The role of empagliflozin-induced metabolic changes for cardiac function in patients with type 2 diabetes. A randomized cross-over magnetic resonance imaging study with insulin as comparator.

BACKGROUND: Metabolic effects of empagliflozin treatment include lowered glucose and insulin concentrations, elevated free fatty acids and ketone bodies and have been suggested to contribute to the cardiovascular benefits of empagliflozin treatment, possibly through an improved cardiac function. We aimed to evaluate the influence of these metabolic changes on cardiac function in patients with T2D. METHODS: In a randomized cross-over design, the SGLT2 inhibitor empagliflozin (E) was compared with insulin (I) treatment titrated to the same level of glycemic control in 17 patients with type 2 diabetes, BMI of > 28 kg/m2, C-peptide > 500 pM. Treatments lasted 5 weeks and were preceded by 3-week washouts (WO). At the end of treatments and washouts, cardiac diastolic function was determined with magnetic resonance imaging from left ventricle early peak-filling rate and left atrial passive emptying fraction (primary and key secondary endpoints); systolic function from left ventricle ejection fraction (secondary endpoint). Coupling between cardiac function and fatty acid concentrations, was studied on a separate day with a second scan after reduction of plasma fatty acids with acipimox. Data are Mean ± standard error. Between treatment difference (ΔT: E-I) and treatments effects (ΔE: E-WO or ΔI: I -WO) were evaluated using Students' t-test or Wilcoxon signed rank test as appropriate. RESULTS: Glucose concentrations were similar, fatty acids, ketone bodies and lipid oxidation increased while insulin concentrations decreased on empagliflozin compared with insulin treatment. Cardiac diastolic and systolic function were unchanged by either treatment. Acipimox decreased fatty acids with 35% at all visits, and this led to reduced cardiac diastolic (ΔT: -51 ± 22 ml/s (p < 0.05); ΔE: -33 ± 26 ml/s (ns); ΔI: 37 ± 26 (ns, p < 0.05 vs ΔE)) and systolic function (ΔT: -3 ± 1% (p < 0.05); ΔE: -3 ± 1% (p < 0.05): ΔI: 1 ± 2 (ns, ns vs ΔE)) under chronotropic stress during empagliflozin compared to insulin treatment. CONCLUSIONS: Despite significant metabolic differences, cardiac function did not differ on empagliflozin compared with insulin treatment. Impaired cardiac function during acipimox treatment, could suggest greater cardiac reliance on lipid metabolism for proper function during empagliflozin treatment in patients with type 2 diabetes. TRIAL REGISTRATION: EudraCT 2017-002101-35, August 2017.

Periodic Repolarization Dynamics Identifies ICD Responders in Nonischemic Cardiomyopathy: A DANISH Substudy.

BACKGROUND: Identification of patients with nonischemic cardiomyopathy who may benefit from prophylactic implantation of a cardioverter-defibrillator. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients who will benefit from prophylactic implantable cardioverter defibrillator (ICD) implantation. METHODS: We performed a post hoc analysis of DANISH (Danish ICD Study in Patients With Dilated Cardiomyopathy), in which patients with nonischemic cardiomyopathy, left ventricular ejection fraction (LVEF) ≤35%, and elevated NT-proBNP (N-terminal probrain natriuretic peptides) 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). PRD was assessed using wavelet analysis according to previously validated methods. The primary end point was all-cause mortality. Cox regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes, cardiac resynchronization therapy, and mean heart rate. We proposed PRD ≥10 deg2 as an exploratory cut-off value for ICD implantation. RESULTS: A total of 748 of the 1116 patients in DANISH 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=0.40). In Cox regression analysis, PRD was independently associated with mortality (hazard ratio [HR], 1.28 [95% CI, 1.09-1.50] per SD increase; P=0.003). PRD was significantly associated with mortality in the control group (HR, 1.51 [95% CI, 1.25-1.81]; P<0.001) but not in the ICD group (HR, 1.04 [95% CI, 0.83-1.54]; P=0.71). There was a significant interaction between PRD and the effect of ICD implantation on mortality (P=0.008), with patients with higher PRD having greater benefit in terms of mortality reduction. ICD implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10 deg2 (HR, 0.54 [95% CI, 0.34-0.84]; P=0.006; number needed to treat=6), but not in the 468 patients with PRD <10 deg2 (HR, 1.17 [95% CI, 0.77-1.78]; P=0.46; P for interaction=0.01). CONCLUSIONS: Increased PRD identified patients with nonischemic cardiomyopathy in whom prophylactic ICD implantation led to significant mortality reduction.

