Increased intramural expression of plasminogen activator inhibitor type 1 after balloon injury: a potential progenitor of restenosis.

Objectives: This study was performed to determine whether altered gene expression of plasminogen activator inhibitor type 1 (PAI-1) occurs within the arterial wall after experimentally induced balloon injury.

Background: PAI-1, known to inhibit fibrinolysis in the circulation and to be present within atherosclerotic vessels, may influence proteolysis in the arterial wall and neointimal formation after angioplasty.

Methods: In rabbit carotid arteries subjected to balloon injury, both PAI-1 gene and protein expression were assayed sequentially with the use of Northern blotting, in situ hybridization and immunohistochemical studies.

Overexpression of plasminogen activator inhibitor type-1 in senescent fibroblasts from normal subjects and those with Werner syndrome.

We previously reported that plasminogen activator inhibitor type-1 (PAI-1) mRNA was present at higher steady-state levels in prematurely senescent fibroblasts derived from a subject with Werner syndrome (WS) compared to early passage (EP) fibroblasts from an age-matched normal subject (Murano et al., 1991, Mol. Cell.

Modulation of expression of monocyte/macrophage plasminogen activator activity and its implications for attenuation of vasculopathy.

Background: The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on cell surfaces has the potential to influence degradation of extracellular matrix (ECM). Thus, uPA bound to monocyte/macrophages and its interactions with plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2) may modify atherogenesis by altering cell-associated proteolytic activity, degradation of ECM, and neointimal formation at sites of vascular injury.

Methods And Results: To determine whether the expression of proteins on the surface of cells involved in fibrinolysis changes in human cells in response to mediators implicated in atherogenesis, we exposed U937 cells (an immortal human monocyte-like cell line) to transforming growth factor-beta (TGF-beta) and to thrombin.

Lack of degradation of antithrombin III by tissue-type plasminogen activator or plasmin.

Background: Coronary thrombolysis is an established initial approach in the treatment of acute transmural myocardial infarction. However, conjunctive anticoagulation regimens are often suboptimal. Heparin is the only intravenously administered anticoagulant approved by the USA Food and Drug Administration commonly used for this purpose.

Inhibition of type-1 plasminogen activator inhibitor production by antisense oligonucleotides in human vascular endothelial and smooth muscle cells.

We have hypothesized that type-1 plasminogen activator inhibitor (PAI-1) may exacerbate accumulation of extracellular matrix in atheroma by inhibiting local generation of plasmin and intramural proteolysis. Thus, suppression of PAI-1 expression would decrease atherogenesis. To inhibit expression of PAI-1 in cultured human umbilical vein endothelial and aortic smooth muscle cells, a 20-base antisense phosphorothioate oligonucleotide targeting specific sequences in the 3'-untranslated region of the PAI-1 gene was used.

Ultrasonic tissue characterization: integrated backscatter imaging for detecting myocardial structural properties and on-line quantitation of cardiac function.

Quantitative myocardial tissue characterization is being developed as an adjunct to conventional echocardiography to delineate the physical state of myocardium under diverse pathophysiological states. Real-time quantitative integrated backscatter imaging has made possible clinical investigations carried out in the United States, Europe, and Japan in patients with ischemic heart disease, hypertrophic cardiomyopathy, and cardiac allograft rejection, among others. A modification of the imaging processing used for characterization of tissue facilitates automatic detection of endocardial blood interfaces and on-line quantification of ventricular size and function, which has been recently introduced in clinical practice.

Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin. A potential risk factor for vascular disease.

Background: Both vascular disease and elevated concentrations in plasma of plasminogen activator inhibitor type-1 (PAI-1) are prominent in patients with non-insulin-dependent diabetes mellitus (NIDDM). We and others have hypothesized that the increased PAI-1 may contribute to acceleration of atherosclerosis in this condition and in other states characterized by insulin resistance as well. Surprisingly, however, elevations of PAI-1 decrease when type II diabetic patients are treated with exogenous insulin, as do circulating concentrations of the precursor of insulin, proinsulin, in plasma.

Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients.

Accelerated atherosclerosis is the leading cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM). Impaired endogenous fibrinolytic activity may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi and clot-associated mitogens. This study was conducted to further characterize endogenous fibrinolysis in lean and obese nondiabetic subjects and in NIDDM patients and to identify mechanisms responsible for the alterations identified.

Attenuation of thrombolysis by release of plasminogen activator inhibitor type-1 from platelets.

Although platelets contain approximately 90% of the total amount of plasminogen activator inhibitor type-1 (PAI-1) present in blood, the functional significance of PAI-1 in platelets has been controversial. Most assessments of platelet PAI-1 have been performed with platelet lysates in which the PAI-1 derived from platelets may have been inactivated during the course of lysis. This study was performed to determine whether elaboration of PAI-1 from platelets activated physiologically by thrombolysis of pre-formed clots inhibits activation of plasminogen by tissue-type plasminogen activator (t-PA).

Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis.

Because of the frequent occurrence of premature cardiovascular disease in patients with non-insulin-dependent, type II diabetes mellitus (NIDDM), the attenuated fibrinolytic activity of plasma from type II diabetic patients with increased concentrations of plasminogen activator inhibitor type-1 (PAI-1), and the fact that insulin stimulates synthesis of PAI-1 by human hepatic cells in vitro, we and others have hypothesized that accelerated vascular disease in type II diabetes may result in part from impaired fibrinolysis secondary to excessive elaboration of PAI-1 stimulated by insulin. Alternatively, the hyperglycemia associated with type II diabetes could influence the synthesis and secretion of PAI-1 directly. The present study was performed to determine whether PAI-1 secretion is or is not sensitive to the prevailing concentration of glucose in the conditioned medium of endothelial and liver cells, which are thought to be the major sources of circulating PAI-1 in vivo.

