Mechanisms Of Arrhythmias Research Articles

Desmin-related myopathy manifested by various types of arrhythmias: a case report and literature review.

Desmin is a type III intermediate filament protein specifically expressed in muscle cells, which is encoded by the DES gene. Defects in the desmin protein and cytoskeletal instability may interfere with cardiac muscle conduction signals, a fundamental mechanism for arrhythmias in patients with desmin-related myopathy. This current case report presents a female patient in her early 20s who presented with early-onset complete atrioventricular block and complete left bundle branch block over the previous decade. More recently, she had developed ventricular tachycardia, ventricular fibrillation, atrial fibrillation and other arrhythmias. Echocardiography revealed non-compaction of the ventricular myocardium and pulmonary hypertension. Whole-exome sequencing analysis identified a heterozygous missense mutation in the DES gene: c.1216C>T (p.Arg406Trp). She was eventually diagnosed with arrhythmias due to desmin-related myopathy. A literature review of international databases was undertaken to summarise the clinical characteristics of the cardiac involvement associated with this DES gene mutation.

Concealed cardiomyopathy as an emerging cause of sudden cardiac arrest and sudden cardiac death.

The inherited cardiomyopathies exhibit a broad spectrum of disease, with some patients remaining asymptomatic throughout life, while, for others, the first symptom of disease is sudden cardiac death at a young age. The risk of malignant ventricular arrhythmia in these conditions has traditionally been linked to the degree of structural myocardial abnormalities and functional impairment. However, recent advances in genetic testing and knowledge of the genetic basis of the diseases have led to the identification of concealed cardiomyopathy, in which sudden cardiac arrest or sudden cardiac death occurs in the absence of observable clinical features of cardiomyopathy, with a diagnosis being made only after the identification of a causative genetic variant. Increased awareness of concealed cardiomyopathy, a better understanding of mechanisms of arrhythmia and identification of risk modulators will be vital to improve care for families with concealed cardiomyopathy.

Aborted coumel sign: a novel diagnostic marker for arrhythmia mechanism recognition.

Aborted coumel sign: a novel diagnostic marker for arrhythmia mechanism recognition.

Biventricular modelling for investigating ventricular arrhythmias in silico

Abstract Background Ventricular arrhythmias have a significant incidence rate worldwide and may potentially lead to sudden cardiac death in severe cases. Despite therapeutic advancements, the intricate mechanisms dictating these arrhythmias remain elusive. Biventricular modelling and deep learning provide a way to investigate the complex electrophysiological substrates underlying cardiac arrhythmogenesis. Purpose This study aims to develop and validate a patient-specific biventricular computational modelling pipeline for simulating ventricular arrhythmias in silico. We provide a comprehensive platform for understanding the initiation, propagation, and treatment response of various ventricular arrhythmias. Methods To facilitate large-scale computational experiments and personalised model predictions within clinical timeframes, it is imperative to establish a rapid and reproducible modelling framework. First, we constructed biventricular volumetric models derived from late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) data from the Cardiac Atlas Project (2018 Atria Segmentation Challenge), and then we calculate biventricular coordinates to facilitate data registration between measures, and fibre and fibrosis inclusion. We also apply the pipeline to cardiac magnetic resonance (CMR) data and electrocardiogram recordings from UK Biobank. Results We have successfully developed a pipeline for constructing biventricular volumetric models and efficiently processed biventricular coordinates (Figure). By systematically exploring interactions between ventricular regions, the model may identify critical factors contributing to arrhythmia susceptibility and guide personalised therapeutic strategies. Furthermore, the model may provide insights into the efficacy of antiarrhythmic interventions, ablation techniques, and device therapies, facilitating the development of precision medicine approaches. Conclusions We demonstrate a pipeline for constructing patient-specific biventricular computational models at scale from imaging data and apply this to LGE-MRI data and UK Biobank CMR data. These biventricular models enable investigation of the complex mechanisms of ventricular arrhythmias, providing novel insights for clinical decision-making and treatment strategies.

