Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC ndSFjXnFL6Q6X9zBTY8vqvR S0066-782X2019000100050 S0066-782X2018005018101 10.5935/abc.20180220 Original Article Left Ventricular Regional Wall Motion Abnormality is a Strong Predictor of Cardiotoxicity in Breast Cancer Patients Undergoing Chemotherapy 0000-0002-6213-3226 Barros Márcio Vinícius Lins de 1 2 Macedo Ariane Vieira Scarlatelli 2 Sarvari Sebastian Imre 3 Faleiros Monica Hermont 2 Felipe Patricia Tavares 2 Silva Jose Luiz Padilha 4 Edvardsen Thor 3 Faculdade de Saúde e Ecologia Humana Vespasiano MG Brazil Faculdade de Saúde e Ecologia Humana, Vespasiano, MG - Brazil Rede Materdei de Saúde Belo Horizonte MG Brazil Rede Materdei de Saúde, Belo Horizonte, MG - Brazil University of Oslo Oslo Noruega University of Oslo, Oslo - Noruega Universidade Federal do Paraná Curitiba PR Brazil Universidade Federal do Paraná, Curitiba, PR - Brazil Mailing Address: Márcio Vinícius Lins de Barros, Rua Paracatu, 1451 Apt 500. Postal Code 30180-091, Santo Agostinho, Belo Horizonte, MG - Brazil. E-mail: mvbarros@cardiol.br, marciovlbarros@gmail.com

Author contributions

Conception and design of the research and critical revision of the manuscript for intellectual contente: Barros MVL, Macedo AVS, Sarvari SI, Faleiros MH, Felipe PT, Silva JLP, Edvardsen T; acquisition of data: Barros MVL, Faleiros MH, Felipe PT; analysis and interpretation of the data: Barros MVL, Macedo AVS, Sarvari SI, Silva JLP; statistical analysis: Silva JLP; writing of the manuscript: Barros MVL, Macedo AVS, Sarvari SI, Felipe PT, Edvardsen T.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 13 12 2018 1 2019 112 1 50 56 30 03 2018 05 07 2018 23 07 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background:

Chemotherapeutic agents of anthracyclines class and humanized monoclonal antibodies are effective treatments for breast cancer, however, they present a potential risk of cardiotoxicity. Several predictors have been recognized as predictors in the development of cardiac toxicity, and the evaluation of left ventricular segmental wall motion abnormalities (LVSWMA) has not been studied.

 Objective:

To analyze prospectively the role of LVSWMA among echocardiographic parameters in the prediction of development of cardiotoxicity in breast cancer patients undergoing treatment with chemotherapy.

 Methods:

Prospective cohort of patients diagnosed with breast cancer and in chemotherapy treatment with potential cardiotoxicity medications including doxorubicin and trastuzumab. Transthoracic echocardiograms including speckle tracking strain echocardiography were performed at standard times before, during and after the treatment to assess the presence (or lack thereof) of cardiotoxicity. Cardiotoxicity was defined by a 10% decrease in the left ventricular ejection fraction, on at least one echocardiogram. Multivariate logistic regression models were used to verify the predictors related to the occurrence of cardiotoxicity over time.

 Results:

Of the 112 patients selected (mean age 51,3 ± 12,9 years), 18 participants (16.1%) had cardiotoxicity. In the multivariate analysis using the logistic regression model, those with LVWMA (OR = 6.25 [CI 95%: 1.03; 37.95], p < 0,05), LV systolic dimension (1.34 [CI 95%: 1.01; 1.79], p < 0,05) and global longitudinal strain by speckle tracking (1.48 [CI 95%: 1.02; 2.12], p < 0,05) were strongly associated with cardiotoxicity.

 Conclusion:

In the present study, we showed that LVWMA, in addition to global longitudinal strains, were strong predictors of cardiotoxicity and could be useful in the risk stratification of these patients.

 Keywords: Ventricular Dysfunction, Left Drug Therapy Cardiotoxicity Breast Neoplasms Anthracyclines Trastuzumab Introduction

The introduction of new chemotherapeutic agents, and the use of advanced and precise radiotherapy techniques in the last decades have dramatically improved breast cancer survival.1 Chemotherapeutic drugs of the anthracycline class, and the humanized monoclonal antibodies, such as trastuzumab, are widely used and highly effective agents for breast cancer treatment.2 Unfortunately, anthracyclines can induce cardiotoxic effects, and the severity of these adverse effects is compounded by concomitant use of trastuzumab.3

Chemotherapy may induce numerous cardiovascular complications, including hypertension, congestive heart failure, thromboembolic diseases, ischemic heart disease, QT prolongation, and bradycardia.3 When used in combination, anthracyclines and trastuzumab may result in heart failure in up to 27% of patients.4 Among cancer survivors, a third will die of cardiovascular disease. Thus, the need for optimal cardiac care in the cancer population has become evident. Early detection of cardiac dysfunction may allow implementation of cardioprotective strategies before potentially irreversible myocardial damage has occured.5

The definition of cancer therapy-related cardiac dysfunction (CTRCD) is based on a serial decline in left ventricular (LV) ejection fraction (EF). Two-dimensional echocardiography (2DE) is increasingly used for monitoring cardiac function during cancer treatment due to its widespread availability and safety. Echocardiography allows assessment of systolic and diastolic function, pulmonary pressures, valvular function, right ventricular function, and the pericardium.6

Reduction in LV EF likely occurs late in the natural history of CTRCD patients as reduction in LV EF may not be overt until a substantial amount of myocardial reserve has been 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). CTRCD was 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 treated with 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.

