Identification of concealed cardiomyopathy using next-generation sequencing-based genetic testing in Korean patients initially diagnosed with idiopathic ventricular fibrillation.

AIMS: Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF. METHODS AND RESULTS: This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing-based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. CONCLUSION: Next-generation sequencing-based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy.

Clinical and Genetic Features of Korean Inherited Arrhythmia Probands.

BACKGROUND AND OBJECTIVES: Inherited arrhythmia (IA) is a more common cause of sudden cardiac death in Asian population, but little is known about the genetic background of Asian IA probands. We aimed to investigate the clinical characteristics and analyze the genetic underpinnings of IA in a Korean cohort. METHODS: This study was conducted in a multicenter cohort of the Korean IA Registry from 2014 to 2017. Genetic testing was performed using a next-generation sequencing panel including 174 causative genes of cardiovascular disease. RESULTS: Among the 265 IA probands, idiopathic ventricular fibrillation (IVF) and Brugada Syndrome (BrS) was the most prevalent diseases (96 and 95 cases respectively), followed by long QT syndrome (LQTS, n=54). Two-hundred-sixteen probands underwent genetic testing, and 69 probands (31.9%) were detected with genetic variant, with yield of pathogenic or likely pathogenic variant as 6.4%. Left ventricular ejection fraction was significantly lower in genotype positive probands (54.7±11.3 vs. 59.3±9.2%, p=0.005). IVF probands showed highest yield of positive genotype (54.0%), followed by LQTS (23.8%), and BrS (19.5%). CONCLUSIONS: There were significant differences in clinical characteristics and genetic yields among BrS, LQTS, and IVF. Genetic testing did not provide better yield for BrS and LQTS. On the other hand, in IVF, genetic testing using multiple gene panel might enable the molecular diagnosis of concealed genotype, which may alter future clinical diagnosis and management strategies.

Development and validation of the Pediatric-Youth Hyperphagia Assessment for Prader-Willi syndrome.

OBJECTIVES: Hyperphagia is a highly stressful, life-threatening feature of Prader-Willi syndrome (PWS). It is important to assess this complex behavior accurately over time. This study aimed to develop and validate the Pediatric-Youth Hyperphagia Assessment for Prader-Willi syndrome (PYHAP) as a tool targeting children and adolescents. METHODS: After an extensive literature review and qualitative interviews, the final version of the PYHAP with 14 questions in 3 domains (verbal [5], behavior [4], and social [5]) was developed and tested at Samsung Medical Center in Seoul, Korea from July 2018 to September 2019. Exploratory factor analysis and confirmatory factor analysis (CFA) were performed to confirm construct validity. The correlations between the PYHAP and the Korean Children's Eating Behavior Questionnaire (K-CEBQ) were calculated to evaluate convergent and discriminant validity. Criterion validity and the validity of the response categories were also tested. RESULTS: Cronbach's alpha coefficient of the PYHAP was 0.91. The fit indices for CFA were good (comparative fit index, 0.87; standardized root mean squared residual, 0.08). The domains of the PYHAP were closely correlated with the relevant domains of the K-CEBQ. The accuracy of the PYHAP score for predicting uncontrolled hyperphagia was good (area under the curve, 0.75; 95% confidence interval, 0.65 to 0.85). CONCLUSIONS: The PYHAP was confirmed to be a reliable and valid tool to evaluate hyperphagia in children and adolescents with PWS via caregivers' assessments. It is recommended to use the PYHAP to communicate with parents or caregivers about patients' hyperphagia or to monitor and manage extreme behaviors in children with PWS.

Cardiovascular outcomes with glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes: A meta-analysis.

