Transcardiac release of leukotriene C4 by neutrophils in patients with coronary artery disease

Leukotriene C4 is a potent constrictor of smooth muscle in vitro and may induce coronary vasoconstriction in vivo. To study leukotriene C4 release by neutrophils in patients with coronary artery disease, neutrophils were separated from blood samples taken from the coronary sinus and aorta in 20 patients with stable exertional angina and angiographically documented coronary artery narrowings (group I). Eight patients with normal coronary arteries were also studied (group II). To assess leukotriene C4 generation, neutrophils were incubated with calcium ionophore A 23187 (0.25 microM) and the supernatants obtained after centrifugation were analyzed for leukotriene C4 by radioimmunoassay. Patients in group I had a significantly lower release of leukotriene C4 from neutrophils separated from the coronary sinus blood than from those separated from aortic blood (4.33 +/- 0.69 versus 5.92 +/- 0.54 ng/ml, p less than 0.025), whereas patients in group II had a similar release of leukotriene C4 by the neutrophils separated from coronary sinus blood and from aortic blood (6.0 +/- 0.72 versus 6.4 +/- 0.66 ng/ml, p = NS). Moreover, in group I patients, a significant correlation was found (p less than 0.01) between the extent of coronary artery disease (expressed by the Leaman coronary score) and the percent reduction in leukotriene C4 released from neutrophils separated from coronary sinus blood as compared with leukotriene C4 produced by neutrophils separated from aortic blood. These data show that neutrophils from patients with coronary artery disease have a reduced ability to produce leukotriene C4 after stimulation by calcium ionophore A 23187.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thromboxane release in coronary artery disease: spontaneous versus pacing-induced angina

To determine thromboxane A2 release in coronary artery disease, we measured its stable metabolite thromboxane B2 by radioimmunoassay in 20 patients. In 15 patients with stable disease (last angina episode greater than 96 hours before study), coronary venous thromboxane B2 concentrations were lower than in aortic blood (mean 109 +/- 36 vs 194 +/- 40 pg/ml, p less than 0.001). In contrast, in five other patients with spontaneous angina, coronary venous thromboxane B2 concentrations were higher than aortic thromboxane B2 concentrations during the angina episode (mean 1716 +/- 316 vs 875 +/- 388 pg/ml, p less than 0.02). Plasma thromboxane B2 levels were in the normal range (mean 175 +/- 35 pg/ml) in patients with stable angina but significantly (p less than 0.02) higher in patients with spontaneous angina. With atrial pacing to the point of chest pain and/or ECG changes in patients with stable coronary artery disease, aortic thromboxane B2 concentrations increased in 10 of 13 patients (mean 283 +/- 70 pg/ml, p less than 0.02). Coronary venous thromboxane B2 concentrations increased in seven patients at peak pacing rates (mean 223 +/- 76 pg/ml) and in three other patients after termination of pacing. These data indicate that release of thromboxane A2 is much greater during spontaneous angina than with pacing stress in patients with coronary artery disease. Thromboxane A2 released during spontaneous or pacing-induced angina may modulate coronary and systemic vascular tone. Enhanced thromboxane A2 activity may either precede or follow myocardial ischemia and could be a factor in the initiation and propagation of the ischemic episode.     

Consumption of vitamin E in coronary circulation in patients with variant angina.

OBJECTIVES: The plasma status of vitamin E has been suggested to be linked to the activity of coronary artery spasm. This study was designed to determine whether vitamin E is actually consumed in the coronary circulation in patients with active variant angina having repetitive spasm-induced transient myocardial ischemia and reperfusion. METHODS: Blood samples were obtained simultaneously from the aortic root, coronary sinus and right atrium in 12 patients with variant angina due to spasm of the left coronary artery, nine patients with stable effort angina and nine control subjects. Plasma vitamin E (alpha- and gamma-tocopherol) concentrations were determined by use of high-performance liquid chromatography and plasma lipid peroxides were measured as thiobarbituric acid-reactive substances (TBARS). RESULTS: At baseline, both plasma alpha- (p < 0.01) and gamma- (p < 0.05) tocopherol levels were significantly lower in the coronary sinus (5.50 +/- 0.50 and 0.55 +/- 0.07 mg/l, mean +/- SEM) than in the aortic root (6.63 +/- 0.57 and 0.63 +/- 0.08 mg/l) and also in the right atrium (6.44 +/- 0.61 and 0.63 +/- 0.09 mg/l) in the variant angina group. The TBARS level was significantly (p < 0.05) higher in the coronary sinus than in the aortic in this group. In contrast, these levels were not significantly different between the samples from the coronary sinus and the aortic root or the right atrium in the control group and also in the stable effort angina group. The coronary sinus-aortic difference in plasma vitamin E levels in the variant angina group was not significantly altered after left coronary artery spasm induced by intracoronary injection of acetylcholine. Also, the plasma vitamin E levels in the aortic root, coronary sinus and right atrium all remained unchanged in the stable effort angina group after pacing-induced angina and in the control group after intracoronary administration of acetylcholine. CONCLUSIONS: Transcardiac reduction in plasma vitamin E concentrations concomitant with lipid peroxide formation was demonstrated in patients with active variant angina, suggesting actual consumption of this major endogenous antioxidant. Oxidative stress and vitamin E exhaustion may be involved in the pathogenesis of coronary artery spasm.     

