Dietary Vitamin K1 Intake and Incident Aortic Valve Stenosis.

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 K1 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 K1 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 K1 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 K1-rich foods was associated with a lower incidence of aortic stenosis and a lower risk of aortic stenosis with subsequent complications.

Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials.

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]; Pinteraction <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.

Benefit of cardiac resynchronization therapy among older patients: A patient-level meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials. METHODS: Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed. RESULTS: The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P = .002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P = .017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P > .1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction = .027) with a similar but nonsignificant trend for mortality (P for interaction = .35). CONCLUSION: Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT.

Source-specific nitrate intake and all-cause mortality in the Danish Diet, Cancer, and Health Study.

INTRODUCTION: Nitrate and nitrite are naturally occurring in both plant- and animal-sourced foods, are used as additives in the processing of meat, and are found in water. There is growing evidence that they exhibit a spectrum of health effects, depending on the dietary source. The aim of the study was to examine source-dependent associations between dietary intakes of nitrate/nitrite and both all-cause and cause-specific mortality. METHODS: In 52,247 participants of the Danish Diet, Cancer and Health Study, associations between source-dependent nitrate and nitrite intakes--calculated using comprehensive food composition and national drinking water quality monitoring databases--and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality over 27 years were examined using restricted cubic splines within Cox proportional hazards models adjusting for demographic, lifestyle, and dietary confounders. Analyses were stratified by factors hypothesised to influence the formation of carcinogenic N-nitroso compounds (namely, smoking and dietary intakes of vitamin C, vitamin E, folate, and polyphenols). RESULTS: Plant-sourced nitrate intake was inversely associated with all-cause mortality [HRQ5vsQ1: 0.83 (0.80, 0.87)] while higher risks of all-cause mortality were seen for higher intakes of naturally occurring animal-sourced nitrate [1.09 (1.04, 1.14)], additive permitted meat-sourced nitrate [1.19 (1.14, 1.25)], and tap water-sourced nitrate [1.19 (1.14, 1.25)]. Similar source-dependent associations were seen for nitrite and for CVD-related and cancer-related mortality except that naturally occurring animal-sourced nitrate and tap water-sourced nitrate were not associated with cancer-related mortality and additive permitted meat-sourced nitrate was not associated with CVD-related mortality. No clear patterns emerged in stratified analyses. CONCLUSION: Nitrate/nitrite from plant sources are inversely associated while those from naturally occurring animal-sources, additive-permitted meat sources, and tap water-sources are positively associated with mortality.

Cardiac resynchronization therapy in patients with a prior history of atrial fibrillation: Insights from four major clinical trials.

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.

Higher Habitual Dietary Intakes of Flavanols and Anthocyanins Differentially Associate with Lower Incidence of Ischemic Stroke Subtypes-A Follow-Up Analysis.

BACKGROUND: We previously reported that habitual consumption of dietary flavanol oligomers + polymers and anthocyanins is associated with a lower risk of ischemic stroke. However, no studies have investigated their relationship with ischemic stroke subtypes. OBJECTIVES: In this follow-up analysis, we aimed to examine the association of flavanol oligomers + polymers and anthocyanin intake with ischemic stroke subtypes, including the following: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) other determined etiology, and 5) undetermined etiology. METHODS: Participants (n = 55,094) from the Danish Diet, Cancer, and Health Study were followed up for <16 y for first-time ischemic stroke events, which were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Intakes of flavanol oligomers + polymers and anthocyanins were calculated from food frequency questionnaires using the Phenol-Explorer database, and their relationships with ischemic stroke subtypes were investigated using restricted cubic splines within Cox proportional hazards models. After multivariable adjustment, higher habitual intakes (quintile 5 compared with quintile 1) of flavanol oligomers + polymers and anthocyanins were associated with a lower risk of specific ischemic stroke subtypes, including large-artery atherosclerosis [flavanol oligomers + polymers, hazard ratio {HR} (95% confidence interval {CI}): 0.64 (0.47, 0.87)], cardioembolism [anthocyanins, HR (95% CI): 0.45 (0.25, 0.82)], and small-vessel occlusion [flavanol oligomers + polymers, HR (95% CI): 0.65 (0.54, 0.80); anthocyanins, HR (95% CI): 0.79 (0.64, 0.97)], but not stroke of other determined or undetermined etiology. CONCLUSIONS: Higher habitual intakes of flavanols and anthocyanins are differentially associated with a lower risk of ischemic stroke from atherosclerosis and/or cardioembolism but not with other subtypes.

