Lethal Ventricular Arrhythmias Research Articles

Importance and limits of cardiovascular risk factors on the prediction of SCD using machine learning approach

Abstract Background SCD is mainly due to lethal ventricular arrhythmias and occurs often among patients with ischemic heart disease. SCD and ischemic heart disease share a similar pattern of cardiovascular risk factors (CVRF). Commonly developed risk scores have been focused on cardiac-related risk factors. We aimed to investigate whether non-CVRF variables could enhance predictive performance beyond standard CVRF of SCD. Method We compared 2 different strategies for variable inclusion. First, we built a prediction model containing EHR data restricted to cardiovascular diseases and risk factors (CVD MR model) that occurred up to 5 years before SCD. We selected all available main cardiovascular variables as surrogate markers for coronary artery disease, stroke, diabetes, hypertension, smoking status, obesity, lipid disorders and chronic renal failure. On the other hand, our global approach (ALL MR model) includes all medical records codes, without any prior selection. To estimate the risk of SCD over three months, we trained a machine learning model on EHR data representing 8,566,229 drug prescriptions and 801,352 hospital diagnoses up to five years prior to SCD. The data were obtained from a cohort of 12,338 SCD in France and 12,338 controls from 2011 to 2015. We then validated the results on two external cohorts: one temporal in the same area between 2016 and 2020 with 11,620 SCD and 11,620 controls and one geographical from the USA with 892 SCD and 892 controls from 2013 to 2021. Results The CVD MR + ML model (CatBoost algorithm) yielded moderate performances with an AUC of 0.68 (95%CI 0.65-0.68), a sensitivity of 45%.(95%CI 42-47) and a specificity of 82% (95%CI 80-84). We found that the EHR model with all medical records (All MR + ML model) offered better performances. In the derivation cohort, this model achieved an AUC of 0.80 (95% CI: 0.78–0.82) with a sensitivity of 67% (95% CI 64-69), a specificity of 80% (95% CI 78-82) (Figure 1). The logistic regression (All MR + LR) applied on all medical records performed better than the CatBoost algorithm when restricted to CVD medical records (Figure 1). Conclusion The inclusion of all potential variables beyond the usual CVRF significantly improves the performances of SCD prediction models, independently of the methods (AI and logistic regression). Figure 1 : Receiver operating characteristic curves of the different models (ALL MR + ML, ALL MR + LR, CVD MR + ML and CVD MR + LR) in the derivation cohort and two validation cohorts (temporal and geographical)Figure 1.ROC curves

The arrhythmic substrate of hypertrophic cardiomyopathy using ECG imaging.

Introduction: Patients with hypertrophic cardiomyopathy (HCM) are at risk for lethal ventricular arrhythmia, but the electrophysiological substrate behind this is not well-understood. We used non-invasive electrocardiographic imaging to characterize patients with HCM, including cardiac arrest survivors. Methods: HCM patients surviving ventricular fibrillation or hemodynamically unstable ventricular tachycardia (n = 17) were compared to HCM patients without a personal history of potentially lethal arrhythmia (n = 20) and a pooled control group with structurally normal hearts. Subjects underwent exercise testing by non-invasive electrocardiographic imaging to estimate epicardial electrophysiology. Results: Visual inspection of reconstructed epicardial HCM maps revealed isolated patches of late activation time (AT), prolonged activation-recovery intervals (ARIs), as well as reversal of apico-basal trends in T-wave inversion and ARI compared to controls (p < 0.005 for all). AT and ARI were compared between groups. The pooled HCM group had longer mean AT (60.1ms vs. 52.2ms, p < 0.001), activation dispersion (55.2ms vs. 48.6ms, p = 0.026), and mean ARI (227ms vs. 217ms, p = 0.016) than structurally normal heart controls. HCM ventricular arrhythmia survivors could be differentiated from HCM patients without a personal history of life-threatening arrhythmia by longer mean AT (63.2ms vs. 57.4ms, p = 0.007), steeper activation gradients (0.45ms/mm vs. 0.36ms/mm, p = 0.011), and longer mean ARI (234.0ms vs. 221.4ms, p = 0.026). A logistic regression model including whole heart mean activation time and activation recovery interval could identify ventricular arrhythmia survivors from the HCM cohort, producing a C statistic of 0.76 (95% confidence interval 0.72-0.81), with an optimal sensitivity of 78.6% and a specificity of 79.8%. Discussion: The HCM epicardial electrotype is characterized by delayed, dispersed conduction and prolonged, dispersed activation-recovery intervals. Combination of electrophysiologic measures with logistic regression can improve differentiation over single variables. Future studies could test such models prospectively for risk stratification of sudden death due to HCM.

