Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBC7TgLSpp534ZcYr4SHL44ysGS0066-782X2021000500727abc.2019065010.36660/abc.20190650Artigo OriginalPerfil Aterosclerótico da Artéria Carótida como Preditor de Risco para Reestenose após Implante de Stent CoronárioRodriguesCássia da Silva Antico1BazanRodrigo1ReisFabrício Moreira1SilveiraCaroline F. S. Mazeto Pupo da1HuebLívia Maria Severino1CarvalhoFábio Cardoso de1NunesHélio Rubens de Carvalho10000-0001-8980-8839OkoshiKatashi1HuebJoão Carlos10000-0002-0607-8189BazanSilméia Garcia Zanati1Universidade Estadual Paulista Julio de Mesquita FilhoFaculdade de Medicina Campus de BotucatuBotucatuSPBrasilUniversidade Estadual Paulista Julio de Mesquita Filho - Faculdade de Medicina Campus de Botucatu, Botucatu, SP – BrasilCorrespondência: Silméia Garcia Zanati Bazan • Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina Campus de Botucatu - Distrito Rubião Jr, s/n. CEP 18618-687, Botucatu, SP – Brasil E-mail: sgz.bazan@unesp.br
Contribuição dos autores
Concepção e desenho da pesquisa: Rodrigues CSA, Nunes HRC, Okoshi K, Hueb JC, Bazan SGZ; Obtenção de dados: Rodrigues CSA, Reis FM, Silveira CFSMP, Hueb LMS; Análise e interpretação dos dados e Redação do manuscrito: Rodrigues CSA, Bazan R, Reis FM, Silveira CFSMP, Hueb LMS, Carvalho FC, Nunes HRC, Okoshi K, Hueb JC, Bazan SGZ; Análise estatística: Bazan R, Nunes HRC; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Bazan SGZ.
Potencial conflito de interesses
Os autores declaram não haver conflito de interesses pertinentes.
160420210420211164727733070120192009201927122019This is an open-access article distributed under the terms of the Creative Commons Attribution LicenseResumoFundamento:
A incidência de reestenose da artéria coronária após o implante de um stent não farmacológico é mais baixa que na angioplastia com balão; no entanto, ainda apresenta altas taxas.
Objetivo:
O objetivo deste estudo foi identificar novos indicadores de risco para reestenose de stent usando ultrassonografia das carótidas que, em conjunto com indicadores já existentes, ajudariam na escolha do stent.
Métodos:
Realizamos um estudo prospectivo transversal incluindo 121 pacientes consecutivos com doença arterial coronariana que foram submetidos à intervenção coronária percutânea com angiografia nos 12 meses anteriores. Após os casos de reestenose de stent serem identificados, os pacientes foram submetidos à ultrassonografia de carótidas para avaliar a espessura da camada íntima média e placas ateroscleróticas. Os dados foram analisados por regressão múltipla de Cox. O nível de significância foi p<0,05.
Resultados:
A idade mediana dos pacientes foi de 60 anos (1º quartil = 55, 3º quartil = 68), e 64,5% dos pacientes eram do sexo masculino. A angiografia coronária mostrou que 57 pacientes (47,1%) apresentaram reestenose de stent. Cinquenta e cinco pacientes (45,5%) apresentaram placas ateroscleróticas ecolucentes nas artérias carótidas e 54,5% apresentaram placas ecogênicas ou nenhuma placa. Dos pacientes que apresentaram placas ecolucentes, 90,9% apresentaram reestenose do stent coronário, e daqueles com placas ecogênicas ou nenhuma placa, 10,6% apresentaram reestenose de stent. A presença de placas ecolucentes nas artérias carótidas aumentou o risco de reestenose de stent coronário em 8,21 vezes (RR=8,21;IC95%: 3,58-18,82; p<0,001).
Conclusões:
A presença de placas ateroscleróticas ecolucentes na artéria carótida constitui um preditor de risco de reestenose de stent coronário e deve ser considerada na escolha do tipo de stenta ser usado na angioplastia coronária.
Palavras-chave:Doença Arterial CoronarianaAteroscleroseReestenose CoronáriaStentsAngioplastia Coronária com BalãoArtérias Carótidas/ultrassonografiaPlaca AteroscleróticaIntrodução
O desenvolvimento de stents não farmacológicos (SNF) foi um avanço importante na angioplastia com balão para o tratamento de doença arterial coronariana sintomática. Com o uso de stents, pode-se evitar a reestenose por meio da atenuação da retração elástica e remodelamento geométrico negativo, resultando na redução do lúmen do vaso.1 Contudo, a necessidade de novas revascularizações devido a reestenoses de stent ainda era alta, ocorrendo em 10-20% dos pacientes, causadas principalmente por crescimento excessivo da neoíntima, muitas vezes superior à hiperplasia intimal observada na angioplastia simples com balão.2,3
Mais recentemente, os stents farmacológicos (SF) foram desenvolvidos para reduzir a elevada taxa de reestenose observada com os SNF e a necessidade de revascularização. Ensaios clínicos confirmaram uma redução de 50% a 70% na necessidade de revascularizações da lesão alvo com o uso de SF em comparação a SNF, apesar de não ter sido observada diferença significativa na taxa de mortalidade global entre eles.4-9 Esses resultados levaram à recomendação do uso de SF na intervenção coronária percutânea. Porém, esses stents são de alto custo e exigem um longo período de terapia antiplaquetária dupla para prevenir a ocorrência de trombose, não sendo recomendados para todos os pacientes.10
Em algumas situações, tais como diabetes mellitus, envolvimento de pequenos vasos, stent dentro de outro stent, lesões de bifurcação, lesões extensas ou múltiplas, e enxerto de veia safena, a angioplastia com implante de stent apresenta alto risco de reestenose (30-60%). Nessas condições, os SF são mais indicados.11
Além das situações mencionadas, pouco se sabe sobre a importância das placas ateroscleróticas nas artérias carótidas e sua correlação com reestenose de stent.12
Tal correlação é possível, uma vez que inflamação é comum em ambos os casos. Segundo Corrado et al.,13 em pacientes submetidos ao implante de stent coronário, observa-se uma maior frequência de reestenose de stent em pacientes com maior espessura da camada íntima-média (EIM) da parede da carótida e mais placas ateroscleróticas nas artérias carótidas.
