Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from L-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism. Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation. Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.
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PMID:Endothelial control of vascular tone in large and small coronary arteries. 240 18

The formation of platelet aggregates and release of platelet-derived vasoactive mediators have been suggested to aggravate ischemic myocardium. The contribution of platelets to myocardial damage induced by 90-min occlusion and 5-h reperfusion in chloralose-anesthetized dogs was assessed after depletion of platelets with specific antidog platelet antiserum. Dogs treated with antiplatelet antiserum showed greater than 90% reduction in circulating platelets and serum TxB2 levels, but showed no reduction in infarct size (58 +/- 3 vs. 51 +/- 3% of risk area for control and thrombocytopenic dogs, respectively). Platelet depletion had no hemodynamic effect during the occlusion or reperfusion phases, nor reduced the incidence of arrhythmias. These results indicate that platelet aggregates or platelet-derived mediators do not contribute directly to the extent of damage in this occlusion-reperfusion model of myocardial ischemia.
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PMID:Platelet depletion and infarct size in an occlusion-reperfusion model of myocardial ischemia in anesthetized dogs. 241 Jul 15

We support the concept of a common anatomic and physiologic link between the acute coronary syndromes, which consists of plaque fissuring or rupture, leading to exposure of the circulating blood to collagen, lipids, and smooth muscle cells. This, in turn, results in marked platelet activation and the initiation of the coagulation sequence, both of which lead to thrombus formation. What determines the clinical outcome in these patients is the suddenness of coronary occlusion, the completeness of blood flow deprivation, and most importantly, its duration. In unstable angina, either plaque disruption resulting in an abrupt change in its morphologic configuration with reduction of coronary blood flow or increased myocardial oxygen demand are associated with increased exertional symptoms. In rest angina, two events may take place: formation of a transient and labile thrombus due to platelet and clotting activation, or vasospasm associated with the release of platelet-derived vasoconstrictive substances or loss of endothelial relaxing properties. As a result, transient myocardial ischemia occurs, which may be intermittent and recurrent and may progress to myocardial infarction or sudden death. In myocardial infarction, plaque rupture is usually more severe, leading to the formation of an occlusive or near-occlusive thrombus which may be more persistent and fixed to the arterial wall. The duration of coronary blood flow deprivation needs to be sufficiently long in order to produce myocardial cell death. Moreover, the difference between Q-wave and non-Q-wave infarction is probably determined by the duration of blood flow obstruction, being longer in the former. The presence of a functionally adequate collateral circulation will, in part, determine the survival of the area of myocardium at jeopardy. The coronary events that take place in ischemic sudden death are probably similar to those in unstable angina, namely plaque rupture with thrombus formation. In sudden death, the resulting myocardial ischemia may precipitate fatal ventricular arrhythmias. Alternatively, platelet microemboli from ulcerated arterial plaques may produce multiple areas of myocardial necrosis which can result in electrical instability and ventricular fibrillation.
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PMID:Thrombosis/platelets and other blood factors in acute coronary syndromes. 265 27

In 19 patients with unstable angina pectoris at rest, plasma levels of the platelet-derived proteins beta-thromboglobulin and platelet factor 4 were significantly elevated in blood samples obtained during or within 4 hours after episodes of angina, but were usually normal during quiescent intervals. Plasma levels of the arachidonic acid metabolite thromboxane B2 were less clearly related to angina, and there was no association of angina with levels of the coagulation product fibrinopeptide A. This demonstration of an association of platelet activation and secretion with unstable angina pectoris by radioimmunoassay of circulating platelet constituents offers a new approach to assessment of therapy in ischemic heart disease and suggests that agents that alter platelet function should be evaluated in patients with unstable angina.
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PMID:Circulating platelet products in unstable angina pectoris. 645 1

