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Left atrial (LA) physiology and hemodynamics are intimately connected to cardiac and lung function in health and disease. This study examined the relationship between MRI-based left atrial (LA) size and function with MRI-based lung volume and pulmonary function testing (PFT) parameters in the population-based KORA study cohort of 400 participants without overt cardiovascular disease. MRI quantification assessed LA size/function in sequences with and without ECG synchronization, alongside lung volume. Regression analysis explored the relationship of LA with MRI lung volume and PFT parameters. Among 378 participants (average age 56.3 ± 9.2 years; 42.3% women), non-gated LA size averaged 16.8 cm 2 , while maximal and minimal LA size from gated measurements were 19.6 cm 2 and 11.9 cm 2 respectively. The average MRI-derived lung volume was 4.0 L, with PFT showing a total lung capacity of 6.2 L, residual lung volume of 2.1 L, and forced vital capacity of 4.1 L. Multivariate regression analysis, adjusted for age, gender, and cardiovascular risk factors, revealed an inverse association between maximum LA size, non-gated LA, and LA area fraction with lung volume (ß = - 0.03, p = 0.006; ß = - 0.03, p = 0.021; ß = - 0.01, p = 0.012), with no significant association with PFT parameters. This suggests that MRI-based assessment may offer greater sensitivity in detecting subclinical LA impairment than PFT., (© 2024. The Author(s).)

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics, glucagon-like peptide-1 receptor agonists (GLP-1ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2-in). Despite new guidelines, clinical inertia, which can be caused by physicians, patients or the healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons for clinical inertia and the poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiatives in diabetes aim to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings.

Obesity is characterized by the accumulation of adipose tissue in different body compartments. Whether adipose tissue directly affects kidney function is still unknown. We aimed to investigate the role of the adipose tissue and circulating creatinine, cystatin C and kidney function in subjects free of cardio-renal diseases. In the KORA-MRI population-based study, 377 subjects (mean age 56.2 ± 9.2 years; 41.6% female) underwent whole-body 3T-MRI examination. Adipose tissue defined as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were quantified from T1-DIXON sequence using a semi-automatic algorithm. Serum creatinine and cystatin C were measured using standard laboratory and estimated glomerular filtration rate (e-GFR) was performed based on creatinine (e-GFR crea ), cystatin C (e-GFR cys ) and creatinine-cystatin C (e-GFR cc ). Linear regression analysis, adjusted for risk factors, was used to investigate the relationship between adipose tissue and circulating creatinine, cystatin C, and kidney function. In multivariate analyses VAT was inversely associated with eGFR cys (ß = - 4.88, p =  < 0.001), and positively associated with serum cystatin C (ß = 0.05, p =  < 0.001), respectively. No association was found between other adipose parameters such as total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) and serum creatinine, urine microalbumin and eGFR crea . Stratified analyses according to BMI revealed confirmatory results for category of BMI > 30. VAT is positively associated with serum cystatin C and inversely with eGFR based on cystatin C, suggesting a direct involvement of visceral adipose tissue in increased metabolism of cystatin C and consequently decreased kidney function., (© 2023. The Author(s).)

To investigate the association between Aorta (Ao), pulmonary artery (PA) diameters and the PA/Ao ratio with right (RV) and left ventricle (LV) volumetric properties in subjects free of cardiovascular diseases. In the KORA-MRI study, 339 subjects (mean age 56.3 ± 9.1 years; 43.7% female) underwent whole-body 3T-MRI. Ao and PA were measured on DIXON sequences. Cvi42 quantified cardiac functional parameters from a SSFP sequence. The relationship between ascending (AAo), and descending aorta (DAo), as well as PA diameters, and RV and LV function were assessed using linear regression models adjusted for age, sex, and cardiovascular risk factors. AAo and DAo diameter were associated with LV end-diastolic volume (β = 4.52, p = 0.015; ß = 7.1, p ≤ 0.001), LV end-systolic volume (β = 2.37, p = 0.031; ß = 3.66, p = 0.002), while DAo associated with RV end-diastolic volume (β = 6.45, p = 0.006) and RV end-systolic volume (β = 3.9, p = 0.011). PA diameter was associated with LV end-diastolic volume (β = 4.81, p = 0.003). Interestingly, the PA/Ao ratio was only associated with RV end-diastolic and end-systolic volume (β = 4.48, p = 0.029; ß = 2.82, p = 0.037). Furthermore, we found different relationships between men and women. Ao and PA diameter were associated with LV and RV volumetric parameters in subjects free of cardiovascular diseases suggesting that ventricular volumetric performance directly relates to vascular diameter properties.

