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. 2021 Feb 22;116(3):466–472. [Article in Portuguese] doi: 10.36660/abc.20200045
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O Escore Gensini e a Carga Trombótica Adicionam Valor Preditivo ao Escore SYNTAX na Detecção de No-Reflow após Infarto do Miocárdio

Luís Carlos V Matos 1,5, Luiz Sergio Carvalho 2,5, Rodrigo Modolo 2, Simone Santos 3,4, José Carlos Quinaglia e Silva 1,5, Osório Luis Rangel de Almeida 1,5, Andrei C Sposito 2
PMCID: PMC8159555  PMID: 33656051

Resumo

Fundamento

O fenômeno de no-reflow após a intervenção coronária percutânea está associado a um pior prognóstico em pacientes com infarto do miocárdio com supradesnivelamento do segmento ST (IAMCSST). O escore SYNTAX é um bom preditor de no-reflow.

Objetivo

Nosso objetivo foi avaliar se a carga aterosclerótica (escore Gensini) e a carga trombótica na artéria coronária culpada melhorariam a capacidade do escore SYNTAX para detectar o no-reflow.

Métodos

Neste estudo coorte prospectivo, foram estudados pacientes com IAMCSST consecutivos que se apresentaram dentro de 12 horas a partir do início dos sintomas. O no-reflow foi definido como fluxo TIMI < 3 ou fluxo TIMI =3 mas grau de blush miocárdico (myocardial blush grade) < 2. A carga trombótica foi quantificada de acordo com o grau TIMI de trombo (0 a 5).

Resultados

Foram incluídos 481 pacientes no estudo, com idade média de 61±11 anos. O fenômeno de no-reflow ocorreu em 32,8% dos pacientes. O escore SYNTAX (OR=1,05, IC95% 1,01–1,08, p<0,01), a carga trombótica (OR=1,17, IC95% 1,06–1,31, p<0,01), e o escore Gensini (OR=1,37, IC95% 1,13–1,65, p<0,01) foram preditores independentes do no-reflow. Os escores combinados apresentaram uma maior área sob a curva quando comparados ao escore SYNTAX isolado (0,78 [0,73–0,82] vs 0,73 [0,68–0,78], p=0,03). A análise da melhora da reclassificação líquida (NRI) categórica (0,11 [0,01–0,22], p=0,02) e contínua (NRI>0) (0,54 [0,035–0,73], p<0.001) mostrou melhora na capacidade preditiva do no-reflow no modelo combinado, com melhora da discriminação integrada (IDI) de 0,07 (0,04–0,09, p<0,001).

Conclusões

Nossos achados sugerem que, em pacientes com IAMCSST submetidos à intervenção coronária percutânea, a carga aterosclerótica e a carga trombótica na artéria culpada adicionam valor preditivo ao escore SYNTAX na detecção do fenômeno no-reflow. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)

Keywords: Intervenção Coronária Percutânea/métodos, Infarto do Miocárdio, Aterosclerose, Trombose, Placa Aterosclerótica, Embolização Terapêutica

Introdução

A intervenção coronária percutânea (ICP) é o método de reperfusão de escolha para infarto do miocárdio com supradesnivelamento do segmento ST (IAMCSST).1 Além de recuperar a patência do lúmen arterial, o objetivo dessa intervenção é promover o fluxo sanguíneo na microcirculação coronária.2 Contudo, um em cada três pacientes permanece com o fluxo microvascular reduzido apesar da restauração da patência da artéria coronária epicárdica. Esse fenômeno é conhecido como “no-reflow” (NR)2,3 O NR está associado a uma maior incidência de insuficiência cardíaca, choque cardiogênico, e morte.3-5

Um número considerável de marcadores de obstrução microvascular já foi descrito, particularmente idade e tempo de reperfusão.6,7 Mais recentemente, foi demonstrado que a complexidade anatômica para ICP, estimada pelo escore SYNTAX, também pode estar relacionada com um maior risco de NR.8-10 Uma vez que a ocorrência de NR é maior que a desses marcadores, é possível que existam outros marcadores de importância clínica. Neste contexto, é plausível a hipótese de que a carga aterosclerótica e trombótica adicione valor preditivo ao escore SYNTAX, idade, e tempo de reperfusão na predição de NR. O presente estudo teve como objetivo testar essa hipótese.

Métodos

Seleção da amostra

Este estudo baseou-se em uma subanálise do Brasilia Heart Study (BHS), cujo delineamento foi descrito previamente.11 Em resumo, o BHS é um estudo coorte, prospectivo, unicêntrico, de pacientes consecutivos com IAMCSST que se apresentaram nas primeiras 24 horas desde o início dos sintomas. IAMCSST foi definido segundo os critérios: 1) elevação do segmento ST em pelo menos 1 mm no plano frontal ou 2 mm no plano horizontal em duas derivações contíguas, ou novo bloqueio de ramo esquerdo pelo eletrocardiograma; 2) resultado positivo para o marcador de necrose miocárdica, definido como CK-MB>25 U/L, correspondendo a valores acima do percentil 99. Pacientes submetidos à ICP nas primeiras 12 horas do IAMCSST foram considerados elegíveis para o estudo. Os participantes assinaram um termo de consentimento e o estudo foi aprovado por um comitê de ética em pesquisa da instituição. Todos os procedimentos estavam de acordo com os padrões éticos do comitê institucional para pesquisa envolvendo humanos e com a declaração de Helsinki de 1964 e suas últimas revisões, ou padrões éticos comparáveis.

