Dose-effect and structure-function relationships in doxorubicin cardiomyopathy

The cardiomyopathy (CM) produced by the anticancer drug doxorubicin (DXR) (Adriamycin) provides a unique opportunity to analyze dose-effect and structure-function relationships during development of myocardial disease. We measured the degree of morphologic damage by ultrastructural examination of endomyocardial biopsy and the degree of performance abnormally by right heart catheterization in patients receiving DXR. Morphologic damage was variable but was proportional to the total cumulative DXR dose between 100 and 600 mg/m2. Performance abnormalities correlated weakly with dose, exhibited a curvilinear relationship, and had a "threshold" for expression. Catheterization abnormalities correlated well with morphologic damage (r = 0.57 to 0.78) in a subgroup of patients in whom exercise hemodynamics were measured, and this relationship also exhibited a curvilinear, threshold configuration. In DXR-CM myocardial damage is proportional to the degree of cytotoxic insult (DXR dose) while myocardial function is preserved until a critical dose or degree of damage is reached, after which myocardial performance deteriorates rapidly.