Papers by Marianne C. Verhaar
European Journal of Vascular and Endovascular Surgery, 2016
WHAT THIS PAPER ADDS The present study investigated quality of life (QoL) at a median of 35 month... more WHAT THIS PAPER ADDS The present study investigated quality of life (QoL) at a median of 35 months follow up after bone marrow derived cell therapy for severe limb ischemia. QoL is becoming a more important outcome measure, as amputation rates drop globally. Studies investigating cell therapy in limb ischemia do not usually have long-term follow up results. In the present study, QoL is still increased after almost 3 years, both in the cell treated and placebo arms. The information in the current manuscript is valuable for future trials, since it shows that QoL improvement persists even after long-term follow up, in both the treatment and placebo groups. This also underlines the importance of placebo controlled studies in (cell therapy) trials in limb ischemia. Objective: Quality of life (QoL) is an important outcome in evaluating treatment effect in severe limb ischemia. The randomized, double blind, placebo controlled JUVENTAS trial, investigating the effect of bone marrow derived mononuclear cell (BMMNC) administration in no option severe limb ischemia, showed an improved QoL at 6 months compared with baseline in both the treatment and placebo groups. The aim of the present study was to evaluate whether the improved QoL persisted beyond 6 months' follow up, whether this differed in both trial arms, and if major amputation influenced QoL. Methods: Short form 36 (SF-36) and EuroQol 5D (EQ5D), including the EQ Visual Analogue Scale (EQ-VAS), questionnaires were sent to JUVENTAS trial participants. In the JUVENTAS trial, a norm based scoring method was applied to report the results of the SF-36. The results of the long-term follow up were compared with baseline and 6 month follow up and the results of both trial arms were compared, as were the results of patients with and without amputation. Results: One hundred and nine patients (86.5% of surviving patients) responded to the questionnaires. Median follow up after inclusion was 33 months (interquartile range [IQR] 21.2e50.6) for the BMMNC and 36 months (IQR 21.4e50.9) for the placebo group. The improvement in QoL at 6 months persisted in both arms at a median follow up of 35 months. The long-term QoL did not differ between the BMMNC and placebo group in any of the SF-36 or EQ5D domains. Patients with and without a major amputation had similar QoL scores. Conclusions: The increased QoL in patients with no option severe limb ischemia persisted until 3 years after inclusion, but did not differ between the BMMNC and placebo arms or between patients with and without a major amputation.
BMJ Open, Feb 1, 2023
Study-an ongoing prospective cohort study of patients at high cardiovascular risk in the Netherla... more Study-an ongoing prospective cohort study of patients at high cardiovascular risk in the Netherlands. BMJ Open 2023;13:e066952.
Journal of the American College of Cardiology, Aug 1, 2023
Journal of Cellular and Molecular Medicine, Jul 31, 2019
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
The FASEB Journal, Apr 1, 2019
Journal of Visualized Experiments, Jul 3, 2013
Acta Physiologica, Feb 7, 2017
Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy ... more Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by
Hypertension, 2006
Endothelial NO synthase (eNOS) produces superoxide when depleted of (6R)-5,6,7,8-tetrahydro-L-bio... more Endothelial NO synthase (eNOS) produces superoxide when depleted of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH 4) and L-arginine by uncoupling the electron flow from NO production. High expression of eNOS has been reported to have beneficial effects in atherosclerotic arteries after relatively short periods of time. However, sustained high expression of eNOS may have disadvantageous vascular effects because of uncoupling. We investigated NO and reactive oxygen species (ROS) production in a microvascular endothelial cell line (bEnd.3) with sustained high eNOS expression and absent inducible NOS and neuronal NOS expression using 4,5-diaminofluorescein diacetate and diacetyldichlorofluorescein as probes, respectively. Unstimulated cells produced both NO and ROS. After stimulation with vascular endothelial growth factor (VEGF), NO and ROS production increased. VEGF-induced ROS production was even further increased by the addition of extra L-arginine. N-nitro-L-arginine methyl ester decreased ROS production. These findings strongly suggest that eNOS is a source of ROS in these cells. Although BH 4 levels were increased as compared with another endothelial cell line, eNOS levels were Ͼ2 orders of magnitude higher. The addition of BH 4 resulted in increased NO production and decreased generation of ROS, indicating that bEnd.3 cells produce ROS through eNOS uncoupling because of relative BH 4 deficiency. Nevertheless, eNOS-dependent ROS production was not completely abolished by the addition of BH 4 , suggesting intrinsic superoxide production by eNOS. This study indicates that potentially beneficial sustained increases in eNOS expression and activity could lead to eNOS uncoupling and superoxide production as a consequence. Therefore, sustained increases of eNOS or VEGF activity should be accompanied by concomitant supplementation of BH 4. (Hypertension. 2006;47:87-94.
