Frederik Dalgaard

BACKGROUND: Leaflet calcification contributes to the development and progression of aortic valve stenosis. Vitamin K activates inhibitors of vascular calcification and may modulate inflammation and skeletal bone loss. Therefore, we aimed to determine whether higher dietary intakes of vitamin K ₁ are associated with a lower incidence of aortic stenosis. METHODS: In the Danish Diet, Cancer and Health study, participants aged 50 to 64 years completed a 192-item food frequency questionnaire at baseline, from which habitual intakes of vitamin K ₁ were estimated. Participants were prospectively followed using linkage to nationwide registers to determine incident aortic valve stenosis (primary outcome) and aortic stenosis with subsequent complications (aortic valve replacement, heart failure, or cardiovascular disease–related mortality; secondary outcome). RESULTS: In 55 545 participants who were followed for a maximum of 21.5 years, 1085 were diagnosed with aortic stenosis and 615 were identified as having subsequent complications. Participants in the highest quintile of vitamin K ₁ intake had a 23% lower risk of aortic stenosis (hazard ratio, 0.77 [95% CI, 0.63–0.94]) and a 27% lower risk of aortic stenosis with subsequent complications (hazard ratio, 0.73 [95% CI, 0.56–0.95]), compared with participants in the lowest quintile after adjusting for demographics and cardiovascular risk factors. CONCLUSIONS: In this study, a high intake of vitamin K ₁ –rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

Aims: To investigate the association of cardiac resynchronization therapy (CRT) on outcomes among participants with and without a history of atrial fibrillation (AF).Methods: Individual‐patient‐data from four randomized trials investigating CRT‐Defibrillators (COMPANION, MADIT‐CRT, REVERSE) or CRT‐Pacemakers (COMPANION, MIRACLE) were analyzed. Outcomes were time to a composite of heart failure hospitalization or all‐cause mortality or to all‐cause mortality alone. The association of CRT on outcomes for patients with and without a history of AF was assessed using a Bayesian‐Weibull survival regression model adjusting for baseline characteristics.Results: Of 3964 patients included, 586 (14.8%) had a history of AF; 2245 (66%) were randomized to CRT. Overall, CRT reduced the risk of the primary composite endpoint (hazard ratio [HR]: 0.69, 95% credible interval [CI]: 0.56–0.81). The effect was similar (posterior probability of no interaction = 0.26) in patients with (HR: 0.78, 95% CI: 0.55–1.10) and without a history of AF (HR: 0.67, 95% CI: 0.55–0.80). In these four trials, CRT did not reduce mortality overall (HR: 0.82, 95% CI: 0.66–1.01) without evidence of interaction (posterior probability of no interaction = 0.14) for patients with (HR: 1.09, 95% CI: 0.70–1.74) or without a history of AF (HR: 0.70, 95% CI: 0.60–0.97).Conclusion: The association of CRT on the composite endpoint or mortality was not statistically different for patients with or without a history of AF, but this could reflect inadequate power. Our results call for trials to confirm the benefit of CRT recipients with a history of AF.

Background: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. Methods: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. Results: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; P _interaction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. Conclusions: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single “non-LBBB” category when selecting patients for CRT should be reconsidered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Objectives Atrial fibrillation (AF) is a predominant risk factor of ischaemic stroke and treatment with oral anticoagulants (OACs) is recommended in all patients with risk factors. This study sought to examine treatment patterns of OACs in older patients with AF. Design Retrospective, cross-sectional study. Setting Danish nationwide administrative and clinical registers and databases. Participants A total of 40 027 patients, >75 years of age, after their first hospital contact due to AF between 2010 and 2018. Primary and secondary outcomes measures The primary event of interest was claimed prescriptions for OACs within 180 days after first hospital contact due to AF. Proportions of patients treated with OACs were estimated and clinical factors associated with the probability of receiving OAC treatment were identified using adjusted logistic regression models. Results A total of 40 027 patients were included with a slight majority of women (54%). The median age was 81 years (IQR 78–86). We found that an overall 32 235 patients (81%) were prescribed an OAC after their first hospital contact due to AF with a marked increase in the proportion of patients treated from 2010 to 2018. Factors related to a decreased probability of receiving treatment were bleeding risk factors such as a history of haemorrhagic stroke (OR 0.21, 95% CI 0.16 to 0.27), any bleeding (OR 0.58, 95% CI 0.53 to 0.62) as well as markers of frailty such as osteoporosis (OR 0.78, 95% CI 0.71 to 0.85). Conclusion In this large nationwide study, we found that in older patients with AF, the overall rates of OAC prescription were generally high (~80%) and increasing during the last decade. Factors associated with not receiving guideline recommended OAC treatment were generally related to bleeding risk factors or frailty.

Aim. To assess evidence for an image-guided approach for cardiac resynchronization therapy (CRT) that targets left ventricular (LV) lead placement at the segment of latest mechanical activation. Methods. A systematic review of EMBASE and PubMed was performed for randomized controlled trials (RCTs) and prospective observational studies from October 2008 through October 2020 that compared an image-guided CRT approach with a non-image-guided approach for LV lead placement. Meta-analyses were performed to assess the association between the image-guided approach and NYHA class improvement or changes in end-systolic volume (LVESV), end-diastolic volume (LVEDV), and ejection fraction (LVEF). Results. From 5897 citations, 5 RCTs including 818 patients (426 image-guided and 392 non-image-guided) were identified. The mean age ranged from 66 to 71 years, 76 were male, and 53 had ischemic cardiomyopathy. Speckle tracking echocardiography was the primary image-guided method in all studies. LV lead placement within the segment of the latest mechanical activation (concordant) was achieved in the image-guided arm in 45 of the evaluable patients. There was a statistically significant improvement in the NYHA class at 6 months (odds ratio 1.66; 95 confidence interval (CI) [1.02, 2.69]) with the image-guided approach, but no statistically significant change in LVESV (MD 7.1; 95 CI [16.0, 1.8]), LVEDV (MD 5.2; 95 CI [15.8, 5.4]), or LVEF (MD 0.68; 95 CI [4.36, 5.73]) versus the non-image-guided approach. Conclusion. The image-guided CRT approach was associated with improvement in the NYHA class but not echocardiographic measures, possibly due to the small sample size and a low rate of concordant LV lead placement despite using the image-guided approach. Therefore, our meta-analysis was not able to identify consistent improvement in CRT outcomes with an image-guided approach.

