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(Circulation. 1995;91:2819-2823.)
© 1995 American Heart Association, Inc.
Articles |
Aspirin Enhances the Benefits of Late Reperfusion on Infarct Shape
A Possible Mechanism of the Beneficial Effects of Aspirin on Survival After Acute Myocardial Infarction
From the Division of Cardiology, Departments of Medicine and Pathology (L.T., R.M.), State University of New York at Stony Brook, Nassau County Medical Center, East Meadow.
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Abstract |
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Background The time window of the benefits of late reperfusion on infarct shape is limited. In rats, these benefits diminish in a wave front over time, with minimal benefits when reperfusion follows 16 hours of coronary occlusion. The mechanism of the benefits of aspirin on survival after acute myocardial infarction is unknown. The purpose of this study was to test the ability of aspirin to enhance the benefits of late coronary artery reperfusion on infarct shape and to examine the mechanism of the benefits of aspirin on infarct shape.
Methods and Results Rats were entered into two different protocols, the morphometric and the histological protocols. In the morphometric protocol, rats were randomized into two groups: the aspirin group, in which rats underwent left coronary artery occlusion followed by treatment with aspirin (12 mg/kg IV), and the control group, in which rats underwent left coronary artery occlusion followed by treatment with placebo. Rats in both groups were reperfused 8 hours after coronary occlusion. Rats in the aspirin group received aspirin in the drinking water (12±2 mg/kg daily). Morphometric analysis was performed 2 weeks after acute myocardial infarction. In the histological protocol, rats underwent the same randomization, coronary occlusion, and reperfusion protocols. Hearts were removed 24 hours after coronary occlusion, and microvessels were assessed for patency. Infarct size expressed as a percent of circumference was similar in the aspirin and placebo treatment groups (28±2% versus 33±3%, P=NS). Septal thickness was also similar in both groups (1.8±0.1 versus 2.1±0.1 mm, P=NS for aspirin versus placebo). The aspirin-treated group had thicker infarcts compared with the placebo-treated group (0.8±0.1 versus 0.5±0.1 mm, P<.05) and less expanded infarcts (expansion index, 1.2±0.1 versus 2.0±0.2, P<.05). Aspirin was associated with increased patency of the microvessels in the infarcted area compared with the placebo group (96% versus 64% of microvessels patent, P<.001).
Conclusions Aspirin enhances the benefit of late coronary artery reperfusion on infarct shape after 8 hours of coronary occlusion. The benefits of aspirin on infarct shape after late reperfusion are related to increased patency of the microvessels in the infarcted area.
Key Words: aspirin • reperfusion • infarction
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Late coronary artery reperfusion without significant infarct size reduction will prevent infarct expansion.1 2 3 4 The time window of the benefits of late coronary reperfusion on infarct shape is limited. In rats, these benefits diminish in a wave front over time, with minimal benefits observed when reperfusion follows 16 hours of coronary occlusion.5
Results from the ISIS-2 trial demonstrate that aspirin is effective alone or with thrombolytic therapy in reducing mortality in patients with evolving myocardial infarction.6 Benefits were observed for the 2-year follow-up period and were associated with reperfusion up to 24 hours after the onset of chest pain. The mechanism of the beneficial effects of aspirin is not known.
During the past two decades, it has been shown that platelet aggregation and formation of thrombi are pathophysiologically important in syndromes of ischemic heart disease. In response to vessel wall injury, platelets aggregate and release granular contents, leading to further platelet aggregation, vasoconstriction, and eventual formation of thrombi. Within platelets, aspirin blocks the synthesis of thromboxane A2, a vasoconstrictor and promoter of platelet aggregation, by irreversibly acetylating a serine residue and thus inhibiting the cyclooxygenase and hydroperoxidase reactions needed for further production of thromboxane A2.7 8 9 10
We focused on late reperfusion, which has a beneficial effect on infarct shape with no associated infarct size reduction. Late reperfusion may work by filling blood vessels in infarcted tissue that act as a baffle and prevent infarct expansion. Occluded microvessels would be expected to decrease the effect of late reperfusion on infarct shape. We hypothesized that aspirin would decrease plugging of microvessels by inhibiting platelet aggregation. Decreased plugging would increase patency and enhance benefits of late reperfusion on infarct shape. The purpose of this study was to test the ability of aspirin to enhance the benefits of late reperfusion on infarct shape and to examine the effect of aspirin on the patency of microvessels in the infarcted area.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Guidelines for Animal Use
All procedures used in this protocol conform to the guidelines, laws, and policies of Nassau County Medical Center, the state of New York, the federal government, and the American Physiological Society. The protocol was approved by the Animal Users' Committee of the Nassau County Medical Center. The medical center is accredited by the American Association for the Accreditation of Laboratory Animal Care.
