Angoli L

Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease.

BackgroundA rapid increase in leukocyte adhesion to endothelial cells is one of the first events in the acute inflammatory response and in the pathogenesis of vascular diseases. A subgroup of cell surface glycoproteins (the CD11/CD18 complex) play a major role in the leukocyte adhesion process; in particular, the CD11b/CD18 receptor can be upregulated severalfold in response to chemotactic factors. The purpose of this study was to assess whether upmodulation of granulocyte and monocyte CD11b/CD18 receptors takes place during the passage of blood through the coronary tree of patients with clinical manifestations of ischemic heart disease. Methods and ResultsThirty-nine patients who underwent diagnostic coronary arteriography were studied. Group 1 (15 patients) had a clinical diagnosis of unstable angina, group 2 (14 patients) had stable exertional angina, and group 3 (10 patients) had atypical chest pain. Simultaneous sampling from the coronary sinus and aorta was obtained before coronary arteriography. Cell surface receptors were detected by direct immunofluorescence evaluated by flow cytofluorimetry using monoclonal antibodies tagged with fluorescent markers. Leukocytes were stained in unseparated blood to avoid in vitro manipulation that could activate phagocytes. Group 1 and 2 patients had significant coronary artery disease (>50%o coronary narrowing in at least one major coronary vessel), whereas group 3 patients had normal coronary arteries. In group 1, granulocytes and monocytes showed a significantly higher expression of the CD11b/CD18 adhesion receptor in the coronary sinus than in the aorta (both P<.01), whereas no difference in CD11b/CD18 expression was seen in groups 2 and 3. ConclusionPatients with unstable angina have an increased expression of granulocyte and monocyte CD11b/CD18 adhesion receptors, indicating that an inflammatory reaction takes place within their coronary tree. Activation of these leukocytes may induce coronary vasoconstriction, favor thrombotic processes, and further activate platelets, thus having potential implications on the pathogenesis of unstable coronary artery disease.

Coronary arterial spasm as a cause of exercise-induced ST-segment elevation in patients with variant angina.

Four patients with variant angina pectoris exhibited reproducible exercise-induced chest pain ST-segment elevation. Coronary arterial spasm was documented with arteriography during exerciseinduced ST-segment elevation (three patients) or after intravenous administration of ergonovine maleate (one patient). Our observations show that in patients with variant angina exercise can trigger coronary arterial spasm, thus inducing anginal pain ST-segment elevation.

Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes: A morphologic, immunohistochemical, and biochemical study

We investigated incidence, severity, and distribution of coronary atherosclerosis, acute thrombosis, and plaque fissuring in ischemic heart disease (both unstable-acute syndromes and chronic ischemia) and in nonischemic controls. We also studied the structural, immunohistochemical, and biochemical profile of plaques, with and without thrombus, including morphometry, immunophenotyping of inflammatory infiltrates, cytokine presence, and ultrastructural features. Critical coronary stenosis was almost the rule in both acute and chronic ischemic series (greater than 90%) whereas it reached 50% in control subjects. Thrombosis was principally characteristic of unstable-acute ischemic syndromes (unstable angina, 32%; acute myocardial infarction, 52%; cardiac sudden death, 26%) but was also found in chronic ischemia (stable angina, 12%; ischemic cardiomyopathy, 14%) and in control subjects (4%). Plaque fissuring without thrombus occurred in low percentages in lipid-rich, severe eccentric plaques in most series. Major differences were found between pultaceous-rich versus fibrous plaques rather than between plaques with or without thrombus. Pultaceous-rich plaques were frequent in sites of critical stenosis, thrombosis, and ulceration. Inflammatory infiltrates, i.e., T cells, macrophages, and a few beta cells, mostly occurred in lipid-rich, plaques unrelated to thrombus. In adventitia, infiltrates were a common finding unrelated to any syndrome. Necrotizing cytokines such as alpha-TNF were immunohistochemically detected in macrophages, smooth muscle, and intimal cells and detected by immunoblotting in 67% of pultaceous-rich plaques, either with or without thrombus. Immune response mediators such as IL-2 were also expressed in analogous plaques but in a minor percentage (50%-40%). Media were extensively damaged in severely diseased vessels with and without thrombus. Ultrastructural study showed that the fibrous cap was either highly cellular or densely fibrillar. Intimal injury with collagen exposure was often associated with platelet adhesion, whereas foamy cell exposure was not. In conclusion, investigated parameters were essentially similar in plaques, both with and without thrombus, whereas major differences were found between pultaceous-rich and fibrous plaques. Since platelets adhere to exposed collagen and not to foam cells, the type of exposed substrates could play a major role in thrombosis.

Granulocyte activation after coronary angioplasty in humans.

