Histamine N-methyltransferase upregulation, cardiac hypertrophy, and heart failure.

Summary

Using genetic mouse models, pharmacologic inhibition, and human biomarker data, the study identifies HNMT as a pathogenic driver of cardiac hypertrophy and failure via a SAM–EZH2–FZD2/CaMKII pathway. Amodiaquine mitigated pressure-overload heart failure, and urinary N-methylhistamine correlated with HF severity, supporting both a drug target and a noninvasive biomarker.

Key Findings

• HNMT expression is upregulated in human HF myocardium, TAC mice, and PE-treated cardiomyocytes.
• Urinary N-methylhistamine is elevated in HF patients and correlates with HF severity.
• Cardiomyocyte Hnmt deletion or pharmacologic inhibition (amodiaquine) attenuates hypertrophy and improves function in TAC/AngII models.
• Mechanism: HNMT decreases SAM, impairs EZH2-mediated H3K27me3 at the FZD2 promoter, activating WNT/CaMKII signaling to promote HF.

Clinical Implications

Suggests HNMT inhibition (e.g., amodiaquine) as a therapeutic strategy for pressure-overload HF and positions urinary N-methylhistamine for risk stratification and monitoring, pending clinical trials.

Limitations

• Human biomarker cohort is modest in size and observational.
• Translational efficacy and safety of amodiaquine for HF remain to be tested in prospective clinical trials.

Future Directions

Prospective clinical studies to validate urinary N-methylhistamine for HF monitoring and dose-finding/phase II trials of HNMT inhibition (e.g., amodiaquine) in pressure-overload phenotypes.