[Plaque vulnerability and disruption].
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Coronary Artery Disease↗
Biomedical subjects
E Falk
Publications and source records attributed to E Falk.
Angina pectoris and disease progression.
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Angina Pectoris↗
Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture.
BACKGROUND: Rupture of the fibrous cap of the atherosclerotic plaque is a key event that predisposes to coronary thrombosis, leading to acute coronary syndromes. Recent studies have shown that the fibrous caps of vulnerable and ruptured atherosclerotic plaques have reduced collagen and glycosaminoglycan content in association with an increased macrophage density and a reduced smooth muscle cell density. Since collagen breakdown in the fibrous caps may contribute to a thinning and weakening of the cap, increasing its vulnerability to rupture, we tested the hypothesis that monocyte-derived macrophages, by producing matrix-degrading metalloproteinases (MMPs), could induce collagen breakdown in human atherosclerotic fibrous caps. METHODS AND RESULTS: Monocytes were isolated from human blood by Ficoll-Paque density gradient and allowed to grow in cell culture until phenotypic and staining characteristics indicated transformation into macrophages (4 to 7 days). Fibrous caps were dissected from human aortic or carotid plaques and incubated for 48 hours with macrophages in serum-free medium without (n = 21) and with (n = 10) an MMP inhibitor or with cell- and serum-free medium only (n = 9). Hydroxyproline released in the culture medium was measured by a spectrophotometric method and used as evidence of collagen breakdown in the fibrous caps. Immunocytochemistry with specific monoclonal antibodies was used to identify expression of MMP-1 (interstitial collagenase) and MMP-2 (72-kD gelatinase) in cell culture, and zymography was used to detect MMP activity in the culture supernatant. The amount of hydroxyproline released was significantly greater when fibrous caps were incubated with macrophages than when incubated with cell-free medium (0.4 +/- 0.16 micrograms.mL-1.mg-1 versus 0.02 +/- 0.03 micrograms.mL-1.mg-1 of tissue; P < .04 by Mann-Whitney test). There was no hydroxyproline release when fibrous caps were incubated with macrophages in the presence of an MMP inhibitor. Immunocytochemistry demonstrated MMP-1 and MMP-2 expression by macrophages between days 4 and 7, and zymography confirmed the presence of MMP-2 activity in the supernatant. CONCLUSIONS: In this study, human monocyte-derived macrophages were shown to induce collagen breakdown in fibrous caps of human atherosclerotic plaques associated with cellular expression and zymographic evidence of MMP activity; no evidence of collagen breakdown was found in the presence of an MMP inhibitor. These findings support the hypothesis that increased macrophage density and/or activation in the atherosclerotic plaque may induce collagen breakdown in the fibrous cap by secreting MMPs and possibly other proteases, thus contributing to vulnerability to plaque rupture.
Arteriosclerosis↗
Coronary plaque disruption.
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Coronary Artery Disease↗
Role of thrombosis in atherosclerosis and its complications.
The endothelium is intact but activated and dysfunctioning during the early phase of atherogenesis. Owing to increased endothelial permeability, many blood-derived components, including hemostatic factors, are present in early as well as advanced atherosclerotic lesions. Insudated fibrin(ogen) and related degradation products and thrombin could contribute to atherogenesis by their chemotactic (attracting monocytes/macrophages) and mitogenic (stimulating cell proliferation) properties. All key cells in plaque may express thrombin receptors, indicating that thrombin may play a role in the genesis of uncomplicated atherosclerosis by mediating inflammatory and proliferative processes. Later, endothelial denudation with platelet adherence occurs over mature plaques. Then, incorporation of microthrombi and probably platelet/thrombus-derived growth factors are critical for the progressive growth of the smooth muscle cell-related plaque component. Besides transendothelial influx and incorporation of mural thrombi, blood products in atherosclerotic plaques may originate from hemorrhage through a ruptured plaque surface or from fragile newly formed vessels (neovascularization) frequently found at the base of advanced plaques. Rupture-related plaque progression due to luminal thrombosis and/or plaque hemorrhage is the most important mechanism underlying the unpredictable rapid progression of coronary lesions responsible for acute coronary syndromes. Both platelets and fibrin play a role in the dynamic thrombotic response to plaque rupture.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hepatobiliary transport of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors conjugated with bile acids.
