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Biomedical subjects

L Badimon

Publications and source records attributed to L Badimon.

At least 73 records · Page 4Linked to original sources
PubMed1996

Human and porcine smooth muscle cells share similar proliferation dependence on the mevalonate pathway: implication for in vivo interventions in the porcine model.

Proliferation of smooth muscle cells (SMCs) plays an important role in vascular pathobiology by being involved in the development of coronary atherosclerosis and restenosis. Competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase have shown antiproliferative properties on different cell types. We have assessed the relative effectiveness of three HMG-CoA reductase inhibitors (compactin, lovastatin and pravastatin) in blocking serum-induced replication of human and porcine SMCs. No effects were seen on DNA synthesis in porcine or human SMCs at the reported therapeutic lipid-lowering concentrations. The effectiveness of statins in blocking SMC proliferation was similar in both species; the IC50 values for porcine cells were 12.2 mumol L-1, 12.6 mumol L-1 and 1.16 mmol L-1 for lovastatin, compactin and pravastatin respectively. Inhibition of SMC proliferation was reversed by addition of mevalonate but not by low-density lipoprotein (LDL)-cholesterol. Statins showed high anti-proliferative efficiency against purified growth factors involved in human restenosis (1 nmol L-1 platelet-derived growth factor (PDGF), 1 nmol L-1 epidermal growth factor (EGF), 10 U mL-1 alpha-thrombin). The porcine model seems to be a suitable system, closely resembling the human model, for assaying in vivo new strategies, formulations and delivery systems targeted to the mevalonate pathway to inhibit local SMC response to percutaneous transluminal coronary angioplasty.

Animals↗
PubMed1996

Wall passivation for unstable angina.

The disruption of an atherosclerotic plaque in a coronary artery, appears to be fundamental for the development of arterial thrombosis and resultant ischaemia. Platelets play a central role in the pathogenesis of unstable angina; they can aggregate and cause mechanical obstruction if large enough. In addition, they can lead to fibrin deposition and extension of the thrombus. The fundamental goal in the treatment of unstable angina is to control the acute disease process that leads to vascular occlusion. In addition to the currently available pharmacological agents used to treat unstable angina, newer agents such as the direct thrombin inhibitors and the glycoprotein IIb/IIIa receptor antagonists may be more effective in achieving 'passivation'. This article summarizes the role of the vessel wall and its interaction with platelets in arterial thrombosis. The different pharmacological approaches used in achieving passivation of platelets in unstable angina are described.

Acute Disease↗
PubMed1995

Cell biology of restenosis post-angioplasty.

PTCA is a well established intervention to reduce the severity of atherosclerotic coronary stenosis. In spite of a primary success rate of 90 - 95%, late restenosis occurs in 30 - 50% of patients within 3/6 months of the procedure. Angioplasty in swine induces similar events to those found in humans, thus providing a model for studying strategies for intervention. Blood interaction to the damaged vessel wall occurs with reperfusion after the intervention. Therefore, the in vivo characterization of the interaction of cellular elements (platelets and white cells) and blood proteins with the exposed vascular cells in the vessel wall post-angioplasty may be necessary to identify early triggers of restenosis. Angioplasty was performed simultaneously in the coronary and carotid arteries of swine by fluoroscopy assisted standard techniques. Angiography was performed acutely post-dilatation and residual lumen diameter evaluated. Dilated vessels from 30 min to 6 h postintervention were processed to prepare RNA and preserved to perform immunohistochemistry. Dilatation injury induces maximal expression of c-fos 30 min and c-myc from 2 to 4 h postdilatation. Platelet deposition is initiated immediately post-dilatation as well as infiltration of fluid phase proteins on the damaged areas.

Angioplasty, Balloon, Coronary↗
PubMed1994

A garlic derivative, ajoene, inhibits platelet deposition on severely damaged vessel wall in an in vivo porcine experimental model.

