Duchenne muscular dystrophy (DMD) is a genetic progressive neuromuscular disorder characterized by early-onset proximal muscle weakness and significant long-term pulmonary and cardiac involvement. Due to the early pharmacological treatments and the wider adoption of non-invasive ventilation, life expectancy has significantly increased in recent years, highlighting the relevance of DMD-related cardiomyopathy and fatal arrhythmias, especially in the late stage of the disease. Current guideline-derived evaluation of sudden cardiac death (SCD) in DMD lacks accuracy, leading to inadequate arrhythmic risk stratification and jeopardized SCD prevention strategies. This review aims to outline these critical issues, proposing an integrative approach encompassing manifold tools such as an imaging-derived systematic and comprehensive evaluation (speckle-tracking echocardiography and magnetic resonance imaging), the electrophysiological study, the 3-dimensional electroanatomic mapping, and a multidimensional clinical examination. This approach might lead to more personalized management along with an effective arrhythmia-prevention strategy aiming to balance clinical care goals, patient expectations, and ethical considerations.

Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder characterized by structural and functional myocardial alterations, often accompanied by ventricular arrhythmias (VAs), which may ultimately result in sudden cardiac death (SCD). While mutations in genes coding for desmosomal components are commonly identified in affected individuals, genetic variants involving non-desmosomal proteins have recently been recognized as contributors to the disease’s etiology. In 2008, a mutation in the transmembrane protein 43 (TMEM43) was identified as being responsible for a fully penetrant, sex-related, and severe form of ACM. This review aimed to systematically synthesize the current evidence on the natural history, electrocardiographic, and imaging findings as well as the clinical outcomes of TMEM43 cardiomyopathy. Methods: A systematic search was performed in the PubMed, Scopus, and Web of Science databases, following the PRISMA guidelines, using the terms “TMEM43” AND “cardiomyopathy”. After an initial screening of 144 retrieved articles, 80 were considered relevant. Upon a full-text review and eligibility assessment, 12 studies involving 903 individuals harboring TMEM43 variants were selected for inclusion. Results: Male patients more frequently carried the pathogenic TMEM43 variant (n = 505, 55.9%) and exhibited an earlier arrhythmic onset of the disease (33.2 years old versus 46.2 years old in female patients), supporting the need for earlier implantable cardioverter–defibrillator implantation (30.4 versus 42.2 years old). Palpitations, chest pain, and syncope were the most common presenting symptoms. Baseline electrocardiograms commonly demonstrated poor R wave progression, QRS prolongation, and premature ventricular contractions (PVCs). Arrhythmic events, including malignant VAs and SCD, were early manifestations of the disease, especially in male patients. Frequent PVCs and left ventricular dilation were considered early markers of the disease and were predictive of arrhythmic events. Conversely, heart failure was reported as a late clinical outcome, requiring heart transplantation in a minority of cases (1.5%). Conclusions:TMEM43 cardiomyopathy is a fully penetrant autosomal dominant form of ACM, characterized by a well-defined clinical phenotype that is more severe and presents earlier in male patients.

Left ventricular hypertrabeculation (LVHT), previously referred to as left ventricular non-compaction (LVNC), has experienced fluctuating recognition in cardiology. Once defined as a primary genetic cardiomyopathy, this intriguing myocardial feature is now considered a “trait” in the most recent guidelines. However, the understanding of this phenomenon remains incomplete. Moreover, data on the association between this feature and other syndromes are inconclusive, and further advances in understanding the associated molecular mechanisms and genetic background are needed. A systematic collection of clinical data is essential to avoid both over- and underdiagnosis, thereby reducing current uncertainties in LVHT management. This review examines the diagnostic, pathophysiological, and management aspects of LVHT, highlighting the challenging nature of this feature and proposing a practical approach for clinicians.

Hypertrophic cardiomyopathy (HCM) is a genetically and phenotypically heterogeneous disease in which management requires integration of clinical assessment, cardiovascular physiology, multimodality imaging, functional evaluation, and arrhythmic risk. This review examines contemporary evaluation, risk stratification, and treatment of sarcomeric HCM across obstructive and non-obstructive phenotypes. In obstructive HCM, conventional negative inotropic therapy and septal reduction therapy remain established treatments, while cardiac myosin inhibitors have introduced a mechanism-based approach that improves left ventricular outflow tract obstruction, symptoms, and exercise capacity. Their role relative to septal reduction therapy should be individualized according to anatomy, hemodynamics, treatment burden, durability, and patient preference. In non-obstructive HCM, treatment remains largely symptom-directed, although recent trials of myosin inhibition have yielded divergent results, emphasizing the importance of appropriate patient selection. Emerging strategies targeting myocardial energetics and earlier disease stages may further expand treatment options. Gene-based therapies, including first-in-human MYBPC3 replacement, offer the possibility of targeting the underlying molecular defect but require careful evaluation of safety, durability, and timing. Overall, HCM remains a paradigmatic disease for physiology-driven, phenotype- and stage-specific care, increasingly complemented by molecularly targeted therapies.

Left ventricular hypertrabeculation (LVHT), previously referred to as left ventricular non-compaction (LVNC), has experienced fluctuating recognition in cardiology. Once defined as a primary genetic cardiomyopathy, this intriguing myocardial feature is now considered a “trait” in the most recent guidelines. However, the understanding of this phenomenon remains incomplete. Moreover, data on the association between this feature and other syndromes are inconclusive, and further advances in understanding the associated molecular mechanisms and genetic background are needed. A systematic collection of clinical data is essential to avoid both over- and underdiagnosis, thereby reducing current uncertainties in LVHT management. This review examines the diagnostic, pathophysiological, and management aspects of LVHT, highlighting the challenging nature of this feature and proposing a practical approach for clinicians.