Change of plasma leukotriene c4 during myocardial ischemia in humans

Changes in leukotriene C4 levels during different degrees of myocardial ischemia in humans were examined by comparing radioimmunoassay measures of leukotriene C4 plasma levels obtained during transient and prolonged myocardial ischemia. Leukotriene C4 levels in systemic arterial and coronary sinus blood were determined in patients with chronic stable angina before and after myocardial ischemia induced either by exercise (supine bicycle ergometer exercise stress testing; n = 14; age, 52 ± 8 years) or by coronary occlusion during angioplasty (n = 14; age 53 ± 7 years). Temporal changes of leukotriene C4 were also followed in arterial and pulmonary artery blood within 24 h after the onset of chest pain (acute phase), and 1 day, 1 week, and 1 month later in 22 patients with acute myocardial infarction (AMI) (12 patients with thrombolytic therapy, age 61 ± 10 years; 10 patients without thrombolytic therapy, age 60 ± 11 years). Clinical characteristics, including coronary risk factors and the severity of coronary artery disease, were not significantly different among the groups. Exercise-induced myocardial ischemia and coronary occlusion did not induce any significant leukotriene C4 changes in the chronic stable angina patients, whereas AMI patients had significantly higher plasma leukotriene C4 levels in both arterial and pulmonary artery blood in the acute phase compared with those of chronic stable angina patients (arterial blood, 471 ± 164 pg/ml and 477 ±235 pg/ml vs. 275 ± 254 pg/ml or 240 ± 66 pg/ml, p< 0.05; pulmonary artery blood in AMI, 543 ± 162 pg/ml vs. 234 ± 125 pg/ml or 225 ±64 pg/ml, coronary sinus blood in chronic stable angina, p < 0.05). These results suggest that leukotriene C4 is involved more in prolonged myocardial ischemia than in transient myocardial is chemia, and that leukocyte function might play a significant role in the pathogenesis of patients with AMI.     

Interleukin-18: a strong predictor of the extent of coronary artery disease in patients with unstable angina

The aim of this study was to confirm that plasma interleukin (IL)-18 level is associated with the extent of coronary artery disease in unstable angina patients. Previous studies have shown that patients with unstable angina have significantly higher plasma IL-18 levels than healthy volunteers. However, the association between IL-18 and the extent of coronary artery atherosclerosis in patients with unstable angina remains unclear. Plasma concentrations of IL-18 and high-sensitivity C-reactive protein (hs-CRP) were measured in 166 consecutive patients admitted for coronary arteriography. One hundred and eighteen patients with unstable angina had coronary artery disease (coronary artery disease group; severity score: 2.32 ± 1.47; Gensini score: 31.3 ± 25.9), and 48 patients with coronary risk factors and without coronary artery lesions served as the risk control group. Plasma levels of IL-18 were higher in the coronary artery disease group than in the risk control group (P = 0.062). Additionally, plasma levels of IL-18 were significantly higher in 77 coronary artery disease patients with severity score ≥2 than in the risk control group (242.3 ± 110.6 vs 209.8 ± 120.3 pg/ml, P = 0.016). By univariate analysis, log-transformed plasma IL-18 concentration was positively correlated with coronary artery disease severity score (r = 0.244, P = 0.009). By multiple regression analyses, the association between coronary artery disease severity score and IL-18 remained significant (β = 0.733, P = 0.017) when controlling for age, diabetes mellitus and left ventricular ejection fraction. Additionally, coronary artery disease severity score was greater in the highest tertile (>246 pg/ml) of plasma IL-18 levels than in the middle (176–246 pg/ml) and the lowest (<176 pg/ml) tertiles (2.79 ± 1.52 vs 2.05 ± 1.08 vs 2.13 ± 1.66, P = 0.028). Of note, plasma hs-CRP level had no significant correlation with coronary artery severity. Plasma IL-18 level is associated with the extent of coronary artery disease in unstable angina patients, suggesting the link between IL-18 and coronary artery atherosclerosis in these patients.     

