Sudden Cardiac Death or Ventricular Arrythmia in Patients Taking Levetiracetam or Oxcarbazepine.

BACKGROUND AND OBJECTIVES: Levetiracetam is a widely used antiseizure medication. Recent concerns have been raised regarding the potential prolongation of the QT interval by levetiracetam and increased risk of sudden cardiac death. This could have profound implications for patient safety and for prescribing practice. This study assessed the potential association of levetiracetam with cardiac outcomes related to QT interval prolongation. We compared outcomes of patients taking levetiracetam with those taking oxcarbazepine as a comparator medication that has not been associated with prolongation of the QT interval. METHODS: The sample included patients who were newly prescribed levetiracetam or oxcarbazepine from January 31, 2010, to December 31, 2019, using administrative claims data from the OptumLabs Data Warehouse (OLDW). The analysis focused on a combined endpoint of sudden cardiac death or ventricular arrythmia, which are both linked to QT interval prolongation. We used a new user design and selected oxcarbazepine as an active comparator with levetiracetam to minimize bias. We used propensity score weighting to balance the levetiracetam and oxcarbazepine cohorts and then performed weighted Cox regressions to evaluate the association of levetiracetam with the combined endpoint. RESULTS: We identified 104,655 enrollees taking levetiracetam and 39,596 enrollees taking oxcarbazepine. At baseline, enrollees taking levetiracetam were older, more likely to have diagnosed epilepsy, and more likely to have diagnosed comorbidities including hypertension, cerebrovascular disease, and coronary artery disease. In the main analysis, we found no significant difference between levetiracetam and oxcarbazepine in the rate of the combined endpoint for the Cox proportional hazards model (hazard ratio [HR] 0.79, 95% CI 0.42-1.47) or Cox regression with time-varying characteristics (HR 0.78, 95% CI 0.41-1.50). DISCUSSION: When compared with oxcarbazepine, levetiracetam does not correlate with increased risk of ventricular arrythmia and sudden cardiac death. Our finding does not support the concern for cardiac risk to indicate restriction of levetiracetam use nor the requirement of cardiac monitoring when using it. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that sudden cardiac death and ventricular arrythmia are not more frequent in patients older than 17 years newly prescribed levetiracetam, compared with those prescribed oxcarbazepine.

State of Gene Therapy for Monogenic Cardiovascular Diseases.

Over the past 2 decades, significant efforts have been made to advance gene therapy into clinical practice. Although successful examples exist in other fields, gene therapy for the treatment of monogenic cardiovascular diseases lags behind. In this review, we (1) highlight a brief history of gene therapy, (2) distinguish between gene silencing, gene replacement, and gene editing technologies, (3) discuss vector modalities used in the field with a special focus on adeno-associated viruses, (4) provide examples of gene therapy approaches in cardiomyopathies, channelopathies, and familial hypercholesterolemia, and (5) present current challenges and limitations in the gene therapy field.

An International Multicenter Cohort Study on Implantable Cardioverter Defibrillators for the Treatment of Symptomatic Children with Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter defibrillators (ICDs) are commonly advised. However, there are limited data on the outcomes of ICD use in children. OBJECTIVE: To compare the risk of arrhythmic events in pediatric CPVT patients with and without ICDs. METHODS: We compared the risk of SCD in RYR2 variant and phenotype positive symptomatic CPVT patients with and without ICDs, who were <19 years of age and had no history of sudden cardiac arrest (SCA) at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite incidences of SCD, SCA, appropriate ICD shocks, with/without arrhythmic syncope. RESULTS: The study included 235 patients, 73 (31.1%) with ICDs and 162 (68.9%) without ICDs. Over a median follow-up of 8.0 years (IQR 4.3-13.4), SCD occurred in 7 (3.0%) patients, of which 4 (57.1%) were non-compliant with medications and none had an ICD. ICD patients had a higher risk of both secondary composite outcomes (without syncope: HR 5.85 (CI 3.40-10.09); p<0.0001; with syncope: HR 2.55 (CI 1.50-4.34); p=0.0005). Thirty-one (42.5%) patients with an ICD experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSIONS: SCD events occurred only in the no ICD group, in those not on optimal medical therapy. ICD patients had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common and risks versus benefits of ICDs need to be considered.

Artificial intelligence-enhanced electrocardiogram for arrhythmogenic right ventricular cardiomyopathy detection.

