Author + information
- Received March 31, 1998
- Revision received July 16, 1998
- Accepted August 6, 1998
- Published online December 1, 1998.
- Terumitsu Tanaka, MD∗,
- Masatoshi Fujita, MD, FACC†,* (, )
- Izuru Nakae, MD∗,
- Shun-Ichi Tamaki, MD∗,
- Koji Hasegawa, MD‡,
- Yasuki Kihara, MD‡,
- Ryuji Nohara, MD‡ and
- Shigetake Sasayama, MD, FACC‡
- ↵*Address for correspondence: Dr. Masatoshi Fujita, College of Medical Technology, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Objectives. The purpose of this study was to evaluate whether a serotonin blocker, sarpogrelate, improves exercise capacity as a result of vasodilation of coronary collateral channels in patients with effort angina.
Background. Serotonin has been reported to decrease coronary collateral blood flow by collateral vasoconstriction in a canine model, suggesting that platelet activation in feeding coronary arteries of the collateral network has the potential to cause collateral vasoconstriction.
Methods. The subjects consisted of 22 patients with effort angina and reproducible ischemic threshold (group A, 11 patients with thrombolysis in myocardial infarction (TIMI) grade 2 or 3 flow of the ischemia-related coronary artery and Rentrop’s collateral index 0 or 1; group B, 11 patients with TIMI grade 0 or 1 flow and Rentrop’s collateral index 2 or 3). We repeated the symptom-limited treadmill exercise test using the Balke–Ware protocol and exercise tetrofosmin myocardial perfusion scintigraphy with and without pretreatment with 200 mg orally administered sarpogrelate. Each exercise test was performed at 9:00 a.m. on different days. The order of tests with and without sarpogrelate was randomized.
Results. In group A, sarpogrelate increased neither exercise time at 0.1 mV ST depression nor double product at 0.1 mV ST depression. In contrast, in group B sarpogrelate increased the exercise duration at 0.1 mV ST depression from 181 ± 112 (SD) to 248 ± 131 s (p < 0.05) and also increased the double product at 0.1 mV ST depression by 21% (p < 0.01). The severity score using myocardial perfusion scintigraphy at the same workload was significantly (p < 0.01) decreased by 37% in group B, but not in group A (11%), due to the sarpogrelate treatment.
Conclusions. Sarpogrelate augments flow reserve of the collateral circulation and improves exercise capacity in anginal patients with well-developed collaterals. These findings indicate that a serotonin blocker, sarpogrelate, is useful not only as an antiplatelet drugs, but as an antianginal drug.
Although well-developed collateral vessels can provide protection against ischemia and infarction in patients with coronary artery disease, vasodilator reserve in the collateral dependent region is limited. Since fully developed collateral vessels have a well-developed muscular layer, their tone can be affected by various vasoactive substances. Indeed, we have previously demonstrated that collateral vasodilation accompanying nitrate administration greatly contributes to the improvement in exercise capacity (1).
Serotonin, as a product of aggregating platelets, is reported to reduce blood flow through well-developed collaterals in a canine model (2). It is assumed that platelet activation in the donor coronary arteries involved in collateral circulation has the potential to decrease blood flow to the collateral dependent jeopardized myocardium by causing collateral vasoconstriction. Accordingly, we hypothesized that a serotonin blocker, sarpogrelate, would improve exercise capacity as a result of vasodilation of coronary collateral vessels.
Thus, the present study was designed to evaluate whether sarpogrelate administration increases blood flow to the collateral dependent area, perfused by the totally occluded coronary artery, in patients with stable effort angina.
We studied 22 patients (17 men and 5 women) between 46 and 83 years of age (mean, 66 ± 10 years) with stable effort angina. All had angiographically proven significant coronary stenosis (≥70%) involving one or more major coronary arteries and developed ≥1 mm ST segment depression during treadmill exercise testing. None had suffered a previous myocardial infarction or acute exacerbation of symptoms in the preceding six months. A treadmill exercise and exercise myocardial scintigraphy were performed after withdrawal of all antianginal medications for at least 48 h. All subjects gave written informed consent for this study.
