Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC HXj5W6s9stZ9pNQDmCYGpnz S0066-782X2018000100102 10.5935/abc.20180009 Letter to the Editor Cardiac Cachexia - A Window to the Wasting Disorders Coats Andrew J Stewart Istituto di Ricovero e Cura a Carattere Scientifico Roma Italy IRCCS, San Raffaele-Pisana, Roma, Italy Mailing Address: Andrew, Monash University, 3068, Melbourne, Australia. 01 2018 110 1 102 103 13 08 2017 28 09 2017 28 09 2017 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: Cachexia Wasting Syndrome Exercise Nutritional Physiological Phenomena

To The Editor

I read with interest the recent review by Okoshi and colleagues in the journal.1 This was a thoroughly enjoyable read that reviewed the main areas of focus. I would like, however, to reinforce some of the arguments. In the section on neurohormonal blockade there has also been a successful phase 2 trial of the fourth generation beta-blocker espindolol in cancer cachexia.2,3 Clearly beta-blockers can be helpful also in cardiac cachexia given their crucial role in heart failure in general. Other cardiovascular drugs are also being explored for their beneficial or protective effects on skeletal muscle. These include, as the authors point out, the ACE inhibitor Imidapril. Others including trimetazidine are also being studied.4 One issue of difficulty is that we are starting from the point of no effective therapies and testing therapies one by one. The true multi-system complexity of cachexia and yet its similarity across different organ failure syndromes implies it will be a multi-barrelled approach that may be needed to solve it. We may need to combine neurohormonal blockade, immune modulation, nutritional and exercise support with pro-anabolic agents to get real clinical benefits. Perhaps as the authors point out Cardiac Cachexia where several of these agents are already on board may be a good place to start. The time for a much greater focus on all cachexias, including of course cardiac cachexia, is truly here and now.5

References 1 Okoshi MP, Capalbo RV, Romeiro FG, Okoshi K. Cardiac cachexia: perspectives for prevention and treatment. Arq Bras Cardiol. 2017;108(1):74-80. doi: 10.5935/abc.20160142. Okoshi MP Capalbo RV Romeiro FG Okoshi K Cardiac cachexia: perspectives for prevention and treatment Arq Bras Cardiol 2017 108 1 74 80 10.5935/abc.20160142 2 Stewart Coats AJ, Ho GF, Prabhash K, von Haehling S, Tilson J, Brown R, Beadle J, Anker SD; for and on behalf of the ACT-ONE study group. Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial). J Cachexia Sarcopenia Muscle. 2016;7(3):355-65. doi: 10.1002/jcsm.12126. Stewart Coats AJ Ho GF Prabhash K von Haehling S Tilson J Brown R Beadle J Anker SD ACT-ONE study group Espindolol for the treatment and prevention of cachexia in patients with stage III/IV non-small cell lung cancer or colorectal cancer: a randomized, double-blind, placebo-controlled, international multicentre phase II study (the ACT-ONE trial) J Cachexia Sarcopenia Muscle 2016 7 3 355 365 10.1002/jcsm.12126 3 Lainscak M, Laviano A. ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action beta-blocker. J Cachexia Sarcopenia Muscle. 2016;7(4):400-2. doi: 10.1002/jcsm.12136. Lainscak M Laviano A ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action beta-blocker J Cachexia Sarcopenia Muscle 2016 7 4 400 402 10.1002/jcsm.12136 4 Ferraro E, Pin F, Gorini S, Pontecorvo L, Ferri A, Mollace V, et al. Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine. J Cachexia Sarcopenia Muscle. 2016;7(4):449-57. doi:10.1002/jcsm.12097. Ferraro E Pin F Gorini S Pontecorvo L Ferri A Mollace V Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine J Cachexia Sarcopenia Muscle 2016 7 4 449 457 10.1002/jcsm.12097 5 Loncar G, Springer J, Anker M, Doehner W, Lainscak M. Cardiac cachexia: hic et nunc. J Cachexia Sarcopenia Muscle. 2016;7(3):246-60. doi: 10.1002/jcsm.12118. Loncar G Springer J Anker M Doehner W Lainscak M Cardiac cachexia: hic et nunc J Cachexia Sarcopenia Muscle 2016 7 3 246 260 10.1002/jcsm.12118 Reply Okoshi Marina P. Capalbo Rafael V. Romeiro Fernando G. Okoshi Katashi

We truly appreciate the comments on our review manuscript published in the journal.1 The authors reinforced our point of view by citing some papers published after the submission of our manuscript. We agree that we should immediately initiate a greater focus on cachexia of all causes aiming its prevention and treatment. While nutritional support has been long recommended for cachexia management, only more recently was exercise highlighted as a tool to manage muscle wasting and sarcopenia.2-4 As correctly pointed out, due the capacity to prevent body weight loss in heart failure patients with reduced ejection fraction, neurohormonal blockade has also been evaluated in non-cardiac cachexia. However, concerning other therapies such as immune modulation and pro-anabolic agents, there is no convincingly evidence for a positive response3,5,6 suggesting that additional studies are needed before we can effectively prevent and treat cachexia associated with different diseases including chronic heart and renal failure, cancer, and chronic obstructive pulmonary disease.

