salicylates and Coronary-Disease

Kawasaki disease is a childhood vasculitis of medium-sized vessels, affecting the coronary arteries in particular. We have treated a therapy-resistant child who met all diagnostic criteria for Kawasaki disease. After the boy was given intravenous immunoglobulins and salicylates, as well as several courses of pulsed methylprednisolone, disease recurred and coronary artery lesions became progressively detectable. Cyclosporin A was started and seemed clinically effective. In contrast to the positive effect on inflammatory parameters, ie, C-reactive protein and white blood cell counts, a novel plasma marker for cytotoxicity (granzyme B) remained elevated. Coronary disease progressed to fatal obstruction and myocardial infarction. Echocardiography, electrocardiograms, and myocardial creatine phosphokinase did not predict impending death. At autopsy an obliterative panarteritis was observed resulting from massive fibrointimal proliferation, affecting the aorta and several large and medium-sized arteries. Immunophenotypic analysis of the inflammatory infiltrates in arteries revealed mainly granzyme-positive cytotoxic T cells and macrophages in the intima and media, as well as nodular aggregates of T cells, B cells, and plasma cells in the adventitia of affected arteries. These findings further endorse the role of specific cellular and humoral immunity in Kawasaki disease. Unremitting coronary arteritis and excessive smooth muscle hyperplasia resulted in coronary occlusion despite the use of cyclosporin A.

Topics: Aneurysm; C-Reactive Protein; Coronary Disease; Cyclosporine; Cytokines; Drug Resistance; Fatal Outcome; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infant; Male; Methylprednisolone; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Salicylates; Serine Endopeptidases

To study the effects of adding a salicylate to the angiotensin converting enzyme inhibitor enalapril in patients with heart failure due to coronary artery disease.. Double blind, crossover study for three days in hospital followed by an extended similar study outside hospital over two months of once daily enalapril plus salicylate and enalapril plus placebo.. Tertiary referral centre.. 20 patients with heart failure due to myocardial infarction (New York Heart Association class II or III) and an ejection fraction less than 0.40. Twelve patients completed the two parts of the study.. Blood pressure, plasma converting enzyme activity; plasma angiotensin II and noradrenaline concentrations; excretion of metabolites of renal and systemic prostanoids.. The unloading effect of first and second dose of enalapril in the morning lasted only during the day; in the extended study it lasted 24 hours because of the drug's accumulation. Converting enzyme inhibitors attenuate the breakdown of bradykinin and therefore enhance prostaglandin E2 synthesis mediated by bradykinin. Evidence was found of such a prostaglandin E2 mediated contribution to ventricular unloading by enalapril, which was blocked by salicylate. The contribution, however, was small and variable, and salicylate addition had on average no significant de-unloading effect during the day. Unloading was abolished in only three of the 20 patients in the short term study and in one of the 12 in the extended study. At night, when other effects of enalapril on blood pressure had waned and the bradykinin induced effect persisted, salicylate significantly reduced the remaining small unloading effect. No effect was seen of salicylate addition on reversal of remodelling. Enalapril reduced angiotensin II induced synthesis of systemic and renal prostaglandin I2 and thromboxane A2, initially only during the day, but later also at night. It thereby masked suppression of thromboxane A2 synthesis by salicylate, which is the effect to which reinfarct prevention by salicylate is attributed.. The risk is low that salicylate will substantially reduce the benefit of enalapril in patients with heart failure by de-unloading the ventricle. Like other effects induced by bradykinin significant de-unloading occurs in only a minority of the patients. In the presence of enalapril, however, salicylate will probably not be as effective as expected in reducing reinfarction risk, because enalapril already reduces thromboxane A2 synthesis effectively in patients with heart failure and no further reduction by salicylate was found.

Topics: Adult; Aged; Angiotensin II; Blood Pressure; Coronary Disease; Creatinine; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Norepinephrine; Peptidyl-Dipeptidase A; Salicylates; Salicylic Acid

Topics: Aspirin; Clopidogrel; Coronary Disease; Cost Savings; Desensitization, Immunologic; Drug Hypersensitivity; Drug Substitution; Humans; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Salicylates; Ticlopidine

Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including endothelial nitric oxide synthase-derived nitric oxide bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element-binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium.. Using cultured endothelial cells challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and angiotensin II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including sirtuin 1, Krüppel-like factor 2, and Krüppel-like factor 4, leading to NOD-like receptor family pyrin domain-containing 3 inflammasome activation and endothelial nitric oxide synthase inhibition. In endothelial cell-specific SREBP2 transgenic mice, locked nucleic acid-modified antisense miR-92a attenuates inflammasome, improves vasodilation, and ameliorates angiotensin II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with endothelial cell-dependent, flow-mediated vasodilation and is positively correlated with serum level of interleukin-1β.. Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in the diagnosis or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.

