Search Results (525)

Atrial cardiomyopathy (ACM) is defined as any complex of structural, architectural, functional, electrophysiological, and molecular changes affecting the atria that may result in clinically significant health consequences. ACM can be caused by a variety of factors, including age-related changes, valvular or vascular disease, genetic diseases, congestive heart failure, metabolic diseases, cardiovascular disease (CVD) risk factors such as arterial hypertension (AH) or obesity, obstructive sleep apnea, and other infectious or noninfectious diseases predisposing to chronic inflammation. The diagnosis of ACM relies on several modalities, including electrocardiography, echocardiography, cardiac magnetic resonance imaging (MRI), computed tomography (CT), electroanatomical mapping (EAM), genetic studies, and biomarkers, which can detect and characterize structural, mechanical, and electrical atrial dysfunction. These changes often include structural atrial remodeling (fibrosis), abnormal structure of the atrial wall and its components, and contractile and electrical dysfunctions. When assessing aspects of ACM, structural changes in the atria such as left atrium (LA) size and fibrosis; LA architectural changes such as the expression of remodeling; changes in LA mechanics such as echocardiographic stress indices; changes in reservoir function and changes in contraction; biological factors determining changes in biomarkers; possible genetic predispositions and higher expression of certain genes encoding certain proteins; and arrhythmogenic factors associated with a higher risk of atrial fibrillation (AF) and stroke and a worse short- and long-term prognosis are very important. When considering the challenges of diagnosing ACM, it should be noted that without standardized diagnostics, most ACM diagnostic situations remain primarily research tools rather than practical clinical diagnostic methods. This review critically evaluates the evidence and translational gaps in the diagnosis of ACM, synthesizing the emerging role of advanced diagnostics and their clinical and prognostic implications as a key future tool for individual risk stratification. Full article

Sports cardiologists frequently face the challenge of distinguishing physiological cardiac adaptation to intensive training (“athlete’s heart”) from early or mild cardiac pathology, a dilemma in which both false-positive and false-negative assessments carry meaningful consequences for the athlete. Cardiopulmonary exercise testing (CPET) provides a dynamic, functional complement to structural and electrical assessment, but its value in this specific differential-diagnosis context has not been comprehensively synthesized. This narrative review examines current evidence on CPET in distinguishing athlete’s heart from hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, and thoracic wall deformities such as pectus excavatum, alongside the physiological basis of high exercise capacity in athletes and the athlete-specific reference values now becoming available. Across conditions, peak oxygen uptake alone proved an unreliable discriminator. Ventilatory efficiency, oxygen-pulse kinetics, and the exercise arrhythmic and blood-pressure response appear to carry additional information when interpreted within a multiparametric framework, although the supporting studies are observational, mostly single-centre, and were not designed to compare these variables against one another. Special populations, including veteran athletes, women, and those with congenital heart disease, require dedicated reference data that remain incomplete, and emerging artificial-intelligence-based interpretive tools require athlete-specific validation before clinical adoption. A practical, stepwise diagnostic framework integrating CPET with imaging and shared decision-making is proposed. It reflects the authors’ synthesis of the reviewed evidence rather than a prospectively validated or society-endorsed pathway. Closing the evidence gaps identified here, particularly for underrepresented athlete populations and prospective outcomes data, should be a priority for future research in sports cardiology. Full article

Myocardial infarction is a major cause of cardiovascular death and a key substrate for sudden cardiac death. Traditionally, histopathological analysis of infarction has focused on the temporal sequence of morphological changes, from coagulative necrosis to inflammatory infiltrate and cicatricial fibrosis. However, recent molecular studies have highlighted how these processes are tightly regulated by cell death pathways, including apoptosis, autophagy, and ferroptosis, and by electrical and microvascular remodeling mechanisms that contribute to cardiac instability. This review integrates histopathological and molecular evidence relating to post-infarction evolution, with particular attention to the infarct border zone, the privileged substrate for arrhythmogenesis. Key molecular markers and cells involved in the inflammatory response and wound healing are discussed, as well as implications for ventricular reentry circuit formation and sudden cardiac death risk. An integrated understanding of these mechanisms offers innovative perspectives for the identification of predictive biomarkers and the development of therapeutic strategies aimed at reducing post-infarction arrhythmic outcomes. Full article

