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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3177-3183
Copyright © 1998 by The Endocrine Society

Original Studies

Acute Cardiovascular Effects of Insulin-Like Growth Factor I in Patients with Chronic Heart Failure1

Marc Y. Donath, Gabor Sütsch, Xia-Wei Yan, Bruno Piva, Hans-Peter Brunner, Yvonne Glatz, Jürgen Zapf, Ferenc Follath, E. Rudolf Froesch and Wolfgang Kiowski

Divisions of Endocrinology and Diabetes (M.Y.D., B.P., Y.G., J.Z., E.R.F.) and Cardiology (G.S., X.-W.Y., H.-P.B., F.F., W.K.), Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland

Address all correspondence and requests for reprints to: Marc Donath, M.D., Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: ndosam{at}usz.unizh.ch


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Insulin-like growth factor I (IGF-I) enhances myofibrillar development in cardiomyocytes of rats in culture and in vivo. In addition, IGF-I has vasodilatory effects and improves cardiac function in healthy volunteers. This study was conducted to evaluate the acute hemodynamic effects of IGF-I in patients with chronic heart failure. Eight patients with chronic heart failure were randomized to receive recombinant human IGF-I (60 µg/kg) or placebo, iv, over 4 h in a cross-over, double blind study on 2 consecutive days. Electrocardiogram as well as systemic hemodynamics were continuously monitored over 7 h by flow-guided thermodilution and radial artery catheters. IGF-I was well tolerated by all patients, and no pathological changes on electrocardiogram were recorded. Compared with placebo, IGF-I increased the cardiac index by 27 ± 3.7% (±SE; P < 0.0005) and the stroke volume index by 21 ± 5.6% (P < 0.05), and decreased systemic vascular resistance by 28 ± 4.4% (P < 0.0002), right atrial pressure by 33 ± 9.0% (P < 0.003), and pulmonary artery wedge pressure by 25 ± 6.1% (P < 0.03). Mean systemic and pulmonary artery pressure as well as heart rate and pulmonary vascular resistance were not significantly influenced by IGF-I treatment. Insulin and C peptide levels were decreased by IGF-I, whereas glucose and electrolyte levels remained unchanged. Urinary levels of norepinephrine decreased significantly (P < 0.05) during IGF-I infusion. Thus, acute administration of IGF-I in patients with chronic heart failure is safe and improves cardiac performance by afterload reduction and possibly by positive inotropic effects. Further investigations to establish whether the observed acute effects of IGF-I are maintained during chronic therapy appear to be warranted.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EXPERIMENTAL evidence has accumulated that insulin-like growth factor I (IGF-I) has specific cardiovascular effects in addition to its well studied growth-promoting and metabolic effects. IGF-I, but not GH, enhances myofibril development in long term cultures of adult rat cardiomyocytes (1). IGF-I also increases the contractility of cultured neonatal rat cardiomyocytes (2) and has positive inotropic effects on the isolated rat heart (3, 4). IGF-I selectively stimulates heart, but not skeletal, muscle growth of rats in vivo, whereas GH stimulates both (5). Moreover, IGF-I stimulates major components of the myofibrils and decreases the expression of atrial natriuretic factor (ANF) (6). Further investigations demonstrated that IGF-I had a cardioprotective effect in doxorubicin-treated rats (7), and that IGF-I improved myocardial function in normal adult rats (8) and in rats after myocardial infarction (9, 10). Furthermore, IGF-I limited the reperfusion injury in rats by inhibiting apoptosis and leukocyte-induced cardiac necrosis (11). Finally, IGF-I prevented weight loss during cardiac overload induced by constriction of the renal artery in young rats (12).

Vasodilator effects of IGF-I have been described in men (13, 14, 15). Recently, it has been shown that IGF-I increases cardiac output, stroke volume, and ejection fraction in healthy human volunteers (16, 17). Furthermore, IGF-I has important metabolic effects. It lowers insulin levels, increases insulin sensitivity (18, 19, 20, 21), and improves the lipid profile (22). Taken together, IGF-I has an attractive therapeutic profile for treatment of cardiac conditions such as heart failure. We have, therefore, in a first step examined the acute hemodynamic effects of recombinant human (rh) IGF-I in eight patients with chronic heart failure.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Eight patients (47 ± 2 yr old; body mass index, 26.2 ± 0.9 kg/m2; one woman and seven men) with congestive heart failure of more than 3-month duration (mean left ventricular ejection fraction, 26 ± 2%; mean cardiac index, 2.6 ± 0.1 L/min·m2) were studied. Five had idiopathic dilated cardiomyopathy, and three had ischemic cardiomyopathy. No patient experienced angina pectoris, but all had dyspnea (New York Heart Association class II–III; Table 1Go). All patients were in sinus rhythm and clinically stable on regimens of diuretics (n = 8), angiotensin-converting enzyme inhibitors (n = 8), coumarins (n = 7), digoxin (n = 6), antiarrhythmic drugs (n = 2), long acting nitrates (n = 1), and low dose ß-blocker (n = 1). Written informed consent was obtained from each patient. The experimental protocol was approved by the ethics committee of the University Hospital of Zurich.


