Natural history of cardiac involvement in myotonic dystrophy type 1 - Emphasis on the need for lifelong follow-up.

BACKGROUND: Cardiac involvement represents a major cause of morbidity and mortality in patients with myotonic dystrophy type 1 (DM1) and prevention of sudden cardiac death (SCD) is a central part of patient care. We investigated the natural history of cardiac involvement in patients with DM1 to provide an evidence-based foundation for adjustment of follow-up protocols. METHODS: Patients with genetically confirmed DM1 were identified. Data on patient characteristics, performed investigations (12 lead ECG, Holter monitoring and echocardiography), and clinical outcomes were retrospectively collected from electronic health records. RESULTS: We included 195 patients (52% men) with a mean age at baseline evaluation of 41 years (range 14-79). The overall prevalence of cardiac involvement increased from 42% to 66% after a median follow-up of 10.5 years. There was a male predominance for cardiac involvement at end of follow-up (74 vs. 44%, p < 0.001). The most common types of cardiac involvement were conduction abnormalities (48%), arrhythmias (35%), and left ventricular systolic dysfunction (21%). Only 17% of patients reported cardiac symptoms. The standard 12­lead ECG was the most sensitive diagnostic modality and documented cardiac involvement in 24% at baseline and in 49% at latest follow-up. However, addition of Holter monitoring and echocardiography significantly increased the diagnostic yield with 18 and 13% points at baseline and latest follow-up, respectively. Despite surveillance 35 patients (18%) died during follow-up; seven due to SCD. CONCLUSIONS: In patients with DM1 cardiac involvement was highly prevalent and developed during follow-up. These findings justify lifelong follow-up with ECG, Holter, and echocardiography. CLINICAL PERSPECTIVE: What is new? What are the clinical implications?

Association between QRS shortening and mortality after cardiac resynchronization therapy: Results from the DANISH study.

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.

Computed tomography or chest X-ray to assess pulmonary congestion in dyspnoeic patients with acute heart failure.

AIMS: While computed tomography (CT) is widely acknowledged as superior to chest radiographs for acute diagnostics, its efficacy in diagnosing acute heart failure (AHF) remains unexplored. This prospective study included consecutive patients with dyspnoea undergoing simultaneous low-dose chest CT (LDCT) and chest radiographs. Here, we aimed to determine if LDCT is superior to chest radiographs to confirm pulmonary congestion in dyspnoeic patients with suspected AHF. METHODS AND RESULTS: An observational, prospective study, including dyspnoeic patients from the emergency department. All patients underwent concurrent clinical examination, laboratory tests, echocardiogram, chest radiographs, and LDCT. The primary efficacy measure to compare the two radiological methods was conditional odds ratio (cOR). The primary outcome was adjudicated AHF, ascertained by comprehensive expert consensus. The secondary outcome, echo-bnp AHF, was an objective AHF diagnosis based on echocardiographic cardiac dysfunction, elevated cardiac filling pressure, loop diuretic administration, and NT-pro brain natriuretic peptide > 300 pg/mL. Of 228 dyspnoeic patients, 64 patients (28%) had adjudicated AHF, and 79 patients (35%) had echo-bnp AHF. Patients with AHF were older (78 years vs. 73 years), had lower left ventricular ejection fraction (36% vs. 55%), had higher elevated left ventricular filling pressures (98% vs. 18%), and had higher NT-pro brain natriuretic peptide levels (3628 pg/mL vs. 470 pg/mL). The odds to diagnose adjudicated AHF and echo-bnp AHF were up to four times greater using LDCT (cOR: 3.89 [2.15, 7.06] and cOR: 2.52 [1.45, 4.38], respectively). For each radiologic sign of pulmonary congestion, the LDCT provided superior or equivalent results as the chest radiographs, and the interrater agreement was higher using LDCT (kappa 0.88 [95% CI: 0.81, 0.95] vs. 0.73 [95% CI: 0.63, 0.82]). As first-line imaging modality, LDCT will find one additional adjudicated AHF in 12.5 patients and prevent one false-positive in 20 patients. Similar results were demonstrated for echo-bnp AHF. CONCLUSIONS: In consecutive dyspnoeic patients admitted to the emergency department, LDCT is significantly better than chest radiographs in detecting pulmonary congestion.