 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.

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/m2) 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).

Of the 112 patients followed up, 18 (16.1%) presented CTRCD.

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.

Characteristics in patients with segmental wall motion abnormality during chemotherapy
Patient Age Treatment* Abnormal contraction Echocardiographic follow-up Risk factors CTRCD Follow-up
2 49 1,2, Infero-septal Hypokinesis 5 no yes Death
5 40 1,2 Abnormal Septal motion 2 no yes NYHA I
12 68 1,2 Ínfero-lateral Hypokinesis 5 no yes NYHA I
21 30 1,2 Abnormal Septal motion 3 dyslipidemia no
27 43 1,2 Abnormal Septal motion 2 no no
52 73 1, inferior Hypokinesis 4 Diabetes, Hypertension yes NYHA I
63 53 1 Septal Hypokinesis 2 no no
67 77 1,2 Abnormal Septal motion 4 hypertension yes NYHA II
72 44 1,2 Abnormal Septal motion 2 no no
84 59 1,2 Inferior Hypokinesis 4 no no
88 34 1 Abnormal Septal motion 3 no no
92 39 1 Abnormal Septal motion 3 no yes death
100 41 1 Infero-septal Hypokinesis 2 no no
110 62 1 Septal hypokinesis 2 no yes NYHA !

1: anthracycline; 2: transtuzumab; CTRCD: cancer therapy-related cardiac dysfunction.

Two-dimensional echocardiography-guided M-mode showing abnormal motion of interventricular septum (arrow) during chemotherapy treatment. LV: left ventricle; RV: right ventricle.

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.

Univariate analyses of predictors related of cardiotoxicity
Variable O.R. 95% CI p
Age 1.03 [0.99; 1,07] 0.151
LVDD 1.22 [0.99; 1.50] 0.061
LVSD 1.69 [1.35; 2.12] 0.000
Diastolic dysfunction 3.55 [1.34; 9.44] 0.011
Regional wall motion abnormality 8,91 [2.75; 28.82] 0.000
LA 0.95 [0.78; 1.16] 0.624
GLS 1.96 [1.25; 3.09] 0.022
PASP 1.86 [0.32; 10.99] 0.491
BNP 1.24 [00.91; 1.70] 0.306
Troponin 3.36 [0.49; 23.14] 0.219
Creatinine 0.04 [0.00; 2.20] 0.113
Hemoglobin 0.90 [0.60; 1.35] 0.608
Sodium 1.01 [0.98; 1.03] 0.623
Potassium 1.33 [0.51; 3.51] 0.559
Calcium 1.06 [0.81; 1.39] 0.657
Magnesium 6.20 [0.67; 57.73] 0.204
Hypertension 0.79 [0.26; 2.39] 0.673
Dyslipidemia 0.41 [0.07; 2.21] 0.298
Diabetes 1.15 [0.15; 8.83] 0.894

LVDD: left ventricular diastolic dimension; LVSD: left ventricular systolic dimension; GLS: global longitudinal strain; LA: left atrium dimension; PASP: pulmonary artery systolic pressure; BNP: brain natriuretic peptidium.

 Multivariate analysis of predictors related of cardiotoxicity
Variable O.R. 95% CI p
LVSD 1.34 [1.01; 1.79] 0.044
Regional wall motion abnormality 6.25 [1.03; 37.95] 0.046
GLS 1,48 [1,02; 2.12] 0.036

LVSD: left ventricular systolic dimension; GLS: global longitudinal strain.

Roc curve of the multivariate model with and without evaluation of segmental abnormal contractility.

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 diffuse myocardial 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 anthracycline24,25 and transtuzumab26,27 induced cardiotoxicity. Development of diastolic dysfunction has been reported in up to 57% of patients after treatment with anthracyclines or anthracyclines plus trastuzumab.28 Cochet et al.28 Serrano et al.29 evaluated MUGA-derived diastolic parameters and found that impaired LV diastolic function before treatment was an independent predictor of trastuzumab-mediated cardiotoxicity. Boyd at al.18 showed in a cohort involving 140 patients followed for seven days that LV diastolic dysfunction grade significantly increased from 46% to 57% (p < 0.001) after treatment with anthracyclines. Importantly, diastolic dysfunction was more prevalent in the subgroup with a significant reduction in GLS, demonstrating the close association between systolic and diastolic dysfunction.18 A study using MUGA-derived diastolic function parameters investigated whether impairment of systolic function was preceded by diastolic dysfunction in a group of 77 female breast cancer patients undergoing trastuzumab therapy. The results of this study showed a nearly even number of patients with diastolic dysfunction preceding systolic dysfunction (54%), as compared to the number of patients with the opposite order (42%).30 Discrepancy among those studies is probably related to the different designs and interpretation of the results.

