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1.  Endovascular treatment of abdominal aortic aneurysms 
Nature reviews. Cardiology  2013;11(2):112-123.
Patients with abdominal aortic aneurysms (AAAs) are usually treated with endovascular aneurysm repair (EVAR), which has become the standard of care in many hospitals for patients with suitable anatomy. Clinical evidence indicates that EVAR is associated with superior perioperative outcomes and similar long-term survival compared with open repair. Since the randomized, controlled trials that provided this evidence were conducted, however, the stent graft technology for infrarenal AAA has been further developed. Improvements include profile downsizing, optimization of sealing and fixation, and the use of low porosity fabrics. In addition, imaging techniques have improved, enabling better preoperative planning, stent graft placement, and postoperative surveillance. Also in the past few years, fenestrated and branched stent grafts have increasingly been used to manage anatomically challenging aneurysms, and experiments with off-label use of stent grafts have been performed to treat patients deemed unfit or unsuitable for other treatment strategies. Overall, the indications for endovascular management of AAA are expanding to include increasingly complex and anatomically challenging aneurysms. Ongoing studies and optimization of imaging, in addition to technological refinement of stent grafts, will hopefully continue to broaden the utilization of EVAR.
PMCID: PMC4128641  PMID: 24343568
2.  Histological Analysis of Extracranial Carotid Artery Aneurysms 
PLoS ONE  2015;10(1):e0117915.
Extracranial carotid artery aneurysms (ECAA) are rare but may be accompanied with significant morbidity. Previous studies mostly focused on diagnostic imaging and treatment. In contrast, the pathophysiological mechanisms and natural course of ECAA are largely unknown. Understanding the pathophysiological background may add to prediction of risk for adverse outcome and need for surgical exclusion. The aim of this study was to investigate the histopathological characteristics of ECAA in patients who underwent complete surgical ECAA resection.
Material and Methods
From March 2004 till June 2013, 13 patients were treated with open ECAA repair. During surgery the aneurysm sac was resected and processed for standardized histological analysis. Sections were stained with routine hematoxylin and eosin and special stains to detect elastin, collagen, different types of inflammatory cells, vascular smooth muscle cells and endothelial cells.
Histopathological characterization revealed two distinct categories: dissection (abrupt interruption of the media; n = 3) and degeneration (general loss of elastin fibers in the media; n = 10). In the degenerative samples the elastin fibers in the media were fragmented and were partly absent. Inflammatory cells were observed in the vessel wall of the aneurysms.
Histological analysis in this small sample size revealed dissection and degeneration as the two distinct underlying mechanisms in ECAA formation.
PMCID: PMC4312019  PMID: 25635813
3.  Symptomatic carotid atherosclerotic disease: correlations between plaque composition and ipsilateral stroke risk 
For symptomatic patients with carotid artery stenosis the risk-benefit for surgical intervention may vary among patient groups. Various modalities of plaque imaging have been promoted as potential tools for additional risk stratification, particularly in patients with moderate stenosis. However, it remains uncertain to what extent carotid plaque components predict risk of future ipsilateral ischaemic stroke.
In two large atherosclerotic carotid plaque biobank studies, we related histological characteristics of 1640 carotid plaques with a validated risk model for the prediction of individual 1- and 5-year stroke risk.
No significant heterogeneity between the studies was found. Predicted 5-year stroke risk (top versus bottom quartile) was related to plaque thrombus (OR=1.42, 95%CI 1.11-1.89, p=0.02), fibrous content (0.65, 0.49-0.87, p=0.004), macrophage infiltration (1.41, 1.05-1.90, p=0.02), high micro-vessel density (1.49, 1.05-2.11, p=0.03), and overall plaque instability (1.40, 1.05-1.87,p=0.02). This association was not observed for cap thickness, calcification, intra-plaque haemorrhage, or lymphocyte infiltration. Plaques removed within 30-days of most recent symptomatic event were most strongly correlated with predicted stroke risk.
Features of ‘the vulnerable carotid plaque’ including plaque thrombus, low fibrous content, macrophage infiltration and microvessel density correlate with predicted stroke risk. This study provides a basis for plaque imaging studies focused on stroke risk stratification.
