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Biomedical subjects

G Pasterkamp

Publications and source records attributed to G Pasterkamp.

At least 19 recordsLinked to original sources

The carotid atherosclerotic plaque and microembolisation during carotid stenting.

Microembolisation is an important issue in carotid artery stenting. During different phases in the stenting process, numerous emboli are dislodged from the atherosclerotic plaque. Embolisation can be measured as microembolic signals detected by transcranial Doppler (TCD) monitoring during the procedure or as new ischemic areas determined by magnetic resonance imaging. This article gives an overview of the principles of emboli detection methods, their clinical relevance, and risk factors associated with microembolisation. In addition, protection devices are discussed in relation to embolisation. Although they potentially protect the brain, particularly filter devices increase the amount of TCD-detected cerebral microemboli. Special attention is paid to the carotid artery plaque, which is subject to ongoing research that may yield important implications for clinical practice in the near future. Evidence is accumulating that unstable, vulnerable plaques are associated with increased microembolisation during carotid interventions. This knowledge of the vulnerable plaque can be translated to the clinical setting by plaque imaging. A first approach has been made by duplex imaging of carotid plaque morphology. More advanced methods such as molecular magnetic resonance imaging and optical coherence tomography could aid in optimal treatment selection based on plaque characteristics thus reducing microembolisation and associated cerebral adverse events.

Angioplasty↗

Carotid atherosclerotic plaque characteristics are associated with microembolization during carotid endarterectomy and procedural outcome.

BACKGROUND AND PURPOSE: During carotid endarterectomy (CEA), microemboli may occur, resulting in perioperative adverse cerebral events. The objective of the present study was to investigate the relation between atherosclerotic plaque characteristics and the occurrence of microemboli or adverse events during CEA. METHODS: Patients (n=200, 205 procedures) eligible for CEA were monitored by perioperative transcranial Doppler. The following phases were discriminated during CEA: dissection, shunting, release of the clamp, and wound closure. Each carotid plaque was stained for collagen, macrophages, smooth muscle cells, hematoxylin, and elastin. Semiquantitative analyses were performed on all stainings. Plaques were categorized into 3 groups based on overall appearance (fibrous, fibroatheromatous, or atheromatous). RESULTS: Fibrous plaques were associated with the occurrence of more microemboli during clamp release and wound closure compared with atheromatous plaques (P=0.04 and P=0.02, respectively). Transient ischemic attacks and minor stroke occurred in 5 of 205 (2.4%) and 6 of 205 (2.9%) patients, respectively. Adverse cerebral outcome was significantly related to the number of microembolic events during dissection (P=0.003) but not during shunting, clamp release, or wound closure. More cerebrovascular adverse events occurred in patients with atheromatous plaques (7/69) compared with patients with fibrous or fibroatheromatous plaques (4/138) (P=0.04). CONCLUSIONS: Intraoperatively, a higher number of microemboli were associated with the presence of a fibrous but not an atheromatous plaque. However, atheromatous plaques were more prevalent in patients with subsequent immediate adverse events. In addition, specifically the number of microemboli detected during the dissection phase were related to immediate adverse events.

Adult↗

Quantitative optical coherence tomography of arterial wall components.

Optical coherence tomography (OCT) can be used to visualize the arterial wall and atherosclerotic plaques with high resolution. In this study, we verified the application of OCT to the quantitative analysis of plaque structural dimensions and optical attenuation coefficients of the components. We assessed the effect of balloon dilation on the OCT signal from the medial layer of porcine carotid artery ex vivo. Imaging of human autopsy samples was performed from the luminal side with a high (3.5 microm axial and 7 microm lateral) resolution OCT system (approximately 800 nm) or a regular (15-20 microm axial and 20 microm lateral resolution) OCT system (approximately 1,300 nm). For each sample, dimensions were measured by histomorphometry and OCT, and the optical attenuation was measured. In a tissue culture set-up, porcine carotid arteries were dilated and the attenuation coefficients of the dilated segments were compared to a control segment for 4 h. Quantitative analysis showed a strong and significant correlation between OCT and histology cap thickness measurements for both OCT systems. For both systems, the measured attenuation coefficients for diffuse intimal thickening and lipid-rich regions differed significantly from that of calcified tissue. Balloon dilation induced a time-dependent increase in the attenuation coefficient, which may be attributed to the induction of apoptosis. In conclusion both the high and regular resolution OCT systems can image the atherosclerotic plaques precisely. Quantitative analysis of the OCT signals allowed in situ determination of the intrinsic optical attenuation coefficient for atherosclerotic tissue components within regions of interest, which can help to discriminate between plaque and arterial wall components.

Analysis of Variance↗

Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development.

BACKGROUND: Toll like receptors (Tlr) are essential in activation of the innate immune system. We recently described that peptidoglycan, an exogenous Tlr2 specific ligand, is present in human atherosclerotic plaques and associated with histological markers for plaque vulnerability. Also, endogenous Tlr2 ligands can be expressed in atherosclerotic tissues. Here, we determined whether Tlr2 stimulation promotes pro-inflammatory cytokine/chemokine production in vitro and augments neointima formation and development of atherosclerotic plaques in vivo. METHODS AND RESULTS: We detected Tlr2 using Western blot and RT-PCR in human coronary arteries and primary adventitial fibroblasts. RNAse protection assay demonstrated significant induction of IL-1, IL-6, IL-8 and MCP-1 mRNA after Tlr2 stimulation in human adventitial fibroblasts in vitro. ELISA demonstrated induction of IL-6, IL-8 and MCP-1. In vivo application of Pam(3)Cys-SK(4), a synthetic Tlr2 ligand, on femoral arteries of C57BL/6 wild type (WT) mice using a peri-adventitial cuff, significantly enhanced neointima formation compared to control arteries. This increased inflammatory response was not observed in Tlr2 knockout (Tlr2-/-) mice. In ApoE knockout mice (ApoE-/-), application of the same Tlr2 ligand led to a significant increase in atherosclerotic plaque development. CONCLUSION: Local arterial Tlr2 stimulation induced neointima and atherosclerotic plaque formation in mouse femoral arteries. Tlr2 stimulation may be an important mediator in arterial occlusive disease.

Animals↗

Identification of genes potentially involved in disease transformation of CML.

In patients with chronic myeloid leukemia (CML) who do not reach a (near) complete cytogenetic response, the disease progresses over several years from an indolent, chronic phase into a rapidly fatal blast crisis. Events that are responsible for this transformation process are largely unknown. To identify changes in gene expression that occurred during the course of the disease, we performed cDNA subtraction on sequentially stored peripheral blood mononuclear cell pellets, collected throughout the course of disease of a single CML patient. In total, 32 differentially expressed sequences were identified, of which 27 corresponded to known genes. On quantitative PCR, eight of these genes, YWHAZ, GAS2, IL8, IL6, PBEF1, CCL4, SAT and MMRN, showed comparable differential expression in additional CML patient samples. This set of genes can be considered as a starting point for further research on causes of disease transformation in CML and may lead to new targets in the treatment of resistant CML.

Apoptosis↗

Modulation of collagen turnover in cardiovascular disease.

Collagen fibers are the most abundant components of the extracellular matrix in arteries and myocardium. Disturbances in the collagen turnover (synthesis and degradation) have been linked to inflammatory diseases including cardiovascular pathological syndromes. In the myocardium, changes in collagen turnover may result in ventricle dilatation and subsequent contractile dysfunction. In arteries, collagen synthesis and degradation are associated with the progression of atherosclerotic disease and intimal hyperplasia following injury. Collagen synthesis is tightly regulated at several levels: synthesis of procollagens, suitable folding of polypeptides, secretion and cross-linking of mature fibers. On the other hand, degradation of newly synthesised procollagen and mature collagen fibers depends on the action of Matrix-Metalloproteinases (MMPs). The major role of collagen turnover in cardiovascular disorders has stimulated the search for pharmacological agents that interfere with collagen turnover at different levels. These drugs can theoretically act through modulation of the synthesis of procollagens or by interference with their post-translational modifications. Another group of pharmacological agents inhibit collagen breakdown (MMP inhibitors). Beneficial effects of compounds that target collagen metabolism have been reported. Unfortunately, many of these compounds also give rise to serious adverse effects due to interference with vital biological processes in which collagen plays an important role. In this paper, we will review cardiovascular diseases in which altered local collagen turnover is a key feature. Subsequently, the effect of compounds that have been developed and tested to modulate collagen synthesis, cross-linking or breakdown will be discussed.

