scholarly journals Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction

2021 ◽  
Vol 118 (4) ◽  
pp. e2019835118
Author(s):  
Angela C. Rieger ◽  
Luiza L. Bagno ◽  
Alessandro Salerno ◽  
Victoria Florea ◽  
Jose Rodriguez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Growth Hormone ◽  
Animal Model ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Large Animal Model ◽  
Large Animal ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction

Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs (n = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; n = 8; 30 µg/kg) or placebo (n = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP (P = 0.03), reduced EDP/EDV ratio (P = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca2+] transient amplitude (P = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio (P = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

scholarly journals Effectiveness of Growth Hormone–Releasing Hormone Agonists (GHRH-A) in Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction

2020 ◽  
Author(s):  
Angela C. Rieger ◽  
Luiza L Bagno ◽  
Alessandro Salerno ◽  
Victoria Florea ◽  
Jose Rodriguez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Growth Hormone ◽  
Animal Model ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Large Animal Model ◽  
Large Animal ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction

ABSTRACTBackgroundTherapies that improve morbidity and mortality in heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone releasing hormone analogues (GHRH-A) reverse fibrosis and improve cardiac function in ischemic and non-ischemic animal models. We tested the hypothesis that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large animal model.MethodsFemale Yorkshire pigs (n=16) underwent 5/6 nephrectomy via renal artery embolization, which induced HFpEF, and 12-weeks later received daily subcutaneous injections of GHRH-A (n=8) or placebo (n=8). Kidney function, renal and cardiac MRI, pressure-volume loops, and electrical stimulation were assessed at baseline, 12-weeks, and 16-18 weeks post-embolization.ResultsThe CKD model was confirmed by increased creatinine and BUN. HFpEF was demonstrated at 12 weeks by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickening, end-diastolic pressure (EDP), end-diastolic pressure-volume relationship (EDPVR), and tau. After 6 weeks of treatment, diastolic function improved in the GHRH-A group, evidenced by normalization of EDP (p=0.03) associated with improved diastolic compliance as measured by EDP/EDV ratio (p=0.018).ConclusionA beneficial effect of GHRH-A in diastolic function was observed in a CKD large animal model that manifests the characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.

Abstract 8: Effectiveness of Combination Allogeneic Stem Cells in a Novel Large Animal Model of Chronic Kidney Disease-induced Heart Failure With Preserved Ejection Fraction (HFpEF)

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Angela Castellanos Rieger ◽  
Bryon A Tompkins ◽  
Makoto Natsumeda ◽  
Victoria Florea ◽  
Kevin Collon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Animal Model ◽  
Cell Therapy ◽  
Renal Artery ◽  
Cardiorenal Syndrome ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction ◽  
Lv Mass

Background: Chronic Kidney Disease (CKD) is an independent risk factor for cardiovascular morbidity and mortality. Left ventricular (LV) hypertrophy and heart failure with preserved ejection fraction (HFpEF) are the primary manifestations of the cardiorenal syndrome in 60 to 80% of CKD patients. Therapies that improve morbidity and mortality in HFpEF are lacking. Stem cell therapy reduces fibrosis, increases neovascularization, and promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model. Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: allogeneic (allo-) MSC (10х10 6 ), allo-kidney c-kit + cells (c-kit; 10х10 6 ), combination (MSC+c-kit; 1:1 ratio [5х10 6 each]), or placebo (each n=5). Cell therapy was delivered via the patent renal artery. Kidney function, renal and cardiac MRI, and PV loops were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization. Results: The CKD model was confirmed by increased creatinine and BUN and decreased GFR. Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks (p=0.7). HFpEF was demonstrated at 4 weeks by increased LV mass (20.3%; p= 0.0001), wall thickening (p<0.008), EDP (p=0.01), EDPVR (p=0.005), and arterial elastance (p=0.03), with no change in EF. Diffuse intramyocardial fibrosis was evident in histological analysis and delayed enhancement MRI imaging. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). GFR significantly improved in the combination group (p=0.033). EDV increased in the placebo (p=0.009) and c-kit (p=0.004) groups. ESV increased most in the placebo group (7.14±1.62ml; p=0.022). EF, wall thickness, and LV mass did not differ between groups at 12 weeks. Conclusion: A CKD large animal model manifests the characteristics of HFpEF. Intra-renal artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the combination and MSC groups. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

scholarly journals Chronic low-intensity exercise attenuates cardiomyocyte contractile dysfunction and impaired adrenergic responsiveness in aortic-banded mini-swine

2018 ◽  
Vol 124 (4) ◽  
pp. 1034-1044 ◽  
Author(s):  
Jessica A. Hiemstra ◽  
Adam B. Veteto ◽  
Michelle D. Lambert ◽  
T. Dylan Olver ◽  
Brian S. Ferguson ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Pressure Overload ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction ◽  
Low Intensity ◽  
Low Intensity Exercise