Uma vez que a maioria dos indicadores de risco para reestenose de stent refere-se a aspectos angiográficos, o objetivo do estudo foi correlacionar, usando-se ultrassonografia, o perfil aterosclerótico da artéria carótida com reestenose de stent coronário, com ênfase na presença de placas ecolucentes.
Pacientes e métodosPacientes
O estudo foi aprovado pelo comitê de ética da Faculdade de Medicina de Botucatu. Todos os pacientes assinaram o termo de consentimento antes de participarem do estudo. Conduzimos um estudo prospectivo transversal incluindo 121 pacientes consecutivos com doença arterial coronariana crônica entre fevereiro e dezembro de 2015. Todos os pacientes haviam sido submetidos à intervenção coronária percutânea e outra angiografia dentro de 12 meses. As angiografias foram indicadas para estratificação de risco de angina, ou realizadas após confirmação de isquemia miocárdica em testes “provocativos” (teste de esforço com exercício ou cintilografia do miocárdio com estresse). Com base na entrevista direta, identificamos quais pacientes apresentaram diabetes mellitus, dislipidemia ou hipertensão arterial. Também identificamos se os pacientes eram fumantes, e quais medicamentos usavam. A angiografia coronária detectou implantação de stent prévia nas artérias coronárias (artéria coronária direita, artéria coronária circunflexa, artéria coronária descendente anterior, e seus respectivos ramos).
Ultrassom com Doppler das Carótidas
Todos os exames foram realizados por um ultrassonografista usando um aparelho Vivid S6 (General Electric Medical Systems, Tirat Carmel, Israel) equipado com um transdutor linear de frequência 8MHz. O ultrassom da artéria carótida com Doppler foi realizado com o paciente na posição supina. As imagens da carótida, incluindo espessura da íntima-média foram analisadas conforme determinado nos consensos da Sociedade Americana de Ecocardiografia (American Society of Echocardiography)14 e de Mannheim,15 e registradas e armazenadas em um CD. A classificação da EIM por sexo e idade foi feita com base nos valores do percentil 75 propostos no estudo CAPS.16
A EIM foi medida utilizando-se um padrão de linha dupla visualizado por ecotomografia em ambas as artérias carótidas comuns em uma imagem longitudinal. Esse padrão de linha dupla corresponde às extremidades das interfaces lúmen–íntima e média–adventícia. Os valores médios foram calculados em um segmento de 10 mm próximo à parede posterior do bulbo carotídeo. A placa foi considerada quando uma estrutura focal invadisse o lúmen arterial em pelo menos 0,5mm, ou correspondesse a 50% do valor da EIM circundante, ou quando a medida da espessura fosse maior que 1,5 mm, medida desde a interface média-adventícia à interface lúmen-íntima. As placas foram descritas segundo classificação de Gray-Weale et al.,17 Em resumo, placas tipo 1 são aquelas uniformemente ecolucentes; placas tipo II são predominantemente ecolucentes; placas tipo III são placas predominantemente ecogênicas; e as placas tipo IV são uniformemente ecogênicas. Para a análise estatística, os tipos I e II foram chamadas ecolucentes e as tipo III e IV ecogênicas.
Angiografia coronária
As angiografias coronárias foram realizadas por cateterismo cardíaco transradial. Após angiografia coronária seletiva e identificação do stent, a reestenose foi avaliada por angiografia quantitativa. Reestenose de stent foi definida como redução do lúmen de 50% ou mais.18,19
Análise estatística
As variáveis contínuas foram apresentadas como medianas e valores mínimos e máximos. As variáveis categóricas foram expressas como valores absolutos ou frequência (%). A análise de preditores de risco para reestenose de stent em 12 meses de seguimento foi realizada em duas etapas. Na etapa 1, foi estimado o risco relativo individual para cada preditor potencial; na fase 2, o modelo de regressão múltipla de Cox foi ajustado para o risco de reestenose de stent com os preditores mais fortemente associados (p<0,05) com reestenose detectados na fase 1. Valores de p<0,05 foram considerados estatisticamente significantes. Todas as análises estatísticas foram realizadas usando o SPSS v21.0.
