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In 40 patients with chronic moderate to severe aortic regurgitation, brain natriuretic peptide, N-brain natriuretic peptide, and atrial natriuretic peptide were higher in symptomatic patients compared with asymptomatic patients after adjustment for age, gender, and ejection fraction, but each natriuretic peptide correlated weakly with echocardiographic measures of left ventricular size and function. In patients with chronic aortic regurgitation, measurement of natriuretic peptide levels may provide information on left ventricular function in addition to echocardiography. [ABSTRACT FROM AUTHOR]

Objectives: This paper will describe associations between plasma natriuretic peptide levels and the severity and symptoms of mitral regurgitation (MR).Background: A biochemical test that assisted grading of the severity of MR and the interpretation of symptoms would be of clinical value.Methods: Forty-nine patients with isolated MR and left ventricular (LV) ejection fractions (EFs) of >55% underwent transthoracic echocardiography, assessment of symptoms, and measurement of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and its amino-terminal portion, N-BNP.Results: The level of each natriuretic peptide rose with increasing severity of MR and with increases in left atrial (LA) dimensions (p < 0.001 for all comparisons), but no significant correlation existed between any natriuretic peptide and the LV dimensions or EF. Natriuretic peptide levels were higher in symptomatic MR (n = 16, BNP geometric mean 16.9 [95% confidence interval (CI) 13.3 to 21.4] pmol/l) compared with asymptomatic MR (n = 33, BNP 7.1 [95% CI 6.0 to 8.4] pmol/l, p < 0.001), and higher in asymptomatic MR than in normal controls (n = 100, BNP 5.3 [95% CI 4.8 to 5.8] pmol/l, p < 0.0001). These differences were similar for N-BNP and ANP and remained statistically significant (p < 0.05) after adjustment for echocardiographic measures of LV function and severity of MR. Both the sensitivity and the specificity for symptoms for the natriuretic peptides (area under receiver-operator characteristic curve for BNP = 0.90, N-BNP = 0.89, ANP = 0.89) were similar to the MR score (0.88) and greater than for LA dimension (0.81), vena contracta width (0.82), and LV end-systolic dimension (0.63).Conclusions: Plasma natriuretic peptides levels increase with the severity of MR and are higher in symptomatic compared to asymptomatic patients, even when LV EF is normal. [ABSTRACT FROM AUTHOR]

Objective: To determine the importance of the duration and intensity of "warm up" exercise for reducing ischaemia during second exercise in patients with exertional angina.Design: Randomised crossover comparison of three warm up exercise protocols.Patients: 18 subjects with stable ischaemic heart disease and > 0.1 mV ST segment depression on treadmill exercise testing.Interventions: The warm up protocols were 20 minutes of slow exercise at 2.7 km/h, symptom limited graded exercise for a mean of 7.4 (range 5.0 to 10.5) minutes, and three minutes of symptom limited fast exercise of similar maximum intensity.Main Outcome Measures: ST segment depression during graded treadmill exercise undertaken 10 minutes after each warm up protocol or no warm up exercise.Results: Compared with exercise with no warm up, the duration of graded exercise after earlier slow warm up increased by 4.9% (95% confidence interval (CI), -3.3% to 13.7%), after graded warm up by 10.3% (95% CI, 5.6% to 15.2%), and after fast warm up by 16% (95% CI, 6.2% to 26.7%). ST segment depression at equivalent submaximal exercise decreased after slow warm up by 27% (95% CI, 5% to 44%), after graded warm up by 31% (95% CI, 17% to 44%), and after fast warm up by 47% (95% CI, 27% to 61%). Compared with slow warm up exercise, the more intense graded and fast warm up protocols significantly increased the duration of second exercise (p = 0.0072) and reduced both peak ST depression (p = 0.0026) and the rate of increase of ST depression (p = 0.0069).Conclusions: In patients with exertional angina the size of the warm up response is related to the maximum intensity rather than the duration of first exercise. [ABSTRACT FROM AUTHOR]