Aims: ECG abnormalities are often the first signs of arrhythmogenic right ventricular cardiomyopathy (ARVC) and we hypothesized that an artificial intelligence (AI)-enhanced ECG could help identify patients with ARVC and serve as a valuable disease-detection tool. Methods and results: We created a convolutional neural network to detect ARVC using a 12-lead ECG. All patients with ARVC who met the 2010 task force criteria and had disease-causative genetic variants were included. All case ECGs were randomly assigned in an 8:1:1 ratio into training, validation, and testing groups. The case ECGs were age- and sex-matched with control ECGs at our institution in a 1:100 ratio. Seventy-seven patients (51% male; mean age 47.2 ± 19.9), including 56 patients with PKP2, 7 with DSG2, 6 with DSC2, 6 with DSP, and 2 with JUP were included. The model was trained using 61 case ECGs and 5009 control ECGs; validated with 7 case ECGs and 678 control ECGs and tested in 22 case ECGs and 1256 control ECGs. The sensitivity, specificity, positive and negative predictive values of the model were 77.3, 62.9, 3.32, and 99.4%, respectively. The area under the curve for rhythm ECG and median beat ECG was 0.75 and 0.76, respectively. Conclusion: Our study found that the model performed well in excluding ARVC and supports the concept that the AI ECG can serve as a biomarker for ARVC if a larger cohort were available for network training. A multicentre study including patients with ARVC from other centres would be the next step in refining, testing, and validating this algorithm.

A Multi-Omics Atlas of Sex-Specific Differences in Obstructive Hypertrophic Cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown. Methods: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples. Results: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1963 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males. Conclusion: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM.

Multifocal Ectopic Purkinje Premature Contractions due to neutralization of an SCN5A negative charge: structural insights into the gating pore hypothesis.

Background: We identified a novel SCN5A variant, E171Q, in a neonate with very frequent ectopy and reduced ejection fraction which normalized after arrhythmia suppression by flecainide. This clinical picture is consistent with multifocal ectopic Purkinje-related premature contractions (MEPPC). Most previous reports of MEPPC have implicated SCN5A variants such as R222Q that neutralize positive charges in the S4 voltage sensor helix of the channel protein NaV1.5 and generate a gating pore current. Methods and Results: E171 is a highly conserved negatively-charged residue located in the S2 transmembrane helix of NaV1.5 domain I. E171 is a key component of the Gating Charge Transfer Center, a region thought to be critical for normal movement of the S4 voltage sensor helix. We used heterologous expression, CRISPR-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and molecular dynamics simulations to demonstrate that E171Q generates a gating pore current, which was suppressed by a low concentration of flecainide (IC50 = 0.71±0.07 µM). R222Q shifts voltage dependence of activation and inactivation in a negative direction but we observed positive shifts with E171Q. E171Q iPSC-CMs demonstrated abnormal spontaneous activity and prolonged action potentials. Molecular dynamics simulations revealed that both R222Q and E171Q proteins generate a water-filled permeation pathway that underlies generation of the gating pore current. Conclusion: Previously identified MEPPC-associated variants that create gating pore currents are located in positively-charged residues in the S4 voltage sensor and generate negative shifts in the voltage dependence of activation and inactivation. We demonstrate that neutralizing a negatively charged S2 helix residue in the Gating Charge Transfer Center generates positive shifts but also create a gating pore pathway. These findings implicate the gating pore pathway as the primary functional and structural determinant of MEPPC and widen the spectrum of variants that are associated with gating pore-related disease in voltage-gated ion channels.

Insights into adherence to medication and lifestyle recommendations in an international cohort of patients with catecholaminergic polymorphic ventricular tachycardia.

AIMS: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. METHODS AND RESULTS: An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22-50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6-31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1-1.3, P < 0.001) were independently associated with non-adherence. CONCLUSION: The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education.

Prognostic Value of Multiplexed Assays of Variant Effect and Automated Patch-clamping for KCNH2-LQTS Risk Stratification.

Background: Long QT syndrome (LQTS) is a lethal arrhythmia condition, frequently caused by rare loss-of-function variants in the cardiac potassium channel encoded by KCNH2. Variant-based risk stratification is complicated by heterogenous clinical data, incomplete penetrance, and low-throughput functional data. Objective: To test the utility of variant-specific features, including high-throughput functional data, to predict cardiac events among KCNH2 variant heterozygotes. Methods: We quantified cell-surface trafficking of 18,323 variants in KCNH2 and recorded potassium current densities for 506 KCNH2 variants. Next, we deeply phenotyped 1150 KCNH2 missense variant patients, including ECG features, cardiac event history (528 total cardiac events), and mortality. We then assessed variant functional, in silico, structural, and LQTS penetrance data to stratify event-free survival for cardiac events in the study cohort. Results: Variant-specific current density (HR 0.28 [0.13-0.60]) and estimates of LQTS penetrance incorporating MAVE data (HR 3.16 [1.59-6.27]) were independently predictive of severe cardiac events when controlling for patient-specific features. Risk prediction models incorporating these data significantly improved prediction of 20 year cardiac events (AUC 0.79 [0.75-0.82]) over patient-only covariates (QTc and sex) (AUC 0.73 [0.70-0.77]). Conclusion: We show that high-throughput functional data, and other variant-specific features, meaningfully contribute to both diagnosis and prognosis of a clinically actionable monogenic disease.