Increased plasma level of endothelin-1-like immunoreactivity during coronary spasm in patients with coronary spastic angina

To examine the role of endothelin in coronary spasm, the plasma endothelin-1-like immunoreactivity in the coronary sinus and the aortic root was measured before and during spasm of the left coronary artery induced by injection of acetylcholine (20 to 100 micrograms) into the left coronary artery in 26 patients with coronary spastic angina. The plasma level of endothelin-1-like immunoreactivity was measured by the radioimmunoassay with a monoclonal antibody against endothelin-1. Plasma lactate levels in the coronary sinus and the aortic root were also measured to evaluate myocardial lactate metabolism during spasm. In 13 patients who had myocardial lactate production during spasm, the plasma level of endothelin-1-like immunoreactivity in the coronary sinus increased from 19.8 +/- 3.0 to 25.7 +/- 6.4 pg/ml (p less than 0.01), while that in the aortic root remained unchanged (from 20.2 +/- 5.9 to 21.3 +/- 5.8 pg/ml). No significant changes in the plasma levels of endothelin-1-like immunoreactivity in the coronary sinus (from 21.1 +/- 7.3 to 19.7 +/- 5.2 pg/ml) and the aortic root (from 21.1 +/- 5.7 to 19.7 +/- 5.6 pg/ml) were observed in 13 patients who did not show myocardial lactate production during spasm. On the other hand, 16 patients without ischemic heart disease showed no significant changes in the plasma levels of endothelin-1-like immunoreactivity in the coronary sinus (from 24.4 +/- 9.7 to 25.8 +/- 6.9 pg/ml) and the aortic root (from 23.0 +/- 7.1 to 23.4 +/- 5.8 pg/ml) by acetylcholine injection (100 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional cardiac prostaglandin release during myocardial ischemia in anesthetized dogs.

Cardiac prostaglandin release was studied in closed-chest dogs during acute coronary occlusion. Aortic and coronary sinus blood was obtained before, and at intervals after, balloon occlusion of the left anterior descending artery in seven dogs. Samples were assayed for prostaglandins F, E, and A by randioimmunoassay. All dogs demonstrated prostaglandin F release, Mean +/- SE postocclusion aortic levels were 0.26 +/- 0.01 ng/ml; coronary sinus levels were 0.67 +/- 0.01 ng/ml (P less than 0.001). In six dogs, prostaglandin E also was released. Mean postocclusion aortic levels were 0.24 +/- 0.01 ng/ml; coronary sinus, 0.44 +/- 0.01 ng/ml (P less than 0.001). There was no release of prostaglandin A. To examine the site of prostaglandin release, simultaneous samples from the aorta, the coronary sinus, and the great cardiac vein were obtained before and after left circumflex artery occlusion in six additional studies. The great cardiac vein drained effluent from nonischemic myocardium, whereas the coronary sinus drainage included blood from both ischemic and nonischemic zones. All six dogs demonstrated prostaglandin F release from the ischemic region. Mean postocclusion aortic prostaglandin F was 0.32 +/- 0.01 ng/ml. Coronary sinus prostaglandin F was 1.69 +/- 0.03 ng/ml (P less than 0.001), whereas the great cardiac vein level remained at 0.34 +/- 0.01 ng/ml (P greater than 0.05). Prostaglandin E was released from both ischemic and nonischemic regions. Mean aortic prostaglandin E was 0.21 +/- 0.01 ng/ml; great cardiac vein, 0.55 +/- 0.02 ng/ml (P less than 0.001); and coronary sinus, 1.07 +/- 0.04 ng/ml (P less than 0.001). These results have led us to conclude that the different local availability of prostaglandins E and F may influence the cardiac response to ischemia.     

