Can retinoic acid receptor (RAR) agonists slow the rate of aortic valve calcification and stenosis?

Retinoic Acid Receptor Agonists and Aortic Valve Calcification

Currently, there is promising preclinical evidence that retinoic acid receptor (RAR) agonists may slow aortic valve calcification, but no clinical guidelines yet recommend their use for this purpose.

Current Understanding of RAR Agonists in Aortic Valve Calcification

Recent research has identified a potential role for retinoic acid receptor alpha (RARα) agonists in preventing or slowing aortic valve calcification. The most compelling evidence comes from a 2025 study that identified aldehyde dehydrogenase 1 family member A1 (ALDH1A1) as significantly downregulated in calcified valves compared to healthy valves 1. This downregulation promotes valvular interstitial cells (VICs) to transition into an osteoblastic phenotype, contributing to valve calcification.

Key findings from this research:

• ALDH1A1 is downregulated in calcified valves through TGF-β in a SMAD2/3-dependent manner
• ALDH1A1 inhibition promotes osteoblast-like VIC phenotype and increases calcium deposition
• All-trans retinoic acid (a RAR agonist) inhibits calcification development in both in vitro and in vivo models
• Treatment with retinoids decreased calcium deposition and attenuated VIC osteoblast activity

Current Guidelines on Aortic Valve Calcification Management

Current clinical guidelines do not yet incorporate RAR agonists for managing aortic valve calcification or stenosis:

1. No Medical Therapy Proven to Alter Disease Progression: The 2014 AHA/ACC guidelines explicitly state that "there are no data to support the use of statins for prevention of progression of AS" 2. This represents a Class III recommendation (No Benefit) with Level of Evidence A.

2. Statins Not Recommended: Multiple guidelines specifically note that statins have failed to show benefit for preventing progression of aortic stenosis despite initial promise:

   • "Statin therapy is not indicated for prevention of hemodynamic progression of AS in patients with mild-to-moderate calcific valve disease" 2
   • "Cholesterol-lowering treatment is not recommended in patients with aortic valvular stenosis without CAD in the absence of other indications for their use" 2

3. Limited Options for Bicuspid Aortic Valve Disease: For bicuspid aortic valve (BAV) disease, guidelines suggest:

   • "It may be reasonable to treat patients with BAV and risk factors for atherosclerosis with statins with the aim of slowing down degenerative changes in the aortic valve and preventing atherosclerosis" 2 (Class IIb, Level of Evidence C)
   • "There are currently no established medical treatments proven to alter the natural history or halt the progression of stenosis in BAV disease" 2

Contrasting Evidence on Potential Therapies

Research on pharmacological interventions for aortic valve calcification shows mixed results:

1. Statins: Despite initial promise in observational studies, randomized controlled trials have consistently failed to demonstrate benefit:

   • Multiple large RCTs showed no benefit in terms of hemodynamic progression or clinical outcomes 2

2. Bone-Targeted Therapies: A 2021 study found that neither denosumab nor alendronic acid affected progression of aortic valve calcification 3

3. Angiotensin Receptor Blockers (ARBs): Some evidence suggests ARBs may be associated with lower aortic valve remodeling scores and weights 4, but this has not been incorporated into guidelines

4. Vitamin A: Interestingly, while RAR agonists show promise, excess vitamin A intake has been shown to promote heart valve calcification in vivo 5, highlighting the complexity of retinoid signaling in valve calcification

Clinical Implications

Given the current evidence and guidelines:

1. No Currently Approved Medical Therapy: There is no FDA-approved or guideline-recommended medical therapy to slow aortic valve calcification or stenosis progression.

2. Surgical/Interventional Management Remains Standard: The only effective treatment for severe aortic stenosis remains valve replacement, either surgical (SAVR) or transcatheter (TAVR) 2, 6.

3. Promising Preclinical Evidence for RAR Agonists: The 2025 research on RAR agonists 1 represents a potentially groundbreaking approach, suggesting that retinoic acid receptor alpha agonists could be repositioned as a pharmacological strategy to prevent calcification.

4. Need for Clinical Trials: Before RAR agonists can be recommended for clinical use, randomized controlled trials are needed to establish safety and efficacy in humans.

Future Directions

The preclinical evidence for RAR agonists is promising and suggests several potential avenues for clinical development:

1. Drug Repositioning: All-trans retinoic acid is already approved for other indications (notably acute promyelocytic leukemia), potentially facilitating faster clinical translation

2. Targeted Populations: Initial clinical trials might focus on high-risk populations such as:

   • Patients with bicuspid aortic valves
   • Patients with early calcific changes but not yet severe stenosis
   • Patients with bioprosthetic valves to prevent structural valve deterioration

3. Biomarker Development: Research into ALDH1A1 levels might help identify patients most likely to benefit from RAR agonist therapy

Conclusion

While RAR agonists show promise in preclinical studies for slowing aortic valve calcification, current clinical guidelines do not yet support any medical therapy for this purpose. The recent identification of the ALDH1A1 pathway and potential benefit of retinoic acid receptor alpha agonists represents an exciting new direction, but requires clinical validation before implementation in practice.