Recurrent syncope in patients with a pacemaker and bradyarrhythmia.

Background. Pacemakers are used to treat syncope in patients with bradyarrhythmia; however, the risk of recurrent syncope has only been investigated in few and smaller studies. Objective. The aim of this study was to investigate the risk of recurrent syncope after pacemaker implantation in patients with bradyarrhythmia and prior syncope. Methods. This retrospective, population-based cohort study included patients with a prior syncope and implantation of a pacemaker using data from the Danish nationwide registers from 1996 to 2017. Cumulative incidence and cox regression was used to estimate the 5-year incidence and the risk of recurrent syncope, respectively. Results. In total, 11,126 patients (median age: 78 years, interquartile range: 69-85, 56% male) were included and the 5-year cumulative incidence of recurrent syncope was 19.6% (95% confidence interval (CI): 18.8-20.3%). Sinus node dysfunction (hazard ratio [HR]: 1.29, 95%CI: 1.17-1.42) and unspecified type of bradyarrhythmia (HR: 1.32, 95%CI: 1.15-1.52) were associated with an increased risk of syncope compared to advanced atrioventricular (AV) block. Male sex (HR: 1.22, 95%CI: 1.22-1.34), cerebrovascular disease (HR: 1.17, 95%CI: 1.05-1.30), and prior number of syncopes were significantly associated with a higher HR of recurrent syncope. Conclusion. Almost one-in-five patients with bradyarrhythmia and prior syncope who had a pacemaker implanted had a recurrent syncope within five years. A higher risk of syncope was observed among patients with sinus node dysfunction and unspecified type of bradyarrhythmia compared to AV block. Male sex, cerebrovascular disease, and prior number of syncopes were associated risk factors of recurrent syncope.

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Flavonoid intakes inversely associate with COPD in smokers.

INTRODUCTION: Higher flavonoid intakes are beneficially associated with pulmonary function parameters; however, their association with chronic obstructive pulmonary disease (COPD) is unknown. This study aimed to examine associations between intakes of 1) total flavonoids, 2) flavonoid subclasses and 3) major flavonoid compounds with incident COPD in participants from the Danish Diet, Cancer and Health study. METHODS: This prospective cohort included 55 413 men and women without COPD, aged 50-65 years at recruitment. Habitual flavonoid intakes at baseline were estimated from a food frequency questionnaire using Phenol-Explorer. Danish nationwide registers were used to identify incident cases of COPD. Associations were modelled using restricted cubic splines within Cox proportional hazards models. RESULTS: During 23 years of follow-up, 5557 participants were diagnosed with COPD. Of these, 4013 were current smokers, 1062 were former smokers and 482 were never-smokers. After multivariable adjustments, participants with the highest total flavonoid intakes had a 20% lower risk of COPD than those with the lowest intakes (quintile 5 versus quintile 1: HR 0.80, 95% CI 0.74-0.87); a 6-22% lower risk was observed for each flavonoid subclass. The inverse association between total flavonoid intake and COPD was present in both men and women but only in current smokers (HR 0.77, 95% CI 0.70-0.84) and former smokers (HR 0.82, 95% CI 0.69-0.97), not never-smokers. Furthermore, higher flavonoid intakes appeared to lessen, but not negate, the higher risk of COPD associated with smoking intensity. CONCLUSION: Dietary flavonoids may be important for partially mitigating the risk of smoking-related COPD. However, smoking cessation should remain the highest priority.

Electrical cardioversion of atrial fibrillation and the risk of brady-arrhythmic events.