Background: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'., Methods: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life., Results: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up., Conclusions: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes., Competing Interests: Declaration of competing interest GPM is supported by a NIHR Research Professorship (2017-08-ST2-007). DEN is supported by the British Heart Foundation (CH/09/002, RE/24/130012, RG/F/22/110093). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. GJM is supported by the British Heart Foundation (CH/12/1/29419, RG/17/9/32812, and AA/18/3/34220). PSM is supported by an Australian National Health and Medical Research Council Investigator Grant (ID 2008079). GSH is supported by a WA Health Research Excellence Award. GPM, AS and GJM receive support from the NIHR Leicester Biomedical Research Centre., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate associations between psychosocial burden and biomarkers reflecting pathophysiological pathways in patients with chronic coronary syndrome., Methods: Psychosocial (PS) factors were collected from self-assessed questionnaires and biomarkers representing inflammation (high-sensitivity [hs]-C-reactive protein [CRP], interleukin-6 [IL-6], lipoprotein-associated phospholipase A2 [Lp-PLA2]) and cardiac injury/stress (hs-troponin T [hs-TnT], N-terminal pro-B type natriuretic peptide [NT-proBNP]) were measured in 12,492 patients with chronic coronary syndrome in the STABILITY trial. Associations between level of each psychosocial factor (never-rarely (reference), sometimes, often-always) and biomarkers were evaluated using linear models with adjusted geometric mean ratios (GMR). A score comprising four factors ('feeling down', 'loss of interest', financial stress', 'living alone') that previously demonstrated association with cardiovascular (CV) outcome was created, and categorized into three levels: low, moderate and high PS burden. Associations between PS score and biomarkers were evaluated similarly., Results: Greater PS burden was significantly associated with a gradual increase in inflammatory biomarkers (GMR [95% CI] for moderate vs low PS burden; and high vs low PS burden): hs-CRP (1.09 [1.04-1.14]; 1.12 [1.06-1.17]), IL-6 (1.05 [1.02-1.07]; 1.08 [1.05-1.11]), LpPLA2 (1.01 [1.00 - 1.02]; 1.02 [1.01-1.04]) and cardiac biomarkers hs-TnT (1.03 [1.01-1.06]; 1.06 [1.03-1.09]) and NT-proBNP (1.09 [1.04-1.13]; 1.21 [1.15-1.27])., Conclusions: In patients with chronic coronary syndrome, greater psychosocial burden was associated with increased levels of inflammatory and cardiac biomarkers. While this observational study does not establish causal nature of these associations, the findings suggest inflammation and cardiac injury/stress as plausible pathways linking psychosocial burden to an elevated CV risk, that needs to be further explored., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Idiopathic acute pericarditis is often presumed to have a viral cause. We hypothesized that if acute viral infection was the cause, the incidence of acute 'idiopathic' pericarditis would decrease during a public health lockdown introduced to prevent the spread of SARS-COVID-19 in New Zealand when acute viral infections decreased by 75% to 99%., Methods: Hospitalization for acute 'idiopathic' pericarditis during 5 months of the national public health lockdown were compared to 54 months before the COVID-19 pandemic from administrative data., Results: The hospitalization rate for acute pericarditis was similar before (n = 1364, 24.8 cases/30 days) compared to during the public health lockdown (n = 132, 25.8 cases/30 days), +4% 95 % confidence interval -25 % to +30 % (P = 0.67)., Conclusion: These observations do not support the hypothesis that acute viral infection is the cause for most cases of acute idiopathic pericarditis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background: Sleep-related breathing disorders (SRBD) are related to cardiovascular outcomes in patients with chronic coronary syndrome (CCS). Whether SRBD-related symptoms are associated with prognostic biomarkers in patients with CCS is not established., Methods: Associations between frequency (never/rarely, sometimes, often, always) of self-reported SRBD-related symptoms (excessive daytime sleepiness [EDS]; morning tiredness [MT]; loud snoring; multiple awakenings/night; gasping, choking, or apnea when asleep) and levels of biomarkers related to cardiovascular prognosis (high-sensitivity C-reactive protein [hs-CRP], interleukin 6 [IL-6], high-sensitivity cardiac troponin T [hs-cTnT], N-terminal pro B-type natriuretic peptide [NT-proBNP], cystatin C, growth differentiation factor 15 [GDF-15] and lipoprotein-associated phospholipase A 2 activity) were assessed at baseline in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. Cross-sectional associations were assessed by adjusted linear regression models testing for trends with the never/rarely category serving as reference., Results: EDS was associated (geometric mean ratio, 95% confidence interval) with increased levels of IL-6 (often 1.07 [1.03-1.10], always 1.15 [1.10-1.21]), GDF-15 (often 1.03 [1.01-1.06], always 1.07 [1.03-1.11]), NT-proBNP (always 1.22 [1.12-1.33]), and hs-cTnT (always 1.07 [1.01-1.12]). MT was associated with increased levels of IL-6 (often 1.05 [1.01-1.09], always 1.09 [1.04-1.15]), and GDF-15 (always 1.06 [1.03-1.10]). All symptoms were to some degree associated with higher levels of hs-CRP and loud snoring was also associated with decreased levels of NT-proBNP and hs-cTnT., Conclusions: In patients with CCS, stepwise increased frequency of SRBD-related symptoms, such as EDS and MT, were associated with gradually higher levels of IL-6 and GDF-15, each reflecting distinct pathophysiological pathways., Competing Interests: Declaration of Competing Interest MO: institutional research grants from GlaxoSmithKline. EH: research grants and speaker fees from Amgen, Sanofi; expert committee fees from NovoNordisk. NH: institutional research grant from GlaxoSmithKline. ML, SD, and AM: no conflict of interest. LW: institutional research grants from AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck&Co, Roche