Coronary artery vasoconstriction routinely occurs after percutaneous transluminal coronary angioplasty. A quantitative arteriographic analysis

To determine whether percutaneous transluminal coronary angioplasty (PTCA) increases coronary artery luminal dimensions by stretching and injuring ("paralyzing") the smooth muscle of the arterial wall, we prospectively analyzed spontaneous changes and then intracoronary nitroglycerin-induced changes in segmental coronary artery diameters during the first 30 minutes after uncomplicated single-vessel PTCA in 10 patients. Five additional patients received intravenous nitroglycerin throughout the procedure to determine whether nitroglycerin could prevent vasoconstriction after PTCA. All of the patients were maintained on oral doses of diltiazem and aspirin at the time of the study. Coronary arteriography was performed at 2, 5, 15, and 30 minutes after PTCA and then 3 minutes after 300 micrograms i.c. nitroglycerin. Quantitative measurements (computerized edge-detection) were performed at each time, in coronary segments centered in the dilated segment, distal to the dilated segment, and in a control vessel not manipulated with the balloon catheter or guidewire. Progressive vasoconstriction (defined as a loss of diameter that was reversed by intracoronary nitroglycerin) was observed after PTCA in the dilated and distal segments (10 of 10 patients) but not in the control segment. The vasoconstriction in the dilated segment at 30 minutes (mean, 30 +/- 4%) was highly statistically significant compared with vasoconstriction at 2 and 5 minutes after PTCA (p less than 0.001) and compared with the control segment at 30 minutes (p less than 0.005). There was no significant loss of diameter after PTCA in the dilated segment in the five patients who received intravenous nitroglycerin. In conclusion, 1) spontaneous coronary artery vasoconstriction after PTCA occurs routinely at and distal to the site of balloon dilatation despite pretreatment with aspirin and calcium channel blockers; 2) coronary artery vasoconstriction after PTCA is rapidly reversed by intracoronary nitroglycerin and can be prevented by the continuous administration of intravenous nitroglycerin during and after the procedure; 3) these results are incompatible with the hypothesis that PTCA improves coronary luminal dimensions by arterial "paralysis"; and 4) these findings have implications concerning the etiology and prophylaxis of abrupt vessel closure after PTCA.     

Prevention of coronary vasoconstriction by diltiazem during dynamic exercise in patients with coronary artery disease

Whether exercise-induced vasoconstriction of coronary artery stenoses is modified by the administration of calcium antagonists was examined in 14 patients with classic angina pectoris. In this group the effect of intracoronary diltiazem (2 to 3 mg) on luminal area was evaluated in normal and stenotic segments of epicardial coronary arteries during symptom-limited supine exercise. The luminal area of a normal and a stenotic coronary artery segment was determined by quantitative coronary arteriography with a computer-assisted system. Patients were studied at rest, 6 min after 2 to 3 mg of intracoronary diltiazem, during supine bicycle exercise (96 W) and 5 min after sublingual administration of 1.6 mg nitroglycerin. Heart rate, mean pulmonary and aortic pressure as well as the percent change of both normal and stenotic luminal area were determined. Intracoronary administration of diltiazem was associated with mild dilation of both normal (19%, p less than 0.01) and stenotic coronary luminal area (11%, p less than 0.05). During subsequent exercise, luminal area of the stenotic vessel segment increased by 23% (p less than 0.001) and that of the normal vessel segment by 24% (p less than 0.001), whereas in a previously reported control group, luminal area of the stenotic vessel segment decreased by 29% during exercise. After sublingual administration of nitroglycerin, the luminal area of both the normal and the stenotic vessel segment increased further by 19% (p less than 0.01) and 22% (p less than 0.01), respectively, compared with the values after intracoronary administration of diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormal coronary vasomotion during exercise in patients with normal coronary arteries and reduced coronary flow reserve