Análise angiográfica

Todos os angiogramas foram revisados por dois cardiologistas intervencionistas experientes, que interpretaram as imagens de maneira independente, e avaliaram os seguintes parâmetros: fluxo coronário: fluxo TIMI;12 2) perfusão miocárdica: myocardial blush grade (MBG);13 3) carga trombótica: escala de trombos TIMI;14 4) escore angiográfico SYNTAX,8 e o escore Gensini modificado.15 Os escores foram obtidos dos angiogramas de diagnóstico antes de qualquer intervenção. Os dois cardiologistas entraram em consenso nas interpretações dos achados, com variabilidade intraobservador e entre observador de 5%.

NR foi definido como um fluxo TIMI < 3 ou TIMI = 3 mas MBG<2 na angiografia coronária realizada após ICP da artéria relacionada ao IAMCSST.

Análise estatística

Os dados quantitativos foram expressos em média e desvio padrão. Os grupos foram comparados pelo teste t de Student para variáveis contínuas paramétricas ou o teste de Mann-Whitney para variáveis contínuas não paramétricas, e pelo teste qui-quadrado para variáveis categóricas. Regressão logística binária foi usada para determinar preditores do fenômeno NR após reperfusão em modelo não ajustado (modelo 1) e ajustado (modelo 2) para escore GRACE e tempo de reperfusão (período entre início de sintomas e reperfusão) após reperfusão. Análise da curva característica de operação do receptor (curva ROC) foi realizada para determinar a capacidade preditiva dos modelos. A melhora da reclassificação líquida (NRI) e a melhora da discriminação integrada (IDI) foram usadas para determinar melhoras obtidas com a adição de novos preditores. Análise estatística foi realizada usando o programa SPSS para Mac, versão 23.0, e o programa R para Mac versão 3.4.2. Um valor de p < 0,05 foi considerado estatisticamente significativo.

Resultados

Um total de 481 pacientes submetidos à ICP na fase aguda do IAMCSST foi incluído no estudo. A idade média dos pacientes foi 61 ± 11 anos, e 74,6% eram homens, 58,0% hipertensos, 54,2% sedentários, 38,0% fumantes, e 30,7% diabéticos. O fenômeno de NR ocorreu em 32,8% dos pacientes (n=158), os quais foram comparados com aqueles que apresentaram ótima reperfusão (n=323). Características clínicas e bioquímicas de ambos os grupos são descritas na Tabela 1.

Tabela 1. – Características clínicas e bioquímicas de 481 pacientes submetidos à intervenção coronária percutânea por infarto do miocárdio com supradesnivelamento do segmento ST que apresentaram reperfusão adequada ou ausência de reperfusão (fenômeno no-reflow) após o procedimento.

Variáveis paramétricas Total (n = 481) Reperfusão adequada (n = 323) No-reflow (n = 158) Valor p*
média ± DP média ± DP média ± DP
Idade (anos) 61±11 61±11 61±12 0,64
IMC (kg.m-2) 27,0±4,2 26,8±3,9 27,3±4,7 0,32
GRACE na admissão hospitalar 136±26 135±27 137±24 0,46
Colesterol total no primeiro dia (mg.mL-1) 192±48 192±45 191±53 0,83
HDL-c no primeiro dia (mg.mL-1) 40±11 38±10 38±11 0,63
HbA1c (%) 6,5±1,8 6,5±1,8 6,4±1,7 0,64
Variáveis não paramétricas Mediana (Q1 - Q3) Mediana (Q1 - Q3) Mediana (Q1 - Q3) Valor p†
Tempo de reperfusão 111 (60 - 210) 96 (60 - 206) 120 (60 - 239) 0,42
LDL-c no primeiro dia (mg.mL-1) 117 (93 - 143) 117 (97 - 145) 118 (94 - 141) 0,50
Triglicerídeos no primeiro dia (mg.mL-1) 134 (87 - 207) 135 (90 - 215) 133 (84 - 195) 0,11
Variáveis categóricas ƒ (%) ƒ (%) ƒ (%) Valor pǂ
Homens, n (%) 359 (75) 235 (73) 124 (78) 0,34
DM, n (%) 148 (31) 94 (29) 54 (34) 0,34
Hipertensão, n (%) 279 (58) 187 (58) 92 (58) 0,97
Acidente vascular cerebral, n (%) 21 (4) 11 (3) 10 (6) 0,24
Tabagismo, n (%) 183 (38) 127 (39) 56 (35) 0,35
Sedentarismo, n (%) 261 (54) 179 (55) 82 (52) 0,37
ICP previa, n (%) 26 (5) 15 (5) 11 (7) 0,35
CABG, n (%) 4 (0,8) 3 (0,9) 1 (0,6) 0,86
Killip >1, n (%) 52 (11) 31 (10) 21 (13,2) 0,44
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DP: desvio padrão; Q1: primeiro quartil; Q3: terceiro quartil. CABG: coronary artery bypass grafting; GRACE: Global Registry of Acute Coronary Eventos; DM: diabetes mellitus tipo 2; ICP: intervenção coronária percutânea; IMC: índice de massa corporal; HbA1C, hemoglobina glicada; LDL, lipoproteína de baixa densidade; HDL, lipoproteína de alta densidade. * teste t de Student não pareado; † teste Mann-Whitney não paramétrico; ǂ teste qui-quadrado.

