Explore the vast range of titles available.

Over 700 patients with drug-refractory paroxysmal atrial fibrillation were randomly assigned to cryoballoon or radiofrequency ablation. Cryoballoon ablation was noninferior to radiofrequency for the composite of recurrent atrial arrhythmia, use of antiarrhythmic drugs, or repeat ablation. According to a 2012 expert consensus statement, catheter ablation of drug-refractory paroxysmal atrial fibrillation is a class I level A indication, 1 and pulmonary-vein isolation is the standard approach. 1 – 3 The two most frequently used ablation technologies for pulmonary-vein isolation differ in the energy source and mode of application. The most common method is the use of radiofrequency current applied in a point-by-point mode, which leads to cellular necrosis by tissue heating; the other method is the use of cryogenic energy applied with a balloon in a single-step mode, which leads to necrosis by freezing (Figure 1). Radiofrequency ablation for atrial . . .

PurposeWe present the preliminary results of the STRA-MI-VT Study (NCT04066517), a spontaneous, phase Ib/II study, designed to prospectively test the safety and efficacy of stereotactic body radiotherapy (SBRT) in patientswith advanced cardiac disease and intractable ventricular tachycardia (VT).MethodsCardiac computed tomography (CT) integrated by electroanatomical mapping was used for substrate identification and merged with dedicated CT scans for treatment plan preparation. A single 25-Gy radioablation dose was delivered by a LINAC-based volumetric modulated arc therapy technique in a non-invasive matter. The primary safety endpoint was treatment-related adverse effects during acute and long-term follow-up (FU), obtained by regular in-hospital controls and implantable cardioverter defibrillator (ICD) remote monitoring. The primary efficacy endpoint was the reduction at 3 and 6 months of VT episodes and ICD shocks.ResultsSeven out of eight patients (men; age, 70 ± 7 years; ejection fraction, 27 ± 11%; 3 ischemic, 4 non-ischemic cardiomyopathies) underwent SBRT. At a median 8-month FU, no treatment-related serious adverse event occurred. Three patients died from non-SBRT-related causes. Four patients completed the 6-month FU: the number of VT decreased from 29 ± 33 to 11 ± 9 (p = .05) and 2 ± 2 (p = .08), at 3 and 6 months, respectively; shocks decreased from 11 to 0 and 2, respectively. At 6 months, all patients. showed a significant reduction of VT episodes and no electrical storm recurrence, with the complete regression of iterative VTs in 2/2 patients.ConclusionThe STRA-MI-VT Study suggests that SBRT can be considered an alternative option for the treatment of VT in patients with structural heart disease and highlights the need for further clinical investigation addressing safety and efficacy.

Sudden cardiac death in athletes is a relatively rare event, but due to the increasing number of individuals practicing high-performance sports, in absolute terms, it has become an important issue to be addressed. Since etiologies are many and the occurrence is rare, tracing the ideal preparticipation screening program is challenging. So far, as screening tools, a comprehensive clinical evaluation and a simple 12-lead electrocardiogram (ECG) seem to be the most cost-effective strategy. Recent technological advances came to significantly help as second-line investigation tools, especially the cardiac magnetic resonance, which allows for a more detailed ventricular evaluation, cardiac tissue characterization, and eliminates the poor acoustic window problem. This article aims to review all aspects related to sudden cardiac death in athletes, beginning with definitions and epidemiology, passing through etiology and clinical characteristics, then finishing with a discussion about the best ambulatory investigational approach.

Primary cardiac mesenchymal stromal cells (C-MSCs) can promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM) by differentiating into adipocytes and myofibroblasts. These cells’ limitations, including restricted access to primary material and its manipulation have been overcome by the advancement of human induced pluripotent stem cells (hiPSCs), and their ability to differentiate towards the cardiac stromal population. C-MSCs derived from hiPSCs make it possible to work with virtually unlimited numbers of cells that are genetically identical to the cells of origin. We performed in vitro experiments on primary stromal cells (Primary) and hiPSC-derived stromal cells (hiPSC-D) to compare them as tools to model ACM. Both Primary and hiPSC-D cells expressed mesenchymal surface markers and possessed typical MSC differentiation potentials. hiPSC-D expressed desmosomal genes and proteins and shared a similar transcriptomic profile with Primary cells. Furthermore, ACM hiPSC-D exhibited higher propensity to accumulate lipid droplets and collagen compared to healthy control cells, similar to their primary counterparts. Therefore, both Primary and hiPSC-D cardiac stromal cells obtained from ACM patients can be used to model aspects of the disease. The choice of the most suitable model will depend on experimental needs and on the availability of human source samples.

Background Cardiac mesenchymal stromal cells (C-MSC) were recently shown to differentiate into adipocytes and myofibroblasts to promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM). A calcium (Ca 2+ ) signaling dysfunction, mainly demonstrated in mouse models, is recognized as a mechanism impacting arrhythmic risk in ACM cardiomyocytes. Whether similar mechanisms influence ACM C-MSC fate is still unknown. Thus, we aim to ascertain whether intracellular Ca 2+ oscillations and the Ca 2+ toolkit are altered in human C-MSC obtained from ACM patients, and to assess their link with C-MSC-specific ACM phenotypes. Methods and results ACM C-MSC show enhanced spontaneous Ca 2+ oscillations and concomitant increased Ca 2+ /Calmodulin dependent kinase II (CaMKII) activation compared to control cells. This is manly linked to a constitutive activation of Store-Operated Ca 2+ Entry (SOCE), which leads to enhanced Ca 2+ release from the endoplasmic reticulum through inositol-1,4,5-trisphosphate receptors. By targeting the Ca 2+ handling machinery or CaMKII activity, we demonstrated a causative link between Ca 2+ oscillations and fibro-adipogenic differentiation of ACM C-MSC. Genetic silencing of the desmosomal gene PKP2 mimics the remodelling of the Ca 2+ signalling machinery occurring in ACM C-MSC. The anti-arrhythmic drug flecainide inhibits intracellular Ca 2+ oscillations and fibro-adipogenic differentiation by selectively targeting SOCE. Conclusions Altogether, our results extend the knowledge of Ca 2+ dysregulation in ACM to the stromal compartment, as an etiologic mechanism of C-MSC-related ACM phenotypes. A new mode of action of flecainide on a novel mechanistic target is unveiled against the fibro-adipose accumulation in ACM.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes sudden cardiac death and progressive heart failure. Besides fibro-fatty replacement and myocyte degenerative changes, inflammatory patchy infiltrates are found in myocardial histological analysis of ACM patients. Inflammatory cells could actively participate in ACM pathogenesis, contributing to the alteration of cardiac microenvironment homeostasis, thus triggering disease evolution. In order to characterize the immune-derived mediators involved in ACM pathogenesis, peripheral blood mononuclear cells from ACM patients were characterized and compared to healthy controls’ ones. Flow cytometry analysis revealed a lower frequency of CD4 + T helper type 1 cells, NK cells, and terminally differentiated CD8 + EMRA + T cells in ACM patients compared to age-matched controls. In contrast, a higher proportion of effector/memory FOXP3 + CCR4 + CD45RO + regulatory CD4 + T cells (Treg) were found in ACM patients. Single-cell RNA-seq performed on isolated memory Treg cells (mTreg) from ACM patients and healthy controls identified 6 clusters characterized by specific gene signatures related to tissue repair and immunosuppressive pathways. Notably, interleukin 32 (IL-32) was the most differentially expressed gene in ACM patients mTreg with respect to healthy controls. Treatment of human cardiac mesenchymal stromal cells with recombinant IL-32 in vitro promoted lipid droplet accumulation and collagen deposition, thus identifying IL-32 as a new potential player in the immune-mediated trigger of cardiac fibro-fatty replacement in ACM. Overall, we here provide the first complete characterization of circulating ACM immune cells, revealing an abundance of Treg. The high expression of IL-32 in ACM Treg may contribute to accelerated cardiac remodeling in ACM patients’ hearts.

Arrhythmogenic cardiomyopathy is a rare genetic disease that is mostly inherited as an autosomal dominant trait. It is associated predominantly with mutations in desmosomal genes and is characterized by the replacement of the ventricular myocardium with fibrous fatty deposits, arrhythmias and a high risk of sudden death. In vitro studies have contributed to our understanding of the pathogenic mechanisms underlying this disease, including its genetic determinants, as well as its cellular, signaling and molecular defects. Here, we review what is currently known about the pathogenesis of arrhythmogenic cardiomyopathy and focus on the in vitro models that have advanced our understanding of the disease. Finally, we assess the potential of established and innovative cell platforms for elucidating unknown aspects of this disease, and for screening new potential therapeutic agents. This appraisal of in vitro models of arrhythmogenic cardiomyopathy highlights the discoveries made about this disease and the uses of these models for future basic and therapeutic research.

Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro‐adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low‐density lipoprotein (oxLDL)‐dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient‐derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock‐out mice through high‐fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies. Synopsis ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo ), leading to an advancement in the knowledge of ACM pathogenesis. ACM patients show high oxLDL plasma levels, which stratify ACM phenotype severity. oxLDL worsen adipogenic differentiation of ACM cells by altering the CD36/13HODE/PPARγ axis. By increasing oxLDL in an ACM mouse model with low penetrance, ACM‐specific tissue remodelling, functional and electrical impairments are unveiled. NAC and Atorvastatin can prevent ACM phenotypes in vitro / in vivo . Graphical Abstract ACM mutations are necessary but not sufficient for disease penetrance. The contribution of oxidised lipids as novel pharmacologically targetable cofactors was demonstrated by a multi‐layer approach (patients – in vitro – in vivo ), leading to an advancement in the knowledge of ACM pathogenesis.

Atrial fibrillation (AF), the most prevalent tachyarrhythmia worldwide, is a complex condition influenced by genetic, structural, and environmental factors. While AF in the elderly is often associated with underlying cardiac disease, early-onset or “lone” AF (LAF) exhibits a stronger genetic predisposition. Studies have identified both monogenic and polygenic contributors to AF risk. Monogenic mutations, inherited in Mendelian patterns, often affect ion channels and regulatory proteins, while polygenic variants modulate susceptibility and interact with environmental factors. Genome-wide association studies (GWAS) and exosome-wide association studies (ExWAS) have expanded our understanding of AF genetics, identifying numerous susceptibility loci, though challenges remain in linking these variants to specific molecular mechanisms. Pathophysiologically, AF results from a balance of triggers, drivers, and substrates. Triggers, such as ectopic foci in the pulmonary veins, initiate AF episodes, while structural and electrical remodeling perpetuates the arrhythmia. Fibrosis, atrial dilation, and tachycardia-induced remodeling promote reentry circuits and irregular conduction, increasing AF vulnerability. The interplay between genetic predisposition and remodeling processes underscores the complexity of AF maintenance, particularly in persistent AF forms. Emerging insights into AF genetics and pathophysiology highlight the need for personalized approaches to its prevention and management. Understanding genetic risk, combined with targeted therapies addressing structural and electrical remodeling, holds promise for improved patient outcomes. Future research into AF’s molecular and genetic mechanisms will be key to advancing precision medicine in this field.