Dilated cardiomyopathy (DCM) remains a leading cause of non-ischemic heart failure and sudden cardiac death, with substantial heterogeneity in clinical presentation and outcomes. Conventional diagnostic tools and circulating protein biomarkers largely reflect late-stage myocardial injury and fail to capture the underlying molecular complexity of the disease. MicroRNAs (miRNAs), small non-coding RNAs that regulate post-transcriptional gene expression, have emerged as promising biomarkers and therapeutic targets in cardiovascular disorders. Dysregulated microRNAs signatures are closely linked to key pathological processes including myocardial fibrosis, inflammation, apoptosis, angiogenesis impairment, and metabolic remodeling. Circulating miRNAs demonstrate remarkable stability in biofluids and show potential for early detection, risk stratification, and monitoring of disease progression. This review focuses on the current evidence on the role of circulating and tissue-derived miRNAs in the pathogenesis, diagnosis, and treatment of dilated cardiomyopathy. It further discusses emerging therapeutic strategies based on miRNA modulation, including the use of miRNA mimics and anti-miRs, which have shown promising preclinical and early clinical outcomes. However, significant translational challenges, including delivery specificity, off-target effects, molecular instability, and lack of methodological standardization, continue to limit the clinical implementation of miRNA-based therapies in DCM.

Pediatric cardiomyopathies (CM) are rare and heterogeneous heart disorders, including hypertrophic, dilated, restrictive, arrhythmogenic, and non-dilated CM. While their genetic basis is well characterized in adults, it remains less clearly defined in children particularly in early-onset apparently isolated and syndromic forms. We conducted a retrospective study (2018-2024) of 59 pediatric patients who underwent Whole-Exome Sequencing (WES) for CM at Amiens and Lille University Hospitals, aiming to characterize the genetic architecture of pediatric CM. WES identified at least one Variant Of Interest (VOI) in 62.7% of patients (37/59), including 45.8% (27/59) of P/LP variants, and 16.9% (10/59) of VUS. VOI identification yields for HCM and DCM were respectively 67.7% and 57.1%. Yield was higher in patients diagnosed before 1 year of age compared with those diagnosed later (72.7% vs. 56.7%). Variants were identified in classical CM genes, including sarcomeric genes, but also in less typical and syndromic genes. Among patients diagnosed before 6 months, 55% carried a variant in genes associated with syndromic cardiomyopathy, including cases with initially isolated cardiac phenotypes. These findings support the use of WES as a first-line approach in pediatric CM and highlight the contribution of complex and syndromic genetic architectures to early-onset and severe diseases.

Background/Objectives: Dilated cardiomyopathy (DCM) is a genetically heterogeneous myocardial disorder. Emerging evidence suggests that some genes implicated in DCM may also be associated with neurological disorders, supporting the concept of genetic pleiotropy. This study explored the intersection between cardiac and neurological genetics, with the aim of identifying candidate genes that may contribute to shared pathogenic pathways linking these clinically distinct conditions. Methods: We performed exome sequencing in 149 patients with echocardiographically confirmed DCM and subsequently applied an in silico filter to a predefined list of 211 genes associated with inherited cardiomyopathies. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Genes with validated evidence for DCM according to the Clinical Genome Resource (ClinGen) were further investigated through the Human Gene Mutation Database (HGMD) and a focused literature review to identify reported associations with neurological disorders. Results: Genetic variants in DCM-associated genes were identified in 105 patients. Overall, 137 variants were detected, including pathogenic variants and variants of uncertain significance. The most frequently involved genes were TTN, FLNC, and MYH6. Several DCM-associated genes also showed reported associations with neurological disorders, including autism spectrum disorder, Alzheimer's disease, Parkinson's disease, epilepsy, and schizophrenia. Among them, TTN, FLNC, RYR2, and SCN5A displayed the broadest overlap between cardiac and neurological phenotypes. Conclusions: These descriptive findings show that variants were most frequently observed in TTN, FLNC, and MYH6 and that several genes included in the ClinGen DCM curation framework have also been independently reported in neurological disorders. Because most identified variants were VUS and no control group or systematic neurological phenotyping was available, the findings indicate gene-level co-annotation only and do not establish variant enrichment, shared pathogenic mechanisms, or clinical overlap.

