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Circulation. 1996;93:800-809

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(Circulation. 1996;93:800-809.)
© 1996 American Heart Association, Inc.

Articles

Differential Cardiac Effects of Growth Hormone and Insulin-like Growth Factor1 in the Rat

A Combined In Vivo and In Vitro Evaluation

Presented in part at the 67th Scientific Session, American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90[suppl I]:I-17).

Antonio Cittadini, MD; Hinrik Strömer, MD, PhD; Sarah E. Katz, BA; Ross Clark, PhD; Alan C. Moses, MD; James P. Morgan, MD, PhD; Pamela S. Douglas, MD

From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory, Department of Medicine (Cardiovascular Division [A.C., H.S., S.E.K., J.P.M., P.S.D.] and Endocrinology [A.C.M.]), Beth Israel Hospital and Harvard Medical School, Boston, Mass; and Genentech Inc (R.C.), South San Francisco, Calif.

Correspondence to Pamela S. Douglas, MD, Cardiovascular Division, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215. E-mail pdouglas@bih.harvard.edu.


*    Abstract
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 *Abstract
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down arrowResults
down arrowDiscussion
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Background Despite their increasing clinical use and recent evidence that growth hormone (GH) and insulin-like growth factor–1 (IGF-1) target the heart, there has been no systematic investigation of the effects of GH and IGF-1 on the cardiovascular system.

Methods and Results Sixty normal but growing adult female rats were randomized to receive 4 weeks of treatment with GH (3.5 mg · kg-1 · d-1), IGF-1 (3 mg · kg-1 · d-1), a combination of the two, or placebo. Transthoracic echocardiograms were performed at baseline and at 2 weeks and 4 weeks of treatment. After the final echocardiography, rats underwent either closed-chest left ventricular (LV) catheterization or Langendorff perfusion studies. Myocyte diameter and interstitial tissue fraction were assessed by morphometric histology. Echocardiographic and ex vivo data demonstrated a LV hypertrophic response in all three groups of treated animals that was most marked in the GH group, which alone exhibited a concentric growth pattern (relative wall thickness, 0.52 versus 0.42 to 0.44 in the other groups; P<.001). At 4 weeks, cardiac index was significantly higher and total systemic vascular resistance was lower in all groups of treated animals than in control animals (both P<.001), whereas arterial blood pressure did not differ significantly. All indexes of in vivo and in vitro cardiac function were higher in GH- and IGF-1–treated rats than in control animals, whereas combination therapy yielded a blunted effect. Myocyte diameter was increased in all three treated groups without an increase in interstitial tissue.

Conclusions Exogenous administration of GH and IGF-1 in the normal adult rat induces a cardiac hypertrophic response without development of significant fibrosis. Cardiac performance is increased both in vivo and in the isolated heart.


Key Words: growth factors • ventricular hypertrophy • cardiac function


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Although the notion that GH and IGF-1 are critical for normal growth, maintenance of skeletal muscle mass, and metabolic homeostasis is well accepted,1 relatively little attention has been focused on the specific influences of GH and IGF-1 on cardiac structure and function. Recent observations suggest links between GH and the cardiovascular system, including (1) excess of cardiac mortality in acromegaly and in hypopituitarism1 2 ; (2) LV and RV dysfunction in acromegaly and GH deficiency3 4 5 6 ; and (3) reversibility of cardiovascular abnormalities during treatment with octreotide in acromegaly or GH in GH deficiency.5 7 8 Studies of GH excess produced by a GH-secreting tumor in rats have yielded conflicting measures of cardiac function in vivo with either increased or decreased contractility.9 10 However, the precise definition of cardiovascular function in this model has been hampered by a significant anemia and the consequent "high output state" and by the concurrent secretion of prolactin. Furthermore, no cardiac evaluation of the combination of both IGF-1 and GH hormones has been performed in the normal rat.

IGF-1 recently has been postulated to initiate, mediate, or modulate cardiac hypertrophy either per se or in response to several stimuli, including pressure and volume overload.11 12 13 14 Due to the availability of rhIGF-1, this protein is entering the therapeutic arena as a possible treatment of a variety of diseases, including GH-resistant short stature, catabolic states, and types I and II diabetes mellitus, both alone and in combination with rhGH.15 Although there is a potential for significant cardiovascular side effects of such treatment, few data are available concerning the effects of chronic rhIGF-1 administration.

