Níveis Elevados de Netrina-1 e IL-1β em Mulheres Idosas com SCA: Pior Prognóstico no Acompanhamento de Dois Anos

Paola Leocádio; Penélope Menta; Melissa Dias; Júlia Fraga; Alessandra Goulart; Itamar Santos; Paulo Lotufo; Isabela Bensenor; Jacqueline Alvarez-Leite

doi:10.36660/abc.20190035

. 2020 Apr 6;114(3):507–514. [Article in Portuguese] doi: 10.36660/abc.20190035

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Níveis Elevados de Netrina-1 e IL-1β em Mulheres Idosas com SCA: Pior Prognóstico no Acompanhamento de Dois Anos

Paola Leocádio ¹, Penélope Menta ¹, Melissa Dias ¹, Júlia Fraga ¹, Alessandra Goulart ², Itamar Santos ², Paulo Lotufo ^2,³, Isabela Bensenor ^2,³, Jacqueline Alvarez-Leite ¹

PMCID: PMC7792717 PMID: 32267322

Resumo

Fundamento

Vários marcadores têm sido avaliados quanto a um potencial impacto nas decisões clínicas ou na predição de mortalidade na síndrome coronariana aguda (SCA), incluindo Netrina-1 e IL-1β.

Objetivo

Examinamos o valor prognóstico de Netrina-1 e IL-1β em pacientes com SCA (2 anos de acompanhamento).

Métodos

Avaliamos Netrina-1, IL-1β e outros fatores de risco em amostras de soro de 803 pacientes. Curvas de Kaplan-Meier e regressão de Cox foram usadas para análise de óbito por todas as causas, óbito por doenças cardiovasculares (DCV) e desfecho combinado de infarto agudo do miocárdio (IAM) fatal ou novo IAM não fatal, considerando p < 0,05.

Resultados

Houve 115 óbitos por todas as causas, 78 óbitos por DCV e 67 eventos no desfecho combinado. Níveis de Netrina-1 acima da mediana (> 44,8 pg/mL) foram associados a pior prognóstico (óbito por todas as causas e por DCV) em mulheres idosas, mesmo após o ajuste do modelo (HR: 2,08, p = 0,038 e HR: 2,68, p = 0,036). Níveis de IL-1β acima da mediana (> 13,4 pg/mL) em mulheres idosas foram associados a risco aumentado para todos os desfechos após o ajuste (todas as causas - HR: 2,03, p = 0,031; DCV - HR: 3,01, p = 0,013; desfecho combinado - HR: 3,05, p = 0,029). Para homens, não foram observadas associações entre Netrina-1 ou IL-1β e os desfechos.

Conclusão

Níveis séricos elevados de Netrina-1 e IL-1β mostraram associação significativa com pior prognóstico em idosas do sexo feminino. Eles podem ser úteis como indicadores prognósticos em SCA. (Arq Bras Cardiol. 2020; 114(3):507-514)

Keywords: Síndrome Coronariana Aguda/fisiopatologia, Nitrina-1, Interleucina- 1 beta, Remodelamento Atrial, Hipertensão, Diabetes Mellitus, Dislipidemias, Acidente Vascular Cerebral, Idoso, Mulheres

Introdução

A doença arterial coronariana (DAC) é a principal causa de morte e anos de vida perdidos.¹ Responsável pelo maior número de óbitos no Brasil, a DAC tem alta prevalência e prognóstico desfavorável.² Apesar da redução na mortalidade por síndrome coronariana aguda (SCA) observada nas últimas décadas,¹ estima-se que aproximadamente 14% dos pacientes que tiveram infarto agudo do miocárdio (IAM) morrerão em decorrência do mesmo.³ O risco de doença e morte é 1,5 a 15 vezes maior para pacientes que sobrevivem ao estágio agudo do IAM do que para a população geral.³ Daqueles que têm um primeiro IAM, aproximadamente 17% dos homens e 21% das mulheres com ≥ 45 anos terão um IAM recorrente ou DAC fatal dentro de cinco anos.³

A inflamação é um fator importante na fisiopatologia da SCA, bem como na remodelação cardíaca após IAM. Diversos marcadores foram avaliados quanto a um impacto potencial nas decisões clínicas ou na predição da mortalidade.⁴ Recentemente, moléculas de orientação neuronal, especialmente Netrina-1, foram identificadas como importantes moduladoras da aterosclerose, embora seu papel específico (protetor ou deletério) ainda seja controverso.^5-7 A Netrina-1 faz parte de uma família de proteínas estruturalmente semelhantes às lamininas, que são componentes estruturais da membrana basal dos tecidos.⁸ O papel da Netrina-1 na doença cardiovascular (DCV) e na inflamação é uma área emergente de estudo.⁵

A interleucina-1 (IL-1) é um dos principais mediadores da coagulação induzida pela inflamação.⁹ A IL-1β é capaz de induzir a expressão de outras moléculas que favorecem o recrutamento de células inflamatórias para a lesão e injúria tecidual.¹⁰ Níveis elevados de IL-1 foram descritos no IAM.^11,12 Recentemente, um ensaio clínico randomizado entre pessoas que sofreram um infarto do miocárdio mostrou que o canakinumab, um agente que bloqueia a IL-1β, reduziu a incidência de doença coronariana não fatal, eventos de acidente vascular cerebral não fatal e morte por DCV.¹³

Apesar da importância dessas duas moléculas na SCA, estudos avaliando o valor prognóstico das mesmas são escassos. Nosso objetivo foi avaliar o papel dessas moléculas como preditores de prognóstico em um acompanhamento de 2 anos.