Macrophage-mediated interleukin-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation

Abstract Background Postoperative atrial fibrillation (poAF) is self-limited AF that occurs within days after cardiac surgery in one-third of patients. Clinical and preclinical studies have demonstrated that the magnitude of the perioperative increase in systemic inflammation, in particular mediated by interleukin (IL)-6, correlates with poAF risk. However, no studies to-date have mechanistically linked IL-6 signaling to fundamental arrhythmia mechanisms or identified the specific cell types driving postoperative atrial IL-6 signaling. Methods We performed single-cell RNA sequencing (scRNAseq), followed by pseudotime trajectory and cell-cell communication analyses on atrial non-myocytes comparing mice with and without poAF. We followed up our scRNAseq findings with pharmacologic and genetic approaches in mice to validate pathways related to macrophage-mediated IL-6 signaling. We used confocal imaging to assess calcium-signaling mechanisms at the single atrial cardiomyocyte (ACM) level and performed parallel patch-clamp studies in isolated human ACMs as well as biochemical analyses of human atrial tissue to assess the translational relevance of our findings. Results Our scRNAseq results demonstrated macrophages to be the most prominently altered cell type in the atria of mice with poAF. Pseudotime trajectory analyses revealed IL-6 to be one of the top inflammatory pathways implicated in macrophage transcriptional state. Indeed, both macrophage depletion and conditional knockout of IL-6 receptors in macrophages were sufficient to prevent poAF. We found that inhibition of STAT3, which is downstream of the IL-6Ra, with FDA-approved phospho-STAT3 inhibitor TTI-101 prevented poAF in mice. Lastly, we demonstrate that enhanced STAT3 activity in poAF promotes arrhythmogenic Ca2+ sparks and waves through ryanodine receptor-2 dysfunction, and that CaMKII inhibition is sufficient to ameliorate Ca2+ mishandling at the single atrial myocyte level. Conclusions Taken together, we use an integrated approach incorporating mouse and human biochemical, functional, and single-cell sequencing data to demonstrate that infiltrating atrial macrophages are fundamentally required for poAF. IL-6 was found to be a critical pathway upregulated in poAF leading to downstream ryanodine receptor-2 dysfunction and atrial arrhythmogenesis. Our findings portend significant therapeutic utility by providing robust mechanistic evidence that targeting the IL-6 axis may be used for poAF prevention and treatment in a clinically amenable timeframe.

Development and implementation of a guideline-based decision support system for etiological diagnosis of Sustained Monomorphic Ventricular Tachycardia (SMVT)

Abstract Background Guideline (GL)-based decision support systems (DSSs) play a significant role in supporting physicians in their decision-making processes by providing structured clinical guidance. While these systems have shown significant success in enhancing practitioner performance and patient outcomes in general practice, their application in the context of ventricular arrhythmias remains limited. Moreover, the clinical etiological diagnosis of ventricular arrhythmias presents various challenges for healthcare professionals, such as adherence to updated diagnostic criteria and understanding of complex arrhythmia mechanisms. Purpose In this study, we aim to design, implement, and evaluate a guideline-based decision support systems for etiological diagnosis of sustained monomorphic ventricular tachycardia (SMVT), which could potentially address critical challenges associated with the disease diagnosis and management. Methods To comprehensively capture the semantics embedded in clinical guidelines, we first developed a dedicated knowledge graph tailored to the clinical decision-making. This involved extracting entities and relationships pertinent to key decision procedures from ESC guidelines for ventricular arrhythmias, clinical textbooks or literatures. Subsequently, we translated instances within the knowledge graph into archetypes within openEHR, amplifying the interoperability of clinical information. To enhance the interpretability of the DSS, we established executable diagnostic and treatment processes to offer visual representation of clinical steps in diagnosis and treatment. Ultimately, we constructed a decision support engine to implement the GL-DSS, and its effectiveness was evaluated with anonymous real-world data. Results The proposed GL-DSS was found to be quite feasible and could provide etiological diagnosis for SMVT. The knowledge base for the constructed GL-DDS included more than 2000 entities and relations, which played a vital role in representing disease pathogenesis. The proposed system can map the clinical entities to a set of openEHR archetypes, thus mitigate the interoperability issues of the hospital information systems and CDSS data integration. Also, this module improved system usability and ensured that guidelines could be easily translated and updated into decision support tools. Real-word medical records from 20 patient were collected for model evaluation, the results showed that the GL-DSS covered most of the entities and relations between diseases and diagnostic evidence recorded in clinical texts and achieved a diagnosis accuracy of 80%. Conclusions The results demonstrated that our proposed GL-DSS could completely and accurately capture the diagnostic information under the concrete EHR data. Thus, the implement decision support system could have the potential to improve clinical decision-making, patient care, and outcomes in this specialized medical domain.

An endogenous cholinergic system controls electrical conduction in the heart.