Lambda-like ST-elevation in Acute MI: A Risk Predictor of Fatal Ventricular Arrhythmia

Despite the increasing use of reperfusion strategies and guideline-directed medical therapy, acute MI remains a leading cause of mortality. Certain ECG abnormalities are associated with lethal ventricular arrhythmia and significant in-hospital mortality during acute MI. This report presents a case of fatal ventricular arrhythmia in a patient with acute MI, highlighting a specific ECG finding – lambda-like ST-elevation. Lambda-like ST-elevation on the ECG in acute MI may serve as a critical indicator for clinicians, predicting the risk of fatal ventricular arrhythmias, cardiogenic shock and sudden cardiac death. Early recognition and aggressive intervention strategies could significantly reduce morbidity and mortality.

Folate as a potential treatment for lethal ventricular arrhythmias in TANGO2-deficiency disorder.

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant using CRISPR editing. Our natural history study in patients with TDD suggests that the intake of multivitamin/B complex greatly diminished the risk of cardiac crises in patients with TDD. In agreement with the clinical findings, we demonstrated that high-dose folate (vitamin B9) virtually abolishes arrhythmias in TDD iPSC-CMs and that folate's effect was blocked by the dihydrofolate reductase inhibitor methotrexate, supporting the need for intracellular folate to mediate antiarrhythmic effects. In summary, data from TDD iPSC-CM models together with clinical observations support the use of B vitamins to mitigate cardiac crises in patients with TDD, providing potentially life-saving treatment strategies during life-threatening events.

A GABAergic system in atrioventricular node pacemaker cells controls electrical conduction between the atria and ventricles

Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABAA receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.

The anesthesiologist’s guide to swine trauma physiology research: a report of two decades of experience from the experimental traumatology laboratory

PurposeSwine are one of the major animal species used in translational research, with unique advantages given the similar anatomic and physiologic characteristics as man, but the investigator needs to be familiar with important differences. This article targets clinical anesthesiologists who are proficient in human monitoring. We summarize our experience during the last two decades, with the aim to facilitate for clinical and non-clinical researchers to improve in porcine research.MethodsThis was a retrospective review of 337 swine with a mean (SD) weight 60 (4.2) kg at the Experimental Traumatology laboratory at Södersjukhuset (Stockholm south general hospital) between 2003 and 2023, including laboratory parameters and six CT-angiography examinations.ResultsSwine may be ventilated through the snout using a size 2 neonatal mask. Intubate using a 35 cm miller laryngoscope and an intubating introducer. Swine are prone to alveolar atelectasis and often require alveolar recruitment. Insert PA-catheters through a cut-down technique in the internal jugular vein, and catheters in arteries and veins using combined cut-down and Seldinger techniques. Cardiopulmonary resuscitation is possible and lateral chest compressions are most effective. Swine are prone to lethal ventricular arrhythmias, which may be reversed by defibrillation. Most vital parameters are similar to man, with the exception of a higher core temperature, higher buffer bases and increased coagulation. Anesthesia methods are similar to man, but swine require five times the dose of ketamine.ConclusionSwine share anatomical and physiological features with man, which allows for seamless utilization of clinical monitoring equipment, medication, and physiological considerations.

The Heart of Rett Syndrome: A Quantitative Analysis of Cardiac Repolarization.

Rett syndrome (RTT) is a developmental encephalopathy disorder that is associated with a high incidence of sudden death presumably from cardiorespiratory etiologies. Electrocardiogram (ECG) abnormalities, such as prolonged heart-rate corrected QT (QTc) interval, are markers of cardiac repolarization and are associated with potentially lethal ventricular arrhythmias. This study investigates the cardiac repolarization characteristics of RTT patients, including QTc and T-wave morphology characteristics. A retrospective quantitative analysis on 110 RTT patients and 124 age and sex-matched healthy controls was conducted. RTT patients had longer QTc, more abnormal T-wave morphology, and greater heterogeneity of cardiac repolarization parameters compared to controls. Even RTT patients without prolonged QTc had more abnormal ECG and T-wave characteristics than controls. Among RTT patients, MECP2 patients had prolonged QTc compared to CDKL5 and FOXG1 patients. A subset of five RTT patients who died had normal QTc, but more abnormal T-wave morphology than the remaining RTT patients. Cardiac repolarization abnormalities are present in RTT patients, even without long QTc. T-wave morphology is related to RTT genotype and may be predictive of mortality. These findings could be used to help the management and monitoring of RTT patients.

Homozygous or compound heterozygous variants in DSG2 are mainly causative of Japanese arrhythmogenic right ventricular cardiomyopathy

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. Previously, we showed that the genetic backgrounds of ARVC in Japanese was different from those in Caucasian and that DSG2 was the most common causative gene. Purpose We aimed to confirm the inheritance mode of Japanese ARVC caused by pathogenic variants in DSG2. Furthermore, we reassessed the difference of phenotypes depending on the genotype. Methods and results Among 153 ARVC probands diagnosed with definite, borderline or possible by TFC2010 excluding the criteria of family history, 66 had one or more DSG2 variants (25 homozygous, 26 compound heterozygous, 11 multiple variants with unknown allele origin and 4 heterozygous). In the family screening, 62 relatives carried DSG2 variants (2 homozygous, 6 compound heterozygous, 54 heterozygous). All family members with a heterozygous DSG2 variant were not fulfilled ARVC diagnostic criteria. These results indicate that most of ARVC caused by DSG2 variants is an autosomal recessive disease. Therefore, 62 probands who have multiple DSG2 variants were included as pathogenic DSG2 variants carriers in following analysis. Figure A shows the genotypes in Japanese ARVC probands. We compared the clinical characteristics of the probands with DSG2 variants to those with PKP2 ones (N = 28). DSG2 variant carriers hospitalized for heart failure at younger age (42 ± 17 vs. 64 ± 13 years, P = 0.003) and had lower LVEF at diagnosis (51 [39 - 60] vs. 60 [55 - 65] %, P = 0.004). On the other hand, PKP2 variant carriers suffered atrial fibrillation more frequently (N = 7 (25%) vs. N = 5(8%), P = 0.04) and sustained VT at younger age though it was not statistically significant (38 ± 18 vs. 47 ± 15 years, P = 0.055). Finally, we analyzed the genotype effect on the incidence of lethal ventricular arrhythmia (LVA). The cumulative incidence in probands with each causative gene is shown in Figure B. Using multivariable analysis, we confirmed that PKP2 variant carriers had higher risk for LVA after adjusted by sex, medication, catheter ablation and device implantation (HR 2.904; 95% CI 1.530 – 5.513, P = 0.001). Conclusion DSG2 was the most common causative gene for ARVC in Japanese, and their mode of inheritance was mainly autosomal recessive. While DSG2 variants were associated with LV involvement and heart failure, PKP2 variants were risk for ventricular arrhythmia. Our findings would be helpful for diagnosis and prognosis for the ARVC patients.Genotype of Japanese ARVC probandsCumulative incidence of LVA

Perfomance of sudden cardiac death prediction strategies before and after Septal Reduction Strategies in patients with Hypertrophic Cardiomyopathy

