A novel DPP6 variant in Chinese families causes early repolarization syndrome.

Previous studies demonstrated that variants in dipeptidyl aminopeptidase-like protein-6 (DPP6) are involved in idiopathic ventricular fibrillation. However, its role in early repolarization syndrome (ERS) remains largely elusive. The aim of this study is to determine whether the novel DPP6-L747P variant is associated with ERS, and explore the underlying mechanisms. In our study, whole genome sequencing was used to identify a genetic variant in 4 Chinese families with sudden cardiac arrest induced by ERS. Then, wild-type (WT) DPP6 or mutant (c.2240T > C/p.L747P) DPP6 were respectively expressed in HEK293 cells, co-expressed with KV4.3 and KChIP2. Western blotting, immunofluorescence, and whole-cell patch clamp experiments were performed to reveal possible underlying mechanisms. A novel missense variant (c.2240T > C/p.L747P) in DPP6 was identified in the 4 families. Both DPP6-WT and DPP6-L747P were mainly located on the cell membrane. Compared with DPP6-WT, the intensity of DPP6 protein bands was downregulated in DPP6-L747P. Functional experiments showed that macroscopic currents exhibited an increase in DPP6-L747P, and the current intensity of DPP6-L747P was increased more than that of DPP6-WT (63.1 ± 8.2 pA/pF vs.86.5 ± 15.1 pA/pF at +50 mV, P < 0.05). Compared with DPP6-WT, the slope of the activation curve of DPP6-L747P was slightly decreased (15.49 ±â€¯0.56 mV vs. 13.88 ±â€¯0.54 mV, P < 0.05), the slope of the inactivation curve was increased (13.65 ±â€¯1.57 mV, vs. 24.44 ±â€¯2.79 mV, P < 0.05) and the recovery time constant was significantly reduced (216.81 ±â€¯18.59 ms vs. 102.11 ±â€¯32.03 ms, P < 0.05). In conclusion, we identified a novel missense variant (c.2240T > C/p. L747P) in DPP6 in 4 Chinese families with sudden cardiac arrest induced by ERS. Patch clamp experiments revealed that this variant could generate a gain of function of Ito and affect the potassium current. These results demonstrated that changes caused by the variant may be the underlying mechanisms of malignant arrhythmias in the individuals with ERS.

SCN1Bß mutations that affect their association with Kv4.3 underlie early repolarization syndrome.

BACKGROUND: Abnormal cardiac ion channels current, including transient outward potassium current (Ito ), is associated with early repolarization syndrome (ERS). Previous studies showed that mutations in SCN1Bß both to increase the Ito current and to decrease the sodium current. Yet its role in ERS remains unknown. OBJECTIVE: To determine the role of mutations in the SCN1Bß subunits in ERS. METHODS: We screened for mutations in the SCN1B genes from four families with ERS. Wild-type and mutant SCN1Bß genes were co-expressed with wild-type KCND3 in human embryonic kidney cells (HEK293). Whole-cell patch-clamp technique and co-immunoprecipitation were used to study the electrophysiological properties and explore the underlying mechanisms. RESULTS: S248R and R250T mutations in SCN1Bß were detected in 4 families' probands. Neither S248R nor R250T mutation had significant influence on the sodium channel current density (INa ) when co-expressed with SCN5A/WT. Co-expression of KCND3/WT and SCN1Bß/S248R or SCN1Bß/R250T increased the transient outward potassium current Ito by 27.44% and 199.89%, respectively (P < 0.05 and P < 0.01, respectively) when compared with SCN1Bß/WT. Electrophysiological properties showed that S248R and R250T mutations decreased the steady-state inactivation and recovery from inactivation of Ito channel. Co-immunoprecipitation study demonstrated an increased association between SCN1Bß mutations and Kv4.3 compared with SCN1Bß/WT (P < 0.05 and P < 0.01, respectively). CONCLUSION: The S248R and R250T mutations of SCN1Bß gene caused gain-of-function of Ito by associated with Kv4.3, which maybe underlie the ERS phenotype of the probands.

Long-Term Outcomes and Improvements in Quality of Life in Patients with Atrial Fibrillation Treated with Catheter Ablation vs. Antiarrhythmic Drugs.

BACKGROUND: Catheter ablation (CA) is a recognized first-line treatment for atrial fibrillation (AF) in selected patients; however, the differences between CA and antiarrhythmic drugs (AADs) in terms of long-term outcomes and quality of life (QoL) have not often been compared. OBJECTIVES: We performed a meta-analysis of randomized controlled trials (RCTs) to compare long-term outcomes and QoL with CA and AADs in the treatment of AF. METHODS: We searched the MEDLINE database for English-language RCTs of CA or AADs in AF from 1 January 2005 to 30 October 2019 with no other restrictions. We included studies that reported sample sizes and the long-term outcomes of interest as well as sample size, mean ± standard deviation or 95% confidence intervals (CIs) for QoL outcomes with CA and AADs. RESULTS: We identified 20 RCTs involving 5425 participants. Compared with patients who received only AADs, patients receiving CA had a significantly decreased risk of all-cause death (relative risk [RR] 0.72; 95% CI 0.58-0.90) and cardiovascular hospitalization (RR 0.85; 95% CI 0.79-0.91). We found a significant increase in the risk of cardiac tamponade (RR 5.86; 95% CI 1.77-19.44) but no difference in the risk of heart failure, stroke or transient ischemic attack, atrial tachycardia, bleeding or hematoma, and pulmonary vein stenosis. For long-term QoL after treatment, both therapies resulted in improved scores on the Medical Outcomes Study 36-Item Short Form Survey (SF-36): weighted mean differences (WMDs) for the physical component score (PCS) were 5.89 for CA and 4.26 for AADs and for the mental component score (MCS) were 7.12 for CA and 5.06 for AADs. At the end of follow-up, groups receiving CA had significantly higher scores in both areas. The change in PCS and MCS between baseline and end of follow-up was also significantly higher in the CA groups: WMD 1.51 for change in PCS and 1.49 for change in MCS. All eight SF-36 subscale scores improved for patients receiving CA, whereas patients receiving AADs recorded no improvement in the general health and bodily pain subscales. At the end of follow-up, CA groups had significantly higher scores than AAD groups in the following subscales: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, and role limitations due to emotional problems. CONCLUSIONS: In the treatment of AF, CA appeared to be superior to AADs, decreasing the risk of all-cause death and cardiovascular hospitalization and improving the long-term QoL of patients with AF. CA was better tolerated and more effective than pharmacological therapy and allowed for improved QoL.

A novel mutation in GPD1­L associated with early repolarization syndrome via modulation of cardiomyocyte fast sodium currents.

Early repolarization syndrome (ERS) is associated with genetic mutations, but the role of the glycerol­3­phosphate dehydrogenase 1­like (GPD1­L) mutation remains unclear. The aim of the present study was to investigate the role and potential underlying mechanism of GPD1­L mutation P112L in the pathogenesis of ERS. Whole­genome sequencing was performed on samples from a family with ERS, and the gene sequencing results were analyzed using bioinformatics. 293 cells were transfected with wild­type (WT) or mutant­type (MT) GPD1­L and SCN5A plasmids. Successful transfection of GPD1­L in 293 cells was verified by western blotting. Whole­cell patch­clamp recording, confocal microscopic observation and western blotting were used to uncover the potential mechanism of GPD1­L P112L in ERS. The results of western blotting indicated that the expression of the GPD1­L protein was lower in the MT group compared with that in the WT group, but the mock group did not express the GPD1­L protein. The whole­cell patch­clamp recording results indicated that the activation current density of INa (at ­30 mV) was ~60% lower in the MT group compared with the WT group (P<0.01). The mutation caused the inactivation voltage to move in a negative direction by ~3 mV compared with that of the WT group. However, there were no significant between­group differences in the steady activation, steady inactivation, and steady recovery of INa. Confocal microscopy demonstrated that MT GPD1­L was less expressed near the cell membrane and more expressed in the cytoplasm compared with WT GPD1­L. Both WT and MT GPD1­L were highly expressed in the cytoplasm and in small amounts in the nucleus. In conclusion, the GPD1­L P112L mutation decreased INa activation and GPD1­L cell expression, including in the region near the cell membrane. These results suggest that GPD1­L P112L may be a pathogenic genetic mutation associated with ERS.

Interleukin-1 blockade treatment decreasing cardiovascular risk.

BACKGROUND: Interleukin-1 (IL-1) played a role in the occurrence and development of atherosclerosis and cardiovascular events. However, the association between IL-1 blockage treatment and reducing of cardiovascular risk remains poorly defined. HYPOTHESIS: IL-1 blockage treatment reduce the risk and incidence rate of overall major adverse cardiovascular events (MACE), all-cause death, acute myocardial infarction(MI), unstable angina and heart failure. METHODS: We performed a search of published reports by using MEDLINE database (January 1, 2005 to April 1, 2018). The randomized controlled trials (RCTs) that reported sample size and occurrence numbers in test group and placebo group for the associations of interest were included. RESULTS: Eight RCT studies involving 15 647 participants were identified. Compared with those who took no IL-1 blockage, patients taking IL-1 blockage experienced a decreased risk of overall MACE (RR 0.88, 95% CI 0.82-0.94), unstable angina (RR 0.80, 95% CI 0.66-0.98), and breakthrough or recurrence of heart failure (RR 0.44, 95% CI 0.22-0.87). No association was found between IL-1 blockage treatment and death from all cause (RR 0.91, 95% CI 0.83-1.00) as well as acute MI (RR 0.85, 95% CI 0.71-1.01). The RRs associated with overall MACE, death from all cause, acute MI, and unstable angina for anakinra were 1.05, 1.16, 2.97, and 0.56, respectively, and for canakinumab were 1.05, 0.91, 0.80, and 0.80, respectively. CONCLUSIONS: Administration of IL-1 blockage was associated with decrease risks of overall MACE, unstable angina, and breakthrough or recurrence of heart failure, but not with death from all cause as well as acute MI.