The left atrial appendage closure by surgery-2 (LAACS-2) trial protocol rationale and design of a randomized multicenter trial investigating if left atrial appendage closure prevents stroke in patients undergoing open-heart surgery irrespective of preoperative atrial fibrillation status and stroke risk.

BACKGROUND: Current recommendations regarding the use of surgical left atrial appendage (LAA) closure to prevent thromboembolisms lack high-level evidence. Patients undergoing open-heart surgery often have several cardiovascular risk factors and a high occurrence of postoperative atrial fibrillation (AF)-with a high recurrence rate-and are thus at a high risk of stroke. Therefore, we hypothesized that concomitant LAA closure during open-heart surgery will reduce mid-term risk of stroke independently of preoperative AF status and CHA2DS2-VASc score. METHODS: This protocol describes a randomized multicenter trial. Consecutive participants ≥18 years scheduled for first-time planned open-heart surgery from cardiac surgery centers in Denmark, Spain, and Sweden are included. Both patients with a previous diagnosis of paroxysmal or chronic AF, as well as those without AF, are eligible to participate, irrespective of their CHA2DS2-VASc score. Patients already planned for ablation or LAA closure during surgery, with current endocarditis, or where follow-up is not possible are considered noneligible. Patients are stratified by site, surgery type, and preoperative or planned oral anticoagulation treatment. Subsequently, patients are randomized 1:1 to either concomitant LAA closure or standard care (ie, open LAA). The primary outcome is stroke, including transient ischemic attack, as assigned by 2 independent neurologists blinded to the treatment allocation. To recognize a 60% relative risk reduction of the primary outcome with LAA closure, 1,500 patients are randomized and followed for 2 years (significance level of 0.05 and power of 90%). CONCLUSIONS: The LAACS-2 trial is likely to impact the LAA closure approach in most patients undergoing open-heart surgery. TRIAL REGISTRATION: NCT03724318.

Feasibility of screening for atrial fibrillation in a domiciliary setting: opportunistic one-time screening at preventive home visits in municipalities.

Current evidence base for atrial fibrillation (AF) screening is insufficient. An important finding in the STROKESTOP study was that non-participants had significantly worse outcomes. In a group of potentially non-participants feasibility of opportunistic screening in a domiciliary setting with municipality preventive home visits to citizens ≥75 years was investigated. Handheld ECG device was used by trained municipality caregivers followed by cardiologist assessment. Eighty-five percent consented to being screened, and seven of 477 screened were found with AF. Opportunistic screening in preventive home visits had a high participation rate and was feasible. Randomized trials are needed before making any firm conclusions.

Atrial fibrillation is a marker of increased mortality risk in nonischemic heart failure-Results from the DANISH trial.

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.

Prevalence and prognostic association of ventricular arrhythmia in non-ischaemic heart failure patients: results from the DANISH trial.

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.

Increasing population height and risk of incident atrial fibrillation: the Copenhagen City Heart Study.

Aims: The incidence of atrial fibrillation (AF) has increased significantly over the last decades. Population height is changing in many countries. Height is an important risk factor for AF. The aim of the present study was to assess the role of changes in population height in the increased risk of AF. Methods and results: The Copenhagen City Heart Study comprises 18 852 randomly selected men and women aged 20-93 years, studied in four separate cross-sectional surveys in 1976-78, 1981-83, 1991-94, and 2001-03, including physical examination, electrocardiogram (ECG), and standard questionnaires. Hospitalization and mortality data were collected from public registers. Prevalent AF was determined from ECGs and incident AF from register diagnoses. During follow-up, age-standardized prevalence of AF increased significantly from 1.35% to 2.11% in men and from 0.67% to 1.07% in women (P < 0.001). Incident AF increased four-fold in both men and women [hazard ratio (HR) 4.16, 95% confidence interval (CI) 3.27-5.29; P < 0.001]. In multivariable Fine and Gray subdistribution hazards regression analyses, height was consistently an important risk factor for incident AF with HRs between 1.35 (95% CI 1.10-1.66; P = 0.004) and 1.65 (95% CI 1.40-1.93; P < 0.001). Population height increased with 3.3 cm for men and 2.1 cm for women, and population attributable risks for height was 20-30%. Conclusion: Height is a powerful risk factor for AF. Adult height is attained at age 20, while AF incidence occurs 50 years later. Given a causal relationship between height and AF incidence, increased population height in Denmark will contribute to an increase in AF occurrence for at least 25 more years.

