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(Circulation. 1996;93:1784-1787.)
© 1996 American Heart Association, Inc.

Articles

Leukocyte Adhesion to the Coronary Microvasculature During Ischemia and Reperfusion in an In Vivo Canine Model

Frank M. Sheridan, MD; Paul G. Cole, MD; David Ramage, MS

From the Cardiology Section, Department of Medicine, Louisiana State University School of Medicine, Shreveport.

	Abstract

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Background Prompt reperfusion of ischemic myocardium or myocardium that is in the process of becoming infarcted is a cornerstone of current therapy for coronary artery disease. Paradoxically, experimental evidence suggests that cardiac damage may be caused by the reperfusion itself. Leukocyte attachment to the coronary vascular endothelium during reperfusion may be an initiating step in this detrimental process. Leukocyte adhesion to microvascular endothelium has never been demonstrated directly in a cardiac model of ischemia and reperfusion.

Methods and Results Fluorescent videomicroscopy through a special "floating" objective that allows a series of lenses to move in unison with the beating dog heart was used on the left ventricular surface of open-chest dogs. Epicardial microvessels (25 to 130 µm), in focus throughout the cardiac cycle, were recorded after infusion of acridine orange (to fluorescently label leukocytes) during either 1 hour of ischemia followed by 2 hours of reperfusion, 3 hours of ischemia, or 3 hours of no ischemia. The amount of net fluorescence recorded along microvessel walls, which represented leukocyte accumulation, significantly increased in dogs during reperfusion (n=8) compared with the same time period in the animals that were kept ischemic (n=5) (21.0±3.8 versus 10.9±4.5 gray scale; P=.0001). The rapid increase in fluorescence during reperfusion was also significantly different from values in the same group during the preceding period of ischemia (21.0±3.8 versus 5.1±2.1 gray scale; P=.0001), whereas no significant increase was seen over the same time periods in the animals that remained ischemic throughout the protocol.

Conclusions Reperfusion, compared with ischemia alone, promotes the rapid accumulation of leukocytes in the coronary microvasculature of dogs.

Key Words: reperfusion • ischemia • leukocytes • endothelium • microcirculation

	Introduction

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Modern treatment of ischemic heart disease involves the prompt reestablishment of blood flow to areas of myocardium that are undersupplied secondary to atherosclerosis and/or thrombosis. The return of oxygenated blood to ischemic myocardium, however, may cause injury to cardiac tissue. Ischemia-reperfusion injury involves an incompletely understood cascade of events that includes the effects of oxygen free radicals, complement activation, and vasoactive, proteolytic, and chemotactic factors.¹ There is resultant endothelial cell dysfunction, a decrease in coronary blood flow, myocyte swelling, and contraction band necrosis.²

The attachment of leukocytes to vascular endothelium is thought to be a key initiating step in ischemia-reperfusion injury. Leukocyte depletion has reduced infarct size in reperfused hearts experimentally^{3 4} and has diminished coronary microvascular endothelium damage.⁵ The importance of leukocyte attachment to endothelium has been illustrated by myocardial salvage and coronary endothelium protection when adhesion molecules on these cells are inhibited.^{6 7 8} Such findings suggest indirectly that the early adhesion and interaction of leukocytes with the coronary vascular endothelium plays an important role in ischemia-reperfusion injury to the heart.

The behavior of leukocytes in the microvasculature has been observed directly and recorded in vivo by use of intravital microscopy in noncardiac models of ischemia-reperfusion. In these stationary models, neutrophils are seen to transiently roll and then avidly attach to the endothelium of vessels during reperfusion.^{9 10} However, direct in vivo observation of leukocyte accumulation in coronary vessels has not been described. The present study uses intravital microscopy to record and quantify leukocyte attachment to coronary microvascular endothelium during ischemia-reperfusion in the beating dog heart.