All patients were referred for conventional diagnostic right and left heart catheterization, together with left ventriculography and selective coronary angiography, to evaluate coronary atherosclerotic lesions and left ventricular function. All medications were withheld for ≥24 h before the procedure. Selective coronary arteriography was performed using the femoral approach. A contrast medium was injected with enough force and in sufficient quantity to provide good visualization of the coronary arteries. Multiple projections of right and left coronary arteries were routinely obtained. After left ventricular pressure had returned to baseline levels, left ventricular cineangiography was performed at a 30° right anterior oblique projection. The diameter of the coronary arteries was measured with a caliper on suitably magnified 35 mm cineframes at end-diastole. A significant coronary stenosis was defined as ≥70% narrowing of a major coronary artery branch.
Grading of coronary perfusion
The degree of perfusion of the ischemia-related coronary artery was graded on a scale of 0 to 3 as follows: 0 = there is no anterograde flow beyond the point of occlusion; 1 = the contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming sequence; 2 = the contrast material passes across the obstruction and opacifies the coronary bed distal to the obstruction. However, the rate of entry of the contrast material into the vessel distal to the obstruction, or its rate of clearance from the distal bed (or both) is perceptibly slower than its entry into or clearance from comparable areas (for example, the opposite coronary artery or the coronary bed proximal to the obstruction); 3 = anterograde flow into the bed distal to the obstruction occurs as quickly as anterograde flows into the bed proximal to the obstruction, and clearance of contrast material from the involved bed is as rapid as clearance from an uninvolved bed in the same vessel or the opposite artery (3).
Grading of coronary collateral filling
Collateral circulation was graded on a scale of 0 to 3 depending on the degree of opacification of the occluded vessel. The score (collateral index) was based on the injection that best opacified the occluded vessel: 0 = none; 1 = filling of side branches of the artery to be perfused with collateral vessels and no visualization of the epicardial segment; 2 = partial filling of the epicardial segment with collateral vessels; 3 = complete filling of the epicardial segment with collateral vessels (4). Three observers assessed the coronary cineangiograms in blinded fashion and reached a consensus regarding the Thrombolysis in Myocardial Infarction (TIMI) grade and collateral filling.
The patients were divided into two groups according to the degree of perfusion of the ischemia-related coronary artery: group A (n = 11), patients with TIMI grade 2 or 3 flow and Rentrop’s collateral index 0 or 1; and group B (n = 11), those with TIMI grade 0 or 1 flow and Rentrop’s collateral index 2 or 3.
Two treadmill tests with and without sarpogrelate pretreatment (200 mg, one hour prior to the test) were performed at 9 a.m. on different days within a week. To minimize the effects of habituation to the treadmill test, the order of tests with and without sarpogrelate was randomized. Over one week, two exercise 99mTc-tetrofosmin myocardial perfusion studies were repeated with and without sarpogrelate pretreatment, with the same workload, at 9 a.m. on different days. All patients received neither a placebo nor an active drug before each test.
Treadmill exercise testing
Symptom-limited graded treadmill exercise testing was performed using the Balke-Ware protocol (5)with all patients undergoing two exercise tests. A 12-lead ECG was recorded at rest and at 30-second intervals until the onset of limiting chest pain, leg fatigue or ≥2 mm ST segment depression. Blood pressure was measured with a sphygmomanometer at the end of each stage. In this study, the heart rate and blood pressure at the onset of 1 mm ST segment depression were measured to determine the ischemic threshold. Analysis on all tests was performed by two independent observers who were not aware of the conditions of the exercise tests.
