Frequency of and outcomes associated with nonadherence to guideline-based recommendations for an implantable cardioverter-defibrillator in patients with congenital long QT syndrome.

BACKGROUND: Guideline-directed device therapy for long QT syndrome (LQTS) has evolved during the years, and indications for an implantable cardioverter-defibrillator (ICD) vary between professional cardiac societies. OBJECTIVE: We aimed to identify the subset of patients with LQTS who satisfied a class I or class II 2022 European Society of Cardiology guideline-based recommendation for an ICD and to determine the outcomes of those patients who received an ICD compared with those treated without an ICD. METHODS: Retrospective analysis was conducted of 2861 patients with LQT1, LQT2, or LQT3 to identify patients meeting contemporary recommendations for guideline-directed device therapy. Basic demographics, clinical characteristics, and frequency/type of breakthrough cardiac events (BCEs) were extracted, and outcomes/complications were compared between patients treated with an ICD and those treated without one. RESULTS: Of the 290 patients (approximately 10%) who met a guideline-based recommendation, 53 (18%) satisfied a class I/level B indication for an ICD; 56 (19%), a class I/level C indication; 19 (7%), a class IIa/level C indication; and 162 (56%), a class IIb/level B indication. However, most patients (156/290 [54%]) did not receive an ICD. Of those who received an ICD, 55 of 134 (41%) experienced ≥1 appropriate ventricular fibrillation-terminating ICD therapy, whereas ICD-related complications occurred in 13 patients (10%). Of those who were treated without an ICD, only 6 of 156 patients (4%) had nonlethal BCEs, which was significantly lower compared with the ICD group (P < .001). CONCLUSION: With >1200 years of combined follow-up, the experience and evidence from our 2 LQTS specialty centers suggest that many patients who satisfy a recommendation for an ICD based on the latest 2022 European Society of Cardiology guidelines may not need one. This is particularly true when the indication stemmed from a BCE while receiving beta blocker therapy or in asymptomatic patients with an increased 1-2-3-LQTS-Risk score.

Therapeutic Efficacy of Mexiletine for Long QT Syndrome Type 2: Evidence From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes, Transgenic Rabbits, and Patients.

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 (APD90) 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 APD90 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.

Long QT syndrome: importance of reassessing arrhythmic risk after treatment initiation.

BACKGROUND AND AIMS: Risk scores are proposed for genetic arrhythmias. Having proposed in 2010 one such score (M-FACT) for the long QT syndrome (LQTS), this study aims to test whether adherence to its suggestions would be appropriate. METHODS: LQT1/2/3 and genotype-negative patients without aborted cardiac arrest (ACA) before diagnosis or cardiac events (CEs) below age 1 were included in the study, focusing on an M-FACT score ≥2 (intermediate/high risk), either at presentation (static) or during follow-up (dynamic), previously associated with 40% risk of implantable cardioverter defibrillator (ICD) shocks within 4 years. RESULTS: Overall, 946 patients (26 ± 19 years at diagnosis, 51% female) were included. Beta-blocker (ßB) therapy in 94% of them reduced the rate of those with a QTc ≥500 ms from 18% to 12% (P < .001). During 7 ± 6 years of follow-up, none died; 4% had CEs, including 0.4% with ACA. A static M-FACT ≥2 was present in 110 patients, of whom 106 received ßBs. In 49/106 patients with persistent dynamic M-FACT ≥2, further therapeutic optimization (left cardiac sympathetic denervation in 55%, mexiletine in 31%, and ICD at 27%) resulted in just 7 (14%) patients with CEs (no ACA), with no CEs in the remaining 57. Additionally, 32 patients developed a dynamic M-FACT ≥2 but, after therapeutic optimization, only 3 (9%) had CEs. According to an M-FACT score ≥2, a total of 142 patients should have received an ICD, but only 22/142 (15%) were implanted, with shocks reported in 3. CONCLUSIONS: Beta-blockers often shorten QTc, thus changing risk scores and ICD indications for primary prevention. Yearly risk reassessment with therapy optimization leads to fewer ICD implants (3%) without increasing life-threatening events.

Can we improve the accuracy of electrocardiographic algorithms for accessory pathway location in children?

BACKGROUND: Predicting an accessory pathway location is extremely important in pediatric patients. AIMS: We designed a study to compare previously published algorithms by Arruda, Boersma, and Chiang. METHODS: This multicenter study included patients who had undergone successful ablation of one accessory pathway. Analysis of resting 12-lead electrocardiograms was carried out. An aggregated prediction score was constructed on the basis of algorithm agreement, and a structured workflow approach was proposed. RESULTS: The total population was 120 patients (mean age, 12.7 [± 3.6] years). The algorithm by Boersma had the highest accuracy (71.7%). The inter-rater agreement among the 3 reference algorithms, according to left-sided accessory pathway (AP) identification, was good between Boersma and Chiang (κ = 0.611; 95% confidence interval [CI], 0.468-0.753) but moderate between Arruda and Chiang and between Arruda and Boersma (κ = 0.566; 95% CI, 0.419-0.713 and κ = 0.582; 95% CI, 0.438-0.727, respectively). Regarding locations at risk of atrioventricular (AV) block, agreement was fair between Arruda and Chiang and between Boersma and Chiang (κ = 0.358; 95% CI, 0.195-0.520 and κ = 0.307; 95% CI, 0.192-0.422, respectively) but moderate between Arruda and Boersma (κ = 0.45; 95% CI, 0.304-0.597). On applying a first-step diagnostic evaluation, when concordance was achieved, we were able to correctly identify left-sided or non-left-sided ablation sites in 96.4% (n = 80) of cases. When concordance was achieved, correct prediction of risk/no risk of AV block was achieved in 92.2% (n = 59) of cases. CONCLUSIONS: An aggregated prediction score based on 3 reference algorithms proved able to predict an accessory pathway location very precisely and could be used to plan safely invasive procedures.

Do the remodeling effects of sacubitril/valsartan treatment depend upon heart failure duration?

AIMS: The angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) is recommended for the treatment of patients with heart failure in New York Heart Association (NYHA) class II-III and left ventricular ejection fraction (LVEF) 35% or less. We examined the effects of sacubitril/valsartan on cardiac remodeling and their correlation with heart failure duration in patients enrolled in our heart failure clinic from March 2017 to December 2019. METHODS: Echocardiographic and clinical/laboratory data were collected at baseline and at 6-month and 12-month follow-up visits in 69 patients (age 67 ±â€Š12 years, disease duration 8.4 ±â€Š5.8 years, 93% men). RESULTS: At both time points, mean NYHA class, NT-proBNP level, LVEF, LV end-systolic volume, and estimated systolic pulmonary pressure significantly (P < 0.05) improved versus baseline, as did the proportion of patients with diastolic dysfunction grade 3 or functional mitral regurgitation grade 3-4. In the subgroup with mean disease duration less than 8.5 years (n = 40), there was a significant improvement in all variables at both time points; in this group, a recovery of right ventricular function was also seen at the 12-month follow-up. On the contrary, patients with heart failure duration of at least 8.5 years (n = 29) showed only a slight improvement in LVEF and mitral regurgitation at 12 months. There were no significant changes in renal function and/or potassium levels in all patients. CONCLUSION: In patients with a relatively short disease duration, sacubitril/valsartan was associated with a strong favorable remodeling of the left ventricle and improvement in pulmonary circulation.