Marina P. OkoshiRafael V. CapalboFernando G. RomeiroKatashi Okoshi References 1 Okoshi MP, Capalbo RV, Romeiro FG, Okoshi K. Cardiac cachexia: perspectives for prevention and treatment. Arq Bras Cardiol. 2017;108(1):74-80. doi: 10.5935/abc.20160142. Okoshi MP Capalbo RV Romeiro FG Okoshi K Cardiac cachexia: perspectives for prevention and treatment Arq Bras Cardiol 2017 108 1 74 80 10.5935/abc.20160142 2 Gomes MJ, Martinez PF, Pagan LU, Damatto RL, Cezar MD, Lima AR, et al. Skeletal muscle aging: influence of oxidative stress and physical exercise. Oncotarget. 2017;8(12):20428-40. doi: 10.18632/oncotarget.14670. Gomes MJ Martinez PF Pagan LU Damatto RL Cezar MD Lima AR Skeletal muscle aging: influence of oxidative stress and physical exercise Oncotarget 2017 108 12 20428 20440 10.18632/oncotarget.14670 3 Aversa Z, Costelli P, Muscaritoli M. Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther Adv Med Oncol. 2017;9(5):369- 82. doi: 10.1177/1758834017698643. Aversa Z Costelli P Muscaritoli M Cancer-induced muscle wasting: latest findings in prevention and treatment Ther Adv Med Oncol 2017 9 5 369 382 10.1177/1758834017698643 4 Belloum Y, Rannou-Bekono F, Favier FB. Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review). Oncol Rep. 2017;37(5):2543-52. doi: 10.3892/or.2017.5542. Belloum Y Rannou-Bekono F Favier FB Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review) Oncol Rep 2017 37 5 2543 2552 10.3892/or.2017.5542 5 von Haehling S, Ebner N, dos Santos MR, Springer J, Anker SD. Muscle wasting and cachexia in heart failure: mechanisms and therapies. Nat Rev Cardiol. 2017;14(6):323-41. doi: 10.1038/nrcardio.2017.51. von Haehling S Ebner N dos Santos MR Springer J Anker SD Muscle wasting and cachexia in heart failure: mechanisms and therapies Nat Rev Cardiol 2017 14 6 323 341 10.1038/nrcardio.2017.51 6 Lima AR, Pagan LU, Damatto RL, Cezar MD, Bonomo C, Gomes MJ. Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure. Oncotarget. 2017;8(47):83009-21. doi: https://doi.org/10.18632/oncotarget.20583. Lima AR Pagan LU Damatto RL Cezar MD Bonomo C Gomes MJ Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure Oncotarget 2017 8 47 83009 830021 https://doi.org/10.18632/oncotarget.20583 Carta ao Editor Caquexia Cardíaca - Uma Janela para os Distúrbios de Emaciação Coats Andrew J Stewart IRCCS, San Raffaele-Pisana, Roma, Itália Correspondência: Andrew, Monash University, 3068, Melbourne, Australia. Palavras-chave: Caquexia Síndrome de Emaciação Exercício Fenômenos Fisiológicos da Nutrição

Ao Editor

Li com interesse a recente revisão de Okoshi et al.1 Foi uma leitura muito agradável que analisou as principais áreas de foco. No entanto, gostaria de reforçar alguns dos argumentos. Na seção sobre bloqueio neuro-hormonal, também houve um teste de fase 2 bem-sucedido do betabloqueador de quarta geração espindolol na caquexia de câncer.2,3 Claramente, os betabloqueadores também podem ser úteis na caquexia cardíaca devido ao seu papel crucial na insuficiência cardíaca em geral. Outras drogas cardiovasculares também estão sendo investigadas pelos seus efeitos benéficos ou protetores sobre o músculo esquelético. Estes incluem, como observam os autores, o inibidor da ECA Imidapril. Outros, incluindo a trimetazidina, também estão sendo estudados.4 Um assunto problemático é que estamos começando do ponto de que não há terapias efetivas e testando as terapias uma a uma. A verdadeira complexidade multisistema da caquexia e ainda a sua semelhança em diferentes síndromes de falência orgânica implica uma abordagem multifocal a qual pode ser necessária para resolvê-la. Podemos precisar combinar bloqueio neuro-hormonal, modulação imunológica, suporte nutricional e exercícios com agentes pró-anabolizantes para obter benefícios clínicos reais. Talvez, como os autores apontam, a Caquexia Cardíaca, onde vários desses agentes já participam, pode ser um bom lugar para começar. O momento para um foco muito maior em todas as caquexias, incluindo, naturalmente, a caquexia cardíaca, é realmente aqui e agora.5

