Ann Thorac Surg 2005;79:1627-1634
© 2005 The Society of Thoracic Surgeons
Original articles: Cardiovascular
Control-Released Hepatocyte Growth Factor Prevents the Progression of Heart Failure in Stroke-Prone Spontaneously Hypertensive Rats
Genichi Sakaguchi, MD, PhDa,
Keiichi Tambara, MDa,
Yutaka Sakakibara, MD, PhDa,
Makoto Ozeki, MEngb,
Masaya Yamamoto, PhDb,
Goditha Premaratne, MDa,
Xue Lin, MDa,
Koji Hasegawa, MD, PhDc,
Yasuhiko Tabata, PhDb,
Kazunobu Nishimura, MD, PhDa,
Masashi Komeda, MD, PhDa,*
a Department of Cardiovascular Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan
b Department of Frontier Medical Science, Kyoto University, Kyoto, Japan
c Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan
Accepted for publication October 20, 2004.
* Address reprint requests to Dr Komeda, Graduate School of Medicine, Dept of Cardiovascular Surgery, Kyoto University, 54 Kawahara-cho Shogoin Sakyo-ku, Kyoto, 606–8507, Japan (E-mail: masakom{at}kuhp.kyoto-u.ac.jp).
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Abstract
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BACKGROUND: We have developed a hepatocyte growth factor (HGF)–incorporating gelatin hydrogel sheet (HGF sheet), which was designed to release HGF more than 2 weeks in vivo. The present study investigated whether the HGF sheet could prevent the progression of heart failure in stroke-prone spontaneously hypertensive rats.
METHODS: Stroke-prone spontaneously hypertensive rats at the age of 25 weeks received placement of an HGF sheet on the left ventricular free wall (HGF, n = 10) or sham-operation (control, n = 10). All animals were followed up with Doppler echocardiography during the next 4 weeks and then underwent histologic analysis. The influence of the hydrogel sheet alone was assessed by echocardiography and left ventricular pressure measurements. Survival study was performed (each group, n = 11) at the age of 30 weeks.
RESULTS: There were two deaths in the control group and no deaths in the HGF group during the 4 weeks. Fractional shortening was significantly higher, and left ventricular diastolic dimension was significantly smaller in the HGF than in the control group. The slope of the peak early diastolic filling velocity and the ratio of that slope to the slope of the peak filling velocity at atrial contraction were significantly lower in the HGF than the control group. Myocardial fibrosis was lower and capillary density was significantly higher in the HGF than the control group. Placement of the hydrogel sheet alone did not affect any cardiac function compared with sham operation. The survival rate at 10 weeks after the surgery was much higher in the HGF than the control group.
CONCLUSIONS: The HGF sheet improves cardiac function, reverses left ventricular remodeling, and markedly improves survival in spontaneously hypertensive rats. These beneficial effects are associated with angiogenesis and reduced fibrosis in the left ventricular myocardium.
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Introduction
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Hepatocyte growth factor (HGF) was originally identified and cloned [1] as the most potent mitogen for hepatocytes. Subsequent studies have demonstrated that HGF possesses pluripotent activities such as mitogenic, motogenic, morphogenic, and antiapoptotic activities in a variety of cell types [2–4]. It has been demonstrated that administration of HGF reduces myocardial infarct size and improves cardiac function after ischemia–reperfusion and that these effects are mediated by the antiapoptotic action as well as angiogenic action of HGF [5, 6]. In addition, HGF is a unique growth factor in that it prevents fibrosis, as shown by the fact that administration of human recombinant HGF (rHGF) prevented or caused regression of fibrosis in liver and pulmonary injury models [7, 8]. For these reasons, administration of HGF is a possible therapeutic approach for the treatment of cardiac diseases with fibrosis.
Long-lasting severe hypertension results in decompensated heart failure characterized by dilated ventricles with systolic dysfunction. Stroke-prone spontaneously hypertensive rats (SHRs) provide a useful model to reproduce this process. Hypertension-induced heart failure in SHRs is associated with increased passive stiffness and impaired contractile function relative to age-matched SHRs with nonfailing hearts and normotensive Wistar-Kyoto rats [9]. Histologic examination of failing SHR hearts reveals marked myocardial fibrosis, reduced capillarization, and microarteriopathy of small intramyocardial arteries [10]. Thus, failing SHR hearts are associated with reduced coronary flow reserve, which may be responsible for further deterioration of cardiac function. On the basis of these facts, we hypothesized that angiogenic and antifibrotic HGF might ameliorate these pathologic changes in heart failure. Recently, Taniyama and colleagues [11] reported that transfection of the HGF gene into the myocardium of cardiomyopathic hamsters, using the Hemagglutination Virus of Japan-liposome method, induces angiogenesis and reduces fibrosis. However, it is unknown whether HGF administration into failing hearts would improve systolic and diastolic ventricular function. In addition, we would like to establish a safer and easier system that does not use virus-derived genes or cause any needle injuries.
We have developed an HGF-incorporating gelatin hydrogel sheet (HGF sheet) that was designed to release HGF more than 2 weeks in vivo. The present study investigated whether this HGF sheet surgically placed on the surface of the left ventricular (LV) free wall could prevent the progression of heart failure in SHRs.
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Material and Methods
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Experimental Animals
Male stroke-prone SHRs/Izumo strain were obtained from Shimizu Laboratory Supplies. All animals were fed an 8% sodium chloride (high-salt) diet starting at the age of 20 weeks. All animals received humane care under daily observation in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press. Our study protocol was approved by the ethics committee for animal research of Kyoto University.
Preparation of Hepatocyte Growth Factor–Incorporating Gelatin Hydrogen Sheets
Gelatin with an isoelectric point of 5.0 was isolated from bovine bone collagen by an alkaline process using calcium hydroxide [gelatin; Nitta Gelatin Co, Osaka, Japan]. Gelatin hydrogel sheets were made using the previously described process [12]. Sheets were freeze-dried and then impregnated with an aqueous solution containing 50 µg of rHGF, to obtain hydrogels with incorporated HGF. The prepared gelatin hydrogel sheets were square shaped (10 x 10 mm) and 0.7 mm thick.
Surgical Procedure
The animals were orally intubated with use of ether and were ventilated (rodent ventilator model 683, Harvard Apparatus, Holliston, MA). Anesthesia was maintained during the operation with 1% isoflurane. A small pericardial incision was made through a left-sided thoracotomy. The HGF sheet was placed on the epicardial surface of the LV free wall through the pericardial incision in the HGF group. In the control group, only a pericardial incision was performed. Thereafter the thoracotomy was closed, and the rats were allowed to recover.
In Vivo Evaluation of Recombinant Hepatocyte Growth Factor
Preparation of iodine 125-labeled rHGF was performed according to the chloramines T method, as reported previously [13]. Gelatin hydrogel sheets incorporating 125I-labeled rHGF were placed on the surface of the LV free wall in 12 SHRs by the method described above. Three animals were killed at each time (1, 3, 7, and 14 days), and myocardial specimens from the LV free wall and the septum and specimens from blood, left and right lungs, and liver were collected. The radioactivity of these specimens was measured using a gamma counter (ARC-301B; Aloka Co, Ltd, Tokyo, Japan). Tissue levels of rHGF were calculated according to the 125I decay.
In Vivo Assessment of Left Ventricular Geometry and Function
Systolic blood pressure was measured by the indirect tail-cuff technique before and 4 weeks after the operation. Transthoracic echocardiography was performed before the operation and followed up every week for the 4 weeks after surgery with a 12-MHz scan probe (SONOS 4500; Hewlett-Packard, Agilent Technologies, Andover, MA). Rats were mildly anesthetized with ethyl ether. End-diastolic and end-systolic dimensions of the LV were derived from two-dimensionally targeted M-mode tracings obtained along the short-axis view of the LV at the level of the papillary muscles. Left ventricular fractional shortening was calculated as previously described [14].
Echocardiographic Doppler Studies
The mitral flow velocity pattern was obtained by a Doppler echocardiographic study to determine peak early diastolic filling velocity (E velocity), peak filling velocity at atrial contraction (A velocity), their ratio (E/A ratio), and the deceleration time of early diastolic filling. The numerical data were obtained for at least three consecutive cardiac cycles, according to the criteria of the American Society for Echocardiology. All measurements were performed by one experienced observer blinded to the treatment groups.
Measurement of Collagen Fraction
After animals were sacrificed with ethyl ether gas, the hearts were removed, fixed with 10% formalin, dehydrated, and embedded in paraffin. Transverse sections (4 µm) of the LV were cut at midlevel and stained with Masson's trichrome. The collagen fraction was determined by measuring the area of blue-stained tissue within a given field with an automated image analysis system (Scion Image Beta 4.02 Win; Scion Corp, Frederick, MD). The stained area was calculated as a percentage of the total area within a field excluding vessels and artifacts. Ten fields were analyzed in the LV free wall and the septum for each animal.
Measurement of Capillary Density
The number of capillary vessels was counted as described previously [15] using paraffin-embedded sections stained with anti-factor VIII antibody (U0034; Dako A/S, Glostrup, Denmark). The number of capillaries in five randomly selected high-power fields in the LV free wall and the septum was averaged and expressed as the number of capillary vessels per high-power field (0.2 mm2).
Assessment of Influence of Hydrogel Sheet Alone
To exclude the possibility that placement of the hydrogel sheet alone causes angiogenesis and affects cardiac function, we performed an additional set of experiments. Eighteen SHRs were randomized into three groups at the age of 25 weeks: group 1 (n = 6), placement of HGF-incorporating gelatin hydrogel sheet; group 2 (n = 6), placement of gelatin hydrogel sheet without HGF; group 3 (n = 6), sham operation (pericardial incision alone). Four weeks later, these rats underwent echocardiography, followed by LV pressure measurements. Under general anesthesia, a 2F micromanometer-tipped catheter (Millar Instruments Inc, Houston, TX) was inserted through the right carotid artery into the LV. Left ventricular pressure and its first derivative were acquired using a multiple recording system under stable conditions.
Survival Study
Twenty-two SHRs were randomized into groups with HGF sheet implantation (HGF group: n = 11) or sham operation (control group: n = 11) at the age of 30 weeks. All animals were fed a high-salt diet under daily observation.
Data Analysis
All data are expressed as the mean ± standard error of the mean. Comparisons of HGF level, collagen fraction, and vascular densities among the groups were performed with the unpaired Student's t test. Comparisons of echocardiographic data among the groups were performed by two-way repeated measures analysis of variance. Comparison of survival was performed according to Kaplan-Meier with the log-rank test. Statistical analyses were performed with StatView for Windows version 5.0 (SAS Institute Inc, Cary, NC).
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Results
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Recombinant Hepatocyte Growth Factor Levels
To evaluate the time profile of in vivo HGF retention, gelatin hydrogel sheets incorporating 125I-labeled rHGF were placed on the surface of the LV free wall. Tissue rHGF levels in the free wall and the septum are shown in Figure 1. The myocardial rHGF levels were higher in the free wall than the septum. These levels were maximal 1 day after surgery and thereafter decreased. Recombinant HGF was not detectable in the septum 7 days after surgery. Histologically, the sheet completely disappeared from the implantation site 4 weeks after surgery in all animals of the HGF group. The blood level of rHGF was 3.0 ± 1.2 ng/g 1 day after surgery and was not detectable thereafter. The rHGF levels in the lung 1 day after surgery were 21.8 ± 4.5 ng/g in the left lung and 10.3 ± 5.6 ng/g in the right lung. At 3 days after surgery, the levels decreased to 3.5 ± 2.5 ng/g in the left lung and 1.5 ± 0.5 ng/g in the right lung, and were not detectable thereafter. The rHGF levels in the liver were undetectable throughout the experimental period.
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Fig 1. Time course of tissue recombinant hepatocyte growth factor (rHGF) levels in the left ventricular free wall (FW) and the septum (SE). Data are expressed as mean ± standard error of the mean from 3 animals at each time.
