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BACKGROUND AND AIMS: The underlying biological mechanisms of ventricular fibrillation (VF) during acute myocardial infarction are largely unknown. To our knowledge, this is the first proteomic study for this trait, with the aim to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI).METHODS: We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n = 110) and without VF (control, n = 120) before guided catheter insertion for primary percutaneous coronary intervention. The plasma proteome was investigated using mass spectrometry-based proteomics on plasma samples collected within 24 hours of symptom onset.RESULTS: In 229 STEMI patients (72% men, median age 62 years (interquartile range (IQR): 54-70)), a median of 257 proteins (IQR: 244-281) were quantified per patient. A total of 26 proteins were associated with VF, these proteins were involved in several biological processes including blood coagulation, hemostasis, and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 (ACTBL2, fold-change (FC) 2.25, p < 0.001, q = 0.023) and coagulation factor XIII-A (F13A1, FC 1.48, p < 0.001, q = 0.023). None of the proteins were correlated with anterior infarct location.CONCLUSION: VF due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1), suggesting that they may represent novel underlying molecular VF mechanisms. Further research is needed to determine whether these proteins are predictive biomarkers or acute phase response proteins to VF during acute ischemia.

Gestational hypertension (GHTN) is associated with an increased cardiovascular risk for mothers and their offspring later in life. High-density lipoproteins (HDL) are anti-atherogenic by promoting efflux of cholesterol from macrophages and suppression of endothelial cell activation. Functional impairment of HDL in GHTN-complicated pregnancies may affect long-term health of both mothers and offspring. We studied functional parameters of maternal and neonatal HDL in 192 obese women (pre-pregnancy BMI >= 29), who were at high risk for GHTN. Maternal blood samples were collected longitudinally at

Individuals with diabetes at risk of developing diabetic kidney disease (DKD) are challenging to identify using currently available clinical methods. Prognostic accuracy and initiation of treatment could be improved by a quantification of the renal microvascular rarefaction and the increased vascular tortuosity during the development of DKD. Super-resolution ultrasound (SRUS) imaging is an in vivo technique capable of visualizing blood vessels at sizes below 75 µm. This preclinical study aimed to investigate the alterations in renal blood vessels’ density and tortuosity in a type 2 diabetes rat model, Zucker diabetic fatty (ZDF) rats, as a prediction of DKD. Lean age-matched Zucker rats were used as controls. A total of 36 rats were studied, subdivided into ages of 12, 22, and 40 weeks. Measured albuminuria indicated the early stage of DKD, and the SRUS was compared with the ex vivo micro-computed tomography (µCT) of the same kidneys. Assessed using the SRUS imaging, a significantly decreased cortical vascular density was detected in the ZDF rats from 22 weeks of age compared to the healthy controls, concomitant with a significantly increased albuminuria. Already by week 12, a trend towards a decreased cortical vascular density was found prior to the increased albuminuria. The quantified vascular density in µCT corresponded with the in vivo SRUS imaging, presenting a consistently lower vascular density in the ZDF rats. Regarding vessel tortuosity, an overall trend towards an increased tortuosity was present in the ZDF rats. SRUS shows promise for becoming an additional tool for monitoring and prognosing DKD. In the future, large-scale animal studies and human trials are needed for confirmation.

Background Vascular calcification is a known risk factor for cardiovascular events and mortality in patients with chronic kidney disease (CKD). However, since there is a lack of studies examining several arterial regions at a time, we aimed to evaluate the risk of major adverse cardiovascular events (MACE) and all-cause mortality according to calcium scores in five major arterial sites. Methods This was a prospective study of 580 patients from the Copenhagen CKD Cohort. Multidetector computed tomography of the coronary and carotid arteries, the thoracic aorta, the abdominal aorta and the iliac arteries was used to determine vascular calcification at baseline. Calcium scores were divided into categories: 0, 1-100, 101-400 and >400. Results During the follow-up period of 4.1 years a total of 59 cardiovascular events and 64 all-cause deaths occurred. In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, hypertension, diabetes mellitus, hypercholesterolemia and smoking, only the coronary and carotid arteries, and the thoracic aorta were independent predictors of the designated endpoints. When examining the potential of calcification in the five arterial sites for predicting MACE, the difference in C-statistic was also most pronounced in these three sites, at 0.21 [95% confidence interval (CI) 0.16%-0.26%, P < .001], 0.26 (95% CI 0.22%-0.3%, P < .001) and 0.20 (95% CI 0.16%-0.24%, P < .001), respectively. This trend also applied to all-cause mortality. Conclusions The overall results, including data on specificity, suggest that calcium scores of the coronary and carotid arteries have the most potential for identifying patients with CKD at high cardiovascular risk and for evaluating new therapies.

