Neves, Raquel

Introduction: Long QT syndrome (LQTS) is a potentially life-threatening genetic heart disease. Patients with LQTS may also have co-existent mental health illnesses that may benefit from psychiatric medications. However, because many of these medications have QT-prolonging potential (www.crediblemeds.org), many of these patients receive suboptimal mental health care. Objective: To evaluate the frequency, management, and incidence of breakthrough cardiac events (BCEs) in patients with LQTS and concomitant mental health issues treated with psychiatric medications. Methods: A retrospective review was conducted on patients cared for in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic between 2000 and 2024 focusing on patients with LQTS and a concomitant psychiatric diagnosis requiring medication with known, possible or conditional risk of torsades de pointes (TdP). Electronic medical records were reviewed for data. BCEs were defined as LQTS-triggered syncope, seizures, appropriate ICD therapy, sudden cardiac arrest (SCA), or sudden cardiac death (SCD). Patients with missing information were excluded. Results: Overall, 195 /1899 LQTS patients [10%, 86 (43%) with LQT1, 83 (42%) with LQT2, and 16 (8%) with LQT3] had a concomitant psychiatric diagnosis requiring medication [150 female (76%), mean age at diagnosis 27 ± 18 years, median follow-up time 6.6 years (IQR 2.9-13)]. The most common psychiatric conditions were depression (71%), anxiety (62%), and ADHD (9%). The mean duration of therapy was 3.36 +/- 3.48 years and the most common medications used were fluoxetine (26%), sertraline (14%), and escitalopram (11%). There was no significant difference in QTc after starting the first psychiatric medication when compared to baseline (473 ± 33 vs 474 ± 35 ms, p=0.6). Prior to their LQTS diagnosis and while therefore untreated, 61/195 (31%) had at least 1 LQTS-associated cardiac event. This occurred in the setting of a psychiatric drug in 7 patients (11%). Following LQTS diagnosis and treatment, 14/195 patients (7%) have experienced a non-lethal BCE of which only 3/14 (21%) while on psychiatric medications. Conclusions: Although avoidance of medications with known QT-prolonging potential is prudent, attention to patient’s overall well-being besides just their LQTS must be given. After correct diagnosis and treatment, LQTS patients with concomitant mental health issues may be safely and effectively treated with medications known to prolong QTc.

AbstractIntroductionLong QT syndrome (LQTS) is a cardiac channelopathy characterized by QT prolongation and a potential for arrhythmic syncope, sudden cardiac arrest or deaths (SCA/SCD). It has been speculated that patients with LQTS might have a primary sinoatrial node (SAN) phenotype of chronotropic insufficiency (CI). This has not been demonstrated convincingly before because of the potentially confounding effects of beta blocker (BB) therapy. Herein, we set out to determine whether untreated patients with LQTS demonstrate intrinsic CI.Methods and ResultsA retrospective review of all treadmill exercise stress tests (TEST) was performed on patients with one of the three most common LQTS genotypes: LQT1, LQT2, and LQT3. For each patient, the first TEST completed while off BB was analyzed. Patients with prior left cardiac sympathetic denervation (LCSD) therapy were excluded. CI was defined as having an age‐ and gender‐predicted peak heart rate (HR) < 85% and/or a predicted HR reserve (HRR) < 80%. Overall, 463 LQTS patients (245 LQT1, 125 LQT2, and 93 LQT3) were included (267 female [58%]; mean age at time of TEST [29 ± 17 years]). Mean % predicted peak HR for all LQTS patients was 87.6% (range 42.9% ‐ 119.1%) and mean % predicted HRR was 80% (range 19.1% ‐ 153%). Overall, half of all LQTS patients (n = 234; 51%) displayed CI; 64% of patients with LQT1 (n = 157), 37% with LQT2 (n = 46), and 33% with LQT3 (n = 31). Patients with LQT1 were most likely to exhibit CI compared to patients with LQT2 (p < .0001) and LQT3 (p < .0001). CI was significantly more common in LQT1 compared to controls (p < .0001), while there was no difference between LQT2 (p = .5) or LQT3 and controls (p > .9). Presence of CI was not a predictor of LQTS‐associated symptoms, BB side effects or likelihood of future breakthrough cardiac events (BCE).ConclusionsPatients with LQTS, particularly LQT1, demonstrate a SAN phenotype of CI. If assessing BB therapy effect by impact on peak HR, the patient's pretreatment peak HR, rather than an age‐ and gender‐predicted maximum HR, should be used.

BACKGROUND: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2 . Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. METHODS: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. RESULTS: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and corrected QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76–0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83–0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81–0.88]). CONCLUSIONS: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

BACKGROUND: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome–causative genes compared with the gold-standard patch clamp. METHODS: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2 , and 50 SCN5A ) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, evolutionary scale modeling, version 1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp. RESULTS: Considering variants in all 3 genes, the evolutionary scale modeling, version 1b model had a receiver operating characteristic curve–area under the curve of 0.75 ( P =0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operating characteristic curve-area under the curve of 0.85 ( P <0.0001), sensitivity of 80%, and specificity of 76%. CONCLUSIONS: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.

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.

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.

