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A 49-year-old man who had undergone coronary artery bypass grafting 16 months earlier presented with complaints of increasing angina pectoris. Initial angiography of the left coronary artery showed that contrast dye went retrograde up the left internal mammary artery (LIMA) and into the subclavian artery (Figure, A). Competitive flow was observed in the chest wall …

Alpha(v)beta3 integrins play an important role in vascular healing. Vascular injury is a stimulus for expression of alpha(v)beta3 by vascular cells and, among other effects, alpha(v)beta3 integrins function in the adhesion of activated platelets to endothelium. white cell/endothelium interactions, platelet-mediated thrombin generation, fibrin clot retraction by nucleated cells, smooth muscle cell (SMC) migration and proliferation, vascular cell apoptosis, and vascular remodeling. There are ten different animal models in which treatment with alpha(v)beta3 antagonists reduced the vascular response, including (neo)intima formation, after mechanical injury. These studies, along with mechanistic data derived from cell culture studies, provide compelling evidence that alpha(v)beta3 integrins are involved in vascular repair processes. The challenge is to develop a therapeutic agent that will prove effective in reducing restenosis in humans following percutaneous coronary intervention (PCI).

Chronic pericardial effusions are a major cause of morbidity in some clinical settings. Although the treatment of choice for acute symptomatic pericardial effusions (tamponade) is pericardiocentesis, the long-term management of symptomatic chronic pericardial effusions provides a greater challenge. The aim of this review is to provide insight into the presentation,diagnosis, and different treatment options available to patients with chronic symptomatic pericardial effusions,with emphasis on malignant pericardial effusions. Peri-cardiocentesis with sclerosing agents, radiation therapy,percutaneous, and surgical pericardiotomy and other surgical techniques are particularly efficacious, depend-ing on the underlying cause and the patient's prognosis.

BackgroundOur objective was to determine whether abciximab, eptifibatide, or tirofiban inhibited ligand binding to αvβ3integrins on human aortic smooth muscle cells (HASMCs) or human umbilical vein endothelial cells (HUVECs). Abciximab binds αIIbβ3on platelets and αvβ3on HUVECs with similar affinity, whereas eptifibatide and tirofiban are thought to be highly specific for αIIbβ3. The conclusion that eptifibatide does not bind vascular αvβ3integrins may be premature, however, because recent studies have demonstrated that the affinity of αvβ3for various ligands, including antagonists, is subject to modulation.Methods and ResultsAbciximab and 7E3, the anti–β3integrin monoclonal antibody from which abciximab was derived, bound αvβ3on HASMCs in a specific and saturable manner and with an affinity similar to binding to αIIbβ3on platelets. 7E3 and eptifibatide inhibited αvβ3-mediated attachment of HASMCs to thrombospondin (TSP) and prothrombin but had no effect on αvβ5- or β1-mediated HASMC attachment to vitronectin-, collagen-, or fibronectin-coated or noncoated tissue culture plates. The inhibitory effect of eptifibatide was similar in magnitude and not additive to that of 7E3. Eptifibatide and 7E3 inhibited αvβ3-mediated attachment of HUVECs. Tirofiban had only nonspecific effects on HASMC attachment to extracellular matrix proteins. In cell proliferation assays, eptifibatide inhibited αvβ3-mediated responses to soluble TSP by HASMCs and β3integrin–expressing HEK cells.ConclusionsEptifibatide and 7E3, but not tirofiban, specifically inhibit αvβ3-mediated binding of human smooth muscle and endothelial cells.

