In situ endothelin in coronary artery disease.

Despite the significant advances made in the understanding and treatment of coronary artery disease much remains unclear about the pathogenesis of this complex atherothrombotic process. Atherogenesis may reflect a combination of multiple factors interacting with one another leading to coronary artery occlusion. One potential participant may be endothelin-1 (ET-1), a potent mitogenic vasoconstrictor. The presence of endothelin within saphenous veins before insertion and after removal during coronary artery bypass grafting (CABG) because of bypass closure, within internal mammary arteries before and after surgical intervention, and within native coronary artery segments resected during CABG was demonstrated immunocytochemically with an antiendothelin antibody and aminoethyl carbazole as the indicator chromogen. Increased amounts of ET-1 were observed in failed venous grafts, in damaged internal mammary artery grafts, and in vessels of the myocardium. These results suggest that ET-1 may play a significant pathophysiologic role in the evolution of coronary heart disease.

Interleukin-1 alpha as a factor in occlusive vascular disease.

The purpose of this study was to examine the recognized ability of interleukin-1 alpha (IL-1 alpha) to alter the functional properties of endothelial cells and to induce replication of smooth muscle and fibroblasts. Such changes could potentially link IL-1 alpha pathogenetically to the myointimal proliferation of vascular sclerosis. Using a peroxidase-immunoperoxidase immunohistochemical method, saphenous veins and internal mammary arteries were examined for the presence of IL-1 alpha before their implantation as aortocoronary bypass grafts. Occluded saphenous vein grafts requiring replacement because of recurrent angina pectoris also were similarly examined. Interleukin-1 alpha, deposited as a scarlet immunoprecipitate, was seen on the luminal surface, in the subintima, and on the spindle cells and infiltrating macrophages in the media of 13 phlebosclerotic veins before surgical insertion. The remaining 30 unchanged veins did not contain IL-1 alpha. Similarly, IL-1 alpha was not identified in any of the 43 sampled internal mammary arteries that were all considered structurally intact. All the 55 bypass grafts, which were examined by biopsy during revascularization and demonstrated diverse histopathologic abnormalities consisting of reduced luminal patency, myointimal proliferation, mononuclear cell infiltration, mural collagenization, and luminal-mural hemorrhage, also contained widely distributed IL-1 alpha. The observation that IL-1 alpha was absent in all of the internal mammary arteries concomitant with maintenance of normal microanatomic structure may help explain, in part, their recognized resistance to reduction in luminal patency and their improved clinical survival when used as coronary artery bypass grafts. Alternatively, the consistent presence of IL-1 alpha in all vessels with sclerotic histopathologic changes suggests that this cytokine may be an important in situ indicator of and a potential participant in vascular injury. Interleukin-1 alpha may be a pathogenetic factor in the complex processes leading to vascular occlusion.

Immunocytochemical features of obstructed saphenous vein coronary artery bypass grafts.

The peroxidase-immunoperoxidase immunocytochemical method was used on 27 saphenous vein coronary artery bypass grafts, which had been resected because of recurrent angina, to identify in situ cellular and humoral elements possibly associated with graft occlusion. Immunostaining was performed on paraffin wax embedded control saphenous vein and graft sections incubated directly with primary antibodies against von Willebrand antigen (vWFAg), fibronectin, fibrinogen, leucocyte common antigen (LCA), lysozyme, vimentin, desmin, platelet factor 4, and thrombospondin. Antigens were visualised by a chromogen providing an orange-red immunoprecipitate at the site of epitope localisation. The intraluminal, amorphous exudate present in most grafts was not composed simply of fibrin or fibrinogen, as previously thought, but was a multiprotein complex including wWFAg, fibronectin, thrombospondin and platelet factor 4. Along with macrophages, these components probably enter the graft after haemodynamic, physical, and chemical injury to, and disruption of, the endothelial cell. Progressive myointimal proliferation and fibrosis of these grafts may be local repetitive responses to macrophages and platelets, cells previously known to participate in vascular disease.

Altered lymphocyte subsets during cardiopulmonary bypass.

Peripheral blood lymphocyte subsets were quantified by immunofluorescence in nine patients undergoing open heart surgery for coronary artery, valvular, and congenital heart disease. Compared with normal preoperative values, all patients developed an absolute lymphopenia, a reduction in T4 (helper) lymphocytes, and a statistically significant reversal of the T4/T8 ratio two hours after cardiopulmonary bypass (CPB). These changes could be caused by mechanical or immunogenic injury. A return to normal of the T4 subset and T4/T8 proportion occurred 24 hours after surgery. Whereas transient inactivation of immunoreactive lymphocyte clones may prevent unwanted immunization to blood products received during surgery, such temporary immune dysfunction could make certain patients liable to infectious sequelae. Viral-induced postperfusion syndromes, transmission of human T lymphotropic virus (HTLV) III by blood products, and reports of acquired immune deficiency syndrome after CPB foster a concern regarding postoperative infections under these circumstances.

Coronary artery deposition of factor VIII-related antigen in ischemic heart disease.