A reduced coronary flow reserve has been reported in patients with ischemialike symptoms and normal coronary arteries. In 13 such patients, both coronary vasomotion and flow reserve were studied. The luminal area of the proximal and distal third of the left anterior descending and left circumflex artery were determined by biplane quantitative coronary arteriography using a computer-assisted system. Patients were studied at rest, during submaximal supine bicycle exercise (4.0 minutes, 116 W), and 5 minutes after sublingual administration of 1.6 mg nitroglycerin. Heart rate, mean pulmonary pressure, and mean aortic pressure as well as the percent change of both proximal and distal luminal area were determined. In 10 of the 13 patients, coronary sinus blood flow was measured by coronary sinus thermodilution technique at rest and after dipyridamole infusion (0.5 mg/kg in 15 minutes) 10 +/- 5 days after quantitative coronary arteriography. Coronary flow ratio (dipyridamole/rest) and coronary resistance ratio (rest/dipyridamole) were determined in these patients. Patients were divided into two groups according to the behavior of the coronary vessels during exercise (vasodilation, group 1; vasoconstriction, group 2). Coronary vasodilation of the proximal (luminal area +26%, p less than 0.001) and distal (+45%, p less than 0.001) artery was observed in seven patients (group 1) during exercise and after sublingual nitroglycerin (+46%, p less than 0.001; and +99%, p less than 0.001, respectively). In group 2 (n = 6), however, there was coronary vasoconstriction of the distal vessel segments (-24%, p less than 0.001) during exercise, whereas the proximal coronary artery showed vasodilation (+26%, p less than 0.001) during exercise. After sublingual nitroglycerin, both vessel segments elicited vasodilation (distal coronary, +44%, p less than 0.001; proximal coronary artery, +47%, p less than 0.001). Coronary flow ratio amounted to 2.5 in group 1 and 1.2 in group 2 (p less than 0.05) and coronary resistance ratio to 2.7 in group 1 and to 1.2 in group 2 (p less than 0.05), respectively. Thus, among patients with ischemialike symptoms and normal coronary arteries, there is a group of patients (group 2) with an abnormal dilator response of the distal coronary arteries to the physiologic dilator stimulus of exercise and a reduced dilator capacity of the resistance vessels after dipyridamole (abnormal coronary vasodilator syndrome). The nature of this exercise-induced distal coronary vasoconstriction is not clear but might be due to an abnormal neurohumoral tone that may cause or contribute to the blunted vascular response during exercise.     

Nitroglycerin-induced coronary vasodilatory responses in patients during isometric handgrip exercise

Intracoronary nitroglycerin is frequently administered during invasive procedures such as coronary angioplasty or thrombolysis which may be associated with pain and sympathetic neural stimulation. Whether sympathetic-mediated reflex vasoconstriction interferes with nitroglycerin-induced augmentation of coronary blood flow is unknown. Therefore, coronary and systemic hemodynamics were measured in 19 patients during isometric handgrip exercise (3 min x 25% maximal effort), during intracoronary nitroglycerin, and during handgrip plus intracoronary nitroglycerin. Nine patients had no significant left anterior descending coronary artery stenosis (group 1) and ten patients had greater than 70% left anterior descending coronary artery stenosis (group 2). Handgrip exercise increased heart rate, mean arterial pressure, and coronary sinus and great vein flow 15% while increasing coronary resistance 10%. Intracoronary nitroglycerin (200 micrograms) reduced mean arterial pressure -4 +/- 6% and increased great cardiac vein flow 35-72%. Anterior left ventricular regional coronary flow responses to intracoronary nitroglycerin were unaffected by sympathetic stimulation for group 1. Group 2 had a greater increase in great vein flow with intracoronary nitroglycerin plus handgrip compared to nitroglycerin alone due to increased mean arterial pressure with no change in the great vein resistance. These data indicate that sympathetic stimulation does not alter the nitroglycerin-induced augmentation of coronary sinus and great vein blood flow in patients with and without significant left anterior descending coronary artery stenosis. In patients undergoing invasive interventions who may have increased circulating catecholamines, mild sympathetic (isometric) stimulation does not appear to interfere with the coronary vasodilatory responses to intracoronary nitroglycerin.     