Resultados
A idade mediana dos 121 pacientes foi 60 anos (1º quartil = 55; 3º quartil = 68); 78 pacientes (64,5%) eram do sexo masculino. Cinquenta e oito (47,9%) dos pacientes eram fumantes, 47 (38,8%) diabéticos, 91 (75,2%) apresentaram hipertensão sistêmica, e 119 (98,3%) apresentaram dislipidemia. Após ajuste do modelo de regressão múltipla de Cox quanto ao risco de reestenose de stent por potenciais preditores, observamos que não houve diferença estatisticamente significante na distribuição dessas variáveis nos subgrupos com ou sem reestenose de stent (Tabela 1).
Risco de reestenose de stent estimado para cada variável
Os locais de stent foram: artéria descendente anterior esquerda (ADA) em 50 pacientes (41,3%); artéria coronária direita (ACD) em 34 pacientes (28,1%); artéria circunflexa esquerda (ACE) em 19 pacientes (15,7%), ADA e ACD em 9 pacientes (7,4%), ADA e ACE em 5 pacientes (4,1%), e ACD e ACE em 4 pacientes (3,3%). As angiografias mostraram que 57 pacientes (47,1%) apresentaram reestenose de stent coronário, e o local do stent não influenciou na taxa de reestenose de stent (Tabela 1).
A maioria dos pacientes tomava aspirina (97,5%), estatina (92,6%), inibidores da enzima conversora de angiotensina ou bloqueadores de receptor de angiotensina (80,2%), betabloqueadores (88,4%), e 27,3% dos pacientes usavam clopidogrel.
Cinquenta e cinco pacientes (45,5%) dos pacientes apresentaram placas ecolucentes nas artérias carótidas e 66 pacientes (54,5%) apresentaram placas ecogênicas ou nenhuma placa. Cinquenta (90,9%) pacientes com placas ecolucentes, e somente sete (10,6%) daqueles com placas ecogênicas ou nenhuma placa apresentaram reestenose de stent (Figura 1).
Porcentagem de pacientes com reestenose de stent coronário nos grupos de pacientes com placa ecolucente e pacientes com placas ecogênicas ou nenhuma placa nas artérias carótidas.
As imagens de ultrassonografia das placas carótidas e os achados angiográficos das artérias coronárias são apresentadas nas Figuras 2 e 3, respectivamente.
Imagens ultrassonográfias de placas ateroscleróticas tipo II na artéria carótida esquerda.
Achados angiográficos coronários com reestenose de stent na artéria coronária direita.
A análise de regressão múltipla revelou que a presença de placas ecolucentes nas artérias carótidas aumentou o risco de reestenose de stent coronário em 8,21 vezes (8,21; IC95% 3,58-18,82; p<0,001). No entanto, observamos que uma EIM elevada não aumentou o risco de reestenose de stent coronário (RR 1,03; IC95% 0,60-1,76; p=0,897).
Discussão
O estudo revelou uma clara correlação entre placas ateroscleróticas ecolucentes nas artérias carótidas e reestenose de stent coronário avaliado 12 meses após o implante do stent. Pacientes com placas ecolucentes nas artérias carótidas apresentaram um risco 8,21 vezes maior de reestenose de stent coronário em comparação àqueles com placas ecogênicas ou nenhuma placa nas carótidas. Um estudo prévio, no entanto, relatou uma correlação entre placas ecolucentes e reestenose de stent coronário com um OR de 3,8.20 Apesar de considerados obsoletos muitas vezes, SNF foram usados em ambos os estudos, o que reflete a realidade na América Latina. Apesar de similares, os estudos diferem-se na etnicidade das populações e no segundo agente antiplaquetário empregado, uma vez que o estudo de 2008 usou ticlopidina. Uma possível justificativa para essa correlação é inflamação, comum a ambas as situações. Os macrófagos foram as primeiras células inflamatórias a serem reconhecidas como associadas à aterosclerose.21 Posteriormente, outros tipos de leucócitos relacionados à inflamação tais como monócitos, neutrófilos, e linfócitos foram detectados nas placas ateroscleróticas.22,23 As citocinas também estão relacionadas à inflamação aguda e crônica, e sua produção depende em muitos fatores rigorosamente regulados durante a inflamação. Uma ampla variedade de citocinas, tais como TNF-α, IL-1, IL-2, IL-3, IL-6, CXCL8, IL-10, IL-12, IL-15, IL-18, IFN-γ, M-CSF, TGF-β1, TGF-β2, e TGF-β3, foi detectada nas placas ateroscleróticas. Ainda, em condições de hiperlipidemia, TNF-α, IL-1, IL-6, IL-12, IL-15, e IL-18 são produzidos por macrófagos.24 Vários estudos sugeriram a hipótese que disfunção endotelial – causada principalmente por níveis elevados de LDL, tabagismo, hipertensão arterial, e diabetes mellitus – é a primeira etapa no desenvolvimento de aterosclerose. Assim, cada etapa da aterosclerose representaria uma diferente fase do processo inflamatório crônico.25