Métodos

Desenho experimental

Os participantes fazem parte do estudo “ERICO” (Estratégia de Registro de Insuficiência Coronariana), descrito detalhadamente em trabalhos anteriores.^14,15 Resumidamente, trata-se de um estudo de coorte prospectivo que incluiu indivíduos internados para tratamento de SCA no Hospital Universitário da Universidade de São Paulo (HU-USP), hospital de ensino com 260 leitos localizado no Butantã, São Paulo, Brasil, de fevereiro de 2009 a dezembro de 2013. O protocolo do estudo está de acordo com a Declaração de Helsinque. Este estudo foi aprovado pelo Comitê de Ética em Pesquisa (CEP-HU/USP 866/08) e todos os pacientes assinaram o Termo de Consentimento Livre e Esclarecido.

O IAM foi definido pela presença de sintomas compatíveis com isquemia miocárdica dentro de 24 horas da admissão hospitalar e nível de troponina I acima do valor do percentil 99 com um coeficiente de variação <10%. O infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCSST) foi definido pelos critérios de IAM, além de: (a) a presença de supradesnivelamento do segmento ST persistente ≥1 mm em dois eletrocardiogramas contíguos (ECG de eletrodo) ou (b) novo (ou supostamente novo) bloqueio de ramo esquerdo (BRE). O infarto agudo do miocárdio sem supradesnivelamento do segmento ST (IAMSSST) foi definido pelos critérios para IAM mais ausência de supradesnivelamento do segmento ST persistente ≥ 1 mm em dois ECGs contíguos e de novo ou supostamente novo BRE. A angina instável (AI) foi definida como a presença de sintomas compatíveis com isquemia miocárdica nas últimas 24 horas, ausência de diagnóstico de IAM e pelo menos um dos cinco critérios a seguir: (a) história prévia de DAC; (b) estratificação positiva de doença isquêmica invasiva ou não invasiva do coração; (c) alterações dinâmicas ou evolutivas do ECG; (D) troponina I > 0,4 ng/mL (assegurando níveis de troponina I acima do percentil 99, independentemente do kit utilizado) ou (e) concordância no diagnóstico de AI entre dois médicos independentes.

Coleta de dados e desfechos

Após seis meses e anualmente por dois anos após a admissão hospitalar, todos os indivíduos foram contatados por telefone para atualizar as informações do estado vital, incluindo desfechos cardiovasculares fatais e não fatais. Sempre que um participante relatou um possível novo evento de IAM, novos procedimentos de investigação foram iniciados para confirmar o evento.

Os desfechos avaliados foram: óbito por todas as causas, óbito por DCV e o desfecho combinado (IAM fatal ou novo IAM não fatal). A estratégia para coletar e classificar os dados de mortalidade, incluindo a busca por registros oficiais de óbitos, foi detalhada em estudo anterior.¹⁵ Nos casos em que não foi possível determinar a causa da morte, os dados foram censurados para todos os desfechos, com exceção da morte por todas as causas.

Durante a fase hospitalar, entrevistadores treinados coletaram dados relacionados às características sociodemográficas, fatores de risco cardiovascular e medicação, conforme descrito anteriormente.¹⁵ Amostras de sangue foram coletadas dentro de 24 horas da admissão. Análises de glicose plasmática, triglicérides, colesterol total e HDL foram realizadas no HU-USP. O colesterol LDL foi calculado pela equação de Friedewald.¹⁶ As concentrações de Netrina-1 e IL-1β na admissão foram avaliadas por Enzyme-Linked Immunosorbent Assay (ELISA), seguindo as instruções do kit (Netrina-1: SEB827HU; USCN Life Science Inc., Wuhan, China e IL-1β: 88- 7010-88 eBioscience Inc., San Diego, CA, EUA). Os pacientes foram classificados de acordo com as concentrações de Netrina-1 e IL-1β nos grupos “baixa” e “alta”, se sua concentração estivesse abaixo ou acima da mediana.

Análise estatística

Os dados foram avaliados quanto à normalidade usando o teste de Kolmogorov-Smirnov. Os testes qui-quadrado e Mann-Whitney (todas as variáveis contínuas apresentaram distribuição não-paramétrica) foram utilizados para comparar os grupos. Os valores foram expressos como mediana (intervalo interquartil) ou n (%). Curvas de Kaplan-Meier foram utilizadas, e o teste log-rank foi utilizado para avaliar a diferença entre os grupos. As estimativas de risco (razões de risco com seus respectivos intervalos de confiança de 95%) para os eventos foram calculadas usando regressão de Cox. Além de Netrina-1 e IL-1β, as seguintes variáveis foram usadas para construir modelos: idade, tipo de SCA, diabetes, hipertensão e dislipidemia. Um valor de p < 0,05 foi considerado significativo.