PMCID: PMC4285579  PMID: 25477221
Acute Stroke; Carotid atherosclerotic plaque; Risk Prediction
4.  The impact of the present on admission indicator on the accuracy of administrative data for carotid endarterectomy and stenting 
Journal of vascular surgery  2013;59(1):10.1016/j.jvs.2013.07.006.
Administrative data are often hampered by coding errors, absent data, and the difficulty of distinguishing pre-existing conditions from perioperative complications. We evaluated whether the introduction of the present on admission (POA) indicator improved outcome analysis of carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS) using administrative data.
State inpatient databases from California (2005-2008), New York (2008), and New Jersey (2008) were used to identify patients undergoing CAS and CEA. We first analyzed morbidity data without the POA indicator, using Inter-national Classification of Diseases, Ninth Revision complication codes (eg, 997.02, iatrogenic cerebrovascular infarction or hemorrhage, postoperative stroke) and diagnosis codes (eg, 433.11, occlusion and stenosis of the carotid artery with cerebral infarction). Then, we applied the POA indicator to both diagnosis and complication codes and calculated the proportion of events that were labeled POA. Symptom status and perioperative stroke rate were compared using these coding approaches.
We identified 21,639 patients who underwent CEA and 3688 patients who underwent CAS. Without the POA indicator, the complication code for stroke indicated a postoperative stroke rate of 1.4% for CEA and 2.4% for CAS. After applying the POA indicator, 54% (CEA) and 62% (CAS) of these strokes were labeled POA. These POA strokes were either preoperative or intraoperative events. Proportion of symptomatic patients ranged from 7% to 16% for CEA and from 5% to 22% for CAS. Perioperative stroke rate was the lowest in the POA method (1.1% CEA, 1.8% CAS) compared with two other methods without POA information (1.4% and 9.5% CEA and 2.4% and 16.4% CAS). Kappa indicated a poor (0.2) to fair (0.7) agreement between these approaches.
Administrative data has known limitations for assignment of symptom status and nonfatal perioperative outcomes. Given the uncertain timing of POA events as preoperative vs intraoperative and its apparent underestimation of the perioperative stroke rate, the use of administrative data even with the POA indicator for symptom status and non-fatal outcomes after CEA and CAS is hazardous.
PMCID: PMC3874266  PMID: 23993438
5.  Carotid Stenting versus Endarterectomy in Patients undergoing Re-intervention after Prior Carotid Endarterectomy 
Journal of vascular surgery  2013;59(1):10.1016/j.jvs.2013.06.070.
Outcomes for patients undergoing intervention for restenosis after prior ipsilateral carotid endarterectomy (CEA) in the era of carotid stenting (CAS) are unclear. We compared perioperative results and durability of CAS versus CEA in patients with symptomatic or asymptomatic restenosis after prior CEA and investigated the risk of re-intervention compared to primary procedures.
Patients undergoing CAS and CEA for restenosis between January 2003 and March 2012 were identified within the Vascular Study Group of New England (VSGNE) database.Endpoints included any stroke, death or myocardial infarction (MI) within 30 days, cranial nerve injury at discharge and restenosis ≥70% at 1-year follow-up. Multivariable logistic regression was done to identify whether prior ipsilateral CEA was an independent predictor for adverse outcome.
Out of 9305 CEA procedures, 212 patients (2.3%) underwent redo-CEA (36% symptomatic). Of 663 CAS procedures, 220 patients (33%) underwent CAS after prior ipsilateral CEA (31% symptomatic). Demographics of patients undergoing redo-CEA were comparable to patients undergoing CAS after prior CEA. Stroke/death/MI rates were statistically similar between redo-CEA vs CAS after prior CEA in both asymptomatic (4.4% vs 3.3%, P=0.8) and symptomatic patients (6.6% vs 5.8%, P=1.0). No significant difference in restenosis ≥70% was identified between redo-CEA and CAS after prior CEA (5.2% vs. 3.0%, P = 0.5). Redo-CEA vs primary CEA had increased stroke/death/MI rate in both symptomatic (6.6% vs 2.3%, P=0.05) and asymptomatic patients 4.4% vs 1.7%, P=0.03). Prior ipsilateral CEA was an independent predictor for stroke/death/MI among all patients undergoing CEA (OR 2.1, 95% CI 1.3 – 3.5). No difference in cranial nerve injury was identified between redo-CEA and primary CEA (5.2% vs 4.7%, P=0.8).