Abstract Background Actual sudden death (SD) risk stratification strategies for Hypertrophic Cardiomyopathy have not been validated for patients after a septal reduction treatment (SRT). Therefore, it is largely unresolved the quantification of the ventricular arrhythmias (VA) burden after an SRT and how risk stratification should be performed in such patients. Purpose To evaluate the performance of ESC SD Risk stratification model and AHA ACC Risk Factors for SD in the identification of patients with lethal ventricular arrhythmias after SRT. Methods Data from 11 high-volume HCM specialty centers from the international SHaRe Registry were used to describe the natural history of patients with SRT. Patients were followed from SRT until last follow-up or meeting the composite outcome of ventricular arrhythmias (sudden cardiac death (SCD), resuscitated cardiac arrest, or appropriate implantable cardioverter-defibrillator (ICD) therapy). Cox proportional hazards models were used to identify predictors of prognosis and incident development. Calculation of SD score was performed before the SRT and at 1 year from the procedure. Results Of the 10385 patients part of the ShaRe Registry, 1835 (18%, 968 (53%) males) underwent a SRT during a median follow-up of 6.8 (IQR 3.4-9.8). A total of 455 (25%) had Alcohol Septal Ablation (ASA) and 1377 (75%) had myectomy. Patients who underwent myectomy were younger (49±18 vs 56±15 years, p&amp;lt;0.01), more frequent with a sarcomeric mutation (396 (29%) vs 111 (24%), p&amp;lt;0.01). Over 6.8 years after the procedure, 77 (4%) died because of HCM (0.6%/year) and 87 (5%) presented a composite VA outcome (0.7%/year). Development of the composite VA event was associated with younger age at procedure (38±20 vs 54±18 years, p&amp;lt;0.01), the development of a LV EF&amp;lt; 50% (29 (33%) vs 351 (20%), p&amp;lt;0.01), a more severely dilated LA (47±7 vs 43±11 years, p&amp;lt;0.01) and greater LV maximal wall thickness (24±6 vs 21±6 years, p&amp;lt;0.01). Significant predictor of the composite VA outcome was the presence of a LA diameter ³ 45 mm (HR, 2.6 [95% CI, 1.7–3.5]). Patients who presented the VA outocome were classified according to ESC SCD Risk pre and post SRT as: 40 (46%) as high risk, 31 (36%) as intermidiate risk, 16 (18%) as low risk pre intervention and 26 (46%) as high risk, 41 (47%) as intermidiate risk, 20 (18%) as low risk post procedure. AHA ACC SCD risk factors pre and post SRT classified patients as: 56 (64%) as class IIA 25 (29%) as Clas IIB, 6 (7%) as Class III and post SRT 42 (48%) as Class IIA, 31(36%) as Class IIB, 14 (16%) as Class III. Conclusions Current stratification strategies potentially underestimate the risk of SD pre and post SRT. Specifically, ESC SD risk strategies underperformed in the identification of intermidiate high risk patient, whereas AHA ACC were capable of identifying 84% of patients who had a malignant VA.

Roles of aldosterone on ventricular arrhythmias, and associated gap junction and ion channel remodeling in hypertrophic heart