Os programas SPSS (IBM SPSS Statistics para Windows, versão 22.0, Armonk, NY: IBM Corp.) e GraphPad Prism (versão 5.01 para Windows, San Diego, Califórnia: GraphPad Software) foram usados para realizar as análises.

Resultados

Um total de 803 pacientes foram incluídos neste estudo, incluindo 333 mulheres e 470 homens. Comparando as principais características dos grupos de homens e mulheres, observamos que as mulheres eram mais velhas e apresentavam maior concentração de HDL que os homens. As mulheres também foram mais afetadas pela hipertensão, diabetes e dislipidemia (Tabela 1). O tipo mais frequente de SCA entre os grupos foi o IAMSSST (cerca de 40% dos casos), seguido por AI e IAMCSST, que tiveram frequência semelhante (cerca de 30% cada).

Tabela 1. – Características gerais na fase hospitalar em homens e mulheres.

Parâmetro	Homens (n = 470)	Mulheres (n = 333)	p
Idade	60 (52 – 71)	65 (56 – 76)	< 0,0001
IMC	26,8 (23,8 – 29,6)	26,8 (24,0 – 30,9)	0,128
Tipo SCA			0,027
IAMSSST	191 (40,6)	142 (42,6)
IAMCSST	147 (31,3)	77 (23,1)
AI	132 (28,1)	114 (34,2)
Tabagismo
Atual	141 (31,3)	85 (27,2)	< 0,0001
Passado	198 (43,9)	82 (26,3)
Nunca	112 (24,8)	145 (46,5)
Hipertensão	339 (73,7)	267 (80,9)	0,018
Diabetes	156 (34,7)	148 (45,0)	0,004
Dislipidemia	197 (48,0)	181 (60,7)	0,001
Glicose	125,0 (101,0 – 157,0)	124,0 (103,0 – 175,0)	0,652
Triglicerídeos	132,0 (94,0 – 190,3)	126,0 (97,0 – 183,0)	0,685
Colesterol total	171,5 (141,0 – 205,0)	170,0 (139,0 – 204,0)	0,720
Colesterol HDL	35,0 (30,0 – 44,0)	39,0 (32,0 – 46,5)	< 0,0001
Colesterol LDL	102,5 (77,0 – 134,3)	99,0 (77,0 – 124,3)	0,386
Netrina-1	44,8 (34,2 – 65,8)	44,8 (34,8 – 62,8)	0,813
IL-1β	15,1 (7,4 - 28,8)	13,8 (7,1 – 29,7)	0,536

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Mediana (intervalo interquartil) ou n (%). AI: angina instável. HDL: lipoproteína de alta densidade. IAMCSST: infarto do miocárdio com supradesnivealmento do segmento ST. IAMSSST: infarto do miocárdio sem supradesnivealmento do segmento ST. IL-1β: interleucina - 1beta. IMC: índice de massa corporal em kg/m². LDL: lipoproteína de baixa densidade. SCA: síndrome coronariana aguda. Dados de glicose plasmática, triglicerídeos, colesterol total, HDL e LDL são apresentados em mg/dL. Netrina-1 e IL-1β são apresentados em pg/mL. Teste de Mann-Whitney ou teste de qui-quadrado. p-valor comparando homens e mulheres.

Durante os dois anos de acompanhamento, houve 115 mortes por todas as causas (65 homens e 50 mulheres), incluindo 78 mortes (67,8%) por causas cardiovasculares. Também identificamos 67 casos de IAM (fatal ou não fatal) neste mesmo seguimento. Como a idade é um fator importante envolvido na taxa de mortalidade, analisamos separadamente em mulheres e homens jovens e com mais de 60 anos.

Para avaliar um possível papel de Netrina-1 e IL-1β como marcadores prognósticos, comparamos a frequência de SCA nos pacientes com níveis de Netrina-1 e IL-1β acima e abaixo da respectiva mediana. Não houve associações entre os níveis de Netrina-1 e IL-1β e todos os desfechos para homens independentemente de sua idade (dados não mostrados). Por esse motivo, focamos nossa investigação no grupo de mulheres (333 pacientes). As principais características do grupo de mulheres (jovens e idosas) são mostradas na Tabela 2.

Tabela 2. – Características gerais na fase hospitalar em mulheres jovens (< 60 anos) e idosas (> 60 anos).

