Desfechos em Pacientes com Fenômeno de No-Reflow Coronário e a Relação entre a Molécula-1 de Lesão Renal e o Fenômeno de No-Reflow Coronário

Mustafa Ahmet Huyut; Aylin Hatice Yamac

doi:10.36660/abc.20190656

. 2021 Feb 19;116(2):238–247. [Article in Portuguese] doi: 10.36660/abc.20190656

View full-text in English

Desfechos em Pacientes com Fenômeno de No-Reflow Coronário e a Relação entre a Molécula-1 de Lesão Renal e o Fenômeno de No-Reflow Coronário

Mustafa Ahmet Huyut ¹, Aylin Hatice Yamac ²

PMCID: PMC7909983 PMID: 33656071

Resumo

Fundamento

O fenômeno de no-reflow coronário (CNP, do inglês Coronary no-reflow phenomenon) está associado a um risco aumentado de eventos cardiovasculares adversos maiores (ECAM).

Objetivo

Este estudo teve como objetivo avaliar a relação entre os níveis séricos da Molécula-1 de lesão renal (KIM-1) e o CNP em pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCSST).

Métodos

Este estudo incluiu um total de 160 pacientes (113 homens e 47 mulheres; média de idade: 61,65 ± 12,14 anos) com diagnóstico de IAMCSST. Os pacientes foram divididos em dois grupos, o grupo reflow (GR) (n = 140) e o grupo no-reflow (GNR) (n = 20). Os pacientes foram acompanhados durante um ano. Um valor de p<0,05 foi considerado significativo.

Resultados

O CNP foi observado em 12,50% dos pacientes. O nível de KIM-1 sérico foi significativamente maior no GNR do que no GR (20,26 ± 7,32 vs. 13,45 ± 6,40, p<0,001). O índice de massa corporal (IMC) foi significativamente maior no GNR do que no GR (29,41 (28,48-31,23) vs. 27,56 (25,44-31,03), p=0,047). A frequência cardíaca (FC) foi significativamente menor no GNR do que no GR (61,6 ± 8,04 vs. 80,37 ± 14,61, p<0,001). O escore do European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) foi significativamente maior no GNR do que no GR (3,06 ± 2,22 vs. 2,36 ± 2,85, p=0,016). A incidência de AVC foi significativamente maior no GNR do que no GR (15% vs. 2,90%, p=0,013). O nível basal de KIM-1 (OR = 1,19, IC 95%: 1,07-1,34, p=0,002) e HR (OR = 0,784, IC 95%: 0,69-0,88, p<0,001) foram os preditores independentes de CNP.

Conclusão

Em conclusão, os níveis séricos basais de KIM-1 e a FC mais baixa estão independentemente associados com CNP em pacientes com IAMCSST, e o acidente vascular cerebral foi significativamente maior no GNR em um ano de seguimento. (Arq Bras Cardiol. 2021; 116(2):238-247)

Keywords: Doenças Cardiovasculares, Infarto do Miocárdio, Acidente Vascular Cerebral, Intervenção Coronária Percutânea, Trombose Coronária, Frequência Cardíaca

Introdução

O fenômeno de no-reflow coronário (CNP, do inglês coronary no-reflow phenomenon) foi definido como falta de perfusão miocárdica apesar da abertura do vaso coronariano no contexto da intervenção coronária percutânea primária (ICP).¹ Geralmente, o CNP angiográfico é definido como a presença de Thrombolysis In Myocardial Infarction (TIMI) 0-I, que se refere à perda súbita de fluxo epicárdico após dilatação com balão ou colocação de um stent sem a presença de dissecção, obstrução mecânica, estenose residual significativa, espasmo ou trombo do vaso coronário.² Os mecanismos subjacentes do CNP são inflamação, microembolização aterotrombótica, ativação de neutrófilos e plaquetas, que causam a liberação de radicais livres de oxigênio, enzimas proteolíticas e mediadores pró-inflamatórios que podem causar dano tecidual e endotelial, particularmente em miócitos gravemente danificados.³ Biomarcadores de lesão tubular renal, como KIM-1, têm sido associados à incidência e progressão de lesão renal aguda (LRA) e doença renal crônica (DRC).⁴ A KIM-1 é uma proteína transmembrana do tipo 1 e é expressa na membrana apical do túbulo proximal de acordo com a lesão.⁵ A LRA e a DRC estão fortemente associadas à doença cardiovascular (DCV), e a LRA foi relatada como associada com eventos cardiovasculares.⁶ A KIM-1 atua como uma molécula pró-inflamatória e tem funções quimioatrativa e de adesão celular.⁴ A estrutura da KIM-1 sugere que ela pode estar envolvida nas interações de adesão de superfície.^4-6 As citocinas pró-inflamatórias contribuem para a inflamação ao aumentar e estimular as células inflamatórias e a resposta inflamatória.⁴ A KIM-1 também tem relação espacial com células T inflamatórias.⁴ A KIM-1 demonstrou interagir com a proliferação de células T, além de interagir com outras proteínas pró-inflamatórias.⁴ Além disso, as células T têm sido implicadas na fisiopatologia da lesão pós-isquêmica do endotélio.⁴ É possível que a KIM-1 desempenhe um papel importante nas células epiteliais sobreviventes para sofrer diferenciação, migração, proliferação e restauração da integridade morfológica e funcional do epitélio. No entanto, a KIM-1 está associada à fibrose e inflamação.⁴ Nossa hipótese é que a expressão de KIM-1 é induzida no IAMCSST e está relacionada ao CNP e ao dano endotelial devido à resposta pró-inflamatória. A associação entre os níveis da proteína KIM-1 e o CNP ainda não foi abordada na literatura. Compreender quais vias biológicas e marcadores estão associados ao CNP pode permitir o desenho de estudos futuros para explorar a ligação mecanicista entre essas vias e avaliar a eficácia das intervenções destinadas a reduzir a carga de DCV nesses pacientes. Além disso, o objetivo deste estudo foi avaliar a relação entre os níveis séricos da proteína KIM-1 e o CNP em pacientes com IAMCSST agudo.

Métodos

Este estudo foi conduzido prospectivamente entre maio de 2016 e maio de 2018 no Bezmialem Vakif University Hospital. Para este estudo de centro único, incluímos 346 pacientes entre 18 e 90 anos que foram diagnosticados com IAMCSST e submetidos a ICP primária no período de 6 horas após o início dos sintomas. Todos os pacientes com IAMCSST foram encaminhados ao laboratório de cateterismo para ICP primária (n = 346). Foram excluídos deste estudo pacientes com cirurgia de revascularização do miocárdio (CRM), choque cardiogênico, edema pulmonar com classe Killip≥2, trombose de stent, aqueles submetidos a aspiração de trombo no evento índice, pacientes com doença infecciosa ou neoplásica aguda ou crônica, doença renal crônica moderada a grave e doença hepática crônica (n=186). De acordo com os resultados finais das características angiográficas do fluxo TIMI da artéria tratada, um total de 20 pacientes com CNP angiograficamente comprovado foram incluídos no GNR, sendo incluídos 140 pacientes no GR. Todos os pacientes receberam tratamento com 300 mg de ácido acetilsalicílico e uma dose de ataque de clopidogrel (600 mg) e heparina NF (100 mg/kg) antes da ICP. Todos os participantes deram consentimento informado por escrito antes da participação e o estudo foi aprovado pelo comitê de ética local. Além disso, o estudo foi conduzido de acordo com as disposições da Declaração de Helsinque.

Análises bioquímicas

Amostras de sangue venoso foram coletadas da veia antecubital imediatamente após a admissão hospitalar antes da ICP. Eletrocardiogramas de 12 derivações foram obtidos no início do estudo e a frequência cardíaca (FC) foi anotada. O IMC foi calculado pela fórmula: peso (kg)/altura² (m²). A taxa de filtração glomerular estimada (TFGe) de cada paciente foi calculada utilizando a equação do Chronic Kidney Disease Epidemiology Collaboration. Análises químicas de rotina do sangue, os parâmetros lipídicos e a troponina-I foram medidos em um autoanalisador padrão. O hemograma foi medido com um autoanalisador Sysmex K-1000 (Block Scientific, Bohemia, NY, EUA). As amostras foram centrifugadas a 3000 rpm durante 10 min, e o sobrenadante e o soro separados das amostras. Em seguida, foram congelados a -80°C até análise posterior. Os níveis séricos de KIM-1 (ng/mL) foram medidos com o kit ELISA de ensaio imunoenzimático, comercialmente disponível (Human KIM-1 ELISA kit, Elabscience Biotech Co., Ltd, Catalog no: E-EL-H0186, Wuhan, China).⁴ Os coeficientes de variação inter e intra-ensaio da análise do kit KIM-1 para o ensaio foi inferior a 10%, e a sensibilidade foi de 0,10 ng/mL.

Diagnóstico de infarto agudo do miocárdio com elevação do segmento ST

O diagnóstico de IAMCSST foi feito na presença das seguintes características com base nas definições de diretrizes de prática clínica: dor típica no tórax com duração superior a 30 minutos, novo início ou supostamente novo supradesnivelamento do segmento ST em duas ou mais derivações contíguas com elevação do segmento ST ≥2,5 mm em homens <40 anos, ≥2 mm em homens ≥40 anos, ou ≥ 1,5 mm em mulheres nas derivações V2-V3 e/ou ≥ 1 mm nas outras derivações (na ausência de hipertrofia ventricular esquerda ou bloqueio de ramo esquerdo). Em pacientes com IM inferior registrado nas derivações precordiais direitas (elevação do segmento ST em V3R e V4R), foi considerado um infarto concomitante do ventrículo direito. Da mesma forma, o infradesnivelamento do segmento ST nas derivações V1-V3 e onda T positiva (elevação equivalente do segmento ST); além disso, a elevação concomitante do segmento ST≥0,5 mm registrada nas derivações V7-V9 foi considerada como um IM posterior.⁷

Fatores de risco cardiovascular

Após exames detalhados, o histórico médico de cada paciente foi coletado pelo mesmo investigador. Fatores de risco para doença arterial coronariana (DAC), incluindo idade, sexo, hipertensão (HT), diabetes mellitus (DM), hiperlipidemia (HL) e tabagismo, foram registrados. Pacientes que estavam anteriormente sob terapia anti-hipertensiva ou cuja pressão arterial, medida pelo menos duas vezes, era ≥140/90 mmHg, foram considerados hipertensos.⁸ Pacientes que estavam anteriormente em uso de antidiabético oral e/ou em terapia com insulina ou cuja glicemia de jejum, medida pelo menos duas vezes, era ≥125 mg/dL, foram considerados diabéticos.⁹ A presença de HL foi considerada quando uma medida de colesterol total >200 mg/dL ou colesterol de lipoproteína de baixa densidade (LDL-C) >100 mg/dL foi obtida ou quando o paciente fazia uso prévio de medicação hipolipemiante de acordo com a diretriz do “Adult Treatment Panel III”.¹⁰ Pacientes que ainda faziam uso de produtos de tabaco na admissão no serviço de emergência e que haviam parado de fumar no último mês foram considerados tabagistas.

