Cardiac Electrical Abnormalities Research Articles

Abstract Mo046: GJA1-20k Restores Connexin-43 Trafficking and β-Catenin Signaling in Myocytes Lacking Desmoplakin

Background: Arrhythmogenic Cardiomyopathy (ACM) is an insidious hereditary heart disease that results in structural and electrical cardiac abnormalities leading to arrhythmogenesis and heart failure. ACM is characterized by cardiomyocyte loss, decreased cellular coupling, and fibrofatty replacement. The disease arises from mutations in desmosomal genes, such as plakophilin (PKP), desmoglein (DSG), and desmoplakin (DSP). The pathogenesis of this disease is linked to dysfunction at the level of several cellular processes and pathways, including Wnt/β-catenin signaling. Recent evidence has shown that GJA1-20k, a truncated isoform of Connexin-43 (Cx43) generated by internal translation, has a therapeutic role in preserving Cx43 trafficking and cell-cell coupling in ACM of DSG origin. This study aims to investigate the role of GJA1-20k in protecting against ACM of DSP origin by evaluating its effect in cell models on Cx43 trafficking and Wnt/β-catenin signaling. Methods: DSP knockdown was performed on HEK cells and mouse neonatal cardiomyocytes. The role of GJA1-20k was determined using imaging, biochemical, and molecular biology techniques. Results: Protein levels of Cx43 and β-catenin were decreased on Western blot (WB) upon DSP knockdown. These findings were corroborated through imaging wherein the signal intensity for Cx43 at cellular junctions and β-catenin at the membrane was significantly decreased compared to the control group. β-catenin signal intensity was also decreased within the nucleus. Upon administration of GJA1-20k, protein levels of Cx43 were normalized on WB. Moreover, the ratio of phosphorylated β-catenin (inactive) to total β-catenin was decreased. Imaging studies identified a significant increase in Cx43 and β-catenin at the membrane in ACM models treated with GJA1-20k. This was also accompanied by an increase in β-catenin signal intensity within the nucleus. A TOP-flash luciferase assay was performed and revealed a significant increase in β-catenin transcriptional activity in the presence of GJA1-20k despite DSP knockdown. Conclusions: These results suggest that GJA1-20k is able to rescue Cx43 trafficking and recover Wnt/β-catenin signaling in cells and cardiomyocytes lacking DSP. The ability of GJA1-20k to restore dysfunctional genetic pathways involved in arrhythmogenesis and fibro-adipogenesis make it an attractive potential candidate for targeted therapy against ACM.

Evolution of the ECG in idiopathic ventricular fibrillation survivors: results from a single-centre UK registry

Abstract Background Idiopathic ventricular fibrillation (VF) is a diagnosis of exclusion in subjects with an unexplained cardiac arrest and no evidence of overt structural or electrical cardiac abnormalities (1). It can be associated with an early repolarisation pattern (ERP)(2). Data on the evolution of the ECG in this population are lacking. Purpose To compare the baseline ECG characteristic of idiopathic VF survivors and age and gender matched controls, and investigate if the presence of an ERP at ECG is a predictor of risk. Methods Forty-nine subjects with idiopathic VF evaluated in our tertiary centre from 1997 to 2022, and followed-up for at least 3 months were included in this study. The first representative ECG available after cardiac arrest was evaluated and compared with that of an age and gender matched control with no symptoms, family history of sudden cardiac death and normal cardiac tests; moreover, comparison was made with a follow-up ECG off antiarrhythmic medications (quinidine, amiodarone and verapamil). Medical notes were reviewed to investigate the presence of events at f-up (SCD/appropriate ICD shock). Results The mean age at presentation was 33±7 years; 63% of patients were males, and 16% had previous syncope. Twelve cases (24%) and 6 controls (12%) showed ERP on the resting ECG (P=NS). Only resting heart rate (HR) and QRS duration differed between the two groups (Table 1). Follow-up ECGs in 46 idiopathic VF survivors indicated that resting HR, QRS axis and QTc values were significantly different compared to the baseline ECG. In addition, 4 subjects with ERP at baseline did not exhibit it on the most recent ECG, and 6 subjects without ERP at baseline showed it on the most recent ECG. Over a median follow-up of 3.3 years (IQR 6), 13 subjects experienced appropriate ICD shocks. Kaplan-Meyer survival estimates showed no differences in events between subjects showing ERP or not (log rank p=0.092). Conclusions Subjects with idiopathic VF show baseline ECGs similar to those of age and gender matched healthy controls from the general population. ECG parameters tend to change only slightly over long-term follow up. The ERP in idiopathic VF survivors is dynamic and thus its relationship with events may be underestimated.Table 1 Table 2

P.064 A case of late onset Pompe Disease presenting in 6th decade

Background: Late onset Pompe disease (LOPD), rare autosomal recessive lysosomal storage disease, resulting from mutation in alpha glucosidase enzyme (GAA) can present even in 6th decade of life. Slowly progressive, subtle, limb girdle pattern of weakness (LGPW), with auxiliary features such as ptosis, enlarged tongue, axial rigidity, facial diplegia, variable degree of respiratory weakness is not uncommon. Hypertrophic and electrical cardiac abnormalities are well described in LOPD. Methods: We present a case of 67-year-old male presenting with proximal weakness, subtle ptosis, bilateral quadriceps and shoulder girdle atrophy, and left toe numbness. PMHx: CABG, NSTEMI. Statin use. FMHx: noncontributory. Results: EMG: L5 radiculopathy, with unexpected myopathic units in hip/pelvic/ shoulder girdle muscles with active denervation and muscle irritability. CK, CRP, SPEP, ANA, LFTs, HMG-CoA reductase: normal. GAA enzymatic activity=0.96µmol/L/hr (low), genetics: pathogenic variants in GAA gene: c.-32-13T>G and c.1194+3G>C. ECHO: severe diastolic dysfunction, restrictive left ventricular filling. PFTs: normal. Diagnosed with LOPD, started on therapy. Conclusions: LOPD remains a differential for LGPW especially in older patient population with history of cardiopulmonary features. Age-appropriate conconminant pathologies may confound the diagnostic process.Symptoms may preceed diagnosis for years.GAA enzymatic activity followed by genetic testing remains readily available and can confirm diagnosis, preventing delay of approved therapy.

Feasibility of using KardiaMobile-L6 for QT interval monitoring during the early phase of the COVID-19 pandemic in critical care patients

The electrocardiogram (ECG) represents an essential tool to determine cardiac electrical abnormalities in COVID-19 patients, the effects of anti-SARS-CoV-2 drugs, and potential drug interactions. Smartphone-based heart monitors have increased the spectrum of ECG monitoring however, we are not aware of its reliability in critically ill COVID-19 patients. We aim to evaluate the feasibility and reliability of nurse-performed smartphone electrocardiography for QT interval monitoring in critically ill COVID-19 patients using KardiaMobile-6L compared with the standard 12-lead ECG. An observational comparative study was conducted comparing consecutive KardiaMobile-6L and 12-lead ECG recordings obtained from 20 patients admitted to the intensive care unit with SARS-CoV-2 infection and on invasive mechanical ventilation. The heart rate-corrected QT (QTc) intervals measured by KardiaMobile-6L and 12-lead ECG were compared. In 60 percent of the recordings, QTc intervals measured by KardiaMobile-6L matched those by 12-lead ECG. The QTc intervals measured by KardiaMobile-6 and 12-lead ECG were 428 ± 45 ms and 425 ± 35 ms (p = 0.82), respectively. The former demonstrated good agreement (bias = 2.9 ms; standard deviation of bias = 29.6 ms) with the latter, using the Bland–Altman method of measurement agreement. In all but one recording, KardiaMobile-6L demonstrated QTc prolongation. QTc interval monitoring with KardiaMobile-6L in critically ill COVID-19 patients was feasible and demonstrated reliability comparable to the standard 12-lead ECG.

