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BACKGROUND: Changes in QRS duration (∆QRS) are often used in the clinical setting to evaluate the effect of cardiac resynchronization therapy (CRT), although an association between ∆QRS and outcomes is not firmly established. We aimed to assess the association between mortality and ∆QRS after CRT in patients from the DANISH (Danish Study to Assess the Efficacy of ICDs in Patients with Non-Ischemic Systolic Heart Failure on Mortality) study.METHODS: We included all patients from DANISH who received a CRT device and had available QRS duration data before and after implantation. Cox proportional hazards models were used to assess associations between ∆QRS (post-CRT QRS minus pre-CRT QRS) and mortality.RESULTS: Complete data were available in 572 patients. Median baseline QRS duration was 160 ms (IQR [146;180]). Post-CRT QRS was recorded a median of 48 days (IQR [33;86]) after implantation, and the median ∆QRS was -14 ms (IQR [-38;-3]). During a median follow-up of 4.1 years (IQR [2.5;5.8]), 106 patients died. In crude Cox regression, all-cause mortality was reduced by 6% per 10 ms shortening of QRS (HR 0.94; CI: 0.88-1.00, p = 0.04). The effect did not remain significant after multivariable adjustment (HR 1.01, CI: 0.93-1.10, p = 0.77). Further, no association was found between ∆QRS and improvement of New York Heart Association functional class at 6 months (OR 1.03, CI: 0.96-1.10, p = 0.42).CONCLUSION: In a large cohort of patients with non-ischemic cardiomyopathy, reduction of QRS duration after CRT was not associated with changes in mortality during long-term follow-up.

Many patients with heart failure and a reduced ejection fraction (HFrEF) with an indication for cardiac resynchronization therapy (CRT) are also eligible for prophylactic implantation of an implantable cardioverter defibrillator (ICD) for the prevention of sudden cardiac death (SCD). However, it is unclear whether patients who are eligible for CRT should routinely receive an ICD. In addition, the risk of SCD has declined in patients with HFrEF, a finding that is consistent with a cumulative benefit of disease-modifying pharmacological therapies and CRT on this cause of death.

BACKGROUND: Men and women may respond differently to certain therapies for heart failure with reduced ejection fraction, including implantable cardioverter defibrillators (ICD). In an extended follow-up study of the DANISH trial (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heart Failure on Mortality), adding 4 years of additional follow-up, we examined the effect of ICD implantation according to sex. METHODS: In the DANISH trial, 1116 patients with nonischemic systolic heart failure were randomized to receive an ICD (N=556) or usual clinical care (N=550). The primary outcome was all-cause mortality. RESULTS: Of the 1116 patients randomized in the DANISH trial, 307 (27.5%) were women. During a median follow-up of 9.5 years, women had a lower associated rate of all-cause mortality (hazard ratio [HR], 0.60 [95% CI, 0.47-0.78]) cardiovascular death (HR, 0.62 [95% CI, 0.46-0.84]), nonsudden cardiovascular death (HR, 0.59 [95% CI, 0.42-0.85]), and a numerically lower rate of sudden cardiovascular death (HR, 0.70 [95% CI, 0.40-1.25]), compared with men. Compared with usual clinical care, ICD implantation did not reduce the rate of all-cause mortality, irrespective of sex (men, HR, 0.85 [95% CI, 0.69-1.06]; women, HR, 0.98 [95% CI, 0.64-1.50]; Pinteraction=0.51). In addition, sex did not modify the effect of ICD implantation on sudden cardiovascular death (men, HR, 0.57 [95% CI, 0.36-0.92]; women, HR, 0.68 [95% CI, 0.26-1.77]; Pinteraction=0.76). CONCLUSIONS: In patients with nonischemic systolic heart failure, ICD implantation did not provide an overall survival benefit, but reduced sudden cardiovascular death, irrespective of sex. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00542945.

