Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia QVyKKFmdfNw5q8tq9HyY8GD S0066-782X2014002100001 00001 10.5935/abc.20140143 Editorial Percutaneous Treatment of Functional Mitral Regurgitation in Heart Failure Attizzani Guilherme F. 1 Lemos Pedro A. 2 University Hospitals Case Medical Center Harrington Heart and Vascular Institute Cleveland OH USA Harrington Heart and Vascular Institute - University Hospitals Case Medical Center, Cleveland, OH - USA Universidade de São Paulo Faculdade de Medicina Hospital das Clínicas São Paulo Brazil Instituto do Coração - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo - Brazil Mailing Address: Pedro A. Lemos. Avenida Doutor Enéas de Carvalho Aguiar, 255, Cerqueira César. Postal Code 05403-000, São Paulo, SP − Brazil. E-mail: pedro.lemos@incor.usp.br 09 2014 103 3 172 173 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Heart Failure/mortality Mitral Valve Insufficiency/physiopathology Ventricular Remodeling Cardiac Catheterization/instrumentation

Congestive heart failure (HF) remains one of the most important and challenging clinical problems in cardiovascular medicine in Brazil and worldwide. Evidence suggests that mortality in this setting has decreased in Brazil over recent years1, which may be related, at least partially, to a more intense and widespread use of neurohormonal blockade (with angiotensin-converting-enzyme inhibitors and beta-blockers) in patients with advanced HF2. To better evaluate the characteristics of end-stage heart disease in Brazil, the ongoing I Brazilian Registry of Heart Failure (BREATHE registry) will evaluate the profile of 1,200 patients admitted with decompensated HF to 60 hospitals representative of the different Brazilian regions3. Final results of the BREATHE registry are expected to be available within the next months. In spite of recent improvements in medical therapy, advanced HF continues to impose an ominous prognosis; in some subsets, mortality rates can reach up to 30% to 50% in the first year of disease, according to contemporary series of Brazilian centers4. In this context, therapeutic alternatives have been intensively investigated in an attempt to improve the outcomes of patients with HF.

Mitral regurgitation (MR) is a frequent finding among individuals with end-stage HF5,6. Indeed, observational studies revealed that most patients with HF and severe (≥ 3+) MR have functional (74%), rather than degenerative (21%), MR7. While surgery is the gold-standard therapy in patients with organic (i.e., degenerative) mitral valve disease associated with symptoms or evidence of left ventricle dysfunction8, its benefit to patients with MR secondary to underlying ventricular dysfunction (i.e., functional MR) remains unclear9. Therefore, individuals with functional MR are frequently referred to isolated clinical management, carrying poor long-term prognosis7.

Percutaneous mitral valve transcatheter therapies, such as direct and indirect annuloplasty, leaflet repairing devices, and valve replacement, have recently emerged as potential alternatives for patients with MR. Percutaneous edge-to-edge mitral valve repair with the MitraClip system (Abbott Vascular, Abbott Park, Illinois) exhibits the largest body of data available among transcatheter therapies for MR10. The procedure has consistently demonstrated to be safe, coupled with efficacious MR reduction, left ventricle reverse remodeling, and improvement in congestive HF symptoms and in the quality of life of patients with either functional or degenerative MR11,12. In fact, MitraClip implantation has been approved for commercial use for many years in Europe, but, in the United States, the approval has been recently given. In Brazil, the system has been just approved by the Brazilian Health Surveillance Agency (Anvisa) and is expected to be available in the near future.

The only prospective, randomized, controlled trial comparing MitraClip therapy and conventional surgery mostly for patients with organic MR (i.e., EVEREST II trial) has shown that the percutaneous procedure had superior safety and similar improvement in clinical outcomes, although the latter led to more effective reduction in the magnitude of MR10. It is currently under intense investigation whether catheter-based therapies could be offered as a minimally invasive strategy also for patients with severe MR secondary to left ventricular dysfunction. Recently, non-randomized studies including high-risk patients with functional MR have confirmed excellent safety and efficacy profiles of MitraClip implantation in more complex clinical scenarios, thus contributing to refine the understanding on the role of this novel therapy in patients with different MR etiologies13,14.