As plaquetas também exercem um importante papel no processo aterogênico. Elas podem regular a resposta imune e inflamatória pela secreção de mediadores inflamatórios que modulam o recrutamento de leucócitos aos tecidos inflamados. Plaquetas ativas, as quais expressam P-selectina, foram detectadas em diferentes fases da aterosclerose.26
Placas ateroscleróticas ecolucentes – diferente das placas ecogênicas, que contêm mais cálcio e tecido fibroso – são mais ricas em lipídios, elastina, e células inflamatórias, com alta concentração de macrófagos e atividade da metaoloproteinase elevada, os quais exercem importante papel na diferenciação, proliferação e migração celular, e na remodelação vascular.27 A presença de placa ecolucente na artéria carótida mostrou ser um preditor independente de acidente vascular cerebral e síndrome coronária aguda, incluindo infarto do miocárdio.28,29
A reestenose de stent é causada por uma combinação de fatores incluindo denudação endotelial, trauma mecânico, e desarranjo da túnica média e adventícia. Uma reação inflamatória ocorre em estruturas do stent, com infiltração de leucócitos, monócitos, e macrófagos. A gravidade da inflamação é diretamente proporcional ao trauma na parede arterial. Além disso, lesão mecânica da parede do vaso estimula a migração de células musculares lisas (da túnica média) e miofibroblastos (da túnica adventícia) à túnica íntima, onde elas se proliferam.30 A exposição das túnicas dos vasos facilita o contato com fatores da circulação sanguínea, estimulando a hiperplasia da túnica íntima. Com o passar do tempo, a celularidade diminui e a matriz extracelular começa a predominar na lesão de reestenose. Estudos histopatológicos descrevem uma relação inflamatória mais prolongada após a implantação do stent que após a angioplastia com balão.31
Kornowski et al.,32 relataram que a relação inflamatória da parede arterial nas artérias coronárias de suínos foi frequentemente observada um mês após o implante de stent. A reação inflamatória foi composta principalmente de histiócitos, linfócitos, e formação de granuloma, e de neutrófilos nas formas inflamatórias graves. Houve uma forte correlação entre a extensão da reação inflamatória e a quantidade de formação neointimal no interior dos stents. Segundo os estudos mencionados, que avaliaram os mecanismos de aterogênese e reestenose de stent, a inflamação é um link comum evidente entre placa ecolucente na artéria carótida e reestenose de stent coronário. Ainda, Rothwell et al.,33 relataram que instabilidade da placa, ou seja, com inflamação, não é meramente um fenômeno vascular local, mas ocorre simultaneamente em vários lugares no leito vascular sistêmico.
Apesar de ser um preditor de doenças cardiovasculares, uma EIM aumentada não elevou o risco para reestenose de stent. Tal fato é consistente com estudos prévios e com o conceito de que o tamanho da placa não contribui tanto como a instabilidade da placa para eventos cardiovasculares.20,34 Isso se deve possivelmente ao fato de que o espessamento da camada íntima-média da artéria carótida faz parte do processo de envelhecimento da parede arterial, e não sinônimo de aterosclerose subclínica. Contudo, alterações celulares e moleculares observadas no espessamento da íntima-média estão envolvidas no desenvolvimento e progressão de placas.14 Assim, um aumento na EIM sem placas concomitantes não teria relação com os processos inflamatórios na aterosclerose.
Limitações do estudo
A validade externa deste estudo é limitada pela avaliação somente de pacientes sintomáticos, diagnosticados com angina estável. No entanto, todos os pacientes neste estudo foram submetidos à angiografia coronária, exame padrão-ouro para o diagnóstico de reestenose de stent coronário, o que aumenta a validade interna do estudo. Outra limitação é o fato de não termos. estudado um grupo de pacientes submetidos ao implante de SF.
Conclusão
A presença de placa aterosclerótica ecolucente na artéria carótida representa um preditor de risco de reestenose de stent coronário e deveria ser considerada, juntamente com outros preditores de risco, na escolha do tipo de stent a ser implantado na angioplastia coronária.
Fontes de financiamento
O presente estudo não contou com fontes de financiamento externas.
Vinculação acadêmica
Este artigo é parte de dissertação de Mestrado de Cássia da Silva Antico Rodrigues pela Universidade Estadual Paulista Julio de Mesquita Filho.