Magnetic Resonance Materials in Physics Biology and Medicine, Sep 20, 2020
Objectives Renal multiparametric MRI (mpMRI) is a promising tool to monitor renal allograft healt... more Objectives Renal multiparametric MRI (mpMRI) is a promising tool to monitor renal allograft health to enable timely treatment of chronic allograft nephropathy. This study aims to validate mpMRI by whole-kidney histology following transplantectomy. Materials and methods A patient with kidney transplant failure underwent mpMRI prior to transplantectomy. The mpMRI included blood oxygenation level-dependent (BOLD) MRI, T 1 and T 2 mapping, diffusion-weighted imaging (DWI), 2D phase contrast (2DPC) and arterial spin labeling (ASL). Parenchymal mpMRI measures were compared to normative values obtained in 19 healthy controls. Differences were expressed in standard deviations (SD) of normative values. The mpMRI measures were compared qualitatively to histology. Results The mpMRI showed a heterogeneous parenchyma consistent with extensive interstitial hemorrhage on histology. A global increase in T 1 (+ 3.0 SD) and restricted diffusivity (− 3.6 SD) were consistent with inflammation and fibrosis. Decreased T 2 (− 1.8 SD) indicated fibrosis or hemorrhage. ASL showed diminished cortical perfusion (− 2.9 SD) with patent proximal arteries. 2DPC revealed a 69% decrease in renal perfusion. Histological evaluation showed a dense inflammatory infiltrate and fibrotic changes, consistent with mpMRI results. Most interlobular arteries were obliterated while proximal arteries were patent, consistent with ASL findings. Discussion mpMRI findings correlated well with histology both globally as well as locally.
Journal of Magnetic Resonance Imaging, Dec 4, 2019
Background: Gadolinium-based contrast agents (GBCAs) are widely used in MRI, despite safety conce... more Background: Gadolinium-based contrast agents (GBCAs) are widely used in MRI, despite safety concerns regarding deposition in brain and other organs. In animal studies gadolinium was detected for weeks after administration in the kidneys, but this has not yet been demonstrated in humans. Purpose: To find evidence for the prolonged presence of gadobutrol in the kidneys in healthy volunteers. Study Type: Combined retrospective and prospective analysis of a repeatability study. Population: Twenty-three healthy volunteers with normal renal function (12 women, age range 40-76 years), of whom 21 were used for analysis. Field Strength/Sequence: Inversion recovery-based T 1 map at 3T. Assessment: T 1 maps were obtained twice with a median interval of 7 (range: 4-16) days. The T 1 difference (ΔT 1) between both scans was compared between the gadolinium group (n = 16, 0.05 mmol/kg gadobutrol administered after T 1 mapping during both scan sessions) and the control group (n = 5, no gadobutrol). T 1 maps were analyzed separately for cortex and medulla. Statistical Tests: Mann-Whitney U-tests to detect differences in ΔT 1 between groups and linear regression to relate time between scans and estimated glomerular filtration rate (eGFR) to ΔT 1. Results: ΔT 1 differed significantly between the gadolinium and control group: median ΔT 1 cortex-98 vs. 7 msec (P < 0.001) and medulla-68 msec vs. 19 msec (P = 0.001), respectively. The bias corresponds to renal gadobutrol concentrations of 8 nmol/g tissue (cortex) and 4 nmol/g tissue (medulla), ie,~2.4 μmol for both kidneys (0.05% of original dose). ΔT 1 correlated in the gadolinium group with duration between acquisitions for both cortex (regression coefficient (β) 16.5 msec/day, R 2 0.50, P < 0.001) and medulla (β 11.5 msec/day, R 2 0.32, P < 0.001). Medullary ΔT 1 correlated with eGFR (β 1.13 msec/(ml/min) R 2 0.25, P = 0.008). Data Conclusion: We found evidence of delayed renal gadobutrol excretion after a single contrast agent administration in subjects with normal renal function. Even within this healthy population, elimination delay increased with decreasing kidney function. Level of Evidence: 3 Technical Efficacy: Stage 3
European Stroke Journal
Introduction: Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons... more Introduction: Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons ⩾35 years with hypertension who smoke(d). Whether screening for intracranial aneurysms (IAs) to prevent aSAH is effective in these patients is unknown. Patients and methods: Participants were retrieved from a cohort of patients with clinically manifest atherosclerotic vascular disease included between 2012 and 2019 at the University Medical Centre Utrecht (SMART-ORACLE, NCT01932671) in whom CT-angiography (CTA) of intracranial arteries was performed. We selected patients ⩾35 years with hypertension who smoke(d). CTAs were reviewed for the presence of IAs by experienced neuroradiologists. Patients with IAs were offered follow-up imaging to detect aneurysmal growth. We determined aneurysm prevalence and developed a diagnostic model for IA risk at screening using multivariable logistic regression. Results: IA were found in 25 of 500 patients (5.0% prevalence, 95%CI: 3.3%–7.3%). Median 5 ye...