Background Plasma (p-)activin A is elevated in chronic kidney disease–mineral and bone disorder (CKD-MBD). Activin A inhibition ameliorates CKD-MBD complications (vascular calcification and bone disease) in rodent CKD models. We examined whether p-activin A was associated with major adverse cardiovascular events (MACE), all-cause mortality and CKD-MBD complications in CKD patients. Methods The study included 916 participants (741 patients and 175 controls) from the prospective Copenhagen CKD cohort. Comparisons of p-activin A with estimated glomerular filtration rate (eGFR), coronary and thoracic aorta Agatston scores, and bone mineral density (BMD) were evaluated by univariable linear regression using Spearman's rank correlation, analysis of covariance and ordinal logistic regression with adjustments. Association of p-activin A with rates of MACE and all-cause mortality was evaluated by the Aalen–Johansen or Kaplan–Meier estimator, with subsequent multiple Cox regression analyses. Results P-activin A was increased by CKD stage 3 (124–225 pg/mL, P < .001) and correlated inversely with eGFR (r = −0.53, P < 0.01). P-activin A was associated with all-cause mortality [97 events, hazard ratio 1.55 (95% confidence interval 1.04; 2.32), P < 0.05] after adjusting for age, sex, diabetes mellitus (DM) and eGFR. Median follow-up was 4.36 (interquartile range 3.64–4.75) years. The association with MACE was not significant after eGFR adjustment. Agatston scores and BMD were not associated with p-activin A. Conclusion P-activin A increased with declining kidney function and was associated with all-cause mortality independently of age, sex, DM and eGFR. No association with MACE, vascular calcification or BMD was demonstrated., Background. Plasma (p-) activin A is elevated in chronic kidney disease–mineral and bone disorder (CKD-MBD). Activin A inhibition ameliorates CKD-MBD complications (vascular calcification and bone disease) in rodent CKD models. We examined whether p-activin A was associated with major adverse cardiovascular events (MACE), all-cause mortality and CKD-MBD complications in CKD patients. Methods. The study included 916 participants (741 patients and 175 controls) from the prospective Copenhagen CKD cohort. Comparisons of p-activin A with estimated glomerular filtration rate (eGFR), coronary and thoracic aorta Agatston scores, and bone mineral density (BMD) were evaluated by univariable linear regression using Spearman’s rank correlation, analysis of covariance and ordinal logistic regression with adjustments. Association of p-activin A with rates of MACE and all-cause mortality was evaluated by the Aalen–Johansen or Kaplan–Meier estimator, with subsequent multiple Cox regression analyses. Results. P-activin A was increased by CKD stage 3 (124–225 pg/mL, P < .001) and correlated inversely with eGFR (r = −0.53, P < 0.01). P-activin A was associated with all-cause mortality [97 events, hazard ratio 1.55 (95% confidence interval 1.04; 2.32), P < 0.05] after adjusting for age, sex, diabetes mellitus (DM) and eGFR. Median follow-up was 4.36 (interquartile range 3.64–4.75) years. The association with MACE was not significant after eGFR adjustment. Agatston scores and BMD were not associated with p-activin A.

Obesity is a risk factor of chronic kidney disease (CKD), leading to alterations in the renal vascular structure. This study tested if renal vascular density and tortuosity was quantifiable in vivo in obese rats using microbubble-based super-resolution ultrasound imaging. The kidneys of two 11-week-old and two 20-week-old male obese Zucker rats were compared with age-matched male lean Zucker rats. The super-resolution ultrasound images were manually divided into inner me-dulla, outer medulla, and cortex, and each area was subdivided into arteries and veins. We quanti-fied vascular density and tortuosity, number of detected microbubbles, and generated tracks. For comparison, we assessed glomerular filtration rate, albumin/creatinine ratio, and renal histology to evaluate CKD. The number of detected microbubbles and generated tracks varied between animals and significantly affected quantification of vessel density. In areas with a comparable number of tracks, density increased in the obese animals, concomitant with a decrease in glomerular filtration rate and an increase in albumin/creatinine ratio, but without any pathology in the histological stain-ing. The results indicate that super-resolution ultrasound imaging can be used to quantify structural alterations in the renal vasculature. Techniques to generate more comparable number of microbub-ble tracks and confirmation of the findings in larger-scale studies are needed.

