Role of adenosine in pathogenesis of anginal pain

The intravenous infusion of adenosine provokes anginalike chest pain. To establish its origin, an intracoronary infusion of increasing adenosine concentrations was given in 22 patients with stable angina pectoris. During adenosine infusion, 20 patients had chest pain without electrocardiographic signs of ischemia. They all reported that the chest pain was similar to their usual anginal pain. In 10 of the 22 patients adenosine was also infused into the right atrium, but it never produced symptoms at the doses that had provoked chest pain during intracoronary infusion. In seven other patients, the intracoronary adenosine infusion was repeated after intravenous administration of aminophylline, an antagonist of adenosine P1-receptors. Aminophylline decreased the severity of adenosine-induced chest pain (assessed with a visual analog scale) from 42 +/- 22 to 23 +/- 17 mm (p less than 0.002). In the remaining five of the 22 patients, monitoring of blood oxygen saturation in the coronary sinus during intracoronary adenosine administration showed that maximum coronary vasodilation was achieved at doses lower than those responsible for chest pain. A single-blind, placebo-controlled, randomized trial of the effect of aminophylline on exercise-induced chest pain was also performed in 20 other patients with stable angina. Aminophylline, compared with placebo, decreased the severity of chest pain at peak exercise from 67 +/- 21 to 51 +/- 23 mm (p less than 0.02), despite the achievement of a similar degree of ST-segment depression. Finally, the effect of intravenous adenosine was compared in 10 patients with predominantly painful myocardial ischemia and in 10 patients with predominantly silent ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine induced chest pain--a comparison between intracoronary bolus injection and steady state infusion.

OBJECTIVE: Adenosine may induce chest pain in at least two ways, either by direct stimulation of sensory afferents before actual ischaemia occurs or secondary to ischaemia. The aim was to study if the mechanism of pain induction may depend on the method of adenosine administration. METHODS: Increasing doses of adenosine were given to seven male patients with ischaemic heart disease referred for coronary angiography: first as a bolus intracoronary injection (2.5-50 mumol), second as a 1 ml.min-1 steady state infusion (0.01-20 mumol.min-1) and third as an intravenous steady state infusion (0.076-0.76 mumol.kg-1 x min-1). Pain, rate-pressure product, coronary sinus blood flow, and ECG were monitored. Lactate was analysed in coronary sinus and arterial blood. RESULTS: After intracoronary bolus injection there were no signs of myocardial ischaemia, whereas during intracoronary steady state infusion, and in spite of a lower, but definite, degree of pain, 5/7 patients showed myocardial lactate production and three patients showed ST depression. During the intravenous steady state infusion 6/6 patients showed ST depression. CONCLUSIONS: These findings suggest that when using adenosine for studies on the mechanisms of chest pain in patients with ischaemic heart disease it is preferable to use an intracoronary bolus injection technique rather than a steady state infusion, as the risk of inducing ischaemia with the latter model cannot be ignored.     

New combined spasm provocation test in patients with rest angina: intracoronary injection of acetylcholine after intracoronary administration of ergonovine

The incidence of provoked coronary spasm with the standard single spasm provocation test has been relatively low in patients with rest angina. The present study examined the clinical usefulness of a newly designed spasm provocation test, an intracoronary injection of acetylcholine (ACh) following an ergonovine (ER) test, in patients with rest angina who demonstrated low disease activity and atypical chest pain. Triple sequential spasm provocation tests were performed in 24 patients with atypical chest pain who had no ischemia and in 40 patients with rest angina who had distinct ischemia. Initially, an ACh test (20-100 microg) and then an ER test (40-64 microg) were performed and then, if no spasm was provoked, an intracoronary injection of ACh was given after the ER test to evaluate coronary spasm. Coronary spasm was defined as total or subtotal occlusion. In the 24 patients with atypical chest pain, no spasm was provoked by intracoronary injection of either ACh or ER, but coronary spasms were induced in 2 patients using the new method, with the remaining 22 not experiencing spasm (specificity of new method, 92%). In the 40 patients with rest angina, intracoronary injection of ACh induced coronary spasm in 22 patients (group I) and 6 (group II) demonstrated spasm with intracoronary injection of ER. Coronary spasm was not induced by either the ACh test or the ER test in 12 patients (group III). The intracoronary administration of ACh after the ER test provoked spasm in 11 of 12 patients. Diffuse spasms were provoked in 10 of 11 patients. In patients with rest angina, the frequency of chest pain attacks in 1 month experienced by patients in group III (0.8+/-0.8) was significantly lower than that of patients in group I (7.0+/-5.3, p<0.01) or II (3.5+/-2.3, p<0.05). No serious or irreversible complications related to this new combined method were observed. In conclusion, this method was safe and reliable for the induction of coronary spasm in patients with rest angina who may have low disease activity.     

