(Circulation. 1995;92:262-267.)
© 1995 American Heart Association, Inc.
Articles |
Growth Hormone Improves Cardiac Performance in Experimental Heart Failure
Presented in part at the 1994 Clinical Research Meeting, Baltimore, Md, April 29 to May 2, 1994.
From the Department of Cardiovascular Research, Pharmacology, and Endocrinology, Genentech, Inc, South San Francisco, Calif.
Correspondence to Hongkui Jin, MD, Mail Stop #42, Department of Cardiovascular Research, Genentech, Inc, 460 Point San Bruno Blvd, South San Francisco, CA 94080.
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Abstract |
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Background Growth hormone has been shown to increase maximum isometric active force of the left ventricular papillary muscle of rats in vitro. Administration of growth hormone causes an increase in myocardial contractility in normal humans. Our preliminary study suggests that treatment with growth hormone results in increased ventricular contractility in rats with left ventricular dysfunction. In the present study, the effects of growth hormone on cardiac function, including cardiac output, stroke volume, and peripheral vascular resistance, were determined in a rat model of heart failure.
Methods and Results Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, recombinant human growth hormone (2 mg/kg per day SC) or vehicle then was administered for 15 days. The animals were catheterized after 13 days of the treatment. Cardiac output, measured by a thermodilution method, and other hemodynamic parameters were measured in the conscious animals 2 days after catheterization. The infarct sizes induced by left coronary ligation were comparable between growth hormone–treated and vehicle-treated rats. Six weeks after ligation, rats treated with vehicle exhibited significant decreases in cardiac index, stroke volume index, and left ventricular maximum dP/dt and increases in left ventricular end-diastolic pressure compared with sham rats. In the ligated rats, treatment with growth hormone increased cardiac index, stroke volume index, and left ventricular maximum dP/dt (P<.05) and reduced left ventricular end-diastolic pressure and systemic vascular resistance (P<.05). In sham rats, growth hormone slightly reduced arterial pressure but did not significantly alter cardiac performance. There was no significant difference in heart rate between the experimental groups.
Conclusions These results suggest that growth hormone treatment may improve cardiac function by both increased myocardial contractility and decreased peripheral vascular resistance in heart failure.
Key Words: heart failure • congestive • myocardial infarction • hemodynamics • stroke volume • cardiac output • catheterization
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Congestive heart failure (CHF) is a multiple-etiology, high-prevalence, poor-prognosis cardiovascular disorder. Current therapy for CHF is insufficient. Although digitalis has occupied a prominent place in the management of CHF for more than 200 years, the therapeutic/toxic dose ratio of this group of drugs is very narrow. Angiotensin-converting enzyme (ACE) inhibitors have been shown to have favorable effects on symptoms, exercise tolerance, and survival in patients with CHF.1 2 3 4 However, improvement of functional capacity and exercise time by ACE inhibitors is limited,5 6 and mortality of CHF, although declined, continues to be high.3 4 5
Several independent lines of evidence suggest that growth hormone (GH) may contribute to the modulation of cardiac performance. In vitro studies have shown that chronic hypersecretion of GH by implantation of a GH-secreting tumor in normal rats is associated with an increase in the maximum isometric force of left ventricular papillary muscle.7 8 9 There is no change in both the unloaded shortening velocity of the isolated muscle and the calcium- and actin-activated myosin ATPase activity. This is observed despite a marked shift of the isomyosin pattern toward the low–ATPase activity V3 isoform. These results suggest that GH may induce a unique pattern of myocardial contraction: A normal shortening speed and an increased force generation are associated with changes in myosin phenotype that allow the cardiac muscle to function more economically.7 8 9 In clinical studies, short-term administration of GH for 1 week results in an increase in myocardial contractility in normal humans.10 Further, chronic GH treatment enhances cardiac output, increases glomerular filtration rate, and improves exercise capacity in GH-deficient adults.11 12 13 14 15 16
Our preliminary study suggests that GH treatment may increase myocardial contractility in rats with cardiac dysfunction.17 The present study was designed to examine the effects of GH on cardiac function in the normal heart and in the setting of cardiac failure using a well-characterized post–myocardial infarction model in the rat. Cardiac output, assessed using a thermodilution method, and other hemodynamic parameters were measured in conscious animals. Our findings suggest that administration of GH enhances cardiac output and stroke volume by increasing myocardial contractility and decreasing peripheral vascular resistance in experimental cardiac failure.