Ajoene, (E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide, is a potent antiplatelet compound isolated from alcoholic extracts of garlic. In vitro, ajoene reversibly inhibits platelet aggregation as well as the release reaction induced by all known agonists. We used a well characterized perfusion chamber to study the in vivo effects of ajoene on platelet deposition onto a highly thrombogenic, severely damaged arterial wall, obtained by stripping off the intimal layer and exposing tunica media. Platelet-vessel wall interaction and the effect of ajoene was studied under flow conditions of high and low local shear rate that mimics laminar blood flow in small and medium size arteries (1690 sec-1 and 212 sec-1). Our results indicate that administration of ajoene to heparinized animals, significantly prevents thrombus formation at local low blood shear rate. Ajoene does not inhibit binding of vWF to GPIb, therefore, it does not affect platelet adhesion. In fact, although ajoene impairs fibrinogen and vWF (less efficient) binding to GPlIb/IIIa, it does not totally inhibits platelet deposition to the substrates at any of the shear rates used in this study. Our present results, under in vivo flow conditions and in the presence of physiological calcium levels, suggest that ajoene may be potentially useful for the acute prevention of thrombus formation induced by severe vascular damage, mainly in arterial sites with local low shear rates.

Animals↗
PubMed1994

Acute biological response to laser balloon angioplasty in the atherosclerotic rabbit.

Laser balloon angioplasty with Nd:YAG energy has been proposed as a method to seal intimal dissection and prevent elastic recoil after balloon angioplasty. To better define the vessel response to laser balloon angioplasty, its effects on luminal diameter, Indium-111 labelled platelet deposition, and histology were studied in 10 atherosclerotic rabbits. Balloon angioplasty was performed in both iliac arteries and was followed by laser balloon angioplasty in only one iliac artery. The nonlased artery served as a control. Single (15-35 W for 20 sec) or repetitive laser pulses (12-25 W for 20 sec x 3) were used. Platelet deposition was quantified 2 hr after the intervention. Lumen diameter (mm) increased following balloon angioplasty from 0.99 +/- 0.47 (mean +/- SD) to 1.92 +/- 0.43 and 0.89 +/- 0.46 to 1.99 +/- 0.57 in the balloon and laser-treated arteries, respectively (P < 0.001 for both groups for comparisons to baseline, P = NS for between groups comparison). Laser balloon angioplasty resulted in a further increase in luminal diameter to 2.42 +/- 0.53 (P < 0.02) when compared to the post balloon angioplasty diameter. Platelet deposition (10(6)/cm vessel) was higher following laser balloon angioplasty (26.9, 10.2-189; median range) than after balloon angioplasty (10.6, 3.4-30), P < 0.001. Histologic evidence of laser "sealing" was present in only one artery. Thus although laser balloon angioplasty results in an improved lumen diameter, it is accompanied by increased platelet deposition. In the atherosclerotic rabbit model, abolition of vascular recoil rather than "sealing" seems to be the most important advantage of laser balloon angioplasty over conventional balloon angioplasty.

Angiography↗
PubMed1994

Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture.

