Pathogenesis Of Arrhythmias Research Articles

Early or late phase cardiac remodelling in metabolic syndrome heart characterized with SQT or LQT

Cardiac conduction abnormalities are the main disorders in metabolic syndrome (MetS), however, their mechanisms are not known yet. Although ventricular arrhythmia pathogenesis reflects the time course of cardiomyocyte action potentials (APs) associated with QT-interval duration, recent studies emphasize the role of intercellular crosstalk between cardiomyocytes and nonmyocytes via passive (electrotonic)-conduction. Therefore, considering the possible intercellular interactions between cardiomyocytes and nonmyocytes as electrophysiological contributors to cardiac-conduction, we hypothesized an early-cardiac-remodeling which is characterized by short QT-interval (SQT) via contributions and modulations of changes in the expressions and localizations of nonmyocytes to the ventricular APs in an early-stage MetS hearts. Significant increases in MetS (14-16 weeks) heart rates and SQT, shortened AP duration with a strong response to β-adrenergic stimulation in the contractile activity of the papillary muscles were determined. The patch-clamp analysis of ventricular cardiomyocytes showed that voltage-dependent Na+-channel currents were increased with decreased L-type Ca2+-channel (LTCC) currents and unchanged K+-channel currents. A hemichannel protein of connexin 43 (Cx43) was highly localized into intercalated discs while phospho-Cx43 was densely localized laterally on the sarcolemma and cytosol with increased total expression levels. A marked high-level positively-stained α-SMA and CD68 cells in interfibrillar spaces of the heart were prominently localized and distributed, implying the possible contributions of myofibroblasts and macrophages to both shortened APs and abnormal electrical conduction in an early-stage MetS heart.Our data propose a previously unrecognized pathway for induction of SQT in the heart: This pathway may include not only the contribution of short ventricular-APs via ionic-mechanisms but also increasing contributions of the electrotonic-cardiomyocyte depolarization, spontaneous electrical activity-associated fast heterogeneous impulse conduction in the heart via non-myocytes. Overall, SQT in early cardiac remodeling may arise with increased interactions between cardiomyocytes and non-myocytes, through increasing contributions of passive-conduction by non-myocytes. TUBITAK SBAG-119S661 & 222S502. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Arrhythmias and their pathophysiological correlations with SARS-COV 2 infection

Introduction: The pandemic caused by SARS-CoV 2 is considered one of the most critical public health events in the last decades. That said, knowledge of the manifestations of the disease is relevant. Of the changes already described in the literature, cardiac arrhythmias have been receiving increasing prominence. Objective: To discuss the pathogenesis of arrhythmias in the context of the Coronavirus infection and, thus, elucidate the mechanisms of aggression of this virus against cardiac tissue. Methods: This is a cross-sectional and integrative review. Research was carried out in databases such as SciELO, PubMed and Google Scholar. Articles in English, Portuguese and Italian published between 2020 and 2023 were selected. Result: Cardiac arrhythmia because of infection is related to the hyperinflammatory state developed in response to the virus or by direct invasion of structures that have the ACE-2 receptor. Ischemic lesions occur in the sinoatrial node and in the myocardium because of the formation of vascular thrombi caused by inflammation, which impair the rhythm and contraction of this organ, taking it from its sinus rhythm. Regarding direct invasion, the sarcolemma of the cardiomyocytes is ruptured, thus impairing the adequate propagation of the electrical impulse throughout the cardiac tissue and compromises its normal functioning. Conclusion: There is a close relationship between COVID-19 infection and the occurrence of arrhythmias, as well as an increase in morbidity and mortality in infected patients.

Cardiac arrhythmia in COVID-19 patients.

The coronavirus disease 2019 (COVID-19) was first introduced in December 2019, which is known as severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2) that is a serious and life-threatening disease. Although pneumonia is the most common manifestation of COVID-19 and was initially introduced as a respiratory infection, in fact, the infection of COVID-19 is a subset of complications and damage to various organs. There are several reports of cardiac involvement with COVID-19. A wide range of cardiac complications may occur following COVID-19 infection, including systolic heart failure, myocarditis, pericarditis, atrial and ventricular arrhythmias, and thromboembolic events. There are various hypotheses about the pathophysiology of cardiovascular involvement by this virus. At the top of these hypotheses is the release of cytokines to the heart. Although there are other assumptions, considering that one of the causes of death in patients with COVID-19 is arrhythmia. It is necessary to know correctly about its pathophysiology and etiology. Therefore, in this study, we have reviewed the articles of recent years in the field of pathophysiology and etiology of arrhythmia in patients with COVID-19 infection. The purpose of this study was to provide a basis for a correct and more comprehensive understanding of the pathogenesis of arrhythmia in patients with COVID-19 infection.

