocardiography 2017 34 2 184 190 https://doi.org/10.1111/echo.13426 19 Garcia R, Labarre Q, Degand B, Ingrand P, Gal FL, Bonnet B, et al. Apical left ventricular myocardial dysfunction is an early feature of cardiac involvement in myotonic dystrophy type 1. Echocardiography. 2017;34(2):184-190. doi: https://doi.org/10.1111/echo.13426 Van Westrum SM Dekker LR Voogt WG Wilde AA Ginjaar IB Visser M Cardiac involvement in Dutch patients with sarcoglycanopathy: a cross-sectional cohort and follow-up study Muscle Nerve 2014 50 6 909 913 10.1002/mus.24233 20 Van Westrum SM, Dekker LR, Voogt WG, Wilde AA, Ginjaar IB, Visser M, et al. Cardiac involvement in Dutch patients with sarcoglycanopathy: a cross-sectional cohort and follow-up study. Muscle Nerve. 2014;50(6):909-13. 10.1002/mus.24233 Petri H Sveen ML Thune JJ Vissing C Dahlqvist JR Witting N Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies: a 9-year follow-up study Int J Cardiol 2015 03 01 182 403 411 https://doi.org/10.1016/j.ijcard.2014.12.090 21 Petri H, Sveen ML, Thune JJ, Vissing C, Dahlqvist JR, Witting N, et al. Progression of cardiac involvement in patients with limb-girdle type 2 and Becker muscular dystrophies: a 9-year follow-up study. Int J Cardiol. 2015. Mar 1;182:403-11. doi: https://doi.org/10.1016/j.ijcard.2014.12.090 Fayssoil A Nardi O Annane D Orlikowski D Left ventricular function in alpha-sarcoglycanopathy and gamma-sarcoglycanopathy Acta Neurol Belg 2014 114 4 257 259 https://doi.org/10.1007/s13760-013-0276-5 22 Fayssoil A, Nardi O, Annane D, Orlikowski D. Left ventricular function in alpha-sarcoglycanopathy and gamma-sarcoglycanopathy. Acta Neurol Belg. 2014;114(4):257-9. doi: https://doi.org/10.1007/s13760-013-0276-5 Libell EM Richardson JA Lutz KL Ng BY Mockler SR Laubscher KM Cardiomyopathy in limb girdle muscular dystrophy R9, FKRP related Muscle Nerve 2020 62 5 626 632 https://doi.org/10.1002/mus.27052 23 Libell EM, Richardson JA, Lutz KL, Ng BY, Mockler SR, Laubscher KM, et al. Cardiomyopathy in limb girdle muscular dystrophy R9, FKRP related. Muscle Nerve. 2020;62(5):626-632. doi: https://doi.org/10.1002/mus.27052 Marchel M Madej-Pilarczyk A Tyminska A Steckiewicz R Kochanowski J Wysinska J Echocardiographic features of cardiomyopathy in Emery-Dreifuss muscular dystrophy Cardiol Res Pract 2021 2021 8812044 8812044 https://doi.org/10.1155/2021/8812044 24 Marchel M, Madej-Pilarczyk A, Tyminska A, Steckiewicz R, Kochanowski J, Wysinska J, et al. Echocardiographic features of cardiomyopathy in Emery-Dreifuss muscular dystrophy. Cardiol Res Pract. 2021;2021:8812044. doi: https://doi.org/10.1155/2021/8812044 Wang S Daoquan P Cardiac involvement in Emery-Dreifuss muscular dystrophy and related management strategies Int Heart J 2019 60 1 12 18 https://doi.org/10.1536/ihj.17-604 25 Wang S, Daoquan P. Cardiac involvement in Emery-Dreifuss muscular dystrophy and related management strategies. Int Heart J. 2019;60(1):12-18. doi: https://doi.org/10.1536/ihj.17-604 Como Eu Faço Como Eu Faço Diagnóstico e Seguimento Ecocardiográfico nas Distrofias Musculares Cirino Raphael Henrique Déa 1 Ducci Renata Dal-Prá 2 Curitiba PR Brasil Serviço de Cardiologia, Departamento de Clínica Médica, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, PR, Brasil. Curitiba PR Brasil Serviço de Doenças Neuromusculares, Departamento de Clínica Médica, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, PR, Brasil. Correspondência: Raphael Henrique Déa Cirino • Rua Herculano Carlos Franco de Souza, 550, apto. 204-A, Água Verde. CEP 80240-290 – Curitiba, PR, Brasil. E-mail: rapha_cirino@yahoo.com.br

Contribuição dos autores

Redação e revisão crítica do manuscrito: Cirino RHD e Ducci RD.