Cardiac contractility modulation (CCM) is an implantable device-based therapy that delivers biphasic, non-excitatory electrical signals to the ventricular myocardium during the absolute refractory period. By enhancing contractile performance without inducing depolarization or altering ventricular activation, CCM acts as bioelectronic myocardial conditioning. Current evidence supports its use in selected patients with symptomatic heart failure, reduced or mildly reduced left ventricular ejection fraction, narrow QRS duration, persistent symptoms despite guideline-directed medical therapy, and no indication for cardiac resynchronization therapy. In this population, CCM improves functional status and quality of life, whereas evidence for reductions in mortality or recurrent heart failure hospitalization remains less definitive. Whether CCM also reduces arrhythmic burden remains uncertain. Candidates for CCM frequently exhibit atrial and ventricular remodeling, neurohormonal activation, implantable cardioverter-defibrillators, and vulnerability to atrial fibrillation, ventricular arrhythmias, and device therapies. Mechanistically, CCM may render the failing myocardium less arrhythmogenic through coordinated effects on calcium handling, electromechanical remodeling, fibrosis-related substrate, contractile efficiency, and heart-failure stability. However, pivotal trials were not designed to assess arrhythmic endpoints, leaving the relationship between CCM and arrhythmic burden insufficiently characterized. This review summarizes CCM evidence, mechanistic rationale, available arrhythmic signals, device-related considerations, and future research priorities for prospective studies in this evolving field. Full article

Cardiovascular diseases (CVDs) remain the foremost cause of death globally, responsible for 19.2 million deaths and 437 million disability-adjusted life years in 2023, with prevalent cases having more than doubled since 1990. No approved therapy restores myocardium lost to infarction. The adult heart replaces cardiomyocytes at approximately 1% per year in young adults, declining to about 0.45% per year with ageing, far below what is needed to recover the more than one billion cells destroyed by a large myocardial infarction. Cell-based regenerative strategies have been investigated for more than two decades, encompassing bone marrow mononuclear cells (BM-MNCs), mesenchymal stromal cells (MSCs), cardiac progenitor cells, cardiosphere-derived cells (CDCs), skeletal myoblasts, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Safety has been consistent. Efficacy has been modest and variable: the CADUCEUS trial demonstrated scar mass reduction with CDCs without proportionate ejection fraction improvement; the Phase 1/2 POSEIDON trial confirmed MSC safety in 30 patients; and the Phase 3 DREAM-HF trial, enrolling 537 patients, failed its primary endpoint (HR 1.2, p = 0.406). Mechanistic work has established that transplanted cells engraft poorly and exert their benefit principally through paracrine signalling mediated by secreted extracellular vesicles and exosomes carrying microRNAs, trophic factors, and immunomodulatory proteins. For iPSC-CMs, electrophysiological immaturity and arrhythmogenic risk in primate models remain unresolved barriers. Emerging strategies include CRISPR-engineered hypoimmune iPSC lines, bioengineered cardiac patches, injectable hydrogel scaffolds, and engineered exosome platforms. This review provides a comprehensive synthesis of preclinical and clinical evidence, examines translational barriers, and identifies the scientific and regulatory priorities required before these therapies can enter routine clinical practice. Full article

Radiofrequency catheter ablation is a minimally invasive electrophysiological procedure that utilizes radiofrequency energy to induce targeted thermal injury within arrhythmogenic myocardial tissue, thereby eliminating the substrate responsible for rapid and irregular cardiac rhythm disturbances. Radiofrequency ablation is a method widely used in human medicine for the permanent treatment of arrhythmias. In veterinary medicine, there are only a few centers worldwide that use this treatment method in dogs. This article presents the experiences of a Polish center in treating supraventricular and ventricular arrhythmias using this method. The first electrophysiological study and ablation were performed using an analog electrophysiological system; subsequent procedures were performed with the aid of a computerized system, and the last three procedures were performed using a 3D electroanatomical system. A total of 14 radiofrequency ablation procedures were performed on dogs weighing 10 to 33 kg, aged 9 months to 9 years, of various sexes and breeds. Fifty percent of the dogs that underwent ablation had both clinical and echocardiographic signs of tachycardia-induced cardiomyopathy. Three dogs required a re-ablation procedure. Complete elimination of clinically significant arrhythmias was achieved in 13 of 14 dogs, while one dog showed partial procedural success. No significant or permanent complications were observed in any of the dogs. Radiofrequency ablation procedures for arrhythmias are effective and safe. Full article

