(Circulation. 2000;101:1430.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Influence of Postangioplasty ß-Irradiation on Endothelial Function in Porcine Coronary Arteries
From Institut de Cardiologie de Montréal, Départements de chirurgie (E.T.) et de médecine (D.M., O.B., P.P., M.J., R.B.), Centre de Recherche, Montréal, Canada.
Correspondence to Raoul Bonan, MD, Institut de Cardiologie de Montréal, 5000 rue Bélanger Est, Montréal (Qc) H1T 1C8, Canada. E-mail icm3{at}MMIC.NET
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Abstract |
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Background—Postangioplasty (PTCA) intracoronary radiation therapy (ICRT) has been demonstrated to limit restenosis. The consequences of these procedures on coronary reactivity are unknown.
Methods and Results—Porcine coronary arteries were
studied after PTCA immediately (n=5) and 6 weeks (n=5) after ICRT (n=5
and 5, respectively), after combined PTCA+ICRT (n=5 and 7,
respectively), and after no intervention (n=11). A 3-cm-long source
train of Sr/Y90 was used in vivo to deliver 16 Gy at a
depth of 2 mm from the source center, as used in clinical trials.
Arterial rings were mounted on myographs to record
isometric tension. After achieving steady-state contraction to
depolarizing physiological solution containing
40 mmol/L KCl, measured baseline tension was significantly
elevated immediately after all interventions. It returned to normal
levels 6 weeks after PTCA and ICRT alone but was significantly reduced
if combined. Active contractions induced by 40 mmol/L KCl were
maintained after combined therapy both immediately after and at 6
weeks. In these depolarizing conditions, nitric oxide–dependent
relaxation to substance P was trivial after PTCA+ICRT and reduced after
ICRT, whereas in the presence of physiological
solution and
N
-nitro-L-arginine, substance
P–induced relaxation was reduced after PTCA and abolished after
PTCA+ICRT 6 weeks after intervention. In rings without
endothelium, the relaxation mediated by sodium
nitroprusside (0.1 µmol/L) was reduced immediately after PTCA
and at 6 weeks.
Conclusions—PTCA+ICRT altered the passive mechanical properties of porcine coronary arterial wall. Furthermore, at 6 weeks, receptor-operated release of endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor was reduced by ICRT and PTCA alone, respectively, and was prevented by their combination.
Key Words: angioplasty • radioisotopes • endothelium
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Introduction |
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Intracoronary radiation therapy (ICRT) after angioplasty has recently been implemented to prevent and treat restenosis. The anatomic antirestenotic effects of these interventions have been reported for the short and medium term.1 2 3 4 Longer-term consequences of these interventions on the patency of the coronary vessels are currently under investigation. Animal studies have shown that irradiation produces immediate endothelial damage, with uniform impairment of response to acetylcholine, serotonin, and nitroglycerin demonstrated immediately after radiation damage.5 6 7 8 9 10 11 In vitro follow-up at 6 months of irradiated rat aorta revealed impairment of the response to nitroglycerin and acetylcholine,5 whereas in vivo follow-up of irradiated porcine coronary arteries demonstrated an impaired response to nitroglycerin with a preserved response to acetylcholine at 4 weeks.6
Prolonged impairment of endothelial function may reflect an increased risk of delayed thrombosis and accelerated atherosclerosis beyond that expected after standard percutaneous transluminal coronary angioplasty (PTCA). Conversely, the rapid return of normal endothelial function would be supportive of the doses used in clinical trials with an associated low restenosis rate. Furthermore, reports of aneurysm and pseudoaneurysm formation in the first postangioplasty radiation study,12 in which higher-than-expected doses were delivered to certain aspects of the arterial wall, raises the possibility that significant vessel wall death took place at those sites. No studies thus far have reported the physiological response of vessels after the combined injury of angioplasty and irradiation.
The aim of this study was to investigate the consequences of ICRT after PTCA on endothelial function and the reactivity of normal pig coronary arteries isolated immediately and 6 weeks after the intervention. This study was performed on isolated coronary vessels to allow for a precise pharmacological characterization of the endothelium-derived factors involved in the regulation of vascular reactivity post PTCA with or without ICRT.