Background: Breast cancer molecular subtypes share various prognostic profiles, and luminal A molecular subtypes have a better prognosis compared with other molecular subtypes. However, whether metabolic syndrome or individual risk factors of metabolic syndrome influence on the development of molecular subtype remains elusive. We aimed to assess the association between metabolic syndrome risk factors and breast cancer molecular subtypes among patients with metabolic syndrome in a clinical setting., Methods: In total, 101 breast cancer patients with mean age, 58.4 ± 8.5 years, and overt metabolic syndrome prospectively were recruited. Immunohistochemistry procedure was used to determine molecular subtypes. Assessment of clinical, biochemical, and anthropometric parameters was performed. Logistic regression analysis was used to assess the relationship between risk factors and breast cancer molecular subtypes categories. A similar approach was used to assess the relation between breast cancer molecular subtypes and menopause., Results: Comparison of metabolic syndrome individual risk factors according to breast cancer molecular subtypes no statistical difference was found for systolic ( P  = .33) and diastolic blood pressure ( P  = .17), fasting glucose ( P  = .77), triglycerides ( P  = .62), high-density lipoprotein ( P  = .33), body mass index ( P  = .87), and waist circumference ( P  = .81). A positive trend was found between high-density lipoprotein and HER2+. No association was found with other risk factors. Moreover, an association was found between HER2+ categories and menopause., Conclusion: In breast cancer patients with metabolic syndrome, we observed an increased trend between high-density lipoprotein and HER2+ molecular subtype, suggesting that underlying dyslipidemia may favor poor prognosis. HER2+ was associated with menopause which may influence further expression of HER2+ ., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Aims: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect., Methods and Results: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041)., Conclusion: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Obesity increases the risk of cardiovascular diseases (CVD), however, whether adipose tissue relates to dyslipidemia, and consequently to cardiovascular events remains unknown. Thus, we investigated the association of adipose tissue with circulating lipoproteins and triglycerides (TG) in subjects without CVD. 384 participants from the KORA-MRI study (mean age 56.2 ± 9.2 years; 41.9% female) underwent whole-body 3T-MRI. Visceral (VAT) and subcutaneous adipose tissue (SAT) derived from T1-DIXON-sequence using a semi-automatic algorithm. Total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and TG were measured. Linear regression was applied to examine the relationships between adipose tissue, circulating lipoproteins, and TG, adjusting for risk factors. VAT was associated with total cholesterol (per SD increase) (ß = 0.39, p < 0.001). Total adipose tissue (TAT) and VAT were inversely associated with HDL (ß = -0.09, p = 0.009; ß = -0.14, p < 0.001), and positively associated with LDL (ß = 0.32, p < 0.001; ß = 0.37, p < 0.001). All adipose tissues were associated with TG (ß = 0.20, p < 0.001; ß = 0.27, p < 0.001; ß = 0.11, p = 0.004). Stratified analysis by sex and body mass index (BMI) was confirmatory in women and in individuals with BMI < 30. Our results suggest that adipose tissue plays an important role in increasing CVD risk independent of BMI, whereas gender imbalance may be explained by accurate characterization and quantification of adipose tissue.

Aims: Recent trials evaluating the effect of aspirin in the primary prevention of cardiovascular disease showed little or no benefit. However, the role of aspirin on the risk of incident heart failure (HF) remains elusive. This study aimed to evaluate the role of aspirin use on HF incidence in primary and secondary prevention and whether aspirin use increases the risk of incident HF in patients at risk., Methods and Results: Data from 30 827 patients at risk for HF enrolled in six observational studies were analysed [women 33.9%, mean age (±standard deviation) 66.8 ± 9.2 years]. Cardiovascular risk factors and aspirin use were recorded at baseline, and patients were followed up for the first incident of fatal or non-fatal HF. The association of incident HF with aspirin use was assessed using multivariable-adjusted proportional hazard regression, which accounted for study and cardiovascular risk factors. Over 5.3 years (median; 5th-95th percentile interval, 2.1-11.7 years), 1330 patients experienced HF. The fully adjusted hazard ratio (HR) associated with aspirin use was 1.26 [95% confidence interval (CI) 1.12-1.41; P ≤ 0.001]. Further, in a propensity-score-matched analysis, the HR was 1.26 (95% CI 1.10-1.44; P ≤ 0.001). In 22 690 patients (73.6%) without history of cardiovascular disease, the HR was 1.27 (95% CI 1.10-1.46; P = 0.001)., Conclusions: In patients, at risk, aspirin use was associated with incident HF, independent of other risk factors. In the absence of conclusive trial evidence, our observations suggest that aspirins should be prescribed with caution in patients at risk of HF or having HF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways., Background: In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF., Methods: Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis., Results: A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B)., Conclusions: Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450)., Competing Interests: FUNDING SUPPORT AND AUTHOR DISCLOSURES HOMAGE was funded by a grant from the European Union 7th Framework Programme for Research and Technological Development (HEALTH-F7-305507 HOMAGE (EU FP7 305507 http://www.homage-hf.eu). Drs. Ferreira, Rossignol, Girerd, and Zannad are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program (reference: ANR-15-RHUS-0004); the French PIA project “Lorraine Université d’Excellence” (reference: ANR-15-IDEX-04-LUE); Contrat de Plan Etat Lorraine IT2MP; and FEDER Lorraine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure., Methods and Results: Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 μg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 μg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone., Conclusions: Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Diabetes mellitus is an established risk factor for cardiovascular diseases. Even impaired levels of glucose and insulin might harm organ function prior to diabetes onset. Whether serum glucose or insulin plays a direct role in cardiac dysfunction or lung volume reduction remains unclear. The aim was to investigate the relationship between glucose and insulin with the right ventricle and lung volumes within KORA-MRI FF4 study., Methods: From the KORA-MRI FF4 cohort study 337 subjects (mean age 55.7 ± 9.1 years; 43% women) underwent a whole-body 3T MRI scan. Cardiac parameters derived from a cine-steady-state free precession sequence using cvi42. MRI-based lung volumes derived semi-automatically using an in-house algorithm. Fasting serum glucose, fasting insulin levels, and HOMA index were calculated in all study subjects. Linear regression analyses were performed to assess the relationships between glucose and insulin levels with right ventricle volumes and lung volumes adjusted for age, sex, BMI, and cardiovascular risk factors., Results: In univariate and multivariate-adjusted models, high serum insulin was inversely associated with end-diastolic volume (β = -12.43, P < 0.001), end-systolic volume (β = -7.12, P < 0.001), stroke volume (β = -5.32, P < 0.001), but not with ejection fraction. The association remained significant after additional adjustment for lung volumes. Similarly, serum insulin was inversely associated with lung volume (β = -0.15, P = 0.04). Sensitivity analysis confirmed results after excluding subjects with known diabetes., Conclusions: Serum insulin was inversely associated with right ventricle function and lung volumes in subjects from the general population free of cardiovascular disease, suggesting that increased insulin levels may contribute to subclinical cardiopulmonary circulation impairment.

