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ObjectivesTo develop a risk assessment model (DAnish REgister Ischaemic Stroke Classifier, DARE-ISC) for predicting 1-year primary ischaemic stroke/systemic embolism (SE) in the general population. Secondly, to validate the accuracy DARE-ISC in atrial fibrillation (AF) patients where well-established models and risk scores exist.DesignRetrospective cohort study. DARE-ISC was developed using gradient boosting decision trees with information from 375 covariates including baseline information on relevant diagnoses, demographic characteristics, registered health-services, lifestyle-related covariates, hereditary stroke components, drug prescriptions and stress proxies.SettingDanish nationwide registries.ParticipantsAll Danish individuals aged ≥18 from 2010 to 2017 (n=35 519 348 person-years). The model was trained on the 2010–2016 cohorts with validation in the 2017 cohort.Primary and secondary outcome measuresModel optimisation and validation were performed through comparison of the area under the receiver operating characteristic curve (AUC) and average precision scores. Additionally, the relative importance of the model covariates was derived using SHAP values.ResultsDARE-ISC had an AUC (95% CI) of 0.874 (0.871 to 0.876) in the general population. In AF patients, DARE-ISC was superior to the GARFIELD-AF risk model and CHA2DS2-VASc score with AUC of 0.779 (95% CI 0.75 to 0.806), 0.704 (95% CI 0.674 to 0.732) and 0.681 (95% CI 0.652 to 0.709), respectively. Furthermore, in AF patients, DARE-ISC had an average threefold and fourfold higher ratio of correctly identified strokes compared with the GARFIELD-AF risk model and CHA2DS2-VASc score, as indicated by average precision scores of 0.119, 0.041 and 0.034, respectively.ConclusionsDARE-ISC had a very high stroke prediction accuracy in the general population and was superior to the GARFIELD-AF risk model and CHA2DS2-VASc score for predicting ischaemic stroke/SE in AF patients.

Coronary computed tomography angiography (CTA) is the preferred primary diagnostic modality when examining patients with low to intermediate pre-test probability of coronary artery disease (CAD). Only 20-30% of these have potentially obstructive CAD. Because of the relatively poor positive predictive value of coronary CTA, unnecessary invasive coronary angiographies (ICAs) are conducted with the costs and risks associated with the procedure. Hence, an optimized diagnostic CAD algorithm may reduce the numbers of ICAs not followed by revascularization. The Dan-NICAD 2 study has 3 equivalent main aims: (1) To examine the diagnostic precision of a sound-based diagnostic algorithm, The CADScor®System (Acarix A/S, Denmark), in patients with a low to intermediate pre-test risk of CAD referred to a primary examination by coronary CTA. We hypothesize that the CADScor®System provides better stratification prior to coronary CTA than clinical risk stratification scores alone. (2) To compare the diagnostic accuracy of 3T cardiac magnetic resonance imaging (3T CMRI), 82rubidium positron emission tomography (82Rb-PET), and CT-derived fractional flow reserve (FFRCT) in patients where obstructive CAD cannot be ruled out by coronary CTA using ICA fractional flow reserve (FFR) as reference standard. (3) To compare the diagnostic performance of quantitative flow ratio (QFR) and ICA-FFR in patients with low to intermediate pre-test probability of CAD using 82Rb-PET as reference standard. Dan-NICAD 2 is a prospective, multicenter, cross-sectional study including approximately 2,000 patients with low to intermediate pre-test probability of CAD and without previous history of CAD. Patients are referred to coronary CTA because of symptoms suggestive of CAD, as evaluated by a cardiologist. Patient interviews, sound recordings, and blood samples are obtained in connection with the coronary CTA. If coronary CTA does not rule out obstructive CAD, patients will be examined by 3T CMRI 82Rb-PET, FFRCT, ICA, and FFR. Reference standard is ICA-FFR. Obstructive CAD is defined as an FFR ≤0.80 or as high-grade stenosis (>90% diameter stenosis) by visual assessment. Diagnostic performance will be evaluated as sensitivity, specificity, predictive values, likelihood ratios, calibration, and discrimination. Enrolment started January 2018 and is expected to be completed by June 2020. Patients are followed for 10 years after inclusion. The results of the Dan-NICAD 2 study are expected to contribute to the improvement of diagnostic strategies for patients suspected of CAD in 3 different steps: risk stratification prior to coronary CTA, diagnostic strategy after coronary CTA, and invasive wireless QFR analysis as an alternative to ICA-FFR.

