Circadian rhythm of acylated ghrelin, leptin, growth hormone, IGF-1, IGFBP-1 and IGFBP-3

This Article


Article Information:

Group: 2011
Subgroup: Volume 9, Issue 4, Autumn
Date: September 2011
Type: Original Article
Start Page: 352
End Page: 359
DOI: 10.5812/Kowsar.1726913X.3334


  • Ghollam Reza Moshtaghi-Kashanian
  • Physiology Research Center and Biochemistry Department of Medical School, Kerman University of Medical Sciences, Kerman, IR Iran
  • Fatemeh Mirzaee
  • 1-Physiology Research Center and Biochemistry Department of Medical School, Kerman University of Medical Sciences, Kerman, IR Iran.2- Physiology Research Center and Cardiology Department, Afzalipoor Hospital, Medical School, Kerman University of Medical Sciences, Kerman, IR Iran
  • Seyyed Hossein khalilzadeh
  • Physiology Research Center and Cardiology Department, Afzalipoor Hospital, Medical School, Kerman University of Medical Sciences, Kerman, IR Iran


      Affiliation: Physiology Research Center and Biochemistry Department of Medical School, Kerman University of Medical Sciences
      City, Province: Kerman,
      Country: IR Iran
      Tel: +98-3412456207
      Fax: +98-3412454968


Background: Following detection of receptors for ghrelin and growth hormone (GH) in the cardiovascular system, different clinical trials have used ghrelin or GH for the treatment of cardiac patients. While some of these trials reported improvements in the patients’ situation, others reported deterioration.
Objectives: To clarify the contradictory outcomes, we designed this study to evaluate the circadian rhythms of acylated ghrelin, GH, and the related factors [Insulin-like Growth Factor-1 (IGF-1), Insulin-like Growth Factor Binding Proteins 1 and 3 (IGFBP-1 and IGFBP-3)], and leptin in patients with reduced ejection fraction (rEF).
Patients and Methods: Ten patients with rEF and an equal number of healthy control subjects matched for age and gender participated in this study according to inclusion criteria. All participants were hospitalized in the cardiac care unit (CCU), under identical conditions during collection of blood (every 2 hours). Primary processing of samples was carried out immediately and the plasma was stored at -20ºC until evaluation of the aforementioned parameters using ELISA methods.
Results: Evaluation of the collected data showed that among aged participants only circulating leptin is gender-dependent, while the patients had significantly (P < 0.001) lower ghrelin, GH, IGF-1, and IGFBP-1, but a higher level of IGFBP-3 compared to the control group. In addition, except for GH that showed a mild circadian rhythm, the parameters we examined did not have a significant circadian rhythm. Correlation analysis of the data showed a positive correlation between ghrelin and GH or IGF-1, and significant negative or positive correlations between leptin and IGFBP-1, or IGFBP-3, respectively, in both groups.
Conclusions: Here, for the first time, we show that circulating ghrelin, GH, and IGF-1 levels are reduced in the patients with rEF, and the condition of patients is deteriorated not only due to reduced IGF-1 but also due to reduction of IGFBP-1 or increase of IGFBP-3, which may be influenced by circulating leptin. Finally, disturbance of the balance between ghrelin/GH/IGF-1 and leptin may be the cause of rEF, and thus evaluation of these parameters could provide diagnostic as well as prognostic tools for the treatment of these patients.

  • Implication for health policy/practice/research/medical education:
    Disturbance of anabolic hormones such as ghrelin and leptin could be the cause of developing cardiovascular diseases. In addition, imbalance between ghrelin/GH/IGF-1 axis and leptin may be the reason for reduction of ejection fraction among cardiovascular patients.
  • Please cite this paper as:
    Moshtaghi-Kashanian GR, Mirzaee F, Khalilzadeh SH. Circadian Rhythm of Acylated Ghrelin, Leptin, Growth Hormone, IGF-1, IGFBP-1, and IGFBP-3 in Chronic Heart Failure Patients and Healthy Subjects. Int J Endocrinol Metab. 2011;9(4):352-9. DOI: 10.5812/Kowsar.1726913X.3334

Copyright © 2011 Kowsar M. P. Co. All rights reserved.

Keywords: Ghrelin; Growth Hormone; Insulin-Like Growth Factor 1; Insulin-Like Growth Factor; Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Leptin

Manuscript Body:

1. Background

Despite recent advances in therapy, chronic heart failure (CHF) remains a common and serious problem, particularly among the increasing proportion of the older population (1, 2). Left ventricular hypertrophy is a strong and independent predictor of cardiovascular morbidity and mortality, in hypertensive patients as well as in the general population, which is associated with a higher risk of myocardial infarction, stroke, sudden death, and death from other causes (3, 4).
It is known that growth hormone (GH) regulates growth in pediatric age as well as inducing anabolic actions directly, or insulin-like growth factor-1 (IGF-1)-mediated effects in adult age. Receptors for GH and IGF-1 have been observed in the cardiac myocyte membrane (5) and investigators in this field believe that GH modifies left ventricle structure and function (5-8), because patients with acromegaly have an increased propensity of developing cardiovascular complications, such as ventricular hypertrophy with interstitial fibrosis. Conversely, patients with GH deficiency can exhibit ventricular dysfunction, increased vascular thickness, and an increased number of atheromatous plaques (8, 9). Therefore, since 1995, many scientists have been investigating the beneficial effects of GH in the treatment of left ventricular hypertrophy (LVH); however, these studies have yielded contradictory results. While some studies suggest that addition of GH in the LVH treatment protocol improves patient outcomes others have found that GH is not advantageous or may even contribute negatively (6, 7, 10-16).
Additionally, IGF-1 is synthesized by almost all tissues and is an important mediator of cell growth, differentiation, and transformation. It exerts all of its known physiologic effects by binding to the IGF-1 receptors and its effects are modulated by multiple IGF-1 binding proteins (IGFBPs) (17-20). The IGFBPs family has at least six members, which serve as transporter proteins and as storage pools for IGF-1 (21). The expressions of IGFBPs are tissue and developmental stage specific, and the concentrations of IGFBPs differ in different body compartments (19). All six IGFBPs have been shown to inhibit IGF-1 action, but IGFBP-1, -3, and -5 have also been shown to stimulate IGF-1 action, whereas some of the effects of IGFBPs might be IGF-1-independent (20).
Ghrelin was discovered in 1999 and it is now well documented that it stimulates GH release from the pituitary through its specific receptor, which is referred to as the growth hormone secretagogue receptor (22-25). Furthermore, the receptor for ghrelin was also detected in the blood vessels and ventricles of the heart (26, 27). Ghrelin also shows anti-cachectic effects through GH-dependent and -independent mechanisms (22, 23, 28-31).

2. Objectives

To our knowledge there is only one published report that has examined the circadian rhythm of GH among CHF patients (8 patients) (32), without considering other factors such as IGF-1, IGFBPs or ghrelin and leptin, which also in fluencing elements in cardiac function. There is also a report that shows leptin strongly predicts levels of GHBPs in CHF, regardless of a hyperleptinaemic state or severely altered body composition as in cardiac cachexia (33). Since there is a circadian rhythm for GH and related factors (IGFs and its carrier proteins) during different periods of life and for acylated ghrelin that depend on the state of feeding, and the lack of studies that have examined the relationship between GH and related proteins or hormones (IGF-1, IGFBP-1, IGFBP-3, ghrelin, and leptin), we sought to address this relationship in this study, and also to obtain data on the circadian rhythm of these factors among the aged patients with low ejection fraction (rEF).

3. Patients and Methods

The research approval and ethic committees of Kerman University of Medical Sciences approved the protocols for this study, which is in accordance with the internationally accepted principles found in the European Community Guidelines (EEC Directive of 1986; 86/609/EEC) or the US Guidelines (NIH publication #85-23, revised in 1985). Our cardiologist selected 10 CHF patients (five male and five female) as the CHF group and 10 healthy subjects as the control group. The inclusion criteria were non-diabetics, with normal lipid profile, and body mass index (BMI) close to 25 kg/m2. A normal ejection fraction (EF) (≥ 50) was considered for the control group, while the corresponding value for the patients was below 30, with a stable clinical condition for the previous 2 months. Exclusion criteria were the presence of chronic renal dysfunction (serum creatinine level ≥ 2.0 mg/dL), liver dysfunction, evidence of malignant diseases, active infection, hematologic abnormalities, or systolic blood pressure < 90 mm Hg.
Our cardiologist gave detailed explanations about the nature of the study to each participant and collected an informed written consent form from all participants. The day after the collection of the written statement, each precipitant was admitted to the cardiac care unit (CCU) under supervision of the cardiologist in the morning (8–9 AM). They were given identical meals throughout hospitalization (breakfast at 6:30, lunch at 12:30 and evening meal at 19:00) and the first sample collection started at 2 PM. For the sample collection, a butterfly needle was used for the first blood collection (3 mL) and repeated blood samples were taken, with 2-hour intervals between sample collections. The vein was kept open by connecting the needle to a normal saline solution (4 drops per minute). Collected samples were sent immediately to the hospitals’ laboratory for primary processing, which included separation of sera by centrifuging at 800 × g for 5 minutes.
The samples were stored at -20º C, until further analysis. All parameters, including GH (Monobind, USA), IGF-1 (IDS,Uk), IGFBP-1 (Medix Biochemica, Finland), IGFBP-3 (Biosource, Belgium), acylated ghrelin (Biovender, Germany), and leptin (DBC, Canada) were evaluated in 1 day using ELISA methods according to the instructions provided by the manufactures of the ELISA kits. Coefficient of variation (CV %) for the medium range analytes, sensitivity, and dynamic range of different commercial kits used are presented in Table 3.

3.1. Statistical Analysis

Data were analyzed using SPSS software (Version 19, IBM). After checking for normal distribution using the Shapiro-Wilk test, we used two-way repeated-measures ANOVA for detection of the circadian rhythms of the evaluated parameters. Independent sample t-tests were used for comparisons between the two groups. Determination of correlations was carried out using Pearson’s two-tailed bivariate model. P-values less than 0.05 were considered as statistically significant differences.