Aims: Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin-3., Methods and Results: The HOMAGE trial is a prospective, randomised, open-label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP, 125 to 1000 ng/L) or B-type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction < 45%, atrial fibrillation, severe renal dysfunction, or treatment with loop diuretics. The primary endpoint was the interaction between change in serum concentrations of procollagen type III N-terminal propeptide (PIIINP) and treatment with spironolactone according to median plasma concentrations of galectin-3 at baseline. For the 527 participants enrolled, median (interquartile range) age was 73 (69-79) years, 135 (26%) were women, 412 (78%) had hypertension, 377 (72%) CAD, and 212 (40%) T2DM. At baseline, medians (interquartile ranges) were for left ventricular ejection fraction 63 (58-67) %, for left atrial volume index 31 (26-37) mL/m 2 , for plasma NT-proBNP 214 (137-356) ng/L, for serum PIIINP 3.9 (3.1-5.0) ng/mL, and for galectin-3 16.1 (13.5-19.7) ng/mL., Conclusions: The HOMAGE trial will provide insights on the effect of spironolactone on pathways that might drive progression to HF., Clinical Trial Registration: ClinicalTrials.gov NCT02556450., (© 2020 European Society of Cardiology.)

Purpose: Arterial stiffness predicts cardiovascular complications. The association between arterial stiffness and blood lead (BL) remains poorly documented. We aimed to assess the association of central hemodynamic measurements, including pulse wave velocity (aPWV), with blood lead in a Flemish population. Materials and Methods: In this Flemish population study (mean age, 37.0 years; 48.3% women), 267 participants had their whole BL and 24-h urinary cadmium (UCd) measured by electrothermal atomic absorption spectrometry in 1985-2005. After 9.4 years (median), they underwent applanation tonometry to estimate central pulse pressure (cPP), the augmentation index (AI), pressure amplification (PA), and aPWV. The amplitudes of the forward (Pf) and backward (Pb) pulse waves and reflection index (RI) were derived by a pressure-based wave separation algorithm. Results: BL averaged 2.93 μg/dL (interquartile range, 1.80-4.70) and UCd 4.79 µg (2.91-7.85). Mean values were 45.0 ± 15.2 mm Hg for cPP, 24.4 ± 12.4% for AI, 1.34 ± 0.21 for PA, 7.65 ± 1.74 m/s for aPWV, 32.7 ± 9.9 mm Hg for Pf, 21.8 ± 8.4 mm Hg for Pb, and 66.9 ± 18.4% for RI. The multivariable-adjusted association sizes for a 2-fold higher BL were: +3.03% (95% confidence interval, 1.56, 4.50) for AI; -0.06 (-0.08, -0.04) for PA; 1.02 mm Hg (0.02, 2.02) for Pb; and 3.98% (1.71, 6.24) for RI ( p  ≤ .045). In 206 participants never on antihypertensive drug treatment, association sizes were +2.59 mm Hg (0.39, 4.79) for cPP and +0.26 m/s (0.03, 0.50) for aPWV. Analyses adjusted for co-exposure to cadmium were consistent. Conclusion: In conclusion, low-level environmental lead exposure possibly contributes to arterial stiffening and wave reflection from peripheral sites.

Background: To investigate the association between fasting serum insulin and glucose levels with atherosclerotic plaque composition in the carotid artery. Impaired insulin and glucose levels are implicated in the etiology of cardiovascular disease; however, their influence on the formation and composition of atherosclerotic plaque remains unclear., Methods: In 1740 participants (mean age 72.9 years, 46% women, 14.4% diabetes mellitus) from the population-based Rotterdam Study, we performed carotid MRI to evaluate the presence of calcification, lipid core, and intraplaque hemorrhage in carotid atherosclerosis. All participants also underwent blood sampling to obtain information on serum insulin and glucose levels. Using logistic regression models, we assessed the association of serum insulin and glucose levels (per s.d. and in tertiles) with the different plaque components, while adjusting for sex, age, intima-media thickness, and cardiovascular risk factors., Results: Serum insulin levels were associated with the presence of intraplaque hemorrhage (adjusted odds ratio (OR): 1.42 (95% CI: 1.12-1.7)) We found no association with the presence of calcification or lipid core. Sensitivity analyses restricted to individuals without diabetes mellitus yielded similar results. No associations were found between serum glucose levels and any of the plaque components., Conclusions: Serum insulin levels are associated with the presence of vulnerable components of carotid plaque, specifically with intraplaque hemorrhage. These findings suggest a complex role for serum insulin in the pathophysiology of carotid atherosclerosis and in plaque vulnerability.

Rationale: The urinary proteome reflects molecular drivers of disease., Objectives: To construct a urinary proteomic biomarker predicting 1-year post-ICU mortality., Methods: In 1243 patients, the urinary proteome was measured on ICU admission, using capillary electrophoresis coupled with mass spectrometry along with clinical variables, circulating biomarkers (BNP, hsTnT, active ADM, and NGAL), and urinary albumin. Methods included support vector modeling to construct the classifier, Cox regression, the integrated discrimination (IDI), and net reclassification (NRI) improvement, and area under the curve (AUC) to assess predictive accuracy, and Proteasix and protein-proteome interactome analyses., Measurements and Main Results: In the discovery (deaths/survivors, 70/299) and test (175/699) datasets, the new classifier ACM128, mainly consisting of collagen fragments, yielding AUCs of 0.755 (95% CI, 0.708-0.798) and 0.688 (0.656-0.719), respectively. While accounting for study site and clinical risk factors, hazard ratios in 1243 patients were 2.41 (2.00-2.91) for ACM128 (+ 1 SD), 1.24 (1.16-1.32) for the Charlson Comorbidity Index (+ 1 point), and ≥ 1.19 (P ≤ 0.022) for other biomarkers (+ 1 SD). ACM128 improved (P ≤ 0.0001) IDI (≥ + 0.50), NRI (≥ + 53.7), and AUC (≥ + 0.037) over and beyond clinical risk indicators and other biomarkers. Interactome mapping, using parental proteins derived from sequenced peptides included in ACM128 and in silico predicted proteases, including/excluding urinary collagen fragments (63/35 peptides), revealed as top molecular pathways protein digestion and absorption, lysosomal activity, and apoptosis., Conclusions: The urinary proteomic classifier ACM128 predicts the 1-year post-ICU mortality over and beyond clinical risk factors and other biomarkers and revealed molecular pathways potentially contributing to a fatal outcome.

Background: Aortic pulse wave velocity (aPWV) predicts cardiovascular complications, but the association of central arterial properties with blood lead level (BL) is poorly documented. We therefore assessed their association with BL in 150 young men prior to occupational lead exposure, using baseline data of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods: Study nurses administered validated questionnaires and performed clinical measurements. Venous blood samples were obtained after 8-12 h of fasting. The radial, carotid and femoral pulse waves were tonometrically recorded. We accounted for ethnicity, age, anthropometric characteristics, mean arterial pressure, heart rate, smoking and drinking, and total and high-density lipoprotein serum cholesterol, as appropriate. Results: Mean values were 4.14 μg/dL for BL, 27 years for age, 108/79/28 mm Hg for central systolic/diastolic/pulse pressure, 100/10% for the augmentation ratio/index, 1.63 for pressure amplification, 5.94 m/s for aPWV, 27/11 mm Hg for the forward/backward pulse pressure height, and 43% for the reflection index. Per 10-fold BL increase, central diastolic pressure and the augmentation ratio were respectively 5.37 mm Hg (95% confidence interval [CI], 1.00-9.75) and 1.57 (CI, 0.20-2.94) greater, whereas central pulse pressure and the forward pulse pressure height were 3.74 mm Hg (CI, 0.60-6.88) and 3.37 mm Hg (CI, 0.22-6.53) smaller ( p  ≤ .036 for all). The other hemodynamic measurements were unrelated to BL. The reflected pulse peak time was inversely correlated with diastolic pressure ( r  = -0.20; p  ≤ .017). Conclusion: At the exposure levels observed in our current study, aPWV, the gold standard to assess arterial stiffness, was not associated with BL. Increased peripheral arterial resistance, as reflected by higher diastolic pressure, might bring reflection points closer to the heart, thereby moving the backward wave into systole and increasing the augmentation ratio in relation to BL.

Objectives: Previous studies relating nervous activity to blood lead (BL) levels have limited relevance, because over time environmental and occupational exposure substantially dropped. We investigated the association of heart rate variability (HRV) and median nerve conduction velocity (NCV) with BL using the baseline measurements collected in the Study for Promotion of Health in Recycling Lead (NCT02243904)., Methods: In 328 newly hired men (mean age 28.3 years; participation rate 82.7%), we derived HRV measures (power expressed in normalised units (nu) in the high-frequency (HF) and low-frequency (LF) domains, and LF/HF) prior to long-term occupational lead exposure. Five-minute ECG recordings, obtained in the supine and standing positions, were analysed by Fourier transform or autoregressive modelling, using Cardiax software. Motor NCV was measured at the median nerve by a handheld device (Brevio Nerve Conduction Monitoring System, NeuMed, West Trenton, NJ, USA). BL was determined by inductively coupled plasma mass spectrometry., Results: Mean BL was 4.54 µg/dL (IQR 2.60-8.90 µg/dL). Mean supine and standing values of LF, HF and LF/HF were 50.5 and 21.1 nu and 2.63, and 59.7 and 10.9 nu and 6.31, respectively. Orthostatic stress decreased HF and increased LF (p<0.001). NCV averaged 3.74 m/s. Analyses across thirds of the BL distribution and multivariable-adjusted regression analyses failed to demonstrate any association of HRV or NCV with BL., Conclusions: At the exposure levels observed in our study, autonomous nervous activity and NCV were not associated with BL., Trial Registration Number: NCT02243904., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Numerous studies suggested that occupational or environmental exposure to lead adversely affects renal function. However, most studies lost relevance because of the substantially lower current environmental lead exposure and all relied on serum creatinine to estimate glomerular filtration. We investigated the association of estimated glomerular filtration rate (eGFR), estimated from serum creatinine, cystatin C or both, with blood lead (BPb) using the baseline measurements of the ongoing Study for Promotion of Health in Recycling Lead (SPHERL; NCT02243904) in newly hired workers prior to significant occupational lead exposure., Methods: Among 447 men (participation rate, 82.7%), we assessed the association of eGFR and the urinary albumin-to-creatinine ratio (ACR) with BPb across thirds of the BPb distribution using linear regression analysis. Fully adjusted models accounted for age, blood pressure, body mass index, the waist-to-hip ratio, smoking, the total-to-high-density-lipoprotein ratio, plasma glucose, serum γ-glutamyltransferase and antihypertensive drug treatment., Results: Age averaged 28.7 (SD, 10.2) years (range, 19.1-31.8). Geometric mean BPb concentration was 4.34 μg/dL (5th-95th percentile interval, 0.9-14.8). In unadjusted and adjusted analyses, eGFR estimated from serum creatinine [mean (SD), 105.26 (15.2) mL/min/1.73 m2], serum cystatin C [mean (SD), 127.8 (13.8) mL/min/1.73 m2] or both [mean (SD), 111.9 (14.8) mL/min/1.73 m2] was not associated with BPb (P  ≥  0.36), whereas ACR [geometric mean, 4.32 mg/g (5th-95th percentile interval, 1.91-12.50)] was lower with higher BPb., Conclusions: At the BPb levels observed in this study, there was no evidence for an association between renal function and lead exposure., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.)

Objectives Higher than contemporary exposure levels and advanced age of study participants have limited the interpretation of previous studies relating neurocognitive function to lead exposure. We reassessed this association in young American men prior to chronic occupational exposure at lead recycling plants, using baseline measurements of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods We administered the Stroop test (ST) and the digit-symbol test (DST) to 339 men (mean age, 28.6 years; participation rate 82.7%). Whole blood lead (BL) was determined by inductively coupled plasma mass spectrometry and related ST and DST test results using multivariable-adjusted regression. Results Average values were 4.26 μg/dL for BL, 1624 ms and 1474 ms for mean reaction time in incongruent and congruent ST trials, and 109 sec for mean total latency in DST. The number of participants with fully correct answers amounted to 281 (82.9%) and 334 (98.5%) in incongruent and congruent ST trials, respectively, and to 198 (58.4%) in the DST. In multivariable-adjusted analyses, there was no association between cognitive performance and BL except for a weak but opposite association in DST; for a 10-fold BL increment, mean total latency was 5.4% (95% confidence interval, -0.4‒11.5%; P=0.066) higher, whereas the error score was 42% (-10‒69%; P=0.096) lower. To exclude an effect of the cumulative lead dose, sensitivity analyses restricted to workers <40, 35 and 30 years were confirmatory. Conclusions At the exposure levels in our current study, we failed to demonstrate a consistent inverse association of BL with neurocognitive performance in young American men.

Active matrix Gla protein (MGP), a potent inhibitor of calcification in large arteries, protects against macrovascular complications. Recent studies suggested that active MGP helps maintaining the integrity of the renal and myocardial microcirculation, but its role in preserving the retinal microcirculation remains unknown. In 935 randomly recruited Flemish participants (mean age, 40.9 years; 50.3% women), we measured plasma desphospho-uncarboxylated MGP (dp-ucMGP), a marker of poor vitamin K status using an ELISA-based assay at baseline (1996-2010) and retinal microvascular diameters using IVAN software (Vasculomatic ala Nicola, version 1.1) including the central retinal arteriolar (CRAE) and venular (CRVE) equivalent and the arteriole-to-venule ratio (AVR) at follow-up (2008-2015). CRAE (P = 0.005) and AVR (P = 0.080) at follow-up decreased across tertiles of the dp-ucMGP distribution. In unadjusted models, for a doubling of dp-ucMGP at baseline, CRAE and AVR at follow-up respectively decreased by 1.40 µm (95% confidence interval [CI], 0.32 to 2.48; P = 0.011) and 0.006 (CI, 0.001 to 0.011; P = 0.016). In multivariable-adjusted models accounting for sex, baseline characteristics and follow-up duration, these estimates were -1.03 µm (CI, -1.96 to -0.11; P = 0.028) and -0.007 (CI, -0.011 to -0.002; P = 0.007). Additional adjustment for changes from baseline to follow-up in major baseline characteristics yielded as estimates -0.91 µm (CI, -1.82 to -0.01; P = 0.048) and -0.006 (95% CI, -0.011 to -0.001; P = 0.014), respectively. Circulating inactive dp-ucMGP is a long-term predictor of smaller retinal arteriolar diameter in the general population. Our observations highlight the possibility that vitamin K supplementation might promote retinal health.