A 45-year-old woman was admitted with severe pain in the right leg and dyspnea. Her medical history included previous Staphylococcus aureus endocarditis, biological aortic valve replacement, and intravenous drug abuse. She was febrile but did not have any focal signs of infection. Blood tests showed raised infectious markers and troponin levels. Electrocardiogram showed sinus rhythm without signs of ischemia. Ultrasound revealed thrombosis of the right popliteal artery. The leg was not critically ischemic, and therefore, treatment with dalteparin was chosen. Transesophageal echocardiography showed an excrescence on the biological aortic valve. Empiric treatment for endocarditis was started with intravenous vancomycin, gentamicin, and oral rifampicin. Blood cultures subsequently grew Staphylococcus pasteuri. On day 2, treatment was changed to intravenous cloxacillin. Due to the comorbidity, the patient was not a candidate for the surgical treatment. On day 10, the patient developed moderate expressive aphasia and weakness in the right upper limb. Magnetic resonance imaging showed micro-embolic lesions scattered across both hemispheres of the brain. Treatment was changed from cloxacillin to cefuroxime. On day 42, infectious markers were normal, and echocardiography showed regression of the excrescence. Antibiotic treatment was stopped. Follow-up on day 52 did not show any signs of active infection. However, on day 143, the patient was readmitted with cardiogenic shock due to aortic root fistulation to the left atrium. She quickly deteriorated and died.

Background The presence of coronary plaques with high-risk characteristics is strongly associated with adverse cardiac events beyond the identification of coronary stenosis. Testing by coronary computed tomography angiography (CCTA) enables the identification of high-risk plaques (HRP). Referral for CCTA is presently based on pre-test probability estimates including clinical risk factors (CRFs); however, proteomics and/or genetic information could potentially improve patient selection for CCTA and, hence, identification of HRP. We aimed to (1) identify proteomic and genetic features associated with HRP presence and (2) investigate the effect of combining CRFs, proteomics, and genetics to predict HRP presence. Methods Consecutive chest pain patients ( n  = 1462) undergoing CCTA to diagnose obstructive coronary artery disease (CAD) were included. Coronary plaques were assessed using a semi-automatic plaque analysis tool. Measurements of 368 circulating proteins were obtained with targeted Olink panels, and DNA genotyping was performed in all patients. Imputed genetic variants were used to compute a multi-trait multi-ancestry genome-wide polygenic score (GPS Mult ). HRP presence was defined as plaques with two or more high-risk characteristics (low attenuation, spotty calcification, positive remodeling, and napkin ring sign). Prediction of HRP presence was performed using the glmnet algorithm with repeated fivefold cross-validation, using CRFs, proteomics, and GPS Mult as input features. Results HRPs were detected in 165 (11%) patients, and 15 input features were associated with HRP presence. Prediction of HRP presence based on CRFs yielded a mean area under the receiver operating curve (AUC) ± standard error of 73.2 ± 0.1, versus 69.0 ± 0.1 for proteomics and 60.1 ± 0.1 for GPS Mult . Combining CRFs with GPS Mult increased prediction accuracy (AUC 74.8 ± 0.1 ( P  = 0.004)), while the inclusion of proteomics provided no significant improvement to either the CRF (AUC 73.2 ± 0.1, P  = 1.00) or the CRF + GPS Mult (AUC 74.6 ± 0.1, P  = 1.00) models, respectively. Conclusions In patients with suspected CAD, incorporating genetic data with either clinical or proteomic data improves the prediction of high-risk plaque presence. Trial registration https://clinicaltrials.gov/ct2/show/NCT02264717 (September 2014).