The cholinergic system is distributed in the nervous system, mediating electrical conduction through acetylcholine (ACh). This study aims to identify whether the heart possesses an intact endogenous cholinergic system and to explore its electrophysiological functions and relationship with arrhythmias in both humans and animals. The components of the heart's endogenous cholinergic system were identified by a combination of multiple molecular cell biology techniques. The relationship of this system with cardiac electrical conduction and arrhythmias was analysed through electrophysiological techniques. An intact cholinergic system including ACh, ACh transmitter vesicles, ACh transporters, ACh metabolic enzymes, and ACh receptors was identified in both human and mouse ventricular cardiomyocytes (VCs). The key components of the system significantly regulated the conductivity of electrical excitation among VCs. The influence of this system on electrical excitation conduction was further confirmed both in the mice with α4 or α7 nicotinic ACh receptors (nAChRs) knockouts and in the monolayers of human induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, ACh induced an inward current through nAChRs to reduce the minimum threshold current required to generate an action potential in VCs, thereby enhancing the excitability that acts as a prerequisite for electrical conduction. Importantly, defects in this system were associated with fatal ventricular arrhythmias in both patients and mice. This study identifies an integrated cholinergic system inherent to the heart, rather than external nerves that can effectively control cardiac electrical conduction. The discovery reveals arrhythmia mechanisms beyond classical theories and opens new directions for arrhythmia research.

Arrhythmias in adult patients after Rastelli surgery: a single-centre experience.

Rastelli surgery is used for the correction of several CHDs. Although late-onset cardiac arrhythmias have emerged as a major complication after corrective surgeries, there is a paucity of data on arrhythmias after Rastelli surgery. This retrospective cohort study was conducted on patients who had undergone Rastelli surgery and have been followed at the adult CHD clinic at our hospital. A total of 55 patients (36.4% female, age 22.2 ± 6.4 years) were followed for a median period of 24.2 (20.6-31.0) years. Tachyarrhythmias occurred in 21 (38.4 %) patients (n = 15 for atrial tachycardia, 5 for ventricular tachycardia, and 1 for both atrial and ventricular tachycardia). Older age at surgery was significantly associated with the risk of tachyarrhythmias (P = 0.022). Bradyarrhythmia occurred in 12 (21.8%) patients and consisted of perioperative AV block (n = 5), late AV block (n = 1), and sinus node dysfunction (n = 6). Nine (16.4%) patients underwent catheter ablation. The mechanisms of atrial arrhythmias include cavotricuspid isthmus-dependent and surgical scar-dependent intra-atrial reentrant tachycardias. Among the three patients who underwent ablation for ventricular tachycardia, all circuits were dependent on the scar at the base of the right ventricle to pulmonary artery conduit. Median survival free from any event (arrhythmia, death, or heart failure) was 31.6 (28.1-35.1) years after Rastelli surgery. The prevalence of arrhythmias late after Rastelli surgery is substantial and increases in the second decade after surgery. Older age at surgery is associated with a higher prevalence of arrhythmias.

Interstitial Fibrosis and Arrhythmic Mitral Valve Prolapse: Unravelling Sex-Based Differences

Interstitial fibrosis as quantified by cardiac magnetic resonance (CMR) has been demonstrated in arrhythmic mitral valve prolapse (AMVP), a condition with known female predominance. Prior studies of interstitial fibrosis in AMVP have only included cases with significant mitral regurgitation (MR) or mitral annular disjunction (MAD), limiting our understanding of alternative arrhythmic mechanisms in MVP. We sought to evaluate the association between interstitial fibrosis and AMVP, regardless of MAD and without severe MR, while also investigating the contribution of sex to this association. We performed research-based contrast CMR in consecutive individuals with MVP between 2019 and 2022. Extracellular volume fraction (ECV%), a surrogate marker for interstitial fibrosis, was quantified using T1 mapping in the basal and mid-LV slices. Replacement fibrosis was assessed using late gadolinium enhancement (LGE). AMVP was defined as MVP with frequent premature ventricular contractions and/or non-sustained/sustained ventricular tachycardia (VT) or fibrillation (VF). We identified 65 MVP cases without severe MR (46% women, 34% no/trace, 44% mild, and 21% moderate MR) and with adequate ECV% measurement. Among these, 38% were classified as AMVP, including two cases of aborted VF arrest, both in premenopausal females. Global ECV% was significantly higher in AMVP versus non-AMVP (31%[27-33] vs 27%[23-30], p=0.002). In the AMVP group, higher segmental ECV% was not limited to the inferolateral/inferior walls, typically subject to myocardial traction by the prolapsing leaflets/MAD but was more diffuse and involved atypical segments such as the anterior/anterolateral walls (p<0.05). The association between AMVP and global ECV% was driven by female sex (32%[30-34] vs 27%[25-30], p=0.002 in females; 28%[23-32] vs 26%[23-30], p=0.41 in males). ECV% remained independently associated with an increased risk of arrhythmic events, including VT/VF (p<0.01), even after adjustment for cardiovascular risk factors, MAD, and LGE (p<0.01). In MVP without significant MR, interstitial fibrosis by CMR is associated with an increased risk of arrhythmic events, suggesting a primary myopathic process. The selective association between interstitial fibrosis and AMVP in females may explain why severe arrhythmic complications are more prevalent among women.