BACKGROUND: Electrical cardioversion (ECV) is a common procedure for terminating atrial fibrillation (AF). ECV is associated with brady-arrhythmic events, however, the age-specific risks of clinically significant brady-arrhythmic events are unknown. METHODS: Using Danish nationwide registers, we identified patients with AF at their first non-emergent ECV between 2005 and 2018 and estimated their 30-day risk of brady-arrhythmic events. Moreover, factors associated with increased risks of brady-arrhythmias were identified. Absolute risks were estimated using logistic regression models fitted with natural splines as well as standardization (G-formula). RESULTS: We identified 20,725 eligible patients with a median age of 66 years (IQR 60-72) and most males (73%). The 30-day risks of brady-arrhythmic events after ECV were highly dependent on age with estimated risks ranging from 0.5% (95% CI 0.2-1.7) and 1.2% (95% CI 0.99-1.5) to 2.7% (95% CI 2.1-3.3) and 5.1% (95% CI 2.6-9.7) in patients aged 40, 65, 80, and 90 years, respectively. Factors associated with brady-arrhythmias were generally related to cardiovascular disease (eg, ischemic heart disease, heart failure, valvular AF) or a history of syncope. We found no indications that pre-treatment with anti-arrhythmic drugs conferred increased risks of brady-arrhythmic events (standardized absolute risk difference -0.25% [95% CI -0.67 to 0.17]). CONCLUSIONS: ECV conferred clinically relevant 30-day risks of brady-arrhythmic events, especially in older patients. Anti-arrhythmic drug treatment was not found to increase the risk of brady-arrhythmias. Given the widespread use of ECV, these data should provide insights regarding the potential risks of brady-arrhythmic events.

Outcomes of Cardiac Resynchronization Therapy with Image-Guided Left Ventricular Lead Placement at the Site of Latest Mechanical Activation: A Systematic Review and Meta-Analysis.

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.

Protocol for detecting unrecognized sleep apnea in patients with atrial fibrillation by a home-monitoring device: the DAN-APNO study.

BACKGROUND: Determining the presence of modifiable risk factors for atrial fibrillation (AF), such as sleep apnea is of clinical importance due to the potential impact targeting these risk factors can have on the progression and burden of AF. Using new digital-based technology is a promising solution to the underreporting of sleep apnea highlighted by academical societies in recent years. The aim of this study is to report the prevalence and severity of sleep apnea in patients with AF and, secondarily, assess the accuracy and feasibility of a new home-screening device for sleep apnea (NightOwl™ by Ectosense). METHODS: DAN-APNO is a cross-sectional study at the Department of Cardiology, Herlev-Gentofte Hospital recruiting patients with AF referred to anticoagulation initiation aged 18 to 90 years without known sleep apnea. At least 150 patients will be recruited and undergo medical history, clinical evaluation, several sleep-apnea questionnaires, and a sleep-recording evaluation for four nights with sleep apnea home-monitoring device NightOwl™. Additionally, the first 20 participants and participants with moderate-severe sleep apnea by screening are referred to cardio-respiratory monitoring (CRM). This clinical evaluation allows the comparison of standard evaluation method and the NightOwl™. Clinical measures include Apnea-Hypopnea Index (AHI), Oxygen Desaturation Index (ODI), pulse rate, as well as questionaries about sleep apnea assessment and the clinical feasibility of the NightOwl™ device. Main outcomes comprise analysis of the prevalence and severity of sleep apnea, and clinical and demographic predictors of moderate and severe sleep apnea. In addition, correlation analyses for accuracy measures between CRM and NightOwl™ will be conducted along with patient ease-of-use and satisfaction questionnaires. DISCUSSION: This study is limited by selection bias; only patients with atrial fibrillation from anticoagulation clinic is asked to participate, which could limit the generalizability of our results. However, this study aims to test whether a miniaturized simple home-monitoring device for detecting sleep apnea in patients with AF potentially can evaluate sleep apnea more conveniently and easier. Trial Registration The study is registered the 18-02-2021 at clinicaltrials.gov with registration number: NCT04760002.

Cardiac resynchronization therapy outcomes with left ventricular lead concordant with latest mechanical activation: A meta-analysis.