	Methods

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Male dogs (weight, 10 to 16 kg) were anesthetized with intravenous thiopental sodium (20 mg/kg) and -chloralose (100 mg/kg) and mechanically ventilated. Anesthesia was maintained with supplemental doses of -chloralose as required. ECG lead II was monitored continuously, and a heparinized catheter was placed in the aorta via the right carotid artery for continuous monitoring of blood pressure. Arterial blood gases were kept within the physiological range by adjustments of the ventilatory rate, oxygen supplementation, and intravenous sodium bicarbonate. A left thoracotomy was performed, and the heart was suspended in a pericardial cradle. A catheter was placed into the left atrium. The coronary artery and/or branches that supplied the area of left ventricular myocardium chosen for microscopic examination were isolated carefully and loose sutures placed around them. In most cases, the left anterior descending artery beyond the first diagonal was chosen, but often other diagonals or obtuse marginals were chosen. To reduce excessive lateral movement of the heart, two 20-gauge needles were horizontally inserted through the midmyocardium of the left ventricle outside the field of interest and were fixed to a steel apparatus connected securely to the operating table.

For hearts subjected to ischemia, coronary arteries that supplied the area of interest were occluded by the encircling suture through a rubber shod. Ischemia was confirmed by cyanosis and akinesia of the left ventricular wall. Three groups of animals were studied. The ischemia-reperfusion (I-R) group (n=9) underwent 60 minutes of ischemia and 120 minutes of reperfusion caused by release of the suture. The ischemia-control (I-Ctl) group (n=5) underwent 180 minutes of ischemia with no reperfusion. The control group (n=5) experienced no ischemia for 180 minutes but otherwise were treated identically to the experimental animals, including isolation of appropriate coronary arteries and placement of sutures.

Visualization of epicardial coronary microvessels was achieved by use of an intravital microscope with a "floating" objective, as initially described by Ashikawa and colleagues.¹¹ This objective rests lightly on the epicardial surface, moving in concert with it, thus keeping the beating heart in focus. The image on the front focus of a convex lens that faces the heart is transmitted to the back focus of a second convex lens. The convex lens that faces the heart is mounted in a thin aluminum tube, the actual "floating" piece. This tube is supported by low-resistance ball bearings that permit the lens to move easily in unison with the cardiac motion. The image is not affected by a change in the distance between the lenses, because the transmitted light is parallel, and thus the focal length equals infinity over this distance. This transmitted image is then observed with a standard microscope. A video camera (Hamamatsu XC-77) mounted on the microscope recorded the images on videotape. Frames from the videotape were transferred to a computer (Macintosh Quadra 950) and analyzed by use of image processing and analysis software (NIH Image).

The fluorescence microscopy optical system consisted of a 100 W high-pressure mercury lamp, an interference excitation filter (420 to 490 nm), and a dichroic mirror barrier filter (515 nm). We labeled leukocytes by infusing acridine orange for 2 minutes into the left atrium through a catheter at 0.5 mg·kg^-1·min^-112 before each recording. Images were recorded 2 minutes after the acridine orange infusion was stopped at the following time points: 15 and 5 minutes before the protocol was begun (period 1); 10, 30 and 55 minutes into the first hour of the protocol (period 2); and 10, 60, and 120 minutes into the second and third hours of the protocol (period 3). The shutter was closed completely when recordings were not being made to keep tissue illumination with the epifluorescence system to a minimum. Vessels with diameters between 25 and 130 µm were selected for study.

We assessed leukocyte attachment to the endothelium by measuring the fluorescence intensity displayed along the microvessel walls. For each time point, three successive frames of videotape were analyzed during end diastole. A region of background tissue located away from the vessel was selected and the average gray level determined. Regions along the vessel wall were selected in the same frame as those for the background, and the average gray level was determined. The background gray level was subtracted from the vessel-wall gray level to provide a measure of the net fluorescence along the vessel wall.¹³

All animal procedures followed were in accordance with institutional guidelines. Data were analyzed by use of planned comparisons in conjunction with univariate repeated measures ANOVA to assess differences between the periods of interest and between the experimental groups.¹⁴ A probability value of P<.05 was considered statistically significant. All results are expressed as mean±SEM.

	Results

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Fluorescence in the microvessels of each experimental group during the three time periods of the protocol is graphically displayed in Fig 1. The typical increase in fluorescence along the vessel walls during ischemia and reperfusion is illustrated in the photographs of a microvessel (60 µm diameter) from a heart subjected to ischemia-reperfusion, shown in Fig 2.