Continuous intracoronary nitroglycerin infusion for spasm after angioplasty

A patient with reversible coronary artery spasm superimposed on fixed atherosclerotic coronary disease was treated with percutaneous transluminal angioplasty. The procedure successfully dilated the atherosclerotic lesion. However, 20 minutes later, the patient developed coronary artery spasm at the angioplasty site. Sublingual nitroglycerin, sublingual nifedipine, intravenous nitroglycerin, and repeated boluses of intracoronary nitroglycerin alleviated episodes of spasm, but failed to prevent recurrence. The patient was successfully treated with a continuous intracoronary infusion of nitroglycerin. Patients with coronary artery spasm in addition to fixed obstructive coronary disease may be at higher risk for spasm after percutaneous transluminal angioplasty. Continuous intracoronary infusion of nitroglycerin may be an effective therapy for recurrent coronary artery spasm occurring in the catheterization laboratory.     

Endothelial injuries of coronary arteries distal to thrombotic sites: role of adhesive interaction between endothelial P-selectin and leukocyte sialyl LewisX

Intracoronary thrombus formation is associated with epicardial vasoconstriction distal to the thrombotic site. To investigate the mechanisms of abnormal vasomotor function of the artery distal to the thrombotic site, we studied coronary vessels in dogs with cyclic flow variations (CFVs) of the left anterior descending coronary artery (LAD) stenosis with endothelial injury. Coronary rings isolated from the LAD (proximal, stenotic, and distal sites) and control circumflex coronary arteries were tested for responsiveness to endothelium-dependent (acetylcholine and A23187) and endothelium-independent vasodilators (NaNO2). Endothelium-independent relaxation was intact in all 4 sites. Endothelium-dependent relaxation was intact in the control and proximal sites and impaired in the stenotic sites. Relaxations not only to acetylcholine and A23187 but also to serotonin, ADP, and thrombin were impaired in the distal sites after observing CFVs for 80 minutes. Electron microscopy revealed the loss of endothelial integrity with leukocyte adherence to the endothelium in the distal sites. Immunohistochemical expression of P-selectin on the endothelial cells was more upregulated in the distal site than in the proximal site, and P-selectin mRNA expression was significantly greater in the ischemic region distal to the thrombotic site than in the proximal nonischemic region. PB1.3, a neutralizing monoclonal antibody against P-selectin, and sialyl LewisX (SLeX)-containing oligosaccharide SLeX, a carbohydrate analogue of selectin ligand, preserved endothelial function without affecting CFVs. SLeX-containing oligosaccharide preserved endothelial integrity of the distal site and inhibited P-selectin expression of the distal site. Thus, the adhesive interaction between endothelial P-selectin and leukocyte SLeX may play an important role in endothelial injuries of the coronary artery distal to the thrombotic site.     

Variable coronary vasomotor responses to acetylcholine in patients with normal coronary arteriograms: evidence for localised endothelial dysfunction.

OBJECTIVE: The vasomotor responses of the epicardial coronary arteries to acetylcholine were examined in patients with normal coronary arteries and chest pain. DESIGN: Quantitative angiography was used to measure minimum lumen diameter of proximal and distal coronary artery segments at baseline, during intracoronary infusion of acetylcholine (10(-7) - 10(-3) mol/l), and following an intracoronary bolus (2 mg) of isosorbide dinitrate. PATIENTS: Coronary arteriograms were obtained in 15 patients (mean (SEM) age 48 (10) years) with normal coronary arteries and chest pain. MAIN RESULTS: In response to the low concentrations of acetylcholine (10(-7) - 10(-6) mol/1) 20 (61%) distal and 11 (41%) proximal segments showed dilatation (group 1), whereas 13 (39%) distal segments and 14 (52%) proximal segments showed constriction (group 2) (P < 0.05 v group 1). In group 1, the maximum dilatation induced by acetylcholine in the proximal and distal segments was 7.83 (1.19)% and 11.6 (2.2)% respectively. In group 2, the maximum constriction at higher concentration was 16.55 (3.3)% and 33.11 (11.63)% in the proximal and distal segments respectively. The two different patterns of the vasomotor response coexisted in eight (53%) of the 15 patients. Intracoronary isosorbide dinitrate caused a greater increase in the coronary luminal diameter of distal segments than in proximal segments in group 1 (25.63 (5.16)% v 12.43 (3.48)%, P < 0.01) but not in group 2 (12.65 (2.53)% v 10.82 (3.33)%. CONCLUSIONS: Constriction and dilatation may occur in proximal and distal coronary artery segments, suggesting local areas of endothelial dysfunction, in response to acetylcholine in patients with chest pain and angiographically normal coronary arteries.     

