© 1999 American Heart Association, Inc.
Thrombosis |
Captopril Administration Reduces Thrombus Formation and Surface Expression of Platelet Glycoprotein IIb/IIIa in Early Postmyocardial Infarction Stage
From the Servicio de Hemoterapia y Hemostasia (M.J.Z., M.L., G.E.) and the Institut de Malalties Cardiovasculars (I.A., M.H., E.R., G.S.), IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), Hospital Clínic de Barcelona, Barcelona, Spain.
Correspondence to María J. Zurbano, Hospital Clínic de Barcelona, Servicio Hemoterapia y Hemostasia, C/Villarroel, 170, 08036 Barcelona, Spain. E-mail mzurbano{at}medicina.ub.es
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Abstract |
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Abstract—Long-term administration of the angiotensin-converting enzyme inhibitor captopril in survivors of myocardial infarction (MI) reduces the risk of cardiovascular death, recurrence of MI, and unstable angina, suggesting that captopril may posses antithrombotic properties that have not been clearly elucidated. We assessed the short-term antithrombotic effects of captopril on platelet aggregation, platelet-subendothelium interaction, and the expression of major glycoproteins on platelet surface. A double-blind study was carried out in 25 patients with MI. Blood samples were taken before (baseline) and 12 days after treatment in both the control and captopril groups. Platelet aggregation was tested by conventional aggregometry using common activating agents. Platelet interaction with deeply damaged subendothelial surface was evaluated in a perfusion model, with blood maintained under flow conditions. Deposition of platelets was quantified by using computer-assisted morphometric techniques on histological sections, and it was expressed as a percentage of total vessel surface covered by platelets (CS) and as a ratio between large aggregates (T) and surface covered by platelets (100xT/CS). Glycoprotein expression was measured using flow cytometric techniques. Aggregometric responses showed no significant variations; however, in the captopril group, 100xT/CS decreased after 12 days of treatment (100xT/CS: 36±12.1% captopril versus 64±8.0% baseline; P=0.05). This parameter was also significantly decreased from that found in control group patients (100xT/CS: 67±4.5%; P=0.008). Flow cytometry showed a 30% reduction in glycoprotein IIb/IIIa expression (P=0.02). Captopril reduced the formation of large aggregates in a perfusion system, which might be related to a down-regulation of glycoprotein IIb/IIIa complex on the platelet surface. These results suggest that captopril exerts an antiplatelet effect that may contribute to its beneficial action in MI.
Key Words: captopril • platelets • vessel wall • flow cytometry
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Introduction |
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Angiotensin-converting enzyme inhibitors (ACEIs) reportedly reduce the rate of recurrent myocardial infarction (MI), sudden death, development of unstable angina, and the need for revascularization in cardiovascular disease.1 2
These drugs can change the hemodynamic parameters in patients surviving MI by both reducing blood pressure and remodeling the left ventricle, which will lead to a reduction in ventricular wall stress.3 ACEIs may decrease coronary vasoconstrictor influences by inhibiting the production of angiotensin II and suppressing the degradation of the vasodilator bradykinin.4 These inhibitors might also increase the production of nitric oxide, prostacyclin, and tissue plasminogen activator and reduce plasminogen activator inhibitor-1 activity.5 6 7 8 9 10 11
Recent observations raise the possibility that angiotensin II may be involved in the thrombotic process. Reportedly, the infusion of large amounts of angiotensin II leads to MI.12 Angiotensin II can adversely affect the balance between increased cardiac oxygen demand and supply by either a direct coronary vasoconstrictor effect or increased inotropy by using its ability to raise cytosolic Ca2+ concentrations in the myocardium. Inhibition of the angiotensin system might have a beneficial effect in acute coronary syndromes.
In the present study, we investigated the possibility that the antithrombotic effects of captopril could be mediated through an inhibitory action on platelet function. Thus, we analyzed modifications in platelet aggregometry and platelet-subendothelium interactions in a group of patients subjected to treatment with captopril (37.5 to 75 mg/d). Modifications in major glycoproteins were monitored by flow cytometry in a subgroup of the study population.
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Methods |
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Patients
A total of 25 patients experiencing a Q-wave MI were evaluated. They ranged in age from 45 to 84 years (mean, 60±7 years) and were admitted to the coronary care unit of the Hospital Clínic of Barcelona with acute MI. A diagnosis of MI was established if no abnormal Q waves (30 ms) appeared in at least 2 adjacent leads and if 1 of the following criteria was also present: chest pain lasting 30 minutes or an increase in the serum creatine kinase MB fraction. Acetylsalicylic acid (125 mg/d) was administered to all patients. Exclusion criteria were (1) secondary coagulation abnormalities associated with the condition and/or known altered platelet function diseases (liver, kidney, or hematologic diseases) and (2) treatment required with antiplatelet agents other than aspirin, with other drugs that might have a negative effect on platelet function (such as nitroglycerin, heparin, and ticlopidine), or with angiotensin-converting enzyme inhibitors, because of the presence of congestive heart failure. Patients with intraventricular thrombus, reinfarction, postinfarction angina, or those undergoing coronary bypass surgery were also excluded.
