Effects of vitamin C on intracoronary L-arginine dependent coronary vasodilatation in patients with stable angina.

OBJECTIVE: To assess the effects of intravenous vitamin C administration on the vasomotor responses to intracoronary L-arginine infusion in epicardial coronary arteries. METHODS: 28 patients with coronary artery disease and stable angina were enrolled in the study. Eight patients received intracoronary infusions of 150 micromol/min L-arginine before and after intravenous infusion of vitamin C, 10 patients received intracoronary infusions of 150 micromol/min L-arginine before and after intravenous infusion of normal saline, and 10 patients received intracoronary normal saline before and after intravenous infusion of vitamin C. The diameter of proximal and distal coronary artery segments was measured by quantitative angiography. RESULTS: Infusion of L-arginine caused significant dilatation of both proximal (4.87 (0.96)%, p < 0.01 v normal saline) and distal (6.33 (1.38)%, p < 0.01 v normal saline) coronary segments. Co-infusion of vitamin C and L-arginine dilated proximal coronary segments by 8.68 (1.40)% (p < 0.01 v normal saline, p < 0.01 v L-arginine) and distal segments by 13.07 (2.15)% (p < 0.01 v normal saline, p < 0.01 v L-arginine). Intravenous infusion of vitamin C caused a borderline increase in proximal and distal coronary segment diameters (1.93 (0.76)% and 2.09 (1.28)%, respectively, not significant). CONCLUSIONS: L-arginine dependent coronary segment vasodilatation was augmented by the antioxidant vitamin C in patients with coronary artery disease. Thus, vitamin C may have beneficial effects on nitric oxide bioavailability induced by L-arginine.

Effects of L-arginine on flow mediated dilatation induced by atrial pacing in diseased epicardial coronary arteries.

OBJECTIVE: To examine the effects of L-arginine on basal coronary tone and flow mediated dilatation induced by atrial pacing in patients with coronary artery disease and stable angina. DESIGN: Atrial pacing was performed during intracoronary infusions of normal saline and L-arginine (150 micromol/min) in 8 patients with coronary artery disease and stable angina. The luminal diameter of epicardial coronary arteries was assessed by quantitative angiography. RESULTS: L-arginine administration significantly increased the diameter of all the coronary segments and stenoses. During atrial pacing with saline infusion, luminal diameter of the proximal, distal, and stenosis reference segments increased significantly (p < 0.01 versus saline) but stenosis diameter did not change. L-arginine administration did not change the magnitude (NS) of atrial pacing induced dilatation in proximal and distal segments and in coronary stenoses and their reference segments. CONCLUSIONS: Non-stenotic segments of diseased coronary arteries dilate in response to atrial pacing but stenoses do not. L-arginine dilates coronary segments and stenoses but does not increase the magnitude of the response to atrial pacing in proximal and distal segments and in coronary stenoses and their reference segments. These findings provide evidence that the shear stress responsive mechanism is absent at stenoses but present in non-stenotic segments of diseased coronary arteries. They also indicate a relative deficiency of L-arginine, except in the shear response mechanism.

Vasomotion and nitric oxide bioactivity in diseased coronary arteries.

Atheromatous coronary stenoses are no longer considered to be passive structures, instead having the capacity for dynamic, often transient, change which may take the form of constriction or dilatation in response to either endogenous or external stimulation.

Complex stenosis morphology and vasomotor responses to inhibition of nitric oxide synthesis.

OBJECTIVE: To assess the relation between coronary vasomotor effects of N(G)-monomethyl-L-arginine (LNMMA) administration and coronary stenosis morphology, length, and severity in patients with stable angina. DESIGN: In 28 patients (24 male, four female) with coronary artery disease and chronic stable angina, intracoronary normal saline and 4 micromol/min LNMMA were infused for four minutes each, followed by an intracoronary bolus of 250 microg glyceryl trinitrate. Coronary stenoses were classified as concentric (smooth), eccentric (smooth), or complicated (irregular). The diameters of these stenoses and their adjacent reference proximal segments were measured by quantitative angiography. RESULTS: During LNMMA infusion a significantly larger proportion of complicated stenoses than concentric and eccentric stenoses constricted by >/= 5% (p < 0.01) and the magnitude of vasoconstriction was greater in complicated than in concentric and eccentric stenoses (p < 0.05). For complicated stenoses the magnitude of constriction (in mm) with reference to normal saline was greater than that of the concentric and eccentric stenoses (p < 0.05), whereas concentric and eccentric stenoses constricted similarly. Irrespective of the type of morphology, there was a correlation (p < 0.05) between both the severity and the length of stenoses and the magnitude of vasoconstriction to LNMMA. A similar proportion of concentric, eccentric, and complicated stenoses showed >/= 5% increase in diameter with glyceryl trinitrate, and the magnitude of the response was similar in the three groups. CONCLUSIONS: In patients with coronary artery disease, the response to LNMMA is greater when stenosis morphology is complex, indicating greater nitric oxide activity. This provides further evidence that plaques with complex morphology are in an active state.

Inhibition of nitric oxide synthesis in human epicardial coronary arteries and stenoses in relation to serum lipid level.

Administration of N(G)-monomethyl-L-arginine (LNMMA), an inhibitor of nitric oxide synthase, causes a reduction in epicardial coronary artery and stenosis diameter in patients with coronary artery disease, indicating that these diseased vessels produce nitric oxide. Elevations of low density lipoprotein cholesterol impair human endothelium-dependent relaxation. The relationship between serum lipid level and nitric oxide production by normal and atheromatous human epicardial coronary arteries in vivo is unknown. The effects of an intracoronary infusion of LNMMA (8 and 16 micromol/min) followed by intracoronary administration of 250 mcg nitroglycerin on non-stenotic proximal and distal coronary segments and coronary stenoses were studied in 11 patients with coronary artery disease and in 19 patients with 'normal arteriograms'. Coronary luminal diameter was measured by computerized quantitative angiography. In patients with cholesterol level> or = 220 mg/dl, no significant response to LNMMA was observed in the proximal segments in either those with 'normal angiograms' or those with coronary disease. In patients with cholesterol <220 mg/dl significant constriction (P<0.01) was observed in the proximal segments of patients with 'normal coronary angiograms' at both 8 and 16 micromol doses, but occurred only at the 16 micromol/min dose (P<0.01) in those with coronary disease. In conclusion the difference in vasomotor response to LNMMA in relation to cholesterol level is localised to the proximal coronary segments, and the response does not correlate with cholesterol or triglyceride level. This is therefore more likely to be an indirect effect of elevated cholesterol, e.g. undetected atheroma, than a direct effect on nitric oxide synthesis.

Evidence of partially preserved endothelial dilator function in diseased coronary arteries.

OBJECTIVE: To examine the effects of substance P (endothelium dependent vasodilator) and glyceryl trinitrate (endothelium independent vasodilator) on epicardial coronary arteries in patients with normal coronary angiograms and patients with coronary artery disease. DESIGN: Intracoronary infusions of normal saline, the receptor mediated nitric oxide stimulant substance P (5.6 and 27.8 pmol/min each for five minutes), and glyceryl trinitrate (250 microg bolus) were given in 24 patients with coronary artery disease and stable angina, and in nine patients with normal angiograms. The diameter of proximal and distal coronary segments was measured by computerised quantitative angiography RESULTS: Proximal segments of patients with coronary artery disease dilated less than those of patients with normal angiograms in response to 27.8 pmol/min substance P (mean (SEM): 7.9 (1.3)% v 15 (2.3)% respectively, p < 0. 01). The proximal segments of diseased arteries also dilated less than those of "normal" arteries in response to glyceryl trinitrate (10.2 (1.6)% v 18.4 (2.9)%, respectively, p < 0.01). The responses of distal segments to substance P and glyceryl trinitrate were similar in the two patient groups. There were correlations (all p < 0.001) between the coronary diameter after substance P and after glyceryl trinitrate in normal proximal segments (r = 0.94) and normal distal segments (r = 0.64), in diseased proximal segments (r = 0.95) and diseased distal segments (r = 0.89), and for coronary stenoses (r = 0.93). CONCLUSIONS: Proximal segments of patients with coronary disease dilated less than the proximal segments of "normal" patients in response to substance P and glyceryl trinitrate. The response to substance P is substantial and closely correlated with the response to glyceryl trinitrate in both "normal" patients and those with coronary disease. This suggests that although the proximal segments of diseased coronary arteries have a reduced capacity to dilate in response to direct stimulation of smooth muscle cell relaxation, they retain much of their endothelium dependent vasodilator function.