Conflito de interesses

Os autores declaram não terem conflitos de interesse.

 Palavras-chave: Distrofias musculares Cardiomiopatia dilatada Ecocardiografia Introdução

As distrofias musculares (DM) são um grupo de doenças heterogêneas, determinadas geneticamente e caracterizadas por atrofia e fraqueza muscular progressivas. Mutações em genes que codificam proteínas da fibra muscular são responsáveis pelo desenvolvimento das DM. Existem diversos tipos de DM, a depender da proteína deficiente, cada qual com sua história natural e suas manifestações clínicas características. Assim como os demais aspectos clínicos, o acometimento cardíaco também é bastante variável.1 , 2

Neste trabalho, revisamos os aspectos mais importantes do seguimento clínico-ecocardiográfico das DM mais frequentemente associadas à cardiomiopatia, dentre elas as distrofinopatias, as DM de cintura (DMC), as distrofias miotônicas e a DM de Emery-Dreifuss (EDMD).

 Aspectos gerais relacionados ao diagnóstico clínico e ecocardiográfico das distrofias musculares

O diagnóstico clínico é realizado considerando a evolução dos sintomas e a história familiar, e, na maioria dos casos, o estudo genético e/ou a análise imunoistoquímica confirmam o diagnóstico e auxiliam na classificação da DM ( Tabela 1 ).1 , 2

Aspectos Genéticos, Patogênese e Achados Ecocardiográficos Típicos das Distrofias Musculares mais Frequentemente Associadas à Cardiomiopatia.
Classificação Herança Gene Patogênese Manifestações Clínicas Não Cardíacas Achados Ecocardiográficos Típicos
Distrofinopatias Distrofia Muscular de Duchenne Recessiva ligada ao X DMD Deficiência total de distrofina Atraso na aquisição da marcha Fraqueza muscular proximal de membros inferiores de início antes dos 5 anos e rápida evolução para perda da deambulação (geralmente antes dos 12 anos) Fraqueza muscular da cintura escapular Dilatação do VE Disfunção sistólica do VE Predileção pelo acometimento da parede ínfero-lateral do VE Redução do SLG, especialmente dos segmentos basais das paredes inferior, ínfero-lateral, ântero-lateral e anterior
Distrofia Muscular de Becker Recessiva ligada ao X DMD Deficiência parcial de distrofina Semelhante à DMD, mas com início ao redor dos 10 anos e progressão mais lenta
Distrofias Miotônicas Tipo 1 Autossômica dominante DMPK Expansão de repetições CTG Fraqueza muscular de predomínio distal associada à fraqueza da musculatura facial, com ptose palpebral e fenômeno miotônico Manifestações sistêmicas: catarata, resistência insulínica, falência gonadal e calvície. Pode iniciar ao nascimento (congênita), na infância ou na vida adulta Disfunção sistólica do VE Redução do SLG, especialmente do strain longitudinal apical Disfunção diastólica do VE com AE normal Prolapso da valva mitral Derrame pericárdico
Tipo 2 Autossômica dominante CNBP/ZNF9 Expansão de repetições CCTG Fraqueza muscular de predomínio proximal Sintomas menos intensos e com evolução mais lenta do que na distrofia miotônica do tipo 1. Não inicia na infância
Distrofias Musculares de Cinturas Laminopatia (LGMD1) Autossômica dominante LMNA Deficiência de lâmina A/C Fraqueza muscular de cintura escapular e pélvica de início durante a infância até a quarta década de vida Dilatação do VE Disfunção sistólica do VE Disfunção diastólica do VE
Sarcoglicanopatias (LGMD2C-F) Autossômica recessiva SGCG SGCA SGCB SGCD Deficiência de beta-sarcoglicana/gama-sarcoglicana
Fukutinopatia (LGMD2I) Autossômica recessiva FKRP Deficiência de proteína relacionada à fukutina
Distrofia Muscular de Emery-Dreifuss Tipo 1 Recessiva ligada ao X EMD/FHL1 Deficiência de emerina/FHL1 Fraqueza muscular de distribuição úmero-peroneal associada a contraturas articulares precoces e proeminentes (extensão do pescoço, flexão do cotovelo e de tornozelos) com início na infância Predomínio de dilatação biatrial sobre dilatação do VE Atrial standstill e aumento do risco cardioembólico Disfunção sistólica do VE Disfunção diastólica do VE
Tipo 2 Autossômica dominante/recessiva LMNA Deficiência de lamina A/C

