Scholarly article on topic 'Somatotropic and cardio-protective effects of ghrelin in experimental models of heart failure: A systematic review'

Somatotropic and cardio-protective effects of ghrelin in experimental models of heart failure: A systematic review Academic research paper on "Basic medicine"

0
0
Share paper
OECD Field of science
Keywords
{""}

Academic research paper on topic "Somatotropic and cardio-protective effects of ghrelin in experimental models of heart failure: A systematic review"

Somatotropic and cardio-protective effects of ghrelin in experimental models of heart failure: A systematic review

Mahalaqua Nazli Khatib1, Dilip Gode2, Padam Simkhada3, Kingsley Agho4, Shilpa Gaidhane5, Deepak Saxena6, Unnikrishnan B7, Yogesh Raut8, Umesh Kawalkar9, Abhay Gaidhane10, Quazi Syed Zahiruddin11

'Associate Professor, Department of Physiology, 5Associate Professor, Department of Medicine, JNMC, DMIMS, Wardha, 2Vice Chancellor, DMIMS, Wardha, Maharashtra, 3Senior Lecturer, School of Health and Related Research, University of Sheffield, UK, 4Senior Lecturer in Biostatistics, School of Science and Health, The University ofWestern Sydney, Australia, 6Associate Professor, IIPH, Gandhinagar, Gujarat, 'Professor and Head, Department of Community Medicine, Kasturba Medical College (Manipal University), Mangalore, Karnataka, 'Assistant Professor, Department of P.S.M., S.R.T.R. Govt. Medical College, Ambajogai, Maharashtra, 8Lecturer, Statistician, '"Associate Dean (International Health), ''Associate Dean (Global Health), Professor, Department of Community Medicine, JNMC, DMIMS, Wardha, Maharashtra, India

ABSTRACT

Background: Ghrelin was initially recognized as an endogenous ligand of growth hormone secretagogue receptor and was implicated in the regulation of food intake, and promoting weight gain. Ghrelin has been shown to improve cardiac function in patients suffering from heart failure (HF) though various mechanisms. The aim of the review is to summarize the main findings in this field, with the purpose of promoting further studies on the role of ghrelin on the cardiovascular system. Materials and Methods: All publications describing trials, systematic reviews, metaanalyses and review papers published within 1999-2014 of ghrelin in animal models of HF were sought through electronic and manual searches. Results: The literature searches identified 126 references and ten trials meeting the inclusion criteria were included in this review. All studies were carried out on male rats and experimental model of HF. Ghrelin has been shown to reduce mortality, increase appetite and body weight, and was found to improve the cardiac function parameters. Review found deficient information about adverse effects of ghrelin. Ghrelin exerts cardioprotective effects through modulation of sympathetic nervous system, inhibiting autophagy, antiinflammatory effects and protection against ischemia/reperfusion injury. Conclusion: Ghrelin seems to have a beneficial effect in rat models of HF and can offer an effective therapeutic target for improving outcome in HF.

Key words: Ghrelin, growth hormone secretagogue receptor, heart failure, isoprenaline, doxorubicin

Introduction

Background

The ultimate outcome of most of the cardiovascular diseases is chronic heart failure (CHF) and it is a major cause of morbidity and mortality in patients with cardiovascular diseases.[1] Ghrelin, a peptide of 28 amino acid polypeptide, was first reported in 1999 by Kojima in rat and human stomachs.[2] Ghrelin, was initially recognized as an endogenous ligand of growth hormone

Access this article online

Quick Response Code: Website: www.atmph.org

HjiasiE aJvSI

DOI: 10.4103/1755-6783.145008

secretagogue receptor (GHS-R) and was implicated in the regulation of food intake, and promoting weight gain.[2-7]

Ghrelin also has a role in modulation of gastrointestinal, cardiovascular, pulmonary and immune functions, cell proliferation/apoptosis.[8] There is a widespread distribution of ghrelin and its receptors in the cardiovascular tissues. The protective effects of ghrelin on heart are mediated through direct effects on the heart and blood vessel and through. Its growth-hormone-releasing effect. Cardioprotective effects of ghrelin have been demonstrated on heart failure (HF) models and exploratory human clinical studies.[9-13] Elevated levels of ghrelin have been found in patients with HF.[14] Various cardioprotective effects of ghrelin have been reported which includes reduction of peripheral vascular resistance,[15,16] improvement in myocardial contractility and antiinflammatory effects.[17] Clinical studies have reported that exogenous administration of ghrelin decreases muscle wasting,

Correspondence:

Prof. Quazi Syed Zahiruddin, Associate Dean (Global Health) and Professor, Department of Community Medicine, JNMC, Datta Meghe Institute of Medical Sciences, Sawangi Meghe, Wardha, Maharashtra, India. E-mail: zahirquazi@gmail.com

improves exercise capacity, improves left ventricular (LV) and endothelial function, increase myocardial contractility, dilate peripheral blood vessels, constricts the coronary arteries, reduces blood pressure, inhibits cardiomyocyte apoptosis, inhibit sympathetic nerve activity (SNA) and protects from HF induced by myocardial infarction.[8,18-22] So also, ghrelin may have other cardiovascular protective effects such as prevention of atherosclerosis as well as protection from ischemia and reperfusion injury.[18,19,23,24] Importantly, administration of ghrelin has been demonstrated to improve the cardiac function and prognosis in patients suffering from end-stage CHF.[13] In vitro, ghrelin decreases inotropism[13,14] and lusitropism.[14] Ghrelin administration also benefits the patients suffering from cardiac cachexia in CHF by inducing a positive energy balance.[25]

Thus, ghrelin seems to exert cardioprotective effects through its broadspectrum effects and the researches points that ghrelin can be a new therapy for HF and other cardiovascular diseases. However, exact effects of ghrelin on the cardiovascular system are inconclusive at present. The purpose of this review is to comprehensively appraise the current literature regarding effectiveness of ghrelin on weight gain and cardiovascular outcomes in experimental rat models of HF and to provide molecular insights that corroborate physiological cardiovascular protection by ghrelin. The aim of the review is to summarize the main findings in this field, with the purpose of promoting further researches on the role of ghrelin on cardiovascular system.

Criteria for considering studies of this review Types of studies

Randomized controlled trials (RCTs) and nonrandomized studies which evaluated the effects of ghrelin in experimental rat models of CHF. Studies published only in abstract forms or nonpeer reviewed journals were excluded.

Types of participants

Trials on rat models of HF were included. Types of interventions

Studies were included in which experimental intervention was done with any ghrelin at any dose, any analog, any route, administered as single agents/combination therapies and in fixed/stepped/titrated doses.

Types of outcome measures

Effects on mortality, food intake, weight gain, lean body mass, expression of myocardial proteins and cardiovascular effects (heart rate [HR], mean arterial

pressure, systemic vascular resistance, mean right atrial pressure, cardiac output, stroke volume, ejection fraction, LVdP/dt max, LVdP/dt min, LV end-diastolic pressure, LV end-systolic pressure, LV fractional shortening and shortening velocity).