To obtain prodrugs with affinity to liver parenchymal cells, the hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors HR 780 and lovastatin (syn. mevinolin) were conjugated with the bile acids cholic acid, taurocholic acid, and glycocholic acid. Hepatic uptake and biliary excretion of the coupled drugs were investigated and compared with the noncoupled drugs. Studies were performed with livers of normal Wistar rats, and TR-/GT- Wistar rats with deficient drug excretion. The experiments showed that the parent drug HR 780 was slowly excreted into bile. In contrast, the excretion of the bile acid-conjugated HR 780 derivatives S 3554 (conjugated with cholate), S 3898 (conjugated with glycocholate), and S 4193 (conjugated with taurocholate) was rapid and very efficient in both groups of rat strains. The bile acid-conjugated HMG-CoA reductase inhibitors showed a 10 to 20 times higher affinity for the uptake systems of bile acids than the noncoupled parent drug compounds, and even higher affinities than the bile acids themselves. The cholate conjugate of HR 780 (compound S 3554) was shown to be a noncompetitive inhibitor of taurocholate uptake and a competitive inhibitor of sodium-independent cholate uptake (Ki = 1 mumol/L). Uptake of radiolabeled S 3554 into isolated rat hepatocytes was observed to be rapid, cell specific, saturable, energy dependent, and carrier mediated. However, the carrier for S 3554 uptake was found not to be the cloned Na(+)-dependent taurocholate cotransporting polypeptide Ntcp. Expression of this carrier cRNA in Xenopus laevis oocytes did not stimulate S 3554 uptake.
ATP-Binding Cassette Transporters↗
The three processes leading to post PTCA restenosis: dependence on the lesion substrate.
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Angioplasty, Balloon, Coronary↗
Vulnerable and dangerous coronary plaques.
The clinical presentation and prognosis of coronary atherosclerosis depend more on plaque type than on plaque size. Stable plaques may narrow the arterial lumen and cause stable angina pectoris but are, otherwise, relatively harmless. In contrast, vulnerable plaques may rupture and thrombose, which is a potentially life-threatening event, being responsible for the development of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death. Gradual lipid accumulation and ongoing inflammation may destabilize a plaque, increasing the risk of sudden plaque disruption and thrombosis. External factors such as mechanical and hemodynamic stresses may be important in precipitating, or 'triggering', disruption of vulnerable plaques. It is, however, the ensuing thrombotic response that makes plaque disruption dangerous. The thrombotic response is dynamic with simultaneously ongoing thrombosis and thrombolysis, frequently causing intermittent flow obstruction leading to an unstable coronary syndrome. The challenge of today is to stabilize the vulnerable plaques, to prevent new formation of vulnerable plaques, and to prevent thrombosis on intact and disrupted plaques.
Animals↗
Bile acid derived HMG-CoA reductase inhibitors.
