title: Utility of tissue Doppler and strain rate imaging in the early detection of trastuzumab and anthracycline mediated cardiomyopathy.
abstract: BACKGROUND
  Trastuzumab provides considerable therapeutic benefits in the adjuvant setting of breast cancer. However, its use is limited by an elevated incidence of cardiotoxicity when used in combination with doxorubicin. Although Myocet (liposomal encapsulated doxorubicin) is less cardiotoxic, its cardiac safety profile with trastuzumab is not well known. The aim of this study was to determine if sensitive indices of left ventricular (LV) dysfunction, specifically Doppler tissue imaging (DTI), would be useful for addressing the early detection of trastuzumab and anthracycline-mediated cardiotoxicity.
  
  
  METHODS
  In an acute murine model, wild-type C57Bl/6 mice (n = 60) received one of the following drug regimens: (1) control, (2) doxorubicin, (3) Myocet, (4) trastuzumab, (5) doxorubicin plus trastuzumab, or (6) Myocet plus trastuzumab. DTI-derived peak endocardial systolic velocity, strain rate, and LV ejection fraction were measured serially for 5 days. On day 5, the hearts, lungs, and livers were removed for histopathologic and Western blot analyses.
  
  
  RESULTS
  Mice treated with Myocet plus trastuzumab demonstrated minimal cardiotoxicity compared with those treated with doxorubicin plus trastuzumab. Progressive LV dilatation and LV systolic dysfunction were observed by day 4 of treatment with doxorubicin plus trastuzumab, compared with preserved LV ejection fraction in the remaining groups. DTI parameters decreased within 24 hours in the doxorubicin alone and doxorubicin plus trastuzumab groups and predicted early mortality. The survival rate was only 20% at day 5 of the experiment in the doxorubicin plus trastuzumab group, whereas 100% of mice receiving trastuzumab, Myocet, or Myocet plus trastuzumab survived the 5 days.
  
  
  CONCLUSIONS
  DTI can detect early LV dysfunction prior to alterations in conventional echocardiographic indices and predicts early mortality in mice receiving doxorubicin plus trastuzumab.
authors.affiliation: Section of Cardiology, Department of Cardiac Sciences, University of Manitoba, Winnipeg, Canada.
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
authors.forename: Song-Yee
authors.initials: SY
authors.lastname: Han
authors.forename: Cecilia
authors.initials: C
authors.lastname: Hans
authors.forename: Anita
authors.initials: A
authors.lastname: Sharma
authors.forename: Tielan
authors.initials: T
authors.lastname: Fang
authors.forename: Roien
authors.initials: R
authors.lastname: Ahmadie
authors.forename: Matthew
authors.initials: M
authors.lastname: Lytwyn
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Walker
authors.forename: Raveen S
authors.initials: RS
authors.lastname: Bhalla
authors.forename: Andrew
authors.initials: A
authors.lastname: Czarnecki
authors.forename: Tarek
authors.initials: T
authors.lastname: Moussa
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000009:adverse effects*; D015150:Echocardiography, Doppler / Q000379:methods*; D054459:Elasticity Imaging Techniques / Q000379:methods*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000000981:diagnostic imaging*
chemical_list: D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab