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Biomedical subjects

Valentin Fuster

Publications and source records attributed to Valentin Fuster.

At least 91 records · Page 5Linked to original sources
PubMed2004

Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury.

BACKGROUND: The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury. METHODS AND RESULTS: Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (P<0.05), resulting in decreased neointima formation at 4 weeks compared with control (P<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (P<0.01) and increased neointima formation at 4 weeks (P<0.01). CONCLUSIONS: VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.

Angioplasty↗
PubMed2004

Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability.

BACKGROUND: Growth of atherosclerotic plaques is accompanied by neovascularization from vasa vasorum microvessels extending through the tunica media into the base of the plaque and by lumen-derived microvessels through the fibrous cap. Microvessels are associated with plaque hemorrhage and may play a role in plaque rupture. Accordingly, we tested this hypothesis by investigating whether microvessels in the tunica media, the base of the plaque, and the fibrous cap are increased in ruptured atherosclerotic plaques in human aorta. METHODS AND RESULTS: Microvessels, defined as CD34-positive tubuloluminal capillaries recognized in cross-sectional and longitudinal profiles, were quantified in 269 advanced human plaques by bicolor immunohistochemistry. Macrophages/T lymphocytes and smooth muscle cells were defined as CD68/CD3-positive and alpha-actin-positive cells. Total microvessel density was increased in ruptured plaques when compared with nonruptured plaques (P=0.0001). Furthermore, microvessel density was increased in lesions with severe macrophage infiltration at the fibrous cap (P=0.0001) and at the shoulders of the plaque (P=0.0001). In addition, microvessel density was also increased in lesions with intraplaque hemorrhage (P=0.04) and in thin-cap fibroatheromas (P=0.038). Logistic regression analysis identified plaque base microvessel density (P=0.003) as an independent correlate to plaque rupture. CONCLUSIONS: Thus, neovascularization as manifested by the localized appearance of microvessels is increased in ruptured plaques in the human aorta. Furthermore, microvessel density is increased in lesions with inflammation, with intraplaque hemorrhage, and in thin-cap fibroatheromas. Microvessels at the base of the plaque are independently correlated with plaque rupture, suggesting a contributory role for neovascularization in the process of plaque rupture.

Adult↗
PubMed2004

In vivo 16-slice, multidetector-row computed tomography for the assessment of experimental atherosclerosis: comparison with magnetic resonance imaging and histopathology.

BACKGROUND: Noninvasive imaging can detect early atherosclerotic disease. Magnetic resonance imaging (MRI), because of its excellent spatial resolution, is already established as a tool for plaque characterization. Sixteen-slice, multidetector-row computed tomography (MDCT) was recently introduced into the field of cardiac imaging, with promising results for noninvasive angiography. We compared the capabilities of MDCT and MRI for the assessment of noncalcified, atherosclerotic plaques. METHODS AND RESULTS: Six atherosclerotic rabbits underwent in vivo imaging by MDCT and 1.5-T MRI. MDCT parameters were 120 kV, 120 mA/s, collimation 12x0.75, and spatial resolution 0.6x0.6 mm. MRI parameters were as follows: for proton density, repetition time/echo time (TR/TE) 2300/5.6; for T2, TR/TE 2300/62; and for T1, TR/TE 800/5.6; slice thickness was 3 mm and spatial resolution, 0.3x0.3 mm. Blinded analysis of 3-mm axial reconstructions from MDCT and the carefully matched MRI images (182 sections) showed excellent agreement between both modalities. MDCT yielded a slightly larger lumen area, anteroposterior diameters, and lateral diameters, with no significant differences in total vessel area. The sensitivity and specificity, respectively, to detect noncalcified, atherosclerotic plaques were 89% and 77% for MDCT and 97% and 94% for MRI. Fibrous-rich and lipid-rich plaque could not be differentiated visually, although they showed different attenuation properties (116+/-27 vs 51+/-25 Hounsfield units, P<0.01). CONCLUSIONS: Both techniques allow reliable detection of noncalcified, atherosclerotic plaques and accurate assessment of vessel areas and diameters. MDCT offers the additive value of a very short image acquisition time when compared with MRI. The subtle measurement differences found between modalities may be due to the better spatial resolution of MRI, which probably explains its superiority for tissue characterization.

Animals↗
PubMed2004

Effects of percutaneous transluminal angioplasty and endovascular brachytherapy on vascular remodeling of human femoropopliteal artery by noninvasive magnetic resonance imaging.