Animals↗

Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease.

The family of Toll-like receptors (TLRs) initiates an innate immune response after recognition of pathogen-associated molecular patterns (PAMPs). Evidence is accumulating that TLRs, and particularly TLR4, are important players in the initiation and progression of atherosclerotic disease. Not only exogenous ligands but also endogenous ligands that are expressed during arterial injury are recognized by TLR4. Mouse knockout studies and epidemiological studies of human TLR4 polymorphisms have demonstrated that the TLR4 might play a role in the initiation and progression of atherosclerosis. This review will summarize the latest progression in research on the role of TLR4 in arterial occlusive disease In addition, the potential of intervention in TLR4 signalling to influence progression of atherosclerotic disease is discussed.

Animals↗

Rapid, arteriovenous graft failure due to intimal hyperplasia: a porcine, bilateral, carotid arteriovenous graft model.

BACKGROUND: The loss of patency constitutes the major complication of arteriovenous (AV) polytetrafluoroethylene hemodialysis grafts. In most cases, this graft failure is due to intimal hyperplasia at the venous outflow tract, including proliferation of vascular, smooth muscle cells and fibroblasts with deposition of extracellular matrix proteins. Thus far, procedures developed for improving patency have proven unsuccessful, which can be partly explained by the lack of relevant animal models. For this purpose, we developed a porcine model for AV graft failure that will allow the assessment of promising therapeutic strategies in the near future. MATERIALS AND METHODS: In 14 pigs, AV grafts were created bilaterally between the carotid artery and the jugular vein using expanded polytetrafluoroethylene. Two, 4 or 8 weeks after AV shunting, the grafts and adjacent vessels were excised and underwent histologic analysis. RESULTS: From 2 weeks onwards, a thick neo-intima developed at the venous anastomosis, predominantly consisting of alpha-actin-positive vascular smooth muscle cells (VSMC). Intimal area increased over time, coinciding with a decreased graft flow. Grafts remained patent for at least 4 weeks. At 8 weeks, patency rates declined to less than 50% due to thrombus formation superimposed on progressive neo-intima formation. CONCLUSIONS: Implantation of an AV graft between the carotid artery and jugular vein in pigs causes a rapid neo-intimal response, accompanied by a loss of patency of 50% at 8 weeks after surgery. This model offers a suitable tool to study local interventions aimed at the improvement of AV graft patency rates.

Animals↗

On-line detection of cholesterol and calcification by catheter based Raman spectroscopy in human atherosclerotic plaque ex vivo.

BACKGROUND: Raman spectroscopy has the unique potential to detect and quantify cholesterol and calcification in an atherosclerotic plaque in vivo. OBJECTIVE: To evaluate the sensitivity and specificity of this technique for detecting cholesterol or calcification in human coronary artery and aorta specimens ex vivo, using a compact clinical fibreoptic based Raman system developed for in vivo applications. DESIGN: From nine coronary arteries and four aorta specimens, 114 sites were evaluated for the presence of cholesterol and calcification by Raman spectroscopy and standard histology. Raman spectra were acquired and evaluated on-line in around five seconds. RESULTS: The correlation between Raman spectroscopy and histology was r = 0.68 for cholesterol and r = 0.71 calcification in the plaque (p < 0.0001). Sensitivity and specificity for detecting cholesterol and calcification were excellent: receiver operating characteristic (ROC) analysis for each of the components revealed areas under the curves of > 0.92 (p < 0.0001). At the optimal cut-off values determined by ROC analysis, positive predictive values of > 80% and negative predictive values of > 90% were obtained. CONCLUSIONS: On-line real time catheter based Raman spectroscopy detects accumulation of cholesterol and calcification in atherosclerotic plaque with high sensitivity and specificity.

Calcinosis↗

Matrix metalloproteinases: a therapeutic target in cardiovascular disease.

Cardiovascular disease is the leading cause of death in Western society. Extracellular matrix turnover is important in many cardiovascular pathologies, such as arterial remodeling, plaque rupture, restenosis, aneurysm formation and heart failure. Matrix metalloproteinases (MMPs) belong to a group of zinc and calcium dependent proteases and cause breakdown of the extracellular matrix. MMP inhibitors have been developed and tested for their effect on the outcome of oncological disease [1]. Recent preclinical research revealed that these MMP inhibitors could also have great potential in the field of cardiovascular disease. This preclinical research has encouraged investigators to design and start the first clinical studies with cardiovascular endpoints. In the present paper, the various aspects of MMP participation in cardiovascular disease will be summarized. Preclinical animal studies that demonstrated the effect and potential of applicable MMP inhibitors on different cardiovascular disease entities will be discussed. We will specifically focus on the role of MMPs and the potential of their inhibitors in de novo atherosclerotic plaque destabilization, arterial remodeling, restenosis after ballon angioplasty and stenting, aneurysm formation and heart failure. We conclude that MMP inhibitors are likely to be useful in the development of pharmacological approaches to reduce cardiovascular death, considering the positive outcomes after usage of MMP inhibitors in restenosis and arterial remodeling.

Aneurysm↗

[Remodelling of the arterial wall: a determinant of luminal stenosis and a factor with prognostic significance].

A structural transversal change in artery size is a type of arterial remodelling. Luminal stenosis in atherosclerosis is not only determined by plaque increase, but also by remodelling of the vessel wall. Expansive remodelling prevents luminal stenosis by atherosclerotic plaque progression, whereas constrictive remodelling increases luminal stenosis. Expansive remodelling is associated with lesions that are frequently observed at sites of acute manifestations of atherosclerotic disease, such as myocardial infarction, and it is therefore a negative prognostic feature. Constrictive remodelling is associated with stable plaque lesions. Remodelling of the vessel wall also plays a role after interventions such as balloon angioplasty, heart transplantation and bypass surgery. For example, the most important determinant of restenosis after balloon angioplasty is constrictive remodeling.

Angioplasty, Balloon↗

Homocysteine and the stage of atherosclerotic disease: a study in patients suffering from clinically silent and clinically manifest atherosclerotic disease.

BACKGROUND: Elevated serum levels of homocysteine are considered a risk factor for cardiovascular disease. It has been suggested that homocysteine is a late stage predictor of adverse cardiovascular events, which might explain reported controversies in literature. The objective of the present study was to study the relationship between homocysteine levels and the stage of atherosclerotic disease. METHODS: In a cross-sectional study we compared the prevalence of hyperhomocysteinemia in high risk patients without silent or clinically overt atherosclerosis (group I, n = 196) with two patient groups: patients with clinically manifest atherosclerosis in the past or asymptomatic atherosclerosis (group II, n = 364) and patients who currently suffer from a clinically relevant manifestation of ischemic cardiovascular disease (group III, n = 967). In addition, we related homocysteine levels with a cumulative index of atherosclerotic disease (SMART-score). RESULTS: Homocysteine levels (micromol L(-1)) for the different groups were 13.5 +/- 8.9 (group I), 13.7 +/- 8.2 (group II) and 14.7 +/- 7.7 (group III). After adjustment for age, body mass index, creatinine levels and current use of vitamins, no significant differences in the prevalence of hyperhomocysteinemia were observed, compared with the reference category. Linear regression analysis revealed a significant relationship between Smart score and homocysteine levels that remained after adjustment for potential confounders (Beta = 0.36 (0.14-0.59), P = 0.001). CONCLUSION: If homocysteine levels are associated with the presence and indicators of atherosclerotic plaque burden, then this relationship is apparently not affected by the stage of atherosclerotic disease.

Adult↗

The erythrocyte: a new player in atheromatous core formation.

The membrane of the red blood cell hides constituents that are lipid rich and can bind to macrophage scavenger receptors, thus posing the challenging hypothesis that erythrocytes contribute to atheroma formation in coronary arteries.

Arteriosclerosis↗

Atherosclerotic plaque burden, plaque vulnerability and arterial remodeling: the role of inflammation.

Atherosclerotic narrowing of the arterial lumen is caused by gradual plaque growth and arterial remodeling. Expansive remodeling retards and constrictive remodeling accelerates narrowing of the lumen by plaque accumulation. In the acute phase luminal narrowing may be accelerated by rupture of a vulnerable plaque and subsequent thrombus formation. Inflammatory cells are key players in all these determinants of atherosclerotic luminal narrowing. Inflammatory cells are present in both early and advanced stages of atherosclerosis. Chronic infections have been suggested as trigger of arterial inflammation, but no causal relationship has yet been proved. Systemic markers of inflammation, like C-reactive protein, are predictors for the occurrence of future adverse cardiovascular events, confirming the role of inflammatory responses in arterial occlusive disease. In this review the central role of inflammation in atherosclerotic luminal narrowing will be discussed.

Acute Disease↗

Furin and membrane type-1 metalloproteinase mRNA levels and activation of metalloproteinase-2 are associated with arterial remodeling.

Matrix metalloproteinase (MMP) activation is an essential feature of pathological and physiological arterial enlargement or shrinkage. Recently, furin-activated membrane type-1 MMP (MT1-MMP) was identified as the in vivo activator of MMP2 in mice. Although arterial enlargement and shrinkage are important in several pathological processes, this proprotein convertase-MT1-MMP axis has not been described during arterial remodeling. In rabbit femoral and carotid arteries, we report an increase in furin and MT1-MMP mRNA levels before and at the onset of arterial remodeling followed by an increase in activated MMP2. This reveals the presence of the proprotein convertase-MT1-MMP axis in flow-induced arterial remodeling and identifies furin as a possible target for local intervention in pathological arterial remodeling.

Animals↗

Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition.

BACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiological conditions VR is associated with normalization of shear stress (SS) and wall stress (WS), after PTA the role of SS and WS in VR is unknown. Furthermore, whereas matrix metalloproteinase inhibition (MMPI) has been shown to modulate VR after PTA, its effect on the SS and WS control mechanisms after PTA is unknown. METHODS AND RESULTS: PTA was performed in external iliac arteries of 12 atherosclerotic Yucatan pigs, of which 6 pigs (7 vessels) received the MMPI batimastat and 6 pigs (10 vessels) served as controls. Before and after the intervention and at 6-week follow-up, intravascular ultrasound pullback was performed, allowing 3D reconstruction of the treated segment and computational fluid dynamics to calculate the media-bounded area and SS. WS was derived from the Laplace formula. Immediately after PTA, media-bounded area, WS, and SS changed by 20%, 16%, and -49%, respectively, in both groups. VR was predicted by SS and WS. In the control group, SS and WS had been normalized at follow-up with respect to the reference segment. In contrast, for the batimastat group, the SS had been normalized, but not the WS. The latter is attributed to an increase in wall area at follow-up. CONCLUSIONS: Vascular remodeling after PTA is controlled by both SS and WS. MMPI inhibited the WS control system.

Angioplasty, Balloon↗

Distribution of Chlamydia pneumoniae in the human arterial system and its relation to the local amount of atherosclerosis within the individual.

BACKGROUND: Chlamydia pneumoniae has been suggested to play a role in the origin of atherosclerosis. We studied the prevalence of C pneumoniae at multiple locations in the arterial system within the same individual. Studying the association between atherosclerosis and C pneumoniae within the individual excludes confounding by interindividual variability. METHODS AND RESULTS: Postmortem, the presence in the intima/plaque and media of C pneumoniae membrane protein was determined by use of a C pneumoniae-specific monoclonal antibody. In 24 individuals, 33 arterial locations were studied (n=738 segments). Area stenosis was determined in adjacent cross sections. In all individuals, immunostaining of C pneumoniae was observed in >/=1 artery. The highest prevalences were observed in the abdominal aorta (67%), internal and common iliac arteries (41%), and coronary arteries (33%). The lowest prevalences were observed in the radial (0%) and cerebral (2%) arteries. Within the individual, area stenosis was larger in cross sections with immunoreactivity compared with cross sections without immunoreactivity (31.0+/-11.9% versus 14.3+/-6.1%, respectively; P:<0.001). In the individual, immunoreactivity was observed in 15+/-10% of the arteries (range, 3% to 45%). Between individuals, the percentage of arteries with immunoreactivity to C pneumoniae was associated with the average area stenosis throughout the arterial system (r(2)=0.56, P:<0.001). CONCLUSIONS: C pneumoniae was mostly observed at locations that are related to clinically relevant features. Within the individual, the distribution of C pneumoniae is associated with the distribution of atherosclerosis. The role of the microorganism in atherosclerotic disease remains to be elucidated.

Aged↗