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3: 4: 5: abc 6: 7: Arquivos Brasileiros de Cardiologia 8: Arq. Bras. Cardiol. 9: 10: 1678-4170 11: 12: Sociedade Brasileira de Cardiologia - SBC 13: 14: 15: 16: 10.5935/abc.20180009 17: 18: 19: Letter to the Editor 20: 21: 22: 23: Cardiac Cachexia - A Window to the Wasting Disorders 24: 25: 26: 27: 28: Coats 29: Andrew J Stewart 30: 31: ¹ 32: 33: 34: 1 35: IRCCS, Roma - Italy 36: IRCCS 37: 38: Roma 39: 40: Italy 41: 42: 43: 44: Mailing Address: Andrew • Monash University, 3068, Melbourne, Australia Manuscript received August 13, 2017, revised manuscript September 28, 2017, accepted September 28, 2017 45: 46: 47: 01 48: 07 49: 2021 50: 51: 52: 06 53: 2021 54: 55: 110 56: 1 57: 102 58: 103 59: 60: 61: 13 62: 08 63: 2017 64: 65: 66: 28 67: 09 68: 2017 69: 70: 71: 28 72: 09 73: 2017 74: 75: 76: 77: 78: This is an open-access article distributed under the terms of the Creative Commons Attribution License 79: 80: 81: 82: Keywords: 83: Cachexia 84: Wasting Syndrome 85: Exercise 86: Nutritional Physiological Phenomena. 87: 88: 89: 90: 91: 92: 93: 94: 95: 96: 97: 98: 99: To The Editor 100:

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^,³Clearly 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.⁵ 101:

102: 103: 104: 105: 106: References 107: 108: 1. 109: 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: http://doi.org/10.5935/abc.20160142. 110: 111: 112: 113: Okoshi 114: MP 115: 116: 117: Capalbo 118: RV 119: 120: 121: Romeiro 122: FG 123: 124: 125: Okoshi 126: K. 127: 128: 129: Cardiac cachexia: perspectives for prevention and treatment 130: Arq Bras Cardiol 131: 2017 132: 108 133: 1 134: 74 135: 80 136: http://doi.org/10.5935/abc.20160142 137: 138: 139: 140: 2. 141: 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: http://doi.org/10.1002/jcsm.12126. 142: 143: 144: 145: Stewart Coats 146: AJ 147: 148: 149: Ho 150: GF 151: 152: 153: Prabhash 154: K 155: 156: 157: von Haehling 158: S 159: 160: 161: Tilson 162: J 163: 164: 165: Brown 166: R 167: 168: 169: Beadle 170: J 171: 172: 173: Anker 174: SD 175: 176: 177: 178: for and on behalf of the ACT-ONE study group 179: 180: 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) 181: J Cachexia Sarcopenia Muscle 182: 2016 183: 7 184: 3 185: 355 186: 365 187: http://doi.org/10.1002/jcsm.12126 188: 189: 190: 191: 3. 192: 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: http://doi.org/10.1002/jcsm.12136. 193: 194: 195: 196: Lainscak 197: M 198: 199: 200: Laviano 201: A. 202: 203: 204: ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action beta-blocker 205: J Cachexia Sarcopenia Muscle 206: 2016 207: 7 208: 4 209: 400 210: 402 211: http://doi.org/10.1002/jcsm.12136 212: 213: 214: 215: 4. 216: 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: http://doi.org/10.1002/jcsm.12097. 217: 218: 219: 220: Ferraro 221: E 222: 223: 224: Pin 225: F 226: 227: 228: Gorini 229: S 230: 231: 232: Pontecorvo 233: L 234: 235: 236: Ferri 237: A 238: 239: 240: Mollace 241: V 242: 243: 244: 245: Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine 246: J Cachexia Sarcopenia Muscle 247: 2016 248: 7 249: 4 250: 449 251: 457 252: http://doi.org/10.1002/jcsm.12097 253: 254: 255: 256: 5. 257: 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: http://doi.org/10.1002/jcsm.12118. 258: 259: 260: 261: Loncar 262: G 263: 264: 265: Springer 266: J 267: 268: 269: Anker 270: M 271: 272: 273: Doehner 274: W 275: 276: 277: Lainscak 278: M. 279: 280: 281: J Cachexia Sarcopenia Muscle 282: 2016 283: 7 284: 3 285: 246 286: 260 287: http://doi.org/10.1002/jcsm.12118 288: 289: 290: 291: 292: 293: 294: 295: 296: Reply 297: 298: 299: 300: Reply 301: 302: 303: 304: 305: Okoshi 306: Marina P. 307: 308: 309: 310: 311: Capalbo 312: Rafael V. 313: 314: 315: 316: 317: Romeiro 318: Fernando G. 319: 320: 321: 322: 323: Okoshi 324: Katashi 325: 326: 327: 328: 329: 330:

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.