Sinoatrial node function and the role of sinoatrial conduction in the typical atrial flutter substrate

BackgroundSinoatrial node (SAN) activation and sinoatrial conduction pathways (SACPs) have been assessed in animals but not in humans. ObjectivesWe used ultrahigh-density mapping and simulated models to characterize the SAN and to investigate whether slowed SAN conduction may contribute to the atrial flutter (AFL) substrate. MethodsTwenty-seven patients undergoing electrophysiologic procedures had right atrial mapping. SAN activation patterns and conduction block were analyzed. The interaction between the SAN and the intercaval line of block (LOB) was analyzed, and right atrial simulations with different degrees of block were created to investigate arrhythmia mechanisms. ResultsFifteen AFL patients and 12 reference patients were enrolled. SACPs were identified in all patients with sinus rhythm maps. An SAN-adjacent LOB was observed in AFL patients. SAN conduction velocity was slower in AFL vs reference (0.60 m/s [0.56–0.78 m/s] vs 1.13 m/s [1.00–1.21 m/s]; P = .0021). Coronary sinus paced maps displayed an intercaval LOB in AFL patients but not in reference patients, which was completed superiorly by the SAN-adjacent LOB. Corrected sinus node recovery time was longer in AFL patients (552.3 ± 182.9 ms vs 325.4 ± 138.3 ms; P < .006) and correlated with degree of intercaval block (r = 0.7236; P = .0003). Computer modeling supported an important role of SAN-associated block in the flutter substrate. ConclusionUltrahigh-density mapping accurately identifies SAN activation and SACPs. The LOB important for typical AFL was longer in AFL patients, and when partial, it was always present inferiorly and completed superiorly because of slowed conduction across the SAN. Corrected sinus node recovery time correlated with intercaval block, suggesting a role for SAN disease in the genesis of the typical AFL substrate.

Efficacy and safety of early postoperative ablation in patients with congenital heart disease

BackgroundPostoperative arrhythmias are most often transient and medically treated, but some patients may require electrophysiology study (EPS) and ablation. ObjectiveThe purpose of this study was to describe the efficacy and safety of early postoperative ablation. MethodsThis study presents a retrospective series of patients who underwent EPS within 12 months of surgery for congenital heart disease between 2000 and 2021. The procedural outcome included complete or partial success, empirical ablation or failure, and complications. The long-term outcome included arrhythmia recurrence and burden according to a 12-point clinical arrhythmia severity score (documented arrhythmia, arrhythmia severity, cardioversion, and antiarrhythmic medication). ResultsAmong 28,902 operations during the study period, 24 patients (0.1%) underwent EPS within 3 months of surgery and 26 (0.1%) 3–12 months after surgery. Most patients had great (n = 27 [50%]) or moderate (n = 21 [42%]) congenital heart disease complexity. Mechanisms of arrhythmias included intra-atrial reentrant tachycardia (n = 23 [46%]), ectopic atrial tachycardia (n = 13 [26%]), accessory pathway (n = 6 [12%]), atrioventricular nodal reentrant tachycardia (n = 7 [14%]), twin atrioventricular node (n = 1 [2%]), atrial fibrillation (n = 1 [2%]), junctional ectopic tachycardia (n = 1 [2%]), and ventricular tachycardia (n = 2 [4%]). The procedure was acutely successful in 41 patients (82%), empirical in 5 (10%), and unsuccessful in 4 (8%). Complications occurred in 4 (8%) patients (major in 1, moderate in 1, and minor in 2). The recurrence of arrhythmia was documented in 27 patients (54%), although the burden of arrhythmia was significantly reduced. ConclusionA minority of patients require early postoperative EPS and ablation. For those, the procedure can be performed with reasonable acute success and manageable morbidity even in critically ill patients with complex surgical anatomy.

Modeling Idiopathic Ventricular Fibrillation Using iPSC Cardiomyocytes and Computational Approaches: A Proof-of-Concept Study.