Association of Non-Alcoholic Fatty Liver Disease with Cardiac Arrhythmias and Cardiac Conduction Defects: A Review of the Literature

Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition that affects a significant portion of the global population and imposes a heavy clinical and economic burden. Recent studies have provided substantial evidence linking NAFLD to cardiac electrical abnormalities, including atrial and ventricular arrhythmias, heart blocks, conduction delays, and ECG changes. These cardiac electrical disturbances play a significant role in cardiac diseases that are the leading cause of death in NAFLD patients. This paper aims to provide an update on the proposed mechanisms underlying arrhythmogenesis in NAFLD and summarize the latest research findings in this field. Managing NAFLD requires a comprehensive approach that includes treating the underlying liver condition and regular ECG monitoring to detect and address any potential cardiac complications. Meta-analyses are recommended for future research further to elucidate the association between NAFLD and cardiac arrhythmias. Understanding and effectively managing the cardiac implications of NAFLD will contribute to improved patient care and outcomes.

How Important are Cardiac Electrical Abnormalities in Duchenne and Becker Muscular Dystrophy?

How Important are Cardiac Electrical Abnormalities in Duchenne and Becker Muscular Dystrophy?

Elevated thyroid-stimulating hormone (TSH) is associated with atrial fibrillation and directly modulates electrophysiological properties of atrial cardiomyocytes

Abstract Background Thyroid dysfunction has a strong association with cardiac arrhythmias. However, subclinical hypothyroidism (SH) is often neglected in studies. SH is characterized by increased values of TSH and normal values of T3/T4. Recent studies indicate that high TSH levels are related to an increased incidence of cardiac electrical abnormalities, especially atrial fibrillation (AF). Purpose The present work aims to investigate direct effects of TSH on ion channel remodelling in cardiomyocytes and a possible causative role in the increased occurrence of arrhythmia in SH. Methods A retrospective monocentric study analysed medical records, ECGs and echocardiographies of 3134 patients between 2007 to 2020. Inclusion criteria comprised patient age ≥18 years, normal fT4, TSH values 4–75 mU/l and available ECGs. The patient cohort was divided into two groups based on current treatment recommendations for SH (TSH level 4–9.9 mU/l; 10–75 mU/l). Direct effects on ion channel remodelling were analysed in HL-1 and neonatal cardiomyocytes with confirmed expression of TSH receptors. TSH concentrations of 15, 30, and 60 mU/l simulated different degrees of hypothyroidism. RT-qPCR analyses, western blots and immunofluorescence stainings were performed after incubation with respective TSH concentrations for 24h. In vitro video analyses of automatism in NRCM before and after TSH incubation were performed. Statistical comparisons were calculated using student's t-tests and the chi-square test. In addition, a multivariate analysis of factors affecting the occurrence of AF in patients with SH was carried out. Results Elevated TSH levels were associated with higher prevalence of AF. In the group of patients with a TSH value of 10–75 mU/l, AF was observed in 42.8% of cases compared to 31.7% in patients with lower TSH levels (p<0.0001). In vitro, TSH application to cardiomyocytes led to significant changes in mRNA and protein expression of key ion channels and regulatory proteins. Incubation of HL-1 cells with 15 mU/l TSH showed a decrease in Kcne1 protein, while 60 mU/l TSH caused an upregulation of K2P3.1 (TASK-1), Kv7.1, and KCa2.1 expression. To further elucidate the TSH signaling cascade in cardiomyocytes, we investigated TSH effects on PKAα, CaMKIIδ and CaMKIIγ. PKAα was upregulated after 24h incubation with 60 mU/l TSH and exhibited an increase of the phosphorylated state. Finally, neonatal cardiomyocytes showed an increased beating rate after incubation with TSH. Conclusion The prevalence of atrial fibrillation is significantly increased in patients with SH. Our findings further reveal a direct effect of TSH on ion channel expression in cardiomyocytes as potential proarrhythmic mechanism. TSH induced changes in the expression of ion channels that determine action potential duration. Subclinical hypothyroidism contributes to the development of atrial fibrillation. Underlying mechanisms and therapeutic implications require further research. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Heidelberg University Medical School - Olympia Morata