Search methods for identification of studies Electronic searches

All publications describing controlled trials of ghrelin in rat models of HF were sought through electronic searches on Cochrane Central Register of Controlled Trials on Cochrane Library, MEDLINE (1999 to May 2014), EMBASE (1999 to May 2014), CINAHL (1999 to May 2014), AMED (1999 to May 2014). Digital dissertations. Conference proceedings were searched on Web of Science. Additional studies were located in Health Technology Assessment and Database of Abstracts of Reviews of Effects. Bibliographies of all papers were searched for further trials. No restrictions regarding language of publication were imposed. Search was focused on randomized and controlled trials, systematic reviews, meta-analyses and review papers published within 1999-2014. To avoid missing of studies in search strategy, consideration was given to spelling of terms used in different countries. If any data were found insufficient, authors were contacted through E-mail. Book chapters and editorials were also scanned. Manufacturers of ghrelin preparations experts and authors on the subject were contacted through emails and asked to contribute published and unpublished material. Hand searches were conducted for journals and conference proceedings.

Data collection

Two authors independently assessed all potentially relevant trials according to prespecified selection criteria with an emphasis on selecting RCTs and nonrandomized trials. References identified by electronic search strategy were screened by title and abstract to determine eligibility for inclusion in this systematic review and studies that appeared irrelevant were discarded. Full text of potentially eligible studies were retrieved (and translated into English where required) and two reviewers then independently determined study eligibility using a standardized inclusion form. Details of the studies were extracted and included in characteristics of studies table [Table 1]. Any disagreement about eligibility of study was resolved by discussion. Furthermore, a third reviewer did an independent review to settle any difference of opinion between two primary reviewers.

Table 1 : Characteristics of included studies

Characteristics Chang et al.l26] Nagaya eta!.m Akashi eta/.1321 Lenk et al. (2012)1311 Palus et o/.1301 Schwenke eto/.1271 Zhang eto/.1181 Mao eto/.20131281 Mao etal. 20141291 Pei etal. 20141331

Country China Japan Germany Germany Germany New Zealand China Japan Japan China

Study Male Sprague- Male Wistar Male Sprague- Male Sprague- Male Sprague- Male Sprague- Male Sprague- Ghrelin- Male C57BL/6J Male C57BL/6J

population Dawley rats rats Dawley rats Dawley rats Dawley rats Dawley rats Dawley rats knockout mice mice mice

Weight: 200-250 g Weight: 200- Weight: 215- Weight: 215-230 Weight: 280-340 g Weight: 250±10g Age: 14-16 weeks Age: 10-12 weeks

Age: 10-12 weeks 240 g 235 g g Age: 8 weeks Age: 1-2 day old

Method of Myocardial injury Ligation of the Ligation of the Ligation of the Ligation of the Ligation of the Myocardial Ligation of the Ligation of left Intraperitoneal

induction of induced by ISO coronary artery coronary artery coronary artery coronary artery coronary artery injury induced left coronary coronary artery injection of

CHF by ISO artery doxorubicin

Sample size 47 47 54 121 121 36 36 58 36

Intervention 5 treatment 4 groups 4 groups 7 groups (n= 18 7groups (/7=18 3 groups 4 treatment 3 groups 3 groups 4 groups

groups groups Sham placebo: Sham (n= 15) each) each) Sham groups Hexarelin Sham (n= 10) Control (n=9)

Control (n=7) 13 Placebo (n=18) Placebo Placebo Ml + saline Control (n=9) Ghrelin Vehicle (n=24) DOX (/7=11)

Ghrelin (n=7) Sham-ghrelin: GL (n=17) BIM 28125 at 50* BIM 28125 at 50* Ml + ghrelin ISO (n=11) Vehicle Hexarelin (n=24) DOX + DAG

ISO group (n=11) 13 GH (n=19) BIM 28125 at 500* BIM 28125 at 500* ISO + G (n=9) (n=10)

ISO + GL group CHF-placebo: BIM 28131 at 50* BIM 28131 at 50* ISO + metformin DOX + DAG +

(n=11) 15 BIM 28131 at 500* BIM 28131 at 500* (n=7) [D-Lys3]-GHRP-6

ISO + GH group CHF-ghrelin: 16 Human ghrelin at Human ghrelin (n=6)

(n=11) 50* at 50*

Human ghrelin at Human ghrelin at

500* 500*

Placebo/ Control: 0.9% Sham operation Sham operation Sham operation of Sham operation Sham operation of Control: 0.9% Sham operation Sham operation of Intraperitoneal

control NaCI (bid, sc) of thoracotomy of thoracotomy thoracotomy and of thoracotomy thoracotomy and NaCI of thoracotomy thoracotomy and injection of

and cardiac and cardiac cardiac exposure and cardiac cardiac exposure and cardiac cardiac exposure saline

exposure exposure without ligation of exposure without without ligation exposure without ligation

without ligation without ligation the coronary artery ligation of the of the coronary without ligation of the coronary

of the coronary of the coronary coronary artery artery of the coronary artery

artery artery artery

Dose Control:0.9%NaCI 100 (xg/kg bid Sham Two different Two different 150 (xg/kg one Control: Saline-2 Hexarelin: 400 Sham: Saline Control: Saline

(bid) or saline in Placebo concentrations concentrations bolus dose of mL/kg/d od for nmol/kg/d, sc Vehicle: Saline DOX: Saline

Ghrelin:Ghrelin of both CHF and GL: 50 nmol/ of 50 and 500 of 50 and 500 ghrelin within 30 2 days Ghrelin:400 Hexarelin: 600 |xg/ DOX + DAG: 100

lOnmol/kg/d (bid) sham-operated kg/day nmol/kg/day of nmol/kg/day of min of the infarct ISO:ISO-20 mg/ nmol/kg/d mouse (xg/kg bw bid of

ISO group: ISO of 40 rats GH: 100 nmol/ two analogues of two analogues procedure kg/d,od for 2 DAG

mg-kg~'-d-1 (bid) kg/day tid ghrelin BIM 28125 of ghrelin BIM days DOX + DAG +

ISO+ GL group: ISO and BIM 28131 28125 and BIM ISO + ghrelin: [D-Lys3]-GHRP-6:

+ ghrelin of 1 nmol/ versus placebo 28131 versus Ghrelin-10-8 3.75-135 mg/

kg/d (bid) placebo mol/kg/d, bid kg of [D-Lys3]-

ISO + GH group: ISO + metformin: GHRP-6 followed

ISO + ghrelin of 10 metformin-250 by 100 (xg/kg bw

nmol/kg/d (bid) mg/kg/d bid) of DAG bid

Route of Subcutaneously Subcutaneously Subcutaneously Subcutaneously Subcutaneously Subcutaneously Subcutaneously Subcutaneously Oral gavage Intraperitoneal

administration

Trial period 2 days 21 days 28 days 28 days Before surgery, 14 days 2 days 15 days 14 days 04 days

on day 28 and on

day 56

A mean of 3

measurements per

animals was used

*nmole/kg/d, ISO: lsoprenaline;GL: Low dosage of ghrelin;GH: High dosage of ghrelin; DOX: Doxorubicin; DOX + DAG: Doxorubicin treated with desacyl ghrelin; DOX + DAG + [D-Lys3]-GHRP-6: Doxorubicin treated with desacyl ghrelin in the presence of [D-Lys3]-GHRP-6) which is a GHS-R 1a antagonist; CHF: Chronic heart failure; ISO: Isoproterenol; Ml: Myocardial infarction; GHRP: Growth hormone-releasing peptide

