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(Circulation. 2001;103:308.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Treatment With a Growth Hormone Secretagogue in a Model of Developing Heart Failure
Effects on Ventricular and Myocyte Function
From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, and Cardiovascular and Metabolic Disease, Pfizer Central Research, Groton, Conn (L.C.P., C.P.).
Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29425.
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Abstract |
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{abs}Background—Exogenous administration of growth hormone (GH) and subsequently increased production of insulin-like growth factor-1 can influence left ventricular (LV) myocardial growth and geometry in the setting of congestive heart failure (CHF). This study determined the effects of an orally active GH secretagogue (GHS) treatment that causes a release of endogenous GH on LV function and myocyte contractility in a model of developing CHF.
Methods and Results—Pigs were randomly assigned to the following treatment groups: (1) chronic rapid pacing at 240 bpm for 3 weeks (n=11); (2) chronic rapid pacing and GHS (CP-424,391 at 10 mg·kg-1·d-1, n=9); and (3) sham controls (n=8). In the untreated pacing CHF group, LV fractional shortening was reduced (21±2% versus 47±2%) and peak wall stress increased (364±21 versus 141±5 g/cm2) from normal control values (P<0.05). In the GHS group, LV fractional shortening was higher (29±2%) and LV peak wall stress lower (187±126 g/cm2) than untreated CHF values (P<0.05). With GHS treatment, the ratio of LV mass to body weight increased by 44% from untreated values. Steady-state myocyte velocity of shortening was reduced with pacing CHF compared with controls (38±1 versus 78±1 µm/s, P<0.05) and was increased from pacing CHF values with GHS treatment (55±7 µm/s, P<0.05).
Conclusions—The improved LV pump function that occurred with GHS treatment in this model of CHF was most likely a result of favorable effects on LV myocardial remodeling and contractile processes. On the basis of these results, further studies are warranted to determine the potential role of GH secretagogues in the treatment of CHF.
Key Words: ventricles • myocytes • contractility • growth substances
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Introduction |
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The progression of congestive heart failure (CHF) is accompanied by left ventricular (LV) remodeling and worsening pump function. The LV remodeling in CHF often results in chamber dilation, which in turn causes increased LV wall stress. This increased LV wall stress further exacerbates LV performance through both increased LV afterload and potentially compromising myocardial contractile function. One approach in the regulation of LV remodeling with CHF would be to augment the failing myocardium with growth factors. Several studies have demonstrated that administration of growth hormone (GH) or insulin-like growth factor-1 (IGF-1) can directly influence LV myocardial structure and function.1 2 3 4 5 6 The results from clinical studies, in which recombinant GH was delivered through subcutaneous injections, provide support for the concept that GH can influence LV geometry with CHF.6 7 Exogenous administration of GH, however, can be difficult for applications in the clinical treatment of CHF. An alternative approach for increasing systemic levels of GH would be to directly stimulate the pituitary to augment the synthesis and release of GH. The production of GH from the pituitary is influenced by the release of GH-releasing hormone from the hypothalamus. Past studies have demonstrated that the release of GH from the pituitary can be mediated by stimulation of the GH-releasing hormone receptor through the use of peptidomimetic agonist, or GH secretagogue (GHS).6 7 Accordingly, the overall goal of this study was to determine whether administration of GHS during the progression of a CHF process would provide beneficial effects on LV structure and function.
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Methods |
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Chronic rapid pacing in pigs causes a reproducible phenotype of CHF, which includes LV pump dysfunction, neurohormonal system activation, and myocyte contractile dysfunction.8 9 10 11 Accordingly, this pacing CHF model was used to examine the effects of GHS treatment. This study used an orally bioavailable GHS (CP-424,391, Pfizer Central Research). Preliminary dose-response studies demonstrated that an oral dose of 10 mg·kg-1·d-1 of this compound for 3 days increased steady-state plasma IGF-1 levels by >2-fold from basal levels in normal pigs (n=3). In additional preliminary studies, a 10-fold increase in GH plasma levels was induced 90 minutes after oral administration of this dose of GHS in normal pigs. Accordingly, 10 mg·kg-1·d-1 of CP-424,391 was chosen for the dosing regimen. GHS treatment was instituted before the onset of chronic rapid pacing and continued throughout the pacing period.