Estimated Glomerular Filtration Rate and Implantable Cardioverter-Defibrillator in Nonischemic Systolic Heart Failure: Extended Follow-Up of DANISH.

BACKGROUND: Patients with heart failure and chronic kidney disease (CKD) may have an increased risk of death from causes competing with arrhythmic death, which could have implications for the efficacy of implantable cardioverter-defibrillators (ICDs). We examined the long-term effects of primary prophylactic ICD implantation, compared with usual care, according to baseline CKD status in an extended follow-up study of DANISH (Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality). METHODS AND RESULTS: In the DANISH trial, 1116 patients with nonischemic heart failure with reduced ejection fraction were randomized to receive an ICD (N=556) or usual care (N=550). Outcomes were analyzed according to CKD status (estimated glomerular filtration rate ≥/<60 mL/min per 1.73 m2) at baseline. In total, 1113 patients had an available estimated glomerular filtration rate measurement at baseline (median estimated glomerular filtration rate 73 mL/min per 1.73 m2), and 316 (28%) had CKD. During a median follow-up of 9.5 years, ICD implantation, compared with usual care, did not reduce the rate of all-cause mortality (no CKD, HR, 0.82 [95% CI, 0.64-1.04]; CKD, HR, 1.02 [95% CI, 0.75-1.38]; Pinteraction=0.31) or cardiovascular death (no CKD, HR, 0.77 [95% CI, 0.58-1.03]; CKD, HR, 1.05 [95% CI, 0.73-1.51]; Pinteraction=0.20), irrespective of baseline CKD status. Similarly, baseline CKD status did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (no CKD, HR, 0.57 [95% CI, 0.32-1.00]; CKD, HR, 0.65 [95% CI, 0.34-1.24]; Pinteraction=0.70). CONCLUSIONS: ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce the rate of sudden cardiovascular death, regardless of baseline kidney function in patients with nonischemic heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945.

Thoracentesis to alleviate pleural effusion in acute heart failure: study protocol for the multicentre, open-label, randomised controlled TAP-IT trial.

INTRODUCTION: Pleural effusion is present in half of the patients hospitalised with acute heart failure. The condition is treated with diuretics and/or therapeutic thoracentesis for larger effusions. No evidence from randomised trials or guidelines supports thoracentesis to alleviate pleural effusion due to acute heart failure. The Thoracentesis to Alleviate cardiac Pleural effusion Interventional Trial (TAP-IT) will investigate if a strategy of referring patients with acute heart failure and pleural effusion to up-front thoracentesis by pleural pigtail catheter insertion in addition to pharmacological therapy compared with pharmacological therapy alone can increase the number of days the participants are alive and not hospitalised during the 90 days following randomisation. METHODS AND ANALYSIS: TAP-IT is a pragmatic, multicentre, open-label, randomised controlled trial aiming to include 126 adult patients with left ventricular ejection fraction ≤45% and a non-negligible pleural effusion due to heart failure. Participants will be randomised 1:1, stratified according to site and anticoagulant treatment, and assigned to referral to up-front ultrasound-guided pleural pigtail catheter thoracentesis in addition to standard pharmacological therapy or to standard pharmacological therapy only. Thoracentesis is performed according to local guidelines and can be performed in participants in the pharmacological treatment arm if their condition deteriorates or if no significant improvement is observed within 5 days. The primary endpoint is how many days participants are alive and not hospitalised within 90 days from randomisation and will be analysed in the intention-to-treat population. Key secondary outcomes include 90-day mortality, complications, readmissions, and quality of life. ETHICS AND DISSEMINATION: The study has been approved by the Capital Region of Denmark Scientific Ethical Committee (H-20060817) and Knowledge Center for Data Reviews (P-2021-149). All participants will sign an informed consent form. Enrolment began in August 2021. Regardless of the nature, results will be published in a peer-reviewed medical journal. TRIAL REGISTRATION NUMBER: NCT05017753.