BACKGROUND: According to available research, there have been no head-to-head studies comparing the effect of glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cardiovascular outcomes among patients with type 2 diabetes not reaching glycemic goal with metformin. METHODS: Relevant studies were identified through electronic searches of PubMed and EMBASE published up to January 15, 2020. Efficacy outcomes of interest included the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, its individual components, all-cause death, and hospitalization for heart failure (HF). Safety outcomes included all suggested side effects of both agents previously reported. RESULTS: Eleven studies, including 94,727 patients were used for the analysis. The risk of composite end point was significantly lower in both groups compared to the control group (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.85-0.92, p < 0.001). The risk of hospitalization for HF was significantly lower in both groups but the magnitude of the effect was more pronounced in the SGLT-2 inhibitors group (HR 0.68, 95% CI 0.60-0.76, p < 0.001) than the GLP-1 agonists group (HR 0.92, 95% CI 0.84-0.99, p = 0.03). Patients treated with GLP-1 agonists discontinued trial medications more frequently compared to conventionally treated patients because of serious side effects. CONCLUSIONS: Both GLP-1 agonists and SGLT-2 inhibitors showed comparable cardiovascular outcomes in patients with type 2 diabetes. However, the SGLT-2 inhibitors were associated with more pronounced reduction of hospitalization for HF and lower risk of treatment discontinuation than GLP-1 agonists.

Long-Term Left Atrial Function after Device Closure and Surgical Closure in Adult Patients with Atrial Septal Defect.

BACKGROUND: Studies comparing left atrial (LA) function after surgical closure or percutaneous closure in patients with an atrial septal defect (ASD) are lacking. METHODS: Between 1 and 3 years after ASD treatment, we retrospectively analyzed the medical records and transthoracic echocardiographic images of patients who had been diagnosed with an ASD after 20 years of age and who had undergone surgical closure (ASD-S) or percutaneous device closure (ASD-D). We measured LA peak systolic, early diastolic, and late diastolic strain values using 2-dimensional (2D) speckle tracking echocardiography (STE) and calculated reservoir, conduit, and contraction strain. RESULTS: The reservoir strain value of the ASD-D groups was 25.2% ± 7.4%, which was lower compared to the control group (33.6% ± 5.5%) (p = 0.004). The LA conduit strain and the LA contraction values of the ASD-D group were also lower compared to the control group (-13.8% ± 5.8% vs. -20.4% ± 4.7%, p = 0.034; -11.3% ± 4.2% vs. -13.2% ± 2.5%, p = 0.037, respectively). The reservoir, conduit, and contraction strains of the ASD-S group were 27.8% ± 8.8%, -15.3% ± 6.4%, and -12.5% ± 5.8%, respectively, and were not different from those of the control group or the ASD-D group. CONCLUSIONS: The 2D STE is a suitable method for evaluating LA function after ASD closure. Our results demonstrate that 1 year after device closure, the LA reservoir, conduit and contraction function were reduced in ASD-D group compared to healthy controls, while there was no difference between the ASD-S and ASD-D groups.

Uniform-thickness electrospun nanofiber mat production system based on real-time thickness measurement.

Electrospinning is a simple versatile process used to produce nanofibers and collect them as a nanofiber mat. However, due to bending instability, electrospinning often produces a nanofiber mat with non-uniform mat thickness. In this study, we developed a uniform-thickness electrospun nanofiber mat (UTEN) production system with a movable collector based on real-time thickness measurement and thickness feedback control. This system is compatible with a collector with void regions such as a mesh-type collector, two-parallel-metal-plate collector, and ring-type collector, which facilitates the measurement of light transmittance across the produced nanofiber mat during electrospinning. A real-time measurement system was developed to measure light transmittance and convert it to the thickness of the nanofiber mat in real time using the Beer-Lambert law. Thickness feedback control was achieved by repeating the following sequences: (1) finding an optimal position of the movable collector based on the measured thickness of the nanofiber mat, (2) shifting the collector to an optimal position, and (3) performing electrospinning for a given time step. We found that the suggested thickness feedback control algorithm could significantly decrease the non-uniformity of the nanofiber mat by reducing the standard deviation by more than 8 and 3 times for the numerical simulation and experiments, respectively, when compared with the conventional electrospinning. As a pioneering research, this study will contribute to the development of an electrospinning system to produce robust and reliable nanofiber mats in many research and industrial fields such as biomedicine, environment, and energy.

The Effects of a Continuous Olfactory Stimulation Using Breast Milk (COSB) on Behavioral State and Physiological Responses in Korean Premature Infants.

