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J Am Coll Cardiol, 2002; 40:2102-2109 © 2002 by the American College of Cardiology Foundation |
* University of Siena, Siena, Italy
Institute of Clinical Physiology CNR, Pisa, Italy
Manuscript received June 6, 2002; revised manuscript received July 18, 2002, accepted September 6, 2002.
* Reprint requests and correspondence: Dr. Mario Marzilli, Chair of Cardiology, Policlinico "Le Scotte," Viale Bracci 53100, Siena, Italy.
marzilli{at}unisi.it
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Abstract |
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BACKGROUND: Platelet GP IIb/IIIa blockers have been proven to be beneficial in acute ischemic syndromes. This effect has also been attributed to the prevention of microvascular obstruction, although the underlying mechanisms have not been fully defined.
METHODS: Eighteen patients with unstable refractory angina pectoris underwent cardiac catheterization and angioplasty. Trans-stenotic and microvascular resistances to flow were measured at baseline, during hyperventilation, and after intracoronary adenosine. Measurements were repeated early after abciximab administration and after successful percutaneous transluminal coronary angioplasty.
RESULTS: Hyperventilation induced an ischemic attack in 12 of 18 patients and increased epicardial (12.8 ± 16.9 vs. 6.1 ± 6.1 mm Hg/ml per min, p < 0.05) and microvascular (9.9 ± 7.5 vs. 6.8 ± 5.8 mm Hg/ml per min, p < 0.05) coronary resistance. Abciximab had no significant effect on epicardial resistance, although it significantly reduced distal coronary resistance under all study conditions, including baseline (4.8 ± 4.8 mm Hg/ml per min, p < 0.01), hyperventilation (5.1 ± 5.4 mm Hg/ml per min, p < 0.01), and intracoronary adenosine (2.7 ± 3.0 vs. 4.3 ± 4.3 mm Hg/ml per min, p < 0.05). The hyperventilation test became negative in all patients after abciximab administration.
CONCLUSIONS: These observations confirm the immediate beneficial effects of platelet GP IIb/IIIa blockade with abciximab in acute ischemic syndromes and suggest that improvement of microvascular function may play a central role in the mechanism of action of this drug.
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Three parenterally administered blocking agents of the glycoprotein (GP) IIb/IIIa receptor have been tested in two different clinical indications—namely, acute coronary syndromes and percutaneous coronary interventions. In both cases, these drugs showed a benefit (3). In unstable patients, inhibition of GP IIb/IIIa reduced the mortality rate, rate of myocardial infarction (MI), need for urgent revascularization, and number and duration of ischemic episodes on Holter monitoring (4,5). Moreover, among patients undergoing percutaneous transluminal coronary angioplasty (PTCA), GP IIb/IIIa blockers reduced the rate of peri-procedural complications (6–8).
Because the precipitation of acute ischemia is classically attributed to thrombus formation on disrupted atherosclerotic plaque, the beneficial effects of GP IIb/IIIa inhibition have generally been attributed to passivation of active plaque and reduction of thrombus burden (9). However, recent studies have challenged the validity of this assumption. In fact, GP IIb/IIIa blockers improved the outcome of high-risk revascularization procedures, independent of either their influence on intracoronary thrombus or baseline lesion morphology (10,11). As an alternative mechanism of action, a direct effect of abciximab on the microcirculation has been reported following direct PTCA in acute MI (12). However, to the best of our knowledge, whether these agents significantly affect microvascular control of perfusion in the jeopardized myocardium has not been fully established.
The purpose of this study was to investigate the effects of GP IIb/IIIa blockade on both atherosclerotic coronary obstruction and the microcirculation in patients with acute ischemic syndromes in order to gain insight into the mechanism of action of these agents.
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Stable blood flow and hemodynamics were verified for at least 10 min before baseline recordings. Adenosine (2-mg bolus) was selectively injected into the culprit artery through the Doppler catheter. When flow velocity was back to baseline, the hyperventilation test was performed.
Abciximab was administered as a 0.25-mg/kg bolus followed by a continuous infusion of 10 µg/min. The study sequence (baseline/adenosine/hyperventilation) was repeated 15 to 20 min after the bolus.
The Doppler catheter was then removed, and an angioplasty catheter was advanced over the pressure wire. After balloon dilation, a coronary stent of adequate size and length was deployed in all patients.
Thereafter, the Doppler catheter was re-advanced in the same position as in the pre-PTCA study, and measurements of flow velocity and pressures were repeated before and after intracoronary adenosine administration.
