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Department of Medicine, Taichung and Taipei Veterans General Hospital, National Yang-Ming University (W.-L.L., J.-W.C., C.-T.T., S.-J.L.), Taipei, Taiwan; and the Departments of Medicine and Biological Chemistry, Division of Endocrinology, Diabetes, and Metabolism, University of California (T.I., M.K., P.H.W.), Irvine, California 92697
Address all correspondence and requests for reprints to: Ping H. Wang, M.D., Department of Medicine, Medical Science Building I, C240, University of California, Irvine, California 92697. E-mail: phwang{at}uci.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In experimental animals, attenuation of cardiomyocyte apoptosis by IGF-I has been demonstrated in ischemic cardiomyopathy (17, 18), but it is not yet known whether IGF-I suppresses the apoptosis of cardiomyocytes in dilated cardiomyopathy. Using a canine model of pacing-induced dilated cardiomyopathy, in this study we have defined the therapeutic effects of IGF-I injection on existing dilated cardiomyopathy, investigated the incidence of apoptosis in myocardium, and determined the relationship between myocardial apoptosis and ventricular function. We obtained results indicating the efficacy of IGF-I injection on multiple aspects of cardiovascular function and demonstrated IGF-I suppression of myocardial apoptosis in this model of dilated cardiomyopathy. Moreover, the good correlation between the occurrence of apoptosis and ventricular function supports the hypothesis that myocardial apoptosis is involved in the pathogenesis of ventricular remodeling and dysfunction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Right ventricular (RV) pacing
Permanent pacemakers and leads were implanted in all dogs at the
beginning of the study. For this purpose, the right jugular vein was
dissected out and cannulated with an 8F peel-away sheath. A 7F unipolar
passive fixation ventricular lead (Capsure SP4023, Medtronic,
Minneapolis, MN) was placed at the RV apex under fluoroscope. The lead
was tunneled to the dorsal neck and connected to a modified Medtronic
8416 generator. For group B and C dogs, ventricular stimulation was
activated after placement of pacemakers and paced at 220 beats/min
continually for 4 weeks. For group A dogs (normal control group),
pacemakers were not activated. The heart was palpated daily to ensure
proper pacing. Adequate pacing was also documented by electrocardiogram
monitoring at 2 and 4 weeks. Clinical signs of heart failure occurred
after 1–2 weeks of pacing. To study the therapeutic effects of IGF-I,
group C dogs were given IGF-I (100 µg/kg BW, sc, twice daily) during
the last 2 weeks of pacing, whereas groups A and B did not receive
IGF-I (sham injected). This dose of IGF-I did not lead to hypoglycemia
when the dogs had free access to chow. Each dog was assigned a code at
the beginning of study, and the investigator who performed cardiac
ultrasound and catheterization was blinded until the study was
completed and the code broken.
Hemodynamic studies
Hemodynamic studies were performed at the beginning and end of
the study under general anesthesia. The femoral artery and vein were
dissected under direct vision and cannulated with 5F and 7F sheaths,
respectively. A 5F Cordis pigtail catheter was inserted and advanced to
the ascending aorta and left ventricular (LV) cavity for hemodynamic
recordings. For right heart catheterization, a 7F Swan-Ganz catheter
was advanced to the right atrium, the RV, and the pulmonary artery,
where it was wedged. Cardiac output was determined by thermodilution
method. All hemodynamic tracings were recorded by a Gould RS 3400
polygraph (Valley View, OH). The tracings were measured off-line, and
all measurements represented the average of five readings.
Transthoracic echocardiography
Echocardiographic studies were performed under general
anesthesia at the beginning of study, at the end of week 2, and at the
end of the study using Hewlett-Packard Co. SONOS 2000
(Palo Alto, CA) with the animals placed in the left lateral position.
All measurements were based on guidelines of the American Society of
Echocardiography (22). The thickness of the anterior septum and
posterior wall, and the diameter of the LV chamber at end-diastole and
peak systole were measured on line with M-mode. LV end-diastolic
meridional wall stress at the midplane was calculated based on the thin
walled ventricular model (23). Each measurement represents the average
of three or four readings.
Cardiomyocyte apoptosis
At the end of study, myocardial specimens were obtained from the
ventricular septum and immediately fixed with 10% neutral formalin for
24 h at 4 C, then paraffin embedded. Tissue sections of anterior
septum, where the most significant hypokinesis/akinesis was found on
echocardiographic study after pacing, were used to determine the
incidence of myocardial apoptosis. In situ DNA fragmentation
was labeled by the terminal deoxynucleotidyltransferase-mediated dUTP
nick end labeling (TUNEL) assay using the ApopTag Plus kit (Oncor,
Gaithersburg, MD). In brief, after deparaffinization, tissue sections
were treated with proteinase K (20 µg/ml) and ribonuclease (50
µg/ml), and then incubated with terminal deoxynucleotidyl transferase
and digoxingenin-labeled UTP at 37 C for 1 h. After PBS washing,
fluorescein isothiocyanate (FITC)-labeled antidigoxingenin antibody was
added and incubated at room temperature for 30 min. Cardiomyocytes were
identified by sequential incubation with mouse antitropomyosin antibody
(1:25 dilution) from Zymed Laboratories, Inc. (South San
Francisco, CA) and rhodamine-labeled rabbit antimouse antibody.
Finally, all nuclei were stained with DAPI for 3 min (24).
Triple-labeled tissue sections were visualized with a Carl Zeiss Axiohot epifluorescent microscopy (New York, NY). DAPI
stain was visualized using the Carl Zeiss filter
combination 487702, and a double band-pass filter (Omega, Brattleboro,
VT) was used to view FITC and rhodamine simultaneously. Under these
conditions, apoptotic nuclei appear in green, and all nuclei appear in
blue. Cardiomyocytes were differentiated from noncardiomyocytes by the
orange staining of tropomyosin. The entire tissue section was scanned,
and the number of nuclei, apoptotic and nonapoptotic, was scored. More
than 200 high power fields (1.25 x 630) were searched in each
tissue section. Cells around the edges of sections may have had false
positive TUNEL stain and thus were excluded from final analysis. In
each sample, 3 different sections were counted and averaged as the
final score. The apoptotic index was calculated as the number of
apoptotic nuclei per million cardiomyocytes.
IGF-I and binding protein assay
Five-milliliter blood samples were drawn from the antecubital
vein at the beginning and end of the study. They were immediately
centrifuged at 4 C (2000 rpm, 10 min) to isolate the serum and were
then frozen at -70 C. All blood samples were drawn before the evening
IGF-I/sham injections. Total IGF-I, free IGF-I, and IGF-binding
protein-3 (IGFBP-3) were determined by two-site immunoradiometric assay
using commercially available kits from Diagnostic Systems Laboratories, Inc. (Webster, TX), according to the
manufacturer’s instruction with serial dilutions of standards. A
previous study has shown that this method, originally developed for
human IGF-I measurements, produces reliable measurement of circulating
IGF-I levels in dog (25).
Statistics
All continuous variables were expressed as the mean ±
SE. Categorical factors were analyzed by 
2
test with Yate’s correction. One-way ANOVA or Student’s t
test was used to compare intergroup differences when indicated.
Correlation analysis was performed with Person’s least square method.
A two-tailed P < 0.05 was considered statistically
significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). IGF-I injection (100 µg/kg BW)
resulted in a significant elevation of circulating total and free IGF-I
levels, but IGF-I levels did not change in the normal control or the
untreated paced dogs at the end of the study. The levels of IGFBP-3 did
not differ among all groups, and 2 weeks of IGF-I treatment did not
alter IGFBP-3 levels in the treated dogs.
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). The baseline characteristics of
ventricular morphology were the same in the three groups of dogs
studied. After 2 weeks of pacing, ventricular walls became thinner, and
left ventricles dilated. There was no difference in anterior septum
diameter, posterior wall diameter, LV end-diastolic diameter, or LV
end-systolic diameter between untreated (group B) and IGF-I-treated
(group C) dogs after 2 weeks of pacing (220 beats/min). By the end of
week 4, as expected, ventricular walls remained thin, and LV chambers
remained dilated in the paced dogs. There was a trend toward partial
restoration of ventricular wall thickness and LV chamber diameter in
the IGF-I-treated group, but the difference between treated and
untreated paced dogs did not reach statistical significance. These
results indicate that significant remodeling of ventricles occurred
upon pacing.
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, the baseline
hemodynamic parameters were compatible in all three groups of dogs.
Cardiac output, stroke volume, and maximum velocity (Vmax)
significantly decreased after 4 weeks of pacing in untreated dogs.
Cardiac output significantly declined in paced dogs and was nearly
restored to control levels in the IGF-I-treated groups (control,
3.5 ± 0.4 liters/min; paced, 1.6 ± 0.2 liters/min;
IGF-I+paced, 2.8 ± 0.2 liters/min; control vs. paced,
P < 0.001; paced vs. IGF-I,
P < 0.001). LV end-systolic pressure decreased, and
end-diastolic pressure increased, whereas pulmonary capillary wedge
pressure and pulmonary artery pressure both increased after pacing.
