Ghrelin Derangements in Idiopathic Dilated Cardiomyopathy: Impact of Myocardial Disease Duration and Left Ventricular Ejection Fraction

Aleksova, Aneta; Beltrami, Antonio Paolo; Bevilacqua, Elisa; Padoan, Laura; Santon, Daniela; Biondi, Federico; Barbati, Giulia; Stenner, Elisabetta; Cappellari, Gianluca Gortan; Barazzoni, Rocco; Ziberna, Fabiana; Zwas, Donna R.; Avraham, Yosefa; Agostoni, Piergiuseppe; Not, Tarcisio; Livi, Ugolino; Sinagra, Gianfranco

doi:10.3390/jcm8081152

Cited by 8 publications

(23 citation statements)

References 39 publications

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“…Moreover, the GHSR is abnormally expressed in cardiac pathology; increased expression has been demonstrated in the myocardium of patients with chronic heart failure and decreased expression in patients with end-stage cardiomyopathy. 41,48 Related to these findings, ghrelin administration has been shown to have several therapeutic effects in cardiac disease including improving cardiac function in models of chronic heart failure. 33 As such, there is growing interest in developing ghrelin analogues for the purpose of imaging the biological processes related to cardiac GHSR.…”

Section: Clinical Relevance Of the Ghsr Expression And Ghrelin Secretionmentioning

confidence: 97%

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

Childs

Luyt

2020

Mol Imaging

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The growth hormone secretagogue receptor 1a (GHSR), also called the ghrelin receptor, is a G protein-coupled receptor known to play an important metabolic role in the regulation of various physiological processes, including energy expenditure, growth hormone secretion, and cell proliferation. This receptor has been implicated in numerous health issues including obesity, gastrointestinal disorders, type II diabetes, and regulation of body weight in patients with Prader-Willi syndrome, and there has been growing interest in studying its mechanism of behavior to unlock further applications of GHSR-targeted therapeutics. In addition, the GHSR is expressed in various types of cancer including prostate, breast, and testicular cancers, while aberrant expression has been reported in cardiac disease. Targeted molecular imaging of the GHSR could provide insights into its role in biological processes related to these disease states. Over the past decade, imaging probes targeting this receptor have been discovered for the imaging modalities PET, SPECT, and optical imaging. High-affinity analogues of ghrelin, the endogenous ligand for the GHSR, as well as small molecule inhibitors have been developed and evaluated both in vitro and in pre-clinical models. This review provides a comprehensive overview of the molecular imaging agents targeting the GHSR reported to the end of 2019.

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Section: Clinical Relevance Of the Ghsr Expression And Ghrelin Secretionmentioning

confidence: 97%

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

Childs

Luyt

2020

Mol Imaging

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“…We have previously shown that GHSR and ghrelin are positively correlated in tissue samples from patients with end-stage HF and are correlated negatively with LVEF. 11 Results from other studies also indicate changes in the dynamics of the ghrelin-GHSR axis in end-stage HF 10 and dilated cardiomyopathy, 12 suggesting this cardioprotective ghrelin-GHSR system is abnormally upregulated when there is injury or stress to the heart. 11 Our present results also show a positive correlation between ghrelin and GHSR in patients with HD, but this time in the absence of a decrease in LVEF.…”

Section: Discussionmentioning

confidence: 97%

“…In contrast, one study has reported decreased GHSR in tissue from patients with dilated cardiomyopathy, which negatively correlated with left ventricular (LV) ejection fraction (LVEF). 12 We 13 and others 14 have shown that tissue GHSR also decreased in mouse models of diabetic cardiomyopathy, suggesting that the dynamics of the myocardial ghrelin-GHSR axis might differ in earlier stages of myocardial decompensation compared with end-stage HF.…”

mentioning

confidence: 89%

Regional Differences in the Ghrelin-Growth Hormone Secretagogue Receptor Signalling System in Human Heart Disease

