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Biological processes underlying decreased cerebral blood flow (CBF) in patients with cardiovascular disease (CVD) are largely unknown. We hypothesized that identification of protein clusters associated with lower CBF in patients with CVD may explain underlying processes. In 428 participants (74% cardiovascular diseases; 26% reference participants) from the Heart-Brain Connection Study, we assessed the relationship between 92 plasma proteins from the Olink® cardiovascular III panel and normal-appearing grey matter CBF, using affinity propagation and hierarchical clustering algorithms, and generated a Biomarker Compound Score (BCS). The BCS was related to cardiovascular risk and observed cardiovascular events within 2-year follow-up using Spearman correlation and logistic regression. Thirteen proteins were associated with CBF (ρ Spearman range: -0.10 to -0.19, p FDR-corrected <0.05), and formed one cluster. The cluster primarily reflected extracellular matrix organization processes. The BCS was higher in patients with CVD compared to reference participants (p FDR-corrected <0.05) and was associated with cardiovascular risk (ρ Spearman 0.42, p < 0.001) and cardiovascular events (OR 2.05, p < 0.01). In conclusion, we identified a cluster of plasma proteins related to CBF, reflecting extracellular matrix organization processes, that is also related to future cardiovascular events in patients with CVD, representing potential targets to preserve CBF and mitigate cardiovascular risk in patients with CVD., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Endovascular thrombectomy (EVT) success to treat acute ischemic stroke varies with factors like stroke etiology and clot composition, which can differ between sexes. We studied if sex-specific blood cell characteristics (BCCs) are related to recanalization success. We analyzed electronic health records of 333 EVT patients from a single intervention center, and extracted 71 BCCs from the Sapphire flow cytometry analyzer. Through Sparse Partial Least Squares Discriminant Analysis, incorporating cross-validation and stability selection, we identified BCCs associated with successful recanalization (TICI 3) in both sexes. Stroke etiology was considered, while controlling for cardiovascular risk factors. Of the patients, successful recanalization was achieved in 51% of women and 49% of men. 21 of the 71 BCCs showed significant differences between sexes  (pFDR-corrected < 0.05). The female-focused recanalization model had lower error rates than both combined [t(192.4) = 5.9, p < 0.001] and male-only models [t(182.6) = - 15.6, p < 0.001]. In women, successful recanalization and cardioembolism were associated with a higher number of reticulocytes, while unsuccessful recanalization and large artery atherosclerosis (LAA) as cause of stroke were associated with a higher mean corpuscular hemoglobin concentration. In men, unsuccessful recanalization and LAA as cause of stroke were associated with a higher coefficient of variance of lymphocyte complexity of the intracellular structure. Sex-specific BCCs related to recanalization success varied and were linked to stroke etiology. This enhanced understanding may facilitate personalized treatment for acute ischemic stroke., (© 2023. The Author(s).)

Background and Aims: Patients who underwent carotid endarterectomy (CEA) still have a residual risk of 13% of developing a major adverse cardiovascular event (MACE) within 3 years. Inflammatory processes leading up to MACE are not fully understood. Therefore, we examined blood cell characteristics (BCCs), possibly reflecting inflammatory processes, in relation to MACE to identify BCCs that may contribute to an increased risk., Methods: We analyzed 75 pretreatment BCCs from the Sapphire analyzer, and clinical data from the Athero-Express biobank in relation to MACE after CEA using Random Survival Forests, and a Generalized Additive Survival Model. To understand biological mechanisms, we related the identified variables to intraplaque hemorrhage (IPH)., Results: Of 783 patients, 97 (12%) developed MACE within 3 years after CEA. Red blood cell distribution width (RDW) (HR 1.23 [1.02, 1.68], p = 0.022), CV of lymphocyte size (LACV) (HR 0.78 [0.63, 0.99], p = 0.043), neutrophil complexity of the intracellular structure (NIMN) (HR 0.80 [0.64, 0.98], p = 0.033), mean neutrophil size (NAMN) (HR 0.67 [0.55, 0.83], p < 0.001), mean corpuscular volume (MCV) (HR 1.35 [1.09, 1.66], p = 0.005), eGFR (HR 0.65 [0.52, 0.80], p < 0.001); and HDL-cholesterol (HR 0.62 [0.45, 0.85], p = 0.003) were related to MACE. NAMN was related to IPH (OR 0.83 [0.71-0.98], p = 0.02)., Conclusions: This is the first study to present a higher RDW and MCV and lower LACV, NIMN and NAMN as biomarkers reflecting inflammatory processes that may contribute to an increased risk of MACE after CEA., 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., (© 2023 The Authors.)

Electronic health records (EHRs) contain valuable data for reuse in science, quality evaluations, and clinical decision support. Because routinely obtained laboratory data are abundantly present, often numeric, generated by certified laboratories, and stored in a structured way, one may assume that they are immediately fit for (re)use in research. However, behind each test result lies an extensive context of choices and considerations, made by both humans and machines, that introduces hidden patterns in the data. If they are unaware, researchers reusing routine laboratory data may eventually draw incorrect conclusions. In this paper, after discussing health care system characteristics on both the macro and micro level, we introduce the reader to hidden aspects of generating structured routine laboratory data in 4 steps (ordering, preanalysis, analysis, and postanalysis) and explain how each of these steps may interfere with the reuse of routine laboratory data. As researchers reusing these data, we underline the importance of domain knowledge of the health care professional, laboratory specialist, data manager, and patient to turn routine laboratory data into meaningful data sets to help obtain relevant insights that create value for clinical care., (©L Malin Overmars, Michael S A Niemantsverdriet, T Katrien J Groenhof, Mark C H De Groot, Cornelia A R Hulsbergen-Veelken, Wouter W Van Solinge, Ruben E A Musson, Maarten J Ten Berg, Imo E Hoefer, Saskia Haitjema. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 18.11.2022.)

Biological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated with the burden of cSVD provides leads on underlying biological processes. In 494 participants (mean age 67.6 ± 8.7 years; 36% female; 75% cardiovascular diseases; 25% reference participants) we assessed the relation between 92 blood-based biomarkers from the OLINK cardiovascular III panel and cSVD, using cluster-based analyses. We focused particularly on white matter hyperintensities (WMH). Nineteen biomarkers individually correlated with WMH ratio (r range: 0.16-0.27, Bonferroni corrected p-values <0.05), of which sixteen biomarkers formed one biomarker cluster. Pathway analysis showed that this biomarker cluster predominantly reflected coagulation processes. This cluster related also significantly to other cSVD manifestations (lacunar infarcts, microbleeds, and enlarged perivascular spaces), which supports generalizability beyond WMHs. To study possible causal effects of biological processes reflected by the cluster we performed a mediation analysis that showed a mediation effect of the cluster on the relation between age and WMH ratio (proportion mediated 17%), and hypertension and WMH-volume (proportion mediated 21%). In conclusion, we identified a cluster of blood-based biomarkers reflecting coagulation, that is related to manifestations of cSVD, corroborating involvement of coagulation abnormalities in the etiology of cSVD.

