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1 Pharma Division, Cardiovascular Preclinical Research, F. Hoffmann-La Roche Ltd., 4070 Basel; and 2 Actelion Ltd., 4123 Allschwil, Switzerland
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic
cardiac ischemia has mainly been studied in large species such
as pigs or dogs. Little research has been performed using small species
such as rabbits. In the present study, 1-3 wk after implantation
of a novel device (ameroid) on the circumflex coronary artery of New
Zealand White rabbits, vessel patency was evaluated by coronary
angiography, corrosion cast, and radiolabeled microspheres. Coronary
angiograms showed, after 21 days, either total occlusion or severe
stenosis in seven of eight arteries, which was confirmed by corrosion
casts. The ameroid group had less blood flow in the epicardial
(
62%) and endocardial (54%) layers of the ischemic area
compared with sham-operated rabbits (P < 0.05).
Blood flow increased in the ischemic area compared with day 0 during acute occlusion, suggesting that progressive coronary occlusion
initiated the growth of de novo collateral vessels. Thus we have
developed a new model of chronic cardiac ischemia in rabbits
with documented progressive coronary stenosis and occlusion that is
suitable to test various therapeutic angiogenesis strategies.
heart; coronary circulation; angiogenesis; regional blood flow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PROGRESSIVE ATHEROSCLEROTIC coronary obstruction results in ischemic heart disease and myocardial infarction. The degree of damage to the heart is mainly determined by the degree of collateral circulation that developed either before the occlusion or within a short period thereafter (12). Thus coronary collateral circulation may limit ischemia and infarct size and ultimately improve long-term outcome (4).
Detailed investigation of collateral circulation and angiogenesis needs appropriate animal models. To date, the ameroid constrictor model (17) in large species like pigs (22, 25, 35) or dogs (18, 29) is the established model for studying myocardial ischemia. It has been used for various types of chronic in vivo studies in large animals such as mechanism and quantification of collateral blood flow (7, 29), investigations on angiogenic growth factor effects (2, 15, 19, 33), tests of coronary reactivity (24), and analysis of concomitant myocardial infarction (23).
A different method for chronic myocardial ischemia is repetitive occlusion, which leads to the development of coronary collaterals in ponies and dogs (26, 37), whereas the absence of compensatory blood flow was shown in rabbits (8). An additional method that induces tissue ischemia is the microembolization model where injected microspheres (25-µm diameter) partially obstruct the microvascular bed (5, 10). However, this approach causes an abrupt focal vessel occlusion and, therefore, does not induce progressive cardiac ischemia. The model of acute coronary occlusion is not suitable for studies of myocardial ischemia in the rabbit, because the complete occlusion of a coronary artery leads to an extensive myocardial infarction because of the lack of a preexisting collateral network (21).
To our knowledge, cardiac angiogenesis in a small species such as the rabbit has been poorly investigated.
We present a new rabbit model of chronic cardiac ischemia induced by a novel ameroid constrictor that gradually occludes a branch of the left coronary artery. The model was validated by three different techniques: 1) coronary angiography that allowed pre- and postameroid assessment of coronary artery patency, 2) postmortem corrosion cast that confirmed coronary occlusion, and 3) radiolabeled microspheres that allowed quantification of coronary blood flow in the area at risk at various time points after ameroid implantation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The study was subdivided into four parts, all of which were performed in New Zealand White rabbits that were implanted with an ameroid. The first, second, and third parts of the study were designed to document the stenosis or occlusion of the coronary artery by the ameroid with different techniques, namely, angiography of the left coronary artery, corrosion cast of the coronary tree, and coronary blood flow measurements with radiolabeled microspheres. In the fourth part of the study, infarct size was determined.
The experimental procedures and protocols used in this investigation were reviewed and approved by the ethics committee of Basel.
Ameroid constrictor.
