Published online before print June 2, 2008, doi: 10.1161/CIRCRESAHA.108.177568
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© 2008 American Heart Association, Inc.
Integrative Physiology |
Mechanisms by Which Late Coronary Reperfusion Mitigates Postinfarction Cardiac Remodeling
From the Division of Cardiology (M.N., G.T., H.K., K.G., R.M., A.T., T.O., H.O., A.O., M.E., S. Miyata, L.L., H.U., T.A., M.K., K.N., S. Minatoguchi, H.F.), Gifu University Graduate School of Medicine; and Department of Food Science (T.F.), Kyoto Women’s University, Japan.
Correspondence to Genzou Takemura, MD, PhD, Division of Cardiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. E-mail gt{at}cc.gifu-u.ac.jp
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Abstract |
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Although recanalization of the infarct-related artery late after myocardial infarction (MI) is known to reduce both cardiac remodeling and mortality, the mechanisms responsible are not yet fully understood. We compared infarcted rat hearts in which the infarct-related coronary artery was opened 24 hours after infarction (late reperfusion [LR] group) with those having a permanently occluded artery. Left ventricular dilatation and dysfunction were significantly mitigated in the LR group 1, 2, and 4 weeks post-MI. Attributable, in large part, to the greater number of cells present, the infarcted wall was significantly thicker in the LR group, which likely reduced wall stress and mitigated cardiac dysfunction. Granulation tissue cell proliferation was increased to a greater degree in the LR group 4 days post-MI, whereas the incidence of apoptosis was significantly lower throughout the subacute stage (4 days, 1 week, and 2 weeks post-MI), further suggesting preservation of granulation tissue cells contributes to the thick, cell-rich scar. Functionally, myocardial debris was more rapidly removed from the infarcted areas in the LR group during subacute stages, and stouter collagen was more rapidly synthesized in those areas. Direct acceleration of Fas-mediated apoptosis by hypoxia was confirmed in vitro using infarct tissue-derived myofibroblasts. In salvaged cardiomyocytes, degenerative changes, but not apoptosis, were mitigated in the LR group, accompanied by restoration of GATA-4 and sarcomeric protein expression. Along with various mechanisms proposed earlier, the present findings appear to provide an additional pathophysiological basis for the benefits of late reperfusion.
Key Words: apoptosis • heart failure • myocardial infarction • remodeling • reperfusion
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Introduction |
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Large myocardial infarctions (MIs) cause severe chronic heart failure, with adverse remodeling of the left ventricle characterized by cavity dilatation and diminished cardiac performance.1 The most critical determinants of subsequent heart failure are the magnitude of the acute MI, which can be determined within several hours of an attack,2 and recanalization of the infarct-related artery, which, if performed early enough for myocardial salvage, reduces the size of the acute infarct, prevents subsequent heart failure, and improves prognosis.3 In addition, the "open artery hypothesis" formulated by Kim and Braunwald proposes that late reperfusion, beyond the window for myocardial salvage, also reduces left ventricular remodeling and decreases mortality.4,5 This proposal is supported by much experimental and clinical evidence, and a number of possible mechanisms by which an open infarct-related artery could confer benefit in ways other than by salvaging ischemic myocardium have been proposed. For instance, when the importance of the early inflammatory response needed to initiate infarct scar formation is considered,6 restoration of blood flow and allowing an influx of inflammatory cells into the infarct may improve healing of the infarcted tissue and prevent ventricular remodeling.4 In addition, an open, blood-filled infarct-related artery and vascular bed may provide a supporting scaffold that helps maintain the structural integrity of the necrotic myocardium and limits infarct expansion and ventricular remodeling.7 Another proposed mechanism suggests that late reperfusion elicits intramyocardial hemorrhage, edema, and contraction band necrosis, within which sarcolemmal tubes persist and prevent collapse of the necrotic tissue.8 Late revascularization of "hibernating" myocardium present within the periinfarct region is also a possible benefit of a patent infarct-related artery.9 Collagen turnover is reportedly more pronounced in patients with an occluded infarct-related artery, and thus prevention of interstitial collagen turnover may be another beneficial effect.10 Finally, a recent study reported a significantly higher rate of apoptosis among cardiomyocytes in patients with persistent occlusion of the infarct-related artery.11 This increased apoptosis was apparent well beyond the acute phase of MI, and those investigators proposed that late reperfusion might inhibit the apoptotic loss of salvaged cardiomyocytes, thereby preventing the progression of heart failure.