Abstract P3080: S100A8/9 Is A Key Regulator For Normal Heart Function During Pseudomonas Aeruginosa Infection

Rationale: P. aeruginosa ( P.a ) infection can cause severe pneumonia in ICU patients that leads to cardiac inflammation and cardiac dysfunction. Growing evidence indicates that a large number of neutrophils are recruited to the site of P.a. infection and releases S100A8/9 into the microenvironment. S100A8/9 has been shown to activate both the immune system (TLR4/RAGE) and has bactericidal properties. Often, hyperactivation of the inflammatory responses by S100A8/9 causes cardiac inflammation and dysfunction. Thus, we hypothesize that excessive production of S100A8/9 restrict bacterial growth and enhances the host immune response in order to control the infection and preserve heart function. Objective: To identify the mechanism of S100A8/9 mediated cardiac inflammation and cardiac dysfunction during P. aeruginosa infection. Methods and Results: To investigate the role of S100A8/9 in cardiac inflammation and cardiac dysfunction, we infected wild type (WT) and S100A8/9KO mice with P.a. intranasally. We monitored bodyweight at 24h intervals and measured weight loss, survival, and bacterial burden in the lungs and heart. We performed multicolor flow cytometry on BAL cells and heart cells for immune cell phenotyping and ELISA for cytokine levels. Also, we measured cardiac electric activity (EKG) and heart function (echocardiography). We found that bacterial burden in the lungs and heart was higher in S100A8/9KO mice than in WT, which correlated with increased mortality. We found severe cardiac electrical abnormalities (second-degree AV block) in S100A8/9KO mice and left ventricular dysfunction. However, there was no significant difference in the BALF immune cell phenotypes of both S100A8/9KO and WT infected mice. Finally, the S100A8/9 inhibitor enhanced the survival of P.a. infected mice. Conclusion: Our data demonstrate that neutrophil recruitment and release of S100A8/9 is critical to control bacterial growth in the lungs, however, uncontrolled neutrophil accumulation leads to excessive production of S100A8/9. Hyperactivation of the immune system by excessive S100A8/9 leads to systemic inflammation and bacterial dissemination of the heart. Furthermore, our studies revealed that blocking S100A8/9 receptor binding enhances the survival of mice during P.a. infection.

Automated Torso Contour Extraction from Clinical Cardiac MR Slices for 3D Torso Reconstruction.

Whilst the electrocardiogram (ECG) is an essential tool for diagnosing cardiac electrical abnormalities, its characteristics are dependent on anatomical variability. Specifically variation in torso geometry affects relative positions of the leads with respect to the heart. We propose a novel pipeline that uses standard cardiac magnetic resonance images to reconstruct the torso and heart, and recreate the ECG considering torso and cardiac anatomy. This requires automated extraction of the torso contours. Our method combines an initial u-net segmenter with a second network that refines contours and removes spurious segments. The networks were evaluated on a cross validation study dataset and an independent test set. The use of two-channel input, including both original image and initial segmentation, in the refinement network significantly improved performance on the independent test set, reducing the Hausdorff distance from 9.1 pixels to 4.3 pixels and increasing Dice coefficient from 0.75 to 0.93. Clinical Relevance- This method can be utilized to allow ECG simulations with personalized torso geometry which has previously been demonstrated to significantly effect QRS parameters. A clinical tool can be developed using this method that accounts for torso geometry in ECG interpretation.

