Citations

Introduction: Type 2 long QT syndrome (LQT2) is caused by loss-of-function variants in the KCNH2 -encoded K v 11.1 potassium channel which is essential for the rapid delayed rectifier channel (I Kr ) that governs phase 3 of cardiac action potential (AP). No current therapies target the molecular cause of LQT2. Methods: A dual-component “suppression-and-replacement” (SupRep) KCNH2 gene therapy was created by cloning into a single construct a custom-designed KCNH2 shRNA that produces ~80% knockdown (suppression) and a “shRNA-immune” (shIMM) KCNH2 cDNA modified by the introduction of synonymous single nucleotide substitutions within the shRNA target site (replacement). The ability of KCNH2-SupRep gene therapy to suppress and replace LQT2-causative variants in KCNH2 was evaluated via heterologous expression in TSA201 cells. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from two patients with LQT2 (KCNH2-G604S and -N633S). CRISPR-Cas9 corrected isogenic control iPSC-CMs were made. Both lines were treated with KCNH2-SupRep or non-targeting control shRNA (shCT). FluoVolt voltage dye was used to measure the APD. Results: KCNH2-SupRep achieved mutation-independent suppression of wild-type KCNH2 and both LQT2-causative variants with simultaneous replacement of KCNH2-shIMM as measured by allele-specific qRT-PCR. Treatment with KCNH2-SupRep resulted in shortening of the pathologically prolonged APD at 90% repolarization (APD 90 ) to near isogenic control APD 90 levels (G604S: isogenic controls, 424 + 39 ms and N633S: isogenic controls, 433 + 16 ms) compared to treatment with non-targeting shCT (G604S: SupRep treated, 399±105 ms vs. shCT treated, 577±39 ms, p<0.0001; N633S: SupRep treated, 432±85 ms vs. shCT treated, 483±65 ms, p<0.005). Conclusions: We provide the first proof-of-principle gene therapy for correction of LQT2. Like our sentinel discovery of SupRep gene therapy for LQT1, KCNH2-SupRep successfully suppressed and replaced KCNH2 to normal wild-type levels. In TSA201 cells, co-transfection of LQT2 variants and KCNH2-SupRep caused mutation-independent suppression-and-replacement of KCNH2 . In LQT2 iPSC-CMs, KCNH2-SupRep shortened the APD, thereby eliminating the pathognomonic feature of LQT2.

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 and Objective: The association of non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) with intensive care unit (ICU) admissions and the need for mechanical ventilation and disease severity in COVID-19 patients. Material and Methods: A systematic literature review was conducted on the databases: Cochrane, Embase, PubMed, ScienceDirect, and the Web of Science from January 2019 to June 2022. Studies evaluating MAFLD using laboratory methods, non-invasive imaging, or liver biopsy were included. The study protocol was registered in PROSPERO (ID CRD42022313259), and PRISMA guidelines were followed. The NIH quality assessment tool was used for quality assessment. RevMan version 5.3 software was used for pooled analysis. A sensitivity analysis was performed to assess the result’s stability. Results: A total of 37,974 patients from 17 studies were assessed for the association between MAFLD and ICU admission. A total of 3396 COVID-19 patients required ICU admission: 1236 (20.41%) in the MAFLD group and 2160 (6.77%) in the non-MAFLD group. The odds ratio was 1.86 for ICU admission, p = 0.007, and a (95% CI) of [1.18–2.91]. A total of 37,166 patients from 13 studies were included in the need for invasive mechanical ventilation analysis. A total of 1676 patients required mechanical ventilation: 805 in the MAFLD group (14.20% of all MAFLD patients) and 871 patients in the non-MAFLD group (2.76% of all non-MAFLD patients). The odds ratio was 2.05, p = 0.02, and a (95% CI) of [1.12–3.74]. A total of 5286 patients from 14 studies were included in the COVID-19 disease severity analysis. Severe COVID-19 was seen in 1623 patients, with 33.17% (901/2716) of MAFLD patients and 28.09% (722/2570) of non-MAFLD patients having severe disease. The odds ratio was 1.59 for disease severity, p = 0.010, and a (95% CI) of [1.12–2.26]. Conclusions: Our meta-analysis suggests that there are significantly increased odds of ICU admissions, a need for invasive mechanical ventilation, and disease severity in MAFLD patients who acquire COVID-19.

