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Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease.Design Registry based observational study.Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients).Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease.Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07).Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research.

Objective: To explore associations between general health-related problems and subclinical coronary artery disease (CAD), determined by CT coronary calcium score (CT-CCS), in a general population., Design: A cross-sectional design., Setting: This study was performed in a prospective population-based cohort, examining the health and health-related behaviour of individuals living in the Northern Netherlands., Participants: The initial cohort comprised 6763 participants ≥45 years of age who underwent CT-scanning. Participants were included for the current analysis if they filled in three validated questionnaires (Symptomatic Checklist-90, Research and Development Survey-36 and Reviving the Early Diagnosis of CardioVascular Diseases questionnaire (RED-CVD)) and did not have a history of cardiovascular disease. The final analysis included 6530 participants., Primary Outcome Measure: Backward-stepwise and forward-stepwise logistic regression analyses were performed to determine associations between general health-related problems and subclinical CAD (CCS≥100 and ≥300)., Results: The median age was 53 years (25th, 75th percentile: 48, 58); 57% were women. CRCS≥100 was found in 1236 (19%) participants, 437 (12%) in women and 799 (29%) men and CCS≥300 in 643 (9.9%) participants of which 180 (4.8%) were women and 463 (16.6%) men. In univariate analysis, in women the expectation of health to worsen (OR=1.13, 95% CI: 1.05 to 1.21), and in men reduced exercise intolerance (OR=1.14, 95% CI: 1.06 to 1.23) were associated with CCS≥100. The total RED-CVD score in women (OR=1.06, (95% CI: 1.05 to 1.08) and men (OR=1.07, 95% CI: 1.06 to 1.09), and in men also reduced exercise intolerance (OR=1.15, 95% CI: 1.06 to 1.25) and headache (OR=0.55, 95% CI: 0.38 to 0.79) were associated with CCS≥300. In multivariate analyses, only general health expectation in women was still significantly associated with subclinical CAD (CCS≥300) (OR=1.92, 95% CI: 1.56 to 2.37)., Conclusion: Only a few general health-related problems were associated with the presence of subclinical CAD in the general population, however, these problems showed no strong association. Therefore, using health-related symptoms does not seem useful to pre-select for CT-CCS., Trial Registration Number: CCMO Register, NL17981.042.07 and NL58592.042.16., Competing Interests: Competing interests: RV has received institutional research grants from Siemens Healthineers, and PvdH has received grant support by Siemens Healthineers and Guerbet. The other authors did not report any potential conflict of interest relevant to this article., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The variety, time patterns and long-term prognosis of persistent COVID-19 symptoms (long COVID-19) in patients who suffered from mild to severe acute COVID-19 are incompletely understood. Cohort studies will be combined to describe the prevalence of long COVID-19 symptoms, and to explore the pathophysiological mechanisms and impact on health-related quality of life. A prediction model for long COVID-19 will be developed and internally validated to guide care in future patients., Methods and Analysis: Data from seven COVID-19 cohorts will be aggregated in the longitudinal multiple cohort CORona Follow Up (CORFU) study. CORFU includes Dutch patients who suffered from COVID-19 at home, were hospitalised without or with intensive care unit treatment, needed inpatient or outpatient rehabilitation and controls who did not suffer from COVID-19. Individual cohort study designs were aligned and follow-up has been synchronised. Cohort participants will be followed up for a maximum of 24 months after acute infection. Next to the clinical characteristics measured in individual cohorts, the CORFU questionnaire on long COVID-19 outcomes and determinants will be administered digitally at 3, 6, 12, 18 and 24 months after the infection. The primary outcome is the prevalence of long COVID-19 symptoms up to 2 years after acute infection. Secondary outcomes are health-related quality of life (eg, EQ-5D), physical functioning, and the prevalence of thromboembolic complications, respiratory complications, cardiovascular diseases and endothelial dysfunction. A prediction model and a patient platform prototype will be developed., Ethics and Dissemination: Approval was obtained from the medical research ethics committee of Maastricht University Medical Center+ and Maastricht University (METC 2021-2990) and local committees of the participating cohorts. The project is supported by ZonMW and EuroQol Research Foundation. Results will be published in open access peer-reviewed scientific journals and presented at (inter)national conferences., Trial Registration Number: NCT05240742., Competing Interests: Competing interests: BCTvB, BH, BLJHK, JH, DK, EB, EBNJJ, GJB, ICCvdH, JH, JWLC, LHW, MSJNW, MW, RW, SCMH, SMJK, SvS and BH declare no competing interests. FAK received research support from Bayer, BMS, Boehringer-Ingelheim, MSD, Daiichi-Sankyo, Actelion, Boston Scientific, The Netherlands Organization for Health Research and Development (ZonMW), The Dutch Thrombosis Association, and The Dutch Heart Foundation. FWA is supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre. For the CAPACITY-COVID cohort participating in CORFU, FWA and ML received support from Dutch Heart Foundation (2020B006 CAPACITY) an The Netherlands Organization for Health Research and Development (ZonMW) (grant number 10430102110006 DEFENCE). HTC received support from Bayer, received consulting fees from Pfizer, Leo, Alveron, Viatris, Astra Zeneca, and Galapagos, and has stock (options) in Coagulation Profile. KV has royalities or licences for Philips, Medtronic, Abbott, and Biosense Webster, received consulting fees from Philips, Biosense Webster, Boston Scientific, and Medtronic, and has a role in the European Heart Rhythm Association congress organization and digital committee. MDdK received a presentation fee from Glaxo Smith Kline. ML is supported by the Alexandre Suerman Stipend of the University Medical Center Utrecht., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Coronavirus disease 2019 (COVID-19) is the cause of a devastating global pandemic and is not likely to be fully resolved in the near future. In most cases COVID-19 presents with mild symptoms, but in a minority of patients respiratory and multi-organ failure may ensue. Previous research has focused on the correlation between COVID-19 and a variety of cardiovascular complications. However, the effect of COVID-19 on pulmonary hypertension (PH) and correlated cardiovascular parameters has not been evaluated extensively., Methods: This study was designed as a single-centre, semi-quantitative analysis. PH was considered to be present if echocardiographic measurements estimated right ventricular systolic pressure at rest to be 36 mm Hg or higher in combination with indirect indicators of right ventricular overload., Results: In total, 101 patients (67.3% male) were included in this study, with a mean age of 66 years (range 23-98 years). PH was diagnosed by echocardiographic estimation in 30 patients (29.7%). Echocardiographically estimated PH (eePH) was not correlated with a diagnosis of heart failure or pulmonary embolism. Mortality was significantly higher among COVID-19 patients with eePH (p = 0.015). In all 10 of 20 surviving eePH patients in whom echocardiographic follow-up was obtained, echocardiographic estimations of pulmonary pressures showed a significant decrease after a median of 144 ± 72 days., Conclusion: eePH is frequently observed in COVID-19 patients and is correlated with increased mortality. COVID-19-related eePH appears to be reversible after recovery. Vigilant attention and a low threshold for performance of echocardiography in COVID-19 patients seems warranted, as eePH may be applicable as a prognostic risk factor., (© 2022. The Author(s).)