O escore Gensini, o escore Gensini da artéria culpada, o escore SYNTAX, e a carga trombótica foram significativamente maiores no grupo NR que no grupo com reperfusão adequada (Tabela 2). Ambos os modelos de regressão logística (ajustado e não ajustado) mostraram que o escore SYNTAX, o escore Gensini, e a carga trombótica foram preditores independentes do NR (Tabela 3). A análise da curva ROC mostrou que os modelos com escores combinados apresentaram maior área sob a curva ROC que o modelo que apresentava somente o escore SYNTAX [0,778 (0,733 – 0,823) vs. 0.737 (0,688 – 0,786)] (Figura 1).

Tabela 2. – Parâmetros angiográficos de 481 pacientes submetidos à intervenção coronária percutânea por infarto do miocárdio com supradesnivelamento do segmento ST.

Parâmetros n = 481 Reperfusão adequada n = 323 No-reflow n = 158 p
Escore Gensini 100±70 82±62 139±69 <0,001
Escore Gensini – artéria culpada 62±49 48±38 87±56 <0,001
Escore SYNTAX 12±10 9±8 17±10 <0,001
Carga trombótica – artéria culpada, n (%) 181 (37,6) 89 (27,5) 92 (58,2) <0,001
Escala TIMI de trombo, n (%)       <0,001
0 300 (63) 234 (72) 66 (42)  
1 9 (1,9) 8 (2,5) 1 (0,6)  
2 21 (4,4) 13 (4) 8 (5)  
3 18 (3,7) 14 (4,3) 4 (2,5)  
4 18 (3,7) 11 (3,4) 7 (4,4)  
5 115 (24) 43 (13,3) 72 (46)  
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Valores expressos em média ± desvio padrão; TIMI: thrombolysis in myocardial infarction.

Tabela 3. – Modelo de regressão logística dos escores SYNTAX, Gensini, e carga trombótica como preditores do fenômeno de no-reflow.

Modelos OR (IC95%) p
Modelo 1 (não ajustado)    
Idade 1,02 (1,00-1,03 0,037
Tempo de reperfusão 1,00 (1,00-1,01) 0,154
Escore SYNTAX 1,10 (1,07-1,12) <0,001
Carga trombótica 1,38 (1,26-1,51) <0,001
Escore Gensini 1,76 (1,50-2,07) <0,001
Modelo 2 (mutivariado)*    
Idade† 1,01 (0,98-1,02) 0,325
Tempo de reperfusão 0,98 (0,99-1,00) 0,645
Escore SYNTAX 1,05 (1,01-1,08) <0,01
Carga trombótica 1,17 (1,06-1,31) <0,01
Escore Gensini 1,37 (1,13-1,65) <0,01
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IC: intervalo de confiança; OR: odds ratio. Todos os modelos foram ajustados para o escore GRACE e tempo de reperfusão (tempo entre início de sintomas e reperfusão). * ajustado para escore GRACE score; † não inclui o escore GRACE

Figura 1. Comparação das curvas ROC entre escores SYNTAX, Gensini, e de carga trombótica (CT) combinados e o escore SYNTAX isolado.

Figura 1

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A NRI e a estratificação do NR entre o escore SYNTAX isolado e os escores combinados (SYNTAX, Gensini e carga trombótica) são apresentadas na Tabela 4. As análises da NRI contínua e categórica mostraram melhora na capacidade preditiva do NR no modelo combinado, o que também foi indicado pela melhora discriminada integrada (IDI) (Tabela 5).

Tabela 4. – Melhora da reclassificação líquida e estratificação do fenômeno no-reflow entre os escores SYNTAX, Gensini, e de carga trombótica combinados e o escore SYNTAX isolado.

Escore SYNTAX isolado Escores combinados
Baixo Intermediário Alto Reclassificação
Baixo 301 26 1 8%
Intermediário 23 22 34 72%
Alto 2 9 6 65%
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Tabela 5. – Melhora da reclassificação líquida (NRI) contínua e categórica, melhora da discriminação integrada (IDI) e valor preditivo do no-reflow entre os escores SYNTAX, Gensini, e de carga trombótica combinados e o escore SYNTAX isolado.