Angiotensin receptor blockers in patients with hypertrophic cardiomyopathy: A comparison of VANISH and INHERIT randomized trials.

PURPOSE: To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM). METHODS: We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results. RESULTS: No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P = .4). With the exception of tissue Doppler systolic (s') velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM. CONCLUSION: Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.

Initiation of eplerenone or spironolactone, treatment adherence, and associated outcomes in patients with new-onset heart failure with reduced ejection fraction: a nationwide cohort study.

BACKGROUND: The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort. METHODS: We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage. RESULTS: We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001). CONCLUSIONS: In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

Reduced inferior wall longitudinal strain is associated with malignant arrhythmias in non-ischemic heart failure.

BACKGROUND: Reduced systolic myocardial function in the inferior region of the left ventricle has been suggested to be associated with malignant arrhythmias. We tested this hypothesis in patients with non-ischemic heart failure. METHODS: Patients with non-ischemic heart failure (left ventricular ejection fraction [LVEF] < 35%) were evaluated by 2D-speckle-tracking echocardiography. The regional longitudinal strain was calculated for each of the six left ventricular walls. The reduced regional function was defined as strain below the median. The outcome was a composite of sudden cardiac death, admission with sustained ventricular arrhythmia, resuscitated cardiac arrest, and appropriate therapy from a primary prophylactic implantable cardioverter defibrillator. Time-to-first-event analysis was performed using a Cox model. RESULTS: From two centers, 401 patients were included (median age: 63 years, 72% male) with a median LVEF of 25% (interquartile range [IQR] 20;30), and a median inferior wall strain of -9.0% (-12.5; -5.4). During a median follow-up of 4.0 years, 52 outcomes occurred. After multivariate adjustment for clinical and electrocardiographic parameters, inferior wall strain was independently associated with the outcome (HR 2.50 [1.35; 4.62], p = .003). No independent association was found between the composite outcome and reduced strain in any of the other left ventricular walls, Global Longitudinal Strain (HR 1.66 [0.93; 2.98], p = .09), or LVEF (HR 1.33 [0.75; 2.33], p = .33). CONCLUSIONS: Below median strain in the left ventricular inferior region was independently associated with a 2.5-fold increase in the risk of malignant arrhythmias and sudden cardiac death in patients with non-ischemic heart failure.

Right Ventricular Free Wall Strain and Effect of Defibrillator Implantation in Patients With Nonischemic Systolic Heart Failure.

BACKGROUND: Patients with nonischemic systolic heart failure have an increased risk of malignant ventricular arrhythmias and sudden cardiovascular death. Because the risk is less pronounced than for patients with ischemic cause of heart failure more discriminating tools are needed to identify patients most likely to benefit from implantable cardioverter-defibrillator (ICD) implantation. Right ventricular (RV) dysfunction is associated with a worse prognosis, but whether RV free wall strain (RV-FWS) measured with echocardiography can identify the patients most likely to benefit from ICD implantation is not known. METHODS AND RESULTS: In this extended follow-up analysis of the Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial, RV-FWS was measured with echocardiography in 445 patients before randomization. RV dysfunction was defined as an RV-FWS of greater than -20%. The primary end point was all-cause mortality. The median RV-FWS was -18% (quartiles -23% to -14%), and RV dysfunction was measured in 255 patients (57%). During a median follow-up of 5.7 years, 170 patients (38%) died. There was a statistically significant interaction between RV dysfunction and the effect of ICD implantation (P = .003), also after adjusting for known cardiovascular risk factors (P = .01). ICD implantation significantly decreased all-cause mortality in patients with RV dysfunction (hazard ratio 0.54, 95% confidence interval 0.36-0.80, P = .002), but not in patients with normal RV function (hazard ratio 1.34, 95% confidence interval 0.84-2.12, P = .22). CONCLUSIONS: In patients with nonischemic systolic heart failure, RV dysfunction on echocardiography was associated with a greater effect of ICD implantation and could be used to select patients with benefit from ICD treatment.

