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1 Abteilungen für Pathophysiologie, 2 Hämatologie, und 3 Kardiologie, Zentrum für Innere Medizin des Universitätsklinikums, 45122 Essen, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 µm diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 ± 1.9% SD at control to 13.3 ± 4.0, 10.3 ± 3.8, and 6.9 ± 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 ± 4.5 vs. 3.4 ± 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.
microspheres; myocardial infarction; ischemia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WITH ACUTE CORONARY INFLOW restriction, contractile function in the ischemic region is rapidly reduced, and after a few minutes, there is a consistent relation between reduced regional myocardial blood flow (RMBF) and reduced myocardial function (13, 14), i.e., perfusion-contraction matching (23) which is maintained over several hours (22) and a hallmark of short-term hibernation (15). Coronary microembolization (ME) secondary to spontaneous (2, 7) or therapeutic (4, 24) plaque rupture occurs clinically and is of pathophysiological significance in acute coronary syndromes (5, 6, 11, 21, 26). The relation of flow and function with coronary microvascular obstruction is not known. Therefore, we compared the effects of coronary ME with those of an epicardial coronary stenosis (STE) on RMBF and function in anesthetized dogs.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The experimental protocol used in this study was approved by the bioethical committee of the district of Düsseldorf, Germany.
Experimental preparation. Fifteen mongrel dogs (24-36 kg body wt) were anesthetized with an initial intravenous bolus of thiamylal sodium (15 mg/kg). After endotracheal intubation, anesthesia was maintained by ventilation using enflurane with an oxygen-nitrous oxide mixture. Left ventricular and aortic pressures were measured with catheter-tip manometers (PC 350; Millar, Houston, TX). For the measurement of RMBF, a Teflon catheter was placed into the left atrium for microspheres injection, and another Teflon catheter was inserted into the upper descending aorta for blood withdrawal. Ultrasonic crystals were implanted in the anterior left ventricular wall (control area) and in the posterolateral wall perfused by the left circumflex coronary artery (LCx) for measurement of regional myocardial wall thickness. A Teflon catheter was inserted into the left carotid artery to supply blood to the extracorporeal circuit. Anticoagulation was induced with 300 U/kg heparin sodium, and additional doses of 300 U/kg heparin sodium were given after 4 h. The LCx was cannulated proximal to its first branch and perfused from an extracorporeal circuit driven by a calibrated, occlusive roller-pump (Masterflex; Cole Parmer, Barrington, IL). Coronary arterial pressure was measured from the sidearm of the cannula.
Measurement of RMBF. Regional myocardial blood flow was determined with four different-colored (yellow, red, blue, violet) 15-µm microspheres (20). For each measurement, ~5 × 106 to 10 × 106 microspheres suspended in 6 ml of saline with 0.02% Tween 80 (Sigma) were injected into the left atrium followed by a flush of 6 ml of saline. The withdrawal of arterial reference blood samples was started 30 s before injection of the microspheres and continued for 150 s at a rate of 5.3 ml/min (model 901A; Harvard Apparatus, S. Natick, MA).
Experimental protocol. After stabilization, control measurements of systemic hemodynamics, RMBF, and function were made. Measurements were repeated after 1, 4, and 8 h.
Coronary ME. The perfusion pump was adjusted so that mean coronary arterial pressure was matched to mean aortic pressure throughout the protocol. After control measurements, 3,000 white-stained (20) microspheres (42 µm Dynospheres; Dyno Particles, Lillestrøm, Norway) per milliliter per minute coronary inflow were injected into the cannulated LCx (n = 6 dogs). The microspheres were made of polysterene cross-linked with 2% divinylbenzene and therefore were chemically inert and without a charge.
Epicardial coronary STE. After control measurements with mean coronary arterial pressure matched to mean aortic pressure, inflow to the LCx was continuously decreased to match posterior systolic wall thickening (PWT) to that of the ME group at 1, 4, and 8 h, respectively (n = 6 dogs). After completion of the protocol, the area at risk was delineated by injection of white 15-µm microspheres.
Sham group, n = 3. Three dogs were subjected to 8 h of continuous pump perfusion and measurements were made at control and after 1, 4, and 8 h.
Postmortem analysis. The heart was removed and about 10 mm × 10 mm transmural tissue specimens were taken from the ischemic and the control area near the site of the ultrasonic crystals and then fixed in 4% buffered formaldehyde. The heart was sectioned from base to apex into five slices in a plane parallel to the atrioventricular groove and immersed in a 0.09 M sodium phosphate buffer (pH 7.4) containing 1.0% 2,3,5-triphenyltetrazolium chloride (Sigma, Deisenhofen, Germany) and 8% dextran (mol wt, 77,800) for 20 min at 37°C to identify infarcted tissue. The left ventricle was then divided into subendocardial, midmyocardial, and subepicardial pieces of ~300 mg weight.
