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J H Chesebro

Publications and source records attributed to J H Chesebro.

At least 91 records · Page 5Linked to original sources
PubMed1993

Circulating and tissue endothelin immunoreactivity in hypercholesterolemic pigs.

BACKGROUND: Hypercholesterolemia is characterized by a coronary vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. This abnormality may be due to reduced synthesis of endothelium-derived relaxing factor and/or enhanced synthesis and release of an endothelium-derived contracting factor. Endothelin is an endothelium-derived vasoconstrictor and mitogenic peptide that is present in normal plasma, and its circulating concentrations are elevated in disease states that are characterized by abnormal endothelium-dependent relaxation to acetylcholine. The current studies were designed to test the hypotheses that experimental hypercholesterolemia results in elevation of plasma and tissue endothelin immunoreactivity and that the abnormal acetylcholine-evoked coronary vasoconstriction in the hypercholesterolemic animals is associated with further elevation of plasma endothelin. METHODS AND RESULTS: Plasma concentrations and molecular forms of endothelin immunoreactivity were determined following 2% cholesterol diet for 4 months in pigs and during intracoronary acetylcholine administration. Second, we assessed the presence of endothelin in the coronary vascular wall by using immunohistochemistry. Hypercholesterolemia elevated plasma endothelin concentration and enhanced coronary artery tissue endothelin immunoreactivity. The endothelium-dependent vasodilator acetylcholine further increases plasma endothelin in hypercholesterolemia in association with coronary vasoconstriction. The predominant molecular form of endothelin in hypercholesterolemia is the biological active endothelin-1. CONCLUSIONS: This study suggests a role for endothelin as an early participant and a marker for the endothelial dysfunction in hypercholesterolemia as well as a participant in the atherogenic process.

Acetylcholine↗
PubMed1993

Coronary atherosclerosis. A multifactorial disease.

BACKGROUND: Several of the theories on the pathogenesis of atherosclerosis may be integrated into a single multifactorial one. According to this theory, the most likely sequence of events involved in early atherosclerosis is vascular dysfunction and/or injury, monocyte recruitment and macrophage formation, lipid deposition, vascular smooth muscle cell proliferation (mitogenic factor mediated), and synthesis of extracellular matrix. The interaction of all these factors will configurate the typical characteristic of the atherosclerotic plaque. METHODS AND RESULTS: Accumulating experimental and clinical data suggest two pathways in atherosclerotic progression. In some cases, the very slow process of the pathogenesis of early lesions may be significantly accelerated by means of thrombus formation and organization. Thrombosis is a key process in the pathogenesis of late atherogenesis and in the development of acute ischemic syndromes. CONCLUSIONS: The possibility of retarding human atherosclerosis or even inducing its regression is one of the present therapeutic challenges. Of the different approaches to this question, one approach aims at better control of risk factors, especially plasma lipid levels. Another approach attempts to enhance the removal of lipids from the arterial wall by increasing plasma high density lipoprotein levels. Each of these approaches, by acting on the lipid-rich plaques more prone to rupture, might prevent plaque progression and induce regression to prevent acute coronary events. A third approach, based on the key role of platelet thrombus formation in the conversion of chronic to acute events, would be the use of antithrombotic therapy. This last approach may partially prevent progression of the disease.

Animals↗
PubMed1992

The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. METHODS: We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. RESULTS: Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. CONCLUSIONS: Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.

Aged↗
PubMed1992

Antithrombotic efficacy of low-molecular-weight heparin in deep arterial injury.

Low-molecular-weight heparin subfractions more specifically inhibit factor Xa than thrombin, and they may have advantages over unfractionated heparin in arterial thrombosis. The antithrombotic efficacy of four dosages of a low-molecular-weight heparin (CY216 at 100, 200, 400, or 500 Institute Choay units/kg) was compared with unfractionated calcium heparin (100 US Pharmacopeia units/kg) and placebo during deep arterial injury produced by balloon dilatation of the carotid artery in the pig. The acute thrombotic end points were 111In-labeled platelet and 125I-labeled fibrinogen/fibrin deposition and macroscopic mural thrombosis; these were related to the anti-factor Xa and antithrombin effects of the heparin preparations. Platelet deposition in segments with deep arterial injury was 42 +/- 28, 22 +/- 5, 29 +/- 12, 9 +/- 2, 9 +/- 2, and 11 +/- 3 x 10(6)/cm2 (mean +/- SEM) for pigs treated with placebo, with 100, 200, 400, and 500 units/kg CY216, and with 100 units/kg unfractionated heparin, respectively. Fibrinogen/fibrin deposition was 35 +/- 8, 19 +/- 2, 19 +/- 4, 21 +/- 3, 14 +/- 4, and 12 +/- 3 molecules x 10(12)/cm2, respectively; deposition was significantly reduced in pigs given 100 units/kg unfractionated heparin compared with placebo (p less than 0.05). Mural thrombosis was present in 74%, 45%, 30%, 14%, 5%, and 9% of deeply injured arterial segments, respectively (p = 0.02). Plasma anti-factor Xa activity and prolongation of the activated partial thromboplastin time (aPTT) with 100 units/kg unfractionated heparin were similar to that produced by 200 units/kg and 500 units/kg CY216, respectively. Thus, low-molecular-weight heparin, which predominantly inhibits factor Xa activity, was only moderately effective at reducing platelet thrombus deposition. It was less effective than 100 units/kg unfractionated heparin, except at high dosages, producing similar prolongation of the aPTT and the thrombin time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cod liver oil alters platelet-arterial wall response to injury in pigs.

