European Heart Journal Supplements (2020) 22 (Supplement E), E13–E19 The Heart of the Matter doi:10.1093/eurheartj/suaa051 Hereditary muscle diseases and the heart: the cardiologist’s perspective Lorenzo Giuliani1, Alessandro Di Toro1, Mario Urtis1, Alexandra Smirnova1, Monica Concardi1, Valentina Favalli2, Alessandra Serio1, Maurizia Grasso1, and Eloisa Arbustini1* 1Centre for Inherited Cardiovascular Diseases, IRCCS Foundation University Hospital Policlinico San Matteo, Pavia, Italy; and 2Ingenomics Srls, Polo Tecnologico, Pavia, Italy KEYWORDS Hereditary muscle disease; Cardiomyopathy; Heart failure Introduction patients in a way to collect data useful in accelerating tar- geted treatment development. Cardiac manifestations in hereditary muscle diseases in- clude cardiomyopathies, defects of cardiac conductions Dilated and hypokinetic phenotypes (DCM) with or without primary myocardial muscle involvement, 1,2 and arrhythmias. Symptoms and signs of these diseases The most common heritable muscle diseases affecting the 3 may exhibit in paediatric as well as in adult age, and in heart and leading to dilated and hypokinetic cardiac phe- many cases only a multidisciplinary clinical approach can notype include dystrophinopathies, limb girdle muscular 4,5 ensure correct diagnosis and management. Cardiologists dystrophies (LGMD), and Emery–Dreifuss Muscular might be the first to recognize an apparently lone cardiac Dystrophies (EDMD). involvement as an important clinical marker of an heredi- tary muscle disease or be the first in line in a multidiscipli- nary team when cardiac involvement represents the major Dystrophinopathies clinical manifestation affecting evolution and prognosis of Mutations in the DMD gene encoding for dystrophin cause the disease.6 dystrophinopathies, a group of rare X-linked recessive The actual classifications of hereditary muscle disorders (XLR) muscle diseases. Dystrophin is a large sarcolemmal are based on phenotype, aetiology, and pathology and may protein that is essential for structural and functional integ- result complex and potentially impractical for a cardiologic rity of the myocyte membranes. Patients affected by dys- clinical approach. For this reason, we are proposing the trophin defects manifest DCM as unique and often fatal grouping of most common cardiac manifestations observed cardiac phenotype. Muscle and cardiac phenotypes are in hereditary muscle diseases on the basis of the cardiac clinically heterogeneous and classified according to the se- phenotypes. A new way of describing the complexity of car- verity of the dystrophy [from the severe Duchenne Muscle diac phenotype and genotype together with extra-cardiac Dystrophy (DMD) to the milder Becker Muscular Dystrophy clinical manifestations, as represented by MOGES nosology (BMD)] or the exclusive involvement of the heart, when for cardiomyopathies,7 is the possible solution for nosology skeletal muscle is clinically spared (i.e. in XLR-DCM). assignment and deep phenotype description of these • DMD (1:4000–1:6000 live male birth)8 is a severe mus- cle dystrophy clinically and genetically diagnosed in *Corresponding author. Email: [email protected] paediatric age. In most of the cases (>70%), the Published on behalf of the European Society of Cardiology. VC The Author(s) 2020. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] E14 L. Giuliani et al. genetic defects are large rearrangements in DMD autosomal recessive (AR, type 2, LGMD2) diseases. gene. The pathologic hallmark is the total absence of Alphabetic letters indicating the mutated protein/gene dystrophin in the skeletal myocyte sarcolemma.9 complement the description.23 Currently, eight AD LGMDs Regular cardiology care is needed since initial diagno- (LGMD1) and more than 25 AR LGMDs are known. sis in all DMD patients and annual echocardiograms The prevalence of LGMDs is estimated to be ranging from represent the minimum follow-up.4,5,8 The prevalence 1:14 500 to 2.27:100 000.24,25 Cardiac and respiratory im- of DCM is age-dependent and in nearly all young–adult pairment is common. The most represented cardiac pheno- patients cardiac involvement is demonstrated.10–13 type in LGMD is DCM26 having a prevalence that varies ECG changes like right axis deviation, Q wave in the between the different subgroups of patients; in sarcoglyca- left precordial leads, and conduction defects may ex- nopathies (a-, b-, d-, c-) more than 30% of patients develop hibit an early onset.10 DCM is diagnosed through trans- DCM.27 The risk of sudden death (SD) is also variable, being thoracic echocardiogram and when feasible, CMR