Results

Description of studies

Literature search identified 126 references that described 57 potentially relevant trials, including two unpublished studies and one conference abstract. Twenty-six trials have been carried out in animal such as rats, mice, pigs and rabbits. There were only three human clinical trials evaluating the role of ghrelin in patients with CHF. Ten trials met the inclusion criteria and were included in this review. Three trials were carried out each in Germany, Japan and China and one trial New Zealand. Sample size ranged from 36 to 121 rats with a total of 382 rats recruited in ten studies. Six studies were done on Sprague-Dawley rats, one on Wistar rats, two on C57BL/6J rats and one on Ghrelin-knockout mice. All studies were done on male rats weighing between 200 and 340 g and experimental model of HF was created by ligation of coronary artery except in three studies. In two studies HF was induced by isoprenaline and in one study, it was induced by doxorubicin. Controls were subjected to sham operation of a thoracotomy and cardiac exposure without ligation of coronary artery or by injection of normal saline. Eight trials administered ghrelin subcutaneously and one trial each administered ghrelin orally and intraperitoneally. Trial periods lasted for as less as 2 days and as long as 28 days. In all trials, ghrelin was not used as an adjunct to conventional treatment for HF. Two trials compared two analogs of ghrelin BIM-28125 and BIM-28131 in two different doses. Review found deficient information about effect of ghrelin on adverse effects of ghrelin needed in recommendation for adoption of this therapy in

treating CHF. Characteristics of included studies are as shown in Table 1.

Results of search Effect on mortality

Mortality was reported in four studies. The mortality was significantly lower after administration of ghrelin[26,27] and hexarelin group.[28] However; mortality did not differ between a single oral dose of hexarelin and vehicle group.[29] Increasing the dose of ghrelin from 1 nmol/kg/d to 10 nmol/kg/d significantly reduces the mortality in HF [Table 2].[26]

Effect on food intake [Table 2]

In Sandra's study[30] food intake per day got lesser during both the treatment periods (treatment period 1: day 28-41, treatment period 2: 42-56). During day 28-41, food intake increased in all high dose of human ghrelin as well as with both the analogues BIM-28131 and BIM-28125 and also with BIM-28131 in low dose when compared to placebo. In second treatment period (from day 42); higher food intake was seen in all the group, which were on ghrelin all groups given ghrelin compounds had a higher food intake than placebo.

Effects of ghrelin on body weight and somatotropic functions Effect on body weight

Body weight was reported in three studies. In Nagaya's study, the greater increase in body weights was seen in HF rats with ghrelin than with placebo.[9] In Sandra's study; after 2 weeks of administration of compounds of ghrelin or placebo, rats that received low dose BIM-28131 or high dose human ghrelin, BIM 28131

Table 2: Effects of ghrelin on mortality and food intake

Outcome Chang et al.12

Lenk et al. (2012)1311 Palus et al.°

Schwenke et al.[271 Zhang et al.[181 Mao et al. 2014[291

Mortality C group: 0% G group: 0% ISO: 45% ISO + GL: 18 % (P>0.05 vs. ISO group) ISO + GH: 0 % (0/11) (P<0.05)

Food intake

MI + saline: 50% Control: 0% Vehicle: 50 ± 7% MI + ghrelin: 25% ISO: 18.18% Hexarelin: 54 ± (P = 0.286) ISO + G: 0% 8% (P = 0.9 (NS))

metformin: 0%

Placebo

BIM 28131 at 50*: 6.26±0.07% Human ghrelin at 50*: 5.72 ± 10.1%, (P < 0.001) BIM 28125 at 50*: 5.80 ± 0.07%, (P < 0.001) during the first but not the second treatment period

BIM 28131 at 500* for 1st and 2nd T/t period:

6.66 ± 0.13% and 5.49 ± 0.1

Human ghrelin at 500*: 6.35 ± 0.12%, P < 0.01

and 5.17 ± 0.13%, P < 0.01

BIM-28131 at 500*: 6.39 ± 0.11%, (P < 0.01

and 5.28 ± 0.08, P < 0.05)

*nmole/kg/d, C group: Control group; G group: Ghrelin alone group; ISO group: Isoprenaline alone group; ISO + GL group: Isoprenaline + low dosage of ghrelin treated group; ISO + GH group: Isoprenaline + high dosage of ghrelin treated group; MI: Myocardial infarction; NS: Not significant

or BIM 28125 demonstrated a significantly higher weight gain than rats that were on placebo and also rats with sham surgery. Insignificant differences in weight gain were seen with a higher dose of BIM 28131 as compared to the low dose.[30] In Mao's study, body weight was lower in hexalin group as compared to Sham group [Table 3].[29]

Effect on body composition (fat: Lean gain) Tibial length and gastrocnemius muscle weight were significantly increased after administration of ghrelin as compared with those given placebo.[9] In Sandra's study, tibial length was similar between the groups and significantly different than the respective placebo group.[30] LV weight/tibial length was significantly higher in CHF rats on ghrelin than in CHF rats on placebo while right ventricle (RV) weight/tibial length was significantly higher in CHF rats treated with placebo than CHF rats treated with ghrelin.[9] The ratio of weight of the gastrocnemius muscle to tibial length and muscle protein content to tibial length were higher significantly in sham rats on ghrelin than in CHF rats on ghrelin.[9] The septum weights were higher in all compounds of ghrelin, except for low dose.[30]

Effect on expression of muscle proteins Expression of MAFbx was down-regulated to normal levels by low dose BIM-28125 and high dose BIM-28131 while expression of MuRF-1 was reduced to sham levels by all ghrelin compounds except high dose BIM-28125 group.[30] After induction of HF in rats, expression of myostatin protein in the gastrocnemius muscle was significantly down regulated in animals administered with human ghrelin or ghrelin analogs in low and high doses (except high dose BIM-28125) when compared to rats on placebo.[31] Plasma ET-1 levels were reduced significantly in ghrelin group when compared to the ISO group, while the expression of myocardial ET-1 mRNA was significantly higher in ISO group when compared with the control group [Table 4].[27]

Cardiovascular effects Heart rate

Lin's study showed that administration with ISO increased HR significantly as compared to the control group, which was not improved by administration of ghrelin.[26] In Daryl's and Nagaya's study, there was an insignificant difference in HR between ghrelin and other groups.[9,27] Effect of chronic administration of ghrelin on HR regulation is similar that observed during acute ghrelin infusion.[34] Higher doses of ghrelin lead to more reductions in HR when compared to lower doses [Table 5].[26,32]

