What is the potential role of Urolithin A in managing cardiac microvascular endothelial function in patients with cardiovascular disease (CVD) and risk factors such as hypertension, diabetes, or hyperlipidemia?

Urolithin A and Cardiac Microvascular Endothelium

Urolithin A shows promising preclinical and early clinical evidence for improving cardiac microvascular endothelial function through mitophagy activation and reduction of cardiovascular disease biomarkers, though it is not yet incorporated into established cardiovascular guidelines and should be considered an adjunctive nutritional intervention rather than a replacement for guideline-directed medical therapy.

Current Guideline-Directed Therapy Takes Priority

The established approach to managing cardiac microvascular endothelial dysfunction in patients with cardiovascular risk factors focuses on proven pharmacological interventions:

• Blood pressure control to <140/90 mmHg (or <130/80 mmHg in select high-risk individuals) using ACE inhibitors or ARBs as foundational therapy 1
• Lipid management with statins or statin/ezetimibe combinations to maximize LDL cholesterol reduction 2
• Diabetes management with SGLT2 inhibitors and GLP-1 receptor agonists, which preserve endothelial and kidney function 2
• Lifestyle modifications including Mediterranean-style dietary patterns, sodium reduction, weight loss if overweight, and regular physical activity 1, 2

These interventions have Class I, Level A evidence for reducing cardiovascular morbidity and mortality 1.

Emerging Evidence for Urolithin A

Preclinical Mechanisms

Urolithin A, a gut microbiota metabolite of ellagitannins from pomegranates, berries, and nuts, demonstrates multiple cardioprotective mechanisms:

• Mitochondrial quality enhancement through activation of mitophagy and mitochondrial biogenesis, addressing a common hallmark of cardiac aging and chronic cardiovascular conditions 3, 4
• Endothelial protection by promoting nitric oxide production, decreasing inflammatory adhesion molecule expression, and reducing monocyte adhesion to endothelial cells 5
• Anti-inflammatory effects through modulation of YAP/TAZ protein expression and TEAD transcriptional activity, independent of the NF-κB pathway 5
• Atherosclerotic plaque stabilization by reducing macrophage content, increasing smooth muscle actin expression, and decreasing necrotic core size in animal models 5

Clinical Translation

The most compelling human evidence comes from a recent 2025 study:

• Four months of urolithin A supplementation in healthy older adults significantly reduced plasma ceramides, which are clinically validated biomarkers that predict cardiovascular disease risk 3
• Safety profile has been established up to 2,500 mg/day in clinical trials, with improvements in mitochondrial biomarkers in elderly patients 4
• Cardiac function improvements were demonstrated preclinically, with reductions in both systolic and diastolic dysfunction in models of natural aging and heart failure 3

Cardiovascular Disease Prevention Potential

Research indicates urolithin A may address multiple cardiovascular pathologies:

• Lipid metabolism regulation through modulation of SREBP1/2 transcription factors in the liver, ameliorating cholesterol metabolism 5
• Vascular smooth muscle cell proliferation inhibition and reduction of cardiomyocyte apoptosis 6
• Prevention of atherosclerosis, hypertension, myocardial infarction, cardiac fibrosis, and cardiomyopathy in animal models 6
• Regulation of calcium handling and reduction of pro-inflammatory factor production 6

Clinical Integration Strategy

When to Consider Urolithin A

Add urolithin A as adjunctive therapy in patients already on guideline-directed medical therapy who:

• Are older adults (≥50 years) with established cardiovascular disease or multiple risk factors 3
• Have optimized traditional risk factors but seek additional cardioprotective interventions 3
• Have evidence of endothelial dysfunction or elevated cardiovascular biomarkers despite standard therapy 3, 5

Dosing Considerations

• Clinical trial dosing ranged from 500-2,500 mg/day, with safety established at the higher end 4
• Duration of therapy in the positive clinical trial was 4 months, suggesting this is a minimum timeframe to assess benefit 3
• Gut microbiota variability affects conversion efficiency of dietary ellagitannins to urolithin A, making direct supplementation more reliable than dietary sources alone 4, 5

Important Caveats

Do not use urolithin A as monotherapy or as a replacement for proven cardiovascular medications like statins, ACE inhibitors/ARBs, or antihypertensive agents, as these have robust mortality and morbidity benefits 1.

Maintain guideline-directed therapy for hypertension, diabetes, and hyperlipidemia as the foundation, with urolithin A serving as a complementary intervention targeting mitochondrial and endothelial health 2, 3.

Monitor cardiovascular biomarkers including lipid panels and inflammatory markers to assess response, as the primary human evidence is based on ceramide reduction rather than hard clinical endpoints 3.

Comparison to Established Nutritional Interventions

The evidence for urolithin A is more mechanistically robust than many nutritional supplements but less established than:

• Omega-3 PUFA supplementation (1 g daily), which has Class IIa, Level B evidence for reducing mortality and cardiovascular hospitalizations in heart failure patients 1
• Mediterranean dietary patterns, which have consistent evidence for cardiovascular risk reduction 2

Unlike statins, which have Class III (No Benefit) recommendations when used solely for heart failure without other indications 1, urolithin A targets distinct pathways (mitochondrial quality and endothelial function) that may complement rather than duplicate existing therapies.

Practical Implementation

Prioritize proven interventions first: Ensure blood pressure targets are met, lipids are optimized with statins, diabetes is controlled with SGLT2 inhibitors or GLP-1 agonists, and lifestyle modifications are implemented 1, 2.

Consider urolithin A supplementation at 500-1,000 mg daily as an adjunctive intervention in motivated patients seeking additional cardioprotection, particularly those with evidence of endothelial dysfunction or elevated cardiovascular risk despite optimal medical therapy 3, 4.

Reassess at 4 months with cardiovascular biomarker testing to determine if continuation is warranted based on individual response 3.

Avoid nephrotoxic agents like NSAIDs that worsen endothelial function, as these directly counteract the benefits of both guideline-directed therapy and urolithin A 2.