Effect of Intracoronary Serotonin on Coronary Vessels in Patients with Stable Angina and Patients with Variant Angina
List of authors.Abstract
Background.
Serotonin, a major product of platelet activation, has potent vasoactive effects in animal models, but its role in human coronary artery disease remains largely speculative.
Methods.
Using quantitative coronary angiography, we compared the effects of the intracoronary infusion of graded concentrations of serotonin (10–7 to 10–4 mol per liter) on coronary vessels in two groups of patients with different clinical presentations of coronary disease (nine with stable angina and five with variant angina), with the effects in a control group of eight subjects with normal vessels on angiography.
Results.
Normal coronary vessels had a biphasic response to intracoronary serotonin: dilation at concentrations up to 10–5 mol per liter, but constriction at 10–4 mol per liter. Vessels in patients with stable angina constricted at all concentrations, with mean (±SEM) maximal decreases in diameter of 23.9±3.6, 33.1±3.9, and 41.7±3.1 percent from base line in proximal, middle, and distal segments at a serotonin concentration of 10–4 mol per liter. Smooth segments constricted more than irregular segments (42.0±4.6 vs. 21.1±1.6 percent). Four patients with stable angina had a marked reduction in collateral filling. All the patients with stable angina had angina during the intracoronary infusion of serotonin, and electrocardiographic changes were noted in six. All the patients with variant angina had angina, electrocardiographic changes, and localized occlusive epicardial coronary-artery spasm at concentrations of 10–6 (n = 2) or 10–5 (n = 3) mol per liter.
Conclusions.
Patients with stable coronary disease do not have the normal vasodilator response to intracoronary serotonin, but rather have progressive constriction, which is particularly intense in small distal and collateral vessels. Patients with variant angina have occlusive Coronary Artery spasm at a dose that dilates normal vessels and causes only slight constriction in vessels from patients with stable angina. These findings suggest that serotonin, released after the intracoronary activation of platelets, may contribute to or cause myocardial ischemia in patients with coronary artery disease. (N Engl J Med 1991; 324:648–54.)
Methods
Patients
We studied 22 patients admitted for routine cardiac catheterization. Written informed consent for the discontinuation of therapy, the intravenous administration of ergonovine, and the intracoronary administration of serotonin was obtained from all patients. The study protocol was approved by the Research Ethics Committee of Hammersmith Hospital. All regular antianginal medication was discontinued 48 hours before catheterization. All the patients with angina and six of the control patients were taking aspirin (75 mg daily), which was continued. Patients were allowed to use sublingual nitroglycerin as needed, but no study was performed within three hours of its administration. No premedication was given. Before catheterization all the patients underwent exercise testing and noninvasive provocation testing for coronary spasm under standardized conditions while receiving no therapy. The modified Bruce protocol11 was used in all exercise tests. For ethical reasons patients with low effort tolerance (positive results on exercise testing before stage III of the modified Bruce protocol) were not asked to participate. Noninvasive provocation testing for coronary spasm was performed with intravenous boluses of ergonovine maleate in incremental doses of 25 to 300 μg at intervals of five minutes, while the electrocardiogram was monitored. Results were considered positive if 1 mm of ST-segment elevation or depression developed.
Group 1 comprised eight patients — five men and three women — with a mean (±SD) age of 47±12.9 years (range, 32 to 72). All presented with atypical chest pain, sufficiently severe to require further investigation. Exercise testing and ergonovine testing for coronary spasm produced negative results in all patients. All had normal coronary arteriograms. Serotonin was infused into the left coronary artery in all patients.
Group 2 comprised nine patients — seven men and two women — with a mean age of 49.3±9.0 years (range, 35 to 66). All presented with chronic stable effort-induced angina and positive results on exercise testing. Intravenous ergonovine testing caused chest pain in two patients but no electrocardiographic (ECG) changes. The artery studied was chosen to comply with the Research Ethics Committee's requirement that severe stenoses (>75 percent reduction in diameter) be avoided. Five left and four right coronary arteries were studied. Five patients had discrete stenoses with a mean (±SEM) reduction in the diameter of the infused vessel of 50.6±3.7 percent. In four patients the infused artery supplied collaterals to an occluded vessel.
