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Heart Institute, Good Samaritan Hospital, and Cardiovascular Division, University of Southern California, Los Angeles, California 90017-2395
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Two independent cardioprotective interventions, Na+/H+ exchange inhibition and ischemic preconditioning (PC), were investigated with respect to differential effects on microvascular and myocardial salvage in anesthetized rabbits (30 min of ischemia, 180 min of reperfusion). Cariporide (Car, 300 µg/kg) administered before occlusion and PC reduced infarct size (IS) as measured by triphenyltetrazolium staining [control, 46.0 ± 4.2% of risk area (RA); Car, 17.6 ± 3.7% (P < 0.01); PC, 27.5 ± 4.1% (P < 0.01)] and concomitantly decreased the area of anatomic no reflow (ANR) as measured by thioflavin S staining [control, 40.4 ± 3.7%; Car, 19.0 ± 2.9% (P < 0.01); PC, 26.9 ± 3.4% (P < 0.05)]. Regional myocardial blood flow (RMBF, measured by radioactive microspheres) in the RA, which deteriorated between 30 and 180 min of reperfusion (control, from 79 ± 6 to 26 ± 2% of nonischemic flow), was shifted to higher values with both treatments [Car, from 110 ± 12 to 49 ± 7% (P < 0.05); PC, from 109 ± 8 to 38 ± 6% (P < 0.05)]. However, neither intervention uncoupled the close relationship between IS and ANR (r = 0.92-0.95) or RMBF. Car given at reperfusion did not alter IS, ANR, RMBF, or the close interrelationships. Because size and spatial distribution of no reflow and myocardial necrosis remained closely coupled with independent cardioprotective interventions, a potential causal connection between microvascular and myocardial salvage is discussed.
infarction; microvasculature; regional blood flow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE NO-REFLOW PHENOMENON after temporary coronary artery occlusion, which is characterized by distinct zones of compromised tissue perfusion and microvascular damage within the previously ischemic tissue (1, 23, 24), is closely correlated with infarct size (IS) after different durations of ischemia and reperfusion (35). Recent investigations of microvascular reperfusion injury in a rabbit model of 30 min of coronary artery occlusion followed by reperfusion demonstrated a dramatic expansion of anatomic no reflow during the first 2 h of reperfusion that finally encompassed ~80% of the necrotic myocardium with a close spatial accordance (36). Hence, any significant IS-reducing intervention may concomitantly require reduction of microvascular injury.
From the various cardioprotective interventions, Na+/H+ exchange inhibition (2, 3, 38) and ischemic preconditioning (PC) (32) represent two of the most powerful and reproducible IS-reducing measures in experimental models of coronary occlusion and reperfusion that exhibit actions via different and independent pathways.
In addition to cardioprotective effects in vivo, experiments in other models including cardiomyocytes and endothelial cells in isolated cell preparations have demonstrated that both Na+/H+ exchange inhibition (2, 14, 16, 17, 42) and PC-like interventions (4, 19, 43) render the cardiomyocyte as well as the vasculature more resistant toward ischemic or hypoxic damage. Furthermore, Na+/H+ exchange inhibition in the canine model of ischemia-reperfusion exhibits modulatory effects on neutrophils (11) that might be involved in microvascular reperfusion injury and may attenuate endothelial dysfunction (14).
Thus if microvascular and myocardial damage in vivo were two different and independent entities, one would expect that different and independent measures of cardioprotection would result in differential microvascular and myocardial protection. However, if microvascular and myocardial salvage during reperfusion were causally linked, one would expect that neither intervention could uncouple no reflow from myocardial necrosis.
Therefore, the present study was designed to investigate the ability of cariporide (Car), which is a specific inhibitor of the Na+/H+ exchanger isoform 1 (39), and ischemic PC to reduce IS and anatomic no reflow in an in vivo model of ischemia-reperfusion and to elucidate whether microvascular salvage and myocardial salvage are affected independently by these interventions.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The experiments were conducted in accordance with national and institutional guides for the care and use of laboratory animals.
Animal Preparation
New Zealand White male rabbits (2.0-3.2 kg body wt) were anesthetized by administration of ketamine (400 mg im) and xylazine (200 mg im). Tracheotomy was performed, and ventilation was initiated with a respirator (model 665; Harvard Apparatus; South Natick, MA) using room air enriched with oxygen (1.5 l/min). Fluid-filled catheters were inserted into the right jugular vein and carotid artery for administration of additional anesthesia (pentobarbital, as needed) and continuous monitoring of arterial blood pressure.Left lateral thoracotomy in the fourth intercostal space and pericardial incision were performed, and a major branch of the circumflex coronary artery was encircled by a 4-0 silk suture (Ethicon; Sommerville, NJ). The two ends of the suture were threaded through a piece of plastic tubing, which formed a snare that could be tightened to achieve coronary artery occlusion. A fluid-filled catheter was inserted into the left atrial appendage and fixed. Body temperature, monitored as rectal temperature, was maintained by a heating pad.