The following signals were continuously monitored and recorded on paper when appropriate: 1) leads I, II, III, and V4 of the surface electrocardiogram; 2) phasic and mean aortic pressures; 3) phasic and mean distal coronary pressures; and 4) phasic and mean coronary blood flow velocities.
Data analysis
Recordings (2.5 cm/s) were obtained at the following times: 1) baseline; 2) 30 s after intracoronary adenosine; 3) at maximal ST-segment shift and/or angina or 2 min after hyperventilation; 4) 15 to 20 min after abciximab; 5) during the first balloon inflation; and 6) 15 min after completion of the dilation procedure.
The vessel diameter at the catheter tip and the severity of stenosis were measured off-line by quantitative angiography (14). Angiography was performed before baseline and after hyperventilation recordings, both before and during abciximab infusion, although it was not performed after adenosine administration. Coronary blood flow was calculated as: 
. Coronary epicardial resistance was calculated as the ratio of the mean trans-stenotic pressure gradient to mean blood flow. Coronary microvascular resistance was calculated as the ratio of mean distal coronary pressure to mean blood flow.
Coronary flow reserve (CFR) was defined as the ratio of maximal flow to corresponding baseline flow. Fractional flow reserve (FFR) was defined as the ratio of distal to aortic pressure after adenosine administration. These two parameters were measured before treatment, after abciximab, and after PTCA.
Statistical analysis
All data are expressed as the mean value ± SD. Analysis of variance, followed by the Newman-Keuls procedure for multiple comparisons and repeated measures, was used to compare the heart rate, arterial and distal coronary pressures, and values of both mean blood flow and coronary resistance at the various stages of the protocol. Linear regression analysis was performed by the least-squares method. A p value <0.05 was considered significant.
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Clinical and angiographic data are shown in Table 1. All patients presented with a complex, tight lesion in the ischemia-related vessel. The percent area stenosis was 96 ± 3%, which was not modified by abciximab (95 ± 3%, p = NS).
Hyperventilation induced ischemia in 12 of 18 patients. Ischemic symptoms and signs completely disappeared by 151 ± 37 s. As ischemia always occurred <2 min after the stop of hyperventilation, flow values at this time were considered in patients with a negative hyperventilation test. After the abciximab bolus, the hyperventilation test became consistently negative. Accordingly, in all patients, blood flow and resistance values were calculated 2 min after the stop of hyperventilation.
All patients underwent successful, uncomplicated dilation and stenting of the culprit lesion. The residual area stenosis was 17 ± 6% (p < 0.01 vs. baseline).
Coronary blood flow
Coronary hemodynamic data are shown in Table 2. Intracoronary adenosine increased coronary blood flow, with a CFR of 1.53 ± 0.41. After hyperventilation, coronary flow decreased. After abciximab, higher flow values were observed under all study conditions (Table 2). Abciximab also increased CFR to 1.71 ± 0.54 (p < 0.05 vs. before treatment) (Fig. 1).
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Coronary pressures
As shown in Table 2, a significant trans-stenotic pressure gradient was present at baseline, confirming the severity of the coronary obstruction. Mean distal coronary pressure decreased after adenosine infusion, giving an FFR of 0.49 ± 0.12. Distal pressure did not decrease during hyperventilation-induced ischemia. As a consequence, despite the marked difference in flow values, the driving pressures at the inlet of the coronary microcirculation, during both hyperventilation-induced ischemia and adenosine-induced hyperemia, were similar.
Abciximab did not affect the post-stenotic coronary pressure under any study condition. Thus, abciximab did not affect either the trans-stenotic pressure gradient during maximal vasodilation or FFR (from 0.49 ± 0.12 to 0.49 ± 0.14, respectively; p = NS).
Balloon inflation caused an abrupt fall in distal coronary pressure (average 20 ± 10 mm Hg), which remained stable throughout the occlusion time and was significantly (p < 0.01) lower than that at baseline, during adenosine vasodilation, and during hyperventilation-induced ischemia.
Stenting virtually abolished the trans-stenotic pressure gradient under all conditions. Accordingly, FFR markedly increased to 0.94 ± 0.05 (p < 0.01 vs. pre-PTCA values with or without abciximab) (Fig. 1). After stenting, no patient had an FFR <0.85, although this parameter was >0.9 in 15 of 18 patients, indicating that most of the epicardial resistance was actually caused by the severe obstruction. Finally, FFR and CFR were not correlated under any study conditions (Fig. 2).