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Methods |
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Male Sprague-Dawley (SD) rats (Charles River Breeding Laboratories, Inc, 8 weeks of age) were acclimated to the facility for at least 1 week before surgery, fed a pelleted rat chow and water ad libitum, and housed in a light- and temperature-controlled room. All experimental procedures, which were approved by Genentech's Institutional Animal Care and Use Committee before initiation of the study, conformed to the guiding principles of the American Physiological Society.
Animal Model
Myocardial infarction was produced by left
coronary
arterial ligation as described
previously.18 19 20 In brief, under
anesthesia
(ketamine 80 mg/kg; Aveco Co, Inc) and xylazine 10 mg/kg IP
(Rugby Laboratories, Inc), rats were intubated via tracheotomy and
ventilated by a respirator (Harvard Apparatus model 683).
After a left-sided thoracotomy, the left coronary artery was
ligated approximately 2 mm from its origin between the
pulmonary outflow tract and the left atrium. There was a 40%
mortality rate within 48 hours after this procedure, and the subsequent
mortality was 9% in the vehicle-treated rats and 5% in the GH-treated
rats. Sham animals underwent the same procedure except that the suture
was passed under the coronary artery and then removed.
Electrocardiogram
One week after surgery, ECGs were obtained
under light metofane
(Pitman-Moor, Inc) anesthesia to document the development
of infarcts. The ligated rats were subgrouped according to the depth
and persistence of pathological Q waves across the precardial
leads.20 21 This provided a gross estimate of small
and
large infarct sizes and avoided uneven distribution of small and large
infarcts in the ligated rats treated with GH and vehicle, when the rats
with small and large infarcts shown by ECG were separated and randomly
received either GH or vehicle. Body weight (BW) was measured twice
weekly during the treatment.
Administration of Growth Hormone
Four weeks after surgery,
recombinant human GH (1 mg/kg twice a
day for 15 days) (Genentech, Inc) or vehicle was injected
subcutaneously in both ligated rats and sham control rats. Previous
studies have shown that this dose of human GH can produce a significant
increase in myocardial contractility in rats with
cardiac dysfunction.17
Catheterization
After 13-day treatment with GH or vehicle,
rats were
anesthetized using ketamine/xylazine as described
above. A catheter (PE-10 fused with PE-50) filled with heparin-saline
solution (50 U/mL) was implanted into the abdominal aorta via the right
femoral artery for measurement of arterial pressure and
heart rate. A second catheter (PE-50) was implanted into the right
atria through the right jugular vein for measurement of right atrial
pressure and for saline injection. For measurement of left
ventricular pressures and dP/dt, a third catheter was
implanted into the left ventricle through the right carotid
artery.22 For measurement of cardiac output by a
thermodilution method,23 24 a thermistor catheter
(Lyons
Medical Instrument Co) was inserted into the aortic arch. The catheters
were exteriorized at the back of the neck with the aid of a stainless
steel wire tunneled subcutaneously and then fixed. After catheter
implantation, all rats were housed individually.
Hemodynamic Measurements
Two days after catheterization, the
thermistor
catheter was connected to and processed in a microcomputer system
(Lyons Medical Instrument Co) for cardiac output determination, and the
other three catheters were connected to a model CP-10 pressure
transducer (Century Technology Co) coupled to a Grass model 7
polygraph. Mean arterial pressure, heart rate, right atrial
pressure, left ventricular systolic pressure, left
ventricular end-diastolic pressure, and left
ventricular maximum dP/dt were measured in conscious,
unrestrained rats. For measurement of cardiac output, 0.1 mL of
isotonic saline at room temperature was injected as a bolus via the
jugular vein catheter. The thermodilution curve was monitored by VR-16
simultrace recorders (Honeywell Co), and cardiac output was
digitally obtained by the microcomputer. Our pilot study showed that
cardiac output was not significantly different in rats with and without
the left ventricular catheter. Stroke volume was calculated
as cardiac output divided by heart rate; cardiac index, cardiac output
divided by BW; stoke volume index, stroke volume divided by BW; and
systemic vascular resistance, mean arterial pressure
divided by cardiac index.
Blood Collection and Tissue Harvest
After measurement of
these hemodynamic
parameters, 1 mL of blood was collected through the
arterial catheter. Serum was separated and stored at
-70°C for measurement of GH and insulin-like growth factor 1
(IGF-1).
