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Original Article

Local Effect of Serotonin Released during Coronary Angioplasty

List of authors.
  • Paolo Golino,
  • Federico Piscione,
  • Claude R. Benedict,
  • H. Vernon Anderson,
  • Maurizio Cappelli-Bigazzi,
  • Ciro Indolfi,
  • Mario Condorelli,
  • Massimo Chiariello,
  • and James T. Willerson

Abstract

Background

Serotonin is released after the aggregation of platelets, a phenomenon that may occur after coronary angioplasty. We sought to determine whether serotonin is released into the coronary circulation during coronary angioplasty and to assess whether serotonin can affect coronary-artery tone during angioplasty.

Methods

Blood samples were drawn from the ascending aorta and the coronary sinus of eight patients scheduled to undergo angioplasty of the left anterior descending or circumflex coronary artery. Samples were obtained before angioplasty and after each balloon dilation. The dimensions of arterial segments distal to the site of dilation were measured angiographically before angioplasty and 5 and 15 minutes after the last dilation in these eight patients and in seven similar patients; the latter group was treated with ketanserin, a serotonin2-receptor antagonist, before angioplasty.

Results

Before the eight patients underwent angioplasty, their mean (±SE) plasma serotonin level in the aorta was 2.5 ±0.7 ng per milliliter and that in the coronary sinus was 2.3 ±0.6 ng per milliliter (P = 0.34). The serotonin level in plasma from the coronary sinus rose significantly, to 31.5 ±13.5, 17.6 ±5.3, and 29.1 ±8.1 ng per milliliter after the first, second, and third dilations, respectively (P = 0.014 for the comparison with preoperative levels). In contrast, the serotonin level in plasma from the ascending aorta did not change. The cross-sectional area of the coronary artery was significantly reduced 5 and 15 minutes after the last dilation (from a preoperative value of 3.7 ±0.5 mm2 to 2.7 ±0.4 mm2 15 minutes after the last dilation; P = 0.011). This vasoconstriction was significantly blunted in the seven patients who received ketanserin (from 3.7 ±0.5 mm2 before angioplasty to 3.9 ±0.4 mm2 after 15 minutes) (P = 0.017 for comparison with the eight patients who did not receive ketanserin).

Conclusions

Serotonin is released into the coronary circulation during angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction distal to the dilated site. The vasoconstriction is attenuated by ketanserin, a serotonin2-receptor antagonist.

Introduction

Recent experimental and clinical observations indicate that intracoronary platelet activation at sites of endothelial injury and coronary-artery stenosis may contribute to the development of acute coronary artery disease syndromes, such as unstable angina1. It has also been suggested that some platelet-derived substances, including serotonin and thromboxane A2, may be involved in sustaining and amplifying this phenomenon1.

Serotonin is a vasoactive substance contained in the dense granules of circulating platelets. Although physiologically the plasma levels of free serotonin are below its threshold of biologic activity, the concentration of this amine can readily increase locally after platelet activation. According to an experimental model of coronary-artery stenosis and endothelial injury, serotonin is known to have a major role in producing cyclic reductions in coronary blood flow owing to recurrent platelet aggregation at the site of the stenosis2,3. Furthermore, marked coronary vasoconstriction occurs in this model4 and can be prevented by the administration of a selective serotonin2-receptor antagonist,4 but not by nitroglycerin or diltiazem,5 thus indicating a prominent role for serotonin in the pathogenesis of platelet-related coronary vasoconstriction.

Clinical studies have also suggested that serotonin may affect coronary-artery tone. It has been shown that patients with complex coronary-artery lesions release serotonin into the coronary circulation6. Rubanyl et al. have also demonstrated that plasma obtained from the coronary sinus of patients with unstable angina possesses vasoconstricting activity, ascribed to the presence of serotonin7. Furthermore, we have shown that serotonin may cause coronary vasodilation or vasoconstriction, its net effect being dependent on the presence of a functional endothelium8.

Another setting in which serotonin may be important is coronary angioplasty. This procedure is associated with coronary-artery damage and a variable degree of residual luminal stenosis9. Under these circumstances, it is possible that serotonin is released by activated platelets into the coronary circulation. Indeed, coronary-artery vasoconstriction distal to the site of dilation has been observed after successful angioplasty10.

Accordingly, the aims of the present study were twofold: to determine whether serotonin is released into the coronary circulation during angioplasty, and to determine whether serotonin contributes to the occurrence of post-angioplasty vasoconstriction.

Methods

Patients

We studied 15 patients scheduled for elective coronary angioplasty of focal stenoses in the left anterior descending coronary artery or the left circumflex coronary artery. Each patient had stable effort angina and a positive standard stress test for myocardial ischemia. Patients with lesions in the right coronary artery, unstable angina, or Prinzmetal's angina were excluded. The study was approved by the institutional review board of the University of Naples, and informed consent was obtained from each patient.

Study Design

The patients were brought to the cardiac catheterization laboratory in a fasting state. All were receiving nifedipine; they could receive nitrates only if needed to relieve angina, but no patient required them. After premedication with diazepam and induction of local anesthesia with 0.25 percent bupivacaine, femoral arterial (8 French) and femoral venous (7 French) sheaths were placed by the single-wall entry technique. Heparin (10,000 U) was administered at the beginning of the procedure and then hourly (5000 U) to increase the activated coagulation time to 2.5 to 3 times the base-line value. Lysine aspirin (500 mg [Aspegic, Lirca, Milan]) was also administered intravenously at the beginning of the procedure.

In 8 of the 15 patients, we tested the hypothesis that intracoronary platelet activation, leading to the release of serotonin into the coronary circulation, occurs during angioplasty. A 6-French catheter was advanced through the femoral venous sheath and positioned in the coronary sinus. Then, a coronary-angioplasty balloon catheter of the appropriate size was advanced into the coronary artery to be dilated (the left anterior descending coronary artery in six patients and the circumflex coronary artery in two patients), through an 8-French large-lumen guiding catheter over a 0.36-mm floppy guide wire. Blood samples for the measurement of plasma serotonin levels (see below) were obtained from the coronary sinus and the ascending aorta before the balloon catheter was advanced into the coronary artery, and immediately after each dilation (with the balloon completely deflated). Blood sampling was performed until an adequate dilation of the stenosis was achieved or for a maximum of three dilations. The extent of coronary vasoconstriction after angioplasty was quantified by measuring the coronary-artery diameter distal to the dilated site by quantitative coronary angiography before angioplasty and 5 and 15 minutes after the last dilation (see below).

In the seven other patients, we tested the hypothesis that serotonin released by activated platelets at the dilated site might contribute to the occurrence of coronary vasoconstriction after successful angioplasty. These patients also were receiving nifedipine and sublingual nitrates only if needed. Heparin and aspirin were administered at the beginning of the procedure just as in the other group of patients. Then, ketanserin (Sufrexal, Janssen Pharmaceutica, Rome), a selective serotonin2-receptor antagonist, was given as an intravenous bolus (0.25 mg per kilogram of body weight). The diameter of the coronary artery was measured angiographically before angioplasty (both before and after the administration of ketanserin) and 5 and 15 minutes after the last dilation.

Angiography

Quantitative coronary angiography was performed as previously described by Spears et al.11. Coronary angiograms were recorded on 35-mm cine film (Kodak CFR, Milan) at a rate of 50 frames per second. Nonionic contrast medium (iohexol [Omnipaque, Schering, Germany]) was injected manually into the coronary artery. The projection that allowed the best visualization of the coronary artery under study was chosen and used throughout the study.

The 35-mm film was projected (Cipro 35 projector, Siemens, Germany), and the end-diastolic frame selected for analysis was scanned with a video camera (Siemens K 30). Light from the illuminated cine frame was projected into the camera, with approximately twofold magnification. The signal produced by the video camera was digitized and processed by a video-digitizer interface and analyzed with a software system (MIP D computer, Kontron, Dortmund, Germany). To ensure reproducibility of the measurements, 1-cm coronary-artery segments were selected, starting approximately 1 cm below the dilated segment. Then, the diameter of the guiding catheter in the field of view was used to scale the data from pixels to millimeters. A series of measurements of the diameter were recorded for each pixel line along the length of the arterial segment, and the data were also displayed as a graph plotting diameter against length. This graph was used in measuring four 2.5-mm segments, and the measurements were averaged.