Aims: Antithrombotic treatment plays a key role in stroke prevention, but their direct effects on the composition of carotid artery atherosclerotic plaques are unknown. To investigate the association of antithrombotic treatment with carotid artery plaque composition, with a specific focus on an intraplaque haemorrhage (IPH)., Methods and Results: From the population-based Rotterdam Study, 1740 participants with carotid atherosclerosis on ultrasound (mean age 72.9 years, 46.0 women) underwent magnetic resonance imaging of the carotid arteries to assess plaque composition. Information on the use of oral anticoagulants [vitamin K antagonists (VKA)] and antiplatelet agents (salicylates), including duration of use and dosage, was obtained from pharmacy records for all participants. We used logistic regression models to assess the association between the use of anticoagulants and antiplatelet agents, and the different plaque components adjusting for confounders. Current and past use of VKA [adjusted odds ratio (OR): 1.88, 95% confidence interval (CI): 0.74-4.75 and OR 1.89, 95% CI: 0.91-3.93] and antiplatelet agents (OR: 1.22, 95% CI: 0.91-1.62), and (OR: 1.23, 95% CI: 0.86-1.75) showed positive trend with a higher presence of IPH. Also, a longer duration of use was associated with a higher frequency of IPH (OR: 3.15, 95% CI: 1.23-8.05) for the use of VKA, and longer duration of the use for antiplatelet agents showed a positive trend (OR: 1.21, 95% CI: 0.88-1.67). We also found that higher levels of international normalized ratio above 2.97 for VKA (OR: 1.48, 95% CI: 1.03-2.15) and higher daily defined dosage than 1.0 for antiplatelet agents (OR: 1.50, 95% CI: 1.21-1.87) were related to a higher frequency of IPH. We found no association with lipid core or calcification., Conclusions: The use of antithrombotic treatment relates to a higher frequency of IPH in carotid atherosclerotic plaques.

Background: Statins represent a key treatment for cardiovascular disease. Nevertheless, the direct effects of statin treatment on the composition of atherosclerotic plaques remain elusive., Objectives: We aimed to investigate the association of statin treatment with the presence of different plaque components located in the carotid arteries within a population-based setting., Methods: From the population-based Rotterdam Study, 1740 participants with carotid atherosclerosis (mean age 72.9 years, 46% women) underwent MRI of the carotid arteries to determine the presence of calcification, lipid core, and intraplaque hemorrhage. Information for the duration and dosage of statin use was obtained from pharmacy records for all participants. We used logistic regression models to study the association of statin use with the presence of plaque components., Results: Statin treatment was associated with a higher presence of calcification (OR: 1.73 [95% CI: 1.22-2.44]). Longer duration of use strengthened this association (OR: 1.82 [95% CI: 1.00-3.33] for 10 to 48 months, and OR 1.74 [95% CI: 1.09-2.77] for >48 months, compared to OR: 1.65 [95% CI: 0.94-2.89] for ≤10 months). Current statin treatment was also associated with a lower presence of lipid core (OR: 0.66 [95% CI: 0.42-1.04]), but only when using statins for 10 months or less. Any dosage of statins was associated with a higher presence of calcification, whilst only high dosages (DDD > 1.33) were associated with a lower presence of lipid core., Conclusions: Active, high-dosage statin use seems to beneficially influence the composition of carotid atherosclerosis by shifting the composition from vulnerable plaque with a lipid core to more stable calcified plaque., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: This proof-of-concept study investigated the feasibility of using biomarkers to monitor right heart pressures (RHP) in heart transplanted (HTx) patients., Methods: In 298 patients, we measured 7.6 years post-HTx mean pressures in the right atrium (mRAP) and pulmonary artery (mPAP) and capillaries (mPCWP) along with plasma high-sensitivity troponin T (hsTnT), a marker of cardiomyocyte injury, and the multidimensional urinary classifiers HF1 and HF2, mainly consisting of dysregulated collagen fragments., Results: In multivariable models, mRAP and mPAP increased with hsTnT (per 1-SD, +0.91 and +1.26 mm Hg; P < 0.0001) and with HF2 (+0.42 and +0.62 mm Hg; P ≤ 0.035), but not with HF1. mPCWP increased with hsTnT (+1.16 mm Hg; P < 0.0001), but not with HF1 or HF2. The adjusted odds ratios for having elevated RHP (mRAP, mPAP or mPCWP ≥10, ≥24, ≥17 mm Hg, respectively) were 1.99 for hsTnT and 1.56 for HF2 ( P ≤ 0.005). In detecting elevated RHPs, areas under the curve were similar for hsTnT and HF2 (0.63 vs 0.65; P = 0.66). Adding hsTnT continuous or per threshold or HF2 continuous to a basic model including all covariables did not increase diagnostic accuracy ( P ≥ 0.11), whereas adding HF2 per optimized threshold increased both the integrated discrimination (+1.92%; P = 0.023) and net reclassification (+30.3%; P = 0.010) improvement., Conclusions: Correlating RHPs with noninvasive biomarkers in HTx patients is feasible. However, further refinement and validation of such biomarkers is required before their clinical application can be considered., Competing Interests: H.M. is the cofounder and a shareholder of Mosaiques Diagnostics AG (Hannover, Germany). E.N.-K. is an employee of Mosaiques Diagnostics AG. The other authors declare no conflicts of interest.

Purpose: Although self-measurement of home blood pressure (HBP) is common in Japan and HBP telemonitoring via the Internet is possible, whether telemonitoring improves HBP control better than conventional practice remains unclear. Furthermore, hypertension care with online communication using telemonitored HBP is feasible, whereas the efficacy and safety of such telemedicine have not been established. We aim to compare traditional care, care with office visits using HBP telemonitoring, and antihypertensive telemedicine based on HBP telemonitoring., Methods and Design: In total, 444 patients with uncontrolled hypertension will be recruited and randomly assigned to three groups: (1) control: usual care with office visits and HBP self-report, (2) telemonitoring: weekly assessment of transmitted HBP by physicians and treatment adjustment upon office visits, or (3) telemedicine: online communication instead of office visits to adjust medication using telemonitored HBP. Primary outcome is the time to control of HBP, and secondary outcomes include achieved HBP levels, adherence, treatment intensity, adverse events, patient satisfaction and cost-effectiveness., Discussion: Hypertension care with telemonitoring and telemedicine are expected to require shorter time to achieve HBP control compared to usual care. Combining HBP telemonitoring with telemedicine may lower the hurdles for starting and persisting to hypertension treatment and eventually reduce cardiovascular events.

