Original Article
Myocardial Ischemia Caused by Distal Coronary-Artery Constriction in Stable Angina Pectoris
N Engl J Med 1990; 323:514-520August 23, 1990
- Abstract
- Abstract
Background.
In patients with stable coronary artery disease, the ischemic threshold for the production of effort-related angina is often quite variable. Although this feature is commonly attributed to changes in the caliber of coronary arteries at the site of stenosis, it could also be caused by the constriction of distal vessels, collateral vessels, or both.
Methods.
In order to test this hypothesis, we studied 11 patients with stable angina, total occlusion of a single coronary artery that was supplied by collateral vessels, normal ventricular function, no evidence of coronary-artery spasm, and no other coronary stenoses. These conditions precluded the modulation of coronary flow by vasomotion at the site of the coronary stenosis.
Results.
The ischemic threshold — assessed by multiplying the heart rate by the systolic blood pressure at a 1-mm depression of the ST segment during exercise testing — increased by 19 percent after the administration of nitroglycerin (P<0.05) and decreased by 18 percent after the administration of ergonovine (P<0.01 ). Ambulatory electrocardiographic monitoring of the patients when not receiving treatment detected 73 ischemic episodes that, in keeping with the history, showed variations of 25 to 52 beats per minute in the heart rate at a 1-mm depression of the ST segment; 12 episodes of sinus tachycardia exceeded the lowest ischemic heart rate by a mean (±SD) of 22±13 beats per minute without ST-segment depression. Furthermore, 21 ischemic episodes occurred at a heart rate more than 25 beats per minute below that at a 1 -mm depression of the ST segment during exercise testing. Delayed and reduced filling of collateral and collateralized vessels associated with depression of the ST segment similar to that observed during ambulatory monitoring was detected on angiographic evaluation after the intracoronary administration of ergonovine in three patients.
Conclusions.
We propose that the constriction of distal coronary arteries, collateral vessels, or both may cause myocardial ischemia in patients with chronic stable angina. (N Engl J Med 1990; 323:514–20.)
Article Activity
- Article
IN patients with chronic stable angina, several studies1 2 3 4 have shown that many episodes of ST-segment depression during daily life are not preceded by an increase in heart rate, or occur at a heart rate much lower than that required to trigger myocardial ischemia during exercise (or both). Because changes in caliber at the site of critical or subcritical coronary stenoses have been documented angiographically in response to exercise,5 , 6 vasodilators,7 , 8 and vasoconstrictors,9 the variability of the ischemic threshold that is frequently observed in patients with stable angina is often attributed to such changes. However, a recent detailed postmortem study10 suggested that as many as 44 percent of the patients with chronic stable angina have important coronary stenoses with morphologic features that exclude the possibility of dynamic changes in residual vessel diameter.
Some patients with total occlusion of a single coronary artery but no stenosis in the other coronary branches have an unpredictable onset of angina at very variable levels of effort and occasionally have angina at rest. This clinical observation prompted us to carry out a systematic study to determine whether variations in the ischemic threshold could be caused by changes in coronary vasomotor tone not occurring at the site of epicardial coronary-artery stenosis. To this end, we studied 11 patients with chronic stable angina, normal left ventricular function, and no evidence of epicardial coronary-artery spasm who had total occlusion of a single coronary-artery branch, with collateral circulation and no other coronary stenosis. In such patients, the coronary anatomy would preclude the modulation of coronary blood flow by means of changes in vasomotor tone at the site of the stenosis.
Methods
Patients
Among the 911 patients with angina undergoing cardiac catheterization at our institution between January 1987 and December 1988, those fulfilling the following criteria were selected for study: the presence of one completely blocked coronary-artery branch filled by collateral circulation arising from angiographically normal coronary arteries; no stenosis in the remaining coronary branches; normal global and segmental left ventricular wall motion; and no evidence of epicardial coronary-artery spasm.