To determine whether percutaneous transluminal coronary angioplasty (PTCA) would lead to neutrophil activation with subsequent discharge of proteolytic enzymes, like elastase, and oxygen free radicals, like superoxide anion, blood samples were taken from the coronary sinus and aorta in 14 patients with stable angina and one-vessel disease who underwent PTCA. Neutrophils were separated by means of the Ficoll-Hypaque system and were stimulated to detect release of elastase and generation of superoxide anion. Plasma levels of elastase were also measured by an immunoenzymatic method. PTCA was successful in all patients. Plasma elastase levels increased significantly at the end of the procedure compared with pre-PTCA values both in the coronary sinus (from 129.2 +/- 16.6 to 286.6 +/- 39.7 micrograms/l, p less than 0.005) and in the aorta (from 117.4 +/- 13.6 to 258.1 +/- 41.3 micrograms/l, p less than 0.005). On the other hand, superoxide anion released in the supernatants after neutrophil stimulation by phorbol-myristate-acetate decreased after PTCA in the coronary sinus (before PTCA, 60.1 +/- 7.1; after PTCA, 40.7 +/- 6.8 nmol 1 x 10(7) granulocytes/ml/15 min, p less than 0.05), whereas a mild but not significant decrease was observed in the aorta (from 58.3 +/- 10.9 to 55.3 +/- 8.6 nmol 1 x 10(7) granulocytes/ml/15 min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of coronary lesions obtained by directional coronary atherectomy in unstable angina, stable angina, and restenosis after either atherectomy or angioplasty.

The present study investigated the incidence of the histopathologic lesions and of growth factor expression in a consecutive series of directional coronary atherectomy (DCA) samples from 40 unstable angina pectoris patients without prior acute myocardial infarction and compared the findings with those obtained in DCA samples from 18 patients with stable angina without previous infarction and 18 patients with restenosis. We investigated coronary thrombosis, neointimal hyperplasia, and inflammation. For unstable angina, we correlated the angiographic Ambrose plaque subtypes with the histopathologic findings. The immunophenotype of plaque cells and the growth factor expression were assessed with specific antibodies for cell characterization and for the expression of basic fibroblast and platelet-derived AA and AB growth factors and receptors. The incidence of coronary thrombosis was 35% in patients with unstable angina, 17% in those with stable angina, and 11% in patients with restenosis. Neointimal hyperplasia was found in 38% of unstable angina cases, in 17% of stable angina cases, and in 83% of restenosis cases. Inflammation without thrombus or accelerated progression occurred in 20% of unstable angina and 6% of stable angina samples. In 52% of unstable angina cases, inflammation coexisted with thrombosis and/or neointimal hyperplasia. In the unstable angina group, 71% of the plaques with thrombus had a corresponding angiographic pattern of complicated lesions. The growth factor expression, reported as percentage of cells immunostaining with different growth factor antibodies, was highest in restenosis, followed by unstable angina and stable angina lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Mental arithmetic stress testing in patients with coronary artery disease

A mental arithmetic stress test was performed by 122 consecutive patients undergoing diagnostic coronary arteriography. Twenty-two patients showed significant ST segment abnormalities during the test (group 1). Of these patients, 20 performed a bicycle exercise test, which was positive in all of them. Seventy patients had a negative mental stress but a positive exercise test (group 2), whereas in 30 patients both tests were negative (group 3). There were no patients with a positive mental stress test and a negative exercise test. Mental stress induced a significant increase in heart rate and systolic blood pressure in the three groups of patients. Group 1 patients, however, achieved higher values of double product during mental stress and had a shorter exercise duration than group 2 and group 3 patients. The extent of coronary artery disease (CAD) was similar in groups 1 and 2, while group 3 patients had a significantly lower prevalence of two or more vessel disease. To investigate the pathogenetic mechanism of mental stress-induced myocardial ischemia, great cardiac vein flow was measured by means of the thermodilution technique in four patients with isolated left anterior descending artery disease, who showed ST segment depression in anterior leads in response to mental stress. In three patients without vasospastic angina the calculated coronary resistance decreased during mental stress, as a result of a normal vasodilatory response to the increased myocardial oxygen consumption induced by the test. By contrast, in one patient with variant angina, coronary resistance increased suggesting coronary vasoconstriction. Our findings demonstrate that mental arithmetic stress testing may induce significant ST segment abnormalities in patients with CAD.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose erythropoietin in patients with acute myocardial infarction: A pilot, randomised, placebo-controlled study

BACKGROUND Mortality and morbidity after acute myocardial infarction (AMI) remain high even when myocardial reperfusion is successful. Erythropoietin (EPO) protects against experimental MI. METHODS The aim of this single-centre study was to investigate the effects of short-term high-dose erythropoietin on peripheral blood cells (PBCs) and infarct size in 30 patients with a first uncomplicated AMI undergoing percutaneous coronary intervention (PCI) who were randomly assigned to treatment with EPO (33 × 10(3)IU before PCI, and 24 and 48 h after admission), or placebo. We considered short-term CD34+ cell mobilisation, quantitative PBC gene expression in the apoptotic, angiogenic and inflammatory pathways, and enzymatically estimated infarct size. Echocardiographic and cardiac magnetic resonance studies were performed in the acute phase and six months later. RESULTS CD34+ cell mobilisation 72 h after admission was greater in the EPO-treated patient group (93 cells/μl [36-217] vs 22 cells/μl [6-51]; p = 0.002), who also showed higher expression of the anti-apoptotic AKT and NFkB, the pro-angiogenic VEGFR-2, and the EPO-R genes, and lower expression of the pro-apoptotic CASP3 and TP53 and pro-inflammatory IL12a genes. Moreover, they showed smaller infarct size (30% reduction in CK-MB release; p = 0.025), and a favourable pattern of left ventricular remodelling. CONCLUSIONS Short-term high-dose EPO administration in patients with AMI treated by PCI and standard anti-platelet therapy increases the levels of circulating CD34+ cells, shifts PBC gene expression towards anti-apoptotic, pro-angiogenic and anti-inflammatory pathways, and decreases infarct size. The clinical relevance of these results needs to be confirmed in specifically tailored trials.