Background: Retinal microvascular traits predict adverse health outcomes. The Singapore I Vessel Assessment (SIVA) software improved automated postprocessing of retinal photographs. In addition to microvessel caliber, it generates measures of arteriolar and venular geometry. Few studies addressed the reproducibility of SIVA measurements across a wide age range., Methods: In the current study, 2 blinded graders read images obtained by nonmydriatic retinal photography twice in 20 11-year-old children, born prematurely (n = 10) or at term (n = 10) and in 60 adults (age range, 18.9-86.1 years)., Results: Former preterm compared with term children had lower microvessel diameter and disorganized vessel geometry with no differences in intraobserver and interobserver variability. Among adults, microvessel caliber decreased with age and blood pressure and arteriolar geometry was inversely correlated with female sex and age. Intraobserver differences estimated by the Bland-Altman method did not reach significance for any measurement. Across measurements, median reproducibility (RM) expressed as percent of the average trait value was 8.8% in children (median intraclass correlation coefficient [ICC], 0.94) and 8.0% (0.97) in adults. Likewise, interobserver differences did not reach significance with RM (ICC) of 10.6% (0.85) in children and 10.4% (0.93) in adults. Reproducibility was best for microvessel caliber (intraobserver/interobserver RM, 4.7%/6.0%; ICC, 0.98/0.96), worst for venular geometry (17.0%/18.8%; 0.93/0.84), and intermediate for arteriolar geometry (10.9%/14.9%; 0.95/0.86)., Conclusions: SIVA produces repeatable measures of the retinal microvasculature in former preterm and term children and in adults, thereby proving its usability from childhood to old age.

Background: No longitudinal study compared associations of echocardiographic indexes of diastolic left ventricular function studies with conventional (CBP) and daytime ambulatory (ABP) blood pressure in the general population., Methods and Results: In 780 Flemish (mean age, 50.2 years; 51.7% women), we measured left atrial volume index (LAVI), peak velocities of the transmitral blood flow (E) and mitral annular movement (e') in early diastole and E/e' 9.6 years (median) after CBP and ABP. In adjusted models including CBP and ABP, we expressed associations per 10/5-mm Hg systolic/diastolic blood pressure increments. LAVI and E/e' were 0.65/0.40 mL/m 2 and 0.17/0.09 greater with higher systolic/diastolic ABP ( P ≤0.028), but not with higher baseline CBP ( P ≥0.086). e' was lower ( P ≤0.032) with higher diastolic CBP (-0.09 cm/s) and ABP (-0.19 cm/s). When we substituted baseline CBP by CBP recorded concurrently with echocardiography, LAVI and E/e' remained 0.45/0.38 mL/m 2 and 0.15/0.08 greater with baseline ABP ( P ≤0.036), while LAVI (+0.53 mL/m 2 ) and E/e' (+0.19) were also greater ( P <0.001) in relation to concurrent systolic CBP. In categorized analyses of baseline data, sustained hypertension or masked hypertension compared with normotension or white-coat hypertension was associated with greater LAVI (24.0 versus 22.6 mL/m 2 ) and E/e' (7.35 versus 6.91) and lower e' (10.7 versus 11.6 cm/s; P ≤0.006 for all) with no differences ( P ≥0.092) between normotension and white-coat hypertension or between masked hypertension and sustained hypertension., Conclusions: ABP is a long-term predictor of diastolic left ventricular function, statistically outperforming distant but not concurrent CBP. Masked hypertension and sustained hypertension carry equal risk for deterioration of diastolic left ventricular function., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The heart ejects in the central elastic arteries. No previous study in workers described the diurnal profile of central blood pressure (BP) or addressed the question whether electrocardiogram (ECG) indexes are more closely associated with central than peripheral BP., Methods: In 177 men (mean age, 29.1 years), we compared the associations of ECG indexes with brachial and central ambulatory BP, measured over 24 hours by the validated oscillometric Mobil-O-Graph 24h PWA monitor., Results: From wakefulness to sleep, as documented by diaries, systolic/diastolic BP decreased by 11.7/13.1 mm Hg peripherally and 9.3/13.6 mm Hg centrally, whereas central pulse pressure (PP) increased by 4.3 mm Hg (P < 0.0001). Over 24 hours and the awake and asleep periods, the peripheral-minus-central differences in systolic/diastolic BPs averaged 11.8/-1.6, 12.7/-1.8, and 10.3/-1.2 mm Hg, respectively (P < 0.0001). Cornell voltage and index averaged 1.18 mV and 114.8 mV·ms. Per 1-SD increment in systolic/diastolic BP, the Cornell voltages were 0.104/0.086 mV and 0.082/0.105 mV higher in relation to brachial 24-hour and asleep BP and 0.088/0.90 mV and 0.087/0.107 mV higher in relation to central BP. The corresponding estimates for the Cornell indexes were 9.6/8.6 and 8.2/10.5 mV·ms peripherally and 8.6/8.9 and 8.8/10.7 mV·ms centrally. The regression slopes (P ≥ 0.067) and correlation coefficients (P ≥ 0.088) were similar for brachial and central BP. Associations of ECG measurements with awake BP and PP were not significant., Conclusions: Peripheral and central BPs run in parallel throughout the day and are similarly associated with the Cornell voltage and index., (© The Author 2017. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Rationale: Sex steroids may play a role in plaque composition and in stroke incidence., Objectives: To study the associations of endogenous estradiol and testosterone with carotid plaque composition in elderly men and postmenopausal women with carotid atherosclerosis, as well as with risk of stroke in this population., Methods and Results: Data of 1023 postmenopausal women and 1124 men (≥45 years) with carotid atherosclerosis, from prospective population-based RS (Rotterdam Study), were available. At baseline, total estradiol (TE) and total testosterone (TT) were measured. Carotid atherosclerosis was assessed by ultrasound, whereas plaque composition (presence of calcification, lipid core, and intraplaque hemorrhage) was assessed by magnetic resonance imaging. TE and TT were not associated with calcified carotid plaques in either sex. TE was associated with presence of lipid core in both sexes (in women odds ratio, 1.48 [95% confidence interval [CI], 1.02-2.15]; in men odds ratio, 1.23 [95% CI, 1.03-1.46]), whereas no association was found between TT and lipid core in either sex. Higher TE (odds ratio, 1.58 [95% CI, 1.03-2.40]) and lower TT (odds ratio, 0.82 [95% CI, 0.68-0.98]) were associated with intraplaque hemorrhage in women but not in men. In women, TE was associated with increased risk of stroke (hazard ratio, 1.98 [95% CI, 1.01-3.88]), whereas no association was found in men. TT was not associated with risk of stroke in either sex., Conclusions: TE was associated with presence of vulnerable carotid plaque as well as increased risk of stroke in women, whereas no consistent associations were found for TT in either sex., (© 2017 American Heart Association, Inc.)