We had previously determined the intraobserver variability of quantitative coronary angiography in our system by means of a pilot study analyzing cine films of 11 plexiglass blocks containing precision-drilled models of coronary arteries filled with contrast medium. The mean (±SD) intraobserver variability (determined by repeated analysis of the cineangiograms by a single observer) was 2.3 ±1.8 percent. All measurements were performed by an investigator who was unaware of the patients' group assignment.

Plasma Serotonin Measurement

Blood for the measurement of serotonin in platelet-poor plasma was obtained from the coronary sinus and ascending aorta as follows. A 5-ml sample was withdrawn into a plastic syringe and immediately transferred to a plastic tube containing EDTA (5 mg) to inhibit coagulation, imipramine (300 μg) to inhibit reuptake of serotonin by platelets, and prostacyclin (5 μg) to prevent in vitro platelet activation. The samples were then centrifuged at 120 × g for 20 minutes to isolate red cells. The upper two thirds of the platelet-rich plasma was aspirated with a pipette, and the platelets were removed by filtering the plasma through a sterilizing filter (pore size, 0.22 micrometer). The platelet-free plasma was stored at -70 °C until assayed. Serotonin in plasma was measured radioenzymatically as previously described by Hussain and Benedict12. The lowest concentration of serotonin detectable by this assay is 1.2 pg per milliliter, and the interassay coefficient of variation is 3.75 percent12.

Statistical Analysis

All values are expressed as means ±SE. Since the data on serotonin release were not normally distributed, we analyzed them after they were transformed into their corresponding natural logarithms. This method is often used when the dispersion of the data increases and affects the overall mean -- i.e., when the standard deviation in the original scale varies directly (or approximately) as the mean,13 as in this case. For comparisons of data on serotonin release, hemodynamic function, and coronary-artery dimensions within each group, a one-way analysis of variance with a design for repeated measures was used; if an F value was found to be significant, a two-tailed Student's t-test for paired observations with Bonferroni's correction was used to test differences among values for dilation. For comparisons of coronary-artery dimensions among groups, a two-way analysis of variance was used; if an F value was found to be significant, a two-tailed Student's t-test for unpaired observations was performed. A P value of less than 0.05 was considered to indicate statistical significance.

Results

Serotonin Release

Figure 1. Figure 1. Plasma Serotonin Concentrations in Eight Patients Undergoing Elective Angioplasty of the Left Anterior Descending or Circumflex Coronary Artery, without Pretreatment with Ketanserin.

Each solid circle represents the serotonin level in one patient, expressed as the ratio of the plasma concentration in the coronary sinus to the concentration in the ascending aorta; each open square represents the group mean. There was a marked increase in the ratio of these serotonin levels in blood obtained immediately after the first balloon dilation, and a similiar increase after the second and third dilations. Since the data were not normally distributed, they were analyzed after they were transformed into their corresponding natural logarithms (see the Methods section for details). Only five patients underwent a second dilation, and only four underwent a third. The group mean at each dilation differed significantly from the base-line value (P<0.05).

Under base-line conditions (before angioplasty), plasma serotonin levels in blood from the coronary sinus and the ascending aorta averaged 2.3 ±0.6 and 2.5 ±0.7 ng per milliliter (0.013 ±0.003 and 0.014 ±0.004 μmol per liter), respectively (P = 0.34). Thus, no significant release of serotonin occurred under base-line conditions. In contrast, although the serotonin concentration in plasma from the ascending aorta did not change significantly after the first, second, or third dilation, the concentration in plasma from the coronary sinus increased markedly, to 31.5 ±13.5, 17.6 ±5.3, and 29.1 ±8.1 ng per milliliter (0.18 ±0.07, 0.10 ±0.03, and 0.16 ±0.04 μmol per liter) after the first, second, and third dilations, respectively. Since the data on serotonin release into the coronary sinus were not normally distributed, we analyzed them after transforming them into their corresponding natural logarithms. The values obtained after each dilation were significantly different from the corresponding base-line values (P = 0.014). As a consequence, the ratio of serotonin levels in the coronary sinus to those in the ascending aorta increased from 0.9 ±0.1 at base line to 10.5 ±4.3, 7.1 ±1.7, and 12.8 ±5.9 after the first, second, and third dilations, respectively (Figure 1).

