Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCrXPM6Sgc9yBKBpv9cD4zNYGS0066-782X201800140014210.5935/abc.20180142Short EditorialPersistent Inflammatory Activity in Blood Cells and Artery Tissue from Patients with Previous Bare Metal StentFonsecaFrancisco Antonio HelfensteinUniversidade Federal de São PauloSão PauloSPBrazilUniversidade Federal de São Paulo (UNIFESP), São Paulo, SP – BrazilMailing Address: Francisco Antonio Helfenstein Fonseca Rua Loefgren, 1350. Postal Code 04040-001, Vila Clementino, São Paulo, SP – Brazil E-mail: fahfonseca@terra.com.br0820181112142143This 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.KeywordsMyocardial RevascularizationStents, InflammationCoronary RestenosisAnti-Inflammatory Agents/therapy
The interesting article by Farsky et al.1 examined the persistence of inflammatory activity after bare metal stent implantation in patients later submitted to coronary artery bypass grafting (CABG).
The authors evidenced a higher systemic expression of the gene that encodes tumor necrosis factor-alpha (TNF-alpha) in peripheral blood cells, as well as a higher tissue expression of TNF-alpha and interleukin-6 (IL-6) in patients with previous bare metal stent implantation as compared to those of revascularized individuals without previous percutaneous stent placement.
Those authors concluded that, even several months or years after stent implantation, there were markers of persistent inflammatory activity, which could be associated with less favorable outcome of CABG.
The relationship between inflammatory markers and coronary restenosis after stent placement has been recognized for years.2 There are few reports on the local inflammatory characteristics expressed by tissue markers in samples obtained during CABG.
The increase in circulating IL-6 levels has been associated with the increase in coronary events. A study of Mendelian randomization involving 40 studies and 133449 patients has shown that polymorphism of the gene encoding the IL-6 receptor was related to a significant reduction in the incidence of coronary events, suggesting a causal role in atherosclerosis.3 Another meta-analysis of genetic data has confirmed the causal role of IL-6 in atherothrombosis.3 Those two studies have suggested that the IL-6-mediated inflammatory pathway, from its interaction with the receptor, is involved in cardiovascular events.
The TNF-alpha, another biomarker of higher expression evidenced in the study by Farsky et al.,1 seems to be implicated in atherosclerotic plaque instability.4
Despite the substantial advance in surgical and percutaneous procedures, as well as in the clinical therapy involving new antiplatelet, anticoagulant, lipid-lowering, anti-hypertensive and anti-hyperglycemic agents, the residual risk remains elevated and new anti-inflammatory therapies have been proposed.5
The CANTOS study,6 a prospective, randomized, placebo-controlled clinical trial, involving post-myocardial infarction patients who maintained elevated high-sensitivity C-reactive protein levels, has shown that treating inflammation with the monoclonal antibody canakinumab reduced inflammatory markers and cardiovascular events during clinical drug treatment.
Those data show the relevance of the findings of the study by Farsky et al.1 and suggest that patients receiving bare metal stents might need additional anti-inflammatory therapy. However, new prospective studies of efficacy and safety, in addition to lower cost of that therapy, are required to its definitive incorporation into clinical practice.7
Short Editorial regarding the article: Persistent Inflammatory Activity in Blood Cells and Artery Tissue from Patients with Previous Bare Metal Stent
References1 Farsky PS, Hirata MH, Arnoni RT, Almeida AFS, Issa M, Lima PHO. Persistent Inflammatory Activity in Blood Cells and Artery Tissue from Patients with Previous Bare Metal Stent. Arq Bras Cardiol. 2018; 111(2):134-141FarskyPSHirataMHArnoniRTAlmeidaAFSIssaMLimaPHOPersistent Inflammatory Activity in Blood Cells and Artery Tissue from Patients with Previous Bare Metal StentArq Bras Cardiol201811121341412 Caixeta AM, Brito FS Jr, Costa MA, Serrano CV Jr, Petriz JL, Da Luz PL. Enhanced inflammatory response to coronary stenting marks the development of clinically relevant restenosis. Catheter Cardiovasc Interv 2007;69(4):500-7.CaixetaAMBritoFSJrCostaMASerranoCVJrPetrizJLDa LuzPLEnhanced inflammatory response to coronary stenting marks the development of clinically relevant restenosisCatheter Cardiovasc Interv20076945005073 The Interleukin-6 Receptor Mendelian Randomisation Analysis(IL6RMR) Consortium; Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JE, Shah T, Sofat R, et al. Lancet. 