Carta-resposta Okoshi Marina P. Capalbo Rafael V. Romeiro Fernando G. Okoshi Katashi

Realmente apreciamos os comentários no nosso manuscrito de revisão publicado na revista.1 Os autores reforçaram nosso ponto de vista citando alguns trabalhos publicados após a submissão do nosso manuscrito. Concordamos que devemos iniciar imediatamente um foco maior na caquexia por todas as causas, visando a sua prevenção e tratamento. Embora o suporte nutricional tenha sido recomendado há muito tempo para o gerenciamento da caquexia, apenas mais recentemente o exercício foi destacado como uma ferramenta para gerenciar a perda de massa muscular e a sarcopenia.2-4 Como corretamente apontado, devido à capacidade de prevenir a perda de peso corporal em pacientes com insuficiência cardíaca com fração de ejeção reduzida, o bloqueio neuro-hormonal também foi avaliado na caquexia não cardíaca. No entanto, no que diz respeito a outras terapias, como a modulação imunológica e agentes pró-anabolizantes, não há provas convincentes de uma resposta positiva3,5,6 sugerindo que são necessários estudos adicionais antes de podermos efetivamente prevenir e tratar a caquexia associada a diferentes doenças, incluindo cardíacas crônicas e insuficiência renal, câncer e doença pulmonar obstrutiva crônica.

Marina P. OkoshiRafael V. CapalboFernando G. RomeiroKatashi Okoshi References 1 Okoshi MP, Capalbo RV, Romeiro FG, Okoshi K. Cardiac cachexia: perspectives for prevention and treatment. Arq Bras Cardiol. 2017;108(1):74-80. doi: 10.5935/abc.20160142. Okoshi MP Capalbo RV Romeiro FG Okoshi K Cardiac cachexia: perspectives for prevention and treatment Arq Bras Cardiol 2017 108 1 74 80 10.5935/abc.20160142 2 Gomes MJ, Martinez PF, Pagan LU, Damatto RL, Cezar MD, Lima AR, et al. Skeletal muscle aging: influence of oxidative stress and physical exercise. Oncotarget. 2017;8(12):20428-40. doi: 10.18632/oncotarget.14670. Gomes MJ Martinez PF Pagan LU Damatto RL Cezar MD Lima AR Skeletal muscle aging: influence of oxidative stress and physical exercise Oncotarget 2017 108 12 20428 20440 10.18632/oncotarget.14670 3 Aversa Z, Costelli P, Muscaritoli M. Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther Adv Med Oncol. 2017;9(5):369- 82. doi: 10.1177/1758834017698643. Aversa Z Costelli P Muscaritoli M Cancer-induced muscle wasting: latest findings in prevention and treatment Ther Adv Med Oncol 2017 9 5 369 382 10.1177/1758834017698643 4 Belloum Y, Rannou-Bekono F, Favier FB. Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review). Oncol Rep. 2017;37(5):2543-52. doi: 10.3892/or.2017.5542. Belloum Y Rannou-Bekono F Favier FB Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review) Oncol Rep 2017 37 5 2543 2552 10.3892/or.2017.5542 5 von Haehling S, Ebner N, dos Santos MR, Springer J, Anker SD. Muscle wasting and cachexia in heart failure: mechanisms and therapies. Nat Rev Cardiol. 2017;14(6):323-41. doi: 10.1038/nrcardio.2017.51. von Haehling S Ebner N dos Santos MR Springer J Anker SD Muscle wasting and cachexia in heart failure: mechanisms and therapies Nat Rev Cardiol 2017 14 6 323 341 10.1038/nrcardio.2017.51 6 Lima AR, Pagan LU, Damatto RL, Cezar MD, Bonomo C, Gomes MJ. Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure. Oncotarget. 2017;8(47):83009-21. doi: https://doi.org/10.18632/oncotarget.20583. Lima AR Pagan LU Damatto RL Cezar MD Bonomo C Gomes MJ Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure Oncotarget 2017 8 47 83009 830021 https://doi.org/10.18632/oncotarget.20583