Hemodynamics
Heart rate and systolic and diastolic blood pressures were measured and averaged over three consecutive cardiac cycles for each sample period.Assessment of Ischemic Risk Area, Area of No Reflow, and IS
At the end of the protocol, 1 ml/kg of 4% thioflavin S (Sigma Chemical; St. Louis, MO) that had been dissolved in 0.9% saline and centrifuged at 1,500 rpm for 5 min was injected into the left atrium. Thioflavin S is a vital fluorescent stain for endothelium. After ~1 min, the coronary artery was reoccluded, and 4 ml of 50% Uniperse blue (Ciba Geigy; Hawthorne, NY) was injected into the left atrium to measure the ischemic risk area (RA). The rabbit was euthanized by an overdose of xylazine (100 mg iv) followed by potassium chloride (12 meq intra-atrial). The heart was removed, and the left ventricle was sliced into six or seven transverse sections that were photographed under water, rephotographed under ultraviolet light (wavelength, 365 nm) in a dark room (model ENF 280 C Spectroline; Spectronics; Westbury, NY) using a Y48 barrier filter (Minolta), and again photographed after incubation in 1% triphenyltetrazolium chloride (TTC, at 37°C for ~15 min). TTC stains viable myocardium red, and necrotic tissue appears pale yellow. The nonfluorescent area within the RA was defined as the area of no reflow (ANR), whereas fluorescence in the rest of the heart appeared to be homogeneous. The contour of each slice, the RA (not stained by the blue dye), the ANR, and the IS not stained by TTC were traced manually from projected slides. After computerized planimetry, the percentage of the area was multiplied by the weight of the slice. The RA was expressed as a percentage of the weight of the left ventricle, and the ANR and IS were expressed as the percentage of the weight of the RA.Regional Myocardial Blood Flow
Regional myocardial blood flow (RMBF) was measured by intra-atrial injection of ~500,000 microspheres/measurement labeled with 141Ce or 103Ru at 30 and 180 min of reperfusion. Simultaneously, a reference blood sample was withdrawn through the arterial catheter at a rate of 2.06 ml/min. The hearts were cut into samples stained by the blue dye (nonischemic tissue) and not stained by the dye (tissue at risk). Tissue and blood-sample radioactivity was counted by a multichannel pulse-height analyzer (model ND62; Nuclear Data; Schaumburg, IL). RMBF was calculated after correction for background and crossover as the ratio of counts in the tissue and the reference blood sample multiplied by the reference flow rate and divided by the tissue sample weight.Protocol 1: Car Before Occlusion vs. Ischemic PC
In protocol 1, animals were randomly assigned to one of three groups (control, Car before occlusion, and PC; n = 12 rabbits/group). Approximately 15 min after surgery, the animals in the Car group received a Car bolus of 300 µg/kg iv (1 g/l of solution in distilled water); the other animals received 300 µl/kg iv of distilled water. In the PC group, the coronary artery was occluded for 5 min, which was followed by 10 min of reperfusion. After that or 15 min after injection of the bolus in the control and Car groups, the coronary artery was occluded for 30 min, which was followed by reperfusion for 180 min. RMBF was measured at 30 min of reperfusion and at the end of the protocol before injection of thioflavin S.Protocol 2: Car at Reperfusion
Approximately 15 min after surgery, the coronary artery was occluded for 30 min. Thereafter, the animals were randomized to either control or Car treatment groups (n = 8 rabbits/group). Control animals received a bolus of 300 µl/kg iv of distilled water 5 min before reflow (25 min of occlusion). In the treatment group, 300 µg/kg of Car was administered at the same time. Again, measurement of RMBF was performed at 30 min of reperfusion and at the end of the protocol.Statistical Analysis
Animals showing an RA of <20% of the left ventricle as well as nonsurviving animals were excluded and replaced. Data are expressed as means ± SE. The RA, ANR, and IS in protocol 1 were compared by one-way ANOVA; in protocol 2, these values were compared by Student's t-test. Hemodynamics, temperature, and RMBF as a percentage of nonischemic RMBF were compared by two-way ANOVA for correlated measurements over time. For post hoc comparisons, Tukey's honestly significant difference test was applied. Linear regression analysis used Pearson's minimal square method with subsequent ANOVA for significance. A P value of <0.05 was considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exclusions
In protocol 1, 4 animals that died during the experimental procedure (2 from Car, 1 from PC, and 1 from control groups) and 2 animals with an RA of <20% (1 from Car and 1 from PC groups) were excluded and replaced. Presented data are based on 12 animals in each group. In protocol 2, 4 animals died (2 control and 2 before randomization) and 1 heart showed an RA of <20% (control). In protocol 2, presented data are based on 8 animals in both groups.Protocol 1: Car Before Occlusion and Ischemic PC vs. Control
Hemodynamics.
