Biomedical subjects
V Fuster
Publications and source records attributed to V Fuster.
ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina).
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Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty.
OBJECTIVES: We investigated the in vivo effects of tissue factor (TF) inhibition with recombinant tissue factor pathway inhibitor (rTFPI) on acute thrombus formation and intimal hyperplasia and the in vitro effects on smooth muscle cell migration and proliferation. BACKGROUND: Inhibition of TF with TFPI has been shown to reduce intimal hyperplasia in experimental models. However, its effects after coronary angioplasty and the cellular mechanisms involved have not been investigated. METHODS: Twenty-three swine underwent multivessel coronary angioplasty. Fifteen (n = 25 arteries) were euthanized at 72 h to assess thrombus formation and eight (n = 24 arteries) at 28 days to assess intimal hyperplasia. Animals in the 72-h time point received: 1) human rTFPI (0.5 mg bolus plus 25 microg/kg/min continuous infusion for 3 days) plus heparin (150 IU/kg intravenous bolus) plus acetyl salicylic acid (ASA) (325 mg/day); 2) rTFPI regimen plus ASA and 3) heparin (150 IU/kg intravenous bolus) plus ASA. RESULTS: On histology the control group had evidence of mural thrombus (area 0.8+/-0.4 mm2). Treatment with TFPI plus heparin abolished thrombus formation (mean area: 0.0+/-0.0 mm2, p < 0.05) but was associated with prolonged activated partial thromboplastin time and extravascular hemorrhage. Recombinant TFPI alone inhibited thrombosis without bleeding complications (mean area: 0.03+/-0.02 mm2, p < 0.05 vs. control). Animals in the 28-day time point received continuous intravenous infusion of rTFPI or control solution for 14 days. Tissue factor pathway inhibitor reduced neointimal formation with mean intimal area of 1.2+/-0.3 mm2 versus 3.2+/-0.4 mm2 in the control group; p < 0.01. Recombinant TFPI had no effect on human aortic smooth muscle cell growth but inhibited platelet-derived growth factor BB-induced migration. CONCLUSIONS: Inhibition of TF with rTFPI can prevent acute thrombosis and intimal hyperplasia after injury. Tissue factor plasma inhibitor may prove useful as an adjunct to intracoronary interventions.
Apoptosis, proliferation, and p27 expression during vessel wall healing: time course study in a mouse model of transluminal femoral artery injury.
OBJECTIVE: The balance between cell death and proliferation in the vessel wall influences neointimal formation, remodeling, and eventual luminal narrowing after arterial injury. In this study, the time course of apoptosis, proliferation, and expression of p27-a critical regulator of cell-cycle progression-is characterized in a mouse model of transluminal arterial injury associated with substantial neointimal formation. METHODS: C57BL/6 mice underwent bilateral femoral artery injury by passage of an angioplasty guidewire. Expression of p27, Ki67 proliferative index, and apoptosis, as well as histomorphometry, were analyzed in cross sections of uninjured arteries and arteries harvested at different time intervals after injury. RESULTS: In the uninjured arteries, no apoptotic cells were detected, and p27 and Ki67 were expressed in less than 5% of medial cells. After injury, apoptosis increased markedly in medial smooth muscle cells from 1 to 24 hours and decreased gradually thereafter. Ki67 proliferative index increased after 1 week, peaked at 2 weeks in both the media and neointima, and decreased thereafter. p27 expression was undetectable from 1 to 48 hours, and increased gradually from 1 to 4 weeks. Well-developed neointima was present at 2 and 4 weeks. CONCLUSIONS: In vivo injury to the mouse femoral artery evokes a rapid apoptotic response and downregulation of p27, followed by gradual increase in proliferation. During later phases of arterial repair, p27 expression increases while a shift of proliferation rates toward baseline occurs. Future experiments using this model in genetically modified mice may help identify specific cell-cycle regulatory molecules as therapeutic targets for control of pathologic arterial healing.
Atherosclerosis and the vulnerable plaque--pathogenesis: Part I.
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Atherosclerosis and the vulnerable plaque--imaging: Part II.
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Characterization of atherosclerotic plaques by magnetic resonance imaging.
The study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of the progression and regression of this disease and will aid in selecting the appropriate medical treatments or surgical interventions. Several invasive and noninvasive imaging techniques are available to assess atherosclerotic vessels. Most of these techniques are strong in identifying the morphological features of the disease, such as lumenal diameter and stenosis or wall thickness, and in some cases provide an assessment of the relative risk associated with the atherosclerosis. However, none of these techniques can fully characterize the composition of the atherosclerotic plaque in the vessel wall and, therefore, are incapable of identifying the vulnerable plaques. High-resolution, multi-contrast, magnetic resonance (MR) can non-invasively image vulnerable plaques, characterize plaques in terms of lipid and fibrous content, and identify the presence of thrombus or calcium. Application of MR imaging opens up whole new areas for diagnosis, prevention, and treatment (e.g., lipid-lowering drug regimens) of atherosclerosis.
Acute antithrombotic effect of a front-loaded regimen of clopidogrel in patients with atherosclerosis on aspirin.
There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (n=20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1+/-8.5% versus baseline (P<0.05). ADP-induced platelet aggregation (with 5 and 10 micromol/L) was also significantly (P<0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2+/-4.4% and 81.8+/-4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (P<0. 05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 micromol/L) at 2 hours in this front-loaded regimen group (36.1+/-2. 0% and 53.2+/-9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.
In vivo dynamic real-time monitoring and quantification of platelet-thrombus formation: use of a local isotope detector.
Current methods for monitoring thrombosis and thrombus growth are invasive and provide only single-time-point data. Animal models rely mainly on flow changes as a surrogate of thrombus formation. Our aim was to validate a unique potentially noninvasive system to detect and quantify dynamic thrombus formation in vivo by using a porcine model of carotid artery injury. Thrombus growth was monitored by deposition of autologous (111)In-labeled platelet activity over the injured artery by use of miniaturized gamma detectors and Doppler blood flow. Counts were recorded at 2-minute intervals for 2 hours. The technique was validated by comparing standard antithrombotic agents against controls. Platelet recruitment was detected before significant change in flow. Thrombus formation, calculated as the area under the curve (platelets x minutes x 10(6)), was greatest for control animals (11.7+/-1.28), followed by animals treated with aspirin (6.13+/-0.91, P<0.05), heparin (2.45+/-0.34, P<0.05), and hirudin (0.2+/-0.01, P<0.01 compared with heparin). The rate of platelet deposition was assessed as the slope of the curve in the first 30 minutes (platelets x 10(6) per minute) for the following treatment groups of animals: control, 3.53+/-0.34; aspirin, 1.67+/-0. 34 (P<0.01); heparin, 1.55+/-0.3 (P<0.01); and hirudin, 0.25+/-0.03 (P<0.001). There was no statistical difference between heparin and aspirin treatments. Change in flow was assessed as reduction from baseline: control, >99+/-0.34%; aspirin, 39+/-9.1%; heparin, 36+/-12. 5%; and hirudin, 17+/-5.4%. There was no statistical difference between the aspirin- and heparin-treated groups. Morphometric analysis revealed >99+/-0.63% occlusion of the luminal area with thrombus for the control group, 43+/-14.3% for the aspirin-treated group, 30+/-5.6% for the heparin-treated group, and <10+/-1.8% for the hirudin-treated group. Assessment of platelet-thrombus formation with this technique was more sensitive than change in flow in determining antithrombotic efficacy, and thrombus formation was detected earlier. This study validates a new quantitative, sensitive, potentially noninvasive, portable, in vivo monitoring of dynamic thrombus growth, which appears applicable to phase II studies in humans.
Predicting plaque rupture: enhancing diagnosis and clinical decision-making in coronary artery disease.
Atherosclerosis is the process underlying coronary artery disease, myocardial infarction and cerebrovascular disease and is a leading cause of morbidity and mortality in industrialized countries. The atherosclerotic plaque is often indolent and progressive and may destabilize without warning. Components of the atherosclerotic plaque, including structural, cellular and molecular characteristics, determine its vulnerability to rupture. The imaging techniques currently available utilize invasive and non-invasive methods to characterize coronary artery stenoses. Detection, however, usually occurs late in the course of disease after symptoms have presented. Much effort has recently been directed at early detection and in defining markers of atherosclerotic disease. Our challenge for the future is to find non-invasive imaging modalities that can predict plaque vulnerability before irreversible damage has occurred. Through early detection and a targeted treatment strategy we hope to reduce the burden of ischemic heart disease.
50th anniversary historical article. Myocardial infarction and coronary care units.
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50th anniversary historical article. Acute coronary syndromes: the degree and morphology of coronary stenoses.
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[Thrombus remodeling. Key factor in the progression of coronary atherosclerosis].
The mechanism of the progression of atherosclerosis involves the rupture of a plaque with thrombus formation, followed by an invasion of monocytes that induce the formation of tissue factor and a second thrombus. This is followed by activation of the smooth muscle cells of the arterial wall with formation of connective tissue that infiltrates both thrombi. We can try to prevent atherosclerosis progression by inhibiting thrombosis with an inhibitor of tissue factor, inhibiting the process of scarring with Rapamycin, or both. Nowadays, we can study these processes using highly sensitive techniques to monitorize the formation and evolution of the thrombus, and magnetic resonance imaging that allow us to study the growth of the connective tissue. With these techniques we can study the natural history of atherosclerosis and the efficacy of different drugs to prevent its progression.
Determinants of birth interval in a rural Mediterranean population (La Alpujarra, Spain).
The fertility pattern, in terms of birth intervals, in a rural population not practicing contraception belonging to La Alta Alpujarra Oriental (southeast Spain) is analyzed. During the first half of the 20th century, this population experienced a considerable degree of geographical and cultural isolation. Because of this population's high variability in fertility and therefore in birth intervals, the analysis was limited to a homogenous subsample of 154 families, each with at least five pregnancies. This limitation allowed us to analyze, among and within families, effects of a set of variables on the interbirth pattern, and to avoid possible problems of pseudoreplication. Information on birth date of the mother, age at marriage, children's birth date and death date, birth order, and frequency of miscarriages was collected. Our results indicate that interbirth intervals depend on an exponential effect of maternal age, especially significant after the age of 35. This effect is probably related to the biological degenerative processes of female fertility with age. A linear increase of birth intervals with birth order within families was found as well as a reduction of intervals among families experiencing an infant death. Our sample size was insufficient to detect a possible replacement behavior in the case of infant death. High natality and mortality rates, a secular decrease of natality rates, a log-normal birth interval, and family-size distributions suggest that La Alpujarra has been a natural fertility population following a demographic transition process.
Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology.
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Passive smoking and coronary heart disease.
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Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue.
Histomorphometric studies for smooth muscle cells, macrophages, tissue factor, collagen, and cell proliferation were performed on 20 atherectomy specimens from patients with in-stent restenosis and 20 specimens from patients with post-balloon PTCA restenosis. Smooth muscle cell content was larger and proliferation index was higher in in-stent restenotic tissue; macrophage, tissue factor, and collagen content were larger in post-balloon percutaneous transluminal coronary angioplasty restenotic tissue, suggesting a more cellular and proliferative response with less thrombogenic potential in human tissue from in-stent restenosis than tissue from post-balloon percutaneous transluminal coronary angioplasty restenosis.