Investigating inherited arrhythmias using hiPSC-derived cardiomyocytes

Fundamental to the functional behavior of cardiac muscle is that the cardiomyocytes are integrated as a functional syncytium. Disrupted electrical activity in the cardiac tissue can lead to serious complications including cardiac arrhythmias. Therefore, it is important to study electrophysiological properties of the cardiac tissue. With advancements in stem cell research, protocols for the production of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been established, providing great potential in modelling cardiac arrhythmias and drug testing. The hiPSC-CM model can be used in conjunction with electrophysiology-based platforms to examine the electrical activity of the cardiac tissue. Techniques for determining the myocardial electrical activity include multielectrode arrays (MEAs), optical mapping (OM), and patch clamping. These techniques provide critical approaches to investigate cardiac electrical abnormalities that underlie arrhythmias.

Primary systemic sclerosis heart involvement: A systematic literature review and preliminary data-driven, consensus-based WSF/HFA definition.

Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5-300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46-1.00) for the first round and 0.55 (0.44-1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47-1.00)). Criterion validity showed a 78 (73-84)% correctness versus gold standard. A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research.

The electrocardiographic forward problem: A benchmark study

BackgroundElectrocardiographic forward problems are crucial components for noninvasive electrocardiographic imaging (ECGI) that compute torso potentials from cardiac source measurements. Forward problems have few sources of error as they are physically well posed and supported by mature numerical and computational techniques. However, the residual errors reported from experimental validation studies between forward computed and measured torso signals remain surprisingly high. ObjectiveTo test the hypothesis that incomplete cardiac source sampling, especially above the atrioventricular (AV) plane is a major contributor to forward solution errors. MethodsWe used a modified Langendorff preparation suspended in a human-shaped electrolytic torso-tank and a novel pericardiac-cage recording array to thoroughly sample the cardiac potentials. With this carefully controlled experimental preparation, we minimized possible sources of error, including geometric error and torso inhomogeneities. We progressively removed recorded signals from above the atrioventricular plane to determine how the forward-computed torso-tank potentials were affected by incomplete source sampling. ResultsWe studied 240 beats total recorded from three different activation sequence types (sinus, and posterior and anterior left-ventricular free-wall pacing) in each of two experiments. With complete sampling by the cage electrodes, all correlation metrics between computed and measured torso-tank potentials were above 0.93 (maximum 0.99). The mean root-mean-squared error across all beat types was also low, less than or equal to 0.10 mV. A precipitous drop in forward solution accuracy was observed when we included only cage measurements below the AV plane. ConclusionFirst, our forward computed potentials using complete cardiac source measurements set a benchmark for similar studies. Second, this study validates the importance of complete cardiac source sampling above the AV plane to produce accurate forward computed torso potentials. Testing ECGI systems and techniques with these more complete and highly accurate datasets will improve inverse techniques and noninvasive detection of cardiac electrical abnormalities.

<p>Assessment of Ventricular Repolarization in Sickle Cell Anemia Patients: The Role of QTc Interval, Tp-e Interval and Tp-e/QTc Ratio and Its Gender Implication</p>

BackgroundMany specific and non-specific electrocardiographic abnormalities including ventricular arrhythmias have been reported in subjects with sickle cell anemia (SCA). In SCA patients, cardiac electrical abnormalities may be the leading cause of increased risk of arrhythmias. The corrected QT (QTc) interval, peak to the end of the T wave (Tp-e) interval and associated Tp-e/QTc ratio are promising measures of altered ventricular repolarization and increased arrhythmogenesis risk.AimThis study assessed ventricular repolarization abnormalities in subjects with SCA using the QTc interval, Tp-e interval and Tp-e/QTc ratio, and also evaluated the gender differences in these parameters, as well as their determinants.MethodsSixty subjects with SCA and 60 healthy control subjects, matched for age and gender, were studied. All participants underwent physical examination, hematological and biochemical evaluation, and 12-lead electrocardiography (ECG) recording. QT and Tp-e intervals were measured from the ECG, and the QTc interval was calculated using Bazett’s formula. Tp-e/QT and Tp-e/QTc ratios were also derived.ResultsQT and QTc intervals were prolonged in subjects with SCA. Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were prolonged in male SCA subjects, with a paradoxical shortening in female SCA subjects. Plasminogen activator inhibitor-1 (PAI-1) was an independent determinant of QTc, while body mass index (BMI) was an independent determinant of both Tp-e interval and Tp-e/QTc ratio.ConclusionOur results suggest an elevated risk for ventricular arrhythmogenesis in male SCA subjects. Furthermore, increased BMI and PAI-1 level are possible markers of ventricular repolarization abnormalities in SCA subjects.

Abstract 15588: Prediction of Mortality Using Standard 12-lead Electrocardiogram With Deep Neural Network

Background: Electrocardiogram (ECG) is a low-cost, inexpensive, non-invasive, and ubiquitous test to detect structural or electrical cardiac abnormalities. The ECG interpretation is a visual task to correlate specific patterns with diseases. Subtle ECG patterns that are invisible to the human eyes may be useful for patient risk stratification. We aimed to develop a deep neural network to predict mortality using standard 12-lead ECG. Methods: We obtained the entire clinical MUSE database of Chang Gung Memorial Hospital for standard resting 12-lead 10-sec ECG voltage-time traces, which were linked to the National Death Registry for all-cause and cause-specific mortality. Ten thousand patients remained alive at one year from the ECG examination date, and 10000 patients died within one year were randomly selected to train a one-dimensional deep neural network to predict mortality risk. Data was split into 16,000 patients for the training and 4,000 patients for the validation sets. We prepared a separate held-out dataset of 19,737 randomly selected patients whose ECG traces were fed to the model to predict their mortality risk. Results: The mean age of the held-out dataset was 60.0±16.7 years, and 50.0% were female. Among them, 3,807 died during a mean follow-up period of 6.0 years (maximum period, 14 years). The model achieved an area under the receiver operator curve of 0.85 on the held-out dataset. The age- and sex-weighted Kaplan-Meier curve for the mortality was shown in figure 1, which stratified by the model prediction for survival status (log-rank test, p < 0.001). Using a Cox proportional hazards model, the ECG algorithm predicted death is associated with an age- and sex-adjusted hazard ratio of 3.2 (95% confidence interval, 3.0-3.4) for all-cause mortality and 2.9 (95% CI, 2.4-3.5) for cardiovascular mortality. Conclusion: The deep learning model could extract prognostic information from standard 12-lead ECG and predict mortality with reasonable precision.

Identification of common cardiometabolic alterations and deregulated pathways in mouse and pig models of aging.

Aging is the main risk factor for cardiovascular and metabolic diseases, which have become a global concern as the world population ages. These diseases and the aging process are exacerbated in Hutchinson–Gilford progeria syndrome (HGPS or progeria). Here, we evaluated the cardiometabolic disease in animal models of premature and normal aging with the aim of identifying alterations that are shared or specific to each condition. Despite differences in body composition and metabolic markers, prematurely and normally aging mice developed heart failure and similar cardiac electrical abnormalities. High‐throughput proteomics of the hearts of progeric and normally aged mice revealed altered protein oxidation and glycation, as well as dysregulated pathways regulating energy metabolism, proteostasis, gene expression, and cardiac muscle contraction. These results were corroborated in the hearts of progeric pigs, underscoring the translational potential of our findings, which could help in the design of strategies to prevent or slow age‐related cardiometabolic disease.

Subclinical cardiac structural and electrical abnormalities in fibromyalgia syndrome

Background/aim In the literature, there is a paucity of data about the effects of fibromyalgia syndrome (FMS) on myocardial function and electrophysiological properties of atrium and ventricles. In this study, we investigated cardiac functions and noninvasive predictors of arrhythmias in patients with FMS.Materials and methods The study included 43 female patients diagnosed with FMS and 30 age- and sex-matched healthy subjects. The presence of fragmented QRS (fQRS) morphology, P dispersion, QT dispersion, inter- and intraatrial electromechanical delay was evaluated in the groups with 12-lead ECG and standard and tissue Doppler echocardiography.Results Among electrocardiographic parameters, P dispersion, QT dispersion, and the ratio of presence of fQRS morphology were found to be significantly higher in the study group as compared to the control group. In lateral and septal, the ratio of the early transmitral flow velocity to the early diastolic tissue velocity (E/Em) was significantly higher in the study group. Additionally, intra- and interatrial electromechanical delay was found significantly prolonged in the study group. Conclusion FMS is found to be associated with significant cardiac electrical alterations that may indicate the increased risk of atrial and ventricular arrhythmias in this group of patients.

222AI-based strategy enables faster Holter ECG analysis with equivalent clinical accuracy compared to a classical strategy

Abstract BACKGROUND Analysis of Holter recordings can be challenging and time-consuming, therefore requiring significant clinical resources in order to achieve a high-quality diagnosis. Such resources depend largely on the qualifications of the person conducting the analysis and the duration of the recordings. A novel Holter analysis platform has been developed, based on deep neural networks trained with a dataset of one million ECGs, to allow fast and reliable Holter recording analysis. PURPOSE This study sought to compare the performance of an artificial intelligence (AI)-based Holter analysis platform using deep learning tools with a classical one used on a daily basis in hospitals (the reference). The main endpoints evaluated were duration to complete the analysis by the physician operating it as well as diagnostic accuracy of each strategy, when platforms are used by electrophysiologists (EPs). METHODS For this prospective evaluation, a total of 159 Holter recordings (24-hour) were selected from a large Holter dataset from 1 hospital, with a relatively high prevalence of electrical rhythm and conduction disorders. Recordings were analysed by four EPs using independently both the AI-based and classical analysis platforms. All four EPs had no previous experience with the AI-based platform, except for an introductory 6-hour training session. Three EPs had multiple years of experience with the traditional platform, while one EP had limited experience. For each recording, in addition to the analysis duration, diagnostic accuracy was evaluated through the analysis of the presence or absence of predefined cardiac arrhythmias and conduction disorders (prevalence): pauses (25.2%), ventricular tachycardia (VT, 30.2%), atrial fibrillation (AF, 26.4%), high grade atrioventricular block (AVB, 10.1%) and burden of premature ventricular complex larger than 10% (PVC, 23.9%). Definite diagnostics were established by an expert EP after a careful examination of all available analysis reports. RESULTS Time required for the AI-based analysis was on average 42% shorter compared to the traditional platform (6.65 min vs 11.5 min, p < 0.0001). Regarding accuracy to detect electrical disorders, there was no statistically significant differences between AI-based and classical platforms (AF: 98.7% vs 96.9%, Pause: 99.4% vs 100%, PVC: 98.7% vs 98.7%, VT: 92.5% vs 96.2%, AVB: 98.7% vs 94.3%). CONCLUSION: These preliminary findings suggest that an AI-based strategy to analyse Holter recordings may be highly accurate in detecting cardiac electrical abnormalities, with significant time savings compared to a classical strategy, even for users with no previous experience with the novel AI-based platform. An AI-based Holter analysis platform may contribute to a broader and more resource-efficient adoption of Holter monitoring. Abstract Figure. analysis duration using each strategy

Arrhythmogenic Cardiomyopathy: Molecular Insights for Improved Therapeutic Design.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by structural and electrical cardiac abnormalities, including myocardial fibro-fatty replacement. Its pathological ventricular substrate predisposes subjects to an increased risk of sudden cardiac death (SCD). ACM is a notorious cause of SCD in young athletes, and exercise has been documented to accelerate its progression. Although the genetic culprits are not exclusively limited to the intercalated disc, the majority of ACM-linked variants reside within desmosomal genes and are transmitted via Mendelian inheritance patterns; however, penetrance is highly variable. Its natural history features an initial “concealed phase” that results in patients being vulnerable to malignant arrhythmias prior to the onset of structural changes. Lack of effective therapies that target its pathophysiology renders management of patients challenging due to its progressive nature, and has highlighted a critical need to improve our understanding of its underlying mechanistic basis. In vitro and in vivo studies have begun to unravel the molecular consequences associated with disease causing variants, including altered Wnt/β-catenin signaling. Characterization of ACM mouse models has facilitated the evaluation of new therapeutic approaches. Improved molecular insight into the condition promises to usher in novel forms of therapy that will lead to improved care at the clinical bedside.

High Thyrotropin Is Critical for Cardiac Electrical Remodeling and Arrhythmia Vulnerability in Hypothyroidism.

Background: Hypothyroidism, the most common endocrine disease, induces cardiac electrical remodeling that creates a substrate for ventricular arrhythmias. Recent studies report that high thyrotropin (TSH) levels are related to cardiac electrical abnormalities and increased mortality rates. The aim of the present work was to investigate the direct effects of TSH on the heart and its possible causative role in the increased incidence of arrhythmia in hypothyroidism.Methods: A new rat model of central hypothyroidism (low TSH levels) was created and characterized together with the classical propylthiouracil-induced primary hypothyroidism model (high TSH levels). Electrocardiograms were recorded in vivo, and ionic currents were recorded from isolated ventricular myocytes in vitro by the patch-clamp technique. Protein and mRNA were measured by Western blot and quantitative reverse transcription polymerase chain reaction in rat and human cardiac myocytes. Adult human action potentials were simulated in silico to incorporate the experimentally observed changes.Results: Both primary and central hypothyroidism models increased the L-type Ca2+ current (ICa-L) and decreased the ultra-rapid delayed rectifier K+ current (IKur) densities. However, only primary but not central hypothyroidism showed electrocardiographic repolarization abnormalities and increased ventricular arrhythmia incidence during caffeine/dobutamine challenge. These changes were paralleled by a decrease in the density of the transient outward K+ current (Ito) in cardiomyocytes from animals with primary but not central hypothyroidism. In vitro treatment with TSH for 24 hours enhanced isoproterenol-induced spontaneous activity in control ventricular cells and diminished Ito density in cardiomyocytes from control and central but not primary hypothyroidism animals. In human myocytes, TSH decreased the expression of KCND3 and KCNQ1, Ito, and the delayed rectifier K+ current (IKs) encoding proteins in a protein kinase A–dependent way. Transposing the changes produced by hypothyroidism and TSH to a computer model of human ventricular action potential resulted in enhanced occurrence of early afterdepolarizations and arrhythmia mostly in primary hypothyroidism, especially under β-adrenergic stimulation.Conclusions: The results suggest that suppression of repolarizing K+ currents by TSH underlies most of the electrical remodeling observed in hypothyroidism. This work demonstrates that the activation of the TSH-receptor/protein kinase A pathway in the heart is responsible for the cardiac electrical remodeling and arrhythmia generation seen in hypothyroidism.

Autoimmune Calcium Channelopathies and Cardiac Electrical Abnormalities.

Patients with autoimmune diseases are at increased risk for developing cardiovascular diseases, and abnormal electrocardiographic findings are common. Voltage-gated calcium channels play a major role in the cardiovascular system and regulate cardiac excitability and contractility. Particularly, by virtue of their localization and expression in the heart, calcium channels modulate pace making at the sinus node, conduction at the atrioventricular node and cardiac repolarization in the working myocardium. Consequently, emerging evidence suggests that calcium channels are targets to autoantibodies in autoimmune diseases. Autoimmune-associated cardiac calcium channelopathies have been recognized in both sinus node dysfunction atrioventricular block in patients positive for anti-Ro/La antibodies, and ventricular arrhythmias in patients with dilated cardiomyopathy. In this review, we discuss mechanisms of autoimmune-associated calcium channelopathies and their relationship with the development of cardiac electrical abnormalities.