Abstract Background Ventricular arrhythmias are critical causes of death in patients with chronic heart failure (CHF). Aldosterone (Ald) is an exacerbating factor of CHF and mineral corticoid receptor antagonist (MRA) is usual drug for the management of CHF. MRA also suppressed sudden cardiac death, however, mechanisms of these effects remain unknown. We investigated the effects of MRA on ventricular arrhythmias and arrhythmogenic factors using Dahl Salt sensitive (DS) rats. Methods (in vivo) DS rats were divided into three groups; low salt group (LS), high salt group (HS), and eplerenone-, an MRA, treated high salt group (HS+EPL). Low salt (0.3% NaCl) or high salt (8% NaCl) were administrated for 8 weeks and EPL was administrated in the last 4 weeks. Cardiac geometry and function were assessed by echocardiography. Susceptibility of ventricular arrhythmias were assessed using programmed stimulation. Myocyte hypertrophy and cardiac fibrosis were examined by Masson’s trichrome staining. Expression and distribution of connexin43 (Cx43) were examined by immunostaining and western blotting. mRNA expression of Ca transient-related factors, such as phospholamban, SERCA2a, and ryanosin 2, and potassium ion channel-related factors, such as KCNE1 and KCNQ1, was examined by RT-PCR. (in vitro) Ald (1-100 nM) was administrated to cultured rat neonatal cardiomyocytes. Expression of Cx43, Ca transient-related, and potassium ion channel-related factors are also examined as mentioned above. Effects of Src tyrosin kinase inhibitor, PP2, and ERK inhibitor, PD98059, on Ald-induced Cx43 reduction were examined by RT-PCR and immunostaining. Results Systolic blood pressure and Ald concentrations in cardiac tissue were higher in HS group than LS group, and EPL did not affect them. In HS group left ventricular hypertrophy, dilatation and systolic dysfunction were observed in association with myocyte hypertrophy and interstitial fibrosis. EPL significantly recovered cardiac function and histological impairments. In addition, elongation of QTc in ECG and susceptibility of ventricular tachycardia were remarkable in HS group rather than LS and EPL attenuated them. Distribution of Cx43 was scattered in HS group, and EPL attenuated these changes. Decrease in SERCA2a and increase in KCNE1/KCNQ1 mRNA expression were found in HS group, and these changes were attenuated by EPL. In cultured myocytes, Ald decreased Cx43 mRNA and protein expression in a dose dependent fashion. Ald-induced Cx43 reduction was inhibited by PP2 and PD98059. In addition, Ald (100 nM) also decreased SERCA2a and increased KCNE1/KCNQ1 mRNA expression. Conclusion These results indicate that Ald reduced and dispersed the Cx43 expression reduction and dispersion through Src tyrosin kinase and ERK signaling pathways, and also mediated SRECA2A and KCNE1/KCNQ1 expression, which induced QTc prolongation and susceptibility of lethal ventricular arrhythmias in hypertensive cardiac hypertrophy.

Arrhythmogenic Right Ventricular Cardiomyopathy - what do we know? A review of current knowledge state

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disorder that is responsible for a considerable number of sudden death cases in young athletes. Its pathological hallmark is a progressive loss of myocytes predominantly in the right ventricle and its simultaneous replacement by fibrous and fat tissue, which in turn leads to an increased risk of potentially lethal ventricular arrhythmias to occur. Over a dozen of mutations have been confirmed as genetic basis of ARVC with most of them affecting genes encoding desmosome proteins, however in up to half of all cases the exact etiology is still unknown. By number of studies, it is implied that physical activity is the most significant environmental factor that impacts the development and course of the disease. The main focus of treatment is to prevent sudden cardiac deaths and additionally to moderate arrhythmic events and heart failure.

Predicting lethal ventricular arrhythmias in hypertrophic cardiomyopathy using non-electrophysiologic methods: Invasive EGM vs. non-invasive ECG analysis of fragmentation.

Predicting lethal ventricular arrhythmias in hypertrophic cardiomyopathy using non-electrophysiologic methods: Invasive EGM vs. non-invasive ECG analysis of fragmentation.

Lethal ventricular arrhythmia due to entrectinib-induced Brugada syndrome: a case report and literature review.

Entrectinib, a multikinase inhibitor of ROS1 and tropomyosin receptor kinases, is recommended to treat ROS1-positive metastatic non-small cell lung cancer (NSCLC). In a previous study, entrectinib-related cardiotoxicity occurred in 2% of patients; however, lethal arrhythmias remain understudied. We encountered a case of fatal arrhythmia due to drug-induced Brugada syndrome caused by entrectinib. An 81-year-old Japanese male with lung adenocarcinoma harboring ROS1-fusion gene was treated with entrectinib. The patient developed lethal arrhythmias three days after drug initiation, including ventricular tachycardia with Brugada-like electrocardiogram changes. Echocardiography and coronary angiography revealed no evidence of acute coronary syndrome or myocarditis. Following the termination of entrectinib, the electrocardiogram abnormality improved within 12days. Hence, paying special attention to and monitoring electrocardiogram changes is necessary. In addition, it is also necessary to consider early therapeutic interventions and discontinuation of the drug in cases of drug-induced Brugada syndrome.