Left main coronary artery arising from right sinus of Valsalva: a rare congenital anomaly associated with distal vasospasm

A 50 year-old female patient was admitted to our outpatient clinic with a two year history of chest pain and dyspnoea on exertion. Echocardiography revealed apical hypokinesia with an ejection fraction of 50% on the left ventricle. Coronary angiography revealed that the left main coronary artery was arising from the right sinus of Valsalva and than coursing posterior to the aorta. There were significant stenoses at the proximal right coronary artery (RCA) and the proximal left anterior descending coronary artery (LAD). The RCA lesion disappeared after intracoronary nitroglycerine administration, and the LAD lesion disappeared the next day when the patient was due to undergo percutaneous intervention. Stress myocardial perfusion scintigraphy revealed anteroseptal ischaemia consistent with reversible ischaemia.     

Coronary artery spasm induced by carotid sinus massage

A 60 year old man with a history of frequent episodes of chest pain and dizziness was referred for evaluation of coronary artery disease. He had no significant coronary artery stenosis at baseline coronary angiography. A carotid sinus massage was performed for evaluation of carotid sinus hypersensitivity in the patient. Both heart rate and blood pressure decreased a little, and returned to baseline level immediately after carotid sinus massage. However, 2.5 minutes after carotid sinus massage, ECG showed ST segment elevation in leads II, III, and aVF. Four minutes after carotid sinus massage, he had chest pain with a progressive elevation in the ST segment in the same leads, when he had 99% focal spasm in the right coronary artery. The vasospasm induced by carotid sinus massage was reproducible over several minutes and resolved spontaneously. Coronary artery spasm may be provoked by the enhanced vagal activation due to carotid sinus massage.


Keywords: coronary vasospasm; vasospastic angina; coronary artery spasm; carotid sinus massage     

Biphasic changes (initial increase and late decrease) in coronary sinus venous oxygen saturation during anginal attacks induced by intracoronary acetylcholine in patients with variant angina.

In order to evaluate the effects of intracoronary acetylcholine on coronary resistance vessels, oxygen saturation in coronary sinus blood was continuously measured to compare its dynamic changes during intracoronary injection of acetylcholine in both patients with variant angina and control subjects. Group 1 consisted of 6 patients without coronary artery disease. Group 2 consisted of 10 patients with variant angina and spasm in the left anterior descending coronary artery. A fiberoptic reflection oximetry system was used for the continuous measurement of coronary sinus venous oxygen saturation. Acetylcholine (20 micrograms) was injected directly into the left coronary artery over 30 s. In the group 1 patients, coronary sinus venous oxygen saturation was increased from 39 +/- 2% (mean +/- SEM) to 54 +/- 3% at 30 s, continuously climbed to 70 +/- 3% at 60 s and then gradually decreased to 53 +/- 5% at 120 s after the initiation of intracoronary injection of acetylcholine. In contrast, in the group 2 patients, coronary sinus venous oxygen saturation was transiently increased from 39 +/- 2% to 56 +/- 4% at 30 s, reversed, decreased to 52 +/- 4% at 60 s and then rapidly decreased to 36 +/- 3% at 120 s with the onset of chest pain associated with electrocardiographic ischemic changes. Coronary arteriography during attacks demonstrated a total or subtotal occlusion of the left anterior descending coronary artery due to severe spasm in all of the 10 patients. The extent of increases in coronary sinus venous oxygen saturation at 30 s after acetylcholine injection was not significantly different between the two groups (group 1: 15 +/- 4%, group 2: 17 +/- 3%). Heart rate, blood pressure and rate-pressure product were essentially unchanged at 30 s after intracoronary injection of acetylcholine in both groups. These data suggest that in control adult humans, coronary blood flow was increased through dilatation of resistance vessels by acetylcholine, while in patients with variant angina, coronary blood flow was transiently increased by dilatation of resistance vessels, after which it was suddenly decreased by spasm of an epicardial artery induced by this agent. Relaxant responses to acetylcholine of coronary resistance vessels appear to be preserved well in patients with variant angina.     