We have used a newly designed hygroscopic ameroid constrictor specially
designed for constricting coronary arteries of small diameter. It is a
two-pored cylinder, stained with a lead dye for X-ray localization and
fixed on the epicardial surface of the heart by a silk thread,
surrounding the coronary artery of interest (Fig.
1). Thus, by use of this constricting
device, the artery gradually narrows and eventually occludes as the
space between the ameroid and the myocardium shrinks. After 21 days the
average volume of the 13 implanted ameroids increased from 98 to 171 mm3 (75% increase). Measurement of the ameroid size at
various time points showed that its final size was reached after ~10
days (Fig. 2).
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Surgical implantation. New Zealand White rabbits (3.5-4.0 kg) were sedated with inravenous 20 mg/kg thiamylat sodium (Surivet, Dr. E. Graeub, Bern, Switzerland), the trachea was intubated (2.5 mm ID; neonatal tube, tracheal end, Cole-Parmer) for mechanical ventilation (Servo Ventilator 900C, Siemens-Elena, Solna, Sweden), and expired air was monitored (Normocap 200, Datex Medical Instruments, Tewksbury, MA). Anesthesia was maintained on 3-4% isoflurane (Forene, Abbott Laboratories, Abbott Park, IL) during sterile surgical procedure. Left thoracotomy was performed at the third intercostal space, and the lungs were gently retracted. After the incision of the pericardium, 1,000 IU heparin (Roche Pharma, Basel, Switzerland) and 150 mg acetylsalicylic acid (Synthélabo, Lausanne, Switzerland) were injected into a marginal ear vein.
The ultrasonic signal of a minor branch of the left coronary artery, either lateral branch of the left circumflex coronary artery or the left circumflex itself, was detected by a Doppler ultrasonic flowmeter (Suction-on Transducer, Iowa Doppler Products, Iowa City, IA). The artery of interest was chosen to provide a sufficiently large myocardial ischemia but without compromising cardiac pump function. Two millimeters proximal to the Doppler probe, a nonabsorbable 5-0 polyester thread (8 mm; Ti-Cron D-1, Davis and Geck, Wayne, NJ) was driven around the coronary artery branch. This technique does not require dissection of the coronary artery, which is sometimes deeply entrenched in the myocardium. As such, the site of puncture was on the long axis, halfway from the apex of the left ventricle to the atrioventricular groove. The knot was tightly tied while the Doppler probe signal was used to ensure that the coronary blood flow would remain undisturbed. The thoracotomy was closed in layers, and the pneumothorax was evacuated by a chest tube (Uno Mini Vacuum Set, Uno Plast). An analgesic (250 mg thiamylal sodium, Novalgin, Hoechst, Frankfurt am Main, Germany) was injected intravenously.Angiography day 0, day 7, and day 21. Coronary artery patency was qualitatively assessed by selective coronary angiography on day 0 (before ameroid implantation), day 7, and day 21. The first angiography of the left coronary artery confirmed full patency. The next angiography on day 7 was carried out to confirm proper ameroid position and to detect stenosis or occlusion of the vessel and was repeated on day 21.
Ten rabbits were anesthetized as described above. The right carotid artery was canulated with a 4F sheath introducer system (Avanti, Cordis, Roden, The Netherlands), and 1,000 IU heparin were injected. 3-Fr radiopaque polyethylene tubing (William Cook Europe) was introduced via the carotid artery to the aortic sinus, and the tip was positioned under fluoroscopy (Angioscop C with a Polydoros 80 generator, a Megalix X-ray tube, and a Sirecon 17/12 high-density image intensifier; Siemens-Albis, Erlangen, Germany). A total of 10-15 ml diluted (1:1) nonionic contrast medium (Iopamiro 370, Bracco, Milano, Italy) was then manually injected for selective opacification of the left coronary artery while serial images of the heart were recorded at a rate of 75 frames/s. With a fixed magnification, the arteriograms of the coronary artery were performed with a tube-to-animal distance of 85 cm. Finally, cine recording was made on a 35-mm GBX-2 Kodak film processed in a Gevamatic R10 developer to a
-value of 1.5. The angiograms, from various
angles (front, lateral right, and right anterior oblique projections),
were projected on a Cap-35E (Elmo, Tokyo, Japan) and qualitatively analyzed.