Diagnostics, Boehringer Ingelheim; consulting fees from Abbott; holds two patents involving GDF-15, both licensed to Roche Diagnostics. HDW: research grants from GlaxoSmithKline; grants and steering committee fees from Eli Lilly and Company, Omthera Pharmaceuticals, Eisai Inc., Dalcor Pharma UK, American Regent; grants and steering committee and advisory board fees from CSL Behring LLC; grants, steering committee, and personal fees from Sanofi-Aventis Australia Pty Ltd., Esperion Therapeutics Inc., Sanofi-Aventis; advisory board fees from Genentech, Inc.; personal fees from AstraZeneca. RAHS: research grants from GlaxoSmithKline. CH: honoraria from Pfizer; consultant and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Treatment of cardiovascular diseases (CVD) is a substantial burden to healthcare systems worldwide. New tools are needed to improve precision of treatment by optimizing the balance between efficacy, safety, and cost. We developed a high-throughput multi-marker decision support instrument which simultaneously quantifies proteins associated with CVD., Methods and Findings: Candidate proteins independently associated with different clinical outcomes were selected from clinical studies by the screening of 368 circulating biomarkers. We then custom-designed a quantitative PEA-panel with 21 proteins (CVD-21) by including recombinant antigens as calibrator samples for normalization and absolute quantification of the proteins. The utility of the CVD-21 tool was evaluated in plasma samples from a case-control cohort of 4224 patients with chronic coronary syndrome (CCS) using multivariable Cox regression analyses and machine learning techniques. The assays in the CVD-21 tool gave good precision and high sensitivity with lower level of determination (LOD) between 0.03-0.7 pg/ml for five of the biomarkers. The dynamic range for the assays was sufficient to accurately quantify the biomarkers in the validation study except for troponin I, which in the modeling was replaced by high-sensitive cardiac troponin T (hs-TnT). We created seven different multimarker models, including a reference model with NT-proBNP, hs-TnT, GDF-15, IL-6, and cystatin C and one model with only clinical variables, for the comparison of the discriminative value of the CVD-21 tool. All models with biomarkers including hs-TnT provided similar discrimination for all outcomes, e.g. c-index between 0.68-0.86 and outperformed models using only clinical variables. Most important prognostic biomarkers were MMP-12, U-PAR, REN, VEGF-D, FGF-23, TFF3, ADM, and SCF., Conclusions: The CVD-21 tool is the very first instrument which with PEA simultaneously quantifies 21 proteins with associations to different CVD. Novel pathophysiologic and prognostic information beyond that of established biomarkers were identified by a number of proteins., Competing Interests: I have read the journals policy and the authors of this manuscript have the following competing interests: AS reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Roche Diagnostics. NE reports institutional research grants from GlaxoSmithKline. EA, ML, and AB are employees of Olink Proteomics AB, Uppsala, Sweden. CH reports honoraria from Pfizer; consultant and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim. RAHS reports research grants from GlaxoSmithKline. HDW reports research grants from GlaxoSmithKline; grants and steering committee fees from Eli Lilly and Company, Omthera Pharmaceuticals, Eisai Inc., DalCor Pharma UK Inc., American Regent and CSL Behring LCC; grants, steering committee fees and personal fees from Sanofi-Aventis Australia Pty Ltd, Esperion Therapeutics, and Sanofi-Aventis; personal fees from AstraZeneca; support for attending the clinical trial forum from SAHMRI. MÅ reports no disclosures LW reports institutional research grants from AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck&Co, Roche Diagnostics, Boehringer Ingelheim. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Siegbahn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Patients at risk of statin non-adherence are often not identified during hospital admission with an acute coronary syndrome (ACS)., Methods: In 19,942 patients hospitalised for ACS, statin dispensing was determined from the national pharmaceutical dispensing database. A risk score for non-adherence was developed from a multivariable Poisson regression model of associations between risk factors and the statin Medication Possession Ratio (MPR) <0.8 6-18 months after hospital discharge., Results: Statin MPR was <0.8 in 4,736 (24%) patients. MPR <0.8 was more likely in patients with a history of cardiovascular disease (CVD) (RR 3.79, CI 95% 3.42-4.20) and those without known CVD (RR 2.25, 95% CI 2.04-2.48) who were not taking a statin on ACS admission, compared to patients with low density lipoprotein (LDL) cholesterol <2 mmol/L who were on a statin. For patients taking a statin on admission, higher LDL was associated with MPR <0.8 (≥3 versus <2 mmol/L, RR 1.96, 95%CI 1.72-2.24). Other independent risk factors for MPR <0.8 were age <45 years, female, disadvantaged ethnic groups, and no coronary revascularisation during the ACS admission. The risk score, which included nine variables, had a C-statistic of 0.67. MPR was <0.8 in 12% of 5,348 patients with a score ≤5 (lowest quartile) and 45% of 5,858 patients with a score ≥11 (highest quartile)., Conclusion: A risk score generated from routinely collected data predicts statin non-adherence in patients hospitalised with ACS. This may be used to target inpatient and outpatient interventions to improve medication adherence., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background The plasma concentration of B-type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured. Methods and Results Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient-years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1-year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1-year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44-1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44-1.60]), and years 10-16 (HR, 1.43 [95% CI, 1.36-1.50]), P <0.0001 for all. Conclusions BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long-term risk prediction.

