(Circulation. 1997;96:2295-2301.)
© 1997 American Heart Association, Inc.
Articles |
Local Delivery of Ethanol Inhibits Intimal Hyperplasia in Pig Coronary Arteries After Balloon Injury
From Interventional Cardiology, Division of Cardiovascular Disease, Department of Medicine and Department of Pathology (P.G.A.), University of Alabama at Birmingham.
Correspondence to Ming W. Liu, MD, 365 BDB, 1808 7th Ave S, Birmingham, AL 35294. E-mail mingliu{at}cardio.dom.uab.edu
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Abstract |
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Background Smooth muscle cell (SMC) hyperplasia is an important mechanism of restenosis after coronary angioplasty and the primary mechanism of restenosis within coronary stents. Ethanol has been shown to reduce the response of SMCs to local growth stimulants in vitro. This study was carried out to determine whether local delivery of ethanol solution could reduce intimal hyperplasia induced by balloon injury.
Methods and Results Three groups of juvenile domestic pigs underwent oversized balloon dilation injury of the left anterior descending and left circumflex coronary arteries. Immediately after the balloon injury, one of the arteries was randomized to local delivery of 15% ethanol with a local delivery balloon catheter, and the other received no further treatment. Histological and morphometric studies were carried out at 2 weeks in group 1 (n=16) and at 4 weeks in group 2 (n=10). In the third group (n=15), animals were killed at days 4, 8, and 14 after balloon injury, and coronary artery segments were studied by immunohistochemical staining against proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU). Histological injury scores were not different between the ethanol-treated and untreated arterial segments in either group 1 or 2. The neointimal areas were significantly smaller in the ethanol-treated arterial segments than in the untreated segments (0.25±0.08 versus 0.57±0.08 mm2, P=.004, at 2 weeks; 0.33±0.05 versus 0.54±0.07 mm2, P=.03, at 4 weeks). SMC proliferative activity was significantly lower in ethanol-treated arteries than in untreated arteries at 4 and 8 days after injury by BrdU and PCNA staining.
Conclusions Local delivery of 15% ethanol solution to pig coronary arteries significantly decreased the SMC proliferative activity and neointimal formation induced by balloon dilation injury.
Key Words: hyperplasia • restenosis • neointima
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Introduction |
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Restenosis after successful coronary angioplasty remains a major limitation to the long-term success of this procedure.1 Despite numerous clinical trials of various pharmacological agents, no agent has been identified that successfully prevents restenosis.2 From a number of clinical and experimental studies that used intracoronary ultrasound and/or histological evaluation of tissues, it is clear that there are three major mechanisms responsible for restenosis: intimal hyperplasia, elastic recoil, and vessel wall remodeling.3 4 5 Vessel wall remodeling and elastic recoil can be effectively counteracted by permanently fixing the vessel size by the placement of an intracoronary stent.6 7 However, restenosis due to intimal hyperplasia and production of extracellular matrix material within the neointima still occurs in a significant percentage of patients, more importantly after intracoronary stenting.6 7 Intimal hyperplasia is a process of vascular SMC proliferation, migration, and transition to a secretory phenotype that is induced by multiple growth stimuli released during the arterial injury. These growth stimuli include local factors and blood-borne growth factors, especially those released from activated platelets.8 Previous studies have shown that ethanol inhibits cellular responses to hormone agonist stimulation, inhibits cellular proliferation, and reduces platelet aggregation.11 12 Because ethanol has proven efficacy in preventing cell proliferation and because local delivery balloon catheters may deliver pharmacological agents into the vessel wall in high concentrations,13 we performed this study to examine the effect of local infusion of ethanol solution on intimal hyperplasia induced by oversized balloon injury in pig coronary arteries.
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Methods |
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Animals
Juvenile domestic pigs weighing 25 to 30 kg were used for these studies. All animals received a normal diet. The study was approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham.
Experimental Protocol
All animals were premedicated with aspirin 325 mg and
diltiazem HCl 60 mg the day before the procedure. The animals underwent
sedation with an injection of ketamine (20 to 30 mg/kg),
acepromazine (0.2 mg/kg), and atropine (0.04 mg/kg) IM.