Systemic inflammation in unstable angina is the result of myocardial necrosis

OBJECTIVES: We investigated whether the source of the acute phase response in unstable angina (UA) lay within the culprit coronary plaque or distal myocardium. BACKGROUND: An inflammatory response is an important component of the acute coronary syndromes. However, its origin and mechanism remain unclear. METHODS: In 94 stable patients undergoing coronary angiography, the relationship between systemic levels of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6) and C-reactive protein (CRP) and extent of atherosclerosis was studied. The temporal relationship between these markers and troponin T (TnT) was determined in 91 patients with UA. Cytokine levels were measured in the aortic root and coronary sinus of 36 unstable patients. RESULTS: There was no relationship found between stable coronary atherosclerosis and inflammatory marker levels. Compared with this group, admission levels of IL-6 (3.6 +/- 0.3 ng/ml vs. 10.7 +/- 1.7 ng/ml, p < 0.05) and CRP (2.3 +/- 0.1 mg/l vs. 4.6 +/- 0.6 mg/l, p < 0.05) were elevated in patients with UA. In this group, IL-6 and CRP remained elevated in those who subsequently experienced major adverse cardiac events. This inflammatory response occurred in parallel to the appearance of TnT. Both TNF-alpha (19.2 +/- 3.4 ng/ml vs. 17.1 +/- 3.3 ng/ml, p < 0.001) and IL-6 (10.3 +/- 1.4 ng/ml vs. 7.7 +/- 1.1 ng/ml, p < 0.01) were elevated in the coronary sinus compared with aortic root in patients with UA. This was principally observed in those who were TnT positive. There was no cytokine gradient across the culprit plaque. CONCLUSIONS: There is an intracardiac inflammatory response in UA that appears to be the result of low-grade myocardial necrosis. The ruptured plaque does not appear to contribute to the acute phase response.     

Intracoronary platelet activation in ischemic heart disease: effects of ticlopidine

Plasma levels of platelet factor 4 have been measured in the aortic and coronary sinus blood of 35 patients: group I (n = 12) with normal coronary arteriograms; group II (n = 15) with angiographically proven coronary artery disease; and group III (n = 8) composed of patients with ischemic heart disease who were being treated with the antiaggregant agent ticlopidine at the time of cardiac catheterization. The mean increase in platelet factor 4 levels through the coronary circulation was 27.4 +/- 21.9 ng/ml (mean +/- standard deviation) in group II, compared with -1 +/- 4.5 ng/ml in group I (p less than 0.01). In group III plasma levels of platelet factor 4 in aortic and coronary sinus samples were all within the normal range. Thus, we conclude that platelet activation constantly occurs in the coronary circulation of patients with stable coronary artery disease, and can be prevented with ticlopidine.     

Atrial natriuretic peptide during pacing in controls and patients with coronary arterial disease

At rest, during cardiac catheterization, aortic plasma levels of immunoreactive atrial natriuretic peptide did not differ between 10 controls with atypical chest pains and normal coronary arteries and 9 patients with stable angina pectoris and coronary arterial disease (55.2 +/- 19.8 vs. 64.8 +/- 19.8 pg/ml, NS). Nor did atrial natriuretic peptide values differ between the two groups during or after atrial pacing (150 beats/minute), which induced electrocardiographic and metabolic signs of acute myocardial ischaemia in the patients with coronary arterial disease but in none of the controls. Pacing, when carried out for more than 300 seconds, induced an increase of plasma atrial natriuretic peptide that correlated with duration of pacing (r = 0.80, P less than 0.001), and similarly in controls and patients with coronary arterial disease. In a second part of the study, which included 2 controls and 2 patients with coronary arterial disease, post-pacing coronary sinus concentrations of atrial natriuretic peptide were 10-20 times higher than peripheral levels (415- greater than 890 pg/ml). The concentration of atrial natriuretic peptide rose as blood from the caval veins (34 +/- 7 pg/ml) entered the right atrium (56 +/- 24 pg/ml), but thereafter was unchanged in the pulmonary artery (51 +/- 3 pg/ml) and the aorta (46 +/- 9 pg/ml). In conclusion, the results gave no evidence for ischaemic heart disease without congestive cardiac failure to be associated with altered levels of atrial natriuretic peptide. It was confirmed that atrial pacing stimulates the secretion of atrial natriuretic peptide which is produced by the heart and released via the coronary sinus into the circulation.     