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous myocardial disorders in which disease progression is influenced by secondary modifiers beyond structural gene mutations. Increasing evidence suggests that inflammatory signalling plays a role in modulating disease phenotype and progression. Among inflammatory mediators, interleukin-6 (IL-6) has emerged as a potential contributor to myocardial remodelling and dysfunction.A structured literature review was performed using Ovid MEDLINE and the Cochrane Library for studies published up to 10 October 2025. Findings were synthesised narratively because of substantial heterogeneity in study design, populations, and outcomes.This review synthesises clinical, genetic, and experimental evidence on the role of IL-6 in HCM and DCM, with a focus on its potential therapeutic relevance. Across studies, elevated IL-6 levels are consistently associated with greater disease severity. Mechanistic data indicate that IL-6 signalling via the gp130/STAT3 pathway may promote cardiomyocyte hypertrophy, fibrosis, and apoptosis, with genetic polymorphisms likely influencing disease susceptibility and phenotypic expression. Pharmacological interventions with anti-inflammatory properties, including statins, pentoxifylline, and growth hormone, have been associated with reductions in IL-6 levels and improvements in cardiac function, although these effects are not specific to IL-6 signalling.In summary, current evidence supports IL-6 as an important component of the inflammatory milieu associated with HCM and DCM and suggests potential utility as a biomarker of disease activity. However, evidence supporting a causal pathogenic role remains limited, and IL-6-directed therapies have not been systematically evaluated in cardiomyopathy populations.

Left atrial (LA) function has emerged as a critical determinant of cardiovascular performance and disease progression across the spectrum of pediatric heart disease. Traditionally viewed as a passive conduit, the left atrium is now increasingly recognized as a dynamic biomechanical chamber that modulates ventricular filling, pulmonary venous pressures, cardiac output, and neurohormonal signaling. In children with congenital and acquired heart disease, alterations in atrial structure and mechanics frequently precede overt ventricular dysfunction, making LA dysfunction an early and potentially reversible marker of cardiovascular injury. Advances in cardiac imaging, particularly speckle-tracking echocardiography and cardiac magnetic resonance imaging, have enabled detailed characterization of atrial reservoir, conduit, and contractile function in pediatric populations. Emerging evidence suggests that impaired left atrial strain is associated with adverse hemodynamics, exercise intolerance, arrhythmogenesis, pulmonary hypertension, Fontan failure, cardiomyopathy progression, and heart failure severity. Mechanobiological processes, including atrial stretch, fibrosis, extracellular matrix remodeling, inflammation, and altered atrioventricular coupling, contribute to the development of pediatric left atrial myopathy. These changes are increasingly recognized in congenital heart lesions, single-ventricle physiology, hypertrophic and dilated cardiomyopathies, Kawasaki disease, obesity-related cardiovascular dysfunction, and cardio-oncology populations. Despite growing interest, important gaps remain regarding normative pediatric reference values, age-related physiological variation, imaging standardization, and long-term prognostic significance. This narrative review summarizes current understanding of left atrial mechanobiology, multimodality imaging assessment, and clinical implications of LA dysfunction in pediatric heart disease. We also discuss emerging technologies, including artificial intelligence-based imaging analysis and future directions for integrating left atrial phenotyping into pediatric cardiovascular risk stratification and therapeutic decision-making.

Over the past decades, the approach to cardiomyopathies has deeply evolved. It has progressively transitioned from one predominantly based on clinical evaluation and conventional imaging towards an integrated and multidimensional approach that incorporates advanced imaging techniques, tissue characterization, and comprehensive genetic testing. In this perspective, the current classification of cardiomyopathies, from the European Society of Cardiology, has introduced the new entity of non-dilated left ventricular cardiomyopathy (NDLVC) that encompasses a spectrum of diseases from hypokinetic non-dilated forms [formerly called dilated cardiomyopathies (DCMs)] to non-hypokinetic non-dilated forms, characterized by left ventricular scar (previously called arrhythmogenic cardiomyopathies). However, the pivotal principle of the new classification is that the phenotype should be considered the starting point of a dynamic diagnostic pathway rather than its ultimate definition. Contemporary evaluation of patients with DCM and NDLVC requires a longitudinal and integrative perspective in which clinical features, imaging markers, and molecular data converge to refine disease characterization. Stated that, several aspects warrant further refinement. Arrhythmic risk stratification of DCM and NDLVC remains incompletely delineated, reflecting the complex and heterogeneous nature of the underlying arrhythmogenic substrate and its variable expression across different stages of the diseases. In addition, a proportion of patients remain genetically elusive despite extensive testing, underscoring the need for deeper molecular insights. At the same time, the expanding recognition of genotype-positive/phenotype-negative individuals introduces clinical scenarios that are not yet fully delineated, particularly with regard to surveillance strategies and preventive decision-making. This review paper aims to provide a structured and evidence-informed framework to guide personalized management of DCM and NDLVC, starting from the phenotype towards precision medicine.