Search Results (247)

Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized to include biventricular and left-dominant forms. Genetic causes account for a substantial proportion of cases and include desmosomal variants, non-desmosomal variants, and familial gene-elusive forms with no identifiable pathogenic mutation. Nongenetic etiologies, including post-inflammatory, autoimmune, and infiltrative mechanisms, may mimic the phenotype. In many patients, the disease remains idiopathic despite comprehensive evaluation. Cardiac magnetic resonance imaging has emerged as a key tool for identifying non-ischemic scar patterns and for distinguishing arrhythmogenic phenotypes from other cardiomyopathies. Emerging classifications propose the unifying concept of scarring cardiomyopathies based on shared structural substrates, although global consensus is evolving. Risk stratification remains challenging, particularly in patients without overt systolic dysfunction or identifiable genetic markers. Advances in tissue phenotyping, multi-omics, and artificial intelligence hold promise for improved prognostic assessment and individualized therapy. Full article

Cardiomyopathies represent a heterogeneous group of myocardial disorders, traditionally classified by phenotype into hypertrophic, dilated, and arrhythmogenic. Historically, these conditions have been attributed to high-penetrance rare variants in key structural genes, consistent with a classical Mendelian pattern of inheritance. However, emerging evidence suggests that this model does not fully capture the full spectrum and complexity of disease expression. Many patients do not harbor identifiable pathogenic variants, while others carrying well-known disease-causing variants remain unaffected. This highlights the role of incomplete penetrance, likely modulated by additional genetic modifiers. Recent advances in genomics have revealed a broader view of the genetic basis of cardiomyopathies, introducing new players such as common genetic variants identified as risk alleles, as well as intermediate-effect variants. This continuum of genetic risk, reflecting an overall genetic influence, interacts further with environmental and lifestyle factors, likely contributing together to the observed variability in clinical presentation. This model offers a more realistic framework for understanding genetic inheritance and helps provide a clearer picture of disease expression and penetrance. This review explores the evolving genetic architecture of cardiomyopathies, spanning from a monogenic foundation to intermediate-risk variants and complex polygenic contribution. Recognizing this continuum is essential for enhancing diagnostic accuracy, guiding family screening strategies, and enabling personalized patient management. Full article

Transmembrane protein 43 (TMEM43 or LUMA) encodes a highly conserved protein found in the nuclear and endoplasmic reticulum membranes of many cell types and the intercalated discs and adherens junctions of cardiac myocytes. TMEM43 is involved in facilitating intra/extracellular signal transduction to the nucleus via the linker of the nucleoskeleton and cytoskeleton complex. Genetic mutations may result in reduced TMEM43 expression and altered TMEM43 protein cellular localization, resulting in impaired cell polarization, intracellular force transmission, and cell–cell connections. The p.S358L mutation causes arrhythmogenic right ventricular cardiomyopathy type-5 and is associated with increased absorption of lipids, fatty acids, and cholesterol in the mouse small intestine, which may promote fibro-fatty replacement of cardiac myocytes. Mutations (p.E85K and p.I91V) have been identified in patients with Emery–Dreifuss Muscular Dystrophy-related myopathies. Other mutations also lead to auditory neuropathy spectrum disorder-associated hearing loss and have a negative association with cancer progression and tumor cell survival. This review explores the pathogenesis of TMEM43 mutation-associated diseases in humans, highlighting animal and in vitro studies that describe the molecular details of disease processes and clinical, histologic, and molecular manifestations. Additionally, we discuss TMEM43 expression-related conditions and how each disease may progress to severe and life-threatening states. Full article

Gender-specific cardiology has gained increasing recognition in recent years, emphasizing the need for tailored management strategies for women with cardiovascular disease. Among these, cardiomyopathies—dilated, arrhythmogenic, hypertrophic, and restrictive—pose unique challenges throughout a woman’s reproductive life, affecting contraception choices, pregnancy outcomes, and breastfeeding feasibility. Despite significant advances in cardiovascular care, there is still limited guidance on balancing maternal safety and neonatal well-being in this complex setting. This review provides a comprehensive overview of the current evidence on reproductive counseling, pregnancy management, and postpartum considerations in women with cardiomyopathies. We discuss the cardiovascular risks associated with each cardiomyopathy subtype during pregnancy, highlighting risk stratification tools and emerging therapeutic strategies. Additionally, we address the safety and implications of breastfeeding, an often overlooked but increasingly relevant aspect of postpartum care. A multidisciplinary approach involving cardiologists, gynecologists, obstetricians, and anesthesiologists is crucial to optimizing maternal and fetal outcomes. Improved risk assessment, tailored patient counseling, and careful management strategies are essential to ensuring safer reproductive choices for women with cardiomyopathy. From now on, greater attention is expected to be given to bridging existing knowledge gaps, promoting a more personalized and evidence-based approach to managing these patients throughout different stages of reproductive life. Full article

