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.

A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome.

BACKGROUND: Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive. METHODS: A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques. RESULTS: The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics. CONCLUSIONS: These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.

Airflow obstruction, impaired lung function and risk of sudden cardiac death: a prospective cohort study.

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.

Longitudinal change in lung function and subsequent risks of cardiovascular events: evidence from four prospective cohort studies.

BACKGROUND: Lung function is constantly changing over the life course. Although the relation of cross-sectional lung function measure and adverse outcomes has been reported, data on longitudinal change and subsequent cardiovascular (CV) events risks are scarce. Therefore, this study is to determine the association of longitudinal change in lung function and subsequent cardiovascular risks. METHODS: This study analyzed the data from four prospective cohorts. Subjects with at least two lung function tests were included. We calculated the rate of forced respiratory volume in 1 s (FEV1) and forced vital capacity (FVC) decline for each subject and categorized them into quartiles. The primary outcome was CV events, defined as a composite of coronary heart disease (CHD), chronic heart failure (CHF), stroke, and any CV death. Cox proportional hazards regression and restricted cubic spline models were applied. RESULTS: The final sample comprised 12,899 participants (mean age 48.58 years; 43.61% male). Following an average of 14.79 (10.69) years, 3950 CV events occurred. Compared with the highest FEV1 quartile (Q4), the multivariable HRs for the lowest (Q1), 2nd (Q2), and 3rd quartiles (Q3) were 1.33 (95%CI 1.19, 1.49), 1.30 (1.16, 1.46), and 1.07 (0.95, 1.21), respectively. Likewise, compared with the reference quartile (Q4), the group that experienced a faster decline in FVC had higher HRs for CV events (1.06 [95%CI 0.94-1.20] for Q3, 1.15 [1.02-1.30] for Q2, and 1.28 [1.14-1.44] for Q1). The association remained robust across a series of sensitivity analyses and nearly all subgroups but was more evident in subjects < 60 years. CONCLUSIONS: We observed a monotonic increase in risks of CV events with a faster decline in FEV1 and FVC. These findings emphasize the value of periodic evaluation of lung function and open new opportunities for disease prevention.

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.

Additional Value of Early Repolarization Pattern in Prediction of Obstructive Coronary Artery Disease as Assessed by Coronary Angiography.

Recent reports show that an early repolarization pattern (ERP) is associated with a higher incidence of sudden cardiac death in patients with obstructive coronary artery disease (CAD). Sporadic case studies have pointed out that ERP might be related to obstructive CAD.In consecutive patients who had undergone coronary angiography, we investigated the relationship between ERP and obstructive CAD by evaluating its association with coronary artery stenosis.The study population consisted of 3785 patients (59.9% men; mean age 63.1 years) with or without obstructive CAD. Adjusting for major cardiovascular risk factors, ERP was significantly associated with obstructive CAD (adjusted odds ratio (OR): 2.24 [95% CI 1.70-2.95]) with an incremental predictive value (ROC AUC 0.76 versus 0.71, P = 0.02; NRI 55.3%, P < 0.001; IDI = 0.05, P = 0.008), specifically in subjects with low risk and intermediate risk. ERP also significantly improved the predictive value for multi-vessel disease (AUC: 0.77 versus 0.72, P = 0.02 for two-vessel disease; 0.79 versus 0.73, P = 0.04 for three-vessel disease). ERP was consistently associated with stenoses of 3 main coronary arteries.ERP is associated with significant increased risk for obstructive CAD.Further studies are warranted to confirm our results and to elucidate the specific pathogenic mechanisms.

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.

Risk of thromboembolic events in atrial fibrillation with chronic kidney disease.

BACKGROUND AND PURPOSE: Chronic kidney disease may increase the risk for ischemic stroke or systemic embolism in patients with nonvalular atrial fibrillation (AF). We conducted a meta-analysis to summarize all published studies to investigate the link between chronic kidney disease and risk of thromboembolic events in AF. METHODS: We performed a literature search using MEDLINE (source PubMed, 1966 to July, 2014) and EMBASE (1980 to July 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. RESULTS: Eighteen studies involving 538 479 patients and 41 719 incident thromboembolic events were identified. From the pooled analysis, AF patients with estimated glomerular filtration rate <60 mL/min compared with those with estimated glomerular filtration rate ≥60 mL/min experienced a significantly increased risk for developing thromboembolic events (relative risk, 1.62 [95% confidence interval, 1.40-1.87; P<0.001]). The annual rate of thromboembolic events increased by 0.41% (95% confidence interval, 0.17%-0.65%) for a 10 mL/min decrease in renal function. Addition of renal impairment to CHADS2 slightly improved the stroke risk stratification. CONCLUSIONS: Impaired renal function is an independent predictor of stroke or systemic embolism in patients with nonvalvular AF. Consideration of renal function may improve stroke risk stratification in patients with AF.

