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J J Badimon

Publications and source records attributed to J J Badimon.

At least 37 records · Page 2Linked to original sources
PubMed2001

Value or desirability of hemorheological-hemostatic parameter changes as endpoints in blood lipid-regulating trials.

High levels of plasma lipids have been recognized as a major risk factor in the development and progression of atherosclerosis, and to influence hemorheological factors that may predispose to thrombotic complications. Lipid-lowering interventions have been associated with a significant reduction of morbidity and mortality. Several mechanisms have been postulated for the observed clinical effect. Serum lipid-regulating therapies may reduce cardiovascular risk not only by altering the arterial wall, improving disturbed endothelial function, atherogenesis and plaque stability, but also through their antithrombogenic effects and influence on blood flow properties associated with hyperlipidemia. In this article, we will review the recent literature and discuss the value of hemorheological-hemostatic findings as surrogate endpoints for clinical trials in dyslipidemic patients.

Blood Platelets↗
PubMed2001

New understanding of atherosclerosis (clinically and experimentally) with evolving MRI technology in vivo.

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in industrialized countries. Despite advances in our understanding of the pathogenetic mechanisms and new treatment modalities, the absence of an adequate noninvasive method for early detection limits the prevention or treatment of patients with various degrees and localizations of atherothrombotic disease. High-resolution magnetic resonance (MR) has recently emerged as one of the most promising techniques for the noninvasive study of atherothrombotic disease. Most importantly, MR can be used to characterize plaque composition and monitor progression. Thus, MR opens new strategies, ranging from the screening of high-risk patients for early detection and treatment as well as the monitoring of target areas for pharmacological intervention.

Animals↗
PubMed2001

Coronary artery disease: pathogenesis and acute coronary syndromes.

Atherosclerotic diseases and their thrombotic complications remain the leading causes of mortality and morbidity in Western society. In the United States, cardiovascular disease is responsible for one in every 2.4 (41.4%) deaths and is the leading single cause of mortality. Furthermore, the presence of atherosclerotic disease (defined as thickening of the arterial wall through the accumulation of lipids, macrophages, T-lymphocytes, smooth muscle cells, extracellular matrix, calcium and necrotic debris) is more prevalent, but by itself rarely fatal. The crucial, final common process for the conversion of a nonocclusive, often clinically silent atherosclerotic lesion to a potentially fatal condition is often plaque disruption. The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death. Substantial clinical, experimental and postmortem evidence demonstrates the central role that a superimposed acute thrombosis on a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes. Therefore, therapeutic approaches to date have focused on reducing such thrombotic complications of atherosclerotic plaques (i.e., antiplatelet, anticoagulant and thrombolytic therapies) to reduce the resulting morbidity and mortality. In this review, we will focus on the current theories of atherogenesis and how they impact on our understanding of acute coronary syndromes.

Chemokines↗
PubMed2001

[Identification of unstable coronary atherosclerotic plaques].

The mechanisms of atherogenesis are better understood and the detection of atherosclerosis has improved with the different diagnostic methods currently available. However, it is almost impossible at present to differentiate high risk, unstable or vulnerable plaques from quiescent or stable plaques of atherosclerosis. This is a crucial problem given the banality of atherosclerosis on the one hand, and, on the other hand, the serious consequences (acute coronary syndromes, cerebrovascular accidents) of thrombotic occlusion at the site of an atherosclerotic plaque. It has now been established that the composition of the plaque is more important than the degree of stenosis, a fundamental concept in the risk of plaque rupture, precipitating the cascade of reactions leading to uncontrolled thrombosis. Consequently, new imaging techniques should address the problem of analysing the composition of atheromatous plaques. Endovascular ultrasonography, fast CT, angioscopy, nuclear imaging techniques and MRI are so many promising tools. However, non-invasive techniques should be distinguished from invasive ones. In all probability, it will be the former which will turn out to be the most useful diagnostic aid in pauci or asymptomatic patients. This article reviews the different imaging techniques under evaluation for the identification of risk of plaque rupture.

Angiography↗
PubMed2000

Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice.

