Anthracycline cardiotoxicity: looking for new therapeutic approaches targeting cell senescence?

Extract

This editorial refers to ‘Co-administration of resveratrol with doxorubicin in young mice attenuates detrimental late-occurring cardiovascular changes’ by N. Matsumura et al., pp. 1350–1359.

Anthracycline cardiotoxicity remains a serious problem in paediatric and adult cancer survivors.¹ Acute anthracycline-induced cardiotoxicity typically occurs within the first treatment week and early-onset cardiotoxicity within a year after treatment completion. The late-onset form of anthracycline cardiotoxicity follows a latent period during which cardiac function appears normal.¹ This form is of major importance in patients given anthracycline at a young age, who are at increased risk for developing acute or chronic cardiac events later in life.²

The article by Matsumura et al. published in this issue addresses this important problem and provides new insight into late-onset anthracycline cardiotoxicity.³ The authors developed an elegant model, in which juvenile mice were exposed to clinically relevant doses of doxorubicin that did not induce acute cardiotoxicity at young ages but were followed in adulthood by cardiotoxicity upon administration of an angiotensin II infusion. The young doxorubicin-treated mice had normal cardiac function but lower cardiac mass compared to control mice. At an older age, all doxorubicin-treated mice developed systemic hypertension without left ventricular hypertrophy. Angiotensin II infusion increased systemic arterial pressure in both groups but failed to induce left ventricular hypertrophy in the doxorubicin group. In keeping with these results, previous studies showed that juvenile doxorubicin exposure impaired blood-vessel development, as shown by a decrease in capillary density.⁴ The same mice subjected to myocardial infarction as adults were at higher risk for heart failure and showed less neovascularization. That doxorubicin-induced cardiotoxicity can be revealed later in life in response to systemic hypertension or other stressors argues for an initial cellular or molecular insult whose effects remain clinically silent but make the heart more vulnerable to stressors occurring later in life.