American Journal of Physiology-Renal Physiology, 2021
This is the first equation, that we know of, which estimates glomerular filtration rate in rats b... more This is the first equation, that we know of, which estimates glomerular filtration rate in rats based on a single measurement of body weight, plasma creatinine, and plasma urea.
Diabetes Care, 2020
OBJECTIVE Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with h... more OBJECTIVE Diabetes is a risk factor for severe limb ischemia (SLI), a condition associated with high mortality, morbidity, and limb loss. The reactive glucose-derived dicarbonyl methylglyoxal (MGO) is a major precursor for advanced glycation end products (AGEs) and a potential driver of cardiovascular disease. We investigated whether plasma MGO levels are associated with poor outcomes in SLI. RESEARCH DESIGN AND METHODS We measured plasma levels of MGO, free AGEs, and d-lactate, the detoxification end product of MGO, with ultraperformance liquid chromatography–tandem mass spectrometry at baseline in 160 patients (64.8 ± 13.3 years, 67.5% male, 37.5% with diabetes) with no-option SLI and recorded major adverse outcomes (n = 86, comprising n = 53 deaths and n = 49 amputations [first event counted]) over the 5-year follow-up. Data were analyzed with linear or Cox regression, after Ln-transformation of the independent variables, adjusted for sex, age, trial arm, diabetes, estimated glom...
Journal of Vascular Surgery, 2020
Objective: Chronic limb-threatening ischemia (CLTI) is associated with high morbidity and mortali... more Objective: Chronic limb-threatening ischemia (CLTI) is associated with high morbidity and mortality rates. More than 50% of all CLTI patients die within 5 years after presentation. Patient-specific survival prediction is critical for informing treatment strategies, even for those without a clear option for revascularization. We validated a survival prediction model, developed in a revascularized Vascular Quality Initiative (VQI) cohort, in a Western European no-option CLTI cohort. Methods: The VQI survival prediction model was applied to the validation cohort (N ¼ 150) to compare estimated mortality and observed mortality at 2 years after baseline. Performance of the VQI model was tested by evaluating discrimination using the receiver operating characteristic area under the curve and calibration using the Hosmer-Lemeshow goodness-of-fit test. Results: The 2-year survival rate was 79% in the validation cohort compared with 83% in the VQI cohort. Baseline characteristics were significantly different for 13 of 17 variables. The C statistic was 0.86 (95% confidence interval, 0.78-0.95), which indicates good discrimination. The Hosmer-Lemeshow goodness-of-fit test had a P value of .30, which indicates good fit. Conclusions: This is the first external validation of the VQI survival prediction model. The good model performance suggests that this model can be used in different CLTI populations, including no-option CLTI, and underlines its contributory role in this challenging population.
Journal of Vascular Surgery, 2019
Background: Chronic limb-threatening ischemia (CLTI) represents the most severe form of periphera... more Background: Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease and has a large impact on quality of life, morbidity, and mortality. Interventions are aimed at improving tissue perfusion and averting amputation and secondary cardiovascular complications with an optimal risk-benefit ratio. Several prediction models regarding postprocedural outcomes in CLTI patients have been developed on the basis of randomized controlled trials to improve clinical decision-making. We aimed to determine model performance in predicting clinical outcomes in selected CLTI cohorts. Methods: This study validated the Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL), Finland National Vascular registry (FINNVASC), and Prevention of Infrainguinal Vein Graft Failure (PREVENT III) models in data sets from a peripheral artery disease registry study (Athero-Express) and two randomized controlled trials of CLTI in The Netherlands, Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) and Percutaneous Transluminal Angioplasty and Drug-eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI). Receiver operating characteristic (ROC) curve analysis was used to calculate their predictive capacity. The primary outcome was amputation-free survival (AFS); secondary outcomes were all-cause mortality and amputation at 12 months after intervention. Results: The BASIL and PREVENT III models showed predictive values regarding postintervention mortality in the JUVENTAS cohort with an area under the ROC curve (AUC) of 81% and 70%, respectively. Prediction of AFS was poor to fair (AUC, 0.60-0.71) for all models in each population, with the highest predictive value of 71% for the BASIL model in the JUVENTAS population. The FINNVASC model showed the highest predictive value regarding amputation risk in the PADI population with AUC of 78% at 12 months. Conclusions: In general, all models performed poor to fair in predicting mortality and amputation. Because the BASIL model performed best in predicting AFS, we propose use of the BASIL model to aid in the clinical decision-making process in CLTI. However, improvements in performance have to be made for any of these models to be of real additional value in clinical practice.
Scientific Reports, 2019
Patients with Severe Limb Ischemia (SLI) have a high risk of amputation and mortality. Here, we i... more Patients with Severe Limb Ischemia (SLI) have a high risk of amputation and mortality. Here, we investigated a panel of serum biomarkers with the aim of identifying biomarkers for major events and mechanisms that contribute to disease progression in established SLI. A panel of biomarkers including GROα, HGF, SCF, SCGFβ, SDF1α, TRAIL, IL-6, IL-8, FGFβ, GCSF, GMCSF, IP10, MCP1, PDGFbb, RANTES, TNFα, VEGF, sICAM, sVCAM, TM, and E-selectin was measured in serum samples from a subset (n = 108) of the JUVENTAS cohort. The primary outcome was major events, defined as major amputation or death. The inflammatory biomarkers IL-6, IL-8, GROα and IP-10 were significantly elevated in patients who reached a major endpoint. Results were validated in a secondary cohort (n = 146). Cox regression showed that adjusted hazard ratios were 1.40 (95% CI: 1.15–1.70, p = 0.0007) and 1.48 (95% CI 1.16–1.87, p = 0.001) for IL-6 and IP-10 in a fully adjusted model containing both biomarkers. A prediction model...
American Journal of Nephrology, 2016
Background: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferr... more Background: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content. Methods: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry. Results: Cardia...
Cytotherapy, Jan 27, 2015
Bone marrow (BM) transplantations are an accepted therapeutic strategy for hematologic conditions... more Bone marrow (BM) transplantations are an accepted therapeutic strategy for hematologic conditions. In the past decades, interest for BM-derived cell therapy has extended toward the field of regenerative medicine. Irrespective of the treatment strategy, its success depends on the amount of cells available for transplantation. Both patient and procedural factors have been shown to influence the cell density of the BM aspirate. In the present study, the influence of core diameter of the BM aspiration device on cell density of the BM aspirate is studied. BM harvesting procedures performed in a clinical trial investigating the effect of BM cell therapy in patients with severe peripheral artery disease were retrospectively studied (clinicaltrials.govNCT00371371). Patients underwent BM harvesting through the use of either a 15-gauge (n = 85) or an 8-gauge (n = 75) needle. The numbers of harvested white blood cells (WBC) and CD34(+) hematopoietic cells (HPC) were quantified. The amount of W...
European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, Jan 9, 2015
Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease (PAD), and m... more Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease (PAD), and many patients with CLI are not eligible for conventional revascularization. In the last decade, cell based therapies have been explored as an alternative treatment option for CLI. A meta-analysis was conducted of randomized placebo controlled trials investigating bone marrow (BM) derived cell therapy in patients with CLI. The MEDLINE, Embase, and the Cochrane Controlled Trials Register databases were systematically searched, and all included studies were critically appraised by two independent reviewers. The meta-analysis was performed using a random effects model. Ten studies, totaling 499 patients, were included in this meta-analysis. No significant differences were observed in major amputation rates (relative risk [RR] 0.91; 95% confidence interval [CI] 0.65-1.27), survival (RR 1.00; 95% CI 0.95-1.06), and amputation free survival (RR 1.03; 95% CI 0.86-1.23) between the cell treated an...
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Papers by Marianne C. Verhaar