Rationale: Transient myopericarditis has been recognised as an uncommon and usually mild adverse event predominantly linked to mRNA-based COVID-19 vaccines. These have mostly occurred in young males after the second dose of mRNA COVID-19 vaccines., Objectives: Fulminant necrotising eosinophilic myocarditis triggered by a variety of drugs or vaccines is an extremely rare hypersensitivity reaction carrying a substantial mortality risk. Early recognition of this medical emergency may facilitate urgent hospital admission for investigation and treatment. Timely intervention can lead to complete cardiac recovery, but the non-specific clinical features and rarity make early diagnosis challenging., Findings: The clinical and pathological observations from a case of fatal fulminant necrotising myocarditis in a 57-year-old woman, following the first dose of the Pfizer-BioNTech vaccine, are described. Other causes have been discounted with reasonable certainty., Conclusion: These extremely rare vaccine-related adverse events are much less common than the risk of myocarditis and other lethal complications from COVID-19 infection. The benefits of vaccination far exceed the risks of COVID-19 infection., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

BACKGROUND The obesity paradox states that patients with higher body mass index (BMI) and cardiovascular disease may experience better prognosis. However, this is less clear in patients with coronary heart disease. METHODS AND RESULTS The prospective STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial included 15 828 patients with stable coronary heart disease with 3 to 5 years' follow-up on optimal secondary preventive treatment. BMI was measured at baseline (n=15 785). Associations between BMI and cardiovascular outcomes were evaluated by Cox regression analyses with multivariable adjustments. Mean age was 64±9 years and 19% women. Most risk markers (diabetes, hypertension, inflammatory biomarkers, triglycerides) showed a graded association with higher BMI. The frequency of smoking, levels of high-density lipoprotein, growth differentiation factor 15, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) were higher at lower BMI. Low BMI (<20 kg/m 2 ; n=244 [1.5%]) was associated with doubled risk of total death (hazard ratio [HR], 2.27; 95% CI, 1.60-3.22), cardiovascular death (HR, 2.26; 95% CI, 1.46-3.49), and heart failure (HR, 2.51; 95% CI, 1.35-4.68) compared with BMI of 25 to <30 kg/m 2 (n=6752 [42.8%]) as reference. Similarly, high BMI of ≥35 kg/m 2 (n=1768 [11.2%]) was associated with increased risk of the same outcomes. A BMI between 20 and <25 kg/m 2 was associated with increased risk of cardiovascular death (HR, 1.26; 95% CI, 1.03-1.54) and total death (HR, 1.21; 95% CI, 1.03-1.42). CONCLUSIONS Patients with stable coronary heart disease showed a graded increase in cardiometabolic and inflammatory risk factors with increasing BMI category >25 kg/m 2 . All-cause and cardiovascular mortality were lowest at BMI of 25 to 35 kg/m 2 . Underweight with BMI of <20 kg/m 2 and very high BMI of ≥35 kg/m 2 were strong risk markers for poor prognosis. REGISTRATION URL: https://clinicaltrials.gov/; Unique identifier NCT00799903.

Importance: Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease., Objective: To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function., Design, Setting, and Participants: This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020., Exposures: Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2])., Main Outcomes and Measures: Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke., Results: This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99])., Conclusions and Relevance: In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.

Improved atrial fibrillation (AF) screening methods are required. We detected AF with pulse rate variability (PRV) parameters using a blood pressure device (BP+; Uscom, Sydney, Australia) and with a Kardia Mobile Cardiac Monitor (KMCM; AliveCor, Mountain View, CA). In 421 primary care patients (mean (range) age: 72 (31-99) years), we diagnosed AF (n = 133) from 12-lead electrocardiogram recordings, and performed PRV and KMCM measurements. PRV parameters detected AF with area under curve (AUC) values of up to 0.92. Using the mean of two sequential readings increased AUC to up to 0.94 and improved positive predictive value at a given sensitivity (by up to 18%). The KMCM detected AF with 83% sensitivity and 68% specificity. 89 KMCM recordings were "unclassified" or blank, and PRV detected AF in these with AUC values of up to 0.88. When non-AF arrhythmias (n = 56) were excluded, the KMCM device had increased specificity (73%) and PRV had higher discrimination performance (maximum AUC = 0.96). In decision curve analysis, all PRV parameters consistently achieved a positive net benefit across the range of clinical thresholds. In primary care, AF can be detected by PRV accurately and by KMCM, especially in the absence of non-AF arrhythmias or when combinations of measurements are used., (© 2021. The Author(s).)

Background: Sleep-related breathing disorders (SRBDs), particularly obstructive sleep apnoea, are associated with increased cardiovascular (CV) risk. However, it is not known whether individual questions used for SRBD screening are associated with major adverse CV events (MACE) and death specifically in patients with chronic coronary syndrome (CCS)., Methods: Symptoms associated with SRBD were assessed by a baseline questionnaire in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. The patients reported the frequency (never/rarely, sometimes, often and always) of: 1) loud snoring; 2) more than one awakening/night; 3) morning tiredness (MT); 4) excessive daytime sleepiness (EDS); or 5) gasping, choking or apnoea when asleep. In adjusted Cox regression models, associations between the frequency of SRBD symptoms and CV outcomes were assessed with never/rarely as reference., Results: During a median follow-up time of 3.7 years, 1,588 MACE events (541 CV deaths, 749 nonfatal myocardial infarctions [MI] and 298 nonfatal strokes) occurred. EDS was associated (hazard ratio [HR], 95% confidence interval [CI]) with increased risk of MACE (sometimes 1.14 [1.01-1.29], often 1.19 [1.01-1.40] and always 1.43 [1.15-1.78]), MI (always 1.61 [1.17-2.20]) and all-cause death (often 1.26 [1.05-1.52] and always 1.71 [1.35-2.15]). MT was associated with higher risk of MACE (often 1.23 [1.04-1.45] and always 1.46 [1.18-1.81]), MI (always 1.61 [1.22-2.14]) and all-cause death (always 1.54 [1.20-1.98]). The other SRBD-related questions were not consistently associated with worse outcomes., Conclusions: In patients with CCS, gradually higher levels of EDS and MT were independently associated with increased risk of MACE, including mortality., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: In patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and biomarkers with incident AF in patients with CHD., Methods and Results: Around 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial. The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios., Conclusions: In patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD., Methods and Findings: The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events., Conclusions: Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD., Trial Registration: ClinicalTrials.gov NCT00799903., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: LW reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck & Co, Roche Diagnostics; consulting fees from Abbott; holds two patents involving GDF-15, both licensed to Roche Diagnostics. NE and MO report institutional research grants from GlaxoSmithKline. EH reports institutional research grants from AstraZeneca, Amgen, GlaxoSmithKline, Sanofi; consulting fees from Amgen, NovoNordisk, Sanofi; speaker fees from AstraZeneca, Amgen, Boehringer Ingelheim, NovoNordisk, Sanofi; principal investigator fees paid to institution from CSL Behring, Dalcor, Regeneron, Sanofi, The Medicines Company. WK reports research grants from Roche Diagnostics, Beckmann, Singulex, Abbott; other research support from European Research Agency (ERA-CVD); honoraria from Novartis, Pfizer, Sanofi, AstraZeneca, Amgen; expert witness fees from Novartis; consultant/advisory board fees from Novartis, Pfizer, DalCor, Sanofi, Kowa, Amgen. CH reports Honoraria from Pfizer; consultant/advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim. MEK reports consulting/speaker fees from Bayer. WM reports grants and personal fees from Siemens Diagnostics, Abbott Diagnostics, AMGEN, Astrazeneca, Sanofi, BASF, Numares AG, employment from SYNLAB Holding Deutschland GmbH. RAHS reports grants and non-financial support from GlaxoSmithKline. HDW reports research grants from Sanofi-Aventis, Dalcor Pharma, NIH, Eisai, Omthera Pharmaceuticals; other support from SAHMRI, ESC, AHA, Sanofi/Regeneron. AS reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Roche Diagnostics, GlaxoSmithKline; consulting fees from Olink Proteomics. TBG and MÅ have nothing to declare.

