LPP expression during in vitro smooth muscle differentiation and stent-induced vascular injury.

Lipoma preferred partner (LPP) has been identified as a protein highly expressed in smooth muscle (SM) tissues. The aim of the present study was to determine mechanisms that regulate LPP expression in an in vitro model of SM cell (SMC) differentiation and in stent-induced pig coronary vessel injury. All trans-retinoic acid treatment of A404 cells induced a strong increase in LPP, as well as SM alpha-actin, SM myosin heavy chain, and smoothelin mRNA levels, in a Rho kinase (ROK)-dependent manner. Adenovirus mediated overexpression of myocardin in A404 cells significantly increased LPP mRNA expression. Interestingly, inactivation of RhoA with C3-exoenzyme or treatment with ROK inhibitors strongly inhibited myocardin mRNA expression in retinoic acid-treated A404 cells or human iliac vein SMCs. LPP silencing with short interfering RNA significantly decreased SMC migration. LPP expression was also markedly decreased in focal adhesion kinase (FAK)-null cells known to have impaired migration but rescued with inducible expression of FAK. LPP expression in FAK-null fibroblasts enhanced cell spreading. In stented pig coronary vessels, LPP was expressed in the neointima of cells lacking smoothelin and showed expression patterns identical to those of SM alpha-actin. In conclusion, LPP appears to be a myocardin-, RhoA/ROK-dependent SMC differentiation marker that plays a role in regulating SMC migration.

The role of inflammation in vascular injury and repair.

Inflammation plays a critical role in the vascular response to injury. In particular, mechanical injury using techniques such as balloon angioplasty and stenting results in complex inflammatory reactions which influence proliferation of vessel wall constituents such as endothelial cells, smooth muscle cells, and extracellular matrix proteins. Inflammatory cells are recruited to the injured vessel wall initially as a reparative mechanism; however, these same inflammatory processes are also pivotal in the development of restenotic lesions. Leukocytes serve as the primary inflammatory cells but we now know that platelets produce a number of important inflammatory mediators. This review describes the mechanisms that regulate endothelial cell migration, smooth muscle cell activation, and extracellular matrix protein production, all of which are key components in the inflammatory response to vascular injury.

Adenosine A(2A) receptor stimulation reduces inflammation and neointimal growth in a murine carotid ligation model.

Endothelial activation and leukocyte recruitment are early events in atherosclerosis and the vascular response to injury. Adenosine has anti-inflammatory effects on leukocytes and endothelial cells mediated through its A(2A) receptor. We tested the hypothesis that A(2A) activation would reduce inflammation and neointimal formation in a murine carotid ligation model. Before injury, mice were randomized to a 7-day subcutaneous infusion of a specific A(2A) receptor agonist (ATL-146e, 0.004 microg/kg per minute), vehicle control, ATL-146e plus ZM241385 (a selective A(2A) antagonist), or ZM241385 alone. Leukocyte recruitment and adhesion molecule expression were assessed at early time points, and the neointimal area was measured at 14 and 28 days after injury. Compared with control mice, ATL-146e-treated mice had significantly less neutrophil and macrophage recruitment and vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and P-selectin expression in the first 7 days after injury. Neointimal area was markedly and persistently reduced by 80% at 14 and 28 days, despite termination of ATL infusion at 7 days. ATL-146e+ZM241385-treated and ZM241385-treated animals had neointimal areas similar to those of control animals, confirming that the observed effects of ATL-146e were mediated specifically by the A(2A) receptor. These data demonstrate that novel stimulation of adenosine A(2A) receptors can inhibit early inflammatory processes that are important in neointimal formation after vascular injury.

Selective alpha(v)beta(3)-receptor blockade reduces macrophage infiltration and restenosis after balloon angioplasty in the atherosclerotic rabbit.