CNBP/ZNF9: Cellular Nucleic Acid-binding Protein/Zinc Finger Protein 9; CTG: Citosina-Timina-Guanina; DMD: Duchenne Muscular Dystrophy; DMPK: Myotonic Dystrophy Protein Kinase; FHL1: Four And A Half LIM Domains 1; FKRP: Fukutin Related Protein LGMD: Limb-girdle Muscular Dystrophy; SLG: Strain longitudinal global; SNC: Sistema Nervoso Central.

Os sintomas e sinais relacionados à cardiomiopatia habitualmente estão ausentes nesses pacientes devido à limitação funcional causada pela fraqueza muscular. Nesse contexto, a ecocardiografia é ferramenta essencial no manejo das DM, pois, além de ser amplamente disponível e apresentar baixo custo, ela permite avaliação cardíaca anatômico-funcional e detecção de alterações pré-clínicas.3

O aumento da sobrevida dos pacientes com alguns tipos de DM, devido ao desenvolvimento de novas terapias específicas, fez com que as complicações cardiológicas surgissem como principal causa de morbimortalidade e, por esse motivo, a detecção de alterações cardíacas e a introdução de terapia direcionada à cardiomiopatia precocemente tornaram-se imprescindíveis.3 , 4

 Manifestações cardíacas e achados ecocardiográficos das distrofinopatias

A DM de Duchenne, doença neuromuscular mais comum da infância, reflete o espectro mais grave das distrofinopatias, que compreendem também a DM de Becker e as carreadoras assintomáticas da mutação no gene DMD .4 As manifestações clínicas cardiológicas, caracterizadas por cardiomiopatia dilatada (CMD) e suas complicações, podem ocorrer em qualquer um dos espectros das distrofinopatias, sem correlação com a gravidade do comprometimento muscular periférico.4 , 5

Nos últimos anos, tem-se questionado o papel da ecocardiografia na avaliação das distrofinopatias, pois alguns estudos demonstram superioridade da ressonância magnética cardíaca (RMc).6 Apesar disso e considerando as limitações inerentes à RMc, a ecocardiografia mantém seu valor na avaliação rotineira desses pacientes, visto que é amplamente disponível, apresenta baixo custo e é isenta de efeitos adversos graves.7 , 8 Estudos comparando a ecocardiografia com a RMc mostram que os parâmetros ecocardiográficos para avaliar a função sistólica do ventrículo esquerdo (VE) com melhor correlação com a RMc são o encurtamento percentual do VE6 , 9 e a fração de ejeção do ventrículo esquerdo (FEVE) pelo método área-comprimento.6