Myocardial ischemia enhances the expression of acidic fibroblast growth factor in human pericardial fluid

Acidic fibroblast growth factor (FGF) is a potent mitogen that can induce angiogenesis in vivo. We have recently reported a marked increase of basic FGF in the pericardial fluid of patients with severe coronary stenosis and an increase in vascular endothelial growth factor (VEGF) in the pericardial fluid of patients with severe myocardial ischemia. The purpose of this study was to evaluate whether acidic FGF levels in the pericardial fluid are associated with severe myocardial ischemia. Immediately after incision of the pericardium in 48 patients during open-heart surgery, 3–5 ml of pericardial fluid was obtained. Concentrations of basic FGF and VEGF in the pericardial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). The ELISA system for human acidic FGF was newly developed using a rabbit antibovine acidic FGF antibody. The patients were divided into three groups (group A: 13 patients undergoing emergency coronary artery bypass grafting (CABG) for unstable angina; group B: 17 patients undergoing elective CABG for stable angina; group C: 18 patients undergoing nonischemic open-heart surgery). The VEGF level in the pericardial fluid in group A was 68 ± 59 pg/ml, which was significantly higher than 33 ± 9 pg/ml in group B and 31 ± 20 pg/ml in group C (P < 0.05). The concentrations of basic FGF in the pericardial fluid in groups A and B were 722 ± 601 and 773 ± 763 pg/ml, respectively, significantly higher than 263 ± 349 pg/ml in group C. The pericardial acidic FGF level in group A was 4 291 ± 2 336 pg/ml, which was also significantly higher than 2 386 ± 1 048 pg/ml in group B and 2 589 ± 990 pg/ml in group C (P < 0.05). The acidic FGF level correlated well with the level of VEGF (r = 0.61, P < 0.0001). It is concluded that the level of acidic FGF in pericardial fluid is associated with severe myocardial ischemia. This result indicates that the release of acidic FGF from the myocardial tissue into pericardial fluid is closely related to severe myocardial ischemia. Received: August 2, 2000 / Accepted: October 14, 2000     

Coronary Angioplasty Results in Leukocyte and Platelet Activation With Adhesion Molecule Expression: Evidence of Inflammatory Responses in Coronary Angioplasty

Objectives. This study sought to characterize leukocyte and platelet activation and adhesion molecule expression after coronary angioplasty.Background. Coronary angioplasty can be regarded as a clinical model of postischemic inflammation because this intervention leads to the release of inflammatory mediators as a result of plaque rupture and endothelial injury.Methods. In 13 patients with stable angina (mean [±SEM] age 56.0 ± 2.4 years, range 44 to 79), blood samples were drawn from the aorta and coronary sinus immediately before and immediately and 15 min after coronary angioplasty. Subsequently, leukocyte and platelet functions were determined. Eleven control patients (57.5 ± 2.3 years, range 52 to 78) underwent coronary arteriography.Results. Coronary arteriography and angioplasty showed no difference in number of leukocytes between the coronary sinus and the aorta. However, 15 min after coronary angioplasty, there was an increase in neutrophil CD18 and CD11b, monocyte CD14 and platelet glycoprotein IIb/IIIa expression and a decrease in neutrophil L-selectin expression (189 ± 25%, 163 ± 27%, 158 ± 35%, 141 ± 22% and 31 ± 10%, respectively, p < 0.01). In the control subjects, no change in adhesion molecule expression occurred. Superoxide production and aggregation in ex vivo-stimulated neutrophils collected from the coronary sinus 15 min after coronary angioplasty was significantly decreased compared with that after coronary arteriography (54 ± 12% vs. 106 ± 30% and 58 ± 11% vs. 102 ± 29%, respectively, p < 0.01). The reduced responses to phorbol ester stimulation may be explained by previous in vivo activation of neutrophils during coronary angioplasty.Conclusions. Coronary angioplasty increases neutrophil, monocyte and platelet adhesion molecule expression and induces a significant decrease in ex vivo-stimulated neutrophil superoxide generation and aggregation. These findings suggest that coronary angioplasty triggers cellular activation with an inflammatory response that could contribute to restenosis.(J Am Coll Cardiol 1997;29:1276–83)     