Angiografia coronária

Os procedimentos de angiografia coronária foram realizados com equipamento de angiografia Philips (Optimus 200 DCA e Integris Allura 9, Philips Medical Systems, Eindhoven, Holanda) por via femoral. A angiografia coronária e a ICP foram realizadas de acordo com a prática clínica padrão com meio de contraste iso-osmolar não iônico (iodixanol, Visipaque 320mg/100mL; GE Healthcare, Cork, Irlanda). Foi realizada a ICP primária da artéria relacionada ao infarto. As imagens angiográficas foram registradas a uma taxa de pelo menos 80 quadros de imagem e com gravação a uma taxa de 25 quadros por segundo. Pelo menos dois cardiologistas examinaram os registros de exames anatômicos coronários offline. A velocidade do fluxo sanguíneo coronário foi determinada pelo número quantitativo de contagem de quadros, conforme descrito por Gibson et al.¹¹ O CNP foi definido angiograficamente como graus de fluxo TIMI pós-ICP ≤1, sem a presença de dissecção, obstrução mecânica, ou estenose significativa.¹ Os pacientes com CNP receberam inibidores da glicoproteína IIb/IIIa intracoronários (IC) (Gp-IIb / IIIa inh.) ou adenosina IC ou epinefrina IC para o tratamento de CNP, respectivamente. Após o procedimento, todos os pacientes foram submetidos a hidratação intravenosa (IV) com solução salina isotônica por pelo menos 12 horas.

Ecocardiografia transtorácica

Cada paciente foi submetido a um exame ecocardiográfico transtorácico com um transdutor de 3,5 MHz (Vivid 7 GE Medical System, Horten, Noruega) pelos mesmos investigadores antes da alta hospitalar. Os exames e medidas foram realizados de acordo com as recomendações da American Echocardiography Unit. O método de Simpson foi utilizado para calcular a fração de ejeção do ventrículo esquerdo (FEVE).

Seguimento

As informações de seguimento foram obtidas por registros hospitalares e dados de visitas dos pacientes ao hospital, 1, 3, 6 e 12 meses pelos mesmos investigadores. Os desfechos deste estudo, ECAM incluindo mortalidade por todas as causas, morte cardiovascular, acidente vascular cerebral, re-infarto do miocárdio, foram obtidos de registros hospitalares e certificados de óbito, ou contato telefônico com parentes dos pacientes.

Análise estatística

A análise dos dados foi realizada com o pacote de software estatístico SPSS versão 24.0 (SPSS Inc., Chicago, IL, EUA). O teste de Kolmogorov-Smirnov foi utilizado para controlar as distribuições das variáveis. O teste t de Student para duas amostras independentes foi usado para dados normalmente distribuídos e relatados como média e desvio padrão, e o teste U de Mann-Whitney foi utilizado para comparar dados não-normalmente distribuídos e relatados como mediana e percentis 25 e 75. Os dados categóricos foram comparados pelo teste Qui-quadrado. As correlações entre as variáveis foram realizadas através da análise de correlação de postos de Spearman. O método de Kaplan-Meier foi utilizado para estimar as taxas de sobrevida livre de eventos. A análise da curva de característica de operação do receptor (ROC) foi realizada para determinar o valor preditivo de KIM-1 para CNP. A análise de regressão logística foi realizada para avaliar os preditores do CNP. Foi realizada análise de regressão logística univariada, e as variáveis que se mostraram estatisticamente significativas (p<0,1) foram avaliadas com a análise de regressão logística multivariada. Um valor de P bicaudal <0,05 foi considerado significativo.

Resultados

Este estudo incluiu um total de 160 pacientes (113 homens e 47 mulheres; média de idade: 61,65 ± 12,14 anos) com diagnóstico de CNP. O CNP foi observado em 12,50% da população estudada. Os achados demográficos e medicamentos entre os grupos são descritos na Tabela 1. Em relação aos fatores de risco cardiovascular, o IMC (kg/m²) foi significativamente maior no GNR do que no GR (29,41 (28,48-31,23) vs. 27,56 (25,44-31,03), p=0,047). As características laboratoriais basais dos pacientes são descritas na Tabela 2. O nível de KIM-1 foi significativamente maior no GNR do que no GR (20,26 ± 7,32 vs. 13,45 ± 6,40, p<0,001), a FC foi significativamente menor no GNR do que no GR (61,60 ± 8,04 vs. 80,37 ± 14,61, p<0,001) e o EuroSCORE II foi significativamente maior no GNR do que no GR (3,06 ± 2,22 vs. 2,36 ± 2,85, p=0,016). Em 4 pacientes, o CNP foi resolvido com inibidores Gp-IIb/IIIa IC, em 8 pacientes, o CNP foi resolvido com inibidores Gp-IIb/IIIa IC mais adenosina IC e em 5 pacientes o CNP foi resolvido com inibidores Gp-IIb/IIIa IC mais adenosina IC e epinefrina IC (Tabela 1). Em 17 pacientes o CNP foi resolvido e eles foram incluídos no GR. O CNP persistiu em 20 pacientes e eles foram incluídos no GNR.

Tabela 1. – Características basais e medicamentos dos pacientes.

Variável, n(%)	GNR n=20 (12,5)	GR n=140 (87,5)	Valor de p
Idade, a	64,35±14,03	61±11,86	0,291
Sexo masculino, n (%)	11 (55,00)	102 (72,90)	0,101
IMC (kg/m²)	29,41 (28,48-31,23)	27,56 (25,44-31,03)	0,047
HT, n (%)	15 (75)	79 (56,40)	0,115
DM, n (%)	7 (35)	50 (35,70)	0,950
HL, n (%)	6 (30)	62 (44,30)	0,227
Fumante, n (%)	11 (55)	90 (64,30)	0,421
Histórico familiar, n (%)	6 (30)	54 (38,60)	0,459
DAP, n (%)	3 (15)	11 (7,90)	0,290
DPOC, n (%)	3 (15)	26 (18,60)	0,698
FEVE (%)	51,25±6,72	52,01±7,49	0,561
Medicamentos n (%)
Inib. ECA	14 (70)	75 (53,60)	0,167
BRA	5 (25)	44 (31,40)	0,560
B Bloqueador	19 (95)	133 (95)	1
BCC	6 (30)	34 (24,30)	0,581
Estatina	20 (100)	124 (88,60)	0,111
Nitrato	9 (45)	49 (35)	0,384
ADO	7 (35)	48 (34,30)	0,950
Inib. Gp-IIb/IIIa IC	20 (100)	17 (12,10)	<0,001
Adenosina IC	20 (100)	13 (9,3)	<0,001
Epinefrina IC	20 (100)	5 (3,6)	<0,001

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Os dados foram relatados como n (%) para variáveis categóricas; mediana e percentil 25-75 para medidas não paramétricas; média e desvio padrão para medidas paramétricas. a: ano; IMC: Índice de Massa Corporal; HT: hipertensão; DM: diabetes mellitus tipo II; HL: hiperlipidemia; DAP: doença arterial periférica; DPOC: doença pulmonar obstrutiva crônica; FEVE: fração de ejeção do ventrículo esquerdo; inib ECA: inibidores da enzima de conversão da angiotensina; BRA: bloqueadores do receptor da angiotensina; B Bloqueador: betabloqueador; BCC: bloqueadores dos canais de cálcio; ADO: fármacos antidiabéticos orais; IC: intracoronário; Inib. Gp-IIb / IIIa: inibidores da glicoproteína-IIb / IIIa.

Tabela 2. – Características laboratoriais basais dos pacientes.

Variável, n(%)	GNR n=20 (12,5)	GR n=140 (87,5)	Valor de p
KIM-1 ng/mL	20,26±7,32	13,45±6,40	<0,001
Glicose, mg/dl	134,25±65,06	136,73±61,27	0,689
Ácido úrico, mg/dl	5,63±1,51	5,73±1,73	0,883
TFGe (mL/min por 1,73 m²)	75,54±22,63	82,3±21,47	0,154
Escore de Mehran	5 (2-8)	3,5 (2-6,75)	0,145
Desenvolvimento NIC, n (%)	1(5)	14(10)	0,473
HC, 10³/uL	9,86±4,32	9,45±3,30	0,796
HTC,%	40,07±3,44	40,36±4,66	0,678
Plaquetas, 10³/uL	231,60±62,13	238,83±73,29	0,520
Internação hospitalar, dias	3,15±0,48	3±1,12	0,408
Triglicérides, (mg/dL)	160,50±37,62	155,37±57,52	0,323
HDL, (mg/dL)	39,70±5,01	41,05±7,83	0,938
LDL, (mg/dL)	138,15±31,86	123,77±33,91	0,076
Colesterol total, (mg/dL)	214,15±33,47	200,75±38,1	0,188
hs-PCR, (mg/dL)	0,10 (0,01-0,43)	0,20 (0,05-0,50)	0,532
Pico da troponina-I (pg/mL)	2293 (432,75-13501,25)	808,50 (68,25-3770,50)	0,220
Frequência cardíaca, (bpm)	61,6±8,04	80,37±14,61	<0,001
TSH, uIU/mL	1,05 (0,70-1,30)	1,10 (0,90-1,40)	0,245
Classe NYHA	2,45±0,51	2,30±0,53	0,278
EuroSCORE II, (%)	3,06±2,22	2,36±2,85	0,016

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Os dados foram relatados como n (%) para variáveis categóricas; mediana e percentil 25-75 para medidas não paramétricas; média e desvio padrão para medidas paramétricas. KIM-1: Molécula-1 de lesão renal; TFGe: taxa de filtração glomerular estimada; NIC: Nefropatia induzida por contraste; HC: hemograma completo; HTC: hematócrito; HDL: lipoproteína de alta densidade; LDL: lipoproteína de baixa densidade; hs-CRP: proteína C reativa de alta sensibilidade; TSH: hormônio estimulador da tireoide; NYHA: Classificação Funcional da New York Heart Association; EuroSCORE II: European System for Cardiac Operative Risk Evaluation II.

