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 Table 1 – Clinical and laboratorial characteristics of 112 patients undergoing chemotherapy Variable n Age (mean ± SD) 51,4 ± 11,1 Female (n/%) 111 (99,1%) BMI (kg/m 2 ) 26,1 ± 5,8 Mastectomy (n/%) 111 (99,1%) Median follow-up time (months) 16 Radiotherapy (n/%) 74 (66) Chemotherapy (n/%) AC-T 90 (80) Anti HER2 29 (26) Others 20 (18) Hormone Therapy (n/%) 72 (64) Cardiovascular risk factors (n/%) Hypertension 39 (35) Diabetes 8 (7) Hyperlipidemia 21 (19) Smoking 25 (22) BMI: body mass index;AC-T: Doxorubicin/cyclophosphamide - Taxol (Paclitaxel). Results Studied population A total of 112 patients were included. Mean follow-up time was 491 days. The characteristics of the population studied are summarized in Table 1. Most of the patients in the cohort were female (98.2%). Mean age was 51.3 ± 12.9 years. Of the112patients followedup, 18 (16.1%) presentedCTRCD. The characteristics of the patients with abnormal LV segmental wall motion are summarized in table 2. LV segmental wall motion abnormality was found in 16 (14%) patients, most commonly at the time of the second echocardiographic study (43%). LV segmental wall motion analyses by visual assessment showed abnormalities most frequently in the interventricular septum (78.5% - Figure 1), the inferior (14.3%), and the inferolateral (7.1%) walls. During the follow-up, no patient presented left bundle branch block by electrocardiography study. Among the variables studied, it was observed at multivariable analysis that GLS measurements as well as LV systolic dimensions and the presence of LV regional wall motion abnormalities at the baseline study could predict development of cardiotoxicity (Tables 3 and 4). The analysis of ROC curve of the final model (Figure 2) showed an area under the curve (AUC) of 0.93 (0.88 – 0.98). When we exclude the presence of wall motion abnormality in the model, the AUC was 0.84 (0.72-0.96) showing additive predictive power of this variable (p = 0.047). Intraobserver variability and interobserver variability for wall motion assessment were 0.89 and 0.81, respectively. Discussion In this prospective, longitudinal cohort study, we showed that the presence of regional wall motion disturbance and decreased GLS are strong predictors of CTRCD. Earlier histopathological studies performed from endomyocardial biopsies have demonstrated an initially focal and dispersed involvement of myocytes, surrounded by normal cells in patients treated with anthracyclines. 16 As the toxicity evolves, the frequency of these alterations increases, leading to significant myocardial damage and later on to diffusemyocardial fibrosis. Thus, segmental contractile dysfunction may precede the intense and diffuse involvement of the heart seen in CTRCD. In this context, interventricular septum dyssynchrony, as well as segmental hypokinesia may be present due to tissue edema and/or focal cellular damage. 17 Indeed, Piotrowsk et al. 9 demonstrated that in 60.9% of patients with LV systolic dysfunction regional wall motion abnormalities were observed in the first echocardiography that revealed a significant drop of LVEF. In the majority of these cases (64%), regional hypokinesis involved the interventricular septum. 9 Previous studies using tissue Doppler and 2D strain have also shown regional contractile alterations in patients treated with chemotherapy. 10,11 Boyd et al. 18 demonstrated that in the group with subclinical LV dysfunction (> 11% reduction in GLS compared to before therapy) 58% of regional segments had a reduction in strain by > 11%, compared to 29% of regional segments in the group without subclinical LV dysfunction (p < 0.001). 18 It is well known that reduction of longitudinal strain is an early predictive factor of cardiotoxicity induced by treatment with anthracyclines and trastuzumab, as confirmed by our results. Negishi et al. showed that GLS was an independent predictor of subsequent reductions in EF, with a discrimination improvement by adding GLS of -18.6% to traditional parameters by echocardiography in patients at risk for trastuzumab-induced cardiotoxicity. 19 In another study, Sawaya el al. 20 showed that in patients with breast cancer treated with chemotherapy, GLS measured at the completion of anthracycline therapy was useful in the prediction of subsequent cardiotoxicity. 20 It was shown in a systematic review that an early reduction of 10% to 15% in GLS was a useful parameter for the prediction of cardiotoxicity. 21 A small cohort study was associated with subclinical LV dysfunction as early as 1 week after treatment, showing a significant decrease in GLS and annular systolic velocity of the lateral LV wall 7 days after by trastuzumab treatment. 22 Fei et al. 23 found, in a cohort of 95 patients treated with anthracycline and trastuzumab, and followed for a mean time of 17 months, 20% with cardiotoxicity, demonstrating a significant association between GLS reduction and LVEF decline. 23 The presence of diastolic dysfunction was not an independent predictor of CTRCD in our study. The use of diastolic dysfunction as a surrogate marker for predicting trastuzmab‑induced cardiotoxicity is controversial. Earlier studies have shown that diastolic impairment of the LV occurs before deterioration in LV EF in anthracycline 24,25 and transtuzumab 26,27 induced cardiotoxicity. Development 52