Publications by authors named "Dominique P V de Kleijn"

174 Publications

Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis.

Theranostics 2021 3;11(19):9243-9261. Epub 2021 Sep 3.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown. Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery. Heart function was monitored with echocardiography. Heart tissue was collected at different time-points for histological, molecular and flow cytometry analysis. Compared with wild-type mice, TF∆CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF∆CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF∆CT mice, as revealed by speckle-tracking strain analysis, was attributed to reduced myocardial deformation in the peri-infarct region. Histological analysis demonstrated that TF∆CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF∆CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) - Rac1 axis. In particular, infarcted TF∆CT hearts displayed markedly lower ratios of inflammatory M1 macrophages and reparative M2 macrophages (M1/M2). experiment with primary macrophages demonstrated that deletion of the TF cytoplasmic domain inhibited macrophage polarization toward the M1 phenotype. Furthermore, infarcted TF∆CT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Finally, the overall cardioprotective effects observed in TF∆CT mice could be abolished by subcutaneously infusing a cocktail of PAR1-activating peptide and PAR2-inhibiting peptide via osmotic minipumps. Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation.
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http://dx.doi.org/10.7150/thno.63354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490508PMC
September 2021

High levels of osteoprotegerin are associated with coronary artery calcification in patients suspected of a chronic coronary syndrome.

Sci Rep 2021 Sep 23;11(1):18946. Epub 2021 Sep 23.

Department of Vascular Surgery (G04129), University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Plasma osteoprotegerin (OPG) and vascular smooth muscle cell (VSMC) derived extracellular vesicles (EVs) are important regulators in the process of vascular calcification (VC). In population studies, high levels of OPG are associated with events. In animal studies, however, high OPG levels result in reduction of VC. VSMC-derived EVs are assumed to be responsible for OPG transport and VC but this role has not been studied. For this, we investigated the association between OPG in plasma and circulating EVs with coronary artery calcium (CAC) as surrogate for VC in symptomatic patients. We retrospectively assessed 742 patients undergoing myocardial perfusion imaging (MPI). CAC scores were determined on the MPI-CT images using a previously developed automated algorithm. Levels of OPG were quantified in plasma and two EV-subpopulations (LDL and TEX), using an electrochemiluminescence immunoassay. Circulating levels of OPG were independently associated with CAC scores in plasma; OR 1.39 (95% CI 1.17-1.65), and both EV populations; EV-LDL; OR 1.51 (95% CI 1.27-1.80) and EV-TEX; OR 1.21 (95% CI 1.02-1.42). High levels of OPG in plasma were independently associated with CAC scores in this symptomatic patient cohort. High levels of EV-derived OPG showed the same positive association with CAC scores, suggesting that EV-derived OPG mirrors the same pathophysiological process as plasma OPG.
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http://dx.doi.org/10.1038/s41598-021-98177-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460823PMC
September 2021

A narrative review of plaque and brain imaging biomarkers for stroke risk stratification in patients with atherosclerotic carotid artery disease.

Ann Transl Med 2021 Aug;9(15):1260

Department of Vascular Surgery, Division of Surgical Specialties, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Objective: In this narrative review, we aim to review imaging biomarkers that carry the potential to non-invasively guide stroke risk stratification for treatment optimization.

Background: Carotid atherosclerosis plays a fundamental part in the occurrence of ischemic stroke. International guidelines select the optimal treatment strategy still mainly based on the presence of clinical symptoms and the degree of stenosis for stroke prevention in patients with atherosclerotic carotid plaques. These guidelines, based on randomized controlled trials that were conducted three decades ago, recommend carotid revascularization in symptomatic patients with high degree of stenosis versus a conservative approach for most asymptomatic patients. Due to optimization of best medical therapy and risk factor control, it is suggested that a subgroup of symptomatic patients is at lower risk of stroke and may not benefit from revascularization, whereas a selective subgroup of high-risk asymptomatic patients would benefit from this procedure.

Methods: A literature search was performed for articles published up to December 2020 using PubMed, EMBASE and Scopus. Based on the literature found, change in stenosis degree and volume, plaque echolucency, plaque surface, intraplaque haemorrhage, lipid-rich necrotic core, thin fibrous cap, inflammation, neovascularization, microembolic signals, cerebrovascular reserve, intracranial collaterals, silent brain infarcts, diffusion weighted imaging lesions and white matters lesions have the potential to predict stroke risk.

Conclusions: The applicability of imaging biomarkers needs to be further improved before the potential synergistic prognostic ability of imaging biomarkers can be verified on top of the clinical biomarkers. In the future, the routine and combined assessment of both plaque and brain imaging biomarkers might help to improve optimization of treatment strategies in individual patients with atherosclerotic carotid artery disease.
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http://dx.doi.org/10.21037/atm-21-1166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421959PMC
August 2021

Mast Cell Distribution in Human Carotid Atherosclerotic Plaque Differs Significantly by Histological Segment.

Eur J Vasc Endovasc Surg 2021 Sep 13. Epub 2021 Sep 13.

Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Objective: Mast cells (MCs) are important contributors to atherosclerotic plaque progression. For prospective studies on mast cell contributions to plaque instability, the distribution of intraplaque MCs needs to be elucidated. Plaque stability is generally histologically assessed by dividing the plaque specimen into segments to be scored on an ordinal scale. However, owing to competitive use, studies may have to deviate to adjacent segments, yet intersegment differences of plaque characteristics, especially MCs, are largely unknown. Therefore, the hypothesis that there is no segment to segment difference in MC distribution between atherosclerotic plaque segments was tested, and intersegment associations between MCs and other plaque characteristics was investigated.

Methods: Twenty-six carotid atherosclerotic plaques from patients undergoing carotid endarterectomy included in the Athero-Express Biobank were analysed. The plaque was divided in 5 mm segments, differentiating between the culprit lesion (segment 0), adjacent segments (-1/+1) and more distant segments (-2/+2) for the presence of MCs. The associations between the intersegment distribution of MCs and smooth muscle cells, macrophage content, and microvessel density in the culprit lesion were studied.

Results: A statistically significant difference in MCs/mm between the different plaque segments (p < .001) was found, with a median of 2.79 (interquartile range [IQR] 1.63 - 7.10) for the culprit lesion, 1.34 (IQR 0.26 - 4.45) for the adjacent segment, and 0.62 (0.14 - 2.07) for the more distant segment. Post hoc analyses showed that intersegment differences were due to differences in MCs/mm between the culprit and adjacent segment (p = .037) and between the culprit lesion and the more distant segment (p < .001). MCs/mm in multiple different segments were positively correlated with microvessel density and macrophage content in the culprit lesion.

Conclusion: MC numbers reveal significant intersegment differences in human carotid plaques. Future histological studies on MCs should use a standardised segment for plaque characterisation as plaque segments cannot be used interchangeably for histological MC analyses.
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http://dx.doi.org/10.1016/j.ejvs.2021.07.008DOI Listing
September 2021

Pre-Operative Plasma Extracellular Vesicle Proteins are Associated with a High Risk of Long Term Secondary Major Cardiovascular Events in Patients Undergoing Carotid Endarterectomy.

Eur J Vasc Endovasc Surg 2021 Sep 9. Epub 2021 Sep 9.

Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Objective: Patients undergoing carotid endarterectomy (CEA) maintain a substantial residual risk of major cardiovascular events (MACE). Improved risk stratification is warranted to select high risk patients qualifying for secondary add on therapy. Plasma extracellular vesicles (EVs) are involved in atherothrombotic processes and their content has been related to the presence and recurrence of cardiovascular events. The association between pre-operative levels of five cardiovascular disease related proteins in plasma EVs and the post-operative risk of MACE was assessed.

Methods: In 864 patients undergoing CEA from 2002 to 2016 included in the Athero-Express biobank, three plasma EV subfractions (low density lipoprotein [LDL], high density lipoprotein [HDL], and tiny extracellular vesicles [TEX]) were isolated from pre-operative blood samples. Using an electrochemiluminescence immunoassay, five proteins were quantified in each EV subfraction: cystatin C, serpin C1, serpin G1, serpin F2, and CD14. The association between EV protein levels and the three year post-operative risk of MACE (any stroke, myocardial infarction, or cardiovascular death) was evaluated using multivariable Cox proportional hazard regression analyses.

Results: During a median follow up of three years (interquartile range 2.2 - 3.0), 137 (16%) patients developed MACE. In the HDL-EV subfraction, increased levels of CD14, cystatin C, serpin F2, and serpin C1 were associated with an increased risk of MACE (adjusted hazard ratios per one standard deviation increase of 1.30, 95% confidence interval [CI] 1.15-1.48; 1.22, 95% CI 1.06-1.42; 1.36, 95% CI 1.16-1.61; and 1.29, 95% CI 1.10-1.51; respectively), independently of cardiovascular risk factors. No significant associations were found for serpin G1. CD14 improved the predictive value of the clinical model encompassing cardiovascular risk factors (net re-classification index = 0.16, 95% CI 0.08-0.21).

Conclusion: EV derived pre-operative plasma levels of cystatin C, serpin C1, CD14, and serpin F2 were independently associated with an increased long term risk of MACE after CEA and are thus markers for residual cardiovascular risk. EV derived CD14 levels could improve the identification of high risk patients who may benefit from secondary preventive add on therapy in order to reduce future risk of MACE.
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http://dx.doi.org/10.1016/j.ejvs.2021.06.039DOI Listing
September 2021

Colchicine reduces extracellular vesicle NLRP3 inflammasome protein levels in chronic coronary disease: A LoDoCo2 biomarker substudy.

Atherosclerosis 2021 Oct 11;334:93-100. Epub 2021 Aug 11.

Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands. Electronic address:

Background And Aims: Colchicine reduces the risk of cardiovascular events in patients with coronary disease. Colchicine has broad anti-inflammatory effects and part of the atheroprotective effects have been suggested to be the result of NLRP3 inflammasome inhibition. We studied the effect of colchicine on extracellular vesicle (EV) NLRP3 protein levels and inflammatory markers, high sensitivity-CRP (hs-CRP) and interleukin (IL)-6, in patients with chronic coronary disease.