Os achados do seguimento clínico, incluindo mortalidade por todas as causas, morte cardiovascular, acidente vascular cerebral, infarto do miocárdio e ECAM foram descritos na Tabela 3. O acidente vascular cerebral foi significativamente maior no GNR do que no GR (15% vs. 2,9%, p=0,013). Não houve diferença entre os dois grupos em relação a outros achados demográficos ou clínicos. As curvas de Kaplan-Meier para as taxas de AVC e ECAM são descritas nas Figuras 1 e 2. Idade, TFGe, escore de Mehran, FEVE e hs-PCR foram significativamente associados ao EuroSCORE II (p<0,05) (Tabela 4). A análise de regressão logística condicional forward demonstrou que KIM-1 (OR = 1,199, IC 95%: 1,07-1,343, p=0,002) e HR (OR = 0,784, IC 95%: 0,696-0,883, p<0,001) foram os preditores independentes de CNP em pacientes com IAMCSST (Tabela 5). Na análise ROC, os valores de KIM-1 sérico acima de 21,53 ng/mL previram a presença de CNP com 85% de sensibilidade e 93,6% de especificidade. A área sob a curva foi de 0,80 (IC 95%: 0,653–0,946, p<0,001) (Figura 3).

Tabela 3. – Achados do seguimento clínico.

Variável, n(%)	GNR n=20 (12,5)	GR n=140 (87,5)	Valor de p
Mortalidade por todas as causas	2 (10)	21 (15)	0,551
Morte Cardiovascular	2 (10)	16 (11,4)	0,850
Derrame	3 (15)	4 (2,9)	0,013
Infarto do miocárdio	2 (10)	17 (12,1)	0,782
ECAM	6 (30)	35 (25)	0,682

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Os dados foram relatados como n (%). ECAM: Eventos cardiovasculares adversos maiores.

Tabela 4. – Correlações entre EuroSCORE II com parâmetros clínicos.

Variável	r-valor	p-valor
Idade	0,64	<0,001
TFGe	-0,64	<0,001
Escore de Mehran	0,77	<0,001
FEVE, (%)	-0,70	<0,001
hs-PCR (mg/dL)	0,24	0,002

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r: coeficiente de correlação de postos de Spearman; TFGe: taxa de filtração glomerular estimada; FEVE: fração de ejeção do ventrículo esquerdo; hs-PCR: proteína C reativa de alta sensibilidade.

Tabela 5. – Preditores independentes de CNP em IAMCSST.

Variável	OR	IC95%	Valor de p
KIM-1	1,199	1,07-1,343	0,002
FC	0,784	0,696-0,883	<0,001

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KIM-1: molécula-1 de lesão renal; FC: frequência cardíaca; bpm: batimento por minuto; OR: Odds ratio; IC: intervalo de confiança.

Discussão

O principal achado deste estudo foi que o aumento dos níveis de KIM-1 e a redução da FC foram os dois determinantes do CNP. Mostramos que os valores de KIM-1 sérica acima de 21,53 ng/mL sugerem a presença de CNP; portanto, níveis elevados de KIM-1 sérica podem ser utilizados como um biomarcador promissor de CNP. Em nosso estudo, descobrimos que o CNP foi independentemente associado às concentrações séricas basais de KIM-1 e menor FC em pacientes com IAMCSST. Que seja de nosso conhecimento, este é o primeiro relato na literatura que demonstra a relação entre as concentrações de KIM-1 e FC mais baixa com CNP. Além disso, em pacientes com IAMCSST, o CNP foi significativamente associado a resultados ruins. No seguimento clínico de um ano, os achados demonstraram que a ocorrência de AVC foi significativamente maior no grupo GNR.

Embora o mecanismo exato do CNP não seja determinado de forma consistente na literatura, existem vários mecanismos sugeridos. Esses mecanismos são relatados como disfunção microvascular pré-existente, espasmo arteriolar microvascular, tromboembolização distal devido à alta atividade plaquetária e carga trombótica, lesão de reperfusão isquêmica, edema das células do miocárdio comprimindo os vasos microvasculares.^1-3 Portanto, a patogênese e mecanismos do CNP permanecem controversos.

O CNP é um marcador prognóstico significativo relacionado a desfechos cardíacos ruins em curto prazo no IAMCSST. Em relação aos dados publicados, a frequência das estimativas do CNP foi de 5% a 60%.¹² Em nosso estudo, o CNP foi observado em 12,50% da população estudada. Consistente com os dados publicados, os pacientes com CNP apresentaram desfechos piores.¹³ Em nosso estudo, os achados de seguimento clínico de um ano demonstraram que a ocorrência de AVC foi significativamente maior no GNR e o AVC foi associado à carga trombótica. De acordo com nosso estudo, o mecanismo associado subjacente a esse evento adverso é a ativação contínua do trombo, ainda em curso após o evento índice, e esta talvez seja a principal razão para o AVC. Embora todos os pacientes com IAMCSST tomassem medicamentos antitrombóticos regularmente, a incidência de AVC foi significativamente maior no GNR. Portanto, tais pacientes devem ser monitorados e acompanhados cuidadosamente. O IMC é a ferramenta mais amplamente utilizada para a avaliação da obesidade.¹⁴Bakirci et al.,¹⁵ descobriram que o aumento da gordura epicárdica em pacientes obesos estava associado ao fluxo coronário prejudicado em pacientes com IMCSST.¹⁵ Estudos recentes sugeriram que o CNP é mais frequentemente visto em associação com hiperglicemia e hipercolesterolemia e insuficiência renal leve a moderada.¹⁶ No entanto, a compreensão desses fatores de risco na patogênese do CNP é limitada e controversa. Em nosso estudo, descobrimos que o IMC foi significativamente maior no GNR. Pode-se comprovar que isso também está associado ao risco de acidente vascular cerebral. Assim, o cálculo do IMC pode ser um método útil para estimar os desfechos cardíacos no CNP. Além disso, diminuir o IMC pode proteger os pacientes contra o AVC. Estudos randomizados utilizaram aspiração manual de trombo e mostraram melhor perfusão microvascular e desfechos em longo prazo em comparação com pacientes controle submetidos a ICP durante o IAMCSST.¹⁷ Entretanto, o uso de aspiração de trombo pode causar acidente vascular cerebral devido à complicações com o dispositivo, e por esse motivo em nosso estudo excluímos os pacientes (n = 12) do estudo nos quais utilizamos cateter de aspiração de trombo. O uso rotineiro de inibidores de plaquetas (inibidores Gp-IIb/IIIa, Abciximab, tirofiban), nicorandil, nitroprussiato e adenosina, demonstraram efeitos benéficos na perfusão miocárdica em IAMCSST.^18-20 Aksu et al.,²¹ descobriram que a epinefrina também tem um efeito benéfico sobre o CNP.²¹ A epinefrina causa um potente efeito vasodilatador coronário através da ativação do receptor beta-2, que faz a mediação da vasodilatação da circulação arteriolar. Além disso, tem efeitos cronotrópicos e inotrópicos no coração.²² A epinefrina IC pode restaurar a pressão arterial normotensa nesses pacientes, uma vez que este agente estimula os receptores vasoconstritores alfa.²¹ Skelding et al.,²⁴ descobriram que o aumento do fluxo coronariano devido à correção da hipotensão pode ser o outro efeito benéfico potencial da epinefrina.²² Em nosso estudo, descobrimos que a FC mais baixa estava independentemente associada ao CNP. Se a microcirculação for lenta, o CNP ocorrerá, e sugerimos que a FC mais baixa pode ser utilizada como um indicador de CNP. Além disso, os operadores devem estar cientes da FC do paciente, e um paciente com FC menor deve ser considerado um candidato ao CNP antes de iniciar a ICP. Apesar dos resultados encorajadores de nosso estudo, os achados de FC mais baixos devem ser explicados por grandes estudos randomizados.

O EuroSCORE II nos mostra a fragilidade e enfermidade do paciente.²³ Gül et al.,²⁴ descobriram que pacientes com IAMCSST com EuroSCORE II maior apresentavam CNP significativamente maior.²⁴ Neste estudo, no GNR, calculamos um EuroSCORE II significativamente maior, o que é consistente com a literatura. Além disso, descobrimos que idade, TFGe, escore de Mehran, FEVE e hs-PCR foram significativamente associados ao EuroSCORE II.

A KIM-1 é eliminada no sangue e na urina e serve como um indicador de diagnóstico precoce e sensível de lesão tubular proximal em humanos quando comparada a qualquer um dos marcadores de diagnóstico convencionais, por exemplo, creatinina sérica e cistatina C ou proteinúria.⁴ Em condições normais, níveis muito baixos de KIM-1 são expressos nos túbulos renais proximais. Entretanto, no rim isquêmico, a expressão de KIM-1 está significativamente aumentada.²⁵ A KIM-1 mostrou interação com a proliferação de células T. Estudos publicados sugeriram que a KIM-1 também interage com outras proteínas pró-inflamatórias.^4-25 Além disso, as células T têm sido implicadas na fisiopatologia da lesão pós-isquêmica do endotélio.⁴A estrutura proteica da KIM-1 atua como um molécula de adesão para a superfície celular.²⁵ Portanto, especulamos que a KIM-1 pode alterar a adesão celular e modular as interações entre a célula epitelial lesada e o conteúdo luminal, que inclui cilindros, detritos e células epiteliais viáveis que foram desalojadas do endotélio intimal e podem causar o CNP. A KIM-1 pode aumentar a mobilidade e a proliferação das células epiteliais sobreviventes.²⁵ Macrófagos e linfócitos T são a principal fonte de várias citocinas e moléculas que interagem com as células endoteliais, o que leva a um agravamento das vias inflamatórias. Disfunção endotelial, inflamação e expressão aumentada desconhecida de agentes vasoativos, como moléculas de endotelina-1 e angiotensina, são os principais responsáveis pelos mecanismos fisiopatológicos.^4-25 A inflamação desempenha um papel importante no desenvolvimento e progressão do CNP. Portanto, parece lógico combinar essas vias pró-inflamatórias para explicar os mecanismos subjacentes do CNP. A KIM-1 não somente leva à agregação de macrófagos e linfócitos T, mas também aumenta a secreção de citocinas oxidativas. O aumento de KIM-1 foi associado à inflamação sistêmica e disfunção endotelial, e foi definido como um novo marcador prognóstico baseado em inflamação na DCV.⁶ As principais ligações fisiopatológicas entre a KIM-1 e o CNP podem ser a adesão celular, disfunção endotelial e pró -inflamação.

