(Circulation. 2000;102:1937.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Acute Endothelin-A Receptor Antagonism Prevents Normal Reduction of Myocardial Ischemia on Repeated Balloon Inflations During Angioplasty
From the Second Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece (Z.S.K., D.T.K., T.M.K., A.T., A.A.), and the Department of Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK (D.J.W.).
Correspondence to Zenon S. Kyriakides, MD, Onassis Cardiac Surgery Center, 356 Sygrou Ave, GR-17674 Athens, Greece. E-mail zskyr{at}otenet.gr
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Abstract |
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Background—Myocardial ischemia and reperfusion are associated with increased production of endothelin (ET)-1.
Methods and Results—We examined the effects of BQ-123, a selective ETA receptor antagonist, in 80 patients. All patients were randomly allocated to an intracoronary infusion of saline or BQ-123 (6 µmol/L over 20 minutes). The reference group consisted of 20 patients undergoing coronary angiography. BQ-123 produced a 10% (P<0.005) increase in distal coronary artery diameter. The main study group consisted of 30 patients undergoing coronary angioplasty. All patients underwent a minimum of 3 balloon inflations (BIs). Surface and intracoronary electrocardiographic ST-segment shift as well as pain score were recorded at the end of each BI. BQ-123 or saline was given by intracoronary infusion between the second and the third BI in random allocation. In the saline group, intracoronary ST-elevation decreased from 1.26±0.55 mV during the first BI to 0.77±0.56 mV during the third BI (P<0.05) and the surface ST elevation decreased from 0.20±0.15 to 0.10±0.07 mV (P<0.05). In the BQ-123 group, the respective values were 1.22±0.48 mV and 1.13±0.62 mV (intracoronary) and 0.17±0.18 and 0.17±0.21 mV (surface) (both P=NS). The decrease in pain score was significantly higher in the saline group (F=5.97, P=0.004). In 30 patients (collateral circulation group), the angioplasty protocol was repeated with the use of a pressure guide wire. BQ-123 produced a significant (F=3.30, P=0.04) decrease in coronary wedge pressure.
Conclusions—Acute ETA receptor antagonism prevents the normal reduction of myocardial ischemia on repeated BIs during angioplasty. This may be explained by a "steal" effect through coronary collaterals.
Key Words: endothelin • ischemia • angioplasty
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Introduction |
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The endothelins (ETs) are a family of 21–amino acid peptides with potent vasoconstrictor actions. ET-1 is the predominant isopeptide generated by the vascular endothelium. ET-1 binds to at least 2 receptors in blood vessels: The ETA receptors are expressed only on vascular smooth muscle cells and cause contraction, whereas the ETB receptors are expressed on endothelium, causing vasodilation, and on vascular smooth muscle cells, causing contraction. In healthy men, the major receptor causing vasoconstriction, at least in the systemic circulation, is the ETA receptor.1 2 Endogenously produced ET-1 contributes to the maintenance of basal coronary artery tone in humans with and without coronary artery disease.3 4 Ischemia and reperfusion are associated with an increased cardiac production of ET-1.5 6 However, the pathophysiological role of ET-1 in these conditions remains contentious because results are conflicting and responses may be species dependent.7 8 9 10 11 12
The aim of the present study was to examine the effects of acute ETA receptor antagonism on myocardial ischemia in patients with stable angina pectoris during coronary angioplasty. Coronary angioplasty is a useful model for the study of the clinical, systemic, metabolic, and coronary hemodynamic responses to controlled coronary arterial occlusion.13 14
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Methods |
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The study was approved by the Hospital Ethics Committee, and all patients gave written informed consent. The study had 3 parts: In the study group, we studied the effects of the ETA antagonism on myocardial ischemia; in the reference group, we examined whether BQ-123 in the dose used in this study was sufficient to evoke coronary vasodilatation as a measure of effective ETA antagonism; in the collateral circulation group, we examined the effects of the ETA antagonism on collateral circulation.
All medications except for aspirin were discontinued 12 hours before the procedure. All patients were studied after an overnight fast and were not premedicated with sedatives. A standard Seldinger technique was used, and 5000 IU of heparin was administered intra-arterially.
Study Group
We studied patients undergoing elective coronary
angioplasty for an isolated obstructive lesion in the proximal one
third of a coronary artery. All lesions displayed an internal
diameter reduction of 50% to 90%, based on the use of quantitative
coronary arteriography.15 Patients with
stenoses of >90% were excluded to avoid "preinflation
ischemia" caused by obstruction from the guide wire across
the lesion, which would prolong the ischemic time of the first
inflation compared with the second one.14 16
All patients fulfilled the following entry criteria: (1) history of
chronic stable angina pectoris 
3 months and (2) normal left
ventricular ejection fraction.
