Background A group of patients has been described who have chestpain resembling angina and positive exercise tests, but normalcoronary angiograms and no coronary-artery spasm. This constellationof features has sometimes been called syndrome X or microvascularangina. We attempted to determine whether endothelium-dependentvasodilatation of the coronary vasculature was impaired in patientswith this syndrome.
Methods We infused the endothelium-dependent vasodilator acetylcholineand the endothelium-independent vasodilators papaverine andisosorbide dinitrate into the left coronary artery of 9 patientsand 10 control subjects. The diameter of the left anterior descendingcoronary artery was assessed by quantitative angiography, andchanges in coronary blood flow were estimated with the use ofan intracoronary Doppler catheter.
Results Acetylcholine, given in doses of 1, 3, 10, and 30 µgper minute, increased coronary blood flow in a dose-dependentmanner in both groups. However, the mean (±SD) acetylcholine-inducedincreases in coronary blood flow were significantly less (P<0.001)in the patients (8 ±14, 37 ±37, 59 ±67,and 103 ±77 percent, respectively) than in the controls(62 ±52, 186 ±93, 341 ±128, and 345 ±78percent, respectively). The changes in coronary blood flow inresponse to 2 mg of isosorbide dinitrate (236 ±66 percentvs. 280 ±56 percent) and 10 mg of papaverine (366 ±168percent vs. 411 ±92 percent) did not differ significantlybetween the patients and controls. The administration of papaverineresulted in myocardial lactate production in the patients butnot in the controls. The three lower doses of acetylcholinecaused a similar degree of dilatation of the left anterior descendingcoronary artery in the two groups, and the highest dose causeda similar degree of constriction in the two groups. Isosorbidedinitrate and papaverine caused a similar degree of dilatationin both groups.
Conclusions These findings suggest that endothelium-dependentdilatation of the resistance coronary arteries is defectivein patients with anginal chest pain and normal coronary arteries,which may contribute to the altered regulation of myocardialperfusion in these patients.
A group of patients who have angina-like chest pain, ischemicST-segment depressions on their electrocardiograms during exercisetesting, angiographically normal coronary arteries without coronary-arteryspasm, and normal ventricular function has been described bymany investigators1,2,3. Some patients with this constellationof findings (sometimes called syndrome X) have attenuated coronaryflow reserve in response to metabolic or pharmacologic vasodilatorstimuli (i.e., microvascular angina)2,3. The implication isthat an abnormality in the microvasculature may be the causeof this syndrome. The impairment of coronary flow reserve mayresult from either abnormal vasomotion of the coronary microcirculationor structural microvascular disease, since the increase in myocardialblood flow evoked by atrial pacing or intravenous dipyridamoleis limited in these patients2,3,4,5,6. The mechanisms underlyingthe abnormal vasomotion in these patients are unknown, but theymay relate to defective endothelial function, inappropriatevasoconstriction, or both.
There is now ample evidence indicating that endothelium-derivedvasoactive substances play an important part in regulating notonly the vasomotion of the large epicardial coronary arteriesbut also coronary blood flow (which is regulated by the smallresistance vessels)7,8,9. Recently, it has been suggested thatendothelium-dependent dilatation of resistance vessels in coronaryand other vascular beds is impaired in hypertension and hypercholesterolemia10,11,12,13.Therefore, altered endothelium-dependent vasomotion of coronaryresistance vessels may contribute to the cause of angina-likechest pain in patients with normal coronary arteries. The presentstudy attempted to determine whether endothelium-dependent vasodilatationof coronary resistance vessels was impaired in patients withthis syndrome.
Methods
Study Patients
Nine patients with angina-like chest pain and normal coronaryarteries and 10 control subjects with atypical chest pain andnormal coronary arteries were studied. The criteria that weused to define the syndrome were angina-like chest pain, positiveexercise tests (>0.1 mV of ST-segment depression in two ormore leads), angiographically normal coronary arteries, andno spasm of the large epicardial coronary arteries. In thisstudy, we enrolled patients with this syndrome in whom an intracoronaryinfusion of 10 mg of papaverine evoked the myocardial productionof lactate. The control subjects had atypical chest pain, normalexercise tests, and angiographically normal coronary arterieswithout spasm. In six control subjects, myocardial lactate wasnot produced in response to intracoronary papaverine; in theother four control subjects, sampling of arterial and coronarysinus venous blood could not be done.