Cardiovascular disease is the leading cause of mortality amongst patients with chronic kidney disease (CKD). This is the first study using 3-dimensional echocardiography (3DE) to investigate associations between adverse changes of the left ventricle, and different stages of CKD. Participants were recruited from the Copenhagen CKD cohort study and the Herlev-Gentofte CKD cohort study. Patients were stratified according to GFR category (G1 + 2: eGFR ≥ 60 mL/min/1.73 m2, G3: eGFR = 30–59 mL/min/1.73 m2, and G4 + 5: eGFR ≤ 29 mL/min/1.73 m2), and according to albuminuria (A1: UACR < 30 mg/g, A2: 30–300 mg/g, A3: > 300 mg/g). Echocardiograms were analysed for left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), and global strain measures. In adjusted analysis, eGFR groups were adjusted for confounders and albuminuria category, while albuminuria groups were adjusted for confounders and GFR category. The study population consisted of 662 outpatients with CKD and 169 controls. Mean age was 57 ± 13 years, and 61% were males. Mean LVEF and global longitudinal strain (GLS) were increasingly impaired across eGFR groups: LVEF = 60.1%, 58.4%, and 57.8% (p = 0.013), GLS = − 16.1%, − 14.8%, and − 14.6% (p < 0.0001) for G1 + 2, G3, and G4 + 5. LVMi and prevalence of LV hypertrophy increased with albuminuria severity: mean LVMi = 87.9 g/m2, 88.1 g/m2, and 92.1 g/m2 (p = 0.007) from A1-3. Adjusted analysis confirmed reduced LVEF in G3 compared with G1 + 2, and increased LVMi in A3 compared with A1. Increasingly impaired eGFR was associated with adverse changes in LV systolic function, while albuminuria was associated with adverse changes in LV mass assessed by 3DE. Their associations were independent of each other.

Background and aims: The relationship between chronic kidney disease (CKD) and cardiovascular events is well-established. Clinically recognised risk factors of cardiovascular disease cannot fully explain this association. The objective of the present cross-sectional study was to investigate associations between serum metabolites and prevalent cardiovascular disease, as well as subclinical cardiovascular disease measured as coronary artery calcium score (CACS) in patients with CKD. Methods: More than 200 preselected metabolites were quantified using nuclear magnetic resonance spectroscopy in 725 patients and 174 controls from the Copenhagen CKD Cohort. CACS was determined by computed tomography. Results: Mean age of patients was 57.8 years, and 444 (61.3%) were men. Most of patients had hypercholesterolemia, and 133 (18.3%) had type 2 diabetes. Overall, 85 metabolites were significantly associated with prevalent cardiovascular disease in a model adjusted for eGFR, age, and sex, as well as Bonferroni correction for multiple testing (p < 0.001). After further adjusting for diabetes, BMI, smoking, and cholesterol-lowering medication, the significance was lost for all but six metabolites (concentration of ApoA-1, cholesterol in total HDL and HDL2, total lipids and phospholipids in large HDL particles, and the ratio of phospholipids to total lipids in smaller VLDL particles). Of the 85 metabolites associated with prevalent cardiovascular disease, 71 were also associated with CACS in a similar pattern. Yet, in the model adjusted for all seven cardiovascular risk factors, only serum glucose levels and the ratio of triglycerides to total lipids in larger LDL particles remained significant. Conclusions: In patients with CKD, associations with prevalent cardiovascular disease were mainly found for HDL-related metabolites, while CACS was associated with glucose levels and increased triglycerides to total lipids ratio in LDL particles.

Blood lipid levels are linked to the risk of cardiovascular disease and regulated by genetic factors. A low-frequency polymorphism Arg82Cys (rs72836561) in the membrane protein nepmucin, encoded by CD300LG, is associated with lower fasting concentration of high-density lipoprotein cholesterol (HDLc) and higher fasting triglycerides. However, whether the variant is linked to postprandial lipids and glycemic status remains elusive.Here, we augment the genetic effect of Arg82Cys on fasting plasma concentrations of HDL subclasses, postprandial lipemia after a standardized high-fat meal, and glycemic status to further untangle its role in HDL metabolism.We elucidated fasting associations with HDL subclasses in a population-based cohort study (Oxford BioBank, OBB), including 4522 healthy men and women. We investigated fasting and postprandial consequences on HDL metabolism in recall-by-genotype (RbG) studies (fasting: 20 carrier/20 noncarrier; postprandial: 7 carrier/17 noncarrier), and shed light on the synergistic interaction with glycemic status.A lower fasting plasma concentration of cholesterol in large HDL particles was found in healthy male carriers of the Cys82 polymorphism compared to noncarriers, both in the OBB (P = .004) and RbG studies (P = .005). In addition, the Cys82 polymorphism was associated with low fasting plasma concentrations of ApoA1 (P = .008) in the OBB cohort. On the contrary, we did not find differences in postprandial lipemia or 2-hour plasma glucose levels.Taken together, our results indicate an association between the Arg82Cys variant and a lower concentration of HDL particles and HDLc, especially in larger HDL subclasses, suggesting a link between nepmucin and HDLc metabolism or maturation.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell-(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-S1pr12/2) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr12/2 mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-S1pr12/2 mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.