Neointimal hyperplasia is a critical component of restenosis, a major complication of angioplasty and related therapeutic procedures. We studied the effects of hyperlipidemia and the nonsteroidal anti-inflammatory drugs, aspirin (acetyl-salicylic acid; ASA), and sulindac, on neointimal formation in a mouse femoral arterial injury model. At 2 months of age, normolipidemic, wild-type (WT), and hyperlipidemic, apolipoprotein E-deficient (apoE-/-) mice were divided into three treatment groups: Western-type diet (WD), WD + ASA (200 mg/kg food), and WD + sulindac (300 mg/kg food). After 1 week, mice underwent arterial injury and treatments were maintained for 4 weeks. Histomorphometry of the injured arteries showed striking effects of plasma cholesterol levels and drug treatment on neointimal hyperplasia. In the WD or WD + ASA groups, apoE-/- mice had twice the neointimal area than WT mice ( approximately 30,000 vs. 13,000 microm(2) per section; P < 0.0001). Compared with ASA or WD alone, sulindac treatment resulted in approximately 70% (P = 0.0001) and 50% (P = 0.01) reductions in the neointimal area in apoE-/- and WT mice, respectively. ASA, at a dose sufficient to inhibit platelet aggregation, did not affect neointimal formation in mice of either genotype. Evidence of macrophages was noted in the lesions of apoE-/- mice in the WD and WD + ASA groups, but remarkably, none was detectable with sulindac treatment, despite hyperlipidemia, suggesting early steps in the response to injury were abrogated. These results demonstrate sulindac reduces neointimal formation in both normolipidemic and hyperlipidemic settings and raise the possibility that similar benefits may be obtained in patients undergoing angioplasty and related procedures.

Animals↗
PubMed2000

Noninvasive in vivo human coronary artery lumen and wall imaging using black-blood magnetic resonance imaging.

BACKGROUND: High-resolution MRI has the potential to noninvasively image the human coronary artery wall and define the degree and nature of coronary artery disease. Coronary artery imaging by MR has been limited by artifacts related to blood flow and motion and by low spatial resolution. METHODS AND RESULTS: We used a noninvasive black-blood (BB) MRI (BB-MR) method, free of motion and blood-flow artifacts, for high-resolution (down to 0.46 mm in-plane resolution and 3-mm slice thickness) imaging of the coronary artery lumen and wall. In vivo BB-MR of both normal and atherosclerotic human coronary arteries was performed in 13 subjects: 8 normal subjects and 5 patients with coronary artery disease. The average coronary wall thickness for each cross-sectional image was 0.75+/-0.17 mm (range, 0.55 to 1.0 mm) in the normal subjects. MR images of coronary arteries in patients with >/=40% stenosis as assessed by x-ray angiography showed localized wall thickness of 4.38+/-0.71 mm (range, 3.30 to 5.73 mm). The difference in maximum wall thickness between the normal subjects and patients was statistically significant (P<0.0001). CONCLUSIONS: In vivo high-spatial-resolution BB-MR provides a unique new method to noninvasively image and assess the morphological features of human coronary arteries. This may allow the identification of atherosclerotic disease before it is symptomatic. Further studies are necessary to identify the different plaque components and to assess lesions in asymptomatic patients and their outcomes.

Adult↗
PubMed2000

In vivo demonstration of an antithrombin effect of abciximab.

Abciximab prolonged the activated clotting time (ACT) in a post hoc analysis from the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications trial and an in vitro study has suggested an antithrombin effect of platelet glycoprotein IIb/IIIa inhibition. The purpose of this study was to evaluate the in vivo effects of abciximab on ACT and thrombin generation. In 46 patients undergoing coronary intervention, 24 received heparin and abciximab (group I), whereas 22 received heparin alone (group II). All received the same dose (70 U/kg) of heparin. Heparin was given after a baseline ACT, and in group I, abciximab was administered after the 5-minute ACT. Serial ACTs were recorded at baseline, 5, 10, 20, and every 30 minutes thereafter and at the procedure's end. No intervention including balloon angioplasty was performed until after the 20-minute ACT. The prothrombin fragment F1.2 (Nm/L) was measured at baseline, 20 minutes, and at the end of the procedure. Before (baseline) heparin and at 5 minutes, ACTs were similar. Abciximab prolonged ACT by a mean of 34 to 64 seconds starting with the 10-minute ACT and extending to the 50-minute ACT (all p <0.01 vs heparin alone). There was a progressive decrease in the F1.2 with abciximab, and baseline minus end F1.2 was 0.12 +/- 0.02 in group I versus 0.05 +/- 0.04 in group II, p <0.05. These data indicate a significant in vivo effect of abciximab plus heparin in increasing ACT and decreasing F1.2, results that are consistent with an effect on reducing thrombin generation.