After intubation, halothane (0.3% to 1.5%) and oxygen were given
throughout the procedure. The ECG and blood pressure were monitored
continuously. Right femoral arterial cutdown or
percutaneous puncture was performed, and an 8F
arterial sheath was placed. Heparin (200 U/kg) and
bretylium (50 mg) were given as an intravenous bolus, and
10 mg nifedipine was given sublingually. An 8F guiding
catheter (hockey-stick, multipurpose, or left Amplatz) was used to
engage the left coronary artery, and a left coronary
angiogram was performed. The diameters of the proximal to mid segments
of the LAD and LCx were determined from the arteriogram, with the
catheter diameter used as a reference. A balloon catheter 20 mm
long with a diameter 20% larger than the arterial diameter
was chosen to perform the balloon dilatation injury. For example, a
3.0-mm balloon catheter is used for an estimated 2.5-mm artery and
3.5-mm balloon catheter for an estimated 3.0-mm artery. After the
guidewire was properly positioned in the coronary artery, the
angioplasty balloon was advanced to the proximal to mid segment of
either the LAD or LCx. Any major side branch was avoided. Three
30-second balloon inflations were performed at a nominal pressure. Each
balloon inflation was separated by 1 to 2 minutes to allow for
coronary perfusion.
Randomization to Local Ethanol Solution Delivery
All animals underwent balloon dilatation of both the LAD and
LCx. After balloon dilation, one of the two arteries was randomized to
receive local delivery of a 15% ethanol solution. The other artery was
assigned as untreated (control) and underwent only balloon
dilatation.
The study was divided into 3 groups. In the first study group of 16 pigs, Wolinsky porous infusion balloon catheters were used for local alcohol delivery (USCI). Details of the Wolinsky catheter have been described.14 In the second group of 10 pigs and the third group of 15 pigs, Dispatch balloon catheters were used for local delivery (SciMed). The size of either Wolinsky or Dispatch balloon catheters usually matched the size of the initial injury balloon catheter. The local delivery catheter was positioned at the previous balloon-dilated site in the arteries randomized to ethanol treatment. Local alcohol delivery was performed after the balloon injury.
For group 1, the ethanol solution (15% by volume) was infused into the balloon-injured vascular segment at 2 to 4 atm for 30 seconds. An average of 2.25±0.18 mL of solution (range, 1 to 3.5 mL) was infused. A final coronary angiogram was performed at the end of the procedure to confirm the patency of vessels. At 14 days after the initial stretch injury and local ethanol delivery procedure, the animals were sedated and anesthetized as previously described. After a left coronary angiogram was performed, the animals were killed by an injection of concentrated KCl. The heart was removed, and the coronary arteries were flushed with 200 mL of normal saline and perfusion-fixed at 100 mm Hg pressure for 15 to 20 minutes with 10% neutral buffered formalin.
Dispatch balloon catheters were used for groups 2 and 3. The infusion was given by a constant injection via a Harvard syringe pump at a rate of 0.5 mL/min for 6 minutes. The infusion pressure was monitored continuously and stayed above the coronary perfusion pressure in most of the pigs studied. No ischemic ECG changes or ventricular arrhythmias were noted in any pig. For group 2, animals were killed and studied as in group 1 at 28 days after the initial procedure.
In group 3, an Alzet osmotic minipump (Alza Corp) containing 500 mg of BrdU (Sigma Chemical Co) was implanted subcutaneously after the local delivery with the Dispatch balloon catheter. At 4, 8, and 14 days after balloon injury, 6, 5, and 4 pigs, respectively, were killed and studied as described earlier.
Tissue Preparation and Analysis
The LAD and LCx containing 
1 to 2 cm of normal
coronary artery just proximal and distal to the injured segment
were dissected from the heart. The vessel was serially sectioned at 2-
to 3-mm intervals starting 1 to 2 cm proximal to the injured segment,
continued through the entire injured segment and including 1 to 2 cm of
normal vessel distal to the injured segment. The coronary
artery sections were embedded in paraffin by standard
histological techniques, and 5-mm sections of each
artery segment were cut. Tissue sections were fixed to glass microscope
slides, and two serial sections were stained with hematoxylin and eosin
or Gomori's aldehyde fuchsin trichrome stain. Additional serial
histological sections of selected artery segments were
cut from the ethanol-treated and untreated arteries of each animal.
