RESUMEN
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.
Asunto(s)
Fibrilación Atrial , Humanos , Fibrilación Atrial/epidemiología , Fibrilación Atrial/genética , Factores de Riesgo , Magnesio , Análisis de la Aleatorización Mendeliana , Calcio , Potasio , Fosfatos , Electrólitos , Estudio de Asociación del Genoma Completo/métodosRESUMEN
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.
RESUMEN
OBJECTIVE: To examine the association of systolic blood pressure (SBP) and cardiovascular risk in normotensive adults. PATIENTS AND METHODS: This study analyzed data from 7 prospective cohorts between September 29, 1948, and December 31, 2018. Complete information on history of hypertension and baseline blood pressure measurements were required for inclusion. We excluded individuals younger than 18 years old, those with a history of hypertension, and patients with baseline SBP measurements of less than 90 mm Hg or 140 mm Hg or higher. Cox proportional hazards regression and restricted cubic spline models were used to evaluate the hazards of cardiovascular outcomes. RESULTS: A total of 31,033 participants were included. The mean ± SD age was 45.3±14.8 years, 16,693 of the participants (53.8%) were female, and the mean ± SD SBP was 115.8±11.7. Over a median follow-up of 23.5 years, 7005 cardiovascular events occurred. Compared with those who had SBP levels of 90 to 99 mm Hg, participants with SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg experienced 23% (hazard ratio [HR], 1.23; 95% CI, 1.07 to 1.42), 53% (HR, 1.53; 95% CI, 1.33 to 1.76), 87% (HR, 1.87; 95% CI, 1.62 to 2.16), and 117% (HR, 2.17; 95% CI, 1.87 to 2.52) increased risks of cardiovascular events, respectively. Compared with follow-up SBP of 90 to 99 mm Hg, the HRs for cardiovascular events were 1.25 (95% CI, 1.02 to 1.54), 1.93 (95% CI, 1.58 to 2.34), 2.55 (95% CI, 2.09 to 3.10), and 3.39 (95% CI, 2.78 to 4.14), respectively, for follow-up SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg. CONCLUSION: In adults without hypertension, there is a stepwise increase in risk of cardiovascular events, with increasing SBP starting at levels as low as 90 mm Hg.
Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Humanos , Adulto , Femenino , Persona de Mediana Edad , Adolescente , Masculino , Presión Sanguínea , Estudios Prospectivos , Factores de Riesgo , Factores de Riesgo de Enfermedad CardiacaRESUMEN
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.
RESUMEN
The electro-cautery lumen apposing metal stent (EC-LAMS) is a newly developed device that integrates the electro-cautery cyctotome with the one-step metal stent delivery and releasing system in recent years. LAMS was first designed to complete the drainage of pancreatic fluid collection under endoscopic ultrasound guidance, and the technological innovation of EC-LAMS has made more off-labeled indications of endoscopic intervention for gastrointestinal diseases realized, such as abdominal fluid drainage, bile duct, or gallbladder drainage through stomach or duodenum, gastrointestinal anastomosis, and the establishment of fistulous channel for further endoscopic operation when necessary. The unique feature of this metal stent is that it has the design of a saddle shape and a large lumen, and can almost connect the adjacent structures to minimize the risk of perforation and leakage. Compared with traditional LAMS, EC-LAMS, an advanced integrated device, can greatly simplify the endoscopic process, shorten the procedure time and reduce the technical difficulty, thus it can help endoscopists complete more complex endoscopic interventions. In this review, we discuss the state of art with regard to EC-LAMS and its endoscopic process, current indications, outcomes, adverse events, and future application prospects.
RESUMEN
BACKGROUND: Growing evidence suggests that compromised lung health may be linked to cardiovascular disease. However, little is known about its association with sudden cardiac death (SCD). OBJECTIVES: We aimed to assess the link between impaired lung function, airflow obstruction and risk of SCD by race and gender in four US communities. METHODS: A total of 14 708 Atherosclerosis Risk in Communities (ARIC) study participants who underwent spirometry and were asked about lung health (1987-1989) were followed. The main outcome was physician-adjudicated SCD. Fine-Gray proportional subdistribution hazard models with Firth's penalised partial likelihood correction were used to estimate the HRs. RESULTS: Over a median follow-up of 25.4 years, 706 (4.8%) subjects experienced SCD. The incidence of SCD was inversely associated with FEV1 in each of the four race and gender groups and across all smoking status categories. After adjusting for multiple measured confounders, HRs of SCD comparing the lowest with the highest quintile of FEV1 were 2.62 (95% CI 1.62 to 4.26) for white males, 1.80 (95% CI 1.03 to 3.15) for white females, 2.07 (95% CI 1.05 to 4.11) for black males and 2.62 (95% CI 1.21 to 5.65) for black females. The above associations were consistently observed among the never smokers. Moderate to very severe airflow obstruction was associated with increased risk of SCD. Addition of FEV1 significantly improved the predictive power for SCD. CONCLUSIONS: Impaired lung function and airflow obstruction were associated with increased risk of SCD in general population. Additional research to elucidate the underlying mechanisms is warranted.
Asunto(s)
Enfermedades Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Femenino , Humanos , Pulmón , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
Despite improvements in cardiovascular disease (CVD) outcomes by cholesterol-lowering statin therapy, the high rate of CVD is still a great concern worldwide. Dehydrocorydaline (DHC) is an alkaloidal compound isolated from the traditional Chinese herb Corydalis yanhusuo. Emerging evidence shows that DHC has anti-inflammatory and antithrombotic benefits, but whether DHC exerts any antiatherosclerotic effects remains unclear. Our study revealed that intraperitoneal (i.p.) injection of DHC in apolipoprotein E-deficient (ApoE-/-) mice not only inhibited atherosclerosis development but also improved aortic compliance and increased plaque stability. In addition, DHC attenuated systemic and vascular inflammation in ApoE-/- mice. As macrophage inflammation plays an essential role in the pathogenesis of atherosclerosis, we next examined the direct effects of DHC on bone marrow-derived macrophages (BMDMs) in vitro. Our RNA-seq data revealed that DHC dramatically decreased the levels of proinflammatory gene clusters. We verified that DHC significantly downregulated proinflammatory interleukin (IL)-1ß and IL-18 mRNA levels in a time- and concentration-dependent manner. Furthermore, DHC decreased lipopolysaccharide (LPS)-induced inflammation in BMDMs, as evidenced by the reduced protein levels of CD80, iNOS, NLRP3, IL-1ß, and IL-18. Importantly, DHC attenuated LPS-induced activation of p65 and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Thus, we conclude that DHC ameliorates atherosclerosis in ApoE-/- mice by inhibiting inflammation, likely by targeting macrophage p65- and ERK1/2-mediated pathways.
Asunto(s)
Aterosclerosis , Interleucina-18 , Alcaloides , Animales , Apolipoproteínas E , Aterosclerosis/metabolismo , Inflamación/metabolismo , Interleucina-18/metabolismo , Lipopolisacáridos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Our understanding of the weight-outcome association mainly comes from single-time body mass index (BMI) measurement. However, data on long-term trajectories of within-person changes in BMI on diverse study outcomes are sparse. Therefore, this study is to determine the associations of individual BMI trajectories and cardiovascular outcomes. METHODS: The present analysis was based on data from 4 large prospective cohorts and restricted to participants aged ≥45 years with at least two BMI measurements. Hazard ratios (HR) and 95% confidence intervals(95%CI) for each outcome according to different BMI trajectories were calculated in Cox regression models. FINDINGS: The final sample comprised 29,311 individuals (mean age 58.31 years, and 77.31% were white), with a median 4 BMI measurements used in this study. During a median follow-up of 21.16 years, there were a total of 10,192 major adverse cardiovascular events (MACE) and 11,589 deaths. A U-shaped relation was seen with all study outcomes. Compared with maintaining stable weight, the multivariate adjusted HR for MACE were 1.53 (95%CI 1.40-1.66), 1.26 (95%CI 1.16-1.37) and 1.08 (95%CI 1.02-1.15) respectively for rapid, moderate and slow weight loss; 1.01 (95%CI 0.95-1.07), 1.13 (95%CI 1.05-1.21) and 1.29 (95%CI 1.20-1.40) respectively for slow, moderate and rapid weight gain. Identical patterns of association were observed for all other outcomes. The development of BMI differed markedly between the outcome-free individuals and those who went on to experience adverse events, generally beginning to diverge 10 years before the occurrence of the events. INTERPRETATION: Our findings may signal an underlying high-risk population and inspire future studies on weight management. FUNDING: National Natural Science Foundation of China, Guangdong Natural Science Foundation.
RESUMEN
Background Although silent myocardial infarction (SMI) is prognostically important, the risk of sudden cardiac death (SCD) among patients with incident SMI is not well established. Methods and Results We examined 2 community-based cohorts: the ARIC (Atherosclerosis Risk in Communities) study (n=13 725) and the CHS (Cardiovascular Health Study) (n=5207). Incident SMI was defined as electrocardiographic evidence of new myocardial infarction during follow-up visits that was not present at the baseline. The primary study end point was physician-adjudicated SCD. In the ARIC study, 513 SMIs, 441 clinically recognized myocardial infarctions (CMIs), and 527 SCD events occurred during a median follow-up of 25.4 years. The multivariable hazard ratios of SMI and CMI for SCD were 5.20 (95% CI, 3.81-7.10) and 3.80 (95% CI, 2.76-5.23), respectively. In the CHS, 1070 SMIs, 632 CMIs, and 526 SCD events occurred during a median follow-up of 12.1 years. The multivariable hazard ratios of SMI and CMI for SCD were 1.70 (95% CI, 1.32-2.19) and 4.08 (95% CI, 3.29-5.06), respectively. The pooled hazard ratios of SMI and CMI for SCD were 2.65 (2.18-3.23) and 3.99 (3.34-4.77), respectively. The risk of SCD associated with SMI is stronger with White individuals, men, and younger age. The population-attributable fraction of SCD was 11.1% for SMI, and SMI was associated with an absolute risk increase of 8.9 SCDs per 1000 person-years. Addition of SMI significantly improved the predictive power for both SCD and non-SCD. Conclusions Incident SMI is independently associated with an increased risk of SCD in the general population. Additional research should address screening for SMI and the role of standard post-myocardial infarction therapy.
Asunto(s)
Enfermedades Asintomáticas/epidemiología , Muerte Súbita Cardíaca , Infarto del Miocardio , Medición de Riesgo , Factores de Edad , China/epidemiología , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/prevención & control , Electrocardiografía/métodos , Etnicidad/estadística & datos numéricos , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/fisiopatología , Evaluación de Necesidades , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores Sexuales , TiempoRESUMEN
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.
Asunto(s)
Antiarrítmicos/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Calidad de Vida , Antiarrítmicos/administración & dosificación , Antiarrítmicos/efectos adversos , Fibrilación Atrial/mortalidad , Ablación por Catéter/efectos adversos , Estado de Salud , Humanos , Dolor/epidemiología , Rendimiento Físico Funcional , Ensayos Clínicos Controlados Aleatorios como Asunto , RecurrenciaRESUMEN
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.
Asunto(s)
Potenciales de Acción , Electrocardiografía Ambulatoria , Frecuencia Cardíaca , Corazón/inervación , Sistema Nervioso Parasimpático/fisiología , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Adulto JovenRESUMEN
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.
Asunto(s)
Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico , Muerte Súbita Cardíaca/etiología , Electrocardiografía/métodos , Infarto del Miocardio/complicaciones , Enfermedad Aguda , Estudios de Casos y Controles , China/epidemiología , Enfermedad de la Arteria Coronaria/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/fisiopatología , Estudios Retrospectivos , Medición de RiesgoRESUMEN
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.
Asunto(s)
Muerte Súbita Cardíaca , Glicerolfosfato Deshidrogenasa , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5 , Adulto , Anciano , Arritmias Cardíacas/genética , Electrocardiografía , Femenino , Glicerolfosfato Deshidrogenasa/genética , Glicerolfosfato Deshidrogenasa/metabolismo , Células HEK293 , Humanos , Masculino , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismoRESUMEN
BACKGOUND: Silent electrocardiographic ST change predicts future coronary heart disease (CHD) incidence and mortality, but the prognostic significance of painless ST-segment depression (STD) with respect to sudden cardiac death (SCD) in subjects without apparent CHD remain unclear. This study sought to test the association between non-ischemic resting STD and risk of SCD in the general population. METHODS: A total of 14,935 middle-aged subjects from the prospective, population-based Atherosclerosis Risk in Communities (ARIC) study were included in this analysis. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. STD was defined as ST-segment depression of ≥0.05â¯mV in two or more contiguous leads. RESULTS: A total of 626 sudden cardiac death occurred during the mean follow-up of 20.4â¯years. Compared with those without STD, subjects with resting painless STD of at least 0.05â¯mV had a significantly increased risk of developing SCD (adjusted HR, 1.45; 95% CI, 1.20 to 1.76), and those with STDâ¯≥â¯0.1â¯mV had even higher risk of SCD (adjusted HR, 1.90; 95% CI, 1.25 to 2.88). Significant interactions were present between gender and STD (Pâ¯=â¯.03), and between race and STD (Pâ¯=â¯.01). STD was significantly predictive of SCD in males (adjusted HR, 1.57; 95% CI, 1.22-2.01) and in whites (adjusted HR, 1.65; 95% CI, 1.27-2.14). STD in lateral leads and global leads were strong predictors of SCD. CONCLUSIONS: Resting painless STD was an independent predictor of SCD in the middle-aged population without previously diagnosed CHD.
Asunto(s)
Enfermedades Asintomáticas/epidemiología , Enfermedad Coronaria , Muerte Súbita Cardíaca , Electrocardiografía , China/epidemiología , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/fisiopatología , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/prevención & control , Electrocardiografía/métodos , Electrocardiografía/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
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.2240Tâ¯>â¯C/p.L747P) DPP6 were respectively expressed in HEK293â¯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.2240Tâ¯>â¯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, Pâ¯<â¯0.05). Compared with DPP6-WT, the slope of the activation curve of DPP6-L747P was slightly decreased (15.49⯱â¯0.56â¯mV vs. 13.88⯱â¯0.54â¯mV, Pâ¯<â¯0.05), the slope of the inactivation curve was increased (13.65⯱â¯1.57â¯mV, vs. 24.44⯱â¯2.79â¯mV, Pâ¯<â¯0.05) and the recovery time constant was significantly reduced (216.81⯱â¯18.59â¯ms vs. 102.11⯱â¯32.03â¯ms, Pâ¯<â¯0.05). In conclusion, we identified a novel missense variant (c.2240Tâ¯>â¯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.
Asunto(s)
Arritmias Cardíacas/genética , Pueblo Asiatico/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Canales de Potasio/genética , Adolescente , Línea Celular , Membrana Celular/genética , Muerte Súbita Cardíaca , Regulación hacia Abajo/genética , Familia , Femenino , Células HEK293 , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-1/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/uso terapéutico , Antiinflamatorios/uso terapéutico , Antirreumáticos/uso terapéutico , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Causas de Muerte , Salud Global , Humanos , Incidencia , Interleucina-1/sangre , Factores de RiesgoRESUMEN
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.
Asunto(s)
Canal de Potasio ERG1/genética , Mutación Missense , Fibrilación Ventricular/genética , Adulto , Muerte Súbita Cardíaca/etiología , Células HEK293 , Heterocigoto , Humanos , Masculino , Linaje , Fibrilación Ventricular/complicacionesRESUMEN
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.
Asunto(s)
Muerte Súbita Cardíaca/patología , Corazón/fisiopatología , Canales de Potasio Shal/genética , Subunidad beta-1 de Canal de Sodio Activado por Voltaje/genética , Adulto , Anciano , Animales , Electrofisiología , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Corazón/diagnóstico por imagen , Humanos , Masculino , Potenciales de la Membrana , Mutación/genética , Técnicas de Placa-Clamp , TransfecciónRESUMEN
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.
Asunto(s)
Mutación/genética , Canales de Potasio con Entrada de Voltaje/genética , Adulto , Anciano , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Masculino , Moduladores del Transporte de Membrana/metabolismo , Persona de Mediana Edad , Linaje , Potasio/metabolismoRESUMEN
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.