Exercise improves clinical outcomes in patients diagnosed with heart failure with reduced ejection fraction (HFrEF), in part via beneficial effects on cardiomyocyte Ca2+ cycling during excitation-contraction coupling (ECC). However, limited data exist regarding the effects of exercise training on cardiomyocyte function in patients diagnosed with heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to investigate cardiomyocyte Ca2+ handling and contractile function following chronic low-intensity exercise training in aortic-banded miniature swine and test the hypothesis that low-intensity exercise improves cardiomyocyte function in a large animal model of pressure overload. Animals were divided into control (CON), aortic-banded sedentary (AB), and aortic-banded low-intensity trained (AB-LIT) groups. Left ventricular cardiomyocytes were electrically stimulated (0.5 Hz) to assess Ca2+ homeostasis (fura-2-AM) and unloaded shortening during ECC under conditions of baseline pacing and pacing with adrenergic stimulation using dobutamine (1 μM). Cardiomyocytes in AB animals exhibited depressed Ca2+ transient amplitude and cardiomyocyte shortening vs. CON under both conditions. Exercise training attenuated AB-induced decreases in cardiomyocyte Ca2+ transient amplitude but did not prevent impaired shortening vs. CON. With dobutamine, AB-LIT exhibited both Ca2+ transient and shortening amplitude similar to CON. Adrenergic sensitivity, assessed as the time to maximum inotropic response following dobutamine treatment, was depressed in the AB group but normal in AB-LIT animals. Taken together, our data suggest exercise training is beneficial for cardiomyocyte function via the effects on Ca2+ homeostasis and adrenergic sensitivity in a large animal model of pressure overload-induced heart failure. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show chronic low-intensity exercise training can prevent cardiomyocyte dysfunction and impaired adrenergic responsiveness in a translational large animal model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

scholarly journals Developing a Large Animal Model of Heart Failure with Preserved Ejection Fraction

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Charlotte Hamilton ◽  
Bindu George ◽  
Julia Shanks ◽  
Rohit Ramchandra
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Ejection Fraction ◽  
Large Animal Model ◽  
Large Animal ◽  
Preserved Ejection Fraction

A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction

2015 ◽  
Vol 309 (9) ◽  
pp. H1407-H1418 ◽  
Author(s):  
Michael Schwarzl ◽  
Nazha Hamdani ◽  
Sebastian Seiler ◽  
Alessio Alogna ◽  
Martin Manninger ◽  
...  
Keyword(s):  
Heart Failure ◽  
Animal Model ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Right Atrial ◽  
Large Animal Model ◽  
Large Animal ◽  
Atrial Pacing ◽  
Preserved Ejection Fraction ◽  
Lv Ejection Fraction

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs ( n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls ( n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

Abstract 56: Growth Hormone Releasing Hormone Improves Sarcomere Relaxation and Calcium Decline in Cardiomyocyte From a Mouse Model of Heart Failure With Preserved Ejection Fraction

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Raul A Dulce ◽  
Rosemeire M Kanashiro-Takeuchi ◽  
Lauro M Takeuchi ◽  
Wayne Balkan ◽  
Renzhi Cai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Mouse Model ◽  
Sarcomere Length ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Calcium Decline ◽  
Ghrh Receptor

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone (GHRH) agonists reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on cardiomyocytes is not known. We hypothesized that activation of GHRH receptor signaling improves impaired cardiomyocyte relaxation in a mouse model of HFpEF. C57BL6N mice (n=4-5) were implanted with a mini-osmotic pump to deliver angiotensin-II (Ang-II: 0.8 mg/kg/day) for 4 weeks and received daily injections of GHRH-Agonist (GHRH-A [MR-409]: 100 μg/kg) or vehicle (DMSO+propylene-glycol). Cardiomyocytes were isolated and calcium and sarcomere shortening assessed. Ang-II-treated cardiomyocytes exhibited reduced sarcomere length, indicating an inability to completely relax, despite lower resting calcium. These cardiomyocytes also exhibited impaired ability to contract with no changes in calcium transient amplitude, deficient relaxation and delayed calcium decay. MR-409 treatment restored resting calcium and resting sarcomere length; improved sarcomere shortening and completely abrogated Ang-II-induced delay in calcium decline and relaxation (see figure 1). Our findings demonstrate that chronic administration of Ang-II mediates structural and functional changes consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways prevents HFpEF-associated cardiomyocyte performance alterations.

scholarly journals Synthetic Growth Hormone-Releasing Hormone Agonist as Novel Treatment for Heart Failure with Preserved Ejection Fraction

2020 ◽  
Author(s):  
Raul A. Dulce ◽  
Rosemeire M. Kanashiro-Takeuchi ◽  
Lauro M. Takeuchi ◽  
Alessandro G. Salerno ◽  
Shathiyah Kulandavelu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Calcium Handling ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Releasing Hormone ◽  
Ghrh Receptor