These sections were deparaffinized and used in immunohistochemical
staining. Immunohistochemical staining was performed by standard
peroxidase-antiperoxidase staining procedures (avidin-biotin-peroxidase
kit, Dako Corp). The primary antibodies included mouse anti-BrdU
antibody (Boehringer Mannheim), anti-PCNA (PC10, Dako),
anti–smooth muscle 
-actin (Dako), anti–factor VIII–related
antigen (Dako), and an anti-macrophage antibody (HAM56, Dako).
Immunostaining for PCNA, smooth muscle actin, and HAM
56 was performed with the Ventana ES automatic immunohistochemical
stainer (Ventana Medical Systems). All the vessel sections along with
positive and negative control slides were stained at the same time
according to protocols optimized and programmed into the machine for
each individual antibody.
Morphometric Measurement
Morphometric measurement was performed in groups 1 and 2. The
presence of medial dissection and disruption of internal or external
elastic lamina was quantified by a modification of the scoring system
described by Karas et al.15 Briefly, the degree of medial
laceration and external elastic lamina stretch was given a grade of 0
for no injury, 1 for partial medial laceration, 2 for complete medial
laceration, and 3 for complete medial laceration and stretching of the
external elastic lamina. The amount of thrombotic material at the
injury site was evaluated at 14 days after injury with a scoring system
of 0 to 5, with zero indicating no thrombotic material discernible
within the neointima and 5 indicating a well-formed
thrombus within the injured vessel segment.
Quantitative analysis of injured vessel segments was done with a video-based Image-1 image analyzer system (Universal Imaging Corp) interfaced with a 486 computer by modifications of techniques previously described.16 17 Digital images of two histological vessel cross sections from each uninjured segment proximal and distal to the injured vessel segment were used to obtain the mean values for vessel outer diameter, vessel wall area (medial area), lumen area, and vessel wall (medial) thickness. Two to three sections of the injured artery segments were evaluated similarly to obtain mean values for the same vessel measurements as described for the uninjured vessel segments. The numbers of vessel segments examined were the same for the ethanol-treated and untreated groups. The maximal neointimal thickness was also measured in the injured segment and was defined as the maximal distance between the lumen and the outermost point of the largest neointimal area. These values from the uninjured and the injured vessel segments of each animal were used to calculate the mean neointimal area of the injured segment. Total vessel area was defined as the area measured by tracing the external elastic lamina, luminal area was defined as the area measured by tracing the luminal border, and the vessel wall area of the injured artery segments (including both media and neointima) was determined by subtracting the luminal area from the vessel wall area. The neointimal area was determined by subtracting the mean medial area of the uninjured control vessel segments from the vessel wall area of the injured segment (containing both media and neointima), thus giving the mean neointimal area for each injured vessel segment. Residual lumen ratio was defined as luminal area divided by (luminal area+neointimal area).
In vessel segments from the third group of animals killed 4 days after balloon injury, the thickness of the thrombotic material at the site of injury was measured by the video imaging system. The average thickness of the adherent thrombus was measured in ethanol-treated and untreated vessel segments, and the mean values for each group were expressed in micrometers.
Quantification of Proliferating SMCs by Immunohistochemical
Staining
Two immunohistochemical methods, anti-BrdU and anti-PCNA, were
used to quantify the proliferative activity of SMCs at the balloon
injury sites. For quantification of SMC proliferation after balloon
injury, all BrdU-positive and PCNA-positive cells were counted
separately in the neointima and media of all vessel cross
sections in the regions of maximal neointima. The total
numbers of intimal and medial SMCs in those areas were also counted.
The percentage of BrdU- or PCNA-stained positive cells divided by the
total number of cells in the neointima or media was used to
express the proliferative activity. In all cross sections studied, the
percentages of BrdU- or PCNA-stained positive cells in the uninjured
media were <1%. Thus, only the percentages of positively stained
cells in the neointima were used to compare the
ethanol-treated and untreated segments.
Due to technical problems, the amount of BrdU administered to each animal was not the same among all the animals in the study group. Thus, it was not possible to compare the absolute numbers of BrdU-labeled cells among all the animals. However, each animal had an ethanol-treated and an untreated (control) vessel segment. Thus, the BrdU labeling of the treated and untreated vessel segments from each animal could be compared to obtain a BrdU labeling index (% BrdU-positive cells in the ethanol-treated segment/% BrdU-positive cells in the untreated segment). This BrdU labeling index could then be compared among all the animals at each time point after balloon injury.
