Search Results (140)

Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson–Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories. Full article

Obstructive sleep apnea (OSA) constitutes a chronic disorder characterized by recurrent upper airway collapse during sleep. This condition is prevalent among patients with cardiac rhythm disturbances and represents a potent independent risk factor for arrhythmia. Although most studies have concentrated on the association between OSA and atrial fibrillation (AF), numerous investigations have established connections with ventricular and supraventricular arrhythmias. Arrhythmogenesis in OSA represents a complex multifactorial phenomenon. Acute mechanisms involve induction of negative intrathoracic pressure during the effort to breathe, which triggers recurrent episodes of hypoxia, hypercapnia, alterations in carbon dioxide and acid–base equilibrium, as well as surges in sympathetic nervous system activity. Chronic intermittent hypoxia (CIH) and negative thoracic pressure (NTP) induce atrial stretch, chronic structural remodeling, and elevated vagal tone, thereby heightening susceptibility to bradycardic and conduction arrhythmias. Intermediate pathways through which OSA may precipitate arrhythmia encompass heightened systemic inflammation, oxidative stress, a prothrombotic state, and vascular dysfunction. Long-term OSA is linked with atrial enlargement and fibrosis, ventricular hypertrophy, hypertension, and coronary artery disease. These factors predispose to cardiac arrhythmias through the following mechanisms: shortening of the atrial effective refractory period, abnormal automaticity, promotion of slowed and heterogeneous conduction, enhancement of reentrant arrhythmia persistence, and prolongation of the QT interval. In this paper, we aim to present the pathophysiological mechanisms underpinning the association between obstructive sleep apnea and cardiac arrhythmias. Understanding the precise pathophysiological pathways by which obstructive sleep apnea contributes to arrhythmogenesis will enable targeted preventive stratification of patients at risk for cardiovascular events and promote the development of innovative therapies to attenuate OSA-induced arrhythmogenicity. Full article

Sudden cardiac death (SCD) in athletes often represents the first manifestation of an underlying inherited cardiovascular disorder exposed by adrenergic stress, altered calcium cycling, mechanical loading, and metabolic demand during intense exercise. This review focuses on the molecular architecture that links genotype to arrhythmogenic phenotype in athletes, emphasizing sarcomeric force generation and energetic inefficiency in hypertrophic cardiomyopathy, desmosomal failure and Hippo/Wnt/transforming growth factor-beta (TGF-β) signaling in arrhythmogenic cardiomyopathy, and ion-channel and calcium/calmodulin-dependent protein kinase II (CaMKII)calcium handling abnormalities in inherited channelopathies. This review further examines how exercise-induced physiological remodeling intersects with these pathways through insulin-like growth factor-1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling, mitochondrial biogenesis, oxidative stress, inflammatory signaling, and epigenetic regulation. Attention is given to the molecular basis of genotype-positive/phenotype-negative states, variable penetrance, and exercise-mediated disease expression. Finally, the integration of molecular biology with genomic data, polygenic risk, and emerging digital phenotyping is discussed to refine mechanism-based risk stratification and identify future therapeutic targets for prevention of SCD in athletes. Full article

Post-acute sequelae of SARS-CoV-2 infection (PASC) extend well beyond the acute respiratory phase, with accumulating virological evidence that SARS-CoV-2 RNA, viral antigens, and proteolytic fragments may persist in cardiovascular and other extrapulmonary tissues, although the extent to which such detection represents replication-competent reservoirs versus residual viral material with uncertain pathological relevance remains under active investigation. Sudden cardiac death (SCD) and fatal pulmonary thromboembolism (PTE) have emerged as forensically and epidemiologically significant outcomes in individuals with prior infection, situated at the intersection of microbiology, public health, and forensic medicine. To synthesize current evidence on the virological mechanisms by which SARS-CoV-2 may contribute to post-acute sudden cardiac death (SCD) and pulmonary thromboembolism (PTE), the population-level epidemiology of these outcomes, and their implications for public health surveillance and forensic practice, we conducted a narrative review of PubMed (MEDLINE), Scopus, and Web of Science Core Collection. The search covered publications from January 2020 to December 2025 and focused on SARS-CoV-2 cellular tropism and tissue persistence, immune-mediated and thromboinflammatory mechanisms, excess cardiovascular and thromboembolic mortality, and autopsy-based pathological findings. After de-duplication of 1837 initially identified records (412 duplicates removed) and screening of 1425 unique records, 78 studies were retained for final synthesis based on virological, epidemiological, and forensic relevance. SARS-CoV-2 enters cardiomyocytes, pericytes, and vascular endothelial cells through ACE2-dependent mechanisms, with cathepsin L compensating for the limited cardiac expression of TMPRSS2. Viral RNA and antigen have been detected in cardiovascular and other extrapulmonary tissues months after symptom onset in selected autopsy series, although persistent detection of viral components does not necessarily indicate ongoing productive infection or direct tissue injury. Endothelial dysfunction, neutrophil extracellular trap (NET) formation, complement activation, and persistent thromboinflammation have been proposed as plausible mechanistic substrates for arrhythmogenic remodelling and thromboembolic events, although definitive causal pathways remain incompletely understood. Population-based studies document persistent excess cardiovascular mortality across multiple jurisdictions, with hazard ratios for pulmonary embolism remaining elevated months after acute infection, particularly in unvaccinated individuals. Autopsy series identify mixed pathological patterns including focal lymphocytic infiltrates, microvascular thrombosis, contraction-band necrosis, and cardiomyocyte vacuolation, although fulminant lymphocytic myocarditis fulfilling Dallas criteria remains uncommon. A microbiology-informed framework uniting tissue-based viral detection, standardized cardiac and pulmonary sampling protocols, and prospective post-mortem registries is needed to better characterize the potential contribution of SARS-CoV-2 to post-acute cardiovascular mortality and to support cause-of-death certification, public health surveillance, and medicolegal practice in the post-pandemic era. Many of the proposed mechanisms remain under active investigation, and definitive causal relationships between viral persistence and adverse cardiovascular outcomes have not yet been conclusively established. Full article

Obesity and obstructive sleep apnea (OSA) frequently coexist and synergistically contribute to cardiovascular disease through interconnected mechanical, metabolic, and autonomic mechanisms. This interplay promotes myocardial electrical instability and structural remodeling, favoring the development and persistence of cardiac arrhythmias, particularly atrial fibrillation. Among the key mediators linking obesity to arrhythmogenesis, epicardial adipose tissue has emerged as a relevant factor that may contribute to local pro-inflammatory, pro-fibrotic, and autonomic effects on the myocardium. In parallel, OSA-related intermittent hypoxia and intrathoracic pressure swings further amplify electrical instability and autonomic imbalance, reinforcing a self-sustaining arrhythmogenic substrate. Therapeutic strategies are increasingly shifting toward upstream interventions targeting these underlying mechanisms. Metabolic therapies, including the dual GIP/GLP-1 receptor agonist tirzepatide, have demonstrated substantial weight reduction and improvement in OSA severity, with potential indirect benefits on arrhythmic risk through modulation of visceral adiposity, inflammation, and metabolic dysfunction. On the electrophysiological side, cardioneuroablation has emerged as a potentially investigational option in selected patients with vagally mediated bradyarrhythmias, although its role remains to be fully defined. Overall, these observations support an integrated, phenotype-driven approach combining respiratory therapy, metabolic modulation, and targeted electrophysiological interventions. This framework may help redefine therapeutic priorities, shifting from symptom control toward modification of the underlying arrhythmogenic substrate and improvement of long-term cardiovascular outcomes. Full article

Background: Per- and polyfluoroalkyl substances (PFAS) represent a large class of synthetic fluorinated compounds characterized by highly stable carbon–fluorine bonds that confer exceptional environmental persistence and bioaccumulative properties. Although regulatory measures have restricted the production of several PFAS, including perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), their environmental persistence continues to maintain widespread human exposure, while newly introduced replacement compounds raise additional toxicological concerns. Notably, the recent evidence demonstrating PFAS-induced alterations in key cardiac ion channel activity and electrocardiographic parameters suggest potential electrophysiological mechanisms that may contribute to arrhythmogenesis and cardiac arrhythmias including the most frequent one, atrial fibrillation (AF). Methods: We conducted a narrative literature review of experimental, epidemiological, and mechanistic studies investigating and reporting the cardiovascular, electrophysiological, and potential arrhythmogenic effects of PFAS. Results: Available evidence indicates that PFAS exposure is associated with alterations in cardiac electrophysiology, including modulation of ion channel activity (notably sodium, calcium, and potassium channels), disruption of calcium handling, and changes in electrocardiographic parameters such as QT interval prolongation, which are key contributors to arrhythmogenesis and AF. Conclusions: This review highlights the need for improved understanding of PFAS-induced electrophysiological alterations, to clarify the role of PFAS in cardiac arrhythmias including AF. Full article