Potential role of leptin and insulin resistance assessed by the glucose clamp technique in coronary artery disease

OBJECTIVES: Leptin may correlate with insulin resistance and be an important factor in patients with coronary artery disease. Therefore, we examined whether plasma leptin levels and insulin resistance are linked with coronary artery disease. METHODS: Plasma leptin levels and insulin resistance, assessed by the hyperinsulinemic euglycemic clamp technique, were measured in control subjects (n = 12, mean age 62 +/- 10 years), and in patients with obstructive coronary artery disease (n = 15, mean age 64 +/- 8 years) or vasospastic angina (n = 12, mean age 62 +/- 12 years). RESULTS: Plasma leptin levels were significantly higher (p < 0.017) in patients with obstructive coronary artery disease (8.4 +/- 2.7 ng/ml) and vasospastic angina (7.9 +/- 2.1 ng/ml) than in patients without obstructive coronary artery disease (4.7 +/- 1.4 ng/ml). Mean glucose infusion rate was significantly (p < 0.017) lower in patients with obstructive coronary artery disease (4.39 +/- 1.78 mg/kg/min) and vasospastic angina (3.57 +/- 1.72 mg/kg/min) than in patients without obstructive coronary artery disease (8.74 +/- 1.05 mg/kg/min). The plasma levels of leptin were negatively correlated with mean glucose infusion rate (r = -0.67, p < 0.01). The other coronary risk factors were similar in these three groups. CONCLUSIONS: Plasma leptin levels are correlated with insulin resistance and may be associated with coronary artery disease.     

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics in humans

Effects of H1-receptor stimulation on coronary arterial diameter and coronary hemodynamics were examined in 11 patients with angiographically normal coronary arteries and without variant angina or resting angina. Selective H1-receptor stimulation was achieved by infusing histamine into the left coronary artery at a rate of 2.0 micrograms/min for 5 minutes after pretreatment with cimetidine (25 mg/kg). Plasma histamine concentration in the coronary sinus, coronary sinus blood flow, heart rate, and aortic pressure were measured before, during, and after the histamine infusion. Coronary arterial diameter was measured by cinevideodensitometric analysis of coronary arteriograms performed before and immediately after the histamine infusion. During the histamine infusion, plasma histamine concentration in the coronary sinus increased from 0.33 +/- 0.06 to 5.86 +/- 0.71 ng/ml (p less than 0.01); coronary sinus blood flow increased from 98 +/- 12 to 124 +/- 13 ml/min (p less than 0.01), and coronary vascular resistance decreased from 1,113 +/- 117 to 851 +/- 91 mm Hg.min/l (p less than 0.01). Heart rate and aortic pressure remained unchanged. The mean luminal diameters of the proximal, middle, and distal left anterior descending artery increased by 9.4 +/- 3.6% (p less than 0.05), 19.2 +/- 3.8% (p less than 0.001), and 31.5 +/- 5.6% (p less than 0.001), respectively, after the histamine infusion. The mean luminal diameters of the proximal, middle, and distal left circumflex artery increased by 15.2 +/- 3.6% (p less than 0.01), 17.5 +/- 5.2% (p less than 0.01), and 20.6 +/- 4.3% (p less than 0.001), respectively, after the histamine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired cardiac PGI2 and PGE2 biosynthesis in patients with angina pectoris

Thirty-four patients with unstable angina and 14 patients with stable effort angina were investigated for cardiac prostacyclin and prostaglandin E2 (PGE2) biosynthesis, under resting conditions and after cold pressor testing. Twenty-seven patients undergoing cardiac catheterization and coronary angiography for congenital or acquired heart diseases other than coronary artery disease were studied as a control group. Prostacyclin (as 6-keto-PGF1 alpha) and PGE2 were measured by specific radioimmunoassay of blood from the coronary sinus and aorta. During resting conditions no significant differences in plasma 6-keto-PGF1 alpha and PGE2 concentrations were found between coronary sinus and aortic blood, and no transcardiac gradient existed either in control subjects or in patients with stable and unstable angina, respectively. In control subjects cold pressor testing induced a significant increase in 6-keto-PGF1 alpha and PGE2 levels in blood from the different sampling sites, and a significant transcardiac gradient occurred (+11.2 +/- 6.4 pg/ml for 6-keto-PGF1 alpha and +5.1 +/- 3.4 pg/ml for PGE2). However, in angina patients no significant increase in 6-keto-PGF1 alpha and PGE2 plasma levels was found and no transcardiac gradient was formed after cold pressor testing. These results indicate impaired cardiac prostacyclin and PGE2 biosynthesis both in patients with stable and unstable effort angina.     