Limitations

All patients were recruited from one center and the study consisted of a limited number of patients. The study was limited by a short duration of patient follow-up, and therefore any possible long term impact of the early echocardiography abnormalities are uncertain. Long term follow up is therefore necessary to determine the significance of these early observations. The proposed treatment was individually defined, including the use of cardio-protective drugs, which may have influenced our results.

 Conclusion

In this prospective cohort of 112 patients undergoing treatment with chemotherapy for breast cancer, we found segmental wall motion abnormality to be a strong predictor of cardiotoxicity. Therefore, assessment of segmental wall motion might be a useful tool in the evaluation of patients at risk of developing CTRCT, resulting in early detection of myocardial dysfunction and potential reduction in morbidity and mortality in these patients.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Faculdade de Saúde e Ecologia Humana (FASEH) under the protocol number CAAE 55029916.6.0000.5101. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

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Med Ultrason. 2015;17(4):496-502. Emren SV Tuluce SY Levent F Tuluce K Kalkan T Alacacioglu A Evaluation of Trastuzumab-induced early cardiac dysfunction using two dimensional Strain Echocardiography Med Ultrason 2015 17 4 496 502 23 Fei HW, Ali MT, Tan TC, Cheng KH, Salama L, Hua L, et al. Left ventricular global longitudinal strain in HER-2 + breast cancer patients treated with anthracyclines and trastuzumab who develop cardiotoxicity is associated with subsequent recovery of left ventricular ejection fraction. Echocardiography. 2016;33(4):519-26. Fei HW Ali MT Tan TC Cheng KH Salama L Hua L Left ventricular global longitudinal strain in HER-2 + breast cancer patients treated with anthracyclines and trastuzumab who develop cardiotoxicity is associated with subsequent recovery of left ventricular ejection fraction Echocardiography 2016 33 4 519 526 24 Lee BH, Goodenday LS, Muswick GJ, Yasnoff WA, Leighton RF, Skeel RT. Alterations in left ventricular diastolic function with doxorubicin therapy. J Am Coll Cardiol. 1987;9(1):184-8. Lee BH Goodenday LS Muswick GJ Yasnoff WA Leighton RF Skeel RT Alterations in left ventricular diastolic function with doxorubicin therapy J Am Coll Cardiol 1987 9 1 184 188 25 Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R, et al. Early detection of doxorubicin cardiotoxicity: Interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J. 1989;118(1):92-8. Marchandise B Schroeder E Bosly A Doyen C Weynants P Kremer R Early detection of doxorubicin cardiotoxicity: Interest of Doppler echocardiographic analysis of left ventricular filling dynamics Am Heart J 1989 118 1 92 98 26 Lange SA, Ebner B, Wess A, Kogel M, Gajda M, Hitschold T, et al. Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy. Clin Res Cardiol. 2012;101(6):415-26. Lange SA Ebner B Wess A Kogel M Gajda M Hitschold T Echocardiography signs of early cardiac impairment in patients with breast cancer and trastuzumab therapy Clin Res Cardiol 2012 101 6 415 426 27 Cao L, Cai G, Chang C, Miao AY, Yu XL, Yang ZZ, et al. Diastolic dysfunction occurs early in her2-positive breast cancer patients treated concurrently with radiation therapy and trastuzumab. Oncologist. 2015;20(6):605-14. Cao L Cai G Chang C Miao AY Yu XL Yang ZZ Diastolic dysfunction occurs early in her2-positive breast cancer patients treated concurrently with radiation therapy and trastuzumab Oncologist 2015 20 6 605 614 28 Cochet A, Quilichini G, Dygai-Cochet I, Touzery C, Toubeau M, Berriolo- Riedinger A, et al. Baseline diastolic dysfunction as a predictive factor of trastuzumab- mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer. Breast Cancer Res Treat. 2011;130(3):845-54. Cochet A Quilichini G Dygai-Cochet I Touzery C Toubeau M Berriolo- Riedinger A Baseline diastolic dysfunction as a predictive factor of trastuzumab- mediated cardiotoxicity after adjuvant anthracycline therapy in breast cancer Breast Cancer Res Treat 2011 130 3 845 854 29 Serrano JM, Gonzalez I, Del Castillo S, Muniz J, Morales LJ, Moreno F, et al. Diastolic dysfunction following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors. Oncologist. 2015;20(8): 864-72. Serrano JM Gonzalez I Del Castillo S Muniz J Morales LJ Moreno F Diastolic dysfunction following anthracycline-based chemotherapy in breast cancer patients: Incidence and predictors Oncologist 2015 20 8 864 872 30 Reuvekamp EJ, Bulten BF, Nieuwenhuis AA, Meekes MRA, de Haan AFJ, Tol J, et al. Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity? Assessment with multigated radionuclide angiography (MUGA). J Nucl Cardiol. 2016;23(4):824-32. Reuvekamp EJ Bulten BF Nieuwenhuis AA Meekes MRA de Haan AFJ Tol J Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity: Assessment with multigated radionuclide angiography (MUGA) J Nucl Cardiol 2016 23 4 824 832 Artigo Original Alteração Contrátil Segmentar Ventricular Esquerda é Preditor Independente de Cardiotoxicidade em Pacientes com Câncer de Mama em Tratamento Quimioterápico 0000-0002-6213-3226 Barros Márcio Vinícius Lins de 1 2 Macedo Ariane Vieira Scarlatelli 2 Sarvari Sebastian Imre 3 Faleiros Monica Hermont 2 Felipe Patricia Tavares 2 Silva Jose Luiz Padilha 4 Edvardsen Thor 3 Faculdade de Saúde e Ecologia Humana, Vespasiano, MG - Brasil Rede Materdei de Saúde Belo Horizonte, MG - Brasil University of Oslo, Oslo - Noruega Universidade Federal do Paraná, Curitiba, PR - Brasil Correspondência: Márcio Vinícius Lins de Barros, Rua Paracatu, 1451 Apt 500. CEP 30180-091, Santo Agostinho, Belo Horizonte, MG - Brasil. E-mail: mvbarros@cardiol.br, marciovlbarros@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa e revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Barros MVL, Macedo AVS, Sarvari SI, Faleiros MH, Felipe PT, Silva JLP, Edvardsen T; obtenção de dados: Barros MVL, Faleiros MH, Felipe PT; análise e interpretação dos dados: Barros MVL, Macedo AVS, Sarvari SI, Silva JLP; análise estatística: Silva JLP; redação do manuscrito: Barros MVL, Macedo AVS, Sarvari SI, Felipe PT, Edvardsen T.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo Fundamento:

Os agentes quimioterápicos da classe das antraciclinas e dos anticorpos monoclonais humanizados são tratamentos eficazes para o câncer de mama, entretanto, apresentam alto risco de cardiotoxicidade. Diversos parâmetros têm sido reconhecidos como preditores no desenvolvimento de toxicidade cardíaca, sendo que a avaliação da alteração contrátil segmentar ventricular esquerda (ACSVE) ainda não foi estudada.

 Objetivo:

Analisar a associação entre o surgimento de ACSVE e o desenvolvimento de cardiotoxicidade em pacientes com câncer de mama em tratamento com quimioterapia.

 Métodos:

Coorte prospectiva de pacientes diagnosticados com câncer de mama e em tratamento quimioterápico com doxorrubicina e/ou trastuzumab. Foram realizados ecocardiogramas transtorácicos antes, durante e depois do tratamento para avaliar a presença ou não de cardiotoxicidade. A cardiotoxicidade foi definida por um decréscimo de 10% na fração de ejeção do ventrículo esquerdo, em pelo menos um ecocardiograma. Modelos de regressão logística multivariada foram utilizados para verificar os fatores preditores na ocorrência de cardiotoxicidade ao longo do tempo.

 Resultados:

Dos 112 pacientes selecionados (idade média = 51,3 ± 12,9 anos), 18 (16,1%) apresentaram cardiotoxicidade. Na análise multivariada os pacientes com ACSVE (OR = 6,25 [IC 95%: 1,03; 37,95], p < 0,05), diâmetro sistólico do VE (OR = 1,34 [IC 95%:1,01; 1,79], p < 0,05) e strain longitudinal global pela técnica de speckle tracking (OR = 1,48 [IC 95%: 1,02; 2,12], p < 0,05) foram preditores significativos e independentes na predição de cardiotoxidade.

 Conclusão:

Mostramos que ACSVE, bem como a redução do strain longitudinal global foram preditores independentes para cardiotoxicidade, podendo ser úteis na estratificação de risco destes pacientes.

 Palavras-chave: Disfunção Ventricular Esquerda Tratamento Farmacológico Cardiotoxicidade Neoplasias da Mama Antraciclinas Trastuzumab Introdução

A introdução de novos agentes quimioterápicos e o uso de técnicas avançadas e precisas de radioterapia nas últimas décadas melhoraram a sobrevida do câncer de mama.1 Os medicamentos quimioterápicos da classe das antraciclinas e os anticorpos monoclonais humanizados, como o trastuzumab, são amplamente utilizados e agentes eficazes para o tratamento do câncer de mama.2 Infelizmente, as antraciclinas podem induzir efeitos cardiotóxicos, e a gravidade desses efeitos adversos é agravada pelo uso concomitante de trastuzumab.3