Objectives: Thoracoscopic ablation for atrial fibrillation (AF) and minimally invasive direct coronary artery bypass (MIDCAB) with robot-assisted left internal mammary artery (LIMA) harvesting may represent a safe and effective alternative to more invasive surgical approaches via sternotomy. The aim of our study was to describe the feasibility, safety and efficacy of a unilateral left-sided thoracoscopic AF ablation and concomitant MIDCAB surgery., Methods: Retrospective analysis of a prospectively gathered cohort was performed of all consecutive patients with AF and at least a critical left anterior descending artery (LAD) stenosis that underwent unilateral left-sided thoracoscopic AF ablation and concomitant off-pump MIDCAB surgery in the Maastricht University Medical Centre between 2017 and 2021., Results: Twenty-three patients were included [age 69 years (standard deviation = 8), paroxysmal AF 61%, left atrial volume index 42 ml/m2 (standard deviation = 11)]. Unilateral left-sided thoracoscopic isolation of the left (n = 23) and right (n = 22) pulmonary veins and box (n = 21) by radiofrequency ablation was succeeded by epicardial validation of exit- and entrance block (n = 22). All patients received robot-assisted LIMA harvesting and off-pump LIMA-LAD anastomosis through a left mini-thoracotomy. The perioperative complications consisted of one bleeding of the thoracotomy wound and one aborted myocardial infarction not requiring intervention. The mean duration of hospital stay was 6 days (standard deviation = 2). After discharge, cardiac hospital readmission occurred in 4 patients (AF n = 1; pleural- and pericardial effusion n = 2, myocardial infarction requiring the percutaneous intervention of the LIMA-LAD n = 1) within 1 year. After 12 months, 17/21 (81%) patients were in sinus rhythm when allowing anti-arrhythmic drugs. Finally, the left atrial ejection fraction improved postoperatively [26% (standard deviation = 11) to 38% (standard deviation = 7), P = 0.01]., Conclusions: In this initial feasibility and early safety study, unilateral left-sided thoracoscopic AF ablation and concomitant MIDCAB for LIMA-LAD grafting is a feasible, safe and efficacious for patients with AF and a critical LAD stenosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objective: Obesity is associated with cardiovascular disease (CVD) and CVD mortality. However, previous reports showed a paradoxical protective effect in patients with known CVD referred as "obesity paradox". Therefore, the aim of the present study was to investigate the association of body mass index (BMI) with coronary artery calcification (CAC) in a large outpatient cardiac CT cohort., Methods: 4.079 patients who underwent cardiac CT between December 2007-May 2014 were analyzed. BMI and clinical risk factors (current smoking, diabetes mellitus type 2, family history, systolic blood pressure, lipid spectrum) were assessed. Missing values were imputed using multiple imputation. CAC extent was categorized as absent (0), mild (>0-100), moderate (>100-400) and severe (>400)., Results: Multivariable multinomial logistic regression analysis, including all risk factors as independent variables, showed no association between BMI and CAC. Using absence of calcification as reference category, the odds ratios per unit increase in BMI were 1.01 for mild; 1.02 for moderate; and 1.00 for severe CAC ( p -values ≥0.103)., Conclusions: No statistically significant association was observed between BMI and CAC after adjustment for other risk factors., Competing Interests: The authors declared no conflict of interest., (© 2022 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Objective: We studied the coaptation angles α and β in bicuspid aortic valve geometry from computed tomography scan images., Methods: In 45 patients, we calculated the coaptation angle α (the angle between the nonfused commissures crossing the center of coaptation), angle β (between the nonfused commissures crossing the center of the reference circle), angles γ 1 and γ 2 and ε 1 and ε 2 (angle between the nonfused commissures and the coaptation point at the raphe or the perfect midpoint, respectively), the length of the raphe, the absolute and relative sinuses' surfaces (relative to the perfect circle and the percentage exceeding the ideal circle). Spearman correlation was employed to investigate the associations among all parameters., Results: The coaptation angles α and β were significantly different ( P  < .001). We found a significant correlation of α with the length of the raphe ( P  = .008), whereas β was dependent on the position of the commissures. Both γ 1 and γ 2 ( P  = .04), or ε 1 and ε 2 ( P  < .001) significantly differed from each other and ε 2 was the most constant angle, although its size geometrically depends on β. The noncoronary was the largest sinus, and β was the primary determinant of its increased size in bicuspid aortic valves with righ/left fusion pattern., Conclusions: The coaptation angle α is influenced by the length of the raphe, whereas angle β is dependent on the position of the commissures. The position of the raphe can vary and is not always situated in the middle of the free edge. The position of the right/non commissure is variable, whereas the right/left commissure is more fixed., (© 2021 The Author(s).)