Higher burden of supraventricular ectopic complexes early after catheter ablation for atrial fibrillation is associated with increased risk of recurrent atrial fibrillation.

Aims: Early identification of patients who could benefit from early re-intervention after catheter ablation is highly warranted. Our aim was to investigate the association between post-procedural burden of supraventricular ectopic complexes (SVEC) and the risk of long-term atrial fibrillation (AF) recurrence. Methods and results: A total of 125 patients undergoing catheter ablation for AF were included. Patients underwent 7-day Holter recordings immediately post-procedural. The number of SVEC in post-procedural Holter recordings was categorized into quartiles: 0-72, 73-212, 213-782 and ≥ 783 SVEC/day. Long-term AF recurrence was defined as a combined endpoint of AF ≥ 1 min during follow-up Holter recordings, cardioversion or hospitalization for AF after a 3-month blanking period and within 24 months of follow-up. High post-procedural supraventricular ectopy burden was associated with an increased risk of long-term AF recurrence in a dose-dependent manner (≥ 783 SVEC: HR 4.6 [1.9-11.5], P < 0.001) irrespective of AF recurrence during the blanking period or other risk factors. In patients with early AF recurrence < 90 days after catheter ablation ectopy burden was also highly predictive of long-term AF recurrence (SVEC ≥ 213: HR 3.0 [1.3-6.7], P = 0.007). Correspondingly, patients with early AF recurrence but low ectopy burden remained at low risk of long-term AF recurrence after the blanking period. Conclusion: Our results indicate that post-procedural ectopy burden is highly associated with long-term AF recurrence and could be a potent risk marker for selection of patients for early re-ablation. Development of future ablation risk stratification and strategies should include focus on post-procedural ectopy burden.

Stromal cell-derived factor 1α (SDF-1α): A marker of disease burden in patients with atrial fibrillation.

OBJECTIVES: Stromal cell-derived factor 1a (SDF-1α), is a chemokine and is able to home hematopoietic progenitor cells to injured areas of heart tissue for structural repair. Previous studies have found increased levels of SDF-1α in several cardiac diseases, but only few studies have investigated SDF-1α in patients with atrial fibrillation (AF). We aimed to test SDF-1α in a large cohort of patients with AF and its role as a prognostic marker. DESIGN: Between January 1st 2008 to December 1st 2012, 290 patients with ECG documented AF were enrolled from the in- and outpatient clinics at the Department of Cardiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark. Plasma levels of SDF-1α were measured using ELISA technique. Clinical data were registered and patient follow-up was conducted. RESULTS: Patients with permanent AF had significantly higher SDF-1α levels (2199.5 pg/ml) than the patients with paroxysmal AF (1982.0 pg/ml) and persistent AF (1906.0 pg/ml), p < 0.0005. Higher SDF-1α level was associated with longer time spent in the hospital per readmission, p < 0.05. CONCLUSION: In AF patients, a higher SDF-1α level was found in patients with a more progressive state of arrhythmia and was associated with longer hospitalizations. These findings suggest that SDF-1α could prove valuable in risk stratification and evaluating the disease burden in AF patients.

Complete paroxysmal atrioventricular block in a 2-year-old girl.

We present a case of atypical syncope in a 2-year-old, otherwise healthy girl. The patient presented with three episodes of syncope without any precipitating factors and no family history of sudden unexpected death. Holter monitoring revealed 24 events of complete atrioventricular block lasting up to 6 seconds. A normal 12-lead electrocardiogram does not necessarily exclude cardiac disease, and Holter monitoring is warranted in children with atypical syncope.

Left atrial passive emptying function is preserved in patients with permanent atrial fibrillation--a 320-slice multidetector computed tomography study.