Background Fracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates. Methods Volumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures. Results The fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z -score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z -score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z -score. Conclusions Bone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation. Trial registration This study was registered at ClinicalTrials.gov with identifier NCT01344434 .

Purpose Assessment of vascular calcification provides the opportunity for risk stratification in kidney transplant candidates (KTCs), as vascular calcification constitutes an independent risk factor for cardiovascular events. The aim of the present study is to explore the feasibility of contrast enhanced computed tomography (CT)-angiography to quantitate vascular calcification, to avoid the extra radiation of an additional non-contrast CT scan. Methods and materials 43 KTCs who underwent concomitant non-contrast CT scans and CT-angiographies of the infrarenal aorta and iliac arteries were included. Vascular calcification was quantified using the Agatston method on non-contrast CT and applying individual Hounsfield Unit thresholds on CT-angiographies based on the radio density of the aortic lumen. The calcium scores and volumes from non-contrast CT scans and CT-angiographies were compared using linear regression and Bland–Altman plots. Results Non-contrast CT revealed vascular calcification in the infrarenal aorta in 92% of KTCs and in the iliac arteries in 90% of KTCs. The calcium scores estimated from CT-angiography correlated linearly with the calcium scores based on non-contrast CT scans (infrarenal aorta: R 2  = 0.71, p < 0.0001; iliac arteries: R 2  = 0.71, p < 0.0001); however, the calcium scores were higher, and volumes were lower compared to the non-contrast CT scans. The median differences in calcium scores were 1517 [48 – 6138] for the infrarenal aorta, and 2361 [59 – 8644] for the iliac arteries. Conclusion Vascular calcification is present in the majority of KTCs. Calcification of the infrarenal aorta and iliac arteries may be assessed using CT-angiography, though higher calcium scores and lower volumes are found compared to the non-contrast CT scan.

ObjectivesThe risk factor-weighted and coronary artery calcium score-weighted clinical likelihood (RF-CL and CACS-CL, respectively) models improve discrimination of patients with suspected obstructive coronary artery disease (CAD). However, external validation is warranted.Compared to the 2019 European Society of Cardiology pretest probability (ESC-PTP) model, the aims were (1) to validate the RF-CL and CACS-CL models for identification of obstructive CAD and revascularisation, and (2) to investigate prognosis by CL thresholds.MethodsStable de novo chest pain patients (n=1585) undergoing coronary CT angiography (CTA) were investigated. Obstructive CAD was defined as >70% diameter stenosis in a major epicardial vessel on CTA. Decision of revascularisation within 120 days was based on onsite judgement. The endpoint was non-fatal myocardial infarction or cardiovascular death. The ESC-PTP was calculated based on age, sex and symptom typicality, the RF-CL additionally included number of risk factors, and the CACS-CL incorporated CACS to the RF-CL.ResultsObstructive CAD was present in 386/1585 (24.4%) patients, and 91/1585 (5.7%) patients underwent revascularisation. Both the RF-CL and CACS-CL classified more patients to very-low CL (<5%) of obstructive CAD compared with the ESC-PTP model (41.4% and 52.2% vs 19.2%, p<0.001). In very-low CL patients, obstructive CAD and revascularisation prevalences (≤6% and <1%) remained similar combined with low event risk during 5.0 years follow-up.ConclusionIn an external validation cohort, the novel RF-CL and CACS-CL models improve categorisation to a very-low CL group with preserved prevalences of obstructive CAD, revascularisation and favourable prognosis.