BACKGROUND: DANISH (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators [ICDs] in Patients With Nonischemic Systolic Heart Failure on Mortality) found that primary-prevention ICD implantation was not associated with an overall survival benefit in patients with nonischemic systolic heart failure during a median follow-up of 5.6 years, although there was a beneficial effect on all-cause mortality in patients ≤70 years. This study presents an additional 4 years of follow-up data from DANISH. METHODS: In DANISH, 556 patients with nonischemic systolic heart failure were randomized to receive an ICD and 560 to receive usual clinical care and followed until June 30, 2016. In this long-term follow-up study, patients were followed until May 18, 2020. Analyses were conducted for the overall population and according to age (≤70 and >70 years). RESULTS: During a median follow-up of 9.5 years (25th-75th percentile, 7.9-10.9 years), 208/556 patients (37%) in the ICD group and 226/560 patients (40%) in the control group died. Compared with the control group, the ICD group did not have significantly lower all-cause mortality (hazard ratio [HR] 0.89, [95% CI, 0.74-1.08]; P = 0.24). In patients ≤70 years (n = 829), all-cause mortality was lower in the ICD group than the control group (117/389 [30%] versus 158/440 [36%]; HR, 0.78 [95% CI, 0.61-0.99]; P = 0.04), whereas in patients >70 years (n = 287), all-cause mortality was not significantly different between the ICD and control group (91/167 [54%] versus 68/120 [57%]; HR, 0.92 [95% CI, 0.67-1.28]; P = 0.75). Cardiovascular death showed similar trends (overall, 147/556 [26%] versus 164/560 [29%]; HR, 0.87 [95% CI, 0.70-1.09]; P = 0.20; ≤70 years, 87/389 [22%] versus 122/440 [28%]; HR, 0.75 [95% CI, 0.57-0.98]; P = 0.04; >70 years, 60/167 [36%] versus 42/120 [35%]; HR, 0.97 [95% CI, 0.65-1.45]; P = 0.91). The ICD group had a significantly lower incidence of sudden cardiovascular death in the

Background: Identification of patients with non-ischemic cardiomyopathy who benefit from prophylactic implantation of a cardioverter-defibrillator (ICD) remains an unmet clinical need. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients that benefit from prophylactic ICD-implantation. Methods: Heart-failure (DANISH) study, in which patients with non-ischemic cardiomyopathy, left-ventricular ejection fraction (LVEF) ≤35% and elevated N-terminal pro-brain natriuretic peptides (NT-proBNP) were randomized to ICD-implantation or control group. Patients were included in the PRD-substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06.00 AM). PRD was assessed using wavelet analysis according to previously validated methods. Primary endpoint was all-cause mortality. Cox-regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes mellitus, cardiac resynchronization therapy and mean heart rate. We proposed PRD ≥10deg2 as exploratory cut-off value for ICD-implantation. Results: Seven-hundred and forty-eight of the 1,116 DANISH patients qualified for the PRD-substudy. During a mean follow-up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group (p-value=0.40). In Cox-regression analysis, PRD was independently associated with mortality (HR 1.28 [1.09-1.50] per SD increase; p-value = 0.003). Moreover, PRD was significantly associated with mortality in the control group (HR 1.51 [1.25-1.81]; p<0.001) but not in the ICD-group 1.04 [0.83-1.54]; p-value=0.71). There was a significant interaction between PRD and the effect of ICD-implantation on mortality (p-value 0.008), with patients with higher PRD having the greater benefit

AIMS: Improved risk stratification to identify non-ischaemic heart failure patients who will benefit from primary prophylactic implantable cardioverter-defibrillator (ICD) is needed. We examined the potential of ventricular arrhythmia to identify patients who could benefit from an ICD. METHODS AND RESULTS: A total of 850 non-ischaemic systolic heart failure patients with left ventricle ≤35% and elevated N-terminal pro-brain natriuretic peptides had a 24-h Holter monitor recording performed. We examined present non-sustained ventricular tachycardia (NSVT), defined as ≥3 consecutive premature ventricular contractions (PVCs) with a rate of ≥100/min, and number of PVCs per hour stratified into low (<30) and high burden (≥30) groups. Outcome measures were overall mortality, sudden cardiac death (SCD), and cardiovascular death (CVD). In total, 193 patients died, 49 from SCD and 125 from CVD. Non-sustained ventricular tachycardia (365 patients) was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.47; 95% confidence interval (CI) 1.07-2.03; P = 0.02] and to CVD (HR 1.89; CI 1.25-2.87; P = 0.003). High burden PVC (352 patients) was associated with increased all-cause mortality (HR1.38; CI 1.00-1.90; P = 0.046) and with CVD (HR 1.78; CI 1.19-2.66; P = 0.005). There was no statistically significant association with SCD for neither NSVT nor PVC. In interaction analyses, neither NSVT (P = 0.56) nor high burden of PVC (P = 0.97) was associated with survival benefit from ICD implantation. CONCLUSION: Ventricular arrhythmia in non-ischaemic heart failure patients was associated with a worse prognosis but could not be used to stratify patients to ICD implantation.