Variáveis NRI IC95% p
Contínuas 0,54 0,351-0,7347 <0,001
Categóricas 0,12 0,0119-0,2223 <0,02
IDI 0,066 0,040-0,092 <0,001
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IC: intervalo de confiança.

Discussão

Entre os principais achados deste estudo, encontramos que (1) o escore SYNTAX, o escore Gensini, e a carga trombótica foram preditores independentes do NR; e (2) a combinação dos escores de carga aterosclerótica e de carga trombótica com o escore SYNTAX aumentou o valor preditivo do escore SYNTAX na detecção do fenômeno NR.

Apesar de o escore SYNTAX ser um bom preditor de disfunção microvascular, a carga aterosclerótica não é considerada no algoritmo, uma vez que ele exclui lesões obstrutivas com estenoses menores que 50%. Ainda, a carga trombótica também não é considerada no algoritmo SYNTAX, uma vez que ele atribui um escore relativamente baixo para a presença ou ausência de trombo.8 Contudo, o escore Gensini é bastante representativo da carga aterosclerótica, uma vez que pontua lesões com pelo menos 25% de estenose15,16 e se associa de maneira significativa com a carga de placa e a área da placa medidas por ultrassom intracoronário.17 Valores altos no escore Gensini podem indicar doença de múltiplos vasos e um aumento na resistência microvascular, ambos associados com NR.5,10,18

No presente estudo, o escore Gensini foi um preditor independente de NR. Modolo et al.,19 mostraram que o escore Gensini total e o escore Gensini da artéria culpada foram mais altos nos indivíduos com NR que nos indivíduos com reperfusão adequada19 No entanto, a gravidade da estenose do lúmen não é o único fator angiográfico preditor de disfunção microvascular. De fato, alterações morfológicas da placa, tais como o alto teor lipídico, centro necrótico extenso, e grande quantidade de placa atenuada também são fortes preditores de NR,20,21 sugerindo que alterações no volume e no conteúdo da placa causem autorregulação inadequada e liberação local de vasoconstritores, aumentando a formação de trombos, microembolização de leitos arteriais e obstrução microvascular.

No presente estudo, 58,5% dos pacientes no grupo NR apresentaram trombos na artéria culpada; 50,4% desses com alta carga trombótica (graus 4 e 5 da escala TIMI de trombos), uma possível razão para a associação com o NR. Em uma grande coorte de pacientes com IAMCSST submetidos à ICP, uma grande carga trombótica foi associada à NR (4,0 vs 0,5, p<0,001) e à embolização distal (17,3 vs 3,4, p<0,001).22

O escore SYNTAX foi significativamente mais alto no grupo com NR que no grupo com reperfusão adequada (17±10 vs 9±8), e um preditor independente de NR. Em um estudo prévio, o escore SYNTAX foi um preditor de NR, e um escore SYNTAX >21 duplicou o risco de se desenvolver NR.9 A oclusão total da artéria relacionada ao IAMCSST, local da oclusão (artéria coronária principal esquerda ou artéria descendente anterior esquerda), presença de trombos, lesões mais extensas, lesões na bifurcação e doença de múltiplos vasos são fatores associados com escores SYNTAX aumentados e podem explicar a associação com NR.9,10,23

No presente estudo, o fenômeno NR ocorreu em 32,8% dos casos, fluxo TIMI <3 ou fluxo TIMI =3 e MBG <2 como critério angiográfico. A incidência de NR é muito maior no IAMCSST que em ICP eletivo, sendo relatada em 30 a 50% dos pacientes submetidos à ICP primária por IAMCSST.3 Rezkalla et al.,3 investigando NR em pacientes com IAMCSST, encontraram uma prevalência de 32% quando avaliados por TIMI e de 52% quando avaliados por MBG.

Idade é um importante marcador de NR. Pacientes idosos têm maior carga de placas, aterosclerose coronária difusa e calcificação vascular grave, o que pode contribuir para a disfunção microvascular.24,25 Zhou et al.,6 identificaram que idade >65 anos (OR= 1,470, IC95%1,460-1,490, p=0,007) foi um preditor independente de NR.6Em nosso estudo, idade foi um fator preditor de NR na análise univariada, mas essa relação não se manteve na análise multivariada.

A reperfusão tardia está associada com NR. Estudos prévios mostraram que pacientes com tempo de reperfusão mais longos (>6 horas) apresentaram um aumento significativo no NR.6,7 No entanto, um estudo utilizando um ponto de corte mais baixo (<6 horas) do início dos sintomas não indicou que a apresentação tardia fosse um preditor independente de NR.23 Em nosso estudo, o tempo de reperfusão foi 2,94 horas no grupo com NR e de 2,5 horas no grupo com reperfusão adequada. A análise multivariada ajustada para o escore GRACE não indicou o tempo de reperfusão como um preditor de NR.

A fisiopatologia do fenômeno de NR é multifatorial e envolve suscetibilidade individual, lesão relacionada à isquemia, lesão relacionada à reperfusão, e embolização distal.26 Durante a ICP, no IAMCSST, a embolização distal do trombo e os componentes da placa aterosclerótica são mecanismos importantes envolvidos na patogênese do NR.27,28 O material aterotrombótico liberado causa obstrução mecânica, vasoconstrição pela liberação de serotonina, tromboxano A2, e endotelina, e disfunção endotelial pela expressão aumentada de fator de necrose tumoral alfa (TNFα).28-30 Ainda, a liberação de micropartículas plaquetárias e endoteliais está associada à perfusão miocárdica reduzida avaliada por MBG e à maior carga trombótica.31 Os neutrófilos liberam microfilamentos , os Neutrophil Extracellular Traps (NETs) que promovem trombose e inflamação na artéria culpada, contribuindo para morte dos miócitos.32,33

Uma limitação deste estudo é seu caráter unicêntrico. Além disso, a angiografia coronária tem capacidade limitada para estimar tanto a carga trombótica como a carga aterosclerótica quando comparada à ultrassonografia intracoronária e à tomografia de coerência ótica.

Conclusão

A carga aterosclerótica avaliada pelo escore Gensini e a carga trombótica na artéria culpada adicionam valor preditivo ao escore SYNTAX na detecção de NR após ICP em pacientes com IAMCSST.

Vinculação acadêmica

Este artigo é Tese de Doutorado de Luís Carlos V. Matos pelo programa de Pós Graduação em Ciências Médicas - Faculdade de Medicina – Universidade de Brasília – UNB.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética da FEPECS/SES-DF sob o número de protocolo 47145515.6.0000.5553. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo.

Fontes de financiamento

O presente estudo foi parcialmente financiado pelo Laboratório Exame/Diagnósticos da América S.A (DASA).

Referências

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Arq Bras Cardiol. 2021 Feb 22;116(3):466–472. [Article in English]

Gensini Score and Thrombus Burden Add Predictive Value to the SYNTAX Score in Detecting No-Reflow after Myocardial Infarction

Luís Carlos V Matos 1,5, Luiz Sergio Carvalho 2,5, Rodrigo Modolo 2, Simone Santos 3,4, José Carlos Quinaglia e Silva 1,5, Osório Luis Rangel de Almeida 1,5, Andrei C Sposito 2

Abstract

Background

No-reflow after percutaneous coronary intervention is associated with poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). SYNTAX score is a good predictor of no-reflow.

Objective

We aimed to evaluate whether atherosclerotic burden (Gensini score) and thrombus burden in the culprit coronary artery would improve the ability of the SYNTAX score to detect no-reflow.

Methods

In this prospective cohort study, consecutive patients with STEMI who presented within 12 h of onset of symptoms were selected for this study. No-reflow was defined as TIMI flow < 3 o r TIMI flow = 3 but myocardial blush grade <2. Thrombus burden was quantified according to the TIMI thrombus grade scale (0 to 5).

Results

A total of 481 patients were included (mean age 61±11 years). No-reflow occurred in 32.8%. SYNTAX score (OR=1.05, 95%CI 1.01–1.08, p<0.01), thrombus burden (OR=1.17, 95%CI 1.06–1.31, p<0.01), and Gensini score (OR=1.37, 95%CI 1.13–1.65, p<0.01) were independent predictors of no-reflow. Combined scores had a larger area under the curve than the SYNTAX score alone (0.78 [0.73–0.82] vs 0.73 [0.68–0.78], p=0.03). Analyses of both categorical (0.11 [0.01–0.22], p=0.02), and continuous net reclassification improvement (NRI>0) (0.54 [0.035–0.73], p<0.001) showed improvement in the predictive ability of no-reflow in the combined model, with integrated discrimination improvement (IDI) of 0.07 (0.04–0.09, p<0.001).

Conclusions

Our findings suggest that, in patients with STEMI undergoing percutaneous coronary intervention, atherosclerotic burden and thrombus burden in the culprit artery add predictive value to the SYNTAX score in detecting the no-reflow phenomenon. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)

Keywords: Percutaneous Coronary Intervention/methods; Myocardial Infarction; Atheroscclerosis; Thrombosis; Plaque, Atherosclerotic; Embolization, Therapeutic

Introduction

Percutaneous coronary intervention (PCI) is the reperfusion strategy of choice for ST-segment elevation myocardial infarction (STEMI).1 More than to restore the patency of the arterial lumen, the objective of this intervention is to provide blood flow in the coronary microcirculation.2 However, in one out of three patients, the microvascular flow remains diminished despite restoration of epicardial coronary artery patency, a phenomenon named no-reflow (NR).2,3 The NR is associated with an increased incidence of heart failure, cardiogenic shock, and death.3-5

A sizeable number of markers for microvascular obstruction have been described, particularly age and time to reperfusion.6,7 More recently, it has been shown that anatomic complexity for PCI, as estimated by the SYNTAX score, may also relate to a higher risk for NR.8-10 As NR occurs more frequently than the above-mentioned markers, it is possible that other clinically relevant markers exist. In this context, it is hypothetically plausible that atherosclerotic and thrombotic burden may add predictive value to the SYNTAX score, age, and time to reperfusion in the prediction of NR. The present study was therefore designed to test this hypothesis.