Topics: Aged; Angiotensin II; Animals; Coronary Disease; Endothelial Cells; Endothelium, Vascular; Female; Free Radical Scavengers; Gene Expression Regulation; Genes, Reporter; HEK293 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen Peroxide; Hypercholesterolemia; Immunity, Innate; Inflammasomes; Interleukin-1beta; Kruppel-Like Factor 4; Lipoproteins, LDL; Male; Mice; Mice, Transgenic; MicroRNAs; Middle Aged; Organometallic Compounds; Oxidative Stress; Recombinant Fusion Proteins; Salicylates; Sterol Regulatory Element Binding Protein 2; Transcriptional Activation; Zebrafish; Zebrafish Proteins

Topics: Aspirin; Coronary Disease; Epoprostenol; Humans; Platelet Aggregation Inhibitors; Radiotherapy; Salicylates; Thromboxane A2

Topics: Acetazolamide; Acidosis, Lactic; Aged; Anorexia; Confusion; Coronary Disease; Diabetes Mellitus, Type 2; Drug Interactions; Drug Therapy, Combination; Glaucoma; Humans; Joint Diseases; Male; Salicylates; Urinary Incontinence

Serum salicylate concentrations were measured in 60 patients with acute phase Kawasaki disease (KD), who were treated with intravenous aspirin (IVASP), to evaluate its anti-inflammatory effect in the treatment of KD. Patients with serum salicylate concentrations > or = 150 micrograms/ml showed shorter durations of fever (7.1 +/- 2.0 vs 10.4 +/- 6.6 days; P < 0.05), shorter durations of positive serum C-reactive protein (14.6 +/- 4.5 vs 22.3 +/- 10.6 days; P < 0.01) and lower incidences of coronary arterial involvements (0/10 vs 6/24; P < 0.05) than did patients with serum salicylate concentrations < 150 micrograms/ml. Significant linear correlations were recognized between daily IVASP dosage and serum salicylate concentrations (r = 0.73; P < 0.01), and between serum salicylate concentrations and serum free salicylate concentrations (r = 0.82; P < 0.01). These correlations did not differ between the presence and absence of coronary arterial involvements. Based on these findings we concluded that a beneficial anti-inflammatory effect in the treatment of KD is achieved when the serum salicylate concentration is > or = 150 micrograms/ml, and that such concentrations could be achieved by increasing the daily IVASP dosage to 100 mg/kg per day or more.

Topics: Acute Disease; Aspirin; Child; Child, Preschool; Coronary Disease; Female; Humans; Infant; Inflammation; Infusions, Intravenous; Male; Mucocutaneous Lymph Node Syndrome; Retrospective Studies; Salicylates; Treatment Outcome

To elucidate the pathophysiological role of the hydroxyl radical (.OH) during the postischemic reperfusion of the heart, we measured the .OH product in the coronary effluent from isolated perfused rat heart during a 30-minute reperfusion period after various ischemic intervals of 5, 10, 15, 20, 30, and 60 minutes. Salicylic acid was used as the probe for .OH, and its derivative, 2,5-dihydroxybenzoic acid (2,5-DHBA), was quantified using high-performance liquid chromatography with ultraviolet detection. 2,5-DHBA was negligible in the effluent from nonischemic hearts, but a significant amount was detected from the hearts rendered ischemic for 10 minutes or longer. The peak of 2,5-DHBA was seen within 90 seconds after the onset of reperfusion in every group. The accumulated amount of 2,5-DHBA was maximal in the group with 15-minute ischemia (6.73 +/- 1.04 nmol/g wet heart wt after 30 minutes of reperfusion); it decreased as the ischemic time was prolonged and was 2.38 +/- 0.84 nmol/g wet wt after 30 minutes of reperfusion in the group with 60-minute ischemia. In the model of 15-minute ischemia/30-minute reperfusion, there was no correlation between the accumulated amount of 2,5-DHBA and functional recovery (+/- dP/dt, heart rate, and coronary flow), lactate dehydrogenase release, and morphological damage. Although treatment with 0.5 mM deferoxamine, an iron chelator, significantly decreased 2,5-DHBA (from 6.73 +/- 1.04 to 2.29 +/- 0.80 nmol/g wet wt after 30 minutes of reperfusion, p less than 0.01), it failed to reduce the postischemic myocardial injury in the group with 15-minute ischemia. The results suggest that .OH production is influenced by the preceding ischemic interval and that .OH does not exert an immediate direct effect on postischemic damage during early reperfusion in the isolated perfused rat heart, although a possibility remains that the small portion of .OH trapped by salicylic acid may not be intimately associated with myocardial injury.