BACKGROUND: For cardiac resynchronization therapy (CRT), image-guided approaches targeting left ventricular (LV) lead placement at the site of latest mechanical activation had inconsistent outcomes. We examined evidence for improved CRT outcomes when LV lead placement concordant with latest mechanical activation occurred. METHODS: A review of EMBASE and PubMed was performed for randomized controlled trials or prospective observational studies from October 2008 through October 2020 comparing outcomes with concordant versus discordant LV lead placement. Meta-analyses were performed to assess the association between concordance and death, death or heart failure (HF) hospitalization, ≥ 15% reduction in LV end systolic volume (LVESV), and changes in LVESV or ejection fraction (LVEF). RESULTS: From 5897 citations, nine publications (eight studies) with 1355 patients were selected; 975 with a concordant LV lead and 380 with a discordant lead. Mean age was 66-68 years, 82% were male, and 64% had ischemic cardiomyopathy. Meta-analyses demonstrated a statistically significant reduction in death/HF hospitalization at 2 years (OR 0.38; 95% CI 0.16, 0.92) and LVESV at 6 months (mean difference [MD] -13.4%; 95% CI -6.7%, -20.0%), and an increase in LVEF (MD 4.03; 95% CI 0.77, 7.30) with the concordant LV lead. There were trends toward decreased death at 2 years (OR 0.49; 95% CI 0.19, 1.23) and ≥ 15% reduction in LVESV at 6 months (OR 3.81; 95% CI 0.24, 61.24) with concordant LV lead placement. CONCLUSION: A concordant LV lead was associated with better CRT outcomes. Further study of feasible methods to achieve LV lead concordance is needed.

Patients With Atrial Fibrillation Taking Nonsteroidal Anti-Inflammatory Drugs and Oral Anticoagulants in the ARISTOTLE Trial.

BACKGROUND: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin. METHODS: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models. RESULTS: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11-2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16-2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome. CONCLUSIONS: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Higher Habitual Flavonoid Intakes Are Associated with a Lower Incidence of Diabetes.

BACKGROUND: Higher flavonoid intakes are hypothesized to confer protection against type 2 diabetes mellitus. OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (Pinteraction > 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. CONCLUSIONS: 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.

Mechanical dyssynchrony: How do we measure it, what it means, and what we can do about it.

Left ventricular mechanical dyssynchrony (LVMD) is defined by a difference in the timing of mechanical contraction or relaxation between different segments of the left ventricle (LV). Mechanical dyssynchrony is distinct from electrical dyssynchrony as measured by QRS duration and has been of increasing interest due to its association with worse prognosis and potential role in patient selection for cardiac resynchronization therapy (CRT). Although echocardiography is the most used modality to assess LVMD, some limitations apply to this modality. Compared to echo-based modalities, nuclear imaging by gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) has clear advantages in evaluating systolic and diastolic LVMD. GSPECT MPI can determine systolic and diastolic mechanical dyssynchrony by the variability in the timing in which different LV segments contract or relax, which has prognostic impact in patients with coronary artery disease and heart failure. As such, by targeting mechanical dyssynchrony instead of electrical dyssynchrony, GSPECT MPI can potentially improve patient selection for CRT. So far, few studies have investigated the role of diastolic dyssynchrony, but recent evidence seems to suggest high prevalence and more prognostic impact than previously recognized. In the present review, we provide an oversight of mechanical dyssynchrony.

Vegetable nitrate intake, blood pressure and incident cardiovascular disease: Danish Diet, Cancer, and Health Study.

Whether the vascular effects of inorganic nitrate, observed in clinical trials, translate to a reduction in cardiovascular disease (CVD) with habitual dietary nitrate intake in prospective studies warrants investigation. We aimed to determine if vegetable nitrate, the major dietary nitrate source, is associated with lower blood pressure (BP) and lower risk of incident CVD. Among 53,150 participants of the Danish Diet, Cancer, and Health Study, without CVD at baseline, vegetable nitrate intake was assessed using a comprehensive vegetable nitrate database. Hazard ratios (HRs) were calculated using restricted cubic splines based on multivariable-adjusted Cox proportional hazards models. During 23 years of follow-up, 14,088 cases of incident CVD were recorded. Participants in the highest vegetable nitrate intake quintile (median, 141 mg/day) had 2.58 mmHg lower baseline systolic BP (95%CI - 3.12, - 2.05) and 1.38 mmHg lower diastolic BP (95%CI - 1.66, - 1.10), compared with participants in the lowest quintile. Vegetable nitrate intake was inversely associated with CVD plateauing at moderate intakes (~ 60 mg/day); this appeared to be mediated by systolic BP (21.9%). Compared to participants in the lowest intake quintile (median, 23 mg/day), a moderate vegetable nitrate intake (median, 59 mg/day) was associated with 15% lower risk of CVD [HR (95% CI) 0.85 (0.82, 0.89)]. Moderate vegetable nitrate intake was associated with 12%, 15%, 17% and 26% lower risk of ischemic heart disease, heart failure, ischemic stroke and peripheral artery disease hospitalizations respectively. Consumption of at least ~ 60 mg/day of vegetable nitrate (~ 1 cup of green leafy vegetables) may mitigate risk of CVD.