The development of myocardial ischemia is known to elicit the formation and enlargement of collateral vessels. The stimulus for these events is unknown. We have investigated the possibility that cardiac tissue releases a factor that can stimulate endothelial cell proliferation. Hearts from New Zealand rabbits were made progressively ischemic by differential hypothermia. Extracts from these hearts were tested for their growth-stimulating ability and were found to increase the proliferation of fetal bovine aortic endothelial cells as well as DNA synthesis by 3T3 cells. The level of activity in the extracts appears to be related to the degree of ischemia as measured by creatine phosphokinase levels. The liberation of an endothelial cell growth factor by ischemic cardiac tissue may function in the initiation and/or potentiation of coronary collateral formation.
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PMID:Do ischemic hearts stimulate endothelial cell growth? 646 72

Activation of the complement cascade is involved in the myocardial injury resulting from transient ischemia and reperfusion. We previously showed that the complement anaphylatoxin C5a causes myocardial ischemia in vivo, mediated in part via thromboxane (Tx) A2. In the present study, we assess the role of platelets in the C5a-induced myocardial ischemia and Tx release. The left anterior descending coronary artery of anesthetized pigs was perfused with arterial blood at constant pressure and measured flow (coronary blood flow). Segment function (percent segment shortening) was measured with sonomicrometry, and regional coronary venous blood was sampled and assayed for TxB2 (by radioimmunoassay). We found that the C5a-induced decrease in coronary blood flow and percent segment shortening and the release of Tx were indistinguishable whether the left anterior descending coronary artery bed was perfused with normal arterial blood, with arterial blood obtained from animals depleted of platelets (cyclophosphamide, n = 6), or with arterial blood from aspirin-treated animals (n = 9) in which the platelets were unable to produce Tx. These data demonstrate that platelet-derived Tx does not contribute to the C5a-induced myocardial ischemia and Tx release in this model and that these cells do not play an integral role in this phenomenon.
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PMID:Effect of platelet depletion and inhibition of platelet cyclooxygenase on C5a-mediated myocardial ischemia. 794 73

Osteonectin is a phosphoglycoprotein exclusively located in bone and platelet alpha-granules. Human platelet-derived osteonectin is released into plasma after thrombin-induced activation. Recognizing the unique distribution of the osteonectin pool, we first sought to investigate whether osteonectin could serve as a sensitive marker of platelet activity, and identify patients with acute myocardial infarction (AMI). The second objective was to define the effects of thrombolytic therapy in these patients on the plasma concentrations of osteonectin at prespecified time points following attempted reperfusion. Osteonectin levels by ELISA were determined in AMI patients before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 12 healthy controls. At baseline, soluble osteonectin plasma levels were similar between controls (447. 7+/-20.6 ng/ml) and AMI patients (425.7+/-43.3 ng/mL; p=NS). A significant increase of the soluble osteonectin was observed at 3 hours after thrombolysis (519.4+/-26.9 ng/mL; p=0.03), and was followed by a decrease to baseline levels at 6 hours after attempted reperfusion. Contrary to expectations, the plasma osteonectin level in our pilot study was not a sensitive marker distinguishing patients with AMI. The early peak of soluble osteonectin at 3 hours after thrombolytic therapy is most likely not related to coronary thrombolysis per se but rather to the phasic changes of platelet activity during myocardial ischemia-reperfusion. The unquestionable platelet origin of this protein and the lack of elevated plasma levels of this alpha-granule constituent, challenge the postulate of uniform platelet activation in AMI patients.
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PMID:Effect of coronary thrombolysis on the plasma concentration of osteonectin (SPARC, BM40) in patients with acute myocardial infarction. 1100 42

