Correction of Ito in human induced pluripotent stem Cell-derived cardiomyocyte carrying DPP6 mutation in early repolarization syndrome by CRISPR/Cas9 genome editing.

Early repolarization syndrome (ERS) is defined as occurring in patients with early repolarization pattern who have survived idiopathic ventricular fibrillation with clinical evaluation unrevealing for other explanations. The pathophysiologic basis of the ERS is currently uncertain. The objective of the present study was to examine the electrophysiological mechanism of ERS utilizing induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing. Whole genome sequencing was used to identify the DPP6 (c.2561T > C/p.L854P) variant in four families with sudden cardiac arrest induced by ERS. Cardiomyocytes were generated from iPSCs from a 14-year-old boy in the four families with ERS and an unrelated healthy control subject. Patch clamp recordings revealed more significant prolongation of the action potential duration (APD) and increased transient outward potassium current (Ito) (103.97 ± 18.73 pA/pF vs 44.36 ± 16.54 pA/pF at +70 mV, P < 0.05) in ERS cardiomyocytes compared with control cardiomyocytes. Of note, the selective correction of the causal variant in iPSC-derived cardiomyocytes using CRISPR/Cas9 gene editing normalized the Ito, whereas prolongation of the APD remained unchanged. ERS cardiomyocytes carrying DPP6 mutation increased Ito and lengthen APD, which maybe lay the electrophysiological foundation of ERS.

Serum electrolyte concentrations and risk of atrial fibrillation: an observational and mendelian randomization study.

BACKGROUND: Atrial fibrillation (AF) is a prevalent arrhythmic condition resulting in increased stroke risk and is associated with high mortality. Electrolyte imbalance can increase the risk of AF, where the relationship between AF and serum electrolytes remains unclear. METHODS: A total of 15,792 individuals were included in the observational study, with incident AF ascertainment in the Atherosclerosis Risk in Communities (ARIC) study. The Cox regression models were applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) for AF based on different serum electrolyte levels. Mendelian randomization (MR) analyses were performed to examine the causal association. RESULTS: In observational study, after a median 19.7 years of follow-up, a total of 2551 developed AF. After full adjustment, participants with serum potassium below the 5th percentile had a higher risk of AF relative to participants in the middle quintile. Serum magnesium was also inversely associated with the risk of AF. An increased incidence of AF was identified in individuals with higher serum phosphate percentiles. Serum calcium levels were not related to AF risk. Moreover, MR analysis indicated that genetically predicted serum electrolyte levels were not causally associated with AF risk. The odds ratio for AF were 0.999 for potassium, 1.044 for magnesium, 0.728 for phosphate, and 0.979 for calcium, respectively. CONCLUSIONS: Serum electrolyte disorders such as hypokalemia, hypomagnesemia and hyperphosphatemia were associated with an increased risk of AF and may also serve to be prognostic factors. However, the present study did not support serum electrolytes as causal mediators for AF development.

Postextrasystolic repolarization changes of ventricular premature beats correlate with structural heart disease and suggest prognostic implications.

Ventricular premature beats (VPBs) can potentially lead to life-threatening arrhythmias, especially in patients with structural heart disease (SHD). However, identifying dangerous VPBs has always been a topic and challenge in clinical research. This study aimed to evaluate the relationship of postextrasystolic repolarization changes of VPBs with SHD and its possible additional prognostic value. 125 cases of frequent VPBs with SHD and 156 cases without SHD were included. VPBs were stratified selected from 24 h Holter recording according to the scale of heart rate. Average QTDV (difference value of QT interval between the first beat follow VPB with beats preceding VPB) and max QTDV were significantly longer in SHD group than that in the non-SHD group. For identifying patients with SHD, the best cutoff value were 19 ms for average QTDV (AUC = 0.931) and 29 ms for max QTDV (AUC = 0.910) respectively. For Tu morphology analysis, PT2 (postextrasystolic T wave amplitude change ≥2 mV), reversed T wave, and Pu (postextrasystolic u wave) change were all highly specific, but low sensitive as identification of SHD. Compared with average QTDV < 19 ms patients, average QTDV ≥ 19 ms patients had significantly larger left heart size and wores left cardiac function. The presence of non-persistent ventricular tachycardia runs was higher in average QTDV ≥ 19 ms group and positive Pu change group than that in control groups. The findings indicated that postextrasystolic repolarization changes of VPBs correlated with SHD and suggested potential value in prognosis asssessment.

[Application of Improved Unet Network in the Recognition and Segmentation of Hemorrhage Regions in Brain CT Images].

OBJECTIVE: To examine the performance and application value of improved Unet network technology in the recognition and segmentation of hemorrhage regions in brain CT images. METHODS: A total of 476 brain CT images of patients with spontaneous intracerebral hemorrhage (SICH) were retrospectively included. The improved Unet network was used to identify and segment the hemorrhage regions in the patients' brain CT images. The CT imaging data of the hemorrhage regions were manually labelled by clinicians. After randomized sorting, 430 data sets from 106 patients were selected for inclusion in the training set and 46 data sets from 11 patients were included in the test set. After data enhancement, the experimental data set underwent network training and model testing in order to assess the segmentation performance. The segmentation results were compared with the those of the Unet network (Base), FCN-8s network and Unet++ network. RESULTS: In the segmentation of brain CT image hemorrhage region with the improved Unet network, the three evaluation indicators of Dice similarity coefficient, positive predictive value (PPV), and sensitivity coefficient (SC) reached 0.8738, 0.9011 and 0.8648, respectively, increasing by 8.80%, 7.14% and 8.96%, respectively, compared with those of FCN-8s, and increasing by 4.56%, 4.44% and 4.15%, respectively, compared with those of Unet network (Base). The improved Unet network also showed better segmentation performance than that of Unet++ network. CONCLUSION: The improved method based on Unet network proposed in this report displayed good performance in the recognition and segmentation of hemorrhage regions in brain CT images, and is an appropriate method for the recognition and segmentation of hemorrhage regions in brain CT images, showing potential application value for assisting clinical decision-making and preventing early hematoma expansion.

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.

Early repolarization pattern associated with coronary artery disease and increased the risk of cardiac death in acute myocardium infarction.

BACKGROUND: Early repolarization pattern (ERP) was associated with sudden cardiac death in recent studies. However, the associations between ERP and coronary artery disease (CAD), and ERP and cardiac death caused by acute myocardial infarction (MI) remains unclear. METHODS: We retrospectively enrolled consecutive 1,545 CAD patients and 908 non-CAD subjects as control group which were confirmed by coronary angiograph. The CAD patients include stable CAD, acute MI patients, and old MI patients. Multivariate logistic regression was employed to evaluate the relationship between ERP and CAD, and ERP and cardiac death caused by acute MI. RESULTS: Of the 1,545 CAD subjects, there were 1,029 stable CAD patients, 404 acute MI patients, and 112 old MI patients. The incidence of ERP was much higher among patients with CAD than without CAD subjects (20.1% vs. 6.2%, p < .001) after adjusting for major cardiovascular risk factors. No significant correlation was observed between lead region of ERP on 12-lead ECG and single abnormal artery. Of the 404 acute MI patients, 342 patients survived and 62 patients died. Incidence of ERP was higher in non-survivor than survivor patients with acute MI (24.2% vs. 17.5%, p = .006) after adjustment for major cardiovascular risk factors. CONCLUSION: The incidence of ERP was higher in CAD patients than subjects without CAD and in non-survivor patients than survivor patients with acute MI. The lead region of ERP on 12-lead ECG was not associated with single abnormal coronary artery.

Mutation in KCNE1 associated to early repolarization syndrome by modulation of slowly activating delayed rectifier K+ current.

BACKGROUND: Recent studies have revealed that mutation in KCNE1, ß-subunits of cardiac potassium channel, involved in ventricular fibrillation. Whereas its role in early repolarization syndrome (ERS) is less well understood. OBJECTIVE: To study whether mutant in KCNE1 is associated with ERS and explore the possible underlying molecular mechanisms. METHODS: Whole genome from four unrelated families with ERS was amplified and sequenced. Wild-type (WT) KCNE1 and/or KCNE1-S38G (S38G) were expressed in HEK293 cells with KCNQ1. Functional studies included whole-cell patch-clamp, western blot and immunofluorescence were performed to reveal the possible underlying mechanisms. RESULTS: The co-expression of KCNE1-S38G and KCNQ1 decreased tail current density of IKs but had little effect in modulation channel kinetics of IKs. Compared with KCNE1-WT, the expression and membrane location of KCNE1-S38G decreased. Co-expression of KCNE1-WT and KCNE1-S38G partially rescued the function of IKs channel. CONCLUSIONS: The S38G mutation induced a loss-of-function of IKs due to decreasing of KCNE1 protein expression and defecting in KCNE1 protein membrane trafficking. Our findings suggested that KCNE1 may be one of the possible modulatory genes associated to 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.

A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome.

BACKGROUND/AIMS: Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic background of ERS has not been fully understood. METHODS: A Chinese family with sudden cardiac death associated with ERS was investigated. Direct sequencing of ERS susceptibility genes was performed on the proband and family members. Whole-cell patch-clamp methods were used to characterize the mutant channel expressed in HEK 293 cells. RESULTS: One missense mutation (p. K801T) was found in the hERG (KCNH2 gene) by the direct sequencing of candidate genes. Whole cell voltage clamp studies of the K801T mutation in HEK 293 cells demonstrated a 1.5-fold increase in maximum steady state current (37.2±7.3 vs 20.3±4.4 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -59.5±1.4 vs K801T -44.3±1.2 mV). Kinetic analysis revealed slower inactivation rates of K801T, but faster rates of activation and deactivation. The hERG channel blockers tested inhibited K801T-hERG channel in concentration response, and the potencies of these drugs can be rank-ordered as follows: quinidine> disopyramide> sotalol> flecainide. CONCLUSION: Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T-hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation.

The Role of Holter Monitoring in the Diagnosis of Early Repolarisation Pattern.

BACKGROUND: A slower heart rate can exaggerate J-point elevation in a 12-lead ECG. This study examined the role of Holter monitoring in the diagnosis of early repolarisation pattern (ERP). METHODS: We examined 24-hour Holter recordings of 4000 consecutive patients seen at an outpatient clinic, and found 500 patients (12.5%) with ERP (based on J-point elevation magnitude maximum value≥0.1mV on the Holter recording). The highest magnitude of J-point elevation, R wave amplitude, the ratio between J-point elevation magnitude and R-wave amplitude on the same ECG lead (J/R ratio), QRS interval, and QT/QTc interval were measured on the Holter recording and on a surface 12-lead ECG of the 500 patients with ERP. The magnitude of J-point elevation, J/R ratio, and QT/QTc interval were compared between three groups: nighttime Holter recording, daytime Holter recording, and daytime surface 12-lead ECG. RESULTS: The magnitude of J-point elevation of the nighttime Holter (0.20±0.10mV) was higher than that of the daytime in Holter (0.12±0.07mV, p<0.001) and the 12-lead ECG (0.12±0.06mV, p<0.001). There was no statistical difference in magnitude of J-point elevation between daytime Holter and surface 12-lead ECG. While all 500 patients were diagnosed with ERP based on J-point elevation maximum value J-point on Holter monitoring, only 425 (85%) patients could be diagnosed with ERP based on the surface 12-lead ECG. The J-point elevation maximum value on the nighttime Holter was negatively correlated with heart rate (r=-0.15, p=0.0007) and QTc (r=-0.13, p=0.0043), and positively correlated with R wave amplitude (r=0.46, p<0.0001), J/R ratio (r=0.69, p<0.0001), and QRS interval (r=0.29, p<0.0001). CONCLUSIONS: The J-point elevation on nighttime Holter recording was higher than that on daytime Holter and daytime surface 12-lead ECG, and there was misdiagnosis of ERP based on daytime surface 12-lead ECG. Holter monitoring has a complementary role in the diagnosis of ERP, especially in patients with a suspected diagnosis of ERP based on daytime surface 12-lead ECG.

Administration of macrolide antibiotics increases cardiovascular risk.

Background: The increased risk of cardiovascular events in patients prescribed macrolides has been subject to debate for decades. Methods: Medline, EMBASE databases and ClinicalTrials.gov were searched from inception until August 31, 2022 for studies investigating the link between macrolides and cardiovascular risk. A meta-analysis was performed using a random-effects model. Results: A total of 80 studies involving 39,374,874 patients were included. No association was found between macrolides and all-cause death. However, compared with the non-macrolide group, macrolides were associated with a significantly increased risk of ventricular arrhythmia or sudden cardiac death (VA or SCD) (azithromycin, relative ratio [RR]: 1.53; 95% confidence interval [CI]: 1.19 to 1.97; clarithromycin, RR: 1.52; 95% CI: 1.07 to 2.16). Besides, administration of macrolides was associated with a higher risk of cardiovascular disease (CVD) death (azithromycin, RR: 1.63; 95% CI: 1.17 to 2.27) and a slightly increased risk of myocardial infarction (MI) (azithromycin, RR: 1.08; 95% CI: 1.02 to 1.15). Interestingly, no association was observed between roxithromycin and adverse cardiac outcomes. Increased risk of VA or SCD was observed for recent or current use of macrolides, MI for former use, and CVD death for current use. Conclusion: Administration of macrolide antibiotics and timing of macrolide use are associated with increased risk for SCD or VTA and cardiovascular death, but not all-cause death.

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.

Autonomic Influences Related to Early Repolarization in Patients Without Structural Heart Disease.

This cross-sectional study focused on the association between heart rate variability (HRV) and early repolarization pattern (ERP). It included 1236 patients categorized into three groups: ERP type 1: J-point elevation with notched/slurred QRS; ERP type 2: ST elevation without dominant J-wave; and non-ERP group. Analyzing time-domain indexes include standard deviation of NN (normal-to-normal) RR intervals (SDNN), root mean square of successive difference in NN RR intervals (RMSSD), and proportion of consecutive NN intervals that differ by more than 50 ms (PNN50), there were significant differences between any two groups (all P < 0.01). All time-domain indexes showed: ERP type 2 > ERP type 1 > non-ERP. Multivariate logistic regression analysis revealed that SDNN at nighttime and gender were independently associated with the maximum magnitude of J-point elevation ≧ 0.2 mV. The findings strongly suggested that based on electrocardiogram characteristics, parasympathetic tone denoted by HRV may be related to different types of ERP.

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.

Long-Term Cardiovascular Risk After Radiotherapy in Women With Breast Cancer.

BACKGROUND: Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of heart disease is uncertain. We performed a meta-analysis to investigate the link between radiotherapy and long-term cardiovascular morbidity and mortality in patients with breast cancer. METHODS AND RESULTS: We performed a literature search using MEDLINE (January 1966 to January 2015) and EMBASE (January 1980 to January 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95%CIs for the associations of interest were included. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-nine studies involving 1 191 371 participants were identified. Patients who received left-sided radiotherapy, as compared with those receiving right-sided radiotherapy, experienced increased risks of developing coronary heart disease (RR 1.29, 95%CI 1.13-1.48), cardiac death (RR 1.22, 95%CI 1.08-1.37) and death from any cause (RR 1.05, 95%CI 1.01-1.10). In a comparison of patients with radiotherapy and without radiotherapy, the RRs were 1.30 (95%CI 1.13-1.49) for coronary heart disease and 1.38 (95%CI 1.18-1.62) for cardiac mortality. Radiotherapy for breast cancer was associated with an absolute risk increase of 76.4 (95%CI 36.8-130.5) cases of coronary heart disease and 125.5 (95%CI 98.8-157.9) cases of cardiac death per 100 000 person-years. The risk started to increase within the first decade for coronary heart disease and from the second decade for cardiac mortality. CONCLUSIONS: Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent risk of coronary heart disease and cardiac mortality.

Long-term prognosis associated with early repolarisation pattern in Chinese population with atherosclerotic risk factors.

BACKGROUND: Recent evidence has linked early repolarisation pattern (ERP) to sudden cardiac death (SCD) in patients without structural heart disease. However, no studies have clarified the prognostic value of ERP in people at high risk for atherosclerotic heart disease. METHODS: We prospectively assessed the prognostic significance of ERP on ECGs in a community-based population of 18 231 subjects with atherosclerotic risk factors (49.3% men, mean age 64.0 years). Mean follow-up was 7.6 years. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. RESULTS: Compared with those without ERP, subjects with ERP had a significantly increased risk of developing SCD (HR 1.91, 95% CI 1.30 to 2.82), death from coronary heart disease (CHD) (HR 1.80, 95% CI 1.45 to 2.22) and death from any cause (HR 1.35, 95% CI 1.22 to 1.50). ERP was not associated with an increased risk of non-sudden CHD death and non-CHD death. ERP with J wave pattern in inferior leads, high amplitude of J wave pattern, notching configuration and horizontal or descending ST segment indicated a higher risk for SCD. ERP was associated with an absolute risk increase of 52.3 additional SCDs per 100 000 person-years in the population at high risk for atherosclerotic heart disease. CONCLUSIONS: ERP is associated with a significantly increased risk for SCD, CHD death and death from any cause in people with atherosclerotic risk factors. The observed association between ERP and all-cause mortality appears to be driven by an association with CHD death, in particular SCD.

Early repolarization is associated with a significantly increased risk of ventricular arrhythmias and sudden cardiac death in patients with structural heart diseases.

BACKGROUND: Early repolarization pattern (ERP) has been proved to increase risk of arrhythmia death in the general population, but its prognostic significance in patients with structural heart disease (SHD) is controversial. OBJECTIVE: The purpose of this study was to conduct a meta-analysis of studies assessing the association between ERP and risk of ventricular arrhythmias (VTAs) and sudden cardiac death (SCD) in patients with SHD. METHODS: We performed a literature search using MEDLINE (January 1, 1966, to September 25, 2016) and EMBASE (January 1, 1980, to September 25, 2016) with no restrictions. Studies that reported odds ratio (OR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. RESULTS: The search yielded 19 observational studies, involving 7268 patients that reported 1127 cases of VTAs or SCD. In the selected studies, the point estimates of the ORs were consistently greater than 1. Compared with those without ERP, patients with ERP experienced a significantly increased risk of developing VTAs or SCD (OR 4.76; 95% CI 3.62-6.26), ventricular fibrillation (OR 7.14; 95% CI 4.31-11.82), and SCD (OR 4.07; 95% CI 1.58-10.51). The results were consistent and statistically significant in all subgroups. ERP with J-point elevation in inferior leads, notching configuration, and horizontal or descending ST segment connote higher risk. CONCLUSION: ERP is associated with a significant increased risk of VTAs or SCD in patients with SHD. Future research should attempt to understand the exact mechanisms for the arrhythmia risk and to introduce ERP in the risk stratification in this patient group.

Role of Early Repolarization Pattern in Increasing Risk of Death.

BACKGROUND: An early repolarization pattern (ERP) has been hypothesized to be arrhythmogenic in experimental studies, but the prognostic significance of the ERP in the general population is controversial. We performed a meta-analysis to examine the link between ERP and the risk of sudden cardiac arrest (SCA), cardiac death, and death from any cause. METHODS AND RESULTS: We performed a literature search using MEDLINE (January 1, 1966 to July 31, 2015) and EMBASE (January 1, 1980 to July 31, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. Sixteen studies involving 334 524 subjects were identified. Compared with those without ERP, subjects with ERP experienced significantly increased risk for developing SCA (RR 2.18; 95% CI 1.29-3.68), cardiac death (RR 1.48; 95% CI 1.06-2.07), and death from any cause (RR 1.21; 95% CI 1.02-1.42), respectively. The increased risk was present predominantly in Asians and whites but not in African Americans. ERP with J-point elevation in inferior leads, notching configuration, and horizontal or descending ST segment connote higher risk. ERP was associated with an absolute risk increase of 139.6 (95% CI 130.3-149.3) additional SCAs per 100 000 person-years and responsible for 7.3% (95% CI 1.9-15.2) of SCA in the general population. CONCLUSIONS: ERP is associated with significant increased risk for SCA, cardiac death, and death from any cause. Future studies should focus on understanding the exact mechanisms for the arrhythmia risk and developing reliable tools for risk stratification.

The Role of the Ratio of J-Point Elevation Magnitude and R-Wave Amplitude on the Same ECG Lead in the Risk Stratification of Subjects With Early Repolarization Pattern.

BACKGROUND: Just as high-risk populations for cardiac arrest exist in patients with Brugada syndrome or long QT syndrome, high-risk and low-risk populations for cardiac arrest also exist in patients with early repolarization pattern (ERP). HYPOTHESIS: Electrocardiographic (ECG) characteristics can aid the risk stratification of patients with ERP. METHODS: Electrocardiographic parameters such as magnitude of J-point elevation and J/R ratio were measured. The magnitude of J-point elevation, leads with J points elevated, J/R ratio, morphology of the ST segment, and QT/QTc interval were used in comparative analysis in 2 groups: 57 patients with ERP and cardiac arrest (cardiac arrest group) and 100 patients with ERP but without cardiac arrest (control group). RESULTS: There was no statistical difference in clinical characteristics of the 2 groups. The J/R ratio in the cardiac arrest group was significantly higher than in the control group (26.8% ± 18.1% vs 16.3% ± 10.3%, respectively; P < 0.001) and the proportion of horizontal/descending ST segments (70.2%) was significantly higher than in the control group (29.0%), but the proportion of ascending/upsloping ST segments (29.8%) was significantly lower than in the control group (71.0%; P < 0.001). Multivariate logistic regression revealed that higher J/R ratio and horizontal/descending ST segment were independently associated with increased risk of cardiac arrest in patients with ERP. CONCLUSIONS: In patients with ERP and cardiac arrest, J/R ratios were relatively higher and mostly with horizontal/descending ST segments, suggesting that J/R ratio and ST-segment morphology may be used as indicators for risk stratification in patients with ERP.