ABC | Volume 110, Nº2, February 2018

Original Article Gripp et al Global Longitudinal Strain Accuracy for Cardiotoxicity Arq Bras Cardiol. 2018; 110(2):140-150 A reduction > 15% in GLS, immediately after or during anthracycline treatment, was the most useful parameter to predict cardiotoxicity, while a reduction < 8%might exclude its diagnosis. 12 However, there is a grey zone between those values. This study was aimed at assessing the incidence of breast cancer treatment-induced cardiotoxicity, identifying the independent risk factors associated with that event (drugs, dose, radiotherapy, clinical data and echocardiographic variables), and at identifying the best GLS cutoff point for the early detection of cardiotoxicity, prior to EF reduction. Methods This is a prospective and observational study of consecutive patients referred to the Oncology Outpatient Clinic of the Clementino Fraga Filho University-Affiliated Hospital (HUCFF), Rio de Janeiro, Brazil, with confirmed diagnosis of breast cancer and indication for potentially cardiotoxic antineoplastic treatment. Data were collected from January 22, 2015, to June 19, 2016, by filling in a form consisting of patient’s clinical information, physical exam, echocardiographic data and proposed treatment. The inclusion criteria were: age ≥ 18 years; diagnosis of breast cancer, with neither previous antineoplastic treatment nor radiotherapy; normal EF, according to the last recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging 13 (> 54%, by use of the Simpson’s method), on the first Doppler echocardiogram before treatment; and antineoplastic treatment planning with anthracyclines and/or trastuzumab. The exclusion criteria were as follows: impossibility of accurately assessing GLS because of an inappropriate acoustic window; presence of cardiac arrhythmias and/or non-sinus rhythms; use of beta-blockers and/or angiotensin-converting- enzyme inhibitors and/or angiotensin receptor blockers; and moderate or severe heart valve disease. The patients who met the inclusion criteria underwent Doppler echocardiography at baseline, before initiating the anthracycline, and then every 3months, during a 6- to 12-month follow-up at the HUCFF. All tests were performed by one single professional, who was blind to the treatment instituted. Two distinct protocols of antineoplastic drugs were used: 1. FEC (5-fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 and cyclophosphamide 500 mg/m 2 ) in 3 cycles, every 21 days, followed by docetaxel 100 mg/m 2 in other 3 cycles, every 21 days; 2. Doxorubicin60mg/m 2 andcyclophosphamide600mg/m 2 in 4 cycles, every 21 days, followed by paclitaxel 80 mg/m 2 weekly, for 12 cycles, for both adjuvant and neoadjuvant treatments. The patients eligible for trastuzumab should undergo genetic assessment with human epidermal growth factor receptor 2 (HER2) test. Those who had a positive HER2 test result (+++/+++) or undetermined HER2 test result (++/+++), but positive FISH ( Fluorescence in Situ Hybridization ), were assigned to adjuvant treatment. Trastuzumab would be offered for 1 year, with 18 applications at 21-day intervals, with an initial dose of 8 mg/kg, followed by a maintenance dose of 6mg/m 2 . In 19 months (01/22/2015 to 06/19/2016), 58 patients were referred to the Oncology Service of the HUCFF to undergo Doppler echocardiography. Of those 58 patients, 9 were excluded because of inappropriate acoustic window (2 were on beta-blockers), leaving 49 patients as the study population. Doppler echocardiography Doppler echocardiography was performed with the patient at rest in the left lateral position, using the Vivid S6-GE device (GE, Vingmed Ultrassound Horten, Norway), LCD 17” monitor, with image acquisition with a 3S transducer and harmonic imaging. The measurements were reassessed by a second observer, also blind to the treatment instituted and specialized in the method. Interobserver agreement was assessed. All tests were performed with the same device. Sector and depth were adjusted to optimize the image. The measurements and image acquisition followed the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. 13 The following echocardiographic variables were assessed: EF, calculated by use of the Simpson’s method, considering the normal value of EF > 54% for the female sex, according to the current recommendations; 13 diastolic function, evaluated by use of mitral flow with anterograde values of E wave and A wave, tissue Doppler of septal and lateral mitral annulus, measures of S’ wave (systolic velocity of the mitral ring) and E/E’ ratio; S wave of the right ventricle (cm/s); indexed left atrial volume (mL/m 2 ); tricuspid annular plane systolic excursion (TAPSE); and pulmonary artery systolic pressure (PASP). In our study, cardiotoxicity was defined, in accordance with the cardiac review committee and expert recommendations on trastuzumab-related cardiotoxicity, as a reduction of at least 5% of EF values < 55% in symptomatic patients, or a reduction of at least 10% of EF values < 55% in asymptomatic patients. 8 The GLS was acquired by use of Automated Functional Imaging (AFI) of three clips with images of the left ventricle on three apical views, so that all myocardial segments could be well visualized: 4-chamber, 2-chamber and 3-chamber views. The events of aortic valve opening and closure were marked. The images were acquired at a frame rate of 40‑90 fps (> 70% of heart rate). Right ventricular (RV) strain was acquired by use of AFI. The acquisition of a clip of apical window projection adapted to RV assessment was necessary to include the entire RV free wall and its tip for further analysis. Three points were marked in the basal segments (inferior septum, tricuspid annulus) and apex. After that marking, the analysis was performed in the same way described for the left ventricle. The images were analyzed in the same device and same working station (EchoPAC 13.0, GE Vingmed Ultrassound Horten, Norway). Reproducibility The measures of left ventricular (LV) GLS, RV strain and RV free wall strain underwent intra- and interobserver agreement analysis by use of intraclass correlation coefficients. Bland-Altman plots were created to show the results of the interobserver analyses. 141