Anthracycline cardiotoxicity: role of metabolic vulnerability induced by cardiac pressure overload.

Summary

In a pig model, pre-existing LV pressure overload created a high-energy-demand state that rendered the heart uniquely vulnerable to even low-dose doxorubicin, leading to excess mortality, LV dysfunction, fibrosis, and impaired mitochondrial respiration. Modulating contractile energetics with mavacamten rescued cardiomyocyte viability under combined anthracycline and hypertrophic stress.

Key Findings

• LV pressure overload increased mortality and reduced LVEF when combined with low-risk-dose doxorubicin, while doxorubicin alone preserved function.
• Pressure overload induced compensatory metabolic remodeling (reduced phosphocreatine) and heightened susceptibility to mitochondrial respiratory impairment with anthracycline.
• Mavacamten reduced energetic demand and rescued cardiomyocyte viability under combined hypertrophic and doxorubicin stress.

Clinical Implications

Patients with hypertension or valvular disease undergoing anthracyclines may warrant intensified cardio-oncology assessment (blood pressure control, imaging/biomarkers), dose tailoring, and exploration of strategies that lower myocardial energy demand.

Limitations

• Preclinical animal model; human generalizability requires clinical validation
• Single anthracycline agent/dose schedule; preventive pharmacologic strategies not tested clinically

Future Directions

Prospective clinical studies in hypertensive/valvular patients receiving anthracyclines to test intensified cardio-oncology pathways and energetics-modulating interventions (e.g., dose optimization, myosin modulation).