After tissue digestion and extraction of the dye, the color spectra of each myocardial and arterial reference withdrawal sample were measured with a spectrophotometer (model 8452A; Hewlett-Packard, Palo Alto, CA), as previously reported (20). Only subendocardial and transmural blood flow and the subendocardium-to-subepicardium ratio (endo/epi) at the site of the ultrasonic crystals are reported. The area at risk was determined from the white 42-µm microspheres in the ME group and from the white 15-µm microspheres in the STE group (27). The transmural formaldehyde-fixed specimens were embedded in paraffin and sectioned into slices of 5 µm thickness. Three such sections (total area 1.8 cm2) each from the ischemic and the control area of each dog were stained with hematoxylin and eosin and examined using light microscopy at ×400 magnification (DMSL; Leica, Bernsheim, Germany). Tissue areas exhibiting hypereosinophilia, contraction bands, and thinning and waviness of fibers were appreciated as necrotic foci using a phase-contrast microscope connected to a video camera module (DC 100; Leica). The area of all necrotic foci was determined by planimetry (dhs Bilddatenbank V4.01; Leica) and expressed as percentage of the total area of all analyzed tissue sections. In the same sections, inflammatory cells were counted in 50 fields of 190,000 µm2 each from the ischemic and the control area. The vast majority of inflammatory cells were polymorphonuclear leukocytes (PMN). In addition, a separate immunohistochemical analysis of mononuclear leukocytes was performed. For that, other tissue sections were dewaxed, rehydrated, rinsed with phosphate buffer saline (PBS), digested with freshly prepared proteinase K (50 µg/ml 10 mM Tris buffer; Boehringer-Mannheim, Mannheim, Germany) for 5 min, rinsed again with PBS, and incubated with rabbit anti-human muramidase antibody (Dako A099; diluted 1:100; Glostrup, Denmark) overnight at room temperature. This antibody in pigs specifically stains macrophages/monocytes (1, 8). A FITC-labeled anti-rabbit antibody (Dako F0205; diluted 1:100, 3 h exposure) was used as a detection system. In all specimens there was a dense infiltration in the immediate subepicardium (up to 1 mm depth) that was not included in the analysis. Excluding this subepicardial zone, the number of macrophages/monocytes was determined in a total area of 1.1 cm2 each from the control and the ischemic zone using fluorescence microscopy at ×400 magnification.Chemotaxis assay in vitro.
Venous blood samples from three additional dogs were collected in
sterile tubes containing preservative-free heparin. PMN and mononuclear
cells (MN) were isolated by centrifugation on Ficoll-hypaque (1.077 g/ml; Lymphoprep; Nycomed, Oslo, Norway) at 400 g for 25 min. The MN at the interface were collected, washed in PBS and
resuspended at 1.5 × 106 cells/ml in Iscove's
modified Dulbecco's medium (350 osmol/kg; IMDM; Life Technologies,
Grand Island, NY) supplemented with 1% fetal calf serum (FCS; PAA
Laboratories, Linz, Austria). The PMN collected below the interface
were washed and resuspended similarly. To obtain medium with
chemotactic activity, 5 ml of the MN suspension was incubated with 200 U/ml of recombinant human tumor necrosis factor-
(rhTNF-, R&D
Systems, Wiesbaden, Germany) at 37°C in 5% CO2 and
removed using filters of 0.2 µm pore size (Minisart, Sartorius,
Göttingen, Germany) after 2 h. Units of rhTNF- activity were calculated according to internal rhTNF- standards (R&D
Systems). Migration experiments were performed using filters of 5-µm
pore size in 6.5-mm transwell chambers (Costar, Cambridge, MA) with 5%
CO2 at 37°C (19). Aliquots of the untreated
PMN suspension (100 µl) or the untreated MN suspension (100 µl),
respectively, were placed in the upper chamber of the transwells. The
lower chamber contained either 600 µl of TNF--conditioned medium
(as a positive control) or 600 µl of IMDM plus 1% fetal calf serum (FCS) without (as a negative control) or with 42 µm white
microspheres (3 microspheres/µl, corresponding to the average number
of 42 µm spheres in 1 mg of myocardium). After the cells were placed in incubation for 8 h at 37°C in 5% CO2, a
hemocytometer was used to count the cells as they migrated into the
lower chamber in duplicate assays. The number of cells in the lower
chamber are presented as a percentage of those in the upper chamber.
Data analysis and statistics. Systemic hemodynamics and regional myocardial wall thickness were continuously monitored on an eight-channel forced-ink chart recorder (MK 200 A; Gould, Cleveland, OH) and stored directly to the hard disk of a computer. Hemodynamic and functional parameters were digitized and recorded over a 20-s period for each intervention (25).
