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J Thorac Cardiovasc Surg 2007;133:1051-1058
© 2007 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

The reduction of hemodynamic loading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing stem-cell recruitment

Ryo Suzuki, MD, Tao-Sheng Li, MD, PhD*, Akihito Mikamo, MD, PhD, Masaya Takahashi, MD, Mako Ohshima, MS, Masayuki Kubo, PhD, Hiroshi Ito, MD, PhD, Kimikazu Hamano, MD, PhD

Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan.

Received for publication September 25, 2006; revisions received December 8, 2006; accepted for publication December 13, 2006.

* Address for reprints: Tao-Sheng Li, MD, PhD, Department of Surgery and Clinical Science, Division of Cardiac Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. (Email: litaoshe{at}yamaguchi-u.ac.jp).


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: Mitotic cardiomyocytes and cardiac stem cells have been identified recently in adult hearts, and both have been found to be increased in acute infarcted myocardium. Although these findings suggest potential self-repair of the heart after injury, obvious self-regeneration of the injured heart has never been observed clinically. We hypothesized that hemodynamic loading impairs myocardial repair.

Methods: Myocardial infarction was induced in C57BL/6 mice by ligating the left anterior descending artery. After 60 minutes, either the infarcted heart was transplanted heterotopically into a healthy recipient C57BL/6 mouse to remove the ventricular hemodynamic loading (unloading group) or it was left as an infarcted heart under normal hemodynamic loading conditions in the same mouse (loading group). The infarcted hearts were dissected for histologic analysis after 3, 7, 14, and 28 days.

Results: Histologic analysis showed that the wall thickness of the infarcted left ventricle was significantly greater and the area of infarction was significantly smaller in the unloading group than in the loading group. Immunostaining analysis revealed significantly more Ki-67-positive cells and significantly fewer apoptotic cells in the infarcted myocardium in the unloading group than in the loading group. There were also significantly more c-kit- and Sca-1-positive stem cells in the infarcted myocardium in the unloading group than in the loading group.

Conclusion: Our findings suggest that hemodynamic unloading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing stem-cell recruitment.

Abbreviations and Acronyms DAPI = 4', 6-diamidino-2-phenylindole; LV = left ventricular; LVAD = left ventricular assist device; PE = phycoerythrin; SDF-1 = stromal cell–derived factor 1; TUNEL = terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 

Figure 1
Dr Suzuki, Prof Hamano, and Dr Li (left to right)


Unlike the skin, liver, muscle, and other organs, it is still thought that the heart cannot regenerate because of the loss of proliferative potential of adult cardiomyocytes and the lack of cardiac stem cells in the adult mammalian heart.1Go However, recent investigations have provided evidence that adult cardiomyocytes do retain limited cell cycle activity2,3Go and that there are in fact cardiac stem cells in the adult heart.4-7Go Furthermore, an increase in either mitotic cardiomyocytes or cardiac stem cells has been identified in failing and infarcted hearts.2,3Go These findings suggest that the injured heart may potentially have regenerative function; however, obvious myocardial regeneration has never been observed clinically after heart injury.

The process of repairing the damaged heart is thought to be related to the balance between regeneration and loss of myocytes. Although the increased number of mitotic cardiomyocytes and cardiac stem cells in the infarcted heart will accelerate the regeneration of new myocardium, an excessive loss of cardiomyocytes may also be induced by the ventricular mechanical stresses and severe milieu in the infarcted heart.8,9Go Because the frequency of mitotic cardiomyocytes in humans is very low (about 0.015% in the failing heart and 0.08% in the acute infarcted heart),2,3Go a negative balance between regeneration and loss of myocytes might provide a reasonable explanation of why self-repair of the damaged heart does not occur clinically.

Interestingly, substantial recovery of cardiac function has been achieved by the implantation of a left ventricular assist device (LVAD) in some patients with end-stage heart failure, and the device has even been explanted successfully in some of these patients.10-12Go A beneficial effect of LVAD support after coronary artery bypass grafting in patients with acute coronary occlusions has also been reported.13Go Although the precise mechanism of self-repair of the injured heart under LVAD support is unclear, we speculate that the reduction in ventricular mechanical stress achieved by LVAD support inhibits the loss of myocytes, resulting in a positive balance between the regeneration and loss of myocytes.