AbstractObjectiveTo test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signaling pathway within the myocardium both prevents and reverses heart failure with preserved ejection fraction (HFpEF).BackgroundHFpEF is characterized by impaired myocardial relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing prevalence of HFpEF, no effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, hypertrophy and improve performance, independently of the growth-hormone axis.MethodsWe generated a HFpEF-like phenotype with continuous infusion of angiotensin-II (Ang-II) in CD1 mice. Mice were injected with either vehicle or a potent synthetic agonist of the growth hormone-releasing hormone, MR-356.ResultsAng-II treated animals had diastolic dysfunction, ventricular hypertrophy, and normal ejection fraction and isolated cardiomyocytes (ex vivo) exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice with HFpEF. MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo.ConclusionThese findings indicate that the GHRH receptor signaling pathway represents a new molecular target to counteract HFpEF-associated cardiomyocyte dysfunction by targeting myofilament phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH agonists may provide a novel therapeutic approach to management of the HFpEF syndrome.Condensed abstractHeart failure with preserved ejection fraction (HFpEF) is characterized by a remodeled myocardium conferring ventricular stiffness and diastolic dysfunction. There are no effective therapies. Agonists of growth hormone-releasing hormone (GHRH) receptors have beneficial effects on the heart. We hypothesize that activation of GHRH receptors suppresses this HFpEF phenotype. Treatment with a synthetic agonist of GHRH, prevented the development of the pathological phenotype in a murine model of HFpEF-induced by chronic angiotensin-II infusion. These findings indicate that activation of GHRH receptors represents a novel molecular strategy to counteract HFpEF-associated cardiomyocyte dysfunction and provide a potential approach to management of HFpEF syndrome.HighlightsA synthetic growth hormone-releasing hormone agonist (GHRH-A) prevents and reverses the pathological remodeling in a mouse model of HFpEF induced by infusion of low dose Ang II.GHRH-A improves intracellular calcium handling by reducing the sarcoplasmic reticulum calcium leakage and enhancing phospholamban phosphorylation.GHRH-A treatment prevents and reverses diastolic dysfunction by enhancing the rate of sarcomere re-lengthening.Activation of the GHRH receptor with the GHRH-A, MR-356, leads to targeting myofibrillar proteins and desensitizing myofilaments in response to calcium.

Abstract 397: Chronic Infusion of Growth Hormone Releasing Hormone Prevents Heart Failure with Preserved Ejection Fraction Phenotype Development in Murine Cardiomyocytes by Reducing Myofilament Sensitivity to Calcium

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Raul A Dulce ◽  
Rosemeire M Kanashiro-Takeuchi ◽  
Lauro M Takeuchi ◽  
Alessandro G Salerno ◽  
Wayne Balkan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Growth Hormone ◽  
Ejection Fraction ◽  
Sarcomere Length ◽  
Growth Hormone Releasing Hormone ◽  
Preserved Ejection Fraction ◽  
Ang Ii ◽  
Releasing Hormone ◽  
Ghrh Receptor ◽  
Cd1 Mice

Introduction: Heart failure with preserved ejection fraction (HFpEF) represents ~50% of heart failure cases and is characterized by impaired relaxation, ventricular stiffening and fibrosis. Growth hormone releasing hormone agonists (GHRH-A) reduce fibrosis in rat and swine models of ischemic myocardial injury. However, their effect on failing cardiomyocytes (CMs) is unknown. We hypothesized that activation of GHRH receptor signaling targets proteins associated with excitation-contraction coupling, reduces affinity of myofilaments for Ca 2+ and prevents the development of HFpEF. Methods: CD1 mice, implanted with mini-osmotic pump (Alzet) to deliver angiotensin-II (Ang-II) for 4 weeks, received daily injections of GHRH-A (MR-356; n=8) or vehicle (n=8). CMs were isolated and Ca 2+ and sarcomere length recorded. Expression and phosphorylation of Ca 2+ handling and sarcomeric proteins were assessed. Unmanipulated CD1 mice (n=7) acted as normal controls. Results: Ang-II-treated CMs exhibited reduced sarcomere length consistent with shorter cell length, indicating an inability to completely relax. These CMs also exhibited impaired contractility that correlated with reduced myosin binding protein C (cMyBPC) expression with no changes in phosphorylation. Response of [Ca 2+ ] transient amplitude to increasing pacing rate was depressed and Ca 2+ decay was delayed and associated with lower expression of SERCA2 and NCX1, increased SR Ca 2+ leak but no change in phospholamban phosphorylation (p-PLB) at Ser16. Slower sarcomere re-lengthening and reduced phospho-cTnI (p-cTnI) at Ser 23/24 were observed in HFpEF CMs. MR-356 treatment maintained resting sarcomere length as well as sarcomere shortening at control values, and completely abrogated Ang-II-induced delay in Ca 2+ decay and sarcomere relaxation. SR Ca 2+ leak was reduced. p-PLB was further enhanced by MR-356, and cMyBPC and p-cTnI were maintained at control levels. Conclusion: Our findings demonstrate that chronic administration of Ang-II mediates functional changes in CMs consistent with HFpEF and suggest that activation of the GHRH receptor signaling pathways desensitizes myofilaments and prevents HFpEF-associated alterations in Ca 2+ handling and dysfunctional CM relaxation.

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