4. Results

Average age, weight, height, BMI, and EF of patients and corresponding control subjects, who were divided according to their gender, are presented in Table 1 and the different chemistries evaluated, irrespective of their gender, are presented in Table 2. Neither age nor BMI (compared according to control group of the corresponding gender) were significantly different between patients and control subjects. As expected, the EF of patients were significantly lower (P < 0.001) than those of the control subjects. Comparison of evaluated data for the male and female participants of both groups showed only values obtained for leptin was gender-dependent (which depended on their BMI) and the sex difference did not influence the circulating values obtained for their fasting glucose (FBS), urea, creatinine, lipid profiles, liver function tests, lactate dehydrogenase (LDH), creatine kinase (CPK), hemoglobin, white blood cell count (WBC), GH, IGF-1, IGFBP-1, IGFBP-3, or acylated ghrelin. For this reason, values obtained for both male and female subjects were combined into a single group when comparing data obtained for the mentioned parameters.

Table 1. Comparison of Ejection Fraction and Anthropometric Parameters in Patients and Healthy Subjects


Control a

Patients a




Male (n = 5)

Female (n = 5)

Age, y

70.6 ± 8.96

66.0 ± 6.82

68.2 ± 10.38

60.6 ± 5.73

Weight, kg

69.0 ± 6.56

64.2 ± 6.02

63.8 ± 6.06

63.2 ± 2.68

Height, m

1.71 ± 0.09

1.59 ± 0.03

1.75 ± 0.04

1.59 ± 0.02

BMI, kg/m2

23.61 ± 2.60

25.51 ± 2.84

20.77 ± 1.59

24.95 ± 1.17

Ejection Fraction

60.4 ± 1.67

62.8 ± 2.17

21.0 ± 7.42 b

26.2 ± 1.64 b


Table 2. Comparison of Biochemical and Hematological Parameters in Patients and Healthy Subjects

Chemistry a, b



P value

FBS c, mg/dL

87.70 (9.53)

89.10 (5.92)


Urea, mg/dL

33.80 (6.53)

32.60 (6.67)


Creatinine, mg/dL

1.38 (0.31)

1.26 (0.23)


Total Bilirubin, mg/dL


0.96 (0.22)


Direct Bilirubin, mg/dL

0.23 (0.12)

0.27 (0.11)



22.90 (6.86)

23.60 (7.07)



23.30 (4.35)

23.40 (4.38)


Alk.P c, IU/L

118.4 (16.9)

112.0 (19.4)


Cholesterol, mg/dL

184.1 (13.7)

180.2 (9.9)


Triglycerides, mg/dL

144.6 (14.4)

151.1 (16.8)


HDL-c c, mg/dL

32.60 (4.12)

31.40 (4.01)


LDL-c c, mg/dL

133.90 (14.7)

135.20 (6.3)



97.20 (14.1)

88.70 (15.1)



72.40 (13.3)

67.50 (14.0)


PT c, second

13.50 (1.18)

13.00 (0.82)


WBC c ×103/µL

6.86 (1.10)

7.46 (0.56)


Hemoglobin, g/dL

14.01 (0.83)

14.57 (0.77)


aNumber of subjects in both groups was equal (n =10 for both groups).
bValues presented are calculated mean ± standard deviations, which are indicated in parentheses.
c Abbriviation: FBS, Fasting blood glucose; AST, Aspartic transaminase; ALT, Alanine transaminase; Alk.p,Alkaline phosphatase; HDL-c, High-density lipoprotein cholesterol; LDL-c, Low-density lipoprotein cholesterol; LDH, Lactate dehydrogenase; CPK, Creatine kinase; PT, prothrombin time; WBC, White blood cell count

The data showed that at all 11 time points (except time 14:00), the circulating GH levels of patients were significantly lower (P < 0.02–0.001) than those of the corresponding control subjects (Figure 1A). Their acylated ghrelin were also significantly lower (P < 0.01–0.001) (Figure 1B), throughout the 24-hour sampling period. Additionally, both the patient and control groups showed a circadian rhythm for GH, such that higher levels were detected during the nighttime, while lower levels were observed during the daytime. Furthermore, due to low circulating GH among the patients, the difference of the highest levels (at midnight) was significantly greater (P < 0.05) than values obtained for 10:00, 12:00, and 14:00 hours, while control subjects had a more prominent diurnal variation (P < 0.001). On the other hand, neither the patient nor control groups showed a significant circadian rhythm for acylated ghrelin, though a non-significant variation was detected.