Abciximab↗
PubMed2000

Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor.

We describe thrombogenic tissue factor (TF) on leukocyte-derived microparticles and their incorporation into spontaneous human thrombi. Polymorphonuclear leukocytes and monocytes transfer TF(+) particles to platelets, thereby making them capable of triggering and propagating thrombosis. This phenomenon calls into question the original dogma that vessel wall injury and exposure of TF within the vasculature to blood is sufficient for the occurrence of arterial thrombosis. The transfer of TF(+) leukocyte-derived particles is dependent on the interaction of CD15 and TF with platelets. Both the inhibition of TF transfer to platelets by antagonizing the interaction CD15 with P-selectin and the direct interaction of TF itself suggest a novel therapeutic approach to prevent thrombosis.

Biological Transport↗
PubMed2000

Noninvasive in vivo magnetic resonance imaging of experimental coronary artery lesions in a porcine model.

BACKGROUND: The ability to characterize and quantify coronary artery atherosclerotic lesions accurately, reproducibly, and noninvasively may allow the stratification of risk for future acute coronary syndromes and help direct therapeutic management. MRI has been shown to accurately characterize and quantify atherosclerosis; however, because of the combination of cardiac and respiratory motion artifacts, nonlinear course, and relatively small size of the coronary arteries, these techniques have not been able to be translated to the coronary system in vivo. METHODS AND RESULTS: Coronary lesions were induced in Yorkshire albino swine (n=6) with balloon angioplasty, and 4 weeks later MRI of the coronary artery lesions was performed. High-resolution in vivo images of the coronary artery wall and lesions were obtained with a double-inversion-recovery fast-spin-echo sequence in a 1.5-T MR system. There was good agreement between measurements of vessel wall thickness and area from MR images of the coronary arteries and the matched histopathology sections (n=43). The mean difference (MRI minus histopathology +/- SD) for mean wall thickness was 0.26+/-0.18 mm, and for vessel wall area, 5.65+/-3.51 mm(2). MRI was also able to visualize intralesion hematoma (sensitivity 82%, specificity 84%). CONCLUSIONS: Using a clinical MR system, we were able to image coronary artery lesions in vivo in an experimental porcine model. Further studies are needed to assess the ability of MRI to characterize coronary atherosclerotic lesions in vivo.

Animals↗
PubMed2000

Comparative study of antithrombotic effect of a low molecular weight heparin and unfractionated heparin in an ex vivo model of deep arterial injury.

Thrombosis after plaque rupture triggers the onset of acute coronary events. The treatment of choice for patients with acute coronary syndromes is conventional unfractionated heparin. Low molecular weight heparin has recently been reported to be as effective and even safer than unfractionated heparin. In this study, the effects of the low molecular weight heparin reviparin and unfractionated heparin on thrombus formation were examined under dynamic conditions using an extracorporeal perfusion chamber in a porcine model. Thrombus formation was assessed by the deposition of porcine 123I-fibrin(ogen) and autologous 111In-platelets on porcine tunica media at high and low shear rates. Reviparin reduced the fibrinogen molecules deposited on injured vessels at high shear rates (252+/-80 molecules x 10(12)/cm2 for reviparine (200 U/kg/hour) vs. 624+/-70 x 10(12)/cm for unfractionated heparin (200 U/kg/hour) (p<0.05). At low shear rates, fibrinogen deposition was also significantly reduced by reviparin (130+/-15 molecules x 10(12)/cm2) compared to unfractionated heparin (192+/-40 x 10(12)/cm2 at 200 U/kg/hour; p<0.05). No change in platelet deposition was detected after heparin administration in either treatment group. In conclusion, the low molecular weight heparin reviparin has a higher antithrombotic potential than unfractionated heparin. Reviparin may have advantages over unfractionated heparin in treatment and prevention of acute coronary syndromes.

Adenosine Diphosphate↗
PubMed2000

In vivo magnetic resonance evaluation of atherosclerotic plaques in the human thoracic aorta: a comparison with transesophageal echocardiography.