Thus, paced dogs had significant biventricular failure. As expected,
systemic vascular resistance and LV wall stress increased in untreated
paced dogs. Compared with the untreated dogs, IGF-I-treated dogs showed
better cardiac output, stroke volume, LV end-systolic pressure, LV
end-diastolic pressure, pulmonary wedge pressure, systemic vascular
resistance, and LV wall stress (Table 2). Cardiac output, stroke
volume, LV peak pressure, and LV Vmax improved by
approximately 50% (Fig. 2). Ultrasound
measurements of cardiac output, stroke volume, and ejection fraction at
baseline, week 2, and week 4 remained unchanged in the normal control
group. Cardiac output, stroke volume, and ejection fraction were much
worse in the untreated paced dog, but these parameters did not differ
between week 2 and week 4 in the untreated paced group (all
P > 0.3), whereas IGF-I-treated dogs showed better
myocardial function than untreated dogs at week 4. This suggests that
in paced dogs IGF-I restored myocardial function rather than delayed
the progression of ventricular dysfunction. Furthermore, afterload was
significantly improved in the IGF-I-treated group, as systemic vascular
resistance nearly returned to the baseline (Fig. 3). We conclude that IGF-I improves the
overall function of the cardiovascular system by augmenting intrinsic
myocardial function and by improving preload and afterload. These
results indicate that exogenous injections of IGF-I improve multiple
aspects of cardiovascular function in established dilated
cardiomyopathy induced by pacing.
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.
The apoptotic nucleus is condensed under a DAPI filter and can be
easily identified by its bright green color under FITC filter. To
quantitate the prevalence of cardiomyocyte apoptosis, the apoptotic
index was calculated from the ratio of the number of apoptotic
cardiomyocyte nuclei to the total number of cardiomyocyte nuclei in
each section as described in Materials and Methods. Compared
with the sham controls, the myocardial apoptotic index increased by
approximately 4-fold in the untreated paced dogs (Fig. 5). Thus, ventricular pacing was
associated with an increased incidence of myocardial apoptosis. IGF-I
treatment resulted in reduction of the apoptotic index by 50%,
indicating that IGF-I treatment suppressed apoptosis of myocardium.
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, upper
panel), suggesting that thinning of ventricular wall upon pacing
might have involved apoptosis of cardiomyocytes. Moreover, the
apoptotic index inversely correlated with cardiac output (Fig. 6, lower panel), indicating that less cardiomyocyte apoptosis
is associated with better myocardial function. These data suggest that
apoptosis of cardiomyocytes might have contributed to remodeling of
ventricles and modulation of myocardial function in this model of
dilated cardiomyopathy.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are a small number of studies suggesting potential therapeutic actions of IGF-I on myocardial dysfunction; most of them used ischemic models of cardiomyopathy in small rodents. In the study by Duerr et al. (9), large dose IGF-I (3 mg/kg·day for 14 days) were given to rats 2 days after ligation of the coronary artery. In this rat model of ischemic cardiomyopathy, IGF-I administration lead to mild ventricular hypertrophy and higher cardiac output and stroke volume. This is somewhat different from what we have observed, as we did not find any evidence of ventricular hypertrophy. The discrepancy may be due to the difference in experimental models used (pacing vs. ischemia), the timing of initiating IGF-I treatments (2 weeks vs. 2 days after induction of cardiomyopathy), the doses of IGF-I used (moderate vs. high), or the species of experimental animals (canine vs. rat). Compared with those in humans and dogs, the normal levels of circulating IGF-I are at least 10 times higher in rodents (27). Therefore, high doses of exogenous IGF-I are needed to show an effect. Another study showed that upon ligation of the coronary artery, ventricular wall stress, ventricular dilatation, and ventricular hypertrophy were all attenuated in transgenic mice overexpressing myocardial IGF-I (16). The transgenic mouse study provides important new insights about the effects of IGF-I on myocardium, but the therapeutic effects of exogenous IGF-I administration could not be determined with this model. Moreover, compared with wild-type mice, the transgenic mice had cardiac hypertrophy and an increased number of cardiomyocytes at the time of study. Although these studies significantly advance our understanding of IGF-I actions in the heart, whether IGF-I can be used to restore cardiac function in human dilated cardiomyopathy or experimental models of cardiomyopathy resembling failing human heart is not known. This present study further extends our knowledge by demonstrating the therapeutic efficacy of exogenous IGF-I injections in a model that closely resembles human congestive heart failure.
IGF-I injection retards the thinning of ventricular walls in the paced dogs. Inhibition of myocardial apoptosis by IGF-I may have lead to restoration of ventricular wall thickness. In transgenic mice overexpressing IGF-I, myocardial infarction produced less myocardial apoptosis than in wild-type mice (16). In a separate study, short term exogenous injection of IGF-I reduced myocardial apoptosis during evolving myocardial infarction in rats (17). The hypothesis that myocardial apoptosis is involved in the regulation of myocardial remodeling and function has drawn intensive research interests. Many studies have shown the occurrence of myocardial apoptosis during the development of cardiomyopathy in experimental animals and humans (16, 17, 20, 28, 29). As adult cardiac muscle cells rarely replicate, the loss of cardiomyocytes may lead to loss of myocardial functioning units. Indeed, previous microscopic studies have shown reduced cardiomyocyte numbers during the development of cardiomyopathy (19). In this canine model of dilated cardiomyopathy, increased apoptosis of cardiac muscle cells may play a major role in the process that leads to loss of cardiomyocytes (29). Despite recent studies that have observed apoptosis of cardiac muscle cells in animal and human cardiomyopathy, a clear relationship between the extent of myocardial apoptosis and myocardial structure/function has not yet been demonstrated. Our results show that a higher incidence of apoptosis in cardiac muscle is associated with a thinner ventricular wall and lower cardiac output, and thus provides further evidence that apoptosis of cardiac muscle is involved in the regulation of myocardial remodeling and function.
Myocardial apoptosis was increased in paced dogs, and IGF-I injection lead to reduction of apoptosis. As the incidence of apoptosis is closely related to cardiac function and myocardial thickness, the antiapoptotic effects of IGF-I probably contributed to improvement of cardiac function in this model. Apoptosis is an important biological mechanism through which tissues shape normal developmental patterns and adapt to new environmental changes (30). The occurrence of apoptosis is regulated by serial alterations of intracellular molecules in response to extracellular signaling changes (30). In cultured cardiomyocytes, IGF-I inhibits the induction of Bax protein, suppresses activation of caspase 3, and attenuates fragmentation of DNA (18). The exact mechanisms that lead to activation of apoptotic signaling in the paced dog remain to be investigated. In paced dogs increased activation of the sympathetic system and renin-angiotensin system has been observed (26). As adrenergic stimulation may induce myocardial apoptosis, and an angiotensin-converting enzyme inhibitor may inhibit myocardial apoptosis, it is possible that activation of the sympathetic and angiotensin systems may have contributed to the occurrence of myocardial apoptosis in paced dogs. Whether administration of IGF-I modulates these and other neurohormonal pathways that then, in turn, suppress myocardial apoptosis signaling will have to be investigated with further studies.
The observation that IGF-I almost completely normalized systemic vascular resistance is quite intriguing. The transgenic mouse study and other studies that investigated in vivo effects of IGF-I on experimental cardiomyopathy did not report data on systemic vascular resistance (5, 9, 10, 16, 17). However, IGF-I reduced vascular resistance in normal rats (31), and injections of IGF-I in diabetic patients were associated with peripheral vasodilatation (32). Thus, a reduction of vascular resistance, although rarely investigated in previous in vivo IGF-I studies of the heart, may represent an important component of IGF-I actions on the cardiovascular system. Alternatively, systemic vascular resistance might have resulted from less physiological stress upon improvement of cardiac function in the IGF-I-treated dogs. The design of the present study did not allow us to dissect the complex interplay between ventricular function and vascular resistance. However, the reduction of peripheral vascular resistance may potentially play a critical role in beneficial actions of IGF-I on cardiovascular function. The reduction of afterload is known to improve myocardial function and myocardial remodeling. Angiotensin-converting enzyme inhibition reduced apoptosis of myocardium in canine heart failure (33), suggesting that a reduction of afterload may decrease myocardial stress and contribute to the suppression of myocardial apoptosis. Therefore, in addition to the direct antiapoptotic action of IGF-I on cardiomyocytes (18), the antiapoptotic effects of in vivo IGF-I administration may be partly mediated by the reduction of afterload.
The occurrence of apoptosis probably represents permanent damage to the myocardium. This is consistent with previous observations that weeks after discontinuation of pacing, the structure of the myocardium was permanently altered as ventricular chambers remained dilated and ventricular wall thinned (26). A better understanding of the mechanisms of the antiapoptotic actions of IGF-I in the heart and its relationship to other actions of IGF-I on the cardiovascular system may ultimately lead to better prevention of and more effective treatments for cardiomyopathy.
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Acknowledgments |
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Footnotes |
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Received March 18, 1999.
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human cell hybrids. Radiat Res 143:34–44[Medline]
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