We retrospectively identified 11 patients — 8 men and 3 women — with a mean (±SD) age of 57±9 years (range, 40 to 69). Their clinical and angiographic characteristics are summarized in Table 1Table 1
Clinical and Angiographic Characteristics of the Study Patients.. All the patients had chronic, stable, predominantly effortrelated angina with no change in their clinical status in the six months preceding the study and a normal resting electrocardiogram, with the exception of Patient 5, who had flat T waves in leads V4 through V6. Six patients described the amount of exercise needed to trigger angina as being very variable, and four patients also reported a history of angina at rest. No patient had a history suggestive of "variant angina" or had cardiac failure, cardiomyopathy, valvular heart disease, or electrocardiographic alterations at rest that might interfere with the interpretation of ST-segment changes.Provocative Tests
All patients underwent exercise testing under standardized conditions on at least two occasions when receiving no therapy. In the seven patients (No. 2 through 6, 9, and 11) who had positive test results, the tests were repeated in random sequence on consecutive days, after the patients had received placebo and after the sublingual administration of 0.5 mg of nitroglycerin. The test was not repeated after the administration of nitroglycerin in the remaining four patients, who had negative test results. The modified Bruce protocol13 was used in all tests; the end points were a 2-mm depression of the ST segment, progressive angina, or fatigue. Twelve-lead electrocardiograms and blood-pressure measurements were obtained during the control period, at one-minute intervals during exercise, and for six minutes during recovery. After signal averaging, the level of the ST segment 80 msec after the J point was measured in all 12 leads with use of a computer-assisted system (CASE Marquette 12). The lead showing the most ST-segment depression was selected for analysis. In patients with positive test results, the duration of exercise, the heart rate, and the rate—pressure product (the product of the heart rate and systolic blood pressure, expressed in beats per minute times millimeters of mercury) were measured at a 1-mm depression of the ST segment; in those with negative test results, the duration of exercise, the heart rate, and the rate—pressure product were measured at peak exercise.
Ergonovine tests were performed in the noninvasive diagnostic laboratory in seven patients — three who had negative results on exercise testing (No. 1, 7, and 8) and four with positive results at an intermediate or high ischemic threshold (No. 2 through 5). The test was not performed in two patients (No. 6 and 9) because their exercise-test results were positive at a low workload; in another (No. 10) because of renal failure; and in the fourth (No. 11) because he did not consent. Ergonovine maleate was administered intravenously in incremental doses of 25, 50, 100, 200, and 300 μg at intervals of five minutes, with blood-pressure and 12-lead electrocardiographic monitoring. When present, myocardial ischemia was promptly relieved by the intravenous injection of isosorbide dinitrate. Results were considered positive if 1 mm of ST-segment elevation or depression developed. In five patients (No. 1 through 5) in whom the results of the ergonovine test were negative, an exercise test was performed five minutes after the last dose of ergonovine.
Ambulatory Electrocardiographic Monitoring
Ambulatory electrocardiographic monitoring was performed when the patients were receiving no antianginal medications: nitrate preparations and calcium-channel blocking agents were withdrawn at least two days before the study, and β-blocking agents at least four days before. Two-channel amplitude-modulated recorders (Marquette 8500) were used; in each patient the two leads showing the most obvious ischemic changes during exercise testing were selected. The effect on the ST segment of changes in posture was carefully assessed. Patients were provided with diaries to note the time at which episodes of angina occurred and the circumstances surrounding them. Analysis was performed with a laser Hoher system (Marquette 8000). An episode of transient ischemia was defined as a horizontal or down-sloping depression of the ST segment of more than 1 mm (0.1 mV) occurring 80 msec after the J point and lasting longer than one minute. The duration of each ischemic episode and the heart rate at the onset of the ST-segment shift, in each of the preceding 10 minutes, and at a 1-mm depression of the ST segment were measured.