Clinical and angiographic correlates of leukocyte activation in unstable angina

OBJECTIVES This study sought to evaluate the relation, if any, between clinical and angiographic findings in patients with unstable angina and monocyte and neutrophil CD11b/CD18 receptor density. The expression of HLA-DR molecules on T lymphocytes, an index of activation of these cells, was also investigated. BACKGROUND Although activation of neutrophils and monocytes has recently been shown in unstable angina, no studies have correlated activation indexes with clinical and angiographic features of patients with this clinical condition. METHODS Sixty patients underwent diagnostic coronary arteriography and simultaneous blood sampling from the aorta and coronary sinus before injection of contrast medium. Cell surface receptors were detected by direct immunofluorescence evaluated by flow cytometry using monoclonal antibodies tagged with fluorescent markers. RESULTS In 38 patients with unstable angina, neutrophils and monocytes showed a significantly higher expression of CD11b/CD18 adhesion receptors in coronary sinus than aortic blood (p < 0.0001 and p < 0.001, respectively). When these patients were analyzed according to clinical characteristics or angiographic findings, no difference in CD11b/CD18 receptor expression in coronary sinus blood was found between the various subgroups, except for patients with at least one episode of chest pain at rest within 48 h of coronary arteriography and a higher neutrophil adhesion molecule density than patients who remained asymptomatic (p = 0.04). Lymphocytes in patients with stable and unstable angina showed a similar percent expression of CD2/CD19 and CD3/HLA-DR antigens, with no difference between aortic and coronary sinus blood. CONCLUSION These results in a larger cohort confirm previous data that neutrophil and monocyte CD11b/CD18 adhesion molecules show a higher expression in the coronary sinus blood of patients with unstable angina. Among clinical and angiographic findings in patients with unstable angina, only the occurrence of chest pain within 48 h of coronary angiography was related to significantly higher values of neutrophil fluorescence intensity, suggesting that the degree of neutrophil activation is related to the proximity of rest angina episodes to blood sampling. Finally, our data do not support the concept of systemic or transcardiac lymphocyte activation in unstable angina.

Interaction Between Exercise Training and Ejection Fraction in Predicting Prognosis After a First Myocardial Infarction

BACKGROUND Although recent meta-analysis trials have shown that exercise training may improve survival after myocardial infarction, the mechanism of this beneficial effect is still unknown. The purpose of this study was to detect possible interactions between exercise training and predictors of prognosis after a first myocardial infarction. METHODS AND RESULTS Patients with uneventful clinical courses after a first myocardial infarction were randomly assigned to a 4-week training period (125 patients, group 1) or to a control group (131 patients, group 2). Before randomization, all patients underwent a symptom-limited exercise test (28 +/- 2 days after myocardial infarction), 24-hour Holter monitoring, and coronary arteriography (31 +/- 3 days after the acute episode). After a mean follow-up period of 34.5 months, 18 patients had cardiac deaths (5 in group 1 and 13 in group 2). Multivariate analysis by Cox regression model showed that ejection fraction was the only independent prognostic indicator (P = .03). Evidence existed of an interaction between ejection fraction and exercise training, showing an effect of physical training on survival that depended on the patients ejection fraction. Among patients with ejection fractions < 41%, the relative risk for an untrained patient was 8.63 times higher than for a trained patient (P = .04), whereas for ejection fractions > 40%, the estimated risks for trained and untrained patients were similar. CONCLUSIONS These data show that exercise training may prolong survival in post-myocardial infarction patients with depressed left ventricular function. A randomized trial in such patients seems warranted.

Expression of neutrophil and monocyte CD11B/CD18 adhesion molecules at different sites of the coronary tree in unstable angina pectoris

To assess the site of leukocyte activation in unstable angina, the expression of neutrophil and monocyte CD11B/CD18 adhesion molecules in 26 patients was measured from blood samples taken from the coronary ostium, the coronary sinus, and the coronary artery just distal to the culprit lesion (postobstructive chamber). CD11B/CD18 adhesion molecules detected by direct immunofluorescence evaluated by flow cytometry were significantly higher in the coronary sinus blood than in both the coronary ostium and the postobstructive chamber blood, suggesting that leukocyte activation takes place at the microcirculatory interface with the injured myocardium, probably as the result of short but repeated episodes of myocardial ischemia.