Angiograms on days 7 and 21 were performed according to
the same procedure.
Corrosion cast. To confirm the occlusion of the coronary artery, the hearts of the 10 New Zealand White rabbits investigated by angiography were later studied by an exact corrosion specimen.
The rabbits were given 1,000 IU heparin intravenously to prevent clotting and then were euthanized. The heart was removed, including the first proximal centimeter of the thoracic aorta. A polyethylene cannula, dilated by heat, was fixed into the aorta, and the heart was gently flushed with saline while the multicomponent plastic mixture (Batson's no. 17 plastic replica and corrosion kit, Polysciences, Warrington, PA) was prepared. Care was taken to avoid introduction of air into the system (14). When the polymerizing mixture just started to solidify, it was retrogradely injected into the ascending aorta with a constant pressure, over a period of a few minutes. The casts were kept then at room temperature during 1 h to allow solidification (exothermic polymerization reaction). Subsequently, the ameroid was gently detached from the heart, and the tie was fixed with a clamp to later identify its location. Macerating the heart tissue in a concentrated solution of sodium hydroxide for ~5 h at 50°C revealed the cast, and finally the corrosion cast was rinsed with warm running water for at least 10 min.Microsphere blood flow measurements. Regional blood flow was sequentially determined with radiolabeled microspheres (13). Different time points were chosen to track the time course of myocardial blood flow changes as coronary occlusion progressed: 1) on day 0 at baseline, without any manipulation; 2) on day 0 during a 25-s mechanical occlusion to define the area at risk; 3) on day 7; 4) on day 14; 5) on day 21 to determine the percentage of myocardial blood flow restoration in the area at risk (vs. time point 2; see above); and 6) on day 21 after mechanical occlusion obtained by gently lifting the ameroid to determine the remaining anterograde flow.
Blood flow determinations at time points 3, 4, and 5 were terminal and from different groups of rabbits. As a control, sham-operated animals underwent all of the surgery without ameroid constrictor placement and were evaluated on day 21 after surgery. Coronary blood flow was determined in 47 female New Zealand White rabbits that were anesthetized and operated as described in Surgical implantation. Catheters were placed in a marginal ear vein (TriCath In, Codan, Espergaede, Denmark) for drug application and in the right femoral artery (Combitrans, Braun, Melsungen, Germany) for reference blood sampling as well as for continuous monitoring of arterial blood pressure and heart rate (Linearcorder WR3300, Hugo Sachs Elektronik, March, Germany). Mean arterial pressure and heart rate were measured before and during adenosine infusion. Left thoracotomy was performed as described in Surgical implantation, and 1,000 IU heparin as well as 150 mg acetylsalicylic acid were injected into the marginal ear vein to prevent premature coronary occlusion. A Silastic catheter (0.8 mm ID) was placed into the left atrium for administration of radiolabeled microspheres. For maximal coronary vasodilation, which abolished the reactive hyperemic response to a 25-s occlusion, an infusion of adenosine (Krenosine, Sanofi Winthrop, Münchenstein, Switzerland) was given at a rate of 0.15 mg · kg
1 · min1
intravenously 10 min before and during microsphere injection (9).
Microspheres marked with the nuclides 85Sr,
114mIn, 113Sn, and 46Sc (NEN Life
Science Products, Boston, MA) were sonicated for 10 min and agitated in
a vortex mixer to prevent aggregation before application. They were
chosen in a random order, and 1 (106) ml was injected into
the left atrial catheter. Reference blood samples were drawn from the
femoral artery at a rate of 2.0 ml/min for 1.5 min (Perpex Jubile Pump,
H. J. Guldener, Zürich, Switzerland), starting 5 s before the
injection of each microsphere bolus. To confirm adequate mixing of the
microspheres suspension, bilateral blood flow of the whole kidney was determined.
After coronary blood flow measurements (baseline and acute coronary
occlusion), the ameroid was implanted, all catheters were removed, and
the thoracotomy was closed as described in Surgical implantation. The rabbits were allowed to recover for 7, 14, or 21 days, until the terminal part of the study.
Animals were euthanized with an intravenous overdose of pentobarbital
sodium. The heart and kidneys were excised and preserved for 2 days in
4% buffered formaldehyde solution. The left ventricle was isolated and
cut into five short-axis slices. The uppermost slice, in most cases
situated above the ameroid and therefore not belonging to the area at
risk, and the slice at the apex of the hearts, generally not
sufficiently thick, were excluded from the analysis. Every slice was
cut into eight circumferential wedges: two septal (nonischemic zone)
and six from the left ventricle free wall that were further subdivided
into epicardial and endocardial halves. Each animal yielded at least 60 pieces, with each of them containing at least 400 microspheres during
baseline conditions. All pieces were placed in plastic tubes and
counted in a multichannel -spectrometer (germanium well-type
detector/PCA multiport analyzer). Counts were converted
into regional myocardial flows by multiplying by the reference blood
withdrawal rate and dividing by the counts in the reference blood
sample (6). Finally, all blood flows were normalized for sample
weights. Myocardial blood flow results were expressed as absolute
values in milliliters per minute per gram wet weight.
A section of the left ventricle was considered to belong to the area at
risk when regional blood flow decreased to <30% of the nonischemic
septum during acute occlusion (20, 35).
Histology. Seven rabbits assigned for histological determination of the infarcted area underwent ameroid implantation as described in Surgical implantation but without application of radioactive microspheres. After 21 days the rabbits were euthanized, and their hearts were fixed in 4% buffered formaldehyde solution for 2 days. The left ventricle was cut into six short-axis slices of ~3-mm thickness. Each slice was embedded in paraffin and sectioned by microtome into 4-µm slices. Microscopic sections were cut from the apical surface of each block and stained to differentiate viable myocardium from scar (Goldner trichrome). The slice with the thread and the ameroid were excluded from analysis, because direct contact by the constrictor usually caused artificial epicardial necrotic foci. Similarly, the uppermost slice of every heart, in all cases situated above the ameroid, was excluded from the analysis. Quantification of the left ventricle as well as the infarcted area was obtained with a digitizing tablet (Diasys, Datalab, Thoerigen, Switzerland). The infarcted area was expressed as a percentage of left ventricle mass, and the average of every heart was determined.
Statistical analysis. Data are expressed as means ± SE. For the statistical analysis, Scheffé's F procedure for multiple comparisons was used. A P value <0.05 was considered as significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The ameroid-implanted animals lost ~7% of their body weight within the first 3 days postoperatively (sham operated lost ~2%), but they regained it within 17 days after surgery.
Angiography. A total of 10 rabbits was chronically instrumented with an ameroid constrictor in the angiography and corrosion cast group. None of them died prematurely. Two had no coronary angiogram because of technical reasons and were excluded from the analysis.
Representative coronary angiograms recorded on days 0, 7, and 21 are illustrated in Fig. 3. Coronary angiograms on day 0 (before ameroid implantation) were normal in all rabbits. Coronary angiograms on day 7 revealed that the ameroid position was either on the left circumflex artery or on its lateral branch. In two rabbits the artery was already occluded after 7 days, in three the flow was severely impaired as seen in a significant slowdown of the contrast medium in the distal coronary artery, and in three the angiogram was unchanged. On day 21, three animals showed total occlusion of the artery, four animals showed a dramatic (TIMI grade I) delay in coronary filling, and only one rabbit showed little change in coronary patency. In some animals blood flow in the coronary artery of interest was interrupted during systole, due to compression of the left ventricular muscle.
