Abstract
BackgroundCardio-Oncology is an evolving discipline that focuses on the management of cancer patients who develop cardiovascular complications as a result of their treatment. Although the current combination of surgical resection, radiation, and chemotherapy may lead to a cure in cancer patients, the administration of anti-cancer drugs, in particular Doxorubicin (DOX) and Trastuzumab (TRZ), is associated with an increased risk of cardiotoxicity. Little is known on the potential cardioprotective role of renin angiotensin system (RAS) antagonists in the prevention of DOX+TRZ mediated cardiotoxicity.ObjectiveThe aim of the study was to determine whether RAS antagonists would be useful in attenuating DOX+TRZ induced cardiotoxicity.MethodsA total of 240 C57Bl/6 mice were randomized to prophylactic treatment with placebo, Aliskiren, Perindopril, or Valsartan for a total of 13 weeks. Within each arm, mice received treatment with either DOX, TRZ, or the combination of both drugs. Serial murine echocardiography was performed weekly to characterize the degree of cardiovascular remodeling within each group.ResultsIn wild-type (WT) mice treated with DOX+TRZ, LV end diastolic internal diameter (LVID) increased from 3.1 ± 0.2 mm at baseline to 4.6 ± 0.3 mm at week 13 (p < 0.05) and the LV fractional shortening (FS) decreased from 52 ± 2% at baseline to 26 ± 2% at week 13 (p < 0.05). Prophylactic treatment with Aliskiren, Perindopril, or Valsartan attenuated the degree of LV cavity dilatation with LVID dimensions of 3.9 ± 0.2 mm, 4.1 ± 0.2 mm, and 4.2 ± 0.1 mm at week 13, respectively (p < 0.05). Similarly, prophylactic treatment with Aliskiren, Perindopril, or Valsartan was partially cardioprotective with FS of 40 ± 1%, 32 ± 1%, and 33 ± 2% at week 13, respectively (p < 0.05). As compared to WT mice receiving DOX+TRZ, prophylactic treatment with RAS inhibition was also associated with improved survival, corroborating the echocardiographic findings.ConclusionThe cardiotoxic effects of DOX+TRZ were partially attenuated by the prophylactic administration of RAS antagonists in a chronic murine model of chemotherapy induced cardiac dysfunction.
Highlights
As the second leading cause of cancer related deaths in women, breast cancer constitutes a major health concern
In wild-type (WT) mice treated with DOX+TRZ, LV end diastolic internal diameter (LVID) increased from 3.1 ± 0.2 mm at baseline to 4.6 ± 0.3 mm at week 13 (p < 0.05) and the LV fractional shortening (FS) decreased from 52 ± 2% at baseline to 26 ± 2% at week 13 (p < 0.05)
The cardiotoxic effects of DOX+TRZ were partially attenuated by the prophylactic administration of renin angiotensin system (RAS) antagonists in a chronic murine model of chemotherapy induced cardiac dysfunction
Summary
Experimental protocol A total of 240 C57Bl/6 male mice were randomized to one of the following prophylactic treatment arms: (A) placebo (saline; n = 60); (B) Aliskiren (50 mg/kg; n = 60); (C) Perindopril (3 mg/kg; n = 60); or (D) Valsartan (10 mg/kg; n = 60) (Figure 1). Mice from each prophylactic treatment arm were randomized to one of the following chemotherapeutic regimens: (i) TRZ (4 mg/kg weekly, intraperitoneal (i.p.); n = 20); (ii) DOX (4 mg/kg weekly, i.p.; n = 20); or (iii) DOX+TRZ (n = 20) (Figure 1). Awake mice were imaged at baseline and weekly thereafter, for the duration of the 13-week study (Figure 2). A total of 40 mice, from various treatment groups, were randomly selected in order to assess the variability associated with echocardiographic measurements of LV cavity dimensions and function. A P value < 0.05 was considered statistically significant
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