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Discussion |
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Comparison with previous studies. Various studies have shown that abciximab reduces the total ischemic burden in patients with acute coronary syndromes and prevents adverse cardiac events before and after percutaneous revascularization in high-risk patients (6–8,11,15). These clinical benefits have been mostly attributed to a reduction in thrombus burden, leading to improved distal perfusion (9). However, several investigators have challenged this hypothesis: a possible or definite thrombus cannot be documented in many unstable patients; the beneficial effects of abciximab seem independent of baseline lesion morphology and the presence of visible thrombus (10,11). Accordingly, alternative mechanisms, including improvement of microvascular function and coronary blood flow regulation, have been suggested (10–12).
Because angiographic measurements are poor indexes of lesion burden and structure, we elected not to rely on subtle angiographic changes to investigate the mechanism of action of GP IIb/IIIa blockers. Rather, we performed simultaneous measurements of intracoronary pressures and flow velocities to assess the overall stenosis severity, independent of lesion morphology and plaque composition. This experimental setup permitted us to separate the drug effect on the proximal stenotic segment from that on the distal microvasculature.
The present study confirms the relevance of atherosclerotic obstruction in the pathogenesis of unstable angina, as all study patients had severe coronary stenosis, and its removal by stenting virtually abolished the pressure gradient, followed by complete relief from angina. However, the present data also confirm the role of an elevated microcirculatory vasoconstrictor tone in precipitating myocardial ischemia in unstable patients. Indeed, in agreement with previous observations (16), hyperventilation-induced ischemia was consistently associated with a paradoxical increase in microvascular resistance.
The presence of a microvascular disorder in the post-stenotic vascular bed is also confirmed by the lack of normalization of coronary reserve after stenting, despite the absence of a significant pressure drop along the epicardial segment. Similarly, CFR and FFR were not correlated. These findings partially disagree with the concept that progressive stenosis decreases coronary reserve by dropping the distal bed pressure relatively more for smaller increases in flow (17). The lack of any correlation between these two physiologic descriptors of stenosis severity might be explained by two considerations. On one hand, we only selected patients with very severe stenosis, thus limiting the variability of both parameters. On the other hand, a reduced maximal flow capacity, caused by abnormal microvascular dilation (18), limits the trans-stenotic pressure drop, thus preserving FFR. Different degrees of microvascular dysfunction, associated with a narrow range of variation in stenosis severity, might have prevented the recognition of a possible relationship between CFR and FFR. Actually, the immediate benefit seen with GP IIb/IIIa blockade was associated with an improvement in coronary microvascular function. More specifically, abciximab lowered microvascular resistances to flow under all study conditions, including baseline, adenosine-induced vasodilation, and hyperventilation-induced vasoconstriction. At unchanged epicardial stenosis, this distal effect would imply a greater trans-stenotic pressure gradient and lower FFR. This phenomenon was not observed, indicating some degree of vasodilation also at the epicardial segment. However, the absence of significant effects of abciximab on stenosis resistance, both under autoregulation and at maximal vasodilation, makes it unlikely that this is the major site of action of the drug. Finally, it is interesting that this piece of information could only be obtained by the simultaneous measurement of resistance in both the epicardial artery and distal coronary microcirculation. Increases in flow or coronary reserve values could not identify, per se, the site of action of the drug. In contrast, the isolated measurements of coronary pressures and FFR would not have identified any improvement in coronary hemodynamics.
Mechanism of action of abciximab
These observations offer an alternative explanation for the clinical benefits of anti-platelet agents. First of all, these data suggest that, besides changes in plaque structure and morphology, microvascular phenomena might contribute to precipitating ischemia in unstable patients. Although the mechanism(s) of the paradoxical constriction of the coronary microcirculation during ischemia are largely unknown, some reports suggest that platelets might interfere with microvascular regulation of coronary blood flow (19,20). Platelets may be activated by exposure to thrombus, injured endothelium, and collagen while crossing the stenotic segment (1). Activated platelets can affect microvascular resistance by microembolization and/or release of constrictive, pro-adhesive, and pro-inflammatory factors. Along this line, acute ischemic syndromes are often associated with evidence of microvascular obstruction (21). Although this phenomenon is generally attributed to microembolization from the epicardial thrombus, it has been documented that interaction with adhesion molecules prevents microvascular obstruction in experimental models of ischemia without coronary thrombosis (22).