Parâmetro	Total (n = 333)	Jovens (< 60 anos) (n = 111)	Idosas (> 60 anos) (n = 222)	p
IMC	26,8 (24,0 – 30,9)	26,8 (24,5 - 31,1)	26,7 (23,8 – 30,8)	0,532
Tipo SCA				0,031
IAMSSST	142 (42,6)	40 (36,0)	102 (45,9)
IAMCSST	77 (23,1)	35 (31,5)	42 (18,9)
AI	114 (34,2)	36 (32,4)	78 (35,1)
Tabagismo				< 0,0001
Atual	85 (27,2)	47 (44,3)	38 (18,4)
Passado	82 (26,3)	28 (26,4)	54 (26,2)
Nunca	145 (46,5)	31 (29,2)	114 (55,3)
Hipertensão	267 (80,9)	79 (72,5)	188 (85,1)	0,006
Diabetes	148 (45,0)	39 (35,8)	109 (49,5)	0,018
Dislipidemia	181 (60,7)	48 (48,5)	133 (66,8)	0,002
Glicose	124,0 (103,0 – 175,0)	121,0 (103,0 – 163,0)	128,0 (104,0 – 180,0)	0,381
Triglicerídeos	126,0 (97,0 – 183,0)	151,0 (97,0 – 201,0)	122,0 (93,5 – 174,0)	0,080
Colesterol total	170,0 (139,0 – 204,0)	185,0 (157,5 – 215,3)	161,0 (134,0 – 196,0)	0,002
Colesterol HDL	39,0 (32,0 – 46,5)	36,0 (32,0 – 45,0)	41,0 (33,0 – 47,2)	0,065
Colesterol LDL	99,0 (77,0 – 124,3)	114,0 (89,0 – 134,0)	93,0 (72,0 – 118,0)	0,0004
Netrina-1	44,8 (34,8 – 62,8)	44,8 (33,8 – 65,8)	44,8 (34,7 – 65,0)	0,861
IL-1β	13,8 (7,1 – 29,7)	15,5 (7,9 – 49,7)	13,4 (7,1 – 24,1)	0,037

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Na admissão, as mulheres apresentaram valores semelhantes de índice de massa corporal, concentrações séricas de glicose, triglicerídeos e colesterol HDL, independentemente do grupo etário. A frequência de fatores de risco como hipertensão, dislipidemia e diabetes foi maior em mulheres idosas. No entanto, os níveis de colesterol LDL foram menores nas idosas. Fumantes atuais foram mais frequentes em mulheres jovens, enquanto mais de 50% das mulheres idosas nunca fumou (Tabela 2). Não encontramos diferenças na mediana de Netrina-1 entre os grupos etários. No entanto, a mediana de IL-1β foi maior no grupo mais jovem.

As associações entre Netrina-1 ou IL1-β baixa e alta e os desfechos, de acordo com a faixa etária, foram apresentadas na Tabela 3 e na Tabela 4, respectivamente. O número de mortes por todas as causas foi muito baixo (3 mortes) nas mulheres com menos de 60 anos e apenas 6 casos do desfecho combinado, dificultando análises confiáveis neste grupo. No entanto, no grupo mais velho (> 60 anos), encontramos associações entre níveis elevados de Netrina-1 e mortes por todas as causas e causas cardiovasculares. Uma associação entre IL-1β alta e morte por DCV também foi encontrada entre as mulheres idosas (p = 0,034).

Tabela 3. – Desfechos de acordo com os níveis de Netrina-1 em mulheres.

	Mulheres - Total			< 60 anos			> 60 anos
Acompanhamento de 2 anos	Netrina-1 baixa	Netrina-1 alta	p	Netrina-1 baixa	Netrina-1 alta	p	Netrina-1 baixa	Netrina-1 alta	p
Óbito por todas as causas	18 (36,0)	32 (64,0)	0,021	2 (66,7)	1 (33,3)	0,612	16 (34,0)	31 (66,0)	0,011
Óbito por DCV	12 (35,3)	22 (64,7)	0,052	2 (66,7)	1 (33,3)	0,612	10 (32,3)	21 (67,7)	0,029
IAM fatal ou novo IAM não fatal	11 (39,3)	17 (60,7)	0,193	4 (66,7)	2 (33,3)	0,467	7 (31,8)	15 (68,2)	0,066

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n (%). DCV: doenças cardiovasculares. IAM: infarto agudo do miocárdio. Teste do qui-quadrado.

Tabela 4. – Desfechos de acordo com os níveis de IL-1β em mulheres.

	Mulheres - Total			< 60 anos			> 60 anos
Acompanhamento de 2 anos	IL-1β baixa	IL-1β alta	p	IL-1β baixa	IL-1β alta	p	IL-1β baixa	IL-1β alta	p
Óbito por todas as causas	21 (42,0)	29 (58,0)	0,221	0 (0,0)	3 (100,0)	0,118	19 (40,4)	28 (59,6)	0,140
Óbito por DCV	12 (35,3)	22 (64,7)	0,071	0 (0,0)	3 (100,0)	0,118	10 (32,3)	21 (67,7)	0,034
IAM fatal ou novo IAM não fatal	10 (35,7)	18 (64,3)	0,117	2 (33,3)	4 (66,7)	0,438	7 (31,8)	15 (68,2)	0,075

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n (%). DCV: doenças cardiovasculares. IAM: infarto agudo do miocárdio. IL-1β: Interleucina - 1beta. Teste do qui-quadrado.

Os dados mostrando um pior prognóstico em mulheres idosas com níveis elevados de Netrina-1 e IL-1β foram confirmados pelas curvas de Kaplan-Meier. Níveis elevados de Netrina-1 resultaram em uma menor taxa de sobrevivência quando se considera a mortalidade por todas as causas (p = 0,011, Figura 1A) e também considerando apenas mortes por DCV (p = 0,024, Figura 1B). Houve tendência de associação a IAM fatal ou novo IAM não fatal (p = 0,067, Figura 1C). Níveis elevados de IL-1β também mostraram uma menor taxa de sobrevivência quando consideradas mortes por DCV (p = 0,031, Figura 1E), com tendência a associação com o desfecho combinado (p = 0,064, Figura 1F).