Inflammatory markers in a 2-year follow-up of coronary artery disease

Our study was designed in an attempt to determine the dynamics of changes in serum tumor necrosis factor (TNF)-α, soluble forms of its receptors (sTNFR 1, sTNFR 2), and adhesion molecules (sE-selectin, sP-selectin, sVCAM-1, sICAM-1) over a 2-year follow-up of patients with coronary artery disease (CAD). The study involved 70 patients with stable CAD (stable angina class II/III according to the Canadian Cardiovascular Society) and 20 apparently healthy subjects. Over the follow-up period a marked attenuation of angina (P < 0.001) was observed. Interventional treatment (percutaneous coronary intervention, coronary artery bypass grafting) was used in 53 CAD patients. Laboratory analysis revealed a significant decrease of serum TNF-α and sTNFR1 at 2 years (TNF-α: 12.1 ± 0.7 pg/ml; sTNFR 1: 1306 ± 46 pg/ml) as compared to baseline levels (16.5 ± 0.7 pg/ml, P = 0.030; 1551 ± 82 pg/ml, P = 0.048, respectively). The levels of sP-selectin (159 ± 7 vs 201 ± 14 ng/ml, P < 0.01) and sICAM-1 (133 ± 4 vs 153 ± 6 ng/ml, P < 0.05) were found to be significantly increased as compared to the baseline. Interventional procedures resulted in suppression of both cytokine (TNF-α, sTNFR 2) and adhesion molecule (sE-selectin, sP-selectin) activation in the CAD group. The baseline and post-follow-up TNF-α and sTNFR 1 levels showed persistent elevation in CAD patients as compared to the controls (9.0, 956.3 pg/ml, respectively; P < 0.01). There were no differences between baseline and final cytokines and adhesion molecules in healthy subjects. The course of CAD as modified by a clinically effective therapy is characterized by changes of immune markers activation. Revascularization seems to be an important factor suppressing both cytokine and adhesion molecule activation in CAD patients.     

Patients with acute coronary syndromes have low tissue factor activity and microparticle count,but normal concentration of tissue factor antigen in platelet free plasma – a pilot study

Objectives: Tissue factor (TF) is a main initiator of coagulation cascade. Its determination in conditions of acute coronary syndrome is logistically difficult. Hence, in our study, the activity and the concentration of TF and the count of microparticles in the platelet free plasma (PFP) were determined. Methods: Blood was drawn from both coronary sinus and femoral vein circulation in a cohort of 40 patients. TF activity was measured by activation of factor X in the presence of factor VIIa, whereas microparticles were detected using flow cytometry. TF antigen concentrations were determined using the ELISA test. Results: TF activity in the stable angina subgroup was not significantly different from the control group (18.12 ± 3.35 mOD/min vs. 17.72 ± 4.05 mOD/min, respectively), but it was significantly lower in the unstable angina (7.62 ± 4.19 mOD/min) and myocardial infarction (MI) (3.56 ± 3.85 mOD/min) subgroups (P < 0.05). Results from the coronary sinus and femoral vein circulations were not significantly different. The count of microparticles decreased according to the severity of the acute coronary syndrome: control group, 520 ± 172; stable angina subgroup, 532 ± 167; unstable angina subgroup, 392 ± 142; and MI subgroup, 165 ± 30 (P < 0.05). There were no significant differences in concentrations of TF antigen in four subgroups. Conclusions: These results suggest that the procoagulant TF‐bearing microparticles could be recruited from PFP by interaction with platelets and blood cells in the conditions of acute coronary syndrome.     

A new noninvasive method of diagnosing vasospastic angina based on dilation response of the left main coronary artery to nitroglycerin as measured by echocardiography

Objectives.The purpose of the present study was to evaluate the feasibility of diagnosing vasospastic angina based on coronary artery tone as assessed by M-mode echocardiographic measurement of the dilation response of the left main coronary artery to nitroglycerin.Background.The definite diagnosis of vasospastic angina is done by a coronary spasm provocative test using ergonovine maleate or acetylcholine during cardiac catherization. Current noninvasive, nonpharmacologic diagnostic methods are not sensitive enough for the diagnosis of vasospastic angina.Methods.Thirty-eight patients who had an angiographically normal left main trunk were studied. These patients were classified into four groups based on the presence or absence of more than 50% stenosis in the coronary arteries except for the left main trunk and the results of the acetylcholine or ergonovine provocative test. At 7 a.m. and at noon on the same day, the left main trunk diameter was measured by M-mode echocardiography before and after sublingual administration of nitroglycerin (0.3 mg), and its percent dilation was calculated to assess coronary artery tone.Results.The percent dilation of the left main trunk diameter induced by sublingual nitroglycerin at 7 a.m. and at noon was 22.4 ± 4.7% (mean ± SD) and 18.1 ± 4.0% in 11 patients with vasospastic angina and without coronary stenosis, 14.9 ± 7.1% and 11.2 ± 6.9% in 9 patients with vasospastic angina and coronary stenosis, 6.1 ± 3.5% and 7.0 ± 5.1% in 8 patients without vasospastic angina but with coronary stenosis and 8.1 ± 5.6% and 7.8 ± 5.7% in 10 control subjects. The percent dilation at 7 a.m. was significantly greater in the vasospastic angina without coronary stenosis group than in the remaining three groups, and in the vasospastic angina groups, the percent dilation at 7 a.m. was significantly greater than that at noon. When percent dilation at 7 a.m. exceeding 15% was defined as positive for the diagnosis of vasospastic angina, the sensitivity was 80% and the specificity 94%.Conclusions.Basal tone of the left main trunk is elevated in the early morning in vasospastic angina. Dilation of the left main trunk diameter exceeding 15% induced by sublingual nitroglycerin in the early morning as measured by M-mode echocardiography is a highly sensitive and specific criterion for the diagnosis of vasospastic angina.     