Group 3 comprised five patients — four men and one woman —with a mean age of 46.8±5.1 years (range, 41 to 54). All had a history of spontaneous, predominantly early-morning angina. Four patients had negative results on exercise testing. One (Patient 5) had positive test results (angina associated with ST-segment depression in leads V5 and V6) at a peak heart rate of 85 percent of the maximum predicted for age. Provocation testing with ergonovine caused angina associated with a marked shift of the ST segment in all patients (elevation in leads V1 through V4 in Patients 1, 2, and 3 and depression in leads V5 and V6 in Patients 4 and 5). All five patients had isolated discrete stenoses (mean reduction in the diameter of the vessel, 55.4±6.8 percent) whose location (left anterior descending artery in Patients 1, 2, and 3 and circumflex artery in Patients 4 and 5) was compatible with the ST-segment alterations induced by ergonovine provocation. Serotonin was therefore infused into the left coronary artery in all patients.
Study Protocol
Femoral arterial pressure, heart rate, and two ECG leads were recorded continuously throughout the study. After diagnostic arteriography, an optimal view was chosen to visualize the artery under study and a single intravenous bolus of heparin (10,000 IU) was given. We have previously shown that random fluctuations or systematic changes due to repeated infusions of saline or injections of contrast medium have no significant effect on coronary diameter.12 The patients therefore received one infusion of vehicle solution (0.9 percent saline), followed by infusions of serotonin creatinine sulfate at room temperature (prepared by the Hammersmith Hospital pharmacy and diluted with saline) at a rate of 1 ml per minute with use of a syringe pump (Perfusor, Braun—Melsungen). Infused concentrations of 10–7 through 10–5 mol per liter were used in the first four patients in group 1; in all the other patients concentrations of 10–7 through 10–4 mol per liter were infused unless chest pain or ECG changes occurred. A concentration of 10–3 mol per liter in two patients from group 1 caused hypertension and tachycardia within 30 seconds of the start of the infusion and was not used again. In four patients from group 2 and three patients from group 3 the sequence of infusions was repeated 10 minutes after the angiographic appearance had returned to base line, which was always within 3 minutes of the end of the infusions. Finally, a bolus dose of isosorbide dinitrate (2 mg in 2 ml of saline) was infused into the coronary artery. Angiography was performed at base line and after each infusion, after the injection of 8 to 10 ml of nonionic contrast medium (Omnipaque 350, Nycomed). Before each angiogram, the catheter was emptied to avoid the effects of bolus administration of serotonin.
Quantitative Coronary Angiography
The coronary arteriograms were analyzed with use of a computerized automatic-analysis system (CAAS, Pie Data Medical). End-diastolic frames from each arteriogram were selected by a cardiologist and analyzed by a technician. Both were unaware of the study protocol or the sequence of infusions. Coronary arterial segments were selected between identifiable branching points. The angiographic catheter was used as a scaling device, and this, together with pincushion-distortion correction, allowed the diameters to be recorded as absolute values (expressed in millimeters). To establish the reproducibility of the method, three observers independently analyzed 24 arterial segments, 8 from the proximal segment (mean diameter, 3.0 mm; range, 2.5 to 3.8), 8 from the middle (mean, 2.1 mm; range, 1.9 to 2.3), and 8 from the distal segment (mean, 1.4 mm; range, 1.1 to 1.7) as defined according to the classification of the American Heart Association committee report.13 Analysis of variance revealed no statistically significant differences between observers (F = 0.29, df = 2.69, P = 0.75). We quantified the reproducibility of the measurement by calculating the difference between each vessel measurement and the average of the measurements of that vessel. In all but one (98.6 percent) the difference was 0.1 mm or less.
