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Pediatric cardiomyopathies are rare diseases, heterogeneous in clinical presentation, etiology and prognosis. Etiological diagnosis, where genetic analysis plays a key role, is of fundamental importance for defining diagnostic and therapeutic pathways. Furthermore, the identification of the genetic substrate represents a prerequisite for cascade screening in the proband's family members and to allow conscious reproductive choices. To date, genetic testing is performed with the analysis of gene panels (targeted panels) or with the study of the entire exome (whole exome sequencing) using next generation sequencing (NGS) technology. The great genetic heterogeneity and the temporal variability of the clinical manifestations lead to unique problems for pediatric cardiomyopathies, distinct from those of the adult, such as the possible indications for access to the test, the type of test to be used (exome or panel of genes), the importance of analyzing parents, especially in cases with neonatal onset; moreover, the correct execution of bioinformatics analysis and the interpretation of NGS data play a crucial role in the impact of the results on clinical management.

Hereditary cardiomyopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, restrictive cardiomyopathy and left ventricular noncompaction, are clinically and genetically very heterogeneous diseases, and they represent a frequent cause of cardiac arrest and sudden death. To date, over 100 genes are known to be associated with the onset of cardiomyopathies. Genetic testing is performed by next generation sequencing, a technology that has made it possible to analyze hundreds of genes in many patients simultaneously, shortening costs and execution times. However, with the use of this technology, new problems have arisen regarding the indications for access to the test, the interpretation of the data and the clinical implications of the results.This document aims to represent an operational support tool for hospital cardiologists to make the use of genetic testing more accessible and appropriate for their patients with suspected or ascertained hereditary cardiomyopathy.

The management of patients with hypertrophic cardiomyopathy (HCM) and refractory symptoms due to massive hypertrophy and severe diastolic dysfunction represents a real challenge for the clinical cardiologist. Such patients often require novel therapeutic approaches, both invasive and pharmacological, involving multidisciplinary teamwork; however, the implementation of potentially viable treatment options is hindered by lack of disease-specific evidence. We report the case of a young woman with severe HCM and restrictive physiology, who underwent extensive myectomy via the transaortic and transapical approach, followed by biventricular pacing for cardiac resynchronization, with significant but incomplete symptomatic improvement. The subsequent introduction of ranolazine, based on promising preclinical data, has led to an excellent final result. An ongoing randomized clinical trial is currently testing the efficacy of ranolazine in symptomatic HCM.

Progressive heart failure associated with left ventricular remodeling and systo-diastolic dysfunction is one of the most severe complications of hypertrophic cardiomyopathy (HCM). Such condition, for the lack of a better term, is referred to as end-stage (ES) HCM. During the last decade, we have begun to understand the mechanisms underlying progression from a hyperdynamic left ventricle to the striking patterns of ES. To date, different aspects of HCM progression remain obscure, including potential strategies for management and prevention. On the basis of recent evidence, it is appropriate to emphasize these aspects, which may be difficult to identify, particularly in the early stages when systolic function appears relatively preserved. Nevertheless, it is at these early stages that treatment may potentially interfere with the clinical evolution of HCM toward ES and heart failure. The possibility of early identification of patients at risk of ES progression may ultimately impact on the natural history of the disease in this challenging patient subgroup.

Isolated left ventricular non-compaction (LVNC) is a rare genetic form of cardiomyopathy (CM) characterized by prominent left ventricular wall trabeculation and intertrabecular recesses communicating with the ventricular cavity. Clinical signs are variable, ranging from lack of symptoms to severe manifestations including heart failure, sustained ventricular arrhythmias, cardioembolism and sudden death. The diagnosis of LVNC is frequently missed, due to limited awareness in the medical community. Contemporary diagnostic sensitivity has been enhanced by the introduction of specific morphologic criteria by high resolution echocardiography and cardiac magnetic resonance. As a consequence, LVNC has been diagnosed more frequently in association with other disorders such as congenital heart disease or genetic CM. The clinical relevance of regional non-compaction in the context of other cardiac diseases is still uncertain. Recent evidence points to an overlapping genetic background encompassing LVNC, hypertrophic and dilated CM, suggesting a continuum of disease associated with sarcomere protein gene mutations. This concept may prove relevant to the understanding of common pathogenetic mechanisms of CM and offer novel research opportunities.