Background: Previous research showed a significant difference in the presence of subclinical coronary artery disease (CAD) on cardiac CT angiography (CTA) between patients with idiopathic paroxysmal atrial fibrillation (iAF) versus a matched sinus rhythm population (iSR). Here we present 5-year follow-up data and the consequences of subclinical CAD on baseline CTA on the development of cardiovascular disease in iAF., Methods: In 99 iAF patients (who underwent CTA as part of work-up for pulmonary vein isolation) and 221 matched iSR controls (who underwent CTA for CAD assessment), the incidence of hypertension, diabetes and major cardiovascular events (MACCE) during follow-up was obtained. Multivariable Cox regression analysis was used to reveal predictors of incident cardiovascular disease in the iAF group., Results: During a follow-up of 68±11 months, over one third of patients developed cardiovascular disease, with no difference between iAF and iSR (log-rank p=0.56), and comparable low rates of MACCE (4.0% vs 5.0%,p=0.71). Within the iAF group, age (HR1.12(1.03-1.20);p=0.006), left atrial diameter (HR1.16(1.03-1.31);p=0.01), Segment Involvement Score (total number of coronary segments with atherosclerotic plaque; HR1.43(1.09-1.89);p=0.01) and the number of calcified plaques on CTA (HR0.53(0.30-0.92);p=0.01) were independent predictors of incident cardiovascular disease., Conclusions: Subclinical coronary disease on CTA may be useful to identify the subset of patients with iAF that harbour concealed cardiovascular risk factors and need intensive clinical follow-up to ensure timely initiation of appropriate therapy once CV disease develops, including anticoagulation and vascular prophylactic therapy.

Background: Pericardial fat (PF) has been suggested to directly act on cardiomyocytes, leading to diastolic dysfunction. The aim of this study was to investigate whether a higher PF volume is associated with a lower diastolic function in healthy subjects., Methods: 254 adults (40-70 years, BMI 18-35 kg/m 2 , normal left ventricular ejection fraction), with (a)typical chest pain (otherwise healthy) from the cardiology outpatient clinic were retrospectively included in this study. All patients underwent a coronary computed tomographic angiography for the measurement of pericardial fat volume, as well as a transthoracic echocardiography for the assessment of diastolic function parameters. To assess the independent association of PF and diastolic function parameters, multivariable linear regression analysis was performed. To maximize differences in PF volume, the group was divided in low (lowest quartile of both sexes) and high (highest quartile of both sexes) PF volume. Multivariable binary logistic analysis was used to study the associations within the groups between PF and diastolic function, adjusted for age, BMI, and sex., Results: Significant associations for all four diastolic parameters with the PF volume were found after adjusting for BMI, age, and sex. In addition, subjects with high pericardial fat had a reduced left atrial volume index (p = 0.02), lower E/e (p < 0.01) and E/A (p = 0.01), reduced e' lateral (p < 0.01), reduced e' septal p = 0.03), compared to subjects with low pericardial fat., Conclusion: These findings confirm that pericardial fat volume, even in healthy subjects with normal cardiac function, is associated with diastolic function. Our results suggest that the mechanical effects of PF may limit the distensibility of the heart and thereby directly contribute to diastolic dysfunction. Trial registration NCT01671930.