Thus, the present study was designed to investigate the cardiovascular effects of chronic (4-week) exogenous administration in normal rats of rhGH, rhIGF-1, and a combination of the two. We postulated that each hormone would have significant effects on LV size and function.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
All of the methods described are consistent with the recommendations of the Panel of Euthanasia of the American Veterinary Medical Association and conform to the requirements of the American Heart Association. Sixty female Sprague-Dawley rats aged 10 to 12 weeks with a body weight ranging from 220 to 250 g were obtained from Charles River Breeding Laboratories, Wilmington, Mass, and were provided water and rat chow (Purina Formulab Chow 5008) ad libitum. The animals were randomized into four groups of 15 animals each: The GH group received 3.5 mg·kg-1 · d-1 of rhGH via two daily subcutaneous injections; the IGF-1 group received 3 mg · kg-1 · d-1 of rhIGF-1 via a subcutaneously implanted osmotic minipump delivering 2.5 µL/h of solution (Alzet Model 2ML4, Alza Corp); and the combination group received a combination of the two hormones at the same dosages via the same delivery systems as the single groups. A control group was infused with vehicle alone via minipump (n=7) or with saline injected subcutaneously twice a day (n=8) to better mimic the methods of drug administration in active treatment groups. The treatment period was 4 weeks. These dosages of hormones were selected on the basis of the results of a pilot study performed at the Genentech laboratories with rats of the same age and strain as ours; this study showed an approximately 40% increase in body weight above baseline at 4 weeks of treatment (unpublished data). rhGH and rhIGF-1 were provided by Genentech, Inc.

Echocardiography
Rats underwent echocardiograms before receiving drug and at 2 and 4 weeks of therapy. Previous reports from our laboratories and others have demonstrated the accuracy and the reproducibility of transthoracic echocardiography in rats for measuring LV size and function.16 Briefly, rats were anesthetized with a combination of ketamine HCl (Parke-Davis) (50 mg/kg) and xylazine (Lloyd Laboratories) (10 mg/kg) IP. After their chests were shaved, rats were placed in the prone decubitus position on a specially designed apparatus. Echocardiograms were performed from underneath with a Hewlett-Packard Sonos 1500 sector scanner equipped with a 7.5-MHz phased-array transducer. Two-dimensionally guided M-mode tracings were recorded on strip-chart paper at a paper speed of 100 mm/s. Anterior and posterior wall thicknesses and LV internal dimensions were measured according to the leading-edge method of the American Society of Echocardiography17 ; leading edges of the anterior wall were excluded. All measurements were performed with an off-line analysis system (Cardiac Workstation, Freeland Systems) by one observer who was blinded to prior results. Relative wall thickness was calculated as


Echocardiographic LV mass (LVMe) was determined using a standard cube formula18 :


where EDD is LV end-diastolic dimension, and PWT and AWT are diastolic posterior and anterior wall thicknesses, respectively. All measurements were the average of three consecutive cardiac cycles and were made to a precision of 0.1 mm. LV end-diastolic and end-systolic volumes were calculated according to the simplified prolate ellipsoid method19 :


From the volume data, stroke volume and cardiac output were calculated according to standard validated formulae20 ; values were also indexed by body weight and tibial length.

Two-dimensionally guided pulsed Doppler recordings of LV and RV inflow were obtained from the apical four-chamber view. The position of the sample volume was optimized to obtain maximal diastolic flow velocities with better defined waveforms, minimal spectral broadening, and no angle correction. Doppler recordings were made at a paper speed of 100 mm/s and analyzed off-line. Measurements were made from six consecutive cycles to minimize beat-to-beat variability. Maximal early and late diastolic flow velocities were derived from atrioventricular inflow velocities.