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Results |
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Twenty-two left anterior descending (LAD) and 21 left circumflex (Cx) arteries were used in this study, for a total of 43 separate porcine coronary arteries. Six arteries were studied as controls from animals that had undergone no irradiation, and another 5 vessels were from animals having undergone treatment in another vessel. There was no difference between these 2 groups, and they are subsequently considered as 1 control group (n=11). The remaining arms were the immediate and 6-week post-PTCA, 5 vessels each; immediate and 6-week post-ICRT, 5 vessels each; and immediate and 6-week post–combined PTCA+ICRT, 5 and 7 vessels, respectively. No difference between the response of the LAD and Cx arteries was noted.
Histology
In the balloon-injured arteries, at the site of internal elastic
membrane (IEM) rupture, there was maximal intimal proliferation, as
shown in Figure 1
. This was composed of
predominantly smooth muscle cells. Twenty percent to 50% of the IEM
circumference was ruptured. Conversely, in the vessels that underwent
angioplasty followed by irradiation, there was limited
neointima and evidence of vessel wall thinning despite
equivalent IEM rupture. These results are consistent with those
previously reported describing and quantifying the effects of both ß-
and 
-irradiation after balloon injury in a porcine coronary
model.13 14 15
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Reactivity Study
Baseline Tension
Figure 2 represents the
resting baseline tension of isolated coronary
arterial rings. This is defined as the passive tension that
promotes a maximal contractile response to a depolarizing solution
containing 40 mmol/L KCl.
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After all immediate interventions, baseline tension was significantly increased (P<0.05). Resting baseline tension of isolated rings 6 weeks after PTCA or ICRT alone had returned to normal levels; however, it was significantly reduced (P<0.05) at 6 weeks after their combination.
Contractile Responses
Immediate PTCA alone decreased the amplitude of the contraction
induced by 40 mmol/L KCl, with no improvement at 6 weeks (Figure 3). ICRT alone potentiated this response
in rings with an intact endothelium immediately
(P<0.05) but not after 6 weeks. PTCA+ICRT had no effect on
this response.
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Contraction induced by prostaglandin
F2
(PGF2) (40
µmol/L) was potentiated by endothelial denudation
(Figure 4). This response was maintained
after immediate ICRT or PTCA alone. Immediately after combination of
the 2 therapies, however, potentiation of
PGF2-induced contraction occurred irrespective
of the presence of the endothelium. After 6 weeks,
PGF2 contraction potentiation was limited to
the endothelium-denuded rings only and thus was similar
to the control response.
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P<0.05 compared with +E. A, Acute (immediate); C,
chronic (long-term).
Endothelium-Dependent Relaxation
In rings preconstricted with PGF2
(40 µmol/L), substance P (0.1 µmol/L) induced a complete
endothelium-dependent relaxation (Figure 5). This relaxation was decreased after
all interventions immediately and did not recover after 6 weeks.
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To identify the respective contributions of release of an endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide (NO) in the alteration of this endothelium-derived relaxing factors (EDRF)-dependent effect, we investigated the relaxant effects of substance P in 2 different experimental conditions. In depolarized conditions (tone induced by 40 mmol/L KCl and in the presence of indomethacin), substance P induced an NO-dependent relaxation that was significantly decreased only after immediate PTCA+ICRT compared with control. After 6 weeks, this NO-dependent relaxation was only trivial.
Although unchanged immediately, 6 weeks after ICRT, substance P–induced NO-dependent relaxation was reduced. PTCA, both immediate and long term, did not significantly modify the NO-dependent relaxation to substance P.
A potent endothelium-dependent, EDHF-mediated
relaxation was induced by substance P (Figure 5
). This
relaxation was observed in control rings preconstricted with
PGF2 (40 µmol/L) combined with NO
synthase inhibition by
N-nitro-L-arginine
(100 µmol/L) and in the presence of
indomethacin. This relaxation was reduced immediately
after all interventions. After 6 weeks, the EDHF-dependent relaxation
mediated by substance P was not significantly reduced by ICRT alone. It
remained lower after PTCA alone and was eliminated after the
combination of PTCA+ICRT.
Endothelium-Independent Relaxation
The sensitivity (pD2) to sodium
nitroprusside (SNP) (1 nmol/L to 10 µmol/L) of isolated rings
preconstricted with a depolarizing solution (40 mmol/L KCl) was
measured (Figure 6). Contrary to control,
the sensitivity to SNP of treated rings was unaffected by
endothelial denudation except immediately after PTCA
alone, in which the pD2 value to SNP decreased.
This opposite effect was absent 6 weeks after PTCA. Finally, the
sensitivity to SNP was higher after long-term PTCA+ICRT.
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Discussion |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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The objectives of this study were to investigate in vitro the consequences of ICRT after PTCA on coronary reactivity and its endothelium-dependent regulation. The results, summarized in the Table
, reveal that PTCA+ICRT
has 2 important consequences: (1) it alters the passive mechanical
properties of normal porcine coronary arterial
wall, and (2) the relaxation mediated by
endothelium-derived NO and EDHF are prevented without
affecting smooth muscle contractility.
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Intracoronary radiation therapy has been used in patients in an
attempt to prevent restenosis. At doses similar to that used in
this study, significant reduction of neointimal formation
was attained.4 However, reports of aneurysm and
pseudoaneurysm formation in the first postangioplasty radiation
study,12 in which higher-than-expected doses were used (up
to a theoretical maximum of 92.5 Gy), raise the possibility that
significant vessel wall death occurred when the combination of PTCA and
ICRT was used. Despite the use of significantly lower doses as in this
study, previously reported quantitative histomorphometric
analyses showed a thinning of the arterial wall at
the site of IEM rupture.13 14 15 In distinction to PTCA
alone, its combination with ICRT reduced the width of the media at the
IEM rupture site. These morphological changes were associated with a
decrease in the passive mechanical properties of the coronary
arterial wall (Figure 2). Arterial rings
were stretched sequentially to a level that sustained a maximal
contractile response induced by high K+ solution.
As shown in Figure 3, PTCA+ICRT did not alter the amplitude of
the contractile response. However, resting basal tension was severely
reduced in this group (Figure 2). The baseline tension is
normally independent of smooth muscle cell contraction in isometric
myographs. Indeed, addition of a supramaximal concentration of SNP in
Ca2+-free physiological
solution does not decrease the tension of arterial rings
below the level of the resting basal tension. Rather, it is the elastic
component of the arterial wall that is responsible for this
tension.16 Dissection after PTCA alone, either immediately
or long term, had no effect on the resting basal tension, suggesting
that the dissection of the intimal layer does not weaken the
arterial wall. Thus, after PTCA, ICRT has multiple effects
on the arterial wall structure, including a reduction in
smooth muscle mass and a loss of elasticity not evidenced when these
treatments are delivered in isolation or immediately.
Contractile responses to high K+ and
PGF2 were maintained 6 weeks after PTCA+ICRT.
Only PTCA alone significantly reduced the contraction induced by high
external K+. There is therefore a discrepancy
between the results obtained with 2 different stimuli after PTCA that
was not modified after 6 weeks of recovery. This discrepancy may be
explained by the difference in amplitude of the contraction induced by
the 2 stimuli: PTCA alone reduced the ability of the isolated vessels
to fully constrict (high K+), whereas a lower
contraction induced by PGF2 was maintained.
This suggests that PTCA alone reduces the maximal contractile response.
However, acute ICRT prevented the decreased response to high
K+ after PTCA. This is most likely due to the
direct effect of ICRT on the endothelium. Indeed, as
seen in Figure 3, there is a strong potentiation of the
contractile response to high K+, suggesting that
ICRT immediately reduces the endothelium-dependent
inhibitory effect on coronary
contractility.
Interestingly, PGF2-induced contractions of
denuded arterial rings were not affected by the different
procedures (Figure 4). Removal of the
endothelium potentiated the contraction mediated by
PGF2, although this potentiation was not
significant 6 weeks after ICRT or PTCA alone. This suggests that the
basal release of EDRFs significantly prevented
PGF2-induced contractions.
The contractile response induced by PGF2 was
increased after acute PTCA+ICRT irrespective of the presence or absence
of endothelium. Thus the
endothelium-dependent regulation of this contractile
response was obliterated. This may be due either to the release of
vasoconstricting factors counterbalancing the relaxant effects of EDRF
or by a lack of basal EDRF production. This effect was
transitory, suggesting recovery of some
endothelium-dependent regulation after 6 weeks. The
endothelium had not been entirely removed by the
PTCA+ICRT because substance P still induced a relaxation immediately,
albeit significantly reduced (Figure 5).