Background: Sudden cardiac death (SCD) is a major challenge in dilated (DCM) and non-dilated left ventricular cardiomyopathy (NDLVC). Current management strategies, based on left ventricular ejection fraction (LVEF), the presence or extent of myocardial scar, and selected high-risk genetic variants, are insufficient to accurately identify patients at risk. Mechanical dispersion (MD), derived from speckle-tracking echocardiography, is a potential marker of arrhythmic risk that reflects variability in regional myocardial contraction timing. Aim: The purpose of this narrative review is to synthesize current evidence on the predictive role of MD for ventricular arrhythmias (VA) and SCD in DCM and NDLVC, with particular emphasis on its relationship to myocardial fibrosis (MF) and established echocardiographic markers. Results: Across prospective and retrospective cohorts of DCM patients, increased MD has consistently identified individuals at higher arrhythmic risk, often independently of LVEF and global longitudinal strain (GLS). Reported threshold values for risk prediction range from 50 ms to 90 ms, with hazard ratios confirming incremental prognostic accuracy. The relationship between MD and MF assessed by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) remains uncertain: some patients experience VA in the absence of LGE, while others display elevated MD despite no detectable focal MF, suggesting that additional mechanisms contribute to the arrhythmogenic substrate in DCM and NDLVC. Conclusions: MD may enhance SCD risk stratification in DCM and NDLVC by reflecting components of the arrhythmic substrate that are not detected by conventional markers. Full article

Inherited cardiomyopathies represent a major cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD), frequently occurring in the absence of advanced systolic dysfunction. Traditional strategies for the primary prevention of SCD have relied predominantly on left ventricular ejection fraction (LVEF), an approach that fails to capture the substantial biological and clinical heterogeneity of non-ischemic cardiomyopathies. Over the past decade, advances in cardiac genetics and cardiac magnetic resonance imaging have identified specific genotypes associated with a disproportionate arrhythmic risk, which often precedes overt ventricular remodeling. The 2023 European Society of Cardiology (ESC) Guidelines on cardiomyopathies formalize this paradigm shift by integrating etiology, myocardial substrate, and electrical phenotype into contemporary risk stratification. In this narrative review, we focus on cardiomyopathy-associated genotypes consistently linked to high arrhythmic risk—LMNA, truncating variants in FLNC, RBM20, PLN p.Arg14del, and desmosomal genes—and examine their molecular mechanisms, phenotypic trajectories, and arrhythmogenic profiles. We discuss how genotype-specific patterns of myocardial fibrosis, conduction disease, and VA inform implantable cardioverter-defibrillator (ICD) decision-making beyond LVEF-based thresholds. By synthesizing genetic, imaging, and clinical evidence in light of ESC 2023 recommendations, this review highlights the evolving role of genotype-informed strategies in the personalized prevention of SCD and underscores remaining gaps in evidence and risk prediction. Full article

Cardiac Ca²⁺ handling is critical for excitation–contraction coupling (ECC), with the ryanodine receptor type 2 (RyR2) serving as the key sarcoplasmic reticulum (SR) Ca²⁺ release channel in cardiomyocytes. The dysfunction of RyR2 is linked to fatal cardiac arrhythmias, including heart failure (HF) and catecholaminergic polymorphic ventricular tachycardia (CPVT). This review aims to elucidate the structural basis of RyR2, its core role in cardiac ECC and Ca²⁺ homeostasis, and the regulatory mechanisms of key modulators on its activity. By integrating recent high-resolution cryo-EM structural analyses with molecular and cellular studies on RyR2 regulation, as well as clinical evidence of RyR2 mutations in arrhythmogenic heart diseases, we provide a comprehensive overview of the field. Cryo-EM has unraveled RyR2’s gating mechanisms, ligand-binding sites, and structural features. Functionally, RyR2 mediates calcium-induced calcium release (CICR) and maintains Ca²⁺ homeostasis through coordination with SERCA2a and NCX. Key modulators (CaM, FKBP12.6, and PKA/CaMKII) and disease-linked mutations regulate RyR2 activity through distinct pathways, with defective RyR2 leading to store-overload-induced Ca²⁺ release (SOICR) and arrhythmias. Furthermore, reactive oxygen species (ROS) can induce RyR2 oxidation, establishing a pathological Ca²⁺ leak-ROS cycle in heart disease. In conclusion, RyR2 is a pivotal sensor of myocardial function, with its structural and regulatory mechanisms now well-characterized by recent studies. However, the effects of numerous RyR2 mutations remain unclear, and deeper mechanistic insights will lay a key foundation for developing novel therapies against RyR2-related cardiac diseases. Full article