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.

Background: Sex hormones influence the arrhythmogenic risk for various genetic heart diseases (GHDs) including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and idiopathic ventricular fibrillation (IVF). Although exogenous hormones are used frequently in transgender medicine for gender-affirming hormone therapy (GAHT), the effect of such treatments on sudden cardiac death (SCD) risk in transgender patients with a GHD is unknown. Objective: To describe the prevalence and spectrum of transgender patients with GHD and to evaluate the impact of GAHT on the treatment and outcomes of their underlying GHD. Methods: We performed a retrospective review of all patients seen and evaluated in Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic from January 1999-2022 to identify transgender patients. Clinical notes were reviewed for sex, gender identity, GAHT, and details of their GHD, therapy, and outcomes. Results: Among 1990 patients with a GHD, we found 7 patients (0.35%) who self-identify as a gender different from their chromosomal sex (transgender). Specifically, there were 4 patients who identified as transgender women (XY males at birth) and 3 as transgender men (XX females at birth). Five of seven patients (71%) have used forms of GAHT, with 2 patients on estradiol and 3 patients on testosterone. GHDs identified include LQT1 (2 transgender women), LQT3 (1 transgender man), LQT3/BrS overlap syndrome (1 transgender woman), genotype negative LQTS (1 transgender man), CPVT (1 transgender woman), and IVF (1 transgender man). Guideline-directed GHD therapy was optimized, not altered nor escalated, for all patients and no patients were advised against initiating GAHT due to perceived interactions. One of seven patients (transgender man with IVF) experienced a breakthrough cardiac event (BCE) while on GAHT, while the other 6 patients have had no BCEs. Conclusion: Although less than 0.5% of patients seen over 20+ years self-identified as transgender, their holistic care must include a careful discussion of the possible cardiac risks associated with GAHT. Additional studies are needed to determine the potential pro-arrhythmic risk of GAHT.

Background: Highly caffeinated energy drinks (HCEDs) can trigger life-threatening cardiac arrhythmias in individuals with and without an underlying genetic predisposition. Though the mechanism(s) responsible for these events remain unclear, it has been postulated that high caffeine may alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a manner that is pro-arrhythmic. Objective: To describe our experience regarding sudden cardiac arrest (SCA) events occurring in proximity to HCED consumption in patients with underling genetic heart diseases. Methods: All SCA survivors referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for clinical and/or molecular evaluation were reviewed to identify those with a history of HCED consumption prior to their event. Patient demographics, clinical characteristics, documented HCED consumption, and temporal relationship of HCED consumption to SCA were extracted from the electronic medical record. Results: Among 144 SCA survivors with a structurally normal heart, 8 (6 females; mean age at event 28 ± 8 years) experienced an unexplained SCA associated temporally with HCED consumption. Of these, 5 (63%) had either long QT syndrome (n=3) or catecholaminergic polymorphic ventricular tachycardia (n=2). The remaining 3 were diagnosed with unexplained SCA/idiopathic ventricular fibrillation after a comprehensive evaluation. Three patients (37%) were habitual HCED consumers while 5 (63%) imbibed for the first time with consumption ranging from several hours to a few minutes before the SCA. Seven patients (88%) required a rescue shock (average 2 ± 2 shocks/patient) while 1 was manually resuscitated. Upon follow-up, 6 (75%) were dismissed with an implantable cardioverter defibrillator, 1 (13%) on pharmacologic therapy, and 1 (13%) underwent denervation surgery. All SCA survivors have quit drinking HCEDs and have been event-free since. Conclusion: Overall, 8/144 (5.6%) of SCA survivors evaluated in our program experienced a SCA in proximity to consuming a HCED. Although larger cohort studies are needed to elucidate the precise mechanism for HCED-triggered/associated SCA and quantify its precise pro-arrhythmic risk, it seems prudent to sound an early warning.