Minimally invasive catheter-based therapies aimed at correcting (or minimizing) functional MR represent a whole new and promising therapeutic strategy for patients with advanced HF15. Notwithstanding its potential, the novel treatment must be scrutinized in the context of studies specifically designed to evaluate its clinical value in improving short- and long-term clinical outcomes.

References Gaui EN, Oliveira GM, Klein CH. Mortality by heart failure and ischemic heart disease in Brazil from 1996 to 2011. Arq Bras Cardiol. 2014;102(6):557-65. Gaui EN Oliveira GM Klein CH Mortality by heart failure and ischemic heart disease in Brazil from 1996 to 2011 Arq Bras Cardiol 2014 102 6 557 565 Carlo CH, Cardoso JN, Ochia ME, Oliveira MT Jr, Ramires JA, Pereira-Barretto AC. Temporal variation in the prognosis and treatment of advanced heart failure - before and after 2000. Arq Bras Cardiol. 2014;102(5):495-504. Carlo CH Cardoso JN Ochia ME Oliveira MT Jr Ramires JA Pereira-Barretto AC Temporal variation in the prognosis and treatment of advanced heart failure - before and after 2000 Arq Bras Cardiol 2014 102 5 495 504 BREATHE investigators. Rationale and design: BREATHE registry--I Brazilian Registry of Heart Failure. Arq Bras Cardiol. 2013;100(5):390-4. BREATHE investigators Rationale and design: BREATHE registry--I Brazilian Registry of Heart Failure Arq Bras Cardiol 2013 100 5 390 394 Pereira-Barretto AC, Carlo CH, Cardoso JN, Ochiai ME, Lima MV, Curiati MC, et al. Role of BNP levels on the prognosis of decompensated advanced heart failure. Arq Bras Cardiol. 2013;100(3):281-7. Pereira-Barretto AC Carlo CH Cardoso JN Ochiai ME Lima MV Curiati MC et al Role of BNP levels on the prognosis of decompensated advanced heart failure Arq Bras Cardiol 2013 100 3 281 287 Mancuso FJ, Moises VA, Almeida DR, Oliveira WA, Poyares D, Brito FS, et al. Criteria for mitral regurgitation classification were inadequate for dilated cardiomyopathy. Arq Bras Cardiol. 2013;101(5):457-65. Mancuso FJ Moises VA Almeida DR Oliveira WA Poyares D Brito FS et al Criteria for mitral regurgitation classification were inadequate for dilated cardiomyopathy Arq Bras Cardiol 2013 101 5 457 465 Mornos C, Petrescu L, Cozma D, Ionac A. A new tissue Doppler index to predict cardiac death in patients with heart failure. Arq Bras Cardiol. 2014;102(1):19-29. Mornos C Petrescu L Cozma D Ionac A A new tissue Doppler index to predict cardiac death in patients with heart failure Arq Bras Cardiol 2014 102 1 19 29 Goel SS, Bajaj N, Aggarwal B, Gupta S, Poddar KL, Ige M, et al. Prevalence and outcomes of unoperated patients with severe symptomatic mitral regurgitation and heart failure: comprehensive analysis to determine the potential role of MitraClip for this unmet need. J Am Coll Cardiol. 2014;63(2):185-6. Goel SS Bajaj N Aggarwal B Gupta S Poddar KL Ige M et al Prevalence and outcomes of unoperated patients with severe symptomatic mitral regurgitation and heart failure: comprehensive analysis to determine the potential role of MitraClip for this unmet need J Am Coll Cardiol 2014 63 2 185 186 Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC)1; European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H,et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33(19):2451-96. Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC)1 European Association for Cardio-Thoracic Surgery (EACTS) Vahanian A. Alfieri O. Andreotti F. Antunes MJ. Barón-Esquivias G. Baumgartner H et al Guidelines on the management of valvular heart disease (version 2012) Eur Heart J 2012 33 19 2451 2496 Mihaljevic T, Lam BK, Rajeswaran J, Takagaki M, Lauer MS, Gillinov AM, et al. Impact of mitral valve annuloplasty combined with revascularization in patients with functional ischemic mitral regurgitation. J Am Coll Cardiol. 