Figure 1. Analysis of ghrelin, GH, and GH-Related Factors in cardiac Patients and Healthy Control Subjects.
Data for patients with reduced ejection fraction (n = 10, 5 male and 5 female), and corresponding age- and gender-matched control subjects (n = 10). Data shown are the mean ± standard error of mean; A, Circadian rhythm of GH (ng/mL) among two groups of participants. Except for two time points, at 14:00 and 16:00, that were not significant (P > 0.05), patients had lower GH than the control group at all the remaining time points; B, Circulating acylated ghrelin (pg/mL) of patients at all time points (P from 0.025 to 0.001) was lower than that of control subjects; C, Data for IGF-1 (ng/mL). From 6:00 to 12:00, there was no significant difference between patients and control subjects, while at remaining time points, differences were significant (P <0.01–0,001); D, IGFBP-1 (ng/mL) levels of the two groups. Except for two time points, at midnight and 2:00 AM, that were not difference between the two groups, patients had lower IGFBP-1 (P < 0.05–0.001) at the remaining time points; E, At all time points, patients had significantly higher circulating IGFBP-3 (ng/mL) than the control group (P <0.05–0.001); F: Leptin (ng/mL) levels of male subjects were similar, while female participants had significantly higher levels of leptin. In addition, female patients had significantly lower circulating leptin levels (P < 0.05) than corresponding control females.

Circulating level of total IGF-1 was also lower among the patients when compared to the values obtained for the control subjects, throughout the 24-hour sampling period. Additionally, while the total IGF-1 of the patients did not fluctuate significantly during 24 hours (uppermost level between 8.00 and 12.00 AM and lowest level between 16.00 and 18.00 PM), this pattern was the converse in the control subjects. The divergence in the patterns of circulating IGF-1 among the two groups did not cause significant differences between the two groups during the morning (6.00–12.00), while marked differences (P < 0.001) were detected during the evening (14.00–24.00) (Figure 1C). The data for IGFBP-1 showed that the patients had lower levels of circulating IGFBP-1, while both patients and control groups had the same pattern during day and night. In addition, both groups had an apparent and non-significant peak during the night (2.00–8.00), while low levels were detected between 18.00 and 22.00 hours. Statistically, except for the data obtained for two time points of 00.00 and 24.00 that were not significant, patients had significantly lower (P < 0.05–0.001) IGFBP-1 levels than the control subjects at other time points (Figure 1D).
During the 24 hours of sample collection, circulating levels of IGFBP-3 of both patient and control groups had approximately the same pattern, without significant changes during day and night. However, the values obtained for the patients were higher than those for the control group (P < 0.01) at all time points (Figure 1E).
The leptin levels of male patients did not differ from the values obtained for the control group (male). On the other hand, female subjects had higher levels of circulating leptin (P < 0.01) when compared with the respective values obtained for the male groups (both patients and control subjects). Furthermore, female patients showed a significant decrease of circulating leptin compared to the respective female control group (P < 0.05). Here also, we did not detect a significant change during day or night, and both groups had approximately the same pattern (Figure 1F).
The fluctuations detected for IGF-1, IGFBP-1, IGFBP-3, and leptin in both groups did not fit the pattern of a circadian rhythm, as determined by statistical analysis of the data using repeated measure of variances. Since we did not detect a considerable circadian rhythm for the evaluated parameters, we carried out a two-tailed bivariate correlation between different parameters. The two-tailed bivariate analysis of the data showed that ghrelin had a positive correlation with total IGF-1 (r = 0.33, P < 0.01) and a negative correlation with leptin (r = -0.28, P < 0.01) in the patient group. On the other hand, the circulating leptin in the patient group showed a negative correlation with GH (r = -0.19, P < 0.05), IGF-1 (r = -0.38, P < 0.01) and IGFBP-1 (r = -0.38, P < 0.01), while leptin had a positive correlation with IGFBP-3 (r = 0.32, P < 0.01). Data for the control group also showed that ghrelin had negative correlations with leptin (r = -0.38, P < 0.01), while leptin showed negative correlations with IGF-1 (r = -0.33, P < 0.01) and IGFBP-1 (r = -0.31, P < 0.01) and a positive correlation with IGFBP-3 (r = 0.361, P < 0.01). Combining the data of both groups and re-analyzing the Pearson’s two-tailed bivariate correlation showed remarkable results. These set of data indicated that ghrelin correlates positively with GH (r = 0.35, P < 0.01), IGF-1 (r = 0.42, P < 0.01), and IGFBP-1 (r = 0.36, P < 0.01), and correlates negatively with IGFBP-3 (r = -0.48, P < 0.01). In addition, GH also showed a significant correlation with circulating IGF-1 (r = 0.47, P < 0.01), and IGFBP-1(r = 0.38, P < 0.01), while it showed a negative correlation with IGFBP-3 (r = -0.43, P < 0.01).

