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1. Pre-existing left ventricular (LV) pressure overload significantly increases susceptibility to anthracycline-induced cardiotoxicity, even at low cumulative doses.
2. Pressure overload creates a high-energy-demand metabolic state in the myocardium that disrupts compensatory mechanisms upon anthracycline exposure.
3. In a large animal model, doxorubicin combined with LV overload increased mortality, induced cardiac dysfunction, fibrosis, and impaired mitochondrial respiration.
4. Energy demand suppression by mavacamten rescued cardiomyocyte viability under combined doxorubicin and hypertrophic stress, highlighting a therapeutic avenue.