Exclusion criteria were unstable angina, patients under medication with sulfonylurea or theophylline drugs (because of their effects on adenosine triphosphate sensitive potassium channels, which have a known effect on ischemic preconditioning), conduction defects or baseline ST-segment abnormalities on the ECG, history or ECG evidence of previous myocardial infarction, angiographic evidence of collateral circulation, evidence of left ventricular hypertrophy on the ECG, or history of systemic hypertension.
Protocol
The patients were randomly allocated in a single-blinded manner
to 1 of 2 groups. The BQ-123 group consisted of 15 patients who
received an intracoronary infusion of BQ-123. The control group
consisted of 15 patients who received intracoronary normal
saline (Table 1
). During the
procedure and until the end of the third balloon inflation (BI), no
medication except for heparin or intracoronary BQ-123 was
given. If 1 or more of the following conditions occurred, the patient
was excluded: (a) if nitroglycerin or any other
medication was needed, (b) if intracoronary ST elevation during
the first BI was <0.5 mV, or (c) if severe chest pain or
arrhythmia was noted.
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After the balloon was positioned across the lesion, 3 BIs of
120-seconds duration were performed (Figure 1). A minimum period of 5 minutes was
allowed for reperfusion between the first and second BIs and a
25-minute period between the second and the third BIs.
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Five minutes after the second BI, the ETA receptor antagonist BQ-123 (Cyclo{-D-Asp-L-Pro-D=Val-L-Leu-D-Trp-} Clinalfa, CH) was administered through the guiding catheter in the dilated artery. The substance was dissolved in 0.9% saline and was given by intracoronary infusion at a constant rate of 1 mL/min (300 nmol/min) for 20 minutes with an infusion pump. Similarly, in the control group, 0.9% saline was infused at a rate of 1 mL/min for 20 minutes.
The dose of BQ-123 administered in this study (total dose of 6
µmol/L) has been shown in other studies not to cause systemic
hemodynamic effects.17 18 In the
present study, this dose was administered directly into the
coronary circulation to maximize delivery of the drug to the
heart. The local concentrations achieved are likely to be greater than
the IC50 at the ETA
receptor but still selective for inhibition of the
ETA receptor, given the 
2500-fold-greater
selectivity of BQ-123 for this receptor, over the
ETB receptor.19
After the third BI sequence, the experimental portion of the procedure was completed and coronary angioplasty then was concluded in accordance with standard clinical criteria.
Assessment of Myocardial Ischemia
Lead V5 of the ECG was connected to the
coronary guide wire.20 The intracoronary
ECG along with 2 other surface ECG leads chosen to reflect likely areas
of ischemia during angioplasty were recorded (Mingograf,
Siemens) at a paper speed of 25 mm/s throughout the study.
Intracoronary and surface ECG estimations were carried out at
the end of 120 seconds during the first 3 BIs. The ECGs were
analyzed by a physician who had no knowledge of the study
protocol. ST-segment elevation was measured 80 ms after the J-point.
The severity of myocardial ischemia was expressed in terms of
(1) the ST elevation from baseline on the intracoronary ECG;
(2) the ST-segment elevation on the surface ECG lead with the largest
ST shift (expressed in mV); and (3) pain score.
Assessment of Cardiac Pain
At the beginning of each coronary angioplasty procedure,
patients were informed that they might have chest pain. At the end of
the first 3 BIs, the intensity of cardiac pain was assessed by the use
of a visual analog scale.21 Patients were asked to put a
mark on a 100-mm scale marked from no symptoms (0) to severe symptoms
(100).
Reference Group
The reference group consisted of 20 patients studied after
diagnostic coronary arteriography (Table 2). ETA-receptor
inhibition was assessed by examining the magnitude of coronary
vasodilation with the use of quantitative computerized analysis
with an automated edge contour detection analysis
system.15
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This group had the same inclusion and exclusion criteria as the study group patients. The patients were randomly assigned to receive either BQ-123 or saline, through the diagnostic catheter, in the diseased artery. Ten patients received intracoronary BQ-123 (300 nmol/min, 1 mL/min, for 20 minutes); the remaining 10 patients received intracoronary saline (1 mL/min for 20 minutes). Before and after the end of BQ-123 or saline infusion, coronary arteriography was performed.
Collateral Circulation Group
We studied 30 patients undergoing elective coronary
angioplasty, having the same inclusion and exclusion criteria as the
study group patients. These patients were randomly allocated to 1 of 2
groups (Table 3). The BQ-123 group
consisted of 15 patients who received intracoronary infusion of
BQ-123. The control group consisted of 15 patients who received
intracoronary saline. The WaveWire, a 0.014-in-diameter,
high-fidelity pressure recording guide wire (Cardiometrics)
with advanced piezoresistive technology, was calibrated externally and
then introduced into the hemostatic valve, advanced to the distal tip
of the guide catheter, and then used to verify that equal pressures
were recorded by both the guiding catheter and the pressure wire.