Substance P stimulated the release of EDRF that produced a maximal
relaxation of control coronary arterial rings
precontracted by PGF2 in the presence of
indomethacin (Figure 5). The contribution of NO
appears to be less than that of EDHF. A similar observation has been
recently reported for acetylcholine-induced dilation of large
epicardial coronary arteries in conscious dogs.17
However, in the context of our experimental conditions, it is important
to consider that NO has been shown to prevent EDHF
production.18 19 Thus, despite the fact that
numeric addition of the NO-dependent (
30%) and EDHF-dependent
(60%) responses corresponds to the relaxation mediated by substance
P (90%), the contribution of EDHF to the combined response cannot
be ascertained.
Endothelium-dependent relaxation was reduced by the
different in vivo interventions used in this study (Figure 5).
Immediately, ICRT or PTCA alone did not affect NO-dependent relaxation,
but it was reduced when these 2 procedures were combined. After 6
weeks, ICRT alone reduced substance P–mediated NO-dependent relaxation
of the vessels. In combination with PTCA, this response was absent.
Thus ICRT damaged the endothelium-dependent release or
availability of NO, which was exacerbated when combined with PTCA.
EDHF-dependent relaxation mediated by substance P was decreased
immediately after ICRT and PTCA, individually and in combination. This
relaxation partly recovered 6 weeks after ICRT but not after PTCA and
combined PTCA+ICRT. Several reasons may explain this result. There are
functional signs of regeneration of the endothelium 6
weeks after PTCA and ICRT alone that are clearly absent after the
double procedure. Second, even if physical endothelial
regeneration is complete, it has been shown that the new
endothelium may be functionally
deficient.20 Surprisingly, however, whereas substance
P–induced relaxation was trivial 6 weeks after PTCA+ICRT, removal of
the endothelium potentiated the contraction induced by
PGF2. This implies that receptor-operated
release of EDRFs is absent 6 weeks after PTCA+ICRT, but the
endothelium still prevents contraction and thus
constitutively produces EDRFs.
Removal of the endothelium potentiated the relaxant
effect of SNP in control arteries (Figure 6), reflecting an
increased guanylate cyclase sensitivity associated with the
loss of NO.21 This supersensitivity to nitrovasodilators
has also been described in vivo after inhibition of vascular NO
synthase.22
The potentiating effect of endothelial removal on
SNP-induced relaxation was blunted in all groups, suggesting a lack of
endothelium-dependent regulation of smooth muscle
sensitivity to SNP. The origin of this alteration is unknown because it
is not specific for 1 type of procedure (ICRT or PTCA). The only link
between these changes is the endothelial dysfunction,
since in denuded vessels SNP-induced relaxation is similar in all
groups except immediately after PTCA. In this latter case, it is
possible that rubbing the endothelium immediately after
the PTCA but not after healing damaged the smooth muscle, as shown by
the decrease in sensitivity to SNP. Also, a clear increase in
SNP-induced relaxation was observed after long-term PTCA+ICRT. This is
most likely to be associated with the decreased NO production
and/or release observed under stimulated conditions (Figure 5).
This would be in agreement with previously published data showing that
NO synthase inhibition increases guanylate cyclase
sensitivity both in vitro and in vivo.21 22
It is important to note that our results differ from a recent in vivo study6 in which SNP-induced dilation was absent immediately and in the long term after ICRT, whereas acetylcholine-induced relaxation was restored after 5 weeks. However, we have no explanation for this discrepancy other than the different methodological approach.
The identical response of the 2 groups of controls from irradiated and nonirradiated animals suggests that the effects are entirely local and that a significant systemic or distant effect, as has been previously suggested,5 can be excluded.
Clinical Implications
The implications of endothelial dysfunction over a
short vessel segment are unclear. First, a patent arterial
segment that has impaired reactivity is a scenario not dissimilar to a
stented segment. This is clearly preferable to a restenosed segment.
This may have different implications if the treated segment is long.
Second, the reduction of vessel wall integrity, as shown by a reduction
in baseline tension, mandates longer-term follow-up than usual in the
clinical situation. Angiographic and intravascular ultrasound studies
can provide bountiful information regarding the stability of these
vessel segments.4 Finally, because of the severity of
endothelial dysfunction demonstrated, the possibility
of very delayed regeneration must be entertained. Although this study
was performed on normal porcine arterial rings, its
findings have significant implications for a treatment currently under
extensive clinical investigation.