BACKGROUND: alpha(v)beta(3)-Integrin receptors are upregulated in atherosclerotic arteries and play a key role in smooth muscle cell and possibly inflammatory cell migration. We hypothesized that after balloon angioplasty (BA) of atherosclerotic arteries, selective inhibition of the alpha(v)beta(3)-receptor by XT199, a small-molecule, non-peptide-selective alpha(v)beta(3)-receptor antagonist, would reduce restenosis. METHODS AND RESULTS: After induction of focal atherosclerosis, rabbits underwent femoral BA and received XT199 (2.5 mg/kg IV bolus plus 2.5 mg. kg(-1). d(-1) IV; n=19) or vehicle (n=20) for 14 days. At 28 days after BA, the XT199 group had a larger lumen (0.75+/-0.26 versus 0.57+/-0.20 mm(2), P=0.03) and a smaller neointimal area (0.49+/-0.18 versus 0.68+/-0.25 mm(2), P=0.01) than the vehicle group. Angiographic analysis confirmed a 30% to 40% reduction in restenosis. Arteries harvested at 28 days after BA did not show a reduction in intima plus media smooth muscle cell content but did show a 50% reduction in macrophage cell density in the XT199 group (716+/-452 versus 1458+/-989 cells/mm(2), P<0.006). Neovessel density at 28 days was also reduced (23+/-42 versus 58+/-46 vessel cross sections/mm(2), P<0.02). Early after BA (ie, 3 to 7 days), there was a decrease in intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, indicative of a reduction in vascular cell activation. CONCLUSIONS: Selective alpha(v)beta(3)-receptor blockade for 14 days after BA in the focally atherosclerotic rabbit significantly reduced restenosis and limited macrophage infiltration and neovascularization in the vessel wall.

Relationship between extent of residual myocardial viability and coronary flow reserve in patients with recent myocardial infarction.

BACKGROUND: The presence of viability in an infarct zone implies an intact microvasculature. We hypothesized that coronary flow reserve (CFR), which assesses the microcirculation, would correlate with the extent of viability in infarction zones. METHODS: CFR was measured after stenting in 17 patients with single vessel disease >48 hours from infarction. Viability was determined with use of single-photon emission computed tomography sestamibi imaging. RESULTS: Sestamibi uptake in the infarct zone correlated with CFR in the infarct artery (r = 0.62, P =.008) and sestamibi uptake in the infarct zone was greater in patients with normal CFR than in patients with abnormal CFR (61.9 +/- 9.1% vs 46.3 +/- 9.6%, P =.004). In addition, CFR was greater in patients with viability compared with patients without viability (2.4 +/- 1.3 vs 1.4 +/- 0.4, P =.015). CONCLUSIONS: CFR correlates with the extent of viability after infarction. Preserved CFR in an infarct-related artery implies preserved viability.

Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits.

Macrophages play a critical role in the development and progression of atherosclerosis. This study was designed to examine the effect of the glucocorticoid, dexamethasone, (Dex), on macrophage accumulation after acute arterial injury. Twenty New Zealand white rabbits were fed a 2% cholesterol, 6% peanut oil, rabbit chow diet for one month prior to bilateral balloon dilatation of the femoral arteries. Ten rabbits received Dex (1 mg/kg, im.) the day before and then daily for 7 days after arterial injury; control rabbits received vehicle only. Seven days after injury, Dex treatment resulted in a 96% and 77% reduction (P < 0.002) in the mean number of macrophages accumulating in the intima and media, respectively. This effect was apparently not due to a reduction in the number of circulating monocytes or to the ability of monocytes from Dex treated animals to adhere to endothelium or migrate in response to a chemotactic signal, determined in vitro under static conditions. It was associated with a 61% reduction in monocyte chemoattractant protein-1 (MCP-1) antigen (P < 0.004) in the injured arterial wall (media+intima). Glucocorticoids may be useful in attenuating the inflammatory response and subsequent foam-cell accumulation after arterial injury.

Absence of p-selectin, but not intercellular adhesion molecule-1, attenuates neointimal growth after arterial injury in apolipoprotein e-deficient mice.

BACKGROUND: We tested the hypothesis that apolipoprotein (apo)E-deficient (apoE-/-) mice with targeted disruption of the intercellular adhesion molecule-1 (ICAM-1) or P-selectin gene (apoE-/- ICAM-1-/- or apoE-/- P-selectin-/- mice, respectively) are protected from neointima formation after arterial injury through inhibition of monocyte trafficking to sites of endothelial denudation. METHODS AND RESULTS: ApoE-/-, apoE-/- ICAM-1-/-, or apoE-/- P-selectin-/- mice were fed an atherogenic Western diet for 5 weeks and underwent wire denudation of the left common carotid artery after 1 week of feeding. The absence of P-selectin in apoE-/- mice inhibited neointima formation by 94% (P<0.0001) after arterial injury and reduced the intima-to-media ratio compared with the presence of P-selectin in apoE-/- mice. ICAM-1 deficiency did not protect against plaque formation after injury. Large numbers of macrophages were found in the neointima and media of apoE-/- and apoE-/- ICAM-1-/- mice. In contrast, almost no macrophages were found in the media or neointima of injured apoE-/- P-selectin-/- arteries. CONCLUSIONS: These findings demonstrate that the complete absence of P-selectin, but not ICAM-1, markedly reduces plaque area and suggest that P-selectin is critical for monocyte recruitment to sites of neointima formation after arterial injury.

