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

Abstract

25Heart failure with preserved ejection fraction (HFpEF) is characterized by a myocardium 26 with impaired relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing 27 prevalence of HFpEF, no effective therapies have emerged. Here we show that a potent 28 synthetic agonist of growth hormone-releasing hormone (GHRH-A) both prevents and reverses 29 the HFpEF phenotype generated in mice through continuous infusion of angiotensin-II (Ang-II). 30Animals treated with Ang-II had diastolic dysfunction, and isolated cardiomyocytes (ex vivo) 31 exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein 32 phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice 33 with HFpEF. The GHRH-A MR-356 prevented the development of the pathological phenotype 34 and reversed the phenotype in vivo and ex vivo in mice with established HFpEF. Taken together 35 these findings indicate that the GHRH receptor signaling pathway represents a new molecular 36 target to counteract HFpEF-associated cardiomyocytye dysfunction by targeting myofilament 37 phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH 38 agonists may provide a novel therapeutic approach to management of HFpEF syndrome. 39 40 41 42 Heart failure (HF) remains a leading cause of death worldwide and is associated with two 43 general clinical variants -heart failure with reduced ejection fraction (HFrEF), characterized by 44 systolic dysfunction, and heart failure with preserved ejection fraction (HFpEF), predominantly 45 due to diastolic dysfunction 1-3 . HFpEF accounts for ~50% of HF cases, a proportion that is 46 predicted to increase at about 1% per year relative to HFrEF 4, 5 . Whereas there are numerous 47 approved and guideline supported drugs for HFrEF, there are no approved therapies targeting 48 HFpEF, and numerous clinical trials with several classes of drugs have failed to produce clinical 49 benefits 6-10 . The HFpEF syndrome is characterized by endothelial dysfunction, hypertension, 50 impaired relaxation and contractile reserve, ventricular stiffening and fibrosis 2, 11, 12 . The 51 underlying molecular mechanisms of HFpEF are poorly understood due to its diverse etiology, 52 which in most cases involves multi-organ pathological conditions 13-15 . Importantly, current 53 therapeutic strategies fail to stop the progression of HFpEF 6, 8, 16-18 , creating a healthcare crisis 54 due to the unmet therapeutic need for HFpEF patients 19, 20 . 55 The development of new potent synthetic growth hormone-releasing hormone agonists 56 (GHRH-As) and their application in different models of myocardial injury (either ischemic 21-25 57 or non-ischemic 26 ) demonstrates the effectiveness of myocardial GHRH receptors (GHRHRs) 58 activation to reduce fibrosis or hypertrophy, respectively, and improve cardiac performance 22-26 . 59 The signaling of GHRHR extends beyond the hypothalamic-pituitary axis 27 as the GHRHRs are 60 present on cardiomyocytes 22, 23 ...

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

“…GHRH-A reparative effects on the myocardium in the setting of HFpEF likely occur through multiple mechanisms (28), including antiapoptotic effects via inhibition of ERK1/2 and PI3K/ Akt signaling associated with elevated Bcl-2 and reduced Bax:Bcl-2 ratio (14, 17), stimulation of cardiac progenitor proliferation (14,29), inhibition of hypertrophy, including Gq signaling and downstream pathways (30), and reduced inflammation, specifically plasma levels of IL-2, IL-6, and TNF-α, reduced expression of profibrotic pathway genes (14), and better organized collagen deposition (14). In a mouse model of angiotensin II-induced HFpEF, GHRH-A inhibited cardiomyocyte sarcomere and contractile dysfunction, preventing Ca 2+ leak from the SR and improving sarcomere relaxation and calcium handling (18). A substantial benefit of GHRH-A on the restoration of the diastolic cardiac function was demonstrated in the treated animals of this study, including EDP (ventricular preload) and end-diastolic/pressure-volume ratio (EDP/EDV, a measure of passive chamber stiffness).…”

“…The GHRH-A, MR-409, improved diastolic strain and reduced myocardial scar in a swine large-animal model with subacute ICM (12). Notably, in a murine HFpEF model using chronic administration of angiotensin II, GHRH-A prevented impairment of cardiomyocyte contractile function and relaxation and development of HFpEF features, including LV hypertrophy, collagen deposition, and diastolic dysfunction compared to placebo (18). Here, we developed a large-animal model of HFpEF using swine with CKD-induced HFpEF, a model that faithfully recapitulated the hemodynamic characteristics observed in humans, to test the hypothesis that GHRH-A ameliorates cardiac diastolic dysfunction.…”

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

“…HFpEF likely occur through multiple mechanisms 15 , including anti-apoptotic effects via inhibition of ERK1/2 and PI3K/Akt signaling associated with elevated Blc-2 and reduced Bax:Bcl-2 6 , stimulation of cardiac progenitor proliferation 6,16 , inhibition of hypertrophy, including Gq signaling and downstream pathways 17 , reduced inflammation, a major HFpEF-characteristic, specifically plasma levels of IL-2, IL-6 and TNF-α 6 , reduced expression of pro-fibrotic pathways genes 6 , and better organized collagen deposition 6 . In a mouse model of HFpEF, GHRH-A inhibited cardiomyocyte sarcomere and contractile dysfunction, preventing Ca 2+ leak from the sarcoplasmic reticulum and improving sarcomere relaxation and calcium handling 9 . The anti-arrhythmogenic effect, independent of the scar reduction seen in GH therapy 18 , was also seen with this GHRH-analogue, a poorly understood effect.…”

“…GHRH-A (MR-409) also improved diastolic strain and reduced myocardial scar in a swine large animal model with subacute ICM 8 . Notably, in a HFpEF murine model using chronic administration of angiotensin, GHRH-A prevented impairment of cardiomyocyte contractile function and relaxation and development of HFpEF features, including LV hypertrophy, collagen deposition, and diastolic dysfunction, compared to the placebo 9 . In this study, we used a swine large animal model of CKD-induced HFpEF that displays the characteristics observed in humans to test the hypothesis that GHRH-A ameliorates the cardiac diastolic dysfunction.…”