Limitation of the Study
Because this study was performed immediately and at 6 weeks after
intervention, no conclusion can be drawn regarding the progression of
this process. Furthermore, the effects demonstrated are limited to the
site of the intervention and the response of proximal and distal vessel
segments were not assessed, although the reactivity of nontreated
coronary arteries from animals in which another
coronary vessel had been irradiated was unaltered. Finally,
atherosclerosis being the background of this clinical
intervention, we do not know what the impact would be of PTCA+ICRT in
this context. This study was designed to investigate the effects of
PTCA+ICRT and ICRT alone on coronary reactivity and
endothelial function; our data cannot predict the
outcome of PTCA+ICRT in a
hypercholesterolemic/atherosclerotic clinical
background.
Conclusions
PTCA+ICRT altered the passive mechanical properties of porcine
coronary arterial wall. Furthermore,
receptor-operated release of endothelium-derived NO and
EDHF were reduced by ICRT and PTCA alone and prevented by the
combination of PTCA+ICRT. The ongoing impairment of
endothelial function after 6 weeks in this model
further supports the longer-term follow-up of all patients undergoing
post-PTCA irradiation.
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Methods |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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Animals
Juvenile Yorkshire pigs (weight 25 to 30 kg, obtained from a local supplier) were treated with 650 mg aspirin and 30 mg nifedipine (to prevent coronary spasm) 24 hours before the procedure. The animals received an intramuscular injection of ketamine (12 mg/kg), xylazine (8 mg/kg), and atropine (1.2 mg/kg) as premedication. After intubation, anesthesia was induced and maintained with 1% halothane in a 2:1 mixture of oxygen and air. After percutaneous puncture of the right or left femoral artery, an 8F femoral sheath was placed and heparin (150 U/kg) and xylocaine (100 mg) were administered as intra-arterial boluses. An 8F right Amplatz guiding catheter (AR2, Cordis Corp)was advanced to the base of the aorta. Under fluoroscopic visualization, the left main coronary ostium was engaged for digital arteriography (View System, Electromed).
Angioplasty and Radiation Therapy
Two vessels, the left anterior descending (LAD) and circumflex
(Cx) coronary arteries, were treated in each animal. Arteries
were randomly assigned to be treated with balloon angioplasty (PTCA),
ICRT, or PTCA+ICRT or were left untouched. Arterial
diameters at treated segment sites were 2.5 to 3.8 mm as assessed
by quantitative coronary angiography. The balloon (Viva, Boston
Scientific) was sized to achieve a balloon-to-artery ratio of 1.2.
Balloon diameter was 2.5 to 4.0 mm and length was 20 mm.
Arterial injury was performed by a single 60-second
inflation at 6 atm.
ICRT was performed with a ß-emitter (Sr/Y90, Novoste Corp) through a noncentered, 5F, closed-end catheter to the LAD or Cx coronary artery. A dose of 16 Gy to a depth of 2 mm from the source center was delivered with a 3-cm source train to adequately cover the balloon-injured segments.
Immediately after these procedures or after 6 weeks, the pigs were killed and the hearts were explanted.
Reactivity Study
Isolation of Vessels
LAD and Cx arteries were isolated 15 to 30 minutes after the
removal of the heart from the chest and placed in cold (4°C)
solution. Approximately 15 minutes later, the surrounding tissues were
removed under a binocular microscope. The blood vessels were cut into
rings (2 mm in length). In some rings, the
endothelium was removed mechanically by insertion of a
wooden peg into the lumen and gentle rolling.23 The
functional removal of the endothelium was assessed by
the disappearance of endothelium-dependent relaxation
induced by substance P (0.1 µmol/L).
Solutions and Drugs
The tissues were incubated in modified Krebs-Ringer bicarbonate
solution with the following composition (mmol/L): NaCl 130, KCl 4.7,
KH2PO4 1.18,
MgSO4 1.17, NaHCO3 14.9,
CaCl2 1.6, EDTA 0.026, and glucose 10, and
aerated with a 12% O2/5%
CO2/83% N2 gas mixture (pH
7.4). The solution contained indomethacin (10
µmol/L, inhibitor of cyclooxygenase).