Methods: In vitro, the NLRP3 inflammasome was stimulated in PMA-differentiated- and undifferentiated THP-1 cells. In vivo, measurements were performed in serum obtained from 278 participants of the LoDoCo2 trial, one year after randomization to colchicine 0.5 mg once daily or placebo. EVs were isolated using precipitation. NLRP3 protein presence in EVs was confirmed using iodixanol density gradient centrifugation. Levels of NLRP3 protein, hs-CRP and IL-6 were measured using ELISA.

Results: In vitro, NLRP3 inflammasome stimulation showed an increase of EV NLRP3 protein levels. EV NLRP3 protein levels were lower in patients treated with colchicine (median 1.38 ng/mL), compared to placebo (median 1.58 ng/mL) (p = 0.025). No difference was observed in serum NLRP3 protein levels. Serum hs-CRP levels were lower in patients treated with colchicine (median 0.80 mg/L) compared to placebo (median 1.34 mg/L) (p < 0.005). IL-6 levels were lower in patients treated with colchicine (median 2.07 ng/L) compared to placebo (median 2.59 ng/L), although this was not statistically significant (p = 0.076).

Conclusions: Colchicine leads to a reduction of EV NLRP3 protein levels. This indicates that inhibitory effects on the NLRP3 inflammasome might contribute to the atheroprotective effects of colchicine in coronary disease.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.08.005DOI Listing
October 2021

Neutral Effects of Combined Treatment With GLP-1R Agonist Exenatide and MR Antagonist Potassium Canrenoate on Cardiac Function in Porcine and Murine Chronic Heart Failure Models.

Front Pharmacol 2021 26;12:702326. Epub 2021 Jul 26.

Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.

Ischemia-reperfusion and cardiac remodeling is associated with cardiomyocyte death, excessive fibrosis formation, and functional decline, eventually resulting in heart failure (HF). Glucagon-like peptide (GLP)-1 agonists are reported to reduce apoptosis and myocardial infarct size after ischemia-reperfusion. Moreover, mineralocorticoid receptor antagonists (MRAs) have been described to reduce reactive fibrosis and improve cardiac function. Here, we investigated whether combined treatment with GLP-1R agonist exenatide and MRA potassium canrenoate could minimize cardiac injury and limit HF progression in animal models of chronic HF. Forty female Topigs Norsvin pigs were subjected to 150 min balloon occlusion of the left anterior descending artery (LAD). Prior to reperfusion, pigs were randomly assigned to placebo or combination therapy (either low dose or high dose). Treatment was applied for two consecutive days or for 8 weeks with a continued high dose a tunneled intravenous catheter. Using 2,3,5-Triphenyltetrazolium chloride (TTC) staining we observed that combination therapy did not affect the scar size after 8 weeks. In line, left ventricular volume and function assessed by three-dimensional (3D) echocardiography (baseline, 7 days and 8 weeks), and cardiac magnetic resonance imaging (CMR, 8 weeks) did not differ between experimental groups. In addition, 36 C57Bl/6JRj mice underwent permanent LAD-occlusion and were treated with either placebo or combination therapy prior to reperfusion, for two consecutive days intravenous injection, followed by continued treatment placement of osmotic mini-pumps for 28 days. Global cardiac function, assessed by 3D echocardiography performed at baseline, 7, 14, and 28 days, did not differ between treatment groups. Also, no differences were observed in cardiac hypertrophy, assessed by heart weight/bodyweight and heart weight/tibia length ratio. In the current study, combined treatment with GLP-1R agonist exenatide and MR antagonist potassium canrenoate did not show beneficial effects on cardiac remodeling nor resulted in functional improvement in a small and large animal chronic HF model.
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http://dx.doi.org/10.3389/fphar.2021.702326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352472PMC
July 2021

Experimental parameters and infarct size in closed chest pig LAD ischemia reperfusion models; lessons learned.

BMC Cardiovasc Disord 2021 04 12;21(1):171. Epub 2021 Apr 12.

Department of Vascular Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA, Utrecht, The Netherlands.

Background: Preclinical models that resemble the clinical setting as closely as possible are essential in translating promising therapies for the treatment of acute myocardial infarction. Closed chest pig left anterior descending coronary artery (LAD) ischemia reperfusion (I/R) models are valuable and clinically relevant. Knowledge on the influence of experimental design on infarct size (IS) in these models is a prerequisite for suitable models. To this end, we investigated the impact of several experimental features (occlusion and follow-up time and influence of area at risk (AAR)) on IS.

Methods: A total of fifty-one female Landrace pigs were subjected to closed chest LAD balloon occlusion and evaluated in three substudies with varying protocols. To assess the relationship between time of occlusion and the IS, 18 pigs were subjected to 60-, 75- and 90 min of occlusion and terminated after 24 h of follow-up. Influence of prolonged follow-up on IS was studied in 18 pigs after 75 min of occlusion that were terminated at 1, 3 and 7 days. The relation between AAR and IS was studied in 28 pigs after 60 min of occlusion and 24 h of follow-up. The relation between VF, number of shocks and IS was studied in the same 28 pigs after 60 min of occlusion.

