Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC sR36kL7tHGCF6wwKBmw4pZq S0066-782X2018000300229 10.5935/abc.20180047 Short Editorial What is the Role of Two-Dimensional Speckle Tracking Echocardiography in the Diagnosis and Management of Anthracycline-Induced Cardiotoxicity? Costa Isabela Bispo Santos da Silva 1 Hajjar Ludhmila Abrahão 1 2 Universidade de São Paulo Faculdade de Medicina Hospital das Clínicas São Paulo SP Brazil Instituto do Câncer do Estado de São Paulo - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (ICESP-HC-FMUSP), São Paulo, SP - Brazil Universidade de São Paulo Universidade de São Paulo Faculdade de Medicina Hospital das Clínicas São Paulo SP Brazil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (INCOR - HC-FMUSP) São Paulo, SP - Brazil Universidade de São Paulo Mailing Address: Ludhmila Abrahão Hajjar, Endereço: Av. Dr. Arnaldo, 251 10 andar. Postal Code 01246-000, Cerqueira César, São Paulo, SP - Brazil. E-mail: ludhmila@usp.br 03 2018 110 3 229 230 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 Keywords: Neoplasms Cardiotoxicity Anthracyclines / toxicity Ventricular Dysfunction Troponin Natriuretic Peptides Echocardiography Speckle-Tracking

The increasing number of patients with neoplasms and survivors1,2 has raised the interest of the scientific community in the diagnosis and early management of the effects of neoplasms and/or their treatments on patients. In that scenario, the injury caused to the cardiovascular system belongs to a spectrum and can impair all cardiovascular system structures in a clinically variable way, ranging from asymptomatic forms to cardiovascular death. Most studies on cardiotoxicity have focused on ventricular dysfunction because of its presentation severity and because it is the major cause of late non-oncologic mortality of neoplasm survivors.3

In oncologic patients, the drugs most commonly related to ventricular dysfunction are anthracyclines.4 Recent studies have reported that the damage related to those drugs, if not identified and treated early, evolves continuously from cell injury to ventricular dysfunction. In the past decade, several studies showed that the subclinical detection of cardiotoxicity, by use of biomarkers, such as troponin and BNP, might be an opportunity to prevent cardiovascular injury, allowing for early treatment and more appropriate individualized follow-up.5-8

Another current challenge regarding cardiotoxicity is to understand the natural history of neoplasm survivors. Little is known about the prevalence of cardiovascular disease in those patients, and, thus, no long-term follow-up strategy has been defined for them.

In this issue of the Arquivos Brasileiros de Cardiologia, Kang et al.9 make a relevant contribution to the diagnosis of anthracycline-induced cardiotoxicity. In a cohort of survivors of non-Hodgkin's diffuse large B cell lymphoma treated with anthracyclines, those authors have shown that, as compared to healthy controls, those patients have lower values of circumferential and longitudinal strains on echocardiography in a population with normal ejection fraction. Such findings have been evidenced mainly by changes in the subendocardial segments. In accordance with previous studies,10 those authors have emphasized the radial strain measure to be of little importance in that population. Inter- and intraobserver analyses reinforce that data obtained can be safely reproducible.

Kang et al.9 have not observed a direct relationship between anthracycline doses and strain values, suggesting that the myocardial damage, reflected on impaired myocardial deformation, can occur even at doses considered non-cardiotoxic (lower than 240 mg/m2), provided that the population studied used doses ranging from 150.94 mg/m2 to 440.00 mg/m2.

That was an observational study with a small sample, but its finding is clinically relevant and should be explored. It is yet to be defined whether that finding is only a marker of chemotherapeutic response or whether it represents the beginning of the pathophysiology of the clinically manifest cardiovascular lesion. Further studies are required to clarify whether the neoplasm itself, through its endothelial changes, could be related to changes in strain.