Mean arterial pressure and LVEDP

Treatment with ghrelin caused insignificant decrease in mean arterial pressure[9,26,27] and LVEDP.[9,26,27] Ghrelin in higher doses causes greater reductions in blood pressure though the difference is insignificant.[32]

Other cardiovascular effects

Systemic vascular resistance[9,27] and mean right atrial pressure were significantly and insignificantly lower respectively[9] in HF rats on ghrelin than on placebo. Values of cardiac output,[9,27-29] stroke volume,[9,27] ejection fraction,[27-30] LVdP/dtmax[9,26,27] was higher in CHF rats treated with ghrelin/hexarelin than given placebo.[9,26,27] LV diastolic dimension was decreased in Nagaya's study,[9] significantly increased in Akashi's study[32] and unaltered in Pei's study.[33] Diastolic thickness of noninfarcted posterior wall,[9] LV fractional shortening19,29! and shortening velocity[9] was higher in CHF on ghrelin than on placebo. Decrease in HR, end-diastolic dimension, ejection fraction and left ventricle fractional shortening after exposure to doxorubicin was not seen in mice treated with desacyl ghrelin.[33]

Discussion

In this review we have compiled the results of eight studies assessing the effect of ghrelin on somatotrophic function, expression of muscle proteins and cardiovascular system on rat experimental model of HF. Ghrelin reduces mortality, promotes weight gain and plays a crucial role in protecting heart function.19,15,26,27,30,33 Ghrelin acts through the GHS-R 1a which is expressed in many areas of the central nervous system (CNS), where it arbitrates appetite and adiposity.[35] Ghrelin is the only known peripheral orexigenic hormone, which plays a short term regulatory role in energy balance by inducing appetite and a long-term regulatory role in energy balance by promoting weight gain and adiposity.[36]

Cardiovascular effects

The high expression of ghrelin and GHSR 1a in the heart, and large vessels provide evidence of its cardiac actions. Administration of ghrelin improves cardiac performance in rat models of HF, as indicated by increases in cardiac output, stroke volume, LV dP/ dtmax, and LV fractional shortening and by increases in fractional cell shortening and shortening velocity of isolated myocytes. Activating GHS-R 1a might be beneficial for cardioprotection, although other mechanism may also be involved.[29] The myocardium of CHF patients shows an impaired production of ghrelin that causes a compensatory increase in the expression of GHS-R 1a.[37] Elevated levels of ghrelin have been

Table 3: Effects of ghrelin on somatotropic function and body weight

Outcome

Nagaya et al.19

Palus et alP

Mao et al. 2014[29]

Body weight (g) Mean ± SD

Sham-placebo BL: 285±12

AT: 315±13 (P<0.05 vs. BL)

Sham-ghrelin

BL: 291±17

AT: 338±16 (P<0.05 vs. respective placebo group and P<0.05 vs. BL)

CHF-placebo

BL: 241±24 (P<0.05 vs. respective sham group) AT: 249±33 (P<0.05 vs. respective sham group) CHF-ghrelin

BL: 245±23 (P<0.05 vs. respective sham group)

AT: 270±32 (P<0.05 vs. respective sham group, P<0.05 vs.

respective placebo group and P<0.05 vs. BL)

Body composition (fat: lean gain)

Tibial length (mm) Mean±SD

Weight of

gastrocnemius muscle (mg)

LV weight/tibial length

RV weight/tibial length

Sham-placebo: 40.9±1.3

Sham-ghrelin: 42.6±1.4 (P<0.05 vs. respective placebo group)

CHF-placebo: 40.3±1.9

CHF-ghrelin: 42.3±2.0 (P<0.05 vs. respective placebo group)

Sham: 504.4±32.9

CHF placebo: 470.9±38.7 (P<0.05)

Sham-placebo: 13.9±1.0

Sham-ghrelin: 15.4±1.2 (P<0.05 vs. respective placebo group)

CHF-placebo: 13.7±1.5 CHF-ghrelin: 14.5±1.6 Values are: Mean±SD in mg/mm

Sham-placebo: 4.2±0.4 Sham-ghrelin: 4.5±0.6

CHF-placebo: 8.9±1.5 (P<0.05 vs. respective sham group) CHF-ghrelin: 6.0±1.5 (P<0.05 vs. respective sham group, P<0.05 vs. respective placebo group) Values are: Mean±SD in mg/mm

Ratios of gastrocnemius muscle weight to tibial length (mg/mm) Mean±SD

Ratios of muscle protein content to tibial length (mg/mm) Mean±SD

Septum weights

Heart weights

Sham placebo: 357.8±7.8

Placebo: 339.4±7.5

BIM-28125 at 50*: 348.16.4

BIM-28131 at 50* : 386.9±8.8 (P<0.001 vs.

placebo)

Human ghrelin at 50*: 352.2±5.4 BIM-28125 at 500*: 376.6±9.5 (P<0.01) BIM-28131 at 500*: 392.3±8.9 (P<0.001 vs. placebo)

Human ghrelin at 500*: 370.9±10.7 (P<0.05)

Placebo: Gained no fat, but lean mass

BIM-28131 at 50*: 0.90±0.07

BIM-28131 at 500*: 0.76±0.07

BIM-28125 at 500*: 68±0.12

Human ghrelin at 500*: 0.48±0.05 (P=0.0001)

Sham placebo: 39.4±0.04

Placebo: 38.0±0.03

BIM-28125 at 50*: 38.7±0.15

BIM-28131at 50*: 39.3±0.04

Human ghrelin at 50*: 38.9±0.03

BIM-28125 at 500*: 38.0±0.05

BIM-28131 at 500*: 38.3±0.03

Human ghrelin at 500*: 38.8±0.03

Sham placebo: 132±4 Placebo: 132±3 BIM-28125 at 50*: 125±5 BIM-28131at 50*: 127±4 Human ghrelin at 50*: 123±4 BIM-28125 at 500*: 135±5 BIM-28131 at 500*: 127±4 Hum ghrelin at 500*: 126±5 Values are: Mean±SEM in mg/cm Sham placebo: 47±2 Placebo: 98±6 BIM-28125 at 50*: 85±7 BIM-28131at 50*: 99±8 Hum ghrelin at 50*: 95±7 BIM-28125 at 500*: 101±9 BIM-28131 at 500*: 100±8 Hum ghrelin at 500*: 94±7 Values are: mean±SEM in mg/cm

Lower in hexalin group versus sham group (P<0.05) No significant difference in 2 MI groups

Sham-placebo: 41±1 Sham-ghrelin: 43±2

CHF-placebo: 28±5 (P<0.05 vs. respective sham group) CHF-ghrelin: 35±4 (P<0.05 vs. respective sham group. P<0.05 vs. respective placebo group) Sham-placebo: 6.8±0.2 Sham-ghrelin: 7.3±0.3

CHF-placebo: 4.5±0.8 (P<0.05 vs. respective sham group) CHF-ghrelin: 5.7±0.4 (P<0.05 vs. respective sham group, P<0.05 vs. respective placebo group)

The septum weights were higher in all compounds of ghrelin except BIM-28125 at 50*. P=0.073 versus placebo or sham animals

