American Heart Journal
Volume 142, Issue 6 , Page E10, December 2001

Plasma insulin-like growth factor-1 elevated in mild-to-moderate but not severe heart failure☆

London, United Kingdom

From the National Heart and Lung Institute, Departments of aCardiology, bCardiothoracic Surgery, cNeuroendocrinology, and dChemical Pathology, Imperial College School of Medicine, London, UK

Received 27 December 2000; accepted 23 May 2001.

Article Outline

Abstract 

Background Insulin-like growth factor 1 (IGF-1) promotes favorable cardiac remodeling in heart failure. However, the relation of plasma IGF-1 in patients with various degrees of heart failure is not known. Methods Venous plasma samples were collected from patients with clinically documented heart failure (n = 24) and from control subjects (n = 21) for measurements of IGF-1 levels. In the heart failure group, functional assessment of the physical capacity was determined by means of the New York Heart Association (NYHA) score. Objective determination of ventricular performance was made by transthoracic echocardiographic measurement of left ventricular fractional shortening (FS). Results IGF-1 levels were higher in patients with heart failure (mean age, 67 ± 2 years; 17 men) than in control subjects (age, 71 ± 2 years; 9 men) (20.2 ± 2 mU/L, 14.1 ± 2 mU/L, respectively, P < .05). However, the elevated IGF-1 levels were demonstrated only in patients with mild-to-moderate symptoms (NYHA classes I and II) of heart failure (24.7 ± 3.3 mU/L, n = 12, P = .005 vs control subjects) but not in patients with severe symptoms (NYHA classes III and IV) (15.7 ± 2.3 mU/L, n = 12). There was a strong positive correlation between IGF-1 levels and left ventricular FS (%) (r = 0.58, P = .003, n = 24). Adjustments for other potential confounders including age, sex, treatment received, and underlying cause of heart failure did not alter the relation between IGF-1 and left ventricular FS (odds ratio, 2.01; 95% confidence interval, 1.26 to 6.24; P = .01). Conclusions Plasma levels of IGF-1 show distinct variations with the severity of heart failure and may play a vital role in compensated heart failure. (Am Heart J 2001;142:e10.)

 

The homeostatic responses to myocardial injury (ischemic, hemodynamic, or idiopathic) have been the focus of numerous experimental and clinical studies. These responses influence the remodeling of surviving myocardial cells in an attempt to preserve myocardial performance and maintain cardiac output. The neuroendocrine response in particular has been well described and forms the focus of many management protocols used in the treatment of heart failure. Angiotensin II is one growth factor that has been shown to promote an unfavorable form of myocardial remodeling, consequently, angiotensin-converting enzyme inhibitors (ACEI) are thought to exert their beneficial effect at least in part by minimizing the nonbeneficial effects of angiotensin II. Likewise, it has been shown that growth hormone (GH) and insulin-like growth factor I (IGF-1) are directly involved in myocardial cell growth and hypertrophy.1, 2 The latter promotes cardiac hypertrophy of a physiologic phenotype3, 4 and has additional cardiovascular effects including systemic vascular vasodilation, inotropic effect on the heart,5 and promotion of specific myofibril hypertrophy.1 Animal studies of experimental heart failure have consistently shown that ischemic or hemodynamic myocardial injury was followed by increased expression of IGF-1 mRNA in surviving myocardial cells; this is thought to modulate surviving myocardial cell growth.6, 7, 8 Furthermore, infusion of IGF-1 after induced myocardial infarction in a rat model was associated with reduced systemic vascular resistance, increased cardiac mass/total body ratio, reduced cardiac remodeling and chamber dilation, and increased cardiac output. In human beings, IGF-1 infused to healthy individuals9 and in patients with chronic heart failure10 similarly was associated with improved left ventricular performance.

Despite the consistent experimental evidence demonstrating the beneficial influence of IGF-1 on ventricular remodeling and its role in improving ventricular performance,11 little is known about the association between IGF-1 levels and development of heart failure in human beings. Furthermore, the role of IGF-1 in the transition of compensated heart failure to decompensated heart failure is unclear. In this study, we report an observational analysis of plasma IGF-1 variations in patients with various degrees of heart failure.

Back to Article Outline

Methods 

Subjects 

Patients with clinically documented chronic heart failure were recruited for the study with the approval of the local ethics committee at Charing Cross Hospital, London, UK. Full clinical details were recorded for all patients including history of the cardiovascular illness and the treatment received. Limitation of physical capacity by breathlessness was assessed for each individual patient by means of the New York Heart Association (NYHA) score for heart failure. Patients were excluded if the symptoms were of acute onset (<6 weeks) or were preceded by an acute coronary event within 6 weeks of assessment. Patients were also excluded if a concomitant endocrinologic, pulmonary, or renal disorder was present. Cardiomyopathy was diagnosed in the absence of a specific cause for heart failure, including ischemic heart disease, hypertension, valvular heart disease, or myocarditis.