To construct segmental dose–response curves, segments 5 mm in length from the proximal, middle, and distal portions of the artery under study were analyzed at base line and after each intervention. Visual inspection of the cine films indicated that the most striking constriction at the highest dose occurred in the small branches (base-line diameter <1 mm). These could not be measured by the CAAS system because of their size and the lack of sufficient contrast between the vessels and the background. In the patients in group 2 involvement of more proximal vessels (base-line diameter >1.5 mm) was patchy, and angiographically smooth segments appeared to react more than those with luminal irregularities. We therefore took the measurements at the end of each infusion period in the segments in which the greatest change had occurred during infusion of the peak concentration. In addition, arterial segments >1.0 mm that three blinded independent observers agreed were entirely smooth or had minimal luminal irregularities on the base-line arteriogram were chosen from eight arteries in group 2 patients that had no marked (>20 percent) stenoses and were analyzed after each intervention. After each intervention the same three observers assessed the degree of collateral filling using the method described by Rentrop et al.,14 in the frames used for vessel measurements. The response of discrete stenotic segments was studied by measuring the minimal diameter in the stenotic segment and the reference diameter proximal to the stenosis at base line and after each intervention. The severity of stenosis was expressed as a percentage, according to the following formula: the severity of stenosis equals the minimal diameter of the stenosis subtracted from the reference diameter and the result divided by the reference diameter.
Statistical Analysis
All values are expressed as means (±SEM). Paired Student's t-tests were used to compare absolute luminal diameters within groups at base line with absolute luminal diameters after interventions (infusion of saline, infusion of the peak concentration of serotonin, or injection of isosorbide dinitrate), to compare hemodynamic measures (heart rate and systolic arterial pressure) during infusion of the peak concentration of serotonin with values at base line, and to compare the difference in the absolute response of regular and irregular segments at the highest concentration of serotonin. A value of P<0.05 was considered to indicate statistical significance.
Results
Hemodynamic Measurements
There was no significant change in heart rate or systolic arterial blood pressure associated with the intracoronary infusion of saline or incremental concentrations of serotonin in any group up to a concentration of 10–4 mol per liter before the onset of myocardial ischemia.
Changes in Vessel Measurements in Response to Saline, Serotonin, and Nitrate
Table 1.
Table 1. Response of Coronary Vessels to Intracoronary Infusion of Graded Concentrations of Serotonin.* Figure 1. 
Figure 1. angiographic Findings in a Patient with Stable Angina (Patient 6, Group 2) at Base Line (Panel A) and after Intracoronary Infusion of 10–4 mol of Serotonin per Liter at 1 ml per Minute for Two Minutes (Panel B). The constriction of the proximal right coronary artery is patchy (long arrow), whereas the distal segment and tertiary branches (short arrows) are intensely constricted.
Figure 2.
Figure 2. Effects of Serotonin on Vessel Segments from the Controls (Group 1) and the Patients with Stable Angina (Group 2). The mean (±SEM) change from base line in the luminal diameter of proximal (•), middle (□), and distal (■) arterial segments is shown after a two-minute infusion of saline (S), increasing concentrations of serotonin, and an intracoronary injection of isosorbide dinitrate (ISDN). The coronary segments from the controls had a small progressive dilation at lower concentrations of serotonin, but constriction (more marked in the distal segments) at the highest concentration. The segments from the patients with coronary atherosclerosis were not dilated and were much more constricted than those from group 1. The distal vessels were the most constricted.
The changes observed in the vessel segments we studied are detailed in Table 1 and Figures 1 and 2.
The intracoronary infusion of 0.9 percent saline was not associated with significant changes in epicardial luminal diameter or the severity of stenosis.
Figure 3.
Figure 3. Dose–Response Curves in Stenotic Segments from Patients with Stable Angina (Group 2) and Patients with Variant Angina (Group 3) after a Two-Minute Infusion of Saline (S), Two-Minute Infusions of Increasing Concentrations of Serotonin, and an Injection of Isosorbide Dinitrate (ISDN). The keys indicate patient numbers and (in parentheses) the percent severity of stenosis at base line. In patients with variant angina, complete occlusion occurred at a concentration of 10–6 or 10–5 mol of serotonin per liter, whereas in those with stable angina there was only a progressive reduction in diameter.