The WaveWire was subsequently advanced into the distal part of the
diseased artery. During BI, this wire gives the coronary wedge
pressure (PW). After the balloon was positioned
across the lesion, 3 BIs of 120-seconds duration were performed (Figure 1
). During the procedure and until the end of the third BI, no
medication was given.
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Five minutes after the second BI, BQ-123 was administered by intracoronary infusion at a constant rate of 1 mL/min (300 nmol/min) for 20 minutes through the guiding catheter in the dilated artery. Similarly, in the control group, 0.9% saline was infused at a rate of 1 mL/min for 20 minutes.
Collateral Measurement
By combining PW, obtained by means of the
wave wire, with simultaneously recorded aortic pressure
(Pa), obtained by means of the guiding catheter,
and central venous pressure (PV) at maximum
arterial vasodilation, a quantitative index of collateral
flow can be calculated.22 This index, called fractional
collateral blood flow, expresses actual collateral flow
(QC) as a ratio to normal maximum myocardial
perfusion (QN).
The collateral circulation can be estimated according to the
formula22
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We performed a correlation between Formula 1 and Formula 2 in 6 patients, and we found a significant correlation (r=0.99, P<0.0001, data not shown). In the present study, Formula 2 was used.
During the 3 tested BIs, before balloon deflation arterial
pressure, coronary wedge pressure and right atrial pressure (in
only 6 patients) were measured (Figure 1).
Statistical Analysis
All data were expressed as mean value±SD. ANOVA with repeated
measures was used for statistical analysis, followed by
Tukey’s honestly significant difference test for post hoc comparisons.
Linear regression analysis with the least-squares difference
and ANOVA were used to examine possible correlations between changes in
variables and coronary artery stenosis severity or
artery studied. A value of P<0.05 was considered
statistically significant.
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Results |
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No adverse effects as a result of the study protocol were recorded.
Reference Group
After BQ-123 administration, the proximal arterial
segment dilated by 4% (P=NS) and the distal segment by 10%
(P<0.005). After saline administration, the
arterial segments did not change significantly. Heart rate
and mean blood pressure did not change in either subgroup after BQ-123
or saline administration (Table 4).
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Study Group
Forty-five consecutive patients were initially included in the
study. Of these, 15 patients were excluded because of the use of
nitroglycerin (5 patients), intracoronary ST
elevation during the first BI <0.5 mV (7 patients), and artery
dissection (3 patients). The remaining 30 patients (age 38 to 74 years)
made up the study group.
Heart rate and blood pressure did not change after BQ-123 or saline
administration. Heart rate, mean blood pressure, and the double
product were unchanged during the 3 BIs in both groups (Table 5).
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In the BQ-123 group, intracoronary ST-segment elevation
decreased during the second BI by 25% (P<0.05) and
increased again during the third BI, so that the value during the third
BI was comparable to that during the first BI. Intracoronary
ST-segment elevation in the saline group decreased by 19% during the
second BI and by 39% (both P<0.05 versus baseline) during
the third BI. The intracoronary ST elevation during the third
BI was higher (P<0.05) in the BQ-123 group than in the
saline group (Figure 2).
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Surface ST-segment shift remained unchanged in the BQ-123 group during
the second and third BIs, whereas it decreased by 40% during the
second BI and by 50% during the third BI (both P<0.05
versus baseline) in the saline group. The surface ST-segment shift was
higher (P<0.05) in the BQ-123 group than in the control
group during the third BI (Table 2). There was a highly
significant correlation (r=0.80, P<0.001)
between the surface and intracoronary ST-segment elevation
decrease (from the first to the third BI).
Pain score decreased significantly between the first and the third BIs
in both groups; however, the reduction was significantly greater in the
saline group (F=5.97, P=0.004), (Figure 3). Pain score decrease (from the first
to the third BI) correlated significantly with the decrease in the
surface ST-segment elevation (r=0.49, P=0.03) and
with the intracoronary ST-segment elevation during the same BIs
(r=0.52, P=0.005).
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Collateral Circulation Group
Heart rate and mean blood pressure were unchanged during the 3 BIs
in both groups (Table 6). The
coronary wedge pressure in the BQ-123 group decreased, and in
the control group it increased (F=3.30, P=0.04).
The coronary wedge/mean arterial pressure in the
BQ-123 group decreased, and in the control group it increased
(F=4.60, P=0.01).
