Search Results (78)

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

Pathologies of the heart (e.g., ischemic disease, valve fibrosis and calcification, progressive myocardial fibrosis, heart failure, and arrhythmogenic disorders) stem from the irreversible deterioration of cardiac tissues, leading to severe clinical consequences. The limited regenerative capacity of the adult myocardium and the architectural complexity of the heart present major challenges for tissue engineering. However, recent advances in biomaterials and biofabrication techniques have opened new avenues for recreating functional cardiac tissues. Particularly relevant in this context is the integration of biomimetic design principles, such as structural anisotropy, mechanical and electrical responsiveness, and tissue-specific composition, into 3D bioprinting platforms. This review aims to provide a comprehensive overview of current approaches in cardiac bioprinting, with a focus on how structural and functional biomimicry can be achieved using advanced hydrogels, bioprinting techniques, and post-fabrication stimulation. By critically evaluating materials, methods, and applications such as patches, vasculature, valves, and chamber models, we define the state of the art and highlight opportunities for developing next-generation bioengineered cardiac constructs. 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

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

Chronic kidney disease (CKD) is a progressive pathology characterized by gradual function loss. It is accompanied by complications including cardiovascular disorders. This study involves 4-h electrocardiographic records from the Telemetric and Holter ECG Warehouse (THEW) project database to analyze the dynamics in heart rate variability (HRV) indices of 51 patients with CKD. It proposes three algorithms to process long-term electrocardiography records: QRS complex and R-wave detection, premature ventricular contraction (PVC) identification, and tachograms. PVCs were analyzed with the consideration of the changes occurring before, during, and after hemodialysis, especially during the interdialytic period. The hour with the highest PVCs occurrence was identified and used to assess HRV fluctuations and segmented into 5 min blocks with a 0.77 min overlap, yielding a dynamic HRV vector, one for each of seven HRV indices selected to evaluate autonomic nervous system balance. R-wave and PVC identification resulted in 97.53% and 85.83% positive predictive values, respectively. PVCs’ prevalence and HRV changes’ relationship in 48 h records could relate to cardiovascular risk. The stratification of hemodialysis patients into three distinct PVC patterns (p < 0.001) identified two clinically significant high-risk subgroups: Class 1, indicative of electrical instability, and Class 3, of advanced autonomic dysfunction, demonstrating divergent arrhythmogenic mechanisms with direct implications for risk stratification. 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

Anderson–Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by the accumulation of globotriaosylceramide, leading to multi-organ involvement and significant morbidity. Cardiovascular manifestations, particularly arrhythmias, are common and pose a considerable risk to affected individuals. This overview examines current approaches to arrhythmic risk stratification in AFD, focusing on the identification, assessment, and management of cardiac arrhythmias associated with the disease. We explore advancements in diagnostic techniques, including echocardiography, cardiac MRI, and ambulatory ECG monitoring, to enhance the detection of arrhythmogenic substrate. Furthermore, we discuss the role of genetic and biochemical markers in predicting arrhythmic risk and the implications for personalized treatment strategies. Current therapeutic interventions, including enzyme replacement therapy and antiarrhythmic medications, are reviewed in the context of their efficacy and limitations. Finally, we highlight ongoing research and future directions with the aim of improving arrhythmic risk assessment and management in AFD. This overview underscores the need for a multidisciplinary approach to optimize care and outcomes for patients with AFD. Full article

Brugada syndrome (BrS) is an inherited arrhythmogenic disorder characterized by distinct electrocardiographic patterns and an increased risk of sudden cardiac death due to ventricular arrhythmias. Effective management of BrS is essential, particularly for high-risk patients with recurrent arrhythmias. While implantable cardioverter–defibrillator (ICD) is effective in terminating life-threatening arrhythmias, it does not prevent arrhythmia onset and can lead to complications such as inappropriate shocks. Epicardial ablation has emerged as a promising treatment option for patients with recurrent ventricular arrhythmias and frequent ICD interventions. This review examines the latest advancements in the management of Brugada syndrome, focusing on the role and rationale of epicardial ablation for the treatment of patients at risk of sudden cardiac death. Full article

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by fibrofatty replacement of myocardial tissue, predominantly affecting the right ventricle (RV), but often involving the left ventricle (LV) as well. The early detection of fibrosis, crucial for risk stratification, has been enhanced by advanced imaging techniques. Global longitudinal strain (GLS) has shown promise as a surrogate marker for late enhancement (LE) in identifying myocardial fibrosis, yet precise cut-off values for strain are lacking. The aim of the study is to evaluate LV strain as a predictor of LE in ACM and to define strain cut-offs for early fibrosis detection, enhancing non-invasive diagnostic accuracy. Methods: This retrospective single-center study included 64 patients diagnosed with ACM. Echocardiographic analysis using speckle-tracking echocardiography was performed to assess LV strain. LE was evaluated through cardiac magnetic resonance (CMR) or via cardiac computed tomography (CCT) in cases with CMR contraindications. The study aimed to correlate regional LV strain values with the presence of LE, identifying cut-off values predictive of fibrosis. Results: The study found significant correlations between reduced LV strain values and the presence of LE, particularly in the anterolateral and inferolateral segments (p < 0.05). Specific strain thresholds, such as those for segment 12 (p = 0.02) and segment 17 (p = 0.03), were identified as predictive markers for LE. These findings suggest that strain imaging could serve as a non-invasive tool for the early detection of myocardial fibrosis in ACM patients. Conclusions: LV strain analysis offers potential as a non-invasive surrogate marker for myocardial fibrosis in ACM. Incorporating strain imaging into routine echocardiographic evaluations could improve early diagnosis and risk stratification, guiding patient management. Full article