M valve prolapse (MVP) is a common valvular disorder characterized by abnormalities of the mitral valve apparatus that result in “billowing” of 1 or both mitral leaflets into the left atrium during systole, with or without mitral regurgitation (MR).1–3 It is the most frequently diagnosed valve abnormality in the industrial world,4,5 and the most common primary cause for dysfunction requiring mitral valve repair or replacement.6 Clinical classification may have significant overlap and “the pathogenesis of symptoms is not completely understood.”7 The overall incidence (by echocardiography) in the Framingham study was 5%, with a frequency in women approximately twice that of men.8 Table 1 highlights the variability in the prevalence of MVP by different diagnostic methods. MVP is classified as an inheritable connective tissue disorder that is regarded as an autosomal dominant disorder with variable penetrance and is divided into primary and secondary MVP. Primary MVP accounts for the vast majority of the cases and many, but not all, of these are associated with myxomatous degeneration of the mitral valve (MV). Secondary MVP is caused by chordae tendineae rupture and/or abnormal left ventricular (LV) wall motion. Potential causes of secondary MVP include coronary artery disease, rheumatic heart disease, cardiomyopathies, and infective endocarditis.9 Also, MVP may be associated with heritable disorders such as the Marfan syndrome, the Ehlers-Danlos syndrome, and other connective tissue disorders in which myxomatous degeneration of the MV is a prominent feature. Variables that decrease LV size can worsen MVP and similarly, variables that increase LV size can mask MVP. LV size is affected by blood volume, body position (supine, standing, etc.), and maneuvers (eg, Valsalva). A decrease in LV volume is the probable cause of the increased incidence of MVP in atrial septal defect and anorexia nervosa.10–12

Abstract —Thrombin is a serine protease that potently activates platelets and catalyzes the conversion of fibrinogen to fibrin. Thrombin also exerts direct effects on vascular cells, such as smooth muscle cells, via interactions with members of the protease-activated receptor family. Evidence in several animal models implicates thrombin-mediated signaling events in the response to injury that typifies vascular lesion formation in atherosclerosis and restenosis. In this review, we examine the activation of protease-activated receptors by thrombin, the downstream signaling events mediated by these receptors, and the physiological role of thrombin in vascular cells and vascular disease.

Transforming growth factor (TGF)-β1 has been implicated in vascular healing responses after mechanical injury. Using cultured rat aortic smooth muscle cells (RASMC), we examined the hypothesis that production and secretion of thrombospondin (TSP) contributes to TGF-β1-induced proliferation. We found that TGF-β1 enhanced production and secretion of TSP, with peak levels of secreted TSP observed 24 h after treatment. RASMC treated with TGF-β1 secreted a mitogenic activity that was transferable in conditioned media and partially inhibited by C6.7, a monoclonal anti-TSP antibody. Exogenous TSP stimulated a proliferative response, with maximal [3H]thymidine incorporation occurring 24 h earlier than maximal [3H]thymidine incorporation in response to TGF-β1-treatment. Pretreatment with C6.7 or polyclonal anti-TSP neutralizing antibodies inhibited TGF-β1-induced proliferation of RASMC. Proliferative responses to TGF-β1 were also inhibited by pretreatment with an anti-β3integrin monoclonal blocking antibody (F11), RGD peptides, and the anti-αvβ3disintegrin echistatin. Treatment with TSP and TGF-β1 increased c-Jun NH2-terminal kinase (JNK)1 activity, with peak effects observed at 15 min and 4 h, respectively. Treatment with C6.7 or F11 inhibited TGF-β-induced activation of JNK1. In summary, these studies support the hypothesis that TGF-β-induced JNK1 activation and proliferation of RASMC require secretion of TSP and ligation of αvβ3-integrins.

This article discusses the cases for four patients with unstable angina. The first case is an example of the "high-risk" patient with widespread ECG changes, heart failure, and enzymatic elevations during an episode of chest pain. The second patient illustrates an unusual cause of unstable angina in a young women. The third patient had a large thrombus visible on angiography and management strategies for dealing with intracoronary thrombus are discussed. The final patient had an extensive past cardiac history with two prior coronary artery bypass operations and we discuss the recent advances made in the treatment of degenerative vein graft disease.