5. Discussion

Except for GH, which showed a circadian rhythm in both groups, other GH-related parameters evaluated in this study did not exhibit a circadian rhythm, although the values obtained for acylated ghrelin, IGF-1, IGFBP-1 and IGFBP-3 in patients were different from those obtained in the control group. Furthermore, while the circulating leptin levels of male participants were the same, female patients had lower leptin levels that control females. The differences detected for the female participants could be due to their higher BMI, as indicated in previous studies (33, 34).
Acylated ghrelin, which is the active form of ghrelin, plays a critical role in a variety of physiological processes, including the stimulation of GH secretion, regulation of energy homeostasis by stimulating food intake, and promoting adiposity via a GH-independent mechanism (34). Growth hormone also regulates IGF-1 levels, which is an anabolic hormone that spares protein stores at the expense of fat utilization during conditions of caloric restriction (22). In the present study, patients had lower circulating acylated ghrelin than corresponding control subjects. They also had lower GH levels with diminished or a decreased circadian rhythm that could result in lower levels of IGF-1, without a significant circadian rhythm.
Indeed, ghrelin inhibits cardiomyocyte and endothelial cell apoptosis (35, 36) and improves left ventricular function (3, 27, 37). Acylated ghrelin also exerts vasodilatory effects in humans, improves cardiac function, and decreases systemic vascular resistance in patients with chronic heart failure (3, 27, 37, 38). Reduction in circulating acylated ghrelin with diminished circadian rhythm (39) not only reduces the functions mentioned, it also decreases the appetite (22, 23) of aged patients. Furthermore, a decrease in circulating ghrelin may be the cause of the decreased circulating GH and, consequently, reduced circulating IGF-1, as observed in the present study and suggested by previously reported data (2, 40, 41). The positive correlation between acylated ghrelin and GH or IGF-1 among our rEF patients may also support the validity of the clinical trials that used ghrelin (37, 42, 43) or GH (9, 13, 14, 44) for treatment of their patients, and observed improvement in the patients’ condition, such as increasing exercising capacity, left ventricular function and reduces proinflamatory cytokins. On the other hand, while our data for ghrelin (45), GH (32, 44), and IGF-1 (46) are consistent with earlier reports, there are reports that showed circulating ghrelin (47, 48) and GH (27, 49) increase in patients with cardiac cachexia and observed deterioration of their patients’ health. The discrepancy in the results have prompted experts in the field to stress the need for evaluating the basal endocrine status of the patients before treating them with GH, and for paying particular attention to those patients who present with a peripheral GH resistance (5). Additionally, patients with GH deficiency exhibit ventricular dysfunction, increased vascular thickness, and an increased number of atheromatous plaques (8). However, most of GH action is via production of IGFs that constitute a system of peptides that promote mitosis, growth, and organ development by both paracrine and endocrine pathways (2, 8, 50). One study has demonstrated a significant correlation between left ventricular ejection fraction and the mean IGF-1 concentrations of the patients (r = 0.24, P = 0.02) (51). In the present study, we observed reduced circulating total IGF-1 among our patients that was coupled with low levels of IGFBP-1 and high levels of IGFBP-3. Previous studies have also reported lower circulating levels of IGFBP-1 (21), while there are reports that showed no change (52) or a decrease (46) in IGFBP-3 among CHF patients, without mentioning the state of ejection fraction among their patients. Under normal circumstances, less than 1% of IGF-1 circulates in free form and is degraded within a few minutes (50, 53). Bioavailability of IGFs in circulation is modulated by at least six specific IGFBPs (53). Thus, circulating levels of these binding proteins act as the main regulators of IGFs bioavailability in circulation (54). Furthermore, while the majority of IGF-1 is bound to IGFBP-3 that is unable to cross the endothelium, IGFBP-1 is comparatively small and has been proposed to be the pivotal acute regulator of IGF-1 activity. IGFBP-1 is also capable of crossing the endothelium and acutely modulating access of IGF to tissues and cell surface receptors (54). Our data indicate that patients with low ejection fraction have lower bioavailability of total IGF-1, not only due to a reduction in acylated ghrelin and/or GH but also due to reduced levels of circulating IGFBP-1 and increased levels of circulating IGFPB-3.
Finally, leptin was the only parameter that showed a difference between male and females of both groups (patient and control groups). Furthermore, while circulating levels of leptin among male participants were the same, female patients had lower levels of leptin compared to the female control patients (P < 0.05). The discrepancy could be due to the higher BMI for the female participants (33, 34). Furthermore, previous studies also did not find significant differences among the control and cardiac patients with identical BMIs (55).
Circulating leptin regulates energy homeostasis and is elevated in obesity, and it influences ventricular and vascular remodeling (56). Here, we did not detect considerable differences between circulating leptin levels of our patients and the corresponding control group, since BMI was less than 25 kg/m2, but detected a negative correlation between circulating leptin and IGFBP-1 and a positive correlation with IGFBP-3 needs more attention. Considering reduced levels of ghrelin, GH, and IGF-1 with unchanged leptin levels suggest that there should be a balance between leptin and ghrelin or GH /IGF-1, to maintain an appropriate level of IGFBPs in circulation. Since this is the first study that demonstrates a relationship between IGFBPs and leptin, further investigation is necessary to confirm this.
In conclusion, in this study, for the first time, we examined the circadian rhythm of acylated ghrelin, leptin, and related components (GH, IGF-1, IGFBP-1, and IGFBP-3) among the patients with low ejection fraction, and showed that except for GH, which showed a decreased circadian rhythm, the remaining factors do not exhibit a circadian rhythm in this age group. Furthermore, while circulating levels of acylated ghrelin, GH, and IGF-1 are reduced among these patients, a reduction of circulating IGFBP-1 and an increase in IGFBP-3 probably worsens the condition of patients by reducing the bioavailability of IGF-1. Finally, the correlation detected between circulating leptin and IGFBPs or reduced ghrelin and its association with GH/IGF-1 may provide diagnostic as well as prognostic tools for the treatment of patients with low ejection fraction, as suggested recently (2).