Coronary Vasoconstriction Distal to the Angioplasty Site

When the operator judged angioplasty to be successful (i.e., when the residual stenosis of the luminal diameter was less than 30 percent), coronary arteriography was performed 5 and 15 minutes after the last balloon dilation.

Figure 2. Figure 2. Coronary Vasoconstriction (Changes in the Coronary-Artery Cross-Sectional Area Measured during Diastole) in Eight Patients Undergoing Angioplasty without Pretreatment with Ketanserin.

Values for the cross-sectional area of the coronary artery were calculated from angiograms obtained at base line and 5 and 15 minutes after the last dilation. Each bar represents the group mean (±SE). Significant vasoconstriction occurred in arterial segments distal to the dilated site after 5 and 15 minutes (P<0.05).

Figure 3. Figure 3. Plasma Serotonin Concentrations in the Coronary Sinus after the First Dilation, in Relation to the Degree of Coronary Vasoconstriction (Decrease in Arterial Cross-Sectional Area) in the Eight Patients Undergoing Angioplasty without Pretreatment with Ketanserin.

A significant correlation was found between the two variables (r = 0.91, P<0.01), suggesting the pathophysiologic role of serotonin in vasoconstriction after angioplasty.

In the eight patients not given ketanserin, the cross-sectional area of the arterial segment distal to the site of dilation averaged 3.7 ±0.5 mm2 at base line. Vasoconstriction of this segment became evident after five minutes, as the cross-sectional area decreased to 2.9 ±0.4 mm2, a 23 percent decrease (P = 0.011) (Figure 2). This vasoconstriction was sustained, since 15 minutes after dilation the area averaged 2.7 ±0.4 mm2, a 28 percent decrease from base line (P = 0.01) (Figure 2). When the plasma level of serotonin in the coronary sinus after the first dilation was plotted against the degree of coronary vasoconstriction, a significant correlation was found (r = 0.91, P = 0.01) (Figure 3), indicating that a higher level of serotonin was associated with a higher degree of vasoconstriction. Correlations between coronary vasoconstriction and serotonin levels in the coronary sinus after the second and third dilation were also noted (r = 0.87, P = 0.054; and r = 0.93, P = 0.064, respectively), although they did not reach statistical significance.

Figure 4. Figure 4. Coronary Vasoconstriction (Changes in Coronary-Artery Cross-Sectional Area Measured during Diastole) in the Eight Patients Not Given Ketanserin before Angioplasty and in Seven Patients Given Ketanserin.

Values for the cross-sectional area of the coronary artery were calculated from angiograms obtained at base line and 5 and 15 minutes after the last dilation. Each bar represents the group mean (±SE). Significant vasoconstriction occurred after 5 and 15 minutes in the group not given ketanserin (P<0.05 for the comparison with base-line values).

In the seven patients given ketanserin, the diameter of the arterial segment at the distal site averaged 3.7 ±0.5 mm2 at base line. The administration of ketanserin before angioplasty did not result in any significant change in the diameter (from 3.7 ±0.5 mm2 to 3.9 ±0.4 mm2) (Figure 4). However, the degree of coronary vasoconstriction in the segment distal to the dilated site was decreased markedly both 5 and 15 minutes after the procedure in the ketanserin-treated patients (P = 0.017, as compared with the patients not given ketanserin) (Figure 4).

Systemic Hemodynamic Function

Table 1. Table 1. Clinical and Hemodynamic Variables and Serotonin Concentrations in the Study Groups.

The mean blood pressure and heart rate of the patients not given ketanserin did not change significantly during angioplasty (Table 1). The mean blood pressure of the patients to be treated with ketanserin averaged 93 ±7 mm Hg at base line; it fell slightly but significantly, to 87 ±6 mm Hg, after they received the drug (P = 0.041) (Table 1). This decrease persisted for the rest of the study period. Heart rates did not change significantly in this group throughout the study.

Discussion

The principal finding of the present study is that serotonin is released into the coronary circulation after angioplasty and that the amount released into the coronary sinus is related to the degree of the coronary vasoconstriction observed in segments distal to the site of balloon dilation. Furthermore, pretreatment with ketanserin, a selective serotonin2-receptor antagonist, significantly blunted this vasoconstriction, thus giving further support to the hypothesis that serotonin may be involved in post-angioplasty vasoconstriction.