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Corrosion cast.
The plastic model of the coronary arteries displays a three-dimensional
image of the arterial tree and thus supports the interpretation of the
angiograms. Seven of eight casts showed a stump on the vessel of
interest, indicating abrupt occlusion, and one artery showed a severe
stenosis at the site of the ameroid while the silk thread remained
around the intact polymer vessel. One representative cast is shown in
Fig. 4.
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Myocardial blood flow in microspheres group. A total of 51 rabbits was implanted with an ameroid constrictor in the microspheres group. Eleven (22%) died, probably because of premature thrombotic coronary artery occlusion. Massive infarction as well as a large area at risk (mean 38% of left ventricular mass) accounted for premature death. In the survivors, the mean area at risk represented 22% of the left ventricular mass. Two animals (1 ameroid, 1 sham) with nonreproducible microsphere data were excluded from the coronary blood flow analysis.
Average blood flow in the ischemic area of the 21-day group (ameroid compared with sham) is shown in Fig. 5. Regional myocardial blood flow of the ischemic area is shown in Fig. 6. During acute coronary occlusion, no difference was observed between the ameroid and sham groups in either the endo- or epicardial regions. In both groups, myocardial blood flow decreased almost to zero in the area at risk (94% blood flow),
whereas the blood flow to the nonischemic area decreased slightly
compared with preocclusion (24% blood flow; Table
1). This result suggests that full
vasodilation was achieved and that no hyperemia occurred in the
adjacent region.
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1 · g
epicardium1; 0.32 ± 0.04 ml · min1 · g
endocardium1) were not significantly higher than
during acute occlusion on day 0 but became significant in the
epicardial layer only on day 14 (1.53 ± 0.2 ml · min1 · g
epicardium1; P < 0.05). Nevertheless,
myocardial blood flow in the area at risk of both layers did not yet
reach the 21-day values either on day 7 or on day 14 (P < 0.05).
Histological analysis.
Mean infarct size was larger in the ameroid group (9 ± 4% of the
left ventricle mass; n = 4) compared with the
sham-operated animals (1 ± 1%; n = 3; Fig.
7). The type of the left ventricular infarct was mainly transmural, and the location was generally posterolateral. Thus necrosis could not be avoided despite progressive coronary occlusion. However, variation of the infarct size in the
ameroid group was wide, ranging from 3 to 20% of the left ventricle
mass.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows for the first time that endogenous cardiac angiogenesis can be studied in a rabbit model of chronic cardiac ischemia.
The rabbit was our model of choice because of its small size, universal availability, low cost, and the similarity of its coronary circulation to the human vasculature where the number of new coronary collateral vessels usually is insufficient to supply the ischemic myocardium. Similarly, the rabbit heart is poorly collateralized, similar to that of the swine, whereas the dog heart has a highly collateralized myocardium (21, 34).
Acute coronary occlusion elicited a profound decrease in blood flow in the area at risk (later ischemic area). Such a marked decrease in regional flow confirmed the findings of Maxwell et al. (21) that rabbits have a sparse innate collateral circulation, which is remarkably similar to the healthy human heart (27). Therefore, the rabbit heart might provide an appropriate model for studying gradual coronary artery occlusion and therapeutic collateral development.
The progressive occlusion was achieved with a newly designed ameroid constrictor that required no dissection of the coronary artery with its intramyocardial situation. We investigated changes in myocardial blood flow and the time course of the coronary artery patency at baseline and after 7, 14, and 21 days after ameroid placement. The results from the microsphere data demonstrated that, 21 days after implantation, myocardial blood flow in the area at risk was significantly reduced compared with that in sham-operated rabbit hearts. The origin of this was a complete occlusion or severe narrowing of the artery as assessed by serial angiograms that showed a dramatic slowdown of the contrast medium.