Controversy exists regarding the diagnostic accuracy, optimal technique, and timing of noninvasive stress testing after percutaneous transluminal coronary angioplasty (PTCA). Many patients return with chest pain after PTCA, and because the incidence of restenosis has been reported to be as high as 50%, a noninvasive test with a high predictive value is needed to reduce the need for unnecessary coronary angiography. Studies have shown that the sensitivity and specificity of stress testing varies depending on the amount of time elapsed since the procedure. Soon after a successful PTCA, perfusion defects on nuclear imaging following exercise or pharmacologic stress may be detected in asymptomatic patients without angiographic restenosis. In many patients, abnormal stress myocardial perfusion scans will normalize spontaneously, and thus stress testing with nuclear imaging within 4 to 6 weeks of PTCA lacks specificity for detecting restenosis. In contrast, stress echocardiography which detects wall motion abnormalities rather than perfusion mismatch has been reported to offer more specific information on myocardial ischemia and restenosis early after PTCA. In patients who develop chest pain more than 6 weeks after PTCA, the ability to accurately identify restenosis is shared by both echocardiographic and nuclear imaging methods. The purpose of this review is to clarify the strengths, pitfalls, and prognostic value of different stress modalities and cardiac imaging techniques in patients who develop chest pain within 6 months of undergoing PTCA.

Alpha-thrombin is a multifunctional serine proteinase that is concentrated at sites of vascular injury and has been implicated in vascular healing responses following balloon injury. In addition to its well-known hemostatic effects, thrombin stimulates smooth muscle cell (SMC) proliferation via binding of protease activated receptor-1 (PAR-1), a seven transmembrane, G-protein-coupled cell surface receptor. Following activation of this receptor, SMC produce and secrete various autocrine growth factors, including platelet-derived growth factor-AA (PDGF-AA), basic fibroblast growth factor (bFGF), heparin binding epidermal growth factor (HBEGF), and transforming growth factor-beta (TGFbeta). The role that autocrine growth factors play in alpha-thrombin-induced proliferation will be discussed in this review.

Integrins are heterodimeric transmembrane glycoproteins involved in cell-cell and cell-extracellular matrix interactions. Two highly homologous β3-containing integrins have been identified: αvβ3 (also known as the vitronectin receptor) and αIIbβ3 (also known as platelet glycoprotein [GP] IIb/IIIa). αvβ3 can be expressed by a variety of cell types including endothelial cells, smooth muscle cells (SMCs), leukocytes, platelets, osteoclasts, and mesangial cells, whereas αIIbβ3 is found only on platelets and megakaryocytes. αvβ3 consists of a 125-kDa α subunit and a 105-kDa β subunit and, in addition to vitronectin, binds other extracellular proteins including osteopontin, fibronectin, fibrinogen, thrombospondin, proteolysed collagen, DEL1 (developmentally regulated endothelial locus-1), plasminogen activator inhibitor (PAI)-1, prothrombin, DANCE (developmental arteries and neural crest epidermal growth factor [EGF]-like), and von Willebrand factor (vWF). Similar to αIIbβ3 integrins on platelets, αvβ3 integrins exist in active and inactive conformations, with variable affinity for ligands, depending on the cell type and modulation by signaling events.1 See page 1376 In the normal artery, vascular expression of αvβ3 integrins is generally limited to the luminal endothelial monolayer.2,3 After vascular injury, αvβ3 expression increases markedly, a finding that has been consistent across numerous animal models including baboons, rats, rabbits, mice, and pigs.4 αvβ3 expression is observed rapidly in the media after injury and is found …

Vascular smooth muscle cell microparticles and coronary no-reflow:another piece of the puzzle?

Two patients, treated with enoxaparin and eptifibatide, developed significant guide catheter-associated thrombus while undergoing intravascular ultrasound (IVUS). Using an ex vivo assay, we found that activation of a multielement IVUS catheter resulted in a decrease in anti-Xa activity and a decrease in clot formation time. This effect occurred rapidly and repeatedly after activation of the IVUS catheter.