Figure 4.
Figure 4. angiographic Findings in a Patient with Stable Angina (Patient 7, Group 2) at Base Line (Panel A) and after Intracoronary Infusion of 10–4 mol of Serotonin per Liter at 1 ml per Minute for Two Minutes (Panel B). Markedly reduced collateral filling of the left anterior descending coronary artery and moderate patchy constriction of the right coronary artery are evident after the infusion of serotonin.
In the control group (group 1) the response to serotonin was biphasic at each measured site; minor dilation occurred at concentrations up to 10–5 mol per liter, but there was constriction at 10–4 mol per liter. By contrast, in vessels from patients with stable angina (group 2) only constriction occurred (Fig. 1). As compared with the constrictor response seen in normal vessels, the dose–response curve was shifted to the left by two orders of magnitude and the maximal response was increased twofold (Fig. 2). Smooth segments showed more marked constriction than irregular segments. Discrete stenotic segments showed dosedependent constriction, but the mean severity of stenosis did not increase as the adjacent reference diameter decreased. In patients with variant angina, discrete stenotic segments became occluded at doses of serotonin that caused only moderate constriction in the adjacent nonspastic artery and in arteries from patients with stable angina (Fig. 3). The constrictor response to serotonin in the two patients in group 2 who had chest pain without ECG changes in response to ergonovine was similar to that observed in the other patients in group 2. Three patients in whom the right coronary was infused with serotonin had a blocked left anterior descending coronary artery supplied by collaterals from the right coronary artery. Two had grade 3 and one grade 214 filling of the collateralized vessel on the base-line angiogram. All had a concentration-dependent reduction in collateral filling, down to grade 0 at an infused serotonin concentration of 10–4 mol per liter (Fig. 4). One patient in whom the left coronary artery was infused had an occluded left anterior descending coronary artery supplied by collateral vessels from both the circumflex and right coronary arteries, with grade 3 filling of the left anterior descending artery by collateral vessels on the base-line angiogram that dropped to grade 1 after the infusion of 10–5 mol of serotonin per liter. In the four patients in group 2 who underwent more than one infusion sequence, the degree of constriction we observed varied by less than 5 percent after repeated infusion of the same concentration (data not shown). In the three patients in group 3 who underwent more than one infusion sequence, focal occlusion of the epicardial vessel occurred at the same concentrations on repeated infusion.
Dilation was consistently observed in all groups after the injection of isosorbide dinitrate.
Symptoms and ECG Changes
No symptoms or ECG changes were seen in the patients in group 1 at serotonin concentrations up to 10–4 mol per liter or in the two patients who received a concentration of 10–3 mol per liter and had systemic effects. By contrast, all the patients in group 2 had angina at the highest infused concentration, although none had focal coronary occlusion as seen in the patients with variant angina. Six of the nine had a shift in the ST segment (elevation in three and depression in three) that was associated with predominantly distal coronary constriction and with the disappearance of collateral vessels in three. All the patients in group 3 had angina with focal occlusion of the epicardial vessel and a shift in the ST segment (elevation in three and depression in two) at concentrations that caused dilation in group 1 and only mild constriction in group 2.
Discussion
Our results demonstrate that serotonin has powerful vasoactive effects on the human coronary circulation but that these effects vary with the dose, the coronary segment examined, and the clinical characteristics of the patient.