View larger version (22K): [in this window] [in a new window]   Figure 1. Fluorescence measurements (gray level of vessel wall minus gray level of background) along the walls of coronary microvessels over 195 minutes. Starting at time 0, the ischemia-reperfusion group (, n=9) was subjected to 60 minutes of ischemia (period 2) and then reperfused for 120 minutes (period 3). The ischemia-control group (, n=5) was subjected to 180 minutes of ischemia only starting at time 0 (periods 2 and 3). The control group (, n=5) was not subjected to ischemia and was perfused under baseline conditions for the duration of the protocol. The vertical dashed line labeled "Ischemia" indicates the time of onset of ischemia for the ischemia-reperfusion and ischemia-control groups. The vertical dashed line labeled "Reperfusion" indicates the time of onset of reperfusion for the ischemia-reperfusion group. Although there were no differences between the three groups during period 2, fluorescence was significantly greater in the ischemia-reperfusion group than in the ischemia-control or control groups during period 3. Fluorescence in the ischemia-reperfusion group during period 3 (reperfusion) was also significantly greater than fluorescence in the same group during period 2 (ischemia). Values are mean±SEM.

View larger version (74K): [in this window] [in a new window]   Figure 2. Photomicrographs of a representative vessel subjected to ischemia and reperfusion. Before ischemia (A), little fluorescence, which represents leukocyte adhesion, is seen. During ischemia (B), fluorescence increases, and it increases more during reperfusion (C). The white bars in A, B, and C represent 100 µm.

During period 3, which constituted minutes 60 to 180 of the protocol, the mean vessel-wall fluorescence in the I-R group (21.0±3.8 gray scale) was greater than that in the I-Ctl (10.9±4.5 gray scale; P=.0001) and control groups (1.8±2.4 gray scale; P=.0008). In the I-R group, the mean fluorescence during reperfusion (period 3) was substantially greater than during ischemia (period 2) in the same group (21.0±3.8 versus 5.1±2.1 gray scale; P=.0001). In contrast, the mean fluorescence observed in the I-Ctl group during the last 2 hours of ischemia (period 3) was not significantly different from fluorescence during the first hour of ischemia in this group (10.9±4.5 versus 4.1±2.6 gray scale; P=.1). There was a significant difference in mean fluorescence in the I-Ctl group compared with the control group during period 3, the last 2 hours of ischemia (10.9±4.5 versus 1.8±2.4 gray scale; P=.03). There was no statistically significant difference in fluorescence between the three groups during period 2 (0 to 60 minutes of the protocol).

Hemodynamic data for each experimental group are displayed in the Table. There were no significant changes in heart rate, systolic blood pressure, or rate-pressure product over time in any of the three groups of animals. There were differences, primarily in systolic blood pressure, between the three groups at baseline that persisted throughout the other time periods.

View this table: [in this window] [in a new window]   Table 1. Summary of Hemodynamic Data

	Discussion

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Whether ischemia-reperfusion injury to the heart and other organs actually exists remains a topic of scientific debate. However, clinically significant coronary vascular injury after reperfusion may occur in patients. Spontaneous coronary artery vasospasm has been demonstrated to occur in about one third of patients in the initial hours to days after their admission for myocardial infarction.^{15 16} Coronary vasospasm also is frequently inducible in patients early after myocardial infarction.¹⁷ Increased vasoreactivity could be responsible for the 26% to 41% rate of recurrent ischemia reported in patients after thrombolytic therapy for acute myocardial infarction.^{18 19} Indeed, both contrast echocardiography²⁰ and positron emission tomography (PET)²¹ have demonstrated inadequate tissue reperfusion ("no reflow") in up to a third of infarction patients with TIMI grade 3 flow at early angiography. This is of particular concern because postinfarction ischemia is an independent predictor of later infarct extension and is associated with increased mortality.²² In addition, reperfusion after lesser degrees of ischemia may induce vascular injury, as previously demonstrated in animals.^{23 24} When used to evaluate coronary vasodilation distal to stenoses treated by angioplasty, this response has been shown by PET to be impaired for more than 7 days after a successful procedure.²⁵