Temporal Association Between Vaping and Risk of Cardiac Events.

OBJECTIVE: To describe our early observations with sudden cardiac arrest (SCA) and sudden death (SD) in patients using vape products. PATIENTS AND METHODS: A retrospective analysis of Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic and Sudden Death Genomics Laboratory was performed on all SCA survivors and decedents who presented between January 1, 2007, and December 31, 2021, to identify patients/decedents with a history of vaping. Data abstraction included patient demographics, clinical characteristics, and documented use of vape products. RESULTS: Among 144 SCA survivors and 360 SD victims, there were six individuals (1%; 3 females) with unexplained SCA (n=4) or SD (n=2) that was temporally associated with vaping use with a mean age at sentinel event of 23±5 years. The SCA survivors include a 19-year-old male who was resuscitated from documented ventricular fibrillation 40 minutes after vaping and a 19-year-old male who was resuscitated from ventricular fibrillation a few hours post vaping. The first SD victim was a 19-year-old female with exercise-induced asthma who died in her sleep after vaping that evening. Autopsy results showed eosinophilic infiltrates in the lung tissue and death was attributed to bronchial asthma. The second vaping-associated death involved a 26-year-old male whose autopsy attributed the death to acute respiratory distress syndrome. CONCLUSION: We have identified six young individuals with a history of vaping who experienced a near fatal episode or a tragic SD. Although larger cohort studies are needed to quantify the actual risk of SD, it seems prudent to sound an early warning about vaping's potential lethality.

Utility of routine follow-up defibrillation safety margin testing in young patients with epicardial implantable cardioverter-defibrillators.

BACKGROUND: Routine defibrillation threshold testing (DFT) of transvenous implantable defibrillators (ICDs) has largely been in decline. In patients with non-transvenous ICDs that utilize subcutaneous and pleural ICD leads, serial DFT testing can detect a significant number of failures. Data about the utility of follow-up defibrillation safety margin testing (DSM) testing in pediatric patients and young adults with an epicardial ICD are lacking. METHODS: Patients aged < 25 years old who underwent epicardial ICD placement at Mayo Clinic from 2014 to 2023 with at least one follow-up DSM test were included. The patients were divided into a "routine" (R) and "clinically indicated" (CI) group based on the index of clinical concern. Inadequate DSM was defined as unsuccessful defibrillation at an output of less than 10 J below the maximum output of the device. The purpose of this study was to assess the utility of follow-up DSM testing. RESULTS: An epicardial ICD system was placed in 122 patients. A total of 26 patients met inclusion criteria and underwent a total of 47 DSM follow up tests. Inadequate DSM occurred in 1/33 (3%) in the R group and 2/14 (14%) DSM tests in the CI group. The median follow-up period was 54 and 36 months for the R and CI group, respectively. CONCLUSIONS: Our data suggest that epicardial ICDs are reliable and routine follow-up DSM testing may not be necessary for all patients. DSM testing should be performed in individuals with epicardial ICD systems when there is clinical concern about lead or coil performance.

Proceed with caution: Standard protocol exercise stress tests fail to replicate the diagnostic utility of supine-stand tests for long QT syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a sudden death predisposing condition characterized by ECG-derived prolongation of the QT interval. Previous studies have demonstrated that the supine-stand test may aid in the diagnosis of LQTS as patients fail to shorten their QT interval in response to standing up. The aim of this study was to evaluate the diagnostic accuracy of ECG data derived from standard protocol, clinically performed treadmill exercise stress tests (TESTs) in their ability to mimic the formal supine-stand test. METHODS: We performed a retrospective review of 478 TESTs from patients evaluated for LQTS. Patients referred for evaluation of LQTS but who were dismissed as normal served as controls. Heart rate & QT values were obtained from standard protocol TESTs. RESULTS: Overall, 243 patients with LQTS (125 LQT1, 63 LQT2, 55 LQT3; 146 [60%] female, mean age at TEST 30 ± 17 years) and 235 controls (142 [60%] female, mean age 24 ± 15 years) were included. The paired ΔQTc (QTcStand -QTcSupine ) was similar between LQTS (-5 ± 26) and controls (-2 ± 25; p = .2). During position change, the QT interval shortened by ≥20 ms in 33% of LQTS patients, remained unchanged in 62%, and increased in 5% of LQTS patients which was similar to controls (shortened in 40%, unchanged in 54%, and increased in 6% of controls; p = .2). Receiver-operator curve analysis to test the diagnostic ability of supine-stand ΔQT performed poorly in differentiating LQTS from controls with an of AUC 0.52 (p = .4). CONCLUSION: TESTs should be used with caution when trying to interpret supine-stand changes for diagnosis of LQTS.