The COVID-19 in athletes (COVA) study: a national study on cardio-pulmonary involvement of SARS-CoV-2 infection among elite athletes.

Background: COVID-19 can cause cardiopulmonary involvement. Physical activity and cardiac complications can worsen prognosis, while pulmonary complications can reduce performance. Aims: To determine the prevalence and clinical implications of SARS-CoV-2 cardiopulmonary involvement in elite athletes. Methods: An observational study between 1 July 2020 and 30 June 2021 with the assessment of coronary biomarkers, electrocardiogram, echocardiography, Holter-monitoring, spirometry, and chest X-ray in Danish elite athletes showed that PCR-tested positive for SARS-CoV-2. The cohort consisted of male football players screened weekly (cohort I) and elite athletes on an international level only tested if they had symptoms, were near-contact, or participated in international competitions (cohort II). All athletes were categorized into two groups based on symptoms and duration of COVID-19: Group 1 had no cardiopulmonary symptoms and duration ≤7 days, and; Group 2 had cardiopulmonary symptoms or disease duration >7 days. Results: In total 121 athletes who tested positive for SARS-CoV-2 were investigated. Cardiac involvement was identified in 2/121 (2%) and pulmonary involvement in 15/121 (12%) participants. In group 1, 87 (72%), no athletes presented with signs of cardiac involvement, and 8 (7%) were diagnosed with radiological COVID-19-related findings or obstructive lung function. In group 2, 34 (28%), two had myocarditis (6%), and 8 (24%) were diagnosed with radiological COVID-19-related findings or obstructive lung function. Conclusions: These clinically-driven data show no signs of cardiac involvement among athletes who tested positive for SARS-CoV-2 infection without cardiopulmonary symptoms and duration <7 days. Athletes with cardiopulmonary symptoms or prolonged duration of COVID-19 display, exercise-limiting cardiopulmonary involvement.

Impact of Nationwide COVID-19 Lockdowns on the Implantation Rate of Cardiac Implantable Electronic Devices.

AIM: The COVID-19 pandemic resulted in a significant decrease in the number of hospital admissions for severe emergent cardiovascular diseases during lockdowns worldwide. This study aimed to determine the impact of both the first and the second Danish nationwide lockdown on the implantation rate of cardiac implantable electronic devices (CIEDs). METHODS: We retrospectively analysed the number of CIED implantations performed in Denmark and stratified them into 3-week intervals. RESULTS: The total number of de novo CIED implantations decreased during the first lockdown by 15.5% and during the second by 5.1%. Comparing each 3-week interval using rate ratios, a significant decrease in the daily rates of the total number of de novo and replacement CIEDs (0.82, 95% CI [0.70, 0.96]), de novo CIEDs only (0.82, 95% CI [0.69, 0.98]), and non-acute pacemaker implantations (0.80, 95% CI [0.63, 0.99]) was observed during the first interval of the first lockdown. During the second lockdown (third interval), a significant decrease was seen in the daily rates of de novo CIEDs (0.73, 95% CI [0.55, 0.97]), and of pacemakers in total during both the second (0.78, 95% CI [0.62, 0.97]) and the third (0.60, 95% CI [0.42, 0.85]) intervals. Additionally, the daily rates of acute pacemaker implantation decreased during the second interval (0.47, 95% CI [0.27, 0.79]) and of non-acute implantation during the third interval (0.57, 95% CI [0.38, 0.84]). A significant increase was observed in the number of replacement procedures during the first interval of the second lockdown (1.70, 95% CI [1.04, 2.85]). CONCLUSIONS: Our study found only modest changes in CIED implantations in Denmark during two national lockdowns.