Adjunctive intracoronary dipyridamole in the interventional treatment of small coronary arteries: a prospectively randomized trial

BACKGROUND: Patients undergoing intracoronary stent placement or balloon angioplasty for the treatment of small coronary arteries are at an increased risk of an adverse outcome from a higher incidence of abrupt closure and restenosis. Intracoronary thrombus formation plays a key role in the pathogenesis of abrupt vessel closure and of restenosis. Dipyridamole prevents platelet aggregation by a mechanism that differs from aspirin. The purpose of this study was to investigate the effect of intracoronary dipyridamole on acute complications and restenosis after percutaneous transluminal coronary angioplasty. METHODS: In a prospectively randomized study including 491 dilatations of coronary arteries with a diameter <2.75 mm, additional intracoronary application of dipyridamole was compared with conventional pretreatment consisting of heparin and aspirin. Study end points were defined as incidence of abrupt vessel closure, myocardial infarction, angiographic restenosis, and target vessel revascularization rate. RESULTS: Intracoronary dipyridamole was associated with a significant reduction of abrupt vessel closure (2.8% vs 8.6%; P =.005) and a nonsignificant reduction of myocardial infarction (1.6% vs 4.5%; P =.07) after percutaneous transluminal coronary angioplasty. Net gain 6 months after angioplasty was significantly higher in the dipyridamole group (0.60 +/- 0.35 mm vs 0.42 +/- 0.34 mm; P <.001). However, dipyridamole failed to reduce the incidence of angiographic restenosis (41.6% vs 49.1%; P =.11) and target vessel revascularization rate (20.6% vs 269%; P =.12). CONCLUSIONS: Intracoronary dipyridamole reduces the incidence of adverse cardiovascular events in the first 48 hours after balloon angioplasty of small coronary arteries. Reduction of restenosis rates failed to reach statistical significance. However, a significant increase in net gain was observed. Thus intracoronary application of dipyridamole should be considered in the treatment of small coronary arteries when intracoronary stenting is not appropriate.     

Morphologic evidence of accelerated left main coronary artery stenosis: a late complication of percutaneous transluminal balloon angioplasty of the proximal left anterior descending coronary artery

Histologic evidence of restenosis after percutaneous transluminal coronary angioplasty has been confined to the site of previous dilation. In this study, attention is focused on the accelerated development of coronary stenosis proximal to the site of previous angioplasty in a necropsy patient who developed severe left main stenosis 4 months after successful dilation of the proximal left anterior descending coronary artery. The unique fibrocellular tissue proliferation at the site of previous angioplasty and involvement of the adjacent distal segment of the left main coronary artery make possible the histologic diagnosis of accelerated left main coronary artery narrowing. Mechanisms for development of coronary stenoses proximal to the angioplasty site include: intimal injury by guiding catheters, guide wires, dilating balloons or combinations; or retrograde extension of the fibrocellular response to an adjacent proximal coronary segment. Histologic analysis of left main coronary arteries from 11 patients who died within 72 hours of angioplasty of the left coronary system disclosed focal loss of luminal endothelium in 9. This finding suggests that intimal injury from catheters or balloons, or both, proximal to the angioplasty site probably initiates a fibrocellular reaction. The amount of underlying atherosclerotic plaque in the injured proximal coronary segment determines the clinical significance of a subsequent fibrocellular response.     

Coronary artery calibre after direct intra-arterial infusion of epoprostenol (prostacyclin).