In this study, we placed the left ventricle of infarcted hearts under hemodynamic unloading conditions by heterotopic transplantation and then investigated the role and relative mechanisms of hemodynamic loading in myocardial repair.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male, 10-week-old C57BL/6 mice (16–18 g) from Japan SLC (Shizuoka, Japan) were used in these experiments, which were approved by the Institutional Animal Care and Use Committee of Yamaguchi University. The animals were bred in clean conditions and allowed free access to food and water in a temperature-controlled environment with a 12-hour light/12-hour dark cycle. This investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

Myocardial Infarction Model and Experimental Protocol
A myocardial infarction model was established in C57BL/6 mice as described previously.14Go Briefly, after inducing general anesthesia with pentobarbital and performing tracheal intubation with a 20-gauge intravenous catheter, the mice were artificially ventilated with room air at 80 breaths per minute. We performed a left thoracotomy through the fourth intercostal space and ligated the left anterior descending artery completely with 8–0 polypropylene under direct vision.

To estimate how the left ventricular (LV) hemodynamic loading effects myocardial regeneration, the infarcted hearts were randomly subjected to an unloading condition or a normal loading condition 60 minutes after ligation of the left anterior descending artery. The normal LV hemodynamic loading condition (loading group, n = 29) was created simply by leaving the infarcted heart in the same mouse and performing a sham laparotomy. The LV hemodynamic unloading condition was created by heterotopic transplantation of the infarcted heart into another healthy C57BL/6 mouse (unloading group, n = 27). Briefly, 60 minutes after left anterior descending artery ligation, the infarcted heart was flushed with 1 mL of cold cardioplegic solution (Na 85.3 mmol/L, K 25.0 mmol/L, Cl 85.5 mmol/L, Mg 10.0 mmol/L, and glucose 25 g/L; pH 7.38) via the inferior vena cava and harvested routinely as a donor heart. Then, the infarcted donor heart was transplanted immediately into the abdomen of another normal C57BL/6 mouse, with anastomosis of the donor ascending aorta to the recipient abdominal aorta and of the donor pulmonary artery to the recipient inferior vena cava, as described previously.15Go The infarcted heart resumed vigorous contraction within 3 minutes of reperfusion. Similar to LVAD support, this donor heart provided hemodynamic unloading to the infarcted left ventricle but coronary perfusion was sustained.

Sample Collection and Morphologic Observation
All the mice were killed and the infarcted hearts were harvested 3, 7, 14, and 28 days after the operation (n = 5–9 at each time point for both groups). The infarcted hearts were flushed thoroughly with saline solution. After excising the atrium and other tissues, we recorded the ventricular weight of each heart. The ventricle was cut into 5 pieces for macromorphologic observation of cross sections (about 1.5 mm thick). Samples were embedded in optimal cutting temperature compound and snap-frozen in liquid nitrogen. Histologic analysis was done on 5-µm-thick frozen sections.

Histologic Analysis
Hematoxylin–eosin staining and Azan staining was done to estimate the LV wall thickness and infarction area, respectively. Using Image-Pro image analysis software (version 5.1.2, Media Cybernetics Inc, Carlsbad, Calif), the LV wall thickness and fibrotic area in each digital picture were measured quantitatively by a single observer blind to the treatment regimen. The mean wall thickness was measured from 3 equidistant points, and the infarction area was calculated as the area stained blue. Measurements were done in at least 5 separated sections of each heart, and the averages of each heart were used for statistical analysis.

Measurement of the Proliferation and Apoptosis of Cells in the Infarcted Hearts
The cell proliferation was identified by immunostaining with phycoerythrin (PE)-labeled Goat anti-mouse Ki-67 antibody (1:20 dilation, Santa Cruz Biotechnology, Inc, Santa Cruz, Calif). The apoptosis of cells was detected by a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method, using Apoptosis Detection Kits (R&D System Inc, Minneapolis, Minn). Sections were also stained with DAPI (4', 6-diamidino-2-phenylindole) to visualize the nuclei. The number of positive cells was counted under 400-fold magnification by a single observer blind to the treatment regimen, and 20 different fields on 3 independent slides from different cross sections were randomly selected for each heart. We calculated the mean number of positively stained cells per field in the infarcted myocardium for statistical analysis.