Methods

Sample selection

This study was based on a subanalysis of the Brasilia Heart Study (BHS), whose design is described elsewhere.11 Briefly, the BHS is a single-center, prospective cohort study of consecutive patients with STEMI who presented within 24 h of onset of symptoms. STEMI was defined as follows: 1) ST-segment elevation of at least 1 mm in the frontal plane or 2 mm in the horizontal plane in two contiguous leads, or new left bundle branch block on electrocardiogram; 2) positive myocardial necrosis marker, defined as troponin I >0.04 ng/mL and CK-MB >25 U/L, corresponding to values above the 99th percentile. Patients undergoing PCI within 12 h of STEMI were eligible for the present study. Written informed consent was obtained from all participants, and the study was approved by the research ethics committee of the institution. All procedures were in accordance with the ethical standards of the institutional committee on human experimentation and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Angiographic analysis

All angiograms were reviewed by two experienced interventional cardiologists who independently interpreted the images and evaluated the following parameters: 1) coronary flow: TIMI flow grade;12 2) myocardial perfusion: myocardial blush grade (MBG);13 3) thrombus burden: TIMI thrombus grade scale;14 4) angiographic SYNTAX score8 and modified Gensini score.15.The scores were obtained from the diagnostic angiogram before any intervention. The two cardiologists agreed on the interpretation of findings, with an intraobserver and interobserver variability of 5%.

NR was defined as a TIMI flow grade < 3 o r T I M I f l o w g r a d e = 3 but MBG <2 at coronary angiography performed after PCI of the STEMI-related artery.

Statistical analysis

Quantitative data were expressed as mean and standard deviation (SD). Groups were compared using Student’s t test for parametric continuous variables or the Mann-Whitney test for nonparametric continuous variables, and the chi-square test was used for categorical variables. Binary logistic regression was used to determine predictors of the NR phenomenon in models unadjusted (model 1) and adjusted (model 2) for GRACE score and reperfusion time (time between symptom onset and reperfusion) after reperfusion. Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive ability of the models. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to determine improvements with the addition of new predictors. Statistical analysis was performed using SPSS for Mac version 23.0 (SPSS Inc., Chicago, IL, USA), and R for Mac version 3.4.2. A p-value <0.05 was considered statistically significant.

Results

A total of 481 patients undergoing PCI in the acute phase of STEMI were included in the present study. Mean patient age was 61 (SD 11) years, and 74.6% were men, 58.0% had hypertension, 54.2% were physically inactive, 38.0% were smokers, and 30.7% had diabetes. NR occurred in 32.8% of the patients (n=158), who were then compared to those who had optimal reperfusion (n=323). Clinical and biochemical characteristics of both groups are described in Table 1.

Table 1. – Clinical and biochemical characteristics of 481 patients undergoing percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) who showed optimal reperfusion or no-reflow after the procedure.

Parametric variables Total (n = 481) Optimal reperfusion (n = 323) No-reflow (n = 158) P- value*
mean ± SD mean ± SD mean ± SD
Age (years) 61±11 61±11 61±12 0.64
BMI (kg.m-2) 27.0±4.2 26.8±3.9 27.3±4.7 0.32
GRACE on hospital admission 136±26 135±27 137±24 0.46
First-day total cholesterol (mg.mL-1) 192±48 192±45 191±53 0.83
First-day HDL-c (mg.mL-1) 40±11 38±10 38±11 0.63
HbA1c (%) 6.5±1.8 6.5±1.8 6.4±1.7 0.64
Non-parametric variables Median (Q1 - Q3) Median (Q1 - Q3) Median (Q1 - Q3) P- value†
Reperfusion time 111 (60 - 210) 96 (60 - 206) 120 (60 - 239) 0.42
First-day LDL-c (mg.mL-1) 117 (93 - 143) 117 (97 - 145) 118 (94 - 141) 0.50
First-day triglycerides (mg.mL-1) 134 (87 - 207) 135 (90 - 215) 133 (84 - 195) 0.11
Categorical variables ƒ (%) ƒ (%) ƒ (%) P- valueǂ
Male, n (%) 359 (75) 235 (73) 124 (78) 0.34
DM, n (%) 148 (31) 94 (29) 54 (34) 0.34
Hypertension, n (%) 279 (58) 187 (58) 92 (58) 0.97
Stroke, n (%) 21 (4) 11 (3) 10 (6) 0.24
Smoking, n (%) 183 (38) 127 (39) 56 (35) 0.35
Physical inactivity, n (%) 261 (54) 179 (55) 82 (52) 0.37
Previous PCI, n (%) 26 (5) 15 (5) 11 (7) 0.35
CABG, n (%) 4 (0.8) 3 (0.9) 1 (0.6) 0.86
Killip >1, n (%) 52 (11) 31 (10) 21 (13.2) 0.44
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SD: standard deviation; Q1: first quartile; Q3: third quartile. CABG: coronary artery bypass grafting; GRACE: Global Registry of Acute Coronary Events; DM: type 2 diabetes mellitus; PCI: percutaneous coronary intervention; BMI: body mass index; HbA1C: glycosylated hemoglobin; LDL: low-density lipoprotein; HDL: high-density lipoprotein. * unpaired Student’s t test; † Non-parametric Mann-Whitney test; ǂ Chi-squared test.