IntroductionCurrent guideline recommend functional imaging for myocardial ischaemia if coronary CT angiography (CTA) has shown coronary artery disease (CAD) of uncertain functional significance. However, diagnostic accuracy of selective myocardial perfusion imaging after coronary CTA is currently unclear. The Danish study of Non-Invasive testing in Coronary Artery Disease 3 trial is designed to evaluate head to head the diagnostic accuracy of myocardial perfusion imaging with positron emission tomography (PET) using the tracers 82Rubidium (82Rb-PET) compared with oxygen-15 labelled water PET (15O-water-PET) in patients with symptoms of obstructive CAD and a coronary CT scan with suspected obstructive CAD.Methods and analysisThis prospective, multicentre, cross-sectional study will include approximately 1000 symptomatic patients without previous CAD. Patients are included after referral to coronary CTA. All patients undergo a structured interview and blood is sampled for genetic and proteomic analysis and a coronary CTA. Patients with possible obstructive CAD at coronary CTA are examined with both 82Rb-PET, 15O-water-PET and invasive coronary angiography with three-vessel fractional flow reserve and thermodilution measurements of coronary flow reserve. After enrolment, patients are followed with Seattle Angina Questionnaires and follow-up PET scans in patients with an initially abnormal PET scan and for cardiovascular events in 10 years.Ethics and disseminationEthical approval was obtained from Danish regional committee on health research ethics. Written informed consent will be provided by all study participants. Results of this study will be disseminated via articles in international peer-reviewed journal.Trial registration numberNCT04707859.

Background: Central blood pressure (BP) assessed noninvasively considerably underestimates true invasively measured aortic BP in chronic kidney disease (CKD) patients. The difference between the estimated and the true aortic BP increases with decreasing estimated glomerular filtration rates (eGFR). The present study investigated whether aortic calcification affects noninvasive estimates of central BP. Methods: Twenty-four patients with CKD stage 4–5 undergoing coronary angiography and an aortic computed tomography scan were included (63% males, age [mean ± SD ] 53 ± 11 years, and eGFR 9 ± 5 mL/min/1.73 m 2 ). Invasive aortic BP was measured through the angiography catheter, while non-invasive central BP was obtained using radial artery tonometry with a SphygmoCor® device. The Agatston calcium score (CS) in the aorta was quantified on CT scans using the CS on CT scans. Results: The invasive aortic systolic BP (SBP) was 152 ± 23 mm Hg, while the estimated central SBP was 133 ± 20 mm Hg. Ten patients had a CS of 0 in the aorta, while 14 patients had a CS >0 in the aorta. The estimated central SBP was lower than the invasive aortic SBP in patients with aortic calcification compared to patients without (mean difference 8 mm Hg, 95% CI 0.3–16; p = 0.04). The brachial SBP was lower than the aortic SBP in patients with aortic calcification compared to patients without (mean difference 10 mm Hg, 95% CI 2–19; p = 0.02). Conclusion: In patients with advanced CKD the presence of aortic calcification is associated with a higher difference between invasively measured central aortic BP and non-invasive estimates of central BP as compared to patients without calcifications.

Background The vitamin D receptor activator paricalcitol has been shown to reduce albuminuria. Whether this is a unique property of paricalcitol, or common to all vitamin D analogues, is unknown. The primary aim of this study was to evaluate the effect of alfacalcidol on proteinuria, measured as 24 hour (24 h) albuminuria, in patients with chronic kidney disease (CKD) stage 4–5 being treated for secondary hyperparathyroidism (sHPT). Methods A retrospective single-center study including adult patients with CKD 4–5, undergoing treatment for sHPT with alfacalcidol, with macroalbuminuria in minimum one 24 h urine collection. Patients were identified in a prospectively collected database of all patients with S-creatinine > 300 μM or creatinine clearance < 30 ml/min. The observation period was from 1 st of January 2005 to 31 st of December 2009. Phosphate binders and alfacalcidol were provided to patients free of charge. Results A total of 146 macroalbuminuric patients were identified, and of these, 59 started alfacalcidol treatment during the observation period. A 12% reduction in 24 h albuminuria was seen after starting treatment. In 19 patients with no change in renin-angiotensin-aldosteron-system (RAAS) inhibition, the reduction in albuminuria was 16%. The reduction remained stable over time (9%) in a subgroup of patients (n = 20) with several urine collections before and after the start of alfacalcidol-treatment. Conclusion The present study supports experimental and clinical data on antiproteinuric actions of activated vitamin D analogues, and suggests that this may be a class-effect.