Background: Atrial fibrillation (AF) in heart failure (HF) patients has been associated with a worse outcome. Similarly, excessive supraventricular ectopic activity (ESVEA) has been linked to development of AF, stroke, and death. This study aimed to investigate AF and ESVEA's association with outcomes and effect of prophylactic implantable cardioverter defibrillator (ICD) implantation in nonischemic HF patients. Methods: A total of 850 patients with nonischemic HF, left ventricle ejection fraction ≤35%, and elevated N-terminal pro-brain natriuretic peptides underwent 24 hours Holter recording. The presence of AF (≥30 seconds) and ESVEA (≥30 supraventricular ectopic complexes (SVEC) per hour or run of SVEC ≥20 beats) were registered. Outcomes were all-cause mortality, cardiovascular death (CVD), and sudden cardiac death (SCD). Results: AF was identified in 188 patients (22%) and ESVEA in 84 patients (10%). After 4 years and 11 months of follow-up, a total of 193 patients (23%) had died. AF was associated with all-cause mortality (hazard ratio [HR] 1.44; confidence interval [CI] 1.04-1.99; P = .03) and CVD (HR 1.59; CI 1.07-2.36; P = .02). ESVEA was associated with all-cause mortality (HR 1.73; CI 1.16-2.57; P = .0073) and CVD (HR 1.76; CI 1.06-2.92; P = .03). Neither AF nor ESVEA was associated with SCD. ICD implantation was not associated with an improved prognosis for neither AF (P value for interaction = .17), nor ESVEA (P value for interaction = .68). Conclusions: Both AF and ESVEA were associated with worsened prognosis in nonischemic HF. However, ICD implantation was not associated with an improved prognosis for either group.

Objectives: To examine the association between health-related quality of life (HRQoL) and mortality in patients with heart failure (HF). Background: The potential association of HRQoL and mortality in patients with HF is unclear. We investigated this association in The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICD) in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH). Methods: In DANISH, a total of 1116 patients with non-ischemic systolic HF on guideline-recommended therapy were randomized to ICD therapy or usual clinical care. HRQoL was assessed at randomization using the disease-specific Minnesota Living with Heart Failure Questionnaire (MLHFQ, 0–105, high score indicating worse HRQoL). Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) for all-cause mortality according to MLHFQ above or below 45, as recommended by a recent meta-analysis, to identify patients with poor HRQoL. Results: HRQoL was completed by 935 (84%) patients at baseline with a median follow-up of 67 months (IQR 47–83). Patients with poor HRQoL (MLHFQ score > 45, median 60 (IQR 53–71), n = 350) had a higher incidence of all-cause mortality than patients with moderate/good HRQoL (MLHFQ ≤45, median 23 (IQR 13–33), n = 585), respectively 26% vs. 18% with an unadjusted HR of 1.57 (95% CI 1.19–2.08, p =.002), and an adjusted HR of 1.39 (95% CI 1.01–1.91, p =.04). Conclusion: Poor HRQoL was associated with an increased risk of all-cause mortality after adjustment for traditional risk factors. Clinical trial registration: https: //clinicaltrials.gov/ct2/show/NCT00542945 (DANISH).