Coronary occlusion resulted in decreased systolic and diastolic blood
pressures accompanied by increased heart rates in all groups (Table
1). During reperfusion, blood pressure
tended to further decrease along with an additional increase in heart
rate. Statistical analysis revealed a time-related effect for all
parameters (P < 0.01) without differences between
groups. For systolic blood pressure values, an interaction effect was
found due to a significant decrease of systolic blood pressure from
baseline to preocclusion levels in the PC group (P < 0.05). During occlusion, blood pressure values were similar among the
groups.
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RA, IS, and ANR.
The RAs in the three groups did not significantly differ from one
another (Table 2 and Fig.
1). Both interventions significantly reduced IS in comparison to control (P < 0.01): Car by
62% (P < 0.01) and ischemic PC by 40%
(P < 0.01). The higher degree of IS reduction by the
Car group did not reach statistical significance compared with the PC
group. Concomitantly, the ANR values were significantly reduced by 53%
in the Car group and 34% for the PC group without significant
differences between the two treatments (Fig. 1A).
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RMBF.
RMBF (Fig. 2) in the RA declined in each
group between 30 and 180 min of reperfusion, whereas blood flow in the
nonischemic tissue remained constant or even slightly increased
(Fig. 2A). RMBF in the RA declined from 79 ± 6 to
26 ± 2% of nonischemic blood flow between 30 and 180 min
of reperfusion in the control group. At both time points during
reperfusion, this percentage was increased in the two treatment groups
(Car, from 110 ± 12 to 49 ± 7%; PC, from 109 ± 8 to
38 ± 6%; group effect, P < 0.05, either
treatment vs. control). The decline over time in either treatment group
was proportional to the decline in the control group (time-related
effect, P < 0.01, no interaction).
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Relationships among IS, ANR, and RMBF.
In each group, the sizes of the ANR and IS were significantly
correlated (r = 0.92-0.95; see Fig. 1A)
and spatial distributions showed a high accordance. Notably, the
regression lines between IS and ANR were very similar in the three
groups, which indicates that the reduction of no reflow with both
interventions was always coupled with a parallel IS reduction. IS and
RMBF in the RA as a percentage of nonischemic flow at 30 and
180 min of reperfusion showed an inverse correlation in each group;
however, probably because of the relatively high variability of these
data, especially at 30 min of reperfusion, these correlations did not
reach statistical significance in every group (Fig.
3A). The distributions of the individual data points and the regression lines again suggested that
the increased RMBF in the Car and PC groups was mainly the result of IS
reduction in these groups.
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Protocol 2: Car at Reperfusion vs. Control
Hemodynamics.
Hemodynamics (Table 3) and temperature in
protocol 2 followed a similar pattern during occlusion and
reperfusion as in protocol 1. Heart rate and temperature in
the control group were slightly but significantly higher than in the
Car group without interaction effect. Blood pressure data were
comparable between the two groups.
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RA, IS, and ANR.
The RA in the Car group did not significantly differ from the control
group (Table 4 and see Fig. 1). Car at
reperfusion did not reduce IS as a percentage of the RA; indeed,
average IS was somewhat higher compared with the controls
(P < 0.31, two-tailed t-test).
Concomitantly, the ANR was slightly larger in the Car group
(P < 0.27, two-tailed t-test).
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RMBF. In both groups, RMBF in the RA declined over time, which was similar to the control group in protocol 1. RMBF within the RA decreased from 79 ± 12 to 35 ± 6% of nonischemic flow in the control group and 84 ± 8 to 28 ± 5% in the Car group. Two-way ANOVA revealed a significant time-related effect (P < 0.01) without significant differences between the two groups or interaction effects (see Fig. 2B).
