Bos, J. Martijn

BACKGROUND: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel–mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2. METHODS: Heart rate–corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD 90 ) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model. RESULTS: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate–corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD 90 by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test ( r = −0.8; P <0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07–0.14) to 0.04 (95% CI, 0.02–0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16–0.84), reflecting a 60% reduction in the event rate ( P =0.01). CONCLUSIONS: Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.

AbstractIntroductionAlthough prior studies indicate that a QTc > 500 ms on a single baseline 12‐lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS.MethodsWe performed a retrospective analysis of 433 patients with LQTS evaluated, risk‐stratified, and undergoing active guideline‐based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF‐terminating ICD shock, and sudden cardiac death (SCD).ResultsDuring the median follow‐up of 5.5 years (interquartile range [IQR] = 3–9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c‐statistic = 0.93–0.95). Patients in the high‐risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%–81%) when compared to patients in both medium‐risk (93%–97%) and low‐risk (98%–99%) groups.ConclusionsThe risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12‐lead ECGs are at the highest risk of BCE while on guideline‐directed medical therapy.

Introduction: Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young and especially in young athletes. The treadmill exercise test (TEST) has an important role in the functional assessment of patients with HCM. Herein, TEST-derived peak oxygen uptake (VO2 max) is a proxy for cardiopulmonary fitness. However, the correlation between symptoms and VO2 - especially in active young patients with HCM - is unclear. Objective: To explore the relationship between TEST-derived VO2 and symptomology in athletes and non-athletes with HCM. Methods: Overall, 91 patients (40% female) with HCM and a TEST with VO 2 data were included in this case-control study. Data were abstracted from the electronic health record using the first TEST performed at Mayo Clinic. Patients were defined as an athlete if they participated in an organized, competitive sport. Results: Overall, 60 HCM patients (33% female) were categorized as an athlete. HCM athletes were younger (17 vs. 27 years; p<0.0001) and less likely to be symptomatic at the time of their TEST (OR=0.24; p=0.01). Additionally, athletes had a higher VO2 max (86% vs. 68% of predicted; p<0.0001) and reached higher exercise times (93% vs 76% of predicted; p<0.0001) compared to the non-athletes with HCM. When comparing symptomatic (n = 18) to asymptomatic patients (n = 73), symptomatic patients had i) a reduced exercise time (68% vs. 92% of predicted; p=0.002) and ii) lower VO2 max (62% vs 84% of predicted; p<0.001). Finally, among the 27 patients (30%) with a VO 2 max < 70% predicted (n=27), they i) more likely had a history of cardiac arrest (4 vs 0; p=0.006) and ii) were more likely to be symptomatic (OR=7.7; p< 0.0001) than those with VO2 ≥ 70% of predicted (n=64). Importantly, however, 15/27 (56%) patients (8 athletes/7 non-athletes) with a VO2 max < 70% were asymptomatic. Conclusions: Reduced exercise capacity is common in athletes with HCM and does not correlate with symptom status. However, if the TEST-derived VO2 max is < 70%, treatment intensification may be necessary as it may portend an adverse outcome both arrhythmically and mechanically.

Introduction: The incidence and etiologies underlying sudden cardiac arrest (SCA) in the young are derived from population- and referral-based cohorts of young SCA survivors. The extent to which the use of these cohorts contributes to discrepancies in our understanding of SCA in the young is unknown. As such, we sought to determine and compare the spectrum of SCA etiologies observed in young SCA survivors evaluated at a single tertiary center on both a primary and referral basis. Methods: Retrospective review of 940 young SCA survivors evaluated between 1990 and 2017 was used to identify all individuals ≤ 50 years of age that experienced a SCA. SCA root cause was determined by review of the medical records and diagnoses classified as ischemic, primary electrical, structural, or unexplained. SCA survivors that initially presented to our institution were classified as primary, while those who presented for secondary evaluation received a referral classification. Results: Overall, 566 SCA survivors were identified (age at event 33 ± 14 years; 39% females). In comparison to primary SCA survivors, referral SCA survivors were younger at the time of SCA (39 ± 12 vs. 30 ± 14 years; p<0.0001) and less likely to experience pre-SCA symptoms (45% vs. 27%; p<0.0001). Among all SCA survivors, the most common etiologies were idiopathic ventricular fibrillation (27%), acute coronary syndrome (21%), long QT syndrome (10%), and hypertrophic (7%) and dilated (6%) cardiomyopathies. Ischemic etiologies were less common (45% vs. 25%; p<0.0001) and primary electrical disorders more common (6% vs. 23%; p<0.0001) in referral SCA survivors. Conversely, genetic heart diseases (hypertrophic cardiomyopathy, long QT syndrome, etc.) were over-represented in referral cases (8% vs. 29%; p<0.0001), whereas no difference was observed in the number of primary and referral SCAs that remained unexplained. Conclusion: This study demonstrates, for the first time, that differences in SCA root cause exist between young SCA survivors evaluated at the same tertiary medical center on a primary vs. referral basis. Ongoing comparison of SCA etiologies between primary and referral SCA survivors may help resolve discrepancies regarding the contribution of specific disorders to SCA in the young.

