A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation.

AIMS: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial. METHODS: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. RESULTS: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h. CONCLUSION: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the IKr channel.

Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial.

BACKGROUND: It is unknown whether screening for atrial fibrillation and subsequent treatment with anticoagulants if atrial fibrillation is detected can prevent stroke. Continuous electrocardiographic monitoring using an implantable loop recorder (ILR) can facilitate detection of asymptomatic atrial fibrillation episodes. We aimed to investigate whether atrial fibrillation screening and use of anticoagulants can prevent stroke in individuals at high risk. METHODS: We did a randomised controlled trial in four centres in Denmark. We included individuals without atrial fibrillation, aged 70-90 years, with at least one additional stroke risk factor (ie, hypertension, diabetes, previous stroke, or heart failure). Participants were randomly assigned in a 1:3 ratio to ILR monitoring or usual care (control) via an online system in permuted blocks with block sizes of four or eight participants stratified according to centre. In the ILR group, anticoagulation was recommended if atrial fibrillation episodes lasted 6 min or longer. The primary outcome was time to first stroke or systemic arterial embolism. This study is registered with ClinicalTrials.gov, NCT02036450. FINDINGS: From Jan 31, 2014, to May 17, 2016, 6205 individuals were screened for inclusion, of whom 6004 were included and randomly assigned: 1501 (25·0%) to ILR monitoring and 4503 (75·0%) to usual care. Mean age was 74·7 years (SD 4·1), 2837 (47·3%) were women, and 5444 (90·7%) had hypertension. No participants were lost to follow-up. During a median follow-up of 64·5 months (IQR 59·3-69·8), atrial fibrillation was diagnosed in 1027 participants: 477 (31·8%) of 1501 in the ILR group versus 550 (12·2%) of 4503 in the control group (hazard ratio [HR] 3·17 [95% CI 2·81-3·59]; p<0·0001). Oral anticoagulation was initiated in 1036 participants: 445 (29·7%) in the ILR group versus 591 (13·1%) in the control group (HR 2·72 [95% CI 2·41-3·08]; p<0·0001), and the primary outcome occurred in 318 participants (315 stroke, three systemic arterial embolism): 67 (4·5%) in the ILR group versus 251 (5·6%) in the control group (HR 0·80 [95% CI 0·61-1·05]; p=0·11). Major bleeding occurred in 221 participants: 65 (4·3%) in the ILR group versus 156 (3·5%) in the control group (HR 1·26 [95% CI 0·95-1·69]; p=0·11). INTERPRETATION: In individuals with stroke risk factors, ILR screening resulted in a three-times increase in atrial fibrillation detection and anticoagulation initiation but no significant reduction in the risk of stroke or systemic arterial embolism. These findings might imply that not all atrial fibrillation is worth screening for, and not all screen-detected atrial fibrillation merits anticoagulation. FUNDING: Innovation Fund Denmark, The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation, Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, The AFFECT-EU Consortium (EU Horizon 2020), Læge Sophus Carl Emil Friis og hustru Olga Doris Friis' Legat, and Medtronic.

Associations between primary care electrocardiography and non-Alzheimer dementia.

OBJECTIVES: To determine whether electrocardiogram (ECG) markers are associated with incident non-Alzheimer's dementia (non-AD) and whether these markers also improve risk prediction for non-AD. MATERIALS AND METHODS: We retrospectively included 170,605 primary care patients aged 60 years or older referred for an ECG by their general practitioner and followed them for a median of 7.6 years. Using Cox regression, we reported hazard ratios (HRs) for electrocardiogram markers. Subsequently, we evaluated if addition of these electrocardiogram markers to a clinical model improved risk prediction for non-AD using change in area under the receiver-operator characteristics curve (AUC). RESULTS: The 5-year cumulative incidence of non-AD was 3.4 %. Increased heart rate (HR=1.06 pr. 10 bpm [95% confidence interval: 1.04-1.08], p<0.001), shorter QRS duration (HR=1.07 pr. 10 ms [1.05-1.09], p<0.001), elevated J-amplitude (HR=1.16 pr. mm [1.08-1.24], p<0.001), decreased T-peak amplitude (HR=1.02 pr. mm [1.01-1.04], p=0.002), and increased QTc (HR=1.08 pr. 20 ms [1.05-1.10], p<0.001) were associated with an increased rate of non-AD. Atrial fibrillation on the ECG (HR=1.18 [1.08-1.28], p<0.001) Sokolow-Lyon index > 35 mm (HR=1.31 [1.18-1.46], p<0.001) and borderline (HR=1.18 [1.11-1.26], p<0.001) or abnormal (HR=1.40 [1.27-1.55], p<0.001) QRS-T angle were also associated with an increased rate of non-AD. Upon addition of ECG markers to the Cox model, 5-year and 10-year C-statistic (AUC) improved significantly (delta-AUC, 0.36 [0.18-0.50] and 0.20 [0.03-0.35] %-points, respectively). CONCLUSIONS: ECG markers typical of an elevated cardiovascular risk profile were associated with non-AD and improved both 5-year and 10-year risk predictions for non-AD.

Effect of diabetes duration on the relationship between glycaemic control and risk of death in older adults with type 2 diabetes.

AIM: To investigate the effect of diabetes duration on glycaemic control, measured using mean glycated haemoglobin (HbA1c) level, and mortality risk within different age, sex and clinically relevant, comorbidity-defined subgroups in an elderly population with type 2 diabetes (T2D). METHODS: We studied older (≥65 years) primary care patients with T2D, who had three successive annual measurements of HbA1c taken between 2005 and 2013. The primary exposure was the mean of all three HbA1c measurements. Follow-up began on the date of the third measurement. Individual mean HbA1c levels were categorized into clinically relevant groups (<6.5% [<48 mmol/mol]; 6.5%-6.9% [48-52 mmol/mol]; 7%-7.9% [53-63 mmol/mol]; 8%-8.9% [64-74 mmol/mol]; and ≥9% [≥75 mmol/mol]). We used multiple Cox regression to study the effect of glycaemic control on the hazard of all-cause mortality, adjusted for age, sex, use of concomitant medication, and age- and disease-related comorbidities. RESULTS: A total of 9734 individuals were included. During a median (interquartile range) follow-up of 7.3 (4.6-8.7) years, 3320 individuals died. We found that the effect of mean HbA1c on all-cause mortality depended on the duration of diabetes (P for interaction <.001). For individuals with short diabetes duration (<5 years), the risk of death increased with poorer glycaemic control (increasing HbA1c), whereas for individuals with longstanding diabetes (≥5 years), we found a J-shaped association, where a mean HbA1c level between 6.5% and 7.9% [48 and 63 mmol/mol] was associated with the lowest risk of death. For individuals with longstanding diabetes, both low (<6.5% [<48 mmol/mol]; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.07-1.37, P = .002) and high mean HbA1c levels (≥9.0% [≥75 mmol/mol]; HR 1.60, 95% CI 1.28-1.99, P < .001) were associated with an increased risk of death. We also calculated 5-year absolute risks of all-cause mortality, separately for short and long diabetes duration, and found similar risk patterns across different age groups, sex and comorbidity strata. CONCLUSIONS: In elderly individuals with T2D, the effect of glycaemic control (measured by HbA1c) on all-cause mortality depended on the duration of diabetes. Of particular clinical importance, we found that strict glycaemic control was associated with an increased risk of death among individuals with long (≥ 5 years) diabetes duration. Conversely, for individuals with short diabetes duration, strict glycaemic control was associated with the lowest risk of death. These results indicate that tight glycemic control may be beneficial in people with short duration of diabetes, whereas a less stringent target may be warranted with longer diabetes exposure.

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

BACKGROUND: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS: We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies.

BACKGROUND: Much controversy surrounds the association of traditional cardiovascular disease risk factors with venous thromboembolism (VTE). METHODS: We performed an individual level random-effect meta-analysis including 9 prospective studies with measured baseline cardiovascular disease risk factors and validated VTE events. Definitions were harmonized across studies. Traditional cardiovascular disease risk factors were modeled categorically and continuously using restricted cubic splines. Estimates were obtained for overall VTE, provoked VTE (ie, VTE occurring in the presence of 1 or more established VTE risk factors), and unprovoked VTE, pulmonary embolism, and deep-vein thrombosis. RESULTS: The studies included 244 865 participants with 4910 VTE events occurring during a mean follow-up of 4.7 to 19.7 years per study. Age, sex, and body mass index-adjusted hazard ratios for overall VTE were 0.98 (95% confidence interval [CI]: 0.89-1.07) for hypertension, 0.97 (95% CI: 0.88-1.08) for hyperlipidemia, 1.01 (95% CI: 0.89-1.15) for diabetes mellitus, and 1.19 (95% CI: 1.08-1.32) for current smoking. After full adjustment, these estimates were numerically similar. When modeled continuously, an inverse association was observed for systolic blood pressure (hazard ratio=0.79 [95% CI: 0.68-0.92] at systolic blood pressure 160 vs 110 mm Hg) but not for diastolic blood pressure or lipid measures with VTE. An important finding from VTE subtype analyses was that cigarette smoking was associated with provoked but not unprovoked VTE. Fully adjusted hazard ratios for the associations of current smoking with provoked and unprovoked VTE were 1.36 (95% CI: 1.22-1.52) and 1.08 (95% CI: 0.90-1.29), respectively. CONCLUSIONS: Except for the association between cigarette smoking and provoked VTE, which is potentially mediated through comorbid conditions such as cancer, the modifiable traditional cardiovascular disease risk factors are not associated with increased VTE risk. Higher systolic blood pressure showed an inverse association with VTE.

Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial.

AIMS: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). METHODS: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). RESULTS: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m2 , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. CONCLUSIONS: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

Risk prediction of cardiovascular death based on the QTc interval: evaluating age and gender differences in a large primary care population.

AIMS: Using a large, contemporary primary care population we aimed to provide absolute long-term risks of cardiovascular death (CVD) based on the QTc interval and to test whether the QTc interval is of value in risk prediction of CVD on an individual level. METHODS AND RESULTS: Digital electrocardiograms from 173 529 primary care patients aged 50-90 years were collected during 2001-11. The Framingham formula was used for heart rate-correction of the QT interval. Data on medication, comorbidity, and outcomes were retrieved from administrative registries. During a median follow-up period of 6.1 years, 6647 persons died from cardiovascular causes. Long-term risks of CVD were estimated for subgroups defined by age, gender, cardiovascular disease, and QTc interval categories. In general, we observed an increased risk of CVD for both very short and long QTc intervals. Prolongation of the QTc interval resulted in the worst prognosis for men whereas in women, a very short QTc interval was equivalent in risk to a borderline prolonged QTc interval. The effect of the QTc interval on the absolute risk of CVD was most pronounced in the elderly and in those with cardiovascular disease whereas the effect was negligible for middle-aged women without cardiovascular disease. The most important improvement in prediction accuracy was noted for women aged 70-90 years. In this subgroup, a total of 9.5% were reclassified (7.2% more accurately vs. 2.3% more inaccurately) within clinically relevant 5-year risk groups when the QTc interval was added to a conventional risk model for CVD. CONCLUSION: Important differences were observed across subgroups when the absolute long-term risk of CVD was estimated based on QTc interval duration. The accuracy of the personalized CVD prognosis can be improved when the QTc interval is introduced to a conventional risk model for CVD.

Right bundle branch block: prevalence, risk factors, and outcome in the general population: results from the Copenhagen City Heart Study.

AIMS: To determine the prevalence, predictors of newly acquired, and the prognostic value of right bundle branch block (RBBB) and incomplete RBBB (IRBBB) on a resting 12-lead electrocardiogram in men and women from the general population. METHODS AND RESULTS: We followed 18 441 participants included in the Copenhagen City Heart Study examined in 1976-2003 free from previous myocardial infarction (MI), chronic heart failure, and left bundle branch block through registry linkage until 2009 for all-cause mortality and cardiovascular outcomes. The prevalence of RBBB/IRBBB was higher in men (1.4%/4.7% in men vs. 0.5%/2.3% in women, P < 0.001). Significant predictors of newly acquired RBBB were male gender, increasing age, high systolic blood pressure, and presence of IRBBB, whereas predictors of newly acquired IRBBB were male gender, increasing age, and low BMI. Right bundle branch block was associated with significantly increased all-cause and cardiovascular mortality in both genders with age-adjusted hazard ratios (HR) of 1.31 [95% confidence interval (CI), 1.11-1.54] and 1.87 (95% CI, 1.48-2.36) in the gender pooled analysis with little attenuation after multiple adjustment. Right bundle branch block was associated with increased risk of MI with an HR of 1.67 (95% CI, 1.16-2.42) and pacemaker insertion with an HR of 2.17 (95% CI, 1.22-3.86), but not with chronic heart failure (HR 1.37; 95% CI, 0.96-1.94), atrial fibrillation (HR 1.10; 95% CI, 0.73-1.67), or chronic obstructive pulmonary disease (HR 0.99; 95% CI, 0.60-1.62). The presence of IRBBB was not associated with any adverse outcome. CONCLUSION: In this cohort study, RBBB and IRBBB were two to three times more common among men than women. Right bundle branch block was associated with increased cardiovascular risk and all-cause mortality, whereas IRBBB was not. Contrary to common perception, RBBB in asymptomatic individuals should alert clinicians to cardiovascular risk.

Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg-1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg-1 AP30663, 5 mg kg-1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg-1 and 5 mg kg-1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg-1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .

Association between primary care electrocardiogram markers and Alzheimer's disease.

OBJECTIVE: The association between common electrocardiogram (ECG) markers and Alzheimer's disease has been scarcely investigated, and it is unknown if ECG markers can improve risk prediction. Thus, we aimed to examine the association between common ECG markers and Alzheimer's disease in a large population. METHODS: We studied the association between ECG markers and Alzheimer's disease using Cox models with adjustment for age, sex, and comorbidities using a large primary care population of patients aged 60 years or more. RESULTS: We followed 172,236 subjects for a median of 7.5 years. Increased PR interval (hazard ratio for PR > 188 ms: 0.76 [95% confidence interval: 0.69-0.83, p < 0.001) and increased QTc interval (hazard ratio for QTc = [426;439]: 0.90 [0.83-0.98], p = 0.02) were associated with a decreased rate of Alzheimer's disease. A positive Sokolow-Lyon index >35 mm (1.22 [1.13-1.33], p < 0.001) and increased T-wave amplitude >4.1 mm (1.15 [1.04-1.27]) were associated with an increased rate of Alzheimer's disease. Upon addition of ECG markers to a reference model, 10-year prediction area under the receiver-operator characteristics curve (AUC) improved by 0.39 [0.06-0.67] %-points. The 10-year absolute risk of Alzheimer's disease was 6.5% and 5.2% for an 82-year old female and a male, respectively, with a favorable ECG, and 12% and 9.2%, respectively, with an unfavorable ECG, almost twice as high. CONCLUSIONS: We identified several common ECG markers which were associated with Alzheimer's disease, and which improved risk prediction for Alzheimer's disease.

Specificity of elevated intercostal space ECG recording for the type 1 Brugada ECG pattern.

BACKGROUND: Right precordial (V1-3) elevated electrode placement ECG (EEP-ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population. METHODS: Two different populations consisting of healthy subjects were used. A total of 340 subjects were included, 80% were men, the median age was 43 year (interquartile range: 31-51) and all were of European ethnicity. RESULTS: No type 1 ECG patterns were identified but 16 (4.7%) subjects with a type 2 ECG and 32 (9.4%) subjects with a type 3 ECG were identified in any lead placement. In total 43 (13%) subjects had any BrS ECG pattern in any lead placement. The specificity was 100% (one-sided 97.5% CI: 99%) for the use of EEP-ECG to uncover type 1 pattern. For type 2 pattern the specificity was 95% (95% CI: 92-97%) and for type 3 pattern 91% (95% CI: 88-94%). CONCLUSIONS: Elevated electrode placement ECG in the diagnosis of BrS seems to have a very high specificity with regards to the finding of a type 1 ECG pattern in a European population; conversely a finding of a type 2 or 3 pattern is of a significantly lower specificity and should perhaps be disregarded.

Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study.

BACKGROUND: Studies have suggested a link between risk factors for atherosclerotic disease and venous thromboembolism (VTE), but results are heterogeneous. We sought to identify risk factors for VTE with a focus on risk factors for atherosclerotic disease. METHODS AND RESULTS: Data were taken from the Copenhagen City Heart Study, a prospective cohort study of a random, age-stratified sample of people living in a defined area in Copenhagen, Denmark, started in 1976 with follow-up until 2007. First VTE (deep vein thrombosis and pulmonary embolism) diagnosis was retrieved from electronic national registries from study baseline to 2007. Of 18 954 subjects (median follow-up, 19.5 years) representing 360 399 person-years of follow-up, 969 subjects experienced at least 1 VTE, corresponding to a crude incidence rate of 2.69 (95% confidence interval [CI], 2.52 to 2.86) per 1000 person-years. The variables found to be significantly associated with VTE in a multivariable model adjusted for age and calendar time were as follows: body mass index (hazard ratio [HR] for >or=35 versus <20=2.10 [95% CI, 1.39 to 3.16]); smoking (HR for >or=25 g tobacco per day versus never smoker=1.52 [95% CI, 1.15 to 2.01]); gender (HR for men versus women=1.24 [95% CI, 1.08 to 1.42]); household income (HR for medium versus low=0.82 [95% CI, 0.70 to 0.95]); and diastolic blood pressure (HR for >100 versus <80 mm Hg=1.34 [95% CI, 1.08 to 1.66]). Other cardiovascular risk factors including total/high-density lipoprotein/low-density lipoprotein cholesterol levels, triglyceride levels, and diabetes mellitus were not associated with VTE. CONCLUSIONS: Obesity and smoking were both found to be important risk factors for VTE whereas total/high-density lipoprotein/low-density lipoprotein cholesterol levels, triglyceride levels, and diabetes mellitus were not.

Screening of KCNN3 in patients with early-onset lone atrial fibrillation.

AIMS: The aim of this study was to screen KCNN3 encoding the small-conductance calcium-activated K+ channel (SK3) in lone atrial fibrillation patients. Atrial fibrillation (AF) is the most common cardiac arrhythmia. A genome-wide association study has recently associated an intronic single-nucleotide polymorphism (SNP) in KCNN3 with lone AF. METHODS AND RESULTS: We sequenced the coding region and splice junctions of KCNN3 in 209 early-onset lone AF patients, screening for variations. A group of 208 healthy blood donors with normal ECGs and without cardiac symptoms were used as controls. All patients and controls were of Danish ethnicity. No mutations were found in the coding regions or splice sites of KCNN3. We found one known exonic synonymous SNP (rs1131820) in KCNN3 that was associated with AF. Both the genotype distribution and allele frequencies of SNP rs1131820 were significantly different between the AF cases and controls (PGenotype=0.047 and PAllele=0.027). Being a homozygous carrier of the major allele (GG) vs. the minor allele (AA) of rs1131820 was associated with an odds ratio of 2.85 (95% CI 1.13-7.18, P=0.026) for lone AF. CONCLUSIONS: In this study of 209 young lone AF patients, we found no mutations in the exons or splice sites of KCNN3, but we found an association between the synonymous SNP rs1131820 in KCNN3 and lone AF.

Common polymorphisms in KCNJ5 [corrected] are associated with early-onset lone atrial fibrillation in Caucasians.

OBJECTIVES: The aim of this study was to screen lone atrial fibrillation (AF) patients for mutations in the genes KCNJ2, KCNJ3 and KCNJ5, all encoding potassium channels. Furthermore, we wanted to replicate the prior association of two single-nucleotide polymorphisms (SNPs) in KCNJ5, C171T (rs6590357) and G810T (rs7118824), with lone AF in Han Chinese. METHODS: We sequenced the coding region and splice site of KCNJ2, KCNJ3 and KCNJ5 in 187 early-onset lone-AF patients screening for mutations and counting SNP frequencies for the two noted SNPs in KCNJ5. RESULTS: No mutations were found in KCNJ2, KCNJ3 or KCNJ5. Both genotype distribution and allele frequencies of the SNPs rs6590357 and rs7118824 significantly differed between the AF and control group (p(genotype) = 0.0067, p(allele) = 0.0021 and p(genotype) = 0.014, p(allele) = 0.0101, respectively). On allele level, the OR for lone AF for rs6590357 was 1.77 (95% CI 1.16-2.73, p = 0.009) and for rs7118824 it was 1.71 (95% CI 1.13-2.57, p = 0.01) in a model adjusted for age and gender. CONCLUSIONS: Our findings indicate that rs6590357 and rs7118824 in KCNJ5 are associated with early-onset lone AF in Caucasians. No mutations were found in the exon or splice site of KCNJ2, KCNJ3 or KCNJ5.

Electrocardiographic T-wave morphology and risk of mortality.

BACKGROUND: Electrocardiographic T-wave morphology is used in drug safety studies as an adjunct to the QTc interval, but few measurements of T-wave morphology can be interpreted in clinical practice. Morphology combination score (MCS) is a combination of T-wave flatness/peakedness, asymmetry, and notching, enabling easy visual assessment of T-wave morphology. We aimed to test the association between T-wave morphology, quantified by MCS, and mortality. METHODS: We included electrocardiograms recorded in 2001-2011 from 342,294 primary care patients. Using Cox regression, we evaluated the association between MCS, cardiovascular death, and all-cause mortality, adjusting for heart rate, QTc, QT-prolonging drugs, diabetes, ischemic heart disease, hypertension, and congestive heart failure. RESULTS: 270,039 individuals (44% men, median age 55 [inter-quartile range: 42-67 years]) were included and followed for a median of 9.3 years, during which time 13,489 (5.0%) died from cardiovascular causes and 50,481 (18.7%) from any cause. High values of MCS (i.e. asymmetric, flattened, and/or notched T waves) were associated with an adjusted mortality Hazard Ratio of 1.75 (95% CI 1.62-1.89) and 1.61 (1.43-1.92) for women and men, respectively. Low values of MCS (i.e. peaked and symmetric T waves) were associated with a Hazard Ratio of 1.18 (1.08-1.28) and 1.71 (1.48-1.98) for women and men, respectively. CONCLUSIONS: In a large primary care population, we found that T-wave asymmetry, flatness, and notching provided prognostic information on mortality independent of heart rate, QTc, and baseline comorbidities.

Early glycaemic changes after initiation of oral antidiabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes.

AIMS: To determine the risk of major adverse cardiovascular events (MACE) and death, associated with an early large and rapid decline in glycated haemoglobin (HbA1C) following first time initiation of an oral antidiabetic drug (OAD). METHODS AND RESULTS: We included 10 518 primary care patients with type 2 diabetes, who initiated an OAD for the first time. For each individual, we measured a decline in HbA1C, as the difference between the pre-treatment HbA1C (within 3 months before OAD initiation) and the post-treatment HbA1C (within 1.5-4.5 months after OAD initiation), divided by the time between the two measurements. The decline was reported in mmol/mol change per 3 months in HbA1C and categorized by the median decline into levels of steep [≥9 mmol/mol (≥0.8%)] and flat decline [<9 mmol/mol per 3 months (<0.8%)]. Pre-treatment HbA1C was categorized by the median, into levels of low (48-62 mmol/mol) and high (>62 mmol/mol). Multiple Cox regression was used to study the effect of decline (steep vs. flat) on the outcome hazard rates separately for patients with low and high pre-treatment HbA1C. Analyses were adjusted for age, sex, traditional cardiovascular risk factors, severe comorbidities, and concomitant medication treatment. During a median follow-up time of 7.7 years, 1625 developed MACE and 2323 died. We found that a steep decline vs. a flat decline was significantly associated with a decreased hazard for MACE, both in individuals with high [hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.69-0.94; P = 0.005] and low pre-treatment HbA1C (HR 0.79; 95% CI 0.66-0.96; P = 0.015). The hazard of MACE was more pronounced on the short-term vs. long-term in individuals with high pre-treatment HbA1C. We found no significant association between combinations of pre-treatment HbA1C and decline categories and hazard of all-cause mortality. However, a combination of a low pre-treatment HbA1C and steep decline was associated with increased 1-year mortality (HR 1.52; 95% CI 1.00-2.29; P = 0.048) and hypoglycaemia (HR 1.82; 95% CI 1.11-2.98; P = 0.017). CONCLUSION: A combination of a high pre-treatment HbA1C and a steep decline in HbA1C was associated with a decreased short-term risk of MACE. A low pre-treatment HbA1C and a steep decline was associated with a long-term reduced risk of MACE, but a short-term increased risk of death and hypoglycaemia.