Experimental Myocardial Infarction
Female Sprague-Dawley rats
(n=54) weighing 175 to 250
g were randomized into two groups before surgery. In the
aspirin-treated group, rats underwent left coronary artery ligation
followed by aspirin treatment (12 mg/kg in 0.5 mL of 0.9% saline IV).
In the placebo-treated group, rats underwent left coronary artery
ligation followed by placebo (0.5 mL of 0.9% saline IV).
After anesthesia with 44 mg/kg methohexital IP and local anesthesia with 1% lidocaine, the tracheas were exposed in the midline, and the rats were intubated under direct vision and ventilated with room air. The heart was exposed through a left intercostal thoracotomy, and a pericardiectomy was performed. The intramyocardial left coronary artery was occluded by snaring and tying a band of myocardium 1 to 2 mm below the left atrial appendage. To facilitate suture removal, the knot was tied over a piece of Gore-Tex measuring 5x5 mm. Successful occlusion was confirmed by the pallor of the anterior wall of the left ventricle and by left ventricular wall motion abnormalities. If neither change was observed, the occlusion was repeated. The ribs were closed with 4-0 chromic suture, and surgical staples were used to close the neck and chest skin incisions. The rats were extubated and allowed to recover. Benzathine penicillin (100 000 U IM) was given prophylactically. For reperfusion, rats were reanesthetized with 44 mg/kg methohexital IP and then intubated and ventilated with room air. Chests were reopened, and hearts were exposed. Reperfusion was performed by cutting of the knots around the left coronary artery 8 hours after coronary artery occlusion. All rats received standard care, including ad libitum food and water and a 12-hour day/night cycle.
Aspirin Therapy
The first dose of aspirin was given
intravenously (12 mg/kg in
0.5 mL of 0.9% saline) after coronary artery ligation. Rats were kept
one to a cage. The aspirin solution was prepared to provide an aspirin
concentration of 0.1 mg/mL. Rats were allowed to drink from the
solution daily for 2 weeks. The water was changed three times per week,
and the exact amount of water ingested was measured. The average daily
dose of aspirin varied minimally for each rat during the course of the
experiment.
Heart Fixation and Preparation
Morphometric Protocol
Two weeks after acute myocardial infarction, rats were
anesthetized with an intraperitoneal injection of ketamine (60 mg/kg)
and diazepam (7.5 mg/kg) and then intubated and ventilated with room
air. Chests were opened by a left parasternal incision; the hearts were
arrested by infusion of ice-cold saturated KCl through the femoral
vein, excised, and placed in ice-cold KCl to achieve uniform diastolic
arrest.
Fixation was achieved by infusing 10% phosphate-buffered formalin into the left ventricular cavity through a double-lumen catheter. The second lumen was an exit port; its height was adjusted to provide a fixation pressure of 7.5 mm Hg and was constant for all hearts. During fixation, the entire heart was submerged in a 10% phosphate-buffered formalin bath for 24 hours. After fixation, the hearts were cut transversely from apex to base into four equal slices. The slices were projected at x10 magnification and traced for morphometric analysis. The precise extent of magnification was determined by photographing a 1-cm ruler with each slice. The bottom of the third slice (third from the base of the heart), which represented the middle of the left ventricle, was used for all morphometric analyses.
Histological Protocol
Four rats, two from
each group, were killed 24 hours after
coronary occlusion as described above. Heart sections were stained with
hematoxylin and eosin. Light microscopy (magnification, x400) was used
to assess microvessel patency in the infarcted area. Occluded vessels
were those with occluding thrombus within the lumen. The vessel was
considered patent when there was no luminal thrombus. The size of the
vessels was calculated with a computerized micrometer. We defined
microvessels as those with a diameter between 15 and 30 µm.
Epicardial vessel diameters ranged from 100 to 260 µm. Eighty
microvessels in each heart were assessed for patency.