OBJECTIVE: Left atrial (LA) mechanical function is thought to be virtually inexistent in patients with permanent atrial fibrillation (AF). Due to recent advances in multidetector computed tomography (MDCT) technology, it is now possible to acquire images of the entire heart in a single heartbeat. The objective of this study was to compare individual components of LA function assessed by MDCT in patients with permanent AF and patients in sinus rhythm (SR). METHODS: 320-slice MDCT was performed in 30 patients with permanent AF. Measurements of LA volumes during the cardiac cycle were compared to 30 patients in SR, who were matched with respect to age, sex, left ventricular ejection fraction and body surface area. RESULTS: LA volumes were significantly larger in patients with AF than SR patients at all times during the cardiac cycle (LA maximal volume; 82 vs. 55 ml/m(2), p < 0.0001, LA minimal volume; 71 vs. 30 ml/m(2), p < 0.0001). However, except for the absence of active LA emptying, the overall trend of the LA time-volume curve was similar in patients with AF and SR. CONCLUSION: Compared to SR patients, patients with permanent AF have significantly increased LA volumes throughout the cardiac cycle. Yet, a residual hemodynamic role of LA function may be maintained during permanent AF.

Predictive value of casual ECG-based resting heart rate compared with resting heart rate obtained from Holter recording.

BACKGROUND: Elevated resting heart rate (RHR) is associated with cardiovascular mortality and morbidity. Assessment of heart rate (HR) from Holter recording may afford a more precise estimate of the effect of RHR on cardiovascular risk, as compared to casual RHR. Comparative analysis was carried out in an age-stratified subsample of 131 subjects in the Copenhagen City Heart Study (CCHS). METHODS: Casual RHR was assessed from electrocardiograms recorded during clinical assessment. Hourly daytime HRs were mapped by Holter recording. Holter RHR was defined as the average of the lowest 3 hourly HRs recorded and mean HR calculated from all daytime HRs. Follow-up was recorded from public registers. Outcome measure was hazard rate for the combined endpoint of cardiovascular mortality, non-fatal heart failure and non-fatal acute myocardial infarction. Comparison of casual RHR, Holter RHR and mean HR by Multivariate Cox regression was performed. RESULTS: A total of 57 composite endpoints occurred during 17.1 years of follow-up. Regression analysis suggests correlation between Casual RHR and Holter RHR. Multivariate Cox regression analysis adjusted for gender and age demonstrated hazard rates of 1.02 (p = 0.079) for casual RHR, 1.04 (p = 0.036*) for Holter RHR, and 1.03 (p = 0.093) for mean HR for each 10 beat increment in HR. CONCLUSIONS: In a comparative analysis on the correlation and significance of differing RHR measurement modalities RHR measured by 24-hour Holter recording was found to be marginally superior as a predictor of cardiovascular morbidity and mortality. The results presented here do not however warrant the abandonment of a tested epidemiological variable.

The acute effects of furosemide in acute heart failure assessed by remote dielectric sensing. A protocol.

INTRODUCTION: Intravenous loop diuretics have been a key component in treating pulmonary oedema since the 1960s and have a Class 1 recommendation in the 2021 guidelines for acute heart failure (AHF). While the diuretic effect of loop diuretics is well established, it remains unclear how furosemide influences pulmonary congestion and cardiac filling pressures in the hyperacute phase before significant diuresis occurs. METHODS: This was a prospective study of adult patients with AHF and objective signs of pulmonary congestion admitted to the cardiac ward. Remote dielectric sensing (ReDS) will directly measure lung fluid content, and cardiac filling pressures will be assessed by echocardiography with Doppler and strain analysis. CONCLUSIONS: This study will examine if furosemide leads to a hyperacute reduction in pulmonary congestion assessed by ReDS independent of diuretic effects in patients with AHF. We hypothesise that the haemodynamic effect of furosemide shown on pulmonary congestion may explain the subjective instant relief in patients with AHF receiving furosemide. FUNDING: Dr. Grand's salary during this project is supported by a research grant from the Danish Cardiovascular Academy funded by Novo Nordisk Foundation grant number NNF20SA0067242 and by the Danish Heart Foundation. TRIAL REGISTRATION: This protocol was approved by the Scientific Ethical Committee, H-23029822, and the Danish Data Protection Agency P-2013-14703. The protocol was registered with ClinicalTrial.org on 29 August 2023 (Identifier: NCT06024889).

Clinical outcomes of a short-term family-focused intervention for patients with atrial fibrillation-A randomised clinical trial.