Study Design
Patients were admitted to the coronary care unit and
received treatment with aspirin, thrombolytic agents,
vasodilators, or ß-blockers, according to standard guidelines of
management of acute MI. The baseline demographic characteristics of the
patients are summarized in Table 1
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Perfusion and aggregating studies were performed before and after the treatment was initiated. Platelet glycoprotein (GP) studies were also performed in some patient blood samples. Patients were randomized to either the captopril (37.5 to 75 mg/d) or control group. The dose of captopril was the highest that the patient could tolerate.
Patients were supine for 60 minutes before venipuncture. Blood was taken from the antecubital vein and collected in acid-citrate-dextrose (final concentration, 19 mmol/L).
Institutional review board approval was obtained, and all patients gave written informed consent. All the procedures followed were in accordance with our institutional guidelines.
Aggregation Studies
An aliquot of the sample (10 mL) was used to prepare
platelet-rich plasma (PRP). The capability of PRP to aggregate was
tested by conventional turbidimetric procedures.13 The
following agonists were tested at concentrations known to cause maximal
aggregations above 80% in PRP from normal individuals: 1.4 mmol/L
arachidonic acid, 4 µmol/L ADP (both from
Menarini), 1 µmol/L synthetic
thromboxane-endoperoxide analogue (Upjohn),
5 µg/mL collagen, 10 µmol/L epinephrine, and 1 mg/mL
ristocetin (all from Menarini).
Perfusion Studies
A second aliquot of the sample (25 mL) was used to perform
perfusion studies. Perfusions were performed at 37°C in perfusion
chambers, as developed by Baumgartner,14 with an effective
annular width of 2.2 mm and a rod length of 72 mm. Flow was
obtained by pumping blood through a peristaltic pump, and perfusion
lasted for 10 minutes at 140 mL/min (the wall shear rate was 800
s-1, which is similar to that found in normal
coronary arteries15 ).
-Chymotrypsin–denuded rabbit aortas were used in all the
experiments in this study. Aortic segments were mounted on plastic rods
and rinsed with PBS for 10 minutes. After 10 minutes of perfusion with
the blood samples, segments were rinsed with the same phosphate buffer
and fixed with 3% glutaraldehyde. After 1 hour,
segments were separated from the rod, washed with PBS, dehydrated
through a graded series of ethanol, embedded in JB-4 embedding material
(Polysciences), thin-sectioned for light microscopy (3 µm), and
stained with methylene blue.
Morphometric Evaluation
Platelet interactions with subendothelium
were morphometrically evaluated using a computerized
image-analysis system.16 The morphometric
parameters were determined using the criteria previously
established by Baumgartner.14 Aggregated platelets
were classified as 1 of the following: contact (percentage of
platelets attached to but not spread on the
subendothelium); adhesion (percentage of platelets
spread on the subendothelial surface, including small
aggregates <5 µm in height); or thrombi (T; percentage of
platelet aggregates 
5 µm in height). All these
parameters were expressed as a percentage of the total
surface examined. Another parameter related to those
previously defined is the total covered surface (CS), which was
determined by adding the previous parameters (contact,
adhesion, and thrombi). The rate of thrombus formation (100xT/CS) was
calculated from the former parameters and used as an
estimate of platelet-platelet interaction.
Platelet Glycoprotein Studies
Platelet immunolabeling with monoclonal antibodies
conjugated with either phicoeritrin (PE) or fluorescein
(FITC) was performed in whole blood using dual-color
analysis.17 18 Briefly, 5 mL of whole blood
collected in citrate-phosphate-dextrose with
paraformaldehyde (final concentration, 0.3%) was added
to polypropylene tubes preloaded with 50 mL PBS. The following
monoclonal antibodies were used for labeling (all from Immunotech):
anti–CD41-PE clone P2 (GP IIb/IIIa), anti–CD42b-FITC (GP Iba, clone
SE2), and anti–CD36-FITC (GP IV, clone FA6.152). Samples for
dual-color analysis were first incubated with saturating
concentrations of anti–CD41a-PE in the dark, without stirring, for 15
minutes at room temperature; this was followed by the addition of
FITC-conjugated monoclonal antibodies and further incubation for 15
minutes in the dark. Samples were then diluted with 1 mL of PBS for
analysis.
