Utility of tissue Doppler and strain rate imaging in the early detection of trastuzumab and anthracycline mediated cardiomyopathy.
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.
Jassal
Davinder S
DS
Section of Cardiology, Department of Cardiac Sciences, University of Manitoba, Winnipeg, Canada.
Han
Song-Yee
SY
Hans
Cecilia
C
Sharma
Anita
A
Fang
Tielan
T
Ahmadie
Roien
R
Lytwyn
Matthew
M
Walker
Jonathan R
JR
Bhalla
Raveen S
RS
Czarnecki
Andrew
A
Moussa
Tarek
T
Singal
Pawan K
PK
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*
D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D000068878:Trastuzumab