Cardiac magnetic resonance imaging (CMRI) has become an indispensable tool in evaluating arrhythmic risk and guiding therapeutic decisions in patients with non-ischemic cardiomyopathies (NICMs), including dilated (DCM), hypertrophic (HCM), and arrhythmogenic cardiomyopathies (ACM). Both European and American guidelines have given an additive and different value of late gadolinium enhancement (LGE) in specific morpho-functional (hypertrophic, dilated, and arrhythmogenic) phenotypes. In particular, LGE plays a different weight in relation to different cardiomyopathies. In dilated cardiomyopathy, LGE is able to predict arrhythmic risk in relationship to the presence and localization (septal and/or ring like LGE). On the contrary, in HCM, LGE is related to increased risk of cardiac death according to the extent (LGE >15%), while in ACM, it has a greater role in the presence of fat infiltration associated with LGE. In this review, we aim to identify predictors of sudden cardiac death related to myocardial structural features seen in CMRI in cardiomyopathies, going beyond the sole assessment of left ventricular function and ejection fraction. Full article

Sudden cardiac death represents an unexpected death for which a strong underlying genetic background has been described. The primary causes are identified in cardiomyopathies and channelopathies, which are heart diseases of the muscle and electrical system, respectively, without coronary artery disease, hypertension, valvular disease, and congenital heart malformations. Genetic variants, especially single nucleotide variants and short insertions/deletions impacting essential myocardial functions, have shown that cardiomyopathies display high heritability. However, genetic heterogeneity, incomplete penetrance, and variable expression may complicate the interpretation of genetic findings, thus delaying the management of seriously at-risk patients. Moreover, recent studies show that the diagnostic yield related to genetic cardiomyopathies ranges from 28 to 40%, raising the need for further research. In this regard, investigating the occurrence of structural variants, especially copy number variants, may be crucial. Based on these considerations, this review aims to provide an overview of copy number variants identified in cardiomyopathies and discuss them, considering diagnostic yield. This review will ultimately address the necessity of incorporating copy number variants into routine genetic testing for cardiomyopathies and channelopathies, a process increasingly enabled by advances in next-generation sequencing technologies. Full article

Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while many studies based on advanced imaging have suggested the presence of subtle structural alterations. On the other hand, electrophysiological study (EPS) and electroanatomic mapping (EAM) techniques have provided important data regarding right ventricular functional and structural arrhythmic substrate. More recently, histology and immunology shed light on the possible role of fibrotic and inflammatory substrates in BrS. Notably, a significant overlap between electro anatomical and structural features in BrS and arrhythmogenic cardiomyopathy has been proposed. In this review, we summarized the physio pathological pathways and substrate underlying BrS. A deeper knowledge of the structural abnormalities involved in the pathogenesis of this disease could improve our diagnostic and prognostic approach, while novel findings regarding the role of inflammation and immune activation could potentially lead to new therapeutic strategies for BrS. Full article

Cardiomyopathies comprise a heterogeneous group of cardiac disorders characterized by structural and functional abnormalities in the absence of significant coronary artery disease, hypertension, valvular disease, or congenital defects. Major subtypes include hypertrophic, dilated, arrhythmogenic, and stress-induced cardiomyopathies. Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, has emerged as a key contributor to the pathogenesis of these conditions. ROS-mediated injury drives inflammation, protease activation, mitochondrial dysfunction, and cardiomyocyte damage, thereby promoting cardiac remodeling and functional decline. Although numerous studies implicate OS in cardiomyopathy progression, the precise molecular mechanisms remain incompletely defined. This review provides an updated synthesis of current findings on OS-related signaling pathways across cardiomyopathy subtypes, emphasizing emerging therapeutic targets within redox-regulatory networks. A deeper understanding of these mechanisms may guide the development of targeted antioxidant strategies to improve clinical outcomes in affected patients. Full article