Os resultados deste estudo mostram que as concentrações séricas de KIM-1 estão positivamente associadas ao CNP. Propomos que inflamação, microembolização aterotrombótica, ativação de neutrófilos e plaquetas, que causam a liberação de radicais livres de oxigênio, enzimas proteolíticas e mediadores pró-inflamatórios que podem causar dano tecidual e endotelial, particularmente em miócitos gravemente danificados durante o IAMCSST, são os mecanismos iniciais de CNP. Esses mecanismos comuns também atuam em todos os órgãos sensíveis à isquemia, especialmente nos rins e no coração. Podemos usar a KIM-1 como um marcador prognóstico precoce do CNP. No entanto, não se determinou o mecanismo exato do KIM-1 na patogênese desse fenômeno. Que seja de nosso conhecimento, este é o primeiro relato na literatura que demonstra a relação entre a KIM-1 e o CNP.

Limitações

Primeiro: embora tenhamos realizado um modelo de Cox multivariado para ajustar os fatores de confusão, um viés foi inevitável, porque este foi um estudo de centro único que incluiu um tamanho de amostra relativamente pequeno. Um estudo multicêntrico envolvendo mais pacientes poderia ter resultados e dados mais significativos. Segundo: Utilizamos apenas parâmetros angiográficos na determinação do CNP, a microcirculação não foi avaliada diretamente, seja por ecocardiografia contrastada ou por ressonância magnética, para confirmar a reperfusão adequada em nível microvascular. Esses fatores são limitações de nosso estudo.

Conclusão

Em conclusão, a inflamação desempenha um papel importante no desenvolvimento e progressão do CNP. Portanto, altas concentrações de KIM-1, que é definida como um marcador pró-inflamatório, podem refletir e conduzir os mecanismos subjacentes ao CNP. Além disso, as concentrações séricas basais de KIM-1 e a FC mais baixa são preditores independentes de CNP em pacientes com IAMCSST, e a incidência de AVC foi significativamente maior nesses pacientes no seguimento de um ano.

Agradecimento

Agradecemos Betul Cetintulum Huyut por suas contribuições para análises estatísticas, Hifa Gulru Caglar por suas contribuições para análises bioquímicas e todos os operadores que trabalharam no laboratório de cateterismo.

Funding Statement

Fontes de financiamento.O presente estudo foi financiado pelo Bezmialem Vakif University, com número de financiamento 5.2016 / 17.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Fontes de financiamento.O presente estudo foi financiado pelo Bezmialem Vakif University, com número de financiamento 5.2016 / 17.

Referências

1.. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation. 2002 Feb 5;105(5):656-62. [DOI] [PubMed]; Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation. 2002 Feb 5;105(5):656–662. doi: 10.1161/hc0502.102867. [DOI] [PubMed] [Google Scholar]
2.. Tasar O, Karabay AK, Oduncu V, Kirma C. Predictors and outcomes of no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis. 2019 Jun;30(4):270-6. [DOI] [PubMed]; Tasar O, Karabay AK, Oduncu V, Kirma C. Predictors and outcomes of no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis. 2019 Jun;30(4):270–276. doi: 10.1097/MCA.0000000000000726. [DOI] [PubMed] [Google Scholar]
3.. Yarlioglues M, Yalcinkaya D, Celik IE, Duran M. CHA2DS2VASc Score and Coronary No-Reflow Phenomenon. Angiology. 2019 May 23:3319719851698. doi: 10.1177/0003319719851698. [DOI] [PubMed]; Yarlioglues M, Yalcinkaya D, Celik IE, Duran M. CHA2DS2VASc Score and Coronary No-Reflow Phenomenon. 3319719851698Angiology. 2019 May 23; doi: 10.1177/0003319719851698. [DOI] [PubMed] [Google Scholar]
4.. van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA. Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol. 2007 Jun;212(2):209-17. [DOI] [PubMed]; van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA. Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol. 2007 Jun;212(2):209–217. doi: 10.1002/path.2175. [DOI] [PubMed] [Google Scholar]
5.. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296-305. Erratum in: N Engl J Med. 2008;18(4):4. [DOI] [PubMed]; Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296–1305. doi: 10.1056/NEJMoa041031. Erratum in: N Engl J Med. 2008;18(4):4. [DOI] [PubMed] [Google Scholar]
6.. Gammelager H, Christiansen CF, Johansen MB, Tønnesen E, Jespersen B, Sørensen HT. Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: A population-based cohort study. Crit Care. 2014 Oct 14;18(5):492. [DOI] [PMC free article] [PubMed]; Gammelager H, Christiansen CF, Johansen MB, Tønnesen E, Jespersen B, Sørensen HT. Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: A population-based cohort study. 492Crit Care. 2014 Oct 14;18(5) doi: 10.1186/s13054-014-0492-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77. [DOI] [PubMed]; Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J. 2018;39(2):119–177. doi: 10.1093/eurheartj/ehx393. [DOI] [PubMed] [Google Scholar]
8.. Armstrong C, Joint National Committee. JNC 8 Guidelines for the Management of Hypertension in Adults, Am Fam Physician 2014 Oct 1;90(7):503-4. [PubMed]; Armstrong C, Joint National Committee JNC 8 Guidelines for the Management of Hypertension in Adults. Am Fam Physician. 2014 Oct 1;90(7):503–504. [PubMed] [Google Scholar]
9.. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1): S5-20. [DOI] [PubMed]; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):S5–20. doi: 10.2337/diacare.26.2007.s5. [DOI] [PubMed] [Google Scholar]
10.. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment Panel III) final report. Circulation. 2002;106:3143-421. [PubMed]; National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment Panel III) final report. Circulation. 2002;106:3143–3421. [PubMed] [Google Scholar]
11.. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996 Mar 1;93(5):879-88. [DOI] [PubMed]; Gibson CM, Cannon CP, Daley WL, Dodge JT, Jr, Alexander B, Jr, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996 Mar 1;93(5):879–888. doi: 10.1161/01.cir.93.5.879. [DOI] [PubMed] [Google Scholar]
12.. Durante A, Camici PG. Novel insights into an “old” phenomenon: the no reflow. Int J Cardiol. 2015;187:273-80. [DOI] [PubMed]; Durante A, Camici PG. Novel insights into an “old” phenomenon: the no reflow. Int J Cardiol. 2015;187:273–280. doi: 10.1016/j.ijcard.2015.03.359. [DOI] [PubMed] [Google Scholar]
13.. Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010 May 25;55(21):2383-9. [DOI] [PubMed]; Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010 May 25;55(21):2383–2389. doi: 10.1016/j.jacc.2009.12.054. [DOI] [PubMed] [Google Scholar]
14.. Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring). 2006 Feb;14(suppl 1):16-19. [DOI] [PubMed]; Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring) 2006 Feb;14(suppl 1):16–19. doi: 10.1038/oby.2006.277. [DOI] [PubMed] [Google Scholar]
15.. Bakirci EM, Degirmenci H, Duman H, Inci S, Hamur H, Buyuklu M, et al. Increased epicardial adipose tissue thickness is associated with angiographic thrombus burden in the patients with non-st-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2015 Oct;21(7):612-8. [DOI] [PubMed]; Bakirci EM, Degirmenci H, Duman H, Inci S, Hamur H, Buyuklu M, et al. Increased epicardial adipose tissue thickness is associated with angiographic thrombus burden in the patients with non-st-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2015 Oct;21(7):612–618. doi: 10.1177/1076029614558113. [DOI] [PubMed] [Google Scholar]
16.. Ipek G, Onuk T, Karatas MB, Gungor B, Osken A, Keskin M, et al. CHA2DS2-VASc score is a predictor of no-reflow in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous intervention. Angiology. 2016 Oct;67(9):840-5. [DOI] [PubMed]; Ipek G, Onuk T, Karatas MB, Gungor B, Osken A, Keskin M, et al. CHA2DS2-VASc score is a predictor of no-reflow in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous intervention. Angiology. 2016 Oct;67(9):840–845. doi: 10.1177/0003319715622844. [DOI] [PubMed] [Google Scholar]
17.. Vlaar PJ, Svilaas T, van der Horst IWC, Diercks GFH, Fokkema ML, de Smet BJGL, et al. Cardiac death and reinfarction after 1 year in the thrombus aspiration during percutaneous coronary intervention in acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008 Jun 7;371(9628):1915-20. [DOI] [PubMed]; Vlaar PJ, Svilaas T, van der Horst IWC, Diercks GFH, Fokkema ML, de Smet BJGL, et al. Cardiac death and reinfarction after 1 year in the thrombus aspiration during percutaneous coronary intervention in acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008 Jun 7;371(9628):1915–1920. doi: 10.1016/S0140-6736(08)60833-8. [DOI] [PubMed] [Google Scholar]
18.. Danzi G, Sesana M, Capuano C, Mauri L, Centurini PB, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function. Am J Cardiol. 2004 Jul 1;94(1):35-9. [DOI] [PubMed]; Danzi G, Sesana M, Capuano C, Mauri L, Centurini PB, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function. Am J Cardiol. 2004 Jul 1;94(1):35–39. doi: 10.1016/j.amjcard.2004.03.026. [DOI] [PubMed] [Google Scholar]
19.. Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol. 2001 Apr;37(5):1335-43. [DOI] [PubMed]; Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol. 2001 Apr;37(5):1335–1343. doi: 10.1016/s0735-1097(01)01138-x. [DOI] [PubMed] [Google Scholar]
20.. Amit G, Cafri C, Yaroslavtsev S, Fuchs S, Paltiel O, Abu-Ful A, et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. Am Heart J. 2006 Nov;152(5):887. e9-14. [DOI] [PubMed]; Amit G, Cafri C, Yaroslavtsev S, Fuchs S, Paltiel O, Abu-Ful A, et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. 887Am Heart J. 2006 Nov;152(5) doi: 10.1016/j.ahj.2006.05.010. e9-14. [DOI] [PubMed] [Google Scholar]
21.. Aksu T, Guler TE, Colak A, Baysal E, Durukan M, Sen T, et al. Intracoronary epinephrine in the treatment of refractory no-reflow after primary percutaneous coronary intervention: a retrospective study. BMC Cardiovasc Disord. 2015 Feb 19;15:10. [DOI] [PMC free article] [PubMed]; Aksu T, Guler TE, Colak A, Baysal E, Durukan M, Sen T, et al. Intracoronary epinephrine in the treatment of refractory no-reflow after primary percutaneous coronary intervention: a retrospective study. 10BMC Cardiovasc Disord. 2015 Feb 19;15 doi: 10.1186/s12872-015-0004-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.. Skelding KA, Goldstein JA, Mehta L, Pica MC, O’Neill WW. Resolution of refractory no-reflow with intracoronary epinephrine. Catheter Cardiovasc Interv. 2002 Nov;57(3):305-9. [DOI] [PubMed]; Skelding KA, Goldstein JA, Mehta L, Pica MC, O’Neill WW. Resolution of refractory no-reflow with intracoronary epinephrine. Catheter Cardiovasc Interv. 2002 Nov;57(3):305–309. doi: 10.1002/ccd.10303. [DOI] [PubMed] [Google Scholar]
23.. Capodanno D, Dipasqua F, Marcantoni C, Ministeri M, Zanoli L, Rastelli S, et al. EuroSCORE II versus additive and logistic EuroSCORE in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2013 Aug 1;112(3):323-9. [DOI] [PubMed]; Capodanno D, Dipasqua F, Marcantoni C, Ministeri M, Zanoli L, Rastelli S, et al. EuroSCORE II versus additive and logistic EuroSCORE in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2013 Aug 1;112(3):323–329. doi: 10.1016/j.amjcard.2013.03.032. [DOI] [PubMed] [Google Scholar]
24.. Gul I, Zungur M, Aykan A, Islamli A, Yildiz B, Bilgin M. Importance of EuroSCORE-II in the Development of Acute Ischemic Heart Failure After Acute Anterior ST Elevation Myocardial Infarction. Koşuyolu Heart Journal. 2016; 19(2): 71-65.; Gul I, Zungur M, Aykan A, Islamli A, Yildiz B, Bilgin M. Importance of EuroSCORE-II in the Development of Acute Ischemic Heart Failure After Acute Anterior ST Elevation Myocardial Infarction. Koşuyolu Heart Journal. 2016;19(2):71–65. [Google Scholar]
25.. Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol. 2004 Mar;286(3):F552-63. [DOI] [PubMed]; Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol. 2004 Mar;286(3):F552–F563. doi: 10.1152/ajprenal.00285.2002. [DOI] [PubMed] [Google Scholar]