*nmole/kg/d, BL: Baseline; AT: After treatment; MI: Myocardial infarction; SEM: Standard error of mean; SD: Standard deviation; CHF: Chronic heart failure

Table 4: Effects of ghrelin on expression of MAFbx, MuRF-1, myostatin mRNA, myostatin protein, mRNA for genes associated with ventricular remodeling, plasma ET-1 level, myocardial ET-1 mRNA expression in myocardium

Outcome

Chang et al.[2

Lenk et al. (2012)[31]

Palus et al.[30]

Schwenke et al.[27]

Expression of MAFbx and MuRF-1

Expression of myostatin mRNA in the gastrocnemius muscle after induction of heart failure

Expression of myostatin protein in the gastrocnemius muscle after induction of heart failure

Expression of mRNA for genes associated with ventricular remodeling Plasma ET-1 level

Myocardial ET-1 mRNA expression in myocardium

BIM-28125 at 500*: 0.033±0.007 BIM-28131 at 500*: 0.038±0.008 versus CHF placebo-treated animals: 0.106±0.015, P<0.05 SOA: 0.041±0.008 versus CHF placebo group: 0.106±0.015, P<0.05

BIM-28125 at 50*: 0.72±0.06, P<0.001 BIM-281231 at 50: 1.22±0.12, P<0.01 BIM-28131 at 500*: 1.26±0.13, P<0.05 Ghrelin at 50*: 1.15±0.12, P<0.01 Ghrelin at 500*: 1.24±0.17, P<0.05 Note: All versus CHF placebo 2.03±0.2 arbitrary units

ISO group: Significantly increased by 58% versus control group (P<0.01) Ghrelin L and H: Reduced by 24% and 30% compared with ISO group (P<0.01) ISO group: Significantly increased by 2.8-fold compared with control group (P<0.01)

MAFbx expression was lowered to normal levels by 500* BIM-28131 and 50* BIM-28125 MuRF-1 was down-regulated to sham levels by all ghrelin compounds except 500* BIM-28125 group

BIM 28125 at 50* and BIM-28131 at 500*: MAFbx expression was lowered to normal levels Except for BIM-28125 at 500*, with all compounds of ghrelin, MuRF-1 was down-regulated to sham levels

MI + saline:

overexpression (P=0.005) MI + ghrelin: overexpression (P=0.01)

*nmol/kg/day; MI: Myocardial infarction; ISO: Isoprenaline; ET-1: Endothelin-1; CHF: Chronic heart failure; SOA: Sham-Operated Animals

found in patients with HF, but the mechanism for this beneficial cardiovascular effect is not yet clear.[38] It can be a protective compensatory mechanism for reduced body weight in order to enhance appetite and weight gain[39] and/or can be a compensatory response to reduced cardiac output and maladaptive neural and hormonal features of HF.[38] As ghrelin acts as on GHS-R, there is a probability that it is increased in response to GH resistance observed in patients suffering from HF.[14] It has been seen that patients of HF are resistant to the appetite-stimulating effects of ghrelin and that after heart transplantation, there is a decrease in the level of ghrelin, and there is an increase in caloric intake suggesting that ghrelin resistance is resolved after heart transplantation.[14] These states reflects cachexia in HF and weight gain after heart transplantation.[38]

Modulation of sympathetic nervous system

Ghrelin mediates cardioprotective effects by

modulating cardiac autonomic nervous activity.[16]

However; the precise mechanisms by which ghrelin regulates sympathetic activity are still unclear and needs further investigation. Peripheral ghrelin may act on GHS-R Ia at the cardiac vagal nerve ending, which goes to the nucleus of tractus solitarius and suppresses the renal SNA.[29,34] Ghrelin can also act directly on the CNS and alter the sensitivity of CNS to other hormones participating in the regulation of sympathetic activity.[40] Endogenously secreted ghrelin reduces mortality, improves heart function and protects the heart from arrhythmias partly by inhibiting sympathetic nervous activity[28] Administration of ghrelin has been shown to lower plasma levels of epinephrine and dopamine and shifts the balance of autonomic nervous activity toward parasympathetic nervous activity.[29]

Insignificant bradycardia after chronic administration of ghrelin[9,26,27] suggests that ghrelin offers a beneficial role in the long-term regulation of HR. The role of ghrelin in pathophysiology of hypertension has been recognized

Table 5: Effect on cardiovascular functions

Outcome Chang eta/.1261 Nagaya eta/.191 Akashiefa/.1321 Palus et a/.1301 Schwenke eta/.1271 Zhang eta/.1181 Maoeta/.20141291 Pei eto/.20141331

Heart rate Cgroup:387±17 Lower in CHF rats treated Sham:319.9±6.5 Sham:383±13 Control:394±13 Control

GH: 394±11 with ghrelin than those (P< 0.05) Ml + saline: 387±15 ISO:429±9 Pre:474±10

ISO:422±6 (P<0.05) given placebo Placebo: 309.0±5.9 Ml + ghrelin:383±14 (P< 0.05) Post:483±11

ISO + GL:422±17 P=NS in each group (P< 0.05) P=NS ISO + G:419±6 DOX

ISO + GH:401 ±9 GL:326.2±4.9 Pre:506±10

GH:318.3±5.6 Post: 304±25 (P< 0.05 vs.

DOX + DAG

Pre: 509±8

Post:428±28

DOX + DAG + [D-Lys3]-

GHRP-6

Pre:471±18

Post:415±33

Mean Control: 82±4 Lower in CHF rats on Sham: 112.0±3.6 No significant difference in Control:89±3

arterial GH:84±4 ghrelin than on placebo Placebo: 101.1 ±2.3 mean ABP between all groups ISO:90±5

pressure ISO:82±5 P=NS GL: 103.3±2.7 of rats (mean ABP range 85-91 ISO + G:89±4

(mmHg) ISO + GL:80±7 Sham-rats:-8; P<0.05 GH:99.5±2.3 mmHg)

ISO + GH:82±5 CHF rats:-7; P<0.05

P=NS between various

groups

SVR Significantly lower in CHF Sham: 0.41 ±0.03 Ml + ghrelin: LVEDV,

rats treated with ghrelin Placebo:0.52±0.03 contractility, SV,and CO were

than in those given placebo GL:0.55±0.03 all significantly improved

Ghrelin decreased SVR in GH:0.53±0.02 compared with Ml + saline rats

sham,CHF (-12%,-13%,

P<0.05, respectively)

Mean Lower in CHF rats treated

right atrial with ghrelin than those

pressure given placebo;P=NS

CO (|xl/min) Significantly higher in CHF Sham: 149.0±11.8 Sham:56.2±1.5 ml/min Sham: 1130±404

rats treated with ghrelin Placebo: 94.8±6.0 Ml + saline:96 36.8±2.6 ml/min. Vehicle: 486±270

than in those given placebo GL:96.6±6.2 Significant different from sham (P< 0.05 vs. sham)

GH:99.3±6.1 rats (P<0.01) Hexalin:

Ml + ghrelin:48.8±4 ml/min 1094±390 (P<0.05

Significant difference between vs. sham)