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Left Ventricular Geometry and Cardiac Function
Twenty SHRs were randomized into two groups at the age of 25 weeks (HGF group: n = 10, control group: n = 10). At this stage, the LV began to dilate and the disease state progressed from compensated hypertrophy to decompensated heart failure. Before the surgery, systolic blood pressure, LV end-diastolic dimensions, end-systolic dimensions, and fractional shortening were similar between the control and HGF groups. There were two deaths in the control group and no deaths in the HGF group during the 4 weeks of the study period. Systolic blood pressure was similar at 4 weeks after implantation of the HGF sheet (230 ± 3 mm Hg) and sham operation (226 ± 4 mm Hg). Although LV fractional shortening decreased in both groups 1 week after surgery, it recovered slightly thereafter in the HGF group but not in the control group. Therefore, LV fractional shortening 3 and 4 weeks after surgery was significantly higher in the HGF group than in the control group (Fig 2A). Compatible with the improvement of LV systolic function, both LV end-diastolic and end-systolic dimensions were significantly smaller in the HGF group than in the control group 3 and 4 weeks after surgery (Fig 2B).
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Fig 2. Time course of left ventricular geometric changes measured by M-mode echocardiography. (A) Left ventricular fractional shortening (FS). (B) Left ventricular end-diastolic dimension (LVDd) and end-systolic dimension (LVDs). Data are expressed as mean ± standard error of the mean. *p < 0.05, **p < 0.01 different from control (filled circles). (HGF [open circles] = hepatocyte growth factor.)
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Doppler Echocardiographic Study
The E wave slope and the E/A ratio before the surgery were similar between the control and HGF groups. Although both the E wave slope and the E/A ratio in the control group progressively increased, those in the HGF group remained unchanged during the period. The E wave slope 3 and 4 weeks after surgery was significantly lower in the HGF group than in the control group (Fig 3A). Similarly, the E/A ratio at 1, 2, 3, and 4 weeks after surgery was significantly lower in the HGF group than in the control group (Fig 3B).
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Fig 3. Time course of changes in diastolic function assessed by transmitral filling patterns in Doppler echocardiography. (A) The slope of the peak early diastolic filling velocity (E wave slope). (B) The ratio of the E wave slope to the slope of the peak filling velocity at atrial contraction (E/A ratio). Data are expressed as mean ± standard error of the mean. *p < 0.05, **p < 0.01 different from the control (filled circles). (HGF [open circles] = hepatocyte growth factor.)
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Collagen Fraction and Capillary Densities
The collagen fraction determined by Masson's trichrome staining is shown in Figure 4. The collagen fraction in the LV free wall was significantly lower in the HGF group than that in the control group. The number of capillary vessels per high-power field (capillary density) is shown in Figure 5. The capillary density in the LV free wall was significantly higher in the HGF group than that in the control group. The collagen fractions and capillary densities in the LV septum exhibited similar tendencies to those in the LV free wall (Figs 4, 5). The collagen fractions were lower and the capillary densities were higher in the HGF than the control group, although these differences in the septum were not significant.
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Fig 4. Myocardial fibrosis at 4 weeks after the surgery. (A) Representative sections from control (left) and hepatocyte growth factor (HGF)–treated (right) hearts are stained with Masson's trichrome. (B) Quantitative analysis of fibrosis area as a percentage in the left ventricular free wall (FW) and the septum (SE). Data are expressed as mean ± standard error of the mean. (NS = not significant.)
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Fig 5. Myocardial capillary densities at 4 weeks after the surgery. (A) Representative sections from control (left) and hepatocyte growth factor (HGF)–treated (right) hearts are stained with anti-factor VIII antibody (original magnification, x400). (B) Capillary densities (vessel numbers) in the left ventricular free wall (FW) and the septum (SE). Data are expressed as mean ± standard error of the mean. (NS = not significant.)
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Placement of Hydrogel Sheet Alone Did Not Influence Cardiac Function
As shown in Table 1, both systolic and diastolic function were better in group 1 than in group 2 or 3. However, there were no significant differences in these variables between groups 2 and 3. Therefore, placement of the hydrogel sheet alone did not affect any cardiac function compared with sham operation. In this experiment, the difference in the E/A ratio did not reach statistical significance between groups 1 and 3 (p = 0.08), despite the significant difference between the HGF and control groups shown in Figure 3B. The smaller number of animals might contribute to the discrepancy. Maximal rate of increase of LV pressure, an indicator of LV systolic function, was higher in group 1 than in group 2 or 3. Minimal rate of increase of LV pressure, an indicator of LV diastolic function, was lower in group 1 than in group 2 or 3. These findings are compatible with echocardiographic data and suggest that HGF improved both systolic and diastolic functions in SHRs.
Survival Rate
Figure 6 shows the survival curves after the surgery. Autopsy revealed that all dead rats exhibited LV dilatation and pulmonary congestion, suggesting that these rats died of congestive heart failure. In the control group, 82% of rats died within 5 weeks, and all rats died within 10 weeks after the surgery. In contrast, only 45% died within 10 weeks in the HGF group. Thus, the survival rate at 10 weeks after the surgery was 0% in the control group and 55% in the HGF group. Twenty weeks after the surgery, 45% of SHRs in the HGF group still survived. Therefore, implantation of the HGF sheet markedly improved the survival in the heart failure stage of SHR.
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Fig 6. Survival after the surgery in stroke-prone spontaneously hypertensive rats. Twenty-two stroke-prone spontaneously hypertensive rats at the age of 30 weeks were randomized into groups with hepatocyte growth factor sheet implantation (open circles: n = 11) or sham operation (filled circles: n = 11). Kaplan-Meier analysis with log-rank test was performed.
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Comment
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Hepatocyte growth factor, originally discovered as a potent mitogen for hepatocytes [1], has been shown to be cardioprotective against ischemia–reperfusion injury [5, 6]. Because of its antifibrotic action as well as angiogenic and antiapoptotic actions, HGF is an attractive option for treating heart failure. However, the lifetime of the biologic activity of HGF is too short for HGF to exert its beneficial effects in chronically diseased states. When rHGF is administered by intracoronary injection or is directly injected into the myocardium in its solution form in vivo, it rapidly diffuses into the circulation and disappears from the myocardium by 1 day after the injection. To overcome these shortcomings, we have developed a gelatin hydrogen sheet that releases HGF gradually as a result of hydrogen degradation. In this study, we showed that the HGF sheet released the peak of rHGF within 24 hours. Although the level gradually decreased thereafter as a function of time, the rHGF level in the sheet-implanted LV free wall was still detectable even 2 weeks after the implantation. These findings suggest that the sheet slowly releases rHGF for a period of weeks. The blood rHGF level stayed under the limit of detection for 2 weeks after the first day. The rHGF level in the septum was much lower than that in the LV free wall. These findings suggest that rHGF released from the sheet directly permeates the myocardium and mostly stays at the implantation site rather than being secreted into the systemic circulation.
The present study demonstrated that the rHGF levels in both lungs were detectable 3 days after the implantation, and not detectable thereafter. The significant levels of rHGF in the lung may be attributable to the fact that both lungs, especially the left lung, are exposed to the HGF sheet through direct contact. Ono and associates [16] have reported that gene transfer of rHGF by means of the pulmonary artery induces angiogenesis in the rat lung. No side effects, including neoplastic changes in the lungs, were observed in their study. Although it is highly unlikely that the presence of HGF in the lungs for a 3-day period causes any problems, further studies are needed to confirm the safety of the HGF sheet implantation.