Detection of Cardiac Stem Cells and Stromal Cell-derived Factor Expression in the Infarcted Hearts
To measure the number of stem cells in the infarcted hearts, 5-µm-thick frozen sections were stained with PE-labeled rat anti-mouse c-kit antibody (1:20 dilation, eBioscience, San Diego, Calif) and rabbit anti-mouse Sca-1 antibody (1:20 dilation, R&D Systems). The number of positive cells was counted under 400-fold magnification by a single observer blind to the treatment regimen, and 20 different fields on 3 independent slides from different cross sections were randomly selected for each heart. We calculated the mean number of positively stained cells per field in the infarcted myocardium for statistical analysis.

We also examined the expression of stromal cell-derived factor 1 (SDF-1), one of the most important factors for mediating stem cells recruitment and homing. Frozen sections were stained with rat polyclonal antibody against SDF-1{alpha} then a universal LSAB2 alkaline phosphatase kit and fuchsin (Dako) for color reaction were used to visualize the immune reaction.

Statistical Analysis
Results of quantitative studies are expressed as means ± SD. Statistical comparisons between groups were performed by the unpaired Student t test using StatView software (version 5.0). Values of P < .05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Myocardial Repair of the Infarcted Hearts
Repair of the infarcted hearts was evaluated 28 days after left anterior descending artery ligation. The LV wall was replaced by a thin layer of white scar tissue in the normal LV hemodynamic loading heart (Figure 1, A and C), whereas the LV wall was obviously thicker (Figure 1, A), and a band of surviving myocardium was seen clearly in the unloading heart (Figure 1, C). The ventricular weight decreased gradually in the unloading heart (Figure 1, B), probably as a result of unloading-related cardiac atrophy. The ventricular weight remained stable in the loading heart during the first 2 weeks but was increased at 28 days (Figure 1, B). This was possibly attributable to the heart failure and followed compensative hypertrophy of the surviving cardiomyocytes in the loading heart. Quantitative analysis showed that the wall thickness of the infarcted left ventricle was significantly greater but the area of infarction was significantly smaller in the unloading group than in the loading group (P < .05, Figure 1, D and F).


Figure 1
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  		Figure 1. Morphologic and histologic findings of self-repair of the infarcted heart under loading and unloading conditions. A, The anterior wall of the infarcted left ventricle was replaced completely by thin scar tissue (arrow) in the loading heart (left), whereas the left ventricle anterior wall appeared to be thick with less scar tissue (arrowhead) in the unloading heart (right) 28 days after infarction. B, The ventricular weight decreased gradually in the unloading group but was increased 28 days after infarction in the loading group. Closed bar, loading group; open bar, unloading group; *P < .05, **P < .01. C, Hematoxylin–eosin staining showed that the infarcted myocardium was replaced completely by fibrotic tissue in the loading heart 28 days after infarction, whereas layers of cardiomyocytes (arrow) were observed distinctly in the endocardium of the infarcted left ventricle in the unloading heart. D, Quantitative analysis showed that the wall thickness of the infarcted left ventricle was significantly less in the loading group than in the unloading group 28 days after infarction. E, Azan staining showed a larger fibrotic area (blue) in the loading heart than in the unloading heart. F, Quantitative analysis showed that the area of infarction was significantly greater in the loading group than in the unloading group 28 days after infarction.

 
Proliferation and Apoptosis of Cells in the Infarcted Hearts
We measured the proliferation and apoptosis of cells by immunostaining analysis 3 and 7 days after infarction. As we did not perform double staining, we counted only Ki-67-positive cells and TUNEL-positive apoptotic cells with a myocyte-specific morphologic structure microscopically. We observed Ki-67-positive cells and TUNEL-positive apoptotic cells mainly within the border area and the infarction area (Figure 2, A and Figure 3, A). Quantitative analysis revealed significantly more Ki-67-positive cells in the infarcted myocardium in the unloading group than in the loading group on day 7 (P < .01, Figure 2, B), but there were no significant differences between the groups on day 3 (P = .12, Figure 2, B). Conversely, there were significantly fewer TUNEL-positive apoptotic cells in the infarcted myocardium in the unloading group than in the loading group 3 and 7 days after infarction (P < .01, Figure 3, B).