Results: Increasing occlusion time resulted in an increased IS as a ratio of the AAR (IS/AAR). This ranged from 53 ± 23% after 60 min of occlusion to 88 ± 2.2% after 90 min (P = 0.01). Increasing follow-up, from 1 to 3 or 7 days after 75 min of occlusion did not effect IS/AAR. Increasing AAR led to a larger IS/AAR (r = 0.34, P = 0.002), earlier VF (r = 0.32, P = 0.027) and a higher number of shocks (r = 0.29, P = 0.004) in pigs subjected to 60 min of occlusion.

Conclusions: These experiments describe the association of occlusion time, follow-up duration, AAR and VF with IS in closed chest pig LAD I/R models. These results have important implications for future I/R studies in pigs and can serve as a guideline for the selection of appropriate parameters and the optimal experimental design.
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http://dx.doi.org/10.1186/s12872-021-01995-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042863PMC
April 2021

Aging-induced isoDGR-modified fibronectin activates monocytic and endothelial cells to promote atherosclerosis.

Atherosclerosis 2021 05 25;324:58-68. Epub 2021 Mar 25.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551. Electronic address:

Background And Aims: Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire 'gain-of-function' isoDGR motifs that might play a role in atherosclerotic pathology.

Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo.

Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor 'outside in' signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNFα to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin β1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68 macrophages in vivo.

Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of 'outside-in' signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.020DOI Listing
May 2021

Response by Waissi et al Regarding Article, "Elevated Lp(a) (Lipoprotein[a]) Levels Increase Risk of 30-Day Major Adverse Cardiovascular Events in Patients Following Carotid Endarterectomy".

Stroke 2021 Jan 25;52(2):e66-e67. Epub 2021 Jan 25.

Department of Experimental Vascular Medicine (J.K.), Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.

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http://dx.doi.org/10.1161/STROKEAHA.120.033240DOI Listing
January 2021

The prognostic value of automated coronary calcium derived by a deep learning approach on non-ECG gated CT images from Rb-PET/CT myocardial perfusion imaging.

Int J Cardiol 2021 04 4;329:9-15. Epub 2021 Jan 4.

Department of Vascular Surgery, University Medical Centre Utrecht, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands.

Background: Assessment of both coronary artery calcium(CAC) scores and myocardial perfusion imaging(MPI) in patients suspected of coronary artery disease(CAD) provides incremental prognostic information. We used an automated method to determine CAC scores on low-dose attenuation correction CT(LDACT) images gathered during MPI in one single assessment. The prognostic value of this automated CAC score is unknown, we therefore investigated the association of this automated CAC scores and major adverse cardiovascular events(MACE) in a large chest-pain cohort.

Method: We analyzed 747 symptomatic patients referred for RubidiumPET/CT, without a history of coronary revascularization. Ischemia was defined as a summed difference score≥2. We used a validated deep learning(DL) method to determine CAC scores. For survival analysis CAC scores were dichotomized as low(<400) and high(≥400). MACE was defined as all cause death, late revascularization (>90 days after scanning) or nonfatal myocardial infarction. Cox proportional hazard analysis were performed to identify predictors of MACE.

Results: During 4 years follow-up, 115 MACEs were observed. High CAC scores showed higher cumulative event rates, irrespective of ischemia (nonischemic: 25.8% vs 11.9% and ischemic: 57.6% vs 23.4%, P-values <0.001). Multivariable cox regression revealed both high CAC scores (HR 2.19 95%CI 1.43-3.35) and ischemia (HR 2.56 95%CI 1.71-3.35) as independent predictors of MACE. Addition of automated CAC scores showed a net reclassification improvement of 0.13(0.022-0.245).

Conclusion: Automatically derived CAC scores determined during a single imaging session are independently associated with MACE. This validated DL method could improve risk stratification and subsequently lead to more personalized treatment in patients suspected of CAD.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.079DOI Listing
April 2021

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success.

Front Immunol 2020 8;11:599511. Epub 2020 Dec 8.

Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient's circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.
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http://dx.doi.org/10.3389/fimmu.2020.599511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752942PMC
June 2021

Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model.

Front Cardiovasc Med 2020 16;7:601990. Epub 2020 Nov 16.

Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore, Singapore.

The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes underpinned our test of the efficacy of MSC exosomes in a porcine model of myocardial infarction (MI) when administered systemically by the convenient method of intravenous (IV) bolus injection. Results show that 7 days of IV exosomes results in clear reduction (30-40%) of infarct size measured at both 7 and 28 days post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Taken together, these results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.
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http://dx.doi.org/10.3389/fcvm.2020.601990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701257PMC
November 2020

Inhibition of PFKFB3 Hampers the Progression of Atherosclerosis and Promotes Plaque Stability.

Front Cell Dev Biol 2020 12;8:581641. Epub 2020 Nov 12.

Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands.

Aims: 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158.

Methods And Results: PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6-8 weeks old male mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization.

Conclusion: High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis.
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http://dx.doi.org/10.3389/fcell.2020.581641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688893PMC
November 2020

Extracellular Vesicles in Diagnosing Chronic Coronary Syndromes the Bumpy Road to Clinical Implementation.

Int J Mol Sci 2020 Nov 30;21(23). Epub 2020 Nov 30.

Department of Vascular Surgery, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

Coronary artery disease (CAD), comprising both acute coronary syndromes (ACS) and chronic coronary syndromes (CCS), remains one of the most important killers throughout the entire world. ACS is often quickly diagnosed by either deviation on an electrocardiogram or elevated levels of troponin, but CCS appears to be more complicated. The most used noninvasive strategies to diagnose CCS are coronary computed tomography and perfusion imaging. Although both show reasonable accuracy (80-90%), these modalities are becoming more and more subject of debate due to costs, radiation and increasing inappropriate use in low-risk patients. A reliable, blood-based biomarker is not available for CCS but would be of great clinical importance. Extracellular vesicles (EVs) are lipid-bilayer membrane vesicles containing bioactive contents e.g., proteins, lipids and nucleic acids. EVs are often referred to as the "liquid biopsy" since their contents reflect changes in the condition of the cell they originate from. Although EVs are studied extensively for their role as biomarkers in the cardiovascular field during the last decade, they are still not incorporated into clinical practice in this field. This review provides an overview on EV biomarkers in CCS and discusses the clinical and technological aspects important for successful clinical application of EVs.
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http://dx.doi.org/10.3390/ijms21239128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729611PMC
November 2020

The TAXINOMISIS Project: A multidisciplinary approach for the development of a new risk stratification model for patients with asymptomatic carotid artery stenosis.

Eur J Clin Invest 2020 Dec 2;50(12):e13411. Epub 2020 Oct 2.

Department of Materials Science and Engineering, Unit of Medical Technology and Intelligent Information Systems, University of Ioannina, Ioannina, Greece.

Introduction: Asymptomatic carotid artery stenosis (ACAS) may cause future stroke and therefore patients with ACAS require best medical treatment. Patients at high risk for stroke may opt for additional revascularization (either surgery or stenting) but the future stroke risk should outweigh the risk for peri/post-operative stroke/death. Current risk stratification for patients with ACAS is largely based on outdated randomized-controlled trials that lack the integration of improved medical therapies and risk factor control. Furthermore, recent circulating and imaging biomarkers for stroke have never been included in a risk stratification model. The TAXINOMISIS Project aims to develop a new risk stratification model for cerebrovascular complications in patients with ACAS and this will be tested through a prospective observational multicentre clinical trial performed in six major European vascular surgery centres.

Methods And Analysis: The risk stratification model will compromise clinical, circulating, plaque and imaging biomarkers. The prospective multicentre observational study will include 300 patients with 50%-99% ACAS. The primary endpoint is the three-year incidence of cerebrovascular complications. Biomarkers will be retrieved from plasma samples, brain MRI, carotid MRA and duplex ultrasound. The TAXINOMISIS Project will serve as a platform for the development of new computer tools that assess plaque progression based on radiology images and a lab-on-chip with genetic variants that could predict medication response in individual patients.

Conclusion: Results from the TAXINOMISIS study could potentially improve future risk stratification in patients with ACAS to assist personalized evidence-based treatment decision-making.
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http://dx.doi.org/10.1111/eci.13411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757200PMC
December 2020

Elevated Lp(a) (Lipoprotein[a]) Levels Increase Risk of 30-Day Major Adverse Cardiovascular Events in Patients Following Carotid Endarterectomy.

Stroke 2020 10 3;51(10):2972-2982. Epub 2020 Sep 3.

Department of Experimental Vascular Medicine (K.E.D., J.G.S., J.K.), Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, the Netherlands.

Background And Purpose: General population studies have shown that elevated Lp(a) (lipoprotein[a]) levels are an emerging risk factor for cardiovascular disease and subsequent cardiovascular events. The role of Lp(a) for the risk of secondary MACE in patients undergoing carotid endarterectomy (CEA) is unknown. Our objective is to assess the association of elevated Lp(a) levels with the risk of secondary MACE in patients undergoing CEA.

Methods: Lp(a) concentrations were determined in preoperative blood samples of 944 consecutive patients with CEA included in the Athero-Express Biobank Study. During 3-year follow-up, major adverse cardiovascular events (MACE), consisting of myocardial infarction, stroke, and cardiovascular death, were documented.

Results: After 3 years follow-up, Kaplan-Meier cumulative event rates for MACE were 15.4% in patients with high Lp(a) levels (>137 nmol/L; >80th cohort percentile) and 10.2% in patients with low Lp(a) levels (≤137 nmol/L; ≤80th cohort percentile; log-rank test: =0.047). Cox regression analyses adjusted for conventional cardiovascular risk factors revealed a significant association between high Lp(a) levels and 3-year MACE with an adjusted hazard ratio of 1.69 (95% CI, 1.07-2.66). One-third of MACE occurred within 30 days after CEA, with an adjusted hazard ratio for the 30-day risk of MACE of 2.05 (95% CI, 1.01-4.17). Kaplan-Meier curves from time point 30 days to 3 years onward revealed no significant association between high Lp(a) levels and MACE. Lp(a) levels were not associated with histological carotid plaque characteristics.

Conclusions: High Lp(a) levels (>137 nmol/L; >80th cohort percentile) are associated with an increased risk of 30-day MACE after CEA. This identifies elevated Lp(a) levels as a new potential risk factor for secondary cardiovascular events in patients after carotid surgery. Future studies are required to investigate whether Lp(a) levels might be useful in guiding treatment algorithms for carotid intervention.
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http://dx.doi.org/10.1161/STROKEAHA.120.030616DOI Listing
October 2020

The age- and sex-specific composition of atherosclerotic plaques in vascular surgery patients.