Because epoprostenol (prostacyclin) is a prostaglandin that causes vasodilatation and inhibits platelet function it may be of benefit during coronary artery angioplasty. The safety and capacity of intracoronary epoprostenol to dilate coronary arteries were assessed in 16 patients undergoing routine coronary angiography. The view that best displayed the left epicardial coronary arteries was selected as a control for each patient. Intracoronary epoprostenol was then given and the angiogram was repeated in the chosen view. The procedure was repeated twice: once with a higher dose of epoprostenol and once after intracoronary isosorbide dinitrate. Angiograms were coded and analysed by an observer who was unaware of the treatment. The calibre of the arteries was measured from traced projections of the angiograms. The blood pressure, heart rate, and electrocardiogram were recorded throughout. The first two patients were given epoprostenol infusions of 2.5 and 5.0 ng/kg per minute to assess safety, and there were no untoward reactions. The next ten patients had epoprostenol infusions of 5.0 and 7.5 ng/kg per minute followed by intracoronary isosorbide dinitrate. No haemodynamic disturbances occurred and coronary luminal calibre did not change with epoprostenol (mean (SD) luminal diameter: 2.85 (0.62) mm control, 2.80 (0.61) mm at 5.0 ng/kg, and 2.80 (0.54) mm at 7.5 ng/kg), but it did increase significantly with isosorbide dinitrate (to 3.17 (0.36) mm). The last four patients had epoprostenol infusions of 7.5 and 10 ng/kg followed by intracoronary isosorbide dinitrate and two of them became hypotensive (one after epoprostenol and one after isosorbide dinitrate). Coronary luminal calibre did not change significantly (3.5 (0.45) mm control, 2.96 (0.81) mm at 7.5 ng/kg, 3.45 (0.96) mm at 10 ng/kg, and 3.20 (0.61) mm with isosorbide dinitrate). Eight patients developed tall T waves on the electrocardiogram during epoprostenol infusion but none had arrhythmias. The results indicate that clinically tolerable doses of intracoronary epoprostenol do not significantly dilate the epicardial coronary arteries. This route of administration is therefore unlikely to be of use during coronary angioplasty, although the antiplatelet action of intravenous epoprostenol might help to prevent restenosis.     

Coronary artery calibre after direct intra-arterial infusion of epoprostenol (prostacyclin)

Because epoprostenol (prostacyclin) is a prostaglandin that causes vasodilatation and inhibits platelet function it may be of benefit during coronary artery angioplasty. The safety and capacity of intracoronary epoprostenol to dilate coronary arteries were assessed in 16 patients undergoing routine coronary angiography. The view that best displayed the left epicardial coronary arteries was selected as a control for each patient. Intracoronary epoprostenol was then given and the angiogram was repeated in the chosen view. The procedure was repeated twice: once with a higher dose of epoprostenol and once after intracoronary isosorbide dinitrate. Angiograms were coded and analysed by an observer who was unaware of the treatment. The calibre of the arteries was measured from traced projections of the angiograms. The blood pressure, heart rate, and electrocardiogram were recorded throughout. The first two patients were given epoprostenol infusions of 2.5 and 5.0 ng/kg per minute to assess safety, and there were no untoward reactions. The next ten patients had epoprostenol infusions of 5.0 and 7.5 ng/kg per minute followed by intracoronary isosorbide dinitrate. No haemodynamic disturbances occurred and coronary luminal calibre did not change with epoprostenol (mean (SD) luminal diameter: 2.85 (0.62) mm control, 2.80 (0.61) mm at 5.0 ng/kg, and 2.80 (0.54) mm at 7.5 ng/kg), but it did increase significantly with isosorbide dinitrate (to 3.17 (0.36) mm). The last four patients had epoprostenol infusions of 7.5 and 10 ng/kg followed by intracoronary isosorbide dinitrate and two of them became hypotensive (one after epoprostenol and one after isosorbide dinitrate). Coronary luminal calibre did not change significantly (3.5 (0.45) mm control, 2.96 (0.81) mm at 7.5 ng/kg, 3.45 (0.96) mm at 10 ng/kg, and 3.20 (0.61) mm with isosorbide dinitrate). Eight patients developed tall T waves on the electrocardiogram during epoprostenol infusion but none had arrhythmias. The results indicate that clinically tolerable doses of intracoronary epoprostenol do not significantly dilate the epicardial coronary arteries. This route of administration is therefore unlikely to be of use during coronary angioplasty, although the antiplatelet action of intravenous epoprostenol might help to prevent restenosis.     

Responses of atherosclerotic human coronary arteries in vivo to the endothelium-dependent vasodilator substance P.

