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Background and Aims: Abdominal aortic aneurysm (AAA) patients undergo uniform imaging surveillance until reaching the surgical threshold. In spite of the ongoing exploration of AAA pathophysiology, biomarkers for personalized surveillance are lacking. This study aims to identify potential circulating biomarkers for AAA growth on serial CT scans., Methods: Patients with an AAA (maximal diameter ≥40 mm) were included in this multicentre, prospective cohort study. Participants underwent baseline blood sampling and yearly CT-imaging to determine AAA diameter and volume. Proteins and metabolites were measured using proximity extension assay (Olink Cardiovascular III) or separate ELISA panels, and mass-spectrometry (LC-TQMS), respectively. Linear mixed-effects, orthogonal partial least squares, and Cox regression were used to explore biomarker associations with AAA volume growth rate and the risk of surpassing the surgical threshold, as formulated by current guidelines., Results: 271 biomarkers (95 proteins, 176 metabolites) were measured in 109 (90.8 % male) patients with mean age 72. Median baseline maximal AAA diameter was 47.8 mm, volume 109 mL. Mean annual AAA volume growth rate was 11.5 %, 95 % confidence interval (CI) (10.4, 12.7). Median follow-up time was 23.2 months, 49 patients reached the surgical threshold. Patients with one standard deviation (SD) higher glutathione and glycine levels at baseline had an AAA volume growth rate that respectively was 1.97 %, 95%CI (0.97, 2.97) and 1.74 %, 95%CI (0.78, 2.71) larger, relative to the actual aneurysm size. Serine was associated with the risk of reaching the surgical threshold, independent of age and baseline AAA size (cause-specific hazard ratio per SD difference 1.78, 95%CI (1.30, 2.44))., Conclusions: Among multiple intertwined biomarkers related to AAA pathophysiology and progression, glutathione, glycine and serine were most promising., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Abdominal aortic aneurysm (AAA) patients undergo uniform surveillance programs both leading up to, and following surgery. Circulating biomarkers could play a pivotal role in individualizing surveillance. We applied a multi-omics approach to identify relevant biomarkers and gain pathophysiological insights., Materials and Methods: In this cross-sectional study, 108 AAA patients and 200 post-endovascular aneurysm repair (post-EVAR) patients were separately investigated. We performed partial least squares regression and ingenuity pathway analysis on circulating concentrations of 96 proteins (92 Olink Cardiovascular-III panel, 4 ELISA-assays) and 199 metabolites (measured by LC-TQMS), and their associations with CT-based AAA/sac volume., Results: The median (25th-75th percentile) maximal diameter was 50.0 mm (46.0, 53.0) in the AAA group, and 55.4 mm (45.0, 64.2) in the post-EVAR group. Correcting for clinical characteristics in AAA patients, the aneurysm volume Z-score differed 0.068 (95 %CI: (0.042, 0.093)), 0.066 (0.047, 0.085) and -0.051 (-0.064, -0.038) per Z-score valine, leucine and uPA, respectively. After correcting for clinical characteristics and orthogonalization in the post-EVAR group, the sac volume Z-score differed 0.049 (0.034, 0.063) per Z-score TIMP-4, -0.050 (-0.064, -0.037) per Z-score LDL-receptor, -0.051 (-0.062, -0.040) per Z-score 1-OG/2-OG and -0.056 (-0.066, -0.045) per Z-score 1-LG/2-LG., Conclusions: The branched-chain amino acids and uPA were related to AAA volume. For post-EVAR patients, LDL-receptor, monoacylglycerols and TIMP-4 are potential biomarkers for sac volume. Additionally, distinct markers for sac change were identified., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Biomarkers might help to improve diagnosis, surveillance and risk stratification of thoracic aortic disease (TAD). We explored the association between a broad spectrum of cardiovascular biomarkers with clinical characteristics and thoracic aortic diameter in TAD patients., Methods: Venous blood-samples were obtained in 158 clinically stable TAD patients visiting our outpatient clinic (2017-2020). TAD was defined as a thoracic aortic diameter ≥ 40 mm, or genetic confirmation (hereditary TAD). The cardiovascular panel III of the Olink multiplex platform was used for batch analysis of 92 proteins. A comparison was made between biomarker levels in patients with and without previous aortic dissection and/or surgery, and with and without hereditary TAD. Linear regression analyses were applied to identify (relative, normalized) biomarker concentrations associated with the absolute thoracic aortic diameter (AD max ), and thoracic aortic diameter indexed for body surface area (ID max )., Results: Median age of study patients was 61.0 (IQR 50.3-68.8) years, 37.3% females. Mean AD max and ID max were 43.3 ± 5.4 mm and 21.3 ± 3.3 mm/m 2 . After multivariable adjustment, Matrix Metalloproteinase-3 (MMP-3) and Insulin-like growth factor binding protein 2 (IGFBP-2) showed a significant positive association with AD max and ID max , respectively. Patients with previous aortic surgery/dissection had higher N-terminal-pro hormone BNP (NTproBNP) (median 3.67 [IQR 3.01-3.99] vs 2.84 [2.32-3.26], p ≤0.001). Patients with hereditary TAD had higher Trem-like transcript protein 2 (TLT-2) (median 4.64 [IQR 4.45-4.84]) than those with non-heriditary TAD (4.40 [4.17-4.64]; p = 0.00042)., Conclusions: Among a broad range of biomarkers, MMP-3 and IGFBP-2 were associated with disease severity in TAD patients. The pathophysiological pathways uncovered by these biomarkers, and their potential clinical use warrants further research., Competing Interests: Declaration of Competing Interest Authors Carlijn Thijssen, Silvy Dekker, Lidia Bons, Laurie Geenen, Arjen Gökalp, Johanna Takkenberg, Mostafa Mokhles, Jos Bekkers, Elke Bouwens, Eric Boersma, Roland van Kimmenade and Jolien Roos-Hesselink declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Acute kidney injury (AKI) is a well known complication following cardiovascular procedures. The objective was to assess the incidence, risk factors, and prognostic significance of AKI after infrarenal endovascular aneurysm repair (EVAR) and complex EVAR (cEVAR; fenestrated or branched EVAR)., Methods: Consecutive patients undergoing elective infrarenal EVAR or cEVAR between 2000 and 2018 in two large teaching hospitals in the Netherlands were included. AKI was determined by serum creatinine levels increasing > 1.5 times or by an absolute increase of 26.5 mmol/L from baseline value (KDIGO criteria). The primary outcome was incidence of peri-operative AKI development. Secondary outcomes included mid-term renal function (RIFLE criteria), overall survival, and risk factors for AKI development. To determine survival and risk factors for AKI, multivariable Cox regression and logistic regression analyses were performed, accounting for pre-operative renal function and other confounders., Results: In total, 540 patients who underwent infrarenal EVAR with 147 patients who underwent cEVAR also included. The incidence of AKI was 8.7% (n = 47) in infrarenal EVAR patients and 23% (n = 34) in cEVAR patients (fenestrated EVAR 18%; branched EVAR 38%). In contrast to patients without AKI, the renal function of surviving patients with AKI remained significantly reduced at six weeks and did not return to pre-operative values following infrarenal EVAR (three year estimated glomerular filtration rate [eGFR] 59.3 ± 23.1 mL/min/1.73m 2 vs. pre-operative eGFR 74.0 ± 21.7 mL/min/1.73m 2 ; p = .006) or following cEVAR (three year eGFR 52.0 ± 23.7 mL/min/1.73m 2 vs. pre-operative eGFR 65.4 ± 18.6 mL/min/1.73m 2 ; p = .082). After risk adjusted analysis, compared with non-AKI, post-operative AKI development was associated with a higher three year mortality rate following both infrarenal and cEVAR (infrarenal EVAR mortality hazard ratio [HR 1.6, 95% confidence interval [CI] 1.01 - 2.7 [p = .046]; cEVAR mortality HR 2.4, 95% CI 1.1 - 5.2 [p = .033]). Following multivariable logistic regression, pre-operative chronic kidney disease (eGFR < 60 mL/min/1.73m 2 ; odds ratio [OR] 2.2, 95% CI 1.03 - 4.8) and neck diameter (OR 1.1, 95% CI 1.01 - 1.2) were significantly associated with AKI following infrarenal EVAR, whereas for cEVAR only contrast volume (OR 1.1, 95% CI 1.0 - 1.2]) was found to be statistically significantly associated with AKI., Conclusion: AKI is a well described complication following infrarenal EVAR and is common after cEVAR. As AKI seems to be associated with permanent renal deterioration and lower survival, efforts to prevent AKI are essential. Future studies are required to assess what factors are associated with a higher risk of developing AKI following cEVAR., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Although proximal neck dilatation following infrarenal endovascular aneurysm repair (EVAR) is common and is associated with proximal graft failure, little is known about sealing zone dilatation and its clinical relevance following fenestrated EVAR (FEVAR). We studied proximal seal dilatation (PSD) dynamics following FEVAR and assessed its clinical significance., Methods: We included all consecutive patients treated for a juxta-/supra-renal aneurysm with fenestrated EVAR using the Zenith Fenestrated Endovascular Graft (Cook Medical, Bloomington, Ind) from 2008 to 2018 in two large teaching hospitals in the Netherlands. The