Aortic Valve Calcification Is Induced by the Loss of ALDH1A1 and Can Be Prevented by Agonists of Retinoic Acid Receptor Alpha: Preclinical Evidence for Drug Repositioning.

Summary

Loss of ALDH1A1 in human valvular interstitial cells drives osteogenic transition and calcification; retinoic acid receptor-α agonism (including all-trans retinoic acid) suppresses calcification in vitro and in two preclinical models (rat pericardial implant and sheep xenograft valve). These findings nominate retinoid signaling as a target for preventing fibro-calcific remodeling of native and bioprosthetic aortic valves, enabling drug repurposing.

Key Findings

• Comparative transcriptomics of human VICs showed downregulation of ALDH1A1 in calcified (bicuspid and tricuspid) versus control valves.
• ALDH1A1 silencing in human VICs increased osteogenic markers and calcific nodule formation.
• All-trans retinoic acid (RARα agonist) reduced calcification in human VICs and in rat pericardial implant and juvenile sheep xenograft valve models.

Clinical Implications

Not practice-changing yet, but it motivates early-phase clinical trials of retinoic acid receptor-α agonists to prevent valve calcification (native and bioprosthetic). Could lead to medical therapies that delay valve interventions.

Limitations

• Preclinical study without randomized clinical trial data
• Mechanistic pathway details between ALDH1A1 and osteogenic transition require further delineation

Future Directions

Phase I/II trials of RARα agonists (e.g., ATRA) to prevent progression of early aortic sclerosis and to improve bioprosthetic valve durability; biomarkers (e.g., retinoid pathway activity) to enrich trial populations.