Os achados ecocardiográficos típicos são a dilatação e a disfunção sistólica do VE, que definem o fenótipo de CMD4 , 5 ( Figura 1 ). Alterações características das distrofinopatias são as alterações segmentares de contratilidade, com predileção pelo acometimento da parede ínfero-lateral do VE.4 , 5 O strain miocárdico avaliado pela técnica de speckle tracking também demonstra alterações em relação a indivíduos saudáveis, com redução do strain longitudinal global (SLG)4 , 7 , 10 , 11 ( Figuras 2 e 3 ), do strain circunferencial global7 , 11 e do strain radial global, especialmente das paredes inferior, ínfero-lateral, anterolateral e anterior, principalmente de seus segmentos basais.7 , 11 Um estudo demonstra também redução do strain miocárdico tridimensional, seja ele no eixo longitudinal, circunferencial ou radial.12 Metanálise recente determinou que o parâmetro ecocardiográfico mais estudado e com maior confiabilidade para a detecção de disfunção sistólica precoce do VE é o SLG,13 que pode apresentar alteração em até 50% dos pacientes com DMD e FEVE normal.8 Em relação à disfunção diastólica do VE, pacientes com DMD apresentam menores valores das ondas e’ septal e lateral, além de maiores relações E/e’, se comparados aos controles,11 mas não preenchem critérios ecocardiográficos para disfunção diastólica do VE significativa. As câmaras direitas, em geral, são preservadas.7

Fenótipo de cardiomiopatia dilatada em paciente deambulante de 15 anos com DM de Becker. Análise do strain longitudinal do ventrículo esquerdo nas incidências apicais de quatro (A), duas (B) e três (C) câmaras, e do strain longitudinal global do ventrículo esquerdo (D) de um paciente com distrofia muscular de Duchenne com fração de ejeção do ventrículo esquerdo normal e strain longitudinal global alterado (strain longitudinal global de -17%). Avaliação do strain longitudinal global de três pacientes com distrofia muscular de Duchenne: (A) paciente do sexo masculino, 10 anos, início dos sintomas há 5 anos, deambulante, função sistólica do ventrículo esquerdo preservada, fração de ejeção do ventrículo esquerdo de 65% e strain longitudinal global de -20%; (B) paciente do sexo masculino, 12 anos, início dos sintomas há 10 anos, cadeirante, disfunção sistólica precoce do ventrículo esquerdo, fração de ejeção do ventrículo esquerdo de 58% e strain longitudinal global de -14%; e (C) paciente do sexo masculino, 17 anos, início dos sintomas há 15 anos, cadeirante, disfunção sistólica franca do ventrículo esquerdo, fração de ejeção do ventrículo esquerdo de 34% e strain longitudinal global de -14%.

Recomendam-se eletrocardiograma (ECG) e ecocardiograma transtorácico ao diagnóstico e a cada 2 anos antes dos 10 anos de idade e, após, anualmente.4 , 5 Deve-se sempre considerar a RMc, especialmente em pacientes mais velhos e com pior qualidade de imagem ecocardiográfica, sendo que muitos advogam a realização da RMc anualmente, principalmente naqueles pacientes que já apresentam cardiomiopatia relacionada às distrofinopatias.4 , 6

 Manifestações cardíacas e achados ecocardiográficos das distrofias miotônicas

As distrofias miotônicas são as DM hereditárias mais comuns do adulto e caracterizadas por um acometimento multissistêmico.14 , 15 As manifestações cardíacas mais características são as arritmias, incluindo distúrbios de condução, taquiarritmias atriais e ventriculares e morte súbita cardíaca e, menos frequentemente, apresentam-se como CMD.14 , 16 Essas complicações são mais comuns no tipo 1 do que no tipo 2,1 , 15 , 17 sendo responsáveis por cerca de 30% das mortes na distrofia miotônica do tipo 1.14

As alterações ecocardiográficas são variáveis, podendo ocorrer dilatação, disfunção sistólica e hipertrabeculação do VE; hipertrofia e disfunção diastólica do VE e prolapso da valva mitral.14 Podem ser observados também esclerose valvar mitral, aórtica e tricúspide, além de derrame pericárdico.14 , 15 A prevalência de disfunção sistólica do VE é de 13,8% na distrofia miotônica do tipo 1.18 A presença e a gravidade da disfunção sistólica do VE auxiliam na decisão de implante de dispositivos intracardíacos, como marca-passo e cardiodesfibrilador implantável, pois são preditores de distúrbios de condução e taquiarritmias graves.14 O SLG do VE é o parâmetro mais confiável para a detecção precoce de disfunção sistólica, sendo a redução do strain longitudinal apical o achado mais característico.19