Although previous indirect evidence has allowed postulation that the coronary microvasculature is attacked during reperfusion by leukocytes,^{5 6 7 26} the use of intravital microscopy in the heart in the present study directly confirms for the first time that reperfusion causes these inflammatory cells to accumulate avidly along the walls of coronary microvessels. The time course of inflammation is also suggested by our experiments, in which fluorescence increased by 10 minutes and maximized approximately 1 hour into reperfusion. This prompt adhesion is consistent with studies¹ that examined the timing of chemotactic factor and adhesion molecule expression as inflammation proceeded after reperfusion. Additionally, recent results from the clinical arena²⁷ demonstrated a similar rapid increase in cytokines, leukocyte adhesion molecules, and thrombomodulin (leaked from damaged endothelium) in the venous drainage from infarcted myocardium of patients whose coronary obstruction had just been opened by angioplasty. Although the increased fluorescence could possibly represent another or an additional phenomenon, such as increased uptake of acridine orange by damaged endothelium, we believe this is unlikely in view of the globular, intraluminal appearance of the fluorescence and the affinity of this marker for leukocytes as demonstrated by other investigators.^{12 28}

The rapid accumulation of leukocytes observed in the reperfused vessels is in contrast to a gradual trend toward increased fluorescence in the vessels that remained occluded in the present study. A similar vascular inflammatory process, albeit of a lesser intensity and which likely transpires over a longer period of time, probably occurs during ischemia and leads to diapedesis and eventual myocardial accumulation. However, in the canine heart, which is well known to possess significant collateral coronary circulation, this experimental group may also represent a state of continuous, gradual, low-flow reperfusion. It is suspected, in any case, that the vascular and clinical implications of the exuberant, early-reperfusion inflammatory response versus the more subtle one seen during ischemia may be quite different.

It is likely that activation and attachment of leukocytes to the microvascular endothelium during reperfusion promote endothelial injury and represent the initial step to diapedesis and invasion of the myocardium. Myocyte injury due to reperfusion may be a consequence of both impaired coronary blood reflow and subsequent leukocyte migration out of the microvasculature. A more complete understanding of this process may lead to beneficial adjunctive therapies to reperfusion for coronary artery syndromes.

	Acknowledgments

 
This work was supported by research grants from the Louisiana Education Quality Support Fund and the Louisiana Affiliate of the American Heart Association. The authors thank Fay Bouldin and Randall Davis for their expertise and technical assistance.

	Footnotes

 
Reprint requests to Frank M. Sheridan, MD, Cardiology Section, Louisiana State University School of Medicine, 1501 Kings Hwy, Shreveport, LA 71130. E-mail fsheri@lsumc.edu.

Received December 28, 1995; revision received February 29, 1996; accepted March 7, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Entman ML, Smith CW. Postreperfusion inflammation: a model for reaction to injury in cardiovascular disease. Cardiovasc Res. 1994;28:1301-1311. [Free Full Text]
   
2. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985;76:1713-1719.
   
3. Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork A, Lucchesi BR. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation. 1983;67:1016-1023. [Abstract/Free Full Text]
   
4. Litt MR, Jeremy RW, Weisman HF, Winkelstein JA, Becker LC. Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Circulation. 1989;80:1816-1827. [Abstract/Free Full Text]
   
5. Sheridan FM, Dauber IM, McMurtry IF, Lesnefsky EJ, Horwitz LD. Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion. Circ Res. 1991;69:1566-1574. [Abstract/Free Full Text]
   
6. Ma X-L, Lefer DJ, Lefer AM, Rothlein R. Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion. Circulation. 1992;86:937-946. [Abstract/Free Full Text]
   
7. Ma X-L, Tsao PS, Lefer AM. Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest. 1991;88:1237-1243.
   
8. Silver MJ, Sutton JM, Hook S, Lee P, Malycky JL, Phillips L, Ellis SG, Topol EJ, Nicolini FA. Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model. Circulation. 1995;92:492-499. [Abstract/Free Full Text]
   
9. Granger DN, Benoit JN, Suzuki M, Grisham MB. Leukocyte adherence to venular endothelium during ischemia-reperfusion. Am J Physiol. 1989;257:G683-G688. [Abstract/Free Full Text]
   
10. Korthuis RJ, Grisham MB, Granger DN. Leukocyte depletion attenuates vascular injury in postischemic skeletal muscle. Am J Physiol. 1988;254:H823-H827. [Abstract/Free Full Text]
    
11. Ashikawa K, Kanatsuka H, Suzuki T, Takishima T. A new microscope system for the continuous observation of the coronary microcirculation in the beating canine left ventricle. Microvasc Res. 1984;28:387-394. [Medline] [Order article via Infotrieve]
    