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Gray-Weale AC, Graham JC, Burnett JR, Lusby RJ. Carotid artery atheroma: comparison of preoperative B-mode ultrasound appearance with carotid endarterectomy specimen pathology. J Cardiovasc Surg. 1988; 29(6):676-81.BeattKJSerruysPWHugenholtzPGRestenosis after coronary angioplasty: new standards for clinical studiesJ Am Coll Cardiol199015249149818. Beatt KJ, Serruys PW, Hugenholtz PG. Restenosis after coronary angioplasty: new standards for clinical studies. J Am Coll Cardiol. 1990;15(2):491-8.CaliffRMOhmanEMFridDJFortinDFMarkDBHlatkyMARestenosis: the clinical issuesTopolEJText book of interventional cardiology W.B. SaundersPhiladelphiaWB Saunders199036339419. Califf RM, Ohman EM, Frid DJ, Fortin DF, Mark DB, Hlatky MA, et al. Restenosis: the clinical issues. In: Topol EJ: Text book of interventional cardiology W.B. Saunders, Philadelphia: WB Saunders;1990.p.363-94.KittaYObataJETakanoHNakamuraTKodamaYFujiokaDEcholucent carotid plaques predict in-stent restenosis after bare metal stenting in native coronary arteriesAtherosclerosis2008197117718220. Kitta Y, Obata JE, Takano H, Nakamura T, Kodama Y, Fujioka D, et al. Echolucent carotid plaques predict in-stent restenosis after bare metal stenting in native coronary arteries. Atherosclerosis 2008;197(1):177-82.GerrityRGNaitoHKRichardsonMSchwartzCJDietary induced atherogenesis in swine. Morphology of the intima in prelesion stagesAm J Pathol197995377579221. Gerrity RG, Naito HK, Richardson M, Schwartz CJ. Dietary induced atherogenesis in swine. Morphology of the intima in prelesion stages. Am J Pathol. 1979;95(3):775-92.HanssonGKLibbyPThe immune response in atherosclerosis: a double-edged swordNat Rev Immunol20066750851922. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006; 6(7):508-19.GalkinaELeyKLeukocyte influx in atherosclerosisCurr Drug Targets20078121239124823. Galkina E, Ley K. Leukocyte influx in atherosclerosis. Curr Drug Targets 2007; 8(12):1239-48.TedguiAMallatZCytokines in atherosclerosis: pathogenic and regulatory pathwaysPhysiol Rev200686251558124. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006; 86(2):515-81.RossRGlomsetJAAtherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosisScience197318040931332133925. Ross R, Glomset JA. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science. 1973;180(4093):1332-9.Von HundelshausenPWeberCPlatelets as immune cells: bridging inflammation and cardiovascular diseaseCirc Res20071001274026. Von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007;100(1):27-40.GronholdtMLNordestgaardBGBentzonJWiebeBMZhouJFalkEMacrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levelsJ Vasc Surg200235113714527. Gronholdt ML, Nordestgaard BG, Bentzon J, Wiebe BM, Zhou J, Falk E, et al. Macrophages are associated with lipid-rich carotid artery plaques, echolucency on B-mode imaging, and elevated plasma lipid levels. J Vasc Surg 2002;35(1):137-45.PolakJFShemanskiLO'LearyDHLefkowitzDPriceTRSavagePJHypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or olderCardiovascular Health Study. Radiology1998208364965428. Polak JF, Shemanski L, O'Leary DH, Lefkowitz D, Price TR, Savage PJ, et al. Hypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. Radiology. 1998; 208(3):649-54.HondaOSugiyamaSKugiyamaKFukushimaHNakamuraSKoideSEcholucent carotid plaques predict future coronary events in patients with coronary artery diseaseJ Am Coll Cardiol20044371177118429. Honda O, Sugiyama S, Kugiyama K, Fukushima H, Nakamura S, Koide S, et al. Echolucent carotid plaques predict future coronary events in patients with coronary artery disease. J Am Coll Cardiol. 2004;43(7):1177-84.KomatsuRUedaMNarukoTKojimaABeckerAENeointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analysesCirculation199898322423330. Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation. 1998; 98(3):224-33.KleinmanMECipollaGDCuiJChronosNKingSBIRobinsonKAStent implantation induces late arterial wall cellular proliferation compared to angioplasty in normal rabbitsJ Am Coll Cardiol199729312A312A31. Kleinman ME, Cipolla GD, Cui J, Chronos N, King SBI, Robinson KA. Stent implantation induces late arterial wall cellular proliferation compared to angioplasty in normal rabbits. J Am Coll Cardiol. 1997;29:312A.KornowskiRHongMKTioFOBramwellOWuHLeonMBIn-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasiaJ Am Coll Cardiol199831122423032. Kornowski R, Hong MK, Tio FO, Bramwell O, Wu H, Leon MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol. 1998;31(1):224-30.RothwellPMVillagraRGibsonRDondersRCWarlowCPEvidence of a chronic systemic cause of instability of atherosclerotic plaquesLancet20003559197192433. Rothwell PM, Villagra R, Gibson R, Donders RC, Warlow CP. Evidence of a chronic systemic cause of instability of atherosclerotic plaques. Lancet. 2000;355(9197):19-24.LibbyPAikawaMStabilization of atherosclerotic plaques: new mechanisms and clinical targetsNat Med20028111257126234. Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nat Med. 2002;8(11):1257-62.Original ArticleCarotid Artery Atherosclerotic Profile as Risk Predictor for Restenosis After Coronary StentingRodriguesCássia da Silva Antico1BazanRodrigo1ReisFabrício Moreira1SilveiraCaroline F. S. Mazeto Pupo da1HuebLívia Maria Severino1CarvalhoFábio Cardoso de1NunesHélio Rubens de Carvalho10000-0001-8980-8839OkoshiKatashi1HuebJoão Carlos10000-0002-0607-8189BazanSilméia Garcia Zanati1BotucatuSPBrazilUniversidade Estadual Paulista Julio de Mesquita Filho - Faculdade de Medicina Campus de Botucatu, Botucatu, SP – BrazilMailing Address: Silméia Garcia Zanati Bazan • Universidade Estadual Paulista Julio de Mesquita Filho Faculdade de Medicina Campus de Botucatu - Distrito Rubião Jr, s/n. Postal Code 18618-687, Botucatu, SP – Brazil E-mail: HYPERLINK “mailto:sgz.bazan@unesp.br” sgz.bazan@unesp.br
Author contributions
Conception and design of the research: Rodrigues CSA, Nunes HRC, Okoshi K, Hueb JC, Bazan SGZ; Data acquisition: Rodrigues CSA, Reis FM, Silveira CFSMP, Hueb LMS; Analysis and interpretation of the data and Writing of the manuscript: Rodrigues CSA, Bazan R, Reis FM, Silveira CFSMP, Hueb LMS, Carvalho FC, Nunes HRC, Okoshi K, Hueb JC, Bazan SGZ; Statistical analysis: Bazan R, Nunes HRC; Critical revision of the manuscript for intellectual content: Bazan SGZ.