Coronary-artery vasoconstriction distal to the site of dilation has been previously observed after successful angioplasty, but the factor or factors responsible for its occurrence are not fully understood. After successful angioplasty, the distal coronary-artery bed may be subjected to a number of stimuli that could alter epicardial coronary-artery tone. For instance, Fischell et al. have proposed that the release of platelet-derived substances at the site of arterial injury induced by balloon dilation may be responsible for this phenomenon10. Although a number of experimental studies provide additional support for this hypothesis,4,14-18 evidence that other factors might be involved has also been reported. For instance, loss of endothelium-derived relaxing factor,19 adrenergic nerve dysfunction,20 altered metabolism of vessel-wall arachidonate,21 and alteration of coronary-artery autoregulatory tone22 have all been implicated in the pathogenesis of this phenomenon.

Our finding that ketanserin was effective in reducing (but not eliminating) post-angioplasty vasoconstriction agrees with a previous experimental study, in which LY53857, another serotonin2-receptor antagonist, prevented vasoconstriction of the femoral arteries of rabbits subjected to angioplasty for diet-induced atherosclerotic lesions,18 and with a preliminary report of a trial in which the intracoronary administration of ketanserin prevented vasoconstriction in patients who had undergone angioplasty23. In our study, ketanserin reduced distal vasoconstriction by about 70 percent, as compared with the level of constriction in patients not given this agent. This finding may reflect the use of an insufficient dose of ketanserin to achieve complete blockade of serotonin2-receptors or, alternatively, other mechanisms may be responsible for the occurrence of post-angioplasty vasoconstriction.

It is noteworthy that in the present study, aspirin was routinely administered to all patients. Therefore, one could question the importance of platelet activation at the dilated site as a possible cause of post-angioplasty vasoconstriction. However, although aspirin can reduce platelet aggregation, it does not reduce the adhesion of platelets to the subendothelial matrix or collagen-containing substrates24,25. After adhesion, platelets usually undergo the so-called release reaction, during which the content of their cytoplasmic granules is released into the milieu. Thus, even though aspirin was administered before the procedure, it is conceivable that a certain number of platelets might have adhered to the dilated coronary segment, leading in turn to serotonin release. Furthermore, since prostaglandin synthesis was blocked at the cyclooxygenase level, one can reasonably rule out the relative contribution of arachidonic acid metabolites, such as thromboxane A2, released from activated platelets participating in post-angioplasty vasoconstriction.

That serotonin may have an important role in affecting coronary tone in humans is also suggested by a study performed in our laboratory8. In patients with normal coronary arteries, serotonin caused a dose-dependent increase in coronary blood flow, as well as an increase in the diameter of the coronary artery where the amine was infused. In contrast, in patients with coronary atherosclerotic lesions, serotonin caused a dose-dependent vasoconstriction that was completely blocked after the administration of ketanserin8. The same findings were confirmed and extended to patients with Prinzmetal's angina by another group of investigators26.

The finding of the present study that serotonin is involved in the occurrence of coronary vasoconstriction after successful angioplasty may also have important implications with respect to the cause of abrupt vessel closure after angioplasty. Acute coronary-artery occlusion after successful angioplasty occurs in 2 to 10 percent of patients, typically within three to six hours after the procedure27,28. The mechanisms of this acute occlusion are probably multifactorial and may include mechanical obstruction due to an intimal flap,29,30 platelet aggregation followed by intracoronary thrombus formation,30,31 coronary-artery spasm,32 or any combination of the three. The possibility that arterial vasospasm contributes to acute vessel closure is also suggested by the observation that some of the acute occlusions after angioplasty can be reversed by administration of nitroglycerin32.

In conclusion, our study provides evidence that the release of serotonin during angioplasty may importantly affect coronary tone in vessel segments distal to the dilated site. It also suggests a possible therapeutic role for ketanserin, a selective serotonin2-receptor antagonist, in reducing such vasoconstriction. Larger studies are needed to clarify whether this drug might be useful in patients undergoing angioplasty.

Funding and Disclosures

Presented in part at the 65th Scientific Session of the American Heart Association, New Orleans, November 16-19, 1992.