Failing SHR hearts are characterized by marked myocardial fibrosis, reduction of capillarization, and microarteriopathy of small intramyocardial arteries [9]. This structural remodeling of the cardiac interstitium accounts for abnormal myocardial stiffness and impaired coronary reserve. Blockade of the renin-angiotensin system reverses these pathologic changes and improves ventricular function. Although it is difficult to determine the independent roles of fibrosis and microangiopathy, both changes may be associated with ventricular diastolic and systolic dysfunction. Because HGF is an antifibrotic and angiogenic factor, administration of HGF into the heart is expected to ameliorate these pathologic changes. The present study demonstrates that implantation of the HGF sheet into failing SHR hearts reduces myocardial fibrosis and induces angiogenesis. Our data are compatible with the data by Taniyama and coworkers [11], who reported that transfection of the HGF gene into the myocardium of cardiomyopathic hamsters results in a significant increase in HGF expression, induction of angiogenesis, and reduction of fibrosis. The present study provides the first evidence that the HGF sheet improved LV systolic and diastolic function as well as survival rate after the surgery. It has been demonstrated that administration of an angiotensin-converting enzyme inhibitor to SHRs results in a significant decrease in LV weight, accompanied by an improvement of systolic and diastolic function [17]. In contrast, the HGF sheet did not change LV weight although it significantly improved LV systolic and diastolic function. The question thus arises as to how implantation of the HGF sheet improves cardiac function. The reduction of myocardial fibrosis may improve passive stiffness, as indicated by the decrease in the E wave slope and the E/A ratio. Reduced fibrosis as well as angiogenesis may stimulate blood flow in the coronary microcirculation, which will contribute to the improvement of global systolic and diastolic function. Furthermore, there is some exciting evidence that activation of the Akt pathway by a growth factor preserves functional cardiac stem cells as well as inhibits myocardial cell apoptosis [18]. However, to elucidate the precise mechanisms by which the HGF sheet improves cardiac function, further studies are needed.
In this study, we demonstrated that implantation of a gelatin hydrogel sheet that gradually releases rHGF on the surface of the LV attenuated cardiac fibrosis and prevented the progression of heart failure in SHRs. The sheet implantation could be an adjunct therapy in open heart surgery. Hein and colleagues [19] showed that the degree of cardiac fibrosis in patients with aortic stenosis undergoing aortic valve replacement correlates well with further deterioration of LV function and with poor prognosis after the surgery. In addition, HGF has been shown to enhance the efficacy of cellular cardiomyoplasty by stimulating angiogenesis, restoring the impaired cell-extracellular matrix, and promoting the integration of the dissociated grafted myocytes [20].
The present study demonstrates that the HGF sheet prevents transition to heart failure in SHRs. We believe that this experimental model resembles the dilated phase of hypertrophic cardiomyopathy as well as hypertensive heart disease in man. We are currently testing whether the HGF sheet is beneficial in other experimental models of heart failure, namely myocardial infarction and myocarditis. Although the biodegradable HGF sheet would be highly useful in many situations, several problems should be resolved if this system is to be applied in the clinical setting in human hearts. First, although HGF was released from the sheet during a 2-week period in this study, the optimal time profile of rHGF release has not been determined. It should be possible to adjust the time profile of HGF release by changing the water content of the gelatin hydrogel sheet [12]. Second, the thickness of the SHR heart is only 2 to 3 mm. It is unclear whether rHGF can permeate into the deep portion of the thicker myocardium (approximately 1 cm) in humans. Third, implantation of the HGF sheet attenuated fibrosis predominantly in the LV free wall rather than the septum. It should be further determined whether the sheet can improve global function in some forms of cardiomyopathy in which fibrosis occurs mainly in the septum. Despite these problems, the combination of this system with other established (coronary artery bypass grafting surgery) and potentially useful (LV plasty and LV assist device) surgeries would provide a powerful option for treating end-stage heart failure in humans.
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Acknowledgments
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This study was supported by a grant for the "Advanced and Innovational Research Program in Life Science" from the Ministry of Education, Science and Culture of Japan.
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References
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K. Tambara, G. U. Premaratne, G. Sakaguchi, N. Kanemitsu, X. Lin, H. Nakajima, Y. Sakakibara, Y. Kimura, M. Yamamoto, Y. Tabata, et al.
Administration of Control-Released Hepatocyte Growth Factor Enhances the Efficacy of Skeletal Myoblast Transplantation in Rat Infarcted Hearts by Greatly Increasing Both Quantity and Quality of the Graft
Circulation,
August 30, 2005;
112(9_suppl):
I-129 - I-134.
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Abstract
Introduction