Background: The estimated prevalence of attention-deficit/hyperactivity disorder (ADHD) globally is about 5%. For patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), ADHD-directed stimulant therapy is relatively contraindicated. However, previous studies have shown that use of these treatments is safe for patients with long QT syndrome, a similar genetic heart disease. Whether this is the same for patients with CPVT remains unknown. Objective: To evaluate ADHD-directed treatment, outcome, and frequency of CPVT-triggered events in patients with CPVT and concomitant ADHD. Methods: A retrospective electronic medical record review of 216 patients with CPVT evaluated in Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic was performed to determine the prevalence of concomitant ADHD and the incidence of CPVT-triggered events in these patients. Results: Overall, 14 patients (6%) were diagnosed with CPVT and concomitant ADHD (6 female, average age 19 ± 3 years). At the time of first evaluation, ADHD-directed stimulant therapy was stopped or advised against in 8/14 patients (57%). It was (re)started in 11 patients (79%) following comprehensive evaluation and treatment initiation for CPVT with pharmacologic therapy in 14/14 patients (100%), denervation surgery in 12 (86%), and an implantable cardioverter defibrillator in 4 (29%). Prior to Mayo Clinic evaluation, 10 patients (71%) treated for CPVT had a breakthrough cardiac event, without being on stimulant therapy, while 4 patients (29%) had an event while being treated for both CPVT and ADHD for an average time on stimulant therapy of 6 ± 6 years. Following CPVT treatment optimization and ADHD stimulant (re)initiation, patients have remained event-free for a total of 82 patient years (mean follow-up 6 ± 5 years). Conclusion: Among patients with CPVT, the prevalence of ADHD was similar to that in the general population, which can be treated safely and effectively with stimulant therapy. Although the rate of adverse events was low in stimulant-treated patients, physicians should weigh the potential effects of suboptimal treatment of ADHD with the theoretical proarrhythmic risk from stimulant medications on a case-by-case basis.

Background: Type 2 long QT syndrome (LQT2) is an inherited arrhythmia syndrome caused by pathogenic variants in the KCNH2 gene which result in QT prolongation and confers susceptibility to arrhythmic syncope/seizures and sudden cardiac arrest/death. Oral progestin-based contraceptives increase the risk of cardiac events in women with LQT2 and we previously reported the case of a LQT2 woman with recurrent cardiac events attributed to the use of the progestin-based contraceptive, Medroxyprogesterone Acetate (“Depo-Provera”, Depo). Objective: To evaluate the arrhythmic-risk of Depo in a LQT2-specific, induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model. Methods: An iPSC-CM line was generated from the previously reported woman (KCNH2-G1006A*fs) as well as a control line. Voltage-sensing dye was used to assess the optical action potential duration (APD) with 10 μM Depo. 3-D erratic beating patterns were then assessed using multiple electrode array (MEA) with Depo and isoproterenol (ISO) to mimic an adrenergic surge. Results: Addition of Depo to the G1006A*fs iPSC-CMs decreased the optical APD from baseline 438±14 ms (n=6) to 363±35 ms (n=12; p=0.0001). Despite the APD shortening at baseline, in the setting of ISO, Depo administration induced erratic beating patterns in MEA, characterized as alternating spike amplitudes, alternans, or early after depolarization-like phenomena. Combined Depo and ISO treatment increased the percent of electrodes displaying erratic beating in G1006A*fs [baseline 8%±13 vs. Depo + ISO 38%±40 (p=0.0097)] but not in controls [baseline 2%±5 vs. Depo + ISO 7%±11 (p=0.14)]. Neither Depo nor ISO alone changed beating patterns in G1006A*fs [baseline 8%±13, Depo 30%±41 (p=0.08), ISO 21%±30, (p=0.17)] and controls [baseline 2%±5, Depo 3%±7 (p=0.61), ISO 0%±0 (p=0.4)]. Conclusion: This patient-specific, re-engineered heart cell study provides a potential mechanism for the patient’s clinically documented, Depo-associated episodes of recurrent ventricular fibrillation. This in-vitro data should prompt a large-scale clinical assessment of Depo’s potential pro-arrhythmic effect in women with LQT2.