Relationships among IS, ANR, and RMBF. The ANR and IS values in these two groups were again significantly correlated (r = 0.77-0.96), and the lines of regression demonstrated a similar relationship between the distribution of IS and the size of no-reflow zones in both groups (see Fig. 1B). Again, RMBF in the RA was inversely correlated with IS, which did not reach statistical significance at 30 min of reperfusion in the Car group. The corresponding regression lines demonstrated (given the variability of the data, especially at 30 min of reperfusion) a similar trend for each group (Fig. 3B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study confirms the powerful IS-reducing potential of ischemic PC and Na+/H+ exchange inhibition when commenced before ischemia in the rabbit model of 30-min coronary occlusion followed by reperfusion (13). Na+/H+ exchange inhibition initiated shortly before reflow did not reduce IS, which is in contrast with a number of studies that demonstrated cardioprotection of Na+/H+ exchange inhibition when limited to reperfusion (21, 33, 37). On the other hand, several investigations did not demonstrate beneficial effects of Na+/H+ exchange inhibition limited to reperfusion (3, 22). Perhaps differences in the experimental protocol, animal model, and statistical power might be put forward to explain some of the contradictory investigations. Also, it seems to be widely accepted that Na+/H+ exchange inhibition initiated before ischemia is much more effective than treatment at reperfusion, and higher doses are needed to accomplish cardioprotection with late treatment (26). However, Linz et al. (26) demonstrated significant IS reduction with Car treatment limited to reperfusion in a rabbit model of coronary occlusion and reperfusion that was very similar to our study. But even in this study by Linz and colleagues (26), IS reduction with a high dose of Car given at reperfusion was markedly less than that seen with the same dose of Car administered before ischemia.
It is unlikely that our study did not show a significant difference because of insufficient power of the statistical test, as IS was even somewhat higher in the Car group. The reasons for these contradictory results remain unexplained.
In the present study, IS reduction as a result of ischemic PC and treatment with Car before occlusion was accompanied by a pronounced reduction of anatomic no reflow. Although the major amount of no reflow in this model depends on reperfusion injury and develops during the first 2 h of reperfusion (36), Car given shortly before reperfusion, which failed to reduce IS in this study, also did not reduce anatomic no reflow. Indeed, linear regression analysis for all of these groups revealed a nearly identical relationship between IS and anatomic no reflow.
Na+/H+ Exchange Inhibition and Ischemic PC: Two Different and Independent Cardioprotective Interventions
Two of the most powerful and reproducible cardioprotective interventions in experimental models of coronary occlusion and reperfusion were chosen in this study (13). Different and independent mechanisms are believed to confer the IS-reducing effects of Na+/H+ exchange inhibition (3, 38) and ischemic PC (29): Na+/H+ exchange inhibition, assumed to protect ischemic myocardium via a delay of intracellular sodium and, subsequently, calcium accumulation (18, 20, 31), exhibits additional IS reduction when combined with ischemic PC (5, 13) and does not abolish the protective effects of PC when the exposure to a Na+/H+ exchange inhibitor is limited to the duration of the PC stimulus (40). On the other hand, inhibitors of the PC pathway, namely, inhibitors of protein kinase C translocation (41, 30), adenosine receptor antagonists (12), or inhibitors of ATP-dependent potassium channels (12, 15), do not diminish IS reduction by Na+/H+ exchange inhibition.Is There a Causal Link Between Microvascular and Myocardial Salvage?
In theory, there are two explanations for the nearly identical relationships between IS and perfusion defects with different interventions: a parallel independent protective effect of the two interventions on the microvasculature and the cardiomyoctes or a causal link between perfusion defects and necrosis. If microvascular and myocardial protection by the two interventions were independent entities and not causally linked, one would have to assume that the apparently proportional amount of microvascular and myocardial protection conferred by Na+/H+ exchange inhibition and ischemic PC were just coincidental. As neither of the two independent cardioprotective interventions investigated in this study uncoupled the relationship between IS and no reflow, a causal connection between microvascular and myocardial damage appears to be the more likely explanation.In a recent study, we analyzed the relationship between no reflow and IS after different durations of myocardial ischemia and reperfusion: after 2 h of reperfusion, IS was the main determining factor for no reflow notwithstanding the duration of ischemia (35). If myocardial and microvascular damage were not causally connected, one would think that lengthening the duration of ischemia would lead to different increases in the necrotic zones and worsening of no reflow. Because this was not the case, the more likely and simpler explanation would be a causal connection between necrosis and no reflow.
