Sermorelin analog MR-409 ameliorated chronic kidney disease-induced heart failure by improving diastolic function in pigs.
Background
Effective therapies for heart failure with preserved ejection fraction (HFpEF) are critically lacking. This condition is characterized by the heart muscle contracting normally but the ventricles not relaxing properly, leading to inadequate filling. Chronic kidney disease (CKD) is a common cause of HFpEF. Previous research has shown that Growth Hormone-Releasing Hormone agonists (GHRH-As) have positive effects in animal models of both ischemic and nonischemic heart failure. This suggests that the GHRH pathway could be a valuable therapeutic target for improving cardiac relaxation and structure in the context of HFpEF, a condition where current treatments offer limited benefits.
Study Design
The study used n=16 female Yorkshire pigs. Chronic kidney disease was induced via 5/6 nephrectomy. After 12 weeks, the pigs, which had developed HFpEF, were randomized into two groups. The treatment group (n=8) received daily subcutaneous injections of the GHRH-A MR-409 (30 µg/kg). The control group (n=8) received a placebo. Treatment lasted for 4 to 6 weeks. Researchers serially assessed renal and cardiac structure and function throughout the study to evaluate the effects of the intervention.
Results
After 4 to 6 weeks of treatment, the GHRH-A group showed significant improvements in cardiac diastolic function. Key hemodynamic markers were restored, including a normalization of left ventricular end-diastolic pressure (P = 0.03) and a reduction in the end-diastolic pressure to end-diastolic volume ratio (P = 0.018), a measure of ventricular stiffness. Molecular analysis revealed a reduction in myocardial pro-brain natriuretic peptide protein abundance, a marker of cardiac stress.
At the cellular level, GHRH-A treatment led to an increased cardiomyocyte
[Ca2+]transient amplitude (P = 0.009), indicating improved calcium handling. Structural protein composition also improved, evidenced by an increased abundance of titin isoforms and a favorable shift in their ratio (P = 0.0022). Ejection fraction was maintained, consistent with the HFpEF phenotype.
Key Findings
- GHRH-A treatment normalized left ventricular end-diastolic pressure (EDP) (P = 0.03).
- The EDP/EDV ratio, a marker of ventricular stiffness, was significantly reduced (P = 0.018).
- Abundance and ratio of titin isoforms were increased, improving structural properties of the heart muscle (P = 0.0022).
- Cardiomyocyte [Ca2+] transient amplitude was increased, indicating improved cellular function (P = 0.009).
- Myocardial pro-brain natriuretic peptide (pro-BNP) protein abundance was reduced.
Why It Matters
These findings suggest GHRH agonists could be a novel and effective therapy for heart failure with preserved ejection fraction (HFpEF), a condition with few treatment options. For clinicians and researchers, this opens a new avenue for treating a difficult cardiac syndrome, particularly when it's driven by chronic kidney disease. This large-animal model provides strong preclinical evidence, moving the therapy closer to potential human trials. The results highlight a specific mechanism—improving diastolic function via changes in calcium handling and structural proteins like titin—that could be targeted in future drug development. While promising, this is an animal study, and translation to human patients with diverse comorbidities will require extensive clinical investigation.
sermorelin
mr-409
ghrh-a
heart failure
hfpef
diastolic dysfunction