Potential Conflict of Interest
The authors report no conflict of interest concerning the materials and methods used in this study or the findings specified in this paper.
AbstractBackground:
The incidence of restenosis of the coronary artery after a bare-metal stent implant has been lower than in simple balloon angioplasty; however, it still shows relatively high rates.
Objective:
The aim of this study was to find new risk indicators for in-stent restenosis using carotid ultrasonography, that, in addition to the already existing indicators, would help in decision-making for stent selection.
Methods:
We carried out a cross-sectional prospective study including 121 consecutive patients with chronic coronary artery disease who had undergone percutaneous coronary intervention with repeat angiography in the previous 12 months. After all cases of in-stent restenosis were identified, patients underwent carotid ultrasonography to evaluate carotid intima-media thickness and atherosclerosis plaques. The data were analyzed by Cox multiple regression. The significance level was set a p<0.05.
Results:
Median age of patients was 60 years (1st quartile = 55, 3rd quartile = 68), and 64.5% of patients were male. Coronary angiography showed that 57 patients (47.1%) presented in-stent restenosis. Fifty-five patients (45.5%) had echolucent atherosclerotic plaques in carotid arteries and 54.5% had echogenic plaques or no plaques. Of patients with who had echolucent plaques, 90.9% presented coronary in-stent restenosis. Of those who had echogenic plaques or no plaques, 10.6% presented in-stent restenosis. The presence of echolucent plaques in carotid arteries increased the risk of coronary in-stent restenosis by 8.21 times (RR=8.21; 95%CI: 3.58-18.82; p<0.001).
Conclusions:
The presence of echolucent atherosclerotic plaques in carotid artery constitutes a risk predictor of coronary instent restenosis and should be considered in the selection of the type of stent to be used in coronary angioplasty.
The development of bare-metal stents (BMS) was a great advance in balloon angioplasty for treating symptomatic coronary artery disease. With the use of stents, restenosis can be avoided by attenuating the elastic recoil and promoting a negative geometric remodeling, resulting in reduction of vessel lumen.1 However, the need for new revascularizations due to in-stent restenosis was still relatively high, occurring in 10% to 20% of patients, mostly caused by excessive neointima growth, sometimes even larger than the intimal hyperplasia observed with a simple balloon angioplasty.2,3
More recently, drug-eluting stents (DES) were developed to reduce the high restenosis rate observed with BMS and the need for revascularization. Clinical trials have confirmed a reduction of 50-70% in the need for revascularizations of the target lesion with DES compared to BMS, although there has been no significant difference in overall mortality rate between them.4-9 These results have led to the preferential recommendation of DES in coronary percutaneous intervention. However, these stents are expensive and require a long period of dual antiplatelet therapy to avoid thrombosis, and hence are not recommended for all patients.10
In some situations such as diabetes mellitus, small vessel involvement, in-stent stent, bifurcation lesions, long or multiple lesions, and saphenous vein graft, angioplasty with stent implantation present a high risk of restenosis (30-60%). In these conditions, DES are more consistently indicated.11
In addition to the above-mentioned situations, little is known about the importance of atherosclerotic plaques in carotid arteries and their correlation to in-stent restenosis. This correlation is possible since inflammation is common in both cases.12 According to Corrado et al.,13 in patients undergoing coronary stent implantation, a higher frequency of in-stent restenosis is observed in those presenting greater carotid intima-media thickness (CIMT) and atherosclerotic plaques in carotid arteries.
As most risk indicators for in-stent restenosis concern coronary angiographic aspects, the objective of this study was to correlate, using ultrasonography, the carotid artery atherosclerotic profile with coronary in-stent restenosis, focusing on the presence of echolucent plaques.
Patients and methodsPatients
This study was approved by Botucatu Medical School Ethics Committee. All patients signed the informed consent form before participating in this study. We carried out a cross-sectional prospective study including 121 consecutive patients with chronic coronary artery disease, from February to December of 2015. All patients had undergone percutaneous coronary intervention and another angiography within 12 months. The angiographies were indicated for stable angina risk stratification, or after any confirmed myocardial ischemia in provocative tests (exercise stress test or cardiac scintigraphy with stress. Based on the directed interview we identified which patients had diabetes mellitus, dyslipidemia, or arterial hypertension. We also identified if they were tobacco users, and which medications they were taking. Coronary angiography detected previous stent implantation in coronary arteries (right coronary artery, circumflex coronary artery, anterior descending coronary artery, and their respective branches).