Atrial fibrillation onset before heart failure or vice versa: what is worst? A nationwide register study.

AIMS: Atrial fibrillation (AF) and heart failure (HF) often coexist. However, whether AF onset before HF or vice versa is associated with the worst outcome remains unclear. A consensus of large studies can guide future research and preventive strategies to better target high-risk patients. METHODS AND RESULTS: We included all Danish cases with the coexistence of AF and HF (2005-17) using nationwide registries. Patients were divided into three separate groups (i) AF before HF, (ii) HF before AF, or (iii) AF and HF diagnosed concurrently (±30 days). Adjusting landmark Cox analyses (index date was the time of the latter diagnosis of AF or HF) were used for evaluating the association of the three groups with a composite outcome of ischaemic stroke or death. Among a total of 49 042 patients included, 40% had AF before HF, 27% had HF before AF, and 33% had AF and HF diagnosed concurrently. The composite endpoint accrued more often in patients with HF before AF compared to the two other groups (<0.001), and this remained significant in the adjusted analyses with hazard ratios (95% confidence intervals) of 1.26 (1.22-1.30) compared to AF before HF. Finally, antihypertensive treatment, oral anticoagulants, amiodarone, statins, and AF ablation were associated with a lower hazard ratio of the composite endpoint (all < 0.001). CONCLUSIONS: In this large Danish national cohort, diagnosis of HF before AF was associated with an increased absolute risk of death compared to AF before HF and AF and HF diagnosed concurrently. Antihypertensive treatment, oral anticoagulants, amiodarone, statins, and AF ablation may improve prognosis.

Long term mortality in patients with hypertrophic cardiomyopathy - A Danish nationwide study.

Background: Patients with hypertrophic cardiomyopathy (HCM) are generally regarded as having increased risk of arrhythmia, stroke, heart failure, and sudden cardiac death, but reported mortality rates vary considerably and originate from selected populations. Study objective: We aimed to investigate the long-term mortality rate in a nationwide cohort of patients with HCM compared to a matched cohort from the general Danish population. Methods: All patients with a first-time HCM diagnosis in Denmark between January 1, 2007 and December 31, 2018 were identified through nationwide registries. In the main analysis, two visits in an outpatient clinic were required in order to increase specificity. Patients were matched to controls from the background population in a 1:3 ratio based on age, sex, selected comorbidities and date of HCM. Mortalities were compared using Kaplan Meier estimator and multivariable Cox regression models. Results: We identified 3126 patients with a first-time diagnosis of HCM. 1197 patients had at least two visits in the outpatient clinic (43 % female, median age 63.1 [25th-75th percentile 52.1-72.1] years). All-cause mortality was significantly higher in HCM patients than in matched controls: 10-year probabilities of death were 36.4 % (95 % CI 30.2-43.5 %) for HCM patients and 19.4 % (95 % CI 16.8-22.5 %) for controls. After adjusting for additional comorbidities and medications, a diagnosis with HCM was associated with an increased mortality rate (HR 1.48 (95 % CI 1.18-1.84, p = 0.001)). Conclusion: Compared to matched controls from the background population, presence of HCM was associated with a significant increase in mortality rate.

Myocardial fibrosis and ventricular ectopy in patients with non-ischemic systolic heart failure: results from the DANISH trial.