Comparison of carbon-11-acetate with fluorine-18-fluorodeoxyglucose for delineating viable myocardium by positron emission tomography.

Objectives: This study was designed to determine in patients with advanced coronary disease whether prediction of recovery of mechanical function after coronary revascularization could be accomplished more effectively by positron emission tomography (PET) with carbon-11 (11C)-acetate than by PET with fluorine-18 (18F)-fluorodeoxyglucose.

Background: Results of previous studies have demonstrated that preservation of myocardial oxidative metabolism (measured by PET with 11C-acetate) is necessary for recovery of systolic function after coronary revascularization.

Methods: Myocardial oxidative metabolism was quantified before revascularization in 34 patients by the analysis of the rate of myocardial clearance of 11C-acetate.

Inhibition of endothelial cell expression of plasminogen activator inhibitor type-1 by gemfibrozil.

Increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) in plasma are associated with impaired fibrinolysis and venous and arterial thrombo-embolic disease. In pilot studies designed to identify pharmacologic approaches capable of diminishing such increases, we found that gemfibrozil attenuated the stimulation of synthesis of PAI-1 in a human, immortal, hepatoma cell line (Hep G2) induced by platelets. The present study was performed to determine whether it exerts analogous effects in non-immortal endothelial cells and whether it may therefore facilitate fibrinolysis locally in vivo.

Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type 1 by endothelial injury.

Accumulation of plasminogen activator inhibitor type 1 (PAI-1) in the arterial wall may accelerate atherogenesis by inhibiting fibrinolysis, diminishing proteolysis of extracellular matrix proteins, or modifying migration of vascular smooth muscle cells. Increased intramural expression of the PAI-1 gene is induced by thrombosis. To determine whether it occurs also in response to a sustained mechanical insult to endothelium, hypercholesterolemia, or both, rabbits were subjected to sustained aortic injury induced by implantation of indwelling polyethylene tubing, to hyperlipidemia induced by cholesterol and peanut oil feeding over a period of 8 weeks, or both.

Constitutive biosynthesis of plasminogen activator inhibitor type-1 (PAI-1) by cultured human aortic endothelial cells independent of insulin.

Background: Both tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) are synthesized by vascular endothelium, whereas hepatocytes synthesize PAI-1 but not t-PA. Non-insulin-dependent diabetes mellitus (NIDDM) is associated with decreased fibrinolytic activity in blood secondary to increased PAI-1 activity, and the increase in PAI-1 activity is correlated with the magnitude of elevation of plasma immunoreactive insulin. To determine whether the increased PAI-1, known to be associated with accelerated coronary artery disease in non-diabetic subjects, is a consequence of direct effects of insulin on endothelial cells, we performed the present study with primary cultures of human aortic endothelial cells.

Maintenance of patency after thrombolysis in stenotic coronary arteries requires combined inhibition of thrombin and platelets.

Objectives: This study was designed to determine whether maintenance of patency in coronary arteries with high grade stenosis after thrombolysis with tissue-type plasminogen activator requires inhibition of thrombin or platelets, or both.

Background: Activation of both thrombin and platelets has been implicated in delaying coronary recanalization induced with fibrinolytic drugs and in predisposing to reocclusion.

Methods: Hirudin (1.

The structure of cardiological revolutions. James B. Herrick Lecture.

Four revolutions are transforming the cardiology of our day. The first is a social revolution. It has resulted in plummeting esteem for the medical profession reflecting disenchantment coupled with the rapid emergence of the recognition that health care is a right rather than a privilege.

Concordance of nutritive myocardial perfusion reserve and flow velocity reserve in conductance vessels in patients with chest pain with angiographically normal coronary arteries.

We have previously shown that myocardial perfusion can be quantified by positron emission tomography (PET) with 15O-labeled water (H2(15)O), as experimentally validated with radiolabeled microspheres in animal hearts. The purpose of our study was to determine whether myocardial nutritive perfusion reserve assessed with PET in human subjects was parallel to flow velocity reserve assessed in conductance vessels measured with intracoronary Doppler probes. We studied nine patients with chest pain and angiographically normal coronary arteries with intracoronary Doppler flow velocity assessments before and after administration of 16 micrograms of intracoronary adenosine.

Detection and assessment by positron emission tomography of a genetically determined defect in myocardial fatty acid utilization (long-chain acyl-CoA dehydrogenase deficiency).

Genetic defects in fatty acid oxidation are important, inherited causes of cardiomyopathy, skeletal myopathies, and childhood sudden death. The clinical manifestations and their severity vary widely among affected subjects and different age groups. Although measurement of serum and urinary fatty acid intermediary metabolites and enzymatic assays establish the diagnosis of a defect in fatty acid oxidation, they do not predict the specific clinical manifestations nor their severity in a given subject.

Persistence of coronary vasodilator responsivity after cardiac transplantation.

Accelerated graft atherosclerosis is a major cause of death after cardiac transplantation. Although its detection currently requires surveillance angiography, loss of vasodilator responsivity may precede obstructive lesions and be detectable by noninvasive assessment of myocardial perfusion. Thirty-five allograft recipients were studied an average of 31 +/- 19 (mean +/- SD) months after transplantation.