Idiopathic ventricular fibrillation (IVF) is an unrefined diagnosis representing a heterogeneous patient group without a structural or genetic definition. IVF treatment is not mechanistic-based due to the lack of experimental patient-models. We sought to create a methodology to assess cellular arrhythmia mechanisms for IVF as a proof-of-concept study. Using IVF patient-specific induced pluripotent stem cell-derived cardiomyocytes, we integrate electrophysiological optical mapping with computational modeling to characterize the cellular phenotype. This approach flips the traditional paradigm using a biophysically detailed computational model to solve the problem inversely. Insight into the cellular mechanisms of this patient's IVF phenotype could also serve as a therapeutic testbed.

Abstract We112: Volumetric imaging to recapitulate cardiac injury and arrhythmias

Advanced understanding of cardiac structure and function is crucial for uncovering the underlying mechanism of injury and arrhythmias. To explore cues to structural and functional abnormalities in extensively established animal models, we have developed optical imaging and computational methods tailored to investigate intact hearts of zebrafish and rodents at cellular resolution. Our cardiac light-field microscopy allows us to capture instantaneous dynamics such as calcium transients, irregular contraction, and blood flow at 200 volumes per second in zebrafish larvae 1 . To improve the spatial resolution and enable the study of rodent models, we have customized two light-sheet imaging systems. One system is empowered by the retrospective synchronization and machine learning for the study of contractile function and focal myocardial mechanics from end-systole to end-diastole 2 , while the other integrates tissue clearing and axially scanning approaches for the exploration of ventricular trabeculation and myocardial compaction 3 . These methods aim to overcome the trade-off in spatial resolution, imaging speed, field of view across the atria and ventricles with minimal photo-damage and maximal penetration depth, enabling long-term investigation of cardiac development and regenerative processes. To further interpret the large volume of datasets, we have customized a successive subspace learning and virtual reality-based platform for interactive image analysis 4 . Collectively, our multi-scale strategy has opened up new landscapes for exploring the cardiac micro-structure and contractile function, both in health and disease.

Abstract Or102: Macrophage-Mediated Interleukin-6 Signaling Drives Ryanodine Receptor-2 Calcium Leak in Postoperative Atrial Fibrillation

Postoperative atrial fibrillation (poAF) is self-limited AF that occurs days after cardiac surgery in one-third of patients. The degree of perioperative increase in systemic inflammation, particularly involving interleukin (IL)-6, correlates with poAF risk. However, no studies to-date have identified the cell types involved nor mechanistically linked IL-6 signaling to fundamental arrhythmia mechanisms. To study poAF, we developed a mouse model consisting of atrial pericardiectomy and transient aortic cross-clamping followed by intracardiac burst pacing on postoperative day three to assess poAF inducibility. Single-cell RNA sequencing of atrial non-myocytes revealed macrophages to be the most prominently altered atrial cell type – increased 2.4-fold ( P &lt;0.001) in mice with versus without poAF. Pseudotime trajectory analyses revealed IL-6 to be the top cytokine altered in macrophages, which we confirmed by western blot demonstrating a 1.7-fold ( P =0.012) increase in atrial IL-6 protein in mice with versus without poAF. Indeed, both macrophage depletion and conditional knockout of IL-6Ra in macrophages decreased poAF inducibility by 5.2-fold ( P =0.048) and 5.5-fold ( P =0.027), respectively. Downstream inhibition using an FDA-approved STAT3 inhibitor also rescued poAF (6.0-fold decrease, P =0.022). At the single atrial cardiomyocyte (ACM) level, IL-6 challenge led to a 6.3-fold ( P &lt;0.001) increase in calcium (Ca 2+ ) spark frequency after normalization to sarcoplasmic reticulum Ca 2+ load, indicative of ryanodine receptor-2 (RyR2) dysfunction. Indeed, RyR2 phosphorylation at Ser2814, the target of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), was increased in the atria of mice with poAF, and CaMKII inhibition was sufficient to rescue arrhythmogenic Ca 2+ sparks in ACMs from mice with poAF. We corroborated our findings in human ACMs and atrial tissue to demonstrate translational relevance. Taken together, we use an integrated approach incorporating mouse and human biochemical, functional, and single-cell sequencing data to demonstrate that infiltrating atrial macrophages, specifically IL-6Ra from macrophages, are fundamentally required for poAF development ( Fig. 1 ). Molecularly, enhanced atrial IL-6 signaling led to arrhythmogenic RyR2 dysfunction through CaMKII. Our findings portend therapeutic utility by providing mechanistic evidence that targeting the IL-6 axis may be used for poAF prevention and treatment in a clinically amenable timeframe.