angiographic Studies
In three patients (No. 2, 7, and 8), in whom coronary angiography had been performed 18 to 24 months before the studies, cardiac catheterization was repeated to ascertain the possible progression of the disease. After the diagnostic procedure, the most appropriate view for visualizing collateral vessels was selected and maintained during subsequent arteriograms. After a control arteriogram had been obtained, ergonovine was administered into the coronary artery supplying the collateral vessels to the blocked artery in graded doses of 1, 5, 10, and 30 μg at five-minute intervals, as previously described.14 Coronary arteriography was repeated if angina or ST-segment changes developed or after the injection of the maximal tolerated dose. Subsequently, intracoronary isosorbide dinitrate (2 mg) was administered, and coronary arteriography repeated. In the other patients, angiography was not repeated because of the absence of a clinical indication, and therefore the effect of intracoronary ergonovine on collateral filling could not be assessed visually.
Statistical Analysis
Continuous data are presented as means ±SD. Statistical analysis was performed with Student's t-tests for paired and unpaired data, as appropriate. A value of P<0.05 was considered to indicate statistical significance.
Informed Consent
Informed consent for the discontinuation of therapy and the ergonovine testing was obtained from all patients. Angiography was repeated in three patients for clinical reasons, and informed consent for the intracoronary injection of ergonovine during the procedure was obtained from them all. The protocols for the administration of ergonovine in the noninvasive diagnostic and catheterization laboratories were approved by the ethics committee of Hammersmith Hospital.
Results
Provocative Tests
Exercise Test
Graded exercise testing produced ST-segment depression of more than 1 mm in seven patients (No. 2 through 6, 9, and 11) (with angina in four); in these seven patients the mean duration, heart rate, and rate—pressure product at a 1-mm depression were 398±217 seconds, 113±18 beats per minute, and 19,900±4500, respectively. In four patients (No. 1, 7, 8, and 10) the exercise test was negative for ischemic electrocardiographic changes, although it provoked typical angina in two. In these four patients, the duration of exercise, the heart rate, and the rate—pressure product at peak exercise were 940±126 seconds, 144±23 beats per minute, and 23,100±5800, respectively. The reproducibility of the ischemic threshold during repeat exercise testing performed under standardized conditions was high: in the seven patients with positive test results, the mean differences in the heart rate and rate—pressure product at a 1-mm depression were 6.6±2.3 beats per minute (5 percent) and 1400±600 (7 percent), respectively.
Exercise Testing after the Administration of Nitroglycerin
In the seven patients with positive exercise-test results, the sublingual administration of 0.5 mg of nitroglycerin significantly decreased resting systolic blood pressure from 144± 11 to 126±9 mm Hg (P<0.05) and increased the resting heart rate from 77±18 to 92±13 beats per minute (P<0.05). Exercise capacity improved after the administration of nitroglycerin in all patients (Fig. 1Figure 1
Heart Rate and Rate—Pressure Product at a 1-mm Depression of the ST Segment during Exercise Testing When Patients Were Receiving No Therapy (Off), after Sublingual Administration of 0.5 mg of Nitroglycerin (NTG), and after the Intravenous Administration of Ergonovine (Ergo).). In one patient (No. 11) the exercise test performed after the administration of nitroglycerin was negative at a peak workload higher than that achieved at a 1-mm depression of the ST segment when the patient was receiving no treatment. In the remaining six patients, the duration, heart rate, and rate—pressure product at a 1-mm depression increased from 503±148 to 588±106 seconds (17 percent; P<0.01), from 117±16 to 133±20 beats per minute (14 percent; P<0.05), and from 21,500±3400 to 25,400±5400 (18 percent; P<0.05), respectively.Effects of Intravenous Ergonovine
Among the three patients with negative test results and the four patients with positive results at a high or intermediate workload, the administration of ergonovine before exercise testing failed to cause ST-segment depression or angina in four patients (No. 2 through 5). It caused chest pain with no detectable ST change in two patients (No. 1 and 8), and angina and ST-segment depression in the remaining patient (No. 7), who had the highest exercise tolerance (Fig. 2Figure 2
Electrocardiograms from Patient 7 during Exercise Testing When Receiving No Therapy, during the Intravenous Administration of Ergonovine at Rest, and Twice during Ambulatory Electrocardiographic Monitoring When Receiving No Therapy.).In five patients (No. 1 through 5) in whom the ergonovine test failed to produce diagnostic changes in the ST segment, exercise tolerance decreased significantly after the administration of ergonovine, and exercise-test results became positive in one patient (No. 1 ) in whom they had been negative when no treatment was given. Duration, heart rate, and rate—pressure product at a 1-mm depression decreased from 694±114 to 524 ±268 seconds (−24 percent; P<0.05), from 129±23 to 114±24 beats per minute (−12 percent; P<0.01), and from 23,500±3600 to 19,300±3500 (−18 percent; P<0.01), respectively.