BACKGROUND: The structure and composition of aortic atherosclerotic plaques are associated with the risk of future cardiovascular events. Magnetic resonance (MR) imaging may allow accurate visualization and characterization of aortic plaques. METHODS AND RESULTS: We developed a noninvasive MR method, free of motion and blood flow artifacts, for submillimeter imaging of the thoracic aortic wall. MR imaging was performed on a clinical MR system in 10 patients with aortic plaques identified by transesophageal echocardiography (TEE). Plaque composition, extent, and size were assessed from T1-, proton density-, and T2- weighted images. Comparison of 25 matched MR and TEE cross-sectional aortic plaque images showed a strong correlation for plaque composition (chi(2) = 43.5, P<0.0001; 80% overall agreement; n = 25) and mean maximum plaque thickness (r = 0.88, n = 25; 4.56+/-0.21 mm by MR and 4.62+/-0.31 mm by TEE). Overall aortic plaque extent as assessed by TEE and MR was also statistically significant (chi(2) = 61.77, P<0.0001; 80% overall agreement; n = 30 regions). CONCLUSIONS: This study demonstrates that noninvasive MR evaluation of the aorta compares well with TEE imaging for the assessment of atherosclerotic plaque thickness, extent, and composition. This MR method may prove useful for the in vivo study of aortic atherosclerosis.

Adult↗
PubMed2000

Antithrombotic effects of abciximab.

The observation that platelet-platelet interaction and thrombosis are ultimately regulated by the glycoprotein (GP) IIb/IIIa receptor complex, triggered the development of agents capable of interfering with this platelet receptor complex. Several large clinical trials have demonstrated the effectiveness of this class of agents. The first of these agents to show beneficial effects after coronary interventions was the mouse/human chimeric Fab fragment antibody c7E3 (abciximab; ReoPro). This study analyzes whether the addition of heparin to the GP IIb/IIIa antagonist abciximab would enhance the antithrombotic effect. Blood drawn directly from patients on aspirin who underwent interventional procedures perfused an ex vivo perfusion chamber containing a severely injured arterial wall at local rheologic conditions of a mildly stenosed coronary artery. Blood was perfused directly from patients at baseline and following administration of heparin, abciximab, or both. The antithrombotic effects of the 3 treatments were assessed by reduction of the thrombus formation on the perfused specimens. Thrombus formation at baseline was not significantly modified by the administration of heparin (13,897 +/- 1,316 vs 11,917 +/- 1,519 microm(2)). Abciximab produced a 58% reduction in thrombus formation (11,631 +/- 861 vs 4, 925 +/- 585 microm(2); p <0.001). The addition of heparin to abciximab did not further reduce thrombus area versus abciximab alone (5,651 +/- 581 vs 4,925 +/- 585 microm(2)). Thus, our data show that abciximab dramatically decreases mural thrombus formation and that combining heparin with abciximab did not add any additional antithrombotic effect to abciximab alone.

Abciximab↗
PubMed2000

Serial in vivo MRI documents arterial remodeling in experimental atherosclerosis.

BACKGROUND: Arterial remodeling in response to atherosclerosis may be outward (positive) or inward (negative) and is an important mechanism in the clinical manifestations of atherosclerosis and restenosis after percutaneous coronary interventions. Postmortem and intravascular ultrasound studies of arterial remodeling do not allow serial and noninvasive data to be obtained. In a rabbit model of atherosclerosis, we sought to validate MRI as a new tool for documentation of arterial remodeling. METHODS AND RESULTS: Watanabe heritable hyperlipidemic rabbits underwent serial MRI at baseline and 6 months after aortic balloon denudation. The lumen area had a small but significant (P=0.006) increase, from 4.36+/-0.16 to 4. 89+/-0.12 mm(2). There was a large, significant (P<0.0001) increase in the outer wall area, from 7.96+/-0.19 to 10.46+/-0.19 mm(2). The vessel wall area (a marker of atherosclerotic burden) increased significantly (P<0.0001), from 3.61+/-0.07 to 5.57+/-0.09 mm(2). Thus, the increase in atherosclerotic burden over time was completely accounted for by positive arterial remodeling. The subgroup used for histopathological validation confirmed a significant (P<0.0001) agreement between histopathology and MRI for assessment of all 3 parameters. CONCLUSIONS: MRI can provide serial and noninvasive data about the arterial wall, allowing assessment of arterial remodeling in this rabbit model. Thus, MRI appears to be a useful tool for the investigation of arterial remodeling both in native atherosclerosis and after percutaneous coronary intervention.

Animals↗
PubMed2000

Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins.