The role of inflammation in vascular diseases.

When the body responds to an infectious insult, it initiates an immune response to eliminate the pathogen. The hallmark of the immune response is an inflammatory cascade that can also do extensive damage to host tissues. Inflammation is a major contributing factor to many vascular events, including atherosclerotic plaque development and rupture, aortic aneurysm formation, angiogenesis, and ischemia/reperfusion damage. The immune response is mediated by both circulating and resident leukocytes and the cells with which they interact (e.g., vascular endothelium and smooth muscle cells). The process is orchestrated by the activity of a changing series of released and displayed mediators. These include the expression of adhesion molecules on leukocytes and underlying vascular endothelium and the release of cytokines, chemokines, and tissue-destructive metalloproteases and reactive oxygen species. This review focuses on the causes, the inflammatory processes involved, and possible strategies for decreasing vascular disease through regulation of the inflammatory response.

Induction of IG9 monocyte adhesion molecule expression in smooth muscle and endothelial cells after balloon arterial injury in cholesterol-fed rabbits.

The expression of monocyte-specific adhesion molecules and chemokines by cell types within the vessel wall plays an important role in foam cell accumulation during atherosclerotic plaque development. We previously identified IG9, a novel monocyte adhesion protein that is expressed on endothelial cells (ECs) overlying human and rabbit advanced atherosclerotic plaques. The present study was designed to determine the temporal and spatial expression of IG9 and the chemokine, monocyte chemoattractant protein-1 (MCP-1), after balloon injury with (double injury) or without (single injury) prior air desiccation EC injury in the femoral arteries of rabbits fed a high-cholesterol diet. By immunohistochemical analyses, intense reactivity with monoclonal antibodies to IG9 and MCP-1 was detected 24 hours after single injury in medial smooth muscle cells (SMCs) and in SMCs of adventitial microvessels. However, monocyte infiltration of the tunica media was minimal or not detected in these sections. IG9 and MCP-1 antibody reactivity in vessel sections 28 days after single injury and 24 hours, 7 days, and 28 days after double injury was localized to medial and neointimal SMCs, foam cells, and luminal ECs overlying the plaques. Uninjured rabbit (cholesterol or normal diet) vessel sections exhibited minimal IG9 and MCP-1 immunostaining. In vitro studies using human aortic SMCs demonstrated IG9 protein induction after 24 hours of treatment with platelet-derived growth factor-BB and interferon-gamma or epidermal growth factor. IG9 expression was further increased by pretreatment of SMCs with the proatherogenic lipid, minimally oxidized low density lipoprotein. After balloon injury (24 hours), IG9 is induced in vascular SMCs before the detectable accumulation of monocytes within the vessel wall. Thus, the expression of IG9 by SMCs as well as by ECs may be an important factor in the accumulation of foam cells in atherosclerotic plaque development after arterial injury.

All-trans-retinoic acid limits restenosis after balloon angioplasty in the focally atherosclerotic rabbit : a favorable effect on vessel remodeling.

All-trans-retinoic acid (atRA) has potent in vitro effects on a number of processes involved in vascular injury and repair, such as modulating smooth muscle cell (SMC) proliferation and inducing SMC differentiation, and may play an important role in the in vivo response to vascular injury. We hypothesized that atRA would limit restenosis after balloon angioplasty through SMC-modulated changes in plaque size and vessel geometry. Balloon angioplasty was performed on rabbits with focal femoral atherosclerosis randomized to treatment with atRA or saline. At 28 days after balloon angioplasty, minimal luminal diameter was significantly larger in the atRA group (1.24+/-0.17 versus 1.12+/-0.22 mm, P=0.02). Histomorphometry confirmed a larger lumen area (0.51+/-0.20 versus 0. 34+/-0.13 mm(2), P=0.004) in the atRA group, with no difference in absolute plaque area. Internal elastic lamina and external elastic lamina areas were significantly larger in the atRA group (0.89+/-0. 27 versus 0.66+/-0.24 mm(2), P=0.001, and 1.29+/-0.38 versus 0. 98+/-0.32 mm(2), P=0.001, respectively). Vessel sections exhibited significantly more alpha-actin and desmin immunostaining (P=0.01) in the atRA-treated group. No differences in early cellular proliferation and collagen content were detected with the use of bromodeoxyuridine. In this atherosclerotic model of vascular injury, atRA limits restenosis after balloon angioplasty by effects secondary to overall vessel segment enlargement at the angioplasty site rather than by effects on plaque size or cellular proliferation. Increased alpha-actin and desmin immunostaining suggest a possible role for phenotypic modulation of SMCs in this favorable remodeling effect.