Association between vitamin K1 intake and mortality in the Danish Diet, Cancer, and Health cohort.

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.

Sudden cardiac death in patients with myocarditis: Evaluation, risk stratification, and management.

Myocarditis is a major cause of sudden cardiac death (SCD) and dilated cardiomyopathy (DCM) in young adults. Cardiac magnetic resonance is the established tool for the diagnosis of myocarditis, and late gadolinium enhancement detected on cardiac magnetic resonance imaging is the strongest independent predictor of SCD, all-cause mortality, and cardiac mortality. Several other factors have been associated with SCD or cardiac transplantation including New York Heart Association functional class III/IV, reduced left ventricular ejection fraction <35%, and right ventricular ejection fraction ≤45%. A fragmented QRS and a prolonged QTc interval on an electrocardiogram are predictors of VAs. The postulated mechanism of VA in acute myocarditis is ion channel dysfunction and inflammation that alter intracellular signaling, producing interstitial edema and fibrosis and thereby causing conduction abnormalities. VAs in chronic myocarditis are generally due to scar-mediated reentry. Treatment of myocarditis is tailored toward supportive care and symptomatic relief. The subset of patients who develop DCM should be treated with heart failure medications according to professional guideline recommendations. Indications for an implantable cardioverter-defibrillator are similar to those for nonischemic cardiomyopathy; however, an implantable cardioverter-defibrillator should be held in the acute phase of myocarditis to allow left ventricular ejection fraction recovery, and a wearable cardioverter-defibrillator may be beneficial for some patients. Antiarrhythmic medications are reserved for patients with symptomatic nonsustained or sustained VAs. Radiofrequency ablation appears to be an effective treatment option for VAs; however, more data on its safety and effectiveness are needed. This review addresses risk factors of SCD and VAs in patients with myocarditis with special emphasis on treatment and prevention of these outcomes.

Risk of major cardiovascular and neurologic events with obstructive sleep apnea among patients with atrial fibrillation.

BACKGROUND: Obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF). However, it remains unclear whether OSA is independently associated with worse cardiovascular and neurological outcomes in patients with AF. METHODS: We used the ORBIT-AF I and ORBIT-AF II to conduct a retrospective cohort study of 22,760 patients with AF with and without OSA. Adjusted multivariable Cox proportional hazards models was used to determine whether OSA was associated with increased risk for major adverse cardiac and neurologic events (MACNEs) (cardiovascular death, myocardial infarction, stroke/transient ischemic attack/non-central nervous system embolism (stroke/SE), and new-onset heart failure], combined and individually. RESULTS: A total of 4,045 (17.8%) patients had OSA at baseline. Median follow-up time was 1.5 (interquartile range: 1-2.2) years, and 1,895 patients experienced a MACNE. OSA patients were younger (median [interquartile range] 68 [61-75] years vs 74 [66-81] years), were more likely male (70.7% vs 55.3%), and had increased body mass index (median 34.6 kg/m2 [29.8-40.2] vs 28.7 kg/m2 [25.2-33.0]). Those with OSA had a higher prevalence of concomitant comorbidities such as diabetes, chronic obstructive pulmonary disease, and heart failure. OSA patients had higher use of antithrombotic therapy. After adjustment, the presence of OSA was significantly associated with MACNE (hazard ratio: 1.16 [95% CI: 1.03-1.31], P = .011). OSA was also an independent risk factor for stroke/SE beyond the CHA2DS2-VASc risk factors (HR: 1.38 [95% CI 1.12-1.70], P = .003) but not cardiovascular death, myocardial infarction, new-onset heart failure, or major bleeding. CONCLUSIONS: Among patients with AF, OSA is an independent risk factor for MACNE and, more specifically, stroke/SE.