Following arterial injury, platelets may activate and adhere to the damaged vessel wall, release vasoactive products, and produce vasoconstriction or even vasospasm. In the last few years the hypothesis of intracoronary thrombosis, triggered by plaque ulceration or fissuration, has gained wide acceptance as one of the key events in the pathophysiology of acute coronary syndromes. Following arterial injury, platelets readily adhere to the subendothelium and release a variety of chemical mediators which, apart from recruiting additional platelets from the circulation, are also powerful vasoactive substances. Platelet-induced coronary vasoconstriction may therefore contribute to the occurrence of myocardial ischemia in patients with acute coronary syndromes. Several studies have also focused on some components of the vessel wall and indicate that endothelial dysfunction in atherosclerosis plays a key role in altered vascular responses. We and others have suggested that augmented constrictor responses of atherosclerotic coronary arteries to platelet-derived substances, such as serotonin and thromboxane A2, perhaps combined with an impaired release of endothelium-derived relaxing factor, may contribute to vasoconstricting responses to aggregating platelets. The purpose of this article is to summarize recent development in knowledge relating to alteration in coronary tone associated with intracoronary platelet activation.
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PMID:How to study the effects of platelet aggregation and thrombosis on coronary vasomotion and their clinical relevance. 1202 69

Angiogenesis, which is defined as the outgrowth of nutritive vessels from locally preexisting ones, is primarily based on the outgrowth of locally present endothelial cells and implies a delicate balance where both stimulating and inhibitory factors can influence the outcome. The primary players starting the process are the vascular endothelial growth factors (VEGFs), which stimulate endothelial cell growth, although some other key factors such as fibroblast growth factors (FGFs), placental growth factors (PIGFs), platelet-derived growth factors (PDGFs) and angiopoietins must come into play for vessels to mature and not deteriorate. Two possibilities exist in terms of local delivery of the angiogenic proteins. One is the delivery of the protein in a slow-release formulation. Fibrin or alginate formulations have been implanted, sub-epicardially releasing FGF. Another approach to get a local delivery over a period of time is gene therapy by local delivery of the vector carrying the therapeutic gene or with the development of vectors that are taken up and expressed only in the organ of interest. A transient overexpression, desirable for the treatment of ischemic heart disease, can be achieved with adenoviral vectors or naked plasmid. With VEGF gene transfection, angiogenesis and reendothelialization were demonstrated in animal cardiac ischemia models showing proof of principle for cardiac therapy and paving the way for clinical trials. Currently, about 200 patients have been treated with intramyocardial VEGF gene therapy for peripheral occlusive artery disease or for myocardial ischemia. Reported adverse events have been few and no worsening of atherosclerosis following treatment has been observed.
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PMID:Angiogenic gene therapy. 1258 71

Platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TP), has been reported to possess angiogenic activity and to inhibit apoptosis. This study was performed to determine whether PD-ECGF/TP can be used to ameliorate chronic myocardial ischemia. Myocardial ischemia was created in 40 mongrel dogs by placement of an ameroid constrictor on the proximal left anterior descending coronary artery (LAD). Plasmid vector encoding human PD-ECGF/TP cDNA (pCIhTP group; n = 12), empty vector pCI (pCI group; n = 12), or saline (Saline group; n = 12) was directly injected into the LAD territory 3 wk after ameroid constrictor implantation. Myocardial blood flow was detected using PET at baseline, 3 wk after ameroid constrictor implantation, and 2 wk after therapeutic treatment. At the end of the experiment, the hearts were isolated for biological and histological analysis. In the pCIhTP group, the transfected heart strongly expressed PD-ECGF/TP. The size of the infarct was smaller in the pCIhTP group than in the pCI or Saline group. The number of apoptotic myocardial cells was decreased in the pCIhTP group compared with the control groups based on triple immunohistochemical staining for von Willebrand factor, alpha-actin smooth muscle cells, and single-strand DNA. The level of proapoptotic protein Bax markedly decreased in the pCIhTP group compared with the other groups. Double immunohistochemical staining for von Willebrand factor and alpha-actin smooth muscle cells demonstrated that angiogenesis and arteriogenesis occurred, and paralleled the changes in myocardial blood flow and myocardial function in the pCIhTP group. We conclude that genetic approaches using PD-ECGF/TP to target the myocardium are effective for alleviating chronic myocardial ischemia.
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PMID:Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs. 1537 22


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