Data are reported as mean values ± SD. Infarct size in both groups was compared by unpaired t-tests. The number of leukocytes in the control and the ischemic area in both groups was compared by two-way ANOVA. Changes in hemodynamics, RMBF, and function were estimated by two-way ANOVA for repeated measures. When a significant overall effect was detected, Fisher's least significant difference tests were performed to compare single mean values. Linear regression analysis was performed to evaluate the relationship between posterior subendocardial (PSBF) and posterior transmural blood flow (PTBF), respectively, and systolic wall thickening, as previously described by Gallagher et al. (13). Posterior blood flow data were normalized as fractions of anterior blood flow; systolic wall thickening data were normalized as fractions of their control values (13). A P value < 0.05 was taken to indicate a significant difference.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the sham group, systemic hemodynamics as well as RMBF and function remained constant throughout the 8-h continuous perfusion period. There was neither macroscopic nor microscopic evidence for myocardial infarction, and there was no inflammatory response.
Chemotaxis assay in vitro. The 42-µm white microspheres were without chemotactic activity on PMN (40.9 ± 3.8 vs. 44.2 ± 3.2% in the negative and 65.4 ± 3.0% in the positive controls, respectively) as well as on MN (3.0 ± 0.5 vs. 2.6 ± 1.2% in the negative and 19.6 ± 3.7% in the positive controls, respectively).
Hemodynamics.
Heart rate, left ventricular peak pressure, first derivative of
pressure development over time (dP/dt), and mean aortic
pressure remained unchanged throughout the protocol in both the ME and the STE group and, except for dP/dt at control, were not
different among groups. Left ventricular end-diastolic pressure was
increased in both groups at 8 h. In the ME group, coronary blood
flow was unaltered, whereas it was progressively reduced in the STE
group (Table 1).
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Regional myocardial blood flow and function.
Anterior systolic wall thickening remained constant throughout the
protocol, whereas PWT was decreased progressively to a similar extent
in both groups (Table 2). Anterior
subendocardial and transmural blood flow were unaltered at 1 and 4 h in both groups, but increased at 8 h. In the ME group, PSBF and
PTBF were also not changed at 1 and 4 h, but increased at 8 h. In contrast, PSBF and PTBF were progressively decreased in the STE
group (Table 2).
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Infarct size and inflammation.
Infarct size was 6.5 ± 4.5% of the area at risk in the ME group
and 3.4 ± 3.2% in the STE group (not significant). In
the STE group, myocardial infarction was confined to the subendocardial layer of the apex in only three of six dogs. The 42-µm embolizing microspheres were more or less homogeneously distributed throughout the
area at risk (Endo/Epi 1.24 ± 0.17), and there was a patchy, transmurally more or less homogeneous distribution (Endo/Epi 1.22 ± 1.18) of multiple, small necrotic foci (area 0.255 ± 0.227 mm2) throughout the ischemic region of all hearts in the ME
group (Fig. 2A). There was no
infarction in the control areas in both groups. There was a
significantly more pronounced inflammatory response in the
microembolized myocardium (Fig. 2, B and C) both versus the intraindividual remote myocardium and the poststenotic myocardium in the STE group (Fig.
3A and B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study confirms perfusion-contraction matching with acute coronary inflow restriction but demonstrates a progressive loss of regional myocardial function with no detectable decrease in RMBF after coronary microembolization, i.e., perfusion-contraction mismatch (Fig. 1).
The slightly preferential deposition of the 42-µm spheres to the subendocardium which has been previously demonstrated (28) was reflected by the transmural distribution of microinfarcts. The 42-µm spheres were chemically inert, as demonstrated in the in vitro chemotaxis assay. Also, infiltrating leukocytes were apparent around and within the microinfarcts, but not adherent to or surrounding the 42-µm spheres.
In previous studies, coronary microembolization has acutely depressed regional myocardial function in proportion to the number of embolizing particles in anesthetized dogs (16, 17), and it has elicited a sustained, adenosine-mediated (17) increase in coronary inflow, reflecting reactive hyperemia of adjacent myocardium. In the present study, microembolization induced a progressive reduction in regional function without a measurable decrease in regional flow or even a hemodilution-associated (hemoglobin from 12.7 ± 1.5 at control to 9.8 ± 1.7 g/dl at 8 h) increase in flow after 8 h. A decrease of blood flow in microregions supplied by embolized microvessels was probably counterbalanced by reactive hyperemia in adjacent regions, but could not be detected in the present study with blood flow measurement limited to a spatial resolution of about 300 mg of tissue (20).