In the present study, abciximab improved baseline and maximal blood flow, as well as vasodilator reserve. In particular, abciximab decreased minimal microvascular resistance (i.e., this drug decreased the resistance of an already maximally dilated microvasculature). It seems conceivable that this additive effect on the large dose of adenosine might not reflect an exclusive improvement of microvascular tone regulation. Rather, this finding strongly suggests the prevention of microvascular obstruction, leading to an increase in the vascular bed reached by perfusion both at baseline and during maximal vasodilation. These observations support the concept that GP IIb/IIIa blockade prevents the negative interaction between activated platelets and microvascular function. This concept has already been suggested by others in the setting of primary PTCA and acute MI (12,23), as well as by studies documenting the beneficial effects of abciximab, as an adjunct to fibrinolytic therapy, on clinical and angiographic correlates of myocardial reperfusion (24). Therefore, it seems possible that the microvascular action of abciximab might have been caused by a peculiar receptor affinity leading to effects not strictly related to the GP IIb/IIIa antagonism (23).
Study limitations
This was an open study of a small group of highly selected patients, and it exclusively explored the short-term effects of GP IIb/IIIa blockade. Additional mechanisms may come into play with prolonged infusion of abciximab or with administration of GP IIb/IIIa antagonists with a longer half-life.
We did not perform platelet function tests in our patients. Therefore, we are attributing the effects we observed to platelet inhibition, but we cannot exclude additional mechanisms, including direct, non-platelet-mediated actions of abciximab on the coronary microcirculation. As a matter of fact, abciximab has equipotent affinity for the vitronectin receptor and demonstrates affinity for the CD11b/18 (Mac-1) receptors, as well (23). Moreover, abciximab has been demonstrated to inhibit leukocyte adhesion and transmigration across the endothelium (25) and the formation of both monocyte-platelet and neutrophil-platelet aggregates (26). All of these actions could influence the coronary microcirculation and appear to be modulated by non–GP IIb/IIIa receptor mediated mechanisms. In fact, pure GP IIb/IIIa receptor blockade did not appear to reduce the white cell content in the infarcted myocardium, as reflected by myeloperoxidase activity after coronary occlusion in an animal model (27). Accordingly, a comparison of the observations made with abciximab to similar measurements made after administration of a more pure GP IIb/IIIa receptor antagonist, such as eptifibatide, tirofiban, or 10E5Mab, might provide more direct insight into the relative role of platelet GP IIb/IIIa blockade and possible extension of these data to a class effect of GP IIb/IIIa inhibitors.
The hyperventilation test has largely been used as a clinical tool to induce coronary spasm. The sensitivity and specificity of this test for the diagnosis of coronary spasm have been reported to be as high as 62% and 100%, respectively (28). However, coronary constriction at the site of atherosclerotic stenoses has been shown to play an important role in modulating the frequency and severity of symptoms in patients with exertional angina and atherosclerotic coronary artery disease (29,30). By triggering coronary constriction, hyperventilation can precipitate angina in unstable patients with severe stenosis. In the present study, the hyperventilation test was positive in 67% of patients; it became negative after abciximab. However, it should also be noted that nitrates were administered in all patients at the beginning of the study, and this might have interfered with the ischemic response. Moreover, the present data do not provide any insight into either the mechanism by which hyperventilation triggers general vasoconstriction or the pathways underlying the effect of treatment on the response to this test.
We are fully aware that the dose of adenosine that we used in this as well as previous studies largely exceeds the recommended dosages. However, with dose-response curve studies, we found that a bolus injection >1 mg is needed to ensure maximal microvascular dilation to accurately measure both FFR and CFR (31). Experience in large patient populations has shown that this approach is well tolerated and free of adverse side effects under different clinical conditions, including normal subjects (32), hypertensive patients (33), patients with stable (32,34) or unstable (16) angina, and patients with acute MI (35). Our clinical protocol is also corroborated by the findings of Shryock et al. (36), who documented large type A2 receptors for adenosine reserve, implying that although very small doses of drug can induce a large submaximal vasodilation, very large doses are needed to guarantee the maximal effect.
Conclusions
Platelet inhibition by GP IIb/IIIa blockade with abciximab markedly improved microvascular function. This effect was independent of changes in stenosis severity, was evident before arterial lumen enlargement by balloon angioplasty, and was associated with an improvement in the ischemic threshold. These observations confirm the immediate clinical benefits of abciximab and offer a possible explanation for the reduction of ischemic events observed early after drug infusion in refractory unstable angina (6). Further studies are needed to verify whether this effect is specific to this drug or is shared by other molecules. However, these observations emphasize the need for developing new, orally active, long-lasting anti-platelet agents capable of passivating acute ischemic patients and preventing patient destabilization.
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