Objective: Circulating biomarkers are useful in detection and monitoring of cardiovascular diseases. However, their role in aortic valve disease is unclear. Mechanisms are rapidly elucidated and sex differences are suggested to be involved. Therefore, we sought to identify biomarkers involved in aortic valve calcification (AVC) stratified by sex., Methods: Blood samples of 34 patients with AVC (without further overt cardiovascular disease, including absence of hemodynamic consequences of valvular calcification) were compared with 136 patients without AVC. AVC was determined using computed tomography calcium scoring. Circulating biomarkers were quantified using a novel antibody-based method (Olink Proseek Multiplex Cardiovascular Panel I) and 92 biomarkers were compared between patients with and without AVC., Results: In the overall population, Interleukin-1 Receptor Antagonist and pappalysin-1 were associated with increased and decreased odds of having AVC. These differences were driven by the male population [IL1RA: OR 2.79 (1.16-6.70), p = 0.022; PAPPA: OR 0.30 (0.11-0.84), p = 0.021]. Furthermore, TNF-related activation-induced cytokine (TRANCE) and fibroblast growth factor-23 were associated decreased odds of having AVC, and monocyte chemotactic protein-1 was associated with increased odds of having AVC [TRANCE: OR 0.32 (0.12-0.80), p = 0.015; FGF23: OR 0.41 (0.170-0.991), p = 0.048; MCP1: OR 2.64 (1.02-6.81), p = 0.045]. In contrast, galanin peptides and ST2 were associated with increased odds of having AVC in females [GAL: OR 12.38 (1.31-116.7), p = 0.028; ST2: OR13.64 (1.21-153.33), p = 0.034]., Conclusion: In this exploratory study, we identified biomarkers involved in inflammation, fibrosis and calcification which may be associated with having AVC. Biomarkers involved in fibrosis may show higher expression in females, whilst biomarkers involved in inflammation and calcification could associate with AVC in males., (Copyright © 2020 Peeters, Dudink, Weijs, Fabritz, Chua, Kietselaer, Wildberger, Meex, Kirchhof, Crijns and Schurgers.)

Background: Patients with non-ST-segment elevation myocardial infarction and elevated high-sensitivity cardiac troponin levels often routinely undergo invasive coronary angiography (ICA), but many do not have obstructive coronary artery disease., Objectives: This study investigated whether cardiovascular magnetic resonance imaging (CMR) or computed tomographic angiography (CTA) may serve as a safe gatekeeper for ICA., Methods: This randomized controlled trial (NCT01559467) in 207 patients (age 64 years; 62% male patients) with acute chest pain, elevated high-sensitivity cardiac troponin T levels (>14 ng/l), and inconclusive electrocardiogram compared a CMR- or CTA-first strategy with a control strategy of routine clinical care. Follow-up ICA was recommended when initial CMR or CTA suggested myocardial ischemia, infarction, or obstructive coronary artery disease (≥70% stenosis). Primary efficacy and secondary safety endpoints were referral to ICA during hospitalization and 1-year outcomes (major adverse cardiac events and complications), respectively., Results: The CMR- and CTA-first strategies reduced ICA compared with routine clinical care (87% [p = 0.001], 66% [p < 0.001], and 100%, respectively), with similar outcome (hazard ratio: CMR vs. routine, 0.78 [95% confidence interval: 0.37 to 1.61]; CTA vs. routine, 0.66 [95% confidence interval: 0.31 to 1.42]; and CMR vs. CTA, 1.19 [95% confidence interval: 0.53 to 2.66]). Obstructive coronary artery disease after ICA was found in 61% of patients in the routine clinical care arm, in 69% in the CMR-first arm (p = 0.308 vs. routine), and in 85% in the CTA-first arm (p = 0.006 vs. routine). In the non-CMR and non-CTA arms, follow-up CMR and CTA were performed in 67% and 13% of patients and led to a new diagnosis in 33% and 3%, respectively (p < 0.001)., Conclusions: A novel strategy of implementing CMR or CTA first in the diagnostic process in non-ST-segment elevation myocardial infarction is a safe gatekeeper for ICA., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Our primary objective was to evaluate the Marburg Heart Score (MHS), a clinical decision rule, or to develop an adapted clinical decision rule for family physicians (FPs) to safely rule out acute coronary syndrome (ACS) in patients referred to secondary care for suspected ACS. The secondary objective was to evaluate the feasibility of using the flash-mob method, an innovative study design, for large-scale research in family medicine., Methods: In this 2-week, nationwide, prospective, observational, flash-mob study, FPs collected data on possible ACS predictors and assessed ACS probability (on a scale of 1-10) in patients referred to secondary care for suspected ACS., Results: We collected data for 258 patients in 2 weeks by mobilizing approximately 1 in 5 FPs throughout the country via ambassadors. A final diagnosis was obtained for 243 patients (94.2%), of whom 45 (18.5%) received a diagnosis of ACS. Sex, sex-adjusted age, and ischemic changes on electrocardiography were significantly associated with ACS. The sensitivity of the MHS (cut-off ≤2) was 75.0%, specificity was 44.0%, positive predictive value was 24.3%, and negative predictive value was 88.0%. For the FP assessment (cut-off ≤5), these test characteristics were 86.7%, 41.4%, 25.2%, and 93.2%, respectively., Conclusions: For patients referred to emergency care, ACS could not be safely ruled out using the MHS or FP clinical assessment. The flash-mob study design may be a feasible alternative research method to investigate relatively simple, clinically relevant research questions in family medicine on a large scale and over a relatively short time frame., (© 2019 Annals of Family Medicine, Inc.)