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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.

332: 333: 334: 335: References 336: 337: 1. 338: 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: http://doi.org/10.5935/abc.20160142. 339: 340: 341: 342: Okoshi 343: MP 344: 345: 346: Capalbo 347: RV 348: 349: 350: Romeiro 351: FG 352: 353: 354: Okoshi 355: K. 356: 357: 358: Cardiac cachexia: perspectives for prevention and treatment 359: Arq Bras Cardiol 360: 2017 361: 108 362: 1 363: 74 364: 80 365: http://doi.org/10.5935/abc.20160142 366: 367: 368: 369: 2. 370: 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: http://doi.org/10.18632/oncotarget.14670. 371: 372: 373: 374: Gomes 375: MJ 376: 377: 378: Martinez 379: PF 380: 381: 382: Pagan 383: LU 384: 385: 386: Damatto 387: RL 388: 389: 390: Cezar 391: MD 392: 393: 394: Lima 395: AR 396: 397: 398: 399: Skeletal muscle aging: influence of oxidative stress and physical exercise 400: Oncotarget 401: 2017 402: 8 403: 12 404: 20428 405: 20440 406: http://doi.org/10.18632/oncotarget.14670 407: 408: 409: 410: 3. 411: 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: http://doi.org/10.1177/1758834017698643. 412: 413: 414: 415: Aversa 416: Z 417: 418: 419: Costelli 420: P 421: 422: 423: Muscaritoli 424: M. 425: 426: 427: Cancer-induced muscle wasting: latest findings in prevention and treatment 428: Ther Adv Med Oncol 429: 2017 430: 9 431: 5 432: 369 433: 82 434: http://doi.org/10.1177/1758834017698643 435: 436: 437: 438: 4. 439: 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: http://doi.org/10.3892/or.2017.5542. 440: 441: 442: 443: Belloum 444: Y 445: 446: 447: Rannou-Bekono 448: F 449: 450: 451: Favier 452: FB. 453: 454: 455: Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review) 456: Oncol Rep 457: 2017 458: 37 459: 5 460: 2543 461: 2552 462: http://doi.org/10.3892/or.2017.5542 463: 464: 465: 466: 5. 467: 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: http://doi.org/10.1038/nrcardio.2017.51. 468: 469: 470: 471: von Haehling 472: S 473: 474: 475: Ebner 476: N 477: 478: 479: dos Santos 480: MR 481: 482: 483: Springer 484: J 485: 486: 487: Anker 488: SD 489: 490: 491: Muscle wasting and cachexia in heart failure: mechanisms and therapies 492: Nat Rev Cardiol 493: 2017 494: 14 495: 6 496: 323 497: 341 498: http://doi.org/10.1038/nrcardio.2017.51 499: 500: 501: 502: 6. 503: 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. 504: 505: 506: 507: 508: Lima 509: AR 510: 511: 512: Pagan 513: LU 514: 515: 516: Damatto 517: RL 518: 519: 520: Cezar 521: MD 522: 523: 524: Bonomo 525: C 526: 527: 528: Gomes 529: MJ 530: 531: 532: Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure 533: Oncotarget 534: 2017 535: 8 536: 47 537: 83009 538: 83021 539: https://doi.org/10.18632/oncotarget.20583. 540: 541: 542: 543: 544: 545: 546: 547: 548: 549: Carta ao Editor 550: 551: 552: 553: 554: Carta-resposta 555: 556: 557: 558: Caquexia Cardíaca - Uma Janela para os Distúrbios de Emaciação 559: 560: 561: 562: 563: Coats 564: Andrew J Stewart 565: 566: ¹ 567: 568: 569: 1 570: IRCCS, Roma - Italy 571: IRCCS 572: 573: Roma 574: 575: Italy 576: 577: 578: 579: Correspondência: Andrew • Monash University, 3068, Melbourne, Australia 580: 581: 582: Palavras-chave: 583: Caquexia 584: Síndrome de Emaciação 585: Exercício 586: Fenômenos Fisiológicos da Nutrição. 587: 588: 589: 590: 591: Ao Editor 592:

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.