et al. 2021

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Background The hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR) are expressed in myocardium. GHSR binding activates signalling pathways coupled to cardiomyocyte survival and contractility. These properties have made the ghrelin-GHSR axis a candidate for a biomarker of cardiac function. The dynamics of ghrelin-GHSR are altered significantly in late stages of heart failure (HF) and cardiomyopathy, when left ventricular (LV) function is failing. We examined the relationship of GHSR with ghrelin in cardiac tissue from patients with valvular disease with no detectable changes in LV function. Methods Biopsy samples from the left ventricle and left atrium were obtained from 25 patients with valvular disease (of whom 13 also had coronary artery disease) and preserved LV ejection fraction, and compared to control samples obtained via autopsy. Using quantitative confocal fluorescence microscopy, levels of GHSR were determined using [Dpr 3 (n-octanoyl),Lys 19 (sulfo-Cy5)]ghrelin(1-19), and immunofluorescence determined ghrelin, the heart failure marker natriuretic peptide type-B (BNP), and contractility marker sarcoplasmic reticulum ATPase pump (SERCA2a). Results A positive correlation between GHSR and ghrelin was apparent in only diseased tissue. Ghrelin and BNP significantly correlated in the left ventricle and strongly colocalized to the same intracellular compartment in diseased and control tissue. GHSR, ghrelin, and BNP all strongly and significantly correlated with SERCA2a in the left ventricle of diseased tissue only. Conclusions Our results suggest that the dynamics of the myocardial ghrelin-GHSR axis is altered in cardiovascular disease in the absence of measurable changes in heart function, and might accompany a regional shift in endocrine programming.

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“…This hypothesis is supported by findings that ghrelin is higher in patients with more recent diagnoses when compared with patients with prolonged dilated cardiomyopathy (DCM). 28 Ghrelin levels are elevated in response to negative energy balances in elderly AHF patients, to reverse metabolic alterations in HF. Itoh et al observed increased ghrelin levels in underweight Figure 4 Kaplan-Meier curves of AHF event risks according to models with dual addition of log ghrelin and log NT-proBNP.…”

Section: Discussionmentioning

confidence: 99%

<p>The Additional Prognostic Value of Ghrelin for Mortality and Readmission in Elderly Patients with Acute Heart Failure</p>

Yuan¹,

Huang²,

Deng³

et al. 2020

CIA

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Purpose: To evaluate the prognostic value of ghrelin, a growth hormone-releasing peptide, for mortality and readmission in elderly patients with acute heart failure (AHF). Patients and Methods: We measured plasma ghrelin and pro B-type natriuretic peptide (NT-proBNP) levels upon emergency admission in 241 prospectively recruited elderly AHF patients (61.0% men). The outcomes were all-cause mortality and/or readmission due to heart failure (HF). Multivariate Cox proportional hazards regression analyses were used to evaluate the prognostic value of ghrelin. Discrimination, calibration, and reclassification indices were compared between models, with or without ghrelin. Results: During 1.2 years of follow-up, we observed 90 events (57 deaths and 33 readmissions due to HF). Plasma ghrelin levels were significantly elevated in elderly AHF patients, when compared to healthy control subjects (P < 0.001). Patients with events had significantly higher baseline ghrelin levels, when compared to those without (P < 0.001). Ghrelin levels were positively correlated with NT-proBNP levels and HF severity, whereas they were negatively correlated with nutritional status (all P < 0.05). Log transformed ghrelin levels were independently associated with AHF events (hazard ratio = 2.64, 95% confidence interval = 1.11-6.25, P = 0.028). The incorporation of ghrelin into the reference model, or reference with the NT-proBNP model, both improved C-statistics (from 0.742-0.780 and 0.836-0.857; P = 0.074 and 0.044, respectively), resulting in an improvement in net reclassification index (14.42% and 10.45%, P = 0.020 and 0.025, respectively), and integrated discrimination index (5.64% and 3.60%, both P < 0.001). Patients who displayed the above NT-proBNP and ghrelin median levels had a markedly higher risk of AHF adverse events (P < 0.001). Conclusion: Plasma ghrelin is an independent predictor of adverse events in elderly AHF patients. Ghrelin may provide additional value to clinical parameters or NT-proBNP for prognostic risk stratification in AHF.

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Ghrelin Derangements in Idiopathic Dilated Cardiomyopathy: Impact of Myocardial Disease Duration and Left Ventricular Ejection Fraction

Cited by 8 publications

References 39 publications

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

A Decade’s Progress in the Development of Molecular Imaging Agents Targeting the Growth Hormone Secretagogue Receptor

Regional Differences in the Ghrelin-Growth Hormone Secretagogue Receptor Signalling System in Human Heart Disease

<p>The Additional Prognostic Value of Ghrelin for Mortality and Readmission in Elderly Patients with Acute Heart Failure</p>

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