Wednesday, April 2, 2025
4/2/2025
A SkeleTal muscle Recovery Intervention with Dietary protein in Heart Failure (ASTRID-HF) - PROJECT SUMMARY Skeletal muscle wasting and catabolic weight loss are highly prevalent among patients with heart failure with reduced ejection fraction (HFrEF) and are independently associated with increased mortality. As many as half of patients with advanced HFrEF have dual X-ray absorptiometry (DXA) evidence of significant muscle mass loss. It currently unknown whether protein supplementation can reverse muscle loss and improve physical function or survival for affected patients. The deranged systemic metabolism thought to accompany skeletal muscle wasting in patients with HFrEF may also be a source of potential therapeutic intervention to improve both muscle mass and survival. We have observed significant gains in skeletal muscle mass in the first 3-6 months after implantation of a left ventricular assist device, which treats the advanced HFrEF syndrome and helps to normalize the deranged systemic metabolism. In the proposed project, we will perform a randomized controlled trial of oral protein supplementation to determine its effectiveness in achieving clinically meaningful increases in muscle mass muscle. We also plan to expand knowledge specific to HFrEF of two of the main catabolic pathways thought to drive muscle wasting downstream from growth-differentiation factor 15 (GDF-15) and the activin type IIA/IIB receptor (ActRII). Successful completion of the proposed Aims will facilitate our long-term goal to develop nutritional and pharmacological interventions that prevent or reverse skeletal muscle wasting and consequently improve physical functioning and survival for patients with HFrEF. Based on our preliminary and published data, we propose to test the innovative hypothesis that skeletal muscle wasting in HFrEF is promoted by neurohumoral activation of catabolic metabolism, including GDF-15 and ActRII pathways, and can be at least partially reversed by enhanced dietary protein intake. We will test this hypothesis by enrolling 140 adults with HFrEF for a cross-sectional assessment of GDF-15 and ActRII pathways (Aim 1) and skeletal mass response to protein supplementation in a mechanistic clinical trial (Aim 2). Aim 1 will determine whether GDF-15 of ActRII inhibition may be future therapies for patients with severe muscle wasting that cannot be overcome by nutritional strategies. Aim 2 will define whether 30 gram/day supplemental dietary protein for 6 months can increase dual X-ray absorptiometry (DXA) appendicular lean maa (ALM). Successful completion of these aims will establish if dietary protein supplementation is indicated in the clinical care of patients with HFrEF and catabolic weight loss and provide a platform for future studies of adjunctive therapies of GDF-15 neutralization or activin A inhibition. Developing innovative interventions to promote skeletal muscle mass and physical function for patients with HFrEF aligns well with the NHLBI’s objective to develop novel therapeutic approaches for treating heart diseases and improving patient outcomes.
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