Patients with Normal Coronary Angiograms
In patients with normal coronary angiograms (group 1), the infusion of serotonin caused a dose-related biphasic response, with dilation at lower concentrations but constriction at the highest concentration. The constriction was most evident in the smallest visible vessels, which were uniformly constricted, but no angina or ECG signs of ischemia occurred. This suggests that the net effect of serotonin on normal epicardial vessels in vivo reflects a balance between a weak relaxant effect, probably mediated by the endothelium, that predominates at lower concentrations, and a direct constrictor effect on smooth muscle that predominates at higher concentrations.15 Marked systemic hemodynamic changes were seen only at a serotonin concentration of 10–3 mol per liter; their occurrence may be a local effect similar to the hypertensive cardiogenic chemoreflex observed in dogs.16
Patients with Stable Angina
In contrast to what we observed in the control patients, the infusion of serotonin in the patients with stable angina (group 2) caused only constriction, not dilation; it caused angina in all nine patients, and diagnostic ischemic ECG changes in six. On average, atherosclerotic vessels constricted at an infused concentration two orders of magnitude lower than that required to constrict epicardial vessels in the control patients, indicating increased sensitivity to the constrictor effects of serotonin. The reactivity of atherosclerotic vessels was also enhanced, since the degree of constriction was greater than that observed in normal vessels. The greater constriction of smooth segments probably reflects a greater pliability, as compared with irregular segments. This also seems a plausible explanation for the small degree of constriction in segments with stenosis, a degree consistently less than that predicted on the basis of MacAlpin's geometric theory.17 The severity of large-vessel constriction never approached that observed during coronary spasm in the patients with variant angina (group 3). Indeed, the constriction was most marked in the distal epicardial segments and the smallest visible branches, raising the possibility that myocardial ischemia may have resulted from the constriction of distal vessels. The interpretation of the effect of serotonin on collateral filling is complicated by the diffuse constrictor effect seen in all angiographically visible vessels. The magnitude of the progressive reduction in collateral filling suggested, however, that additional constriction occurred in arteries too small to be seen angiographically or in the collateral vessels themselves, and this constriction may have contributed to the observed ischemia, as suggested by experiments in animals.18
The intense patchy constriction of large branches and the diffuse constriction of small branches (Fig. 4) that were consistently observed in patients with stable angina after intracoronary infusion of serotonin were quite different from the reported effects of ergonovine. Ergonovine can cause mild, uniform constriction of normal and atheromatous arteries; usually it causes segmental occlusive spasm, together with ischemia, in patients with variant angina. Only occasionally does it cause diffuse constriction of all angiographically visible branches, but no ischemia.19 Studies in animals suggest that endothelial dysfunction (whether alone20 or associated with atherosclerosis21) or an increased sensitivity of vascular smooth muscle may contribute to an exaggerated constrictor response to serotonin. It is difficult, however, to reconcile the predominantly distal distribution of the constriction with the known predilection of atheroma for the more proximal segments of the coronary vasculature. This alteration of distal vessels could be due to the atheroma of proximal arteries, but might also be an independent associated phenomenon. Whatever its cause, the sheer magnitude of the change in the response to serotonin suggests that this alteration may be important in the genesis of myocardial ischemia, when platelets are activated in the coronary arterial system.
