ABC | Volume 112, Nº1, January 2019

Original Article Barros et al Regional wall motion and cardiotoxicity prediction Arq Bras Cardiol. 2019; 112(1):50-56 exhausted, therefore more sensitive screening modalities for LV dysfunction are needed. Despite the recognition of several echocardiographic parameters associated with CTRCD, including novel echocardiography-derived parameters of myocardial mechanics, such as strain and strain rate, currently there is no consensus in the medical practice to fully predict which patients are prone to develop cardiotoxicity. 6-8 Previous studies have demonstrated the presence of regional myocardial dysfunction in patients with CTRCD, 9-11 however its role as a risk predictor has not been established. The purpose of this study is to verify the association between the occurrence of LV segmental wall motion abnormality and the development of cardiotoxicity in patients with breast cancer undergoing chemotherapy. Methods Study population This study is part of a prospective cohort study of patients with breast cancer recruited from the Mater Dei Hospital in the city of Belo Horizonte - MG from January 2010 through December 2016. Inclusion criteria were, age above 18 years, histologically confirmed breast cancer diagnosis, treatment with doxorubicin and/or trastuzumab, and who underwent echocardiography, according to the rules of the hospital protocol. Exclusion criteria were patients with previous diagnosis of ventricular dysfunction including regional wall motion abnormality, significant valve disease, congenital heart disease, arrhythmias, chronic coronary artery disease and left bundle branch block by electrocardiography. Treatment regimens were at the discretion of the oncologist and consisted of the use of the following drugs alone or in combination: 1) doxorubicin and cyclophosphamide; 2) paclitaxel; 3) trastuzumab. The dosages of the medications were prescribed according to guidelines. 12 Clinical (e.g., hypertension, dyslipidemia, diabetes) laboratorial (e.g., sodium, potassium, calcium, magnesium, hemoglobin, creatinine and BNP) and transthoracic echocardiograms were collected at baseline and standardized time intervals for each treatment regimen, 6 months after treatment completion and annually thereafter. Echocardiography All patients were referred to a transthoracic echocardiogram, including longitudinal strain assessment with two‑dimensional speckle-tracking echocardiography (2D STE). The echocardiographic studies and analyses were performed by an experienced cardiologist (M.V.L.B.). The following echocardiographic parameters were assessed: LV end‑systolic and end-diastolic diameters and left atrial diameter. LV ejection fraction was assessed using Simpson’s biplane method. Visual assessment of regional myocardial function was assessed on the basis of the observed wall thickening and endocardial motion of the myocardial segment, as described previously. 13 Abnormal septal motion was characterized as a atypical movement of the interventricular septum during cardiac cycle with a two-dimensional echocardiography–guided M-mode approach. Diastolic function was assessed and classified using published criteria. 14 LV diastolic dysfunction was stratified into four grades as normal, impaired relaxation, pseudo normal filling or restrictive. Longitudinal strain by 2D STE was obtained from apical four-chamber, two- chamber, and long-axis views. Three cardiac cycles from each view were recorded for offline analyses with a frame rate > 50 frames/sec. Peak negative longitudinal strain was assessed in 16 LV segments, defined as the peak negative value during the entire cardiac cycle, hence including post systolic shortening, and was averaged to global longitudinal strain (GLS). CTRCDwas defined as a decrease in LVEF of > 10 percentage points, to a value<53% at repeated cardiac imaging studies during follow‑up after chemotherapy. 15 The echocardiographic studies were performed at standardized intervals according to the treatment regimen. 1) Patients treated with anthracyclines without trastuzumab underwent an echocardiographic study at baseline, at completion of chemotherapy, and every six months after completed treatment. 2) Patients treatedwith anthracyclines and trastuzumab underwent an echocardiographic study at baseline, after completion of the anthracycline treatment regimen, every 3 months during trastuzumab therapy, and every six months after completed treatment. 3) Patients treated with trastuzumab without anthracyclines underwent an echocardiographic study at baseline, every 3 months during trastuzumab therapy, and every six months after completed treatment. Echocardiographic assessment was completed in patients with at least three echocardiographic studies performed during the research period. Statistical Analysis To describe the qualitative variables, the absolute and relative frequencies were used, while to describe the quantitative variables, measures of central tendency, dispersion and position were used. In order to identify the factors that influenced the occurrence of cardiotoxicity over time, the Generalized Estimation Equations (GEE) approach was used. An exchangeable correlation structure was assumed for the repeated observations of the same individual. Univariable and multivariable models with a logit link function were considered. There was no occurrence of cardiotoxicity at the first measurement occasion and therefore we also included the baseline values of the time-dependent predictors. Missing values were excluded from the analyses. Variables that were statistically significant at the 0.20 level were included in the multivariable model. For this final model, a level of significance of 0.05 was adopted. Reproducibility of visual assessment of abnormal regional myocardial function was evaluated by the kappa statistics. ROC curves were built and the discrimination ability of the model was assessed by the area under the ROC curve. All statistical analysis was performed using R Statistical Software 3.4.1 and the R packages gee, pROC and PredictABEL. Ethical considerations The study complies with the Declaration of Helsinki and was approved by the Research and Ethical Council of the Mater Dei Hospital. 51