Blood samples were evaluated with a FACScan flow cytometer (Becton-Dickinson) at an excitation wavelength of 488 nm. Fluorescence and scatter signals were calibrated with 2 Tm Calibrite beads (Becton-Dickinson). FITC and PE fluorescence were detected with 530/30- and 575/26-nm band pass filters, respectively, and overlap in the emission spectra of FITC and PE was corrected. Platelets were differentiated from red and white cells by their specific anti–CD41-PE membrane immunofluorescence; histograms were composed from fluorescence data obtained in the logarithmic mode from 5000 events analyzed in each sample. Mean fluorescence intensities corresponding to antibody binding (GP Ib, GP IIb/IIIa, and GP IV) were expressed using LYSYS II 1.1 conversion software (Becton Dickinson) in arithmetic mode on a Hewlett-Packard H-P 217 computer. To analyze the data, mean fluorescence intensities were expressed as a percentage of the existing value before captopril treatment.
Statistical Analysis
An unpaired Student’s t test was used for
statistical comparisons. The results are expressed as mean±SEM.
P
0.05 was considered statistically significant.
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Results |
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No significant differences existed in the clinical characteristics of patients treated with captopril and those in the control group.
Platelet Aggregation Studies
In baseline tests, the sensitivity of platelets to some of the
routine aggregating agents used was diminished when compared with
normal values (Table 2). The magnitude of
this decreased platelet response was similar to that commonly
observed in blood samples obtained from patients treated with
aspirin.19
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Aggregometric tracings remained unmodified after 12 days in both the
control and captopril groups (Table 2
). Moreover, neither among
the baseline and follow-up studies for each group nor among groups in
the follow-up study were statistically significant differences
found.
Interaction of Platelets With the Subendothelium
Captopril reduced the formation of large aggregates after 12 days
of treatment. In the captopril group, a 56% reduction of thrombi
formation existed when values obtained after 12 days were compared with
those obtained at baseline conditions (64±8.0% before treatment
versus 36±12.1% after treatment; P=0.05). Conversely, the
control group did not show any significant change after 12 days
(56±5.8% before treatment versus 67±4.5% after 12 days) (Figures 1 and 2).
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Furthermore, after 12 days of treatment with captopril, a 53%
reduction in thrombi-covered surfaces existed when results were
compared with those obtained in the control group using the same
follow-up tests (67±4.5% control versus 36±12.1% captopril;
P=0.008) (Figures 1 and 2).
Total surface covered by platelets was similar in both groups at
baseline conditions (18.8±2.2% control versus 22.7±3.4% captopril).
After 12 days, no significant changes existed in this morphometric
parameter between the control and captopril groups
(22±1.8% control versus 19.8±1.8% captopril) (Figures 1 and 2).
Surface Expression of Platelet Glycoproteins
No relevant changes were noted in the expression of major
glycoproteins in platelets from patients in the control
group. In the group treated with captopril, no significant variations
existed in mean fluorescence intensities for CD42b (GP Ib)
or CD36 (GP IV), before (50±7.6% and 99.9±11.2%, respectively) or
after treatment (51.2±3.5% and 98.3±19.8%, respectively). However,
a statistically significant decrease existed in the binding of
monoclonal antibodies directed against CD41 (GP IIb/IIIa) after 12 days
of treatment with captopril (119±28.27 before versus 77±19.4 after
treatment; P=0.02). Figure 3
shows the percentage of reduction in GP IIb/IIIa expression in the
captopril group.
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) and
captopril group patients (
). Values are expressed as percentage of
reduction in mean fluorescence intensity (MFI) (mean±SEM). A
significant reduction in levels of GP IIb/IIIa (P=0.02)
was observed in captopril group after 12 days of treatment. |
Discussion |
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We investigated the possible antiplatelet effects of the ACEI captopril in patients with MI. Results of this study indicate that captopril reduces the formation of large aggregates when blood is exposed to a thrombogenic vascular surface under flow conditions. Flow cytometry studies revealed a concomitant decrease in the expression of platelet GP IIb/IIIa in these patients. These results suggest that administering captopril to patients with MI may cause additional antiplatelet effects, which could explain its beneficial effects in cardiovascular events.
Captopril is used in the treatment of hypertension and congestive heart failure. Several clinical trials have shown an improvement in exercise capability and life quality in patients taking it.20 21 Moreover, the administration of ACEIs in patients who have suffered MI reduces cardiovascular mortality and reinfarction.1 2 22
The present study investigated the antiplatelet effects of captopril after its oral administration in patients who had suffered a first MI. Our routine aggregometric studies were unable to demonstrate important modifications in the aggregometric patterns other than those that could be ascribed to the standard treatment with acetylsalicylic acid (ASA), which is recommended for these patients.23 24
Data from perfusion studies performed with blood from the same patients showed a statistically significant reduction (56%) in the morphometric parameters that quantify the building of large aggregates onto previously spread platelets (100xT/CS) without affecting the overall ability of platelets to interact with the subendothelium (CS). These results are consistent with the idea that captopril treatment could interfere with mechanisms mediating platelet-platelet interactions.