Na nossa prática, devido à escassez de sintomas, à elevada prevalência de alterações eletrocardiográficas e ecocardiográficas subclínicas e ao pior prognóstico conferido por essas alterações, recomendamos avaliação no momento do diagnóstico, seguida por rotina anual com ECG, Holter 24 horas e ecocardiograma transtorácico, além de considerar precocemente prevenção primária com implante de dispositivos intracardíacos, como marca-passo e cardiodesfibrilador implantável.17 , 19

 Manifestações cardíacas e achados ecocardiográficos das distrofias musculares de cinturas

As DMC são um grupo de doenças caracterizadas por atrofia e fraqueza muscular da cintura pélvica e escapular.1 , 16 , 17 As DMC mais frequentemente associadas à cardiomiopatia são laminopatia (LGMD1B), sarcoglicanopatias (LGMD2C-F) e fukutinopatia (LGMD2I).1 , 17 , 20 As manifestações clínicas cardíacas são semelhantes àquelas de outras DM, incluindo CMD, arritmias cardíacas e morte súbita cardíaca.1 , 17

O padrão ecocardiográfico mais característico é o de CMD, com dilatação e disfunção sistólica e diastólica do VE,20 sendo que FEVE <50% ocorre em cerca de 80%, 50% e 39 a 45% dos pacientes com LGMD2E (beta-sarcoglicanopatia), LGMD2C (gama-sarcoglicanopatia) e LGMD2I, respectivamente.17 , 21 - 23

As recomendações quanto à periodicidade da avaliação ecocardiográfica nas DMC são baseadas em consensos de especialistas.17 Na nossa prática, realizamos ECG e ecocardiograma transtorácico no diagnóstico e, após, anualmente. Estudos são necessários para investigar os benefícios da avaliação do strain miocárdico e de outras técnicas ecocardiográficas recentes nas DMC.

 Manifestações cardíacas e achados ecocardiográficos na distrofia muscular de Emery-Dreifuss

A EDMD é uma doença rara, caracterizada pela elevada frequência de acometimento cardíaco, habitualmente se manifestando como arritmias supraventriculares e ventriculares, distúrbios de condução, dilatação de câmaras e disfunção sistólica.1 , 2 , 16 , 24 , 25

Os achados ecocardiográficos mais frequentemente encontrados em pacientes com EDMD caracterizam o fenótipo de CMD, com dilatação e disfunção sistólica do VE, disfunção diastólica do VE e aumento biatrial.1 , 2 , 25 Atrial standstill e aumento do risco de fenômenos embólicos também podem ocorrer.16 Marchel et al. demonstraram que, em pacientes com EDMD e mediana de idade de 43 anos, até 41% apresentam dilatação do VE e 32% FEVE inferior a 50%. Aumentos biatriais estão presentes em mais de dois terços dos casos e predominam sobre a dilatação ventricular. As alterações ecocardiográficas foram semelhantes entre EDMD dos tipos 1 e 2, apesar de classicamente as mutações do gene LMNA estarem mais frequentemente associadas à CMD, insuficiência cardíaca e morte súbita cardíaca, independente da presença ou não de envolvimento da musculatura esquelética periférica.24

A periodicidade da avaliação ecocardiográfica não está bem estabelecida, mas, na nossa prática clínica, recomendamos ECG, Holter 24 horas e ecocardiograma transtorácico no diagnóstico e, após, anualmente. A literatura é escassa em relação ao uso de novas técnicas ecocardiográficas, como o strain miocárdico, na EDMD. Devido ao elevado risco de distúrbios de condução, arritmias ventriculares e morte súbita cardíaca associado à EDMD, o rastreio cardíaco de familiares de primeiro grau e carreadoras assintomáticas deve ser realizado rotineiramente. Pelo mesmo motivo, cardiodesfibrilador implantável como prevenção primária deve ser considerado na EDMD do tipo 2.17