  • Acknowledgments
    The authors express their deepest thanks to the participants of this study, without their contribution this research could not be conducted. The Research deputy of Kerman University of Medical Sciences, Kerman, Iran, provided the funding for this study. Research approval and ethic committees of Kerman University approved the protocols for this study.
  • Financial Disclosure
    None declared.
  • Funding/Support
    The Research deputy of Kerman University of Medical Sciences, Kerman, Iran, provided the funding for this study.

References: (56)

  1. Witte KK, Nikitin NP, Parker AC, von Haehling S, Volk HD, Anker SD, et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. European heart journal. 2005;26(21):2238-44. [PubMed][DOI: 10.1093/eurheartj/ehi442 ]
  2. Perkel D, Naghi J, Agarwal M, Morrissey RP, Phan A, Willix RD, Jr., et al. The Potential Effects of IGF-1 and GH on Patients With Chronic Heart Failure. J Cardiovasc Pharmacol Ther. 2011. [PubMed]
  3. Rodriguez A, Gomez-Ambrosi J, Catalan V, Becerril S, Sainz N, Gil MJ, et al. Association of plasma acylated ghrelin with blood pressure and left ventricular mass in patients with metabolic syndrome. J Hypertens. 2010;28(3):560-7. [PubMed][DOI: 10.1097/HJH.0b013e328334327c ]
  4. Skudicky D, Sareli P, Libhaber E, Candy G, Radevski I, Valtchanova Z, et al. Relationship between treatment-induced changes in left ventricular mass and blood pressure in black african hypertensive patients: results of the Baragwanath Trial. Circulation. 2002;105(7):830-6. [PubMed][DOI: 10.1161/hc0702.104162 ]
  5. Giustina A, Bonadonna S, Burattin A, Manelli F, Lorusso R, Volterrani M, et al. [Growth hormone secretion in heart failure]. Minerva endocrinologica. 2003;28(1):1-11. [PubMed]
  6. Isgaard J, Barlind A, Johansson I. Cardiovascular effects of ghrelin and growth hormone secretagogues. Cardiovasc Hematol Disord Drug Targets. 2008;8(2):133-7. [PubMed]
  7. Agarwal M, Naghi J, Philip K, Phan A, Willix RD, Jr., Schwarz ER. Growth hormone and testosterone in heart failure therapy. Expert opinion on pharmacotherapy. 2010;11(11):1835-44. [PubMed][DOI: 10.1517/14656566.2010.485615 ]
  8. Volterrani M, Giustina A, Lorusso R, Giordano A. Does growth hormone play a role in chronic heart failure? Heart failure monitor. 2002;3(2):60-4. [PubMed]
  9. Volterrani M, Manelli F, Cicoira M, Lorusso R, Giustina A. Role of growth hormone in chronic heart failure. Therapeutic implications. Drugs. [PubMed][DOI: 10.2165/00003495-200060040-00002 ]
  10. Yang R, Bunting S, Gillett N, Clark R, Jin H. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995;92(2):262-7. [PubMed]
  11. Tajima M, Weinberg EO, Bartunek J, Jin H, Yang R, Paoni NF, et al. Treatment with growth hormone enhances contractile reserve and intracellular calcium transients in myocytes from rats with postinfarction heart failure. Circulation. 1999;99(1):127-34. [PubMed]
  12. Cittadini A, Isgaard J, Monti MG, Casaburi C, Di Gianni A, Serpico R, et al. Growth hormone prolongs survival in experimental postinfarction heart failure. Journal of the American College of Cardiology. 2003;41(12):2154-63. [PubMed][DOI: 10.1016/S0735-1097(03)00483-2 ]
  13. Acevedo M, Corbalan R, Chamorro G, Jalil J, Nazzal C, Campusano C, et al. Administration of growth hormone to patients with advanced cardiac heart failure: effects upon left ventricular function, exercise capacity, and neurohormonal status. International journal of cardiology. 2003;87(2-3):185-91. [PubMed][DOI: 10.1016/S0167-5273(02)00249-8 ]
  14. Adamopoulos S, Parissis JT, Georgiadis M, Karatzas D, Paraskevaidis J, Kroupis C, et al. Growth hormone administration reduces circulating proinflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy. American heart journal. 2002;144(2):359-64. [PubMed][DOI: 10.1067/mhj.2002.124052 ]
  15. Qi X, Reed J, Englander EW, Chandrashekar V, Bartke A, Greeley GH, Jr. Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion. Experimental biology and medicine (Maywood, NJ. 2003;228(9):1028-32. [PubMed]
  16. Popovic V, Miljic D, Micic D, Damjanovic S, Arvat E, Ghigo E, et al. Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level. The Journal of clinical endocrinology and metabolism. 2003;88(7):3450-3. [PubMed]
  17. Conti E, Musumeci MB, De Giusti M, Dito E, Mastromarino V, Autore C, et al. IGF-1 and atherothrombosis: relevance to pathophysiology and therapy. Clin Sci (Lond). 2011;120(9):377-402. [PubMed][DOI: 10.1042/CS20100400 ]
  18. Abbas A, Grant PJ, Kearney MT. Role of IGF-1 in glucose regulation and cardiovascular disease. Expert Rev Cardiovasc Ther. 2008;6(8):1135-49. [PubMed][DOI: 10.1586/14779072.6.8.1135 ]
  19. Lelbach A, Muzes G, Feher J. The insulin-like growth factor system: IGFs, IGF-binding proteins and IGFBP-proteases. Acta physiologica Hungarica. 2005;92(2):97-107. [PubMed][DOI: 10.1556/APhysiol.92.2005.2.1 ]
  20. Delafontaine P, Song YH, Li Y. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arteriosclerosis, thrombosis, and vascular biology. 2004;24(3):435-44. [PubMed][DOI: 10.1161/01.ATV.0000105902.89459.09 ]
  21. Borai A, Livingstone C, Ghayour-Mobarhan M, Abuosa A, Shafi S, Mehta S, et al. Serum insulin-like growth factor binding protein-1 (IGFBP-1) phosphorylation status in subjects with and without ischaemic heart disease. Atherosclerosis. 2010;208(2):593-8. [PubMed][DOI: 10.1016/j.atherosclerosis.2009.08.010 ]
  22. Akamizu T, Kangawa K. Therapeutic applications of ghrelin to cachexia utilizing its appetite-stimulating effect. Peptides. 2011. [PubMed]
  23. Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachex Sarcopenia Muscle. 2010;1(2):169-76. [PubMed][DOI: 10.1007/s13539-010-0011-5 ]
  24. Kamiji MM, Inui A. The role of ghrelin and ghrelin analogues in wasting disease. Curr Opin Clin Nutr Metab Care. 2008;11(4):443-51. [PubMed][DOI: 10.1097/MCO.0b013e328303dee4 ]
  25. De Vriese C, Delporte C. Ghrelin: A new peptide regulating growth hormone release and food intake. Int J Biochem Cell Biol. 2007. [PubMed]
  26. Muccioli G, Baragli A, Granata R, Papotti M, Ghigo E. Heterogeneity of Ghrelin/Growth Hormone Secretagogue Receptors. Toward the Understanding of the Molecular Identity of Novel Ghrelin/GHS Receptors. Neuroendocrinology. 2007. [PubMed]
  27. Nagaya N, Kangawa K. Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol. 2003;3(2):146-51. [PubMed][DOI: 10.1016/S1471-4892(03)00013-4 ]
  28. Ueno H, Shiiya T, Nakazato M. Translational research of ghrelin. Ann N Y Acad Sci. 2010;1200:120-7. [PubMed][DOI: 10.1111/j.1749-6632.2010.05509.x ]
  29. Akashi YJ, Palus S, Datta R, Halem H, Taylor JE, Thoene-Reineke C, et al. No effects of human ghrelin on cardiac function despite profound effects on body composition in a rat model of heart failure. International journal of cardiology. 2009;137(3):267-75. [PubMed][DOI: 10.1016/j.ijcard.2008.06.094 ]
  30. Nagaya N, Kangawa K. Therapeutic potential of ghrelin in the treatment of heart failure. Drugs. 2006;66(4):439-48. [PubMed][DOI: 10.2165/00003495-200666040-00004 ]
  31. Nagaya N, Kojima M, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of cardiopulmonary-associated cachexia. Intern Med. 2006;45(3):127-34. [PubMed][DOI: 10.2169/internalmedicine.45.1402 ]
  32. Duncan B, Moyna NM, Heller GV, McGill C, Katten D, Finta L, et al. A 24-hour comparison of serum growth hormone concentrations in patients with heart failure versus healthy controls. Pharmacotherapy. 2003;23(2):147-52. [PubMed][DOI: 10.1592/phco. ]
  33. Doehner W, Pflaum CD, Rauchhaus M, Godsland IF, Egerer K, Cicoira M, et al. Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia. European journal of endocrinology / European Federation of Endocrine Societies. 2001;145(6):727-35. [PubMed]
  34. Moshtaghi-Kashanian GR, Razavi F. Ghrelin and leptin levels in relation to puberty and reproductive function in patients with beta-thalassemia. Hormones (Athens). 2009;8(3):207-13. [PubMed]
  35. Caliskan Y, Gorgulu N, Yelken B, Yazici H, Oflaz H, Elitok A, et al. Plasma ghrelin levels are associated with coronary microvascular and endothelial dysfunction in peritoneal dialysis patients. Ren Fail. 2009;31(9):807-13. [PubMed][DOI: 10.3109/08860220903151419 ]
  36. Shimizu Y, Nagaya N, Teranishi Y, Imazu M, Yamamoto H, Shokawa T, et al. Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun. 2003;310(3):830-5. [PubMed][DOI: 10.1016/j.bbrc.2003.09.085 ]
  37. Nagaya N, Moriya J, Yasumura Y, Uematsu M, Ono F, Shimizu W, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation. 2004;110(24):3674-9. [PubMed][DOI: 10.1161/01.CIR.0000149746.62908.BB ]