Abstract Mo125: Translating ECG responses to drugs across sexes: model development and validation in the clinic

Background: Sex-based differences in cardiac electrophysiology and their potential to impact susceptibility to cardiac arrhythmia and response to treatment are widely recognized. For example, female sex is an independent risk factor for drug-induced Long QT syndrome, Torsade de Pointes, and sudden cardiac death. However, arrhythmia studies have been predominantly performed in males, thus limiting our understanding of sex-specific arrhythmia mechanisms and the development of sex-specific metrics for arrhythmia risk. Computational tools are a powerful approach for integrating sex differences across scales and studying such multi-level phenomena, accelerating challenging and costly human and animal experiments. Aim: To develop a quantitative tool that predicts drug-induced responses in female electrocardiogram (ECG) features based on ECG data collected in males (and vice versa). Methods: Male and female 1D cable models of ventricular cardiomyocytes were constructed by incorporating transmural heterogeneity and sex-specific parameterizations. We constructed populations of male and female models by randomly perturbing baseline parameters, and derived pseudo-ECGs from computed extracellular potentials. We then utilized lasso regression to map ECG features (QRS duration, QT interval, T-peak-end duration, and T-wave amplitude) extracted from the male pseudo-ECG onto the female ECG features (and vice versa) ( Fig 1 ). Results: Our simulated data-driven translator accurately predicted female pseudo-ECG features from male data in an independent simulated test set (R 2 &gt;0.95). This predictive capability was further assessed in an independent dataset simulating the effects of 95 drugs at different concentrations ( Fig 2A ), exhibiting an average translation error &lt;1% for the QT interval ( Fig 2B ). Proof-of-concept application to ECG data sourced from publicly available FDA-approved datasets, in patients of both sexes under various anti-arrhythmic drugs and drug combinations, demonstrates high accuracy ( Fig 3 ) and validates the translator's applicability to the clinic. Conclusions: Our findings underscore the translator's potential in conducting sex-specific cardiac safety and efficacy assessments, enhancing the precision of evaluations in females. We plan to expand our translator capability to predict sex-specific effects of perturbations, including physiological and pathophysiological stressors.

HEART RHYTHM DISTURBANCES IN CONNECTIVE TISSUE DYSPLASIA

The article discusses the association between connective tissue dysplasia (CTD) and arrhythmias, particularly focusing on mitral valve prolapse as a potential risk factor for life-threatening ventricular arrhythmias and sudden cardiac death. Various studies emphasize the structural and mechanical abnormalities in the heart that contribute to arrhythmogenic phenotypes in CTD patients, such as fibrosis, mitral annular disjunction, and accessory chordae. Additionally, the text explores the role of autoantibodies, cardiac remodeling, and autoimmune processes in mediating rhythm disturbances and cardiac complications in CTD. The importance of ECG analysis, neural networks, and stress tests in detecting and monitoring arrhythmias in CTD patients is highlighted. The research underscores the significance of understanding the morphological basisand pathophysiological mechanisms of arrhythmias in CTD patients to improve therapeutic strategies and enhance patient outcomes.

Interplay of electrical and mechanical properties in transgenic rabbit models of long-QT and short-QT syndrome