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  		Table 1. Clinical characteristics of the patient population

 
Experimental protocol

The study consisted of two periods of 7 h on 2 subsequent days on the ward with catheters left in place overnight. In the morning, after completion of instrumentation, hemodynamic measurements were obtained. Thirty-five minutes later, the measurements were repeated. When cardiac output differed less than 10% between these two measurements, the study was started. Otherwise, measurements were repeated until hemodynamic stability was achieved. This was the case for three patients (two on day 1 and one on day 2) in whom stability was achieved after an additional 35 min. Twenty, 40, 60, 120, 180, 240, 300, 360, and 420 min after starting the infusion of the study drug, hemodynamic measurements were repeated. Immediately before use, rhIGF-I was dissolved in 0.9% saline at a concentration of 6 mg/mL and added to 100 mL of a solution with 5% glucose and 1% albumin. rhIGF-I (60 µg/kg; Chiron, Emeryville, CA) or placebo (solvent) was administered in a continuous iv infusion over 4 h in a cross-over, randomized, double blind fashion. Angiotensin-converting enzyme inhibitors were withheld on the morning of the tests and administered in the evening. The other medications were given at the start of the infusion of the study drug (0 min). The patients were fasted overnight until the end of study drug administration (4 h), and then a standard meal was given.

Hemodynamic measurements

During the entire study period the patients were lying in bed. Systemic hemodynamics were measured by standard techniques with a flow-guided thermodilution and a radial artery catheter (23). The heart rate was obtained from the electrocardiogram, which was monitored throughout the study.

Analytical determination

Blood was drawn from the right atrial port of the pulmonary artery catheter, immediately placed on ice, and centrifuged at 4 C. Plasma and serum were then stored at -20 C until assayed. All samples from a given patient were analyzed in the same assay. Serum IGF-I was separated from IGF-binding proteins by chromatography of 250 µL serum on Sep-Pak C18 cartridges (Waters, Millipore, Milford, MA) according to the protocol supplied by Immunonuclear (Stillwater, MN). After reconstitution with 2.5 mL phosphate-buffered saline-0.2% HSA, pH 7.4, samples were assayed at three different dilutions. Immunoreactive IGF-I was determined by RIA (24) using a rabbit antihuman IGF-I antiserum diluted 1:1000 and rhIGF-I as a standard. [125I]rhIGF-I (~350 Ci/g; Anawa, Wangen, Switzerland) was used as a tracer. Free IGF-I and C peptide levels were measured in serum with commercially available RIA kits [Diagnostic Systems Laboratories (Webster, TX) and Medipro (Teufen, Switzerland), respectively]. Insulin was measured in serum with a commercially available enzyme-linked immunosorbent assay kit (Dako Diagnostics, Ely, UK). ANF levels were measured in serum stored after the addition of aprotinin (Bayer, Leverkusen, Germany) at a final concentration of 500 kU/mL with a RIA kit (Eiken Chemical Co., Tokyo, Japan). Blood samples for glucose and lactate determinations were aspirated in a Vacutainer containing sodium fluoride (Becton Dickinson, Meylan, France). Plasma glucose was measured using an automated glucose oxidase method (Glucose Analyzer 2, Beckman Instruments, Fullerton, CA). Plasma lactate was measured in an autoanalyzer (TDX Abbott, Chicago, IL). Serum sodium, potassium, chloride, and phosphate determinations were performed in an autoanalyzer (model 747 Hitachi, Zurich, Switzerland). Catecholamines (dopamine, norepinephrine, and epinephrine) in acidified urine were determined by high performance liquid chromatography (Detector 16, 40, Bio-Rad, Hercules, CA).

Statistics

All data are expressed as the mean ± SE. Student’s two-tailed t test was used for comparison of means. Multiple measurements obtained over time were analyzed by ANOVA for repeated measures. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical symptoms

Three of eight subjects experienced a feeling of warmth 40–60 min after beginning the IGF-I infusion, but none did so during placebo administration. This feeling disappeared within 10–20 min. One patient had an orthostatic collapse on day 2 (during therapy with IGF-I for this patient) at the end of the study while taking a shower. He was never unconscious and recovered rapidly. No other symptoms were reported.

Hemodynamic measurements

IGF-I treatment tended to decrease mean systemic and pulmonary artery pressure as well as increase heart rate; however, neither change reached statistical significance, with the exception of systemic artery pressure 5 h after the beginning of the IGF-I infusion (Figs. 1Go and 2Go). Compared to placebo, right atrial and pulmonary artery wedge pressure were decreased by IGF-I (Fig. 1Go). After the administration of diuretics at time zero, cardiac index and stroke volume index decreased during placebo infusion, whereas systemic vascular resistance increased (Fig. 2Go) (25). IGF-I prevented these changes. The meal, taken after 4 h, was followed by increases in cardiac index and stroke volume index and a decrease in systemic vascular resistance. These changes were more pronounced with IGF-I infusion. After 7 h, the effects of IGF-I tended to disappear. Pulmonary vascular resistance was not influenced by IGF-I (Fig. 2Go). No pathological changes were recorded on the electrocardiogram (not shown).



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  		Figure 1. Percent change from baseline of arterial, pulmonary artery, right atrial, and pulmonary artery wedge pressure during IGF-I and placebo treatment in eight patients with cardiac failure. rhIGF-I (60 µg/kg) or placebo was infused iv over 4 h. Basic medications were given at the beginning of the infusion of study drug (0 min), and a standard meal was given at the end of the infusion (240 min). P values refer to differences between curves (by repeated measures ANOVA). *, P < 0.05; P < 0.01; **, P < 0.005 (placebo vs. IGF-I at each time point).

 


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  		Figure 2. Percent change from baseline of cardiac and stroke volume index, systemic and pulmonary vascular resistance, and heart rate during IGF-I and placebo treatment in eight patients with cardiac failure. rhIGF-I (60 µg/kg) or placebo were infused iv over 4 h. Basic medications were given at the beginning of the infusion of study drug (0 min), and a standard meal was given at the end of the infusion (240 min). P values refer to differences between curves (by repeated measures ANOVA). *, P < 0.05; P < 0.01; ***, P < 0.001 (placebo vs. IGF-I at each time point).

 
Metabolic effects

In response to the iv infusion of 60 µg/kg rhIGF-I, there was a significant increase in circulating IGF-I in all subjects (Table 2Go). In the four patients treated with IGF-I on day 1, total IGF-I levels were still elevated on the following morning, before placebo infusion was started. Nevertheless, free IGF-I had almost returned to baseline values (Table 2Go).


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  		Table 2. Circulating IGF-I, free IGF-I, insulin, C peptide, and glucose during IGF-I and placebo infusion in the basal state (0 h), at the end of a 4-h iv infusion of 60 µg/kg rhIGF-I or solvent (placebo), and after 7 h in eight patients with chronic heart failure

 
IGF-I treatment led to a decrease in insulin and C peptide levels at the end of the IGF-I infusion (4 h). Three hours after the end of the IGF-I infusion and after the standard meal, no difference in the levels of insulin and C peptide was found. Plasma glucose levels remained unaffected (Table 2Go). There were no significant changes in ANF, sodium, potassium, chloride, phosphate, and lactate levels during both treatment periods (Table 3Go). Urinary epinephrine, norepinephrine, and dopamine were slightly decreased by IGF-I during the period of treatment (0–4 h), reaching statistical significance only for norepinephrine (Table 4Go).


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  		Table 3. Circulating ANF, electrolytes, and plasma lactate during IGF-I and placebo infusion in the basal state (0 h), at the end of a 4-h iv infusion of 60 µg/kg rhIGF-I or solvent (placebo), and after 7 h in eight patients with chronic heart failure

 

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  		Table 4. Urinary catecholamines during IGF-I and placebo infusion in eight patients with chronic heart failure

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study show that IGF-I increases cardiac output and stroke volume in patients with chronic heart failure, as previously shown in healthy human volunteers (16, 17). Moreover, it reduces left and right heart filling pressures. The reduction of peripheral vascular resistance suggests that the increase in cardiac output was due to arteriolar vasodilatation and reduction of afterload. In the absence of direct measurements of myocardial inotropy, it is not possible to differentiate between these two mechanisms. Vasodilatory effects of IGF-I have been previously demonstrated to occur (13, 14, 15, 18, 26, 27). On the other hand, inotropic effects of IGF-I in neonatal rat cardiomyocytes in vitro (2) and in the isolated rat heart (3, 4) have been described. Another explanation for the increase in cardiac output would be an increase in catecholamines, which we did not observe. Rather, urinary norepinephrine significantly decreased during the IGF-I infusion, which might indicate a beneficial effect on neurohumoral activation in patients with chronic heart failure. The reduction in filling pressure also suggests a decrease in venous tone. Accordingly, IGF-I appears to be a balanced vasodilator, with mixed arterial and venous dilator effects. IGF-I did not lower pulmonary vascular resistance. However, baseline values were not elevated, and no conclusion can be drawn about potential pulmonary vasodilator effects under pathological conditions. As in healthy subjects (16, 17, 28), IGF-I had no significant effect on systemic arterial pressure in patients with heart failure, although it tended to decrease. Heart rate was slightly, but not significantly, increased by IGF-I. This result is in keeping with that in healthy volunteers receiving the same dose of IGF-I sc (17). However, when the same dose of IGF-I was infused faster than in the present study, heart rate increased significantly in normal individuals (16). This difference in heart rate response between patients and normal subjects might be related to the blunted baroreflex response present in heart failure patients (29).

The interpretation of our results is somewhat hampered by the fact that IGF-I infused on day 1 was carried over to day 2, i.e. the placebo day in four of the patients. However, free IGF-I has a half-life of only 10–12 min (30), and consequently, free IGF-I levels were no longer significantly elevated on the morning after IGF-I administration. It can therefore be assumed that the still elevated total IGF-I levels on the day after IGF-I infusion no longer had important metabolic or cardiovascular repercussions. In fact, by 3 h after the IGF-I infusion, insulin and C peptide levels were no longer decreased.

Systemic adverse events associated with IGF-I infusion in men ranging from dizziness, fatigue, palpitations, and flushing to dyspnea or even transient cerebral dysfunction have been described (16, 31, 32, 33). These events occurred during rapid iv infusions or very high doses of IGF-I. With 60 µg/kg IGF-I injected sc, we observed no adverse effects even during exercise to exhaustion in healthy volunteers (17). The continuous iv infusions of the same dose of IGF-I in our patients with heart failure were also well tolerated, apart from one patient who experienced an orthostatic collapse after the end of IGF-I treatment while taking a shower. He never was unconscious and recovered rapidly when lying down. This event was probably due to a cardiovascular inability to adapt from the long lasting supine position to standing under a warm shower. The vasodilator effect of IGF-I may have aggravated the inability to adjust appropriately. We did not observe any pathological changes on the electrocardiogram or changes in electrolyte levels, which have been hypothesized to be at the origin of adverse effects of IGF-I.

During IGF-I treatment, glucose levels remained unchanged, whereas insulin and C peptide levels were decreased. This is in line with the described IGF-I-induced increase in insulin sensitivity (19, 20, 21).

IGF-I mediates most of the effects of pituitary GH (34, 35). The relationship between GH and the cardiovascular system has been extensively investigated, as patients with acromegaly have an increased incidence of cardiovascular disease (36, 37). On the other hand, subjects with GH deficiency tend to exhibit impaired cardiac performance (38, 39, 40). Recently, Fazio et al. (41) reported a beneficial effect of GH in the treatment of dilated cardiomyopathy. Part of these GH-induced cardiovascular effects may be promoted by GH stimulation of circulating IGF-I levels and of locally produced IGF-I in the heart (42, 43, 44). In line with this explanation, we (1) and others (45) did not observe direct GH effects on cultured cardiomyocytes. On the other hand, IGF-I induces cardiomyocyte hypertrophy and myofibril development in vitro (1, 45, 46) and in vivo (5, 6, 9). Nevertheless, sequelae of GH excess such as hypertension, hyperinsulinemia, insulin resistance, and hyperlipidemia (47, 48, 49, 50) are not mediated by GH-induced IGF-I. On the contrary, IGF-I administration diminishes GH secretion, lowers insulin, very low density lipoprotein, and low density lipoprotein plasma levels and increases insulin sensitivity (18, 19, 20, 21, 22), thereby reducing risk factors of cardiovascular disease.

The observed hemodynamic effects of IGF-I together with stimulation of the formation of cardiac myofibrils observed in vitro and animal experiments (1, 6) make IGF-I of potential interest for the treatment of heart failure. It remains to be investigated whether the observed acute effects of IGF-I administration are beneficial during prolonged IGF-I therapy.


   Footnotes
 
1 This work was supported by the Swiss National Science Foundation (Grant 32-31281-91). Back

Received April 14, 1998.

Revised May 26, 1998.

Accepted June 5, 1998.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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