Decision Support System Detecting Patients at Risk of Prolonged QT and Associated Mortality.

Prolonged QT interval is an independent risk factor for all-cause mortality. However, evaluation of mortality associated to the implementation of a clinical decision support system to increase awareness and provide management recommendations has been challenging. Here we present our attempt to develop a model using only electronic data and different control groups.

Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex-Specific Risk Stratification in Potassium Channel-Mediated Long QT Syndrome.

BACKGROUND: Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS. METHODS AND RESULTS: The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and ß-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (P<0.001), whereas intermediate-risk patients had a 2.1-fold (P=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%. CONCLUSIONS: Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.

Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study.

BACKGROUND: Understanding the incidence, causes, and trends of sudden cardiac death (SCD) among young competitive athletes is critical to inform preventive policies. METHODS: This study included National Collegiate Athletic Association athlete deaths during a 20-year time frame (July 1, 2002, through June 30, 2022). Athlete deaths were identified through 4 separate independent databases and search strategies (National Collegiate Athletic Association resolutions list, Parent Heart Watch database and media reports, National Center for Catastrophic Sports Injury Research database, and insurance claims). Autopsy reports and medical history were reviewed by an expert panel to adjudicate causes of SCD. RESULTS: A total of 143 SCD cases in National Collegiate Athletic Association athletes were identified from 1102 total deaths. The National Collegiate Athletic Association resolutions list identified 117 of 143 (82%), the Parent Heart Watch database or media reports identified 89 of 143 (62%), the National Center for Catastrophic Sports Injury Research database identified 63 of 143 (44%), and insurance claims identified 27 of 143 (19%) SCD cases. The overall incidence of SCD was 1:63 682 athlete-years (95% CI, 1:54 065-1:75 010). Incidence was higher in male athletes than in female athletes (1:43 348 [95% CI, 1:36 228-1:51 867] versus 1:164 504 [95% CI, 1:110 552-1:244 787] athlete-years, respectively) and Black athletes compared with White athletes (1:26 704 [1:20 417-1:34 925] versus 1:74 581 [1:60 247-1:92 326] athlete-years, respectively). The highest incidence of SCD was among Division I male basketball players (1:8188 [White, 1:5848; Black, 1:7696 athlete-years]). The incidence rate for SCD decreased over the study period (5-year incidence rate ratio, 0.71 [95% CI, 0.61-0.82]), whereas the rate of noncardiovascular deaths remained stable (5-year incidence rate ratio, 0.98 [95% CI, 0.94-1.04]). Autopsy-negative sudden unexplained death (19.5%) was the most common postmortem examination finding, followed by idiopathic left ventricular hypertrophy or possible cardiomyopathy (16.9%) and hypertrophic cardiomyopathy (12.7%), in cases with enough information for adjudication (118 of 143). Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection. SCD events were exertional in 50% of cases. Exertional SCD was more common among those with coronary artery anomalies (100%) and arrhythmogenic cardiomyopathy (83%). CONCLUSIONS: The incidence of SCD in college athletes has decreased. Male sex, Black race, and basketball are associated with a higher incidence of SCD.

The Incidence of Torsades de Pointes With Perioperative Triple Antiemetic Administration.

BACKGROUND: The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown. OBJECTIVE: To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy. METHODS: A retrospective cohort study identified 19,874 patients who received 22,202 doses of triple antiemetics during the 2.5-year time frame from March 4, 2020 to September 7, 2022 for surgical nausea prophylaxis or treatment of nausea. These patients above were cross-matched with an electrocardiogram and adverse outcome database; this identified 226 patients with documentation of a QTc > 450 ms, all ventricular tachycardias including TdP within 48 hours of receiving triple antiemetic therapy, or death within 7 days of receiving ondansetron. RESULTS: There were 3 patients who had documented VT (n = 3), but there were no documented incidents of TdP (n = 0). There were 9 codes called on patients within 48 hours of medication administration, and none of them were due to ventricular arrythmias (n = 0). A total of 11 patients died within 7 days of triple antiemetic therapy. Ten of the 11 deaths were determined to not be from the triple antiemetic. One patient died at home within 24 hours of the procedure of an unknown cause (n = 1). CONCLUSIONS AND RELEVANCE: No episodes of TdP were identified in patients receiving triple antiemetic therapy perioperatively, though the cause of death in 1 patient could not be determined. This suggest that low-dose triple antiemetic therapy is low risk for the development of TdP.