All patients were normotensive and had no evidence of left ventricularhypertrophy as assessed by electrocardiography, echocardiography,and contrast left ventriculography. None of the patients werereceiving antihypertensive or cholesterol-lowering drugs. Theleft-ventricular-mass index was determined by biplanar leftventriculography14. Patients with hypercholesterolemia (totalcholesterol level, >220 mg per deciliter [5.7 mmol per liter]),diabetes mellitus, cardiomyopathy, valvular heart disease, ora conduction disturbance on electrocardiography were excluded.Hypercholesterolemia was assessed from duplicate measurementsof serum total cholesterol levels performed within a month ofeach other. We confirmed that all patients had a total cholesterollevel of less than 220 mg per deciliter three months after thestudy. Patients who had angiographically documented coronary-arteryspasm in any coronary-artery segment (reduction in the diameterto <50 percent of the base line) in response to the intracoronaryinfusion of acetylcholine (100 µg per minute) or ergonovine(50 µg per minute) were also excluded.
The research proposal was approved by the institutional reviewcommittee for clinical research. Written informed consent wasobtained from each patient after the study protocol was explained.
Quantitative Coronary Arteriography
Coronary cineangiograms were recorded on 35-mm cinefilm (60frames per second) with a cineangiographic system (Siemens,Erlangen, Germany). Non-ionic contrast material (iohexol 350)was used. An appropriate view that allowed the best visualizationof the left anterior descending coronary artery (the study artery)was selected.
An end-diastolic frame was selected on the cineprojector, andthe arterial segments under study were scanned with a videocamera. The images were digitized and analyzed with a videodensitometricanalysis system15 (Kontron Instruments, Dortmund, Germany).The diameter of the segment of interest (3 to 4 mm in length)was measured four times, and the average value was used foranalysis. The diameter of the Judkins catheter was used to calibratethe arterial diameter in millimeters. The arterial diameterswere measured blindly.
We measured the changes in the luminal diameter of the proximaland distal segments of the left anterior descending coronaryartery. The proximal segment was defined as a segment 3 to 4mm distal to the tip of the Doppler catheter, and the distalsegment as that distal to the second or third diagonal branch.
Measurements of Coronary Blood Flow Velocity and Blood Flow
An 8-French angioplasty-guiding catheter was introduced intothe left main coronary artery by a femoral approach. A 3-FrenchDoppler flow-velocity catheter (model DC-201, Millar Instruments,Houston) was introduced into the proximal left anterior descendingcoronary artery. The Doppler catheter was then connected toa DC-101 velocimeter (Millar Instruments) to measure mean andphasic velocity signals. The use of this device to assess coronaryblood flow velocity in humans has been described elsewhere13,16,17,18.Coronary blood flow was estimated from the product of the meancoronary blood flow velocity and the cross-sectional area ofthe proximal arterial segment at the tip of the Doppler catheter.
Study Protocol
Cardiac catheterization was performed in the patients afteran overnight fast; the patients were premedicated with a 5-mgoral dose of diazepam. All antianginal medications were discontinuedat least 24 hours before the study.
After the diagnostic catheterization was completed, the followinginterventions were performed in a random order: a bolus injectionof papaverine (10 mg per 5 ml; Dai-Nippon Pharmaceutical, Tokyo,Japan) was administered through the guiding catheter, saline(0.5 ml per minute for two minutes) was infused through theDoppler catheter, and acetylcholine (0.5 ml per minute; Dai-IchiPharmaceutical, Tokyo) was infused at doses of 1, 3, 10, and30 µg per minute (for two minutes at each dose) throughthe Doppler catheter. Finally, a 2-mg dose of isosorbide dinitrate(2 mg per 4 ml; Ei-Zai Pharmaceutical, Tokyo) was infused throughthe guiding catheter over a one-minute period. In three patientswho had a limited response of coronary blood flow (<300 percent-- the lower limit of the normal range in our laboratory) toa 10-mg dose of papaverine, we administered an additional 14-mgdose of papaverine and found that the response of coronary bloodflow to this dose was not greater than that to the 10-mg dose.Thus, the data obtained with the 10-mg dose of papaverine wereused for analysis.
After completing the protocol with one drug, we waited for atleast five minutes before beginning the infusion of the nextdrug, by which time the coronary diameter and coronary bloodflow velocity had returned to the base-line values. Coronaryarteriography was performed before and two minutes after theadministration of each agent. Coronary blood flow velocity,arterial pressure, heart rate, and electrocardiograms were continuouslymonitored and recorded on a polygraph system (Nihon-Kohden,Tokyo). The values obtained during a steady-state conditionwere used for analysis.