Discrepancies between the effects of captopril in aggregation versus perfusion studies could be explained by the different conditions of the tests. The shear rate is high in perfusion studies and low in standard aggregometric procedures. Moreover, the rheological effects of red blood cells are present in the perfusion system and absent in standard aggregometric procedures, which were performed in PRP. Red blood cells have a dramatic impact on platelet diffusivity, which is the rapidity with which platelets move perpendicular to flow streamlines. The rate of platelet deposition is markedly influenced by the presence of red blood cells. Baumgartner and Muggli25 reported a 50-fold increase in platelet deposition when red blood cells were present. A moderate rise in hematocrit leads to a significant increase in platelet deposition in patients with moderate anemia.26 Standard turbidimetric techniques may have inherent limitations when used to detect platelet aggregability, and it is not surprising that captopril had no effect on the aggregation studies referred to here. It is evident that experimental conditions in both systems can explain the differences in their sensitivity to detect alterations of platelet-platelet interactions.
Studies in perfusion models have clearly stated that attachment of platelets onto the subendothelium is mediated through interactions of subendothelial von Willebrand factor with platelet GP Ib.27 28 Perfusion studies with blood from patients with severe deficiencies in plasma fibrinogen or platelet GP IIb/IIIa have confirmed that platelet-platelet interactions are mediated through the binding of fibrinogen to platelet GP IIb/IIIa.29 The ability of captopril to interfere with the formation of aggregates suggests that the antiplatelet mechanisms of this drug could be related to quantitative or qualitative modifications at the level of platelet GP IIb/IIIa.
Flow cytometric studies performed on blood samples from a subgroup of patients revealed a statistically significant reduction in the surface expression of GP IIb/IIIa in platelets from these patients. Despite the statistical significance, it is difficult to claim that the quantitative reduction in this glycoprotein (30% as an average) observed in our studies could have a dramatic impact on clinical outcomes. Studies in heterozygotic forms of congenital glycoprotein deficiencies reveal that quantitative reductions in major glycoprotein receptors must be >40% to have a clinical impact.30
A recent report demonstrated that the administration of ACEIs in patients with acute MI reduces levels of free circulating tissue factor.31 Experimental studies by the same group suggest that there would be a reduction in the expression of tissue factor on monocytes and smooth muscle cells in human coronary artery injuries. Exposure of tissue factor at sites of vascular damage increases local thrombin generation.32 Thrombin is a powerful aggregating agent for platelets, even at very low concentrations.33 Moreover, several studies34 35 have shown that treatment with captopril can reduce catecholamine production. Increased levels of catecholamines potentiate platelet aggregation induced by several agents and can even reverse the antiplatelet effects of ASA.36 37 Platelet exposition to excessive circulating levels of catecholamines or to trace amounts of thrombin might increase the expression of GP IIb/IIIa. We think that the reduction of GP IIb/IIIa observed with captopril might be related to a down-regulation of the proaggregatory mechanisms (thrombin and catecholamines) and due to desensitization of the prothrombotic mechanisms subjacent in these patients. The antithrombotic effects of captopril were observed in vivo. The sole incubation of isolated platelets from normal individuals or from patients with captopril had no effects on the expression of major glycoproteins (data not shown). These observations would agree with the concept that the antiplatelet action of captopril is only noticed in vivo and that it is probably related to a general effect on vasculature.
In conclusion, the results from the present study indicate that the oral administration of captopril to patients suffering from MI reduces excessive platelet aggregate formation in an in vitro perfusion model. Such an antithrombotic effect may explain, at least in part, the beneficial action of captopril in survivors of acute cardiovascular events. The antiplatelet role observed with captopril might be common with other ACEIs. However, specific studies are required to test this hypothesis.
Study Limitations
In the authors’ experience, the platelet-covered surfaces
measured in these perfusion studies were relatively low. In fact, in
studies by our group under similar flow conditions in normal donors,
covered surfaces ranged from 30% to 45%.
In addition, rates of thrombus formation (100xT/CS) were also higher than those measured in normal donors treated with ASA. We believe that these discrepancies may be related to the following 2 facts: (1) the study was performed in patients (not in normal donors) with an underlying thrombotic state that had probably caused the coronary event; and (2) current therapeutic protocols may interfere with our tests.
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Acknowledgments |
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This work was supported by grants from the Societat Catalana de Cardiologia, FIS 98/321, DGICYT PM 95-0103, SGR 97/133, and CIRIT 1998TDOC 00026.
Received May 19, 1998; accepted December 22, 1998.
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