Myocardial ischemia due to vasospasm of small coronary arteries detected by methylergometrine maleate stress myocardial scintigraphy

BACKGROUND: Recently, several case reports have implicated vasospasm of small coronary arteries in vasospastic angina pectoris. Vasospasm of small coronary arteries was also considered from angiographic findings in patients with atypical chest pain. In Syrian hamster, vasospasm in small coronary arteries was considered to be the cause of dilated cardiomyopathy. HYPOTHESIS: This study was undertaken to determine whether vasospasm in small coronary arteries can be induced by methylergometrine maleate stress thallium-201 (201Tl) myocardial scintigraphy. METHODS: Twenty-five patients with chest pain, all of whom had intact coronary arteries, were studied. After intracoronary methylergometrine maleate injection, coronary arteriograms also looked normal in all cases. Thallium-201 myocardial scintigraphy was carried out immediately after intracoronary methylergometrine maleate injection in four patients with chest pain. In the remaining 21 patients with chest pain, methylergometrine maleate was given intravenously within up to 2 weeks before 201Tl myocardial scintigraphy. RESULTS: In the intracoronary injection study, one patient had chest discomfort after methylergometrine maleate injection, and ST-segment elevation was observed on electrocardiogram (ECG). Of the 21 patients with chest pain, 11 patients felt angina-like chest pain after intravenous injection of methylergometrine maleate, but their ECGs showed no ischemic changes. Stress 201Tl myocardial scintigrams showed methylergometrine maleate-induced perfusion defects with complete redistribution in 3 of 4 patients in the intracoronary injection study and in 12 of 21 patients in the intravenous injection study. These findings suggest that vasospasm in small coronary arteries caused myocardial ischemia in 15 of 25 patients (60%) with chest pain. CONCLUSION: Vasospasm in small coronary arteries may be involved in the myocardial ischemia of some patients with chest pain who do not show any large coronary artery vasospasm.     

Congenital anomalies of the coronary arteries with associated ischemic ST depression on exercise: a report of three cases

This report presented evidence of myocardial ischemia as the etiology of angina pectoris in three patients with congenital anomalies of the coronary arteries but without arteriosclerotic disease. All of three cases showed angina pectoris and ST depressions on their exercise electrocardiogram. Case 1: This 58-year-old man developed angina pectoris at the age of 50 years. His treadmill exercise test precipitated chest pain and ST depression. His coronary arteriograms disclosed an ectopic origin of the right coronary artery just anterior to the origin of the left coronary artery in the left coronary sinus. No significant atherosclerotic stenosis was present. An apparent ischemic manifestation appeared to be caused by compression of an aberrant right coronary artery between the aorta and the right ventricular infundibulum. Case 2: A 49-year-old woman had a history of angina. Her treadmill exercise test induced chest pain and an abnormal exercise electrocardiographic finding. Her coronary arteriograms revealed a single left coronary artery. Insufficient perfusion was postulated as a cause of apparent myocardial ischemia in this case though angiographically, there was adequate perfusion. Case 3: This 31-year-old man had a six-year history of angina. His treadmill exercise electrocardiograms revealed ischemic changes accompanied by chest pain. Coronary arteriograms disclosed a coronary artery fistula. The ischemic manifestation was apparently caused by inadequate perfusion due to coronary steal. With the increasing use of coronary arteriography, unusual origins and courses of coronary arteries will be more frequently encountered. Precise knowledge of anomalies is prerequisite for evaluating variations in the location of the coronary artery ostia and their statistical probabilities.     