Plasma soluble intercellular adhesion molecule-1 levels in coronary circulation in patients with unstable angina

It has been suggested that active inflammation plays an important role in the pathogenesis of acute coronary syndromes, including unstable angina. Intracellular adhesion molecule-1 (ICAM-1) is a major ligand on the endothelial cells for adherence of the activated polymorphonuclear leukocytes. Recently, it has been demonstrated that the soluble form of ICAM-1 has been detected in human serum and has been increased in many other inflammatory or autoimmune disorders. To evaluate the involvement of ICAM-1 in unstable angina, we examined plasma soluble ICAM-1 (sICAM-1) levels in coronary circulation. The plasma sICAM-1 levels in the coronary sinus and aortic root were simultaneously examined in 20 patients with unstable angina, 19 patients with stable exertional angina, and 16 control subjects. The plasma levels of sICAM-1 were measured by enzyme-linked immunosorbent assay. The mean plasma sICAM-1 levels (nanograms per milliliter) both in the coronary sinus and aortic root were significantly higher (p <0.01) in patients with unstable angina than in those with stable exertional angina and in control subjects (217+/-14 vs 126+/-8; 120+/-10 in the coronary sinus, 202+/-13 vs 125+/-9; 123+/-10 in the aortic root). Furthermore, the mean value was higher in the coronary sinus than in the aortic root in patients with unstable angina. There were no significant differences in the values between in the coronary sinus and aortic root in patients with stable exertional angina and control subjects. Thus, sICAM-1 release is increased, especially in coronary circulation in unstable angina.     

Osteopontin is released from the heart into the coronary circulation in patients with a previous anterior wall myocardial infarction.

The present study was designed to clarify whether osteopontin, an extracellular matrix protein, is released from the heart into the coronary circulation in patients with a previous (>3 months) anterior wall myocardial infarction (MI). Using a commercially available enzyme immunoassay kit, plasma concentrations of osteopontin were measured in 30 patients (26 men, 4 women; mean age, 61+/-12 years). Blood samples were obtained from the aortic root and coronary sinus. The difference in the plasma concentrations of osteopontin in the aortic root and coronary sinus, which reflects the cardiac production of osteopontin released into the coronary circulation, was compared with the left ventricular ejection fraction (LVEF) and volumes obtained from contrast left ventriculography. Plasma osteopontin concentrations were significantly higher in the coronary sinus than in the aortic root (672+/-446 vs 610+/-398 ng/ml, p=0.02). The transcardiac gradient of plasma osteopontin concentration correlated negatively with LVEF (r=-0.55, p=0.0005) and positively with left ventricular (LV) end-diastolic (r=0.63, p=0.0001) and end-systolic volume indexes (r=0.79, p<0.0001). This is the first study to show that in patients with a previous anterior wall MI osteopontin is released from the heart into the coronary circulation in proportion to the LV systolic function and volumes, suggesting that this extramatrix protein is associated with post-MI LV remodeling.     

Soluble P-selectin levels in diabetes mellitus patients with coronary artery disease

Type 2 (non-insulin-dependent) diabetes is associated with a marked increase in the risk of coronary heart disease. Platelets play a significant role in coronary artery disease. Soluble P-selectin is an index of platelets activation. In this study, Soluble P-selectin levels were measured by ELISA in the peripheral blood of 55 diabetic patients with coronary artery disease [21 acute myocardial infarction (AMI), 20 with unstable angina (UA), 14 with stable angina (SA)], 20 patients with diabetes mellitus without coronary artery disease (DM without), and 10 healthy controls.Soluble P-selectin level was significantly higher in patients with AMI (M+/-SD; 239.3+/-13.0 ng/ml), than those with UA (141.5+/-15.2 ng/ml), SA (92.1+/-7.7 ng/ml), DM without (89.8+/-7.1 ng/ml), and healthy control (86.1+/-4.5 ng/ml) (P < 0.001). In patients with US, sP-selectin was found to be significantly elevated as compared to the SA, DM without and control group. sP-selectin was not significantly different in DM without as compared to healthy controls. The sP-selectin levels was correlated to the duration of diabetes mellitus(R=0.33, P=0.03 ). Moreover, sP-selectin level was significantly higher in AMI patients with recurrent anginal attack as compared to that in those with single attack Multivariate analysis revealed that sP-selectin level at presentation had high adverse influence on coronary artery insult compared to healthy LDL cholesterol level, and the degree of hypertension. IN CONCLUSION: Plasma levels of soluble P-selectin were increased in patients with AMI, and UA compared to patients with SA and normal controls. Measurement of soluble P-selectin may be helpful marker of impending coronary artery insult in diabetic patients.     