In view of decreasing lead exposure and guidelines endorsing ambulatory above office blood pressure (BP) measurement, we reassessed association of BP with blood lead (BL) in 236 newly employed men (mean age, 28.6 years) without previous lead exposure not treated for hypertension. Office BP was the mean of five auscultatory readings at one visit. Twenty-four-hour BP was recorded at 15- and 30-minute intervals during wakefulness and sleep. BL was determined by inductively coupled plasma mass spectrometry. Systolic/diastolic office BP averaged 120.0/80.7 mm Hg, and the 24-hour, awake, and asleep BP 125.5/73.6, 129.3/77.9, and 117.6/65.0 mm Hg, respectively. The geometric mean of blood lead was 4.5 μg/dL (interquartile range, 2.60-9.15 μg/dL). In multivariable-adjusted analyses, effect sizes associated with BL doubling were 0.79/0.87 mm Hg (P = .11/.043) for office BP and 0.29/-0.25, 0.60/-0.10, and -0.40/-0.43 mm Hg for 24-hour, awake, and asleep BP (P ≥ .33). Neither office nor 24-hour ambulatory hypertension was related to BL (P ≥ .14). A clinically relevant white coat effect (WCE; office minus awake BP, ≥20/≥10 mm Hg) was attributable to exceeding the systolic or diastolic threshold in 1 and 45 workers, respectively. With BL doubling, the systolic/diastolic WCE increased by 0.20/0.97 mm Hg (P = .57/.046). Accounting for the presence of a diastolic WCE, reduced the association size of office diastolic BP with BL to 0.39 mm Hg (95% confidence interval, -0.20 to 1.33; P = .15). In conclusion, a cross-sectional analysis of newly hired workers before lead exposure identified the WCE as confounder of the association between office BP and BL and did not reveal any association between ambulatory BP and BL., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients., Methods: HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement., Results: Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade ≥ 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy., Conclusions: uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients.

Background: Carotid artery atherosclerosis is an important risk factor for stroke. As such, quantitative imaging of carotid artery calcification, as a proxy of atherosclerosis, has become a cornerstone of current stroke research. Yet, population-based data comparing the computed tomography (CT) and cardiovascular magnetic resonance (CMR) for the detection and quantification of calcification remain scarce., Methods: A total of 684 participants from the population-based Rotterdam Study underwent both a CT and CMR of the carotid artery bifurcation to quantify the amount of carotid artery calcification (mean interscan interval: 4.9 ± 1.2 years). We investigated the correlation between the amount of calcification measured on CT and CMR using Spearman's correlation coefficient, Bland-Altman plots, and linear regression. In addition, using logistic regression modeling, we assessed the association of CT and CMR based calcification volumes with a history of stroke., Results: We found a strong correlation between CT and CMR based calcification volumes (Spearman's correlation coefficient:0.86, p-value ≤0.01). Bland-Altman analyses showed a good agreement, though CT based calcification volumes were systematically larger. Finally, calcification volume assessed with either imaging modality was associated with a history of stroke with similar effect estimates (odds ratio (OR) per 1-SD increase in calcification volume: 1.52 (95% CI:1.00;2.30) for CT, and 1.47 (95% CI:1.01;2.14) for CMR., Conclusion: CT based and CMR based volumes of carotid artery calcification are highly correlated, but CMR based calcification is systematically smaller than those obtained with CT. Despite this difference, both provide comparable information with regard to a history of stroke.