Background: Since QT prolongation is a risk factor for sudden death, stroke, and all-cause mortality, we developed an electronic, institution-wide QT alert system to identify patients with significant QT prolongation (i.e. QTc≥500 ms if QRS <120 ms). These patients encountered a significant increased mortality within 1 year, and nearly 40% of patients with ≥4 QTc inciting factors have died. Herein, we examined the patients with ≤1 identifiable QTc inciting factor. Methods: Between November 2010 and June 2011, 53,732 patients underwent ECG-evaluation, 1,145 QT-alerts (2.1%) were triggered, and 470 of the QT-alerted patients had ECG-isolated QT prolongation. Clinical, laboratory, and therapeutic information were collected. Excluding female gender and bradycardia, other potential QT inciting factors (drugs, electrolyte disturbances, and co-morbidities) were synthesized into a pro-QT score and patients with a score of ≤1 were compared to patients with a pro-QT score >1. Results: About one-third (N=150, 59% female) of this QT-alerted cohort had a pro-QT score of ≤1 including 42 patients with an established diagnosis of congenital long QT syndrome (LQTS). Excluding LQTS patients, the remaining 108 patients (60 female, age 59±25 years) were significantly more likely to have a QT prolonging cardiovascular co-morbidity (44%) than those with a QT-score >1 (29%; p=0.006). However, mortality was similar between those with a QT-score ≤1 (19%) and those with a QT-score >1 (27%, p=0.09). Fourteen patients (9 female; age 64±22 years; QTc 507±14 ms) had no discernible QT inciting factors (i.e. pro-QT score=0) including 6 patients with previously documented QT prolongation. Conclusions: Only a minority of patients with ECG-isolated QT-prolongation (~3%) had no discernible QT-inciting factors other than female gender in 9. Careful scrutiny of these patients with seemingly idiopathic QT prolongation may identify novel QT provoking conditions. Alternatively, considering that 14 of 53,732 patients (1 in 3888) activated the alert system without obvious QT inciting factors and that congenital LQTS has an estimated prevalence of 1 in 2000, it is possible that this universal QT alert system has caught patients with yet to be diagnosed LQTS.

AbstractBackgroundLong 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.MethodsWe 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.ResultsOverall, 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).ConclusionTESTs should be used with caution when trying to interpret supine‐stand changes for diagnosis of LQTS.

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.

Introduction: Over 100 FDA-approved medications, electrolyte perturbations, and many disease states can prolong the QT interval in up to 10% of patients. In contrast, approximately 1 in 2,000 people have congenital long QT syndrome (LQTS) hallmarked by pathological QT prolongation secondary to LQTS-causative mutations. Hypothesis: an artificial intelligence (AI) deep neural network (DNN) analysis of the 12-lead ECG can distinguish patients with LQTS from those with acquired QT prolongation. Methods: The study cohort included 1599 patients with genetically confirmed LQTS and over 2.5 million controls from Mayo Clinic’s ECG data vault. Every patient/control with ≥ 1 ECG above age- and sex- specific 99 th percentile values for QTc [> 460 ms for all patients (male/female) < 13 years of age, or > 470 ms for men and > 480 ms for women above this age] was included. An AI-DNN involving a multi-layer convolutional neural network was developed. To simulate screening conditions, patients were matched at a ratio of 1:2,000 (incidence of LQTS) or 1:200 (balance of LQTS vs acquired QT prolongation in a tertiary referral center). Results: Among the 1,599 patients with LQTS, 808 (> 50%) had ≥ 1 ECG with QTc above the aforementioned QTc thresholds (2,987 ECGs) compared to 361,069/2.5M controls (14% of Mayo Clinic patients getting an ECG, 989,313 ECGs). Following age- and sex- matching and splitting, the model successfully distinguished LQTS from those with acquired QT prolongation at 1:2,000 matching with an AUC of 0.937 (accuracy 89%, sensitivity 81%, specificity 90%, PPV 0.05, NPV 0.99). Furthermore, when matching at a rate that genetically-mediated QT prolongation would be encountered in clinic (1:200), the model still successfully separated the two groups (AUC 0.912, accuracy 88%, sensitivity 78%, specificity 89%, PPV 0.1, NPV 0.99). Conclusion: For patients with a QTc exceeding its 99 th percentile values seen in health, this novel AI-DNN 12-lead ECG distinguishes abnormal QT prolongation stemming from LQTS versus acquired QT prolongation with high performance characteristics (AUC > 0.93). Even when scaled to referral center and LQTS incidence ratios, a negative AI-DNN signal rules out the presence of a LQTS disease-causative mutation with 99% negative predictive value.

