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BACKGROUND: Cardiotoxicity associated with anthracycline-based chemotherapies has limited their use in patients with preexisting cardiomyopathy or heart failure. Dexrazoxane protects against the cardiotoxic effects of anthracyclines, but in the USA and some European countries, its use had been restricted to adults with advanced breast cancer receiving a cumulative doxorubicin (an anthracycline) dose > 300 mg/m2. We evaluated the off-label use of dexrazoxane as a cardioprotectant in adult patients with preexisting cardiomyopathy, undergoing anthracycline chemotherapy.
METHODS: Between July 2015 and June 2017, five consecutive patients, with preexisting, asymptomatic, systolic left ventricular (LV) dysfunction who required anthracycline-based chemotherapy, were concomitantly treated with off-label dexrazoxane, administered 30 min before each anthracycline dose, regardless of cancer type or stage. Demographic, cardiovascular, and cancer-related outcomes were compared to those of three consecutive patients with asymptomatic cardiomyopathy treated earlier at the same hospital without dexrazoxane.
RESULTS: Mean age of the five dexrazoxane-treated patients and three patients treated without dexrazoxane was 70.6 and 72.6 years, respectively. All five dexrazoxane-treated patients successfully completed their planned chemotherapy (doxorubicin, 280 to 300 mg/m2). With dexrazoxane therapy, changes in LV systolic function were minimal with mean left ventricular ejection fraction (LVEF) decreasing from 39% at baseline to 34% after chemotherapy. None of the dexrazoxane-treated patients experienced symptomatic heart failure or elevated biomarkers (cardiac troponin I or brain natriuretic peptide). Of the three patients treated without dexrazoxane, two received doxorubicin (mean dose, 210 mg/m2), and one received daunorubicin (540 mg/m2). Anthracycline therapy resulted in a marked reduction in LVEF from 42.5% at baseline to 18%. All three developed symptomatic heart failure requiring hospitalization and intravenous diuretic therapy. Two of them died from cardiogenic shock and multi-organ failure.
CONCLUSIONS: The concomitant administration of dexrazoxane in patients with preexisting cardiomyopathy permitted successful delivery of anthracycline-based chemotherapy without cardiac decompensation. Larger prospective trials are warranted to examine the use of dexrazoxane as a cardioprotectant in patients with preexisting cardiomyopathy who require anthracyclines.

Pulmonary hypertension (PH) is defined as elevated mean pulmonary artery pressure secondary to e.g. congenital heart disease and chronic obstructive pulmonary disease. It elevates right ventricular afterload that eventually leads to cor pulmonale and right heart failure. Experimental research has shown that cardioprotective strategies may improve morbidity and reduce mortality in PH patients. PH and consequent right heart failure are underpinned by dysregulated mitochondrial dynamics, and therefore mitochondrial regulators may be targeted as cardioprotective agents in PH. Mitochondrial regulators such as the metallothioneins (MTs) confer cardioprotection against several forms of heart/lung disease. Furthermore, MT expression is up or downregulated in biopsies or blood from patients with PH. However, despite the overwhelming evidence that MT has potential as cardioprotective agents in PH, MT-induced cardioprotection has not been tested in experimental models of PH. Therefore, it is necessary to evaluate the attributes of MTs that make them candidates for cardioprotection in PH. The hypothesis presented in this paper is that upregulation of cardiac MTs can confer cardioprotection in PH and associated right ventricular remodelling. Mainly due to their ability to detoxify the myocardium of excess heavy metals, scavenging of free radicals and modulation of mitochondrial dynamics. These processes are instrumental in the development of PH and right ventricular remodelling. With this hypothesis we propose that the upregulation of cardiac MTs can confer cardioprotection in PH by detoxifying the myocardium of heavy metals and improving cardiac mitochondrial efficiency (i.e. reducing ROS, reducing oxidative stress, and improving antioxidant capacity and improving mitochondrial respiration).