Exercise Testing in the Detection of Severe Coronary Artery Disease

Summary: The clinical value of exercise testing in the detection of severe coronary artery disease remains undefined. This question was examined in 289 men and 45 women. The diagnosis of coronary artery disease could be reliably made without exercise testing in patients with angina pectoris which markedly restricted walking or which was accompanied by pathological Q waves on the ECG. Such patients usually had coronary artery disease involving two or three major vessels.
Exercise testing was an aid to diagnosis in patients with a normal standard ECG and chest pain suspicious of myocardial ischaemia, either mild angina or atypical. When exercise testing resulted in both angina and ST segment depression in men, coronary artery disease was present in 38 of 41 (93%) of cases. On the other hand, three vessel disease was found in only six of 100 (6%) of men whose exercise test did not evoke angina and ST segment change. A normal exercise test in a woman with suspicious chest pain and a normal ECG was associated with normal coronary arteries in 14 of 15 (93%) of cases. It may be concluded that exercise testing is of most diagnostic value in the assessment of patients with a normal standard ECG and a differential diagnosis of mild angina pectoris and atypical chest pain.     

A change in the pattern of vasospasm after stenting in a patient with vasospastic angina

We report an unusual case of a male patient with vasospastic angina in whom the pattern of coronary artery spasm changed after coronary stenting. The patient was admitted to our hospital with an acute coronary syndrome. Coronary angiography revealed an intermediate grade stenosis in the right coronary artery, and focal coronary spasm was provoked by intracoronary acetylcholine. A diagnosis of vasospastic angina was made, and the patient was followed medically. He subsequently was readmitted with refractory vasospastic angina and underwent coronary stenting. He was pain-free after stent implantation. Repeat angiography 6 months later showed no restenosis in the stented segment; however, coronary spasm was provoked in all areas except the stented segment by intracoronary acetylcholine injection.     

Comparative sensitivity of intracoronary injection of acetylcholine for the induction of coronary spasm in patients with various types of angina pectoris

To elucidate the possible contribution of coronary artery spasm to the pathogenesis of angina pectoris, coronary arterial responses to intracoronary injection of acetylcholine were examined in patients with various types of angina pectoris. Coronary artery spasm with chest pain and/or electrocardiographic ischemic changes was angiographically demonstrated in 50 (85%) of 59 patients with angina pectoris. The sensitivity for coronary spasm was 92% (24 of 26) in patients with rest angina, 100% (16 of 16) in patients with both rest and effort angina, and 59% (10 of 17) in patients with effort angina, while it was only 6% (1 of 16) in patients without coronary artery disease. When patients with effort angina were subdivided according to the variability of anginal threshold for exertional angina, the sensitivity for coronary spasm was as high as 90% (9 out of 10) in patients with variable-threshold angina. In contrast, coronary spasm was less frequently (p less than 0.05) induced in patients with fixed-threshold angina (1 of 7, 14%). These results suggest that coronary arteries in patients with angina pectoris are quite susceptible to acetylcholine except in those patients with stable exercise tolerance or anginal threshold. Thus coronary artery spasm appears to play a significant role for the pathogenesis of angina pectoris in a large proportion of patients with effort angina as well as in patients with rest angina.     

Anomalous course of the left anterior descending coronary artery between the aorta and pulmonary trunk: a rare cause of myocardial ischaemia at rest.

When the left anterior descending coronary artery follows an anomalous course between the aorta and pulmonary artery it can cause myocardial ischaemia or sudden death during exercise in young people. Coronary arteriography in a 27 year old man with angina pectoris at rest showed a left anterior descending coronary artery arising from a common right trunk and running from the aorta to the pulmonary artery. Follow up after revascularisation was uneventful.     