In four patients (No. 2 through 5) who underwent exercise testing after receiving ergonovine and after receiving nitroglycerin, the heart rate and rate—pressure product at a 1-mm depression varied from 105±12 to 138±20 beats per minute (31 percent) and from 18,400±3300 to 27,100±4400 (47 percent), respectively. It is worth noting that the changes in heart rate and rate—pressure product after the administration of ergonovine and nitroglycerin were of similar magnitude in all four patients (Fig. 1).
Ambulatory Electrocardiographic Monitoring
A total of 795 hours of recording (range, 23 to 145 per patient) were available for analysis. A total of 73 ischemic episodes were observed in eight patients (No. 2 through 7, 9, and 11); three patients (No. 1, 8, and 10) had negative recordings. Ambulatory electrocardiographic monitoring showed episodes of ST-segment depression in all seven patients with positive results on exercise testing and in one (No. 7) of the four patients with negative exercise-test results. The duration of the episodes ranged from 5 to 180 minutes (mean, 32±33). Forty-five episodes (62 percent) were not associated with angina, and the mean duration of painful and painless episodes was similar (28±27 vs. 34±36 minutes; P not significant). Seven (25 percent) of the 28 episodes of ST-segment depression associated with angina occurred at rest or during activities usually well tolerated by the patients.
Evidence of a variable ischemic threshold was found in seven of the eight patients with documented ischemic episodes, since they had at least two of the following features: in five patients, 29 episodes of ST-segment depression were preceded by only a negligible increase in the heart rate (less than 10 beats per minute) in the 10 minutes immediately preceding each episode (Fig. 3Figure 3
Ischemic Episode Detected on Ambulatory Electrocardiographic Monitoring in Patient 5.); in four patients, 12 episodes of prolonged sinus tachycardia (exceeding the lowest ische- mic heart rate by 22±13 beats per minute [range, 8 to 45]) occurred without ST-segment depression or angina; in four patients, during 11 ischemic episodes the heart rate at a 1-mm depression of the ST segment varied between 25 and 52 beats per minute; and in four patients, 21 episodes occurred at a heart rate at least 25 beats per minute below that at a 1-mm depression during exercise testing (Fig. 4Figure 4
Heart Rate during Ambulatory Electrocardiographic Monitoring and Exercise Testing.). The remaining patient (No. 6) had only one episode of ST-segment depression at a heart rate similar to that during exercise testing; she also had three episodes of angina at rest, without diagnostic changes in the ST segment. It is worth noting that the lack of correlation between heart rate and myocardial ischemia — as evidenced by episodes of marked tachycardia without ischemic changes or, conversely, episodes of myocardial ischemia at a heart rate much lower than that at the onset of ischemia during exercise testing — was more apparent in the patients (No. 2, 5, and 7) who had several ischemic episodes.angiographic Findings
In Patient 7, who had angina and ST-segment depression after the intravenous administration of ergonovine in the noninvasive diagnostic laboratory, intracoronary ergonovine was administered during angiography. It reproduced angina and ST-segment changes and resulted in delayed and reduced filling of the collateral and collateralized vessels, without epicardial coronary-artery spasm (Fig. 5Figure 5
Angiograms from Patient 7 under Basal Conditions (Panel A), during an Episode of Angina and ST-Segment Depression after the Intracoronary Administration of Ergonovine (Panel B), and after the Intracoronary Administration of Isosorbide Dinitrate (Panel C).). Similar findings were obtained in the other two patients (No. 2 and 8) who received intracoronary ergonovine during repeat angiography. Neither of them had ischemic changes in the ST segment, but Patient 8 had angina. The intracoronary administration of isosorbide dinitrate reversed the ergonovine-induced constriction in all three patients and dilated the collateral and collateralized vessels. None of the three patients had progression of coronary atherosclerosis relative to the previous angiogram. The other patients in whom there was no clinical indication for coronary angiography were not restudied, and hence the effects of ergonovine on collateral filling could not be assessed visually.Discussion