PURPOSE: This study aimed to evaluate the effects of continuous olfactory stimulation with breast milk (COSB) on behavioral and physiologic states of Korean premature infants. DESIGN AND METHODS: We examined the COSB effects on the behavioral states and physiological responses, including heart rate and oxygen saturation, in 30 premature infants using a non-equivalent control group pre- and post-test design. Sterile 2 cm × 2 cm gauzes wet with 2 cc breast milk were placed 10 cm away from the infants' nostrils 8 times per day for 3 consecutive days. We obtained five measurements each of the behavioral state, heart rate, and oxygen saturation of the premature infants in the neonatal intensive care unit (NICU). Statistical analysis was conducted using descriptive statistics and two-way repeated-measures ANOVA. RESULTS: The experiment group presented significantly reduced heart rate variations (p = .039). There were significant differences in the heart rate at all time-points in the control group (p < .001) but not in the experimental group, indicating more stable (p > .089) heart rates in the latter group. There were positive COSB effects on the behavioral states of premature infants at some time points. CONCLUSIONS: COSB can be a useful intervention program for high-risk infants for partial behavioral state stabilization and significant heart rate stabilization. PRACTICE IMPLICATIONS: COSB might enable NICU nurses to provide a useful and safe developmental care plan for the premature infants hospitalized in the NICU to improve their physiologic and behavioral condition.

Associates and Prognosis of Giant Left Atrium; Single Center Experience.

BACKGROUND: Left atrial (LA) remodeling develops as a result of longstanding pressure overload. However, determinants and clinical outcome of excessive remodeling, so called giant left atrium (GLA), are not clear. METHODS: Clinical characteristics of patients with GLA (antero-posterior diameter higher than 65 mm), including echo-Doppler parameters, and follow-up clinical outcomes from a tertiary referral hospital were investigated. RESULTS: Among 68519 consecutive primary patients who underwent echocardiography over a period of 10 years, data from 163 GLA cases (0.24%) were analyzed. Main causes were significant rheumatic mitral stenosis (n = 58, 36%); other causes comprised significant rheumatic mitral regurgitation (MR; n = 10, 6%), mitral valve (MV) prolapse or congenital mitral valvular disease (MVD) (n = 20, 12%), and functional MR (n = 25, 15%). However, mild rheumatic MV disease (n = 4, 3%) or left ventricular (LV) systolic or diastolic dysfunction without significant MR (n = 46, 28%) were also causes of GLA. During median follow-up of 22 months, 42 cases (26%) underwent composite events. MV surgery was related to lower rate of composite events. In multivariate analysis, MV surgery, elevated pulmonary arterial systolic pressure, and increased LA volume index were independent predictors of future events (p < 0.05) regardless of underlying diseases or history of MV surgery. CONCLUSION: Although rheumatic MVD with atrial fibrillation is the main contributor to GLA, longstanding atrial fibrillation with LV dysfunction but without MVD also could be related to GLA. Even in GLA state, accurate measurement of LA volume is crucial for risk stratification for future events, regardless of underlying disease.

Which patients recur as atrial tachycardia rather than atrial fibrillation after catheter ablation of atrial fibrillation?

INTRODUCTION: The ablation gaps have been known as the main mechanism of recurrence as atrial tachycardia (AT) rather than atrial fibrillation (AF) after AF catheter ablation. However, AF organization due to reduction of critical mass or focal trigger may also be the mechanism of AT recurrence. We sought to find out the main clinical factors of recurrence as AT rather than AF after AF ablation in the absence of antiarrhythmic drug effect. METHODS: We analyzed 521 patients (70.8% men, 64.1% paroxysmal AF) who experienced AT or AF recurrence without antiarrhythmic drug effect during 44.7 ± 25.4 months follow-up. RESULTS: Among 521 patients with recurrence, 42.0% (219 of 521) recurred with AT. The proportion of AT recurrence was not different between the pulmonary vein isolation only group and additional linear ablation group (45.1% vs. 38.1%, p = 0.128). The absence of hypertension (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.29-0.83, p = 0.007), small left atrial (LA) volume index (OR 0.89 per 10 mL/m2, 95% CI 0.79-1.00, p = 0.049), and high mean LA bipolar voltage (OR 2.03 per 1 mV, 95% CI 1.30-3.16, p = 0.002) were independently associated with AT recurrence, whereas additional linear ablation was not. Among 90 patients who underwent repeat ablation procedure, rates of PV reconnection (p = 0.358) and gap in prior linear ablations (p = 0.269) were not significantly different between AT recurrence group and AF recurrence group. CONCLUSION: The degree of LA remodeling is significantly associated with recurrence as AT after AF ablation, irrespective of potential ablation gap in linear lesion.