Hemodynamic Studies
Within 12 hours of the final echocardiogram, rats were anesthetized with ketamine and xylazine at the same doses used for the echocardiograms. A calibrated 2F micromanometer-tipped catheter (Millar Instruments) was passed via the carotid artery into the LV under constant pressure monitoring. LV end-diastolic pressure was recorded with an expanded scale, and LV dP/dt was obtained from a differentiating circuit in the physiological recorder (model 2400, Gould, Inc) with the high-frequency filter cutoff set at 300 Hz. Pressure tracings were digitally converted and entered into a Gateway 486 computer and digitized at 1000 Hz. The time constant of relaxation of LV isovolumic pressure decline ({tau}) was calculated according to the variable asymptote methods21 :


Total peripheral resistance index was calculated as Mean Arterial Blood Pressure/Cardiac Index.

Estimation of LV Wall Stress
LV meridional peak systolic and end-diastolic wall stresses were estimated using the following validated formula22 :


where LVID is LV internal diameter (end-systolic or end-diastolic), PWT is posterior wall thickness, and LV pressure is LV peak systolic or end-diastolic pressure. LV dimensions and wall thickness were measured based on the M-mode recordings. LV pressure was estimated within 12 hours of the final echo under identical anesthetic conditions.

One limitation of this approach is that pressures and LV dimensions are not measured simultaneously; nevertheless, because all animals were handled similarly, we believe that useful information for relative comparison could be derived from these data.

Perfusion Technique
Seven rats from each group were killed, and the isolated hearts were placed in an isovolumic, buffer-perfused rat heart preparation according to the Langendorff technique, as previously described.23 The person performing the experiments was blinded as to the groups to which the rats belonged. Briefly, the rats were anesthetized with ketamine and xylazine, followed by an injection of 200 IU heparin into the femoral vein. One minute later, the thorax was opened, and the heart was removed quickly and placed into ice-cold Krebs-Henseleit solution (vide infra), weighed, and mounted on a cannula inserted into the ascending aorta. Retrograde aortic perfusion of the coronary arteries was performed within 30 seconds after the thoracotomy via a constant flow of 10 mL · min-1 · g-1 heart wt, and the pressure was monitored with a Statham P23Db transducer. This flow rate was chosen because preliminary experiments with graded ischemia have yielded an aerobic pattern of lactate consumption measured according to Apstein et al.24 Cardiac temperature was set at 25°C, measured by a temperature probe inserted into the right ventricle. The composition of the perfusate was as follows (in mmol/L): NaCl 118, KCl 4.7, KH2PO4 1.2, CaCl2 1.5, MgCl2 1.2, NaHCO3 23, and dextrose 5.5, and saturated with a 95% O2/5% CO2 gas mixture to pH 7.4±0.2. LV pressure was measured using a fluid-filled latex balloon inserted into the left ventricle via the mitral valve. After an equilibration period of 15 to 30 minutes at 25°C, the temperature was gradually increased to 36°C and the hearts were finally paced at 4 Hz. Measurements of LV systolic function were obtained when the preparation achieved a steady state after instrumentation (approximately 15 minutes) after adjustment of the balloon volume to achieve a LV end-diastolic pressure of 10 mm Hg in all groups. This level of end-diastolic pressure was chosen because it allowed the study of the control and hormone-treated animals at a single common operational point on the LV pressure-volume curves.25

After in vivo or in vitro hemodynamic evaluation, hearts were rapidly removed, and the right and left ventricles were dissected, blotted, and weighed; samples of the left ventricle from the rats undergoing catheterization (n=7) were placed in a fixative solution for subsequent histological examination.

Blood Analysis
Blood samples were obtained at the time of death. Duplicate hematocrit samples were prepared in microhematocrit tubes. Serum was prepared from the remainder of the sample and frozen at -20°C for subsequent analysis. GH and IGF-1 were measured at Genentech. Human GH was measured in rat serum by ELISA and total serum IGF-1 by radioimmunoassay, according to previously described methods.26 27

Histology
The tissues were immersion-fixed in 10% buffered formalin. Specimens for histological examination were obtained from each heart, which was cut into cross sections at four levels from apex to base. The samples were embedded in paraffin and stained with hematoxylin and eosin for measurements of muscle fiber diameter and with Masson's trichrome for assessment of interstitial fibrosis. Quantitative evaluation was carried out by morphometry, according to previously described methods.28 Muscle fiber diameter was evaluated by direct measurements at a magnification of 400x, using only cross sections that included a nuclear profile. A total of 100 cells per animal were evaluated. Quantitative assessment of interstitial tissue as a measure of fibrosis was accomplished with a special grid on which horizontal and vertical lines provided 100 intersecting points, at 400x magnification. Four fields at each of the four sample sites were examined for each animal, yielding a total of 16 fields in each rat. Reproducibility studies showed a good correlation between data obtained at two studies in four rats, for both techniques, with an r value of .90.