Atherosclerosis 2020 10 29;310:1-10. Epub 2020 Jul 29.

Laboratory of Experimental Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands. Electronic address:

Background And Aims: The sex- and age-related differences in the composition of iliofemoral atherosclerotic plaques are largely unknown. Therefore, the aim of the current study is to gain insight into plaque composition across strata of age and sex in a large cohort of vascular surgery patients.

Methods: Peripheral atherosclerotic plaques of patients who underwent iliofemoral endarterectomy (n = 790) were harvested between 2002 and 2014. The plaques were semi-quantitatively analyzed for the presence of lipid cores, calcifications, plaque hemorrhages (PH), collagen, macrophage and smooth muscle cell (SMC) content, and quantitatively for microvessel density. Patients were stratified by age tertiles and sex.

Results: Ageing was independently associated with rupture-prone iliofemoral plaque characteristics, such as higher prevalence of plaque calcifications (OR 1.52 (95%CI:1.03-2.24) p = 0.035) and PH (OR 1.46 (95%CI:1.01-2.09) p = 0.042), and lower prevalence of collagen (OR 0.52 (95%CI:0.31-0.86) p = 0.012) and SMCs (OR 0.59 (95%CI:0.39-0.90) p = 0.015). Sex-stratified data showed that men had a higher prevalence of lipid cores (OR 1.62 (95%CI:1.06-2.45) p = 0.025) and PH (OR 1.62 (95%CI:1.16-2.54) p = 0.004) compared to women. These sex-differences attenuated with increasing age, with women showing an age-related increase in calcifications (p = 0.002), PH (p = 0.015) and decrease in macrophages (p = 0.005). In contrast, men only showed a decrease in collagen (p = 0.043).

Conclusions: Atherosclerotic iliofemoral plaques derived from men display more rupture-prone characteristics compared to women. Yet, this difference is attenuated with an increase in age, with older women having more rupture-prone characteristics compared to younger women.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.07.016DOI Listing
October 2020

Extracellular Vesicle cystatin c is associated with unstable angina in troponin negative patients with acute chest pain.

PLoS One 2020 5;15(8):e0237036. Epub 2020 Aug 5.

Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands.

Background: Despite the use of high-sensitive cardiac troponin there remains a group of high-sensitive cardiac troponin negative patients with unstable angina with a non-neglectable risk for future adverse cardiovascular events, emphasising the need for additional risk stratification. Plasma extracellular vesicles are small bilayer membrane vesicles known for their potential role as biomarker source. Their role in unstable angina remains unexplored. We investigate if extracellular vesicle proteins are associated with unstable angina in patients with chest pain and low high-sensitive cardiac troponin.

Methods: The MINERVA study included patients presenting with acute chest pain but no acute coronary syndrome. We performed an exploratory retrospective case-control analysis among 269 patients. Cases were defined as patients with low high-sensitive cardiac troponin and proven ischemia. Patients without ischemia were selected as controls. Blood samples were fractionated to analyse the EV proteins in three plasma-subfractions: TEX, HDL and LDL. Protein levels were quantified using electrochemiluminescence immunoassay.

Results: Lower levels of (adjusted) EV cystatin c in the TEX subfraction were associated with having unstable angina (OR 0.93 95% CI 0.88-0.99).

Conclusion: In patients with acute chest pain but low high-sensitive cardiac troponin, lower levels of plasma extracellular vesicle cystatin c are associated with having unstable angina. This finding is hypothesis generating only considering the small sample size and needs to be confirmed in larger cohort studies, but still identifies extracellular vesicle proteins as source for additional risk stratification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237036PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406038PMC
October 2020

Plasma extracellular vesicle proteins are associated with stress-induced myocardial ischemia in women presenting with chest pain.

Sci Rep 2020 07 23;10(1):12257. Epub 2020 Jul 23.

Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands.

Diagnosing stable ischemic heart disease (IHD) is challenging, especially in females. Currently, no blood test is available. Plasma extracellular vesicles (EV) are emerging as potential biomarker source. We therefore aimed to identify stress induced ischemia due to stable IHD with plasma extracellular vesicle protein levels in chest pain patients. We analyzed 450 patients suspected for stable IHD who were referred for Rb PET/CT in the outpatient clinic. Blood samples were collected before PET/CT and plasma EVs were isolated in 3 plasma subfractions named: TEX, HDL, LDL. In total 6 proteins were quantified in each of these subfractions using immuno-bead assays. CD14 and CystatinC protein levels were independent significant predictors of stress-induced ischemia in the LDL and the HDL subfraction and SerpinC1 and SerpinG1 protein levels in the HDL fraction. Subgroup-analysis on sex revealed that these associations were completely attributed to the associations in women. None of the significant EV proteins remained significant in men. Plasma EV proteins levels are associated with the presence of stable IHD in females presenting with chest pain. This finding, if confirmed in larger cohort studies could be a crucial step in improving diagnostic assessment of women with suspected IHD.
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http://dx.doi.org/10.1038/s41598-020-69297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378184PMC
July 2020

Sex differences in flow cytometry-based platelet reactivity in stable outpatients suspected of myocardial ischemia.