Controlled Atrial Fibrillation after Pulmonary Vein Stenting.

When there is no pulmonary vein reconnection after catheter ablation for atrial fibrillation, patients can experience recurrence of atrial fibrillation without clear evidence of non-pulmonary vein foci. We describe a patient with significant pulmonary vein stenosis and recurrent atrial fibrillation after four ablation procedures. After successful pulmonary vein stenting, the symptoms were resolved, and sinus rhythm was maintained for 2 years without treatment with antiarrhythmic medication. We believe pulmonary vein stenting potentially controlled atrial fibrillation by providing pulmonary vein pressure relief or by compressing the epicardial triggers occurring at the pulmonary vein ostium.

Comparison of the Antiplatelet Effects of Once and Twice Daily Low-Dose Ticagrelor and Clopidogrel After Percutaneous Coronary Intervention.

Although Asian people are believed to be more susceptible to bleeding on currently recommended dose of ticagrelor, there is limited evidence supporting low-dose ticagrelor. We prospectively randomized patients receiving dual antiplatelet therapy with aspirin and clopidogrel into 3 groups; aspirin plus clopidogrel 75 mg versus aspirin plus ticagrelor 90 mg once daily versus aspirin plus ticagrelor 45 mg twice daily. Platelet function assessments were conducted using VerifyNow P2Y12 assay at baseline and 28 days after randomization. No differences in baseline P2Y12 reaction unit (PRU) values were observed among the 3 groups. PRU values at the end of the treatment periods were significantly lower in low-dose ticagrelor (90 mg QD group, 98.6 ± 73.4 and 45 mg BID group, 65.5 ± 58.8) compared with clopidogrel (221.2 ± 50.1, both p <0.001). There was no significant difference in PRU values between 2 groups of low-dose ticagrelor (p = 0.208). The rates of high on-treatment platelet reactivity were significantly lower in low-dose ticagrelor compared with clopidogrel, whereas clopidogrel showed higher rate of optimal on-treatment platelet reactivity than ticagrelor 45 mg BID. However, similar rate of optimal on-treatment platelet reactivity was observed in clopidogrel and ticagrelor 90 mg QD. In conclusion, low-dose ticagrelor treatment, either with 90 mg QD or 45 mg BID, was associated with a more potent antiplatelet effect compared with clopidogrel treatment and once daily dose provided similar antiplatelet effect but favorable effect on optimal platelet inhibition compared with twice daily dose.

Long-Term Prognosis of Patients with an Implantable Cardioverter-Defibrillator in Korea.

PURPOSE: The objective of this study was to elucidate the long-term prognosis of patients with implantable cardioverter-defibrillators (ICDs) in Korea. MATERIALS AND METHODS: We enrolled 405 patients (age, 57.7±16.7 years; 311 men) who had undergone ICD implantation. The patients were divided into three groups: heart failure (HF) and ICD for primary (group 1, n=118) and secondary prevention (group 2, n=93) and non-HF (group 3, n=194). We compared appropriate and inappropriate ICD therapy delivery among the groups and between high- (heart rate ≥200 /min) and low-rate (<200 /min) ICD therapy zones. RESULTS: During the follow-up period (58.9±49.8 months), the annual appropriate ICD therapy rate was higher in group 2 (10.4%) than in groups 1 and 3 (6.1% and 5.9%, respectively, p<0.001). There were no significant differences in annual inappropriate ICD therapy rate among the three groups. In group 1, the annual appropriate ICD therapy rate was significantly lower in patients with a high-rate versus a low-rate therapy zone (4.5% and 9.6%, respectively, p=0.026). In group 3, the annual inappropriate ICD therapy rate was significantly lower in patients with a high-rate versus a low-rate therapy zone (3.1% and 4.0%, respectively, p=0.048). CONCLUSION: Appropriate ICD therapy rates are not low in Korean patients with ICD, relative to prior large-scale studies in Western countries. Appropriate and inappropriate ICD therapy could be reduced by a high-rate therapy zone in patients with HF and ICD for primary prevention, as well as non-HF patients, respectively.