Arq Bras Cardiol. 2021 Feb 19;116(2):238–247. [Article in English]

Outcomes in Coronary No-Reflow Phenomenon Patients and the Relationship between Kidney Injury Molecule-1 and Coronary No-Reflow Phenomenon

Mustafa Ahmet Huyut ¹, Aylin Hatice Yamac ²

Abstract

Background

Coronary no-reflow phenomenon (CNP) is associated with an increased risk of major cardiovascular adverse events (MACE).

Objective

This study aimed to evaluate the relationship between serum Kidney Injury Molecule-1 (KIM-1) levels and CNP in patients with acute ST-segment elevation myocardial infarction (STEMI).

Methods

This study included a total of 160 patients (113 males and 47 females; mean age: 61.65±12.14 years) who were diagnosed with STEMI. The patients were divided into two groups, the reflow group (RG) (n=140) and the no-reflow group (NRG) (n=20). Patients were followed during one year. A p-value of <0.05 was considered significant.

Results

CNP was observed in 12.50% of the patients. Serum KIM-1 was significantly higher in the NRG than in the RG (20.26±7,32 vs. 13.45±6.40, p<0.001). Body mass index (BMI) was significantly higher in the NRG than in the RG (29.41 (28.48-31.23) vs. 27.56 (25.44-31.03), p=0.047). Heart rate (HR) was significantly lower in the NRG than in the RG (61.6±8.04 vs. 80.37±14.61, p<0.001). The European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) was significantly higher in the NRG than in the RG (3.06±2.22 vs. 2.36±2.85, p=0.016). The incidence of stroke was significantly higher in the NRG than in the RG (15% vs. 2.90%, p=0.013). The baseline KIM-1 level (OR=1.19, 95% CI:1.07 to 1.34, p=0.002) and HR (OR=0.784, 95% CI:0.69 to 0.88, p<0.001) were the independent predictors of CNP.

Conclusion

In conclusion, baseline serum KIM-1 concentrations and lower HR are independently associated with CNP in STEMI patients and the incidence of stroke was significantly higher in the NRG in the one-year follow-up. (Arq Bras Cardiol. 2021; 116(2):238-247)

Keywords: Cardiovascular Diseassses, Myocardial Infarction Stroke, Percutaneous Coronary Intervention, Coronary Thrombosis, Heart Rate

Introduction

The coronary no-reflow phenomenon (CNP) was defined as the lack of myocardial perfusion despite the opening of the coronary vessel in the setting of primary percutaneous coronary intervention (PCI).¹ Overall, angiographic CNP is defined as the presence of Thrombolysis In Myocardial Infarction (TIMI) score of 0-I, which refers to the sudden loss of epicardial flow, after balloon dilatation or stent placement without the presence of dissection, mechanical obstruction, significant residual stenosis, spasm or thrombus of the coronary vessel.²The underlying mechanisms of CNP are inflammation, atherothrombotic microembolization, and activation of neutrophils and platelets, which cause the release of oxygen-free radicals, proteolytic enzymes, and proinflammatory mediators that can cause tissue and endothelial damage, particularly in critically-injured myocytes.³ Biomarkers of kidney tubular injury, such as KIM-1, have been associated with both the incidence and progression of acute kidney injury (AKI) and chronic kidney disease (CKD).⁴ KIM-1 is a type-1 transmembrane protein, which is expressed in the proximal tubule apical membrane according to the injury.⁵AKI and CKD are strongly associated with cardiovascular disease (CVD), and AKI has been reported as being associated with cardiovascular events.⁶ KIM-1 acts as a pro-inflammatory molecule and has both chemo-attractant and cell-adhesion functions.⁴ The structure of KIM-1 suggests that it may be involved in surface adhesion interactions.^4-6 The pro-inflammatory cytokines contribute to the inflammation by enhancing and stimulating the inflammatory cells and inflammatory response.⁴ KIM-1 also has a spatial relation with inflammatory T-cells.⁴ KIM-1 has been shown to interact with T-cell proliferation, and KIM-1 also interacts with other pro-inflammatory proteins.⁴ Moreover, T-cells have been implicated in the pathophysiology of the post-ischemic injury of the endothelium.⁴ It is possible that KIM-1 plays an important role for the surviving epithelial cells to undergo differentiation, migration, proliferation, and the restoration of morphological and functional epithelial integrity. Nevertheless, KIM-1 is associated with fibrosis and inflammation.⁴We hypothesized that KIM-1 expression is induced in STEMI and is related to CNP and endothelial damage due to the pro-inflammatory response. The association between KIM-1 protein levels and CNP has not been addressed in the literature yet. Understanding which biologic pathways and markers are associated with CNP may allow for the design of future studies to explore the mechanistic link between these pathways and to evaluate the efficacy of interventions designed to reduce the burden of CVD in these patients. Furthermore, the aim of this study was to evaluate the relationship between baseline serum KIM-1 protein levels and CNP in patients with acute STEMI.

Methods

This study was prospectively conducted between May 2016 and May 2018 at Bezmialem Vakif University Hospital. For this single-center study, we enrolled 346 patients between 18 and 90 years who were diagnosed with STEMI and underwent primary PCI within 6 hours of symptom onset. All STEMI patients referred to the cath lab to undergo primary PCI were included (n=346). Patients with coronary artery bypass graft (CABG), cardiogenic shock, pulmonary edema, Killip class ≥2, stent thrombosis, who underwent thrombus aspiration in the index event, had acute or chronic infective or neoplastic disease, moderate-to-severe chronic kidney disease, and chronic liver disease were excluded from this study (n=186). Accordng to the final results of the angiographic features of TIMI flow of the treated artery, a total of 20 patients with angiographically proven CNP were enrolled in the NRG and we included 140 patients in the RG. All patients were given a therapy consisting of 300 mg acetylsalicylic acid and a loading dose of clopidogrel (600mg) and UF heparin (100mg/kg) prior to PCI. All participants gave written informed consent prior to participation and the study was approved by the local ethics committee. Furthermore, the study was conducted under the provisions of the Declaration of Helsinki.

Biochemical analyses

Venous blood samples were taken immediately after hospital admission before PCI from the antecubital vein. The 12-lead electrocardiograms were obtained at baseline and HR was noted. BMI was calculated using the formula weight (kg)/ height² (m²). The estimated glomerular filtration rate (eGFR) of each patient was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Routine blood chemistry, lipid parameters, and troponin-I were measured using standard auto-analyzer equipment. Blood counts were measured using a Sysmex K-1000 (Block Scientific, Bohemia, NY, USA) auto-analyzer. Samples were centrifuged at 3000 rpm for 10 min, and the supernatant and serum separated from the samples. Then they were frozen at -80° C until further analysis. Serum KIM-1 levels (ng/mL) were measured using a commercially available enzyme-linked immunosorbent assay ELISA kit (Human KIM-1 ELISA kit, Elabscience Biotech Co., Ltd, Catalog no: E-EL-H0186, Wuhan, China).⁴ The KIM-1 kit analysis inter and intra-assay coefficients of variation for the assay was less than 10%, and sensitivity was 0.10 ng/mL.

Diagnosis of acute ST-segment elevation myocardial infarction

The STEMI diagnosis was attained in the presence of the following characteristics based on definitions from clinical practice guidelines: typical chest pain lasting more than 30 minutes, new-onset or presumably new ST-segment elevation in two or more contiguous leads with ST-segment elevation ≥ 2.5 mm in men < 40 years, ≥2 mm in men ≥ 40 years, or ≥ 1.5 mm in women in leads V2–V3 and/or ≥ 1 mm in the other leads (in the absence of left ventricular hypertrophy or left bundle-branch block). In patients with inferior MI recorded with right precordial leads (V3R and V4R ST-segment elevation), it was considered a case of concomitant right ventricular infarction. Likewise, ST-segment depression in leads V1–V3 and positive T-wave (ST-segment elevation equivalent), additionally concomitant ST-segment elevation ≥ 0.5 mm recorded in leads V7–V9 was considered as a posterior MI.⁷

Cardiovascular risk factors

After detailed examinations, the medical history of each patient was collected by the same investigator. Risk factors for coronary artery disease (CAD), including age, gender, hypertension (HT), diabetes mellitus (DM), hyperlipidemia (HPL), and smoking status, were noted. Patients who were previously receiving antihypertensive therapy or whose blood pressure levels, measured at least twice, were ≥140/90 mmHg were considered to be hypertensive.⁸ Patients who were previously receiving an oral antidiabetic and/or using insulin therapy or whose fasting blood glucose, measured at least twice, was ≥125 mg/dL were considered to be diabetic.⁹ The presence of HPL was considered when total cholesterol level was >200 mg/dL or low-density lipoprotein cholesterol (LDL-C) was >100 mg/dL or when the patient was previously receiving a lipid-lowering medication in accordance with the “Adult Treatment Panel III” guideline.¹⁰ Patients who were still using tobacco products on admission to the emergency service and those who had ceased smoking within the past month were considered smokers.