Local adenovirus-mediated delivery of hirudin in a rabbit arterial injury model.

UNLABELLED: Intravascular delivery of an E1/E3 deleted adenovirus encoding the hirudin protein reduces neointimal formation in the rat arterial injury model. Given the interspecies variability in response to adenoviral vectors, we tested this same construct in the hirudin-sensitive cholesterol-fed rabbit arterial balloon injury model. We hypothesized that local delivery of an E1/E3-deleted adenovirus encoding hirudin (Ad-Hir) in addition to early hirudin infusion would limit neointimal formation compared to early hirudin alone. METHODS AND RESULTS: Local delivery of Ad-Hir, 2.5 x 10(10) PFU/ml, using a double balloon catheter [n = 6 vessels (v)] produced a 79% reduction in vessel wall thrombin activity at 48 h after balloon angioplasty (BA) compared with vehicle (Veh, n = 6v; p = 0. 05). In chronic experiments, hypercholesterolemic rabbits underwent femoral BA, and received either early hirudin alone (n = 9v) or early hirudin plus locally delivered Ad-Hir (early hirudin + Ad-Hir; n = 9v), an E1/E3-deleted adenovirus encoding beta-galactosidase (early hirudin + AdGal; n = 7v), or Veh (early hirudin + Veh; n = 10v). Early hirudin + Ad-Hir did not limit the arterial response to injury versus the other groups at 4 weeks after BA. Plaque area, cross-sectional luminal area narrowing by plaque, and T cell infiltration were significantly increased in the adenovirus- versus non-adenovirus-treated arteries. Plaque area correlated with T cell density. CONCLUSION: Following BA in cholesterol-fed rabbits, local transduction with A-Hir produced a marked reduction in vessel wall-associated thrombin activity. However, this strategy increased rather than decreased the arterial response to BA injury. Our results suggest that the lack of therapeutic effect resulted from adenovirus-stimulated plaque formation, possibly resulting from a T cell-mediated inflammatory response.

Arterial injury increases expression of inflammatory adhesion molecules in the carotid arteries of apolipoprotein-E-deficient mice.

Recent studies demonstrate increased cellular adhesion molecule expression by neointimal endothelium overlying primary and restenotic atherosclerotic plaque. In this study, we developed an atherosclerotic mouse model of arterial injury and characterized adhesion molecule expression after injury. Sixteen apolipoprotein-E-(ApoE)-deficient mice fed a Western-type diet for 4 weeks underwent carotid artery wire denudation at week 2. For each segment, the extent of neointima formation and medial thickening, or adhesion molecule expression, were scored separately on a scale from 0 (no plaque/thickening or expression) to 3 (extensive plaque/thickening or expression) using Movat staining (n = 3) or immunohistochemical analysis (n = 13). Histology revealed significant medial thickening (1.8 +/- 0.9 vs. 0.3 +/- 0.5, p < 0. 001) versus controls and pronounced staining for monocytes/macrophages in the wall of injured vessels. Immunohistochemical analysis showed more robust expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the luminal surface of injured arteries versus controls (2.2 +/- 0.6 vs. 1.4 +/- 0.7, p < 0.01, and 2.5 +/- 0.5 vs. 1.2 +/- 0.6, p < 0.001, respectively). Injury increased adventitial ICAM-1 expression (2.6 +/- 0.5 vs. 1.6 +/- 0.5, p < 0.002) and medial VCAM-1 expression (2.2 +/- 0.6 vs. 1.2 +/- 0. 7, p < 0.004). Thus, carotid injury results in significant medial thickening and increases adhesion molecule expression beyond that induced in ApoE-deficient mice fed a Western diet alone. The observation of macrophage infiltration into the media at sites of increased ICAM-1 and VCAM-1 expression suggests that these molecules may mediate monocyte/macrophage trafficking into the wall of injured arteries.

Angiographic findings in patients undergoing catheterization for recurrent symptoms within 30 days of successful coronary intervention.

In 108 consecutive patients without abrupt vessel closure referred for repeat coronary angiography within 30 days of successful coronary intervention, 28 (26%) were found with restenosis at the treated site. None of the 27 patients who underwent stenting were found to have early restenosis; balloon angioplasty without stenting was the only independent predictor of early restenosis in patients with recurrent symptoms within 30 days of intervention.

Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice.

Apolipoprotein E-deficient (ApoE-/-) mice develop atherosclerotic lesions throughout the arterial tree, including the carotid bifurcation. Although the expression of adhesion molecules such as ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and P-selectin on endothelium that overlie atherosclerotic plaques has been implicated in monocyte recruitment to developing lesions, monocyte adhesion in atherosclerotic vessels has not been observed directly. To investigate which adhesion molecules may be important in monocyte adhesion to atherosclerotic lesions, an isolated mouse carotid artery preparation was developed and perfused with mononuclear cells. We show rolling and attachment of the human monocytic cell line U937 and the mouse monocyte-macrophage cell line P388D1 in carotid arteries from 10- to 12-week-old ApoE-/- and C57BL/6 wild-type mice fed a Western-type diet (21% fat wt/wt) for 4 to 5 weeks. No rolling was observed in carotid arteries from C57BL/6 or BALB/c wild-type mice fed a chow diet and little was observed in BALB/c mice fed a Western-type diet. This model represents early lesion development as shown by minimal macrophage infiltration in the intima of carotid arteries from ApoE-/- mice fed a Western-type diet. Rolling was observed at shear stresses that were characteristic of the low-shear recirculation zone near the carotid bifurcation. Mononuclear cell attachment and rolling were significantly inhibited by monoclonal antibody blockade of P-selectin or its leukocyte ligand P-selectin glycoprotein ligand-1. Rolling velocities increased after monoclonal antibody blockade of mononuclear cell alpha4-integrin or VCAM-1, which indicates that alpha4-integrin interacting with VCAM-1 stabilizes rolling interactions and prolongs monocyte transit times.

Effectiveness of heparin in preventing thrombin generation and thrombin activity in patients undergoing coronary intervention.

BACKGROUND: Thrombus is important in the pathophysiology of several complications of angioplasty, including abrupt closure and restenosis. Levels of prothrombin fragment F1.2 and fibrinopeptide A reflect thrombin generation and activity. The effect of angioplasty on levels of these markers is unclear. METHODS: Patients undergoing either balloon angioplasty (n = 30) or directional atherectomy (n = 9) were treated with heparin to maintain an activated clotting time of >300 seconds. Levels of F1.2, fibrinopeptide A, and thrombin-antithrombin complex were measured in the coronary sinus and coronary artery before and after intervention. Angiograms were reviewed for lesion morphologic characteristics and dissection. RESULTS: There was no evidence for thrombin generation or increased thrombin activity after angioplasty regardless of lesion morphologic characteristics, dissection, type of intervention, or blood sampling site. In fact, coronary sinus concentrations of F1.2 decreased after intervention (median 0.31 nmol/L; 25th percentile 0.26 nmol/L, 75th percentile 0.37 nmol/L) before intervention to 0.23 nmol/L (25th percentile 0.19 nmol/L, 75th percentile 0.34 nmol/L) after intervention (P =.002). CONCLUSIONS: Angioplasty performed in the presence of adequate heparin inhibited thrombin even when there was complex lesion morphology or dissection. These data suggest that heparin provides satisfactory thrombin inhibition during routine angioplasty.

Early plus delayed hirudin reduces restenosis in the atherosclerotic rabbit more than early administration alone: potential implications for dosing of antithrombin agents.

BACKGROUND: A 2-hour infusion of r-hirudin at the time of balloon angioplasty limits restenosis in atherosclerotic rabbits. Because thrombin activity in the vessel wall after angioplasty remains high for 48 to 72 hours, we hypothesized that a second infusion of hirudin at 24 hours would reduce restenosis more than early treatment alone. METHODS AND RESULTS: Femoral atherosclerosis was induced in 35 rabbits by air desiccation injury and a high-cholesterol diet. At the time of angioplasty, rabbits were randomly assigned to 1 of 4 groups: controls: heparin bolus, saline infusion at 24 hours; early hirudin: hirudin bolus+2 hours' infusion, saline infusion at 24 hours; delayed hirudin: heparin bolus, hirudin infusion+/-bolus at 24 hours; and early+delayed hirudin: hirudin bolus+2 hours' infusion, hirudin infusion+/-bolus at 24 hours. Rabbits were euthanized after 28 days. The early+delayed hirudin treatment group had less loss of minimal lumen diameter by angiography at 28 days. By histomorphometry, cross-sectional area narrowing by plaque was least in the early+delayed treatment group compared with controls (P=0.0001), early hirudin (P=0.01), or delayed hirudin (P=0.001). The early+delayed hirudin group also had a significant reduction in absolute plaque area and an improvement in lumen area compared with the other groups. No differences were observed between treatment groups with respect to the cross-sectional area encompassed by the internal or external elastic laminae. CONCLUSIONS: Combined early+delayed administration of hirudin significantly reduces angiographic restenosis and cross-sectional area narrowing by plaque compared with early or late treatment alone. These results suggest that restenosis after balloon angioplasty is markedly influenced by thrombin-mediated events not only occurring early but also extending beyond the first 24 hours in this model.

Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries.

BACKGROUND: Tissue factor (TF) is a transmembrane glycoprotein that, after binding to factor VII/VIIa, initiates the extrinsic coagulation pathway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth muscle cells, further perpetuating the thrombogenic cycle. This study was designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon angioplasty in the cholesterol-fed rabbit femoral artery and porcine coronary artery models. METHODS AND RESULTS: Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arteries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig coronary arteries (double or single injury), TF-antibody and Dig-VIIa staining were noted in association with endothelial cells, smooth muscle cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater after balloon angioplasty than in vessels that had not undergone angioplasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1 mg/kg bolus plus 0.7 mg x kg(-1) x d(-1) infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin only). This effect was more prominent on the neointima and was more striking in the porcine than the rabbit model. CONCLUSIONS: TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteries and porcine coronary arteries, is attenuated by specific thrombin inhibition with hirudin. These results suggest that thrombin inhibition, in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque through this effect on TF expression.

Cardiogenic shock: therapy and prevention.

Cardiogenic shock is defined as profound circulatory failure resulting in insufficient tissue perfusion to meet resting metabolic demands. It occurs in approximately 7.5% of patients with acute myocardial infarction. Treatment strategies include inotropic agents, use of intra-aortic balloon counterpulsation, and revascularization. Current evidence supports the use of primary angioplasty. Surgery should be considered in patients with triple-vessel disease. If early catheterization is not available, thrombolytic therapy should be given to eligible patients and transfer to an interventional facility should be considered. Effective therapy for shock must also include a prevention strategy. This requires identification of patients at high risk for shock development and selection of patients who are candidates for aggressive intervention.

A new single-injury model of balloon angioplasty in cholesterol-fed rabbits: beneficial effect of hirudin and comparison with double-injury model.

Air desiccation endothelial injury followed by cholesterol feeding is known to induce focal femoral atherosclerosis in rabbits. We previously demonstrated the effectiveness of hirudin in limiting restenosis after balloon angioplasty (BA) in this double instrumentation injury (DI) model. In the present study, we sought to determine whether BA without prior air desiccation endothelial injury (single instrumentation injury (SI)) would lead to similar femoral lesions, and whether the response to this injury might also be limited by hirudin. Accordingly, 38 femoral arteries of cholesterol-fed rabbits underwent BA with (n = 18, DI group) or without (n = 20, SI group) prior air desiccation endothelial injury. Animals were killed 24 hours or 28 days after BA. Twenty-four hours after BA, the SI group (n = 10) had a significantly smaller percentage of cross-sectional area narrowing by plaque than the DI group (n = 8) (0% versus 42% +/- 9%, p = 0.008). However, 28 days after BA, the percentages of cross-sectional area narrowing by plaque in the SI (n = 10) and DI (n = 10) groups were similar (59% +/- 6% versus 68% +/- 1%, p = NS). The percentages of intima (16% +/- 3% versus 16% +/- 3%, p = NS) and media occupied by foam cells were also similar in the two groups. To test whether hirudin administration would limit arterial narrowing after injury in the SI model, we randomly assigned cholesterol-fed rabbits that had not undergone air desiccation injury to either bolus hirudin followed by repeat dosing 24 hours after BA or bolus heparin (150 U/kg) at the time of BA. The hirudin-treated group showed significantly less angiographic and histologic restenosis 28 days after BA, despite no difference in early (0 to 72 hours) cumulative cellular proliferation between the two groups. Thus, in the cholesterol-fed rabbit, plaque formation and foam cell accumulation are similar after BA of a non-air-desiccated (SI) or focally atherosclerotic (DI) artery. Thrombin inhibition with hirudin limits arterial narrowing after SI, further emphasizing the role of thrombin in neointimal growth after injury.