A quimioterapia pode trazer várias complicações cardiovasculares, incluindo hipertensão, insuficiência cardíaca congestiva, doenças tromboembólicas, cardiopatia isquêmica, prolongamento do intervalo QT e bradicardia.3 Quando usadas em conjunto, as antraciclinas e trastuzumab podem causar insuficiência cardíaca em até 27% dos pacientes.4 Entre os sobreviventes de câncer, um terço morrerá de doença cardiovascular, tornando-se importante a necessidade de cuidados cardíacos na população com câncer. A detecção precoce da disfunção cardíaca pode permitir a implementação de estratégias cardioprotetoras antes que o dano miocárdico, potencialmente irreversível, tenha ocorrido.5

A definição de disfunção cardíaca relacionada à terapia do câncer (DCRTA) é baseada em um declínio em série na fração de ejeção (FE) do ventrículo esquerdo (VE). A ecocardiografia bidimensional (2DE) é cada vez mais usada para monitorar a função cardíaca durante o tratamento do câncer devido à sua ampla disponibilidade e acurácia. A ecocardiografia permite avaliar a função sistólica e diastólica, as pressões pulmonares, a função valvular, a função ventricular direita e o pericárdio.6

A redução na FEVE provavelmente ocorre tardiamente na história natural dos pacientes com DCRTA, já que a redução da FEVE pode não ser evidente até que uma quantidade substancial de reserva miocárdica esteja esgotada. Portanto são necessárias modalidades mais sensíveis para a avaliação da disfunção subclínica do VE. Apesar do reconhecimento de vários parâmetros ecocardiográficos associados à DCRTA, incluindo avaliação da mecânica miocárdica derivados da ecocardiografia, como strain e strain rate, atualmente não há consenso na prática médica para prever quais pacientes estão propensos a desenvolver cardiotoxicidade.6-8 Estudos anteriores demonstraram a presença de disfunção miocárdica regional em pacientes com DCRTA,9-11 no entanto, seu papel como preditor de risco não foi estabelecido. O objetivo deste estudo é verificar a associação entre a ocorrência da alteração contrátil segmentar ventricular esquerda e o desenvolvimento de cardiotoxicidade em pacientes com câncer de mama em tratamento com quimioterapia.

 Métodos População do estudo

Este estudo é parte de um estudo de coorte prospectivo de pacientes com câncer de mama recrutados no Hospital Mater Dei em Belo Horizonte - MG de janeiro de 2010 a dezembro de 2016. Os critérios de inclusão foram: idade acima de 18 anos, diagnóstico de câncer de mama histologicamente confirmado, tratamento com doxorrubicina e/ou trastuzumab, e que realizaram ecocardiograma, de acordo com as normas do protocolo hospitalar. Os critérios de exclusão foram pacientes com diagnóstico prévio de disfunção ventricular, incluindo anormalidade contrátil regional, valvopatia significativa, cardiopatia congênita, arritmias, doença arterial coronariana crônica e bloqueio de ramo esquerdo por eletrocardiografia. Os esquemas de tratamento ficaram a critério do oncologista e consistiram no uso dos seguintes medicamentos isoladamente ou em combinação: 1) doxorrubicina e ciclofosfamida; 2) paclitaxel; 3) trastuzumab. As dosagens dos medicamentos foram prescritas de acordo com as diretrizes.12

Foram avaliados diversos parâmetros clínicos (por exemplo: hipertensão, dislipidemia, diabetes), laboratoriais (por exemplo: sódio, potássio, cálcio, magnésio, hemoglobina, creatinina e BNP) e ecocardiográficos antes, durante e após o término do tratamento coletados em intervalos de tempo padronizados para cada regime de tratamento.

 Ecocardiografia

Todos os pacientes fizeram um ecocardiograma transtorácico, incluindo avaliação strain longitudinal com ecocardiograma bidimensional de rastreamento do speckle-tracking (2D STE). Os estudos e análises ecocardiográficas foram realizados por um Ecocardiografista experiente (M.V.L.B.). Os seguintes parâmetros ecocardiográficos foram avaliados: diâmetros sistólico final e diastólico final do VE e diâmetro atrial esquerdo. A FEVE foi avaliada pelo método de Simpson. A avaliação visual da função miocárdica regional foi avaliada com base no espessamento parietal e no movimento endocárdico do segmento miocárdico, como descrito previamente.13 O movimento septal anormal foi caracterizado como um movimento atípico do septo interventricular durante o ciclo cardíaco com uma abordagem do modo M guiada pela ecocardiografia bidimensional. A função diastólica foi avaliada e classificada por meio de critérios previamente publicados.14 A disfunção diastólica do VE foi estratificada em quatro graus como: 0-normal, 1-relaxamento alterado, 2-padrão pseudonormal e 3-restritivo.