In 36 normolipemic pigs randomized to a 4-week feeding with regular pig chow (n = 18, control group) or chow supplemented with cod liver oil (1 ml/kg per day) (n = 18, treated group), treatment with cod liver oil produced a significant decrease in serum cholesterol, low density lipoprotein cholesterol, and triglycerides. Deep carotid arterial wall injury (media exposed) by balloon angioplasty was associated with less 111In-labeled platelet deposition (24.6 +/- 4.8 x 10(6)/cm2 versus 62.5 +/- 17.0 x 10(6)/cm2, p less than 0.05; difference, -33.8 x 10(6)/cm2; 95% confidence interval [CI], -1.9 x 10(6)/cm2 to -73.9 x 10(6)/cm2) and injury-related vasoconstriction (21.3 +/- 2.2% versus 30.9 +/- 2.9%, p less than 0.05; difference, -9.6%; 95% CI, -2.2% to -17.0%) in the cod liver oil-treated group than in the control group; with mild injury (media not exposed), platelet deposition was low and unchanged (6.2 +/- 0.5 x 10(6)/cm2 versus 7.8 +/- 0.7 x 10(6)/cm2; difference, -1.6 x 10(6)/cm2; 95% CI, -1.1 x 10(6)/cm2 to +4.3 x 10(6)/cm2), but associated vasoconstriction was reduced respectively (16.3 +/- 2.0% versus 23.0 +/- 2.2%, p less than 0.05; difference, -6.7%; 95% CI, -0.6% to -12.8%). When arterial blood from cod liver oil-treated pigs superfused normal aortic media ex vivo, platelet deposition onto the normal aortic media was lower than when arterial blood from control pigs superfused the normal aortic media (43.7 +/- 8.8 x 10(6)/cm2 versus 66.8 +/- 13.0 x 10(6)/cm2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗
PubMed1992

Antithrombotic therapy and progression of coronary artery disease. Antiplatelet versus antithrombins.

Coronary artery disease develops and progresses over decades with lipid incorporation and coalescence into the arterial wall, leading to recurrent plaque disruption, thrombosis, and organization into fibromuscular lesions. The role of thrombin in arterial thrombosis is documented by observations that specific thrombin inhibition can completely prevent intraluminal mural thrombus in vivo, even though other factors that activate platelets are not inhibited. Platelet-rich thrombi associated with deep injury have a high thrombin content and require blood levels of specific thrombin inhibition with hirudin that are eight to 10 times those required to prevent thrombi associated with lesser injury or stasis. Total prevention of mural thrombus in deeply injured arteries is impossible with aspirin or conventional antithrombotic therapy, which can reduce occlusive thrombus. Thus, conventional antithrombotic therapies can reduce clinical events but are not effective in reducing progression of coronary artery disease. Whether newer antithrombins that can totally prevent mural thrombus after deep injury can be developed and administered orally and chronically without high risk of bleeding and will be able to reduce progression of coronary artery disease is unknown. Lesion growth, vascular injury, acute coronary syndromes, and principles of thrombus formation on ruptured plaque are discussed elsewhere in this issue. This article extends these findings and discusses the prevention and treatment of mural thrombosis, the pivotal role of thrombin in arterial thrombosis, and antithrombotic therapy for the prevention and the progression of coronary artery disease.

Aspirin↗
PubMed1992

Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi.