Infarcted tissue is highly dynamic and shows remarkable changes during the course of healing12,13: necrotic tissue is infiltrated by inflammatory cells during the acute stage of MI; granulation tissue forms during the subacute stage; and scar tissue forms during the chronic stage. Most cellular components that infiltrate and proliferate within an infarct, including inflammatory and granulation tissue cells, disappear via apoptosis during the subacute and chronic stages.14,15 In that regard, we previously reported that inhibition of apoptosis among granulation tissue cells during the subacute stage of MI alters infarct tissue dynamics, making the infarct scar thicker and rich in preserved cellular components. Most likely by attenuating wall stress, such effects mitigate the adverse remodeling and dysfunction otherwise seen during the chronic stage.16,17 With that said, the impact of late reperfusion on nonmyocyte dynamics within infarcted tissue has not yet been well described. Likewise, the effect of late reperfusion on the degenerative changes seen in the morphology and molecular biology of salvaged cardiomyocytes remains unclear. We hypothesize that late reperfusion may affect the cell dynamics of infarcted tissue as well as the surrounding salvaged myocardium, perhaps altering rates of cell proliferation and/or death within infarcted tissue, as well as the degenerative changes that occur in salvaged cardiomyocytes. To test that idea and to better understand the mechanisms underlying the beneficial effects of late reperfusion of the infarct-related artery, we compared changes in both the nonmyocytes within the infarcted tissue and the salvaged cardiomyocytes in hearts in which the occluded artery was recanalized 24 hours after occlusion (late perfusion) and those in which the artery remained permanently occluded.
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Materials and Methods |
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This study was approved by our Institutional Animal Research Committee. MI was induced in male Wister rats weighing 250 to 300 g (Chubu Kagaku, Nagoya, Japan) by ligating the left coronary artery as previously described.16 In sham-operated animals, the suture was passed around the artery but not tied. Twenty-four hours later, the chests of the surviving rats were reopened, and the rats were randomly assigned to a permanent occlusion (PO) group, in which the coronary artery ligation was maintained, or a late reperfusion (LR) group, in which the ligature was completely removed. The chests were then closed again, and the rats had free access to standard laboratory food and tap water. Rats were euthanized with overdose of pentobarbital 48 hours (PO, n=7; LR, n=6), 4 days (PO, n=6; LR, n=6), 1 week (PO, n=7; LR, n=6), 2 weeks (PO, n=7; LR, n=7), or 4 weeks (PO, n=18; LR, n=18) after the first surgery.
An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org.
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Results |
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Acute MI
To characterize the acute myocardial infarcts induced for this study, we intravenously injected rats with the fluorescent indicator DiOC7(3) 24 hours after they were assigned to the PO (n=7) or LR (n=6) group. This enabled us to confirm perfusion of vessels in the infarcted areas of all hearts in the LR group and the absence of perfusion in the infarcted areas of all hearts in the PO group (Figure 1A). The size of the infarcted area expressed as a percentage of the total left ventricular area did not differ between the 2 groups 48 hours post-MI (PO, 41±7.2%, versus LR, 40±5.6%; P=NS) (Figure 1B).
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Cardiac Function and Histology During the Chronic Stage of MI
Rats in the PO and LR groups (n=18 each) were followed up 4 weeks post-MI. The survival rate was 100% in both groups at euthanasia. Echocardiography and cardiac catheterization revealed that postinfarction left ventricular dysfunction (both systolic and diastolic) and remodeling were significantly attenuated in the LR group, ie, hearts in the LR group showed greater fractional shortening, a less dilated left ventricular cavity, a thicker ventricular septum, smaller left ventricular diastolic average wall stress, and better ±dP/dt (Figure 2). The left ventricular peak systolic pressure was similar between the groups. Examination at autopsy confirmed the smaller left ventricular cavity in hearts receiving late reperfusion (Figure 3A). The area of the infarct scar as a percentage of the total left ventricular area did not significantly differ between the groups (22.2±3.7% in the PO group versus 23.4±2.6% in the LR group, P=NS). We noted, however, that the segmental length of the infarct scar was shorter and the scar was thicker in the LR group (Figure 3B).
