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Aims: Current guidelines recommend implantable cardioverter‐defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II–III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long‐term effects of primary prevention ICD implantation according to NYHA class in an extended follow‐up study of the DANISH trial. Methods and results: The DANISH trial randomized 1116 patients with non‐ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all‐cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow‐up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long‐term rate of all‐cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20–1.93) and cardiovascular death (HR 1.95 [1.47–2.60]). ICD implantation, compared with usual care, did not reduce the long‐term rate of all‐cause mortality (all participants: HR 0.89 [95% CI 0.74–1.08]; NYHA class II: HR 0.85 [0.64–1.13]; NYHA class III/IV: HR 0.89 [0.69–1.14]; pinteraction = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70–1.09]; NYHA class II: HR 0.78 [0.54–1.12]; NYHA class III/IV: HR 0.89 [0.67–1.19]; pinteraction = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40–0.92]; NYHA class II: HR 0.73 [0.40–1.36]; NYHA class III/IV: HR 0.52 [0.29–0.94]; pinteraction = 0.39). Conclusions: In patients with non‐ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class. Clinical Trial Registration: ClinicalTrials.gov NCT00542945. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Hundreds of genetic variants have been described as disease causing in dilated cardiomyopathy ( DCM). Some of these associations are now being questioned. We aimed to identify the prevalence of previously DCM associated variants in the Exome Aggregation Consortium (Ex AC), in order to identify potentially false-positive DCM variants. Methods Variants listed as DCM disease-causing variants in the Human Gene Mutation Database were extracted from Ex AC. Pathogenicity predictions for these variants were mined from db NSFP v 2.9 database. Results Of the 473 DCM variants listed in HGMD, 148 (31%) were found in Ex AC. The expected number of individuals with DCM in Ex AC is 25 based on the prevalence in the general population. Yet, 35 variants were found in more than 25 individuals. In 13 genes, we identified all variants previously associated with DCM; four genes contained variants above our estimated cut-off. Prediction tools found Ex AC variants to be significantly more tolerated when compared to variants not found in Ex AC ( P = 0.004). Conclusion In Ex AC, we identified a higher genotype prevalence of variants considered disease-causing than expected. More importantly, we found 13 genes in which all variants previously associated with DCM were identified in Ex AC, questioning the association of these genes with the monogenic form of DCM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Abnormal P-wave morphology (PWM) has been associated with a history of atrial fibrillation (AF) in earlier studies. Although lone AF is believed to have substantial genetic basis, studies on associations between single nucleotide polymorphisms (SNP) linked to lone AF and PWM have not been reported. We aimed to assess whether SNPs previously associated with lone AF (rs2200733, rs13376333, rs3807989, and rs11047543) are also linked to P-wave abnormalities.Methods: Four SNPs were studied in 176 unrelated individuals with early-onset lone AF (age at onset <50 years), median age 38 years (19-63 years), 149 men. Using sinus rhythm ECG, orthogonal PWM was classified as Type 1-positive in leads X and Y and negative in lead Z, Type 2-positive in leads X and Y and biphasic (-/+) in lead Z, Type 3-positive in lead X and biphasic in lead Y (+/-), and the remaining as atypical.Results: Two SNPs were found to be significantly associated with altered P-wave morphology distribution: rs3807989 near the gene CAV1/CAV2 and rs11047543 near the gene SOX5. Both SNPs were associated with a higher risk of non-Type 1 P-wave morphology (rs3807989: OR = 4.8, 95% CI = 2.3-10.2, p < 0.001; rs11047543: OR = 4.7, 95% CI = 1.1-20.5, p = 0.04). No association was observed for rs2200733 and rs13376333.Conclusion: In this study, the two variants rs3807989 and rs11047543, previously associated with PR interval and lone AF, were associated with altered P-wave morphology distribution in patients with early-onset lone AF. These findings suggest that common genetic variants may modify atrial conduction properties. [ABSTRACT FROM AUTHOR]