Angiography in patients with unstable angina or myocardial infarction with subtotal coronary occlusion often reveals eccentric stenoses with irregular borders, suggesting ruptured atherosclerotic plaques and thrombosis, as documented by angioscopy and at autopsy. We have simulated and studied these processes in an ex vivo perfusion chamber and in an in vivo swine model. Our results suggest that specific local factors at the time of plaque disruption influence the degree of thrombogenicity, the stability of the growing thrombus, and, therefore, possibly also the various clinical syndromes. These factors can be divided into two groups: local vessel wall-related factors and systemic factors with local action at the area of risk. These factors include the following. 1) Exposed substrate-related effects: Plaque rupture produces a rough surface and stimulates the development of occlusive thrombus in proportion to the degree of damage. 2) Fluid dynamics-related factors: The more severe the stenotic lesion after plaque rupture, the higher the local shear rate, resulting in enhanced platelet deposition and thrombus formation. 3) Vasoconstrictive effects: Vasospasm is an important contributor to the pathogenesis of ischemic heart disease. 4) Systemic factors: There is clinical and experimental evidence to suggest that various systemic factors at the time of plaque rupture may enhance thrombogenicity (i.e., levels of epinephrine, levels of serum cholesterol, impaired fibrinolysis). We have investigated the role of residual thrombus on the process of rethrombosis and found that a residual thrombus is a very thrombogenic surface that may significantly contribute to reocclusion even in heparinized blood. Using recombinant hirudin as a pharmacological tool in our flow studies, we observed that rethrombosis is partially caused by thrombin bound to fibrin in the original thrombus, because the effect is abolished by the specific thrombin inhibitor.

Angina, Unstable↗
PubMed1992

Endothelium and atherosclerosis.

PURPOSE: To review the effect of damaged endothelium on the development of atherosclerotic disease. BACKGROUND: Atherosclerotic cardiovascular disease is a complex problem involving lipid deposition, blood pressure, rheologic forces, carbohydrate tolerance and thrombogenic factors. The loss of functional, if not structural, integrity of the vascular endothelium is closely related to the initiation of atherosclerosis. The endothelium contributes to local vascular regulation. Normal endothelial cells are thrombo-resistant; they prevent leukocyte adhesion and control vascular tone by converting angiotensin I into angiotensin II, inactivating bradykinin, norepinephrine, serotonin and ADP, and by secreting vasodilator substances, such as prostacyclin and endothelium-derived relaxing factor (EDRF), and contracting factors such as endothelin. Endothelin is a potent vasoconstrictor peptide that increases intracellular calcium, causing a rapid and transient increase in c-fos and c-myc messenger (m)RNA levels and DNA synthesis in rat vascular smooth muscle cells. In isolated vessel segments, altered endothelial vasoreactivity is usually demonstrated following mechanical trauma to the endothelium. METHODS AND RESULTS: We investigated the function of normal and damaged endothelium in pigs, following superficial balloon injury, which produces a significant alteration in endothelium-dependent coronary vasoreactivity. The anesthetized pigs were given an intracoronary (left anterior descending artery) infusion of acetylcholine. The balloon injury caused a local transient spasm while the distal uninjured vessel did not change. When acetylcholine was given before the balloon injury, the diameter of the left anterior descending artery did not change, even after preconstriction in vivo with prostaglandin (PG) F2 alpha, but acetylcholine given after the balloon angioplasty caused dose-dependent vasoconstriction. It is known that vasoconstriction in arteries can reduce blood flow and increase arterial wall-shear forces, which increase platelet deposition in injured arteries and may precipitate rupture of atherosclerotic plaques. CONCLUSION: The intact endothelium is one of the greatest sources of protection from arterial thrombosis, atherosclerosis and vasoconstriction.

Acetylcholine↗
PubMed1991

Plaque disruption and thrombosis in unstable angina pectoris.

Therapeutic strategies and clinical trials in unstable angina should be based on the pathogenesis, risk, and mechanisms of thrombosis. The mechanisms of thrombosis and the differences in the effects of anticoagulant, antithrombotic, antifibrin, and antiplatelet drugs must be taken into account when determining the dosage and duration of therapy. Ignoring these principles may prevent identification of new therapy, increase the cost of new drug development and research, increase the cost of new drugs, and increase the cost of medical care.

Angina, Unstable↗
PubMed1991

Pathogenesis of thrombosis in unstable angina.

Plaque rupture of the thinned, weak fibrous cap infiltrated by macrophages and overlying a pool of lipid in the arterial wall initiates the acute thrombotic event of unstable angina. Thrombosis may be advanced within minutes. Most lesions that precede plaque rupture are minor (less than 50% stenosis); thus, thrombus greatly contributes to sudden flow limitation and onset of symptoms. If thrombosis can be totally blocked (not possible with current antithrombotic agents), clinical events should be preventable, and endogenous thrombolysis may be possible within days. Local and systemic factors contribute to arterial thrombosis. With type III injury (fissure into plaque or media) platelet-rich thrombus anchors in the fissure, tracks along the site of deep injury, extends into the lumen, and requires the highest blood level of specific thrombin inhibition (a molar concentration that inhibits the total concentration of prothrombin in circulating blood). Thus, the thrombin content requiring inhibition in type III injury is highest. Local factors for thrombosis associated with type III injury include the rheology of blood flow (increased shear rate forces platelets to the periphery) and substrates in the arterial wall. Plaque substrates include the more thrombogenic collagens (types I and III and diabetic or glycosylated collagen), tissue thromboplastin, lipid gruel, thrombin bound to arterial wall matrix, and decreased prostacyclin. There is a direct relation between platelet deposition (thrombus) and local vasoconstriction, which may perpetuate each other. Thrombus as a substrate is more thrombogenic than type III arterial injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina, Unstable↗
PubMed1991

Thrombin regulation of platelet interaction with damaged vessel wall and isolated collagen type I at arterial flow conditions in a porcine model: effects of hirudins, heparin, and calcium chelation.

The role of thrombin inhibition in platelet vessel wall interaction and thrombus growth was studied under controlled flow conditions. Natural hirudin and recombinant hirudin (r-hirudin), which are specific thrombin inhibitors, were compared with heparinized blood (1.8 +/- 0.2 U/mL) and Ca(2+)-chelated blood in their potential to inhibit platelet interaction and thrombus growth on two biologic vascular surfaces and one immobilized vessel wall component. The substrates were perfused by flowing blood at shear rates typical of patent and stenosed arteries (212 to 1,690/s) for 5 minutes. Platelet deposition was measured by In-111-labeled platelets. We found that both natural and r-hirudin have similar effects on platelet-substrate interaction. As compared with heparin, platelet deposition to mildly damaged vessel wall and digested collagen type I was not reduced by hirudin or citrate. However, hirudin and citrate significantly reduced platelet deposition to severely damaged vessel wall (platelets x 10(6)/cm2: 93 +/- 10 in heparinized blood v 50 +/- 7 in blood treated with 100 U/mL r-hirudin). Therefore, thrombus growth on areas of severe wall damage is in part dependent on local thrombin production at the site of vascular damage. We also found that hirudin added to heparinized blood reduced platelet deposition to severely injured wall but not to subendothelium or collagen-coated slides. Hirudin added to citrated blood did not affect platelet deposition. Our study indicates that local thrombin generation at the site of severe injury will induce platelet activation and deposition even in the presence of average therapeutic heparin levels that inhibit blood coagulation.

Adenosine Diphosphate↗
PubMed1991

Limitations of the electrocardiogram in estimating infarction size after acute reperfusion therapy for myocardial infarction.

OBJECTIVE: To assess the ability of the 12-lead electrocardiogram to estimate infarction size after reperfusion therapy for acute myocardial infarction. DESIGN: The presence or absence of Q waves and the Selvester QRS score obtained before and after hospital discharge were compared with radionuclide estimates of infarction size and ejection fraction at discharge and 6 weeks later, regional wall motion at discharge and 6 weeks later, and myocardial perfusion defect size quantitated with Tc-99m-sestamibi at discharge. SETTING: A tertiary referral center. PATIENTS: A consecutive series of 43 patients with acute myocardial infarction who received acute reperfusion therapy and were assessed using 12-lead electrocardiography, radionuclide angiography, and Tc-99m-sestamibi tomographic imaging before discharge. INTERVENTIONS: All 43 patients received acute reperfusion therapy: 21 patients received intravenous tissue plasminogen activator, and 22 patients underwent primary percutaneous transluminal coronary angioplasty. MAIN OUTCOME MEASURE: The correlation of QRS score and Q waves with three radionuclide estimates of infarction size. RESULTS: A significant correlation was found between myocardial perfusion defect size at discharge and both left ventricular ejection fraction and regional wall motion at discharge and 6 weeks later (r = -0.71 to -0.81; all comparisons, P less than 0.001). Little correlation was found between electrocardiographic findings and radionuclide measurements of left ventricular function and perfusion. Presence or absence of Q waves at discharge was not associated with any difference in ejection fraction, regional wall motion, or perfusion defect at discharge. No correlation was found between QRS score and ejection fraction or myocardial perfusion defect size at discharge. The QRS score at discharge correlated only weakly with regional wall motion at discharge and 6 weeks later. This lack of correlation was unchanged when electrocardiograms obtained after hospital discharge were analyzed. CONCLUSION: Although inexpensive and readily available, the 12-lead electrocardiogram does not appear to provide a reliable estimate of infarction size after reperfusion therapy for acute myocardial infarction.

Adult↗
PubMed1991

Antithrombotic therapy in the coronary vein graft patient.

Coronary artery bypass grafting is an important therapeutic modality in the treatment of the patient with coronary artery disease; however, long-term results are limited by the development of saphenous vein graft disease early and late after operation. The pathogenesis of early vein graft occlusion is primarily thrombotic, while that occurring later frequently involves thrombosis superimposed on intimal hyperplasia or vein graft atherosclerosis. We describe the role of various platelet inhibitors and anticoagulants in the prevention of saphenous vein graft occlusion following coronary artery bypass grafting.

Coronary Artery Bypass↗