Introduction: Disease-causative variants in LMNA -encoded lamin A/C cause a penetrant dilated cardiomyopathy associated with conduction disease (CD) and ventricular arrhythmias (VA). Prior studies show conflicting results regarding the effect of sex, variant type, and CD on severity and sudden death risk in cardiac laminopathy. Methods: In this retrospective study, we utilized a single-center genetic arrhythmogenic cardiomyopathy registry (N=432) to identify patients with ultra-rare LMNA variants and ascertain the effect of sex, mutation type, and clinical presentation on disease severity. Advanced heart failure (AHF) events were defined as ventricular assist device placement or cardiac transplantation whereas VA events were defined as sudden cardiac arrest, sustained ventricular arrhythmia, or appropriate implantable cardioverter-defibrillator shock. Results: The LMNA variant-positive cohort (N=83) had an age of diagnosis of 36 ± 10 years with 80% showing a cardiac phenotype. No difference in the age at diagnosis (37 vs. 34 years; p=0.3) or prevalence of AHF events (14% vs. 18%; p=0.8) and VA events (34% vs. 36%; p=0.9) was observed between females (N=50) and males (N=33). Furthermore, there was no difference in age of diagnosis (37 vs. 33 years; p=0.1) or prevalence of AHF (14% vs. 12%; p=0.9) and VA events (33% vs. 34%; p=0.9) between individuals with missense (N=42) or frameshift (N=32) variants. Interestingly, in comparison to individuals that presented with isolated CD (N=11) those that first presented with left ventricular dysfunction or arrhythmias (atrial or ventricular) (N=41) were more likely to have VA events (9% vs. 53%; p=0.01) and AHF events (0% vs 29%; p=0.05). In addition, those with structural/arrhythmic presentation had earlier time to VA events (15 years vs. 22 years; p=0.04) and AHF events (23 vs undefined; p=0.09) than those with CD. Conclusions: Contrary to prior studies, in this large single-center cardiac laminopathy study, sex and mutation type were not associated with increased risk of AHF or VA events. However, patients presenting with isolated CD had a lower risk of AHF and VA events. Contemporary multi-center studies are needed to better ascertain risk factors associated with AHF and VA events in cardiac laminopathy.

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.

Background: Long QT syndrome (LQTS) is a genetic heart disease affecting about 1 in 2000 persons. Around 40% of patients with LQTS can have a nondiagnostic, normal QTc at rest. The treadmill exercise stress test (TEST) can help unmask patients with concealed LQTS with a characteristic maladaptive, paradoxical increase in QTc ( 460 ms) during the recovery phase. In fact, the recovery phase QTc value has been added to the latest diagnostic score for LQTS. Objective: To characterize the TEST-derived QTc profile of untreated patients with LQTS and determine its diagnostic and prognostic utility. Methods: Retrospective analysis was performed on TEST data derived from 249 patients with LQTS (129 LQT1, 64 LQT2 and 56 LQT3) untreated at the time of their TEST compared with 236 controls. The Bazett’s corrected QTc was calculated at rest (sitting, supine, and standing), during exercise at 1 min, 3 mins, and peak exercise, and during recovery phase at 1, 3 and 5 mins. Results: The mean resting QTc was significantly higher in LQTS patients (457 ± 30 ms) compared to controls (420 ± 24 ms; p<0.0001) as well as at every stage during the TEST (p<0.001). For LQT1 patients, highest QTc was observed at peak exercise (mean 496 ± 38 ms) and during the third minute of recovery phase (mean 500 ± 40 ms). In contrast, LQT2 patients showed the lowest QTc (mean 452 ± 48 ms) during peak exercise but the greatest QTc latency (QTc at 5 min - QTc at 1 min recovery; mean QTc latency 33 ± 77 ms; p=0.005) compared to controls. For LQT3, the mean QTc was greatest at rest compared to controls (p<0.001), and there was no difference during exercise and recovery phases. Among 162 LQT1 and LQT2 patients that presented with concealed LQTS, 119 (73%) showed a maladaptive QT response. ROC analysis showed that in patients with LQT1, a maladaptive QTc > 523 ms at 3 min of recovery was highly predictive of breakthrough cardiac events (AUC 0.84; sensitivity 100%, specificity 72%); no such association was identified for LQT2 or 3. Conclusions: This comprehensive characterization of the QTc response before, during, and after a TEST in the largest untreated cohort of patients with LQTS provides important genotype-specific characteristics and can be used as a predictor for potential LQT1-triggered cardiac events after diagnosis and treatment.

Abstract Background Pathogenic variants in the lamin A/C gene (LMNA) can lead to a wide range of phenotypes from dilated and arrhythmogenic cardiomyopathies and conduction abnormalities to partial lipodystrophies. This case highlights a coincidental pathogenic LMNA variant identified in a patient with sudden cardiac arrest (SCA). We demonstrate the need for careful interpretation of pathogenic variants identified in cardiomyopathy genes by highlighting a case in which a coincidental pathogenic LMNA variant was found in a patient with premature ventricular complex (PVC)-induced ventricular fibrillation (VF). Case summary We present the case of a 16-year-old male with SCA secondary to VF. Genetic testing identified a maternally inherited pathogenic variant in LMNA annotated c.1961dup; p.T655Nfs*49. The patient received an implantable cardiac defibrillator and was discharged on nadolol. The patient’s two brothers were also variant-positive. However, the patient and both brothers had normal chamber dimensions on echocardiogram and no late gadolinium enhancement on cardiac magnetic resonance imaging. The family members with the variant were recommended to have prophylactic implantable cardiac defibrillators and thus sought a second opinion. The patient received an appropriate shock and device interrogation identified PVCs. Electrophysiology study identified PVC-induced VF which was ablated with no recurrent ventricular arrhythmias/implantable cardioverter defibrillator therapies over 8 months of follow-up. Although the variant in LMNA could lead to cardiac arrest, the clinical phenotype was consistent with a non-genetic aetiology. The family members were told to have periodic cardiac evaluation. Discussion This case demonstrates the identification of a coincidental pathogenic variant in a cardiomyopathy gene in a patient with cardiac arrest. Although this variant could lead to cardiomyopathy, it appears the cardiac arrest was not due to the pathogenic variant. This highlights the need to consider the clinical phenotype when interpreting genetic test results for cardiomyopathies even in the presence of a positive genetic test result.