may particularly high in LGMD1B (laminopathy) where is also as- add information on adipose and fibrous replacement sociated with DCM and conduction defects.28 Disease- of left ventricle (LV) wall structure and LV trabecular specific biomarkers exist but hyperCKemia represent a anatomy.11 Patients have to be treated for cardiac common finding in all LGMDs. Functional studies of cardiac manifestations according to heart failure (HF) guide- (echocardiography and CMR) and skeletal muscle (electro- lines and disease-specific recommendations4,5 with myography, muscle ultrasound, and magnetic resonance ACE-I and ARBs as cornerstone therapy. Multiple con- imaging) are useful to characterize the involvement of the tributors to cardio-respiratory failure determine end- heart and skeletal muscles.29,30 Patients usually need a stage evolution of the disease13 precluding indication scheduled monitoring in multidisciplinary settings and the to heart transplantation (HTx). In recent years, life actual therapeutic options include steroids with variable expectancy has increased from the late 20s12 to early effectiveness.30 Since actionable targeted therapies cur- 40s14 thanks to steroid treatment, spinal stabilization rently does not exist, DCM, arrhythmias and, conduction surgery, nocturnal ventilation, and physiotherapy. defects have to be treated according to contemporary • In patients with BMD [1:18 000 live male birth15] DCM guidelines4,5,19,26 fully manifests in the second to fourth decade of life but it can be recognized even earlier when BMD is clinically suspected.16 Skeletal muscle involvement is Emery–Dreifuss muscle dystrophy milder than in DMD and variable, depending on the se- Contractures of elbows, ankles, and cervical spine associ- verity of the loss of protein expression.17 Patients usu- ated with slowly progressive muscle weakness are the ma- ally remain ambulatory until advanced adult age.8,9,15 jor traits in EDMD.31 The cardiac phenotype is DCM may be the first clinically overt manifestation of characterized by LV dilation and dysfunction often pre- the disease18 but hyperCKemia is common and by it- ceded by conduction disease that requires PM implanta- self may represent a reason for neurological consulta- tion. HyperCKemia is common. The disease is genetically tion. The most common cause of end-stage disease is heterogeneous and is caused by mutations in genes that HF.4,5,19 Patients with BMD-DCM have to be treated code for nuclear envelope protein. Half of the patients di- according to HF guidelines and HTx may be indicated. agnosed with EDMD are carriers of mutations in genes that Post-transplant outcome is similar to that of (non- code for emerin, lamin A/C, nesprin-1, and nesprin-2.31 BMD) idiopathic DCM.4,5,19 Depending upon the disease gene, the pattern of inheri- • XLR-DCM can be the unique overt manifestation in tance is either X-Linked or autosomal, both dominant patients with dystrophin defects. The prevalence (common) or recessive (rare). ranges from 3% to 7% in consecutive male patients In XLR emerinopathies, patients are usually referred to with familial, non-paternally inherited DCM.20,21 cardiologists for arrhythmia consultation and consideration Patients have no history or symptoms of muscular dys- of possible pacemaker (PM) placement; AV conduction trophy but almost always present hyperCKemia. defects and arrhythmias, mostly of atrial origin, may ap- Clinical management is based on HF guidelines; trans- pear before LV systolic dysfunction.32,33 In AD EDMD caused plantation is the elective treatment for patients with by mutations in LMNA gene,33 the risk of ventricular end-stage HF and has the same outcome as in BMD- arrhythmias is high. DCM, arrhythmias and conduction dis- DCM.22 ease should be treated according to HF guidelines. However, the disease-causing gene and the type of muta- tion should be taken into account in the stratification of Limb girdle muscle dystrophy arrhythmogenic risk.2 The LGMD phenotype includes genetically heterogeneous group of more than 30 disorders in which skeletal, respira- Hypertrophic phenotypes tory, gastrointestinal, and nervous systems may be variably involved. They are characterized by weakness and wasting HCM represents the cardiac phenotype in a large group of of pelvic and shoulder girdle muscles. Recently, a novel clinically and genetically heterogeneous hereditary muscle gene-based nosology23 has classified LGMDs using the clini- disorders caused by impaired synthesis and utilization of cal descriptor (LGMD) followed by a number that distin- energy substrates with proliferation of abnormal