Gensini score, Gensini score of the culprit artery, SYNTAX score, and thrombus burden were significantly higher in the NR group than in the optimal reperfusion group (Table 2). Both unadjusted and adjusted logistic regression models showed that SYNTAX score, Gensini score, and thrombus burden were independent predictors of NR (Table 3). ROC curve analysis showed that the model with combined scores had a larger area under the ROC curve than the model with the SYNTAX score alone (0.778 [0.733 - 0.823] vs. 0.737 [0.688 - 0.786]) (Figure 1).

Table 2. – Angiographic parameters of 481 patients undergoing percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI).

Parameters n = 481 Optimal reperfusion n = 323 No-reflow n = 158 p
Gensini score 100±70 82±62 139±69 <0.001
Gensini score – culprit artery 62±49 48±38 87±56 <0.001
SYNTAX score 12±10 9±8 17±10 <0.001
Thrombus burden – culprit artery, n (%) 181 (37.6) 89 (27.5) 92 (58.2) <0.001
TIMI thrombus grade scale, n (%)       <0.001
0 300 (63) 234 (72) 66 (42)  
1 9 (1.9) 8 (2.5) 1 (0.6)  
2 21 (4.4) 13 (4) 8 (5)  
3 18 (3.7) 14 (4.3) 4 (2.5)  
4 18 (3.7) 11 (3.4) 7 (4.4)  
5 115 (24) 43 (13.3) 72 (46)  
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Values are expressed as mean ± standard deviation. TIMI: thrombolysis in myocardial infarction.

Table 3. – Logistic regression model of the SYNTAX, Gensini, and thrombus burden scores as predictors of the no-reflow phenomenon.

Models OR (95%CI) p
Model 1 (unadjusted)    
Age 1.02 (1.00-1.03 0.037
Reperfusion time 1.00 (1.00-1.01) 0.154
SYNTAX score 1.10 (1.07-1.12) <0.001
Thrombus burden 1.38 (1.26-1.51) <0.001
Gensini score 1.76 (1.50-2.07) <0.001
Model 2 (multivariate)*    
Age† 1.01 (0.98-1.02) 0.325
Reperfusion time 0.98 (0.99-1.00) 0.645
SYNTAX score 1.05 (1.01-1.08) <0.01
Thrombus burden 1.17 (1.06-1.31) <0.01
Gensini score 1.37 (1.13-1.65) <0.01
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CI: confidence interval; OR: odds ratio. All models were adjusted for GRACE score and reperfusion time (time between symptom onset and reperfusion). * adjusted for GRACE score; † not including GRACE score.

Figure 1. Comparison of ROC curves between combined SYNTAX, Gensini, and thrombus burden (TB) scores and the SYNTAX score alone.

Figure 1

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NRI and stratification of NR between the SYNTAX score alone and combined SYNTAX, Gensini, and thrombus burden scores are shown in Table 4. Both categorical and continuous NRI analyses showed improvement in the predictive ability of NR in the combined model, which was also indicated by the integrated discrimination improvement (IDI) (Table 5).

Table 4. – Net reclassification improvement (NRI) and stratification of no-reflow between combined SYNTAX, Gensini, and thrombus burden scores and the SYNTAX score alone.

SYNTAX score alone Combined scores
Low Intermediate High Reclassification
Low 301 26 1 8%
Intermediate 23 22 34 72%
High 2 9 6 65%
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Table 5. – Continuous and categorical net reclassification improvement (NRI), integrated discrimination improvement (IDI), and predictive value of no-reflow between combined SYNTAX, Gensini, and thrombus burden scores and the SYNTAX score alone.

Variables NRI 95%CI p
Continuous 0.54 0.351-0.7347 <0.001
Categorical 0.12 0.0119-0.2223 <0.02
IDI 0.066 0.040-0.092 <0.001
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CI: confidence interval.

Discussion

Among the main findings of this study, we found that (1) SYNTAX score, Gensini score, and thrombus burden were all independent predictors of NR; and (2) the combination of atherosclerotic burden and thrombus burden scores with the SYNTAX score increased the predictive value of the SYNTAX score in detecting the NR phenomenon.