We could demonstrate a progressive build up of collateral flow as denoted by various blood flow measurements on days 7, 14, and 21. Similarly, blood flow in the ischemic area decreased on day 7 and progressively increased on days 14 and 21. Indeed, partial restoration of blood flow after 21 days is in line with the concept that chronic ischemia is a strong stimulus for endogenous coronary collateral development (28).
In some hearts, we could macroscopically show on corrosion casts that blood supply to the ischemic area stemmed from other branches, such as the right coronary artery or the ramus interventricularis anterior, a branch of the left coronary artery. White et al. (35) stressed that the extracardiac collateral vessels in swine sprout into the epicardial region and that the intercoronary collaterals occur primarily in the midmyocardial and endocardial regions. Whether the origin of the increased coronary blood flow in this ameroid model was from radial growth of preexisting capillaries or, alternatively, was the resulted of vascular sprouting was not addressed in this study.
Progressive increase of myocardial blood flow in the area at risk for up to 21 days contrasts with results obtained from iterative and short occlusions in a rabbit model that did not induce improvement of coronary blood flow (8). This discrepancy suggests that in the rabbits a sustained coronary occlusion is needed to trigger the cascade of events leading to the development of coronary collateral circulation.
Coronary blood flow in the ameroid group reached one-half of the baseline value in the endocardial layer and was, surprisingly, almost back to the baseline value in the epicardial layer despite total coronary occlusion. This difference can be explained by the fact that subendocardial layers are more vulnerable to ischemia than are subepicardial layers (3, 20) and that, similar to humans, major collaterals grow from the epicardium in rabbits. This observation is reminiscent of the situation in the dog in which collateral development mainly occurs at the epicardial level (3, 36) and contrasts with that in the pig in which collateral development is rapid but predominantly within the endo- and midmyocardium (25, 35). Thus although coronary blood flow (in the area at risk of ameroid-implanted rabbits) did not reach the level of the nonoccluded arteries in the sham group, collateral vessel development was adequate to prevent extensive myocardial infarction and allowed normal resting myocardial flow, at least in the epicardial layers.
Ameroid-induced coronary occlusion could not prevent some degree of myocardial infarction. Moreover, autopsy of rabbits that died before the study was completed revealed massive infarct because of early occlusion of a coronary branch supplying a large myocardial area. Consequently, the extent of infarction must be a function of the size of the area at risk and of the amount of collaterals that were either preexisting or newly developed. Thus without preventing infarction, collaterals may limit the damage and may result in smaller infarcts than would have been predicted by the region at risk (30). In contrast, it is well established that acute occlusion in rabbits in the branch of the circumflex coronary artery can result in a large infarct that can commonly involve up to 30% of the left ventricle mass (34). In species such as dogs that have extensive native collaterals, progressive occlusion of a coronary artery with an ameroid constrictor results in smaller infarcts, between 1 and 5% of the left ventricle area (2, 32). Sudden and premature cardiac death was frequent (±22%) and corresponded to large infarct as mentioned above. Fatal arrhythmias as cause of early death could not be excluded on top of an acute thrombotic coronary occlusion.
In conclusion, we have developed for the first time a small-animal model of progressive coronary constriction associated with coronary angiogenesis. This model should provide a powerful tool to assess the in vivo effect of new angiogenic drugs that represent today a very promising area of research (1, 2, 11, 16, 32).
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ACKNOWLEDGEMENTS |
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We thank Robert Wolfgang and Jurg Widmer for technical assistance.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: C. Operschall, F. Hoffmann-La Roche Ltd., Cardiovascular Res., CH-4070 Basel, Switzerland (E-mail: christine.operschall{at}roche.com).
Received 3 May 1999; accepted in final form 2 December 1999.
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TOP
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RESULTS
DISCUSSION
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). Average
volume on day 21 (completion of the study) was 171 mm3 (
).
Significant vs.
occl, ameroid group, P < 0.05. ¶ Significant vs.occl, sham group, P < 0.05.