Tetrofosmin myocardial perfusion scintigraphy
Following an overnight fast, a tetrofosmin study was performed at rest and during exercise (6). For the stress tetrofosmin study, a bicycle ergometer exercise was begun at a workload of 25 watts and increased in steps of 25 watts every 2 min. Blood pressure was measured once a minute using a sphygmomanometer. The electrocardiogram was closely monitored throughout the exercise and recovery. In the initial test, exercise was terminated when patients experienced severe chest pain or the ST segment was depressed more than 2 mm. At peak exercise, 370 to 592 MBq (10 to 16 mCi) of 99mTc-tetrofosmin was intravenously injected, and exercise was extended for an additional minute. After 10 to 15 min of recovery time, each patient was asked to have a light meal or a glass of milk to accelerate hepatobiliary clearance. Imaging was done approximately 30 to 40 min after the radiopharmaceutical administration. Tomography was obtained with a rotational gamma camera collecting 32 20 s views over 180°. The total acquisition time was approximately 12 min. The resting tetrofosmin study was performed 24 to 72 h after the stress imaging. Following administration of 370 to 592 MBq (10 to 16 mCi) of 99mTc-tetrofosmin at rest in a fasting state, a light meal or a glass of milk was given. About 40 min after the tracer administration, resting tomography was performed in a similar fashion (6).
Myocardial images were divided into 18 segments in the short axis (apical, midventricular and basal slices) plus two segments in the vertical long axis for apical perfusion. Three expert observers assessed tetrofosmin uptake by visual inspection based on a 0 to 3 score, in which 0 = normal perfusion, 1 = mild perfusion defects, 2 = moderate perfusion defects and 3 = severe perfusion defects (7). Disagreements were resolved by consensus.
Data are expressed as the mean ± SD. A two-way ANOVA using Bonferroni’s method was carried out to investigate differences in the treadmill exercise test. Student ttest was used to compare the severity score in stress myocardial perfusion scintigraphy. Significance was designated at the probability value of p < 0.05.
The clinical and angiographic characteristics of all patients are shown in Table 1. The distribution of the ischemia-related artery was quite similar in each group. The incidence of multivessel disease was also comparable in the two groups. The left ventricular ejection fraction was 60 ± 5% in group A, which was greater than the 54 ± 10% in group B.
Exercise capacity with and without sarpogrelate treatment
Exercise time and hemodynamic parameters at rest and at 0.1 mV ST depression during the treadmill exercise test, with and without sarpogrelate pretreatment, are summarized in Table 2. In group A, the exercise time remained unchanged despite sarpogrelate pretreatment (243 ± 72 s vs. 259 ± 64 s, p = NS). In contrast, in group B sarpogrelate increased the total exercise time from 181 ± 112 to 248 ± 131 s (p < 0.05) (Fig. 1). There were no significant differences in resting hemodynamic parameters between groups A and B. Sarpogrelate did not change resting hemodynamic parameters in either group. In group A, the baseline double product at 0.1 mV ST depression was 23300 ± 2800 mmHg beats/min which was significantly (p < 0.05) higher than 16800 ± 4800 mmHg beats/min in group B. Sarpogrelate did not increase the double product of ischemia in group A. However, in group B it was significantly (p < 0.01) increased to 20300 ± 4700 mmHg beats/min with sarpogrelate pretreatment (Fig. 2).
Severity score with and without sarpogrelate treatment
At the baseline, the severity score of resting tetrofosmin myocardial perfusion scintigraphy was comparable in both groups (2.8 ± 1.9 in group A vs. 4.7 ± 3.9 in group B). The severity score of the exercise scintigraphy was 5.1 ± 3.5 in group A which was smaller than 9.3 ± 4.5 in group B. After treatment with sarpogrelate, the resting severity score remained unchanged in each group (3.0 ± 2.2 in group A; 3.3 ± 2.9 in group B). Although the severity score of the exercise scintigraphy was not different from the baseline study in group A (5.1 ± 3.5 to 3.0 ± 2.2), it significantly (p < 0.01) decreased from 9.3 ± 4.5 to 5.8 ± 3.6 in group B (Fig. 3).
The present study clearly demonstrates that sarpogrelate attenuates exercise-induced myocardial ischemia as a result of enhancement of preexisting collateral circulation in patients with stable effort angina. This is the first report, to the best of our knowledge, which documents a drug in the antiplatelet drug category which is effective in alleviating exercise-induced myocardial ischemia in patients with coronary artery disease.