Arteriography
Vessel diameters and the balloon diameter for each injured
segment were measured from arteriograms by an experienced angiographer
using digital electronic calipers.
Statistical Analysis
All the morphometric measurements and quantification of
proliferative activity were performed by a pathologist (P.G.A.) blinded
to the treatment of the arteries. Data were expressed as mean±SEM. An
unpaired t test was used to compare the morphometric data of
the ethanol-treated and untreated arteries. Two-way ANOVA was used to
compare the proliferative activity of the ethanol-treated and untreated
arteries as assessed by PCNA staining over the three time points
studied. One-way ANOVA was used to analyze the BrdU labeling
index. The Student-Newman-Keuls test was used for multiple comparison.
A value of P<.05 was considered significant.
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Arteriography
The balloon/artery ratios determined angiographically were no different in untreated and ethanol-treated vascular segments either in group 1 (1.30±0.04 versus 1.34±0.06, P=NS) or group 2 (1.25±0.02 versus 1.26±0.02, P=NS).
Morphometric Analysis
The lesions produced by balloon overstretch injury in these
pig arteries were similar to lesions previously
described,15 17 and the degree of injury was similar in
the ethanol-treated and untreated vessel segments, as demonstrated by
the histological injury score (Tables 1
and 2).
The balloon injury resulted in rupture of the internal elastic membrane
and laceration of the media. The extent of medial laceration and
adventitial stretching of each vessel was somewhat variable;
however, the degree of injury was similar among all the groups. At 4
days after balloon injury, there was evidence of thrombotic material at
the injury site. The average thickness of the thrombus present at
the site of injury was significantly less in the ethanol-treated artery
segments (7.75±0.93 µm) compared with the untreated vessel
segments (18.75±2.91 µm, P=.011) (Fig 1). This is consistent with the
results of the scoring for the degree of thrombus accumulation in the
neointima at 14 days (Table 1 and Fig 2).
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The neointima consisted primarily of SMCs, as characterized
by the immunohistochemical staining for smooth muscle -actin. These
cells had the typical morphological appearance of the synthetic
phenotype of SMCs. At the early time points (4 and 8 days),
there were occasional macrophages within the
neointima, but these cells made up <3% of the total cell
population. At 8 and 14 days after balloon injury,
endothelial cells (factor VIII positive) were
present overlying the neointima. At 14 days, the
neointima comprised SMCs of the secretory
phenotype, and there was abundant extracellular matrix.
Immunohistochemical staining of consecutive
histological sections for smooth muscle -actin,
BrdU, and PCNA demonstrated that the proliferating cells were SMCs.
Many endothelial cells were also positive for BrdU and
PCNA. In the vessel cross sections from the injured segments, there
were very few proliferating cells in the uninjured region of the media
away from the area of medial laceration. At 28 days after PTCA injury,
the neointima was morphologically similar to
neointima at 14 days after injury. There were, however,
subtle changes in the orientation of the SMCs within the
neointima. At 28 days after PTCA injury, the SMCs tended to
be more fusiform, and the cells were aligned parallel to the lumen
surface. There were fewer SMCs that were proliferating, as evidenced by
fewer BrdU- and PCNA-positive cells.
At 14 days (group 1) after initial balloon injury, 6 vascular segments
(3 LAD segments and 3 LCx segments) showed no evidence of internal
elastic membrane rupture or neointimal proliferation and
were excluded from the morphometric analysis because of the
absence of discernible balloon injury. Neointimal area was
significantly reduced in the ethanol-treated group (0.25±0.08
mm2, n=13) compared with the untreated group
(0.57±0.08 mm2, n=13) (Table 1
and Fig 2). The
maximal neointimal thickness was also reduced in the
ethanol-treated vessel segments compared with the untreated group
(0.33±0.03 versus 0.49±0.05 mm, P<.002). The luminal
areas were similar in both groups (1.84±0.12 mm2 in
the treatment group versus 2.05±0.19 mm2 in the
untreated group). The residual luminal ratio was larger in the treated
group (0.89±0.03 in the treated group versus 0.78±0.03 in the
untreated group).