2007;49(22):2191-201. Mihaljevic T Lam BK Rajeswaran J Takagaki M Lauer MS Gillinov AM et al Impact of mitral valve annuloplasty combined with revascularization in patients with functional ischemic mitral regurgitation J Am Coll Cardiol 2007 49 22 2191 2201 Feldman T, Foster E, Glower DD, Kar S, Rinaldi MJ, Fail PS, et al. EVEREST II Investigators. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med. 2011;364(15):1395-406. Feldman T Foster E Glower DD Kar S Rinaldi MJ Fail PS et al EVEREST II Investigators. Percutaneous repair or surgery for mitral regurgitation N Engl J Med 2011 364 15 1395 1406 Attizzani GF, Ohno Y, Capodanno D. Extended use of percutaneous edge-to-edge mitral valve repair beyond EVEREST Criteria: thirty-day and twelve-month clinical and echocardiographic outcomes from the GRASP Registry. J Am Coll Cardiol Interv. [In Press]; Attizzani GF Ohno Y Capodanno D Extended use of percutaneous edge-to-edge mitral valve repair beyond EVEREST Criteria: thirty-day and twelve-month clinical and echocardiographic outcomes from the GRASP Registry J Am Coll Cardiol Interv [In Press] Glower DD, Kar S, Trento A, Lim DS, Bajwa T, Quesada R, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II Study. J Am Coll Cardiol. 2014;64(2):172-81. Glower DD Kar S Trento A Lim DS Bajwa T Quesada R et al Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II Study J Am Coll Cardiol 2014 64 2 172 181 Maisano F, Franzen O, Baldus S, Schäfer U, Hausleiter J, Butter C, et al. Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol. 2013;62(12):1052-61. Maisano F Franzen O Baldus S Schäfer U Hausleiter J Butter C et al Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe J Am Coll Cardiol 2013 62 12 1052 1061 Taramasso M, Denti P, Buzzatti N, De Bonis M, La Canna G, Colombo A, et al. Mitraclip therapy and surgical mitral repair in patients with moderate to severe left ventricular failure causing functional mitral regurgitation: a single-centre experience. Eur J Cardiothorac Surg. 2012;42(6):920-6. Taramasso M Denti P Buzzatti N De Bonis M La Canna G Colombo A et al Mitraclip therapy and surgical mitral repair in patients with moderate to severe left ventricular failure causing functional mitral regurgitation: a single-centre experience Eur J Cardiothorac Surg 2012 42 6 920 926 Franzen O, van der Heyden J, Baldus S, Schlüter M, Schillinger W, Butter C, et al. MitraClip(R) therapy in patients with end-stage systolic heart failure. Eur J Heart Fail. 2011;13(5):569-76 Franzen O van der Heyden J. Baldus S. Schlüter M. Schillinger W. Butter C. et al MitraClip(R) therapy in patients with end-stage systolic heart failure Eur J Heart Fail 2011 13 5 569 576 Tratamento Percutâneo de Regurgitação Mitral Funcional em Insuficiência Cardíaca Attizzani Guilherme F. 1 Lemos Pedro A. 2 University Hospitals Case Medical Center Harrington Heart and Vascular Institute Cleveland OH USA Harrington Heart and Vascular Institute - University Hospitals Case Medical Center, Cleveland, OH - USA Universidade de São Paulo Faculdade de Medicina Hospital das Clínicas São Paulo Brasil Instituto do Coração - Hospital das Clínicas - Faculdade de Medicina - Universidade de São Paulo, São Paulo - Brasil Correspondência: Pedro A. Lemos. Avenida Doutor Enéas de Carvalho Aguiar, 255, Cerqueira César. CEP 05403-000, São Paulo, SP − Brasil. E-mail: pedro.lemos@incor.usp.br Insuficiência Cardíaca/mortalidade Insuficiência da Valva Mitral/fisiopatologia Remodelação Ventricular Cateterismo Cardíaco/instrumentação