Patients with non-ischemic systolic heart failure (HF) have increased risk of sudden cardiovascular death (SCD). The initiation and substrate for ventricular arrhythmias remains poorly understood. Our purpose was to describe the relationship between cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) and Holter recorded ventricular arrhythmic activity. Patients from the DANISH trial underwent a Holter-recording and a CMR-scan. The presence of non-sustained ventricular tachycardia (NSVT) and premature ventricular contractions (PVC) were examined in relation to presence and amount of LGE. Outcome measures were all-cause mortality and SCD. Overall, 180 patients were included. LGE was present in 86 (47%). NSVT occurred in 72 (40%), not different according to LGE status (p = 0.65). The amount of LGE was not correlated to the occurrence of NSVT (p = 0.40). The occurrence of couplet PVCs (p = 0.997), frequent PVCs (p = 0.12), PVCs in bigemini (p = 0.29), in trigemini (p = 0.26), or in quadrimini (p = 0.35) did not differ according to LGE status. LGE was significantly associated with risk of all-cause mortality (HR 2.14; 95% CI 1.05-4.37, p = 0.04). NSVT did not increase risk of all-cause mortality in either patients with LGE (HR 1.00; 95% CI 0.46-2.16, p = 0.996) or without LGE (HR 1.37; 95% CI 0.46-4.08, p = 0.57). There was no interaction between LGE and NSVT for the risk of all-cause mortality (p = 0.62). In patients with non-ischemic systolic HF there was no relationship between the presence of LGE and NSVT or any other Holter recorded ventricular tachyarrhythmia. LGE was associated with increased risk of mortality, independent of the presence of NSVT.

Cholesterol not particle concentration mediates the atherogenic risk conferred by apolipoprotein B particles: a Mendelian randomization analysis.

BACKGROUND AND AIMS: The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. METHOD AND RESULTS: We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses.In univariate MR analysis, both exposures associated with CAD (ßnon-HDL-C = 0.40, P = 2.8 × 10-48 and ßapoB = 0.38, P = 1.3 × 10-44). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P = 3.9 × 10-5), while adding apoB into the model including non-HDL-C did not (P = 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P < 2.1 × 10-4 (0.05/235). Fifty-one variants associated at genome-wide significance. CONCLUSION: Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.

Efficacy of Implantable Cardioverter Defibrillator in Nonischemic Systolic Heart Failure According to Sex: Extended Follow-Up Study of the DANISH Trial.

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.

NT-proBNP and ICD in Nonischemic Systolic Heart Failure: Extended Follow-Up of the DANISH Trial.

OBJECTIVES: In this extended follow-up study of the DANISH (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality) trial, adding 4 years of additional follow-up, we examined the effect of implantable cardioverter-defibrillator (ICD) implantation according to baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) level. BACKGROUND: In the DANISH trial, NT-proBNP level at baseline appeared to modify the response to ICD implantation. METHODS: In the DANISH trial, 1,116 patients with nonischemic systolic HF were randomized to receive an ICD (N = 556) or usual clinical care (N = 550). Outcomes were analyzed according to NT-proBNP levels (below/above median) at baseline. The primary outcome was death from any cause. RESULTS: All 1,116 patients in the DANISH trial had an available NT-proBNP measurement at baseline (median: 1,177 pg/mL; range: 200-22,918 pg/mL). There was a trend toward a reduction in all-cause death with ICD implantation, compared with usual clinical care, in patients with NT-proBNP levels lower than the median (HR: 0.75 [95% CI: 0.55-1.03]), but not in those with higher NT-proBNP levels (HR: 0.95 [95% CI: 0.74-1.21]) (Pinteraction = 0.28). Similarly, ICD implantation significantly reduced the rate of cardiovascular (CV) and sudden cardiovascular death (SCD) in patients with NT-proBNP levels lower than the median (CV death, HR: 0.69 [95% CI: 0.47-1.00]; SCD, HR: 0.37 [95% CI: 0.19-0.75]), but not in those with higher levels (CV death, HR: 0.94 [95% CI: 0.70-1.25]; SCD, HR: 0.86 [95% CI: 0.49-1.51]) (Pinteraction = 0.20 and 0.08 for CV death and SCD, respectively). CONCLUSIONS: Lower baseline NT-proBNP levels could identify patients with nonischemic systolic HF who may derive benefit from ICD implantation. (Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators in Patients with Non-ischemic Systolic Heart Failure on Mortality [DANISH]; NCT00542945).