The target organ for HMG-CoA reductase inhibitors to decrease cholesterol biosynthesis in hypercholesterolemic patients is the liver. Since bile acids undergo an enterohepatic circulation showing a strict organotropism for the liver and the small intestine, the structural elements of an inhibitor for HMG-CoA reductase were combined with those for specific molecular recognition of a bile acid molecule for selective uptake by hepatocytes. Either, the HMG-CoA reductase inhibitors HR 780 and mevinolin were covalently attached to 3 xi-(omega-aminoalkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acids to obtain bile acid prodrugs, or the side chain of bile acids at C-17 was replaced by 3,5-dihydroxy-heptanoic acid--a structural element essential for inhibition of HMG-CoA reductase--to obtain hybrid bile acid: HMG-CoA reductase inhibitors. The prodrugs could, as expected, not inhibit rat liver HMG-CoA reductase to a significant extent, whereas the hybrid inhibitors showed a stereospecific inhibition of HMG-CoA reductase from rat liver microsomes with an IC50-value of 0.7 microM for the most potent compound S 2467 and 6 microM for its diastereomere S 2468. Uptake measurements with isolated rat hepatocytes and ileal brush-border membrane vesicles from rabbit small intestine revealed a specific interaction of both classes of bile acid-derived HMG-CoA reductase inhibitors with the hepatocyte and ileocyte bile acid uptake systems. Photoaffinity labeling studies using 3-azi- or 7-azi-derivatives of taurocholate with freshly isolated rat hepatocytes or rabbit ileal brush-border membrane vesicles revealed a specific interaction of bile acid derived HMG-CoA reductase inhibitors with the respective putative bile acid transporters in the liver and the ileum demonstrating the bile acid character of these derivatives, both for the prodrugs and the hybrids. Cholesterol biosynthesis in Hep G2 cells was inhibited by the bile acid prodrugs with IC50-values in the range of 68 nM to 600 nM compared to 13 nM for HR 780 and 130 nM for mevinolin. Among the hybrid inhibitors, S 2467 was the most active compound with an IC50-value of 16 microM compared to 55 microM for its diastereomere S 2468. Preliminary in vivo experiments showed an inhibition of hepatic cholesterol biosynthesis after oral dosage only with prodrugs such as S 3554, whereas the hybrid molecules were inactive after oral application.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
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↗
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↗
Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture.
BACKGROUND: Rupture of atherosclerotic plaques is probably the most important mechanism underlying the sudden onset of acute coronary syndromes. Macrophages may release lytic enzymes that degrade the fibrous cap and therefore produce rupture of the atherosclerotic plaque. This study was designed to quantify macrophage content in coronary plaque tissue from patients with stable and unstable coronary syndromes. METHODS AND RESULTS: Hematoxylin and eosin and immunostaining with anti-human macrophage monoclonal antibody (PG-M1) were performed. Computerized planimetry was used to analyze 26 atherectomy specimens comprising 524 pieces of tissue from 8 patients with chronic stable angina, 8 patients with unstable angina, and 10 patients with non-Q-wave myocardial infarction. Total plaque area was 417 +/- 87 mm2 x 10(-2) in patients with stable angina, 601 +/- 157 mm2 x 10(-2) in patients with unstable angina, and 499 +/- 87 mm2 x 10(-2) in patients with non-Q-wave myocardial infarction (P = NS). The macrophage-rich area was larger in plaques from patients with unstable angina (61 +/- 18 mm2 x 10(-2)) and non-Q-wave myocardial infarction (87 +/- 32 mm2 x 10(-2)) than in plaques from patients with stable angina (14 +/- 5 mm2 x 10(-2)) (P = .024). The percentage of the total plaque area occupied by macrophages was also larger in patients with unstable angina (13.3 +/- 5.6%) and non-Q-wave myocardial infarction (14.6 +/- 4.6%) than in patients with stable angina (3.14 +/- 1%) (P = .018). Macrophage-rich sclerotic tissue was largest in patients with non-Q-wave myocardial infarction (67 +/- 30 mm2 x 10(-2)) and unstable angina (55 +/- 19 mm2 x 10(-2)) than in patients with stable angina (11.5 +/- 4.1 mm2 x 10(-2)) (P = .046). Macrophage-rich atheromatous gruel was also largest in patients with non-Q-wave myocardial infarction (15 +/- 4 mm2 x 10(-2)) than in patients with unstable angina (3.3 +/- 1.7 mm2 x 10(-2)) or stable angina (2.4 +/- 1.2 mm2 x 10(-2)) (P = .026). CONCLUSIONS: Macrophage-rich areas are more frequently found in patients with unstable angina and non-Q-wave myocardial infarction. This suggests that macrophages are a marker of unstable atherosclerotic plaques and may play a significant role in the pathophysiology of acute coronary syndromes.
Aged↗
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↗
Dynamics in thrombus formation.
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Arterial Occlusive Diseases↗
Why do plaques rupture?