Coronary angiography

Coronary angiography procedures were performed using a Philips (Optimus 200 DCA and Integris Allura 9, Philips Medical Systems, Eindhoven, Netherlands) angiography device using the femoral approach. Coronary angiography and PCI were performed according to the standard clinical practice with nonionic, iso-osmolar contrast medium (iodixanol, Visipaque 320mg/100mL; GE Healthcare, Cork, Ireland). Primary PCI of the infarct-related artery was performed. Angiographic images were shot at a rate of at least 80 image frames and were recorded at a rate of 25 frames per second. At least two cardiologists assessed the coronary anatomic examination records offline. Coronary blood flow velocity was determined by the quantitative number of frame count as described by Gibson et al.¹¹ The CNP was defined angiographically as post-PCI TIMI flow grades ≤1, without the presence of dissection, mechanical obstruction, or significant stenosis.¹ CNP patients received intracoronary (IC) glycoprotein IIb/IIIa inhibitors (Gp-IIb/IIIa inh.) or IC adenosine or epinephrine for the treatment of CNP, respectively. After the procedure, all patients received intravenous (IV) hydration with isotonic saline for at least 12 hours.

Transthoracic echocardiography

Each patient underwent a transthoracic echocardiographic examination with a 3.5-MHz transducer (Vivid 7 GE Medical System, Horten, Norway) by the same investigators before hospital discharge. Examinations and measurements were performed according to the recommendations of the American Echocardiography Unit. Simpson’s method was used to calculate left ventricular ejection fraction (LVEF).

Follow-up

The follow-up information was obtained through hospital records and at the patients’ consultations carried out at the hospital at 1, 3, 6 and 12 months by the same investigators. The endpoints of this study, MACE including all-cause mortality, cardiovascular death, stroke, and myocardial re-infarction were obtained from hospital records and death certificates, or by telephone contact with the patients’ relatives.

Statistical analysis

Data analyses were performed using SPSS version 24.0 statistical software package (SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov test was used to control the variable distributions. Student’s t test for two independent samples, was used for normally distributed data and reported as mean and standard deviation, and Mann–Whitney U test was used to compare non-normally distributed data and reported as median and 25^th and 75^th percentiles. Categorical data were compared using the Chi-square test. The correlations between variables were performed using Spearman’s rank-order correlation analysis. The Kaplan-Meier method was used to estimate event-free survival rates. Receiver operating characteristic (ROC) curve analysis was performed to determine KIM-1 predictive value for CNP. Logistic regression analysis was performed to assess the predictors of CNP. Univariate logistic regression analysis was performed, and the variables that were found to be statistically significant (p<0.1) were analyzed with multivariate logistic regression analysis. A two-tailed p value of <0.05 was considered significant.

Results

This study included a total of 160 patients (113 males and 47 females; mean age: 61.65±12.14 years) who were diagnosed with CNP. CNP was observed in 12.50% of the study population. Demographic findings and medications in the groups were described in Table 1. Regarding the cardiovascular risk factors, BMI (kg/m²) was significantly higher in the NRG than in the RG (29.41 (28.48-31.23) vs. 27.56 (25.44-31.03), p=0.047). The baseline laboratory characteristics of the patients are described in Table 2. KIM-1 was significantly higher in the NRG than in the RG (20.26±7.32 vs 13.45±6.40, p<0.001), HR was significantly lower in the NRG than in the RG (61.60±8.04 vs 80.37±14.61, p<0.001) and EuroSCORE II was significantly higher in the NRG than in the RG (3.06±2.22 vs 2.36±2.85, p=0.016). In 4 patients, CNP was resolved with IC Gp-IIb/IIIa inh., in 8 patients CNP was resolved with intracoronary (IC) Gp-IIb/IIIa inh. plus IC adenosine and in 5 patients CNP was resolved with IC Gp-IIb/IIIainhibitor plus IC adenosine and IC epinephrine (Table 1). In 17 patients CNP was resolved and they were added to the RG. CNP persisted in 20 patients and they were added to the NRG.

Table 1. – Baseline characteristics and medications of the patients.

Variable, n(%)	NRG n=20 (12.5)	RG n=140 (87.5)	p-value
Age, y	64.35±14.03	61±11.86	0.291
Male gender, n(%)	11 (55.00)	102 (72.90)	0.101
BMI (kg/m²)	29.41 (28.48-31.23)	27.56 (25.44-31.03)	0.047
HT, n(%)	15 (75)	79 (56.40)	0.115
DM, n(%)	7 (35)	50 (35.70)	0.950
HL, n(%)	6 (30)	62 (44.30)	0.227
Smoker, n(%)	11 (55)	90 (64.30)	0.421
Family History, n(%)	6 (30)	54 (38.60)	0.459
PAD, n(%)	3 (15)	11 (7.90)	0.290
COPD, n(%)	3 (15)	26 (18.60)	0.698
LVEF (%)	51.25±6.72	52.01±7.49	0.561
Medications n(%)
Ace inh	14 (70)	75 (53.60)	0.167
ARB	5 (25)	44 (31.40)	0.560
B blocker	19 (95)	133 (95)	1
CCB	6 (30)	34 (24.30)	0.581
Statin	20 (100)	124 (88.60)	0.111
Nitrat	9 (45)	49 (35)	0.384
OAD	7 (35)	48 (34.30)	0.950
IC Gp-IIb/IIIa inh.	20 (100)	17 (12.10)	<0.001
IC adenosine	20 (100)	13 (9.3)	<0.001
IC epinephrine	20 (100)	5 (3.6)	<0.001

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Data were reported as n(%) for categorical variables; median and 25th-75th percentile for non-parametric measurements; mean and standard deviation for parametric measurements. Y: year; BMI: Body Mass Index; HT: hypertension; DM: diabetes mellitus type II; HL: hyperlipidemia; PAD: peripheral arterial disease; COPD: chronic obstructive pulmonary disease; LVEF: left ventricular ejection fraction; ACE inh: angiotensin-converting enzyme inhibitors; ARB: angiotensin receptor blockers; B blocker: beta-blocker; CCB: calcium channel blockers; OAD: oral antihyperglycemic drugs; IC: intracoronary; Gp-IIb/IIIa inh: glycoprotein-IIb/IIIa inhibitors.

Table 2. – Baseline laboratory characteristics of the patients.

Variable, n(%)	NRG n=20 (12.5)	RG n=140 (87.5)	p-value
KIM-1 ng/mL	20.26±7.32	13.45±6.40	<0.001
Glucose, mg/dl	134.25±65.06	136.73±61.27	0.689
Uric acid, mg/dl	5.63±1.51	5.73±1.73	0.883
eGFR (mL/min per 1.73 m2)	75.54±22.63	82.3±21.47	0.154
Mehran Score	5 (2-8)	3.5 (2-6.75)	0.145
CIN development, n(%)	1(5)	14(10)	0.473
WBC, 10³/uL	9.86±4.32	9.45±3.30	0.796
HTC, %	40.07±3.44	40.36±4.66	0.678
Platelet, 10³/uL	231.60±62.13	238.83±73.29	0.520
In-hospital stay, day	3.15±0.48	3±1.12	0.408
Trigliseride, (mg/dL)	160.50±37.62	155.37±57.52	0.323
HDL, (mg/dL)	39.70±5.01	41.05±7.83	0.938
LDL, (mg/dL)	138.15±31.86	123.77±33.91	0.076
Total Cholesterol, (mg/dL)	214.15±33.47	200.75±38.1	0.188
hs-CRP, (mg/dL)	0.10 (0.01-0.43)	0.20 (0.05-0.50)	0.532
Peak Troponin-I (pg/ml)	2293 (432.75-13501.25)	808.50 (68.25-3770.50)	0.220
Heart Rate, (bpm)	61.6±8.04	80.37±14.61	<0.001
TSH, uIU/mL	1.05 (0.70-1.30)	1.10 (0.90-1.40)	0.245
NYHA class	2.45±0.51	2.30±0.53	0.278
EuroSCORE II, (%)	3.06±2.22	2.36±2.85	0.016

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Data were reported as n(%) for categorical variables; median and 25th-75th percentile for non-parametric measurements; mean and standard deviation for parametric measurements. KIM-1: Kidney injury molecule-1; eGFR: estimated glomerular filtration rate; CIN: Contrast-induced nephropathy; HTC: hematocrit; HDL: high-density lipoprotein; LDL: low-density lipoprotein; hs-CRP: high-sensitivity C-reactive protein; TSH: thyroid-stimulating hormone; NYHA: the New York Heart Association Functional Classification; EuroSCORE II: European System for Cardiac Operative Risk Evaluation II.

Clinical follow-up findings, including all-cause mortality, cardiovascular death, stroke, myocardial infarction, and MACE are described in Table 3. Stroke was significantly higher in the NRG than in the RG (15% vs. 2.9%, p=0.013). There were no differences between the two groups regarding other demographic or clinical findings. Kaplan-Meier curves for stroke and MACE rates are described in Figures 1 and 2. Age, eGFR, Mehran score, LVEF, and hs-CRP were significantly associated with EuroSCORE II (p<0.05) (Table 4). Forward conditional logistic regression analysis demonstrated that KIM-1 (OR=1.199, 95%CI: 1.07-1.343, p=0.002) and HR (OR=0.784, 95%CI: 0.696-0.883, p<0.001) were the independent predictors of CNP in STEMI patients (Table 5). In the ROC analysis, the values of serum KIM-1 above 21,53 ng/mL predicted the presence of CNP with 85% of sensitivity and 93,6% of specificity. The area under the curve was 0.80 (95% CI: 0.653–0.946, p<0.001) (Figure3).

Table 3. – Clinical follow-up findings.

Variable, n(%)	NRG n=20 (12.5)	RG n=140 (87.5)	p-value
All-Cause Mortality	2 (10)	21 (15)	0.551
Cardiovascular Death	2 (10)	16 (11.4)	0.850
Stroke	3 (15)	4 (2.9)	0.013
Myocardial infarction	2 (10)	17 (12.1)	0.782
MACE	6 (30)	35 (25)	0.682

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Data were reported as n(%). MACE: Major Adverse cardiovascular events.

Table 4. – Correlations between EuroSCORE II with clinical parameters.

Variable	r-value	p-value
Age	0.64	<0.001
eGFR	-0.64	<0.001
Mehran Score	0.77	<0.001
LVEF, (%)	-0.70	<0.001
hs-CRP (mg/dL)	0.24	0.002

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r: Spearman’s rank correlation coefficient; eGFR: estimated glomerular filtration rate; LVEF: left ventricular ejection fraction; hs-CRP: high-sensitivity C-reactive protein.