BACKGROUND. The effects of the endothelium-dependent vasodilator substance P (SP) on atherosclerotic human coronary arteries was studied. METHODS AND RESULTS. [125I]-SP binding to luminal cells was shown to be preserved in the atherosclerotic epicardial coronary arteries of four patients. No binding to medial smooth muscle cells was demonstrated. Intracoronary infusions of SP were undertaken in patients with coronary artery disease. SP was infused for 2-minute periods starting at a dose of 2.8 pmol/min rising by doubling increments to 22.4 pmol/min. Analysis of the epicardial coronary artery diameter, using a computerized analysis system (CAAS) of the angiograms, was performed at the end of each infusion. Analysis of seven smooth vessel segments from seven coronary vessels, which were stenosed at more proximal sites, was performed. Significant dose-dependent dilatation was seen (p = 0.04), which was maximal at 5.6 pmol/min SP. No additional dilatation was produced with 2 mg intracoronary isosorbide dinitrate (ISDN). Two of these seven patients showed no response to SP, and only one of these appeared to sustain dilatation with ISDN (2 mg intracoronary). In a second group of six patients with discrete coronary stenoses, analysis at the site of the stenosed segments appeared to reveal dilatation in response to SP in only one instance. One other stenotic segment dilated with isosorbide dinitrate but failed to dilate with SP; the remaining four were fixed. The segment immediately proximal to the stenosis preserved a dose-dependent vasodilator response. CONCLUSIONS. These findings demonstrate that the endothelium-dependent vasodilator substance P can still produce epicardial vasodilatation in vivo in the presence of coronary atherosclerosis.     

Diameter changes of epicardial coronary arteries and coronary stenoses after intracoronary application of SIN 1, a molsidomine metabolite

The vasodilating effects of intracoronary injections of 0.4 mg SIN 1, the active metabolite of molsidomine, on epicardial coronary arteries and coronary stenoses were evaluated in 14 patients with coronary artery disease in a double-blind randomized fashion versus placebo. 9 additional patients with well-definable coronary stenoses received 0.4 mg SIN 1 as well. Diameter changes of nonstenotic coronary arteries in proximal, medial and distal coronary segments as well as changes of the residual luminal diameters within coronary stenoses were determined before (K), immediately after (M1) and 10 minutes after (M2) intracoronary application of SIN 1; in addition, aortic pressure and heart rate were monitored continuously. Aortic pressure and heart rate did not change after SIN 1 or placebo. After SIN 1, the diameter of nonstenotic coronary arteries increased in proximal segments by + 9% (M1) and + 11.7% (M2), in medial segments by + 17.6% (M1) and + 17.6% (M2), in distal segments by + 26.4% (M1) and + 28.8% (M2). Within coronary stenoses, the residual luminal diameters showed a mean increase by 31.5% (M1) and 48.3% (M2). Placebo did not alter coronary diameters significantly. SIN 1 effectively dilates nonstenotic and especially stenotic epicardial coronary arteries, as it is already known for nitrates and calcium-channel blockers. By intracoronary injections, the direct effects on coronary vessels can be detected without interference with systemic effects. The increase in residual luminal diameters within dynamic coronary stenoses after SIN 1 is most likely an important antianginal mechanism also for molsidomine.     

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.     

Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus

To assess whether spontaneous coronary artery spasm in patients with variant angina results from local coronary hyperreactivity to a generalized constrictor stimulus or from a stimulus generated only at the site of the hyperreactive segment, the behavior of spastic and nonspastic coronary segments was studied in six patients with variant angina in whom focal coronary spasm developed spontaneously during cardiac catheterization. None of the patients had critical (greater than 50% luminal diameter reduction) organic coronary stenoses. Coronary diameters were measured by computerized quantitative arteriography during control, spontaneous spasm and ergonovine-induced spasm and after intracoronary nitrates were given. During spontaneous spasm, the luminal diameter of spastic and both proximal and distal nonspastic coronary segments was significantly reduced from control values, 64.2%, 13.2% and 14.8%, respectively. Average diameter reduction of unrelated arteries was 12.3%. Ergonovine, which was also administered to four patients, provoked focal spasm at the same site as spontaneous spasm. During intravenous ergonovine, luminal diameter of spastic segments was reduced by 91.5%, that of nonspastic proximal segments by 17.8% and that of nonspastic distal segments by 11.5%. Luminal diameter of unrelated arteries during ergonovine-induced spasm was reduced by 17.7%. Constriction of spastic segments was greater during ergonovine-induced spasm (p less than 0.05), whereas the extent of diameter reduction of nonspastic segments was not significantly different during spontaneous spasm and ergonovine-induced spasm. Intracoronary isosorbide dinitrate dilated spastic and nonspastic coronary segments to a similar extent from control (20.7%, 18% and 16.5%, respectively; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous alterations in coronary blood flow velocity before and after coronary angioplasty in patients with severe angina