This study localized Factor VIII-related antigen (FVIIIRAg) directly in the intramural coronary arteries of patients with coronary artery disease (CAD). Assays were performed on myocardial autopsy sections from 17 patients with and 15 patients without CAD, using a monospecific FVIIIRAg antibody in the peroxidase-immunoperoxidase technic. FVIIIRAg was quantified by a FVIIIRAg index (FRI), as a numerical score based on distribution, thickness, and extension of immunostaining. The mean FRI for the CAD patients was 55 +/- 11 and that for the control patients 12 +/- 5 (P less than 0.001). The increased amounts of in situ FVIIIRAg suggest this glycoprotein may be involved in the pathogenesis of atherosclerosis.

Concentrations of factor VIII-related antigen and factor XIII during open heart surgery.

Plasma levels of factor VIII-related antigen (fVIIIRA) and factor XIII S and A subunits (fXIIIS, fXIIIA) were assayed by counterimmunoelectrophoresis before, during, and after cardiopulmonary bypass (CPB) in patients with coronary artery and valvular heart disease to define the basis for clinical and laboratory abnormalities of hemostasis occurring in this form of surgery. During CPB, concentrations of fXIIIA dropped in both patient groups but returned to preoperative levels promptly after pump removal. In contrast, fVIIIRA and fXIIIS, which are not incorporated into the clot, remained unchanged even during fluid administration. These data provide evidence of a transient consumption coagulopathy as a feature of CPB. Hemodilution probably plays a secondary role in these changes.

The behavior of antithrombin III, alpha 2 macroglobulin, and alpha 1 antitrypsin during cardiopulmonary bypass.

We serially measured concentrations of three protease inhibitors, antithrombin III, alpha 2 macroglobulin, and alpha 1 antitrypsin in patients with coronary artery and valvular heart disease during extracorporeal circulation. Assays for immunoreactive antiproteases and for functional antithrombin III were performed on plasma samples obtained at selected intervals before, during, and after cardiopulmonary bypass. Significant reductions of all protease inhibitors occurred at some time during cardiopulmonary bypass, although patterns of change were dissimilar for the two patient groups. A return toward preoperative levels was observed after cardiopulmonary bypass was discontinued, but antithrombin III remained diminished in the patients with coronary artery disease. The acute serial changes in this group of alpha globulins is evidence of their participation during the dynamic stress of extracorporeal circulation. Their timely intervention as serine protease antagonists deters sustained thrombogenesis and fibrinolysis during cardiopulmonary bypass.

Anorexic activity of cocaine and coca extract in naive and cocaine tolerant rats.

Dose response curves for reducing limited access food consumption were determined for cocaine HCl IP, cocaine HCl PO, and whole Erythroxylum coca extract PO. The ED50's for cocaine HCl in drug naive rats were 19.6 mg/kg (IP) and 34.6 mg/kg (PO). When the dose of E. coca extract was expressed in terms of cocaine HCl content, the ED50 was 52.6 mg/kg (PO). When dose response curves were determined in rats that had received cocaine (45 mg/kg, PO) for 30 days, a shift to the right in the cocaine HCl curve (an ED50 of 98.4 mg/kg PO) indicated tolerance. However, the shift to the right was less for E. coca extract than for cocaine HCl. Although the anorexic activity of E. coca extract was less than that of an equivalent amount of cocaine in naive rats it was often more than that of equivalent doses of cocaine HCl in tolerant rats. Interaction with other constituents of E. coca extract appears to alter the potency of the cocaine content of the extract in different directions in naive and tolerant rats.

A quantitative study of the face in Down's syndrome.

The large number of persons with Down's syndrome among the group of physically and mentally retarded demands that continuing study be directed toward its causes and effects. Much conflicting data are reported in the literature concerning the facial and cranial effects of this syndrome. The cephalic proportions, in profile, of a group of male Caucasian trisomic Mongoloids were compared with the proportions of a control group of male Caucasians of similar age range. Using the areas of the midface, mandible, and endocranium obtained from cephlograms of the two groups, the following ratios were studied: (1) midfacial area/endocranial area (2) mandibular area/endocranial area, and (3) midfacial area/mandibular area. A significant degree of deficiency in midfacial area, mandibular area, and endocranial area was found in the Mongoloid group. In studying the facial proportions, we found that the Down's syndrome group's ratios were significantly smaller in all three areas. The magnitude of the deficiency in the Mongoloid midface, both in gross area and in relation to endocranial area, remained nearly constant with age. The ratio of midfacial area to mandibular area in Mongoloids was much more comparable to that of the normal group than the other two ratios studied. In both groups the ratio of the midfacial area to the mandibular area became smaller with age. The decrease was more rapid in the Down's syndrome group. The findings of this study imply that all areas of the face and skull are deficient in persons with Down's syndrome. The data point to the possibility that the characteristics of this syndrome and the deficiencies described are polygenic in origin. Also, contrary to the majority of reports in the literature, the mandible and the midface grow in approximately the same proportion in both study and control groups