Dissecting the associations of KCNH2 genetic polymorphisms with various types of cardiac arrhythmias

BackgroundCardiac arrhythmia, a common cardiovascular disease, is closely related to genetic polymorphisms. However, the associations between polymorphisms in KCNH2 and various arrhythmias remain inadequately explored. MethodsGuided by the assumption that KCNH2 genetic polymorphisms significantly contribute to the development of arrhythmias, we thoroughly explored the associations between 85 KCNH2 genetic variations and 16 cardiac arrhythmias in a sample obtained from the UK Biobank (UKBB, N = 307,473). The illnesses documented in the electronic medical records of the sample were mapped to a phecode system for a more accurate representation of distinct phenotypes. Survival analysis was used to test the effect of KCNH2 variants on arrhythmia incidence, and a phenotype-wide association study (PheWAS) was performed to investigate the effect of KCNH2 polymorphisms on 102 traits, including physical measurements, biomarkers, and hematological indicators. ResultsNovel associations of variants rs2269001 and rs7789585 in KCNH2 with paroxysmal tachycardia (PT) and atrial fibrillation/flutter (AF/AFL), respectively, were identified. Moreover, with an increase in the number of minor alleles of these two variants, the incidence rates of PT and AF/AFL decreased. In addition, the PheWAS results suggested that these two single nucleotide polymorphisms were associated with multiple parameters in physical measurements and neutrophil percentage. ConclusionThe multiple novel associations observed in this study illustrate the importance of KCNH2 genetic variations in the pathogenesis of arrhythmia.

Roles of β-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

β-Adrenoceptors (β-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three β-ARs, β1-AR, β2-AR, β3-AR are localized to the human heart. Activation of β1-AR and β2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of β1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of β1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of β2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of β2-AR in cardiovascular disease, particularly arrhythmia generation. All β-blockers used therapeutically to treat cardiovascular disease block β1-AR with variable blockade of β2-AR depending on relative affinity for β1-AR vs β2-AR. Since the introduction of β-blockers into clinical practice in 1965, β-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. β-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. β-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The β-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other β-blockers and is used successfully in the treatment of heart failure. The discovery of β3-AR in human heart created interest in the role of β3-AR in heart failure but has not resulted in therapeutics at this stage.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) for modeling cardiac arrhythmias: strengths, challenges and potential solutions.

Ion channels and cytoskeletal proteins in the cardiac dyad play a critical role in maintaining excitation-contraction (E-C) coupling and provide cardiac homeostasis. Functional changes in these dyad proteins, whether induced by genetic, epigenetic, metabolic, therapeutic, or environmental factors, can disrupt normal cardiac electrophysiology, leading to abnormal E-C coupling and arrhythmias. Animal models and heterologous cell cultures provide platforms to elucidate the pathogenesis of arrhythmias for basic cardiac research; however, these traditional systems do not truly reflect human cardiac electro-pathophysiology. Notably, patients with the same genetic variants of inherited channelopathies (ICC) often exhibit incomplete penetrance and variable expressivity which underscores the need to establish patient-specific disease models to comprehend the mechanistic pathways of arrhythmias and determine personalized therapies. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) inherit the genetic background of the patient and reflect the electrophysiological characteristics of the native cardiomyocytes. Thus, iPSC-CMs provide an innovative and translational pivotal platform in cardiac disease modeling and therapeutic screening. In this review, we will examine how patient-specific iPSC-CMs historically evolved to model arrhythmia syndromes in a dish, and their utility in understanding the role of specific ion channels and their functional characteristics in causing arrhythmias. We will also examine how CRISPR/Cas9 have enabled the establishment of patient-independent and variant-induced iPSC-CMs-based arrhythmia models. Next, we will examine the limitations of using human iPSC-CMs with respect to in vitro arrhythmia modeling that stems from variations in iPSCs or toxicity due to gene editing on iPSC or iPSC-CMs and explore how such hurdles are being addressed. Importantly, we will also discuss how novel 3D iPSC-CM models can better capture in vitro characteristics and how all-optical platforms provide non-invasive and high- throughput electrophysiological data that is useful for stratification of emerging arrhythmogenic variants and drug discovery. Finally, we will examine strategies to improve iPSC-CM maturity, including powerful gene editing and optogenetic tools that can introduce/modify specific ion channels in iPSC-CMs and tailor cellular and functional characteristics. We anticipate that an elegant synergy of iPSCs, novel gene editing, 3D- culture models, and all-optical platforms will offer a high-throughput template to faithfully recapitulate in vitro arrhythmogenic events necessary for personalized arrhythmia monitoring and drug screening process.