2012;379(9822) 1214-24.The Interleukin-6 Receptor Mendelian Randomisation Analysis(IL6RMR) ConsortiumSwerdlowDIHolmesMVKuchenbaeckerKBEngmannJEShahTSofatRLancet20123799822121412244 Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, Gorman DN, et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379(9822):1205-13.SarwarNButterworthASFreitagDFGregsonJWilleitPGormanDNInterleukin-6 receptor pathways in coronary heart disease a collaborative meta-analysis of 82 studiesLancet20123799822120512135 Rao VH, Rai V, Stoupa S, Subramanian S, Agrawal DK. Tumor necrosis factor-a regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosis. Atherosclerosis. 2016 May;248:160-9.RaoVHRaiVStoupaSSubramanianSAgrawalDKTumor necrosis factor-a regulates triggering receptor expressed on myeloid cells-1-dependent matrix metalloproteinases in the carotid plaques of symptomatic patients with carotid stenosisAtherosclerosis2016052481601696 Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J. 2014;35(27):1782-91.RidkerPMLüscherTFAnti-inflammatory therapies for cardiovascular diseaseEur Heart J20143527178217917 Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-31.RidkerPMEverettBMThurenTMacFadyenJGChangWHBallantyneCAntiinflammatory therapy with canakinumab for atherosclerotic diseaseN Engl J Med20173771211191131MinieditorialAtividade Inflamatória Persistente em Células Circulantes e Tecido Arterial de Pacientes com Stent Convencional PrévioFonsecaFrancisco Antonio HelfensteinUniversidade Federal de São Paulo (UNIFESP), São Paulo, SP – BrasilCorrespondência: Francisco Antonio Helfenstein Fonseca Rua Loefgren, 1350. CEP 04040-001, Vila Clementino, São Paulo, SP – Brasil E-mail: fahfonseca@terra.com.brPalavras-chaveRevascularização do MiocárdioStentsInflamaçãoReestenose CoronáriaAnti-Inflamatórios/terapia
O interessante artigo publicado por Farsky et al.,1 examinou a persistência de atividade inflamatória após implante de stent convencional em pacientes posteriormente submetidos à cirurgia de revascularização coronariana.
Os autores evidenciaram maior expressão sistêmica do gene que codifica o fator de necrose tumoral alfa (TNF-alfa) em células do sangue periférico e também maior expressão tecidual do TNF-alfa e da interleucina-6 (IL-6) entre os pacientes com prévio implante de stent convencional em comparação a indivíduos revascularizados sem prévia intervenção percutânea com stents.
Os autores concluíram que, mesmo vários meses ou anos após o implante do stent, havia marcadores de atividade inflamatória persistente, o que poderia se associar a evolução menos favorável da cirurgia de revascularização miocárdica.
A relação entre marcadores inflamatórios e reestenose coronária após inserção de stent já foi reconhecida há alguns anos.2 Muito menos descrito é o relato das características inflamatórias locais por meio de marcadores teciduais em amostras obtidas por ocasião da cirurgia de revascularização miocárdica.
Aumento nos níveis circulantes de IL-6 tem sido associado com aumento de desfechos coronarianos e, de fato, estudo de randomização mendeliana envolvendo 40 estudos e 133.449 pacientes mostrou que polimorfismo envolvendo o gene que codifica o receptor da IL-6 foi relacionado a significante redução na incidência de desfechos coronarianos, sugerindo papel causal na aterosclerose.3 Outra meta-análise de dados genéticos também confirmou papel causal na aterotrombose relacionada à IL-6.3 Esses dois estudos sugerem que a via inflamatória intermediada pela IL-6 a partir de sua interação com o receptor está envolvida nos desfechos cardiovasculares.
O TNF-alfa, outro biomarcador de maior expressão evidenciado no estudo de Farsky et al.,1 também parece implicado na instabilidade de placas ateroscleróticas.4
A despeito de substancial avanço nos procedimentos cirúrgicos, percutâneos e na terapia clínica envolvendo novos agentes antiplaquetários, anticoagulantes, hipolipemiantes, anti-hipertensivos e anti-hiperglicemiantes, o risco residual permanece elevado e novas terapias anti-inflamatórias têm sido propostas.5
O estudo CANTOS,6 ensaio clínico prospectivo, randomizado, controlado por placebo, envolvendo pacientes após infarto do miocárdio que mantinham proteína C reativa de alta sensibilidade elevada, mostrou que o tratamento da inflamação com anticorpo monoclonal canaquinumabe reduziu marcadores inflamatórios e desfechos cardiovasculares no topo do tratamento clínico medicamentoso.
Esses dados em conjunto mostram que os achados de Farsky et al.1 são relevantes e sugerem que pacientes recebendo stents convencionais possam necessitar de terapias anti-inflamatórias adicionais. Entretanto, novos estudos prospectivos de eficácia e segurança, além de menor custo dessas terapias, serão necessários para sua definitiva incorporação à prática clínica.7
Minieditorial referente ao artigo: Atividade Inflamatória Persistente em Células Circulantes e Tecido Arterial de Pacientes com Stent Convencional Prévio