Vasomotor responses of coronary stenoses to acetylcholine and their relation to serum lipid levels in stable angina pectoris.

The effects of acetylcholine administration on coronary stenoses in relation to serum lipids level were evaluated in 18 patients (15 men, 3 women) with coronary artery disease and stable angina. Intracoronary acetylcholine was infused in concentrations 10(-7), 10(-6), 10(-5) M, followed by intracoronary bolus administration of isosorbide dinitrate. Computerized angiography was used to assess the changes in the diameter of stenoses and of proximal and distal segments. During acetylcholine infusion, at concentrations between 10(-7) to 10(-5) M, there was a significant (p <0.01) dose-dependent constriction of proximal and distal segments and of stenoses reversed by isosorbide dinitrate. There was no correlation between the serum total cholesterol level and the responses of proximal and distal segments to acetylcholine or nitrate. A correlation (p <0.05) was found between the serum total cholesterol level and the response of stenoses to acetylcholine, but there was no correlation with the response to isosorbide dinitrate. In conclusion, in patients with stable angina current serum total cholesterol level correlates with the vasomotor response of coronary stenoses to intracoronary acetylcholine. These findings are consistent with a direct effect of cholesterol, increasing basal coronary vasomotor tone and increasing the stimulated vasoconstrictor response of stenoses.

Effects of L- and D-arginine on the basal tone of human diseased coronary arteries and their responses to substance P.

OBJECTIVE: To assess the effects of substance P administration alone and in combination with L- and D-arginine in patients with normal angiograms and in patients with coronary artery disease. DESIGN: Intracoronary infusions of (a) normal saline, (b) the receptor mediated nitric oxide stimulant substance P (5.6 and 27.8 pmol/min) before and after L- or D-arginine (50 and 150 micromol/min), and (c) glyceryl trinitrate (250 microg bolus) were given to 17 patients with coronary artery disease and stable angina, and to six patients with normal angiograms. The diameter of angiographically normal proximal and distal segments and coronary stenoses were measured by computerised quantitative angiography. RESULTS: L-arginine administration was associated with significant dilatation of stenoses (p < 0.01) of proximal segments of both "normal" (p < 0.05) and diseased (p < 0.01) arteries, and of distal segments of diseased arteries (p < 0.01). No significant changes were associated with D-arginine administration. Dose dependent dilatation of all segments including stenoses, was observed with substance P both before and after L-arginine infusion (p < 0.01). The magnitude of dilatation of stenoses and all segments of both "normal" and diseased coronaries was greater after L-arginine (p < 0.05) but not D-arginine and substance P infusion, than it was after saline and substance P infusion. Administration of D- or L-arginine did not change the magnitude of substance P induced dilatation. CONCLUSIONS: Diseased and "normal" coronary arteries dilated in response to substance P and L-arginine but were unaffected by D-arginine infusion. The magnitude of the response to substance P was not increased by L-arginine administration, indicating that it is not critically dependent on the availability of substrate for nitric oxide synthase.

Effects of changing the availability of the substrate for nitric oxide synthase by L-arginine administration on coronary vasomotor tone in angina patients with angiographically narrowed and in patients with normal coronary arteries.

We assessed the effects of intracoronary administration of substance P, LNMMA, L-arginine, and nitroglycerin in patients with normal coronary angiograms and in patients with coronary artery disease. LNMMA constricted (p <0.01) and both substance P and nitroglycerin dilated normal and diseased proximal and distal segments and stenoses (p <0.01). L-Arginine reversed the effect of LNMMA in all segments and caused greater dilation of the diseased arteries, including stenoses (p <0.05), indicating that there is a relative deficiency of L-arginine in diseased coronary arteries.

Angiographic characteristics of infarct-related and non-infarct-related stenoses in patients in whom stable angina progressed to acute myocardial infarction.