Figure 2
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  		Figure 2. The proliferation of cells in the injured heart. A, Representative photograph of the proliferating cells. The proliferation of cells was identified by immunostaining with the nuclear antigen of Ki-67 (red, left), and nuclei were stained by DAPI (blue, middle). Scale bars: 20 µm. B, Quantitative counting of Ki-67-positive cells with a myocyte-specific morphologic structure revealed significantly fewer proliferating cells in the loading group than in the unloading group 7 days after infarction.

 

Figure 3
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  		Figure 3. The apoptosis of cells in the injured heart. A, Representative photograph of the apoptotic cells. TUNEL-positive cells were labeled by green (left), and nuclei were stained by DAPI (blue, middle). Scale bars: 20 µm. B, Quantitative counting of TUNEL-positive cells with a myocyte-specific morphologic structure revealed significantly more apoptotic cells in the loading group than in the unloading group 3 and 7 days after infarction.

 
Cardiac Stem Cells and SDF-1 Expression in the Infarcted Hearts
The recruitment of cardiac stem cells was also detected by immunostaining analysis 3 and 7 days after infarction. The c-kit- and Sca-1-positive stem cells were observed most frequently in the border area of the infarcted myocardium (Figure 4, A and Figure 5, A). Our quantitative data showed that there were significantly more c-kit-positive stem cells in the border area of the infarcted myocardium in the unloading group than in the loading group on day 7 (P < .05) but not on day 3 (P = .28, Figure 4, B). Similarly, there were more Sca-1-positive stem cells in the unloading group than in the loading group on day 7 (P < .05) but only a tendency was seen on day 3 (P = .10, Figure 5, B). Immunostaining analysis revealed that the expression of SDF-1 was localized mainly in the border area of the infarcted myocardium and that the expression of SDF-1 was relatively stronger in the unloading heart than in the loading heart (Figure 6).


Figure 4
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  		Figure 4. The c-kit-positive stem cells in the injured heart. A, Representative photograph of the c-kit-positive stem cells in the infarcted heart. The c-kit-positive cells were stained by red (left), and nuclei were stained by DAPI (blue, middle). Scale bars: 20 µm. B, Quantitative analysis revealed significantly more c-kit-positive cells in the loading group than in the unloading group 7 days after infarction.

 

Figure 5
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  		Figure 5. Sca-1-positive stem cells in the injured heart. A, Representative photograph of the Sca-1-positive cells in the infarcted heart. The Sca-1-positive cells were stained by red (left), and nuclei were stained by DAPI (blue, middle). Scales bars: 20 µm. B, Quantitative analysis revealed significantly more Sca-1-positive cells in the loading group than in the unloading group 7 days after infarction.

 

Figure 6
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  		Figure 6. The expression of SDF-1{alpha} in the heart 3 and 7 days after infarction. Immunostaining analysis revealed that the expression of SDF-1{alpha} was relatively weak in the loading heart (A); however, intensive expression of SDF-1{alpha} was observed in the unloading heart, especially in the border area of the infarcted myocardium.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Studies have demonstrated that recovery of cardiac function can be achieved by LVAD support, reducing the LV chamber size,16-18Go increasing contractility of the cardiomyocytes,19Go normalizing the cardiac extracellular matrix,20,21Go improving the expression of individual genes,22-24Go and depressing cell apoptosis.25Go Although reverse remodeling and normalization of the neurohormonal milieu under unloading conditions with LVAD support is well documented, the role of hemodynamic loading on the activity of myocytes and cardiac stem cells is still unclear.