Aims: With the ageing European population, the incidence of coronary artery disease (CAD) is expected to rise. This will likely result in an increased imaging use. Symptom recognition can be complicated, as symptoms caused by CAD can be atypical, particularly in women. Early CAD exclusion may help to optimize use of diagnostic resources and thus improve the sustainability of the healthcare system. To develop sex-stratified algorithms, trained on routinely available electronic health records (EHRs), raw electrocardiograms, and haematology data to exclude CAD in patients upfront., Methods and Results: We trained XGBoost algorithms on data from patients from the Utrecht Patient-Oriented Database, who underwent coronary computed tomography angiography (CCTA), and/or stress cardiac magnetic resonance (CMR) imaging, or stress single-photon emission computerized tomography (SPECT) in the UMC Utrecht. Outcomes were extracted from radiology reports. We aimed to maximize negative predictive value (NPV) to minimize the false negative risk with acceptable specificity. Of 6808 CCTA patients (31% female), 1029 females (48%) and 1908 males (45%) had no diagnosis of CAD. Of 3053 CMR/SPECT patients (45% female), 650 females (47%) and 881 males (48%) had no diagnosis of CAD. On the train and test set, the CCTA models achieved NPVs and specificities of 0.95 and 0.19 (females) and 0.96 and 0.09 (males). The CMR/SPECT models achieved NPVs and specificities of 0.75 and 0.041 (females) and 0.92 and 0.026 (males)., Conclusion: Coronary artery disease can be excluded from EHRs with high NPV. Our study demonstrates new possibilities to reduce unnecessary imaging in women and men suspected of CAD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The new concept of difficult-to-treat rheumatoid arthritis (D2T RA) refers to RA patients who remain symptomatic after several lines of treatment, resulting in a high patient and economic burden. During a hackathon, we aimed to identify and predict D2T RA patients in structured and unstructured routine care data., Methods: Routine care data of 1873 RA patients were extracted from the Utrecht Patient Oriented Database. Data from a previous cross-sectional study, in which 152 RA patients were clinically classified as either D2T or non-D2T, served as a validation set. Machine learning techniques, text mining, and feature importance analyses were performed to identify and predict D2T RA patients based on structured and unstructured routine care data., Results: We identified 123 potentially new D2T RA patients by applying the D2T RA definition in structured and unstructured routine care data. Additionally, we developed a D2T RA identification model derived from a feature importance analysis of all available structured data (AUC-ROC 0.88 (95% CI 0.82-0.94)), and we demonstrated the potential of longitudinal hematological data to differentiate D2T from non-D2T RA patients using supervised dimension reduction. Lastly, using data up to the time of starting the first biological treatment, we predicted future development of D2TRA (AUC-ROC 0.73 (95% CI 0.71-0.75))., Conclusions: During this hackathon, we have demonstrated the potential of different techniques for the identification and prediction of D2T RA patients in structured as well as unstructured routine care data. The results are promising and should be optimized and validated in future research.

Introduction: Chest pain or discomfort affects 20%-40% of the general population over the course of their life and may be a symptom of myocardial ischaemia. For the diagnosis of obstructive macrovascular coronary artery disease (CAD), algorithms have been developed; however, these do not exclude microvascular angina. This may lead to false reassurance of symptomatic patients, mainly women, with functionally significant, yet non-obstructive coronary vascular disease. Therefore, this study aims to estimate the prevalence of both macrovascular and microvascular coronary vascular disease in women and men presenting with chest pain or discomfort, and to subsequently develop a decision-support tool to aid cardiologists in referral to cardiovascular imaging for both macrovascular and microvascular CAD evaluation., Methods and Analysis: Women and men with chest pain or discomfort, aged 45 years and older, without a history of cardiovascular disease, who are referred to an outpatient cardiology clinic by their general practitioner are eligible for inclusion. Coronary CT angiography is used for anatomical imaging. Additionally, myocardial perfusion imaging by adenosine stress cardiac MRI is performed to detect functionally significant coronary vascular disease. Electronic health record data, collected during regular cardiac work-up, including medical history, cardiovascular risk factors, physical examination, echocardiography, (exercise) ECG and blood samples for standard cardiovascular biomarkers and research purposes, are obtained. Participants will be classified as positive or negative for coronary vascular disease based on all available data by expert panel consensus (a cardiovascular radiologist and two cardiologists). After completion of the clinical study, all collected data will be used to develop a decision support tool using predictive modelling and machine-learning techniques., Ethics and Dissemination: The study protocol was approved by the Institutional Review Board of the University Medical Center Utrecht. Results will be disseminated through national and international conferences and in peer-reviewed journals in cardiovascular disease., Trial Registration Number: Trialregister.nl Registry NL8702., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)