A patient was evaluated for complaints of right lower extremity claudication that had persisted for 2 years. Ankle-brachial index was normal in both legs but Doppler evaluation detected a stenosis at the origin of the right common iliac artery. Angiography revealed a complex stenosis of intermediate severity (Figure, A). The pressure gradient across the lesion under basal conditions was 6 mm Hg (mean arterial pressure [MAP] was 99 mm Hg in the aorta and was …

Transforming growth factor-beta 1 (TGF-beta 1) has been implicated in mediating smooth muscle cell (SMC) growth after vascular injury. Studies examining TGF-beta-induced growth of cultured SMC have identified only modest mitogenic effects which are largely dependent on autocrine production of platelet-derived growth factor-AA (PDGF-AA). Recent studies have suggested, however, that TGF-beta also may have delayed growth effects independent of PDGF-AA. The aims of the present studies were to examine the effects of TGF-beta on chronic growth responses of cultured SMC. Results demonstrated that TGF-beta elicited a delayed growth response (24 fold increase in 3H-TdR incorp. from 48-72 h) and enhanced SMC production of PDGF-AA (eightfold increase at 24 h). Neutralizing antibodies to PDGF-AA, however, inhibited only 10-40% of delayed TGF-beta-induced growth. Co-treatment with TGF-beta transiently delayed epidermal growth factor (EGF)-, basic fibroblast growth factor (bFGF)-, or PDGF-BB-induced entry into S phase but enhanced the delayed growth responses to these growth factors by 16.0-, 5.8-, or 4.2-fold, respectively. Neutralizing antibodies to PDGF-AA had no effect on these synergistic responses and exogenous PDGF-AA did not increase growth responses to EGF, bFGF, or PDGF-BB. In summary, TGF-beta induces marked delayed growth responses, alone and in combination with EGF, bFGF or PDGF-BB, that are largely independent of PDGF-AA.

Previous studies have shown that alpha-thrombin (Thr) is a mitogen for cultured smooth muscle cells (SMC), but controversy exists concerning mechanisms of growth stimulation. The purpose of these studies was to determine whether autocrine production of platelet-derived growth factor-AA (PDGF-AA) mediated Thr-induced SMC mitogenesis. SMC derived from aortae of Sprague-Dawley rats were grown to confluence, growth arrested in serum-free medium, and treated. Conditioned medium (CM) was harvested by adding bovine serum albumin as a carrier and hirudin to neutralize residual Thr. Results demonstrated that CM from Thr-treated SMC (Thr CM) had increased mitogenic activity compared with control CM (Cnt CM) and that PDGF-AA levels were increased 12-fold in Thr CM compared with Cnt CM. The excess mitogenic activity in Thr CM was markedly inhibited by PDGF-AA-neutralizing antibodies. Cotreatment with Thr and PDGF-AA-neutralizing antibodies resulted in a 30% decrease in Thr-induced [3H]thymidine incorporation. These results demonstrate that autocrine production of PDGF-AA partially mediated Thr-induced SMC mitogenesis.

Angiotensin II (Ang II) is the dominant effector of the renin-angiotensin system. In addition to its well-known hemodynamic and endocrine effects, Ang II regulates the cardiovascular remodeling associated with hypertension, atherosclerosis, heart failure, and diabetes mellitus. The importance of Ang II in cardiovascular disease states is highlighted by the prominent role that ACE inhibitors and angiotensin receptor blockers play in cardiovascular medicine. These drugs reduce clinical events and improve survival in patients with vascular disease or congestive heart failure and are among the most widely used medications in the world.1 2 There is accumulating evidence that Ang II has direct effects on smooth muscle cells (SMCs) that contribute to abnormalities ranging from subtle vascular dysfunction to severe atherosclerosis, ischemia, and necrosis. Ang II stimulates proliferation, hypertrophy, and migration of cultured vascular SMCs (VSMCs) via binding to the angiotensin type 1 (AT1) receptor.3 This receptor is a member of the superfamily of 7 transmembrane–spanning, G protein–coupled cell surface receptors (GPCRs). Traditionally, these receptors were thought to elicit intracellular signaling solely via activation of heterotrimeric G proteins, …

Background The use of abciximab (c7E3 Fab) or eptifibatide improves clinical outcomes in diabetics undergoing percutaneous coronary intervention. These β3 integrin inhibitors antagonize fibrinogen binding to αIIbβ3 integrins on platelets and ligand binding to αvβ3 integrins on vascular cells. αvβ3 integrins influence responses to insulin in various cell types but effects in human aortic smooth muscle cells (HASMC) are unknown. Results and discussion Insulin elicited a dose-dependent proliferative response in HASMC. Pretreatment with m7E3 (an anti-β3 integrin monoclonal antibody from which abciximab is derived), c7E3 or LM609 inhibited proliferative responses to insulin by 81%, 59% and 28%, respectively. Eptifibatide or cyclic RGD peptides completely abolished insulin-induced proliferation whereas tirofiban, which binds αIIbβ3 but not αvβ3, had no effect. Insulin-induced increases in c-Jun NH2-terminal kinase-1 (JNK1) activity were partially inhibited by m7E3 and eptifibatide whereas antagonism of αvβ3 integrins had no effect on insulin-induced increases in extracellular signal-regulated kinase (ERK) activity. Insulin stimulated a rapid increase in the number of vinculin-containing focal adhesions per cell and treatment with m7E3, c7E3 or eptifibatide inhibited insulin-induced increases in focal adhesions by 100%, 74% and 73%, respectively. Conclusion These results demonstrate that αvβ3 antagonists inhibit signaling, focal adhesion formation and proliferation of insulin-treated HASMC.

And diff'ring judgments serve but to declare, that Truth lies somewhere, if we knew but where.—William Cowper, Hope Ever since the advent of percutaneous treatment of coronary disease, restenosis has been the “Achilles' heel,” limiting long-term success. Early clinical studies evaluated

GP IIb/IIIa inhibitors are one of the most exciting pharmacological advances in the treatment of coronary artery disease to be developed this decade. They have proven benefit in the treatment of patients undergoing high-risk percutaneous interventions and in patients with unstable angina or non-Q-wave myocardial infarction. In all of these patients, they should be used in conjunction with aspirin and heparin. Although bleeding complications are high in initial studies, they are much less common with increased clinical experience and careful attention to heparin dosing. Important questions that will be answered in the next several years include whether there are significant differences between the available agents and whether oral formulations will be safe and effective.

Background: Myocardial necrosis (Ml) after percutaneous coronary intervention (PCI) IS associated with an increased incidence of late adverse outcomes. Methods: We conducted a prospective randomized. placebo-controlled trial in 150 PCI patients to determine whether intracoronary (IC) propranolol ( 0.015mglkg) decreases post PCI MI and in which subgroups this effect occurs. Results: Post -PCI Ml &K-MB > upper limit of normal) developed in 17% of IC propranolol pts (13/75) and 36% of placebo pts ( 27175) (p=O.Ol). The figure shows that this effect is widely applicable including the subgroup receiving prophylactic GP llbillla inhibitors (28% of pts) and chronic oral pre-PCI betablockers (64%). Factors associated with decreased risk of MI were IC propranolol (OR: 0.40, Cl: 0.17-0.91, p= 0.03) and prophylactic GP Ilb/llla use (OR: 0.41, Cl: 0.14-I .08, p= 0.08). IC propranolol decreased MIS in GP llblllla pts ( O%vs. 41%) and pts on chronic beta blockers ( 16% vs. 35%).Factors associated with increased Ml were age > 60 years old and mechanical complications during PCI. IC propranolol decreased MI risk in older pts (19% vs. 46%) and in patients with mechanical complications (41% vs. 61%). Conclusion: These data are consistent with IC propranolol being a broadly effective cardioprotective agent during PCI. *ak*n