AIMS: To evaluate a family-focused intervention for patients with atrial fibrillation (AF) in addition to conventional care and to establish its effect on health-related quality of life (HRQoL), anxiety, depression, AF symptoms, and family support. BACKGROUND: AF is a widespread heart disease affecting the well-being of patients and their family members physically and psychologically. Supporting patients and their family members could potentially facilitate regaining family strength and improve HRQoL. METHODS: Patients with newly diagnosed AF were randomised to standard care or additional family-focused intervention with change in global score of the Atrial Fibrillation Quality of Life Questionnaire (AFEQT) as primary outcome after six months' follow-up. Secondary outcomes included the Hospital Anxiety and Depression Score, the European Heart Rhythm Association score, the Ice Expressive Family Functioning Questionnaire, and the Ice Family-Perceived Support Questionnaire (ICE-FPSQ). RESULTS: Sixty-eight patients received standard care (n = 35) or family focused intervention (n = 33). The median change at the six-month follow-up on the global AFEQT score was 4.17 (-1.46-9.17) in the control group and 5.83 (-2.5-30) in the intervention group, yielding a median difference of -1.67 (p = 0.500). Change in ICE-FPSQ showed significant positive scores in favour of intervention (p < 0.001); other secondary outcome changes were non-significant. CONCLUSION: The family-focused intervention had a small positive but non-significant effect on HRQoL compared to standard care. To address the impact of AF on the patients and family members seems to improve anxiety and depression scores and perceived family support.

Prognostic value of myocardial performance index in individuals with type 1 and type 2 diabetes: Thousand&1 and Thousand&2 studies.

AIMS: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in type 1 (T1D) and type 2 diabetes (T2D). Despite diabetes affects the myocardium, risk prediction models do not include myocardial function parameters. Myocardial performance index (MPI) reflects left ventricular function. The prognostic value of MPI has not been evaluated in large-scale diabetes populations. METHODS AND RESULTS: We evaluated two prospective cohort studies: Thousand&1 (1093 individuals with T1D) and Thousand&2 (1030 individuals with T2D). Clinical data, including echocardiography, were collected at baseline. We collected follow-up data from national registries. We defined major adverse cardiovascular events (MACE) as incident events of hospital admission for acute coronary syndrome, heart failure, stroke, or all-cause mortality. For included individuals (56% male, 54 ± 15 years, MPI 0.51 ± 0.1, 63% T1D), follow-up was 100% after median of 5.3 years (range: 4.8-6.3). MPI was associated with MACE (HR 1.2, 95%CI 1.0-1.3, P = 0.012, per 0.10-unit increase) and heart failure (HR 1.3, 95%CI 1.1-1.6, P = 0.005, per 0.10-unit increase) after adjusting for clinical and echocardiographic variables. MPI predicted MACE and heart failure better in T1D than T2D (P = 0.031 for interaction). MPI added discriminatory power to the Steno T1 Risk Engine, based on clinical characteristics, in predicting MACE [area under the curve (AUC) from 0.77 to 0.79, P = 0.030] and heart failure (AUC from 0.77 to 0.83, P = 0.009) in T1D. CONCLUSION: MPI is independently associated with MACE and heart failure in T1D but not T2D and improves prediction in T1D. Echocardiographic assessment in T1D may enhance risk prediction.

Lenient rate control versus strict rate control for atrial fibrillation: a statistical analysis plan for the Danish Atrial Fibrillation (DanAF) randomized clinical trial.

BACKGROUND: A key decision in the treatment of atrial fibrillation is choosing between a rhythm control strategy or a rate control strategy as the main strategy. When choosing rate control, the optimal heart rate target is uncertain. The Danish Atrial Fibrillation trial is a randomized, multicenter, two-group, superiority trial comparing strict rate control versus lenient rate control in patients with either persistent or permanent atrial fibrillation at inclusion. To prevent bias arising from selective reporting and data-driven analyses, we developed a predefined description of the statistical analysis. METHODS: The primary outcome of this trial is the physical component score of the SF-36 questionnaire. A total of 350 participants will be enrolled based on a minimal important difference of 3 points on the physical component score of the SF-36 questionnaire, a standard deviation of 10 points, a statistical power of 80% (beta of 20%), and an acceptable risk of type I error of 5%. All secondary, exploratory, and echocardiographic outcomes will be hypothesis-generating. The analyses of all outcomes will be based on the intention-to-treat principle. We will analyze continuous outcomes using linear regression adjusting for "site," type of atrial fibrillation at inclusion (persistent/ permanent), left ventricular ejection fraction (≥ 40% or < 40%), and the baseline value of the outcome (all as fixed effects). We define our threshold for statistical significance as a p-value of 0.05 and assessments of clinical significance will be based on the anticipated intervention effects defined in the sample size and power estimations. Thresholds for both statistical and clinical significance will be assessed according to the 5-step procedure proposed by Jakobsen and colleagues. DISCUSSION: This statistical analysis plan will be published prior to enrolment completion and before any data are available and is sought to increase the validity of the DANish Atrial Fibrillation trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT04542785. Registered on Sept 09, 2020.