The plant-derived alkaloid aloperine prevents ischemia/reperfusion injury-induced sudden cardiac death.

Sudden cardiac death (SCD) remains a major cause of global mortality. In addition to modern interventions, botanical folk medicines have long been used to treat cardiovascular disease, although the efficacy and underlying mechanisms are often unresolved. Aloperine, a bioactive quinolizidine alkaloid isolated from Sophora alopecuroides plants, exhibits antioxidant, anti-inflammatory, antitumor, and vasorelaxant properties, but possible antiarrhythmic effects of aloperine in SCD are unclear. Here, we examined whether aloperine protects against ischemia and reperfusion injury-associated lethal ventricular arrhythmia and sudden cardiac death. Rats were divided into sham, control, and aloperine groups, and reperfusion-provoked ventricular arrhythmogenesis, cardiac damage markers, and signaling pathways quantified following left main coronary artery ischemia and reperfusion. In vitro studies of effects of aloperine on hERG and Kv4.3 cardiac voltage-gated potassium (Kv) channels were performed using two-electrode voltage clamp analysis of cloned channels expressed in Xenopus laevis oocytes. Aloperine pretreatment (10 mg/kg) did not affect baseline cardiac electrical stability; yet, it reduced ventricular arrhythmogenesis and susceptibility to SCD (mortality rate: control: 64.3%; aloperine: 0%) induced by reperfusion injury. Aloperine also reduced serum levels of LDH, CK-MB, α-HBDH, and cTnI post-I/R, and stimulated phosphorylation of ventricular ERK1/2 and STAT-3, which are key components of RISK and SAFE signaling pathways. Inhibition of either ERK1/2 (with U0126) or STAT-3 (with Ag490) abolished aloperine-induced anti-arrhythmic effects and ERK1/2 and STAT-3 phosphorylation. Interestingly, while aloperine (100 μM) had no effect on cloned Kv4.3 activity, aloperine (1 μM and up) negative-shifted the voltage dependence of hERG activation by ~10 mV and increased peak hERG current by 35%. Thus, aloperine exerts striking anti-arrhythmic effects against myocardial ischemia and reperfusion injury-induced severe lethal ventricular arrhythmia and sudden cardiac death via the ERK1/2/STAT-3 signaling pathway, with potential additional contribution from increased cardiac myocyte repolarization capacity via augmented hERG activity.

Artificial Intelligence in Ventricular Arrhythmias and Sudden Death.

Sudden cardiac arrest due to lethal ventricular arrhythmias is a major cause of mortality worldwide and results in more years of potential life lost than any individual cancer. Most of these sudden cardiac arrest events occur unexpectedly in individuals who have not been identified as high-risk due to the inadequacy of current risk stratification tools. Artificial intelligence tools are increasingly being used to solve complex problems and are poised to help with this major unmet need in the field of clinical electrophysiology. By leveraging large and detailed datasets, artificial intelligence-based prediction models have the potential to enhance the risk stratification of lethal ventricular arrhythmias. This review presents a synthesis of the published literature and a discussion of future directions in this field.

Electropharmacological Characterization of Licorice Using the Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Sheets and the Chronic Atrioventricular Block Dogs.