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Histological examination revealed a significantly greater cell population in the infracted areas of LR hearts, which immunohistochemical analysis showed to be made up of CD31-positive endothelial cells and 
-smooth muscle actin–positive myofibroblasts (Figure 4). The macrophage population did not differ between the groups. Most myofibroblasts were oriented with their long axis parallel to the coronal plane of the infarct scar.
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The surviving cardiomyocytes adjacent to the infarct scar showed degenerative changes, including cytoplasmic vacuolization and myofibrillar defects. However, cardiomyocytes in LR hearts showed less degeneration than those in PO hearts: under an immunofluorescence microscope, cardiomyocytes from hearts in the LR group showed a greater abundance of myosin heavy chain (MHC) than those in the PO group (Figure 4). In addition, Sirius red staining showed significantly less fibrosis in the noninfarcted areas of LR hearts than PO hearts (2.09±0.27% in LR versus 4.41±0.12% in PO, P<0.05) (Figure 4), particularly in the border area.
In summary, hearts receiving late reperfusion of the infarct-related artery showed greater numbers of endothelial cells and myofibroblasts within the infarct scar and less severe fibrosis and degenerative changes to cardiomyocytes in noninfarcted areas than hearts with persistent occlusion.
Granulation Tissue Dynamics at the Subacute Stages of MI
To better understand the effects of late perfusion on the infarct scar, we next used hearts bearing 4-day-, 1-week-, and 2-week-old infarcts to examine the changes in cardiac geometry and function and in the histology of the infarct tissue over the course of the subacute stages of MI. As shown in Figure 5A, a significant difference in the degree of LV dilatation and dysfunction in the PO and LR groups was apparent 1 week post-MI and later. Histological analysis revealed that the area of necrotic myocardium (myocardial debris) within the infarct was significantly smaller in the LR group 4 days and 1 week post-MI (Figure 5B and Figure IA in the online data supplement). The total nonmyocyte cell population was already significantly larger in the LR group 4 days post-MI. Collagen fibers appeared earlier and were stouter in the infarcted tissue of the LR group and were distributed in a reticulated manner among the infiltrated cells (percentage of collagen area: 1.3±0.039% in PO versus 1.9±0.096% in LR 4 days post-MI; P<0.05) (supplemental Figure IB). The larger cell population and greater collagen content was observed in the LR group throughout the subacute stages (Figure 5B). These findings suggest that late reperfusion accelerates the post-MI healing process, during which the greater population of the infiltrating cells might play a significant role in synthesizing collagen and scavenging necrotic myocardium.
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We then examined cell proliferation and apoptosis, both of which could affect the cell population. The incidence of Ki-67–positive cells was significantly greater in the LR group 4 days post-MI but was found to be similar in the 2 groups, thereafter (Figure 6A). The incidence of TUNEL-positive cells was always greater in the PO group (Figure 6B). Granulation tissue cell apoptosis is reportedly Fas- and caspase-3–dependent,16,17 and our Western blotting showed expression of both Fas and Fas ligand to be upregulated in all hearts 1 week post-MI, but their levels were significantly lower in the LR group than the PO group (supplemental Figure IIA). Furthermore, the degree of caspase-3 activation was significantly lower in the LR group (supplemental Figure IIB). We also found many granulation tissue cells that were positive for both TUNEL and activated caspase-3 in the 2 groups (supplemental Figure IIC), but the incidence was significantly smaller in the LR group. These findings suggest that late reperfusion not only promotes proliferation of granulation tissue cells but also protects those cells from apoptotic loss, which likely explains the greater abundance of cells in the infarct scars in the LR group during the chronic stage of MI.