Rupture of the plaque surface, often with thrombosis superimposed, occurs frequently during the evolution of coronary atherosclerotic lesions. It is probably the most important mechanism underlying the sudden, rapid plaque progression responsible for acute coronary syndromes. The risk of plaque rupture depends on plaque type (composition) rather than plaque size (volume), because only plaques rich in soft extracellular lipids are vulnerable (rupture-prone). Most ruptures are tiny, occurring at the periphery of the fibrous cap that covers the lipid-rich core--points where the cap is usually thinnest and most heavily infiltrated by macrophage foam cells. Compared with intact caps, ruptured ones usually have less tensile strength and are more extensible, containing less collagen and glycosaminoglycans, more extracellular lipid, fewer smooth muscle cells, and more macrophages. Progressive extracellular lipid accumulation (lipid core formation) and cap weakening (macrophage related?) predispose the plaque to rupture and determine the actual vulnerability, which may change with time. Luckily, the plaque components responsible for vulnerability (soft lipid and probably macrophages) are apparently most likely to regress with treatment. The dynamic interplay between the actual plaque vulnerability and external stresses ("triggers") probably determines the particular moment and point of rupture, if this occurs. Vulnerability probably plays a more important role in rupture than triggers, because exercise stress testing of patients with advanced coronary artery disease rarely triggers a rupture/thrombus-related acute heart attack. A prerequisite is the presence of a vulnerable plaque.
Aging↗
[Dermatological laser treatment].
This article reviews the different lasers used in dermatology. Special emphasis is placed on the treatment of naevus flammeus ("portwine stain") where lasers are the treatment of choice. Argon laser and pulsed dye laser are the main lasers used in vascular skin diseases, and the article focuses on these two types. Copper vapour laser, neodymium-YAG-laser and CO2-laser are also presented. Information is provided about the availability of laser technology in the different health regions in Norway.
Adult↗
Coronary thrombosis: pathogenesis and clinical manifestations.
The majority (greater than 75%) of major coronary thrombi are precipitated by a sudden rupture of the surface of an atherosclerotic plaque (plaque fissuring) causing platelet aggregation where thrombogenic subendothelial tissue has been exposed. Whether the thrombus remains mural and limited, just sealing the rupture, or evolves into an occlusive thrombus seems to depend on: (1) the amount and character of exposed thrombogenic material; (2) the actual thrombotic-thrombolytic equilibrium; and (3) local flow disturbances due to preexisting atherosclerotic stenosis. Thrombus formation may take place within the stenosis, where blood velocity and shear forces are highest, or it may take place or extend poststenotically, where flow separation, recirculation, and turbulence prevail. Platelet aggregation within the stenosis is responsible for the primary flow obstruction, but fibrin subsequently enmeshes the platelets and thus stabilizes the thrombus. Most thrombi have a layered structure, indicating an episodic growth that may alternate with thrombus fragmentation and peripheral embolization: thrombosis and thrombolysis are dynamic processes occurring simultaneously. If the platelet-rich thrombus at the rupture site evolves into an occlusive thrombus, the blood proximal and distal to the occlusion may stagnate and coagulate, giving rise to a secondarily formed red stagnation thrombosis consisting predominantly of erythrocytes held together by fibrin membranes. A ruptured plaque with a dynamic thrombosis superimposed (with or without spasm) seems to underlie the great majority of acute ischemic syndromes: unstable angina, acute infarction, and sudden death. The clinical presentation and the outcome depend on the severity and duration of ischemia: whether the obstruction is occlusive or nonocclusive, transient or persistent--modified by the magnitude of collateral flow.
Coronary Artery Disease↗
Photoaffinity labeling of leukotriene binding sites in hepatocytes and hepatoma cells.
The method of direct photoaffinity labeling in the frozen state using the leukotrienes as suitable photolabile compounds may serve to identify and characterize polypeptides which interact with these eicosanoids during their hepatobiliary transport and metabolism. Furthermore, it will be a helpful technique to evaluate changes in the cell-specific protein pattern during neoplastic dedifferentiation of hepatocytes.
Affinity Labels↗