All patients with a diagnosis of heart failure had a transthoracic echocardiography assessment of left ventricular performance; two examiners who were blinded to the results of the study cross-checked this independently. Parasternal long-axis views were recorded at the level of the tip of the mitral valve leaflets. Superimposed electrocardiographic recordings were used to determine left ventricular dimensions in end-systole and end-diastole. Left ventricular fractional shortening was then estimated by the equation LVD – LVS/LVD × 100, where LVD is left ventricular diameter in end-diastole and LVS is left ventricular diameter in end-systole.

Control group 

Because of the possibility of both GH and IGF-1 responses to stress, it was important to have a control group subjected to the same hospital environmental factors as the patients with heart failure. Patients with no history of cardiovascular illness, shortness of breath, or renal, hepatic, or endocrine disease were recruited from the hospital outpatient departments. All control patients had a chest radiograph (independently reported by radiologists at the same hospital). Patients with a cardiothoracic ratio of >0.5 were excluded.

Protocol 

Venous blood samples were collected for all individuals from an antecubital vein in a sitting or lying position by means of a Vacutainer method into bottles containing lithium-heparin anticoagulant (Becton Dickinson, Meylan Cedex, France). All sampling was performed between 9 AM and 2 PM . Within 1 hour of collection, plasma was separated by 3000g centrifugation at –4°C. Plasma was then stored at –20°C, pending batch analysis.

Biochemical assays 

GH levels were determined with the use of an automated ELISA method (Boehringer Mannheim ES700); IGF-1 concentrations were measured with an extraction and radioimmunoassay procedure.

Statistical analysis 

Results are summarized throughout the text and figures as mean ± standard error of the mean. Group comparisons were made by nonparametric methods; Mann-Whitney test for 2 groups, and analysis of variance (Kruskal–Wallis H) for more than 2 groups. Nonparametric correlations between variables were performed with the Spearman-rank method and correlation coefficients (r 2). The association of IGF-1 levels with other potential confounders were examined in a multivariate linear regression model with IGF-1 as the dependent variable. All reported probability values are 2-sided. Analyses were performed with the use of SPSS for Windows (SPSS Inc).

Back to Article Outline

Results 

The basic characteristics of the heart failure group are shown in Table I.

Table I. Basic characteristics of patients with heart failure (n = 24)
Age (y)67 ± 2
Male sex17 (70)
Heart failure cause
IHD15 (62)
Hypertension + IHD4 (17)
Hypertension1 (4)
Cardiomyopathy4 (17)
Treatment received
Diuretic18 (75)
ACEI13 (54)
ACEI + diuretic11 (46)
Creatinine (mmol/L)108 ± 7
NYHA class
I and II12 (50)
III and IV12 (50)
Fractional shortening (%)
>1019 (80)
<105 (20)

Values in parentheses are percentages.

Table II illustrates the absence of significant differences in either IGF-1 or GH levels in patients with heart failure, based on the underlying cause or treatment received.

Table II. IGF-1 and GH levels in patients with heart failure (n = 24) categorized by cause, treatment received, and left ventricular fractional shortening
IGF-1 (mU/L)GH (mU/L)Fractional shortening
Heart failure cause
IHD (n = 15)22.3 ± 2.82.7 ± 0.620.5 ± 1.5*
IHD + hypertension (n = 4)19.7 ± 5.21.4 ± 0.412.3 ± 4.8
Hypertension (n =1)22.30.916.0
Cardiomyopathy (n =4)12.2 ± 4.56.9 ± 3.510.0 ± 3.21*
Treatment received
ACEI (n = 13)19.0 ± 3.44.2 ± 1.314.5 ± 1.9*
No ACEI (n = 11)21.5 ± 2.62.1 ± 0.721.6 ± 1.8*
ACEI + diuretic (n = 11)18.3 ± 3.93.3 ± 114.0 ± 2.3
*P < .05.
However, left ventricular fractional shortening was lower in patients with cardiomyopathy than in patients with ischemic heart disease (IHD) (P < .05). In addition, patients who were receiving ACEI treatment tended to have a more severe impairment of left ventricular function.

The control patients (n = 21; 9 men; mean age, 71 ± 2 years) were age- and sex-matched to the patients with heart failure. The cause for hospital presentation of the control group was as follows: 5 patients had chest infection, 13 had musculoskeletal pain, 2 had urinary tract infection, and 1 patient had deep-vein thrombosis.

IGF-1 levels were significantly higher in patients with heart failure than in the control group (20.2 ± 2 mU/L, 14.1 ± 2 mU/L, respectively; P < .05; Figure 1).

GH levels were not different between the two groups (3.1 ± 0.8 mU/L and 3.5 ± 0.8 mU/L, respectively).

Categorizing the patients with heart failure by the NYHA classification revealed patients with milder symptoms (NYHA classes I and II) having a prominent elevation of IGF-1 (24.7 ± 3.3 mU/L, n = 12) over the control group (14.1 ± 2 mU/L; n = 21; P < .003). In contrast, patients with more severe symptoms (NYHA classes III and IV) had IGF-1 levels (15.7 ± 2.3 mU/L, n = 12) that were not different from the control group (Figure 1).

Further analysis of the relations between IGF-1 and the degree of myocardial impairment was sought by correlation analysis. Figure 2 illustrates a strong positive correlation between IGF-1 levels and left ventricular fractional shortening (r = 0.58, P = .003, n = 24).

No correlation was noted between GH levels and fractional shortening (r = –0.14, P = .5). Adjustments for other potential confounders including age, sex, treatment received, and underlying cause of heart failure did not alter the relation between IGF-1 and left ventricular fractional shortening (P = .01; odds ratio, 2.01; 95% confidence interval, 1.26 to 6.24; Table III).
Table III. Multiple linear regression analysis of IGF-1 (dependent variable) with other variables
Unstandardized coefficientsStandardized coefficients95% Confidence interval for BP
BβLowerUpper
Constant19.26 –29.4467.97.41
Age–0.22–.18–0.750.31.39
Sex–5.03–.22–15.145.09.31
Heart failure cause1.00.09–4.356.35.70
Treatment4.76.24–4.9314.44.31
Fractional shortening (%)1.06.690.231.89.01

Treatment refers to patients receiving ACEI.

Categorizing the patients with heart failure by the degree of myocardial impairment determined by fractional shortening estimation further confirmed the split of IGF-1 levels in the patients with heart failure. Mild-to-moderate impairment of left ventricular function (fractional shortening >10) was associated with a significantly higher IGF-1 level (23.5 ± 2.2 mU/L, n = 19) when compared with the control group (n = 21, P < .001) or with the patients with severe impairment of left ventricular function (fractional shortening <10; 8.3 ± 2.5 mU/L, n = 5, P < .0001; Figure 3).

  • View full-size image.
  • Fig. 3. 

    Plasma IGF-1 levels in patients with heart failure (n = 24) grouped by left ventricular fractional shortening compared with control group (n = 21). ANOVA, Analysis of variance.

GH levels did not differ between those groups (2.9 ± 0.8 mU/L, 3.4 ± 0.8 mU/L, and 5.4 ± 2.4, mU/L, respectively).

Back to Article Outline

Discussion 

The main finding in this study is the inverse relation observed between IGF-1 levels and the severity of heart failure determined by both clinical assessment and by left ventricular contractile performance. The latter defined more clearly a group with left ventricular fractional shortening of <10% as having significantly lower IGF-1 levels than patients with high fractional shortening. The finding of low IGF-1 levels in severe heart failure was also reported by Anker et al12 in patients with cachectic heart failure; however, our study is the first to examine variations of IGF-1 in a range of patients with heart failure with varying severity.

Although disease progression from mild-to-moderate to severe heart failure may be multifactorial and poorly understood, our data suggest that IGF-1 may be implicated in this process. Recent communication by Serneri et al13 suggested that participation by IGF-1 in left ventricular hypertrophy is selectively related to both the type of hemodynamic overload and to ventricular function. They reported undetectable levels of IGF-1 in the coronary sinus of patients with end-systolic ventricular wall stress of >90 kdyne/cm2. Our data are consistent with their findings; however, it is important to mention that neither our study nor the other mentioned studies establish a cause-and-effect relation between severity of heart failure and IGF-1 levels. Nevertheless, on the basis of the evidence available thus far, it may be possible to speculate that progression of disease from compensated to decompensated heart failure may be partly influenced by myocardial ability to generate IGF-1 for the purpose of promotion of specific myofibril hypertrophy1 and modulation of surviving myocardial cell growth.6, 7, 8 Further larger-scale studies will be needed to validate this hypothesis.

IGF-1 is a mediator of GH at the tissue level. It was previously thought that IGF-1 is synthesized in the liver in response to GH stimulation. Although this concept may still hold true, new evidence has shown that IGF-1 is also synthesized in a wide range of tissues including myocardial tissue.1 The extrahepatic source of IGF-1 appears to be largely independent from GH stimulation. In the heart, hemodynamic overload or ischemic injury is associated with increased local generation of IGF-1.6, 7, 8 The relative contribution of either hepatic or extrahepatic sources of the measured plasma levels of IGF-1 is not known; therefore, our measurements of plasma IGF-1 may reflect the combined variations of both sources of IGF-1. Heart failure of any cause is associated with changes in the hemodynamic load on the left ventricle; changes in wall stress also influence the remodeling of the left ventricle after myocardial injury. In animal models, both of these influences have been shown to increase local myocardial IGF-1 receptor expression and synthesis.14 How these changes are reflected in the total plasma IGF-1 concentration is not known. In our study, GH levels showed very little variation between the various degrees of heart failure. This would suggest that the observed elevations in IGF-1 in patients with heart failure are from a source that synthesizes IGF-1 independent from GH influence, for example, local myocardial source.

Angiotensin II is a potent inhibitor of local IGF-1 synthesis; it has therefore been suggested that ACEI exert their beneficial effect at least in part by enhancing local IGF-1 formation, thereby improving myocardial contractile performance.15 However, our study did not show significant variations in IGF-1 levels between patients who are receiving ACEI and those who were not receiving the medication. This could partly be explained by the possibility of ACEI to normalize IGF-1 expression in those patients who otherwise would have low IGF-1 expression.

We conclude that plasma IGF-1 levels show distinct variations with severity of heart failure and may play a vital role in compensated heart failure.

Back to Article Outline

References 

  1. Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res. 1995;30:825–834
  2. Ross J, Hongo M. The role of hypertrophy and growth factors in heart failure. J Card Fail. 1996;2(suppl 4):S121–S128
  3. Stromer H, Cittadini A, Douglas PS, et al.  Exogenously administered growth hormone and insulin-like growth factor-I alter intracellular Ca2+ handling and enhance cardiac performance: in vitro evaluation in the isolated isovolumic buffer-perfused rat heart. Circ Res. 1996;79:227–236
  4. Duerr RL, Huang S, Miraliakbar HR, et al.  Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest. 1995;95:619–627
  5. Kinugawa S, Tsutsui H, Ide T, et al.  Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes. Cardiovasc Res. 1999;43:157–164
  6. Hanson MC, Fath KA, Alexander RW, et al.  Induction of cardiac insulin-like growth factor I gene expression in pressure overload hypertrophy. Am J Med Sci. 1993;306:69–74
  7. Isgaard J, Wahlander H, Adams MA, et al.  Increased expression of growth hormone receptor mRNA and insulin-like growth factor-I mRNA in volume-overloaded hearts. Hypertension. 1994;23(6 Pt 2):884–888
  8. Reiss K, Kajstura J, Zhang X, et al.  Acute myocardial infarction leads to upregulation of the IGF-1 autocrine system, DNA replication, and nuclear mitotic division in the remaining viable cardiac myocytes. Exp Cell Res. 1994;213:463–472
  9. Donath MY, Jenni R, Brunner HP, et al.  Cardiovascular and metabolic effects of insulin-like growth factor I at rest and during exercise in humans. J Clin Endocrinol Metab. 1996;81:4089–4094
  10. Donath MY, Sutsch G, Yan XW, et al.  Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure. J Clin Endocrinol Metab. 1998;83:3177–3183
  11. Delafontaine P, Brink M. The growth hormone and insulin-like growth factor 1 axis in heart failure. Ann Endocrinol (Paris). 2000;61:22–26
  12. Anker SD, Chua TP, Ponikowski P, et al.  Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997;96:526–534
  13. Serneri GG, Modesti PA, Boddi M, et al.  Cardiac growth factors in human hypertrophy: relations with myocardial contractility and wall stress. Circ Res. 1999;85:57–67
  14. Donohue TJ, Dworkin LD, Lango MN, et al.  Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy. Circulation. 1994;89:799–809
  15. Jin H, Yang R, Gillett N, et al.  Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition. J Cardiovasc Pharmacol. 1995;26:420–425

☆ Reprint requests: M. Al-Obaidi, MD, Cardiology Department, Harefield Hospital, Hill End Road, Middlesex UB9 6JH, UK. E-mail: m.al-obaidi@rbh.nthames.nhs.uk

PII: S0002-8703(01)22494-6

doi:10.1067/mhj.2001.118116

American Heart Journal
Volume 142, Issue 6 , Page E10, December 2001

Article Tools

* Image Usage & Resolution