Mitochondrial Dysfunction in Arrhythmia and Cardiac Hypertrophy.

Arrhythmia and cardiac hypertrophy are two very common cardiovascular diseases that can lead to heart failure and even sudden death, thus presenting a serious threat to human life and health. According to global statistics, nearly one million people per year die from arrhythmia, cardiac hypertrophy and other associated cardiovascular diseases. Hence, there is an urgent need to find new treatment targets and to develop new intervention measures. Recently, mitochondrial dysfunction has been examined in relation to heart disease with a view to lowering the incidence of arrhythmia and cardiac hypertrophy. The heart is the body's largest energy consuming organ, turning over about 20 kg of adenosine triphosphate (ATP) per day in the mitochondria. Mitochondrial oxidative phosphorylation (OXPHOS) produces up to 90% of the ATP needed by cardiac muscle cells for contraction and relaxation. Dysfunction of heart mitochondria can therefore induce arrhythmia, cardiac hypertrophy and other cardiovascular diseases. Mitochondrial DNA (mtDNA) mutations cause disorders in OXPHOS and defects in the synthesis of muscle contraction proteins. These lead to insufficient production of secondary ATP, increased metabolic requirements for ATP by the myocardium, and the accumulation of reactive oxygen species (ROS). The resulting damage to myocardial cells eventually induces arrhythmia and cardiac hypertrophy. Mitochondrial damage decreases the efficiency of energy production, which further increases the production of ROS. The accumulation of ROS causes mitochondrial damage and eventually leads to a vicious cycle of mitochondrial damage and low efficiency of mitochondrial energy production. In this review, the mechanism underlying the development of arrhythmia and cardiac hypertrophy is described in relation to mitochondrial energy supply, oxidative stress, mtDNA mutation and Mitochondrial dynamics. Targeted therapy for arrhythmia and cardiac hypertrophy induced by mitochondrial dysfunction is also discussed in terms of its potential clinical value. These strategies should improve our understanding of mitochondrial biology and the pathogenesis of arrhythmia and cardiac hypertrophy. They may also identify novel strategies for targeting mitochondria in the treatment of these diseases.

Implications for neutrophils in cardiac arrhythmias.

Cardiac arrhythmias commonly occur as a result of aberrant electrical impulse formation or conduction in the myocardium. Frequently discussed triggers include underlying heart diseases such as myocardial ischemia, electrolyte imbalances, or genetic anomalies of ion channels involved in the tightly regulated cardiac action potential. Recently, the role of innate immune cells in the onset of arrhythmic events has been highlighted in numerous studies, correlating leukocyte expansion in the myocardium to increased arrhythmic burden. Here, we aim to call attention to the role of neutrophils in the pathogenesis of cardiac arrhythmias and their expansion during myocardial ischemia and infectious disease manifestation. In addition, we will elucidate molecular mechanisms associated with neutrophil activation and discuss their involvement as direct mediators of arrhythmogenicity.

Redox imbalance in patients with heart failure and ICD/CRT-D intervention. Can it be an underappreciated and overlooked arrhythmogenic factor? A first preliminary clinical study.

Introduction: Redox imbalance and oxidative stress are involved in the pathogenesis of arrhythmias. They also play a significant role in pathogenesis of heart failure (HF). In patients with HFand implanted cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D), the direct current shocks may be responsible for additional redox disturbances and additionally increase arrhythmia risk. However, the precise role of oxidative stress in potentially fatal arrhythmias and shock induction remains unclear. Methods: 36 patients with diagnosed HF and implanted ICD/CRT-D were included in this study. Patients were qualified to the study group in case of registered ventricular arrhythmia and adequate ICD/CRT-D intervention. The control group consisted of patients without arrhythmia with elective replacement indicator (ERI) status. Activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH) in erythrocyte (RBC), SOD, GPx activity and reactive oxygen/nitrogen species (ROS/RNS) concentration in plasma were determined. The values were correlated with glucose, TSH, uric acid, Mg and ion concentrations. Results: In the perishock period, we found a significant decrease in RBC and extracellular (EC) SOD and RBC CAT activity (p = 0.0110, p = 0.0055 and p = 0.0002, respectively). EC GPx activity was also lower (p = 0.0313). In all patients, a decrease in the concentration of all forms of glutathione was observed compared to the ERI group. Important association between ROS/RNS and GSH, Mg, TSH and uric acid was shown. A relationship between the activity of GSH and antioxidant enzymes was found. Furthermore, an association between oxidative stress and ionic imbalance has also been demonstrated. The patients had an unchanged de Haan antioxidant ratio and glutathione redox potential. Conclusion: Here we show significant redox disturbances in patients with HF and ICD/CRT-D interventions. Oxidative stress may be an additional risk factor for the development of arrhythmia in patients with HF. The detailed role of oxidative stress in ventricular arrhythmias requires further research already undertaken by our team.

Remodeling of lipid landscape in high fat fed very-long chain acyl-CoA dehydrogenase null mice favors pro-arrhythmic polyunsaturated fatty acids and their downstream metabolites

Very-long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial long chain (LC) fatty acid β-oxidation (FAO). Inherited VLCAD deficiency (VLCADD) predisposes to neonatal arrhythmias whose pathophysiology is still not understood. We hypothesized that VLCADD results in global disruption of cardiac complex lipid homeostasis, which may set conditions predisposing to arrhythmia. To test this, we assessed the cardiac lipidome and related molecular markers in seven-month-old VLCAD−/− mice, which mimic to some extent the human cardiac phenotype. Mice were sacrificed in the fed or fasted state after receiving for two weeks a chow or a high-fat diet (HFD), the latter condition being known to worsen symptoms in human VLCADD. Compared to their littermate counterparts, HFD/fasted VLCAD−/− mouse hearts displayed the following lipid alterations: (1) Lower LC, but higher VLC-acylcarnitines accumulation, (2) higher levels of arachidonic acid (AA) and lower docosahexaenoic acid (DHA) contents in glycerophospholipids (GPLs), as well as (3) corresponding changes in pro-arrhythmogenic AA-derived isoprostanes and thromboxane B2 (higher), and anti-arrythmogenic DHA-derived neuroprostanes (lower). These changes were associated with remodeling in the expression of gene or protein markers of (1) GPLs remodeling: higher calcium-dependent phospholipase A2 and lysophosphatidylcholine-acyltransferase 2, (2) calcium handling perturbations, and (3) endoplasmic reticulum stress. Altogether, these results highlight global lipid dyshomeostasis beyond FAO in VLCAD−/− mouse hearts, which may set conditions predisposing the hearts to calcium mishandling and endoplasmic reticulum stress and thereby may contribute to the pathogenesis of arrhythmias in VLCADD in mice as well as in humans.

Effect of Smokeless Tobacco (Maras Powder) on the Epicardial Fat Thickness and Ventricular Repolarization Parameters.

Background and Objectives: Smokeless tobacco (ST) use has recently become an alternative to cigarettes, and it has been concluded that ST is at least as harmful as cigarettes. ST use is thought to play a role in the pathogenesis of arrhythmia by affecting ventricular repolarization. In this study, we aimed to examine the relationships of Maras powder (MP), one of the ST varieties, with epicardial fat thickness and new ventricular repolarization parameters, which have not previously been described. Materials and Methods: A total of 289 male individuals were included in this study between April 2022 and December 2022. Three groups, 97 MP users, 97 smokers, and 95 healthy (non-tobacco), were compared according to electrocardiographic and echocardiographic data. Electrocardiograms (ECG) were evaluated with a magnifying glass by two expert cardiologists at a speed of 50 m/s. Epicardial fat thickness (EFT) was measured by echocardiography in the parasternal short- and long-axis images. A model was created with variables that could affect epicardial fat thickness. Results: There were no differences between the groups regarding body mass index (p = 0.672) and age (p = 0.306). The low-density lipoprotein value was higher in the MP user group (p = 0.003). The QT interval was similar between groups. Tp-e (p = 0.022), cTp-e (p = 0.013), Tp-e/QT (p =0.005), and Tp-e/cQT (p = 0.012) were higher in the MP user group. While the Tp-e/QT ratio did not affect EFT, MP predicted the epicardial fat thickness (p < 0.001, B = 0.522, 95%CI 0.272-0.773). Conclusions: Maras powder may play a role in ventricular arrhythmia by affecting EFT and causing an increase in the Tp-e interval.