In all nine patients and six of the control subjects, a catheterwas inserted into the coronary sinus vein. Paired samples ofarterial and coronary sinus venous blood were taken before andtwo minutes after the administration of papaverine (10 mg) andacetylcholine (30 µg per minute) for the measurement ofplasma lactate. The plasma lactate concentration was measuredimmediately after sampling with a calibrated lactate analyzer(OMRON, Tokyo). The average value of duplicate measurementswas used for analysis.
Statistical Analysis
Data are expressed as means ±SD. When serial changesin the arterial pressure, heart rate, arterial diameter, andcoronary blood flow were compared within a group or betweenthe groups, analysis of variance for repeated measures followedby Bonferroni's multiple-comparison test was used19. Student'st-tests were used to compare paired or unpaired data. A two-tailedprobability level of less than 0.05 was considered to indicatesignificance.
Results
Clinical Characteristics and Measurements
Clinical characteristics such as age, sex, arterial pressure,smoking status, left-ventricular-mass index, and previous medicationsare presented in Table 1, all of which were comparable betweenthe two groups. The base-line mean arterial pressure was 89±11 mm Hg in the control subjects and 84 ±11 mmHg in the patients (P>0.5). A 10-mg dose of papaverine insignificantlydecreased the mean arterial pressure in the control subjects(to 82 ±6 mm Hg, P = 0.13) and in the patients (to 80±7 mm Hg, P = 0.4). An infusion of acetylcholine (1 to30 µg per minute) did not affect the mean arterial pressurein either group.
Table 1. Clinical Characteristics of the Control Subjects and the Patients with Microvascular Angina.
The base-line heart rate was 69 ±12 beats per minutein the control subjects and 72 ±12 beats per minute inthe patients (P>0.5). The heart rate did not change significantlyduring the study.
Changes in the Diameter of the Left Anterior Descending Coronary Artery
The base-line diameters of the proximal and distal arterialsegments were 2.9 ±0.4 and 1.8 ±0.3 mm, respectively,in the control subjects and 3.0 ±0.4 mm and 1.9 ±0.4mm, respectively, in the patients (P>0.5 for the differencebetween groups). An intracoronary infusion of saline did notchange the arterial diameters. The administration of acetylcholineproduced biphasic changes in the arterial diameters. In bothgroups, the diameter of the proximal and distal segments ofthe study artery increased significantly after the infusionof acetylcholine at a dose of 10 µg per minute (P = 0.01)and decreased after a dose of 30 µg per minute (P<0.01by one-way analysis of variance). The percent changes in thearterial diameter induced by the graded doses of acetylcholinedid not differ significantly between the two groups (Figure 1).A 2-mg dose of isosorbide dinitrate caused a comparabledegree of dilatation of the proximal and distal arterial diametersin the control subjects (21.2 ±3.8 percent and 25.0 ±5.4percent, respectively) and the patients (29.1 ±4.5 percentand 31.9 ±6.6 percent, respectively) (P>0.5 for thedifference between groups). A 10-mg dose of papaverine alsocaused a comparable degree of dilatation of the proximal anddistal arterial segments in the patients (8.1 ±4.0 percentand 11.3 ±4.6 percent, respectively) and the controls(6.4 ±3.9 percent and 9.2 ±3.6 percent, respectively)(P>0.5 for the difference between groups).
Figure 1. Change in the Diameter of Proximal and Distal Coronary Arteries Produced by an Intracoronary Infusion of Graded Doses of Acetylcholine in Control Subjects and Patients with Microvascular Angina.
The vasomotor responses of the proximal and distal coronary arteries to acetylcholine did not differ significantly between the two groups. Bars indicate the standard deviation.
Changes in Coronary Blood Flow
The percent increases in estimated coronary blood flow evokedby acetylcholine, papaverine, and isosorbide dinitrate in eachpatient are presented in Table 2. The infusion of saline didnot alter coronary blood flow (Figure 2). The administrationof graded doses of acetylcholine resulted in dose-dependentincreases in coronary blood flow, but the progressive increasesin coronary blood flow in the patients were significantly (P<0.001by analysis of variance) less than those in the control subjects(Figure 2). There was no significant difference in the percentincreases in coronary blood flow in response to papaverine betweenthe control subjects and the patients (411 ±92 percentvs. 366 ±168 percent, P = 0.47). The percent increasein coronary blood flow produced by isosorbide dinitrate didnot differ significantly between the control subjects and thepatients (280 ±56 percent vs. 236 ±66 percent,P = 0.2).