Ml + saline and Ml + ghrelin

rats (P< 0.05)

SV (nl) Significantly higher in CHF Sham: 148±7 |xl,P=NS Sham: 18±4 1

rats treated with ghrelin Ml + saline:96±8(xl.Significant Vehicle: 13±3

than in those given placebo different from sham rats (P<0.01) Hexalin: 16±5

Ml + ghrelin: 126±6 significant

difference between Ml + saline

and Ml + ghrelin rats (P<0.05)

Table 5: (Continued)

Outcome Chang eta/.1261 Nagaya etal.t9] Akashieto/.1321 Palus et al.1301 Schwenke et al.1271 Zhang eta/.1181 Maoeta/.20141291 Pei et ai. 20141331

Ejection Sham:63.3±1.1 (P< 0.05) A small, Sham:57.9±3.8 Sham: 76 ±7 Control

fraction (%) Placebo: 29.9± 1.9 improvement Ml + saline: 27.5±2.6 Vehicle: 24 ±4 Pre:87.0±1.3

GL:29.0±2.2 of BIM-28131 significantly different from (P< 0.05 vs. sham) Post: 89.3± 1.6

GH:28.9±1.7 (P=0.127) sham rats (P<0.01) Hexalin:32±7 DOX

Ml + ghrelin:43.2±1.3 (P< 0.05 vs. sham Pre: 86.2±1.3

significantly different from and vehicle) Post:65.8±4.3*

sham rats (P<0.05) DOX + DAG

Significant difference between Pre:87.6±1.8

Ml + saline and Ml + ghrelin Post: 88.1 ±2.9

rats (P<0.01) DOX + DAG + [D-Lys3]-

GHRP-6

Pre: 90.4±1.7

Post:87.6±1.8

LVdP/ Control: 3381 ±172 Significantly higher in CHF Sham: 1466.4±49.9 Sham: 11.3 ±0.9 Control: Sham:7395±2638 1

dtmax GH:3197±282 rats with ghrelin than in Placebo: 1331.3±54.5 Ml + saline: 7.4±0.7 6794±114.3 Vehicle: 5117

ISO: 1761 ±183 (P<0.05) those given placebo GL: 1339.5±42.5 Significantly different from ISO:5469±259.2 ±2165

ISO + GL: 3664±266. P=NS in each group GH: 1273.9±43.3 sham rats (P=0.01) (P<0.01 vs. C) Hexalin:

P<0.01 versus ISO group Ml + ghrelin:9.4±0.7 (value in ISO + G: 2.2±0.6 5042±1516 (value

ISO + GH:4038±166. mmHg/ms) (P<0.01 vs. ISO) in mmHg/s)

P<0.01 versus ISO group (value in mmHg/ms)

(value in mmHg/s)

LVdP/dtmin Control: 2808±192 Significantly lower in CHF Sham: 1066.5±38.3 Sham:-7.6±0.8 Sham:7473±1870

(mmHg/ms) GH:3197±282 rats given ghrelin Placebo:907.2±41.1 Ml + saline:-5.4 ±0.5 Vehicle: 4846

ISO: 1750±179b GL:928.7±35.2 significantly different from ±2619 (P<0.05 vs.

ISO + GL:2741±327. GH:926.5±31.5 sham rats (P<0.05) sham)

P<0.01 versus ISO Ml + ghrelin:-5.8±0.2 Hexalin:

group 4598±1219

ISO + GH: 2657±231. (P<0.05 vs. sham)

P<0.01 versus ISO group (value in mmHg/s)

LVend- Control: 6±2 Significantly lower in CHF Sham:4.07±1.61 Control: 2.1 ±0.8 Sham: 11 ±6

diastolic GH:4±2 rats given ghrelin Ml + saline:6.22±1.26 ISO:8.5±1.8 Vehicle: 11 ±8

pressure ISO:24±6.P<0.01 P=NS in each group Ml + ghrelin:3.12±1.17. (P<0.01 vs. C) (P< 0.05 vs. sham)

(mmHg) versus control group Significant difference between ISO + G: 2.2±0.6 Hexalin: 10±6

ISO + GL:2±1.P<0.01 Ml + saline and Ml + ghrelin (P<0.01 vs. ISO) (P<0.05 vs.

versus ISO group rats (P< 0.05) sham and

ISO + GH:4±1.P<0.01 vehicle) (value in

versus ISO group mmHg/s)

LV end- Sham:113±14 Control:

systolic Ml + saline:254±18 significantly 124.1 ±2.8

pressure different from sham rats (P<0.01) ISO: 117.5±2.1

(mmHg) Ml + ghrelin: 165±4 significantly (P< 0.05)

different from sham rats (P<0.05) ISO + G: Significant difference between 125.1 ±3.9 Ml + saline and Ml + ghrelin rats (P<0.05) (P<0.01)

Table 5: (Continued)

Outcome Chang eta/.1261 Nagaya eta/.191 Akashi eta/.1321 Palus eta/.1301 Schwenke eta/.1271 Zhang cto/.1181 Mao etal. 20141291 Pei et at. 20141331

Diastolic Increased in both CHF and Sham: 1.69±0.08

thickness of sham ratsT/t with ghrelin Placebo: 1.55±0.08

noninfarcted GL: 1.46±0.07 (P<0.05 vs.

posterior sham and GH)

wall GH:1.67±0.07

LV diastolic Decreased in CHF rats T/t Sham:8.60±0.20 Control

dimension with ghrelin and increased Placebo: 10.81 ±0.24 Pre:0.30±0.01

in those given placebo. LV (P<0.001) Post:0.31±0.01

wall stresses in systole and GL: 10.79±0.20 (P<0.01) DOX

diastole were significantly GH: 11.14±0.21 (P<0.01) Pre:0.32±0.01

lower in CHF rats T/t with Post:0.26±0.01 (P<0.05

ghrelin than those given vs. pre)

placebo DOX + DAG

Pre:0.33±0.01

Post:0.30±0.01

DOX + DAG + [D-Lys3]-

GHRP-6

Pre:0.32±0.01

Post:0.30±0.01

LV fractional CHF ghrelin: 19±1% Sham: 39.1 ±1.1 (P< 0.05) Control:

shortening CHF placebo: 17±1%, Placebo: 15.5± 1.0 Pre:61.3±1.8<

(%) P< 0.05 GL: 14.4±1.2 Post:65.4±2.7

NS altered by each dose of GH: 14.7±1.0 DOX

ghrelin (99±3% for 1 pmol/ Pre:60.3±2.1

mL,97± 17% for 10 pmol/ Post: 37.7± 1.6 (P<0.05

mL,and 91 ±15% for 100 vs. pre)

pmol/mL) DOX + DAG

Pre:62.4±2.5

Post:64.2±4.0

DOX + DAG + [D-Lys3]-

GHRP-6

Pre:68.2±1.8

Post:62.7±2.6

Shortening In ghrelin-treated CHF rats A small,

velocity was significantly increased improvement

compared with that in CHF of BIM-28131

rats given placebo (278±14 in fractional

vs.213±10 |xm/s,P<0.001) shortening

(P=0.137)