Instrumentation and Induction of Pacing
CHF
Twenty Yorkshire pigs (20 kg, male, Hambone Farms,
Orangeburg, SC) were chronically instrumented with an aortic catheter
and a modified atrial pacemaker, as described
previously.8 12
After a 14- to 21-day recovery from the surgical procedure, the pigs
were randomly assigned to 1 of the following treatment groups: (1)
chronic rapid pacing at 240 bpm for 3 weeks with placebo treatment
(n=11), (2) chronic rapid pacing and GHS supplementation (n=9),
and (3) sham controls (n=8). GHS treatment (8:00
AM daily) was started 7
days before the activation of the pacemaker and continued throughout
the 21-day pacing protocol. At each week after enrollment in the study,
the animals were returned to the laboratory for evaluation of LV
function and plasma collection, as described in the following section.
All animals were treated and cared for in accordance with the National
Institutes of Health Guide for the Care
and Use of Laboratory Animals (National Research Council,
Washington, DC, 1996).
LV Function Measurements
All studies were performed in a conscious state with
the pacemaker deactivated. LV dimensions and fractional shortening were
obtained by echocardiography, and resting aortic pressure was obtained
as previously described. From the LV echocardiographic and blood
pressure measurements, LV peak and systolic circumferential wall stress
values were computed by use of a spherical model of
reference.12 13
LV myocardial velocity of circumferential fiber shortening, corrected
for heart rate (Vcfc), was computed from the LV dimensions and pressure
data. Simultaneously drawn blood samples were assayed for
norepinephrine, IGF-1, and blood glucose, as previously
described.11
After the LV function measurements on day 21 of the protocol, the animals were deeply anesthetized with 4% isoflurane, and a sternotomy was performed. The heart was quickly removed and processed for studies as described below.
LV Myocyte Contractile Function and
Cross-Sectional Area
Isolated LV myocyte contractility was examined by
computer-assisted
videomicroscopy.8 10
After baseline measurements, contractile function was examined either
after ß-adrenergic receptor stimulation with 25 nmol/L isoproterenol
(-isoproterenol, Sigma Chemical Co) or in the presence of 8 mmol/L
extracellular calcium
(Ca2+).10
Myocardial sections cut in the circumferential orientation were
examined by light microscopy to evaluate the myocyte cross-sectional
area by use of computer-assisted methods described
previously.8 9
Data Analysis
Indices of LV function, systemic hemodynamics,
and neurohormonal profiles were first compared among the treatment
groups by ANOVA for repeated measures. For the myocyte function
studies, an ANOVA using a randomized block split-plot design was used.
If the ANOVA revealed significant differences, pairwise tests of
individual group means were compared by use of Bonferroni
probabilities. LV cross-sectional area measurements were examined to
ensure a normal gaussian distribution and then subjected to ANOVA and
mean separation by the Student-Newman-Keuls test. All statistical
procedures were performed with the BMDP statistical software package.
Results were presented as mean±SEM. Values of
P<0.05 were considered to be
statistically significant.
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Results |
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All of the pigs that entered the rapid-pacing protocols were successfully studied. In the GHS-treated group, plasma IGF-1 levels were increased by
2-fold over untreated pacing values and
normal control values
(Figure 1
).
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LV Geometry and Function With Rapid Pacing:
Effects of GHS Treatment
LV wall stress measurements and fractional shortening
obtained with each week of chronic rapid pacing with and without GHS
treatment are summarized in
Figure 2. In the untreated rapid-pacing group, LV
end-systolic and peak wall stress increased and LV fractional
shortening decreased in a time-dependent manner. In the rapid-pacing
and GHS-treated group, the change in LV wall stress patterns was
markedly attenuated from untreated values and was associated with a
significant improvement in LV fractional shortening. In the GHS-treated
group, however, LV wall stress increased and LV fractional shortening
decreased from baseline values.
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Systemic hemodynamics and LV dimensions after the 3-week
protocol are summarized in
Table 1. In both rapid-pacing groups, ambient
resting heart rate was increased and resting blood pressure decreased
from control values. LV end-diastolic dimension was increased in both
rapid-pacing groups compared with controls but was reduced in the
GHS-treated group compared with untreated pacing values. LV
end-diastolic wall thickness was decreased from control values in the
untreated pacing group but remained unchanged from control values in
the GHS-treated group. Vcfc was reduced by 50% in the rapid-pacing
group compared with control values. In the GHS-treated group, LV Vcfc
was also reduced from control values but was increased from untreated
pacing values.
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Plasma norepinephrine values were increased by >10-fold in
the rapid-pacing group compared with control values
(Table 1
). In the GHS-treated group, plasma norepinephrine
levels were similar to untreated pacing values. Steady-state blood
glucose levels were reduced in the rapid-pacing-only group but were
similar to control values in the GHS-treated group.
The initial 7-day GHS treatment before pacemaker activation did not cause a significant increase from untreated values in the ratio of LV mass to body weight. LV mass/body weight ratio increased slightly in the rapid-pacing group compared with control values (4.8±0.3 versus 4.2±0.2 g/kg, respectively, P<0.05). With GHS treatment, LV mass/body weight ratio increased from both control and rapid-pacing-only values (7.5±0.5 g/kg, P<0.05). LV myocyte cross-sectional area was reduced in the rapid-pacing-only group (205±25 µm2) compared with control values (250±15 µm2, P<0.05) and was significantly increased from both control and rapid-pacing values in the GHS-treated group (310±15 µm2, P<0.05).
LV Myocyte Contractility With Rapid Pacing:
Effects of GHS Treatment
Steady-state isolated LV myocyte contractile function
was examined in >1200 myocytes from each of the 3 study groups
(Table 2). LV myocyte length was increased in the untreated
rapid-pacing group compared with controls, and a small, yet
significant, increase in resting length was observed in the GHS
treatment group. Indices of steady-state myocyte contractile function
were significantly reduced in the untreated rapid-pacing group compared
with normal control values. In the GHS treatment group, myocyte
contractile function was increased from rapid-pacing-only values but
remained significantly reduced from normal control values.
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The capacity of the isolated myocyte to respond to an
inotropic stimulus was examined through ß-receptor stimulation with
either isoproterenol or exposure to increased extracellular
Ca2+
(Table 2). In the presence of isoproterenol, myocyte
contractile function was significantly blunted in the untreated
rapid-pacing group. Although it remained reduced from normal control
values, myocyte contractility was higher after ß-receptor stimulation
in the rapid-pacing and GHS-treated groups than the untreated pacing
values. With exposure to extracellular Ca2+,
indices of myocyte contractile function remained reduced from control
values in the untreated rapid-pacing group. In the GHS treatment group,
myocyte function after exposure to extracellular
Ca2+ was increased compared with untreated
rapid-pacing values but remained significantly lower than normal
control values.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The administration of recombinant GH or IGF-1 has been demonstrated to influence LV myocardial growth in the setting of both experimental and clinical forms of CHF.3 4 6 7 14 Whether and to what degree treatment with a GHS would influence LV geometry and function in the setting of a developing CHF process, however, remained unexplored. The present study used an orally active GHS in a porcine model of CHF and demonstrated that circulating IGF-1 levels were increased by
2-fold, indicating a biological response to
this form of treatment. More importantly, GHS treatment during
pacing-induced CHF was associated with a significant improvement in LV
pump function. The present study provided a mechanistic basis for this
improvement in LV ejection performance with GHS treatment. First, GHS
treatment induced LV myocardial growth, which in turn reduced LV
afterload through a reduction in wall stress patterns. Second, GHS
treatment was associated with an intrinsic improvement in myocyte
contractile function and inotropic capacity. Thus, the unique findings
from this study demonstrated that it is possible to stimulate the
GH-pituitary axis through oral GHS treatment and that this approach
provides beneficial effects on LV function and contractile processes
with developing CHF. GH treatment and subsequent changes in circulating levels of IGF-1 can influence a number of cardiovascular processes, including LV loading conditions and contractility.5 7 15 16 In patients with dilated cardiomyopathy, GH treatment that subsequently increased IGF-1 levels reduced LV wall stress and improved LV pump function.6 Increased IGF-1 levels have been demonstrated to potentially influence vascular resistive properties. For example, recombinant GH treatment in CHF patients was associated with a reduction in resting mean arterial pressure and systemic vascular resistance.7 In addition, IGF-1 has been demonstrated to induce nitric oxide (NO) production in vitro and has vasodilatory properties consistent with an NO-mediated effect in vivo.15 16 The present study did not measure vascular reactivity or NO production with GHS treatment, and this area warrants further investigation. Nevertheless, in the present study, a significant reduction in LV wall stress was observed with GHS treatment, which in turn would provide a favorable effect on LV loading conditions and therefore pump function.