Background: Cardiovascular implications in systemic lupus erythematosus (SLE) are common and varied, including impacts on the pericardium, myocardium, valves, coronary arteries, and conduction system; all of these could be potential substrates or triggers of cardiac arrhythmias by interfering with disease severity and specific medication. Therefore, this narrative review aimed to assess the cardiac involvement in SLE underlying, mainly, cardiac arrhythmias. Methods: We analyzed studies, published between 2015 and 2025 on PubMed, which explore cardiovascular involvement with a focus on arrhythmias in SLE from the perspectives of epidemiology, underlying mechanisms, diagnostic techniques, and the impact of standard and biologic therapies. Results: The cardiac manifestation of LES (lupus pericarditis, lupus myocarditis, Libman–Sacks endocarditis, coronary artery disease, coronary vasculitis or myocardial fibrosis) represents a substrate for arrhythmia risk. These substrates, in association with other arrhythmias mechanisms considered as triggers or conduction abnormalities, determined arrhythmogenic conditions in these patients. In addition to structural heart disease, arrhythmias in SLE are caused by ongoing inflammation, immune system irregularities, microvascular problems, autonomic imbalance, oxidative stress, and side effects from treatments. Despite this complex background, arrhythmias are often overlooked and not routinely investigated in SLE care. Data that show how disease-modifying drugs may affect arrhythmias are limited and inconsistent, highlighting significant gaps in knowledge. Cardiac arrhythmias are a significant but, as yet, insufficiently underrecognized aspect of SLE, with serious implications for prognosis. Conclusions: Systemic lupus erythematosus causes cardiovascular involvement that is associated with arrhythmias through various and complexes mechanisms, mainly related to direct cardiovascular structural damage, systemic inflammation or specific therapies. Data on arrhythmias secondary to cardiovascular damage in patients with SLE in the literature are limited. Therefore, early detection of electrical issues, regular cardiovascular evaluation in high-risk patients, and careful management of treatment effects are vital. A coordinated, multidisciplinary cardio-rheumatology approach is essential to improving arrhythmia detection, tailoring treatments, and ultimately decreasing cardiovascular complications and deaths in SLE patients. Full article

Cardiomyopathies represent a heterogeneous group of myocardial diseases that share overlapping clinical and genetic profiles but distinct morphological and molecular signatures. Advances in molecular genetics and next-generation sequencing have revolutionized the diagnostic landscape, revealing that up to 60% of cardiomyopathies have an identifiable genetic basis. From a pathologist’s perspective, integrating histopathological findings with molecular data is crucial for understanding genotype–phenotype correlations and for guiding precision medicine. This review provides an updated overview of the molecular pathology of major cardiomyopathy subtypes, including dilated, hypertrophic, restrictive, arrhythmogenic, and non-compaction forms. For each entity, we discuss morphologic hallmarks, genetic mechanisms, and their impact on disease progression and sudden cardiac death. Special emphasis is placed on the role of desmosomal, sarcomeric, and cytoskeletal proteins in myocardial structure and function, and on how their mutations disrupt cardiomyocyte integrity and signaling pathways. Furthermore, we address the emerging role of molecular autopsy in unexplained sudden cardiac death, underscoring the importance of multidisciplinary collaboration among pathologists, geneticists, and clinicians. Finally, we highlight future directions in molecular diagnostics and targeted therapies, which are reshaping the classification and management of cardiomyopathies. Full article

Atrial dilated cardiomyopathy with progression to atrial standstill is an ultrarare arrhythmogenic disorder characterized by complete loss of atrial electrical and mechanical activity. This condition, which may occur sporadically or in familial clusters, is associated with a markedly increased thromboembolic risk. The electrocardiographic hallmark is the absence of P waves combined with a bradycardic junctional escape rhythm. Biatrial enlargement gradually evolves into giant atria with preserved biventricular systolic function, while supraventricular arrhythmias and progressive atrial inexcitability dominate the clinical course. Valvular regurgitation frequently worsens in parallel with atrial remodelling, and patients often require permanent pacemaker implantation as well as lifelong anticoagulation. Among the few genetic determinants identified, the homozygous c.449G>A (p.Arg150Gln) mutation in the Natriuretic Peptide A gene represents one of the best characterized mechanisms. Disertori et al. first reported this pathogenic variant in 13 affected individuals from Italian families, establishing a recessive inheritance pattern. More recently, Silva et al. and Forleo et al. described additional cases, expanding the phenotypic spectrum of NPPA-related atrial cardiomyopathy. These findings confirm that homozygous carriers develop a severe atrial phenotype, whereas heterozygous relatives typically remain asymptomatic, underlining the importance of genetic testing in young patients with unexplained atrial fibrillation or standstill. Recognition of atrial cardiomyopathy as a distinct clinical entity is crucial, since early diagnosis may guide timely anticoagulation, arrhythmia management, and tailored follow-up. Broader adoption of genetic screening in patients with isolated atrial dysfunction could support precision medicine approaches, improve risk stratification, and ultimately prevent adverse outcomes in this ultrarare but highly morbid condition. Full article