Intracoronary serotonin release after high-pressure coronary stenting

It is known that platelet-derived serotonin at the site of coronary angioplasty induces an increase in coronary tone and plays a role in vasoconstriction after balloon angioplasty. The goal of the present investigation was to compare local release of serotonin with changes in coronary tone after coronary stenting and coronary angioplasty. Twenty patients with significant stenosis (> or =50% diameter narrowing) of the left anterior descending coronary artery were referred to traditional coronary angioplasty (10 patients; group 1) or high-pressure coronary stenting (10 patients; group 2). An additional 16 patients with similar angiographic characteristics were referred to the coronary angioplasty group (8 patients; group 1a) or stenting group (8 patients; group 2a) after pretreatment with ketanserin. Serotonin plasma levels in coronary sinus and coronary cross-sectional area distal to the site of dilatation were measured before and after bath revascularization procedures. In groups 1 and 1a, plasma serotonin levels in coronary sinus increased from basal values of 3.2+/-0.8 and 3.2+/-0.5 ng/ml to 29.5+/-13 and 25.6+/-9 ng/ml after ballooning (p <0.001 vs baseline). In groups 2 and 2a, plasma serotonin levels in coronary sinus increased from basal values of 3.5+/-0.3 and 3.5+/-0.7 ng/ml to 114.6+/-34 and 113+/-29 ng/ml after stenting (p <0.001 vs baseline and vs postangioplasty values in groups 1 and 1a). Coronary cross-sectional area distal to the site of dilatation significantly decreased after angioplasty in group 1 (from 4.33+/-0.4 to 3.32+/-0.3 mm2; p <0.001), and after stenting in group 2 (from 4.27+/-0.3 to 2.86+/-0.2 mm2; p <0.001 vs baseline, and p <0.02 vs values after coronary angioplasty in group 1). Pretreatment with ketanserin significantly reduced distal coronary vasoconstriction after angioplasty and stenting. It is concluded that the higher local serotonin release after coronary stenting may explain the more marked coronary constriction observed after prosthesis deployment with respect to traditional coronary angioplasty. Ketanserin is able to significantly attenuate the increase in distal coronary tone induced by both revascularization procedures.     

Prognostic value of serum hepatocyte growth factor in patients with acute coronary syndromes.

The present study examined whether or not hepatocyte growth factor (HGF), an endothelium-specific growth factor that stimulates regeneration of the endothelium, is increased or has a prognostic significance in patients with acute coronary syndromes. HGF was measured in 106 patients with coronary artery disease (20 stable effort angina, 12 unstable angina without adverse events, 24 unstable angina with adverse events and 50 acute myocardial infarction) on admission and 21 normal volunteers. The measurements in all patients were recorded before administration of heparin, and in acute myocardial infarction patients they were recorded from days 2 to 6 after heparin discontinuation on day 1. HGF levels (ng/ml) were 0.30+/-0.06 for the controls, 0.31+/-0.08 for stable effort angina patients, 0.31+/-0.08 for unstable angina patients without adverse events, 0.40+/-0.20 for unstable angina patients with adverse events and in acute myocardial infarction patients they were 0.45+/-0.18 on day 0, 0.57+/-0.45 on day 2, 0.50+/-0.35 on day 3, 0.48+/-0.32 on day 4, 0.44+/-0.20 on day 5, and 0.38+/-0.14 on day 6. HGF plays a crucial role in the restoration of injured endothelial cells and is a predictor of adverse events in patients with acute coronary syndromes.     

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.     