Arterial and coronary sinus catecholamines in the course of spontaneous coronary artery spasm

We studied plasma catecholamine levels in 10 patients with frequent spontaneous episodes of coronary artery spasm to evaluate the role of the sympathetic nervous system. Peripheral venous norepinephrine in supine and upright postures, urinary excretion of catecholamines, and functional testing of the sympathetic nervous system did not differ from the same measurements in control subjects. Arterial and coronary sinus levels of norepinephrine and epinephrine drawn early in ischemia were not elevated over baseline; coronary sinus norepinephrine levels were higher than those in arterial samples and rose from 315 ± 32 (pg/ml ± SE) at the onset of ST elevation to 490 ± 49 pg/ml late in ischemia (p < 0.05). Plasma epinephrine levels, higher in arterial than coronary sinus samples, also rose significantly only late in ischemia, from 44 ± 14 pg/ml to 148 ± 35 pg/ml (p < 0.05) in arterial blood and from 33 ± 10 pg/ml to 108 ± 29 pg/ml in coronary sinus samples (p < 0.05). Generalized sympathetic nervous system activation is not likely to be the sole cause of coronary artery spasm.     

Increased soluble glycoprotein V concentration during the acute onset of unstable angina pectoris in association with chronic cigarette smoking

Platelet hyperactivity is important in the pathobiology of acute coronary syndromes. Glycoprotein V (GPV) is an integral membrane protein of platelets in the function of the GPIb-V-IX receptor for vWf/shear-dependent platelet adhesion in arteries. Soluble GPV is a novel marker of platelet activation. The aim of this study is to assess circulating soluble GPV levels in unstable angina pectoris (UA). Twenty-one patients (15 men, six women, aged 52?±?7 years) with UA pectoris were studied. The inclusion criteria were angina at rest lasting >20?min during the preceding 6?h, with transient ST segment depression and/or T wave inversion and no evidence of myocardial infarction detected with the use of cardiac troponin-T. Coronary artery stenosis was angiographically confirmed in all patients. Twenty age- and sex-matched healthy adults (14 men, six women, aged 48?±?7 years) served as controls. There were no significant differences among the studied groups with respect to age, sex, obesity, smoking, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride and platelet counts. Plasma-soluble GPV concentrations were higher in the UA patient group (126?±?46?ng/ml) than those in the healthy controls (82?±?15?ng/ml) (P?=?0.001). There was a significant correlation only between plasma-soluble GPV levels and smoking (r?=?0.526, P?=?0.0001). Smoker UA patients had higher levels of soluble GPV than the non-smoker patients (139?±?40 vs. 113?±?50?ng/ml, respectively, P?=?0.02). However, soluble GPV levels were similar in smoker and non-smoker healthy controls (P?=?0.2). It is concluded that soluble GPV concentrations are significantly increased during the acute clinical course of unstable angina pectoris, indicating that soluble GPV may be useful marker of platelet activation in those patients. The level of the molecule is significantly affected from smoking in those patients.     