Carotid Artery Duplex Ultrasonography
All procedures were performed by an experienced sonographer using a Vivid S6 echocardiograph (General Electric Medical Systems, Tirat Carmel, Israel) equipped with an 8.0 MHz frequency linear array probe. Duplex ultrasonography of the carotid artery was performed with patient in supine decubitus position. Carotid images were analyzed according to the consensus statement from the American Society of Echocardiography carotid intima-media thickness task force14 and the Mannheim Carotid Intima-Media Thickness Consensus,15 and recorded on a compact disc. Classification of CIMT by age and gender were determined based on the 75th percentile of values proposed in the CAPS study.16
CIMT was measured using a double-line pattern visualized by echotomography on both common carotid arteries in a longitudinal image. This double-line pattern comprises the leading edges of the lumen–intima and media–adventitia interfaces. Mean values were calculated on a 10 mm segment next to the posterior wall of carotid bulb. Plaque was considered a focal structure when it encroached into the arterial lumen by at least 0.5 mm, or corresponded to 50% of surrounding CIMT value, or demonstrated a thickness of >1.5 mm, as measured from the media–adventitia to lumen–intima interface. Plaques were described according to the classification by Gray-Weale et al.17 In brief, type I plaque is uniformly echolucent; type II is predominantly echolucent; type III is predominantly echogenic; and type IV is uniformly echogenic. For statistical analysis, types I and II were called echolucent and types III and IV echogenic.
Coronary angiography
Coronary angiographies were performed by transradial cardiac catheterization. After selective coronary angiography and stent identification, restenosis was evaluated by quantitative angiography. In-stent restenosis was defined as a lumen reduction of 50% or greater.18,19
Statistical analysis
Continuous variables were presented as medians and minimum and maximum values. Categorical variables were expressed as absolute values or frequency (%). The analysis of predictors of risk for in-stent restenosis at 12 months of follow-up was performed in two stages. In step 1, individual relative risk for each potential predictor was estimated. Then in phase 2, the model of multiple Cox regression was adjusted for the risk of in-stent restenosis with the predictors most strongly associated (p <0.05) with restenosis detected in phase 1. Values of p <0.05 were considered as statistically significant. All statistical analyses were performed using SPSS v21.0 software.
Results
The median age of the 121 patients was 60 years (1st quartile = 55, 3rd quartile = 68); 78 patients (64.5%) were male. Fifty-eight (47.9%) patients were smokers, 47 (38.8%) were diabetic, 91 (75.2%) had systemic hypertension, and 119 (98.3%) had dyslipidemia. After adjusting the Cox multiple-regression model for the risk of in-stent restenosis by potential predictors of restenosis, we observed that there was no statistically significant difference in distribution of these variables in the subgroups with or without in-stent restenosis (Table 1).
In-stent restenosis risk estimated for each variable
Variable
RR
95%CI
p
Age
0.99
0.96-1.02
0.555
Males
1.87
1.01-3.46
0.048
Medical history
AH
0.85
0.47-1.51
0.567
DM
1.07
0.63-1.81
0.815
Tobacco use
1.21
0.72-2.03
0.478
Dyslipidemia
0.94
0.13-6.80
0.952
Carotid artery US
Echolucent plaques
8.57
3.89-18.90
<0.001
CIMT (increased)
1.88
1.11-3.15
0.017
Coronary with stent
LAD
1.23
0.72-2.07
0.450
RCA
0.76
0.44-1.32
0.330
LCX
0.85
0.45-1.60
0.607
AH: arterial hypertension; DM: diabetes mellitus; US: ultrasonography; CIMT: carotid intima-media thickness; LAD: left anterior descending artery; RCA: right coronary artery; LCX: left circumflex artery.
Stent locations were as follow: left anterior descending artery (LAD) in 50 patients (41.3%), right coronary artery (RCA) in 34 patients (28.1%), left circumflex artery (LCX) in 19 patients (15.7%), both LAD and RCA in 9 patients (7.4%), both LAD and LCX in 5 patients (4.1%), and both RCA and LCX in 4 patients (3.3%). Angiographies showed that 57 patients (47.1%) presented coronary in-stent restenosis, and the stent location did not influence in-stent restenosis rates (Table 1).
Most patients were taking aspirin (97.5%), statin (92.6%), angiotensin converting enzyme inhibitors or angiotensin receptor blockers (80.2%), beta-blockers (88.4%), and 27.3% were taking clopidogrel.
Fifty-five patients (45.5%) showed echolucent plaques in carotid arteries and 66 patients (54.5%) presented echogenic plaques or no plaques. Fifty patients (90.9%) with echolucent plaques and only seven (10.6%) of those with echogenic plaques or no plaques showed in-stent restenosis (Figure 1).
Percentage of patients with coronary in-stent restenosis in the subgroups of patients with echolucent plaques and patients with echogenic/no plaque in carotid arteries.
Ultrasonography images of carotid plaques and coronary angiographic findings are shown in Figures 2 and 3, respectively.
Ultrasound images of type II atherosclerotic plaque in the left carotid artery.
Coronary angiographic findings with stent restenosis in the right coronary artery.
The analysis of multiple regression revealed that the presence of echolucent plaques in carotid arteries increased the risk of coronary in-stent restenosis by 8.21 times (RR 8.21; 95%CI; 3.58-18.82; p<0.001). However, we observed that increased CIMT did not increase the risk of coronary in-stent restenosis (RR 1.03; 95%CI 0.60-1.76; p=0.897).