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Discussion |
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Our results indicate that acute ETA-receptor blockade prevents the normal reduction in myocardial ischemia on repeated BIs in patients undergoing coronary angioplasty. These observations are based on intracoronary and surface ST-segment elevation and pain score.
We discuss 2 mechanisms that provide possible explanations for our findings: (1) alteration of coronary artery tone and a steal effect on coronary collaterals and (2) reversal of ischemic preconditioning.
Alteration of Artery Tone and Steal Effect on Coronary
Collaterals
Collateral vessels demonstrate increased sensitivity to
certain vasoconstrictors. Donckier et al23 demonstrated in
dogs that exogenously administered ET-1 increases collateral blood flow
in the ischemic myocardium. The response of
coronary collateral vessels to exogenously administered ET-1
may be biphasic, depending on the concentration of ET-124 :
After an initial increase, collateral blood flow decreases at
significantly elevated plasma concentrations of ET-1.
Recently, we demonstrated that local ETA-receptor antagonism with BQ-123 causes coronary vasodilation, mainly at the distal coronary arterial segments, an increase in coronary blood flow, and a decrease in the coronary artery resistance.3 Our results in the collateral circulation group indicate that acute ETA-receptor antagonism decreases coronary collateral circulation in patients with coronary artery disease during angioplasty.
Therefore, ETA receptor antagonism may increase
coronary blood flow and decrease coronary artery
resistance and distal coronary pressure by dilating the distal
arterial segments and the resistance arteries in the
nonischemic region. These effects may cause a "steal"
effect on the coronary collateral circulation (Figure 4).
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Preconditioning and Endothelin
Myocardial preconditioning is an endogenous mechanism
by which a transient period of ischemia protects the
myocardium from a subsequent, longer period of
ischemia. Preconditioning and activation of ET-1 during
ischemia may have common pathophysiological
pathways, such as activation of G proteins, phospholipase
A2, and 5'-mononucleotide
phosphatase.25 Wang et al26 tested the
hypothesis that ET-1 can mimic ischemic preconditioning in
isolated rabbit hearts. They concluded that high concentrations of
exogenously administered ET-1 can mimic ischemic
preconditioning but that endogenous ET-1 seems to
contribute little to this phenomenon.26 Similar
conclusions were drawn by Erikson and Velasko,27 who
demonstrated that ETA-receptor blockade did not
alter infarct size in preconditioned dogs. Therefore, it seems unlikely
that the prevention of the normal reduction of myocardial
ischemia on repeated BIs is the result of an effect on
ischemic preconditioning.
Previous Studies of the Role of Endothelin Antagonists
on Myocardial Ischemia
Studies performed in rats7 have suggested that
monoclonal antibodies directed against ET-1 could reduce infarct size
in experimental models of myocardial ischemia and reperfusion.
A beneficial effect of BQ-123 on experimental infarct size has also been reported in dogs.8 A decrease in infarct size was also observed in pigs receiving bosentan, a nonpeptide ETA/ETB receptor antagonist.9 However, these beneficial infarct-limiting effects were not confirmed by other investigators.10 11 12 Administration of BQ-123 in dogs,10 ETA receptor antagonist FR-139317 in rabbits11 and bosentan in rats12 did not affect infarct size. The explanation of these apparently conflicting results is not known and may be related to several factors, including species differences, route of administration, experimental protocol, and the chemical nature (peptide versus nonpeptide) and the dosage of the given antagonist.
Dosage and Safety of BQ-123
No adverse effect was seen during or after intracoronary
BQ-123 administration in either the present or our previous
study.3 The dosage used in the reference group produced
coronary vasodilation similar to that in our previous
study.3 The effects of BQ-123 on coronary tone
show an effect consistent with blockade of the
ETA receptor. It is not known whether the adverse
effect of BQ-123 on myocardial ischemia is dose-related and is
a subject for future research. In our study, we used a selective
ETA-receptor antagonist. Further
studies with an ETB receptor as well as a
nonselective antagonist will be important to fully explore
the role of ET-1 in myocardial ischemia.
Conclusions
Acute ETA receptor blockade prevents the
normal reduction in myocardial ischemia on repeated BIs during
angioplasty, possibly secondary to a steal effect on collateral blood
flow. Our findings may have important implications for the clinical use
of selective ET receptor blockers.
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Acknowledgments |
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Prof David J. Webb is the recipient of the Research Leave Fellowship from the Wellcome Trust (WT 0526330).
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Footnotes |
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Guest Editor for this article was Donald S. Baim, MD, Beth Israel–Deaconess Medical Center, Boston, Mass.
Received October 12, 1999; revision received May 22, 2000; accepted May 23, 2000.
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