A análise das razões de risco (Tabela 5) mostrou um aumento no risco de morte por todas as causas para o grupo Netrina-1 alta, que permaneceu significativo no modelo ajustado. Os mesmos resultados foram observados para o risco de morte por DCV.

Tabela 5. – Razão de risco (HR) para os níveis de Netrina-1 e IL-1β e óbito por todas as causas, óbito por doenças cardiovasculares e desfecho combinado de IAM fatal ou novo IAM não fatal em mulheres idosas (> 60 anos).

	Óbito por todas as causas		Óbito por DCV		IAM fatal ou novo IAM não fatal
	HR (IC 95%)	p	HR (IC 95%)	p	HR (IC 95%)	p
	Netrina-1
Crua	2,15 (1,17 – 3,93)	0,013	2,31 (1,09 – 4,92)	0,029	2,25 (0,92 – 5,54)	0,075
Ajustada *	2,08 (1,04 – 4,16)	0,038	2,68 (1,06 – 6,74)	0,036	1,82 (0,65 – 5,07)	0,247
	IL-1β
Crua	1,57 (0,87 – 2,81)	0,127	2,23 (1,05 – 4,75)	0,036	2,27 (0,92 – 5,58)	0,073
Ajustada *	2,03 (1,06 – 3,89)	0,031	3,01 (1,26 – 7,17)	0,013	3,05 (1,12 – 8,32)	0,029

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HR: razão de risco. IAM: infarto agudo do miocárdio. IC: intervalo de confiança. IL-1β: Interleucina - 1beta. * Ajustado por idade, tipo de síndrome coronariana aguda, diabetes, hipertensão e dislipidemia.

Considerando os níveis elevados de IL-1β, não encontramos HR significativa no modelo cru para mortalidade por todas as causas e para o desfecho combinado (Tabela 5). No entanto, foi observada HR significativa para mortalidade por todas as causas e desfecho combinado no modelo ajustado. Observamos também um risco aumentado de morte por causas cardiovasculares para o grupo IL-1β alta, mesmo após o ajuste do modelo.

Discussão

Este trabalho é pioneiro na avaliação do valor prognóstico da Netrina-1 na SCA e apresenta novas informações sobre o valor prognóstico da IL-1β nessa condição.

Em nosso estudo, observamos uma associação entre níveis elevados de Netrina-1 e pior prognóstico quando foram analisados óbito por todas as causas e por DCV em mulheres idosas.

A Netrina-1 plasmática é um biomarcador diagnóstico de muitos tipos de câncer.^17-19 Verificou-se que a maior expressão gênica ou concentração de Netrina-1 nesses tecidos é associada a um pior prognóstico, provavelmente relacionado aos efeitos antiapoptóticos e angiogênicos da molécula. No entanto, o papel da Netrina-1 na aterosclerose e na remodelação cardíaca após o IAM ainda é controverso. Foi descrito que Netrina-1 poderia promover ou proteger contra a aterosclerose, dependendo das condições ambientais.²⁰ Níveis endógenos reduzidos de Netrina-1 também podem levar a efeitos deletérios, uma vez que fatores pró-aterogênicos podem reduzir a expressão dessa molécula.²⁰ Em modelos de IAM, a administração de netrina-1 reduziu a gravidade da lesão miocárdica quando comparada aos controles não suplementados.^21,22

Em nosso estudo, é possível que o grupo “Netrina-1 alta" seja composto por pacientes que tiveram um evento mais grave de SCA. Nossa hipótese é que o nível de Netrina-1 aumenta em casos mais graves de SCA. Esta hipótese baseia-se em estudos que indicam que a expressão de Netrina-1 é induzida após lesão celular e pode ser usada como um biomarcador para danos ou doenças de órgãos,²³ como visto na cirurgia cardíaca.²⁴ Além disso, a hipóxia, uma condição intimamente ligada à aterosclerose e à SCA, também é um indutor da expressão da Netrina-1.²⁵ Ainda, Van Gils et al.⁶ observaram aumento da expressão da molécula em macrófagos carregados de colesterol promovendo a retenção dessas células in vitro, o que poderia contribuir para uma evolução mais rápida da placa aterosclerótica e, consequentemente, aumentar a chance de formação de trombo e ocorrência de infarto.

Esses fatores nos levam a acreditar que o maior número de desfechos desfavoráveis, bem como o maior risco de morte por todas as causas e por DCV observados em mulheres idosas com níveis mais elevados de Netrina-1 estão associados à gravidade do evento e ao maior grau de inflamação (como sugerido pelos altos níveis de IL-1β) que podem ter contribuído para um pior prognóstico.

Em relação a IL-1β, níveis elevados desta e de outras citocinas pró-inflamatórias já foram identificados em pacientes com SCA.²⁶ No entanto, poucos estudos foram direcionados ao valor prognóstico dessa citocina.^27,28 Corroborando nossos resultados, esses estudos sugerem que níveis mais altos de IL-1β foram observados em pacientes com SCA que sofreram novos eventos durante o acompanhamento.

A IL-1β é capaz de aumentar a expressão de moléculas que contribuem para a ruptura da placa e formação de trombos, culminando na ocorrência de SCA.^10,29 Assim, níveis mais elevados de IL-1β sérica poderiam refletir inflamação exacerbada, favorecendo a ocorrência de complicações cardiovasculares.