  38. Granata R, Isgaard J, Alloatti G, Ghigo E. Cardiovascular actions of the ghrelin gene-derived peptides and growth hormone-releasing hormone. Experimental biology and medicine (Maywood, NJ. 2011;236(5):505-14. [PubMed]
  39. Yannielli PC, Molyneux PC, Harrington ME, Golombek DA. Ghrelin effects on the circadian system of mice. J Neurosci. 2007;27(11):2890-5. [PubMed][DOI: 10.1523/JNEUROSCI.3913-06.2007 ]
  40. Castellano G, Affuso F, Conza PD, Fazio S. The GH/IGF-1 Axis and Heart Failure. Curr Cardiol Rev. 2009;5(3):203-15. [PubMed][DOI: 10.2174/157340309788970306 ]
  41. Dalla Libera L, Ravara B, Volterrani M, Gobbo V, Della Barbera M, Angelini A, et al. Beneficial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure. Am J Physiol Cell Physiol. 2004;286(1):C138-44. [PubMed][DOI: 10.1152/ajpcell.00114.2003 ]
  42. Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, et al. Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci (Lond). 2003;105(4):431-5. [PubMed][DOI: 10.1042/CS20030184 ]
  43. Vestergaard ET, Andersen NH, Hansen TK, Rasmussen LM, Moller N, Sorensen KE, et al. Cardiovascular effects of intravenous ghrelin infusion in healthy young men. Am J Physiol Heart Circ Physiol. 2007;293(5):H3020-6. [PubMed][DOI: 10.1152/ajpheart.00496.2007 ]
  44. Spallarossa P, Rossettin P, Minuto F, Caruso D, Cordera R, Battistini M, et al. Evaluation of growth hormone administration in patients with chronic heart failure secondary to coronary artery disease. The American journal of cardiology. 1999;84(4):430-3. [PubMed][DOI: 10.1016/S0002-9149(99)00328-8 ]
  45. Beiras-Fernandez A, Kreth S, Weis F, Ledderose C, Pottinger T, Dieguez C, et al. Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides. 2010;31(12):2222-8. [PubMed][DOI: 10.1016/j.peptides.2010.08.019 ]
  46. Akanji AO, Suresh CG, Al-Radwan R, Fatania HR. Insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein (IGFBP)-3 levels in Arab subjects with coronary heart disease. Scandinavian journal of clinical and laboratory investigation. 2007;67(5):553-9. [PubMed][DOI: 10.1080/00365510601173153 ]
  47. Xin X, Ren AJ, Zheng X, Qin YW, Zhao XX, Yuan WJ, et al. Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexia. Peptides. 2009;30(12):2281-5. [PubMed][DOI: 10.1016/j.peptides.2009.07.026 ]
  48. Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation. 2001;104(17):2034-8. [PubMed][DOI: 10.1161/hc4201.097836 ]
  49. Anker SD, Volterrani M, Pflaum CD, Strasburger CJ, Osterziel KJ, Doehner W, et al. Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone. Journal of the American College of Cardiology. 2001;38(2):443-52. [PubMed][DOI: 10.1016/S0735-1097(01)01385-7 ]
  50. Bach LA, Headey SJ, Norton RS. IGF-binding proteins--the pieces are falling into place. Trends in endocrinology and metabolism: TEM. 2005;16(5):228-34. [PubMed]
  51. Grogaard HK, Seljeflot I, Lunde K, Solheim S, Aakhus S, Forfang K, et al. Cell treatment after acute myocardial infarction prevents early decline in circulating IGF-1. Scand Cardiovasc J. 2010;44(5):267-72. [PubMed][DOI: 10.3109/14017431.2010.490949 ]
  52. Broglio F, Benso A, Arvat E, Aimaretti G, Gottero C, Granata R, et al. Normal IGF-I and enhanced IGFBP-3 response to very low rhGH dose in patients with dilated cardiomyopathy. J Endocrinol Invest. 2000;23(8):520-5. [PubMed]
  53. Lauszus FF. The clinical significance of IGF-I in maternal serum during pregnancy in type 1 diabetes. Current diabetes reviews. 2007;3(3):194-7. [PubMed][DOI: 10.2174/157339907781368922 ]
  54. Ezzat VA, Duncan ER, Wheatcroft SB, Kearney MT. The role of IGF-I and its binding proteins in the development of type 2 diabetes and cardiovascular disease. Diabetes, obesity & metabolism. 2008;10(3):198-211. [PubMed][DOI: 10.1111/j.1463-1326.2007.00709.x ]
  55. Bienertova-Vasku JA, Spinarova L, Bienert P, Vasku A. Association between variants in the genes for leptin, leptin receptor, and proopiomelanocortin with chronic heart failure in the Czech population. Heart Vessels. 2009;24(2):131-7. [PubMed][DOI: 10.1007/s00380-008-1090-5 ]
  56. Lieb W, Sullivan LM, Harris TB, Roubenoff R, Benjamin EJ, Levy D, et al. Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals. Diabetes Care. 2009;32(4):612-6. [PubMed][DOI: 10.2337/dc08-1596]