Res Pract Thromb Haemost 2020 Jul 15;4(5):879-885. Epub 2020 May 15.

Department of Cardiology University Medical Center Utrecht Utrecht The Netherlands.

Background: Antiplatelet therapy is the mainstay of secondary prevention of cardiovascular events. Studies suggest that women do not obtain equal therapeutic benefit from antiplatelet therapy compared with men. The link between sex differences in platelet biology and response to antiplatelet therapies is unclear. We therefore investigated the role of sex differences in platelet reactivity in a cohort of outpatients with chest pain, in response to treatment with antiplatelet agents.

Methods: Platelet reactivity was measured in 382 randomly selected patients participating in the Myocardial Ischemia Detection by Circulating Biomarkers (MYOMARKER) study, an observational cohort study of outpatients suspected of myocardial ischemia. In all patients, blood was collected during diagnostic workup, and platelet reactivity was assessed with a flow cytometry-based platelet activation test that quantifies both platelet degranulation (P-selectin expression) and platelet aggregation (fibrinogen binding to integrin αIIbβ3) in whole blood.

Results: Platelet reactivity was higher in women compared with men when activated with protease activating receptor 1-activating peptide SFLLRN (PAR1-AP) and adenosine 5'-phosphate (ADP), independent of age, basal activation status, estimated glomerular filtration rate < 60, platelet count, statin use, the use of P2Y12 inhibitors, or the use of aspirin. P2Y12 inhibitor use strongly reduced fibrinogen binding after stimulation with PAR1-AP, but only slightly reduced platelet P-selectin expression. Calculation of the relative inhibition in P2Y12 users indicated 62% inhibition of the response toward ADP. Stratified analysis showed that women (n = 14) using P2Y12 inhibitors showed less inhibition of fibrinogen binding after PAR1-AP stimulation than men (n = 38) using P2Y12 inhibitors.

Conclusions: These findings call for further study of differential effects of P2Y12 inhibitors in women with suspected myocardial ischemia.
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http://dx.doi.org/10.1002/rth2.12344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354392PMC
July 2020

Extracellular vesicle Cystatin C and CD14 are associated with both renal dysfunction and heart failure.

ESC Heart Fail 2020 10 10;7(5):2240-2249. Epub 2020 Jul 10.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Aims: Extracellular vesicles (EVs) are small double-membrane plasma vesicles that play key roles in cellular crosstalk and mechanisms such as inflammation. The role of EVs in combined organ failure such as cardiorenal syndrome has not been investigated. The aim of this study is to identify EV proteins that are associated with renal dysfunction, heart failure, and their combination in dyspnoeic patients.

Methods And Results: Blood samples were prospectively collected in 404 patients presenting with breathlessness at the emergency department at National University Hospital, Singapore. Renal dysfunction was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m . The presence of heart failure was independently adjudicated by two clinicians on the basis of the criteria of the European Society of Cardiology guidelines. Protein levels of SerpinG1, SerpinF2, Cystatin C, and CD14 were measured with a quantitative immune assay within three EV sub-fractions and in plasma and were tested for their associations with renal dysfunction, heart failure, and the concurrence of both conditions using multinomial regression analysis, thereby correcting for confounders such as age, gender, ethnicity, and co-morbidities. Renal dysfunction was found in 92 patients (23%), while heart failure was present in 141 (35%). In total, 58 patients (14%) were diagnosed with both renal dysfunction and heart failure. Regression analysis showed that Cystatin C was associated with renal dysfunction, heart failure, and their combination in all three EV sub-fractions and in plasma. CD14 was associated with both renal dysfunction and the combined renal dysfunction and heart failure in all EV sub-fractions, and with presence of heart failure in the high density lipoprotein sub-fraction. SerpinG1 and SerpinF2 were associated with heart failure in, respectively, two and one out of three EV sub-fractions and in plasma, but not with renal dysfunction.

Conclusions: We provide the first data showing that Cystatin C and CD14 in circulating EVs are associated with both renal dysfunction and heart failure in patients presenting with acute dyspnoea. This suggests that EV proteins may be involved in the combined organ failure of the cardiorenal syndrome and may represent possible targets for prevention or treatment.
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http://dx.doi.org/10.1002/ehf2.12699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524227PMC
October 2020

Immunomodulation of the NLRP3 Inflammasome in Atherosclerosis, Coronary Artery Disease, and Acute Myocardial Infarction.

J Cardiovasc Transl Res 2021 02 9;14(1):23-34. Epub 2020 Jul 9.

Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands.

Cardiovascular disease (CVD) remains the leading cause of mortality and morbidity worldwide. Atherosclerosis is responsible for the majority of cardiovascular disorders with inflammation as one of its driving processes. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, responsible for the release of the pro-inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18), has been studied extensively and showed to play a pivotal role in the progression of atherosclerosis, coronary artery disease (CAD), and myocardial ischemia reperfusion (I/R) injury. Both the NLRP3 inflammasome and its downstream cytokines, IL-1ß and IL-18, could therefore be promising targets in cardiovascular disease. This review summarizes the role of the NLRP3 inflammasome in atherosclerosis, CAD, and myocardial I/R injury. Furthermore, the current therapeutic approaches targeting the NLRP3 inflammasome and its downstream signaling cascade in atherosclerosis, CAD, and myocardial I/R injury are discussed.
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http://dx.doi.org/10.1007/s12265-020-10049-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892681PMC
February 2021

Family history and polygenic risk of cardiovascular disease: Independent factors associated with secondary cardiovascular events in patients undergoing carotid endarterectomy.

Atherosclerosis 2020 08 3;307:121-129. Epub 2020 May 3.

Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.04.013DOI Listing
August 2020

In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors.

Cell Rep 2020 May;31(8):107714

Cardiovascular & Metabolic Disorders Program, Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore; Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.celrep.2020.107714DOI Listing
May 2020

Cerebral Small Vessel Disease in Standard Pre-operative Imaging Reports Is Independently Associated with Increased Risk of Cardiovascular Death Following Carotid Endarterectomy.

Eur J Vasc Endovasc Surg 2020 Jun 21;59(6):872-880. Epub 2020 Apr 21.

Department of Vascular Surgery, Division of Surgical Specialties, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Objective: Cerebral white matter lesions (WMLs) and lacunar infarcts are surrogates of cerebral small vessel disease (SVD). WML severity as determined by trained radiologists predicts post-operative stroke or death in patients undergoing carotid endarterectomy (CEA). It is unknown whether routine pre-operative brain imaging reports as part of standard clinical practice also predict short and long term risk of stroke and death after CEA.

Methods: Consecutive patients from the Athero-Express biobank study that underwent CEA for symptomatic high degree stenosis between March 2002 and November 2014 were included. Pre-operative brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) reports were reviewed for reporting of SVD, defined as WMLs or any lacunar infarcts. The primary outcome was defined as any stroke or any cardiovascular death over three year follow up. The secondary outcome was defined as the 30 day peri-operative risk of stroke or cardiovascular death.

Results: A total of 1038 patients were included (34% women), of whom 659 (63.5%) had CT images and 379 (36.5%) MRI images available. Of all patients, 697 (67%) had SVD reported by radiologists. Patients with SVD had a higher three year risk of cardiovascular death than those without (6.5% vs. 2.1%, adjusted HR 2.52 [95% CI 1.12-5.67]; p = .026) but no association was observed for the three year risk of stroke (9.0% vs. 6.7%, for patients with SVD vs. those without, adjusted HR 1.24 [95% CI 0.76-2.02]; p = .395). No differences in 30 day peri-operative risk were observed for stroke (4.4% vs. 2.9%, for patients with vs. those without SVD; adjusted HR 1.49 [95% CI 0.73-3.05]; p = .28), and for the combined stroke/cardiovascular death risk (4.4% vs. 3.5%, adjusted HR 1.20 [95% CI 0.61-2.35]; p = .59).

Conclusion: Presence of SVD in pre-operative brain imaging reports can serve as a predictor for the three year risk of cardiovascular death in symptomatic patients undergoing CEA but does not predict peri-operative or long term risk of stroke.
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http://dx.doi.org/10.1016/j.ejvs.2020.02.004DOI Listing
June 2020

Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation.

Circ Res 2020 05 12;126(10):1346-1359. Epub 2020 Mar 12.

From the Experimental Vascular Medicine (J.G.S., L.A., J.C.B., M.V., A.K.G., J.K.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands.

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state.

Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism.

Methods And Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3-mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration.

Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208285PMC
May 2020

Co-prevalence of extracranial carotid aneurysms differs between European intracranial aneurysm cohorts.

PLoS One 2020 23;15(1):e0228041. Epub 2020 Jan 23.

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background And Purpose: Previously, we showed that co-prevalence of extracranial carotid artery aneurysms (ECAAs) in patients with intracranial aneurysms (IAs) was 2% in a Dutch cohort. In order to obtain more precise estimates and discover potential predictors of ECAA co-prevalence in the European population, we retrospectively compared differences and similarities of our Dutch cohort with a Finnish cohort using protocolled imaging of the cerebrovascular tree.

Methods: IA patients within the prospective database of the Kuopio University Hospital were eligible for this study (n = 1,118). Image analysis and hospital chart review were conducted.

Results: In total, 458 patients with complete carotid imaging conform protocol were analyzed. Twenty-four ECAAs in 21 patients were identified (4.6%, 95% CI 2.9-6.9), a higher co-prevalence than in the Dutch cohort (1.9%; 95% CI 1.0-3.3), prevalence odds ratio (POR) 2.45 (95% CI 1.19-5.03). In the Finnish cohort, 25% of all ECAAs were located around the carotid bifurcation, others in the internal carotid artery distally from the bifurcation. Independent predictors for ECAA co-prevalence were origin of country (POR 2.41, 95% CI 1.15-5.06) and male gender (POR 2.25, 95% CI 1.09-4.64).

Conclusion: The co-prevalence of ECAA in IA patients was twice as high in the Finnish compared to the Dutch IA cohort, with origin of country and male gender as independent predictors. Twenty-five percent of ECAAs would be missed, if the carotid bifurcation was not imaged. Therefore, we propose to always include imaging of the carotid bifurcation as the gold standard technique to identify ECAA in IA patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228041PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977743PMC
April 2020
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