Tibial Length
At the end of the experiment, right hind legs of the rats were removed by disarticulating the femurs from the acetabulum at the hip. The tibias were dissected free of soft tissue and frozen at -20°C. Four radiographic films (X-Omat XTL2, Eastman Kodak Co) of the tibias were then obtained, and the tibial length of each animal was assessed with a caliper from the radiograph.

In summary, all groups (n=15) underwent Doppler echocardiography at baseline and at 2 and 4 weeks. After 4 weeks of treatment, 7 of 15 rats in each group were chosen at random for closed-chest cardiac catheterization, whereas the remaining 8 rats from each group underwent perfusion studies. The 7 rats that underwent cardiac catheterization were used for subsequent histological analysis. Blood work, including hematocrit, was carried out in each animal.

Statistical Analysis
All values are given as mean±SEM. Statistical analysis was performed using a Sun Microsystem Station equipped with the PROPHET software package. Between-group comparisons of echocardiographic indexes were performed using the two-factor factorial (two-way) ANOVA with repeated measures in one factor (time). One-factor factorial one-way ANOVA was used for the other comparisons. Where appropriate, comparisons to determine the significance of changes within the same group over time and between groups at each time point were performed with blocked (within groups) and unblocked (between groups) Neuman-Keuls tests after the samples were tested for normal distribution. Linear regression analysis was used as appropriate. If the distribution was not normal, corresponding nonparametric tests were used. A value of P<.05 was considered significant.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
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Blood Analysis and Histological Data
Hematocrit remained constant in all treatment groups (Table 1Down). High plasma levels of human GH were present in rats treated with rhGH and with rhGH plus rhIGF-1. Human GH levels were not measurable in the control group or in the group receiving rhIGF-1 alone. IGF-1 levels increased approximately twofold in the IGF-1 group and approximately threefold in the combination group. There were no significant correlations between GH and IGF-1 levels and any index of cardiac performance. Morphometric examination of the histological samples demonstrated a significant increase of fiber diameter in the three groups of hormone-treated animals compared with control rats. The percent of interstitial tissue as an index of fibrosis did not differ between any of the study groups.


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  		Table 1. Blood Analysis and Histological Data

Somatic and Cardiac Growth
Over the 4 weeks of treatment, body weight increased in all animals, whereas increases in tibial length were less marked (Table 2Down). Therefore, the ratios of LV and RV weight to tibial length were all significantly higher in the three groups of treated animals compared with control values. Although the optimal method for comparing heart weights in the rat is unknown, normalizing LV and RV weights to tibial length relates cardiac size to the amount of lean body tissue and to cell size more than does normalization to body weight.29 We present both (Tables 2Down and 5Down).


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  		Table 2. Somatic and Cardiac Growth


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  		Table 5. Normalized 4-Week Echocardiographic Data

Echocardiography
Geometry
The close correlation between echocardiography-derived LV mass and ex vivo LV weight in a combined group of control and treated animals (y=1.03x+0.05, r=.85; SEE=0.095 g, P<.00001) confirms the accuracy of echocardiographic measurements (Table 3Down). Both anterior and posterior wall thicknesses increased over time in the treated animals compared with control animals, which showed little or no changes. In contrast to the control group, treated animals showed a significant increase of LV diastolic diameters and volumes after 2 and 4 weeks of treatment, particularly the IGF-1 and combination groups. LV systolic diameters and volumes tended to be smaller in GH and IGF-1 groups after treatment.