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): SNF Introduction Long-QT syndrome (LQTS) and short-QT syndrome (SQTS) are cardiac disorders primarily affecting electrical function but secondarily also impacting on mechanical features through electro-mechanical coupling (EMC). This study delves into in vivo and cellular electro-mechanical function and explores the impact of acute mechanical changes on the electrical phenotype, termed mechano-electrical coupling (MEC), in transgenic rabbit models. Aim This study aims to investigate the interrelationship between electrical and mechanical properties in LQTS and SQTS rabbit models, examining how acute mechanical alterations influence the electrical phenotype and exploring cellular electro-mechanical characteristics. Methods We examined 12-lead ECGs in LQT2, wildtype (WT), and SQT1 adult rabbits under various preload and afterload conditions. Additionally, patch-clamp and ionoptix experiments on isolated ventricular cardiomyocytes were conducted to investigate cellular electrical and mechanical characteristics. Results Baseline heart-rate corrected QTc intervals were prolonged in LQT2 (p&amp;lt;0.0001) and shortened in SQT1 (p=0.012) compared to WT. QT-dispersion was solely increased in LQT2 (p&amp;lt;0.05). Acute increase in preload and in afterload prolonged QTc intervals in all groups, while reduced preload shortened QTc intervals. MEC (mechano-induced ΔQTc) varied among genotypes; in LQT2, QTc changes were more significant than in WT (p&amp;lt;0.0001 with increased preload, p&amp;lt;0.001 with decreased preload, and p&amp;lt;0.05 with increased afterload). SQT1 showed a trend towards less pronounced changes compared to WT only after increased preload (p=0.11). At the cellular level, action potential duration was longer in LQT2 (p&amp;lt;0.001) and shorter in SQT1 (p&amp;lt;0.0001) compared to WT. While cardiomyocytes from WT and SQT1 showed similar Ca2+ transient durations at 1Hz, 0.5Hz, and 0.25Hz, in LQT2 cardiomyocytes Ca2+ transients were significantly prolonged at 0.5 (p&amp;lt;0.001) and 0.25Hz (p&amp;lt;0.05) in line with the pronounced APD prolongation. Additionally, LQT2 exhibited significantly more pro-arrhythmic Ca2+ oscillations, which may contribute to arrhythmia formation in LQT2s. Moreover, LQT2 exhibited a slower calcium transient upstroke velocity and a reduced cellular contraction velocity and peak sarcomere shortening at all frequencies, demonstrating a mechanical impairment compared to WT and SQTS cardiomyocytes. Conclusions Acute mechanical alterations induce electrical changes through MEC in LQT2, WT, SQT1 rabbits. The magnitude of these changes correlates with baseline QTc, exhibiting the most prominent effects in LQT2. Consistent findings between cellular electro-mechanical assessments and in vivo measurements underscore the significance of cardiomyocytes in unravelling the mechanisms behind EMC and MEC. This intricate interplay between electro-mechanical properties in cardiac disorders, highlighting the necessity of considering both aspects when investigating arrhythmia mechanisms.

Source-sink mismatch and conduction block: simulation study

Abstract Background Source-sink mismatch is one of the key concepts in arrhythmia mechanism such as relationship between pulmonary veins and the left atrium in atrial fibrillation. We sought to find the condition for conduction block in various geometries. Methods To simulate cardiac atrial tissue, the finite element method was used to discretize the governing equation in a 2D mesh. We evaluated under the following conditions: 6 sizes of source width (0.1, 0.2, 0.3, 0.4, 0.5 and 0.6 mm), 64 types of angle (θ) at the junction (30-330 degrees), 3 conditions of conduction velocity (CV) (x0.5, x0.75, and x1 of normal CV of atrial myocardium). Results Conduction block was not observed with source width &amp;gt; 0.5 mm in any settings. In reduced CV condition, conduction block was not observed in θ &amp;lt; 300 degrees when source width &amp;gt; 0.3 mm. The higher CV, conduction block was observed in the narrower θ. In cases of CV of x1.0 and x0.75, conduction block was observed in θ &amp;lt; 180 degrees when source width &amp;lt; 0.3 mm. The smaller source width, conduction block was observed in the narrower θ. The wider θ, the easier conduction block occurred. Conclusion Conditions for conduction block due to source-sink mismatch are as follows: smaller source width, higher CV, and wider θ. Source with width &amp;gt; 0.5 mm may not be associated with source-sink mismatch in the atrial tissue. CV slowing by antiarrhythmic drugs can be effective in the aspect of source-sink mismatch.

Slow pathway ablation in pediatric patients: long-term outcomes in a high-volume center according to baseline electrophysiologic characteristics