Objective: Cardiac biomarkers hold promise for follow-up and management of aortic valve stenosis (AVS). When interpreting serial biomarker measurements of patients with AVS, it can be challenging to distinguish 'real changes' from 'random fluctuation'. Hence, robust estimation of the biological variation of these biomarkers is essential. In the present study we assessed biological variation of B-type natriuretic peptide (BNP), N-terminus pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin-T and high-sensitivity troponin-I (hs-TnT and hs-TnI), and ST2 in subjects with stable AVS., Methods: Serial blood sampling was performed in 25 subjects with moderate AVS-confirmed by echocardiography-and all free from acute cardiovascular events in the past 6 months. Blood samples were taken on seven standardised occasions during 1 year. Analytical variation (CV A ), within-subject biological variation (CV I ), between-subject biological variation (CV G ), index of individuality (II) and reference change values were calculated for all cardiac biomarkers., Results: CV I was highest for BNP (62.0%, 95% CI 52.5 to 75.4) and lowest for hs-TnI (9.2%, 95% CI 2.8 to 13.8). CV G exceeded the CV I for all biomarkers except BNP, and ranged from 19.8% (95% CI 13.8 to 33.4) for ST2 to 57.2% (95% CI 40.4 to 97.3) for hs-TnT. NT-proBNP, hs-TnT and ST2 revealed CV A <5%, while BNP and hs-TnI showed a higher CV A (19.7 and 14.9, respectively). All biomarkers except BNP showed marked individuality, with II ranging from 0.21 to 0.67 (BNP 1.34)., Conclusion: This study provides the first biological variation estimates of cardiac biomarkers in patients with stable AVS. These estimates allow a more evidence-based interpretation of biomarker changes in the follow-up and management of patients with AVS., Trial Registration Number: NCT02510482., Competing Interests: Competing interests: None declared.

Background: Normal high sensitivity cardiac troponin (hs-cTn) assays rule out acute myocardial infarction (AMI) with great accuracy, but additional non-invasive testing is frequently ordered. This observational study evaluates whether clinical characteristics can contribute to risk stratification and could guide referral for additional testing., Methods: This observational study included 918 patients with acute chest pain and normal hs-cTnT values. Major adverse cardiac events (MACE) and non-invasive test results were assessed during one-year follow-up. Patients were classified as low and high risk based on clinical characteristics., Results: In total, 6,4% of patients experienced MACE during follow-up and mainly comprised revascularisations (86%). Absence of both recent abnormal stress test and suspicious history identified 86% of patients. These patients were at very low risk for MACE (0,4% in 30-days). Despite this, the majority (287/345=83%) of additional tests were performed in low risk patients, with 8% abnormal test findings (positive predictive value for MACE was 17%). The diagnostic yield was significantly higher in the remaining higher risk patients, 40% abnormal test findings and a positive predictive value of 70% for MACE., Conclusion: Clinical characteristics can be used to identify low risk patients with acute chest pain and normal hs-cTnT levels. Current strategies in the emergency department result in numerous additional tests, which are mostly ordered in patients at very low risk and have a low diagnostic yield.

Objectives: A standard coronary artery calcium scan includes part of the aorta. This additional information is often not included in routine analyses. We aimed to determine the feasibility of assessing the Agatston score of the descending aorta calcification (DAC) on standard coronary calcium scans and the association of this score with coronary events in a low-risk study population., Methods: Between January 2008 and March 2011, 390 consecutive patients who were referred for cardiac CT as part of work-up for pulmonary vein isolation (n=115) or assessment of presence of coronary artery disease (n=275) were included. At baseline, all patients were free of a history of cardiovascular disease. Two independent observers determined the Agatston score of the ascending aorta and descending aorta., Results: A total of 16 patients (4.1%) developed coronary events (acute coronary syndrome (n=6) and symptomatic significant coronary artery disease requiring treatment (n=10)) during a follow-up of 67±12 months, with more events in patients with calcifications in the descending aorta than in those without (8.4% vs 3.7 %; p=0.08). Multivariable Cox regression, corrected for Framingham Risk Score (FRS) and coronary Agatston score (CAC), revealed that DAC was independently associated with coronary events (per 100 units; HR: 1.06, 95% CI 1.02 to 1.09; p=0.001). DAC furthermore increased the identification of patients that will experience a coronary event (area under the curve: 0.68 for FRS only, 0.75 for FRS+CAC and 0.78 for FRS+CAC+DAC)., Conclusions: The Agatston score of the descending aorta could be included in the standard analysis of cardiac CT scans of low-risk patients since it holds valuable information for the prediction of coronary events., Competing Interests: Competing interests: One author (JW) of this manuscript declares institutional relationships with the following companies: Siemens AG, Bayer Healthcare, Philips, GE, all outside submitted work.

