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Background and Aims: Family history (FHx) of cardiovascular disease (CVD) is a risk factor for CVD and a proxy for cardiovascular heritability. Polygenic risk scores (PRS) summarizing >1 million variants for coronary artery disease (CAD) are associated with incident and recurrent CAD events. However, little is known about the influence of FHx or PRS on secondary cardiovascular events (sCVE) in patients undergoing carotid endarterectomy (CEA)., Methods: We included 1788 CEA patients from the Athero-Express Biobank. A weighted PRS for CAD including 1.7 million variants was calculated (MetaGRS). The composite endpoint of sCVE during three years of follow-up included coronary, cerebrovascular and peripheral events and cardiovascular death. We assessed the impact of FHx and MetaGRS on sCVE and carotid plaque composition., Results: Positive FHx was associated with a higher 3-year risk of sCVE independent of cardiovascular risk factors and MetaGRS (adjusted HR 1.40, 95%CI 1.07-1.82, p = 0.013). Patients in the highest MetaGRS quintile had a higher 3-year risk of sCVE compared to the rest of the cohort independent of cardiovascular risk factors including FHx (adjusted HR 1.35, 95%CI 1.01-1.79, p = 0.043), and their atherosclerotic plaques contained more fat (adjusted OR 1.59, 95%CI, 1.11-2.29, p = 0.013) and more macrophages (OR 1.49, 95%CI 1.12-1.99, p = 0.006)., Conclusions: In CEA patients, both positive FHx and higher MetaGRS were independently associated with increased risk of sCVE. Moreover, higher MetaGRS was associated with vulnerable plaque characteristics. Future studies should unravel underlying mechanisms and focus on the added value of PRS and FHx in individual risk prediction for sCVE., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: We aimed to improve the understanding of potential associations between commonly available hematological biomarkers and the coronary artery calcification (CAC) score, which may help unravel the pathophysiology of coronary calcifications and subclinical coronary artery disease., Methods: A cross-sectional study was performed within the Utrecht Patient Oriented Database (UPOD). Patients with suspected or known coronary artery disease who underwent CT CAC scoring as well as standard hematology analysis that was part of routine clinical care (within 3 months of CT acquisition) were included. Complete hematology datasets were extracted from hematology analyzers. Linear regression adjusted for potential confounders was used to assess if hematological biomarkers were related to the CAC score., Results: In total, 1504 patients were included, of whom 43% (n = 647) had a CAC score of 0. Mean age (±SD) was 53 ± 13 years, and 34% of patients were women. Red blood cell distribution width (RDW, β = 0.20 [0.05-0.36], p=0.007), the fraction of immature reticulocytes (β = 0.97 [0.10-6.43], p=0.004), coefficient of variation of neutrophil lobularity (β = 0.13 [0.01-0.25], p=0.040) and mean lymphocyte cell size (β = 0.21 [0.08-0.34], p=0.001) were positively associated with the CAC score after adjustment for age, sex, body mass index (BMI), diabetes, glomerular filtration rate (GFR) and high-density lipoprotein (HDL)., Conclusions: This study confirms the known association of RDW with the CAC score, and presents the fraction of immature reticulocytes, coefficient of variation of neutrophil lobularity, and mean lymphocyte cell size as new markers associated with a higher CAC score., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: Previously, we showed that patients undergoing carotid endarterectomy have an increased risk for major atherosclerotic events in the presence of moderate or poor kidney function. Acceleration of vascular inflammatory responses is considered to be causally involved in progression of atherogenesis and poor outcome in chronic kidney disease patients. The association between kidney function and plaque composition has not been thoroughly investigated yet. The aim of this study was to investigate the association between kidney function and atherosclerotic plaque composition in patients undergoing carotid endarterectomy., Methods: Atherosclerotic plaques, harvested from 1796 patients who underwent carotid endarterectomy, were immunohistochemically stained for macrophages, smooth muscle cells, calcifications, collagen, microvessels, lipid core size and intraplaque hemorrhage. Cytokines were measured in plaque and plasma and associated with kidney function. Quantitative proteomics were performed on 40 carotid plaques and associated with kidney function., Results: Decreased kidney function was associated with increased odds ratio of intraplaque hemorrhage, OR 1.15 (95% CI; 1.02-1.29 (p = 0.024)) and increased odds ratio of fibrous-atheromatous plaques (plaques with lipid core presenting more than 10% of total plaque surface) OR 1.21 (95% CI; 1.07-1.38 (p = 0.003)) per decrease of 20 points in eGFR. Proteomics revealed that decreased kidney function was associated with upregulation of the classical pathway of the complement system and the intrinsic pathway of the coagulation system., Conclusions: Decreased kidney function was associated with plaque hemorrhage but not with inflammatory plaque characteristics. Our data suggests that other pathways than the inflammation-pathway are involved in plaque vulnerability and poor outcome in patients with decreased kidney function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Haplogroup I, a common European paternal lineage of the Y chromosome, is associated with increased risk of coronary artery disease in British men. It is unclear whether this haplogroup or any other haplogroup on the Y chromosome is associated with histological characteristics of the diseased vessel wall in other vascular manifestations of cardiovascular diseases showing a male preponderance., Methods: We examined Dutch men undergoing either carotid endarterectomy from the Athero-Express biobank (AE, n = 1217) or open aneurysm repair from the Aneurysm-Express biobank (AAA, n = 393). Upon resolving the Y chromosome phylogeny, each man was assigned to