Table 2. Changes in Estimated Coronary Blood Flow Produced by Papaverine, Acetylcholine, and Isosorbide Dinitrate in the Control Subjects and Patients with Microvascular Angina.
Figure 2. Increase in Coronary Blood Flow Evoked by Graded Doses of Acetylcholine in Control Subjects and Patients with Microvascular Angina.
The dose-dependent increases in coronary blood flow produced by acetylcholine were significantly less in patients with microvascular angina than in control subjects (P<0.001 by two-way analysis of variance). Bars indicate the standard deviation.
Plasma Lactate Concentrations
Paired samples of coronary arterial and coronary sinus venousblood were obtained from six of the control subjects and allnine of the patients. The plasma concentrations of lactate inarterial and coronary sinus venous blood before the administrationof papaverine were 7.3 ±2.0 and 5.3 ±1.4 mg perdeciliter, respectively, in the control subjects and 6.2 ±1.8and 4.4 ±0.9 mg per deciliter, respectively, in the patients(P>0.5 for the difference between groups). The lactate-extractionratio ([arterial lactate concentration - venous lactate concentration]/arteriallactate concentration x 100 [%]) before and after the intracoronaryinfusion of papaverine was 24.0 ±8.1 percent (range,10 to 32 percent) and 14.0 ±4.2 percent (range, 8 to18 percent) in the control subjects and 25.9 ±7.5 percent(range, 15 to 41 percent) and -13.4 ±11.2 percent (range,-1 to -30 percent) in the patients, indicating that myocardialproduction of lactate occurred in response to papaverine inthe patients but not in the control subjects.
After the intracoronary infusion of papaverine, six of the ninepatients had anginal chest pain, with ischemic ST-segment depression( 0.2 mV) in leads V3 through V6, II, III, and aVF, whereasnone of the control subjects had chest pain or ST-segment changes.Ventricular tachycardia developed in one of the patients aftera 14-mg dose of papaverine and resolved spontaneously. No otheradverse events, except prolongation of the QT interval, occurredafter the administration of papaverine.
Discussion
In this study, we assumed that acetylcholine increased coronaryblood flow by causing endotheliumdependent dilatation of thecoronary vasculature. This assumption is tenable because thevasodilative responses of the coronary and forearm vascularbeds in humans to acetylcholine can be prevented by methyleneblue, which inhibits guanylate cyclase in vascular smooth muscle,20and by L-arginine analogues, which inhibit the synthesis ofnitric oxide (an endothelium-derived relaxing factor) from L-argininein endothelial cells21,22.
Our most important finding was that in patients with anginaand normal coronary arteries, there was marked attenuation ofthe increase in coronary blood flow evoked by intracoronaryacetylcholine, whereas the increase in coronary blood flow inresponse to isosorbide dinitrate and papaverine was not affected.These findings suggest that endothelium-dependent vasodilatationof resistance coronary vessels was impaired in our patientswith angina and normal coronary arteries.
Motz et al.23 examined the responses of coronary blood flowto acetylcholine and dipyridamole in 23 patients with anginaand normal coronary arteries. They showed that in eight patientsthe response to acetylcholine was less than the response todipyridamole, suggesting defective endothelium-dependent vasodilatation.Another 12 patients had similar responses to the two agents,whereas 3 had coronary spasm provoked by acetylcholine. Theirfindings are suggestive of defective endothelium-dependent vasodilatationin some patients with angina and normal coronary arteries andare consistent with our results. However, many of their patientshad arterial hypertension and diabetes mellitus, which are knownto impair endothelium-dependent vasodilatation7,8,9,11,12,13.We excluded patients with hypertension, hypercholesterolemia,diabetes mellitus, and other coronary risk factors from thestudy. Thus, the difference between the results of Motz et al.and our own might be related to the patient populations.
We observed myocardial lactate production in our patients duringthe infusion of papaverine -- a response that suggests myocardialischemia results from a microvascular abnormality not dependenton the endothelium. Thus, our patients represent a subgroupof patients with angina and normal coronary arteries who metstrict inclusion criteria. Myocardial production of lactateand increased coronary blood flow during the infusion of papaverinemay seem paradoxical. With the use of cardiac positron-emissiontomography, Galassi et al.6 demonstrated that the increase inmyocardial perfusion after the administration of dipyridamolewas not uniform in patients with angina and normal coronaryarteries but was uniform in the control subjects. Other investigatorshave proposed that the abnormality of the coronary microcirculationresponsible for myocardial ischemia in patients with microvascularangina may be distributed unevenly in the heart2,3,24. Thus,we consider that uneven dilatation of prearteriolar coronaryarteries resulting in inhomogeneous myocardial perfusion duringthe infusion of papaverine may have resulted in a "steal phenomenon,"with ensuing ischemia in patients with microvascular angina.Anginal pain developed in six of our nine patients in associationwith ST-segment depression during the infusion of papaverine,suggesting that they indeed had myocardial ischemia. However,further studies, such as radionuclide ventriculography duringthe infusion of papaverine or exercise, are needed to confirmthat myocardial ischemia results from a microvascular abnormalityin these patients.