Background  Vitamin K antagonists (VKAs) are associated with coronary artery calcification in low-risk populations, but their effect on calcification of large arteries remains uncertain. The effect of non-vitamin K antagonist oral anticoagulants (NOACs) on vascular calcification is unknown. We investigated the influence of use of VKA and NOAC on calcification of the aorta and aortic valve. Methods  In patients with atrial fibrillation without a history of major adverse cardiac or cerebrovascular events who underwent computed tomographic angiography, the presence of ascending aorta calcification (AsAC), descending aorta calcification (DAC), and aortic valve calcification (AVC) was determined. Confounders for VKA/NOAC treatment were identified and propensity score adjusted logistic regression explored the association between treatment and calcification (Agatston score > 0). AsAC, DAC, and AVC differences were assessed in propensity score-matched groups. Results  Of 236 patients (33% female, age: 58 ± 9 years), 71 (30%) used VKA (median duration: 122 weeks) and 79 (34%) used NOAC (median duration: 16 weeks). Propensity score-adjusted logistic regression revealed that use of VKA was significantly associated with AsAC (odds ratio [OR]: 2.31; 95% confidence interval [CI]: 1.16-4.59; p  = 0.017) and DAC (OR: 2.38; 95% CI: 1.22-4.67; p  = 0.012) and a trend in AVC (OR: 1.92; 95% CI: 0.98-3.80; p  = 0.059) compared with non-anticoagulation. This association was absent in NOAC versus non-anticoagulant (AsAC OR: 0.51; 95% CI: 0.21-1.21; p  = 0.127; DAC OR: 0.80; 95% CI: 0.36-1.76; p  = 0.577; AVC OR: 0.62; 95% CI: 0.27-1.40; p  = 0.248). A total of 178 patients were propensity score matched in three pairwise comparisons. Again, use of VKA was associated with DAC ( p  = 0.043) and a trend toward more AsAC ( p  = 0.059), while use of NOAC was not (AsAC p  = 0.264; DAC p  = 0.154; AVC p  = 0.280). Conclusion  This cross-sectional study shows that use of VKA seems to contribute to vascular calcification. The calcification effect was not observed in NOAC users.

Purpose: The aim was to assess personalised contrast media (CM) protocols-based on patient's blood volume (BV) and automated tube voltage selection (ATVS)-in coronary computed tomography angiography (CCTA)., Methods: A total of 114 consecutive patients received an ECG-triggered or ECG-gated helical scan on a 3rd-generation dual-source CT with 70-120kV (ATVS) and 330mAsqual.ref. CM was adapted to BV, scan time (s) and kV. Image quality (IQ) was assessed in a 17-segment coronary model using attenuation values (HU), contrast-to-noise (CNR), signal-to-noise ratio (SNR) (objective IQ) and a Likert scale (subjective IQ: 1 = poor/2 = sufficient/3 = good/4 = excellent). ig., Results: Patient distribution was: n = 60 for 70kV, n = 37 80kV and n = 17 90kV. Mean BV was 5.4±0.6L for men and 4.1±0.6L for women. Mean CM volume (300 mg I/mL) and flow rate were: 30.9±6.4mL and 3.3±0.5mL/s (70kV); 40.8±7.1mL and 4.5±0.6mL/s (80kV); 53.6±8.6mL and 5.7±0.6mL/s (90kV). Overall mean HU was >300HU in 98.2% (112/114) of patients. Overall mean attenuation was below 300HU in two scans (70kV) due to late scan timing. Of 1.661 segments, 95.4% was assessable. Mean CNR was 14±4(70kV), 13±3(80kV) and 14±4(90kV); mean SNR was 10±2(both 70kV+80kV) and 9±2(90kV). Objective IQ was comparable between kV settings, protocols and sex. Subjective IQ was diagnostic in all scans and excellent-sufficient in 95.4% of segments., Conclusions: Personalisation of CCTA CM injection protocols to BV and ATVS is a promising technique to tailor CM administration to the individual patient, while maintaining diagnostic IQ., Competing Interests: The authors have read the journal's policy and have the following conflicts: MD receives institutional grants from Philips, Siemens and Bayer and personal fees (speakers bureau) from Cook, Siemens, and Bayer. JEW reports institutional research grants from Philips, AGFA, GE, BRACCO, Siemens and Bayer and personal fees (speakers bureau) from Siemens and Bayer. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background: The purpose of this study was to illustrate the additive value of computed tomography angiography (CTA) for visualisation of the coronary venous anatomy prior to cardiac resynchronisation therapy (CRT) implantation., Methods: Eighteen patients planned for CRT implantation were prospectively included. A specific CTA protocol designed for visualisation of the coronary veins was carried out on a third-generation dual-source CT platform. Coronary veins were semi-automatically segmented to construct a 3D model. CTA-derived coronary venous anatomy was compared with intra-procedural fluoroscopic angiography (FA) in right and left anterior oblique views., Results: Coronary venous CTA was successfully performed in all 18 patients. CRT implantation and FA were performed in 15 patients. A total of 62 veins were visualised; the number of veins per patient was 3.8 (range: 2-5). Eighty-five per cent (53/62) of the veins were visualised on both CTA and FA, while 10% (6/62) were visualised on CTA only, and 5% (3/62) on FA only. Twenty-two veins were present on the lateral or inferolateral wall; of these, 95% (21/22) were visualised by CTA. A left-sided implantation was performed in 13 patients, while a right-sided implantation was performed in the remaining 2 patients because of a persistent left-sided superior vena cava with no left innominate vein on CTA., Conclusion: Imaging of the coronary veins by CTA using a designated protocol is technically feasible and facilitates the CRT implantation approach, potentially improving the outcome.

