title: The role of renin angiotensin system antagonists in the prevention of doxorubicin and trastuzumab induced cardiotoxicity.
abstract: BACKGROUND
  Cardio-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.
  
  
  OBJECTIVE
  The aim of the study was to determine whether RAS antagonists would be useful in attenuating DOX+TRZ induced cardiotoxicity.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  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). 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. GAkolkar@sbrc.ca.
authors.forename: Gauri
authors.initials: G
authors.lastname: Akolkar
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. bhullar.navdeep@gmail.com.
authors.forename: Navdeep
authors.initials: N
authors.lastname: Bhullar
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. bewsh@myumanitoba.ca.
authors.forename: Hilary
authors.initials: H
authors.lastname: Bews
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. bilal_2113@hotmail.com.
authors.forename: Bilal
authors.initials: B
authors.lastname: Shaikh
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. sheenabohonis@yahoo.ca.
authors.forename: Sheena
authors.initials: S
authors.lastname: Premecz
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. kbordun@sbrc.ca.
authors.forename: Kimberly-Ann
authors.initials: KA
authors.lastname: Bordun
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. dcheung@sbrc.ca.
authors.forename: David Yc
authors.initials: DY
authors.lastname: Cheung
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. vgoyal@sbrc.ca.
authors.forename: Vineet
authors.initials: V
authors.lastname: Goyal
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. asharma@sbrc.ca.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. pgarber@sbgh.mb.ca.
authors.forename: Philip
authors.initials: P
authors.lastname: Garber
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. psingal@sbrc.ca.
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada. djassal@sbgh.mb.ca.|Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. djassal@sbgh.mb.ca.|Section of Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. djassal@sbgh.mb.ca.|Department of Radiology, St. Boniface General Hospital, University of Manitoba, Winnipeg, Manitoba, Canada. djassal@sbgh.mb.ca.|Associate Professor of Medicine, Radiology, and Physiology, Section of Cardiology, Department of Internal Medicine, College of Medicine, Faculty of Health Sciences, Rm Y3531, Bergen Cardiac Care Centre, St. Boniface General Hospital, 409 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada. djassal@sbgh.mb.ca.
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D004317:Doxorubicin / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012084:Renin-Angiotensin System / Q000187:drug effects; D000068878:Trastuzumab / Q000009:adverse effects*; D016896:Treatment Outcome; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000517:prevention & control*; D000092502:Renin Inhibitors
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab; D000092502:Renin Inhibitors