Effects of Nardostachys chinensis on spontaneous ventricular arrhythmias in rats with acute myocardial infarction.

OBJECTIVES: To investigate the effects and mechanisms of Nardostachys chinensis (NC) on spontaneous ventricular arrhythmias in rats with hyper-acute myocardial infarction (AMI). METHODS: Seventy-two rats were randomly divided into the control group (n = 24), metoprolol group (n = 24), and the NC group (n = 24). Premature ventricular contractions (PVCs), ventricular tachycardias (VTs), ventricular fibrillations (VFs), and blood pressure were monitored for 4 hours after coronary artery ligation. The connexin 43 (Cx43) expression in ventricular myocardium was measured by immunohistochemistry, Western blot, and real-time RT-PCR. RESULTS: Compared with the control, metoprolol and NC decreased the VF incidence (50% vs. 4.2%, P < 0.001, and 50% vs. 12.5%, P = 0.005, respectively). There was a steady decrease in the cumulative number of PVCs and VTs within 4 hours from ligating in 3 groups. Compared with the control, metoprolol and NC reduced the cumulative number of VTs and PVCs. Compared with control, metoprolol and NC decreased the infarct size of the left ventricular tissue (55.98% ± 6.20% vs. 39.13% ± 4.53%, P < 0.001, and 55.98% ± 6.20% vs. 42.39% ± 3.44%, P < 0.001, respectively). The results from immunohistochemistry, Western blot, and real-time RT-PCR showed that the protein expression of Cx43 in the control group was significantly lower than that in the metoprolol and NC groups in the infarcted zone. CONCLUSIONS: NC decreased the incidence of spontaneous ventricular arrhythmias (especially VF), reduced Cx43 degradation, and improved Cx43 redistribution in myocardial infarcted zone in rats with hyper-AMI. The data of the present study indicated that NC may be a promising drug in the future to prevent patients with AMI from lethal ventricular arrhythmias in prehospital setting.

Role of ideal cardiovascular health metrics in reducing risk of incident arrhythmias.

AIMS: Cardiovascular health (CVH) has been proven to reduce cardiovascular disease burden and mortality, but data are lacking regarding cardiac arrhythmias. The aim of this study was to assess the association between CVH metrics and atrial fibrillation/flutter (AF), ventricular arrhythmias, and bradyarrhythmias. METHODS AND RESULTS: This study analysed data from the Atherosclerosis Risk in Communities (ARIC) cohort, with participants recruited from four different communities across the United States. Cardiovascular health metrics were scored at baseline (1987-89) following the American Heart Association's recommendations and categorized as poor, intermediate, or ideal. Arrhythmia episodes were diagnosed by International Classification of Diseases (ICD)-9 code. Adjusted associations were estimated using Cox models and event rates and population attributable fractions were calculated by CVH metrics category. The study population consisted of 13 078 participants, with 2548 AF, 1363 ventricular arrhythmias, and 706 bradyarrhythmias occurred. The adjusted hazard ratios (HRs) for ideal (vs. poor) CVH metrics were 0.59 [95% confidence interval (CI): 0.50-0.69] for AF, 0.38 (95% CI: 0.28-0.51) for ventricular arrhythmias, and 0.70 (95% CI: 0.51-0.97) for bradyarrhythmia. The risk of incident arrhythmias decreased steadily as the CVH metrics improved from 0 to 14 scores. The adjusted population attributable fractions were calculated to be 29.9% for AF, 54.4% for ventricular arrhythmias, and 21.9% for bradyarrhythmia, respectively. The association between CVH metrics and incident arrhythmias was also seen in people who remained free of coronary heart disease over the follow-up. CONCLUSION: Achieving ideal CVH metrics recommendations by AHA in midlife was associated with a lower risk of incident arrhythmias later in life.

Intermediate and ideal levels of cardiovascular health (CVH) metrics are associated with a markedly reduced risk of developing incident arrhythmias, including atrial fibrillation/flutter, ventricular arrhythmias, and bradyarrhythmia, independent of coronary heart disease. A majority of incident arrhythmias could be prevented if the risk profile of the entire population was optimized. These findings emphasize the significance of public health policies that improve CVH to reduce the social and economic burden of arrhythmias.

Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis.

BACKGROUND: Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose-response relationship exists. METHODS AND FINDINGS: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09-1.25) for ever smokers, 1.23 (95% CI 1.14-1.33) for current smokers, and 1.10 (95% CI 1.03-1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%-11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%-8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24-1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%-12.3%) for ever smoking, 5.8% (95% CI 3.6%-8.2%) for current smoking, and 2.7% (95% CI 0.8%-4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4-26.7) cases per 100,000 person-years. CONCLUSIONS: Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE. Please see later in the article for the Editors' Summary.

Associations of Renal Function Trajectories and Long-Term Cardiovascular Risks Among a Population Without Chronic Kidney Disease.

Background The longitudinal trajectories of renal function have been associated with cardiovascular events in patients with chronic kidney disease (CKD). However, the change pattern of renal function in those without CKD has not yet been reported. We aim to explore patterns of renal function change in a non-CKD population and its associated risks with cardiovascular outcomes. Methods and Results The present study analyzed data from 4 prospective cohorts and was restricted to participants without baseline CKD. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, chronic heart failure, stroke, and cardiovascular deaths. We used a group-based trajectory model to identify latent groups and analyzed the associated risk with Cox regression models. The complete dates of this study were June 1, 2020, through January 1, 2021. The final sample comprised 23 760 participants (mean age, 58.63 [9.12] years, 10 618 men, and 17 799 White participants). During 20.56 years follow-up, 8328 (35.05%) first major adverse cardiovascular events happened. Four trajectories in estimated glomerular renal function and 3 patterns of CKD progression were identified. Compared with subjects assigned to class I trajectory (high to mildly decreased group), the adjusted hazard ratios of major adverse cardiovascular events for class II (normal to mildly decreased group), class III (normal to moderately decreased group), and class IV (mildly to severely decreased group) were 1.11 (95% CI, 1.01-1.23), 1.27 (95% CI, 1.14-1.40), and 1.56 (95% CI, 1.38-1.77), respectively. Likewise, participants assigned to the slow and rapid progression groups had elevated HRs for major adverse cardiovascular events (1.75 [95% CI, 1.39-2.21] and 2.19 [95% CI, 1.68-2.86], respectively) when compared with the stable group. Findings were generally consistent in stratification analysis, but significant interaction effects by age and smoking status were detected. Conclusions In this study, we identified unique trajectory groups for renal function. These findings may signal an underlying high-risk population and inspire future studies on individualized risk management.

Systolic Blood Pressure and Cardiovascular Risk in Normotensive Adults.

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.

The role of glucocorticoids in increasing cardiovascular risk.

Introduction: Different studies provide conflicting evidence regarding the potential for glucocorticoids (GCs) to increase the risk of cardiovascular diseases. This study performed a systematic review and meta-analysis to determine the correlation between GCs and cardiovascular risk, including major adverse cardiovascular events (MACE), death from any cause, coronary heart disease (CHD), heart failure (HF), and stroke. Methods: We performed a comprehensive search in PubMed and Embase (from inception to June 1, 2022). Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. Results: A total of 43 studies with 15,572,512 subjects were included. Patients taking GCs had a higher risk of MACE (RR = 1.27, 95% CI: 1.15-1.40), CHD (RR = 1.25, 95% CI: 1.11-1.41), and HF (RR = 1.92, 95% CI: 1.51-2.45). The MACE risk increased by 10% (95% CI: 6%-15%) for each additional gram of GCs cumulative dose or by 63% (95% CI: 46%-83%) for an additional 10 µg daily dose. The subgroup analysis suggested that not inhaled GCs and current GCs use were associated with increasing MACE risk. Similarly, GCs were linked to an increase in absolute MACE risk of 13.94 (95% CI: 10.29-17.58) cases per 1,000 person-years. Conclusions: Administration of GCs is possibly related with increased risk for MACE, CHD, and HF but not increased all-cause death or stroke. Furthermore, it seems that the risk of MACE increased with increasing cumulative or daily dose of GCs.

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.