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Contributed by Andrew V. Schally, December 4, 2020 (sent for review September 23, 2020; reviewed by Wilson Colucci and Lior Gepstein)
Significance
This randomized, blinded study used rigorous hemodynamic tools to test the efficacy of a synthetic growth hormone-releasing hormone agonist (GHRH‐A) on the restoration of diastolic function in a large animal model of chronic kidney disease (CKD)-induced heart failure with preserved ejection fraction (HFpEF). CKD was produced in Yorkshire swine by performing a 5/6 nephrectomy via catheter-based renal artery embolization. HFpEF was evident at 12 wk postembolization. Daily injection of GHRH-A improved cardiac diastolic hemodynamics, including end-diastolic pressure, end-diastolic pressure–volume ratio, and stroke work, compared to placebo. Development of this swine model and therapeutic approach has important implications because of the high prevalence of CKD-induced HFpEF and cardiorenal syndromes, lack of effective therapies, and few large-animal models available for investigation.
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.
- cardiorenal syndrome
- chronic kidney disease
- heart failure with preserved ejection fraction
- large animal model
Footnotes
- ↵1To whom correspondence may be addressed. Email: andrew.schally{at}va.gov or jhare{at}med.miami.edu.
Author contributions: A.C.R., W.B., I.H.S., and J.M.H. designed research; A.C.R., L.L.B., A.S., V.F., J.R., M.R., R.A.D., L.M.T., R.M.K.-T., and A.C.B.A.W. performed research; A.V.S. contributed new reagents/analytic tools; A.C.R., L.L.B., A.S., V.F., J.R., D.T., R.A.D., L.M.T., R.M.K.-T., P.B., and A.C.B.A.W. analyzed data; and A.C.R., L.L.B., R.A.D., R.M.K.-T., W.B., I.H.S., and J.M.H. wrote the paper.
Reviewers: W.C., Boston University School of Medicine; and L.G., Technion–Israel Institute of Technology.
Competing interest statement: A.V.S and J.M.H. are listed as co-inventors on patents on GHRH analogs, which were assigned to the University of Miami and Veterans Affairs Department. J.M.H. previously owned equity in Biscayne Pharmaceuticals, licensee of intellectual property used in this study. Biscayne Pharmaceuticals did not provide funding for this study. J.M.H. is the chief scientific officer, a compensated consultant, and advisory board member for Longeveron and holds equity in Longeveron. J.M.H. is also the co-inventor of intellectual property licensed to Longeveron. Longeveron did not play a role in the design, conduct, or funding of the study. J.M.H.’s relationships are reported to the University of Miami, and an appropriate management plan is in place. I.H.S. contributed to this manuscript in her personal capacity. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2019835118/-/DCSupplemental.
Data Availability.
All study data are included in the article and SI Appendix.
Published under the PNAS license.
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Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction
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