Introduction: Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by fibrofatty replacement of the myocardium and is associated with heart failure and sudden cardiac death. It can involve either ventricle, including left-dominant forms defined partly by genetic findings. Methods: We investigated a consanguineous family with four affected daughters presenting with ACM, epidermolytic palmoplantar keratoderma, and woolly hair. The two eldest siblings died suddenly during childhood. The remaining two affected siblings underwent genetic analysis using autozygosity mapping and whole-exome sequencing, followed by segregation analysis. Results: Autozygosity mapping identified a shared identity-by-descent (IBD) interval at the DSP locus on chromosome 6. Exome sequencing revealed a novel homozygous nonsense variant (c.4297C>T; p.Gln1433*; rs1554108283) in exon 23 of DSP. This variant introduces a premature termination codon within the region specific to transcript variant 1, sparing transcript variant 2. Both parents were heterozygous carriers. Cardiac imaging in the affected siblings demonstrated biventricular involvement, including left ventricular systolic dysfunction and right ventricular dilatation. Skin biopsy in one patient confirmed epidermolytic palmoplantar keratoderma. Conclusions: We describe a novel homozygous nonsense variant in the transcript 1-specific region of DSP causing Carvajal syndrome, characterized by severe biventricular ACM, epidermolytic palmoplantar keratoderma, and woolly hair, in a consanguineous Arabian family with four affected sisters. Full article

Background: Inherited arrhythmic syndromes (IAS) are an important but under-recognized cause of sudden cardiac death (SCD), particularly in younger individuals. Understanding long-term mortality trends is essential to evaluate their public health impact. Objective: To assess temporal trends and demographic disparities of IAS-related sudden cardiac death among individuals aged 5–44 years in the United States using CDC WONDER data. Methods: This retrospective observational study utilized the CDC WONDER Multiple Cause-of-Death database from 1999 to 2024. Deaths were identified using ICD-10 codes for non-ischemic arrhythmogenic conditions (I42, I44, I45, I47, I49) in combination with sudden cardiac arrest or unexplained death (I46, R96). Ischemic heart disease (I20–I25) was excluded to enhance specificity for inherited causes. Crude and age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated and stratified by age, sex, race/ethnicity, region, urbanization, and place of death. Joinpoint software helped us calculate the average annual percentage change (AAPC)/annual percent change (APC) in AAMRs and the 95% CIs for these changes. Results: A total of 8879 deaths were identified over the study period. The AAMR increased from 1.46 (95% CI: 1.27–1.64) in 1999 to 3.15 (95% CI: 2.89–3.42) in 2024, peaking at 4.54 in 2021, with an overall AAPC of 3.71% (p < 0.000001). Mortality was higher in males; however, females demonstrated a greater relative increase over time. Non-Hispanic Black individuals exhibited the highest mortality rates and fastest rise. The 25–44-year age group accounted for most deaths and showed the steepest increase. Regional and urban–rural disparities were observed, with higher mortality rates in the South and rural areas. Conclusions: It is concluded that mortality related to inherited arrhythmic syndromes and sudden cardiac death is rising among young individuals in the United States. The findings highlight a growing burden of potentially inherited arrhythmogenic conditions and underscore the need for early detection strategies, including genetic screening and targeted public health interventions, to reduce premature cardiovascular mortality. Full article

Objectives: Sudden cardiac death (SCD) is a leading cause of mortality, accounting for approximately 50% of all cardiovascular deaths and 20% of all-natural deaths in Western countries. In individuals over 50 years of age, coronary artery disease (CAD) is responsible for more than 80% of cases, whereas in younger subjects SCD is more frequently associated with non-ischemic myocardial diseases, including hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM), and myocarditis. Additional causes in young adults include coronary artery anomalies and primary arrhythmic disorders related to channelopathies. This study evaluated the diagnostic performance of post-mortem cardiac magnetic resonance imaging (PM-CMR) in identifying morphological substrates underlying SCD in formalin-fixed explanted hearts, with particular attention to the concordance between PM-CMR findings and autopsy results in cases of sudden coronary death. Material and Methods: We retrospectively reviewed 110 PM-CMR examinations from the Regional Register of Sudden Cardiac Death of Friuli-Venezia Giulia, of which 101 were included in the final analysis. Results: PM-CMR detected pathological findings in 60 hearts (59%), including acute ischemic lesions in 39 cases and other conditions, such as hypertrophic cardiomyopathy, chronic fibrotic ischemic changes, and adipose metaplasia in 21 cases. A good agreement between PM-CMR and autopsy findings was observed (Cohen’s kappa = 0.8). Conclusions: Overall, PM-CMR proved effective in identifying relevant morphological and signal alterations, supporting conventional autopsy. Despite some limitations, particularly in hyperacute ischemic lesions, PM-CMR appears to play a promising role in the diagnostic work-up of SCD and in supporting family screening programs for primary prevention. Full article