Níveis mais altos de IL-1β sugerem uma inflamação exacerbada que pode prejudicar o remodelamento cardíaco. A remodelação adversa após o IAM é a base estrutural da insuficiência cardíaca isquêmica. Embora quantidades adequadas de IL-1β e outras citocinas inflamatórias sejam essenciais na fase inicial do remodelamento, a diminuição dos níveis de citocinas é necessária para promover uma cicatrização efetiva.³⁰ Foi descrito que níveis elevados de IL-1β até dois meses após o infarto em pacientes com IAMCSST estavam fortemente associados à piora da função cardíaca após um ano de acompanhamento.³¹ Além disso, a citocina foi um forte preditor de hipertrofia ventricular esquerda, importante na predição da morbidade e mortalidade cardiovascular.³¹

Vários fatores podem ajudar a entender a ausência de associação com pior prognóstico encontrada em homens e mulheres mais jovens. Os tecidos cardíacos e vasculares são influenciados por hormônios como estrógeno e testosterona, variando de acordo com sexo e idade.^32,33 Mulheres mais velhas têm maior massa do ventrículo esquerdo do que homens, devido a fatores que indicam menor capacidade arterial, como redução da espessura da parede da carotída.³³

A relação entre citocinas inflamatórias e gênero ainda não foi elucidada, embora diferenças na concentração sejam observadas na literatura.³² Estudos indicam que a concentração de IL-β é maior no sexo masculino.^33,34 Além disso, níveis de citocinas estão inversamente relacionados à idade, como visto em nosso trabalho e na literatura.³⁵ A literatura não fornece dados sobre diferenças de sexo para Netrina-1. Como não observamos diferenças estatísticas entre os sexos nos níveis dos marcadores, nossa hipótese é de que no sexo feminino os níveis destes eram mais altos que os normais. Esse possível aumento pode estar relacionado à maior frequência de fatores de risco cardiovasculares neste grupo no presente estudo, fatores que podem levar a um aumento dos níveis de marcadores inflamatórios.³⁶ No entanto, mesmo após o ajuste desses fatores, níveis elevados de Netrina 1 e IL-1β permaneceram associados a pior prognóstico, demonstrando que esses marcadores inflamatórios estão independentemente associados a pior prognóstico e podem estar relacionados à redução da capacidade arterial já observada em mulheres idosas, quando comparados aos homens.

Apontamos como limitações do estudo sua característica unicêntrica e a ausência de um grupo controle. Ainda, não coletamos dados do período pré-evento, o que nos permitiria determinar a variação na concentração do marcador após a SCA.

Conclusão

Níveis elevados de Netrina-1 e IL-1β estão associados a pior prognóstico em mulheres idosas com SCA. O mecanismo para tal associação pode estar relacionado à manutenção da inflamação e remodelação cardíaca adversa, propiciando novos eventos cardiovasculares.

Vinculação acadêmica

Este artigo é parte de tese de Doutorado de Paola Leocádio pela Universidade Federal do Minas Gerais.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética do Hospital Universitário - USP sob o número de protocolo CEP-HU/USP 866/08. 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 financiado pela Fundação de Amparo à Pesquisa do Estado de São Paulo e Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

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Arq Bras Cardiol. 2020 Apr 6;114(3):507–514. [Article in English]

High Serum Netrin-1 and IL-1β in Elderly Females with ACS: Worse Prognosis in 2-years Follow-up

Paola Leocádio ¹, Penélope Menta ¹, Melissa Dias ¹, Júlia Fraga ¹, Alessandra Goulart ², Itamar Santos ², Paulo Lotufo ^2,³, Isabela Bensenor ^2,³, Jacqueline Alvarez-Leite ¹

Abstract

Background

Several markers have been evaluated for a potential impact on clinical decisions or mortality prediction in acute coronary syndrome (ACS), including Netrin-1 and IL-1β that have been associated with cardiovascular disease.

Objective

Our study examined the prognostic value of Netrin-1 and IL-1β in patients with ACS (2-year follow-up).

Methods

We evaluate Netrin-1, IL-1β and other risk factors in the serum sample of 803 patients. Kaplan-Meier curves and Cox regression were used for the analysis of all-cause mortality, cardiovascular mortality, and a combined outcome of fatal myocardial infarction (MI) or new non-fatal MI, considering p-value < 0.05.

Results

There were 115 deaths from all causes, 78 deaths due to cardiovascular causes and 67 events in combined outcomes. Netrin-1 levels above the median (>44.8 pg/mL) were associated with a worse prognosis (all-cause mortality and cardiovascular mortality) in elderly females, even after model adjustment (HR: 2.08, p = 0.038 and HR: 2.68, p = 0.036). IL-1β levels above the median (>13.4 pg/mL) in elderly females were associated with increased risk of all outcomes after adjustment (all-cause mortality - HR: 2.03, p = 0.031; cardiovascular mortality - HR: 3.01, p = 0.013; fatal MI or new non-fatal MI - HR: 3.05, p = 0.029). For males, no associations were observed between Netrin-1 or IL-1β and outcomes.

