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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere2019835118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number4
DOIs
StatePublished - Jan 26 2021
Externally publishedYes

Keywords

  • Cardiorenal syndrome
  • Chronic kidney disease
  • Ejection fraction
  • Heart failure with preserved
  • Large animal model

ASJC Scopus subject areas

  • General

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