A insuficiência cardíaca (IC) congestiva continua sendo um dos mais importantes e desafiadores problemas clínicos da medicina cardiovascular no Brasil e no mundo. Há evidência de que a mortalidade nesse cenário decresceu no Brasil nos últimos anos1, provavelmente devido, pelo menos em parte, ao uso mais intenso e disseminado de bloqueio neurohormonal (com os inibidores da enzima conversora de angiotensina e os beta-bloqueadores) para IC avançada2. Para melhor avaliar as características da doença cardíaca terminal no Brasil, o Primeiro Registro Brasileiro de Insuficiência Cardíaca (I Brazilian Registry of Heart Failure - BREATHE registry) em andamento avaliará o perfil de 1.200 pacientes admitidos com IC descompensada em 60 hospitais representantes das diferentes regiões brasileiras3. Espera-se que os resultados finais do registro BREATHE estejam disponíveis nos próximos meses. A despeito das recentes melhoras na terapia médica, a IC avançada continua a apresentar um mau prognóstico; em séries contemporâneas de centros brasileiros, as taxas de mortalidade podem alcançar 30% a 50% no primeiro ano de doença4. Nesse contexto, alternativas terapêuticas tem sido intensamente investigadas na tentativa de melhorar os desfechos de pacientes com IC.

A regurgitação mitral (RM) é achado frequente em indivíduos com IC terminal5,6. Estudos observacionais revelaram que a maioria dos pacientes com IC e RM grave (≥ 3+) apresenta mais RM funcional (74%) do que degenerativa (21%)7. Embora a cirurgia seja a terapia padrão-ouro para pacientes com valvopatia mitral orgânica (i.e., degenerativa) associada a sintomas ou evidência de disfunção ventricular esquerda8, seu benefício para pacientes com RM secundária a disfunção ventricular subjacente (i.e., RM funcional) permanece incerto9. Portanto, indivíduos com RM funcional são com frequência encaminhados para manejo clínico isolado e apresentam mau prognóstico de longo prazo7.

Terapias percutâneas transcateter de válvula mitral, como anuloplastia direta e indireta, dispositivos de correção de folheto valvar e substituição valvar, recentemente surgiram como potenciais alternativas para pacientes com RM. Dentre as terapias transcateter para RM, o tratamento percutâneo 'edge-to-edge' com clip mitral (sistema MitraClip, Abbott Vascular, Abbott Park, Illinois, EUA) exibe a maior quantidade de dados disponíveis10. O procedimento mostrou-se consistentemente seguro, sendo acompanhado por eficiente redução da RM, remodelamento reverso do ventrículo esquerdo, e melhora dos sintomas na IC congestiva e da qualidade de vida dos pacientes com RM funcional ou degenerativa11,12. A implantação do sistema MitraClip já foi aprovado para uso comercial há muitos anos na Europa, mas apenas recentemente nos Estados Unidos. No Brasil, a Agência Nacional de Vigilância Sanitária (Anvisa) já aprovou o sistema, que deve estar disponível em breve.

O único ensaio prospectivo, randomizado, controlado comparando a terapia MitraClip com cirurgia convencional principalmente para pacientes com RM orgânica (i.e., estudo EVEREST II) mostrou que o procedimento percutâneo apresentava segurança superior e semelhante melhora nos desfechos clínicos, embora a cirurgia leve a uma redução mais efetiva na magnitude da RM10. Atualmente há uma intensa investigação para esclarecer se as terapias envolvendo cateter podem ser oferecidas como estratégia minimamente invasiva também para pacientes com RM grave secundária a disfunção ventricular esquerda. Recentemente, estudos não randomizados incluindo pacientes de alto risco e com RM funcional confirmaram excelentes segurança e eficácia dos perfis de implantação de MitraClip em cenários clínicos mais complexos, contribuindo para refinar o entendimento do papel dessa nova terapia em pacientes com RM de diferentes etiologias13,14.

As terapias transcateter minimamente invasivas para corrigir (ou minimizar) RM funcional representam uma nova e promissora estratégia terapêutica para pacientes com IC avançada15. Não obstante seu potencial, o novo tratamento deve ser investigado com cuidado no contexto dos estudos especificamente desenhados com o objetivo de avaliar seu valor clínico para melhorar os desfechos clínicos de curto e longo prazo.