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In infants with HCM, after exclusion of reversible causes (maternal diabetes,253 twin–twin syndrome, corticosteroid use254,255), it is important to define, along with the pattern of hypertrophy (asymmetric, concentric, biventricular), the presence of LVOTO, diastolic and/or systolic dysfunction,1,256 and RV involvement. Early-onset sarcomeric disease (including double/compound variants) should be excluded even in the absence of a family history for HCM and SCD; these infants present with severe heart failure symptoms, and survival beyond the first year of life is uncommon.257 In contrast, clinical presentation with heart failure is rare in infants with heterozygous sarcomeric disease compared with malformation syndromes or metabolic disorders, in whom survival rates are <90% and <70% at 1 year, respectively.248,258,259 In infants with HCM, in the presence of biventricular outflow tract obstruction and ≥1 red flag for a neurocardiofaciocutaneous syndrome (dysmorphisms, cutaneous abnormalities, skeletal anomalies, etc.), a diagnosis of RASopathies should be strongly suspected.260–263 Severe LVOTO in RASopathy-related HCM often requires high-dose beta blockade and, in some cases, consideration of septal myectomy.264– 267 In infants with HCM, biventricular hypertrophy, often presenting with signs of heart failure and systolic dysfunction, and ≥1 red flag for metabolic disease (muscle hypotonia, increased CK, and transaminases, consanguinity or matrilineal pattern of inheritance), it is mandatory to exclude inborn errors of metabolism, including glycogenosis type II (Pompe disease), fatty acid oxidation defects, and mitochondrial disorders.268–272 In infants with Pompe disease, enzyme replacement therapy (ERT) has been shown to result in reversal of LVH.269,273–275 In infants with DCM, reversible causes (i.e. hypocalcaemic vitamin D-dependent rickets) and CHD (aortic coarctation and ALCAPA, requiring immediate surgical management) should be ruled out.249,276,277 Viral myocarditis should also be excluded by non-invasive (i.e. laboratory) and invasive (EMB) investigations, in selected cases.278,279 Neuromuscular (dystrophin- and sarcoglycan-related cardiomyopathies) should be excluded in patients presenting with muscle hypotonia and increased CK, and a multidisciplinary approach involving a neurologist and experts in metabolic disease is required.280–282 When a DCM phenotype is associated with LV hypertrabeculation, other mitochondrial/metabolic diseases, including Barth syndrome, should be considered.283–285 Isolated RCM is rare in infants, but a mixed RCM/HCM phenotype is more frequently encountered. Familial cases are frequent, particularly in patients with an RCM/HCM phenotype.286–289 Independently of the phenotype, it is generally associated with poor prognosis, though the RCM/HCM phenotype has significantly better transplant-free survival than isolated RCM.286 Arrhythmogenic RV cardiomyopathy and non-dilated LV cardiomyopathy phenotypes are very rare in infants, and are most commonly autosomal recessive forms associated with cutaneous manifestations (e.g. Naxos disease and Carvajal syndrome),290–292 although this may reflect a lack of systematic clinical screening for these conditions in early childhood. Recent data suggest that ∼15% of ARVC patients present with paediatric-onset disease and paediatric ARVC patients more often present with severe phenotype and higher risk of SCD.293 Increasingly, children with ARVC and NDLVC phenotypes presenting with acute myocarditic presentations are recognized.294–297

6.10 General principles in the

management of patients with cardiomyopathy 6.10.1. Assessment of symptoms Some people with subtle structural abnormalities with cardiomyopathy remain asymptomatic and have a normal lifespan; however, others may develop symptoms, often many years after the appearance of ECG or imaging evidence of disease. In infants, symptoms and signs of heart failure include tachypnoea, poor feeding, excessive sweating, and failure to thrive. Older children, adolescents, and adults complain of fatigue and dyspnoea as well as chest pain, palpitations, and syncope. Because the New York Heart Association (NYHA) classification to grade heart failure is not applicable to children under the age of 5 years, the Ross Heart Failure classification has been adopted in children <5 years of age but has not been validated against outcomes.298 Systematic two-dimensional (2D) and Doppler echocardiography, resting and ambulatory ECG monitoring, and exercise testing are usually sufficient to determine the most likely cause of symptoms. Additional investigations (e.g. coronary CT scanning or coronary angiography, cardio-pulmonary exercise testing [CPET], electrophysiological study, loop recorder implantation) should be considered to investigate specific symptoms of chest pain, syncope, and palpitation, according to established clinical practice and guidelines.1,4,69,299–301 Cardiac catheterization to evaluate right and left heart function and pulmonary arterial resistance, and CPET with simultaneous measurement of respiratory gases, is not a standard part of the work-up, but remains recommended in severely symptomatic patients with systolic and/or diastolic LV dysfunction when uncertainty about filling status exists, or for those being considered for heart transplantation or mechanical circulatory support.69

6.10.2 Heart failure management

The clinical management of heart failure has been described in the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.69 In that document, recommendations are generally independent from the aetiology of heart failure and include current medical therapy, devices, and LV assist device (LVAD)/transplantation. As such, the treatment recommendations must be regarded as generic and not specific to the different forms of cardiomyopathy. Medical therapies for HFrEF based on randomized controlled trials (RCTs) from large cohorts, including angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRA), and sodium–glucose co-transporter 2 inhibitors (SGLT2i), would be mostly applicable to genetic DCM, NDLVC, and other phenotypes associated with LV dysfunction (e.g. end-stage HCM, RCM, and ARVC). Indications for a cardiac resynchronization therapy (CRT) device and heart transplant would also be generally applicable accordingly. Recommendations for management of HFpEF would be mainly applicable to non-obstructive HCM, RCM, and cardiac amyloidosis. A Focused Update is due to be published in 2023.69a Individual response to heart failure therapies may not be the same for different specific genetic causes, as has been demonstrated in several observational studies.302,303 Further management considerations applicable to specific cardiomyopathy subtypes in adults and children, and in particular contexts, such as pregnancy and rare metabolic genocopies, are rapidly developing304 and are discussed in the specific cardiomyopathy sections (see Sections 7.6 and 8.2.2). Cardiac amyloidosis and some forms of RCM deserve special consideration regarding heart failure management. Fluid control and maintenance of euvolaemia are central. If heart failure symptoms are present, loop diuretics should be given, although orthostatic hypotension may cause intolerance, and excessive fluid loss may worsen symptoms due to restriction (e.g. in HCM or amyloidosis). The role of betablockers, ACE-Is, angiotensin receptor blockers (ARBs), or ARNIs in the treatment of these patients has not been determined and they may not be well tolerated because of hypotension.305 Moreover,

ESC Guidelines                                                                                                                                                                                          3539

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