At the conclusion of the experiments, rats were anesthetized with pentobarbital sodium (60 mg/kg IP), and the heart was arrested in diastole with intra-atrial injection of KCl (1 mol/L). The heart was removed, and the atria and great vessels were trimmed from the ventricle. The ventricle was weighed and fixed in 10% buffered formalin.
Infarct Size Measurements
The right ventricular free wall was
dissected from
the left ventricle. The left ventricle was cut in four transverse
slices from apex to base. Five-micron sections were cut and stained
with Massons' trichrome stain and mounted.25 26
The
endocardial and epicardial circumferences of the infarcted and
noninfarcted circumference were determined with a planimeter Digital
Image Analyzer. The infarcted circumference and the total left
ventricular circumference of all four slices were summed
separately for each of the epicardial and endocardial surfaces, and the
sums were expressed as a ratio of the infarcted circumference to the
left ventricular circumference for each surface. These two
ratios were then averaged and expressed as a percentage for infarct
size.
Hormone Assays
Serum human GH was measured by a specific and
sensitive
ELISA27 that does not detect rat GH. Total serum IGF-1 was
measured after acid-ethanol extraction by
radioimmunoassay28 29 with use of human IGF-1
(Genentech
M3-RD1) as the standard and a rabbit anti–IGF-1 polyclonal antiserum.
For the IGF-1 assay, the acceptable range was 1.25 to 40 ng/mL; the
intra-assay and interassay variabilities were 5% to 9% and 6% to
15%, respectively.
Statistical Analysis
Results are expressed as
mean±SEM. Two-way ANOVA and one-way
ANOVA were performed to assess differences in parameters
between groups. Significant differences were then subjected to post hoc
analysis using the Newman-Keuls method. P<.05 was
considered significant.
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Results |
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Effects of Coronary Ligation
Six weeks after coronary ligation and vehicle treatment, infarct size was 32±2% of the left ventricle. Coronary ligation caused a significant increase in ventricular weight and the ratio of ventricular weight to BW (Table 1
). The
following parameters were all
significantly reduced in the ligation-plus-vehicle group compared with
the sham-plus-vehicle group: mean arterial pressure, left
ventricular maximum dP/dt, left ventricular
systolic pressure, cardiac index, and stroke volume index (Table
2 and Figure), whereas left
ventricular end-diastolic pressure was
significantly elevated (Table 2). However, coronary ligation
did not cause significant differences in heart rate, right atrial
pressure, and systemic vascular resistance (Table 2 and
Figure).
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Effects of GH Treatment
Infarct size in the ligation-plus-GH
group was 31±3%, which was
not significantly different from that in the ligation-plus-vehicle
group. Rats treated with GH showed a significantly greater increase in
BW than vehicle-treated animals, whereas GH treatment did not alter
ventricular weight and the ratio of ventricular
weight to BW significantly (Table 1
). Treatment with GH
elevated serum
levels of GH and IGF-1 similarly in both ligated and sham-operated
animals (Table 1).
Left ventricular maximum dP/dt, left
ventricular systolic pressure, cardiac index, and stroke
volume index were significantly increased, whereas left
ventricular end-diastolic pressure and systemic
vascular resistance were significantly decreased in the
ligation-plus-GH group compared with the ligation-plus-vehicle group
(Table 2 and Figure), indicating that GH
treatment improved cardiac
performance in the ligated animals. However, GH treatment did
not produce significant alterations in mean arterial
pressure, heart rate, and right atrial pressure significantly in the
ligated rats (Table 2).
In sham-operated animals, GH
treatment significantly lowered mean
arterial pressure (Table 2) and tended to lower systemic
vascular resistance (P<.1, Figure) but did not
affect the
other hemodynamic parameters (Table 2).
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Discussion |
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In the present study, in which hemodynamic measurements were made 6 weeks after myocardial infarction, depressed cardiac performance was documented by significant reductions in left ventricular maximum dP/dt, cardiac index, and stroke volume index and elevations in left ventricular end-diastolic pressure in the vehicle-treated rats, indicating that heart failure occurred in this animal model. GH treatment at the dose of 1 mg/kg twice daily for 15 days significantly increased left ventricular dP/dt, cardiac index, and stroke volume index and reduced left ventricular end-diastolic pressure and systemic vascular resistance in the ligated rats, whereas this dose of GH slightly lowered arterial pressure without affecting cardiac function significantly in sham rats. This is the first demonstration that GH enhances stroke volume and cardiac output in conscious animals with heart failure. This improvement of cardiac performance may be secondary to both increased myocardial contractility and decreased peripheral vascular resistance. Since heart failure in this model was primarily caused by decreased myocardial contractility due to loss of myocardial mass, and GH treatment augmented the depressed contractility, it is possible that improved cardiac function observed in the ligation-plus-GH group may be attributed to enhanced contractility. However, the reduction in afterload also may contribute by reducing the impedance of left ventricular ejection and thereby increasing stroke volume.
The present study confirms the observation of our preliminary study that GH treatment results in a significant increase in myocardial contractility, as measured by left ventricular maximum dP/dt, in the ligated rats.17 The results are also consistent with previous observations from other investigators that GH can increase in vitro myocardial contractility in rats and in vivo in humans.7 8 9 10 Interestingly, unlike other inotropic agents, GH has been shown to increase contractile performance of myocardium at a lower energy cost.7 8 Further, the present study demonstrated that GH treatment did not affect heart rate in conscious animals, suggesting that the effect of GH may not be secondary to changes in sympathetic tone. An increase in myocardial contractility associated with low energy consumption and unaltered heart rate could be a favorable effect on a failing heart.
The mechanism by which GH increases myocardial contractility is not entirely clear. Chronic GH hypersecretion in rats is associated with an increase in the contractile performance of papillary muscles isolated from the left ventricle.7 8 An electrophysiological study has shown a prolonged action potential in this model of GH hypersecretion,30 which could explain, at least in part, the increased contractile performance observed with the intact papillary muscles, since an increase in duration of action potential favors Ca2+ influx through L-type calcium channels, thereby increasing the amount of calcium available for myofilaments. An in vitro study using rat cardiac skinned fibers suggests that the increase in myocardial contractility is due to specific alterations in the properties of the contractile apparatus, including increases in both maximal tension and myofibrillar sensitivity to calcium.9 In addition, chronically high circulating GH levels are also associated with normal myosin ATPase activity and normal shortening velocity of the unloaded muscle despite a phenoconversion of myosin toward V3, an increase in proportion of ß-myosin heavy chain (MHC) protein and in ß-MHC mRNA, and a decrease in the rate of myosin crossbridge cycling.7 8 9 It is suggested that the increase in active force and maintenance of normal myosin ATPase activity may be due to an increase in the number of active crossbridges.7 8 9 Thus, the model of GH hypersecretion with normal shortening velocity and increased active force contrasts with all models of chronic hemodynamic overload associated with decreases in both shortening velocity and active force.31 32 33 34 35
Several types of hemodynamic overload, including that
caused by myocardial infarction, have been found to produce a decrease
in the percentage of V1 myosin isoform (
-MHC) and an increase in the
percentage of the V3 myosin isoform (or
ß-MHC).36 37 In
the thyrotoxic heart, there is an increase in -MHC.38
It was hypothesized that thyroxine might improve myocardial
performance by correction of the abnormal myosin isoenzymatic
pattern if the abnormal myosin pattern underlies the depressed
performance of hypertrophied and failing heart. Gay et
al39 have reported that in rats with
ventricular dysfunction after myocardial infarction,
treatment with thyroxine for 10 to 12 days produces an increase in the
V1 myosin isoform and a decrease in the V3 form in association with
increased left ventricular dP/dt, increased heart rate, and
unchanged high left ventricular end-diastolic
pressure. Since increased V1 (-MHC) is associated with a high ATPase
activity, a fast rate of force development, and a low thermal
economy,38 the inotropic effect of thyroxine is apparently
accompanied by decreased economy of the heart and increased energy
consumption, which must limit the clinical use of thyroxin for
treatment of heart failure. However, GH can increase active force by
increasing the numbers of active crossbridges, and this is associated
with an increase in ß-MHC and with a shift of isomyosin pattern
toward the V3 isoform.7 8 9 Therefore,
the inotropic effect
of GH is accompanied by increased economy of the heart, since increased
V3 (ß-MHC) is associated with a low ATPase activity, a slow rate of
force development, and a high thermal economy.38
It is important to note that the shift of myosin isoforms is not the biological mechanism for depressed myocardial performance in humans, because normal human ventricular myocardium primarily consists of one myosin isoform (V3), and no significant isoform shift is obvious in hypertrophied and in failing human myocardium.40 41 42 Recent studies indicate that reduced peak isometric twitch tension observed in muscle strips from failing hearts with dilated cardiomyopathy results from a decrease in the number of crossbridge interactions during the isometric twitch, which may be related to a reduced amount of calcium released.43 44 This is further supported by the finding that the mRNA for Ca2+ release channels and ß-MHC mRNA are decreased in hearts with severe heart failure.45 Taken together with the observations that chronically high circulating GH levels are associated with increases in myocardial performance, in the number of active crossbridges, in the amount of calcium available for myofilament activation, in ß-MHC mRNA expression, and, to lesser degree, in calcium sensitivity of the contractile proteins,7 8 9 30 the data may provide a biological basis for treatment with GH for human heart failure, at least for that caused by dilated cardiomyopathy. Further studies are needed to explore the effects of GH in failing hearts at cellular and molecular levels.