Christensen et al. have recently shown in dogs that the intracoronaryinfusion of papaverine caused myocardial lactate productionand an abnormal contractile pattern despite the increase incoronary blood flow25. This result suggests that lactate productionduring papaverine infusion may not be a pathologic finding.However, other studies in normal dogs did not report abnormalmyocardial systolic function during the intracoronary infusionof papaverine26,27. Importantly, we found that the infusionof papaverine evoked myocardial lactate production only in thepatients, suggesting that this response was related to an abnormalityin the coronary microcirculation.
In addition to studying endothelium-dependent vasodilatationof resistance coronary arteries, we also examined the effectsof acetylcholine on the caliber of a large epicardial coronaryartery. As shown in previous studies,28,29,30,31 lower dosesof acetylcholine induced vasodilatation, but a high dose causedvasoconstriction. This biphasic response of the large coronaryartery to acetylcholine did not differ between the patientsand the control subjects. These results suggest that the endothelium-dependentvasodilatation of large coronary arteries produced by acetylcholinewas not altered in the patients with angina and normal coronaryarteries. More important, the results indicate that the attenuatedresponse of coronary blood flow to acetylcholine in our patientsdid not result from excessive vasoconstriction of the largecoronary arteries. Our results differ in part from those ofVrints et al.,32 who found that patients with angina pectorisand normal coronary arteries had a loss of endothelium-dependentdilatation of the large coronary arteries with acetylcholine.The reason for the different responses in our study and thestudy by Vrints et al.32 is not known, but it may be relatedeither to differences in the patient populations or to differencesin the dose of acetylcholine. It has been shown that many factors,such as coronary risk factors, age, and the presence of atherosclerosis,alter the response of epicardial coronary arteries to acetylcholine10,11,12,13.
We consider that the attenuated response of coronary blood flowto acetylcholine, but the intact response of coronary bloodflow to papaverine and isosorbide dinitrate, in our patientssuggests defective endothelium-dependent vasodilatation of resistancecoronary arteries. However, we must consider the possibilitythat the impaired response of coronary blood flow to acetylcholinemay have resulted from augmented microvascular vasoconstriction,because acetylcholine not only releases endothelium-derivedrelaxing factors but also has a direct vasoconstricting action7,8,9.Acetylcholine-induced coronary-artery spasm may be caused bydirect vasoconstriction, defective endothelium-dependent vasodilatation,or both33,34,35. It is also possible that the impaired responseof coronary blood flow to acetylcholine could be related tothe concomitant release of endothelium-derived constrictingfactors7,8,9. Further studies are needed to clarify the underlyingmechanisms of the attenuated response of coronary blood flowto acetylcholine in patients with microvascular angina. Theuse of a drug such as substance P35 would be more appropriateto assess dysfunction of the coronary microvascular endothelium,since substance P does not act directly on vascular smooth muscle.
In conclusion, our results indicate that a subgroup of patientswith angina and normal coronary arteries (microvascular angina)have an attenuated response of coronary blood flow to acetylcholine.Defective endothelium-dependent dilatation in the coronary microcirculationmay contribute to the altered regulation of myocardial perfusionand the ischemic manifestations in these patients.
Supported in part by grants-in-aid for scientific research (02404045and 02454259); by a grant-in-aid for scientific research onpriority areas (03268226) from the Ministry of Education, Scienceand Culture, Tokyo, Japan; by a research development award fromthe Japan Heart Foundation, Tokyo; and by a research grant for1992 from the Naito Memorial Foundation, Tokyo.
Source Information
From the Research Institute of Angiocardiology and the Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812, Japan, where reprint requests should be addressed to Dr. Egashira.
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0.2 mV) in leads V3 through V6, II, III, and aVF, whereas none of the control subjects had chest pain or ST-segment changes. Ventricular tachycardia developed in one of the patients after a 14-mg dose of papaverine and resolved spontaneously. No other adverse events, except prolongation of the QT interval, occurred after the administration of papaverine. 
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