Cyclic coronary artery flow variations with a spontaneous decline in coronary blood flow to very low levels have been documented in stenosed canine coronary arteries with endothelial injury. These flow variations are associated with transient platelet aggregation and dislodgment and the release of selected mediators, including thromboxane A2 and serotonin. However, cyclic or spontaneous flow variations have not been demonstrated in stenosed coronary arteries in humans. In this study, the hypothesis was tested that spontaneous coronary blood flow velocity variations occur in some patients with stenosed coronary arteries before or after coronary artery angioplasty. Thus, 13 patients with severe and limiting angina underwent intracoronary pulsed Doppler velocimetry of their dilated artery immediately before and after percutaneous transluminal coronary angioplasty, whereas 9 control patients underwent velocimetry of an angiographically normal coronary artery. A 3F catheter with a 20 MHz Doppler crystal was positioned to achieve a maximal stable signal, and the flow velocity signal was recorded continuously for 20 min. Spontaneous flow velocity variations (greater than or equal to 38% change in Doppler frequency shift with wide morphologic changes) were present in 3 of the 13 patients tested. Spontaneous flow velocity variations occurred before angioplasty in one patient, after angioplasty in another and both before and after angioplasty in a third. In addition, 2 of the 13 patients, 1 with spontaneous coronary artery flow velocity variations before angioplasty, had frank vasospasm in an adjacent area just distal to the area of coronary dilation immediately after balloon inflation. These data establish that spontaneous coronary artery flow velocity variations occur in some patients with severe and limiting angina before and after coronary angioplasty. These variations may be related to platelet aggregation or coronary vasoconstriction, or both, at sites of endothelial injury resulting from plaque fissuring or ulceration and endothelial and medial injury occurring during coronary angioplasty.     

Detection of intracoronary fibrin degradation after coronary balloon angioplasty

Intracoronary thrombus formation may be involved in the pathogenesis of arterial closure after coronary angioplasty and may contribute to restenosis. It is hypothesized that, unlike markers of platelet activation and fibrin formation, D-dimer, a product of plasmin-mediated proteolysis of cross-linked fibrin, is not subject to significant catheter-induced artifact and could be used to study intracoronary fibrin degradation during angioplasty. No significant difference in D-dimer levels was noted in serial plasma samples obtained from an 8Fr arterial sheath and the wire lumen of an angioplasty balloon catheter, indicating that sampling through the catheter lumen did not induce artifactual D-dimer elevations. Translesion (proximal and distal to the lesion) coronary blood samples were collected in 31 patients undergoing elective coronary angioplasty pretreated with aspirin, dipyridamole and heparin. In 20 of those in whom translesion coronary samples for plasma D-dimer levels (mean ± standard deviation) were collected before balloon dilation, there was no evidence of ongoing intracoronary fibrinolysis (proximal D-dimer levels, 289 ± 145 ng/ml; distal, 299 ± 156 ng/ml; difference not significant). After coronary angioplasty (n = 31), there was a relatively small, but significant (p < 0.001) increase (45 ± 71 ng/ml) in translesional D-dimer levels (proximal, 396 ± 223 ng/ml; distal, 441 ± 257 ng/ml). The results from this study suggest (1) D-dimer levels are not subject to significant catheter-induced artifact and may be useful for assessment of intracoronary fibrin metabolism, and (2) intracoronary degradation of fibrin can be detected after (but not before) routine coronary angioplasty despite pretreatment with antithrombotic therapy, presumably in response to balloon-induced arterial injury and fibrin formation.     

Incidence of spasm at the site of previous successful transluminal coronary angioplasty: effect of ergometrine maleate in consecutive patients.