Effect of tyramine on myocardial catecholamine release in coronary heart disease

The influence of tyramine on myocardial catecholamine release and on coronary blood flow has not previously been determined in man. Therefore, the effect of tyramine was measured on coronary and systemic hemodynamics and on norepinephrine (NE) and epinephrine levels in blood from the aorta and coronary sinus in 9 patients with coronary artery disease. Tyramine produced a striking increase in coronary sinus NE, from a baseline of 344 ± 56 to a peak level of 1416 ± 310 pg/ml (p < 0.01) 2 minutes after tyramine. The increase in aortic NE was less striking, from 265 ± 32 to 421 ± 63 pg/ml (difference not significant). Therefore, the net release of NE from the heart was increased by tyramine from 12,007 ± 393 to 139,357 ± 46,156 pg/ ml/min (p < 0.03). There was no release of epinephrine across the coronary bed. There was a variable response of coronary blood flow and resistance after tyramine. Thus, the rich innervation of the heart by sympathetic nerve endings can result in marked NE release into the coronary sinus.     

Platelet-monocyte cross talk and tissue factor expression in stable angina vs. unstable angina/non ST-elevation myocardial infarction

Tissue factor (TF), the major procoagulant in vivo, is usually absent from blood cells. However, since both monocyte TF (MoTF) expression and platelet activation are present in acute coronary syndrome we hypothesized that MoTF expression may in part depend on monocyte platelet aggregate (MPA) formation in coronary artery disease (CAD). Patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI, n?=?20) had significantly higher levels of MoTF (17.4?±?3.1MFI) and MPAs (CD42b:273?±?183MFI; CD62P:256.3?±?48.5MFI) than patients with stable angina (SA, n?=?40; MoTF:13.2?±?2.2MFI, p?=?0.001; CD42b:160?±?113MFI, p?=?0.025; CD62P:118.7?±?24.5MFI, p?=?0.018) as measured by whole blood flow cytometry on CD14⁺-cells. TF-activity of isolated mononuclear cells (MNC) was elevated in UA/NSTEMI (75?±?27?pg/mL) in comparison to SA (47?±?17?pg/mL, p?=?0.001) as determined by chromogenic assay, and TF mRNA expression in isolated MNC was more frequent in UA/NSTEMI than in SA (50% vs. 18.2%; p?=?0.017). MoTF expression significantly correlated with the constitutive platelet marker CD42b (r?=?0.69, p?<?0.001) and the platelet activation marker CD62P (r?=?0.47, p?=?0.001) on CD14⁺-cells suggesting its association with MPAs in UA/NSTEMI. In addition, MoTF expression correlated with MoTF activity of isolated MNC (r?=?0.41, p?=?0.01) and plasma levels of the F1.2 prothrombin fragment (r?=?0.35, p?=?0.02). In conclusion, MoTF and MPAs are elevated in UA/NSTEMI compared with SA. MoTF expression correlates with platelet mass and activity attached to monocytes.     

Erythrocyte magnesium and prostaglandin dynamics in chronic sleep deprivation

Background and hypothesis: The mechanism of sudden cardiac death occurring in patients with chronic fatigue is controversial. This study was designed to define a hypothesis that coronary arterial spasm and thrombus formation can occur during chronic fatigue. Methods: For evaluating the feasibility of coronary arterial spasm, erythrocyte magnesium (Mg) was measured. Blood coagulability was evaluated by the change of prostaglandin concentration. Subjects included 16 healthy male volunteers (mean age 21.6 ± 2.5 years). Test conditions were as follows: (A) control state: a day following a night of good sleep; (B) temporary sleep deprivation: a day preceded by < 3 h of sleep; (C) chronic sleep deprivation: a day preceded by a month during which sleep lasted < 60% of that in condition (A) above. The erythrocyte Mg concentration was measured by the atomic absorption method. The plasma concentration of thromboxane B₂ and 6-keto-prostaglandin F_1α were measured in eight subjects by radioimmunoassay method. Results: (1) Mean erythrocyte Mg concentration was significantly less in chronic sleep deprivation (1.1 ±0.4 mg/dl) than in the control state (1.8 ± 0.4 mg/dl, p<0.01) or in temporary sleep deprivation (1.6 ± 0.4, p<0.01). (2) The level of thromboxane B₂ was significantly higher during chronic sleep deprivation than under control conditions (104.4 ± 78.0 vs. 20.4 ± 9.0 pg/ml, p<0.05). (3) There were no significant intergroup differences in 6-keto-prostaglandin F_1α level. Conclusion: These findings could support the hypothesis that coronary arterial spasm and thrombus formation occur in chronic sleep deprivation.     