Although the SYNTAX score is a good predictor of microvascular dysfunction, total atherosclerotic burden is not considered in the algorithm, as it excludes occlusive lesions with less than 50% stenosis. Furthermore, thrombotic burden is also not considered in the SYNTAX algorithm, as it only assigns a relatively small score for the presence or absence of thrombus.8 Conversely, Gensini score is very representative of total atherosclerotic burden, because it considers lesions as from 25% luminal stenosis,15,16 and is significantly associated with average plaque burden and plaque area as measured by intracoronary ultrasound.17 High Gensini scores may indicate multivessel disease and an increase in microvascular resistance, both of which are factors associated with NR.5,10,18

In the present study, Gensini score was an independent predictor of NR. Modolo et al.19 showed that total Gensini score and Gensini score of the culprit artery were higher in individuals with NR than in individuals with optimal reperfusion.19 However, the severity of luminal stenosis is not the only angiographic predictor of microvascular dysfunction. In fact, plaque morphological changes such as lipid-rich content, large necrotic core, and large amount of attenuated plaque are also strong predictors of NR,20,21 suggesting that altered plaque volume and content cause impaired autoregulation and local release of vasoconstrictors, boosting thrombus formation, microembolization of arterial beds and microvascular obstruction.

In the present study, 58.5% of patients in the NR group had thrombus in the culprit artery; 50.4% of these with large thrombus burden (grades 4 and 5 of the TIMI thrombus grade scale), a possible reason for the association with NR. In a large cohort of patients with STEMI undergoing PCI, large thrombus burden was associated with NR (4.0 vs 0.5, p<0.001) and distal embolization (17.3 vs 3.4, p<0.001).22

The SYNTAX score was significantly higher in the NR group than in the optimal reperfusion group (17±10 vs 9±8) and was an independent predictor of NR. In a previous study, the SYNTAX score was a predictor of NR, and a SYNTAX score >21 doubled the risk of developing NR.9 Total occlusion of the STEMI-related artery, site of occlusion (left main or left anterior descending coronary artery), presence of thrombus, longer lesions, bifurcation lesions and multivessel disease are factors associated with increased SYNTAX scores and may explain the association with NR.9,10,23

In the present study, the NR phenomenon occurred in 32.8% of cases, with TIMI flow <3 or TIMI flow =3 but MBG <2 as angiographic criteria. The incidence of NR is much higher in STEMI than in elective PCI, being reported in 30 to 50% of patients undergoing primary PCI for STEMI.3 Rezkalla et al.,3 investigating NR in patients with STEMI, found a prevalence of 32% as assessed by TIMI and of 52% by MBG.

Age is an important marker of NR. Older patients have higher plaque burden, diffuse coronary atherosclerosis and severe vascular calcification, which may contribute to microvascular dysfunction.24,25 Zhou et al.6 identified that age > 65 years (OR= 1.470, 95%CI 1.460-1.490, p=0.007), was an independent predictor of NR.6 In our study, in univariate analysis, age predicted NR, but in multivariate analysis this relationship was not maintained.

Delayed reperfusion is associated with NR. Previous studies have shown that patients with longer reperfusion time (> 6 h) show a significant increase in NR.6,7 However, a study using a shorter cut-off point (< 6 h) from symptom onset did not indicate delayed presentation as an independent predictor of NR.23 In our study, reperfusion time was 2.94 h in the NR group and 2.5 h in the optimal reperfusion group. Multivariate analysis adjusted for GRACE score did not show reperfusion time as a predictor of NR.

The pathophysiology of the NR phenomenon is multifactorial and involves individual susceptibility, ischemia-related injury, reperfusion-related injury, and distal embolization.26 During PCI, in the setting of STEMI, distal embolization of thrombus and atherosclerotic plaque components are important mechanisms involved in the pathogenesis of NR.27,28 The released atherothrombotic material causes mechanical obstruction, vasoconstriction due to the release of serotonin, thromboxane A2, and endothelin, and endothelial dysfunction due to increased expression of tumor necrosis factor alpha (TNFα).28-30 Likewise, the release of platelet- and endothelial-derived microparticles is associated with reduced myocardial perfusion as assessed by MBG and with larger thrombus burden.31 The burden of neutrophil extracellular traps may propagate thrombosis and inflammation distally into the culprit artery, contributing to myocyte death.32,33

A limitation of this study is that it represents the experience of a single center. Also, coronary angiography has limited ability to estimate both thrombotic and atherosclerotic plaque burden compared with intracoronary ultrasound and optical coherence tomography.

Conclusion

Atherosclerotic burden assessed by Gensini score and thrombus burden in the culprit artery add predictive value to the SYNTAX score in detecting the NR phenomenon after PCI in patients with STEMI.

Study Association

This article is part of the doctoral thesis submitted by Luís Carlos V. Matos, from programa de Pós Graduação em Ciências Médicas - Faculdade de Medicina – Universidade de Brasília – UNB.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the FEPECS/SES-DF under the protocol number 47145515.6.0000.5553. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

Sources of Funding

This study was partially funded by Laboratório Exame/Diagnósticos da América S.A (DASA).

Articles from Arquivos Brasileiros de Cardiologia are provided here courtesy of Sociedade Brasileira de Cardiologia

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