Conclusion

High serum levels of Netrin-1 and IL-1β showed significant association with worse prognosis in elderly females. They may be useful as prognostic indicators in ACS. (Arq Bras Cardiol. 2020; 114(3):507-514)

Keywords: Acute Coronary Syndrome/physiopathology, Netrin-1, Interleukin-1 beta, Atrial Remodeling, Hypertension, Diabetes Mellitus, Dyslipidemias, Stroke, Aged, Women

Introduction

Coronary heart disease (CHD) is the leading cause of death and years of life lost.¹ Responsible for the largest number of deaths in Brazil, CHD has high prevalence and a poor prognosis.² Despite the reduction in acute coronary syndrome (ACS) mortality observed in recent decades,¹ it is estimated that near 14% of patients who have had a myocardial infarction (MI) will die of it.³ The risk of illness and death is 1.5 to 15 times higher for patients who survive the acute stage of MI than for the general population.³ Of those who have a first MI, approximately 17% of males and 21% of females at ≥ 45 years will have a recurrent MI or fatal CHD within five years.³

Inflammation is an important factor in the pathophysiology of ACS as well as in the cardiac remodeling after AMI. Several markers have been evaluated for a potential impact on clinical decisions or mortality prediction.⁴ Recently, neuronal guidance molecules, especially Netrin-1, have been identified as important modulators of atherosclerosis, although their specific role (protective or deleterious) is still controversial.^5-7 Netrin-1 is a member of a family of proteins structurally similar to laminins, which are structural components of the basal membrane of tissues.⁸ The role of Netrin-1 in cardiovascular disease and inflammation is an emerging area of study.⁵

Interleukin-1 (IL-1) is one of the major mediators of inflammation-induced coagulation.⁹ IL-1β is capable of inducing the expression of other molecules that favor the recruitment of inflammatory cells to the lesion and tissue injury.¹⁰ A high level of IL-1 has been described in MI.^11,12 Recently, a randomized clinical trial among people who suffered a MI showed that canakinumab, an agent that block IL-1β reduced the incidence of non-fatal CHD, non-fatal stroke events and cardiovascular death.¹³

Despite the importance of these two molecules in ACS, studies evaluating their prognostic value are scarce. Our objective was to evaluate the role of these molecules as predictors of prognosis in a 2-year follow-up.

Methods

Study design

The patients were participants of the “ERICO” (Strategy of Registry of Acute Coronary Syndrome) study, described in detail in previous reports.^14,15 Briefly, it is a prospective cohort study that included individuals admitted to treatment for ACS at the University of São Paulo Hospital (HU-USP), a teaching community hospital with 260 beds located in the District of Butantan, São Paulo, Brazil, from February 2009 to December 2013. The study protocol was in accordance with the Declaration of Helsinki. This study was approved by the Research Ethics Committee (CEP-HU/USP 866/08), and all patients signed the Informed Consent Form.

Acute myocardial infarction (AMI) was defined by the presence of symptoms consistent with myocardial ischemia within 24 hours of hospital admission and troponin I level above the 99th percentile value with a coefficient of variation <10%. ST-segment elevation myocardial infarction (STEMI) was defined by the criteria for AMI, in addition to (a) the presence of persistent ST-segment elevation ≥1 mm in two contiguous electrocardiographic leads (lead ECG) or (b) new (or supposedly new) left bundle branch block (LBBB). Non-ST-segment elevation myocardial infarction (NSTEMI) was defined by the criteria for AMI plus the absence of persistent ST-segment elevation ≥1 mm in two contiguous ECG leads and of new or supposedly new LBBB. Unstable angina (UA) was defined as the presence of symptoms compatible with myocardial ischemia in the last 24 hours, absence of AMI diagnosis and at least one of the following five criteria: (a) history of previous coronary artery disease; (b) positive stratification of invasive or non-invasive ischemic heart disease; (c) dynamic or evolutionary ECG changes; (D) troponin I >0.4 ng/mL (ensuring troponin I levels above the 99th percentile regardless of the utilized kit) or (e) agreement on UA diagnosis between two independent physicians.

Data collection and outcomes

After 6 months and annually for 2 years after the hospital admission, all individuals were contacted by telephone to update vital status information, including fatal and nonfatal cardiovascular outcomes. Whenever a participant reported a potential new MI event, new investigation procedures were initiated to confirm the event.

Study outcomes were all-cause mortality, cardiovascular mortality, and the combined outcome (fatal AMI and new non-fatal AMI). The strategy for collecting and classifying mortality data, including searching for official death records, was detailed in a previous report.¹⁵ In cases where it was not possible to determine the cause of death, the data were censored for all outcomes, except for death from all causes.

During the hospital phase, trained interviewers collected data related to sociodemographic characteristics, cardiovascular risk factors, and medication, as previously described.¹⁵ Blood samples were collected within 24 hours of admission. Analyses of plasma glucose, triglycerides, and total and HDL cholesterol were performed at HU-USP. LDL cholesterol was calculated using the Friedewald equation.¹⁶ Concentrations of Netrin-1 and IL-1β on admission were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA), following the kit instructions (Netrin-1: SEB827HU; USCN Life Science Inc., Wuhan, China and IL-1β: 88-7010-88 eBioscience Inc., San Diego, CA, USA). Patients were classified according to Netrin-1 and IL-1β concentrations in “low” and “high” groups if their concentration were below or above the median.