Abnormal cardiocoronary thromboxane A2 production in patients with unstable angina

Thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2), was measured in the coronary sinus and in aortic blood before and after cold pressor test (CPT) in 21 patients suffering from ischemic heart disease (7 affected by stable effort angina and 14 by unstable angina) and in 12 patients not suffering from myocardial ischemia (control group) during coronary angiography. Aspirin (10 mg/kg intravenously) was administered before catheterization in order to prevent platelet and leukocyte TXA2 formation. Control subjects and patients with effort angina had TXB2 resting levels lower than unstable angina patients without a transcardiac gradient which, on the contrary, was found in unstable angina patients. Only in these patients CPT resulted in a significant TXB2 increase more marked in the coronary sinus (from 50.0 +/- 18.9 pg/ml to 73.0 +/- 35.1 pg/ml, p less than 0.001) than in the aorta (from 33.4 +/- 17.1 pg/ml to 42.6 +/- 24.0 pg/ml, p less than 0.05), so that the transcardiac TXB2 gradient significantly increased. In all but two unstable angina patients, TXB2 elevation was not associated with a fall of cardiac lactate extraction. The resting and CPT-induced TXB2 gradients were unrelated to the presence and severity of coronary angiographic lesions. These results indicate that unstable angina patients show an abnormal cardiocoronary capacity to synthesize TXA2, which seems not to be elicited by the occurrence of myocardial ischemia.     

Disparity between serotonin- and acetylcholine-provoked coronary artery Spasm

Background and hypothesis: Intrinsic vasoactive substances, such as serotonin and acetylcholine, are known to provoke coronary artery spasm in patients with vasospastic angina. It remains unclear, however, whether these different agents, which activate different receptors, produce spasms at the same sites in these patients. The present study was designed to clarify the disparity of receptor agonist-induced coronary artery spasms in the same patients. Methods: We conducted sequential provocative tests of coronary artery spasm by acetylcholine, serotonin, and ergonovine in 20 patients with rest angina examined with quantitative coronary angiography. Results: Coronary artery spasms were provoked in all patients at 27 spastic sites. In 13 patients, ergonovine provoked spasms and in 10 of 13 patients who were diagnosed with variant angina, both acetylcholine and serotonin provoked spasms at the same sites where ergonovine also did. In 4 of 13 patients, spasms were provoked by serotonin but not by acetylcholine. In the remaining seven patients, whose spasms were induced by ergonovine, spasms were produced by acetylcholine but not by serotonin. On coronary angiography, the spastic sites for both acetylcholine and serotonin, and those for serotonin alone, were located in the proximal segments of coronary arteries, whereas the spastic sites for acetylcholine alone were located in the distal segments. Conclusions: This study documented the disparity between serotonin- and acetylcholine-induced spasms. Provocative tests using agents that activate different receptors may produce coronary artery spasms at the same and/or different sites, and this disparity may reflect the clinical heterogeneity of vasospastic ischemic syndrome.     

Effects induced on blood platelets in ischemic and nonischemic myocardium

The function of blood platelets sampled from the coronary sinus and the superior vena cava was studied in 50 men with coronary artery disease at rest and during pacing-induced angina. At rest, a lower platelet aggregation and retention response was found in coronary sinus compared with vena caval blood. This may be due to refractoriness after previous platelet stimulation or to release of platelet inhibitors in the coronary circulation. During pacing-induced angina, lactate levels indicated that blood was sampled from ischemic myocardium in only 27 of the patients. Pacing-induced angina influenced platelet function differently in blood from ischemic and nonischemic regions. Adenosine diphosphate- and collagen-induced aggregation, platelet retention and plasma beta-thromboglobulin levels remained unchanged in blood from ischemic myocardium during pacing, but increased in blood from nonischemic regions. Thus, factors other than ischemia activated platelets in the coronary circulation during tachycardia-induced stress.     

Determinants of rebound thrombin activity after cessation of heparin in patients undergoing coronary interventions