Microvascular and Myocardial Damage in Reperfused Infarcts
Although a causal connection between microvascular and myocardial damage is a reasonable explanation for our results in this model of reperfused myocardial infarction without relevant collateral flow (36), the findings do not identify the factor connecting them. Different concepts on the origin of no reflow have been developed to explain its occurrence and progression during early reperfusion, but the significance and mutual interactions are still matters of debate.Ultrastructural signs of microvascular damage in canine infarcts such as localized endothelial swelling and protrusions were always confined to areas of myocyte necrosis and temporarily lagged behind myocyte cell death with various durations of ischemia (25). During reperfusion, accumulation of leukocytes in the microvasculature that leads to mechanical plugging (1, 7, 8) and interactions with platelets, the endothelium, and cardiomyocytes has been put forward to explain the progression of anatomic no reflow. In addition, tissue edema (27) and oxygen free radicals (6) derived from polymorphonuclear cells, the xanthine oxidase reaction, or mitochondria may be involved in reperfusion-related expansion of anatomic no reflow (34) and hence contribute to the size of perfusion defects after 3 h of reperfusion. Accordingly, the irreversible damage of cardiomyocytes could initiate a chain reaction and serve as the inflammatory stimulus that leads to leukocyte accumulation, oxygen free radical production, tissue edema, and, subsequently, microvascular perfusion defects with the observed close accordance in size and spatial distribution of no reflow and necrosis.
However, the results of the present investigation are also consistent with the idea that microvascular perfusion defects in this model limit the amount of myocardial salvage that occurs during reperfusion. In the early investigations by Ambrosio et al. (1) of microvascular reperfusion injury in the canine, which is associated with higher collateral flow to the ischemic tissue during occlusion, "the size of infarct and low flow areas were linearly correlated...with a minimum infarct size of about 20% of the risk region required before any low flow area was seen." Interestingly, ANRs in this study were characterized by very low collateral flow during occlusion. In the present study, however, linear regression analysis in either group consistently demonstrated a positive ordinate intercept (see Fig. 1), which means that a certain amount of no reflow was already present with minimal amounts of necrosis. To date, no-reflow zones using thioflavin S as a marker for perfused tissue accompanying such small infarcts have not yet been investigated, and one might reach the limit of reliable spatial discrimination of this technique. On the other hand, if microvascular perfusion defects were the limiting factor for cardiomyocyte salvage during reperfusion in the rabbit, and if small border zones of the no-reflow area could be salvaged by diffusion of oxygen from the surrounding perfused tissue, one might expect exactly the observed relationship between anatomic no reflow and IS with a positive ordinate intercept and a slope of <1: small infarcts would be accompanied by proportionally larger no-reflow zones, and as the diffusional component becomes negligible with lower surface-to-volume ratios of larger zones of microvascular obstruction, larger infarcts would be associated with proportionally smaller no-reflow zones. This causal chain between microvascular and myocardial damage would support studies that showed simultaneous reduction of anatomic no reflow and necrosis by interventions initiated at reflow (10) and suggest a contribution of no reflow to myocardial damage (9). However, a recent study in the canine that provided evidence for a quantitatively relevant transition of reversible cardiomyocyte injury to irreversible cardiomyocyte cell death during reperfusion emphasized that cardiomyocytes from no-reflow zones had already been dead at the time of initiation of reperfusion (28).
Summary and conclusions. In this study, ischemic PC and Na+/H+ exchange inhibition when commenced before ischemia exhibited pronounced microvascular and myocardial protection. Despite a similar temporal progression of no reflow during reperfusion in comparison with previous studies (as evident by measurement of RMBF), Na+/H+ exchange inhibition initiated shortly before reflow did not reduce anatomic no reflow or IS. Regression analysis suggested that reduction of no reflow was always coupled with IS reduction. The findings might be explained by postulating a causal connection between the amount of microvascular and myocardial damage in this in vivo model of reperfused myocardial infarction without relevant collateral flow.
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ACKNOWLEDGEMENTS |
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Cariporide was a generous gift of Aventis Pharma Deutschland, Frankfurt am Main, Germany.
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FOOTNOTES |
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This work is supported in part by National Heart, Lung, and Blood Institute Grant HL-61488.
Address for reprint requests and other correspondence: R. A. Kloner, Heart Institute, Good Samaritan Hospital, Univ. of Southern California, 1225 Wilshire Blvd., Los Angeles, CA 90017-2395 (E-mail: RKloner{at}goodsam.org).
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. Section 1734 solely to indicate this fact.
First published October 10, 2002;10.1152/ajpheart.00563.2002
Received 8 July 2002; accepted in final form 4 October 2002.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, solid line)
ANR = 3.1 + 0.8 IS; r = 0.92;
P < 0.0001. Cariporide (Car) before occlusion group
(
, dashed line) ANR = 5.8 + 0.8 IS;
r = 0.93; P < 0.0001. Preconditioning
(PC) group (
, dotted line) ANR = 5.2 + 0.8 IS; r = 0.95; P < 0.0001. B: protocol 2. Control group (
0.68 IS,
r =