Table 5. – Independent predictors of CNP in STEMI.

Variable	OR	95% CI	p-value
KIM-1	1.199	1.07-1.343	0.002
HR	0.784	0.696-0.883	<0.001

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KIM-1: kidney injury molecule-1; HR: heart rate; bpm: beat per minute; OR: Odds ratio; CI: Confidence interval.

Discussion

The main finding of this study was that increased KIM-1 levels and lower HR were the two determinants of CNP. We have shown that the values of serum KIM-1 above 21.53 ng/mL suggest the presence of CNP;thus, elevated serum KIM-1 levels can be used as a promising biomarker of CNP. In our study, we found that CNP was independently associated with baseline serum KIM-1 concentrations and lower HR in STEMI patients. To the best of our knowledge, this is the first report in the literature demonstrating the relationship between KIM-1 concentrations and lower HR with CNP. Additionally, in patients with STEMI, CNP was significantly associated with poor outcomes. In the one-year clinical follow-up, findings demonstrated that stroke was significantly higher in the NRG.

Although the exact mechanism of CNP is not consistently determined in the literature, there are several suggested CNP mechanisms. These reported mechanisms are such as pre-existing microvascular dysfunction, microvascular arteriolar spasm, distal thrombo-embolization due to high platelet activity and thrombus burden, ischemic-reperfusion injury, and swelling of myocardial cells compressing microvascular vessels.^1-3 Therefore, the pathogenesis and mechanisms of CNP remain controversial.

CNP is a significant prognostic marker related to short-term poor cardiac outcomes in STEMI. Regarding the published data, the estimated frequency of CNP ranged from 5% to 60%.¹² In our study, CNP was observed in 12.50% of the study population. Consistent with the published data, patients with CNP had worse outcomes.¹³ In our study, one-year clinical follow-up findings demonstrated that stroke incidence was significantly higher in the NRG. Stroke was associated with thrombus burden. According to our study, the associated mechanism underlying this adverse event is continuing thrombus activation still ongoing after the index event, and this may be the main reason for stroke. Despite the fact that all STEMI patients were taking antithrombotic medications regularly, stoke incidence was significantly higher in the NRG. Thus, such patients should be monitored and followed carefully. BMI is the most widely used tool for the assessment of obesity.¹⁴ Bakirci et al.¹⁵ found that increased epicardial fat in obese patients was associated with impaired coronary flow in patients with non-STEMI.¹⁵Recent studies suggested that CNP is more frequently seen in association with hyperglycemia, hypercholesterolemia, and mild-to-moderate renal insufficiency.¹⁶ However, the understanding of these risk factors for the pathogenesis of CNP is limited and controversial. In our study, we found that BMI was significantly higher in the NRG. This may be proven to be associated with the risk of stroke as well. Thus, calculating the BMI may be a useful method for estimating cardiac outcomes in CNP. In addition, decreasing BMI may protect patients against stroke. Randomized studies that have utilized manual thrombus aspiration have shown better microvascular perfusion and long-term outcomes compared to control patients undergoing PCI during STEMI.¹⁷ However, using thrombus aspiration can cause stroke due to device complications, and for that reason in our study we excluded the patients (n=12) from the studies that used thrombus aspiration catheter. The routine use of platelet inhibitors (Gp-IIb/IIIa inh., abciximab, tirofiban), nicorandil, nitroprusside, and adenosine have shown beneficial effects on myocardial perfusion in STEMI.^18-20 Aksu et al. found that epinephrine has a beneficial effect on CNP too.²¹ Epinephrine causes a potent coronary vasodilator effect via beta-2 receptor activation, which then mediate vasodilatation of the arteriolar circulation. Also, it has chronotropic and inotropic effects on the heart.²² IC epinephrine may restore normotensive blood pressure in these patients, since this agent stimulates alpha vasoconstrictor receptors.²¹ Skelding et al.²⁴ found that the increase in coronary flow due to correction of hypotension may be the other potential beneficial effect of epinephrine.²² In our study, we found that lower HR was independently associated with CNP. If the microcirculation is slow, CNP will occurr and we have suggested that a lower HR can be used as an indicator of CNP. Moreover, operators have to be aware of the patient’s HR, and a lower HR should be considered as a candidate for CNP before starting PCI. Despite the encouraging results of our study, lower HR findings should be explained by large randomized studies.

EuroSCORE II shows us the patient’s fragility and frailty.²³ Gül et al.²⁴ found that STEMI patients with higher EuroSCORE II had significantly higher CNP.²⁴ In this study, in the NRG, we calculated a significantly higher EuroSCORE II, consistent with the literature. Additionally, we found that age, eGFR, Mehran score, LVEF, and hs-CRP, were significantly associated with EuroSCORE II.

KIM-1 is released in the blood and urine and can be used as a sensitive and early diagnostic indicator of proximal tubular injury in humans when compared to any of the conventional diagnostic markers, e.g., serum creatinine and cystatin C or proteinuria.⁴ Under normal conditions, very low KIM-1 levels are expressed in kidney proximal tubulesa. However, in the ischemic kidney, KIM-1 expression is significantly increased.²⁵ KIM-1 has been shown to interact with T-cell proliferation. Published studies have suggested that KIM-1 also interact with other pro-inflammatory proteins.^4-25 Moreover, T-cells have been implicated in the pathophysiology of the post-ischemic injury of the endothelium.⁴ The protein structure of KIM-1 acts as an adhesion molecule for the cell surface.²⁵ Therefore, we speculate that KIM-1 might alter cell adhesion and modulate interactions between the injured epithelial cells and the luminal contents that include casts, debris, and viable epithelial cells that have become dislodged from the intimal endothelium and might cause the CNP. KIM-1 may enhance mobility and proliferation of the surviving epithelial cells.²⁵Macrophages and T-lymphocytes are the main source of various cytokines and molecules that interact with endothelial cells, which leads to an aggravation of inflammatory pathways. Endothelial dysfunction, inflammation and unknown increased expression of vasoactive agents, such as endothelin-1 and angiotensin molecules are the main agents responsible for the pathophysiological mechanisms.^4-25 Inflammation plays a major role in CNP development and progression. Therefore, it seems logical to combine these pro-inflammatory pathways to explain the underlying mechanisms of CNP. KIM-1 not only leads to macrophage and T-lymphocyte aggregation but also increases the oxidative cytokine secretion. Increased KIM-1 was associated with systemic inflammation and endothelial dysfunction, and it was defined as a novel inflammation-based prognostic marker in CVD.⁶ The main pathophysiological links between KIM-1 and CNP might be cell adhesion, endothelial dysfunction, and pro-inflammation.

The results of this study show that serum KIM-1 concentrations are positively associated with CNP. We propose that inflammation, atherothrombotic microembolization, activation of neutrophils and platelets, which cause the release of oxygen-free radicals, proteolytic enzymes, and proinflammatory mediators that can cause tissue and endothelial damage, particularly in critically injured myocytes during STEMI, are the initial mechanisms of CNP. These common mechanisms also work on every ischemia-sensitive organ, especially on the kidney and heart. KIM-1 can be used as an early prognostic marker of CNP. However, we did not determine the exact mechanism of KIM-1 in the pathogenesis of this phenomenon. To the best of our knowledge, this is the first report in the literature demonstrating the relationship between KIM-1 and CNP.

Limitations

First: Although we performed a multivariate Cox model to adjust for confounding factors, a bias was unavoidable, because this was a single-center study that included a relatively small sample size. A multicenter study involving more patients could yield more significant results and data. Second: We used only angiographic parameters in determining CNP, the microcirculation was not directly evaluated by contrast echocardiography or by magnetic resonance imaging to confirm the adequate reperfusion at the microvascular level. These factors are limitations of our study.

Conclusion

In conclusion, inflammation plays a major role in CNP development and progression. Therefore, high concentrations of KIM-1, which is defined as a pro-inflammatory marker, can reflect and lead the underlying mechanisms of CNP. Moreover, baseline serum KIM-1 concentrations and lower HR are the independent predictors of CNP in STEMI patients, and stroke was significantly higher in those patients in one-year follow-up.

Acknowledgment

We thanks, Betul Cetintulum Huyut for her statistical analysis contributions, Hifa Gulru Caglar for her biochemical analysis contributions, and all the operators who worked in the cath lab.

Study Association

This study is not associated with any thesis or dissertation work.

Sources of Funding.This study was funded by Bezmialem Vakif University, with 5.2016/17 funding number

[B1] 1.. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation. 2002 Feb 5;105(5):656-62. [DOI] [PubMed]; Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation. 2002 Feb 5;105(5):656–662. doi: 10.1161/hc0502.102867. [DOI] [PubMed] [Google Scholar]

[B2] 2.. Tasar O, Karabay AK, Oduncu V, Kirma C. Predictors and outcomes of no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis. 2019 Jun;30(4):270-6. [DOI] [PubMed]; Tasar O, Karabay AK, Oduncu V, Kirma C. Predictors and outcomes of no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis. 2019 Jun;30(4):270–276. doi: 10.1097/MCA.0000000000000726. [DOI] [PubMed] [Google Scholar]

[B3] 3.. Yarlioglues M, Yalcinkaya D, Celik IE, Duran M. CHA2DS2VASc Score and Coronary No-Reflow Phenomenon. Angiology. 2019 May 23:3319719851698. doi: 10.1177/0003319719851698. [DOI] [PubMed]; Yarlioglues M, Yalcinkaya D, Celik IE, Duran M. CHA2DS2VASc Score and Coronary No-Reflow Phenomenon. 3319719851698Angiology. 2019 May 23; doi: 10.1177/0003319719851698. [DOI] [PubMed] [Google Scholar]

[B4] 4.. van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA. Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol. 2007 Jun;212(2):209-17. [DOI] [PubMed]; van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA. Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol. 2007 Jun;212(2):209–217. doi: 10.1002/path.2175. [DOI] [PubMed] [Google Scholar]

[B5] 5.. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296-305. Erratum in: N Engl J Med. 2008;18(4):4. [DOI] [PubMed]; Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296–1305. doi: 10.1056/NEJMoa041031. Erratum in: N Engl J Med. 2008;18(4):4. [DOI] [PubMed] [Google Scholar]

[B6] 6.. Gammelager H, Christiansen CF, Johansen MB, Tønnesen E, Jespersen B, Sørensen HT. Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: A population-based cohort study. Crit Care. 2014 Oct 14;18(5):492. [DOI] [PMC free article] [PubMed]; Gammelager H, Christiansen CF, Johansen MB, Tønnesen E, Jespersen B, Sørensen HT. Three-year risk of cardiovascular disease among intensive care patients with acute kidney injury: A population-based cohort study. 492Crit Care. 2014 Oct 14;18(5) doi: 10.1186/s13054-014-0492-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7] 7.. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–77. [DOI] [PubMed]; Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J. 2018;39(2):119–177. doi: 10.1093/eurheartj/ehx393. [DOI] [PubMed] [Google Scholar]