Reported associations between vitamin K₁ and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52–60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K₁ (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87–192 µg/d) intake of vitamin K₁ was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K₁ intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K₁ may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level.

Higher flavonoid intakes are hypothesized to confer protection against type 2 diabetes mellitus. We aimed to 1) investigate associations between flavonoid intakes and diabetes, 2) examine the mediating impact of body fat, and 3) identify subpopulations that may receive the greatest benefit from higher flavonoid intakes in participants of the Danish Diet, Cancer, and Health Study followed up for 23 y. Cross-sectional associations between baseline flavonoid intake, estimated using FFQs and the Phenol Explorer database, and body fat, estimated by bioelectrical impedance, were assessed using multivariable-adjusted linear regression models. Nonlinear associations between flavonoid intake and incident diabetes were examined using restricted cubic splines with multivariable-adjusted Cox proportional hazards models. Among 54,787 participants (median age: 56 y; IQR: 52–60 y; 47.3% men), 6700 individuals were diagnosed with diabetes. Participants in the highest total flavonoid intake quintile (median, 1202 mg/d) had a 1.52 kg lower body fat (95% CI: –1.74, –1.30 kg) and a 19% lower risk of diabetes (HR: 0.81; 95% CI: 0.75, 0.87) after multivariable adjustments and compared with participants in the lowest intake quintile (median: 174 mg/d). Body fat mediated 57% (95% CI: 42, 83%) of the association between flavonoid intake and incident diabetes. Of the flavonoid subclasses, moderate to high intakes of flavonols, flavanol monomers, flavanol oligo + polymers, and anthocyanins were significantly associated with a lower risk of diabetes. Although associations were not modified by sex, smoking status, BMI, or physical activity (P_interaction > 0.05 for all), findings on an absolute scale suggest that those at a higher risk (those with obesity) may benefit the most from a higher flavonoid intake. The findings reported in this study suggest that a diet abundant in flavonoid-rich foods may help ameliorate diabetes risk, in part through a reduction in body fat.

Background: Dietary vitamin K (K ₁ and K ₂ ) may reduce atherosclerotic cardiovascular disease (ASCVD) risk via several mechanisms. However, studies linking vitamin K intake with incident ASCVD are limited. We aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. Methods and Results: In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food‐frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K ₁ and vitamin K ₂ were estimated from the food‐frequency questionnaire, and their relationship with ASCVD hospitalizations was determined using Cox proportional hazards models. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52–60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17–22) years of follow‐up. Compared with participants with the lowest vitamin K ₁ intakes, participants with the highest intakes had a 21% lower risk of an ASCVD‐related hospitalization (hazard ratio, 0.79; 95% CI: 0.74–0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K ₂ , the risk of an ASCVD‐related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K ₂ intake (hazard ratio, 0.86; 95% CI, 0.81–0.91). Conclusions: Risk of ASCVD was inversely associated with diets high in vitamin K ₁ or K ₂ . The similar inverse associations with both vitamin K ₁ and K ₂ , despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.

To determine whether the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) integrated risk tool predicts mortality, non-haemorrhagic stroke/systemic embolism, and major bleeding for up to 2 years after new-onset AF and to assess how this risk tool performs compared with CHA₂DS₂-VASc and HAS-BLED. Potential predictors of events included demographic and clinical characteristics, choice of treatment, and lifestyle factors. A Cox proportional hazards model was identified for each outcome by least absolute shrinkage and selection operator methods. Indices were evaluated in comparison with CHA₂DS₂-VASc and HAS-BLED risk predictors. Models were validated internally and externally in ORBIT-AF and Danish nationwide registries. Among the 52 080 patients enrolled in GARFIELD-AF, 52 032 had follow-up data. The GARFIELD-AF risk tool outperformed CHA₂DS₂-VASc for all-cause mortality in all cohorts. The GARFIELD-AF risk score was superior to CHA₂DS₂-VASc for non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in internal validation and in the Danish AF cohort. In very low- to low-risk patients [CHA₂DS₂-VASc 0 or 1 (men) and 1 or 2 (women)], the GARFIELD-AF risk score offered strong discriminatory value for all the endpoints when compared to CHA₂DS₂-VASc and HAS-BLED. The GARFIELD-AF tool also included the effect of oral anticoagulation (OAC) therapy, thus allowing clinicians to compare the expected outcome of different anticoagulant treatment decisions [i.e. no OAC, non-vitamin K antagonist (VKA) oral anticoagulants, or VKAs]. The GARFIELD-AF risk tool outperformed CHA₂DS₂-VASc at predicting death and non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in overall as well as in very low- to low-risk group patients with AF. URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF: NCT01090362, ORBIT-AF I: NCT01165710; ORBIT-AF II: NCT01701817.