PO-05-164 IMPACT OF ARRHYTHMIAS IN PATIENTS WITH HEMOCHROMATOSIS: A NATIONAL INPATIENT SAMPLE (NIS) ANALYSIS

Hemochromatosis is a relatively rare genetic disease that results in restrictive cardiomyopathy caused by the deposition of iron. Iron has a higher affinity to deposit in the conduction system of the heart resulting in a lower threshold for developing arrhythmias. We sought to assess the data on the burden of arrhythmias in hospitalized patients with hemochromatosis. To study the impact of arrythmia in a special study cohort i.e. adults with hemochromatosis The national inpatient sample (NIS) from 2018-2020 was queried for adult patients (age>18 yrs) admitted with a secondary diagnosis of hemochromatosis. These patients were stratified for arrhythmias [atrial fibrillation (AF), atrial flutters, SVTs, heart blocks (first degree, second degree, complete heart blocks [CHB], ventricular tachycardia (VT), and fibrillation(VF)]. Baseline risk factors and cardiac complications were compared. Multiple regression analysis was performed using mortality as the primary outcome. Results were further validated with propensity-matched analysis. A total of 141755 adult patients hospitalized from 2018-2020 had hemochromatosis with a mean age of 55 years. Of these, 33.84% were females and 16.59% had an underlying arrhythmia. In the cohort of hemochromatosis, patients with concurrent arrhythmias had a higher prevalence of diabetes mellitus (27.67% vs 18.55%; P<0.0001), hyperlipidemia (41.08% vs 22.83%; P<0.0002), tobacco abuse (30.5% vs 24.05%; P<0.0001) and obesity than those without arrhythmias (14.77% vs 10.98%; P<0.0001). The prevalence of valvular abnormalities (36.39% vs 24.55%; P<0.0001), old myocardial infarction (6.91% vs 3.25%; P<0.0001), and coronary artery disease (28.06% vs 10.68%; P< 0.0001) was also significantly higher in these patients. Multivariate regression analysis revealed higher odds of mortality with AF, VF, and VT in adult patients with hemochromatosis (Table 1). Propensity-matched analysis confirmed these findings. (Table 2) The odds of mortality were not significant with CHB in these patients. Hemochromatosis portends worse outcomes with arrhythmias compared to without it. Arrhythmias in hemochromatosis should be better managed to improve patient outcomes. Further studies are warranted to determine the pathogenesis of arrhythmias in patients with hemochromatosis to develop therapeutics and mitigate complications.

Antiarrhythmic active components in traditional Chinese medicine acting on potassium channels

Arrhythmia is an external manifestation of cardiac electrophysiological disorder. It exists in healthy people and patients with various heart diseases, which is often associated with other cardiovascular diseases. The contraction and diastole of myocardium are inseparable from the movement of ions. There are many ion channels in the membrane and organelle membrane of myocardium. The dynamic balance of myocardial ions is vital in maintaining myocardial electrical homeostasis. Potassium ion channels that have a complex variety and a wide distribution are involved in the whole process of resting potential and action potential of cardiomyocytes. Potassium ion channels play a vital role in maintaining normal electrophysiological activity of myocardium and is one of the pathogenesis of arrhythmia. Traditional Chinese medicine(TCM)has unique advantages in treating arrhythmia for its complex active components and diverse targets. A large number of TCM preparations have definite effect on treating arrhythmia-related diseases, whose antiarrhythmic mechanism may be related to the effect on potassium channel. This article mainly reviewed the relevant studies on the active components in TCM acting on different potassium channels to provide references for clinical drug use and development.

Reversible QRS attenuation/fragmentation in patients with takotsubo syndrome.

To the Editor: I read with great interest the paper by Li et al,1 about the 80-year-old woman whose electrocardiogram (ECG), in the setting of takotsubo syndrome (TTS), revealed “fragmentation of the QRS complexes across precordial leads V4-6, lead aVR, and a positive deflection embedded within the QRS complex in lead V1.” The comprehensive analysis of the authors about the pathogenesis of arrhythmias in patients with TTS, in connection with the vagal influences, and underlying myocardial edema and microfibrosis, are highly appreciated. I have some comments and questions for the authors: (1) In reference to the statement that these ECG changes were resolved in 3 months, it will be of interest to the readers to know whether other ECGs in this patient were recorded between the admission and the 3-month time point, and if such ECGs revealed QRS fragmentation or its earlier resolution. (2) Reversible attenuation of the QRS amplitude has been previously described in various combinations of the ECG leads, and lead aVR, in connection with TTS, and attributed to myocardial edema2, 3; careful inspection of Figure 1 of the present paper reveals attenuation of the QRS amplitude in leads I, II, III, aVR, aVL, aVF, V1, and V3–V6. (3) Did the patient have any ECGs prior to her admission with TTS, to compare it with the ECG obtained on admission? None.

Serum Uric Acid to HDL-Cholesterol Ratio Could Be Promising Predictor of Atrioventricular Nodal Reentrant Tachycardia

Objective: Paroxysmal supraventricular tachycardia (PSVT), particularly atrioventricular nodal reentrant tachycardia (AVNRT), is a common arrhythmia with no associated structural heart disease. Inflammation has been implicated in the pathogenesis of arrhythmias. Uric acid to HDL-cholesterol ratio (UHR) is a novel inflammation marker that has been investigated in various conditions. This study aimed to explore the potential association between UHR and AVNRT. Material and Methods: A total of 136 patients were included in the study, including 86 patients with AVNRT and 50 controls with normal electrophysiologic study. All patients' medical records were reviewed, and data were obtained retrospectively. We recorded baseline features, hematologic and biochemical markers, and determined the UHR value. Results: UHR (p=0.031) and uric acid (p&lt;0.001) levels were significantly higher, while HDL cholesterol (p=0.031) levels were significantly lower in the AVNRT group. Neutrophil leukocyte ratio (NLR) was also higher in the AVNRT group (p=0.034). However, in multivariate analysis, only UHR emerged as an independent predictor for AVNRT (OR: 1.088; 95%CI: 1.022 – 1.159; p=0.008). ROC curve analysis suggested a UHR cut-off &gt; 14.05 for predicting AVNRT with 56% sensitivity and 76% specificity. Conclusion: This study identifies UHR as a promising predictor for AVNRT, shedding light on the potential role of inflammation in the arrhythmia's development. Utilizing UHR as a readily accessible marker in the evaluation of AVNRT patients may have clinical implications.

Development of a Visualization Deep Learning Model for Classifying Origins of Ventricular Arrhythmias.

Several algorithms have been proposed for differentiating the right and left outflow tracts (RVOT/LVOT) arrhythmia origins from 12-lead electrocardiograms (ECGs); however, the procedure is complicated. A deep learning (DL) model, a form of artificial intelligence, can directly use ECGs and depict the importance of the leads and waveforms. This study aimed to create a visualized DL model that could classify arrhythmia origins more accurately.Methods and Results: This study enrolled 80 patients who underwent catheter ablation. A convolutional neural network-based model that could classify arrhythmia origins with 12-lead ECGs and visualize the leads that contributed to the diagnosis using a gradient-weighted class activation mapping method was developed. The average prediction results of the origins by the DL model were 89.4% (88.2-90.6) for accuracy and 95.2% (94.3-96.2) for recall, which were significantly better than when a conventional algorithm is used. The ratio of the contribution to the prediction differed between RVOT and LVOT origins. Although leads V1 to V3 and the limb leads had a focused balance in the LVOT group, the contribution ratio of leads aVR, aVL, and aVF was higher in the RVOT group. This study diagnosed the arrhythmia origins more accurately than the conventional algorithm, and clarified which part of the 12-lead waveforms contributed to the diagnosis. The visualized DL model was convincing and may play a role in understanding the pathogenesis of arrhythmias.

The Pathogenesis of Cardiac Arrhythmias in Vitamin D Deficiency.

The global prevalence of vitamin D deficiency is more than 20%, and the main causes include insufficient intake, reduced absorption, abnormal metabolism, or resistance to its effects. The levels of serum vitamin D appear to influence cardiovascular risk, and the mechanism involved is linked to the transient outward current and the ultrarapid delayed rectifier K+ current densities, activated through the nuclear vitamin D receptor and Akt pathway. A significant number of studies have correlated vitamin D deficiency with an increased risk of developing cardiac arrhythmias and sudden cardiac death. For this reason, the purpose of this review is to analyze the relation between vitamin D deficiency and the pathogenesis of cardiac arrhythmias. Atrial fibrillation, increased QT interval, and QT dispersion were the most common findings associated with vitamin D deficiency. Due to the heterogeneity among existing studies, further research is necessary to confirm the existing data and to analyze its relationship with other types of arrhythmias.

Regulation of Ion Channel Function in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes by Cancer Cell Secretion Through DNA Methylation.

BackgroundCardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy. Experimental studies investigating the effects of cancer cell secretion without chemotherapy on ion channel function in human cardiomyocytes are still lacking.MethodsThe human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from three healthy donors were treated with gastrointestinal (GI) cancer (AGS and SW480 cells) medium for 48 h. The qPCR, patch-clamp, western blotting, immunostaining, dot blotting, bisulfite sequence, and overexpression of the ten-eleven translocation (TET) enzyme were performed for the study.ResultsAfter treated with cancer cell secretion, the maximum depolarization velocity and the action potential amplitude were reduced, the action potential duration prolonged, peak Na+ current, and the transient outward current were decreased, late Na+ and the slowly activating delayed rectifier K+ current were increased. Changes of mRNA and protein level of respective channels were detected along with altered DNA methylation level in CpG island in the promoter regions of ion channel genes and increased protein levels of DNA methyltransferases. Phosphoinositide 3-kinase (PI3K) inhibitor attenuated and transforming growth factor-β (TGF-β) mimicked the effects of cancer cell secretion.ConclusionsGI cancer cell secretion could induce ion channel dysfunction, which may contribute to occurrence of arrhythmias in cancer patients. The ion channel dysfunction could result from DNA methylation of ion channel genes via activation of TGF-β/PI3K signaling. This study may provide new insights into pathogenesis of arrhythmia in cancer patients.

The role of inflammation in the pathogenesis and treatment of arrhythmias.

The pathogenesis of arrhythmias is complex and multifactorial. The role of inflammation in the pathogenesis of both atrial and ventricular arrhythmias (VA) has been explored. However, developing successful pharmacotherapy regimens based on those pathways has proven more of a challenge. This narrative review provides an overview of five common arrhythmias impacted by inflammation, including atrial fibrillation (AF), myocardial infarction, arrhythmogenic cardiomyopathy, cardiac sarcoidosis, and QT prolongation, and the potential role for anti-inflammatory therapy in their management. We identified arrhythmias and arrhythmogenic disease states with the most evidence linking pathogenesis to inflammation and conducted comprehensive searches of United States National Library of Medicine MEDLINE® and PubMed databases. Although a variety of agents have been studied for the management of AF, primarily in an effort to reduce postoperative AF following cardiac surgery, no standard anti-inflammatory agents are used in clinical practice at this time. Although inflammation following myocardial infarction may contribute to the development of VA, there is no clear benefit with the use of anti-inflammatory agents at this time. Similarly, although inflammation is clearly linked to the development of arrhythmias in arrhythmogenic cardiomyopathy, data demonstrating a benefit with anti-inflammatory agents are limited. Cardiac sarcoidosis, an infiltrative disease eliciting an immune response, is primarily treated by immunosuppressive therapy and steroids, despite a lack of primary literature to support such regimens. In this case, anti-inflammatory agents are frequently used in clinical practice. The pathophysiology of arrhythmias is complex, and inflammation likely plays a role in both onset and duration, however, for most arrhythmias the role of pharmacotherapy targeting inflammation remains unclear.

Burden and Impact of Arrhythmias in Repaired Tetralogy of Fallot.

Arrhythmias are a leading cause of morbidity and mortality following repair of tetralogy of Fallot (TOF). This review will highlight current understanding of arrhythmia pathogenesis in this patient population and review novel therapeutic options. Risk factors for developing ventricular arrhythmias in repaired TOF have thus far been better defined than for atrial arrhythmias. Growing understanding of the pathophysiology of arrhythmias, development of risk stratification models, and novel techniques such as electrophysiologic ultrahigh-density mapping should help to better identify patients that benefit from advanced therapies such as ablation and implantable cardioverter defibrillators. Atrial and ventricular arrhythmias are common in TOF patients. Methods of risk stratification and therapeutic approaches are rapidly evolving, leading to ever improving clinical outcomes in this patient population.