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic disorder associated with an elevated risk of life-threatening arrhythmias and progressive ventricular impairment. Risk stratification is essential to prevent major adverse cardiac events (MACE). Our study aimed to investigate the incremental value of strain measured by two-dimensional speckle-tracking echocardiography in predicting MACE in ARVC patients compared to conventional echocardiographic parameters. Methods and Results This was a retrospective, single-centre cohort study of 83 patients with ARVC (51% males, median age 37 years (IQR: 23, 53)) under the care of the Inherited Cardiac Conditions clinic at University Hospital Birmingham. MACE was defined as one of the following: sustained ventricular tachycardia (Sus VT), ventricular fibrillation (VF), appropriate implantable cardio-defibrillator (ICD) therapy [shock/anti-tachycardia pacing (ATP)], heart failure (defined as decompensated heart failure, cardiac index by heart catheter, HF medication, and symptoms), cardiac transplantation, or cardiac death. Echocardiography images were analysed by a single observer for right ventricle (RV) and left ventricular (LV) global longitudinal strain (GLS). Multivariable Cox regression was performed in combination with RV fractional area change and tricuspid annular plane systolic excursion. During three years of follow-up, 12% of patients suffered a MACE. ARVC patients with MACE had significantly reduced RV GLS (−13 ± 6% vs. −23 ± 6%, p < 0.001) and RV free wall longitudinal strain (−15 ± 5% vs. −25 ± 7%, p < 0.001) compared to those without MACE. Conclusions Right ventricular free wall longitudinal strain (RVFWLS) may be a more sensitive predictor of MACE than conventional echocardiographic parameters of RV function. Moreover, RV-free wall longitudinal strain may have superior predictive value compared to RV GLS. Full article

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder responsible for nearly a quarter of sports-related sudden cardiac deaths. ACM cases caused by mutations in desmosome proteins lead to right ventricular enlargement, the loss of cardiomyocytes, and fibrofatty tissue replacement, disrupting electrical and mechanical stability. It is currently unknown how paracrine factors secreted by infiltrating fatty tissues affect ACM cardiomyocyte electrophysiology. Methods: A normal and a PKP2 mutant (c.971_972InsT) ACM hiPSC line were cultivated and differentiated into cardiomyocytes (CMs). Adipocytes were differentiated from human adipose stem cells, and adipocyte conditioned medium (AdCM) was collected. Optical mapping and phenotypic analyses were conducted on human iPSC-cardiomyocytes (hiPSC-CMs) cultured in cardiac maintenance medium (CMM) and either with AdCM or specific cytokines. Results: Significant differences were observed in voltage parameters such as the action potential duration (APD₈₀, APD₃₀), conduction velocity (CV), and CV heterogeneity. When cultured in AdCM relative to CMM, the APD₈₀ increased and the CV decreased significantly in both groups; however, the magnitudes of changes often differed significantly between 1 and 7 days of cultivation. Cytokine exposure (IL-6, IL-8, MCP-1, CFD) affected the APD and CV in both the normal and PKP2 mutant hiPSC-CMs, with opposite effects. NF-kB signaling was also found to differ between the normal and PKP2 mutant hiPSC-CMs in response to AdCM and IL-6. Conclusions: Our study shows that hiPSC-CMs from normal and mPKP2 ACM lines exhibit distinct molecular and functional responses to paracrine factors, with differences in RNA expression and electrophysiology. These different responses to paracrine factors may contribute to arrhythmogenic propensity. Full article

Mutations in the ryanodine receptor (RyR2) gene have been linked to arrhythmia and possibly sudden cardiac death (SCD) during acute emotional stress, physical activities, or catecholamine perfusion. The most prevalent disorder is catecholaminergic polymorphic ventricular tachycardia (CPVT1). Four primary mechanisms have been proposed to describe CPVT1 with a RyR2 mutation: (a) gain-of-function, (b) destabilization of binding proteins, (c) store-overload-induced Ca²⁺ release (SOICR), and (d) loss of function. The goal of this study was to use computational models to understand these four mechanisms and how they might contribute to arrhythmia. To this end, we have developed a local control stochastic model of a ventricular cardiac myocyte and used it to investigate how the Ca²⁺ dynamics in the mutant RyR2 are responsible for the development of an arrhythmogenic episode under the condition of β-adrenergic (β-AR) stimulation or pauses afterward. Into the model, we have incorporated 20,000 distinct cardiac dyads consisting of stochastically gated L-type Ca²⁺ channels (LCCs) and ryanodine receptors (RyR2s) and the intervening dyadic cleft to analyze the alterations in Ca²⁺ dynamics. Recent experimental findings were incorporated into the model parameters to test these proposed mechanisms and their role in triggering arrhythmias. The model could not find any connection between SOICR and the destabilization of binding proteins as the arrhythmic mechanisms in the mutant myocyte. On the other hand, the model was able to observe loss-of-function and gain-of-function mutations resulting in EADs (Early Afterdepolarizations) and variations in action potential amplitudes and durations as the precursors to generate arrhythmia, respectively. These computational studies demonstrate how GOF and LOF mutations can lead to arrhythmia and cast doubt on the feasibility of SOICR as a mechanism of arrhythmia. Full article

The electrical arrhythmogenic substrate underlying the most common cardiac arrhythmia atrial fibrillation (AF) may consist of conduction disorders, low-voltage areas, or fractionated potentials. High-density and resolution epicardial mapping (HDREM) approaches have been introduced to quantify and visualize electrophysiological properties of the atria. These approaches are essential for obtaining innovative insights into arrhythmogenic substrates and identifying novel targets for therapy. The aim of this review is to summarize and discuss the (1) contribution of HDREM studies to the knowledge on atrial arrhythmogenesis and (2) future applications of HDREM of atria in daily clinical practice. Full article