Vasospastic angina induced by nonsteroidal anti-inflammatory drugs

We report two cases of vasospastic angina associated with anaphylactic reaction caused by nonsteroidal antiinflammatory drugs (NSAIDs). Both patients exhibited anaphylactic manifestations, such as general rash and urticaria, along with angina pectoris with electrocardiographic ST-segment elevations after suppository administration of diclofenac sodium or indomethacin, the most commonly used NSAIDs. Although these patients had normal coronary arteriograms, intracoronary administration of ergonovine or acetylcholine provoked diffuse coronary artery spasms accompanied by chest pain and ischemic ST-segment changes. It is therefore suggested that an allergic mechanism may be involved as a causative factor of the coronary artery spasm induced by NSAIDs.     

Inappropriate microvascular constriction produced transient ST-segment elevation in patients with syndrome X

Objectives. The aim of this project was to study the responsible site(s) and underlying cardiac disease(s) of patients with transient ST-segment elevation and normal coronary angiograms.Background. Transient ST-segment elevation has been demonstrated in patients with variant angina or unstable angina. In those patients, epicardial coronary arteries, not microvessels, are always the responsible site for the transient ST-segment elevation.Methods. This study consisted of three cases with a transient ST-segment elevation and normal coronary angiograms. Treadmill testings were performed before coronary angiography in all cases. Coronary angiography was undertaken during the control state and during ST-segment elevation and, when possible, a Doppler guide wire was positioned in the left anterior descending artery (LAD). Coronary responses to vasodilators were observed. Finally, cardiac biopsy was performed and pathologic observation was conducted.Results. All three cases had significant ST-segment depression during treadmill testing in II, III, aVF and V_4–6leads; however, no angiographic coronary stenosis was demonstrated and vasospasm was not provoked. A transient ST-segment elevation associated with chest pain was observed in V_1–5leads, but normal coronary angiograms during ST-segment elevation were observed in every case. Coronary blood flow (CBF) velocity profile remained normal during ST-segment elevation. In one case, vasodilator responses to the LAD during ST-segment elevation were also measured. A 0.5 mg intracoronary injection of nitroglycerin increased CBF velocity (220%), but ST-segment elevation was not normalized and chest pain persisted. A 10 mg intracoronary injection of papaverine (PVN) further increased CBF velocity up to 340%, and this normalized ST-segment elevation and relieved chest pain quickly. Either endothelium-dependent coronary flow reserve (CFR) measured with a 100 μg intracoronary infusion of acetylcholine, or flow-dependent CFR by a 10 mg intracoronary injection of PVN was reduced in one of two cases measured. Pathologic findings supported syndrome X as the underlying cardiac disease in all cases.Conclusions. These findings suggested a new clinical implication involving transient ST-segment elevation mimicking variant angina and normal coronary angiograms in patients with syndrome X. The major responsible site for this phenomenon was suggested to be coronary arterioles of less than 200 μm in diameter.     

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.     

Exercise Testing in the Detection of Severe Coronary Artery Disease

Summary: The clinical value of exercise testing in the detection of severe coronary artery disease remains undefined. This question was examined in 289 men and 45 women. The diagnosis of coronary artery disease could be reliably made without exercise testing in patients with angina pectoris which markedly restricted walking or which was accompanied by pathological Q waves on the ECG. Such patients usually had coronary artery disease involving two or three major vessels. Exercise testing was an aid to diagnosis in patients with a normal standard ECG and chest pain suspicious of myocardial ischaemia, either mild angina or atypical. When exercise testing resulted in both angina and ST segment depression in men, coronary artery disease was present in 38 of 41 (93%) of cases. On the other hand, three vessel disease was found in only six of 100 (6%) of men whose exercise test did not evoke angina and ST segment change. A normal exercise test in a woman with suspicious chest pain and a normal ECG was associated with normal coronary arteries in 14 of 15 (93%) of cases. It may be concluded that exercise testing is of most diagnostic value in the assessment of patients with a normal standard ECG and a differential diagnosis of mild angina pectoris and atypical chest pain.     