At 28 days, similar results were obtained (Table 2). Both
neointimal areas and maximal intimal thickness were
significantly reduced in the ethanol-treated group (0.33±0.05 versus
0.54±0.07 mm2, P=.03, and 0.27±0.03
versus 0.48±0.04 mm, P=.0001, respectively). Luminal
areas were similar between the groups. As in the 14-day study, residual
lumen ratios were larger in the ethanol-treated group (0.89±0.02
versus 0.74±0.05, P=.008).
Quantification of SMC Proliferation With BrdU and PCNA
Immunohistochemical Staining
Consistent immunohistochemical staining was achieved in
all vessel segments by use of the Venta automatic stainer. The number
of proliferating cells within the media was <1%. Within the area of
medial laceration and neointima formation, there were
significant numbers of proliferating cells (Fig 3). Serial histological
sections stained with SMC and macrophage markers showed that
most of the PCNA- and BrdU-positive cells were SMCs. The percentages of
PCNA-positive cells in the neointima at days 4, 8, and 14
were 49±5%, 23±2%, and 12±2% in the untreated sites and 25±3%,
15±2%, and 9±2% in the ethanol-treated sites, respectively (Fig 4). Two-way ANOVA showed values of
P<.002 for the treatment effect and P<.0001 for
the time effect, indicating that there were significant differences in
the number of proliferating cells at the three time points and that
ethanol treatment had a significant effect on cell proliferation. The
multiple-comparison test showed that at 4 and 8 days after balloon
injury, the percentage of PCNA-labeled cells in the
neointima of ethanol-treated arteries was significantly
reduced compared with untreated injured vessel segments. By 14 days,
however, there was no difference in PCNA labeling between treated and
untreated vessel segments.
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The BrdU labeling indices were 0.46±0.05 at day 4, 0.75±0.06 at day
8, and 0.86±0.07 at day 14 (Fig 5). A
BrdU labeling index of <1 indicates a decrease in BrdU labeling in the
ethanol-treated artery segments compared with the untreated artery
segment of the same animal. One-way ANOVA showed a value of
P=.001, and the multiple-comparison test showed a
significant reduction in BrdU labeling of ethanol-treated vessel
segments at day 4 but no difference at day 8 and day 14. These data are
similar to the PCNA results.
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Effect on Adventitia
There was no discernible difference in the number of BrdU- or
PCNA-positive cells in the adventitia after PTCA injury. At 4 days,
most of the proliferating cells were inflammatory cells (lymphocytes,
macrophages, and a few neutrophils), and there were few smooth
muscle actin–positive cells in the adventitia. By 7 days, there were
fewer proliferating cells; again, most of these were
macrophages, but there were numerous smooth muscle
actin–positive cells in the adventitia adjacent to the PTCA injury
site. The numbers of proliferating cells were even smaller at 14 days,
and by then the majority of cells in the adventitia adjacent to the
PTCA site were smooth muscle actin positive. These findings are similar
to the recent study that demonstrated myofibroblasts (smooth muscle
actin–positive fibroblasts) in the adventitia around PTCA injury
sites.18 The numbers of proliferating cells in the
adventitia adjacent to the injury site were similar in the
ethanol-treated and the untreated groups.
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Findings of the Study
In this model of balloon injury in pig coronary arteries, the degree of vascular injury was very similar between the ethanol-treated and control arteries as assessed either by histological injury scores or by balloon/artery diameter ratio. The results showed that local delivery of 15% ethanol immediately after injury resulted in decreased thrombus formation at days 4 and 14 and decreased neointima at days 14 and 28. Quantification of the proliferative activity of SMCs induced by balloon injury showed that the proliferative activity peaked at day 4, then persisted at a much lower rate through day 14, the last time point studied (Figs 4
and 5). These results were similar to the results of
pig coronary arteries studied with PCNA by Carter et
al19 and those of rabbit carotid arteries studied with
BrdU labeling by Hanke et al.20 In both studies, the
proliferation index reached a peak at day 3 to 7 and declined to
baseline after day 14 to 21. Most importantly, this study showed that
the initial burst of proliferative activity (days 4 and 8) was
significantly decreased in the ethanol-treated vessel segments by PCNA
immunochemical staining. The BrdU indices also showed similar results.