Calcific aortic valve stenosis (CAVS) is common in the ageing population and set to become an increasing economic and health burden. Once present, it inevitably progresses and has a poor prognosis in symptomatic patients. No medical therapies are proven to be effective in holding or reducing disease progression. Therefore, aortic valve replacement remains the only available treatment option. Improved knowledge of the mechanisms underlying disease progression has provided us with insights that CAVS is not a passive disease. Rather, CAVS is regulated by numerous mechanisms with a key role for calcification. Aortic valve calcification (AVC) is actively regulated involving cellular and humoral factors that may offer targets for diagnosis and intervention. The discovery that the vitamin K-dependent proteins are involved in the inhibition of AVC has boosted our mechanistic understanding of this process and has opened up novel avenues in disease exploration. This review discusses processes involved in CAVS progression, with an emphasis on recent insights into calcification, methods for imaging calcification activity, and potential therapeutic options.

Background: Pre-procedural TAVI planning requires highly sophisticated and time-consuming manual measurements performed by experienced readers. Semi-automatic software may assist with partial automation of assessment of multiple parameters. The aim of this study was to evaluate differences between manual and semi-automatic measurements in terms of agreement and time., Methods: One hundred and twenty TAVI candidates referred for the retrospectively ECG-gated CTA (2nd and 3rd generation dual source CT) were evaluated. Fully manual and semi-automatic measurements of fourteen aortic root parameters were assessed in the 20% phase of the R-R interval. Reading time was compared using paired samples t-test. Inter-software agreement was calculated using the Intraclass correlation coefficient (ICC) in a 2-way mixed effects model. Differences between manual and semi-automatic measurements were evaluated using Bland-Altman analysis., Results: The time needed for evaluation using semi-automatic assessment (3 min 24 s ± 1 min 7 s) was significantly lower (p<0.001) compared to a fully manual approach (6 min 31 sec ± 1 min 1 sec). Excellent inter-software agreement was found (ICC = 0.93 ± 0.0; range:0.90-0.95). The same prosthesis size from manual and semi-automatic measurements was selected in 92% of cases, when sizing was based on annular area. Prosthesis sizing based on annular short diameter and perimeter agreed in 99% and 96% cases, respectively., Conclusion: Use of semi-automatic software in pre-TAVI evaluation results in comparable results in respect of measurements and selected valve prosthesis size, while necessary reading time is significantly lower., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The Siemens Healthcare GmbH provided support in the form of salaries for author [CS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section. The remaining authors of this manuscript declare relationships with the following companies in form of institutional funding: Agfa, Bayer, GE, Philips, Optimed, Siemens and personal fees from speakers bureau outside the submitted work: Bayer [BH; CM]; Bayer, Siemens [JW]; Bayer, Siemens, Cook [MD]. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors state that this work has not received any specific funding.

BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild-moderate CAVS will be included in the study, and baseline 18 F-sodiumfluoride ( 18 F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second 18 F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR 18 F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT)., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the writing of the manuscript.