Licorice has been traditionally prescribed for palpitation, whereas its overdose has caused lethal arrhythmias including torsade de pointes. Licorice contains glycyrrhizic acid of ≥ 2% (w/w), which is hydrolyzed to glycyrrhetinic acid (GRA) in the intestine. Since their cardiac electropharmacological properties are not fully understood, we assessed them to ask mechanism of licorice-induced torsade de pointes. GRA at 0.1, 1 and 10μg/mL was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes sheets (n = 6). GRA shortened spontaneous activation interval and repolarization period, and decreased maximum contraction velocity, indicating Ca2+ channel blockade. It prolonged effective refractory period and post-repolarization refractoriness with a steep frequency-dependency, whereas it delayed conduction with a modest use-dependency, resembling lidocaine in the mode of Na+ channel-blocking action. Meanwhile, Kanzoto containing a decoction of licorice alone in a dose of 2 or 6g/body/day was orally administered to the conscious chronic atrioventricular block dogs for 3days (n = 4). Kanzoto prolonged QT interval with increasing its temporal dispersion, suggesting K+ channel suppression, and slightly decreased the plasma K+ concentration without inducing torsade de pointes. Moreover, it significantly suppressed atrial and idioventricular rates, leading to sinus arrest along with the onset of ventricular fibrillation in one animal, possibly due to Na+ channel blockade. These results indicate that electropharmacological profile of licorice can be explained by Na+, Ca2+ and K+ channels blockade, which may be associated with low torsadogenic risk, but might contribute to the onset of other types of lethal ventricular arrhythmias.

LB-456090-4 NEAR-TERM PREDICTION OF LIFE-THREATENING VENTRICULAR ARRHYTHMIAS USING ARTIFICIAL INTELLIGENCE-ENABLED SINGLE LEAD AMBULATORY ECG

Identifying patients at high-risk of sudden cardiac death (SCD) in the mid to long-term remains particularly challenging. Accurate prediction of lethal ventricular arrhythmias in the near-term would enable preemptive actions to eventually prevent SCD. We hypothesized that artificial intelligence could be leveraged to identify a dynamic electrical profile on Holter ECG data heralding the near-term occurrence of sustained ventricular tachycardia (VT).

PO-01-217 FUNCTIONAL CHARACTERIZATION OF CALCIUM HANDLING KINETICS IN RE-ENGINEERED CARDIOMYOCYTES FROM A PATIENT WITH TYPE 2 LONG QT SYNDROME

Type 2 long QT syndrome (LQT2) is caused by pathogenic variants in the KCNH2-encoded Kv11.1 K+ channel resulting in prolongation of the action potential duration (APD) at the cellular level and QT prolongation in the patient, predisposing LQT2 patients to potentially lethal ventricular arrhythmias. Limited evidence, namely prolonged Ca2+ transient in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) and enhanced Ca2+ leak in transgenic LQT2 rabbit model, suggests that KCNH2 pathogenic variants may be associated with perturbations in intracellular Ca2+ handling. To characterize the APD and Ca2+ handling properties of an iPSC-CM model of LQT2. iPSC-CMs were generated from a patient with a pathogenic KCNH2 frame-shift variant (p.Q901fs/71) and an unrelated healthy control. Confocal imaging of FluoVolt voltage dye was used to measure the APD at 90% repolarization (APD90) in iPSC-CMs. Ca2+ kinetics was characterized using Ca2+ sensing dye Fluo4-AM before and after treatment with 100 nM isoproterenol (ISO). Q901fs/71-iPSC-CMs had a significantly prolonged APD90 compared to wild-type (WT) iPSC-CMs (444 ±9 ms vs 631±8 ms, p<0.001). Q901fs/71-iPSC-CMs had a higher Ca2+ amplitude (DF/F0) before (0.423±0.043 vs 0.97±0.07, p=0.001) and after ISO treatment (0.602±0.051 vs 1.056 ±0.06, p<0.001) compared to WT. The Ca2+ transient duration (CTD90) was longer in Q901fs/71-iPSC-CMs than in WT before (1.062±0.041 s vs 1.306±0.038 s, p=0.01), but not after ISO (1.071±0.062 s vs 1.092±0.044 s, p=0.96). Peak to 90% Ca2+ decay time was increased in Q901fs/71-iPSC-CMs before (0.785±0.04 s vs 0.942±0.033 s, p=0.028), but not after ISO (0.748±0.054 s vs 0.767±0.038 s, p=0.95). Upstroke time was longer in Q901fs/71-iPSC-CMs compared to WT before (0.281±0.006 s vs 0.364±0.014 s; p=0.002) but not after ISO (0.327±0.014 s vs 0.344±0.025 s; p=0.88). Upstroke velocity (DF/F0/t) was increased in Q901fs/71-iPSC-CMs before (1.092±0.122 vs 2.278±0.278, p<0.001) and after ISO (1.310±0.117 vs 2.2±0.139, p=0.005). Ca2+ leak from sarcoplasmic reticulum was higher in Q901fs/71-iPSC-CMs before (16% vs 38%) and after ISO (16% vs 55%). We show that iPSC-CMs derived from the patient with a truncating LQT2-causative variant (yielding likely Kv11.1 channel haploinsufficiency) have prolonged APD90 and display abnormal Ca2+ handling properties such as higher amplitude, increase in Ca2+ leak, prolonged transient duration, Ca2+ decay time, and upstroke velocity compared to WT iPSC-CMs.