BACKGROUND: In patients with coronary artery disease, angiographic and postmortem studies have shown that coronary stenoses in infarct-related arteries often have complex morphology. It is not known whether in patients with multivessel disease stenosis morphology in non-infarct-related arteries is different from those of the infarct-related arteries. METHODS AND RESULTS: In 24 consecutive patients we examined the angiographic characteristics of both the infarct-related stenoses and non-infarct-related stenoses before and after spontaneous acute myocardial infarction, by visual inspection and computerized edge detection of coronary angiograms. Before myocardial infarction, the severity of the infarct-related stenoses was <50% in 14 patients and > or =50% in 10 patients (p=not significant) and of non-infarct-related stenoses was <50% in 16 and > or=50% in 13. A significantly greater proportion of infarct-related stenoses with severity > or =50% progressed to non-Q-wave than to Q-wave myocardial infarction (71% vs 50%, p < 0.05). Before myocardial infarction, the percentage of concentric, eccentric, and irregular infarct-related stenoses was 8%, 13%, and 50%, respectively, whereas in the non-infarct-related stenoses it was 62%, 17%, and 21%, respectively (p < 0.01). A similar proportion of irregular morphology progressed to Q-wave or non-Q-wave myocardial infarction. CONCLUSIONS: In patients with stable angina who had acute myocardial infarction develop, the infarct-related and non-infarct-related stenoses on average are similar in severity but different in morphology. Nonsevere stenoses more frequently progress to Q-wave than to non-Q-wave myocardial infarction.

Platelet and Thrombin Activity Following Cardiac Catheterization Despite Treatment with Aspirin.

Thromboembolic complications are reported to occur in up to 0.5-2% of left cardiac catheterizations and angiographies. Activation of the hemostatic system may contribute to their onset. To prevent platelet and thrombin activity during catheterization, aspirin or systemic heparin are often used in addition to heparinized flush solutions. We investigated whether aspirin alone can prevent platelet and thrombin activity induced by catheterization in ten consecutive patients (nine males, mean 50 +/- 8 years) undergoing elective left cardiac catheterization after at least 5 days of oral aspirin (75-300 mg/d). Anticoagulant drugs were not given. Peripheral venous samples were drawn before, immediately after (time 0), and at 15, 60, and 180 minutes after the procedure for measurement of thrombin-antithrombin (TAT), prothrombin fragment 1.2 (F 1.2), fibrinopeptide A (FPA), and beta-thromboglobulin (beta-TG). TAT, F1.2, and FPA increased significantly at time 0 compared with both before and 180 minutes after the procedure (P < 0.04); beta-TG values were higher at time 0 compared with 180 minutes later (P = 0.01). TAT levels were related to those of FPA (r = 0.66; P = 0.0003), F1.2 (r = 0.35; P = 0.01), and beta-TG (r = 0.37; p = 0.04). Thus, routine left cardiac catheterization is associated with transient, systematically detectable, activation of coagulation and platelets, despite aspirin therapy. Newer antiplatelet agents may be more effective in preventing hemostatic activation induced by catheterization.

Cardiac troponin T does not increase after electrical cardioversion for atrial fibrillation or atrial flutter.

OBJECTIVE: To determine whether cardiac troponin T increases after electrical cardioversion in patients with atrial fibrillation or atrial flutter. DESIGN: Serum creatine kinase (CK), creatine kinase-MB (CKMB), and cardiac troponin T were measured before, 24 hours, and 48 hours after cardioversion in 15 patients with atrial fibrillation or atrial flutter. RESULTS: 12 of the 15 patients (80%) were successfully cardioverted to sinus rhythm. The median number of shocks was three (range one to six), the median cumulative energy 710 J (50 to 1430 J), and the median peak energy 300 J (50 to 360 J). Total CK increased from a baseline median concentration of 92 (45 to 259) to 1324 (96 to 6660) U/l at 24 hours and 1529 (120 to 4774) U/l at 48 hours after cardioversion. There was a small increase in CKMB but the ratio of CKMB to CK did not increase. There was no increase in cardiac troponin T in any patient. CONCLUSIONS: Following electrical cardioversion of atrial fibrillation or atrial flutter, cardiac troponin T remains unchanged despite a large rise in total CK, indicating that the CK is derived from skeletal muscle and that myocardial injury does not occur. If cardiac troponin T is increased after cardioversion for atrial arrhythmias then other causes of myocardial damage should be sought.