Aims: The incidence of left ventricular (LV) thrombus following ST segment elevation myocardial infarction (STEMI) has reduced with modern reperfusion therapies. There is scant local data on the incidence and outcomes of LV thrombus in the contemporary era of rapid reperfusion., Methods: Patients with STEMI admitted to Auckland City Hospital between January 2014 and December 2015 were identified using the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry and their clinical notes were retrospectively reviewed., Results: Among the 997 patients admitted with STEMI, 53 patients (5%) had LV thrombus. Most patients with LV thrombus had an anterior STEMI (87%). The median time from admission to echocardiography was 48 hours (range 6-552 hours); the median LV ejection fraction was 38% (range 15-53%). Oral anticoagulation was initiated in 44 (83%) patients. LV thrombus resolved in 81% by six months in 42 patients given warfarin. Total mortality at 12 months was 13%. Bleeding occurred in 11% and was the most common treatment-related morbidity., Conclusions: The incidence of LV thrombus following STEMI was low and it was associated with a low rate of stroke and systemic embolism but high mortality. Randomised studies are needed to evaluate the efficacy of NOAC's in this context., Competing Interests: Nil.

Background: In patients with stable coronary heart disease, it is not known whether achievement of standard of care (SOC) targets in addition to evidence-based medicine (EBM) is associated with lower major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, and stroke., Methods: EBM use was recommended in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY trial. SOC targets were blood pressure (BP) <140/90 mm Hg and low-density lipoprotein-cholesterol (LDL-C) <100 mg/dL and <70 mg/dL. In patients with diabetes, glycosylated hemoglobin A1c (HbA1c) < 7% and BP of <130/80 mm Hg were recommended. Feedback to investigators about rates of EBM and SOC was provided regularly., Results: In 13,623 patients, 1-year landmark analysis assessed the association between EBM, SOC targets, and MACE during follow-up of 2.7 years (median) after adjustment in a Cox proportional hazards model. At 1 year, aspirin was prescribed in 92.5% of patients, statins in 97.2%, β-blockers in 79.0%, and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers in 76.9%. MACE was lower with LDL-C < 100 mg/dL (70-99 mg/dL) compared with LDL-C ≥ 100 mg/dL (hazard ratio [HR] 0.694, 95% CI 0.594-0.811) and lower with LDL-C < 70 mg/dL compared with LDL-C < 100 mg/dL (70-99 mg/dL) (HR 0.834, 95% CI 0.708-0.983). MACE was lower with HbA1c < 7% compared with HbA1c ≥ 7% (HR 0.705, 95% CI 0.573-0.866). There was no effect of BP targets on MACE., Conclusions: MACE was lower with LDL-C < 100 mg/dL (70-99 mg/dL) and even lower with LDL-C < 70 mg/dL. MACE in patients with diabetes was lower with HbA1c < 7%. Achievement of targets is associated with improved patient outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide- and phospholipid-based risk score, the Cardiovascular Event Risk Test (CERT2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography-mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein-associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow-up of 3.7 years. Hazard ratios per SD for the CERT2 risk score were 1.32 (95% CI, 1.25-1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35-1.59) for cardiovascular death, 1.32 (95% CI, 1.16-1.49) for stroke, 1.23 (95% CI, 1.14-1.33) for myocardial infarction, and 1.56 (95% CI, 1.39-1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT2 showed correlation ( P <0.001, r >0.2) with inflammatory markers high-sensitivity C-reactive protein, interleukin 6, the heart failure marker N-terminal pro-B-type natriuretic peptide, and low-density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT00799903.