PURPOSE: The "distressed" (Type D) personality trait has been reported to be over-represented in patients with heart failure (HF) compared to the background population and may provide prognostic information for mortality. We examined the association between Type D personality and outcomes in the DANISH trial (The Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality).METHODS: The DANISH trial included a total of 1116 patients with non-ischemic HF on guideline-recommended therapy. Type D personality was assessed with the Type D Scale (DS14) at baseline and investigated through follow-up accordingly. Multivariable Cox proportional hazard models were used to compare hazard ratios (HR) of cardiovascular and all-cause mortality.RESULTS: Type D personality assessment was completed by 873 (78%) patients at baseline and Type D personality was found in 120 (14%) patients. The median follow-up was 67 months (interquartile range [IQR] 48-83). Among patients with versus without Type D personality, 22% versus 19% died from all-cause yielding similar incidence rates of 4.62 (95% CI 3.14-6.87) versus 3.95 (95% CI 3.37-4.66) per 100 person-years. The adjusted risk of all-cause mortality was not significantly different in patients with versus without Type D personality with an adjusted HR of 1.31 (95% CI 0.84-2.03, p = 0.23) with similar results for cardiovascular death (HR 1.46 (95% CI 0.88-2.44, p = 0.15).CONCLUSION: Type D personality was not significantly associated with increased risk of all-cause mortality or cardiovascular death in patients with non-ischemic HF.

The objective of this study was to determine whether a first myocardial infarction leads to increased plasma levels of hemostatic factors and high sensitive C-reactive protein (hs-CRP) and whether the association between theses biomarkers and myocardial infarction was greater at follow-up compared with baseline. Of more than 36,000 persons screened in northern Sweden, 78 developed a first myocardial infarction (on average 18 months after sampling) in a population-based, prospective, nested patient-referent study. Fifty of these had participated in a follow-up health survey (on average 8 and a half years between surveys) and were sex-matched and age-matched with 56 referents. The mean increases in hs-CRP, tissue plasminogen activator (tPA) mass, plasminogen activator inhibitor-1 mass, and tPA/plasminogen activator inhibitor-1 complex concentration and von Willebrand factor among patients and referents were comparable during follow-up. Conditional logistic regression indicated that hs-CRP was not significantly associated with first myocardial infarction in a univariate analysis, whereas high plasma levels of tPA and creatinine were significantly associated with outcome at baseline and follow-up. tPA/plasminogen activator inhibitor-1 complex was not superior to tPA as a risk marker in this study. A first myocardial infarction did not in this study induce significantly different changes in plasma levels of hs-CRP and hemostatic factors among patients compared with referents during follow-up.

BACKGROUND: The summarized importance of haemostatic and metabolic variables (insulin, lipids including lipoprotein (a) [Lp(a)] and leptin) in predicting first myocardial infarction, as well as possible interactions among these variables, have not been reported. DESIGN: A prospective case-control study nested within the Northern Sweden Health and Disease Cohort. METHODS: Sixty-two men diagnosed with a first myocardial infarction were sex- and age-matched with 124 controls. Conditional logistic regression was conducted including established risk factors, plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) mass concentration, von Willebrand factor, insulin, proinsulin, specific insulin, apolipoprotein A-I (apo A-I), Lp(a), and leptin. Interaction analysis was also performed for tPA, apo A-I, Lp(a), leptin and proinsulin. RESULTS: Smoking, low plasma levels of apo A-I and high plasma levels of cholesterol, Lp(a), tPA, PAI-1, proinsulin and leptin were associated with myocardial infarction in univariate conditional logistic regression analysis. High tPA [odds ratio (OR), 21.3; 95% confidence interval (CI), 2.04-222] and Lp(a) (OR, 7.21; 95% CI, 1.31-39.8) and low apo A-I (OR, 0.15; 95% CI, 0.02-0.93) remained significant risk determinants in multivariate analysis with smoking habits, body mass index, hypertension, cholesterol, and diabetes included as covariates. There were non-significant synergic interactions between high Lp(a) and leptin and tPA, respectively, and between high Lp(a) and low apo A-I. CONCLUSION: Plasma levels of tPA, Lp(a), and apo A-I are independently associated with subsequent development of a first myocardial infarction in men.