In the presence of epicardial coronary stenoses, it would be difficult to prove that residual coronary blood flow can be modulated by changes of vasomotor tone in distal coronary vessels. In order to avoid the confounding effects of dynamic coronary stenoses, we selected patients with stable angina with the following features: one totally occluded coronary-artery branch filled by collateral vessels; normal ventricular function; no evidence of coronary spasm; and no stenosis in the remaining coronary branches. Therefore, the anatomical conditions precluded the dynamic modulation of coronary blood flow by changes of vasomotor tone at the site of the stenosis. The results of our study show that, in this highly selected group of patients, pharmacologic vasoactive stimuli can cause marked variations in the rate—pressure product at the onset of ischemia during exercise testing, thus unmasking the potential for large variations in residual coronary blood flow.
The occurrence of these wide variations in the ischemic threshold (assessed by measuring the heart rate at the onset of ischemia) during unrestricted daily life could be demonstrated by ambulatory electrocardiographic monitoring. This variability was consistent with the patients' reports of the unpredictable onset of angina and of angina at rest. Although blood-pressure recordings were not obtained during electrocardiographic monitoring, no striking dissociation in the behavior of the heart rate and systemic arterial pressure is usually noted during ambulatory monitoring studies,15 and changes in stroke volume or the catecholamine oxygen-wasting effect have a relatively minor influence on myocardial oxygen consumption as compared with the effect of the heart rate.16 Furthermore, the sheer magnitude of the differences in heart rate at the onset of ischemia during ambulatory monitoring and exercise testing in some patients makes it unlikely that the differences in ischemic threshold were due merely to different levels of myocardial oxygen consumption. In fact, about 30 percent of the spontaneous episodes of transient myocardial ischemia occurred at heart rates at least 25 beats per minute below those observed at the onset of ischemia during exercise testing. Conversely, episodes of sinus tachycardia exceeding the lowest heart rate at the onset of ischemia by up to 45 beats per minute occurred without ST-segment depression or angina. Therefore, as previously observed in unselected patients with chronic stable angina,2 , 4 in the patients in this study the ischemic episodes may have been caused by an excessive increase in myocardial oxygen consumption, by a transient impairment of myocardial blood flow, or by a coincidental combination of a subliminal, transient reduction in coronary blood flow and a transient, subliminal increase in myocardial oxygen consumption. On the basis of these findings it would seem reasonable to propose that the constriction of distal coronary vessels, collateral vessels, or both may represent an additional precipitating or facilitating mechanism of myocardial ischemia. This hypothesis is supported by the observation in our patients of a marked reduction in collateral filling after the intracoronary administration of ergonovine, associated with electrocardiographic changes similar to those observed during ambulatory electrocardiographic monitoring, in the absence of epicardial coronary-artery spasm, as seen in variant angina.17 We previously reported a reduction in collateral filling during a spontaneous transient ischemic episode and after the administration of ergonovine in one patient with unstable angina18; the disappearance of collateral vessels after the administration of ergonovine was also recently described in a case report.19