one of the paternal lineages based on combinations of single nucleotide polymorphisms of the male-specific region of the Y chromosome. We examined the associations between the Y chromosome and the histological characteristics of the carotid plaque and aneurysm wall, including lipid content, leukocyte infiltration and intraplaque haemorrhage, in all men., Results: A majority of men were carriers of either haplogroup I (AE: 28% AAA: 24%) or haplogroup R (AE: 59% AAA: 61%). We found no association between Y chromosomal haplogroups and histological characteristics of plaque collected from carotid arteries or tissue specimens of aneurysms. Moreover, the distribution of frequency for all Y chromosomal haplogroups in both cohorts was similar to that of a general population of Dutch men., Conclusions: Our data show that genetic variation on the Y chromosome is not associated with histological characteristics of the plaques from carotid arteries or specimens of aneurysms in men of Dutch origin., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis with an increasing incidence worldwide. The disease is still associated with high morbidity and mortality risks. Previous research in carotid arteries indicates that atherosclerotic plaque characteristics have stabilized over time in patients considered for surgery. It is currently unknown whether this time-dependent stabilization occurs in ilio-femoral arteries as well. Our objective was to analyze whether local ilio-femoral atherosclerotic plaque characteristics have changed over time., Methods: 497 patients within the Athero-Express biobank who underwent primary endarterectomy of the iliac or femoral artery between 2002 and 2013 were analyzed. We investigated six histological plaque characteristics: calcification, collagen, fat content, intraplaque haemorrhage, macrophages and smooth muscle cells., Results: Over the course of 10 years, we observed a lower percentage of all plaque characteristics that are considered indicators of a vulnerable plaque, such as: plaques with a large lipid core from 37.9% to 14.9% and plaques with intraplaque haemorrhage from 69.0% to 34.8% when the two-year cohorts 2003-2004 and 2011-2012 were compared, respectively. Multivariable analyses showed that time-dependent changes occurred independently of changing procedural and patient characteristics., Conclusions: In this cohort of peripheral arterial disease patients undergoing primary endarterectomy, we observed a time dependent shift of plaque characteristics towards a less lipid rich lesion with less intraplaque haemorrhage. These findings indicate research in cardiovascular disease would benefit from contemporary patient characteristics and plaque specimens to optimize translational potential., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The aim of this study is to determine sex differences in long-term outcome after coronary artery bypass grafting (CABG)., Methods: The international randomized controlled IMAGINE study included 2553 consecutive patients with a left ventricular ejection fraction of >40% who underwent isolated CABG. Median follow-up was 32 months (IQR 17-42 months). The composite endpoint comprised of death, myocardial infarction (MI), cerebrovascular event, angina, revascularization and congestive heart failure. Cox regression analysis was used to examine sex differences in outcome post-CABG., Results: Of the 2553 patients, 2229 were men and 324 (13%) were women. Women were older and more often reported diabetes and hypertension. Smoking and impaired renal function were more prevalent in men. Women experienced a higher event rate during follow-up (composite endpoint 18% vs 12%; P = 0.007). Cox regression showed an increased risk of the composite endpoint in women after adjustment for age (HR 1.48 (95% CI: 1.11-1.97)) which was non-significant after additional adjustment for other confounders (HR 1.26 (95% CI: 0.92-1.72))., Conclusion: Women have a worse long-term outcome after CABG than men in univariate analysis. However, after adjusting for potential confounders female sex became a non-significant predictor for prognosis, possibly due to the small sample size of women. Definite answers regarding sex-differences in long-term outcome after CABG should come from future pooling of studies comprising a larger number of women., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Long-term age- and sex-specific mortality data in patients undergoing carotid endarterectomy (CEA) and iliac/femoral endarterectomy (FEA) are scarce. We examined long-term mortality in these patient groups, stratified by age and sex., Methods: Between 2002 and 2012, 1771 patients (1200 men, 571 women) treated by CEA, and 685 patients (495 men, 190 women) who underwent FEA, were included and linked to the national mortality registry of the Netherlands. Absolute mortality risks during follow-up were analyzed by life-table and Kaplan Meier survival analyses in two age groups and stratified by sex, and compared to a matched sample from the general population. In addition, multivariable Cox regression analyses were performed., Results: After CEA, with a median follow-up duration of 4.3 years (interquartile range 2.0-7.1), 298 all-cause deaths had occurred in men (25%) and 105 (18%) in women. As in the general population, cumulative survival after CEA was significantly better in women compared to men (P = 0.002) and absolute CEA-associated mortality risk in women was similar to that of the general population. For FEA patients, mortality risk was worse than for CEA patients and the general population in both sexes and surprisingly, female sex did not have a favorable effect on survival. Following FEA, 130 men (26%) and 51 women (27%) died after a median follow-up time of 3.0 years (interquartile range 1.5-5.9). Stratifying by age, and adjusting for cardiovascular risk factors did not change these trends., Conclusions: Long-term mortality after CEA is higher in men than in women, and in women mortality risk is similar to the general population. After FEA, the benefit of women as seen after CEA is lost., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)