Consistent with past studies, the development of pacing CHF was accompanied by reduced LV myocyte steady-state contractile function and depressed inotropic responsiveness.10 12 Past studies have demonstrated that IGF-1 can directly influence contractile function in the setting of a compromised myocardium.3 4 With GHS treatment, indices of steady-state myocyte contractile function were improved from CHF values. Thus, a contributory factor for the improved LV pump function with GHS treatment was an intrinsic beneficial effect on myocyte contractile function. GHS treatment resulted in an improvement in myocyte responsiveness to the ß-receptor agonist isoproterenol. This effect on myocyte ß-adrenergic responsiveness with GHS treatment was achieved in the absence of a reduction in circulating norepinephrine levels. This observation suggests that the improved ß-adrenergic response with GHS treatment was probably due to improved inotropic capacity that lay beyond the receptor transduction system itself. In the present study as well as in past reports using GH supplementation,11 the increased myocyte ß-adrenergic response was not associated with an increased incidence of arrhythmias in vivo. Whether chronic GH or GHS supplementation causes a predisposition to arrhythmogenesis, however, warrants further study. Stromer and colleagues5 demonstrated that chronic IGF-1 supplementation in rats increased the maximal Ca2+ response in myocardial preparations. In the present study, myocyte responsiveness to extracellular Ca2+ was improved with GHS treatment compared with untreated CHF values. Tajima et al1 reported that in a rat CHF model, myocyte inotropic response was increased after chronic GH treatment and improved Ca2+ handling in isolated myocyte preparations. Thus, GHS supplementation may have direct effects on myocyte Ca2+ homeostatic mechanisms and improvements in myofilament sensitivity to Ca2+. In a previous study, GH supplementation with chronic rapid pacing improved indices of LV ejection performance but was not associated with improved steady-state myocyte contractile function.11 A recent study demonstrated the presence of a GHS receptor within the myocardium.17 Thus, the differential effects of GHS treatment on intrinsic myocyte contractile function may be due to direct activation of a myocardial GHS receptor.
Favorable effects of GH supplementation on LV structure and
function have been demonstrated in several animal models of
CHF.1 2 3 4 6
With pacing CHF, the LV dilation and increased wall stress are not
accompanied by significant changes in LV mass or steady-state
contractile protein
content.9 18 The
failure of a hypertrophic response with pacing CHF may be due to an
acceleration of contractile protein degradative
rates.18 In the present
study, GHS treatment in pigs undergoing chronic pacing caused LV
myocardial growth, which was accompanied by an 2-fold increase in
circulating IGF-1 levels. IGF-1 has been reported to accelerate
contractile protein synthesis rates in neonatal rat myocyte
preparations.17
Consequently, an important mechanism for the increased LV mass in this
model of pacing CHF was probably due to the direct effects of IGF-1 on
myocardial contractile protein synthesis and degradative processes.
Although a major contributory factor for the effects of GHS treatment
in this model of pacing CHF was the augmentation of IGF-1, some recent
studies have provided evidence that a GHS may act directly on target
tissue, such as the
myocardium.14 Thus, GHS may
induce effects on LV myocardial structure that are independent of IGF-1
levels. GH supplementation in the pacing CHF model was not associated
with increased collagen
accumulation.11 Moreover,
this previous study provided evidence to suggest that GH
supplementation may attenuate myocyte loss. In the present study, the
basis for the increased LV mass with chronic rapid pacing was myocyte
hypertrophy, as evidenced by a significant increase in length and
cross-sectional area.
Pituitary dysfunction and a deficiency in GH have
historically been associated with cardiovascular
disease.19 Strategies to
stimulate normal pituitary function, such as increased GH synthesis and
release, may be a useful adjunctive therapy in patients with CHF. It
has been demonstrated previously that treatment of normal humans with
an orally active GHS provided a robust but pulsatile release of GH from
the pituitary.20 Thus,
unlike direct exogenous administration of GH, GHS treatment may afford
the advantage of inducing GH levels in a more physiological temporal
profile. If this is the case, GHS treatment may be a more appropriate
approach to restoring and/or enhancing GH production in the setting of
CHF. In GH-deficient patients, oral administration of a GHS for a 4-day
period increased serum IGF-1 levels by 50% to 75% and was accompanied
by a small rise in plasma glucose
levels.20 In the present
study, GHS treatment induced an 2-fold increase in IGF-1 levels
compared with untreated pacing CHF values. In the pacing CHF group,
plasma glucose levels were reduced from normal values and returned to
normal values with GHS treatment. The increase in glucose values with
GHS treatment may be due to metabolic effects secondary to the robust
increase in IGF-1. These findings, however, raise an important clinical
consideration with respect to the clinical application of GHS treatment
in CHF patients with diabetes and poor glucose control.
Although the majority of studies have demonstrated that GH supplementation influences LV pump function in CHF, some past reports have demonstrated that this treatment modality has neutral effects with respect to LV function.7 21 For example, in a dog pacing model, there was no significant change in LV mass between the untreated paced dogs and the dogs with GH supplementation, indicating a failure of a myocardial growth response.21 In the present study, GHS treatment was used in pigs during chronic rapid pacing and resulted in a significant myocardial hypertrophic response. GH supplementation in patients with CHF has been uniformly associated with a myocardial growth response.6 7 22 Results from the present study and past reports suggest that a mechanism by which GH supplementation improves LV pump function is through increased LV wall thickness and a reduction in LV wall stress patterns. In a recent double-blind placebo-controlled trial, short-term GH supplementation induced a directional change in LV wall thickness and wall stress patterns similar to that of the present study. These changes did not reach statistical significance, however.7 Another important feature of this past clinical trial was that the CHF patients were treated with high-dose ACE inhibition, which may have influenced the myocardial growth effects of GH treatment. ACE inhibition is now recognized as an important treatment modality for patients with CHF, and new treatment strategies must be considered with respect to this "background therapy." Thus, the potential additive/synergistic effects on LV and myocyte function by the augmentation of GH levels with ACE inhibition in the setting of CHF warrant further study. Nevertheless, GHS treatment at a dose that significantly increased basal levels of IGF-1 in a model of developing CHF increased LV pump function and improved myocyte contractile performance.
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Acknowledgments |
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This study was supported in part by National Institutes of Health grant HL-45024, a basic research grant from Pfizer, and an American Heart Association Grant-in-Aid (all to Dr Spinale). Dr Spinale is an Established Investigator of the American Heart Association. The authors wish to express their sincere appreciation to Drs Brent New and Jeffrey Mandel for their surgical assistance during the execution of this project and Michelle Holloman for assistance in the isolated myocyte studies. The authors also wish to express their appreciation to Melissa Mathews for her assistance in the preparation of the manuscript.
Received March 8, 2000; revision received July 26, 2000; accepted July 28, 2000.
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