To prepare K+-rich solutions (40 mmol/L and
127 mmol/L), equimolar amounts of NaCl were replaced with KCl. The
following drugs were used: indomethacin,
N-nitro-L-arginine,
prostaglandin F2
(PGF2), sodium nitroprusside (SNP) (Sigma),
and substance P (American Peptide Co). Stock solutions were prepared in
distilled water except for indomethacin (dissolved in
ethanol) and substance P (30% dimethylsulfoxide/70% distilled water,
vol/vol). Preliminary experiments indicated that none of the solvents
used produced detectable changes in isometric force at the
concentrations used (data not shown).
Organ Chamber Experiments
The rings were mounted on 20-µm tungsten wires in microvessel
myographs (IMF, University of Vermont) filled with control solution (10
mL) and maintained at 37°C. One of the tissue holders was connected
to a force transducer (Minebea UL-10) to record changes in
isometric tension. The rings were stretched to the optimal point of
their length-active tension relation, as determined by the contractile
response to 40 mmol/L K+ solution at
progressive levels of stretch as previously described.23
More specifically in this study, rings were initially subjected to 2
tension loads of 1.5 g and 1 of 1 g at 20-minute intervals.
After these 3 cumulative tension loads, rings were stimulated with high
K+. Then, an additional tension load of 0.5
g was applied and rings stimulated with high K+
after 20 minutes. If the contraction was greater by >20% compared
with the previous response, a second 0.5-g load was applied. A total
force of 5.0±0.5 g was necessary to obtain a stable contractile
response, with no difference between the 7 groups in this study.
Two rings of each vessel, one with and one without endothelium, were mounted in parallel on myographs. In denuded arteries, substance P (0.1 µmol/L) did not induce relaxation.
Histology
To confirm that the PTCA and irradiation protocol used produces
anatomic results equivalent to those previously
reported,13 14 15 in a separate series of experiments, 4
arteries were treated with balloon angioplasty alone as described above
and a further 4 vessels were treated with ICRT immediately after
balloon angioplasty. The pigs were killed 6 weeks after the procedure
as described above. The treated arteries were rapidly cannulated and
flushed with saline. Perfusion fixation was performed with 2.5%
phosphate-buffered glutaraldehyde at 100 to 110
mm Hg for 30 minutes. Gross ischemic myocardial damage was
excluded by macroscopic assessment. The treated vessel segments were
localized and dissected from the epicardial surface and cut into 3- to
4-mm sections. These sections were processed and embedded in paraffin.
Cross-sections (4 µm) were stained with Movat
Pentachrome for histological examination.
Animal Care
The pigs were fed regular chow with no additive. They received
no medication during the follow-up period; in particular, they did not
receive aspirin or ticlopidine. All animals were cared for in
accordance with the "Principles of Laboratory Animal Care"
formulated by the National Society for Medical Research and the
"Guide for the Care and Use of Laboratory Animals" prepared by the
National Academy of Sciences (NIH publication 85-23, revised 1985).
Statistical Analysis
Results are expressed as mean±SEM. In all experiments, n
represents the number of arteries. Vasoconstrictions are
expressed as percent of the maximal response
(Emax) obtained in the presence of 40 mmol/L
K+ at the beginning of each individual
experiment; vasorelaxations are expressed as the percent inhibition of
the preconstricting tone. The level of tone was measured at the plateau
of constriction. The half-maximum effective concentrations
(EC50) of SNP were measured from each individual
dose-response curve with a logistic curve-fitting program (Allfit,
University of Montréal). The pD2 value is
the negative log of the EC50. Statistical
differences between means were determined by ANOVA followed by a
Scheffé’s F test. A value of P<0.05 was
accepted as significant for differences between groups of data.
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada, the Fonds de la Recherche en Santé du Québec, the Heart and Stroke Foundation of Québec, and the Fonds de Recherche de l’Institut de Cardiologie de Montréal. E. Thorin is a research scholar from the Heart and Stroke Foundation of Canada. The authors are indebted to Nathalie Nadeau and Danielle deRepentigny, nuclear medicine technicians, and Jean Laurier, radiation safety officer, for their assistance in performing this study.
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Footnotes |
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The Methods section of this article can be found at http://www.circulationaha.org
Received July 16, 1999; revision received September 29, 1999; accepted October 11, 1999.
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