Patients with Variant Angina
Occlusion at the site of a preexisting stenosis is the typical response in patients with variant angina during spontaneous episodes of ischemia and episodes induced by ergonovine or any other constrictor stimulus.22 In our patients with variant angina (group 3), localized vessel hyperreactivity, rather than diffuse hypersensitivity, probably accounted for the exaggerated response of the spastic segments to serotonin, since it occurred at concentrations that produced only mild constriction in nonspastic segments.23
Conclusions
Elucidating the role of serotonin in the human coronary circulation has proved difficult because of its rapid metabolism by adsorption onto circulating platelets or by endothelial and neural reuptake.10 Mean aortic serotonin concentrations of 0.5×10–8 mol per liter have been reported in patients without coronary disease,24 and in a canine model of coronary thrombosis, coronary sinus levels exceeding 2×10–6 mol per liter were found.25 If one allows for dilution by coronary blood flow, the doses of serotonin we infused would encompass these reported plasma concentrations. Sampling of the coronary sinus has provided evidence of a role for serotonin in ischemic syndromes in humans,24 , 26 but the true levels of serotonin close to the sites of platelet activation in the coronary arterial system are probably much higher. The demonstration that in all patients with variant angina and the majority of those with stable angina, but in none of the control patients, myocardial ischemia developed at concentrations of serotonin likely to occur in vivo supports the hypothesis that the release of serotonin that occurs with platelet activation may contribute to or cause myocardial ischemia in atherosclerotic arteries.1 , 24 , 26 , 27 Whereas the interruption of flow occurred in major epicardial coronary arteries in the patients with variant angina, constriction in the distal epicardial and collateral vessels in patients with stable angina may contribute to the development of myocardial ischemia, as recently reported in patients with chronic stable angina.28
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Citing Articles (273)
Figures/Media
- Table 1. Response of Coronary Vessels to Intracoronary Infusion of Graded Concentrations of Serotonin.*
Table 1. Response of Coronary Vessels to Intracoronary Infusion of Graded Concentrations of Serotonin.* - Figure 1. angiographic Findings in a Patient with Stable Angina (Patient 6, Group 2) at Base Line (Panel A) and after Intracoronary Infusion of 10–4 mol of Serotonin per Liter at 1 ml per Minute for Two Minutes (Panel B).
Figure 1. angiographic Findings in a Patient with Stable Angina (Patient 6, Group 2) at Base Line (Panel A) and after Intracoronary Infusion of 10–4 mol of Serotonin per Liter at 1 ml per Minute for Two Minutes (Panel B). The constriction of the proximal right coronary artery is patchy (long arrow), whereas the distal segment and tertiary branches (short arrows) are intensely constricted.
- Figure 2. Effects of Serotonin on Vessel Segments from the Controls (Group 1) and the Patients with Stable Angina (Group 2).
Figure 2. Effects of Serotonin on Vessel Segments from the Controls (Group 1) and the Patients with Stable Angina (Group 2). The mean (±SEM) change from base line in the luminal diameter of proximal (•), middle (□), and distal (■) arterial segments is shown after a two-minute infusion of saline (S), increasing concentrations of serotonin, and an intracoronary injection of isosorbide dinitrate (ISDN). The coronary segments from the controls had a small progressive dilation at lower concentrations of serotonin, but constriction (more marked in the distal segments) at the highest concentration. The segments from the patients with coronary atherosclerosis were not dilated and were much more constricted than those from group 1. The distal vessels were the most constricted.
- Figure 3. Dose–Response Curves in Stenotic Segments from Patients with Stable Angina (Group 2) and Patients with Variant Angina (Group 3) after a Two-Minute Infusion of Saline (S), Two-Minute Infusions of Increasing Concentrations of Serotonin, and an Injection of Isosorbide Dinitrate (ISDN).
Figure 3. Dose–Response Curves in Stenotic Segments from Patients with Stable Angina (Group 2) and Patients with Variant Angina (Group 3) after a Two-Minute Infusion of Saline (S), Two-Minute Infusions of Increasing Concentrations of Serotonin, and an Injection of Isosorbide Dinitrate (ISDN). The keys indicate patient numbers and (in parentheses) the percent severity of stenosis at base line. In patients with variant angina, complete occlusion occurred at a concentration of 10–6 or 10–5 mol of serotonin per liter, whereas in those with stable angina there was only a progressive reduction in diameter.
- Figure 4. angiographic Findings in a Patient with Stable Angina (Patient 7, Group 2) at Base Line (Panel A) and after Intracoronary Infusion of 10–4 mol of Serotonin per Liter at 1 ml per Minute for Two Minutes (Panel B).
Figure 4. angiographic Findings in a Patient with Stable Angina (Patient 7, Group 2) at Base Line (Panel A) and after Intracoronary Infusion of 10–4 mol of Serotonin per Liter at 1 ml per Minute for Two Minutes (Panel B). Markedly reduced collateral filling of the left anterior descending coronary artery and moderate patchy constriction of the right coronary artery are evident after the infusion of serotonin.