Our study did not establish whether the constriction occurs in distal coronary vessels before the takeoff of collateral vessels, in collateral vessels themselves, or in the distal vessels of coronary branches receiving collateral vessels. Although the walls of "mature" collateral vessels have been demonstrated to have the anatomical constituents necessary for vasomotion,20 21 22 23 24 25 26 coronary blood flow may also be modulated by changes in the diameter of distal coronary vessels. Ischemia mediated by activation of postsynaptic alpha-2 receptors was documented in anesthetized dogs during stimulation of the cervicothoracic ganglion, although in our patients the reduction in coronary blood flow was not as severe as that required to produce ischemia in this experimental model.27 The potent coronary constrictors neuropeptide Y28 and endothelin29 have been found to constrict distal vessels rather than large coronary arteries and may have a role in the transient reduction of myocardial blood flow suggested by our findings. The impairment of coronary flow after successful angioplasty has been reported in patients with unstable angina.30 The constriction of distal coronary vessels is also likely to cause angina in patients with normal coronary angiograms.31 , 32 Therefore, there is considerable scope to explore the mechanisms that control the tone of distal coronary vessels in order to develop more specific forms of anti-ischemic therapy.
Supported in part by grants from the Medical Research Council (7910332) and the British Heart Foundation.
Source Information
From the Cardiovascular Unit, Royal Postgraduate Medical School, Hammer-smith Hospital, London, United Kingdom. Address reprint requests to Dr. Maseri at the Cardiovascular Unit, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Rd., London W12 ONN, United Kingdom.
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Maseri
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Alfredo R. Galassi, Salvatore D. Tomasello, Filippo Crea, Luca Costanzo, Maria Barbara Campisano, Francesco Marzá, Corrado Tamburino. (2012) Transient Impairment of Vasomotion Function After Successful Chronic Total Occlusion Recanalization. Journal of the American College of Cardiology 59:8, 711-718
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Mario Marzilli, Alda Huqi, Doralisa Morrone. (2010) Persistent Angina. American Journal Cardiovascular Drugs 10, 27-32
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John F. Beltrame, Filippo Crea, Paolo Camici. (2009) Advances in Coronary Microvascular Dysfunction. Heart, Lung and Circulation 18:1, 19-27
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Camici, Paolo G., Crea, Filippo, . (2007) Coronary Microvascular Dysfunction. New England Journal of Medicine 356:8, 830-840
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Paolo G Camici. (2004) Coronary microvascular remodeling and ischaemia in hypertension. American Journal of Cardiovascular Drugs 4:Special Issue 1, 25-30
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Hermann W. Eichstädt, Claudia B. Abletshauser, Thomas Störk, Gottfried Weidinger. (2000) Beneficial Effects of Fluvastatin on Myocardial Blood Flow at Two Time-Points in Hypercholesterolemic Patients with Coronary Artery Disease. Journal of Cardiovascular Pharmacology 35:5, 735-740
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Mario Marzilli, Gianmario Sambuceti, Silvio Fedele, Antonio L’Abbate. (2000) Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina. Journal of the American College of Cardiology 35:2, 327-334
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H.R. Hellstrom. (1999) Occlusions of epicardial arteries might not directly induce symptoms in ischemic heart disease. Medical Hypotheses 53:6, 533-542
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Ornella Rimoldi, Paolo G. Camici. (1999) PET measurement of the coronary flow reserve and microcirculatory function. Herz 24:7, 522-530
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Dan Tzivoni, Simon Maybaum. (1997) Attenuation of Severity of Myocardial Ischemia During Repeated Daily Ischemic Episodes. Journal of the American College of Cardiology 30:1, 119-124