12. Zeintl H, Sack F-U, Intaglietta M, Messmer K. Computer assisted leukocyte adhesion measurement in intravital microscopy. Int J Microcirc Clin Exp. 1989;8:293-302. [Medline] [Order article via Infotrieve]
    
13. Bertuglia S, Colantuoni A, Intaglietta M. Effect of leukocyte adhesion and microvascular permeability on capillary perfusion during ischemia-reperfusion injury in hamster cheek pouch. Int J Microcirc Clin Exp. 1993;13:13-26. [Medline] [Order article via Infotrieve]
    
14. Keppel G. Design and Analysis: A Researcher's Handbook. 3rd ed. Englewood Cliffs, NJ: Prentice Hall; 1991:164-184.
    
15. Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation. 1977;56:366-374. [Abstract/Free Full Text]
    
16. Koiwaya Y, Torii S, Takeshita A, Nakagaki O, Nakamura M. Postinfarction angina caused by coronary arterial spasm. Circulation. 1982;65:275-280. [Abstract/Free Full Text]
    
17. Bertrand ME, LaBlanche JM, Tilmant PY, Thieuleux FA, Delforge MR, Carre AG, Asseman P, Berzin B, Libersa C, Laurent JM. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation. 1982;65:1299-1306. [Abstract/Free Full Text]
    
18. Roux S, Christeller S, Ludin E. Effects of aspirin on coronary reocclusion and recurrent ischemia after thrombolysis: a meta-analysis. J Am Coll Cardiol. 1992;19:671-677. [Abstract]
    
19. The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med. 1989;320:618-627. [Abstract]
    
20. Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K, Masuyama T, Kitabatake A, Minamino T. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation. 1992;85:1699-1705. [Abstract/Free Full Text]
    
21. Maes A, Van de Werf F, Nuyts JM, Bormans G, Desmet W, Mortelmans L. Impaired myocardial tissue perfusion early after successful thrombolysis: impact on myocardial flow, metabolism, and function at late follow-up. Circulation. 1995;92:2072-2078. [Abstract/Free Full Text]
    
22. Muller JE, Rude RE, Braunwald E, Hartwell TD, Roberts R, Sobel BE, Ritter C, Parker CB, Jaffe AS, Stone PH, Raabe DS, Willerson JT, Robertson T, for the MILIS Study Group. Myocardial infarct extension: occurrence, outcome, and risk factors in the Multicenter Investigation of Limitation of Infarct Size. Ann Intern Med. 1988;108:1-6.
    
23. Dauber IM, VanBenthuysen KM, McMurtry IF, Wheeler GS, Lesnefsky EJ, Horwitz LD, Weil JV. Functional coronary microvascular injury evident as increased permeability due to brief ischemia and reperfusion. Circ Res. 1990;66:986-998. [Abstract/Free Full Text]
    
24. Headrick JP, Angello DA, Berne RM. Effects of brief coronary occlusion and reperfusion on porcine coronary artery reactivity. Circulation. 1990;82:2163-2169. [Abstract/Free Full Text]
    
25. Uren NG, Crake T, Lefroy DC, De Silva R, Davies GJ, Maseri A. Delayed recovery of coronary resistive vessel function after coronary angioplasty. J Am Coll Cardiol. 1993;21:612-621. [Abstract]
    
26. Engler RL, Dahlgren MD, Morris DD, Peterson MA, Schmid-Schonbein GW. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs. Am J Physiol. 1986;251:H314-H322. [Abstract/Free Full Text]
    
27. Neumann F-J, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M, Schomig A. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation. 1995;92:748-755. [Abstract/Free Full Text]
    
28. Suematsu M, Miura S, Suzuki M, Nagata H, Morishita T, Oshio C, Tsuchiya M. 5-Lipoxygenase inhibitor (AA-861) attenuates neutrophil-mediated oxidative stress on the venular endothelium in endotoxemia. J Clin Lab Immunol. 1988;25:41-45.[Medline] [Order article via Infotrieve]
    

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sheridan, F. M. Articles by Ramage, D. Search for Related Content PubMed PubMed Citation Articles by Sheridan, F. M. Articles by Ramage, D.