Calmodulin (CaM) plays a central role in cardiac excitation–contraction coupling by regulating ion channels, including the L-type calcium (Ca²⁺) channel Ca_v1.2 and the voltage-gated potassium (K⁺) channel K_v7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca²⁺ binding at the C-terminal lobe of CaM, altering its Ca²⁺-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca²⁺-dependent inactivation (CDI) of Ca_v1.2, prolonging Ca²⁺ influx, while also reducing activation of K_v7.1, thereby limiting repolarising K⁺ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca²⁺ and K⁺ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability. Full article

Arrhythmogenic cardiomyopathy (ACM) is a cardiac disorder manifesting through electrical and contractile dysfunction of the ventricles, characterized by fibro-fatty substitution of the myocardium. Cardiac mesenchymal stromal cells (CMSCs) are key contributors to this remodeling. In clinical management, several pharmacological approaches address ACM arrhythmias and heart failure, but, to date, none specifically target fibro-adipose replacement. Despite genetic origin, several studies have reported that non-genetic aspects influence ACM phenotype, including epigenetic factors. Little is known about their mechanisms in ACM and their potential therapeutic applications. In this work, we aimed to test whether, by perturbing the epigenetic landscape of ACM CMSCs, we could influence their propensity to fibro-fatty differentiation. We conducted a hypothesis-free screening of 157 epigenetic drugs on CMSCs, isolated from ACM patients. Through fluorescence assays, we evaluated lipid droplet accumulation, collagen deposition, and cell viability. Of the 157 drugs screened, five (splitomicin, suberohydroxamic acid, CPTH6, BVT-948, and PBIT) attenuated adipogenic differentiation of ACM CMSCs, with BVT-948 and CPTH6 also reducing collagen production. Overall, this study identified specific epigenetic drugs that were effective in reducing the fibro-fatty phenotype of ACM stromal cells, thus offering potential for adjunctive therapies in the clinical management of ACM patients. Full article

Acute myocarditis (AM) is an inflammatory cardiac condition resulting from infections, toxic exposures, or immune-mediated mechanisms, with clinical presentations ranging from mild symptoms to heart failure (HF) or cardiogenic shock. Although viral infections remain the predominant cause, both the absolute prevalence and the relative distribution of different etiologies may change over time and across regions depending on endemic diseases. Immune checkpoint inhibitor (ICI)-associated myocarditis has emerged as a newly recognized entity, with diagnostic rates increasing in parallel with growing awareness and the expanding population of cancer patients eligible for ICI therapy. Additionally, genetic predisposition—particularly mutations linked to arrhythmogenic cardiomyopathy—is also being increasingly acknowledged as a susceptibility factor. Recent advances have markedly improved the diagnostic approach to AM. The availability of high-sensitivity cardiac troponins and the widespread use of cardiac magnetic resonance imaging (CMRI) have enhanced early detection and tissue characterization. CMRI, especially following the updated Lake Louise Criteria (2018), which incorporate T1 and T2 mapping, enables accurate assessment of myocardial inflammation and fibrosis. Endomyocardial biopsy (EMB) remains essential in complicated cases, particularly to identify histologic subtypes that may benefit from immunosuppressive therapy. Early EMB (within 48 h) has been associated with better outcomes in fulminant presentations. The use of immunohistochemistry with leukocyte-specific markers has further increased the sensitivity of EMB. Therapeutic strategies now integrate etiology-specific approaches. Immunosuppressive therapy is indicated for distinct histological forms such as eosinophilic (EM) and giant cell myocarditis (GCM) or cases associated with systemic autoimmune disease. Conversely, in most patients with acute myocarditis complicated by acute HF or cardiogenic shock, no specific treatment is currently recommended beyond evidence-based management of acute HF and general supportive therapy. Full article