In the VSGNE, CEA and CAS showed statistically equivalent outcomes in asymptomatic and symptomatic patients treated for restenosis after prior ipsilateral CEA.However, regardless of symptom status, the risk of re-intervention was increased compared to patients undergoing primary CEA.
PMCID: PMC3852203  PMID: 23972527
6.  In vivo measurements of regional hemoglobin oxygen saturation values and limb-to-arm ratios of near-infrared spectroscopy for tissue oxygenation monitoring of lower extremities in healthy subjects 
Near-infrared spectroscopy (NIRS) is a noninvasive technique that allows monitoring of regional hemoglobin oxygen saturation (rSO2) values and might have a role in the diagnosis of peripheral arterial disease. We assessed the reproducibility and inter-subject variability of rSO2 values and rSO2 limb-to-arm ratios (LARs) in lower extremities of healthy subjects.
The rSO2 values and rSO2 LARs were calculated in eight healthy subjects without peripheral arterial disease. The rSO2 values were measured at rest at six fixed spots at each lower limb and a reference spot at each upper arm. NIRS provided the rSO2 values without involvement of any other processing technique. After measurements were completed, rSO2 LARs were calculated by dividing the rSO2 value of a lower extremity spot by the rSO2 value of the arm. Measurements were performed twice on 1 day and repeated on 4 different days.
Mean coefficients of variation of measurements of rSO2 values and rSO2 LARs at the same spot in the same subject were respectively less than 6% and 8% for every measurement spot over time. Coefficients of variation of measurements at the same spot between different subjects were less than 15% and 19% for every measurement spot respectively.
NIRS is an easily applicable, noninvasive tool for measurement of tissue oxygenation of lower extremities in healthy subjects. The reproducibility of rSO2 values and rSO2 LARs at the same measurement spot in the same subject is good.
PMCID: PMC4284046  PMID: 25565906
NIRS; rSO2; lower extremities; tissue oxygenation
7.  High Reproducibility of Histological Characterization by Whole Virtual Slide Quantification; An Example Using Carotid Plaque Specimens 
PLoS ONE  2014;9(12):e115907.
Tissue biobanks are an important source for discovery and validation studies aiming for new proteins that are causally related with disease development. There is an increasing demand for accurate and reproducible histological characterization, especially for subsequent analysis and interpretation of data in association studies. We assessed reproducibility of one semiquantative and two quantitative methods for histological tissue characterization. We introduce a new automated method for whole digital slide quantification. Carotid atherosclerotic plaques were used to test reproducibility.
50 atherosclerotic plaques that were obtained during carotid endarterectomy were analysed. For the semiquantitative analysis, 6 different plaque characteristics were scored in categories by two independent observers, and Cohen's κ was used to test intra- and interobserver reproducibility. The computer-aided method (assessed by two independent observers) and automated method were tested on CD68 (for macrophages) and α smooth muscle actin (for smooth muscle cells) stainings. Agreement for these two methods (done on a continuous scale) was assessed by intraclass correlation coefficients (ICCs).
For the semiquantitative analysis, κ values ranged from 0.55 to 0.69 for interobserver variability, and were slightly higher for intraobserver reproducibility in both observers. The computer-aided method yielded intra- and interobserver ICCs between 0.6 and 0.9. The new automated method performed most optimal regarding reproducibility, with ICCs ranging from 0.92 to 0.97.
The analysis of performance of three methods for histological slide characterization on carotid atherosclerotic plaques showed high precision and agreement in repeated measurements for the automated method for whole digital slide quantification. We suggest that this method can fulfill the need for reproducible histological quantification.
PMCID: PMC4277457  PMID: 25541691
8.  SlideToolkit: An Assistive Toolset for the Histological Quantification of Whole Slide Images 
PLoS ONE  2014;9(11):e110289.
The demand for accurate and reproducible phenotyping of a disease trait increases with the rising number of biobanks and genome wide association studies. Detailed analysis of histology is a powerful way of phenotyping human tissues. Nonetheless, purely visual assessment of histological slides is time-consuming and liable to sampling variation and optical illusions and thereby observer variation, and external validation may be cumbersome. Therefore, within our own biobank, computerized quantification of digitized histological slides is often preferred as a more precise and reproducible, and sometimes more sensitive approach. Relatively few free toolkits are, however, available for fully digitized microscopic slides, usually known as whole slides images. In order to comply with this need, we developed the slideToolkit as a fast method to handle large quantities of low contrast whole slides images using advanced cell detecting algorithms. The slideToolkit has been developed for modern personal computers and high-performance clusters (HPCs) and is available as an open-source project on We here illustrate the power of slideToolkit by a repeated measurement of 303 digital slides containing CD3 stained (DAB) abdominal aortic aneurysm tissue from a tissue biobank. Our workflow consists of four consecutive steps. In the first step (acquisition), whole slide images are collected and converted to TIFF files. In the second step (preparation), files are organized. The third step (tiles), creates multiple manageable tiles to count. In the fourth step (analysis), tissue is analyzed and results are stored in a data set. Using this method, two consecutive measurements of 303 slides showed an intraclass correlation of 0.99. In conclusion, slideToolkit provides a free, powerful and versatile collection of tools for automated feature analysis of whole slide images to create reproducible and meaningful phenotypic data sets.
PMCID: PMC4220929  PMID: 25372389
9.  Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability 
Mediators of Inflammation  2014;2014:276457.
Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14hi  TIMP-3lo rabbit foam cells are more invasive and more prone to apoptosis than MMP-14lo  TIMP-3hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.
PMCID: PMC4163186  PMID: 25301980
10.  Increased Platelet Reactivity Is Associated with Circulating Platelet-Monocyte Complexes and Macrophages in Human Atherosclerotic Plaques 
PLoS ONE  2014;9(8):e105019.
Platelet reactivity, platelet binding to monocytes and monocyte infiltration play a detrimental role in atherosclerotic plaque progression. We investigated whether platelet reactivity was associated with levels of circulating platelet-monocyte complexes (PMCs) and macrophages in human atherosclerotic carotid plaques.
Platelet reactivity was determined by measuring platelet P-selectin expression after platelet stimulation with increasing concentrations of adenosine diphosphate (ADP), in two independent cohorts: the Circulating Cells cohort (n = 244) and the Athero-Express cohort (n = 91). Levels of PMCs were assessed by flow cytometry in blood samples of patients who were scheduled for percutaneous coronary intervention (Circulating Cells cohort). Monocyte infiltration was semi-quantitatively determined by histological examination of atherosclerotic carotid plaques collected during carotid endarterectomy (Athero-Express cohort).
We found increased platelet reactivity in patients with high PMCs as compared to patients with low PMCs (median (interquartile range): 4153 (1585–11267) area under the curve (AUC) vs. 9633 (3580–21565) AUC, P<0.001). Also, we observed increased platelet reactivity in patients with high macrophage levels in atherosclerotic plaques as compared to patients with low macrophage levels in atherosclerotic plaques (mean±SD; 8969±3485 AUC vs. 7020±3442 AUC, P = 0.02). All associations remained significant after adjustment for age, sex and use of drugs against platelet activation.
Platelet reactivity towards ADP is associated with levels of PMCs and macrophages in human atherosclerotic carotid plaques.
PMCID: PMC4133361  PMID: 25122139
11.  Importance of dynamic aortic evaluation in planning TEVAR 
Annals of Cardiothoracic Surgery  2014;3(3):300-306.
Dynamic aortic evaluation in planning thoracic endovascular aortic repair (TEVAR) is important to provide optimal stent graft sizing. Static imaging protocols do not consider normal aortic dynamics and may lead to stent graft to aorta mismatch, causing stent graft related complications, such as type I endoleak and stent graft migration. Dynamic imaging can assist in accurate stent graft selection and sizing preoperatively, and evaluate stent graft performance during follow-up. To create new imaging technologies, integration of knowledge between diverse scientific fields is essential (i.e., engineering, informatics and medicine). Different dynamic imaging modalities, such as electrocardiographic-gated computed tomography angiography (ECG-gated CTA) and four-dimensional phase-contrast MRI (4D PC-MRI), are progressively investigated and implemented into clinical practice as important instruments in preoperative planning for TEVAR. In time, further application of dynamic imaging tools for preoperative screening and follow-up after TEVAR might lead to better outcomes for patients. The advances in dynamic imaging for evaluation of the thoracic aorta using new imaging modalities and their future perspectives are addressed in this manuscript.
PMCID: PMC4052412  PMID: 24967170
Dynamic imaging; thoracic endovascular aortic repair (TEVAR); type B aortic dissection; thoracic aortic disease; computational fluid dynamics (CFD)
13.  Predicting aortic enlargement in type B aortic dissection 
Annals of Cardiothoracic Surgery  2014;3(3):285-291.
Patients with uncomplicated acute type B aortic dissection (ABAD) can generally be treated with conservative medical management. However, these patients may develop aortic enlargement during follow-up, with the risk of rupture. Several predictors have been studied in recent years to identify ABAD patients at high risk of aortic enlargement, who may benefit from early surgical or endovascular intervention. This study reviewed and summarized the current available literature on prognostic variables related to aortic enlargement during follow-up in uncomplicated ABAD patients. It revealed multiple factors affecting aortic expansion including demographic, clinical, pharmacologic and radiologic variables. Such predictors may be used to identify those ABAD patients at higher risk for aortic enlargement who may benefit from closer radiologic surveillance or early endovascular intervention. This approach deserves even more consideration because a significant number of patients develop aneurysmal degeneration along the dissected segments during follow-up, and may lose the opportunity for endovascular treatment if not identified at an early stage.
PMCID: PMC4052419  PMID: 24967168
Aortic dissection; aneurysm; complications; rupture; intervention
14.  Circulating Immunoglobulins Are Not Associated with Intraplaque Mast Cell Number and Other Vulnerable Plaque Characteristics in Patients with Carotid Artery Stenosis 
PLoS ONE  2014;9(2):e88984.
Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data.
Methods and Results
OxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels.
In patients suffering from carotid artery disease, total IgE, total IgG and oxLDL-IgG levels do not associate with plaque mast cell numbers or other vulnerable plaque histopathological characteristics. This study thus does not provide evidence that the immunoglobulins tested in our cohort play a role in intraplaque mast cell activation or grade of atherosclerosis.
PMCID: PMC3931690  PMID: 24586471
15.  Leukotriene B4 Levels in Human Atherosclerotic Plaques and Abdominal Aortic Aneurysms 
PLoS ONE  2014;9(1):e86522.
Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome.
Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls.
LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017).
LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions.
PMCID: PMC3903534  PMID: 24475136
17.  Phenylephrine versus ephedrine on cerebral perfusion during carotid endarterectomy (PEPPER): study protocol for a randomized controlled trial 
Trials  2013;14:43.
Intraoperative arterial hypotension can lead to severe complications in patients undergoing carotid endarterectomy, in particular if cerebral auto-regulation is impaired. Short-acting agents, such as phenylephrine or ephedrine, commonly used to correct intra-operative hypotension, have different hemodynamic effects. Recently, it was reported that, in healthy anesthetized subjects with intact cerebral auto-regulation, frontal lobe cerebral tissue oxygenation declined after phenylephrine bolus administration, while it was preserved after ephedrine use (Br J Anaesth 107:209–217, 2011; Neurocrit Care 12:17–23, 2010). However, the effect of both agents in patients undergoing carotid endarterectomy is unknown. The aim of this study is to assess the effect of two routinely used vasopressors (phenylephrine and ephedrine) on the cerebral hemodynamics during carotid endarterectomy.
Patients undergoing carotid endarterectomy will be prospectively included and randomized for correction of intraoperative hypotension with either phenylephrine (50 to 100 μg) or ephedrine (5 to 10 mg). If hypotension persists for more than five minutes after treatment, the patient will be classified as a non-responder and escape medication as preferred by the anesthesiologist will be administered. Changes in cerebral hemodynamics will be quantified by changes in transcranial Doppler-derived middle cerebral artery blood velocity and near infra-red spectroscopy-derived frontal lobe cerebral tissue oxygenation, when intra-operative hypotension is treated with phenylephrine or ephedrine in patients who undergo carotid endarterectomy with or without an adequate functioning cerebral auto-regulation.
To quantify whether the intra-operative cerebral auto-regulation is impaired or not, a decrease in breathing frequency from the normal 12 breaths per minute to 6 breaths per minute for an episode of three minutes will be performed.
Phenylephrine and ephedrine are two of the most commonly used short-acting agents to increase blood pressure in clinical anesthesiologic practice. Monitoring of middle cerebral artery blood velocity with transcranial Doppler and frontal lobe cerebral tissue oxygenation with near infra-red spectroscopy are part of the standard of care. Furthermore, there are no reports that the three-minute modification in breathing frequency described in the “intervention”-section is harmful. Therefore, the risks for participating patients are negligible and the burden minimal.
Trial registration
Clinical NCT01451294
PMCID: PMC3598872  PMID: 23410186
Carotid endarterectomy; Cerebral oxygenation; Intraoperative hypotension; Phenylephrine; Ephedrine
18.  Bone Marrow Alterations and Lower Endothelial Progenitor Cell Numbers in Critical Limb Ischemia Patients 
PLoS ONE  2013;8(1):e55592.
Critical limb ischemia (CLI) is characterized by lower extremity artery obstruction and a largely unexplained impaired ischemic neovascularization response. Bone marrow (BM) derived endothelial progenitor cells (EPC) contribute to neovascularization. We hypothesize that reduced levels and function of circulating progenitor cells and alterations in the BM contribute to impaired neovascularization in CLI.
Levels of primitive (CD34+ and CD133+) progenitors and CD34+KDR+ EPC were analyzed using flow cytometry in blood and BM from 101 CLI patients in the JUVENTAS-trial (NCT00371371) and healthy controls. Blood levels of markers for endothelial injury (sE-selectin, sICAM-1, sVCAM-1, and thrombomodulin), and progenitor cell mobilizing and inflammatory factors were assessed by conventional and multiplex ELISA. BM levels and activity of the EPC mobilizing protease MMP-9 were assessed by ELISA and zymography. Circulating angiogenic cells (CAC) were cultured and their paracrine function was assessed.
Endothelial injury markers were higher in CLI (P<0.01). CLI patients had higher levels of VEGF, SDF-1α, SCF, G-CSF (P<0.05) and of IL-6, IL-8 and IP-10 (P<0.05). Circulating EPC and BM CD34+ cells (P<0.05), lymphocytic expression of CXCR4 and CD26 in BM (P<0.05), and BM levels and activity of MMP-9 (P<0.01) were lower in CLI. Multivariate regression analysis showed an inverse association between IL-6 and BM CD34+ cell levels (P = 0.007). CAC from CLI patients had reduced paracrine function (P<0.0001).
CLI patients have reduced levels of circulating EPC, despite profound endothelial injury and an EPC mobilizing response. Moreover, CLI patients have lower BM CD34+-cell levels, which were inversely associated with the inflammatory marker IL-6, and lower BM MMP-9 levels and activity. The results of this study suggest that inflammation-induced BM exhaustion and a disturbed progenitor cell mobilization response due to reduced levels and activity of MMP-9 in the BM and alterations in the SDF-1α/CXCR4 interaction contribute to the attenuated neovascularization in CLI patients.
PMCID: PMC3561321  PMID: 23383236
19.  Carotid Atherosclerotic Plaque Matrix Metalloproteinase-12–Positive Macrophage Subpopulation Predicts Adverse Outcome After Endarterectomy 
Matrix metalloproteinase-12 (MMP-12) promotes atherosclerosis in animal models. MMP-12 is expressed in only a subset of foam-cell macrophages (FCMs) in human plaques. We investigated whether the prevalence of this MMP-12–expressing subpopulation is a prognostic indicator of adverse outcome in patients after carotid endarterectomy (CEA).
Methods and Results
Serial sections of culprit lesions from 236 patients who underwent CEA and had undergone 3 years of clinical follow-up were stained immunocytochemically for MMP-12 and for CD68, and the MMP-12/CD68 ratio was used to quantify the MMP-12–expressing subpopulation. A high MMP-12/CD68 ratio correlated with a high content of lipid and total macrophages and a low content of vascular smooth muscle cells, as well as with MMP-8 (R=0.211, P=0.001), MMP-9 (R=0.251, P<0.001), and cleaved caspase-3 (R=0.142, P=0.036) activity measured in a neighboring segment. Dual immunohistochemical examination confirmed the location of MMP-12 in a subpopulation of MMP-8– and MMP-9–positive FCMs, whereas all apoptotic FCMs were MMP-12 positive. Patients who yielded plaques within the highest quartile compared with the lowest quartile of MMP-12/CD68 ratio had a 2.4-fold (hazard ratio, 2.4; 95% CI, 1.1- to 5.1-fold; adjusted P=0.027) increased risk of major adverse cardiovascular event and a 3.4-fold (3.4; 1.2- to 9.6-fold, P=0.024) increased risk for stroke.
The prevalence of an MMP-12–positive subset of FCMs is a prognostic marker for adverse clinical outcome after CEA.
PMCID: PMC3540663  PMID: 23316311
atherosclerosis; macrophages; MMP-12; outcome
20.  10-years experience with the Athero-Express study 
From cross-sectional studies we have learned that composition of atherosclerotic plaques differs, and that thrombosis on top of an inflammatory lipid rich plaque is a frequently observed pathological substrate of a cerebral or coronary event. Atherosclerosis develops over decades which hampers human studies on the natural history of the diseases. Therefore, the predictive value of atherosclerotic plaque composition for development of an adverse cardiovascular event is not clear. The elucidation of markers for atherosclerotic disease progression is essential to identify patients at high risk for vascular events, to refine treatment allocation and to serve as surrogate endpoints in pharmaceutical studies. The Athero-Express study is a large scale vascular biobank that collects vascular specimens including a clinical follow-up. This study design allows the prospective study of the local atherosclerotic plaque in relation to future local and systemic vascular outcome. The readout of the study can be assessed in terms of histology as well as RNA or protein level. This paper aims to give an overview of the results of the Athero-Express biobank since its initiation in 2002. We will also discuss the clinical implications and future directions in biobanking research.
PMCID: PMC3839168  PMID: 24282698
Athero-Express study; atherosclerosis; thrombosis; biobanking research
21.  Is Age of 80 Years a Threshold for Carotid Revascularization? 
Current Cardiology Reviews  2011;7(1):15-21.
Background and purpose:
Carotid Angioplasty and Stenting (CAS) has emerged as an alternative to Carotid Endarterectomy (CEA) in treatment of carotid stenotic disease. With increasing life expectancy clinicians are more often confronted with patients of higher age. Octogenarians were often excluded from randomized trials comparing CAS to CEA because they were considered high-risk for revascularization. Conflicting results on the peri-procedural outcome of carotid revascularization in these patients have been reported. In order to objectively evaluate whether age above 80 years should be an upper limit for indicating carotid revascularization we systematically reviewed the currently available literature.
Literature was systematically reviewed between January 2000 and June 2010 using Pubmed and Embase, to identify all relevant studies concerning CAS and CEA in octogenarians. Inclusion criteria were 1) reporting outcome on either CEA or CAS; and 2) data subanalysis on treatment outcome by age. The 30-day Major Adverse Event (MAE) rate (disabling stroke, myocardial infarction or death) was extracted as well as demographic features of included patients.
After exclusion of 23 articles, 46 studies were included in this review, 18 involving CAS and 28 involving CEA. A total of 2.963 CAS patients and 14.365 CEA patients with an age >80 years were reviewed. The MAE rate was 6.9% (range 1.6 - 24.0%) following CAS and 4.2% (range 0 – 8.8%) following CEA.
A separate analysis in this review included the results of one major registry 140.376 patients) analyzing CEA in octogenarians only reporting on 30-day mortality and not on neurological or cardiac adverse events. When these data were included the MAE following CEA is 2.4% (range 0 – 8.8%)
MAE rates after CEA in octogenarians are comparable with the results of large randomized trials in younger patients. Higher complication rates are described for CAS in octogenarians. In general, age > 80 years is not an absolute cut off point to exclude patients from carotid surgery. In our opinion, CEA should remain the golden standard in the treatment of significant carotid artery stenoses, even in the very elderly.
PMCID: PMC3131710  PMID: 22294970
Carotid revascularization; angioplasty; stenting; octogenarians; demographic features; revascularization.
22.  RANTES/CCL5 and Risk for Coronary Events: Results from the MONICA/KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM Studies 
PLoS ONE  2011;6(12):e25734.
The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.
Methods and Findings
We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75–1.42] and 1.11 [0.81–1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).
High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.
PMCID: PMC3232218  PMID: 22162987
23.  Atherosclerotic Plaque Stability Is Affected by the Chemokine CXCL10 in Both Mice and Humans 
Background. The chemokine CXCL10 is specifically upregulated during experimental development of plaque with an unstable phenotype. In this study we evaluated the functional consequences of these findings in mice and humans. Methods and Results. In ApoE−/− mice, we induced unstable plaque with using a flow-altering device around the carotid artery. From week 1 to 4, mice were injected with a neutralizing CXCL10 antibody. After 9 weeks, CXCL10 inhibition resulted in a more stable plaque phenotype: collagen increased by 58% (P = 0.002), smooth muscle cell content increased 2-fold (P = 0.03), while macrophage MHC class II expression decreased by 50% (P = 0.005). Also, the size of necrotic cores decreased by 41% (P = 0.01). In 106 human carotid endarterectomy specimens we found that increasing concentrations of CXCL10 strongly associate with an increase in atheromatous plaque phenotype (ANOVA, P = 0.003), with high macrophage, low smooth muscle cell, and low collagen content. Conclusions. In the present study we showed that CXCL10 is associated with the development of vulnerable plaque in human and mice. We conclude that CXCL10 might provide a new lead towards plaque-stabilizing therapy.
PMCID: PMC3227498  PMID: 22164344
24.  An animal paired crossover ePTFE arteriovenous graft model 
Previously, we developed a porcine model for Arterio Venous Graft (AVG) failure to allow assessment of new access strategies. This model was limited concerning graft length. In the present technical report, we describe a modification of our model allowing the assessment of long AVGs.
In 4 pigs, AVGs of 15 cm length were created bilaterally in a cross-over fashion between the carotid artery and the contralateral jugular vein. Two days (2 pigs) and two weeks (2 pigs) after AV shunting, graft patency was evaluated by angiography, showing all four grafts to be patent, with no sign of angiographic or macroscopic narrowing at the anastomoses sites.
In this modified pig AVG failure model, implantation of a bilateral cross-over long AVG is a feasible approach. The present model offers a suitable tool to study local interventions or compare various long graft designs aimed at improvement of AVG patency.
PMCID: PMC3006397  PMID: 21110903
25.  Predictors of adverse events after endovascular abdominal aortic aneurysm repair: A meta-analysis of case reports 
Endovascular abdominal aortic aneurysm repair is a life-saving intervention. Nevertheless, complications have a major impact. We review the evidence from case reports for risk factors of complications after endovascular abdominal aortic aneurysm repair.
Case presentation
We selected case reports from PubMed reporting original data on adverse events after endovascular abdominal aortic aneurysm repair. Extracted risk factors were: age, sex, aneurysm diameter, comorbidities, re-interventions, at least one follow-up visit being missed or refusal of a re-intervention by the patient. Extracted outcomes were: death, rupture and (non-)device-related complications.
In total 113 relevant articles were selected. These reported on 173 patients. A fatal outcome was reported in 15% (N = 26) of which 50% came after an aneurysm rupture (N = 13). Non-fatal aneurysm rupture occurred in 15% (N = 25). Endoleaks were reported in 52% of the patients (N = 90). In half of the patients with a rupture no prior endoleak was discovered during follow-up. In 83% of the patients one or more re-interventions were performed (N = 143). Mortality was higher among women (risk ratio 2.9; 95% confidence interval 1.4 to 6.0), while the presence of comorbidities was strongly associated with both ruptures (risk ratio 1.6; 95% confidence interval 0.9 to 2.9) and mortality (risk ratio 2.1; 95% confidence interval 1.0 to 4.7). Missing one or more follow-up visits (≥1) or refusal of a re-intervention by the patient was strongly related to both ruptures (risk ratio 4.7; 95% confidence interval 3.1 to 7.0) and mortality (risk ratio 3.8; 95% confidence interval 1.7 to 8.3).
Female gender, the presence of comorbidities and at least one follow-up visit being missed or refusal of a re-intervention by the patient appear to increase the risk for mortality after endovascular abdominal aortic aneurysm repair. Larger aneurysm diameter, higher age and multimorbidity at the time of surgery appear to increase the risk for rupture and other complications after endovascular abdominal aortic aneurysm repair. These risk factors deserve further attention in future studies.
PMCID: PMC2567336  PMID: 23158207

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