Topics: Animals; Coronary Disease; Deferoxamine; Free Radicals; Gentisates; Heart; Hydroxides; Hydroxybenzoates; Hydroxyl Radical; Male; Myocardial Reperfusion Injury; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Time Factors

The safety of the combination of heparin and ridogrel therapy and its antiplatelet efficacy was examined in the setting of percutaneous transluminal coronary angioplasty (PTCA). In 32 patients without known aspirin intake for 10 days before PTCA, therapy with ridogrel (300-mg intravenous bolus) was begun just before PTCA and continued orally at a dose of 300 mg twice daily until discharge. Heparin was administered as a 10,000 IU bolus dose before PTCA and followed by an intravenous infusion at a rate of 1,000 IU/hour for 24 hours. Bleeding problems at the arterial entry site occurred in 13 patients, which required a blood transfusion in only 2 patients. One patient underwent emergency bypass surgery without specific problems of hemostasis. Ridogrel virtually eliminated thromboxane B2 from the serum (29,990 +/- 6,555 pg/0.1 ml before vs 63 +/- 7 pg/0.1 ml at 2 hours after ridogrel), with a concomitant increase in serum 6-keto-prostaglandin F1 alpha (511 +/- 34 pg/0.1 ml before vs 1,190 +/- 146 pg/0.1 ml at 24 hours after ridogrel). There were no acute reocclusions in the ridogrel-treated patients, whereas acute reocclusions occurred in 5.6% of the patients taking the standard aspirin + heparin regimen during the same period. Furthermore, at 6-month clinical follow-up patients treated with ridogrel compared favorably with those receiving standard treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Angioplasty, Balloon, Coronary; Coronary Disease; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pentanoic Acids; Pilot Projects; Pyridines; Radiography; Recurrence; Salicylates; Thromboxane B2; Thromboxane-A Synthase

Although the presence of free radicals has been indicated in ischemic-reperfused heart, the exact nature and source of these free radicals are not known. The present study utilized a chemical trap, salicylic acid, to trap hydroxyl radical which could be detected as hydroxylated benzoic acid using high pressure liquid chromatography. Since the hydroxylated product is extremely stable, heart was subjected to subcellular fractionation after ischemia and reperfusion, and each fraction was separately examined for the presence of hydroxyl radical. The results indicated for the first time the presence of hydroxyl radical in the mitochondrial fraction during early reperfusion, which decreased in intensity as the reperfusion progressed.

Topics: Animals; Catalase; Chromatography, High Pressure Liquid; Coronary Disease; Dimethyl Sulfoxide; Free Radicals; Hydroxides; Hydroxyl Radical; Male; Mitochondria, Heart; Myocardial Reperfusion; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Superoxide Dismutase; Thiourea

Between June 1, 1979, and May 31, 1984, at The Hospital for Sick Children in Toronto, Kawasaki disease was diagnosed in 163 patients (112 boys, 51 girls, P less than 0.001). Fifteen percent of the children had coronary artery aneurysms. Prior to diagnosis, 24% had been given low doses of aspirin, and 50% acetaminophen. Children with coronary aneurysms had significantly higher temperature during days 10 to 13 of the disease. The febrile phase of the disease was also significantly longer in these children. Coronary artery involvement occurred with equal frequency in boys and girls. There was no significantly greater incidence of coronary artery involvement in infants younger than 1 year of age than in older children. Duration of fever (greater than or equal to 14 days vs less than 14 days) was equally as predictive of the eventual occurrence of coronary aneurysms as the modified Asai score.

Topics: Acetaminophen; Age Factors; Aneurysm; Child; Child, Preschool; Coronary Disease; Female; Fever; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Probability; Retrospective Studies; Risk; Salicylates; Seasons; Sex Factors; Time Factors

Topics: Arteriosclerosis; Coronary Disease; Heart Failure; Humans; Protein Binding; Rheumatic Fever; Salicylates

Topics: Aspirin; Coronary Artery Disease; Coronary Disease; Humans; Lipids; Lipoproteins; Salicylates