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The attenuation of infarct expansion suggests late reperfusion may modulate matrix metalloproteinase (MMP) activation and cell slippage.18,19 We therefore examined expression of MMP-2 and -9 in hearts with 1-week-old MIs. Western blotting revealed significantly less expression of both MMPs in the LR than the PO group (supplemental Figure IIIA), and immunohistochemistry showed the reduced MMP expression was in endothelial cells and (myo)fibroblasts in the infarct area (supplemental Figure IIIB).
Salvaged Cardiomyocytes After MI
It has been proposed that loss of surviving cardiomyocytes attributable to apoptosis contributes to the progression of postinfarction heart failure20 and, more importantly, that late reperfusion mitigates this apoptosis.11 To address that issue, we evaluated apoptosis among cardiomyocytes in the border zone 1 and 4 weeks post-MI using the same histological preparations used to examine the infarct scar. We rarely observed TUNEL-positive cardiomyocytes in the border zone of hearts from either the PO (0.013±0.009% 1 week post-MI and 0.013±0.013% 4 weeks post-MI) or LR (0.008±0.008% 1 week post-MI and 0.005±0.005% 4 weeks post-MI; P=NS versus the PO group) group (supplemental Figure IVA). Furthermore, we detected no cardiomyocytes positive for both TUNEL and activated caspase-3 in either group (supplemental Figure IVB). Electron microscopy with TUNEL revealed degenerative, but never apoptotic, cardiomyocytes in both groups, with Immunogold labeling indicating fragmented DNA in the nuclei (supplemental Figure IVC). The nuclei were bizarrely shaped and contained diffusely clumped heterochromatin ("hypertrophied nuclei").21 Such cardiomyocytes also have been observed in hearts with dilated and hypertrophic cardiomyopathies and in hypertensive hearts and are known to give false-positive TUNEL reactions.22
Electron microscopic examination of hearts 4 weeks post-MI revealed degenerative, but not apoptotic, changes. These included myofibrillar disorganization and loss, vacuolization, and marked accumulation of mitochondria with deformity or degeneration (mitochondriosis) in cardiomyocytes at the border zone in hearts from both groups, but the changes appeared less severe in the LR group (Figure 7A). Morphometric analysis at the electron microscopic level revealed that the percentage volume comprised of myofibrils in cardiomyocytes was significantly greater in the LR group (43±1.5%) than the PO group (35±1.5%, P<0.05) (Figure 7A), indicating less severe degeneration in cardiomyocytes in the LR group. This finding prompted us to compare expression of GATA-4, a transcription factor that stimulates expression of important sarcomeric proteins, such as MHC and troponin I,23,24 in the 2 groups. We found that immunohistochemical staining for GATA-4 was more intense in the nuclei of cardiomyocytes in the LR group, and Western blotting confirmed greater expression of GATA-4 in the LR group (Figure 7B).
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In Vitro Effects of Hypoxia on Granulation Tissue Cells
Because we found that late reperfusion suppressed apoptosis among granulation tissue cells, we also tested whether hypoxia exerts a direct effect on the incidence of apoptosis among granulation tissue cells in vitro. We found that culture for 24 hours under hypoxic conditions (1% O2) had no effect on the incidence of apoptosis among infarct tissue-derived myofibroblasts. On the other hand, hypoxia accelerated Fas-mediated apoptosis when the cells were pretreated with Fas ligand plus actinomycin D (Figure 8). There was no difference in the apoptotic responses between myofibroblasts obtained from the infarcted area of a heart in the PO group (Figure 8) and those from a heart in the LR group (data not shown). This is likely because after 24 hours in culture under the same conditions, the phenotypes of the cells were similar.
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Discussion |
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Antiapoptotic and Proliferative Effects of Late Reperfusion on Granulation Tissue Cells
Increased wall thickness without reduction of infarct scar area is reportedly among the morphological characteristics of postinfarction hearts receiving late reperfusion.4,5,25,26 Our results confirm those findings. On the other hand, the histological characteristics of the thickened wall had not been well described. In the present study, hearts from the LR group showed a greater abundance of cells within the infarct scar than those from the PO group, which likely contributed to the thickening of the infarcted wall in LR hearts. The majority of these cells were myofibroblasts and endothelial cells, which are also the main cellular components of granulation tissue at the subacute stage of MI. That prompted us to compare the cellular dynamics of granulation tissue cells in LR and PO hearts. We found that the proliferation rate was greater during the early subacute stage in the LR group, whereas the incidence of apoptosis was significantly lower throughout the subacute stages. Moreover, hypoxic conditions directly accelerated Fas-mediated apoptosis in infarct tissue-derived cultured myofibroblasts. Taken together, these findings suggest that late reperfusion stimulated proliferation of granulation tissue cells and protected the cells from apoptosis, enabling them to contribute to the formation of a thick infarct scar that was rich in cellular components. In addition, collagen fibers appeared earlier and were stouter in the infarcted tissue in the LR group, and myocardial debris disappeared earlier. This suggests that late reperfusion accelerated the healing process after MI, perhaps because the larger population of infiltrating cells, is better able to synthesize collagen and scavenge necrotic myocardium.
According to Laplace’s law, wall thickness is a key determinant of left ventricular wall stress, ie, wall stress is proportional to the cavity diameter and intracavity pressure and inversely proportional to the wall thickness.27 Consequently, wall stress increases as wall thickness decreases and accelerates cavity dilatation, which in turn further increases wall stress (vicious relationship). Because increased wall stress promotes both overload and ischemia in myocardial tissue, a thick infarct scar could be a significant factor, reducing the load on postinfarction hearts.
In addition to the greater scar thickness, the infarct segmental length was shorter in the LR group, which may be attributable to the lower wall stress in this group. On the other hand, we also noted an abundance of myofibroblasts in the infarcted area of LR hearts, and these cells are known to play a key role during wound healing, contracting the wound and producing collagen.28 Because the long axis of the myofibroblasts was oriented parallel to the coronal plane within the infarct scar, we presume that they contribute to the shrinkage of the infarct in the coronal direction. In addition, the greater number of small vessels may contribute to maintaining the activity of cells in the old infarct tissue.
MMPs are a family of enzymes that catalyze the degradation of extracellular matrix and are believed to play important roles in heart disease.18,19 MMPs play a crucial role in the complex interplay between inflammatory and vascular cells, fibroblasts, and cardiomyocytes, which can result in myocardial protection or destruction, depending on the etiology of the cardiac damage.19 In the present study, downregulation of MMP-2 and MMP-9 was noted in infarcted tissue from the LR group, where fibrosis was less developed and the infarct segment was less elongated. Although their activities remain to be confirmed because the antibodies for MMPs used here detect only their proforms, our findings suggest late reperfusion modulates MMP activation in the infarcted tissue, which could affect the infarct tissue dynamics. Clarification of the roles of MMPs during the healing process after MI, however, awaits further study.