Introduction: Recently, we demonstrated transcriptional down-regulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of associated hypertrophy pathways. Previous studies of other forms of cardiac hypertrophy demonstrate hypertrophy pathways are activated via histone acetylation and histone deacetylase (HDAC) inhibitors prevented development of hypertrophy. Whether histone modifications regulate hypertrophy pathways in HCM remains unexplored. Methods: Chromatin immunoprecipitation sequencing (ChIP-seq) was performed on myectomy tissues from 40 patients with HCM and 23 controls to characterize differential histone marks for H3K4me3 (active promoter), H3K9ac (active promoter), H3K9me3 (heterochromatin), H3K27ac (active enhancer), H3K27me3 (repression) across the genome. The differential histone marks were integrated with RNA-sequencing (RNA-seq) data derived from the same patients. Results: Overall, we identified 2,912 (7%) differential H3K4me3 peaks impacting 5 pathways, 23,339 (21%) differential H3K9ac peaks impacting 87 pathways, 33 (0.05%) differential H3K9me3 peaks, and 58,837 (42%) differential H3K27ac peaks impacting 50 pathways. There was increased H3K27ac (q-value = 0.002) and H3K9ac (q-value = 0.009) at RAS-MAPK loci. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling (z-score=4.5; -log [BH p-value] = 3.1), while H3K27me showed down-regulation of cardiac hypertrophy signaling (z-score=-2.4; -log [BH p-value] = 2.4). Multivariate integration of the ChIP-seq data with RNA-seq data identified 3,189 transcripts concordant with all five histone marks impacting 254 pathways, 18 (7%) of which are involved in cardiac hypertrophy. Conclusions: Myectomy tissue from patients with obstructive HCM shows enrichment of histone modifications at cardiac hypertrophy loci with activation via H3K27 and H3K9 acetylation and repression via H3K27 methylation. Further studies are needed to understand the balance and temporal relationship between these competing regulators in HCM pathobiology and the potential for epigenetic therapies.

Introduction: Treatment options for patients with recurrent ventricular arrhythmias (VAs) refractory to pharmacotherapy and/or ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), LCSD’s role in idiopathic ventricular fibrillation (IVF) is less clear. Here, we report our single-center experience regarding the early outcomes of LCSD in patients with IVF. Hypothesis: To determine the efficacy of LCSD on reducing VAs in IVF patients refractory to conventional therapy. Methods: A retrospective analysis of the electronic health record of patients with IVF between January 2000 to April 2023 was performed. Cardiac event rates [defined as arrhythmic syncope/seizure, appropriate implantable cardioverter defibrillator (ICD) therapy, sudden cardiac arrest (SCA), or sudden cardiac death (SCD)] before and after LCSD for each patient were calculated and a Wilcoxon signed rank test was performed. Results: In total, 94 patients (41% female) were classified as IVF. Overall, 15/94 patients (16%) had LCSD due to refractory VAs (60% male; mean age at LCSD 36 ± 20 years) despite beta-blocker treatment (100%) or combined drug therapy (67%). In total, 14 patients (15%) had an electrophysiology study performed before LCSD of which 10 (67%) had VAs ablation. All patients had a structurally normal heart and genetic testing performed in 14/15 patients (93%) confirmed absence of genetic cardiomyopathies and channelopathies. SCA was the sentinel event in 10 of 15 patients (67%); 14 patients (93%) had an ICD in place. The average follow-up time after LCSD was 3 ± 4 years. The VA event rate before LCSD was 4 ± 3 events per year and was reduced to 1 ± 3 per year (p<0.04) after LCSD. Patients had a median of 3.2 less events per year after LCSD (p=0.02) with 7 patients (47%) having no post-LCSD recurrences thus far while 3 (20%) patients were deemed LCSD non-responders with no reduction of event rate. Conclusions: LCSD represents a substrate-independent, anti-fibrillatory treatment option for patients with life-threatening, genetic arrhythmias. While not curative, the early outcomes of LCSD for patients with medically refractory IVF are promising.