In this study, we investigated how hemodynamic loading affects self-repair of the injured heart and examined the relative cellular and molecular mechanisms. To establish an LV hemodynamic unloading model in mice, we transplanted heterotopically an acute infarcted heart into the abdomen of another healthy mouse, with anastomosis of the donor ascending aorta to the recipient abdominal aorta and the donor pulmonary artery to the recipient inferior vena cava.15Go In the donor heart, blood from the abdominal aorta of the recipient mouse retroperfused into the coronary arteries of the donor heart, then drained into the right atrium, and entered the right ventricle of the donor heart, finally being ejected into the inferior vena cava of the recipient mouse. Thus, there was no hemodynamic loading in the infarcted left ventricle, but coronary perfusion was sustained. This condition is similar to that created by LVAD support.26,27Go

We found a smaller area of infarction and greater wall thickness in the unloading heart than in the normal loading heart. Moreover, we observed distinctly that layers of cardiomyocytes remained in the endocardium of the unloading heart 28 days after infarction, but this was not observed in the loading infarcted heart. The ventricular weight was also increased significantly in the loading heart 28 days after infarction. Although we did not measure or compare the size of the cardiomyocytes, the increased ventricular weight might be related to the hypertrophy of the cardiomyocytes in response to heart failure. All of these findings suggest that the self-repair of the infarcted hearts was better under hemodynamic unloading conditions than under loading conditions.

The fact that more proliferating cells but fewer apoptotic cells were observed in the unloading heart than in the loading heart 3 and 7 days postinfarction indicates that hemodynamic unloading increases the proliferation activity but decreases the apoptosis of cells in the infarcted heart. There were also more proliferating cells than apoptotic cells in the unloading heart, at a ratio of about 2 proliferating cells to 3 apoptotic cells per high-power field, but it was reversed in the loading heart, with a ratio of about 3 proliferating cells to 1.5 apoptotic cells per high-power field. According to our data, the balance between proliferation (regeneration) and apoptosis (loss) of cells was positive in the unloading heart but negative in the loading heart. Although many other factors need to be taken into consideration in the balance of regeneration and loss of myocytes, self-repair of the injured heart may occur under hemodynamic unloading conditions. This evidence may explain why obvious self-regeneration was not observed clinically in the injured heart under LV hemodynamic loading but cardiac function recovered frequently in the failing heart under LVAD support.9-13Go However, we counted about 300 nuclei per high-power field, so the proportion of Ki-67-positive cells would be about 1.0%. The proportion of Ki67-positive cells was comparable with the acute infarcted human heart.3Go As the level of proliferating cells is relative low, the increased proliferation and the decreased apoptosis of cells under LVAD support should contribute in a limited manner to repair the heart after infarction.

We also found significantly more c-kit- and Sca-1-positive stem cells in the unloading heart than in the loading heart, although we could not identify the origination and fate of these stem cells, so we were unable to ascertain if they were heart-specific endogenous precursors or bone marrow–derived stem cells. We do not know if these stem cells will differentiate and mature into myocytes for functional myocardial repair, although we previously found evidence that c-kit- and Sca-1-positive stem cells in the heart originate from bone marrow (data not shown). Thus, it is possible that the increased expression of SDF-1 in the unloading heart will induce the recruitment of stem cells from bone marrow into the injured heart for myocardial repair.28Go

Although we focused only on the mechanisms of myocardial repair in the turnover of myocytes and cardiac stem cells in the present study, previous investigations have found complex changes in the milium of the heart after LVAD support. These changes include a decrease in wall tension (pressure stress),29Go improvement of coronary flow,30Go reduction in lymphocyte infiltration and inflammatory cytokines,31Go and normalization of the extracellular matrix.23Go Thus, it is possible that the friendly milium in the unloading heart favors the survival and proliferation of myocytes and improves the survival, proliferation, differentiation, and maturation of cardiac stem cells for myocardial repair.

The limitation of this study lies in the fact that the unloading model we used is not the same as that used for LVAD implantation. Moreover, we did not compare the recovery of LV function in the loading and unloading hearts; therefore, our data need to be confirmed in a large-animal model and in clinical trials. Nevertheless, the results of this study provide the first evidence that hemodynamic unloading creates a positive balance between the regeneration and loss of myocytes in the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and improving stem-cell recruitment. Accordingly, reducing hemodynamic loading may be a new strategy to assist self-regeneration of the injured heart.


   Footnotes
 
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture and by the JSPS Fujita Memorial Fund for Medical Research.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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