Collateral vascular reactivity
Well-developed collateral vessels have several layers of muscular media and are capable of vasomotion. These findings indicate that modulation of collateral vessel tone can influence blood flow to the collateral dependent myocardial area. Indeed, we have previously shown that collateral vasodilation with nitrate administration contributes greatly to the improvement in exercise capacity of patients with well-developed collaterals (1). In contrast, vasoactive drugs that cause arteriolar vasodilation can be detrimental because these agents can generate coronary steal. Adenosine is one such agent which deteriorates myocardial ischemia by reducing collateral blood flow as a result of coronary steal (8). Data reported here strongly suggest that sarpogrelate is a potent vasodilator of not only arteriolar resistance vessels but also coronary collateral vessels.
Increase in collateral blood flow by sarpogrelate
In our patients with well-developed collateral vessels, the rate-pressure product at 0.1 mV ST depression increased by 21% with sarpogrelate pretreatment. This implies an increase in blood flow supply to the potentially ischemic collateral dependent area (1,9,10). Furthermore, the augmentation of collateral flow by sarpogrelate was confirmed by the stress myocardial perfusion scintigraphy at the same workload. These findings suggest that platelet activation, and the resultant serotonin production and release in a coronary artery proximal to the origin of collateral vessels, has the potential to decrease blood flow to the dependent myocardium by causing collateral vasoconstriction (2). Furthermore, a serotonin blocker, sarpogrelate, attenuated the effects of serotonin on coronary collateral vessels.
Unchanged coronary flow through a stenosis with sarpogrelate
In patients with severe coronary stenosis, but without a significant collateral circulation, sarpogrelate did not increase the rate-pressure product at 0.1 mV ST depression, nor did it reduce the perfusion defect in the stress myocardial scintigraphy. These findings suggest that it is unlikely that platelet aggregation and serotonin production and release at the site of a coronary stenosis have the potential to produce coronary vasoconstriction, either at the site of a stenosis, or in the distal parts of the ischemia-related coronary artery. A report by Ganz and Marcus (11)supports the above mentioned speculation. In their study, intracoronary nitroglycerin had no effect in reducing pacing-induced ischemia, probably because of the absence of intact vascular smooth muscle cells responsible for dealing with nitroglycerin at the site of stenosis.
First, to minimize the effects of habituation to the treadmill exercise, it was repeated several times before the study. However, the variation in exercise tolerance may exist between the exercise tests with and without sarpogrelate pretreatment. Nevertheless, Waters et al. (12)demonstrated in patients with effort angina that the rate-pressure product at the onset of ischemia remains relatively constant at repeated treadmill exercise tests, despite considerable variations in the exercise time up to the onset of ischemia. Second, although it has previously been demonstrated that serotonin is released into the coronary circulation of selected patients with coronary artery disease (13), we did not measure aortic and coronary sinus serotonin concentration in our patients. Further studies are necessary to define the role of serotonin in patients with effort angina. Finally, it is possible that sarpogrelate has some other independent vasoactive properties which block some other potential vasoconstrictor pathways. Sarpogrelate is reported to be a specific 5HT2-receptor antagonist; a compound having weak displacement potencies for other receptors such as α1-, α2-, β-adrenoceptors, 5HT1-, or muscarinic receptors (14). Thus, the beneficial effect of sarpogrelate mainly depends on its action as a specific serotonin antagonist.
We demonstrated that sarpogrelate increases exercise capacity as a result of enhancement of collateral circulation in anginal patients with well-developed collateral channels. These findings indicate that sarpogrelate is useful not only for suppressing platelet function, but also alleviating exercise-induced myocardial ischemia in patients with effort angina and well-developed collateral circulation.
☆ This study was supported by “Research for the Future” Program (JSPS-RFTF 97 I 00201) from the Japan Society for the Promotion of Science, a Grant-in-Aid from the Uehara Memorial Foundation, and a Grant from the Japan Cardiovascular Research Foundation.
- Received March 31, 1998.
- Revision received July 16, 1998.
- Accepted August 6, 1998.
- American College of Cardiology
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