Arrhythmogenic cardiomyopathy is a heart disease in which the heart muscle is replaced by scar tissue. This is the main substrate for the development of malignant ventricular arrhythmias. Sudden cardiac death is the most common manifestation and can often be the first sign of the disease, especially in young people. Correct stratification of arrhythmic risk is essential for the management of these patients but remains a challenge for the clinical cardiologist. In this context, the aim of our work was to review the literature and to analyse the most important studies and new developments with regard to the stratification of the risk of arrhythmia in patients suffering from arrhythmogenic cardiopathy. Full article

Background/Objectives: PKP2 (MIM *602861) is the most commonly gene associated with Arrhythmogenic Cardiomyopathy (ACM), an inherited cardiac muscle disorder. The aim of this study was to characterize the phenotypical effect of a heterozygous pathogenic c.2443_2448delAACACCinsGAAA variant in PKP2 gene (NM_004572), detected in two Italian families. Methods: Next Generation Sequencing (NGS) analysis was carried out on two probands, testing a multigenic targeted panel. Segregation analysis through Sanger sequencing detected other three and six positive members, in Family 1 and 2, respectively. Thus, eleven positive patients were identified overall. A deep clinical evaluation was performed according to age groups and clinical parameters (symptoms, electrocardiogram, imaging, and devices). To investigate the molecular effect of the identified variant on PKP2 expression level, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) and quantitative RT-polymerase chain reaction was performed. PKP2 expression at the protein level was analyzed on PBMCs by Western blot analysis. Results: PKP2 transcriptional levels resulted to be reduced by 48% in cells carrying c.2443_2448delAACACCinsGAAA variant compared to WT cells (p = 0.00015). Importantly, Western blot confirmed the reduced level of PKP2 protein in two heterozygous carriers of the variant, confirming the haploinsufficiency effect. Conclusions: The clinical onset of ACM can be Sudden Cardiac Death, and hence, it is recommended to perform a segregation test on first-degree relatives of pathogenic variant carriers, even if they are asymptomatic, with the purpose of promptly detecting those at risk. Full article

Background: Cardiomyopathies are a significant cause of heart failure, arrhythmia, and cardiac morbidity in the general population. Cardiovascular magnetic resonance (CMR) is a valuable tool for the diagnostic work-up of patients with acute cardiac events. Objectives: This study evaluated the diagnostic value of CMR and the yield of cardiomyopathies in hospitalized cardiac patients with acute presentation. Methods: A retrospective analysis was conducted with 535 consecutive hospitalized patients who underwent CMR at Hippokration Hospital, Athens, Greece, to identify a subset of scans performed on an urgent basis of hospitalized patients. Demographic data, causes of admission, CMR findings, and plasma cardiac biomarkers (hs-Troponin I, NT-proBNP, and CRP) were systematically recorded. Results: Out of the initial 535 CMR scans evaluated, a further analysis was conducted with 104 patients who were in hospital and underwent CMR on an urgent basis. From the total population of hospitalized patients, 33% had CMR findings indicative of underlying cardiomyopathy, with dilated cardiomyopathy being the most common subtype (36%), followed by arrhythmogenic cardiomyopathy (27%), hypertrophic cardiomyopathy (15%), or other subtypes (e.g., cardiac amyloidosis, sarcoidosis, endomyocardial fibrosis, EGPA, or unclassified). CMR led to the reclassification of the initial diagnosis into that of underlying cardiomyopathy in 32% of cases. The highest reclassification rate was observed within the subgroup with heart failure (71%), followed by that of acute myocardial infarction/ischemic heart disease (24%) and myocarditis (22%). Conclusions: CMR imaging effectively contributed to the differential diagnosis of hospitalized patients with acute cardiac events that remained without a definitive diagnosis after their initial work-up and uncovered underlying cardiomyopathy in almost one-third of this cohort. Full article