Short-term effects of atrial versus atrio-ventricular pacing on myocardial ischaemia in coronary artery disease patients

This investigation was undertaken to evaluate the effects ofshort-term atrial vs atrio-ventricular pacing on myocardialischaemia. The study was in two parts. In part one, 12 coronary arterydisease patients were studied to investigate the effects ofthe two pacing modes on angina pectoris, coronary sinus O₂ saturationand lactate. The two pacing modes were each applied for 5 minat 25 beats. min^–1 more than the maximum heart rate ofthe exercise test. Coronary sinus O₂ saturation and lactatewere estimated before and after pacing. In part two, 13 patientswith left anterior descending coronary artery disease were studiedto investigate the effects of the two pacing modes on coronaryflow reserve, using a Doppler catheter in the above mentionedbranch after the administration of 10 mg intracoronary papaverine.The pacing rate was 15 beats . min^–1 greater than theresting heart rate. Coronary sinus lactate and O₂ saturation changes were the sameand angina pectoris developed at about the same time from thebeginning of pacing under both modes. Coronary flow reservewas 2.1±0.7 during atrial pacing and 2.1±1.1 duringatrio-ventricular pacing (ns). It is concluded that short-term atrial and atrio-ventricularpacing have the same effects on myocardial ischaemia in coronaryartery disease patients.     

Coexistence of familial hypertrophic cardiomyopathy and vasospastic angina pectoris in two brothers

Two brothers had familial hypertrophic cardiomyopathy and vasospastic angina pectoris concurrently. Their family history showed that one of their sisters had hypertrophic cardiomyopathy and another brother died suddenly at age 52. The clinical diagnosis of hypertrophic cardiomyopathy was confirmed by an echocardiogram and left ventriculography. They had typical chest pain at rest, and a significant vasospasm of coronary arteries with chest pain and obvious ST-T changes in the electrocardiograms was provoked by intracoronary injection of acetylcholine in both patients. The administration of a calcium antagonist and nitrate was effective for ameliorating chest pain with no cardiovascular events during the follow up period of more than 3 years. Although underlying pathophysiologic abnormalities of familial hypertrophic cardiomyopathy and vasospastic angina pectoris are considered to be transmitted genetically, the genetic backgrounds of these cases remain to be clarified.     

Decreased coronary flow reserve after transient myocardial ischemia in dogs

The effect of a transient (15 min) period of regional ischemia on coronary flow reserve in the postischemic myocardium was studied in 24 open chest dogs. Coronary flow was measured with electromagnetic flow probes, and flow reserve was determined during reactive hyperemia after 30 s coronary occlusions and during intracoronary infusions of adenosine. Measures of flow reserve after 15 min of ischemia were made after coronary flow returned to basal levels and flow reserve was then monitored for 1 h. All measures of coronary flow reserve were significantly reduced after transient ischemia: peak flows during reactive hyperemia and intracoronary adenosine infusions decreased by 20 and 24%, respectively, the peak/basal flow ratio by 16% and the repayment/debt ratio by 54%; minimal coronary vascular resistance during reactive hyperemia and intracoronary adenosine increased by 29 and 33%, respectively. Abnormal flow reserve was present for at least 1 h. No changes in flow reserve were detected in control animals over the same time period. Thus, a transient period of myocardial ischemia significantly decreases coronary flow reserve for a prolonged period of time. This "vascular stunning" must be considered when flow reserve is used to assess the functional significance of a coronary stenosis and could be the cause of variable exercise tolerance in patients with angina pectoris.     

Anomalous origin of the right coronary artery from the left sinus of valsalva with associated chest pain: Report of two cases

Ectopic origin of the right coronary artery from the left sinus of Valsalva is an infrequent coronary anomaly. The right coronary artery then passes between the aorta and pulmonary artery. We report two such cases with chest pain suggestive of angina pectoris in the absence of atherosclerosis, as demonstrated by selective coronary arteriography. A technique for selectively catheterizing the ectopic right coronary artery is described.