Abstract Background Slow pathway ablation (SPA) in pediatric patients with documented paroxysmal supraventricular tachycardia (PSVT) has been proven safe and effective. Arrhythmia induction is often difficult in the pediatric population. Accordingly, empirical SPA is frequently adopted in this population. Real-world data about long-term outcomes of slow pathway ablation (SPA) in relation to tachycardia inducibility and electrophysiologic characteristics in pediatric patients with PSVT in a high-volume center are lacking. Purpose To compare long-term clinical outcomes of SPA in pediatric patients with and without intraprocedural documentation of DAVP and AV nodal reentrant tachycardia induction. Methods In this retrospective sigle-center study, all SPA procedures performed on pediatric patients (under 18 years) at our Institution since 2016 were considered. All patients had documented PSVT with short RP interval, no evidet ventricular pre-excitatio on surface ECG and normal echocardiography. Baseline EPS was performed to exclude the presence of concealed accessory pathway and isoproterenol infusion was used to exclude focal atrial tachycardias. According to intraprocedural EP characteristics, three group of patients were identified: Group 1 with AVNRT induction; Group 2 with dual atrioventricular nodal physiology (DAVP) and no tachycardia induction; Group 3 without DAVP. According to previous documentation of a short RP PSVT and after discussion with patients’ families, SPA was performed in all patients. The endpoint of the ablation was to eliminate slow pathway conduction and AV node re-entrant beat. Follow up visits were scheduled three and twelve months after ablation for all patients. Results 1734 patients underwent SPA since 2016 at our Institution. 1092 patients (73.4%) showed AVNRT induction during EPS (Group 1). 433 patients (14.2%) showed DAVP without tachycardia induction (Group 2). 209 patients (12.4%) didn’t show DAVP at EPS (Group 3). Age and gender were similar among the three groups. SPA was performed with acute procedural success in all patients. After 36-month median follow-up, freedom from palpitations was 98.5% in Group 1, 97.1% in Group 2 and 92.3% in Group 3. A survival analysis showed the best outcomes in group 1 and no significant difference in recurrence rate among the groups 2 and 3 (Figure 1). No permanent heart blocks, neither other major complication was observed. Conclusions When performed by experienced operators and in high-volume centers, SPA is a safe and effective procedure in pediatric patients with documented short RP PSVT. Success rate is highest with AVNRT induction and good without AVNRT induction, regardless of AV node dual conduction at baseline EPS. Such high success rate depends on careful exclusion of others arrhythmia mechanisms (i.e., focal atrial tachycardias, AV re-entrant tachycardias) that, although infrequent in children, are the main determinants of arrhythmia recurrences.

Long-term success and predictors of atrial arrhythmia recurrence following left atrial flutter ablation

Abstract Background In recent years, success rate of left atrial flutter (LAFL) ablation has witnessed improvement, attributed to enhanced comprehension of the arrhythmia mechanism and technological advancements. However, the recurrence rate and specific types of atrial arrhythmias, along with their potential predictors, remain inadequately understood. Purpose The aim of this study is to assess the factors influencing the efficacy, safety, and long-term success of radiofrequency (RF) ablation for LAFL. Methods Patients with sustained LAFL undergoing RF ablation were included in the study. LAFL mapping employed a combination of activation, voltage, and entrainment with 3D electroanatomical mapping. RF ablation targeted a protected isthmus of slow conduction, and if not localized, it involved creating lines of conduction block transecting the reentrant circuit or empirically created lines. Ablation success was defined as clean arrhythmia termination during RF application and no LAFL induction with pacing maneuvers. Follow-up included outpatient visits at 6 and 12 months. Ablation success at follow-up was defined as the absence of arrhythmia recurrence (≥30s) at regular outpatient or emergency department visits. Clinical and electrophysiological characteristics were analyzed and correlated with ablation success, complications, and freedom from arrhythmia recurrences at follow-up. Results The study included 104 consecutive patients undergoing LAFL ablation (67.5 ± 11.3 years, 67% male). Clinical characteristics comprised 12 with HFrEF, 44 with structural heart disease, 25 with valvular heart disease, 43 with previous pulmonary vein isolation (PVI) ablation, and 39 with significant left atrium enlargement. Simultaneous cavotricuspid isthmus ablation (CTI) was performed in 46 patients. LAFL cycle length was 293±68 ms, with more than one LAFL mechanism (2.0±0.8 mechanisms) demonstrated in 76 patients (73%). The most common LAFL mechanism was perimetral reentry (37%). LAFL was successfully ablated 83% of cases, with 7 patients experiencing complications (4 tamponades and 3 sinus node dysfunctions following LAFL termination). At a median follow-up of 28 months, 35 patients (34%) had AFL recurrence, and 15 of them required a second ablation procedure. No factor was associated with LAFL recurrence, except for a short LAFL cycle length (P=0.04) at the ablation procedure. Demonstration of more than one LAFL mechanism (P=0.48) or LAFL termination by focal or linear RF application (P=0.99) were not associated with AFL recurrences at follow-up. Conclusions Despite the relatively high efficacy of LAFL ablation, the rate of atrial arrhythmia recurrences at follow-up after a single procedure remains elevated, predominantly in the form of AFL rather than AF. Short LAFL cycle length at the index procedure appears to be a significant predictor of these recurrences. Arrythmia cycle length proved to be predictive factor of LAFL ablation success rate.Peri-veinal left AFL, LAT map, CranialPeri-veinal left AFL, LAT map, PA