Fibrinopeptide A is released into the coronary circulation after coronary spasm

To examine whether acute myocardial ischemia activates the coagulation system and platelet activation in the coronary circulation, we measured plasma levels of fibrinopeptide A and beta-thromboglobulin in the coronary sinus and the aortic root simultaneously in 15 patients with coronary spastic angina before and after the left coronary spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Fifteen patients with chest pain but normal coronary arteries and no coronary spasm served as controls. The coronary sinus-arterial difference of fibrinopeptide A increased markedly (p less than 0.001) from 0.1 +/- 0.2 to 4.3 +/- 0.7 ng/ml after the anginal attacks in the coronary spastic angina group. However, fibrinopeptide A levels remained unchanged after the attacks in the stable exertional angina group and after intracoronary injection of acetylcholine in the control group. Plasma beta-thromboglobulin levels remained unchanged after the attacks in both patient groups and after acetylcholine in the control group. Our data indicate that coronary spasm induces thrombin generation and may lead to thrombus formation in the coronary artery involved, but pacing-induced ischemia does not activate the coagulation system.     

Changes of serum hepatocyte growth factor in coronary artery disease

Hepatocyte growth factor (HGF) is an endothelial cell specific growth factor involved in the repair of endothelial cells and collateral formation, however, the role for coronary artery disease is still unknown. We measured serum HGF level in various coronary artery diseases to examine the clinical significance. Serum HGF level was measured using the enzyme-linked immunosorbent assay method in patients with stable effort angina pectoris (n = 26), old myocardial infarction (n = 18), unstable angina pectoris (UAP; n = 10) and acute myocardial infarction (AMI; n = 21). As a control group, we selected 11 patients with neurocirculatory asthenia. Blood samples from peripheral veins were collected at cardiac catheterization before heparin administration. In the AMI group, blood samples were also collected at 48, 72 hr, 1, 2, 3 and 4 weeks from the peripheral veins and 48 and 72 hr after reperfusion from the coronary sinus. Serum HGF level was significantly higher in the UAP (0.41 +/- 0.12 ng/ml, p < 0.001) and AMI groups (0.38 +/- 0.26 ng/ml, p < 0.05) compared to the control group (0.19 +/- 0.09 ng/ml). Serum HGF level peaked 48 hr after reperfusion in both the peripheral veins (0.42 +/- 0.16 ng/ml) and coronary sinus (0.58 +/- 0.23 ng/ml) in the AMI group, with a significantly higher level in the coronary sinus than the peripheral veins (p < 0.05). No significant correlation between peak HGF level in the peripheral veins and peak creatine kinase (CK), CK-MB, ejection fraction and cardiac index was observed. Serum HGF was elevated in acute coronary syndrome, indicating advanced endothelial cell damage. HGF is produced, at least partially, in the heart in patients with AMI. Serum HGF level may be useful to detect endothelial cell damage rather than myocardial cell damage.     

Coronary hemodynamic effects of atrial natriuretic peptide in humans

Studies of the effects of atrial natriuretic peptide on the coronary circulation have yielded conflicting results in animals and have not been fully investigated in human subjects. To further characterize the direct coronary hemodynamic actions of atrial natriuretic peptide in humans and to assess the safety of its administration in patients with coronary artery disease, incremental doses of synthetic atrial natriuretic peptide and nitroglycerin were infused into the left coronary artery in 14 patients, 11 of whom had coronary artery disease. Both agents caused dose-related increases in total coronary sinus blood flow. The largest dose of atrial natriuretic peptide given to all patients (100 micrograms) increased mean coronary sinus blood flow from 127 +/- 7 to 149 +/- 9 ml/min (p less than 0.05) and decreased coronary vascular resistance from 0.93 +/- 0.07 to 0.81 +/- 0.05 mm Hg/ml per min (p less than 0.05); mean arterial blood pressure and heart rate were not affected by this dose of atrial natriuretic peptide. The greatest changes in coronary sinus blood flow (+25%) and coronary vascular resistance (-18%) after atrial natriuretic peptide administration occurred in the patients with coronary artery disease and no other associated cardiovascular disease. The maximal effects of atrial natriuretic peptide were similar to those of nitroglycerin, and no untoward effects were observed. Thus, atrial natriuretic peptide is a direct coronary vasodilator in humans. Its maximal dose effects are similar to those of nitroglycerin and were well tolerated in this small group of patients. The physiologic importance and therapeutic potential of atrial natriuretic peptide in patients with coronary artery disease merit further investigation.