CHF: Chronic heart failure; LV:Left ventricular; GH: High dosage of ghrelin; ISO:lsoprenaline;GL: Low dosage of ghrelin;NS:Not significant; SVR: Systemic vascular resistance; Ml: Myocardial infarction; ABP: Androgen-binding protein; LVEDV: Left ventricle end-systolic volumes; SV: Stroke volume; CO: Cardiac output; DOX: Doxorubicin; DAG: Desacyl ghrelin; GHRP: Growth hormone-releasing peptide

widely. Researches show that there is an inverse relation between the amount of circulating ghrelin and arterial stiffness and that circulating level of ghrelin increase after antihypertensive treatment.[23] These evidences suggest that ghrelin is actively involved in the pathophysiology of hypertension and is an independent determinant of stiffness of the arterial wall.[24] However; it has been observed that long-term hypotensive action of ghrelin mediated by the CNS is not as powerful as ghrelin's acute effect on binding protein (BP) regulation as it causes only a modest reduction of BP. This suggests that the effect of ghrelin in the long-term regulation of BP may be reduced by its orexigenic effect.[40]

to release antiinflammatory cytokine Interleukin-10 (IL-10) is independent of NF-kB pathway; administration of ghrelin also stimulates the p38 mitogen-activated protein kinases (p38 MAPK), involved in the regulation of release of IL-10 from macrophages.[17,48]

Protection against ischemia/reperfusion injury

Ghrelin is well-known as a potent activator of release

of growth hormone and as growth hormone is involved

in tissue regeneration and maintenance of integrity;

ghrelin also contributes to the processes of healing and

regeneration.

Inhibits autophagy

Amongst many causes of HF, a gradual decrease in the number of cardiomyocytes is one of the important contributing factors.[41,42] Studies have suggested that during CHF; cardiomyocyte apoptosis is one of the significant forms of cardiomyocyte loss and can be dangerous at low levels. [43,44] Therefore, limiting the loss of cardiomyocytes by preventing apoptosis may have implications for the treatment of HF. Ghrelin plays a cardioprotective role against cardiomyopathy through mechanisms that are independent of GHS-R. Ghrelin increases the size of cardiomyocytes, prevents the activation of cardiac fibrosis, reduces autophagy and prolongs their life.[8,33] It does this by inhibiting the reactive oxygen species and inducing mammalian or mechanistic target of rapamycin that functions in coordinating cell growth and proliferation and also regulates survival of cells.[45] Ghrelin protects the cardiomyocytes against apoptosis, and myocardial injury induced by endoplasmic reticulum stress (ERS) through a GHS-R 1a, Calmodulin-dependent protein kinase kinase (CaMKK) and AMP-activated protein kinase (AMPK) pathway.[18,40] Subcutaneous administration or preincubation of cardiomyocytes with ghrelin has been shown to stimulate the AMPK.[18,40,46] The AMPK on activation is known to inhibit cell proliferation and is involved in autophagy.[47] Preincubation of ghrelin also up regulates ERS markers and cytosine-cytosine-adenosine-adenosine-thymidine/enhancer-binding protein (C/EBP) homologous protein (CHOP). AMPK inhibitors blocks the antiapoptotic actions and ERS inhibitory effects of ghrelin on heart.[40] Ghrelin protects cardiomyocytes against hypoxic injury (induced by COCl2) by inducing autophagy, reducing the expression of NADPH oxidase 1, and increasing the expression and function of antioxidants.[22]

Antiinflammatory effects

Administration of ghrelin reduces nuclear factor-kB (NF-kB) activation and stimulates the macrophages

Ghrelin and hexarelin

Hexarelin; a synthetic analogue of ghrelin is superior to ghrelin in improving heart function which can be because of activation of GHS-R Ia and CD36.[28,29]

Conclusion

Ghrelin is endogenous peptide acting against cardiomyocyte damage. Ghrelin improves cardiac function in rat models of HF though various mechanisms such as modulation of sympathetic nervous system, inhibiting autophagy, antiinflammatory effects and protection against ischemia/reperfusion injury. Ghrelin protects cardiomyocytes against apoptosis induced by ERS through GHS-R1a/CaMKK/AMPK pathways. Ghrelin seems to offer an effective therapeutic target for improving cardiovascular outcomes in experimental models of HF and thus warrants further research.

Meta-analysis of the results was not done as the characteristics of animal models and adopted methodologies of the included studies were quite disparate to coalesce into a single statistical result. In addition, some trials were not randomized and in some trials Ghrelin was administered as a single dose or was administered for a short duration. Also, adverse events and long-term efficacy and safety of ghrelin administration were not available. However; we have explicitly described all the trials in the characteristics of studies table. Though we acknowledge these limitations, the overall data suggests a supporting view that experimental models of rat failure benefit from the effects of ghrelin and that ghrelin can be a tolerable and short-term therapeutic tool in the treatment of HF.

Implications for practice

Exogenous administration with ghrelin may serve as a novel therapeutic drug for various cardiovascular diseases.

Implications for research

Underlying mechanisms governing effect of ghrelin are unexplored. Effects of different analogs of ghrelin in different doses and different rotes warrant further research. Substantiation of hypothesis for the increase in SNA after ghrelin requires further research to study the cellular and molecular pathways involved. More high quality, large, multicentric, human trials are needed to assess the beneficial effects of ghrelin in patients suffering from HF.

References

1. Tsutsui H, Tsuchihashi-Makaya M, Kinugawa S, Goto D, Takeshita A, JCARE-GENERAL Investigators. Characteristics and outcomes of patients with heart failure in general practices and hospitals. Circ J 2007;71:449-54.

2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-60.

3. Akamizu T, Kangawa K. Ghrelin for cachexia. J Cachexia Sarcopenia Muscle 2010;1:169-76.

4. Costantini VJ, Vicentini E, Sabbatini FM, Valerio E, Lepore S, Tessari M, et al. GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs. Neuroendocrinology 2011;94:158-68.

5. Müller TD, Perez-Tilve D, Tong J, Pfluger PT, Tschöp MH. Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia. J Cachexia Sarcopenia Muscle 2010;1:159-67.

6. Oner-Iyidogan Y, Gurdol F, Kocak H, Oner P, Cetinalp-Demircan P, Caliskan Y, et al. Appetite-regulating hormones in chronic kidney disease patients. J Ren Nutr 2011;21:316-21.

7. Zhang L, Yagi M, Herzog H. The role of NPY and ghrelin in anorexia nervosa. Curr Pharm Des 2012;18:4766-78.

8. Zhang G, Yin X, Qi Y, Pendyala L, Chen J, Hou D, et al. Ghrelin and cardiovascular diseases. Curr Cardiol Rev 2010;6:62-70.

9. Nagaya N, Uematsu M, Kojima M, Ikeda Y, Yoshihara F, Shimizu W, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001;104:1430-5.

10. 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;105:431-5.

11. Nagaya N, Kangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure. Regul Pept 2003;114:71-7.

12. Nagaya N, Kangawa K. Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol 2003;3:146-51.

13. 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;110:3674-9.