Impairment of the myocardial vasomotor response to cold pressor stress in collateral dependent myocardium.

OBJECTIVE: To study the vasomotor response (cold pressor/basal flow) in myocardium perfused entirely by collaterals, using the reflex sympathetic stimulation of cold pressor stress. DESIGN: Regional myocardial blood flow was measured in collateral dependent and in remote myocardium using positron emission tomography with 15O water at basal and at cold pressor stress. Regional ischaemia was measured with 18F-fluorodeoxyglucose (FDG). PATIENTS: Nine patients (mean (SD) age 53 (6) years) with an occluded coronary artery supplied entirely by collaterals from other angiographically normal arteries. RESULTS: In remote myocardium, basal and cold pressor flow were 0.99 (0.26) and 1.46 (0.60) ml/min/g (P < 0.05), respectively, a myocardial vasomotor response of 1.46 (0.45). In collateral dependent myocardium, basal and cold pressor flow were 0.91 (0.20) and 0.87 (0.35) ml/min/g, respectively (the latter value, P < 0.05 v remote region), a myocardial vasomotor response of 0.97 (0.43) (P < 0.05 v remote region). The myocardial vascular resistance (mean arterial pressure/flow) during cold pressor was higher in the collateral dependent than in remote myocardium, at 147.0 (61.1) and 85.6 (32.3) mm Hg.min.g/ml (P < 0.05), respectively, but with no relative increase in FDG uptake. CONCLUSIONS: In contrast to the decrease in myocardial resistance in remote myocardium with cold pressor, an increase was observed in collateral dependent myocardium suggesting a vasoconstrictor response in resistive vessels, without demonstrable myocardial ischaemia.

Inhibition of nitric oxide synthesis during the cold pressor test in patients with coronary artery disease.

The effects of a cold pressor test during intracoronary infusions of L-NMMA and normal saline were studied in patients with chronic stable angina and in patients with normal coronary arteriograms. The cold pressor test during saline infusion caused significant dilation of proximal and distal segments in patients with normal coronary arteriograms, and this dilation was abolished by L-NMMA infusion; in patients with coronary disease the cold pressor test during saline caused constriction of the stenoses and distal segments and this constriction was augmented by L-NMMA infusion.

Basal and flow-mediated nitric oxide production by atheromatous coronary arteries.

OBJECTIVES: This study assessed the effects of inhibition of nitric oxide synthesis on epicardial human coronary arteries and on coronary flow velocity during baseline conditions and during atrial pacing. BACKGROUND: Epicardial coronary artery dilation occurs in response to an increase in heart rate. It is not known whether the dilation of both angiographically normal and diseased epicardial coronary arteries during atrial pacing is nitric oxide dependent in humans. METHODS: The effects of an intracoronary infusion (4 mumol/min for 8 min) of NG-monomethyl-L-arginine (LNMMA), an inhibitor of nitric oxide synthesis, was studied in 16 patients with coronary artery disease and in 6 patients with normal coronary arteriograms. In all patients atrial pacing was performed during normal saline and during LNMMA infusion. the lumen diameter of epicardial coronary arteries was assessed by quantitative angiography, and changes in blood flow velocity were measured with a Doppler catheter. RESULTS: During saline infusion a significant increase in the lumen diameter of the proximal (p < 0.05) and distal (p < 0.01) segments of both normal and diseased arteries occurred during atrial pacing. No significant lumen diameter changes occurred in either group when atrial pacing was performed during LNMMA infusion. Stenosis diameter decreased during LNMMA infusion but did not change with atrial pacing either during saline infusion or during LNMMA infusion. The mean percent change in coronary blood flow with atrial pacing was less (p < 0.05) during LNMMA infusion than during saline infusion in both groups. CONCLUSIONS: These findings confirm that epicardial coronary artery dilation induced by pacing is nitric oxide dependent. Nitric oxide production contributes to the vasomotor tone of coronary resistance vessels. Nitric oxide is produced at the site of atheromatous stenosis but is unaffected by pacing.