Synthetic GHRH Peptide Agonist Reverses Heart Failure Features in a Mouse Model of Cardiometabolic HFpEF | Research

The takeaway

The synthetic growth hormone-releasing hormone agonist MR-356 reversed cardiac hypertrophy, fibrosis, diastolic dysfunction, and pulmonary congestion in a mouse model of cardiometabolic heart failure with preserved ejection fraction.

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End-diastolic pressure and pressure-volume relationship were normalized by MR-356 treatment in HFpEF mice

What the researchers found

MR-356, a synthetic GHRH agonist, reversed multiple hallmarks of HFpEF in the cardiometabolic mouse model:

- Reduced cardiac hypertrophy (heart thickening) and fibrosis (scarring)

- Reversed capillary rarefaction (loss of small blood vessels)

- Reduced pulmonary congestion

- Improved diastolic function — end-diastolic pressure and the end-diastolic pressure-volume relationship were reset to control levels

- Improved global longitudinal strain (GLS) and exercise capacity

- Normalized elevated pro-BNP, iNOS, and VEGF-A expression, indicating reduced myocardial stress and metabolic inflammation

Why it matters

HFpEF accounts for roughly half of all heart failure cases and is one of the biggest unmet needs in cardiovascular medicine — there are essentially no disease-modifying therapies. The cardiometabolic phenotype (driven by obesity and metabolic dysfunction) is particularly common. Finding a peptide that reverses multiple features of this condition in a rigorous animal model is a significant preclinical advance that could lead to human trials.

How the study worked

C57BL6N mice were fed a high-fat diet combined with the nitric oxide synthase inhibitor L-NAME for 9 weeks to induce cardiometabolic HFpEF. After 5 weeks of disease induction, mice were randomized to receive daily injections of MR-356 or placebo for 4 weeks. Control mice received neither disease induction nor treatment. Cardiac function was assessed with rigorous hemodynamic tools including pressure-volume measurements, echocardiography, and exercise testing. Tissue analysis evaluated hypertrophy, fibrosis, capillary density, and molecular markers.

What this study cannot tell us

This is a mouse study using a specific diet-induced model of HFpEF, which may not fully capture the complexity of human HFpEF. The treatment period was only 4 weeks, and long-term effects are unknown. The sample size is not specified in the abstract. Whether the benefits persist after treatment cessation was not tested. Human pharmacokinetics and tolerability of MR-356 may differ from the mouse model.

How to read the evidence

This is a randomized, controlled animal study using rigorous hemodynamic assessment tools. While the methodology is strong for a preclinical study, these are mouse results that have not yet been replicated in humans.

When this study was published

Published in 2023, this represents current preclinical research on GHRH agonists for heart failure applications.

The bigger picture

GHRH agonists like MR-356 and MR-409 have previously shown benefits in models of heart failure with reduced ejection fraction (HFrEF). This study extends those findings to the more treatment-resistant HFpEF phenotype. The broad effects — on inflammation, fibrosis, vascular remodeling, and cardiac mechanics — suggest GHRH agonists may address the multi-factorial pathophysiology of HFpEF in ways that single-target drugs cannot. This positions GHRH peptide agonists as a potentially unique therapeutic class for cardiovascular disease.

Questions still open

Will MR-356 show similar efficacy in human HFpEF patients, given the more complex and heterogeneous nature of the disease in humans?
How do the cardiac benefits of GHRH agonists compare to emerging HFpEF treatments like SGLT2 inhibitors?
What is the optimal duration and dosing of GHRH agonist therapy for sustained cardiac benefit?

Common questions

What is HFpEF and why is it so hard to treat?

Heart failure with preserved ejection fraction (HFpEF) is a condition where the heart pumps normally but becomes stiff and can't fill properly. It accounts for about half of all heart failure cases and is often driven by obesity, diabetes, and aging. Unlike other forms of heart failure, almost no medications have been shown to significantly improve outcomes in HFpEF, making it one of the biggest unmet needs in cardiology.

How does a growth hormone-releasing hormone agonist help the heart?

GHRH agonists like MR-356 activate receptors found on heart cells, triggering protective effects that go beyond just stimulating growth hormone release. In this study, MR-356 reduced inflammation, reversed scarring and thickening of the heart muscle, restored small blood vessels, and improved the heart's ability to relax and fill — essentially addressing multiple disease mechanisms simultaneously.

Read the original research

Efficacy of a growth hormone-releasing hormone agonist in a murine model of cardiometabolic heart failure with preserved ejection fraction.

American journal of physiology. Heart and circulatory physiology, 324(6), H739-H750

View on PubMed ↗Publisher’s paper ↗

Citation

Kanashiro-Takeuchi, Rosemeire M; Takeuchi, Lauro M; Dulce, Raul A; Kazmierczak, Katarzyna; Balkan, Wayne; Cai, Renzhi; Sha, Wei; Schally, Andrew V; Hare, Joshua M. (2023). Efficacy of a growth hormone-releasing hormone agonist in a murine model of cardiometabolic heart failure with preserved ejection fraction.. American journal of physiology. Heart and circulatory physiology, 324(6), H739-H750. https://doi.org/10.1152/ajpheart.00601.2022