14. Lund LH, Freda P, Williams JJ, LaManca JJ, LeJemtel TH, Mancini DM. Growth hormone resistance in severe heart failure resolves after cardiac transplantation. Eur J Heart Fail 2009;11:525-8.

15. Mao Y, Tokudome T, Otani K, Kishimoto I, Miyazato M, Kangawa K. Excessive sympathoactivation and deteriorated heart function after myocardial infarction in male ghrelin knockout mice. Endocrinology 2013;154:1854-63.

16. Soeki T, Niki T, Uematsu E, Bando S, Matsuura T, Kusunose K, et al. Ghrelin protects the heart against ischemia-induced arrhythmias by preserving connexin-43 protein. Heart Vessels 2013;28:795-801.

17. Waseem T, Duxbury M, Ito H, Ashley SW, Robinson MK. Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery 2008;143:334-42.

18. Zhang GG, Cai HQ, Li YH, Sui YB, Zhang JS, Chang JR, et al. Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase. Peptides 2013;48:156-65.

19. Zhao YT, Shao L, Yang HB, Li L, Teng LL. Effects of Ghrelin on hypertension and insulin resistance in fructose-fed rats. Zhonghua Yi Xue Za Zhi 2013;93:935-8.

20. Yano Y, Nakazato M, Toshinai K, Inokuchi T, Matsuda S, Hidaka T, et al. Circulating des-acyl ghrelin improves cardiovascular risk prediction in older hypertensive patients. Am J Hypertens 2014;27:727-33.

21. Yang D, Liu Z, Luo Q. Plasma ghrelin and pro-inflammatory markers in patients with obstructive sleep apnea and stable coronary heart disease. Med Sci Monit 2013;19:251-6.

22. Tong XX, Wu D, Wang X, Chen HL, Chen JX, Wang XX, et al. Ghrelin protects against cobalt chloride-induced hypoxic injury in cardiac H9c2 cells by inhibiting oxidative stress and inducing autophagy. Peptides 2012;38:217-27.

23. Meriç C, Aydogdu A, Tasçi I, Deniz F, Baysan O, Serdar M, et al. Effects of valsartan treatment on serum ghrelin level and left ventricular mass index in patients with untreated primary hypertension. Anadolu Kardiyol Derg 2014;14:234-8.

24. Zhao YT, Yang HB, Li L, Gao K, Li PF, Xie WW. Reciprocal relationship between plasma ghrelin level and arterial stiffness in hypertensive subjects. Clin Exp Pharmacol Physiol 2013;40:735-9.

25. Invernizzi M, Carda S, Cisari C, Società Italiana per lo Studio della Sarcopenia e della Disabilità Muscolo-Scheletrica (SISDIM). Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure. Aging Clin Exp Res 2014;26:341-51.

26. Chang L, Zhao J, Li GZ, Geng B, Pan CS, Qi YF, et al. Ghrelin protects myocardium from isoproterenol-induced injury in rats. Acta Pharmacol Sin 2004;25:1131-7.

27. Schwenke DO, Tokudome T, Kishimoto I, Horio T, Cragg PA, Shirai M, et al. One dose of ghrelin prevents the acute and sustained increase in cardiac sympathetic tone after myocardial infarction. Endocrinology 2012;153:2436-43.

28. Mao Y, Tokudome T, Kishimoto I, Otani K, Hosoda H, Nagai C, et al. Hexarelin treatment in male ghrelin knockout mice after myocardial infarction. Endocrinology 2013;154:3847-54.

29. Mao Y, Tokudome T, Kishimoto I, Otani K, Miyazato M, Kangawa K. One dose of oral hexarelin protects chronic cardiac function after myocardial infarction. Peptides 2014;56:156-62.

30. Palus S, Schur R, Akashi YJ, Bockmeyer B, Datta R, Halem H, et al. Ghrelin and its analogues, BIM-28131 and BIM-28125, improve body weight and regulate the expression of MuRF-1 and MAFbx in a rat heart failure model. PLoS One 2011;6:e26865.

31. Lenk K, Palus S, Schur R, Datta R, Dong J, Culler MD, et al. Effect of ghrelin and its analogues, BIM-28131 and BIM-28125, on the expression of myostatin in a rat heart failure model. J Cachexia Sarcopenia Muscle 2013;4:63-9.

32. 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. Int J Cardiol 2009;137:267-75.

33. Pei XM, Yung BY, Yip SP, Ying M, Benzie IF, Siu PM. Desacyl ghrelin prevents doxorubicin-induced myocardial fibrosis and apoptosis via the GHSR-independent pathway. Am J Physiol Endocrinol Metab 2014;306:E311-23.

34. Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M. Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 2002;40:694-9.

35. Heppner KM, Piechowski CL, Müller A, Ottaway N, Sisley S, Smiley DL, et al. Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors. Diabetes 2014;63:122-31.

36. Al Massadi O, Lear PV, Müller TD, Lopez M, Dieguez C, Tschop MH, et al. Review of Novel Aspects of the Regulation of Ghrelin Secretion. Curr Drug Metab 2014.

37. Beiras-Fernandez A, Kreth S, Weis F, Ledderose C, Pöttinger T, Dieguez C, et al. Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides 2010;31:2222-8.

38. Lund LH, Williams JJ, Freda P, LaManca JJ, LeJemtel TH, Mancini DM. Ghrelin resistance occurs in severe heart failure and resolves after heart transplantation. Eur J Heart Fail 2009;11:789-94.

39. Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001;145:669-73.

40. Freeman JN, do Carmo JM, Adi AH, da Silva AA. Chronic central ghrelin infusion reduces blood pressure and heart rate despite increasing appetite and promoting weight gain in normotensive and hypertensive rats. Peptides 2013;42:35-42.

41. Kang PM, Izumo S. Apoptosis and heart failure: A critical review of the literature. Circ Res 2000;86:1107-13.

42. Nishida K, Otsu K. Cell death in heart failure. Circ J 2008;72 Suppl A:A17-21.

43. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 2003;111:1497-504.

44. van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ. Myocyte apoptosis in heart failure. Cardiovasc Res 2005;67:21-9.

45. Zhang YJ, Duan Y, Zheng XF. Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 2011;16:325-31.

46. Xu X, Jhun BS, Ha CH, Jin ZG. Molecular mechanisms of ghrelin-mediated endothelial nitric oxide synthase activation. Endocrinology 2008;149:4183-92.

47. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011;13:1016-23.

48. Wang X, Wang XL, Chen HL, Wu D, Chen JX, Wang XX, et al. Ghrelin inhibits doxorubicin cardiotoxicity by inhibiting excessive autophagy through AMPK and p38-MAPK. Biochem Pharmacol 2014;88:334-50.

Cite this article as: Khatib MN, Gode D, Simkhada P, Agho K, Gaidhane S, Saxena D, et al. Somatotropic and cardioprotective effects of ghrelin in experimental models of heart failure: A systematic review. Ann Trop Med Public Health 2014;7:30-42. Source of Support: Nil, Conflict of Interest: None declared.

Copyright of Annals of Tropical Medicine & Public Health is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.