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Outras drogas cardiovasculares também estão sendo investigadas pelos seus efeitos benéficos ou protetores sobre o músculo esquelético. Estes incluem, como observamos 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.⁵ 594:

595: 596: 597: 598: 599: 600: 601: Carta-resposta 602: 603: 604: 605: Carta-resposta 606: 607: 608: 609: 610: Okoshi 611: Marina P. 612: 613: 614: 615: 616: 617: Capalbo 618: Rafael V. 619: 620: 621: 622: 623: 624: Romeiro 625: Fernando G. 626: 627: 628: 629: 630: 631: Okoshi 632: Katashi 633: 634: 635: 636: 637: 638: 639:

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.

640: 641: 642: 643: References 644: 645: 1. 646: 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: http://doi.org/10.5935/abc.20160142. 647: 648: 649: 650: Okoshi 651: MP 652: 653: 654: Capalbo 655: RV 656: 657: 658: Romeiro 659: FG 660: 661: 662: Okoshi 663: K. 664: 665: 666: Cardiac cachexia: perspectives for prevention and treatment 667: Arq Bras Cardiol 668: 2017 669: 108 670: 1 671: 74 672: 80 673: http://doi.org/10.5935/abc.20160142 674: 675: 676: 677: 2. 678: 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: http://doi.org/10.18632/oncotarget.14670. 679: 680: 681: 682: Gomes 683: MJ 684: 685: 686: Martinez 687: PF 688: 689: 690: Pagan 691: LU 692: 693: 694: Damatto 695: RL 696: 697: 698: Cezar 699: MD 700: 701: 702: Lima 703: AR 704: 705: 706: 707: Skeletal muscle aging: influence of oxidative stress and physical exercise 708: Oncotarget 709: 2017 710: 8 711: 12 712: 20428 713: 20440 714: http://doi.org/10.18632/oncotarget.14670 715: 716: 717: 718: 3. 719: 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: http://doi.org/10.1177/1758834017698643. 720: 721: 722: 723: Aversa 724: Z 725: 726: 727: Costelli 728: P 729: 730: 731: Muscaritoli 732: M. 733: 734: 735: Cancer-induced muscle wasting: latest findings in prevention and treatment 736: Ther Adv Med Oncol 737: 2017 738: 9 739: 5 740: 369 741: 82 742: http://doi.org/10.1177/1758834017698643 743: 744: 745: 746: 4. 747: 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: http://doi.org/10.3892/or.2017.5542. 748: 749: 750: 751: Belloum 752: Y 753: 754: 755: Rannou-Bekono 756: F 757: 758: 759: Favier 760: FB. 761: 762: 763: Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review) 764: Oncol Rep 765: 2017 766: 37 767: 5 768: 2543 769: 2552 770: http://doi.org/10.3892/or.2017.5542 771: 772: 773: 774: 5. 775: 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: http://doi.org/10.1038/nrcardio.2017.51. 776: 777: 778: 779: von Haehling 780: S 781: 782: 783: Ebner 784: N 785: 786: 787: dos Santos 788: MR 789: 790: 791: Springer 792: J 793: 794: 795: Anker 796: SD 797: 798: 799: Muscle wasting and cachexia in heart failure: mechanisms and therapies 800: Nat Rev Cardiol 801: 2017 802: 14 803: 6 804: 323 805: 341 806: http://doi.org/10.1038/nrcardio.2017.51 807: 808: 809: 810: 6. 811: 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. 812: 813: 814: 815: 816: Lima 817: AR 818: 819: 820: Pagan 821: LU 822: 823: 824: Damatto 825: RL 826: 827: 828: Cezar 829: MD 830: 831: 832: Bonomo 833: C 834: 835: 836: Gomes 837: MJ 838: 839: 840: Effects of growth hormone on cardiac remodeling and soleus muscle in rats with aortic stenosis-induced heart failure 841: Oncotarget 842: 2017 843: 8 844: 47 845: 83009 846: 83021 847: https://doi.org/10.18632/oncotarget.20583. 848: 849: 850: 851: 852: 853: 854: