Marco Merlo

Metabolic disorders represent a growing epidemiological and clinical challenge, associated with worsening prognosis of cardiovascular disease. These conditions cluster in patients with heart failure and cardiomyopathies, limiting therapeutic options. Although cardiomyopathies contribute substantially to the burden of heart failure, the impact of metabolic disorders on their progression remains underexplored. This review explores the complex cardiorenal and metabolic dimensions of cardiomyopathies, focusing on pathophysiological mechanisms, therapeutic innovations, and future organizational models. Metabolic disorders likely modulate genotype-phenotype expression, aggravate myocardial dysfunction, and accelerate disease progression through converging molecular mechanisms and pathways leading to energetic imbalance, inflammation and fibrosis. Novel therapies act on these pathways favouring microscopic and macroscopic reverse remodelling. A holistic and multidisciplinary approach is required to select appropriate therapies, improve disease progression and quality of life of these patients. Cardiomyopathies exemplify the complexity of heart failure, where genetic and metabolic dysfunctions coexist and act as both triggers and amplifiers of myocardial damage. DCM, HCM, HCM phenocopies and ARVC all present the burden of metabolic disorders and some of them benefit from novel therapies. SGLT2i, GLP1-RA, and non-steroidal MRA represent the forefront of a new therapeutic era, aiming at pleiotropic targets beyond neurohormonal blockade. Integrated care models will reshape disease management and improve patients' outcomes. Future research should investigate on metabolic disorders prevalence in cardiomyopathies and better characterize molecular pathways and phenotypic profiles that mostly benefit from novel therapies.

In the past decade, advancements in knowledge on the immune system have partially unveiled the complex interplay between the heart and the immune system. This new branch of cardiology is now called cardio-immunology. It encompasses different areas from preclinical to translational and purely clinical research aiming to identify the relationship between the immune system and different cardiovascular diseases. Inflammatory cardiomyopathies are a heterogeneous subgroup of non-ischaemic cardiomyopathies characterized by left ventricular, or biventricular, dysfunction after an inflammatory insult. Recently, genetic testing allowed to identify specific genotype–phenotype correlation in the diagnosis and, mostly, in the prognosis of different cardiomyopathies. Some pathogenic variants might lead to a clinical phenotype in overlap with inflammatory myocardial diseases and inflammation can be found in cardiac magnetic resonance or endomyocardial biopsies of different cardiomyopathies. Although prognostic predictors of adverse events and indication to immunosuppressive therapies have been identified in myocarditis, data are lacking in the context of genetic cardiomyopathies presenting myocardial inflammation. As for pericardial diseases, genetic variants in immune-related genes, such as IL1B have been described, specifically in recurrent pericarditis. A growing body of evidence starting form genetics and cardio-immunology are trying to elucidate the basic mechanisms of the disease and may play a significant role in the understanding the pathophysiology and potentially the treatment of patients. Some examples are represented by arrhythmogenic cardiomyopathy presenting with hot-phases or biopsy-proven myocarditis presenting genetic mutations in specific genes as TTN or DSP. The aim of this review paper is to highlight the current knowledge and the unmet clinical needs, providing a practical and concise guidance for specific areas of research and management of patients affected by myo-pericardial diseases with overlap between genetics and inflammation, ranging from genetic testing to medical and device therapy.

Cardiomyopathies are a heterogeneous group of cardiac disorders with significant morbidity and mortality that often manifest as heart failure or sudden cardiac death. Although these conditions can be influenced by environmental factors, genetic causes play a critical role, with both Mendelian and non-Mendelian inheritance patterns contributing to their development. Advances in genetic testing have transformed clinical practice, offering new opportunities for diagnostic and prognostic characterization of cardiomyopathies, and supporting personalized interventions based on genetic profiles. This review explores the diagnostic utility of genetic testing for some specific cardiomyopathies and the complex prognostic insights it provides, especially for assessing arrhythmic risk and guiding implantable cardioverter defibrillator (ICD) implantation in primary prevention. In addition, the review highlights the emerging potential of gene-targeted therapies, which aim to improve outcomes for patients with variants in specific genes. As inherited cardiomyopathies often exhibit familial patterns, genetic testing is also crucial in family screening and management, enabling tailored monitoring and care. Recognizing the challenges posed by phenotypic variability and the interplay of genetic, comorbid, and lifestyle factors, this review emphasizes the need for a deeper understanding of these complexities to optimize precision medicine approaches in the care of inherited cardiomyopathies.

Last year, the European Society of Cardiology (ESC) published the first guidelines to comprehensively address the management of cardiomyopathies. This document by the Working Group on Myocardial and Pericardial Diseases of the Italian Society of Cardiology aims at highlighting the most relevant messages and novelties introduced by these guidelines for the management of patients affected by cardiomyopathies. Five main messages are summarized: the key role of the phenotype, the new classification of cardiomyopathies provided in the ESC guidelines, the importance given to new techniques such as cardiac magnetic resonance (CMR) and genetic testing, the newly provided recommendations given on sport activities and finally how the importance of follow-up evaluations is highlighted. These five main messages are then further analyzed more in depth so as to inform the reader on all the main novelties of the guidelines and to provide a critical approach to this important document.