Experiences from COVID-19-driven use of telephone consultations in a cardiology clinic-The CoviTel study.

INTRODUCTION: The COVID-19 pandemic triggered a rapid shift towards telephone consultations (TC) in the out-patient clinic setting with little knowledge of the consequences. The aims of this study were to evaluate patient-centred experiences with TC, to describe patterns in clinical outcomes from TC and to pinpoint benefits and drawbacks associated with this type of consultations. METHODS: This mixed methods study combined an analysis of quantitative and qualitative data. A quantitative, retrospective observational study was conducted employing data from all 248 patients who received TC at an out-patient cardiology clinic during April 2020 with a one-month follow-up. Semi-structured interviews were conducted; Ten eligible patients were recruited from the outpatient clinic by purposive sampling. RESULTS: Within the follow-up period, no patients died or were acutely hospitalised. Approximately one in every four patients was transferred to their general practitioner, while the remaining three-quarter of the patients had a new examination or a new consultation planned. The cardiologist failed to establish contact with more than a fifth of the patients, often due to missing phone numbers. Ten patients were interviewed. Five themes emerged from the interviews: 1) Knowing an estimated time of the consultation is essential for patient satisfaction, 2) TC are well perceived when individually adapted, 3) TC can be a barrier to patient questions, 4) Video consultations should only be offered to patients who request it, and 5) Prescriptions or instructions made via TC do not cause uncertainty in patients. CONCLUSIONS: The TC program was overall safe and the patients felt comfortable. Crucial issues include precise time planning, the patient's availability on the phone and a correct phone number. Patients stressed that TC are unsuitable when addressing sensitive topics. A proposed visitation tool is presented.

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.

Investigating the roles of hyperglycaemia, hyperinsulinaemia and elevated free fatty acids in cardiac function in patients with type 2 diabetes via treatment with insulin compared with empagliflozin: protocol for the HyperCarD2 randomised, crossover trial.

INTRODUCTION: Type 2 diabetes (T2D) is characterised by elevated plasma glucose, free fatty acid (FFA) and insulin concentrations, and this metabolic profile is linked to diabetic cardiomyopathy, a diastolic dysfunction at first and increased cardiovascular disease (CVD) risk. Shifting cardiac metabolism towards glucose utilisation has been suggested to improve cardiovascular function and CVD risk, but insulin treatment increases overall glucose oxidation and lowers lipid oxidation, without reducing CVD risk, whereas SGLT2 inhibitors (SGLT2i) increase FFA, ketone body concentrations and lipid oxidation, while decreasing insulin concentrations and CVD risk. The aim of the present study is to elucidate the importance of different metabolic profiles obtained during treatment with a SGLT2i versus insulin for myocardial function in patients with T2D. METHODS AND ANALYSES: Randomised, crossover study, where 20 patients with T2D and body mass index>28 kg/m2 receive 25 mg empagliflozin daily or NPH insulin two times per day first for 5 weeks followed by a 3-week washout before crossing over to the remaining treatment. Insulin treatment is titrated to achieve similar glycaemic control as with empagliflozin. In those randomised to insulin first, glycaemia during an initial empagliflozin run-in period prior to randomisation serves as target glucose. Metabolic and cardiac evaluation is performed before and at the end of each treatment period.The primary endpoint is change (treatment-washout) in left ventricular peak filling rate, as assessed by cardiac MRI with and without acute lowering of plasma FFAs with acipimox. Secondary and explorative endpoints are changes in left atrial passive emptying fraction, left ventricular ejection fraction, central blood volume and metabolic parameters. ETHICS AND DISSEMINATION: This study is approved by the Danish Medicines Agency (ref. nr.: 2017061587), the Danish Data Protection Agency (ref. nr.: AHH-2017-093) and the Capital Region Ethics Committee (ref. nr.: H-17018846). The trial will be conducted in accordance with ICH-GCP guidelines and the Declaration of Helsinki and all participants will provide oral and written informed consent. Our results, regardless of outcome, will be published in relevant scientific journals and we also will seek to disseminate results through presentations at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2017-002101.

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).