Ventricular tachycardia and sudden cardiac death remain the principal late causes of mortality in repaired tetralogy of Fallot. Clinical practice is evolving from a “reactive” paradigm centered on defibrillator therapy and post-event ablation toward a “proactive” paradigm targeting slowly conducting anatomical isthmuses before clinical arrhythmias become manifest. Monomorphic ventricular tachycardia in this population typically occurs due to a discrete, anatomically defined set of slowly conducting isthmuses bounded by surgical patches or incisions and valve annuli. Substrate-targeted catheter and surgical ablation are technically feasible, safe, and associated with high arrhythmia-free survival when complete bidirectional block is achieved. The current indication for “proactive” ablation is for substrate evaluation before transcatheter pulmonary valve replacement, after which endocardial access to the dominant isthmus may be permanently obscured. Pulmonary valve replacement alone does not abolish the arrhythmogenic substrate, thus providing the rationale for combining valve intervention with proactive ablation. This narrative review discusses substrate biology, risk stratification, comparative outcomes of reactive and proactive ablation strategies, and the role of pulmonary valve replacement. It also proposes an operational pathway integrating both approaches within shared decision-making. The ongoing CATAPULT-TOF study and subsequent multicenter work will determine the populations in which proactive substrate evaluation should become routine. Full article

During acute coronary occlusion, ischemia is a major determinant of the cell response to subsequent reperfusion and is the major precursor of the typical “ischemia–reperfusion injury” (IRI). Therefore, elucidating the full IRI process primarily relies on a good understanding of ischemia-induced alterations. Ischemic arrhythmias frequently arise during the acute phase of a myocardial infarction (MI) and originate in the terminal arborisations of the cardiac conduction system. These ventricular arrhythmias are triggered by abnormal Ca²⁺-dependent depolarisations (DADs) of Purkinje cells (Pcells) due to increased spontaneous Ca²⁺ release by the sarcoplasmic reticulum (SR). This early alteration of the conduction tissue is also likely to provide a substrate for IRI-related arrhythmogenicity. Recent evidence associates the ischemic phase of the MI with a significant increase in SERCA2 pump expression in Pcells, suggesting that enhanced SR-Ca²⁺ release results from an augmentation of Ca²⁺ sequestration by the SR in those cells. We examined this hypothesis by assessing the impact of ischemia on the dynamics of SR-Ca²⁺ uptake in live Pcells by high-resolution confocal microscopy in a classical canine model of LAD coronary ligation. Pcells from five normal hearts were compared with cells from five hearts 48 Hrs after coronary occlusion. Purkinje-specific Ca²⁺ events, namely peripheral Ca²⁺ wavelets (Wlets) and central cell-wide waves (CWWs), were analysed to assess the regional SR-Ca²⁺ transport of Pcells. A total of 83 normal and 126 MI Wlets, along with 10 normal and 30 MI CWWs, were analysed to compare the peripheral and central SR-Ca²⁺ transports of Pcells between normal and ischemic hearts. Forty-eight hours following the onset of ischemia, individual SR-Ca²⁺ release sites exhibited a 60% increase in Ca²⁺ spark firing rate. However, the site density remained unchanged, indicating an acceleration of intra-SR-Ca²⁺ cycling rather than direct alteration of the SR-Ca²⁺ release channels. While central CWWs remained unchanged, a 37% acceleration of resting Ca²⁺ restoration was readily visible in peripheral Wlets, consistent with enhanced SR-Ca²⁺ uptake at the cell periphery. Computational modelling reproduced these findings when the Ca²⁺ uptake rate was numerically increased by 35%, confirming that augmented SERCA activity is sufficient to explain the pro-arrhythmic SR-Ca²⁺ release of Pcells after MI. Our findings confirm that the augmentation of Ca²⁺ pump density in the periphery of Pcells is associated with an increase in SR-Ca²⁺ uptake, explaining the arrhythmogenicity of Purkinje fibres in an ischemic heart. This ischemia-mediated pro-arrhythmic remodelling of intracellular Ca²⁺ handling in the conduction system is also likely to contribute to triggered activity during subsequent reperfusion. Full article