[B8] 8.. Armstrong C, Joint National Committee. JNC 8 Guidelines for the Management of Hypertension in Adults, Am Fam Physician 2014 Oct 1;90(7):503-4. [PubMed]; Armstrong C, Joint National Committee JNC 8 Guidelines for the Management of Hypertension in Adults. Am Fam Physician. 2014 Oct 1;90(7):503–504. [PubMed] [Google Scholar]

[B9] 9.. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1): S5-20. [DOI] [PubMed]; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):S5–20. doi: 10.2337/diacare.26.2007.s5. [DOI] [PubMed] [Google Scholar]

[B10] 10.. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment Panel III) final report. Circulation. 2002;106:3143-421. [PubMed]; National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment Panel III) final report. Circulation. 2002;106:3143–3421. [PubMed] [Google Scholar]

[B11] 11.. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996 Mar 1;93(5):879-88. [DOI] [PubMed]; Gibson CM, Cannon CP, Daley WL, Dodge JT, Jr, Alexander B, Jr, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996 Mar 1;93(5):879–888. doi: 10.1161/01.cir.93.5.879. [DOI] [PubMed] [Google Scholar]

[B12] 12.. Durante A, Camici PG. Novel insights into an “old” phenomenon: the no reflow. Int J Cardiol. 2015;187:273-80. [DOI] [PubMed]; Durante A, Camici PG. Novel insights into an “old” phenomenon: the no reflow. Int J Cardiol. 2015;187:273–280. doi: 10.1016/j.ijcard.2015.03.359. [DOI] [PubMed] [Google Scholar]

[B13] 13.. Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010 May 25;55(21):2383-9. [DOI] [PubMed]; Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010 May 25;55(21):2383–2389. doi: 10.1016/j.jacc.2009.12.054. [DOI] [PubMed] [Google Scholar]

[B14] 14.. Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring). 2006 Feb;14(suppl 1):16-19. [DOI] [PubMed]; Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, et al. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity (Silver Spring) 2006 Feb;14(suppl 1):16–19. doi: 10.1038/oby.2006.277. [DOI] [PubMed] [Google Scholar]

[B15] 15.. Bakirci EM, Degirmenci H, Duman H, Inci S, Hamur H, Buyuklu M, et al. Increased epicardial adipose tissue thickness is associated with angiographic thrombus burden in the patients with non-st-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2015 Oct;21(7):612-8. [DOI] [PubMed]; Bakirci EM, Degirmenci H, Duman H, Inci S, Hamur H, Buyuklu M, et al. Increased epicardial adipose tissue thickness is associated with angiographic thrombus burden in the patients with non-st-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2015 Oct;21(7):612–618. doi: 10.1177/1076029614558113. [DOI] [PubMed] [Google Scholar]

[B16] 16.. Ipek G, Onuk T, Karatas MB, Gungor B, Osken A, Keskin M, et al. CHA2DS2-VASc score is a predictor of no-reflow in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous intervention. Angiology. 2016 Oct;67(9):840-5. [DOI] [PubMed]; Ipek G, Onuk T, Karatas MB, Gungor B, Osken A, Keskin M, et al. CHA2DS2-VASc score is a predictor of no-reflow in patients with ST-segment elevation myocardial infarction who underwent primary percutaneous intervention. Angiology. 2016 Oct;67(9):840–845. doi: 10.1177/0003319715622844. [DOI] [PubMed] [Google Scholar]

[B17] 17.. Vlaar PJ, Svilaas T, van der Horst IWC, Diercks GFH, Fokkema ML, de Smet BJGL, et al. Cardiac death and reinfarction after 1 year in the thrombus aspiration during percutaneous coronary intervention in acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008 Jun 7;371(9628):1915-20. [DOI] [PubMed]; Vlaar PJ, Svilaas T, van der Horst IWC, Diercks GFH, Fokkema ML, de Smet BJGL, et al. Cardiac death and reinfarction after 1 year in the thrombus aspiration during percutaneous coronary intervention in acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008 Jun 7;371(9628):1915–1920. doi: 10.1016/S0140-6736(08)60833-8. [DOI] [PubMed] [Google Scholar]

[B18] 18.. Danzi G, Sesana M, Capuano C, Mauri L, Centurini PB, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function. Am J Cardiol. 2004 Jul 1;94(1):35-9. [DOI] [PubMed]; Danzi G, Sesana M, Capuano C, Mauri L, Centurini PB, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function. Am J Cardiol. 2004 Jul 1;94(1):35–39. doi: 10.1016/j.amjcard.2004.03.026. [DOI] [PubMed] [Google Scholar]

[B19] 19.. Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol. 2001 Apr;37(5):1335-43. [DOI] [PubMed]; Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol. 2001 Apr;37(5):1335–1343. doi: 10.1016/s0735-1097(01)01138-x. [DOI] [PubMed] [Google Scholar]

[B20] 20.. Amit G, Cafri C, Yaroslavtsev S, Fuchs S, Paltiel O, Abu-Ful A, et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. Am Heart J. 2006 Nov;152(5):887. e9-14. [DOI] [PubMed]; Amit G, Cafri C, Yaroslavtsev S, Fuchs S, Paltiel O, Abu-Ful A, et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. 887Am Heart J. 2006 Nov;152(5) doi: 10.1016/j.ahj.2006.05.010. e9-14. [DOI] [PubMed] [Google Scholar]

[B21] 21.. Aksu T, Guler TE, Colak A, Baysal E, Durukan M, Sen T, et al. Intracoronary epinephrine in the treatment of refractory no-reflow after primary percutaneous coronary intervention: a retrospective study. BMC Cardiovasc Disord. 2015 Feb 19;15:10. [DOI] [PMC free article] [PubMed]; Aksu T, Guler TE, Colak A, Baysal E, Durukan M, Sen T, et al. Intracoronary epinephrine in the treatment of refractory no-reflow after primary percutaneous coronary intervention: a retrospective study. 10BMC Cardiovasc Disord. 2015 Feb 19;15 doi: 10.1186/s12872-015-0004-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B22] 22.. Skelding KA, Goldstein JA, Mehta L, Pica MC, O’Neill WW. Resolution of refractory no-reflow with intracoronary epinephrine. Catheter Cardiovasc Interv. 2002 Nov;57(3):305-9. [DOI] [PubMed]; Skelding KA, Goldstein JA, Mehta L, Pica MC, O’Neill WW. Resolution of refractory no-reflow with intracoronary epinephrine. Catheter Cardiovasc Interv. 2002 Nov;57(3):305–309. doi: 10.1002/ccd.10303. [DOI] [PubMed] [Google Scholar]

[B23] 23.. Capodanno D, Dipasqua F, Marcantoni C, Ministeri M, Zanoli L, Rastelli S, et al. EuroSCORE II versus additive and logistic EuroSCORE in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2013 Aug 1;112(3):323-9. [DOI] [PubMed]; Capodanno D, Dipasqua F, Marcantoni C, Ministeri M, Zanoli L, Rastelli S, et al. EuroSCORE II versus additive and logistic EuroSCORE in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2013 Aug 1;112(3):323–329. doi: 10.1016/j.amjcard.2013.03.032. [DOI] [PubMed] [Google Scholar]

[B24] 24.. Gul I, Zungur M, Aykan A, Islamli A, Yildiz B, Bilgin M. Importance of EuroSCORE-II in the Development of Acute Ischemic Heart Failure After Acute Anterior ST Elevation Myocardial Infarction. Koşuyolu Heart Journal. 2016; 19(2): 71-65.; Gul I, Zungur M, Aykan A, Islamli A, Yildiz B, Bilgin M. Importance of EuroSCORE-II in the Development of Acute Ischemic Heart Failure After Acute Anterior ST Elevation Myocardial Infarction. Koşuyolu Heart Journal. 2016;19(2):71–65. [Google Scholar]

[B25] 25.. Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol. 2004 Mar;286(3):F552-63. [DOI] [PubMed]; Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol. 2004 Mar;286(3):F552–F563. doi: 10.1152/ajprenal.00285.2002. [DOI] [PubMed] [Google Scholar]

PERMALINK

Desfechos em Pacientes com Fenômeno de No-Reflow Coronário e a Relação entre a Molécula-1 de Lesão Renal e o Fenômeno de No-Reflow Coronário

Mustafa Ahmet Huyut

Aylin Hatice Yamac

Resumo

Fundamento

Objetivo

Métodos

Resultados

Conclusão

Introdução

Métodos

Análises bioquímicas

Diagnóstico de infarto agudo do miocárdio com elevação do segmento ST

Fatores de risco cardiovascular

Angiografia coronária

Ecocardiografia transtorácica

Seguimento

Análise estatística

Resultados

Tabela 1. – Características basais e medicamentos dos pacientes.

Tabela 2. – Características laboratoriais basais dos pacientes.

Tabela 3. – Achados do seguimento clínico.

Figura 1. – Curva de Kaplan-Meier para AVC.

Figura 2. – Curva de Kaplan-Meier para ECAM.

Tabela 4. – Correlações entre EuroSCORE II com parâmetros clínicos.

Tabela 5. – Preditores independentes de CNP em IAMCSST.

Figura 3. – Curva de análise ROC para a especificidade e sensibilidade da KIM-1 sérica.

Discussão

Limitações

Conclusão

Agradecimento

Funding Statement

Referências

Outcomes in Coronary No-Reflow Phenomenon Patients and the Relationship between Kidney Injury Molecule-1 and Coronary No-Reflow Phenomenon

Mustafa Ahmet Huyut

Aylin Hatice Yamac

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Methods

Biochemical analyses

Diagnosis of acute ST-segment elevation myocardial infarction

Cardiovascular risk factors

Coronary angiography

Transthoracic echocardiography

Follow-up

Statistical analysis

Results

Table 1. – Baseline characteristics and medications of the patients.

Table 2. – Baseline laboratory characteristics of the patients.

Table 3. – Clinical follow-up findings.

Figure 1. – Kaplan-Meier curve for Stroke.

Figure 2. – Kaplan-Meier curve for MACE.

Table 4. – Correlations between EuroSCORE II with clinical parameters.

Table 5. – Independent predictors of CNP in STEMI.

Figure 3. – ROC analysis curve for the specificity and sensitivity of serum KIM-1.

Discussion

Limitations

Conclusion

Acknowledgment

ACTIONS

PERMALINK

RESOURCES

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