The reduction in afterload is also a beneficial effect of GH in cardiac failure. The present study showed that treatment with GH produced significant decrease in systemic vascular resistance in rats with heart failure. This finding is consistent with the clinical observation that GH treatment enhances cardiac output and reduces peripheral vascular resistance in patients with GH deficiency.11 In addition, a multicenter clinical study has demonstrated that circulating levels of GH are significantly elevated in patients with various heart failure syndromes.46 47 48 In untreated patients with CHF, the GH level is not correlated with circulating levels of other hormones including cortisol, atrial natriuretic factor, aldosterone, or catecholamines, suggesting that high GH is independent of increases in other hormones.48 Further, there is a significant negative correlation between the GH level and systemic vascular resistance in untreated CHF, suggesting that the increase in GH might be an endogenous compensatory mechanism to reduce afterload.48 This concept also supports the hypothesis that treatment with exogenous GH may be beneficial in the setting of heart failure.
In the present study, 6 weeks after left coronary ligation, rats showed ventricular hypertrophy, as assessed by either ventricular weight or the ratio of ventricular weight to BW, in both vehicle-treated and GH-treated groups. This is in agreement with previous findings from many investigators that myocardial hypertrophy develops in rats with moderate and large myocardial infarction after coronary ligation.49 50 51 52 53 54 55 GH treatment, however, did not affect ventricular weight or the ratio of ventricular weight to BW in ligated rats or sham rats, suggesting that GH administration at this dose is not associated with cardiac hypertrophy. It is likely that the effects of GH on cardiac performance may be independent of the mechanism of cardiac hypertrophy.
There are two theories regarding the actions of GH: the GH (direct effector) hypothesis and the somatomedin (IGF-1) hypothesis.56 The somatomedin hypothesis of GH action proposes that GH induces IGF-1 production in peripheral tissues, and it is this IGF-1 that produces many of the effects of GH. In the present study, GH administration resulted in significant elevations in both circulating GH and IGF-1 levels. IGF-1 has been shown to increase the contractility of neonatal rat cardiocytes in vitro.57 In vivo studies have also shown that IGF-1 treatment enhances cardiac output and stoke volume in rats with doxorubicin-induced cardiomyopathy.58 The cardiac effects of GH observed in the present study could be direct and not involve local IGF-1 generation or could be due to IGF-1 being produced either in the heart or systemically.
Summary
GH treatment for 15 days enhanced myocardial
contractility, cardiac output, and stroke volume,
reduced left ventricular end-diastolic pressure
and peripheral vascular resistance, and did not alter heart
rate in conscious animals with heart failure, suggesting a potential
therapeutic role in patients with CHF. Our study, however, cannot
evaluate the effect of GH on survival in this model because
administration of human GH for a longer term (more than 15 days) would
produce the antibody against the human GH in rats. A further study for
determining the effect of long-term therapy with GH will be done as
soon as recombinant rat GH is developed. In addition, based on the
beneficial responses to GH in experimental cardiac failure, we are
planning to initiate a clinical study of GH treatment in patients with
CHF.
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Acknowledgments |
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We are grateful to Dr Joffre Baker, Dr John Ross, Dr Kenneth R. Chien, and Dr Michael Cronin for their support and to David Finkle, Carrie Kyle, and Joanne Mathias for their technical assistance.
Received November 11, 1994; revision received January 9, 1995; accepted January 17, 1995.
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