The total area of necrosis resulting from microembolization in
the present study was probably too small to account for the progressive
dysfunction. However, the mechanical disadvantage from multiple
ischemic and subsequently necrotic foci may be greater than that from a
compact ischemic, subsequently necrotic area of the same size, due to a
largely greater border zone and tethering of normal to ischemic areas
(12). Alternatively, the infiltration of leukocytes in the
microembolized myocardium that has been previously observed in pigs
(1) suggests a role of inflammatory mediators such as
TNF- (1, 9, 18, 29) and/or free radicals
(16) in inducing the cardiodepressive response. An
inflammatory process as the cause of the observed dysfunction is also
supported by its progressive nature. The specific cytokines and
mediators involved and the potential recovery from the inflammatory
response will have to be determined in future studies.
Coronary microembolization occurs clinically secondary to
spontaneous or therapeutic plaque rupture (2, 4-7, 24,
26). The frequently observed myocardial dysfunction that
persists after reperfusion in these scenarios may indeed be related to
microembolization, such as observed microscopically at autopsy
(7), and an associated inflammatory response. The
inflammatory response to inert microspheres in the present heparinized
preparation (10) certainly underestimates the response to
true atherosclerotic plaque material with its thrombogenic,
vasoconstrictor, and inflammatory potential. Recently, a prognostic
impact of the inflammatory mediators TNF- and interleukin-6 in
patients with unstable angina has been shown (3), further emphasizing the role of microembolization and inflammation in acute
coronary syndromes and their sequelae.
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ACKNOWLEDGEMENTS |
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The authors thank Anita van de Sand and Ina Konietzka for technical assistance.
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FOOTNOTES |
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H. Dörge was supported by Deutsche Forschungsgemeinschaft Grant Do 641/1-1. This study was also funded by the Medical Faculty of Essen Interne Forschungsfoerderung Medizinische Fauultaet Essen Grants 107421-0 and 107509-0, and by the Hans und Gertie Fischer Stiftung.
Address for reprint requests and other correspondence: G. Heusch, Abteilung für Pathophysiologie, Zentrum für Innere
Medizin, Universitätsklinikum Essen, Hufelandstra
e 55, 45122 Essen, Germany (E-mail: gerd.heusch{at}uni-essen.de).
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.
Received 23 February 2000; accepted in final form 28 April 2000.
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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N. M. Malyar, L. O. Lerman, M. Gossl, P. E. Beighley, and E. L. Ritman Relation of Nonperfused Myocardial Volume and Surface Area to Left Ventricular Performance in Coronary Microembolization Circulation, October 5, 2004; 110(14): 1946 - 1952. [Abstract] [Full Text] [PDF]
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G. Heusch, R. Schulz, R. Erbel, T. A. Pearson, G. A. Mensah, R. W. Alexander, J. L. Anderson, R. O. Cannon III, M. H. Criqui, Y. Y. Fadl, et al. Inflammatory Markers in Coronary Heart Disease: Coronary Vascular Versus Myocardial Origin? * Response Circulation, July 8, 2003; 108 (1): e4 - e4. [Full Text] [PDF]
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G. K. Lund, N. Watzinger, M. Saeed, G. P. Reddy, M. Yang, P. A. Araoz, D. Curatola, M. Bedigian, and C. B. Higgins Chronic Heart Failure: Global Left Ventricular Perfusion and Coronary Flow Reserve with Velocity-encoded Cine MR Imaging: Initial Results Radiology, April 1, 2003; 227(1): 209 - 215. [Abstract] [Full Text] [PDF]
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W. M. Chilian and D. D. Gutterman Prologue: new insights into the regulation of the coronary microcirculation Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2585 - H2586. [Full Text] [PDF]
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A. Skyschally, R. Schulz, R. Erbel, and G. Heusch Reduced coronary and inotropic reserves with coronary microembolization Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H611 - H614. [Abstract] [Full Text] [PDF]
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M. Thielmann, H. Dorge, C. Martin, S. Belosjorow, U. Schwanke, A. van de Sand, I. Konietzka, A. Buchert, A. Kruger, R. Schulz, et al. Myocardial Dysfunction With Coronary Microembolization: Signal Transduction Through a Sequence of Nitric Oxide, Tumor Necrosis Factor-{alpha}, and Sphingosine Circ. Res., April 19, 2002; 90(7): 807 - 813. [Abstract] [Full Text] [PDF]
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)
and the microembolism (ME) group (
) at control, 1, 4, and
8 h of ischemia. Values are means ± SD. In the STE group but
not in the ME group, there were good linear relationships between PWT
and PSBF (y = 0.89 · x + 0.05, r
= 0.87, solid line) and PTBF (y =
0.90 · x 
0.07, r = 0.82, solid line),
respectively.