This study was designed to characterize hemostatic activation (using fibrinopeptide A (FPA), a marker of thrombin activity, and β-thromboglobulin (BTG), a marker of platelet activation) sequentially in the coronary and peripheral circulation in patients during percutaneous coronary intervention (PCI) and several hours after PCI and discontinuation of heparin therapy. Heparin administered during PCI is known to nonuniformly suppress thrombin activity in the coronary. Persistent elevations of FPA in coronary sinus (CS) blood during PCI have been associated with subsequent ischemic events. As a related consideration, rebound thrombin activity has been demonstrated in peripheral blood samples several hours after cessation of heparin therapy in patients with acute coronary syndromes. Accordingly, we hypothesized that increased thrombin activity occurs in the coronary circulation after PCI and is induced by cessation of intravenous heparin to facilitate vascular sheath removal. Such a rebound prothrombotic effect, may contribute to suboptimal outcomes after PCI. In 21 patients undergoing PCI, heparin-bonded catheters were employed to obtain sequential CS and femoral vein (FV) blood samples for measurement in the coronary and peripheral circulation of plasma FPA, a marker of thrombin activity in vivo, and BTG released by platelets during degranulation. Following heparin administration samples were obtained immediately prior to (base) and during (start and end) PCI. Late samples were obtained several hours after PCI (284 ± 46 min, mean ± SD) following the cessation of heparin and prior to planned vascular sheath removal. Mean FPA concentration in CS blood was low at baseline (3.82 ± 2.09 ng/ml) and did not increase during PCI. Mean FPA concentration in CS blood increased significantly several hours after cessation of heparin (3.42 ± 2.36 vs. 7.82 ± 9.98, end vs. late, P < 0.001). In contrast, mean FPA concentration in FV blood was highest at baseline following vascular sheath insertion, decreased during PCI (69%, P < 0.05, base vs. end), and trended upward after PCI and cessation of heparin. Mean FPA values were higher at all times in FV compared with CS blood samples and were not concordant after PCI. Elevation of coronary circulation FPA after PCI was maximal in patients with myocardial infarction within 7 days (13.7 ± 12.4 vs. 5.6 ± 7.9 ng/ml, P = 0.08), but was not influenced by heparin treatment prior to PCI, a history of unstable angina, or coronary stent placement during PCI (9 of 21 patients). BTG values showed less variation than did FPA values, and cessation of heparin after PCI was not associated with an increase in BTG in CS or FV blood samples. An increase in thrombin activity occurs in the coronary circulation after PCI following discontinuation of heparin. The extent of increased thrombin activity was greatest in patients with recent myocardial infarction and was not exacerbated by coronary stent placement during PCI. This phenomenon may contribute to the important minority of ischemic complications early after PCI. Cathet. Cardiovasc. Diagn. 44:257–264, 1998. © 1998 Wiley-Liss, Inc.     

Effect of the Composition of Atherosclerotic Plaques and Rate of Platelet Aggregation on Elevation of Serum Levels of Cardiac Troponin T After Percutaneous Coronary Interventions

Purpose: Elevation of the levels of myocardial biomarkers after percutaneous coronary intervention (PCI) has prognostic value in patients with coronary heart disease. We explored the relationship between elevation of the serum level of cardiac troponin T (cTnT) after PCI and platelet aggregation rate and coronary plaque composition. Methods: Eighty patients with unstable angina pectoris underwent PCI and were divided into two groups according to serum cTnT level 24 hours after PCI: group I (cTnT ≥2 times the normal level) and group II (cTnT <2 times the normal level). Coronary plaque composition was measured with virtual histology‐intravascular ultrasound. Platelet aggregation rate was detected immediately before and 24 hours after PCI. Results: Compared with the patients in group II, patients in group I showed more unstable plaques, a larger necrotic core area (20.88 ± 8.04% vs. 15.31 ± 5.48%, P < 0.05), higher platelet aggregation rate (51.47 ± 12.72% vs. 44.78 ± 13.29%, P < 0.05), and longer stents. The serum cTnT level 24 hours after PCI was positively correlated with the necrotic core area. Conclusions: In patients with unstable angina pectoris, a large necrotic core, high rate of platelet aggregation, and stent length are predictors of cTnT elevation after PCI. (J Interven Cardiol 2012;25:433–438)     

Evaluation of the effects of catheter sampling for the study of platelet behavior in the pulmonary and coronary circulation