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Anoop Chauhan, Paul A. Mullins, Ged Taylor, Michael C. Petch, Peter M. Schofield. (1996) Cardioesophageal reflex: A mechanism for “linked angina” in patients with angiographically proven coronary artery disease. Journal of the American College of Cardiology 27:7, 1621-1628
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Gianmario Sambuceti, Oberdan Parodi, Assuero Giorgetti, Piero Salvadori, Mario Marzilli, Piero Dabizzi, Paolo Marzullo, Danilo Neglia, Antonio L'Abbate. (1995) Microvascular dysfunction in collateral-dependent myocardium. Journal of the American College of Cardiology 26:3, 615-623
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Nico H.J. Pijls, G. Jan Willem Bech, Mamdouh I.H. El Gamal, Hans J.R.M. Bonnier, Bernard De Bruyne, Berry Van Gelder, H. Rolf Michels, Jacques J. Koolen. (1995) Quantification of recruitable coronary collateral blood flow in conscious humans and its potential to predict future ischemic events. Journal of the American College of Cardiology 25:7, 1522-1528
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Masatoshi Fujita, Kazuto Yamanishi, Moriaki Inoko, Kunihisa Miwa. (1994) Preferential dilation of recipient coronary arteries of the collateral circulation by intracoronary administration of nitroglycerin. Journal of the American College of Cardiology 24:3, 631-635
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NICO H.J. PIJLS, BERNARD DE, MAMDOUH EL, HANS J.R.M. BONNIER, GUY R. HEYNDRICKX, G. JAN WILLEM BECH, JACQUES J. KOOLEN, H. ROLFMICHELS, FRANK A.L.E. BRACKE, WILLIAM WIJNS. (1993) Fractional Flow Reserve: The Ideal Parameter for Evaluation of Coronary, Myocardial, and Collateral Blood Flow by Pressure Measurements at PTCA. Journal of Interventional Cardiology 6:4, 331-344
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Hassan El-Tamimi, Graham J. Davies, Filippo Crea, Attilio Maseri. (1993) Response of human coronary arteries to acetylcholine after injury by coronary angioplasty. Journal of the American College of Cardiology 21:5, 1152-1157
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Neal G. Uren, Tom Crake, David C. Lefroy, Ranil De Silva, Graham J. Davies, Attilio Maseri. (1993) Delayed recovery of coronary resistive vessel function after coronary angioplasty. Journal of the American College of Cardiology 21:3, 612-621
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Kazuto Yamanishi, Masatoshi Fujita, Kunihisa Miwa, Akihiko Igawa. (1993) Effects of intracoronary injection of acetylcholine on coronary collateral circulation. Catheterization and Cardiovascular Diagnosis 28:2, 114-118
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Julio A. Panza, Arshed A. Quyyumi, Jean G. Diodati, Timothy S. Callahan, Robert O. Bonow, Stephen E. Epstein. (1992) Long-term variation in myocardial ischemia during daily life in patients with stable coronary artery disease: Its relation to changes in the ischemic threshold. Journal of the American College of Cardiology 19:3, 500-506
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Christiaan J.M. Vrints, Hidde Bult, Erwin Hitter, Arnold G. Herman, Joseph P. Snoeck. (1992) Impaired endothelium-dependent cholinergic coronary vasodilation in patients with angina and normal coronary arteriograms. Journal of the American College of Cardiology 19:1, 21-31
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Maseri, Attilio, . (1991) Coronary Vasoconstriction: Visible and Invisible. New England Journal of Medicine 325:22, 1579-1580
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Juan Carlos Kaski, Dimitris Tousoulis, Agha W. Haider, Stavros Gavrielides, Filippo Crea, Attilio Maseri. (1991) Reactivity of eccentric and concentric coronary stenoses in patients with chronic stable angina. Journal of the American College of Cardiology 17:3, 627-633
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Attilio Maseri, Filippo Crea, Juan Carlos Kaski, Tom Crake. (1991) Mechanisms of angina pectoris in syndrome X. Journal of the American College of Cardiology 17:2, 499-506
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(1991) Distal Coronary-Artery Constriction in Angina Pectoris. New England Journal of Medicine 324:5, 340-341
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