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  		Table 3. Echo Geometry: Unnormalized Data

Representative echocardiograms of a normal and a GH-treated rat are shown in Fig 1Down. Echocardiographic LV mass increased in all of the hormone-treated groups but did not change significantly in the control group (Fig 2Down). When normalized to body weight, only GH-treated rats showed a significantly higher ratio of LV mass to body weight, in keeping with postmortem observations, although the ratios of both the IGF-1 and combination groups tended to be higher than in control animals. Relative wall thickness was significantly increased only in the GH group, indicating a concentrical growth pattern (Fig 2Down), whereas in the other groups the growth pattern was symmetrical.



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  		Figure 1. M-mode recording of LV cavity in a normal rat (left) and in a GH-treated rat (right) after 4 weeks of treatment.



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  		Figure 2. Graphs showing serial changes in LV mass (top) and relative wall thickness (bottom) at baseline and at 2 and 4 weeks of treatment. All data are shown as mean±SEM. *P<.05 compared with baseline; {dagger}P<.05 compared with control; {ddagger}P<.05 compared with IGF-1; §P<.05 compared with combination group.

Function
Calculated indexes of ejection phase function, such as fractional shortening and ejection fraction, did not change in the control group over time (Table 4Down). On the other hand, both indexes increased significantly in all groups of treated animals at 2 and 4 weeks versus both baseline values and values in control animals (Fig 3Down). Stroke volume and cardiac output showed no changes in the control group over time; both significantly increased in all three groups of treated animals, almost doubling their baseline values in the IGF-1 and combination groups (Fig 3Down). The Doppler-derived ratios of LV and RV early-to-late diastolic filling velocities and heart rate were not different between control and treated animals at any time.


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  		Table 4. Echo Function: Unnormalized Data



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  		Figure 3. Graphs showing serial changes in fractional shortening (top) and cardiac index (bottom) at baseline and at 2 and 4 weeks of treatment. All data are shown as mean±SEM. *P<.05 compared with baseline; {dagger}P<.05 compared with control.

In Vivo Hemodynamic Studies
Systolic, diastolic, and mean arterial blood pressures did not differ among the four study groups at the time of cardiac catheterization (Table 5Up). Total systemic vascular resistance was reduced in all treated groups. LV systolic pressure was similar in all groups, whereas small increases in LV diastolic pressure and stress, although significant, did not exceed the normal range in the combination group. Peak positive dP/dt and dP/dt values normalized to developed pressure were similar in all treated groups and significantly higher than in controls in all except the combination group. The {tau} was shorter in the GH group than in other groups. Systolic wall stress was significantly decreased in GH-treated animals compared with the other groups, whereas the IGF-1 group showed a trend toward a decrease.

Perfusion Studies
At 10 mm Hg of diastolic pressure, there were no significant differences in balloon volumes among the three groups of treated animals, although they tended to be higher in all treated groups (Table 6Down). LV functional parameters showed a significant increase of developed pressure in GH- and IGF-1–treated animals, whereas these values did not differ significantly between the control and combination groups. Peak positive dP/dt and dP/dt values normalized to developed pressure were higher in both IGF-1 and GH groups, suggesting enhanced cardiac performance.


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  		Table 6. In Vivo Hemodynamic Data


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
Evidence suggests that the heart is a target organ of GH and IGF-1.30 Despite the availability of rhGH and rhIGF-1 and a growing interest in their therapeutic use, few reports address the consequences of the chronic administration of rhGH and rhIGF-1 on the normal cardiovascular system. Our data demonstrate that exogenous administration of either rhGH or rhIGF-1 in the normal rat evokes a hypertrophic response in vivo, which is independent of changes in arterial blood pressure or preload. Cardiac performance is enhanced both in vivo and in vitro, whereas total peripheral vascular resistance is reduced in the hormone-treated animals. The two drugs combined do not exhibit a synergistic or additive effect on cardiac function or growth.

The differential effects of GH, IGF-1, and their combination on cardiac structure and function prompt a separate discussion of each of the three groups of hormone-treated animals.