Obesity increases susceptibility to ventricular arrhythmias due to an arrhythmogenic substrate by promoting oxidative stress and inflammation-driven cardiac remodeling. Klotho, an anti-aging protein that is reduced in obesity-related cardiovascular disease, protects against oxidative injury and inflammation. Berberine (BBR) has been demonstrated to have antiarrhythmic properties, but Klotho mediates these effects in obesity remains unclear. Here, high-fat diet (HFD)-induced obese rats were treated with BBR for 8 weeks. Surface electrocardiography showed BBR shortened prolonged QT, QTc, and Tp-Te intervals. Optical mapping of isolated hearts revealed that BBR eliminated arrhythmia susceptibility (60% to 0%) and stabilized cardiac electrophysiology by shortening action potential duration (APD₅₀/APD₉₀), reducing repolarization dispersion, normalizing conduction velocity, and improving abnormal intracellular Ca²⁺ handling. BBR also attenuated cardiac hypertrophy and fibrosis and increased expression of the potassium channel subunits Kv4.2, Kv4.3, and KChIP2. Furthermore, BBR suppressed oxidative stress and inflammation while upregulating circulating and tissue Klotho levels in obese rats. In ox-LDL-treated H9C2 cells, Klotho silencing abolished the antioxidative and anti-inflammatory effects of BBR, indicating that Klotho is required for its cardioprotective actions. These findings demonstrate that BBR stabilizes the arrhythmogenic substrate in obesity-related cardiac remodeling, at least partly through upregulation of Klotho expression and subsequent attenuation of oxidative stress and inflammation. Full article

Background: Cerebral aneurysms and aneurysmal subarachnoid hemorrhage (aSAH) may induce cardiac electrical instability through autonomic dysregulation and an exaggerated neurohumoral stress response. Electrocardiographic (ECG) abnormalities, including QT/QTc prolongation, QTc dispersion, and P-wave dispersion, are recognized markers of ventricular repolarization heterogeneity and atrial conduction abnormalities associated with arrhythmogenic risk. However, data regarding the reversibility of these electrophysiological alterations following definitive aneurysm treatment remain limited. Methods: This retrospective, single-center study included 39 patients with cerebral aneurysms who underwent microsurgical clipping between January 2025 and May 2026 and 35 age- and sex-matched healthy controls. Standard 12-lead ECGs were evaluated at baseline (preoperative) and one month after surgery in the aneurysm group. QT interval, corrected QT (QTc) interval, QTc dispersion, and P-wave dispersion were assessed using standardized methods. Baseline transthoracic echocardiographic parameters, including left ventricular ejection fraction and left atrial diameter, were evaluated to minimize potential confounding related to structural cardiac abnormalities. Between-group and within-group comparisons were performed using appropriate statistical analyses. Results: Baseline demographic and echocardiographic characteristics were comparable between the aneurysm and control groups. Patients with cerebral aneurysms demonstrated significantly higher baseline QT interval, QTc interval, QTc dispersion, and P-wave dispersion compared with healthy controls. Following microsurgical treatment, significant reductions in QT interval, QTc interval, QTc dispersion, and P-wave dispersion were observed at one month compared with preoperative values, whereas PR interval and QRS duration remained unchanged. These findings suggest a partial normalization of cardiac electrical heterogeneity after definitive aneurysm treatment. Conclusions: Cerebral aneurysms are associated with increased ventricular repolarization and atrial conduction heterogeneity, reflecting autonomic-mediated cardiac electrical instability. The significant reduction in QTc dispersion and P-wave dispersion following microsurgical treatment suggests that these electrophysiological abnormalities may be at least partially reversible after aneurysm repair. ECG-derived markers such as QTc dispersion and P-wave dispersion may represent practical and non-invasive tools for monitoring cardiac electrical instability and recovery in patients with cerebral aneurysms. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

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