BACKGROUND: Percutaneous transluminal angioplasty (PTA) of severely stenotic peripheral vascular lesions is hampered by a higher restenosis rate. The effects of PTA on vascular wall as well as the effects of the antirestenotic properties of endovascular brachytherapy (EVBT) remain unclear. MRI allows in vivo noninvasive assessment of the vascular effects of such treatment strategies. We sought to elucidate the vascular effect of PTA and PTA+EVBT by serial MRI. METHODS AND RESULTS: Twenty symptomatic patients with severe stenosis of the femoropopliteal artery were randomly assigned to PTA (n=10) or PTA+EVBT (n=10; 14 Gy by gamma-irradiation source) and imaged by high-resolution MRI before and 24 hours and 3 months after intervention. An independent observer blinded to the procedure analyzed the MRI data. At 24 hours, cross-sectional MRI revealed that lumen area (86% and 67%) and total vessel area (47% and 34%) increased similarly in the PTA and PTA+EVBT groups, respectively. All patients showed severe splitting of the atherosclerotic plaque, resulting in an irregularly shaped lumen. At 3 months, MRI revealed a significant difference in lumen area change between the PTA and PTA+EVBT groups (40% and 106%, respectively; P=0.026) and in the total vessel area (14% and 39%, respectively; P=0.018). At 3 months, plaque disruption was still present in 50% of the patients treated with PTA+EVBT. CONCLUSIONS: After PTA, there is deep disruption of the atherosclerotic plaques and an extensive remodeling process of the arterial wall. Luminal loss after PTA is partially due to inward vessel remodeling. Brachytherapy prevents inward remodeling and induces an increase in lumen area but partially prevents healing of disrupted vessel surface.

Aged↗
PubMed2004

Lipid-rich atherosclerotic plaques detected by gadofluorine-enhanced in vivo magnetic resonance imaging.

BACKGROUND: MRI of specific components in atherosclerotic plaque may provide information on plaque stability and its potential to rupture. We evaluated gadofluorine in atherosclerotic rabbits using a new MR sequence that allows plaque detection within 1 hour after injection and assessed enhancement in lipid-rich and non-lipid-rich plaques. METHODS AND RESULTS: Twelve rabbits with aortic plaque and 6 controls underwent MRI before and up to 24 hours after gadofluorine injection (50 micromol/kg). Two T1-weighted, segmented gradient-echo sequences (TFL) were compared to enhance vessel wall delineation after injection: (1) an inversion-recovery prepulse (IR-TFL) or (2) a combination of inversion-recovery and diffusion-based flow suppression prepulses (IR-DIFF-TFL). With the use of IR-TFL at 1 hour after injection, the vessel wall was not delineated because of poor flow suppression; at 24 hours after injection, the enhancement was 37% (P<0.01). IR-DIFF-TFL showed significant enhancement after versus before contrast (1 hour: 164% [P<0.005]; 24 hours: 207% [P<0.001]). At 1 hour and 24 hours after injection, the contrast-to-noise ratio was higher with the use of IR-DIFF-TFL than with IR-TFL (1 hour: 13.0+/-7.7 versus -19.8+/-10.3 [P<0.001]; 24 hours: 15.2+/-5.9 versus 11.4+/-8.9, respectively [P=0.052]). There was no enhancement in the vessel wall after gadofluorine injection in the control group. A strong correlation was found (r2=0.87; P<0.001) between the lipid-rich areas in histological sections and signal intensity in corresponding MR images. This suggests a high affinity of gadofluorine for lipid-rich plaques. CONCLUSIONS: Gadofluorine-enhanced MRI improves atherosclerotic plaque detection. The IR-DIFF-TFL method allows early detection of atherosclerotic plaque within 1 hour after gadofluorine injection.

Animals↗
PubMed2004

Training cardiovascular fellows in cardiovascular magnetic resonance and vascular imaging; Current status following the core cardiovascular training symposium (COCATS-2) guidelines.

OBJECTIVES: This survey study sought to characterize the current training environment in cardiovascular magnetic resonance (CMR) and vascular imaging and to quantify the magnitude of any gaps between current training practice and the recommendations of the Core Cardiovascular Training Symposium (COCATS-2) guidelines. BACKGROUND: The COCATS-2 guidelines published in 2002 newly included specific educational components of CMR and vascular imaging. An understanding of the current capabilities of training programs to meet these guidelines could produce efforts to improve training opportunities. METHODS: We surveyed all accredited adult cardiovascular training programs by using a 21-question, multiple-response survey. Data were collected on center and program characteristics, clinical activities, control of clinical activities, and needs and attitudes. Parallel data were collected for nuclear cardiology capabilities as a "base case." RESULTS: Only 13% of training programs reported "ownership" of CMR equipment, compared with 48% for nuclear equipment (p = 0.001). Dedicated fellow rotations in nuclear imaging are nearly universally present, whereas vascular (64%) and CMR imaging (29%) lag behind. A majority of programs do not use formal educational curricula for CMR and vascular imaging. Among centers with CMR training capabilities, the breadth of training opportunities is typically very limited, with most having only aortic imaging as their sole capability, except in predominately large training centers. The greatest need expressed by programs was educational assistance in the form of written and lecture curriculum materials. CONCLUSIONS: A substantial gap exists between the current training environment in CMR and vascular imaging and the recommendations of COCATS-2. Sharing training opportunities between centers is encouraged, particularly for smaller training programs, in order to capitalize on limited equipment, personnel, and curriculum resources.

Cardiology↗
PubMed2004

Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis.

BACKGROUND: Macrophages associated with arterial wall lipid deposition contribute to inflammatory processes. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. Intimal cells undergoing apoptosis have been postulated as a source for TF. However, there is only limited knowledge of cell type, plaque component, and conditions associated with TF expression and apoptosis. We examined the hypothesis that macrophages exposed to conditions of lipid-rich plaque undergo apoptosis and express TF. METHODS AND RESULTS: In human carotid (n=15) and coronary (n=6) atherosclerotic plaques, TF and caspase-3 mRNA and protein expression (evaluated by in situ hybridization and immunohistochemistry) were increased significantly in lipid-rich compared with fibrous plaque components (P<0.01) and correlated with high macrophage content (P<0.05). Double-labeling studies demonstrated colocalization of TF and active caspase-3. In hyperlipidemic mice, expression of TF and active caspase-3 was observed simultaneously and colocalized in neointimal macrophages after arterial injury. In neointima of normolipidemic animals, TF and active caspase-3 were absent after arterial injury. In monocytes cultured in the presence of oxidized LDL, strong induction and colocalization of TF and active caspase-3 were found compared with baseline (P<0.05). Both antigens were significantly decreased after cotreatment with a caspase inhibitor (P<0.05) and were absent in untreated control cells. CONCLUSIONS: The expression of TF as the primary cell-associated activator of the coagulation pathway proves to be closely related to macrophages undergoing apoptosis in conditions of lipid-rich plaque, pointing to a key role of lipid content and inflammatory cell viability in determining plaque thrombogenicity.

Animals↗
PubMed2004

The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging.

OBJECTIVES: We sought to investigate the anti-atherogenic effects of a selective peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and simvastatin, as well as their combination, over time, in a rabbit model of experimental atherosclerosis. BACKGROUND: The PPARs are nuclear transcription factors that control a variety of cellular functions, with the potential effects required to induce plaque regression and stabilization. METHODS: Atherosclerosis was induced in rabbits (n = 37) by the combination of double-balloon injury and a nine-month high-cholesterol (HC) diet. The rabbits were randomized into a continued HC diet, a normal chow (NC) diet, NC plus simvastatin, NC plus PPAR-gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits underwent magnetic resonance imaging (MRI) at randomization and after six months of treatment and were then sacrificed for histopathologic study. RESULTS: All groups had a similar vessel wall area by MRI (8.45 +/- 0.65 mm(2), p = NS between groups) at randomization. Significant progression was seen in the HC diet group (15 +/- 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups, progression was abolished (-2.5 +/- 3% and -4.5 +/- 5%, respectively; p = NS). The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups had significant plaque regression (-12 +/- 4% [p < 0.05] and -22 +/- 4% [p < 0.01], respectively). Regression was independent of plasma lipid levels. All NC groups had similar lipid profiles at the end of treatment. Histopathologic analysis of the NC groups showed a decreased macrophage content and matrix metalloproteinase activity and an increased smooth muscle cell/collagen content of lesions. CONCLUSIONS: Our data indicate that normalization of plasma lipid levels abolishes progression of atherosclerosis. Simvastatin elicits regression of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma agonist has additive regression effects on plaque. This is paralleled by structural alterations in plaque composition, which may increase plaque stability. These observations support the beneficial effects of statins on atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR-gamma agonist with simvastatin.

Animals↗
PubMed2004

Should standard medical therapy for angina include a statin?

Although a wealth of evidence supports the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in patients with clinically evident coronary artery disease, these agents are still underutilized. Statins are the most effective agents in reducing low-density lipoprotein-cholesterol among lipid-lowering drugs, and studies have recently shown that they improve endothelial function and plaque stabilization, and induce regression of atherosclerotic lesions. This article reviews the most recent evidence and guideline recommendations supporting the use of statins in chronic stable angina pectoris and acute coronary syndromes.

Acute Disease↗