The incidence of coronary artery spasm at the site of previous successful angioplasty and its importance in leading to subsequent restenosis or recurrence of symptoms are unknown. Fourteen consecutive patients with single vessel coronary artery disease who had undergone successful percutaneous transluminal angioplasty were studied. All patients were given ergometrine maleate (ergonovine maleate) intravenously during repeat cardiac catheterisation six weeks to three months after angioplasty. Five patients demonstrated excessive luminal reduction (spasm) at the site of previous angioplasty that led to luminal stenoses ranging from 50% to 79%. Two of these patients developed chest pain and ST segment changes during ergometrine maleate provocation and they also showed maximal vasoconstriction. The remaining nine patients did not develop important luminal change at the site of angioplasty after ergometrine maleate. Ergometrine maleate administration resulted in less than or equal to 20% reduction in lumen diameter of adjacent apparently normal sections of the coronary arteries in all but two patients. At the site of previous angioplasty in the five patients with spasm, however, the lumen was constricted by a mean (SD) of 51 (12)%, whereas in the nine patients not demonstrating spasm mean reduction was 12 (7)%. Thus hypersensitivity to ergometrine maleate at the site of previous successful angioplasty was demonstrated in over a third of consecutive patients with single vessel coronary artery disease. The importance of this finding to long term results of coronary angioplasty needs to be investigated further.     

Effects of intracoronary injection of acetylcholine on coronary arterial hemodynamics and diameter

To examine the effects of intracoronary injection of acetylcholine on coronary blood flow and on coronary arterial diameter in humans, acetylcholine was injected into the left coronary artery in 32 adult patients (21 men and 11 women with a mean age of 54 years, range 37 to 65) with normal or almost normal coronary arteriographic findings. Patients with angina pectoris, myocardial infarction and severe cardiac diseases were excluded. Temporary right ventricular pacing was set at a rate of 60 beats/min to prevent transient bradyarrhythmias during intracoronary injection of acetylcholine. Measurements of coronary sinus blood flow and coronary vascular resistance and quantification of coronary arterial diameters using a computer-assisted technique were performed before and after each injection of 20, 50 and 100 micrograms of acetylcholine. Significant increase in coronary sinus blood flow and significant decrease in coronary vascular resistance occurred after intracoronary injection of acetylcholine. In contrast, mean diameter of normal epicardial coronary artery tended to decrease and that of irregular epicardial coronary artery decreased significantly after intracoronary injection of acetylcholine. Intracoronary injection of acetylcholine increases coronary blood flow, suggesting vasodilation in the coronary arteriolar bed, while it induces vasoconstriction in most of epicardial coronary arteries in adult humans.     

Response of normal and diseased epicardial coronary arteries to vasoactive drugs: quantitative arteriographic studies

Coronary vasodilators known to be effective in effort and vasospastic angina were studied in 93 patients undergoing catheterization for evaluation of chest pain. The ischemia-provoking stresses were isometric handgrip (25% of maximum for 4 to 5 minutes) or ergonovine maleate (0.2 mg intravenously). Hemodynamic changes and changes in angiographic diameter of epicardial coronary arteries were measured during these stresses, with and without drug administration. Drugs included intravenous diltiazem (0.25 mg/kg load + 0.003 mg/kg/min), intravenous verapamil (0.14 mg/kg load + 0.0075 mg/kg/min) and intracoronary (0.012 mg/min X 4 minutes) and sublingual (0.4 mg) nitroglycerin. From these studies, the following statistically valid conclusions were reached. First, nitroglycerin is a potent dilator of epicardial coronary arteries, increasing normal luminal area an average of 28% and luminal area in significantly stenotic segments by 29%. Second, verapamil and diltiazem are nonsignificant epicardial coronary dilators (9% and 4% luminal area increase, respectively). Similarly, diltiazem does not dilate significant coronary stenoses. Third, sustained isometric handgrip increases systemic blood pressure and heart rate by reflex activation of the sympathetic nervous system. By this means, handgrip also constricts luminal area in normal and diseased coronary segments by 20% and 22%, respectively. One result of these changes is a handgrip-induced, ischemic 56% rise in pulmonary wedge pressure in patients with significant stenosis. Fourth, intracoronary nitroglycerin, in very small doses, does not block the systemic hemodynamic response to handgrip, but prevents handgrip-induced coronary constriction and the associated ischemic left ventricular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)