Supported in part by a grant (91.00122.PF41) from the Consiglio Nazionale delle Ricerche (Progetto Finalizzato Prevenzione e Controllo dei Fattori di Malattia), Italy, and a Specialized Center of Research (SCOR) grant (HL-1669) from the National Heart, Lung, and Blood Institute.

Author Affiliations

From the Division of Cardiology (P.G., F.P., M.C.-B., C.I., M. Chiariello) and the Department of Internal Medicine (M. Condorelli), Second School of Medicine, University of Naples, Naples, Italy; and the Department of Internal Medicine (J.T.W.) and the Division of Cardiology (C.R.B., H.V.A.), University of Texas Health Science Center, Houston.

Address reprint requests to Dr. Golino at the Division of Cardiology, Second School of Medicine, Via Sergio Pansini 5, 80131 Naples, Italy.

References (32)

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Citing Articles (102)

    Letters

    Figures/Media

    1. Figure 1. Plasma Serotonin Concentrations in Eight Patients Undergoing Elective Angioplasty of the Left Anterior Descending or Circumflex Coronary Artery, without Pretreatment with Ketanserin.
      Figure 1. Plasma Serotonin Concentrations in Eight Patients Undergoing Elective Angioplasty of the Left Anterior Descending or Circumflex Coronary Artery, without Pretreatment with Ketanserin.

      Each solid circle represents the serotonin level in one patient, expressed as the ratio of the plasma concentration in the coronary sinus to the concentration in the ascending aorta; each open square represents the group mean. There was a marked increase in the ratio of these serotonin levels in blood obtained immediately after the first balloon dilation, and a similiar increase after the second and third dilations. Since the data were not normally distributed, they were analyzed after they were transformed into their corresponding natural logarithms (see the Methods section for details). Only five patients underwent a second dilation, and only four underwent a third. The group mean at each dilation differed significantly from the base-line value (P<0.05).

    2. Figure 2. Coronary Vasoconstriction (Changes in the Coronary-Artery Cross-Sectional Area Measured during Diastole) in Eight Patients Undergoing Angioplasty without Pretreatment with Ketanserin.
      Figure 2. Coronary Vasoconstriction (Changes in the Coronary-Artery Cross-Sectional Area Measured during Diastole) in Eight Patients Undergoing Angioplasty without Pretreatment with Ketanserin.

      Values for the cross-sectional area of the coronary artery were calculated from angiograms obtained at base line and 5 and 15 minutes after the last dilation. Each bar represents the group mean (±SE). Significant vasoconstriction occurred in arterial segments distal to the dilated site after 5 and 15 minutes (P<0.05).

    3. Figure 3. Plasma Serotonin Concentrations in the Coronary Sinus after the First Dilation, in Relation to the Degree of Coronary Vasoconstriction (Decrease in Arterial Cross-Sectional Area) in the Eight Patients Undergoing Angioplasty without Pretreatment with Ketanserin.
      Figure 3. Plasma Serotonin Concentrations in the Coronary Sinus after the First Dilation, in Relation to the Degree of Coronary Vasoconstriction (Decrease in Arterial Cross-Sectional Area) in the Eight Patients Undergoing Angioplasty without Pretreatment with Ketanserin.

      A significant correlation was found between the two variables (r = 0.91, P<0.01), suggesting the pathophysiologic role of serotonin in vasoconstriction after angioplasty.

    4. Figure 4. Coronary Vasoconstriction (Changes in Coronary-Artery Cross-Sectional Area Measured during Diastole) in the Eight Patients Not Given Ketanserin before Angioplasty and in Seven Patients Given Ketanserin.
      Figure 4. Coronary Vasoconstriction (Changes in Coronary-Artery Cross-Sectional Area Measured during Diastole) in the Eight Patients Not Given Ketanserin before Angioplasty and in Seven Patients Given Ketanserin.

      Values for the cross-sectional area of the coronary artery were calculated from angiograms obtained at base line and 5 and 15 minutes after the last dilation. Each bar represents the group mean (±SE). Significant vasoconstriction occurred after 5 and 15 minutes in the group not given ketanserin (P<0.05 for the comparison with base-line values).

    5. Table 1. Clinical and Hemodynamic Variables and Serotonin Concentrations in the Study Groups.
      Table 1. Clinical and Hemodynamic Variables and Serotonin Concentrations in the Study Groups.

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