Objectives: To evaluate the importance of the frequency and duration of lifestyle interventions for achieving weight loss over ≥1 year and associations with all-cause mortality., Design: Meta-analysis of randomised trials using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and RevMan software version 5·2 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen)., Data Sources: MEDLINE, CENTRAL, Google and Science Direct databases alongside reference lists of appropriate articles and meta-analyses., Eligibility Criteria: Randomised studies published in English-language journals from 1980 to June 2018 that assessed lifestyle compared with control interventions on weight loss and that included ≥100 subjects and reported weight change and mortality for ≥1 year., Data Extraction and Synthesis: Two independent reviewers extracted data and assessed risk of bias. Data were pooled using the generic inverse-variance method and expressed as mean differences (MDs) with 95% CI and OR with 95% CI as appropriate. Heterogeneity was assessed (Cochran Q statistic) and quantified (I 2 statistic). The Grading of Recommendations Assessment, Development, and Evaluation score was used to assess the certainty of the evidence., Results: 31 randomised trials with a total of 20 816 overweight or obese participants were included. 70% of participants had cardiometabolic risk factors. Body weight was lower for lifestyle intervention compared with the control at 1 year (3.63 kg, 95% CI 2.58 to 4.67) and at 3 years (2.45 kg, 95% CI 1.17 to 3.73). Weight loss at 1 year was greater in studies with >28 compared with ≤28 interventions per year (4.50 kg, 95% CI 3.03, 5.97 vs 2.38, 95% CI 0.78 to 3.98 kg, p=0.001). In all studies, there were 593 deaths (~0.3%/year). The ORs for mortality for weight loss interventions compared with the controls was 0.86 (95% CI 0.73 to 1.02), p=0.09., Conclusion: In predominantly healthy populations with risk factors, there is a dose response with number of lifestyle interventions and weight loss. Frequent and sustained interventions are needed to achieve a clinically significant 5% weight loss. There was insufficient evidence to reliably evaluate the benefits in persons with known cardiovascular disease or cancer., Trial Registration Number: CRD42018095067., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Vascular risk factors have been associated with differences in cognitive performance in epidemiological studies, but evidence in patients with coronary heart disease is more limited. Methods and Results The Montreal Cognitive Assessment score obtained 3.2±0.37 years after randomization to darapladib, a reversible inhibitor of lipoprotein phospholipase A 2 or placebo was evaluated for 10 634 patients with coronary heart disease from 38 countries in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial. The Montreal Cognitive Assessment scores for darapladib and placebo groups were similar (mean± SD , 25.3±3.84 versus 25.4±3.73, respectively; P=0.27) and the adjusted odds ratio ( OR ) for mild cognitive impairment (Montreal Cognitive Assessment score <26) was 1.00 (95% CI , 0.93-1.09). Mild cognitive impairment was more likely with increasing age ( OR , 1.33 [1.27-1.41], +5 years after 65). For other baseline clinical characteristics, the strongest independent predictors of cognitive impairment were education (≤8 years versus college/university, OR , 2.95 [2.60-3.35]; >8 years/trade school versus college/university, OR , 1.38 [1.25-1.52] and geographic grouping). Cardiovascular risk factors independently associated with cognitive impairment were history of stroke ( OR , 1.43 [1.20-1.71]); <2.5 hours of moderate or vigorous intensity exercise/week ( OR , 1.19 [1.04-1.37]); high-density lipoprotein cholesterol <1.16 mmol/L ( OR , 1.19 [1.04-1.37]); diabetes mellitus requiring treatment ( OR , yes versus no: 1.15 [1.05-1.26]); and history of hypertension ( OR , 1.12 [1.02-1.23]). Conclusions In patients with stable coronary heart disease, cognitive performance was associated with modifiable cardiovascular risk factors, educational level, and global region, but was not influenced by darapladib. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00799903.