GH Group
The concentric hypertrophy observed with rhGH is consistent with previous observations in normotensive acromegalic patients, who demonstrate increased LV mass and reduced systolic wall stress, and suggests a humoral rather than a hemodynamic stimulus to hypertrophy.3 Systolic and diastolic cardiac performances were also augmented, whether assessed echocardiographically, hemodynamically, or in the preload-independent isolated whole heart. This combination of effects, if translatable to humans, could have great potential therapeutic application.

The only previous studies examining cardiac structure and function in conditions of GH excess used rats with a GH-secreting tumor and yielded conflicting results, with either increased or decreased contractility.9 10 Several factors hamper the definition of cardiac performance in this tumor model: (1) GH3 cells, used to induce tumor formation in these studies, also secrete prolactin, which has cardiac effects31 ; (2) cardiac loading conditions are significantly altered by the tumor because of the development of a significant anemia, with hematocrit falling to 20% to 30% from baseline values of 42% to 45%; and (3) heart rate decreases significantly. Given the peculiarities of this model, it is possible that the conflicting results obtained in vivo thus far are due mostly to different tumor sizes or secretion rates, which may in turn produce different loading conditions. Results obtained from the tumor model would not adequately reflect the effects of pure GH excess on the cardiovascular system.

More relevant to our results are those studies dealing with GH administration in normal humans and GH-deficient patients. These have demonstrated similar findings, including increases in fractional shortening, stroke volume, and cardiac output; a decrease of total vascular resistance; and no significant change in arterial blood pressure. Invasive measures of contractility were not assessed.32 33

IGF-1 Group
The cardiac response to IGF-1 included a similar increase in LV function, although growth was less marked than in the GH group and relative wall thickness did not change. However, LV diastolic volumes tended to be larger, suggesting possible early eccentric remodeling, perhaps due to an increase of venous return in turn due to the greater decrease of total peripheral vascular resistance (vide infra) or fluid overload (unlikely in the absence of anemia). This observation is consistent with the recent demonstration of an arterial vasodilator effect of IGF-1 on forearm vasculature34 and suggests that peripheral as well as central effects may be important.

Although the cardiovascular effects of IGF-1 have not been investigated systematically, studies performed in normal subjects and in diabetic and GH-deficient patients report cardiovascular side effects after IGF-1 administration, including a modest increase in heart rate, tachycardia with palpitations, and orthostatic hypotension.35 Fluid retention and edema have also been described, sometimes leading to therapy withdrawal; cardiac function has not been assessed. We did not directly measure plasma volume, but the absence of significant elevation in preload indexes such as diastolic wall stress or end-diastolic pressure and the unchanged hematocrit make significant fluid overload unlikely. No increase in heart rate was observed in our IGF-1–treated rats, although the assessment of a drug's possible chronotropic effect during anesthesia is not ideal.

Combination Group
The results of combination therapy were not compatible with an additive or synergistic effect of GH and IGF-1 on cardiac tissue. Instead, the combination group exhibited several peculiarities: LV end-diastolic pressure and wall stress were significantly increased compared with all the other groups, suggesting an increased preload. Whether this reflects an increased intravascular volume or a shift toward an initial stage of cardiac dysfunction is unclear, although the latter is suggested by the lack of enhanced performance seen only in this group. Furthermore, GH and IGF-1 combined appeared to partially block the hormones' positive effects on in vivo and in vitro LV function indexes. The reason(s) underlying these findings are unclear and likely complex.

To the best of our knowledge, no previous studies of any kind have addressed the issue of cardiovascular effects of combined GH/IGF-1 therapy. Although their effects in some other systems are additive,15 we recently reported a similar absence of an additive effect on areal bone density in the same model of hormone excess.36

Pathogenesis of Cardiac Growth and Contractile Changes
Evidence that IGF-1 and GH are direct cardiac growth factors can be summarized as follows: (1) GH has an anabolic effect on skeletal and cardiac muscle tissue consisting of activation of protein synthesis37 38 ; (2) the GH receptor gene is expressed in the myocardium and to a greater extent than in other tissues39 ; (3) acromegalic patients without concomitant diseases show LV and RV hypertrophy related to the duration of GH excess that is reversible with a somatostatin analogue, octreotide3 7 ; (4) GH-deficient humans have cardiac atrophy, which is partially reversible after 6 months of GH replacement therapy8 ; (5) there is a significant relation between IGF-1 serum concentration and LV mass in humans with hypopituitary disease40 ; (6) cardiac myocytes of rats express IGF-1 receptors41 ; (7) IGF-1 administration to cultured neonatal cardiomyocytes increases cell size and induces transcripts of specific genes11 ; and (8) induction of volume and of pressure overload increases IGF-1 gene expression in the heart.12 13 14 Taken together, these observations suggest a possible direct "trophic" effect of GH and IGF-1 on the myocardium, despite the prior lack of direct evidence in vivo. Our data now confirm such an effect, demonstrating a hypertrophic response to both GH and IGF-1 in the normal rat, with enhancement of systolic function, all in the absence of an increased hemodynamic load. Interestingly, this type of cardiac growth is different from both normal growth of the juvenile heart, in which no changes in LV function are usually observed, and from pathological growth resulting from systolic overload in rats and rabbits, consistently associated with depression of contractile performance.42

Regarding the mode of cellular growth, histological examination excluded an increase in interstitial tissue as a major component of cardiac growth and showed enlargement of the diameter of individual muscle cells. A similar finding has been described by previous studies of rats with GH-secreting tumors.43 Even though cell length and myocyte number were not assessed, this finding suggests that cellular hypertrophy is an important component of the hypertrophic response to GH and IGF-1 administration.

There are several possible explanations for enhanced cardiac performance in vivo and in vitro. The lower values of systolic wall stress in both GH and IGF-1 groups and the decrease of total systemic vascular resistance in both groups could be partially responsible for the enhanced cardiac performance.21 However, the results of the perfusion studies obtained in the absence of systemic vascular and neurohumoral effects suggest that increased myocardial contractility in both GH and IGF-1 groups might also contribute. The mechanism(s) underlying increased contractile performance are unclear but might be related to altered calcium handling in the excitation/contraction coupling. In this regard, GH excess has been shown to increase the duration of the action potential, which in turn increases calcium influx into the myocyte.44 Increased calcium responsiveness at the myofibrillar level also has been demonstrated in cardiac skinned fiber preparation in rats with the tumor model of GH excess.45 Studies concerning the role of calcium in excitation/contraction coupling in our laboratory with the same model of GH and IGF-1 excess recently demonstrated an increase of calcium responsiveness of myofilaments, mostly due to an increase in maximal calcium-activated force capacity.46 Changes at the level of the myofilaments, often referred to as downstream mechanisms, might well have occurred in our model, since several authors have reported a significant isomyosin shift toward V3 isoform paralleled by enhanced contractility in the tumor model of GH excess10 45 47 ; the apparent paradox of a V3 myosin phenoconversion accompanied by increased contractile performance has been explained by an increase in the number of active enzymatic sites.47

The possibility that GH and IGF-1 might have acted indirectly via insulin metabolism48 or adrenergic stimulation49 50 should be considered but cannot be addressed in the present study.

Differential Effects of GH and IGF-1
The exact mechanisms governing GH and IGF-1 differential effects are still unclear. GH stimulates IGF-1 production in either a paracrine manner at the target tissue or through a distal endocrine mechanism by IGF-1 production at tissues such as the liver.1 However, GH also has its own receptors in several tissues such as heart, liver, kidney, lung, and testis, through which it is capable of acting independently.39 Given this intricate scenario of the direct and IGF-1–mediated effects of GH and of the direct paracrine and/or autocrine effects of IGF-1, our observations of differential effects of GH and IGF-1 on cardiac structure and possibly on peripheral resistance are not unexpected.

Another possibility is that the differential effects of the two hormones are simply related to physiological differences in the doses used. Our approach was to use doses of hormone able to induce similar increases in body weight; otherwise, it would have been very difficult to compare cardiac structural and functional parameters with different body weights. However, it is conceivable that similar increases in body weights do not necessarily represent similar effects on the heart or on other systems.

Study Limitations
The exogenous administration of a drug, in particular, of hormones endowed with paracrine and autocrine functions, does not necessarily mimic the physiological activity of such hormones. This may be especially true for GH and IGF-1, both of which act as classic endocrine factors and, in the case of IGF-1, as a paracrine and autocrine factor. Despite these potential limitations, we feel this approach is useful in assessing the pharmacological roles of GH and IGF-1, with the aim of determining the cardiovascular safety during their therapeutic use.

Considering the well-known GH stimulation of IGF-1 hepatic production,1 an apparent discrepancy of our findings is the lack of an increase in IGF-1 levels in the GH group. Although we cannot provide a definitive answer, possible explanations may be as follows: (1) the time interval between the last injection of rhGH was 8 to 16 hours, which may not represent the peak effect of GH on IGF-1 release, and (2) the assay used for IGF-1 determination might have been less sensitive to rat IGF-1 than to human IGF-1 because of lower efficacy of the acid-ethanol extraction of the serum in removing rat binding proteins than in removing human binding proteins, which in turn possibly interfere with the IGF-1 assay.27 Also, the use of human rather than rat GH in the rat may lead to neutralizing antibody formation and thus might have diminished effectiveness over time, both on cardiac muscle and on hepatic IGF-1 production. However, the steady increase in body and cardiac weights in all of the hormone-treated rats suggests a continuing biological activity over time for both preparations used.

Our protocol was specifically designed to define and to characterize the cardiovascular effects of GH and IGF-1 rather than to address pathophysiological mechanisms. Once the effects of hormones are clearly demonstrated, hypotheses should be generated to stimulate the additional research needed to clarify the mechanism involved.

Although conclusions regarding cardiac loading conditions (eg, stress, peripheral resistance) are difficult to draw in anesthetized animals, all groups were treated identically, so results should be comparable and reliably reflect underlying intergroup differences when present.

Clinical Implications
The administration of high doses of rhGH and rhIGF-1 had a significant impact on cardiac structure and function. Whether the hypertrophic response encountered, even in the presence of enhanced cardiac performance, should be considered potentially harmful is still an open issue. However, our data provide evidence that the cardiovascular effects of each hormone must be taken into account when considering a possible therapeutic use of GH or IGF-1. Given the growing interest in using these hormones in a variety of noncardiovascular pathological conditions, longer-term preclinical studies are needed to confirm these findings before clinical trials are undertaken.

Interestingly, the exogenous administration of GH and IGF-1 appears to have favorable effects on the cardiovascular system that might have great therapeutic potential. A drug that causes myocyte hypertrophy without increasing fibrosis enhances contractility in vivo and in vitro, enhances relaxation (GH only), and decreases systemic vascular resistance would be highly desirable for treatment of conditions such as heart failure. Further investigations are needed to test this hypothesis and to select the optimal dose regimen(s) to maximize the beneficial effects for each target disease(s). In this respect, three independent groups have already reported beneficial effects of GH and IGF-1 in postinfarction and doxorubicin-induced heart failure in the rat.51 52 53

Conclusions
The effects of GH and IGF-1 administration have been described in a new model of hormone excess in the heart. Our results lend support to the hypothesis that the heart is a target organ for both GH and IGF-1. Considering the overall favorable effects on the cardiovascular system, additional studies are warranted to better elucidate their mechanism of action and their possible use in conditions such as congestive heart failure.


*    Selected Abbreviations and Acronyms
 
GH = growth hormone
IGF-1 = insulin-like growth factor–1
LV = left ventricular
rh = recombinant human
RV = right ventricular


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  		Table 7. Isolated Whole Heart Data


*    Acknowledgments
 
This work was supported in part by grants from Consiglio Nazionale delle Ricerche, Italy (Dr Cittadini), the Deutsche Forschungsgemeinschaft, Germany (Dr Strömer), and the US Public Health Service (grants HL-31117 and HL-51307-01 (Dr Morgan); Dr Cittadini was on leave from the Federico II University Medical School, Napoli, Italy. We thank Stephen Gladstone for performing the radiographs of the rats' tibias, Wesley Woon for performing the hGH and IGF-1 assays, and Bernard Ransil, MD, PhD, for statistical consulting.

Received July 17, 1995; revision received September 15, 1995; accepted September 25, 1995.


*    References
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