In both assessment methods of proliferation, the SMC proliferative
activity was reduced by nearly half in the ethanol-treated
segments. It is interesting to note that the total vessel areas (areas surrounded by external elastic lamina) were significantly larger in the control group than in the ethanol-treated group at 14 days, but this difference diminished at 28 days. When analyzed in individual groups, either a control or ethanol-treated group, we found that there was no significant relationship between the intimal area and total vessel area. When the combined data from both control and ethanol-treated groups were used to analyze the relationship, there was a positive correlation between the neointimal area and total vessel area (r=.4, P=.01). Therefore, the smaller total vessel area at 14 days in the ethanol-treated group may be due to a smaller neointimal area. At 28 days, there was a small increase in neointimal area. This may increase the total vessel area. Therefore, the difference of total vessel area between the groups became insignificant at 28 days.
Mechanisms of Action
The mechanisms of action are not clear. It is likely that one
mechanism responsible for the reduction in neointima
formation by local ethanol delivery was the direct effect of ethanol on
SMC proliferation. A number of in vitro studies had shown that ethanol
solution (<3%) can cause nonspecific desensitization of cell membrane
receptors and reduce the cellular responsiveness to agonist stimulation
for a prolonged period of time even after a relatively brief
exposure.9 10 21 22 Ethanol may also downregulate
c-myc and c-myb gene expression, both of which
were associated with cell growth.23 Furthermore, a number
of in vitro studies have shown that ethanol may inhibit cellular
proliferation and cause growth arrest in many cell
types.11 24 25 26 27 28 29 30 31 Therefore, we speculate that local delivery
of ethanol solution may readily penetrate the vascular wall,
infiltrating and exposing the SMCs to ethanol in vivo. This may lead to
alterations in cell membrane receptors that reduce the cellular
responses to the multiple growth stimulants induced by injury. This
would explain the inhibition of cellular proliferation and subsequent
reduction of neointimal formation in this study.
Our study also showed a reduction in thrombus formation after injury at days 4 and 14. Platelet aggregation and thrombus formation have been considered to play a significant role in intimal proliferation. This finding of decreasing neointimal formation by reducing thrombus formation at the site of injury has been described previously.32 Ethanol inhibits platelet aggregation induced by mechanical stimulation or thrombin.12 33 34 35 Inhibition of platelet aggregation by local ethanol treatment may also be responsible for the reduction in intimal proliferation.
Choice of an Agent for Local Delivery
The development of the technology for local delivery of
pharmacological agents into the vascular wall has allowed an excellent
opportunity to study the effects of high concentrations of
pharmacological agents on vascular SMCs. Because restenosis is
confined to the vascular segment of intervention, the local delivery
approach is logical and appealing. However, this approach has
limitations. After local delivery, the concentration of the agents in
the vessel wall decreases precipitously over the course of a few days
because of the rapid diffusion of the agents from the intima to the
adventitia.36 The proliferative activity of vascular SMCs
and growth-stimulatory factors usually lasts for a longer period.
Significant intimal proliferation may still occur even if initial
inhibition is achieved by an effective agent delivered to the site at
the time of injury. Other delivery modalities, such as slow-releasing
microspheres or coated stents, may overcome this
problem.37 Locally delivered ethanol solution that can act
on the cell instantly and produce a lasting effect may have several
advantages over alternative agents such as antisense
oligonucleotides38 and chimeric toxins,
which have unknown potential side effects.
Implications
The major mechanisms of restenosis include elastic recoil,
vessel wall remodeling, and intimal hyperplasia. Of these mechanisms,
elastic recoil and vessel wall remodeling can be counteracted by
intracoronary stenting, but intimal hyperplasia remains a
significant problem because effective clinical therapy to reduce
intimal hyperplasia is still unavailable. The efficacy of the local
ethanol delivery in preventing neointimal proliferation in
the pig coronary balloon injury model and the well-known
properties of dilute ethanol solution strongly support a potential
clinical use of local ethanol delivery to reduce restenosis in
humans.
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Acknowledgments |
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This study was partially sponsored by a grant from SciMed, Maple Grove, Minn. We thank Kerry Lyle for technical assistance.
Received March 7, 1997; revision received April 30, 1997; accepted May 2, 1997.
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