Background: Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease., Methods: Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results., Results: In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03])., Conclusions: The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Compare the effects and costs of remotely monitored exercise-based cardiac telerehabilitation (REMOTE-CR) with centre-based programmes (CBexCR) in adults with coronary heart disease (CHD)., Methods: Participants were randomised to receive 12 weeks of telerehabilitation or centre-based rehabilitation. REMOTE-CR provided individualised exercise prescription, real-time exercise monitoring/coaching and theory-based behavioural strategies via a bespoke telerehabilitation platform; CBexCR provided individualised exercise prescription and coaching via established rehabilitation clinics. Outcomes assessed at baseline, 12 and/or 24 weeks included maximal oxygen uptake (V̇O 2 max, primary) modifiable cardiovascular risk factors, exercise adherence, motivation, health-related quality of life and programme delivery, hospital service utilisation and medication costs. The primary hypothesis was a non-inferior between-group difference in V̇O 2 max at 12 weeks (inferiority margin=-1.25 mL/kg/min); inferiority margins were not set for secondary outcomes., Results: 162 participants (mean 61±12.7 years, 86% men) were randomised. V̇O 2 max was comparable in both groups at 12 weeks and REMOTE-CR was non-inferior to CBexCR (REMOTE-CR-CBexCR adjusted mean difference (AMD)=0.51 (95% CI -0.97 to 1.98) mL/kg/min, p=0.48). REMOTE-CR participants were less sedentary at 24 weeks (AMD=-61.5 (95% CI -117.8 to -5.3) min/day, p=0.03), while CBexCR participants had smaller waist (AMD=1.71 (95% CI 0.09 to 3.34) cm, p=0.04) and hip circumferences (AMD=1.16 (95% CI 0.06 to 2.27) cm, p=0.04) at 12 weeks. No other between-group differences were detected. Per capita programme delivery (NZD1130/GBP573 vs NZD3466/GBP1758) and medication costs (NZD331/GBP168 vs NZD605/GBP307, p=0.02) were lower for REMOTE-CR. Hospital service utilisation costs were not statistically significantly different (NZD3459/GBP1754 vs NZD5464/GBP2771, p=0.20)., Conclusion: REMOTE-CR is an effective, cost-efficient alternative delivery model that could-as a complement to existing services-improve overall utilisation rates by increasing reach and satisfying unique participant preferences., Competing Interests: Competing interests: RM was supported by the New Zealand Health Research Council (Sir Charles Hercus health research fellowship). MM is supported by the Australian National Health and Medical Research Council (Centre for Research Excellence, 1041020). We declare no further competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is increasing evidence that plant based diets are associated with lower cardiovascular risk., Objective: To evaluate effects of a vegan compared to an omnivorous diet on cardio-metabolic risk factors., Methods: Meta-analysis of observational studies published between 1960 and June 2018 that reported one or more cardio-metabolic risk factors in vegans and controls eating an omnivorous diet were undertaken. Macro-nutrient intake and cardio-metabolic risk factors were compared by dietary pattern. The Newcastle Ottawa Scale (NOS) was used to assess the quality of each study. The inverse-variance method was used to pool mean differences. Statistical analyses were performed using RevMan software version 5•2 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen., Results: 40 studies with 12 619 vegans and 179 630 omnivores were included. From food frequency questionnaires in 28 studies, vegans compared to omnivores consumed less energy (-11%, 95% confidence interval -14 to -8) and less saturated fat (- 51%, CI -57 to -45). Compared to controls vegans had a lower body mass index (-1.72 kg/m2, CI -2.30 to -1.16), waist circumference (-2.35 cm, CI -3.93 to -0.76), low density lipoprotein cholesterol (-0.49 mmol/L CI -0.62 to -0.36), triglycerides (-0.14 mmol/L, CI -0.24 to -0.05), fasting blood glucose (-0.23 mmol/, CI -0.35 to -0.10), and systolic (-2.56 mmHg, CI -4.66 to -0.45) and diastolic blood pressure (-1.33 mmHg, CI -2.67 to -0.02), p<0.0001 for all. Results were consistent for studies with < and ≥ 50 vegans, and published before and after 2010. However in several large studies from Taiwan a vegan diet was not associated with favourable cardio-metabolic risk factors compared to the control diets., Conclusion: In most countries a vegan diet is associated with a more favourable cardio- metabolic profile compared to an omnivorous diet., Competing Interests: The authors have declared that no competing interests exist.

Dairy, as a major component of a high protein diet, is a critical dietary source of branched chain amino acids (BCAA), which are biomarkers of health and diseases. While BCAA are known to be key stimulators of protein synthesis, elevated circulatory BCAA is an independent risk factor for type 2 diabetes mellitus. This study examined the impact of altered dairy intake on plasma BCAA and their potential relationship to insulin sensitivity. Healthy adults ( n = 102) were randomized to receive dietary advice to reduce, maintain, or increase habitual dairy intake for 1 month. Food intake was recorded with food frequency questionnaires. Self-reported protein intake from dairy was reported to be reduced (-14.6 ± 3.0 g/day), maintained (-4.0 ± 2.0 g/day) or increased (+13.8 ± 4.1 g/day) according to group allocation. No significant alterations in circulating free amino acids (AA), including BCAA, were measured. Insulin sensitivity, as assessed by homeostatic model assessment-insulin resistance (HOMA-IR), was also unaltered. A significant change in dairy protein intake showed no significant effect on fasting circulatory BCAA and insulin sensitivity in healthy populations.

Purpose: Existing knowledge of medicines that increase the risk of an adverse event may be corroborated and augmented by population studies specifically assessing the risk associated with the concurrent use of these medicines and use by patients with existing comorbidity. An American Heart Association review recently identified a variety of medicines that may cause or exacerbate heart failure (HF), many with evidence from limited evaluation of population data. We assessed the risk of first-time HF associated with the use of 50 of these medicines by New Zealand's primary care population., Methods: Case-control study utilising national pharmaceutical use and hospital admissions data 2007-2015; 22,989 patients with first-time HF 2008-2015 were matched with 114 498 control patients. The primary outcome was first-time HF and its association with medicine exposure in the prior 90 days, estimated using conditional logistic regression. We also assessed the risk associated with new use of medicines in the prior month, concurrent use, and in patients with existing comorbidity., Results: Eleven medicines were significantly associated with HF with several other infrequently used medicines providing signals of increased risk. A high risk was associated with the use of salbutamol (adjusted odds ratio 2.63; 95% CI, 2.48-2.78), clozapine (2.70; 2.46-4.98), diltiazem (1.52; 1.44-1.60), indomethacin (2.51; 1.54-4.10), pioglitazone (1.50; 1.16-1.95), and antifungal medicines. New use of medicines and use of medicine combinations increased this risk in many cases., Conclusions: Our study provides further evidence to inform cautious use of these medicines in patients with HF or at risk of developing HF., (© 2018 John Wiley & Sons, Ltd.)

