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

Abstract

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.

• Authors: Angela C Rieger, Luiza L Bagno, Alessandro Salerno, Victoria Florea, Jose Rodriguez, Marcos Rosado, Darren Turner, Raul A Dulce, Lauro M Takeuchi, Rosemeire M Kanashiro-Takeuchi, Peter Buchwald, Amarylis C B A Wanschel, Wayne Balkan, Ivonne H Schulman, Andrew V Schally, Joshua M Hare
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 4 (01 26 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33468654 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cardiotonic Agents
• Connectin
• N-Me-Tyr1,D-Ala2,Asn8,Arg29-NHCH3-JI-38
• Peptide Fragments
• Protein Isoforms
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• Sermorelin
• Growth Hormone-Releasing Hormone
• Creatinine
• Calcium

Topics

• Animals
• Blood Urea Nitrogen
• Calcium (metabolism)
• Cardiotonic Agents (pharmacology)
• Connectin (genetics, metabolism)
• Creatinine (blood)
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Growth Hormone-Releasing Hormone (agonists, genetics, metabolism)
• Heart Failure (drug therapy, etiology, genetics, pathology)
• Myocytes, Cardiac (drug effects, metabolism)
• Natriuretic Peptide, Brain (blood, genetics)
• Nephrectomy (methods)
• Peptide Fragments (blood, genetics)
• Protein Isoforms (genetics, metabolism)
• Renal Insufficiency, Chronic (complications, drug therapy, genetics, pathology)
• Sermorelin (analogs & derivatives, pharmacology)
• Stroke Volume (physiology)
• Swine