Late Reperfusion Protects Salvaged Cardiomyocytes From Degenerative Changes but Has No Effect on the Incidence of Cardiomyocyte Apoptosis
It has been suggested that cardiomyocyte apoptosis contributes to the progression of heart failure stemming from various heart ailments.29–31 On the other hand, some investigators, including ourselves, are uncertain about the impact of cardiomyocyte apoptosis in chronic heart failure. This is because, in contrast to granulation tissue cell apoptosis,15,16 apoptosis among cardiomyocytes appears to be so rare that there is no ultrastructural evidence of its occurrence.32–35 Baldi et al reported seeing apoptosis among salvaged cardiomyocytes during both the subacute and chronic stages of human MI.20 Moreover, the same group reported a lower incidence of such apoptosis in patients with a patent infarct-related artery than in those with an occluded artery and suggested that a reduction in the incidence of apoptosis among salvaged cardiomyocytes was a beneficial effect of late reperfusion.11 By contrast, our present findings do not support the notion that cardiomyocyte apoptosis plays a major role in post-MI hearts. Furthermore, we suggest that the incidence of TUNEL-positive cardiomyocytes reported by Baldi and colleagues is unreasonably high (>35% of salvaged cardiomyocytes at the border zone)11,20; such a high rate of cardiomyocyte loss would totally extinguish the salvaged myocardium within weeks. Evidence indicates that assays for DNA breaks, TUNEL in particular, are unreliable methods for detecting apoptotic cells, if used alone.35 Baldi and colleagues did count TUNEL-positive cardiomyocytes coexpressing caspase-3,11,20 but the antibody they used detects not only cleaved caspase-3 but also its precursor, which is ubiquitously expressed in all cells, making their evaluation of apoptosis no more reliable than if it had been based on TUNEL alone. In the present study, Western blotting clearly showed that the level of activated caspase-3 was indeed higher in the PO group, but the immunolabeling occurred exclusively in nonmyocytes within the infarcted area, not in salvaged cardiomyocytes in the same histological sections. Most importantly, ultrastructural evidence of cardiomyocyte apoptosis, which is the gold standard for diagnosis,36 is still lacking in actual cases of heart disease.35 By contrast, ultrastructural evidence of apoptosis among granulation tissue cells has been well documented.15,16 Although in a more recent study Abbate et al showed an electron micrograph of a section of infarcted heart containing what they claimed was an apoptotic cardiomyocyte, the cell shown was not apoptotic, nor even a cardiomyocyte.37
Instead of apoptosis, we noted a significant difference in the degree of degenerative changes in salvaged cardiomyocytes in the PO and LR groups. Degenerative changes characterized by myofibrillar loss and increased numbers of subcellular organelles (eg, mitochondria) were conspicuous in cardiomyocytes from PO hearts, whereas those from LR hearts showed significantly fewer degenerative changes. Importantly, expression of GATA-4, a transcription factor stimulating MHC and troponin I expression, was weaker in PO hearts than in LR hearts. Moreover, our in vitro experiment showed that hypoxia directly downregulates GATA-4 expression, leading to lower MHC levels in cultured cardiomyocytes, and that subsequent normoxia restores expression of both GATA-4 and MHC. We therefore suggest that restoration of contractile proteins in cardiomyocytes following reperfusion likely contributed to the improved global left ventricular systolic function seen the LR group.
Conclusions and Clinical Considerations
Along with the various mechanisms proposed in earlier reports,6–10 the phenotypic changes described here provide novel insight into the pathophysiology underlying the beneficially effects of late reperfusion of the infarct-related artery on cardiac function. Furthermore, our findings suggest that late reperfusion may be most effective if accomplished during the granulation tissue phase after MI, which may justify late reperfusion therapy in clinical settings.
In contrast to earlier findings, however, 2 recent clinical studies from the same authors reported an absence of clinical benefits of late reperfusion in post-MI patients.38,39 A possible explanation for this discrepancy relates to both the magnitude of the acute MI and the heterogeneity of the timing of the late reperfusion in those studies. The time at which reperfusion was accomplished varied from 3 to 28 days after MI in both studies.38,39 Such within-group heterogeneity makes it difficult to resolve differences between groups. Moreover, solid transmural infarcts developing an aneurysm, such as those caused by the experimental protocol in present study, are relatively rare in human MIs, probably because of collateral development. In the case of small and nontransmural MIs, the beneficial effects of late reperfusion may be far smaller, given their mechanisms. For those reasons, clinical trials using more homogenous patient populations would be desirable in the future.
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Acknowledgments |
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We thank the staff of Kyoto Women’s University (Chikako Koda, Aya Sakagami, Makiko Takeuchi, Megumi Tanigaki, Yuko Nakajima, and Ayako Nozu) for technical assistance.
Sources of Funding
This study was supported in part by grants-in-aid for scientific research from the Ministry of Education, Science and Culture of Japan (nos. 15209027, 15590732, 14570700, and 13470143).
Disclosures
None.
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Footnotes |
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Original received September 5, 2007; resubmission received April 14, 2008; revised resubmission received May 16, 2008; accepted May 20, 2008.
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References |
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