PO-04-143 CARDIOVASCULAR OUTCOMES IN LMNA-MEDIATED CARDIAC LAMINOPATHY: THE MAYO CLINIC EXPERIENCE

Pathogenic loss-of-function variants in LMNA-encoding lamin A/C cause a range of phenotypes, including lipodystrophy, premature aging, muscular dystrophy, and cardiomyopathy. LMNA-mediated cardiac laminopathy is viewed as a particularly malignant form of arrhythmogenic dilated cardiomyopathy (DCM). However, a paucity of data exists comparing the cardiovascular outcomes in cardiac laminopathy to other DCM genotypes. Therefore, we sought to ascertain whether the prevalence of advanced heart failure (AHF), ventricular arrhythmia (VA), and stroke events differ between patients with either LMNA-mediated DCM or TTN-mediated DCM who were evaluated in a single tertiary medical center. All patients with either a pathogenic (P) or likely pathogenic (LP) variant in either LMNA or TTN in the Mayo Clinic Genetic ACM Registry (n=389) were included. A VA event was defined as sudden cardiac death (SCD), sudden cardiac arrest (SCA), sustained VA, or an appropriate ICD shock while an AHF event was defined as ventricular assist device implantation or heart transplantation. Overall, 88 patients with a P/LP variant in LMNA (61% female) and 72 patients with a P/LP variant in TTN (42% female) were identified. LMNA-positive patients were more likely to have a family history of SCA/SCD (56% vs 35%; p=0.008) and more likely to receive an ICD (60% versus 33%; p=0.001). Interestingly, the prevalence of atrial fibrillation (51% vs. 40%; p=0.2), stroke (8% vs. 8%; p=0.9), and AHF events (12% vs 8%; p=0.4) was similar between LMNA- and TTN-positive patients. However, LMNA-positive patients trended towards more VA events (32% vs 20%; p=0.08). Independent of sex, time-to-event analysis showed LMNA patients had an earlier time (p=0.0009) to a composite endpoint (AHF event or VA event) and remained significant when separating the endpoints: AHF event (p=0.008) and VA event (p=0.0009). LMNA-mediated cardiac laminopathy is a highly arrhythmogenic form of DCM with nearly one-third experiencing a SCA and/or appropriate ICD therapy and half with a history of atrial fibrillation. Although the overall rate of ventricular arrhythmic and AHF events was similar between LMNA and TTN P/LP variant-positive patients, cardiac laminopathy results in earlier end stage heart failure and potentially lethal ventricular arrhythmias.

Electrocardiogram in arrhytmogenic cardiomyopathy.

Criteria for diagnosis of arrhythmogenic cardiomyopathy (ACM) were first proposed in 1994 and subsequently revised in 2010 and in 2020 by an international task force. According to the last consensus of 2020, ACM is defined as a heart muscle disease affecting right ventricle, left ventricle or both, whose principal pathologic feature is fibrofatty myocardial replacement that impairs systolic ventricular function and predisposes to lethal ventricular arrhythmias. ECG findings not only could help to early recognize affected patients but also could identify the ones with maximum risk of ventricular arrhythmias and sudden cardiac death.