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by fibrofatty replacement of the ventricular myocardium, with an estimated prevalence of 1:5000 people in the general population. Sudden cardiac death is the first manifestation of this disease in 16–23% of patients with ACM. Fibrofatty infiltration can be identified with noninvasive cardiac magnetic resonance. Studies of epicardial fat deposits have suggested pathogenic roles of epicardial fats in mediating cardiac diseases and arrhythmias. Although myocardial fat infiltration has been well described in ACM, changes in epicardial fat deposits with this disease have not been well investigated. Our study shows that patients with ACM have a higher amount of EAT compared to controls. Additionally, the EAT amount seems to increase with the evolution of the disease. Full article

Cardiac sarcoidosis (CS) and inherited cardiomyopathies (inherited CM) are associated with advanced heart failure, cardiac conduction defects, ventricular arrhythmias and sudden cardiac death. Both conditions can have similar clinical presentations. Differentiating between the two disease cohorts is important in delivering specific management to patients, such as immunosuppressive therapy for CS patients and genetic screening for inherited CM. In this review, we examined the existing evidence on the overlap between CS and common inherited CM, such as hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, restrictive cardiomyopathy and dilated cardiomyopathy. In patients where both CS and inherited CM were implicated, CS tended to be diagnosed much later, often when patients presented with complications warranting a workup or cardiac histological confirmation. CS can masquerade as an inherited CM, leading to delays in the instigation of CS therapy. Confirmed dual pathology overlap between inherited CM and CS is rarer. Advanced cardiac imaging, such as cardiovascular magnetic resonance, plays an important role in the clinical workup of both CS and inherited CM. However, findings on cardiac imaging alone often cannot differentiate between the two conditions. Definitive differentiation between CS and inherited CM requires both clinical experience and, at times, a myocardial biopsy. Full article

Acute heart failure (AHF) is a complex clinical syndrome characterized by the rapid or gradual onset of symptoms and/or signs of heart failure (HF), leading to an unplanned hospital admission or an emergency department visit. AHF is the leading cause of hospitalization in patients over 65 years, thus significantly impacting public health care. However, its prognosis remains poor with high rates of mortality and rehospitalization. Many pre-existing cardiac conditions can lead to AHF, but it can also arise de novo due to acute events. Therefore, understanding AHF etiology could improve patient management and outcomes. Cardiomyopathies (CMPs) are a heterogeneous group of heart muscle diseases, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), non-dilated cardiomyopathy (NDLVC), and arrhythmogenic right ventricular cardiomyopathy (ARVC), that frequently present with HF. Patients with CMPs are under-represented in AHF studies compared to other etiologies, and therefore therapeutic responses and prognoses remain unknown. In DCM, AHF represents the most frequent cause of death despite treatment improvements. Additionally, DCM is the first indication for heart transplant (HT) among young and middle-aged adults. In HCM, the progression to AHF is rare and more frequent in patients with concomitant severe left ventricle (LV) obstruction and hypertrophy or severe LV systolic dysfunction. HF is the natural evolution of patients with RCM and HF is associated with poor outcomes irrespective of RCM etiology. Furthermore, while the occurrence of AHF is rare among patients with ARVC, this condition in NDLVC patients is currently unknown. In this manuscript, we assessed the available evidence on AHF in patients with CMPs. Data on clinical presentation, therapeutic management, and clinical outcomes according to specific CMPs are limited. Future HF studies assessing the clinical presentation, treatment, and prognosis of specific CMPs are warranted. Full article

Sudden cardiac death (SCD), the most devastating complication of hypertrophic cardiomyopathy (HCM), is primarily triggered by ventricular tachycardia or fibrillation. Despite advances in knowledge, the mechanisms driving ventricular arrhythmia in HCM remain incompletely understood, stemming from an interplay of multiple pro-arrhythmic factors. Myocyte disarray and myocardial fibrosis form a structural substrate favorable to re-entrant arrhythmias by altering myocardial electrophysiological properties, while cellular abnormalities predominate in patients without evident structural remodeling. Traditional SCD risk prediction models rely on clinical risk factors and regression-based risk estimation, often overlooking specific arrhythmic substrates. Emerging techniques now allow for the direct assessment of these substrates, providing deeper insights into the arrhythmogenic mechanisms and paving the way for more personalized SCD risk stratification. This review explores the contribution of cellular, structural, and electrophysiological substrates to arrhythmic risk in HCM, emphasizing their distinct roles. Furthermore, it highlights the potential of substrate-based approaches to refining SCD prevention strategies and improving outcomes for patients with HCM. Full article