A deformação longitudinal pelo 2D STE foi obtida a partir de cortes apicais de quatro câmaras, duas câmaras e eixo longo. Três ciclos cardíacos de cada visualização foram registrados para análises com uma taxa de frame rate > 50 frames/seg. A deformação longitudinal máxima negativa foi avaliada em 16 segmentos do VE, definidos como o valor máximo de pico durante todo o ciclo cardíaco, portanto incluindo o encurtamento pós-sistólico, e foi calculada a média da strain longitudinal global (SLG). DCRTA foi definida como uma diminuição na FEVE > 10 pontos percentuais, para um valor < 53% em exames de imagem cardíaca repetidos durante o acompanhamento após a quimioterapia.15

Os estudos ecocardiográficos foram realizados em intervalos padronizados de acordo com o tratamento. 1) os pacientes tratados com antraciclinas sem trastuzumab foram submetidos a um estudo ecocardiográfico no início, no final e a cada seis meses após o término da quimioterapia. 2) os doentes tratados com antraciclinas e trastuzumab foram submetidos a um estudo ecocardiográfico no início e após a conclusão de tratamento com antraciclina, a cada 3 meses durante a terapêutica com trastuzumab e a cada seis meses após o tratamento completo. 3) os doentes tratados com trastuzumab sem antraciclinas foram submetidos a um estudo ecocardiográfico no início, a cada 3 meses durante o tratamento com trastuzumab e a cada seis meses após o tratamento completo.

A avaliação ecocardiográfica foi concluída em pacientes com pelo menos três estudos ecocardiográficos realizados durante o período do tratamento.

 Análise estatística

Para descrever as variáveis qualitativas, foram utilizadas as frequências absolutas e relativas, enquanto para descrever as variáveis quantitativas, foram utilizadas medidas de tendência central e dispersão.

A fim de identificar os fatores que influenciaram a ocorrência de cardiotoxicidade ao longo do tempo, foi utilizada a abordagem de Equações de Estimação Generalizadas (GEE). Uma estrutura de correlação substituível foi assumida para as observações repetidas do mesmo indivíduo. Modelos univariados e multiariados foram considerados. Não houve ocorrência de cardiotoxicidade na primeira ocasião da medição e, portanto, também incluímos os valores basais dos preditores dependentes. Valores faltantes foram excluídos das análises. Variáveis estatisticamente significantes no nível 0,20 foram incluídas no modelo multivariado. Para este modelo final, adotou-se um nível de significância de 0,05. A reprodutibilidade da avaliação visual da função miocárdica regional anormal foi avaliada pela estatística kappa.

Curvas ROC foram criadas e a habilidade de discriminação do modelo foi avaliada pela área sob a curva ROC. Todas as análises estatísticas foram realizadas usando o R Statistical Software 3.4.1 e os pacotes R gee, pROC e PredictABEL.

 Considerações éticas

O estudo está em conformidade com a Declaração de Helsinque e foi aprovado pelo Comitê de Ética do Hospital.

 Resultados População estudada

Um total de 112 pacientes foram incluídos. O tempo médio de seguimento foi de 491 dias. As características da população estudada estão resumidas na Tabela 1. A maioria dos pacientes da coorte era do sexo feminino (98,2%). A idade média foi de 51,3 ± 12,9 anos.

Características clínicas e laboratoriais de 112 pacientes submetidos a quimioterapia
Variável n
Idade (média ± DP) 51,4 ± 11,1
Feminino (n/%) 111 (99,1%)
IMC (kg/m2) 26,1 ± 5,8
Mastectomia (n/%) 111 (99,1%)
Tempomédiode acompanhamento (meses) 16
Radioterapia (n/%) 74 (66)
Quimioterapia (n/%)
AC-T 90 (80)
Anti HER2 29 (26)
Outras 20 (18)
Terapia hormonal (n/%) 72 (64)
Fatores de risco cardiovascular (n/%)
Hipertensão 39 (35)
Diabetes 8 (7)
Hiperlipidemia 21 (19)
Tabagismo 25 (22)

IMC: índice de massa corporal; AC-T: Doxorrubicina/ ciclofosfamida -Taxol (Paclitaxel).

Dos 112 pacientes acompanhados, 18 (16,1%) apresentavam DCRTA.

As características dos pacientes com alteração contrátil segmentar ventricular esquerda estão resumidas na tabela 2. A alteração contrátil segmentar ventricular esquerda foi encontrada em 16 (14%) pacientes, mais frequente no segundo estudo ecocardiográfico (43%). A análise da alteração contrátil segmentar ventricular esquerda por avaliação visual mostrou anormalidades mais frequentes nas paredes do septo interventricular (78,5% - Figura 1), inferior (14,3%) e inferolateral (7,1%). Durante o seguimento, nenhum paciente apresentou bloqueio de ramo esquerdo pelo estudo eletrocardiográfico.

Características em pacientes com alteração contrátil segmentar durante a quimioterapia
Paciente Idade Tratamento* Contração anormal Acompanhamento ecocardiografico Fatores de risco DCRTA Acompanhamento
2 49 1,2 Hipocinesia Infero-septal 5 Não Sim Morte
5 40 1,2 Movimento septal anormal 2 Não Sim NYHA I
12 68 1,2 Hipocinesia Ínferolateral 5 Não Sim NYHA I
21 30 1,2 Movimento septal anormal 3 Dislipidemia Não
27 43 1,2 Movimento septal anormal 2 Não Não
52 73 1 Hipocinesia Inferior 4 Diabetes, Hipertensão Sim NYHA I
63 53 1 Hipocinesia septal 2 Não Não
67 77 1,2 Movimento septal anormal 4 Hipertensão Sim NYHA II
72 44 1,2 Movimento septal anormal 2 Não Não
84 59 1,2 Hipocinesia Inferior 4 Não Não
88 34 1 Movimento septal anormal 3 Não Não
92 39 1 Movimento septal anormal 3 Não Sim Morte
100 41 1 Hipocinesia Infero-septal 2 Não Não
110 62 1 Hipocinesia septal 2 Não Sim NYHA I

1: antraciclina; 2: transtuzumab; DCRTA: disfunção cardíaca relacionada à terapia do câncer; NYHA: New York Heart Association.

Ecocardiograma bidimensional modo M guiado que mostra o movimento anormal do septo interventricular (seta) durante a quimioterapia. VE: ventrículo esquerdo; VD: ventrículo direito.

Entre as variáveis estudadas, observou-se, na análise multivariada, que as medidas da SLG, bem como as dimensões sistólicas do VE e a presença de anormalidades de movimento da parede regional do VE no estudo basal, poderiam predizer o desenvolvimento de cardiotoxicidade (Tabelas 3 e 4). A análise da curva ROC do modelo final (Figura 2) mostrou área sob a curva (AUC) de 0,93 (0,88 - 0,98). Quando excluímos a presença de anormalidade de movimento de parede no modelo, a AUC foi de 0,84 (0,72- 0,96) mostrando poder preditivo aditivo dessa variável (p = 0,047). A variabilidade intra- observador e a variabilidade interobservador para a avaliação do movimento de parede foram de 0,89 e 0,81, respectivamente.

Análise univariada de preditores relacionados à cardiotoxicidade
Variável OR IC 95% p
Idade 1,03 [0,99; 1,07] 0,151
DDVE 1,22 [0,99; 1,50] 0,061
DSVE 1,69 [1,35; 2,12] 0,000
Disfunsão diastólica 3,55 [1,34; 9,44] 0,011
Alteração contrátil segmentar do VE 8,91 [2,75; 28,82] 0,000
AE 0,95 [0,78; 1,16] 0,624
SLG 1,96 [1,25; 3,09] 0,022
PSAP 1,86 [0,32; 10,99] 0,491
BNP 1,24 [00,91; 1,70] 0,306
Troponina 3,36 [0,49; 23,14] 0,219
Creatinina 0,04 [0,00; 2,20] 0,113
Hemoglobina 0,90 [0,60; 1,35] 0,608
Sódio 1,01 [0,98; 1,03] 0,623
Potássio 1,33 [0,51; 3,51] 0,559
Cálcio 1,06 [0,81; 1,39] 0,657
Magnésio 6,20 [0,67; 57,73] 0,204
Hipertensão 0,79 [0,26; 2,39] 0,673
Dislipidemia 0,41 [0,07; 2,21] 0,298
Diabetes 1,15 [0,15; 8,83] 0,894

DDVE: dimensão diastólica do ventrículo esquerdo; DSVE: dimensão sistólica do ventrículo esquerdo; SLG: strain longitudinal global; AE: dimensão do átrio esquerdo; PSAP: pressão sistólica da artéria pulmonar; BNP: peptídio natriurético cerebral.

 Análise multivariada de preditores relacionados à cardiotoxicidade
Variável OR IC 95% p
DSVE 1,34 [1,01; 1,79] 0,044
Alteração contrátil segmentar do VE 6,25 [1,03; 37,95] 0,046
SLG 1,48 [1,02; 2,12] 0,036

DSVE: dimensão sistólica do ventrículo esquerdo; SLG: strain longitudinal global.

Curva ROC do modelo multivariado com e sem alteração da contratilidade segmentar ventricular esquerda.

Discussão

Neste estudo de coorte longitudinal prospectivo, mostramos que a presença de distúrbios de movimento de parede regional e diminuição de SLG são preditores independentes de DCRTA.