Even without definite responses, the study by Kang et al.9 contributes to reinforce the importance of combining the clinical practice with a sensitive non-invasive method to aid the management of oncologic patients during and after chemotherapy.10,11

References 1 Instituto Nacional de Câncer José Alencar Gomes da Silva (INCA). Estimativa 2018: incidência de câncer no Brasil. Rio de Janeiro; 2017. Instituto Nacional de Câncer José Alencar Gomes da Silva Estimativa 2018: incidência de câncer no Brasil Rio de Janeiro 2017 2 Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220-41. Erratum in: CA Cancer J Clin. 2012;62(5):348. Siegel R DeSantis C Virgo K Stein K Mariotto A Smith T Cancer treatment and survivorship statistics, 2012 nullErratum in CA Cancer J Clin. 2012;62(5):348 CA Cancer J Clin 2012 62 4 220 241 3 Reulen RC, Winter DL, Frobisher C, Lancashire ER, Stiller CA, Jenney ME, et al; British Childhood Cancer Survivor Study Steering Group. Long-term cause-specific mortality among survivors of childhood cancer. JAMA. 2010;304(2):172-9. Reulen RC Winter DL Frobisher C Lancashire ER Stiller CA Jenney ME British Childhood Cancer Survivor Study Steering Group Long-term cause-specific mortality among survivors of childhood cancer JAMA 2010 304 2 172 179 4 Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2010 Jun 29;10:337. Smith LA Cornelius VR Plummer CJ Levitt G Verrill M Canney P Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomized controlled trials BMC Cancer 2010 06 29 10 337 337 5 Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Fabrizio V, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981-8. Cardinale D Colombo A Bacchiani G Tedeschi I Meroni CA Fabrizio V Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy Circulation 2015 131 22 1981 1988 6 Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M,et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474-81. Cardinale D Colombo A Sandri MT Lamantia G Colombo N Civelli M Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition Circulation 2006 114 23 2474 2481 7 Bosch X, Rovira M, Sitges M, Domènech A, Ortiz-Pérez JT, de Caralt TM, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013;61(23):2355-62. Bosch X Rovira M Sitges M Domènech A Ortiz-Pérez JT de Caralt TM Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) J Am Coll Cardiol 2013 61 23 2355 2362 8 Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37(21):1671-80. Gulati G Heck SL Ree AH Hoffmann P Schulz-Menger J Fagerland MW Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol Eur Heart J 2016 37 21 1671 1680 9 Kang Y, Xiao F, Chen H, Wang W, Shen L, Zhao H, et al. Subclinical Anthracycline-Induced Cardiotoxicity in the Long-Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis. Arq Bras Cardiol. 2018; 110(3):219-228. Kang Y Xiao F Chen H Wang W Shen L Zhao H Subclinical Anthracycline-Induced Cardiotoxicity in the Long-Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis Arq Bras Cardiol 2018 110 3 219 228 10 Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5(5):596-603. Sawaya H Sebag IA Plana JC Januzzi JL Ky B Tan TC Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab Circ Cardiovasc Imaging 2012 5 5 596 603 11 Yu W, Li SN, Chan GC, Ha SY, Wong SJ, Cheung YF. Transmural strain and rotation gradient in survivors of childhood cancers. Eur Heart J Cardiovasc Imaging 2013;14(2):175-82. Yu W Li SN Chan GC Ha SY Wong SJ Cheung YF Transmural strain and rotation gradient in survivors of childhood cancers Eur Heart J Cardiovasc Imaging 2013 14 2 175 182 Minieditorial Qual o Papel da Ecocardiografia Bidimensional com Speckle Tracking no Diagnóstico e Manejo da Cardiotoxicidade Induzida por Antraciclinas? Costa Isabela Bispo Santos da Silva 1 Hajjar Ludhmila Abrahão 1 2 Instituto do Câncer do Estado de São Paulo - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (ICESP-HC-FMUSP), São Paulo, SP - Brasil Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (INCOR - HC-FMUSP) São Paulo, SP - Brasil Correspondência: Ludhmila Abrahão Hajjar, Endereço: Av. Dr. Arnaldo, 251 10 andar. CEP 01246-000, Cerqueira César, São Paulo, SP - Brasil. E-mail: ludhmila@usp.br Palavras-chave: Neoplasias Cardiotoxicidade Antraciclinas / toxicidade Disfunção Ventricular Troponina Peptídeos Natriuréticos Ecocardiografia Speckle-Tracking