Cholesterol lowering involving different therapies improves the clinical outcome of patients. To define the underlying pathomechanism, we studied whether treatment with statins was associated with changes in blood thrombogenicity, endothelial dysfunction and soluble adhesion molecule levels. Fifty hypercholesterolemic patients were treated with pravastatin (40 mg/day, n=24) or simvastatin (20 mg/day, n=26). Lipid profile and blood thrombogenicity were assessed in all patients before and after 3 months of cholesterol reducing therapy. Blood thrombogenicity was assessed as thrombus formation, perfusing non-anticoagulated blood directly from the patients' vein through the Badimon perfusion chamber (shear rate 1690/s). Endothelial-dependent vasomotor response was tested by laser-Doppler flowmeter. Soluble adhesion molecule level were measured by ELISA. Total and LDL cholesterol were reduced in the two treatment groups by statin therapy. Statin therapy was associated with a significant reduction in blood thrombogenicity and endothelium-dependent vasoresponse. No differences were observed between simvastatin or pravastatin treatment. Lipid lowering by statins had no effect on plasma levels of fibrinogen, sL-selectin, sP-selectin and sICAM-1 antigen. Cholesterol lowering by both statins reduced the increased blood reactivity and endothelial dysfunction present under hypercholesterolemia. The multiple effects of lipid lowering therapy by statins may explain the benefits observed in recent epidemiological trials.

Anticholesteremic Agents↗
PubMed2000

Modulation of apoptosis, proliferation, and p27 expression in a porcine coronary angioplasty model.

Smooth muscle cell (SMC) proliferation is a prominent feature of intimal hyperplasia after percutaneous coronary interventions. p27 is a critical regulator of cell proliferation. Our aims were to analyze the time course of p27 expression, Ki67 proliferative index, and apoptosis after angioplasty in the porcine coronary artery. We also investigated the effects of rapamycin--an antiproliferative drug--on these events. The expression of p27 and Ki67, and apoptosis were determined in porcine coronary arteries harvested at timed intervals from 1 h to 28 days after angioplasty. A gradual increase in p27 expression was observed from 7 to 28 days. Ki67 expression peaked by 7-14 days after angioplasty. By 21-28 days, Ki67 expression decreased, while p27 reached maximal levels. An early apoptotic response was found by 6 h, followed by a gradual return to baseline. Rapamycin induced a reduction in Ki67 proliferative index (2 +/- 0.5%) and an increase in apoptosis (7 +/- 1%) versus untreated animals at the 28-day time point (5 +/- 1 and 1 +/- 0.5%, respectively; P < 0.05). In summary, coronary angioplasty induced a rapid apoptotic response, followed by a progressive increase in proliferation. Later on, as p27 expression increased in the vessel wall, cell proliferation decreased. Modulation of cell cycle progression may be a useful therapeutic approach in the treatment of intimal hyperplasia after angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed2000

High resolution ex vivo magnetic resonance imaging of in situ coronary and aortic atherosclerotic plaque in a porcine model.

Atherosclerotic plaque composition is central to the pathogenesis of plaque disruption and acute thrombosis. Thus, there is a need for accurate imaging and characterization of atherosclerotic lesions. Even though there is no ideal animal model of atherosclerosis, the porcine model is considered to most closely resemble human atherosclerosis. We report the feasibility of MR imaging and characterizing of atherosclerotic lesions from in situ coronary arteries and aortas in an ex vivo setting and validate this with histopathology. Coronary and aortic atherosclerosis was induced in Yucatan mini-swine (n=4) by a combination of atherogenic diet (6 months) and balloon injury. All coronary arteries were imaged ex vivo on the intact heart, preserving the curvature of their course. The aorta also underwent MR imaging. The MR images were correlated with the matched histopathology sections for both the coronary arteries (n=54) and the aortas (n=43). MR imaging accurately characterized complex atherosclerotic lesions, including calcified, lipid rich, fibrocellular and hemorrhagic regions. Mean wall thickness for the coronary arteries (r=0.94, slope: 0.81) and aortas (r=0.94, slope: 0.81) as well as aortic plaque area (r=0.97, slope: 0.90) was accurately determined by MR imaging (P<0.0001). Coronary artery MR imaging is not limited by the curvature of the coronary arteries in the heart. MR imaging accurately quantifies and characterizes coronary and aortic atherosclerotic lesions, including the vessel wall, in this experimental porcine model of complex atherosclerosis. This model may be useful for future study of MR imaging of atherosclerosis in vivo.

Animals↗