The Heart Has Intrinsic Ketogenic Capacity that Mediates NAD
Summary
The study establishes that human myocardium has intrinsic ketogenic capacity via HMGCS2 and that NAD+ repletion rescues HFpEF by deacetylating and restoring HMGCS2 activity, normalizing lipid metabolism and mitochondrial function. Cardiomyocyte‑specific HMGCS2 is necessary for the therapeutic effect, linking cardiac ketogenesis to HFpEF treatment response.
Key Findings
- Human hearts produce ketones intrinsically via HMGCS2; enzyme acetylation reduces activity.
- NAD+ repletion deacetylates and restores HMGCS2, enhances fatty acid oxidation, and rescues HFpEF function.
- Cardiomyocyte-specific HMGCS2 knockdown abrogates the therapeutic benefit of NAD+ repletion in HFpEF.
Clinical Implications
Supports metabolic precision approaches in HFpEF (e.g., NAD+ augmentation) and suggests HMGCS2 status could stratify responders. It motivates therapeutic combinations that enhance cardiac ketogenesis or modulate protein acetylation.
Why It Matters
Provides first direct evidence of cardiac ketogenesis in humans and mechanistic necessity of HMGCS2 for NAD+ therapy in HFpEF. It reframes metabolic therapeutics and biomarker strategies for HFpEF.
Limitations
- Translational bridge to clinical NAD+ interventions requires controlled trials
- Heterogeneity of human HFpEF etiology may influence generalizability
Future Directions
Develop biomarkers of cardiac ketogenesis/HMGCS2 activity, test NAD+ augmentation and deacetylation modulators in HFpEF trials, and map patient subgroups most likely to benefit.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- V - Mechanistic human tissue and animal model study with multi-omics
- Study Design
- OTHER