Modern high-performance computed tomography (CT) scanners with improved scan acquisition times now allow for routine assessment of cardiac pathologies on chest CTs, which can result in numerous incidental cardiac findings. The CaPaCT study, an observer blinded, single-centre study, aims to assess the visibility, management and possible clinical impact of incidental cardiac pathologies that are now becoming visible on standard chest CTs. A total of 217 consecutive patients referred for a chest CT on a high-performance third-generation dual-source CT scanner will be included. Tube voltage settings will be chosen via automated kV selection. Dedicated cardiac reconstructions will be added to the standard post-processing: 0.6-mm slice thickness, 0.4-mm increment and Bv36 kernel (iterative reconstruction/strength 3). Primary endpoints will be the presence and extent of coronary artery disease (CAD) assessed via a 17-segment model. These data will be collected and analysed by two experienced, blinded cardiac radiologists. Furthermore, information on aortic and mitral valve morphology/calcification and pericardial abnormalities will be collected. The CAD Reporting and Data System classification will subsequently be used to assess the management and possible clinical burden of any incidentally detected CAD. Additionally, objective and subjective image quality (attenuation, contrast-to-noise, signal-to-noise and 5-point Likert scale) of the obtained cardiac reconstructions will be assessed., Competing Interests: Written informed consent was waived by the local ethical committee (medical ethical committee Academisch ziekenhuis Maastricht/Universiteit Maastricht). Institutional Review Board approval was obtained.Not applicable.The authors of this manuscript declare relationships with the following companies: Siemens, Bayer, Philips, AGFA, Cook, General Electric, Bracco.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: In syncope patients, presence of coronary artery disease (CAD) is associated with poor prognosis. However, data concerning CAD prevalence in syncope patients without known cardiovascular disease are lacking. Therefore, the aim of this study was to investigate presence and extent of CAD in syncope patients., Methods: We included 142 consecutive patients presenting with syncope at the outpatient cardiology clinic who underwent coronary computed tomography (CT) angiography. Syncope type was ascertained by two reviewers, blinded for coronary CT angiography results. Of the patients, 49 had cardiac syncope (arrhythmia or structural cardiopulmonary disease) and 93 had non-cardiac syncope (reflex [neurally-mediated], orthostatic or of unknown cause). Cardiac syncope patients were compared with matched stable chest pain patients regarding age, gender, smoking status, diabetes mellitus type 2 and systolic blood pressure., Results: Distribution of CAD presence and extent in cardiac and non-cardiac syncope patients was as follows: 72% versus 48% any CAD; 31% versus 26% mild, 8% versus 14% moderate and 33% versus 7% severe CAD. Compared with non-cardiac syncope, patients with cardiac syncope had a significantly higher CAD presence and extent (p = 0.001). Coronary calcium score, segment involvement and stenosis score were also higher in cardiac syncope patients (p-values ≤0.004). Compared to the chest pain control group, patients with cardiac syncope showed a higher, however, non-significant, prevalence of any CAD (72% versus 63%) and severe CAD (33% versus 19%)., Conclusion: Patients with cardiac syncope show a high presence and extent of CAD in contrast to non-cardiac syncope patients. These results suggest that CAD may play an important role in the occurrence of cardiac syncope.

Objectives: The purpose of this study was to evaluate the accuracy of noninvasive reconstructions of epicardial potentials, electrograms, activation and recovery isochrones, and beat origins by simultaneously performing electrocardiographic imaging (ECGI) and invasive epicardial electrography in intact animals., Background: Noninvasive imaging of electrical potentials at the epicardium, known as ECGI, is increasingly applied in patients to assess normal and abnormal cardiac electrical activity., Methods: Body-surface potentials and epicardial potentials were recorded in normal anesthetized dogs. Computed tomography scanning provided a torso-heart geometry that was used to reconstruct epicardial potentials from body-surface potentials., Results: Electrogram reconstructions attained a moderate accuracy compared with epicardial recordings (median correlation coefficient: 0.71), but with considerable variation (interquartile range: 0.36 to 0.86). This variation could be explained by a spatial mismatch (overall resolution was <20 mm) that was most apparent in regions with electrographic transition. More accurate derivation of activation times (Pearson R: 0.82), recovery times (R: 0.73), and the origin of paced beats (median error: 10 mm; interquartile range: 7 to 17 mm) was achieved by a spatiotemporal approach that incorporates the characteristics of the respective electrogram and neighboring electrograms. Reconstruction of beats from repeated single-site pacing showed a stable localization of origin. Cardiac motion, currently ignored in ECGI, correlates negatively with reconstruction accuracy., Conclusions: ECGI shows a decent median accuracy, but variability in electrogram reconstruction can be sizable. At present, therefore, clinical interpretations of ECGI should not be made on the basis of single electrograms only. Incorporating local spatiotemporal characteristics allows for accurate reconstruction of epicardial activation and recovery patterns, and beat origin localization to a 10-mm precision. Even more reliable interpretations are expected when the influences of cardiac motion are accounted for in ECGI., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Bicuspid aortic valve (BAV) disease is associated with aortic dilatation. Timing of follow-up and surgery is challenging. Hence, there is an unmet clinical need for additional risk stratification. It is unclear whether valve morphology is associated with dilatation rates. Therefore, the objective of this study was to examine the association between clinical and echocardiographic determinants (including valve morphology) and aortic dimension and the progression rate of dilatation.Aortic dimensions were assessed on serial echocardiographic images between 1999 and 2014 in a population of 392 patients with BAVs in a tertiary care center in the Netherlands. Analyses using mixed linear models were performed.Mean age of participants was 48 ± 17 years and 69% were male. BAV morphology was associated with aortic dimensions, as well as age, sex, BSA, and valvular dysfunction. Tubular ascending aorta, sinus of Valsalva, and sinotubular junction showed a dilatation rate of 0.32, 0.18, and 0.06 mm/year, respectively. Dilatation rate was not associated with valve morphology.In the present study, there is no association between BAV morphology and aortic dilatation rates. Therefore, morphology is of limited use in prediction of aortic growth. Discovering fast progressors remains challenging., Competing Interests: The authors have no conflicts of interest to disclose.

Objective: Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state., Approach and Results: In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26-3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events., Conclusions: Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.