Background: In patients with ischaemic left ventricular dysfunction, coronary artery bypass surgery (CABG) may decrease mortality, but it is not known whether CABG improves functional capacity., Objective: To determine whether CABG compared with medical therapy alone (MED) increases 6 min walk distance in patients with ischaemic left ventricular dysfunction and coronary artery disease amenable to revascularisation., Methods: The Surgical Treatment in Ischemic Heart disease trial randomised 1212 patients with ischaemic left ventricular dysfunction to CABG or MED. A 6 min walk distance test was performed both at baseline and at least one follow-up assessment at 4, 12, 24 and/or 36 months in 409 patients randomised to CABG and 466 to MED. Change in 6 min walk distance between baseline and follow-up were compared by treatment allocation., Results: 6 min walk distance at baseline for CABG was mean 340±117 m and for MED 339±118 m. Change in walk distance from baseline was similar for CABG and MED groups at 4 months (mean +38 vs +28 m), 12 months (+47 vs +36 m), 24 months (+31 vs +34 m) and 36 months (-7 vs +7 m), P>0.10 for all. Change in walk distance between CABG and MED groups over all assessments was also similar after adjusting for covariates and imputation for missing values (+8 m, 95% CI -7 to 23 m, P=0.29). Results were consistent for subgroups defined by angina, New York Heart Association class ≥3, left ventricular ejection fraction, baseline walk distance and geographic region., Conclusion: In patients with ischaemic left ventricular dysfunction CABG compared with MED alone is known to reduce mortality but is unlikely to result in a clinically significant improvement in functional capacity., Trial Registration Number: NCT00023595., Competing Interests: Competing interests: JGHC: Medtronic advisory board. HDW: grants and non-financial support from GlaxoSmithKline during the conduct of the study; grants from Sanofi Aventis, Eli Lilly and Company, National Institutes of Health, Merck Sharpe & Dohm, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics Inc, Elsai Inc, DalGenE Products and Services; grants and personal fees from AstraZeneca, outside the submitted work. EJV: research grants from NHLBI, Alnylam Pharmaceuticals, Amgen, Novartis Pharmaceutical Corp and Pfizer; consulting services for Amgen, Merck & Co and Novartis Pharmaceutical Corp; and speakers bureau honoraria from Expert Exchange.

Objectives: Assess the risk of ischaemic events associated with psychosocial stress in patients with stable coronary heart disease (CHD)., Methods: Psychosocial stress was assessed by a questionnaire in 14 577 patients (median age 65.0, IQR 59, 71; 81.6% males) with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial. Adjusted Cox regression models were used to assess associations between individual stressors, baseline cardiovascular risk factors and outcomes., Results: After 3.7 years of follow-up, depressive symptoms, loss of interest and financial stress were associated with increased risk (hazard ratio, 95% confidence interval) of CV death (1.21, 1.09-1.34; 1.15, 1.05-1.27; and 1.19, 1.08-1.30, respectively) and the primary composite end-point of CV death, nonfatal MI or nonfatal stroke (1.21, 1.13-1.30; 1.19, 1.11-1.27; and 1.17, 1.10-1.24, respectively). Living alone was related to higher risk of CV death (1.68, 1.38-2.05) and the primary composite end-point (1.28, 1.11-1.48), whereas being married as compared with being widowed, was associated with lower risk of CV death (0.64, 0.49-0.82) and the primary composite end-point (0.81, 0.67-0.97)., Conclusions: Psychosocial stress, such as depressive symptoms, loss of interest, living alone and financial stress, were associated with increased CV mortality in patients with stable CHD despite optimal medical secondary prevention treatment. Secondary prevention of CHD should therefore focus also on psychosocial issues both in clinical management and in future clinical trials., (© 2017 The Association for the Publication of the Journal of Internal Medicine.)

Background: A single assessment of psychological distress, which includes depression and anxiety, has been associated with increased mortality in patients with coronary heart disease, but the prognostic importance of persistence of distress symptoms is less certain., Aim: To determine whether intermittent and/or persistent psychological distress is associated with long-term cardiovascular (CV) and total mortality in patients with stable coronary artery disease., Methods: 950 participants in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial completed at least four General Health Questionnaires (GHQ-30) at baseline and after ½, 1, 2 and 4 years. In a landmark analysis from 4 years, Cox proportional hazards models evaluated the risk of CV and total mortality by increasing levels of psychological distress: never distressed, sometimes any severity (GHQ score >5), persistent mild (GHQ score >5 on three or more occasions) and persistent moderate distress (GHQ score >10) on three or more occasions, over a median of 12.1 (IQR 8.6-12.5) years. The models were both unadjusted and adjusted for known baseline risk factors., Results: Persistent moderate or greater psychological stress was reported on three or more assessments by 35 (3.7%) subjects. These patients had a higher risk of both CV death (adjusted HR 3.94, 95% CI 2.05 to 7.56, p<0.001) and all-cause mortality (adjusted HR 2.85, 95% CI 1.74 to 4.66, p<0.001) compared with patients with no distress. In contrast, patients who reported persistent mild distress (n=73, 7.7%) on three or more visits, and those who met criteria for distress on only one or two assessments (n=255, 26.8%), did not have an increased risk of CV or all-cause mortality during follow-up., Conclusion: In patients with stable coronary artery disease, persistent psychological distress of at least moderate severity is associated with a substantial increase in CV and all-cause mortality., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population., Methods and Results: Overall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were 2.1 (interquartile range, 1.4-3.2) ng/L and 1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; P <0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; P <0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; P <0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; P <0.0001); and risk of hospitalization for heart failure (HR, 2.28; 95% CI, 1.34-3.89; P <0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; P <0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and non-cardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments., Conclusions: IL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903., (© 2017 The Authors and GlaxoSmithKline. Published on behalf of the American Heart Association, Inc., by Wiley.)