Discussion
This study revealed a clear correlation between echolucent atherosclerotic plaques in carotid arteries and coronary in-stent restenosis evaluated at 12 months after stent implantation. Patients with echolucent plaques in carotid arteries presented an 8.21 times greater risk of coronary in-stent restenosis than those with echogenic plaques or no atherosclerotic plaques in carotid. A previous study, however, reported a correlation between echolucent plaques and coronary in-stent restenosis with an OR of 3.8.20 Although often considered obsolete, BMS were used in both studies, which reflects most appropriately the current reality in Latin America. Though similar, the studies differ as to ethnicity and the second antiplatelet agent employed, as the 2008 study used ticlopidine. A possible justification for this correlation is an inflammatory state, which is common in both situations. Macrophages were the first inflammatory cells to be recognized to be associated with atherosclerosis.21 Later, other types of inflammation-related leukocytes such as monocytes, neutrophils, and lymphocytes were detected in atherosclerotic plaques.22,23 Cytokines are also related to acute and chronic inflammation, and their production depends on many strictly regulated factors during inflammation. A wide range of cytokines, such as TNF-α, IL-1, IL-2, IL-3, IL-6, CXCL8, IL-10, IL-12, IL-15, IL-18, IFN-γ, M-CSF, TGF-β1, TGF-β2, and TGF-β3 have been found in atherosclerotic plaques. Furthermore, under hyperlipidemic conditions TNF-α, IL-1, IL-6, IL-12, IL-15, and IL-18 are produced by macrophages.24 Several studies have suggested the hypothesis that endothelial dysfunction — mostly caused by elevated LDL, tobacco, arterial hypertension, and diabetes mellitus — is the first step towards atherosclerosis. Therefore, each step of atherosclerosis would represent a different phase of the chronic inflammatory process.25
Platelets also play an important role in the atherogenic process. They can regulate immune and inflammatory responses by secreting inflammatory mediators that modulate leukocyte recruitment to the inflamed tissues. Activated platelets, which express P-selectin, have been detected in different phases of atherosclerosis.26
Echolucent atherosclerotic plaques — unlike echogenic plaques, which contain more calcium and fibrous tissue — are much richer in lipids, elastin, and inflammatory cells, with high macrophage concentration and metalloproteinase activity, which plays an important role in cellular differentiation, proliferation and migration, and also in vascular remodeling.27 Echolucent plaque in carotid artery has been shown to be an independent predictor of stroke and acute coronary syndrome, including myocardial infarction.28,29
In-stent restenosis is caused by a combination of factors including endothelial denudation, mechanical trauma, and derangement of the tunica media and adventitia. An inflammatory reaction occurs in the stent structures, with leukocyte, monocyte, and macrophage infiltration; inflammation severity is directly proportional to arterial wall trauma. Mechanical injury of the vessel wall stimulates the migration of smooth muscle cells (from the tunica media) and myofibroblasts (from the tunica adventitia) to the tunica intima, where they proliferate.30 Exposure of the vessel tunics facilitates contact with blood circulating factors, stimulating intima tunic hyperplasia. As time passes, cellularity decreases and the extracellular matrix begins to predominate in the restenosis lesion. Histopathological studies describe a more prolonged inflammatory reaction after stent implantation than after balloon angioplasty.31
Kornowski et al.32 reported that inflammatory reaction of arterial wall in porcine coronary arteries was frequently observed 1 month after stent implantation. The inflammatory reaction was mainly composed of histiocytes, lymphocytes, and granuloma formation, and also neutrophils in the most severe inflammatory forms. There was a strong correlation between the extent of inflammatory reaction and the amount of neointimal formation within the stents. According to the above studies that evaluated the mechanisms of atherogenesis and in-stent restenosis, inflammation is an evident common link between echolucent plaque in carotid artery and coronary in-stent restenosis. Furthermore, Rothwell et al.33 reported that plaque instability, i.e., with inflammation, is not a merely local vascular phenomenon, but occurs simultaneously at multiple sites in the systemic vascular bed.
Despite being a predictor of cardiovascular diseases, increased CIMT did not elevate the risk of in-stent restenosis. This is consistent with previous studies and with the concept that plaque size does not contribute as much as plaque instability to cardiovascular events.20,34 This was possibly because carotid intima-media thickening is part of the arterial wall aging process, and not synonymous of subclinical atherosclerosis. However, cellular and molecular changes observed in intima-media thickening have been implicated in plaque development and progression.14 Thus, an increase in CIMT with no concomitant plaques would have no relation to the inflammatory processes in atherosclerosis.
Study limitations
The external validity of this study is limited due to the evaluation of symptomatic patients diagnosed with stable angina only. However, the fact that all patients in this study underwent coronary angiography, which is the gold standard exam for the diagnosis of coronary stent restenosis, increases its internal validity. Another limitation found was that we did not study a group of patients submitted to DES.
Conclusion
The presence of echolucent atherosclerotic plaque in carotid artery represents a risk predictor of coronary in-stent restenosis and should be considered along with other risk predictors in the decision-making on the type of stent to be implanted in coronary angioplasty.
Sources of Funding
There was no external funding source for this study.
Study Association
This article is part of the thesis of master submitted by Cássia da Silva Antico Rodrigues from Universidade Estadual Paulista Julio de Mesquita Filho.