OBJECTIVES: The purpose of this study was to determine whether different components of human atherosclerotic plaques exposed to flowing blood resulted in different degrees of thrombus formation. BACKGROUND: It is likely that the nature of the substrate exposed after spontaneous or angioplasty-induced plaque rupture is one factor determining whether an unstable plaque proceeds rapidly to an occlusive thrombus or persists as a nonocclusive mural thrombus. Although observational data show that plaque rupture is a potent stimulus for thrombosis, and exposed collagen is suggested to have a predominant role in thrombosis, the relative thrombogenicity of different components of human atherosclerotic plaques is not well established. METHODS: We investigated thrombus formation on foam cell-rich matrix (obtained from fatty streaks), collagen-rich matrix (from sclerotic plaques), collagen-poor matrix without cholesterol crystals (from fibrolipid plaques), atheromatous core with abundant cholesterol crystals (from atheromatous plaques) and segments of normal intima derived from human aortas at necropsy. Specimens were mounted in a tubular chamber placed within an ex vivo extracorporeal perfusion system and exposed to heparinized porcine blood (mean [+/- SEM] activated partial thromboplastin time ratio 1.5 +/- 0.04) for 5 min under high shear rate conditions (1,690 s-1). Thrombus was quantitated by measurement of indium-labeled platelets and morphometric analysis. Under similar conditions, substrates were perfused with heparinized human blood (2 IU/ml) in an in vitro system, and thrombus formation was similarly evaluated. RESULTS: Thrombus formation on atheromatous core was up to sixfold greater than that on other substrates, including collagen-rich matrix (p = 0.0001) in both heterologous and homologous systems. Although the atheromatous core had a more irregular exposed surface and thrombus formation tended to increase with increasing roughness, the atheromatous core remained the most thrombogenic substrate when the substrates were normalized by the degree of irregularity as defined by the roughness index (p = 0.002). CONCLUSIONS: The atheromatous core is the most thrombogenic component of human atherosclerotic plaques. Therefore, plaques with a large atheromatous core content are at high risk of leading to acute coronary syndromes after spontaneous or mechanically induced rupture because of the increased thrombogenicity of their content.

Animals↗
PubMed1994

Synergistic action of severe wall injury and shear forces on thrombus formation in arterial stenosis: definition of a thrombotic shear rate threshold.

OBJECTIVES: This study attempted to determine the influence of progressive degrees of stenosis on platelet deposition onto a severely damaged vessel wall. BACKGROUND: The severity of wall injury and increased shear forces have been proposed as the determinants of thrombus formation and growth in arterial stenosis. METHODS: Carotid angioplasty was performed in 15 mongrel dogs to produce severe wall damage. Group I (n = 9) had arteries with damage only. In group II (n = 14), progressive degrees of stenosis were produced at the center of the dilated area. Acute thrombus formation was evaluated by angiography at the time of angioplasty and platelet deposition/cm2 quantified by indium-111 labeling 1 h after the procedure. RESULTS: Severe wall damage (group I) produced a significant increase in platelet deposition compared with control arterial segments (8.19 +/- 3.82 vs. 3.62 +/- 2.52 platelets x 10(6)/cm2 [mean +/- SD], p < 0.05), and the presence of a stenosis (group II) further increased platelet deposition (36.98 +/- 3.82 platelets x 10(6)/cm2, p < 0.05). Angiographic filling defects or total occlusion was found in seven of the arteries in group II but in none in group I (p < 0.05). A shear rate of approximately 5,000 s-1, corresponding to a critical stenosis of 70% and a 1.5- to 1.6-mm diameter, was found to identify the arteries in which thrombosis was likely to occur (p < 0.05). Four of 5 arteries < 1.5 to 1.6 mm in diameter had angiographic filling defects or occlusion compared with 1 of 13 with less severe stenosis (p < 0.01). CONCLUSIONS: In low shear rate conditions, deep arterial injury will lead to mural thrombosis without further thrombus growth. When deep arterial injury occurs under critical local shear conditions, platelet deposition will be enhanced, and thrombosis may progress to total occlusion.

Angioplasty, Balloon↗
PubMed1994

A new approach for local intravascular drug delivery. Iontophoretic balloon.

BACKGROUND: Catheter-based systems are being developed to deliver drugs directly into the vessel wall. Pressure-mediated trauma and lack of homogeneous delivery are key limitations of these approaches. METHODS AND RESULTS: We studied a new catheter-based delivery system that uses electrical current to force the drug into the vessel wall. The in vivo feasibility of this approach has been assessed by delivering 125I-hirudin into porcine carotid arteries. Vascular levels of hirudin after active iontophoresis (4 mA/cm2, 5 minutes) were 80-fold greater than those achieved by passive diffusion (without electricity). Tissue hirudin levels declined over time; by 1 hour after delivery, 80% of the drug had left the vessel wall, and by 3 hours later, the levels of hirudin within the wall were similar to those achieved by passive diffusion. Autoradiography revealed distribution of the drug throughout the entire circumference of the arterial wall within the intima, media, and adventitia. Iontophoresis-mediated vessel wall trauma was minimal (less than 10% endothelial denudation and medial smooth muscle cell damage). Balloon injury after local delivery changed neither kinetics nor distribution of the drug into the arterial wall. CONCLUSIONS: (1) High local concentrations of hirudin in the arterial wall may be achieved with the iontophoretic balloon catheter. (2) The drug is distributed throughout the entire vessel wall without significant damage. (3) The retention of hirudin in the arterial wall is time dependent. (4) This technique might be useful to deliver therapeutic agents before or after percutaneous vascular interventions.

Angioplasty, Balloon↗
PubMed1994

Effect of an eccentric severe stenosis on fibrin(ogen) deposition on severely damaged vessel wall in arterial thrombosis. Relative contribution of fibrin(ogen) and platelets.

BACKGROUND: Coronary thrombosis is a dynamic process dependent on the pathological substrate, the local shear forces, and blood factors. METHODS AND RESULTS: We investigated the effect of a severe (80%) eccentric stenosis on fibrin(ogen) interaction with a deeply damaged vessel wall, its relation to platelet deposition in thrombus formation, and the influence of time on thrombus growth. Porcine 125I-fibrinogen and autologous 111In-platelets were injected into pigs instrumented for extracorporeal circulation and treated with low-dose heparin (aPTT ratio < 1.5) that has been previously shown and herein confirmed not to affect platelet and/or fibrin(ogen) attachment. Tunica media, as a model of severely injured vessel wall, was mounted in a tubular perfusion chamber containing an eccentric axisymmetric sinusoidal stenosis obstructing the lumen and exposed for 1, 5, and 10 minutes to perfusing blood. A shear rate of 424 s-1 at the laminar, parallel parabolic local flow perfused segments one to two orders of magnitude greater at the apex of the stenosis. Fibrin(ogen) deposition, its axial distribution with respect to the apex, and its relation to platelet deposition were determined by an ex vivo analysis of the test substrates. Fibrin(ogen) and platelet deposition were both significantly higher at the apex of the stenosis than at either the prestenotic or poststenotic area at all the studied perfusion times (P < .02). However, fibrin(ogen) deposition demonstrated a significantly smaller degree of increase from the prestenotic area to the apex as well as a smaller degree of decrease from the latter to the poststenotic region, compared with platelet deposition (P < .05). Although both fibrin(ogen) and platelet deposition increased over time, the ratio of fibrin(ogen) to platelets showed a progressive decrease that became significant from 5 to 10 minutes (P < .03) at either low or high shear rate. The rate of platelet deposition was relatively constant; however, fibrin(ogen) deposition progressively decreased, especially at the apex. CONCLUSIONS: On severely damaged vessel wall, fibrin(ogen) and platelet deposition is maximal at the apex of the stenosis where shear rate is extremely high and parallel streamlines are deformed. Nevertheless, fibrin(ogen) deposition is significantly less dependent on high shear rate than is platelet deposition, and the pattern is not influenced by time. Finally, fibrin(ogen) deposition appears to be predominant in the thrombus layers adjacent to a severely damaged vessel wall regardless of the local shear stress levels and flow conditions.

Animals↗
PubMed1994

Inhibition of growth of thrombus on fresh mural thrombus. Targeting optimal therapy.

BACKGROUND: Residual mural thrombus on severely damaged arterial wall is very thrombogenic. We tested the hypothesis that direct thrombin inhibition will block thrombus growth on fresh thrombus better than indirect thrombin inhibition, cyclooxygenase inhibition, or both. METHODS AND RESULTS: A fresh mural thrombus was formed by directly perfusing fresh porcine blood for 5 minutes over severely damaged arterial wall at a high shear rate in a well-characterized ex vivo perfusion system. The average platelet (P) and fibrinogen (F) deposition (D) achieved in 5 minutes were 382 +/- 32 x 10(6) platelets/cm2 and 296 +/- 36 x 10(12) fibrinogen molecules/cm2, respectively. Thrombus growth on the fresh mural thrombus was quantitated by directly perfusing blood from pigs with 111In-labeled platelets and 125I-labeled fibrinogen for an additional 5 minutes over the preformed mural thrombus. Treatment included recombinant hirudin (1 mg/kg per hour IV) as a probe for thrombin, aspirin (5 mg/kg IV) as a platelet inhibitor of cyclooxygenase, heparin (moderate, 100 IU/kg per hour IV; high-dose, 250 IU/kg per hour IV) as an indirect thrombin inhibitor, and heparin (100 IU/kg per hour) plus aspirin (5 mg/kg IV). Thrombus growth as measured by labeled PD (x 10(6)/cm2) and FD (x 10(12) molecules/cm2) was mildly but not significantly reduced by aspirin (1034 +/- 92 and 436 +/- 78, respectively) compared with baseline (1113 +/- 67 and 545 +/- 52, respectively). Inhibition of thrombus growth with heparin was dose dependent. A regression analysis showed an inverse correlation of PD and FD with mean plasma heparin concentrations (r = -.81, P = .0001 and r = -.49, P = .0007, respectively). Recombinant hirudin led to a profound inhibition of thrombus growth (PD, 30 +/- 12; FD, 109 +/- 21), which was significant compared with all groups, even the highest dosage of heparin (250 IU/kg per hour). CONCLUSIONS: Specific thrombin inhibition markedly inhibits platelet and fibrinogen deposition onto fresh mural thrombus at a high shear rate. Aspirin alone or in combination with heparin has little effect on evolving thrombosis. Heparin dose dependently reduces thrombus growth, but even the highest dosage is less effective than hirudin. Thrombin appears to be the primary activator of platelets by fresh thrombus.

Animals↗
PubMed1994

Local delivery of r-hirudin by a double-balloon perfusion catheter prevents mural thrombosis and minimizes platelet deposition after angioplasty.

BACKGROUND: The major morbidity of percutaneous transluminal coronary angioplasty is acute thrombosis and restenosis of the dilated lesion. Platelet-thrombus deposition occurs within minutes after injury, is primarily mediated by thrombin, causes acute occlusion, and contributes to late restenosis. Experimentally, specific thrombin inhibitors have prevented mural thrombosis. However, local therapy may be more effective than systemic treatment. We tested the hypothesis that high local concentrations of an antithrombin drug at the site of arterial injury following balloon angioplasty inhibit platelet thrombus formation equally or better than conventional systemic treatment and at lower systemic anticoagulant levels. METHODS AND RESULTS: Balloon angioplasty of the carotid arteries of 29 pigs was performed using systemic intravenous treatment with heparin (100 U/kg, groups I and II), suboptimal r-hirudin (0.3 mg/kg, group III), and higher-dose r-hirudin (0.7 mg/kg, group IV), which is the lowest dose that completely inhibited arterial thrombosis in the pig. Immediately after balloon angioplasty of the first carotid, additional local therapy with placebo (group I) or r-hirudin (groups II, III, and IV; 0.3 mg/kg in 1 mL) was administered with distal perfusion through a new percutaneous double-balloon catheter. After 1 hour of local drug delivery, angioplasty of the contralateral carotid was performed. Reflow for 1 hour was permitted to both carotids to compare the short-term effect of local plus systemic treatment with systemic treatment on quantitative 111In-labeled platelet deposition and macroscopic mural thrombus formation on deeply injured carotid segments. Local drug delivery of placebo compared with systemic heparin treatment resulted in no change of platelet deposition (x 10(6)/cm2, mean +/- SEM) in controls (group I, 91.0 +/- 23.5 versus 80.8 +/- 19.4), but local delivery of r-hirudin resulted in a significant reduction in group II (15 +/- 2.5 versus 71.3 +/- 14.5; P < .02) and group III (11.4 +/- 2.5 versus 80.5 +/- 11.4; P < .01) and was borderline in group IV (7.4 +/- 1.8 versus 14.1 +/- 7.4; P = .05), respectively. The incidence of macroscopic mural thrombus formation with local and systemic treatment was 86% and 75% in group I, 16% and 70% in group II, 14% and 71% in group III, and 0% and 16% in group IV, respectively. CONCLUSIONS: Local therapy with the specific thrombin inhibitor r-hirudin significantly reduces short-term quantitative platelet deposition and macroscopic mural thrombus formation following balloon angioplasty compared with systemic treatment of conventional doses of heparin and hirudin and requires a significantly smaller amount of the recombinant drug.

Angioplasty, Balloon, Coronary↗
PubMed1994

Inhibition of platelet recruitment to arterial lesions by predeposition of platelets containing encapsulated iloprost.

Drugs can be encapsulated within blood platelets by reversible electroporation and can be haemostatically targeted to vessel wall injury sites. Initial studies with iloprost-loaded pig platelets and pig aorta tunica media in perfusion circuits are presented. After autologous reconstitution into blood, no significant difference was observed in the deposition of 111Indium labelled sham-loaded and untreated platelets onto the tunica media during perfusion under low and high shear conditions. In paired experiments (n = 10 pairs), the deposition of iloprost-loaded platelets was significantly lower (mean 61%) after 5 min perfusion than the deposition from blood containing sham-loaded (control) platelets. A similar significant reduction (mean 54%) was seen after 10 min perfusion. Pre-perfusion of iloprost-loaded platelets for 10 min under low shear conditions (212/s), followed by 5 min perfusion of 111Indium labelled normal platelets, significantly reduced the secondary platelet deposition (p < 0.01) when compared with the deposition seen when control untreated platelets were preperfused. Significant differences (p < 0.001) in secondary deposition were also observed when primary and secondary platelet perfusions were made under high shear (1690/s). Histology of the tunica media segments post perfusion, supported the inhibitory effect of predeposited iloprost-loaded platelets on secondary platelet recruitment. By exploiting their natural haemostatic propensity, drug-loaded platelets can be targeted to vessel wall injury sites. Appropriate drugs could be packaged that may passivate the carrier platelets at the lesion inhibiting thrombus formation or they may act as a depot for sustained drug release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Platelet deposition induced by severely damaged vessel wall is inhibited by a boroarginine synthetic peptide with antithrombin activity.

Thrombin plays a key role in platelet activation and thrombosis. Specific inhibition of thrombin appears to be one of the best approaches to prevent thrombus formation. We have studied the effects of a synthetic alpha-aminoboronic acid derivative- [Ac, (D) Phe-Pro-Boro-Arg-Hydrochloric acid] - on platelet deposition on severely damaged arterial wall. Platelet deposition was evaluated under well characterized rheological conditions in an original perfusion chamber and detected by autologous 111In-labeled platelets. The study was performed "in vivo" in a porcine model of arterial thrombosis triggered by severely damaged vessel wall at blood flow conditions mimicking mild stenosis (1690 s-1) and patent (212 s-1) vessels. In addition, ex-vivo platelet aggregation activity was evaluated by whole blood impedance aggregometry using collagen, ADP and thrombin as agonists. The synthetic alpha-aminoboronic peptide was intravenously administered as a bolus followed by continuous infusion. Ex vivo thrombin-induced whole blood platelet aggregation was totally abolished, while ADP- and Collagen-induced whole blood platelet aggregation was not modified. The effects of the synthetic antithrombin on platelet deposition were evaluated in native blood (non-anticoagulated) conditions and in combination with heparin. Under both experimental conditions, the synthetic peptide significantly inhibited platelet deposition at local flow conditions of both high (1690 s-1) and low (212s-1) shear rates. Our results suggest that specific inhibition of locally generated thrombin might be a good strategy to prevent platelet dependent arterial thrombus formation independently of the local flow shear rate of the area at risk.

Adenosine Diphosphate↗