O crescente número de pacientes com neoplasias e de sobreviventes1,2 tem despertado na comunidade científica o interesse em diagnosticar e tratar precocemente os efeitos que as neoplasias e/ou seus tratamentos trazem aos pacientes. Nesse cenário, a injúria causada ao sistema cardiovascular é espectral, podendo acometer todas as estruturas do sistema cardiovascular, com variabilidade clínica desde formas assintomáticas até morte cardiovascular. A disfunção ventricular é o foco da maioria dos estudos de cardiotoxicidade pela gravidade de sua apresentação e por representar a principal causa de mortalidade tardia não oncológica nos sobreviventes de neoplasias.3

As antraciclinas são as drogas mais comumente relacionadas à disfunção ventricular em pacientes oncológicos.4 Estudos recentes relataram que o dano relacionado a essas drogas ocorre de modo contínuo a partir da lesão celular e evolui para a disfunção ventricular quando não identificado e tratado de modo precoce. Na última década, vários estudos foram publicados demonstrando que a detecção subclínica de cardiotoxicidade, por meio da liberação de biomarcadores como a troponina e o BNP, pode representar uma oportunidade de prevenção da injúria cardiovascular propriamente dita, propiciando tratamento precoce e seguimento individualizado mais adequado.5-8

Outro desafio atual na cardiotoxicidade é o entendimento da história natural dos sobreviventes das neoplasias. Pouco se conhece sobre a prevalência de doença cardiovascular nesse grupo, não estando definidas, portanto, as estratégias de seguimento a longo prazo desses pacientes.

Nessa edição, Kang et al.,9 apresentam contribuição relevante ao diagnóstico da cardiotoxicidade induzida por antraciclina. Em uma coorte de sobreviventes de linfoma não Hodgkin difuso de grandes células B tratados com antraciclinas, aqueles autores mostram que, quando comparados a controles saudáveis, esses pacientes têm menores valores de strain circunferencial e longitudinal mensurados pelo ecocardiograma em uma população de pacientes com fração de ejeção normal. Esses achados foram evidenciados primordialmente por alterações nos segmentos subendocárdicos. De modo semelhante a estudos anteriores,10 eles reforçam que a medida do strain radial tem pouca importância nessa população. A análise inter- e intraobservador reforça que os dados obtidos são reprodutíveis de modo seguro.

Kang et al.,9 não observaram relação direta entre a dose de antraciclina e os valores do strain, suscitando a ideia de que o dano ao miocárdio, refletido pela alteração da deformação miocárdica, pode ocorrer mesmo em doses consideradas não cardiotóxicas (menores que 240 mg/m2), uma vez que a população estudada fez uso de doses que variavam de 150,94 mg/m2 a 440,00 mg/m2.

Trata-se de um estudo observacional com pequeno número de pacientes, porém o achado tem relevância clínica a ser explorada à luz do conhecimento da cardiotoxicidade. Persiste a ser definido se tal achado é apenas um marcador de resposta quimioterápica ou se representa o início da fisiopatologia da lesão cardiovascular clinicamente manifesta. Outro fato a ser esclarecido com novos estudos é se a própria neoplasia, por suas alterações endoteliais, poderia estar relacionada a alterações no strain.

Mesmo sem respostas definitivas, o estudo de Kang et al.,9 adiciona à literatura mais dados para reforçar a importância de se aliar à prática clínica um método não invasivo com boa sensibilidade para auxiliar no manejo do paciente oncológico, durante e após o tratamento quimioterápico.10,11