Estudos histopatológicos anteriores realizados a partir de biópsias endomiocárdicas demonstraram um envolvimento inicialmente focal e disperso de miócitos, circundados por células normais em pacientes tratados com antraciclinas.16 À medida que a toxicidade evolui, a frequência dessas alterações aumenta, levando a danos miocárdicos significativos e, posteriormente, a fibrose miocárdica. Assim, a disfunção contrátil segmentar pode preceder o envolvimento intenso e difuso do coração visto no DCRTA. Nesse contexto, a dissincronia do septo interventricular, bem como a hipocinesia segmentar, podem estar presentes devido a edema tecidual e/ou dano celular focal.17

De fato, Piotrowsk et al.,9 demonstraram que em 60,9% dos pacientes com disfunção sistólica do VE foram observadas anormalidades regionais de movimento de parede no primeiro ecocardiograma que revelou uma queda significativa da FEVE. Na maioria desses casos (64%), a hipocinesia regional envolveu o septo interventricular.9 Estudos prévios utilizando Doppler tecidual e strain 2D também mostraram alterações contráteis regionais em pacientes tratados com quimioterapia.10,11 Boyd et al.18 demonstraram que no grupo com disfunção subclínica do VE (> 11% de redução no SLG comparado com antes do tratamento) 58% dos segmentos regionais tiveram uma redução no SLG > 11%, comparado a 29% dos segmentos regionais no grupo sem disfunção subclínica do VE (p < 0,001).18

É bem conhecido que a redução da deformação longitudinal é um fator preditivo precoce da cardiotoxicidade induzida pelo tratamento com antraciclinas e trastuzumab, como confirmado por nossos resultados. Negishi et al. mostraram que o SLG foi um preditor independente de reduções subsequentes na FE, com uma melhoria de discriminação pela adição de SLG de -18,6% dos parâmetros tradicionais pela ecocardiografia em pacientes com risco de cardiotoxicidade induzida pelo trastuzumab.19 Em outro estudo, Sawaya el al.,20 mostraram que, em pacientes com câncer de mama tratados com quimioterapia, a SLG medida no término da terapia com antraciclina foi útil na predição de cardiotoxicidade subsequente.20

Foi demonstrado em uma revisão sistemática que uma redução precoce de 10% a 15% na SLG foi um parâmetro útil para a predição de cardiotoxicidade.21 Um pequeno estudo de coorte associado à disfunção subclínica do VE mostrou que em 7 dias após o tratamento com trastuzumab22 apresentou diminuição significativa da SLG e da velocidade sistólica anular da parede lateral do VE. Fei et al.,23 encontraram em uma coorte de 95 pacientes tratados com antraciclina e trastuzumab, e acompanharam por um tempo médio de 17 meses, 20% com cardiotoxicidade, demonstrando uma associação significativa entre a redução da SLG e o declínio da FEVE.23

A presença de disfunção diastólica não foi um preditor independente de DCRTA em nosso estudo. O uso de disfunção diastólica como um marcador substituto para a predição da cardiotoxicidade induzida pelo trastuzmab é controverso. Estudos anteriores demonstraram que o comprometimento diastólico do VE ocorre antes da deterioração da FEVE na antraciclina24,25 e da cardiotoxicidade induzida pelo transtuzumab.26,27 O desenvolvimento de disfunção diastólica foi relatado em até 57% dos pacientes após o tratamento com antraciclinas ou antraciclinas mais trastuzumab.28 Cochet et al.,28 Serrano et al.,29 avaliaram os parâmetros diastólicos derivados da MUGA e demonstraram que redução da função diastólica do VE antes do tratamento era um preditor independente de cardiotoxicidade mediada pelo trastuzumab. Boyd et al.,18 mostraram em uma coorte envolvendo 140 pacientes que o grau de disfunção diastólica do VE aumentou significativamente de 46% para 57% (p < 0,001) em sete dias após o tratamento com antraciclinas. É importante ressaltar que a disfunção diastólica foi mais predominante no subgrupo com uma redução significativa do SLG, demonstrando a íntima associação entre disfunção sistólica e diastólica.18 Um estudo usando parâmetros de função diastólica derivados da MUGA investigou se o comprometimento da função sistólica era precedido por disfunção diastólica em um grupo de 77 mulheres com câncer de mama em tratamento com trastuzumab. Os resultados deste estudo mostraram um número quase igual de pacientes com disfunção diastólica precedendo a disfunção sistólica (54%), em comparação com o número de pacientes com ordem inversa (42%).30 A discrepância entre esses estudos provavelmente está relacionada aos diferentes desenhos metodológicos e interpretação dos resultados.

Limitações

Todos os pacientes foram recrutados no centro e o estudo consistiu com um número limitado de pacientes. O estudo foi limitado por um curto período de acompanhamento do paciente e, portanto, qualquer possível impacto a longo prazo das alterações evidenciadas pelo estudo é incerto. O acompanhamento a longo prazo é, portanto, necessário para determinar a significância dessas observações iniciais. O tratamento proposto foi definido individualmente, incluindo o uso de drogas cardioprotetoras, o que pode ter influenciado nossos resultados.

 Conclusão

Nesta coorte de 112 pacientes submetidos a tratamento de câncer de mama com quimioterapia, demonstramos que a alteração contrátil segmentar é um preditor independente de cardiotoxicidade, podendo ser uma ferramenta útil na avaliação de pacientes com risco de desenvolver CTRCT, resultando na detecção precoce da disfunção miocárdica e potencial redução na morbidade e mortalidade nesses pacientes.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética da Faculdade de Saúde e Ecologia Humana (FASEH) sob o número de protocolo CAAE 55029916.6.0000.5101. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo.