Background: Congenital long QT syndrome (LQTS) is a monogenic predisposition to lethal cardiac arrhythmias.Despite decades of investigation and discovery of multiple responsible genes, a molecular ...
A 75-year-old man was admitted to our hospital in January 2010 for evaluation of syncope and abnormal ECG. ECG showed type 1 ST elevation in lead V(1) and he was diagnosed as Brugada syndrome. During cardiac catheterization, baseline coronary angiography was normal, but intracoronary ergonovine maleate induced spasms of the right and left coronary arteries concomitant with chest pain and ST elevation on ECG. J waves were accentuated or newly developed. Soon after an intracoronary injection of nitroglycerin, chest pain was relieved and ischemia-induced J wave disappeared and the ST segment returned to the same morphology as baseline. Extrastimuli induced ventricular fibrillation. He received an implantable cardioverter-defibrillator. He was also treated with Ca antagonist and isosorbide dinitrate and has had an uneventful course for 5 months.
Early repolarization syndrome is a recently proposed condition characterized by an early repolarization pattern in the electrocardiogram (ECG) and ventricular fibrillation in the absence of structural heart abnormalities. Although some studies have suggested that early repolarization is associated with frequency of atrial fibrillation, the association of early repolarization with atrial fibrillation is not well known.Early repolarization indicates the substrate for atrial fibrillation in addition to that for ventricular fibrillation.This study included 79 patients (57 men [72%]; age, 45 ± 12 years) aged less than 60 years who had paroxysmal lone atrial fibrillation and 395 age- and sex-matched healthy controls (patient:control ratio, 1:5). Patients who had structural heart disease, hypertension, diabetes, hyperthyroidism, history of successful resuscitation, or the Brugada type ECG were excluded. ECGs recorded during sinus rhythm were compared between patients with atrial fibrillation and healthy controls.Early repolarization in the inferior and/or lateral leads was more common in patients with atrial fibrillation (25%) than controls (10%; P = 0.001). The location and magnitude of early repolarization were similar between the two groups. Other electrocardiographic measurements were not different between the two groups. Among patients with atrial fibrillation, there was no difference in clinical characteristics including age at atrial fibrillation development, sex, and body mass index between patients with early repolarization and those without early repolarization. Electrocardiographic measurements were not different between patients with early repolarization and those without early repolarization.Early repolarization was associated with lone atrial fibrillation. Early repolarization may indicate increased susceptibility to atrial fibrillation.
We thank Dr. Karakus et al. for their interest in our recently published paper assessing the usefulness of electrocardiogram recordings in the high intercostal space to identify the risk of sudden death. (Hasegawa et al., 2020) In their letter to the editor, they expressed two concerns about the findings of our study. First, they suggested the need to include clinical data of modular factors including age, heart rate, electrolyte imbalance, hyperthermia, and usage of pharmacological agents on analysis for making clear the relationship between J point elevation in high precordial leads and ventricular fibrillation. These factors could influence the development of ventricular fibrillation in J wave syndrome, (Antzelevitch et al., 2017) and we agree with the importance of considering their influences. However, in our cohort, there was no patient showing abnormalities in electrolytes or body temperature. Regarding medications, as described in our paper, only two patients with Brugada syndrome received antiarrhythmic drugs, but in other ones did not have any drugs that can affect the J wave. We showed that there is no difference in the baseline heart rate in each group. Therefore, we subjected the other factors including J point elevation in the 3rd intercostal spaces, age, and sex at diagnosis to Cox proportional hazard analysis followed by stepwise forwards and backward regression modeling. We found that J point elevation in the 3rd intercostal spaces was significantly associated with the development of ventricular fibrillation in the patients with idiopathic ventricular fibrillation, as shown in the Table 1. Second, Karakus et al. pointed out the problems of the statistical measurement methods regarding the skewness in our cohort and the comparison between the three groups. We had confirmed that all of the parameters in three groups were normally distributed and used one-way ANOVA for the comparisons. None declared. All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, writing, or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in the Annals of Noninvasive Electrocardiology. This study was approved by the ethics committee of Niigata University Medical & Dental Hospital. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Mutation in the lamin A/C gene (LMNA) is associated with several cardiac phenotypes, such as cardiac conduction disorders (CCD), atrial arrhythmia (AA), malignant ventricular arrhythmia (MVA) and left ventricular dysfunction (LVD), leading to sudden cardiac death (SCD) and/or end-stage heart failure. We investigated how these phenotypes are associated with each other and which of them are most important for total mortality. Methods and Results: A multicenter registry included 110 LMNA mutation carriers (age, 43±15 years, male: 62%) from 60 families. After genetic diagnosis of LMNA mutation (missense: 27%, non-missense: 73%), patients or subjects were followed to evaluate the manifestations of their phenotypes and the risk of total mortality; 90 patients could be followed (median: 5 [0-35] years). Prevalence of the 4 clinical phenotypes was significantly increased during follow-up. Among these phenotypes, AA was significantly associated with MVA. CCD was significantly associated with LVD. LVD, meanwhile, was significantly associated with CCD and MVA. Male sex was significantly associated with MVA. Furthermore, during follow-up, 17 patients died: 12 end-stage heart failure, 4 SCD and 1 stroke. LVD was the only independent predictor for all-cause death (OR: 41.7, 95% CI: 4.1-422.3; P=0.0016).Several cardiac phenotypes were age-dependently increased in LMNA mutation carriers, suggesting that ICD or CRT-D could suppress SCD after middle age; however, LVD leading to end-stage heart failure was the only independent predictor for total mortality.
Abstract Background Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adopt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients. Methods We classified a pathogenicity of 142 KCNQ1 variants among 927 LQT1 patients (536 probands and 391 family members) based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines and evaluated whether the ACMG/AMP-based classification was associated with arrhythmic risk in LQT1 patients. Results Among 142 KCNQ1 variants, 60 (42.3%), 58 (40.8%), and 24 (16.9%) variants were classified into pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS), respectively. The ACMG/AMP guideline-based classification was significantly associated with syncopal events (particularly those during exercise) and LQT risk score (Schwartz score) in overall population. On the other hand, arrhythmic risk was completely different between probands and families even in the same variants. The baseline QTc interval and variant location could stratify the risk in family members but not in probands, however, the ACMG/AMP-based KCNQ1 variant classification stratified the risk in LQT1 probands as well as family members. Multivariate analysis showed that proband (HR=2.52; 95% CI: 1.93–3.30; p<0.0001), longer QTc interval (≥500ms) (HR=1.41; 95% CI: 1.11–1.79; p<0.0001), variants at membrane spanning (MS) (vs. those at N/C terminus) (HR=1.40; 95% CI: 1.07–1.85; p=0.02), C-loop (vs. N/C terminus) (HR=1.58; 95% CI: 1.11–2.24; p=0.01), and P variants [(vs. LP) (HR=1.71; 95% CI: 1.33–2.23; p<0.0001), (vs. VUS) (HR=1.96; 95% CI: 1.19–3.46; p=0.007)] were significantly associated with syncopal events. A clinical score (0–4) based on the proband, QTc (≥500ms), variant location (MS or C-loop) and P variant by the ACMG/AMP guidelines allowed identification of patients more likely to have arrhythmic events (Figure A and B). Conclusion Comprehensive evaluation of clinical findings and pathogenicity of KCNQ1 variants based on the ACMG/AMP-based evaluation may stratify arrhythmic risk of congenital long-QT syndrome type 1. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Health Science Research Grant from the Ministry of Health,Labor and Welfare of Japan for Clinical Research on Measures for Intractable Diseases (H24-033, H26-040, H27-032) and a research grant from the Japan Agency for Medical Research and Development (AMED) (15km0305015h0101, 16ek0210073h0001)