primary outcome was PSD over time and was determined using a linear mixed-effects model. Secondary outcomes included associations for early PSD and difference in aortic dilatation at the level of the covered stent compared with the bare stent. Proximal seal-related adverse events were also obtained., Results: Our cohort included 84 patients with a median computed tomography angiography follow-up time of 24.5 months (interquartile range [IQR], 17-42 months). Maximum aneurysm diameter was 60.1 mm (IQR, 56.9-67.2 mm). Mean proximal seal diameter at baseline was 26.2 mm (standard deviation [SD], ±2.8 mm), mean stent oversizing was 20.1% (SD, ±9.1%), and mean proximal seal length was 29.5 mm (SD, ±11.7 mm). Proximal seal dilatation of 1.7 mm (95% confidence interval [CI], 1.4-2.1 mm) was found in the first year, decelerating thereafter (second year, 0.9 mm/year; 95% CI, 0.7-1.1 mm/y). Over 10% PSD at 1 year occurred in 22 patients (27%) and was associated with stent graft oversizing (odds ratio, 1.1; 95% CI, 1.03-1.2; P = .008) and a lower number of target vessels (four fenestrations/ref two fenestrations: odds ratio, 0.13; 95% CI, 0.02-0.74; P = .029). At last available imaging, dilatation difference was higher at the level of the covered stent compared with the bare stent (3.0 mm [IQR, 1.3-5.1 mm] vs 1.6 mm [IQR, 0.8-2.5 mm]; P < .001). During the study period, only one patient (1.2%) developed a proximal seal-related adverse event (type IA endoleak)., Conclusions: PSD is present following FEVAR, occurring at a faster rate in the first year and subsequently decelerating thereafter, similarly to neck dilatation after standard infrarenal EVAR. Although its clinical implication seems to remain limited in the first years following implantation, further research is required to assess the effect of PSD on long-term FEVAR outcomes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In this prospective cohort study of 250 stable heart failure patients with trimonthly blood sampling, we investigated associations of 17 repeatedly measured cytokines and cytokine receptors with clinical outcome during a median follow-up of 2.2 (25th-75th percentile, 1.4-2.5) years. Sixty-six patients reached the primary end point (composite of cardiovascular mortality, heart failure hospitalization, heart transplantation, left ventricular assist device implantation). Repeatedly measured levels of 8 biomarkers correlated with clinical outcomes independent of clinical characteristics. Rates of change over time (slopes of biomarker evolutions) remained independently associated with outcome for 15 biomarkers. Thus, temporal patterns of cytokines and cytokine receptors, in particular tumour necrosis factor ligand superfamily member 13B and interleukin-1 receptor type 1, might contribute to personalized risk assessment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The protein C pathway provides multiple important functions to maintain a regulated balance between hemostasis and host defense systems in response to vascular and inflammatory injury. The anticoagulant protein C pathway is designed to regulate coagulation, maintain the fluidity of blood within the vasculature, and prevent thrombosis, whereas the cytoprotective protein C pathway prevents vascular damage and stress. The cytoprotective activities of activated protein C (APC) include anti-apoptotic activity, anti-inflammatory activity, beneficial alterations of gene expression profiles, and endothelial barrier stabilization. These cytoprotective activities of APC, which require the endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR1), have been a major research focus. Recent insights, such as non-canonical activation of PAR1 at Arg46 by APC and biased PAR1 signaling, provided better understanding of the molecular mechanisms by which APC elicits cytoprotective signaling through cleavage of PAR1. The discovery and development of anticoagulant-selective and cytoprotective-selective APC mutants provided unique opportunities for preclinical research that has been and may continue to be translated to clinical research. New mechanisms for the regulation of EPCR functionality, such as modulation of EPCR-bound lipids that affect APC's cytoprotective activities, may provide new research directions to improve the efficacy of APC to convey its cytoprotective activities to cells. Moreover, emerging novel functions for EPCR expand the roles of EPCR beyond mediating protein C activation and APC-induced PAR1 cleavage. These discoveries increasingly develop our understanding of the protein C pathway, which will conceivably expand its physiological implications to many areas in the future., (© 2013 International Society on Thrombosis and Haemostasis.)