Data Analysis
Measurement of Infarct Size
Infarct size was determined as the percentage of epicardial and
endocardial circumference occupied by the infarct on all heart slices.
A blinded observer assessed the photographed slice magnified 10x to
determine the infarcted from the noninfarcted segment. With planimetry,
infarct endocardial length, total endocardial length, infarct
epicardial length, and total epicardial length were measured. Infarct
size was calculated as follows: Infarct Size={[(Infarct
Endocardial
Length/Total Endocardial Length)+(Infarct Epicardial Length/Total
Epicardial Length)]/2}x100. Six values for each heart were
obtained
from the different slices. The average infarct size for each heart was
calculated.
Infarcted and Noninfarcted Wall Thickness
Infarcted wall thickness was determined as follows. Using the
bottom of the third heart slice from the base magnified 10x, 5 evenly
spaced radians were passed through the infarct with the center of the
left ventricular cavity as a reference, and the average infarct
thickness was calculated. Noninfarcted septal thickness was measured
similarly.
Myocardial Infarct Expansion
Expansion
was determined by previously described
methods.2 11 The bottom of the third heart slice was
magnified x10. Infarcted and noninfarcted thicknesses were determined
as above. Left ventricular cavity area and total left ventricular area
were measured with planimetry; then the expansion index was calculated:
Expansion Index=(Left Ventricular Cavity Area/Total Left Ventricular
Area)x(Noninfarcted Septal Thickness/Infarct Thickness).
Statistical Analysis
Results are expressed as
mean±SEM. Statistical comparisons of
infarct size, infarct thickness, septal thickness, expansion index, and
left ventricular weight between the aspirin-treated and control groups
were performed with unpaired Student's t tests. The
percentages of all the microvessels patent in each group were compared
by 
2 analysis. In total, 160 microvessels
were scanned for each of the two study groups. Significance was assumed
when P<.05. All data were gathered and analyzed by
observers blinded to the treatment group.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Of the 45 rats entered into the morphometric protocol and randomized before surgery into aspirin or placebo treatment groups, 19 died within 24 hours of surgery, 5 died 24 hours after surgery, and 1 had no myocardial infarction. Thus, 20 rats were available for morphometric analysis. Of the 9 rats entered into the histology protocol and randomized as above, 5 died within 24 hours of coronary occlusion. Therefore, 4 rats were available for histological analysis.
Morphometric Analysis
The Table
shows the
morphometric
measurements. Aspirin therapy had no effect on infarct size; infarct
size was similar in both groups (P=NS). Septal thickness and
left ventricular weight were also similar in both groups
(P=NS), indicating no difference in the extent of
hypertrophy in the noninfarcted segment during the 2-week experimental
period. Aspirin therapy combined with reperfusion after 8 hours of
coronary occlusion benefited infarct shape. Rats treated with aspirin
had thicker and less expanded infarcts compared with rats that
underwent reperfusion with no aspirin treatment (P<.05)
(Fig 1).
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Histological Analysis
Microvessel Patency
In
reperfused rats not treated with aspirin, 64% of the examined
microvessels were patent; in rats receiving aspirin, 96% of the
examined microvessels were patent (P<.001) (Fig 2).
In examinations of epicardial vessels, no difference
was noted between the two groups; all epicardial vessels in both groups
were patent 24 hours after coronary artery occlusion. Fig 3
shows representative photomicrographs of
infarcted myocardium from the two groups.
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Infarct
Hemorrhage, Edema, and Inflammatory Reaction
Qualitative analysis by
visual estimation of infarct
hemorrhage, edema, and inflammatory reaction revealed no difference
between the two treatment groups when examined 24 hours after acute
myocardial infarction.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study demonstrates that aspirin treatment, combined with late coronary artery reperfusion, has a beneficial effect on infarct shape after experimental rat myocardial infarction. Aspirin-treated late-reperfused infarcts were thicker and less expanded than late-reperfused hearts in non–aspirin-treated rats. These benefits were associated with increased patency of microvessels in the infarcted area when evaluated 24 hours after coronary occlusion.
After coronary occlusion, ischemia and hypoxemia of the infarcted zone will initiate injury and damage to the endothelial lining of blood vessels.12 As a response, platelets aggregate and release granular contents, leading to further platelet aggregation, vasoconstriction, and eventual formation of thrombi. Aspirin, by irreversible inhibition of the cyclooxygenase pathway, results in blockage of thromboxane A2 synthesis.7 8 Thromboxane A2 is a potent vasoconstrictor and promoter of platelet aggregation. The result of aspirin treatment is diminished platelet aggregation and the prevention of thrombus formation, which would be expected to result in increased patency of the microvessels in the infarcted area. In this study, aspirin did result in increased patency of microvessels, which was associated with improved infarct shape. These findings support our hypothesis that late reperfusion benefits infarct shape by filling vessels in infarcted tissues, which baffle the infarct and prevent infarct expansion.
Although aspirin treatment was associated with increased microvessel patency, other mechanisms for improved infarct shape are possible. First, reperfusion causes increased hemorrhage, cell swelling, and edema in the reperfused myocardium.13 14 15 16 17 These changes may make the infarcted wall stiffer and more resistant to systolic bulging with subsequently less expansion. By causing platelet dysfunction, aspirin may exacerbate hemorrhage and the resulting edema in the infarcted area, which could cause stiffer myocardium and decreased expansion. However, in the hearts examined at 24 hours, no difference in the extent of intramyocardial hemorrhage was noted. Second, by reducing the generation of oxygen free radicals,18 aspirin may decrease reperfusion injury and result in less endothelial damage and increased patency.
Other nonsteroidal antiinflammatory agents, including indomethacin and ibuprofen, have an adverse effect on infarct healing and promote thinning and expansion.19 20 Why aspirin does not share this adverse effect is not clear. Unlike other nonsteroidal antiinflammatory agents, aspirin has a salicylate moiety that may exert other antithrombotic effects in addition to platelet inhibition. The salicylate moiety inhibits the synthesis of vitamin K–dependent clotting factors, stimulates fibrinolysis, and antagonizes the lipoxygenase pathway of arachidonate metabolism in platelets.21 Another potential difference between aspirin and other nonsteroidal agents is that, while low-dose aspirin suppresses prostaglandin synthesis by irreversible inhibition of cyclooxygenase, other nonsteroidal agents inhibit prostaglandin synthesis by competitive inhibition of cyclooxygenase activity. In platelets, which cannot synthesize protein, this action is irreversible for the life of the cell.22 23 24 25 26 The effect of aspirin on endothelial cells is limited because of their ability to synthesize new cyclooxygenase; therefore, prostacyclin (PGI2) production continues.26 27 28 29 30
Clinical Implications
Aspirin was given as an initial loading
dose of 12 mg/kg IV after
coronary artery ligation. Maintenance aspirin was administered in the
drinking water at a dose of 12±2
mg · kg-1 · d-1. This
approximately
corresponds to an average dose of 720 mg/d in a 60-kg adult
patient.
Reperfusion therapy benefits patients with acute myocardial infarction by decreasing infarct size when performed early after the onset of coronary occlusion. Reperfusion at a later time improves survival and left ventricular function6 31 in the absence of any demonstrable benefits on infarct size. Decreasing infarct expansion is a likely mechanism by which late reperfusion benefits patients. Late reperfusion does not continue to decrease infarct expansion indefinitely. Beneficial effects on shape diminish progressively over time.5 Aspirin appears to extend the time window during which late reperfusion is beneficial to infarct shape. Improved left ventricular shape leads to better left ventricular function with subsequent better outcome in the form of improved survival and decreased morbidity. Increased patency of the microvessels associated with aspirin, combined with late reperfusion, may explain the clinical benefits of aspirin in acute myocardial infarction.
Study Limitations
The histological evaluation was performed
on four hearts, two
hearts from each group. Although the number of hearts was small, a
large number of microvessels were evaluated for patency. The
analysis was performed by an observer blinded to the treatment
group and to the results of morphometric analysis. Although
salicylate levels and platelet function tests were not measured, it is
assumed that blood levels of aspirin adequate to alter platelet
function were achieved because morphometric and histological end points
were altered.
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Footnotes |
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Reprint requests to Edward J. Brown, Jr, MD, Cardiology Division, Bronx-Lebanon Hospital Center, 1650 Grand Concourse, Bronx, NY 10457.
Received October 17, 1994; revision received December 8, 1994; accepted December 18, 1994.
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