To study the effects of sampling through cardiac catheters on indices of platelet function, we measured the levels of platelet factor 4 (PF₄), beta thromboglobulin (BTG), and platelet aggregate ratio (PAR) in 10 patients with atrioventricular accessory pathway (AVNAP), six patients with primary pulmonary hypertension (PPH), and six patients with critical narrowing of the left anterior descending artery (LAD). In AVNAP and LAD patients samples were drawn simultaneously from a peripheral vein, coronary sinus, and brachial artery; in AVNAP patients samples were also obtained from the axillary vein before the coronary sinus was entered. In PPH patients samples were drawn from pulmonary artery, aorta, and a peripheral vein; in these patients the effects of an intravenous infusion of prostacyclin (PGl₂) (2 to 8 ng/kg/min) on PF₄, BTG, and PAR were also studied at all sampling sites. In all patients arterial, coronary sinus, pulmonary arterial, and axillary venous levels of PF₄, BTG, and PAR significantly exceeded those measured in the peripheral vein. PGl₂ infusion resulted in a significant decrease of PF₄ at all sampling sites, while no consistent BTG changes were observed and PAR levels did not decrease in the peripheral vein. Although a considerable interpatient variability in PF₄ levels was observed, a significant (r = 0.91) correlation was found in patients with AVNAP between simultaneous coronary sinus and arterial PF₄ levels. The value of PF₄ coronary sinus-arterial difference in LAD patients was consistently higher than that calculated in AVNAP patients (54.5 ± 28.9 vs 4.2 ± 3.8 ng/ml). In conclusion: (1) a considerable and variable degree of platelet activation occurs with catheter sampling, preventing the measurement of absolute levels of platelet metabolites; (2) among the indices examined PF₄ appears the most sensitive for detecting changes in platelet activity; and (3) the measurement of coronary sinus-arterial PF₄ differences may provide information on directional changes in transcardiac platelet behavior.     

Mean Platelet Volume in the Patients with Cardiac Syndrome X

Background:Angina with normal coronary arteries, cardiac syndrome X, is a diagnosis of exclusion. The exact mechanism of this clinical syndrome remains unclear. Although the prognosis is as good as equal to that of normal population, symptoms related with the syndrome impair largely quality of life. Mean platelet volume showing the platelet size is an indicator of platelet function. Larger platelets are more active than smaller ones. Methods and results: We designed a study, evaluated mean platelet volume of the patients with cardiac syndrome X (group A) and stable angina (group B) and investigated the relation between groups. Eighty patients with cardiac syndrome X with a mean age of 51.08 ± 9.79 years and 67 patients with stable angina with a mean age of 55.16 ± 11.96 years were studied. At the end of the study, mean platelet volume of group A was significantly higher than that of group B, 10.55 ± 1.08 fl vs. 9.39 ± 0.58 fl, respectively (P < 0.001). Conclusion: Raised platelet size has been shown to be associated with adverse cardiac events. Mean platelet volume has increased in acute coronary syndromes and also in cardiac syndrome X in our study. Life style modification may optimize platelet size and improve symptoms in these patients.     

Activation of polymorphonuclear leukocytes and increased plasma vasoconstrictors in vasospastic and nonvasospastic angina

Background

The cause of coronary vasoconstriction in patients with angina at rest, nonsignificant coronary stenosis, and endothelial dysfunction remains unknown. Our objective was to investigate the association between enhanced coronary vasoconstriction and increased circulating levels of vasoconstrictor agents.

Methods

Plasma levels of big endothelin-1, serotonin, and superoxide produced by polymorphonuclear leukocytes were measured in 38 patients with stable angina at rest without significant coronary artery stenosis—23 with nonvasospastic angina and 15 with vasospastic angina—and were compared with 10 patients with stable coronary disease and 20 age-matched controls.

Results

Patients with angina at rest showed higher big endothelin-1 (1.28 vs 0.72 fmol/mL, P < 0.001), serotonin (18.0 vs 9.1 ng/mL, P = 0.002), and superoxide produced by polymorphonuclear leukocytes (177 vs 67 nmol/10 × E8 × minutes, P = 0.001) than did controls. Serotonin and superoxide produced by polymorphonuclear leukocytes were also higher than in coronary disease patients (5.4 ng/mL, P = 0.001, and 97 nmol/10 x E8 x minutes, P = 0.005), and big endothelin-1 levels tended to be higher (0.99 fmol/mL, P = 0.073). Moreover, there were no significant differences in these 3 parameters between patients with vasospastic and nonvasospastic angina, and among the latter, between patients with a positive and those with a negative exercise stress test.

Conclusion

Systemic plasma levels of agents with the potential to produce coronary vasoconstriction are increased in patients with stable vasospastic or nonvasospastic angina and, hence, may contribute to their angina, increased coronary tone, and impaired vasodilatory capacity. Furthermore, they may establish a mechanistic link between the 2 conditions.