Anticoagulation therapy in atrial fibrillation after intracranial hemorrhage.

BACKGROUND: The effect of oral anticoagulation therapy (OAT) in patients with atrial fibrillation (AF) with a history of intracranial hemorrhage (ICH) is poorly defined. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of OAT in patients with AF with an ICH history. METHODS: We retrospectively compared the composite end point, including thromboembolic and major bleeding events, between patients with AF with a history of ICH who were (OAT group, n = 254) and those who were not (no-OAT group, n = 174) taking OAT. RESULTS: During a mean follow-up of 39.5 ± 31.9 months, 5.5 and 3.1 major bleeding events/100 patient-years were observed in the OAT and no-OAT groups, respectively (P = .024). Recurrent ICH was observed only in patient with OAT. Thromboembolic events occurred in 2.4 and 8.3 events/100 patient-years in OAT and no-OAT groups, respectively (P < .001). There was no significant differences in composite end points between OAT and no-OAT groups (11.5 events/100 patient-years vs 7.9 events/100 patient-years; P = .154). Patients with OAT who achieved a time-in-therapeutic range of ≥60% of the international normalized ratio of 2.0-3.0 demonstrated a better cumulative survival free of the composite end point (P < .001) than did patients without OAT. Early (<2 weeks) OAT after an index ICH did not improve composite end points because of the increased incidence of major bleeding events. However, OAT at 2 weeks after an index ICH was associated with decreased clinical events including thromboembolic events and composite end point. CONCLUSION: In patients with AF who require anticoagulation and have a history of ICH, maintaining optimal OAT with time-in-therapeutic range ≥ 60% and the initiation of OAT at least 2 weeks after an index ICH were associated with improved clinical outcomes.

Meta-analysis of plaque composition by intravascular ultrasound and its relation to distal embolization after percutaneous coronary intervention.

Controversies exist regarding the association between plaque composition and distal embolization phenomenon after percutaneous coronary intervention (PCI). We evaluated the effect of plaque characteristics on embolization after PCI by grayscale and virtual histology-intravascular ultrasound (IVUS). We searched PubMed, Ovid MEDLINE, and Cochrane databases for IVUS studies evaluating the coronary plaque characteristics in no reflow, distal embolization, and periprocedural myocardial infarction after PCI. Sixteen studies were included, totaling 1,697 patients who underwent PCI (292 patients with embolization and 1,405 patients without embolization). At the minimum lumen sites, the external elastic membrane (weighted mean difference 2.38 mm(2), 95% confidence interval [CI] 1.02 to 3.74) and the plaque and media cross-sectional areas (weighted mean difference 2.44 mm(2), 95% CI 1.44 to 3.45) were significantly greater in the embolization group than in the no embolization group. Pooled analysis showed that the absolute necrotic core volume (standardized mean difference 0.49, 95% CI 0.13 to 0.85), absolute (standardized mean difference 0.73, 95% CI 0.14 to 1.31) and relative (standardized mean difference 1.02, 95% CI 0.72 to 1.31) necrotic core areas at the minimum lumen sites were significantly greater in the embolization group than in the no embolization group, but the other plaque components were similar in the 2 groups. In conclusion, the necrotic core component derived from virtual histology-IVUS and the morphologic characteristics of plaque derived from grayscale IVUS are closely related to the distal embolization phenomenon after PCI.