Statistical analysis

Data were assessed for normality using the Kolmogorov-Smirnov test. The chi-square and Mann-Whitney (all continuous variables presented nonparametric distribution) tests were used to compare groups. Values were expressed as median (interquartile interval) or n (%). Kaplan-Meier curves were used, and the log-rank test was used to evaluate the difference between low and high groups. Risk estimates (hazard ratios with their respective 95% confidence intervals) for the events were calculated using Cox regression. In addition to Netrin-1 and IL-1β, the following variables were used to construct models: age, type of ACS, diabetes, hypertension, and dyslipidemia. A two-tailed p-value < 0.05 was considered significant.

The software programs SPSS (IBM SPSS Statistics for Windows, version 22.0, Armonk, NY: IBM Corp.) and GraphPad Prism (version 5.01 for Windows, San Diego, California: GraphPad Software) were used to carry out the analyses.

Results

A total of 803 patients were included in this study, including 333 women and 470 men. Comparing the main characteristics of male and female groups, we observed that women were older and had higher HDL-c concentration than men. Women were also more frequently affected by hypertension, diabetes, and dyslipidemia (Table 1). The most frequent type of ACS in male and female groups was NSTEMI (about 40% of cases) followed by UA and STEMI that had a similar frequency (about 30% each).

Table 1. – General characteristics in the hospital phase in males and females.

Parameter	Male (n = 470)	Female (n = 333)	p
Age	60 (52 – 71)	65 (56 – 76)	< 0.0001
BMI	26.8 (23.8 – 29.6)	26.8 (24.0 – 30.9)	0.128
ACS type			0.027
NSTEMI	191 (40.6)	142 (42.6)
STEMI	147 (31.3)	77 (23.1)
UA	132 (28.1)	114 (34.2)
Smoking habits
Current	141 (31.3)	85 (27.2)	< 0.0001
Former	198 (43.9)	82 (26.3)
Never	112 (24.8)	145 (46.5)
Hypertension	339 (73.7)	267 (80.9)	0.018
Diabetes	156 (34.7)	148 (45.0)	0.004
Dyslipidemia	197 (48.0)	181 (60.7)	0.001
Glucose	125.0 (101.0 – 157.0)	124.0 (103.0 – 175.0)	0.652
Triacylglycerol	132.0 (94.0 – 190.3)	126.0 (97.0 – 183.0)	0.685
Total Cholesterol	171.5 (141.0 – 205.0)	170.0 (139.0 – 204.0)	0.720
HDL - Cholesterol	35.0 (30.0 – 44.0)	39.0 (32.0 – 46.5)	< 0.0001
LDL - Cholesterol	102.5 (77.0 – 134.3)	99.0 (77.0 – 124.3)	0.386
Netrin-1	44.8 (34.2 – 65.8)	44.8 (34.8 – 62.8)	0.813
IL-1β	15.1 (7.4 - 28.8)	13.8 (7.1 – 29.7)	0.536

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Values are median (interquartile interval) or n (%). ACS: acute coronary syndrome. BMI: body mass index in kg/m². HDL: high-density lipoprotein. LDL: low-density lipoprotein. NSTEMI: non-STsegment elevation Myocardial Infarction. STEMI: ST-segment elevation Myocardial Infarction. UA: unstable angina. Data of plasma glucose, triglyceridemia, total cholesterol, HDL and LDL are presented as mg/dL. Netrin-1 and IL-1β are presented as pg/mL. Mann-Whitney test or chi-square test. p-value comparing male and female groups.

During the 2 years follow up, there were 115 deaths from all causes (65 men and 50 women) including 78 deaths (67.8%) due to cardiovascular causes. We also identified 67 cases of AMI (fatal or non-fatal) in this same follow-up. Since age is an important factor involved in the mortality rate, we analyzed separately in women and men younger and older than 60 years.

To evaluate a possible role of Netrin-1 and IL-1β as prognostic markers, we compared the frequency of ACS in the patients with levels of Netrin-1 and IL-1β levels above and below the respective median. There were no associations between levels of Netrin-1 and IL-1β and all-cause mortality, cardiovascular mortality and fatal or new non-fatal MI outcomes for males independently of their age (data not shown). For this reason, we focused our investigation on the female group (333 patients). The main characteristics of the female group (younger and older than 60 years) are shown in Table 2.

Table 2. – General characteristics in the hospital phase in younger (<60 y) and older (>60 years) females.

Parameter	Total (n = 333)	Younger (<60 years) (n = 111)	Older (>60 years) (n = 222)	p
BMI	26.8 (24.0 – 30.9)	26.8 (24.5 - 31.1)	26.7 (23.8 – 30.8)	0.532
ACS type				0.031
NSTEMI	142 (42.6)	40 (36.0)	102 (45.9)
STEMI	77 (23.1)	35 (31.5)	42 (18.9)
UA	114 (34.2)	36 (32.4)	78 (35.1)
Smoking habits				< 0.0001
Current	85 (27.2)	47 (44.3)	38 (18.4)
Former	82 (26.3)	28 (26.4)	54 (26.2)
Never	145 (46.5)	31 (29.2)	114 (55.3)
Hypertension	267 (80.9)	79 (72.5)	188 (85.1)	0.006
Diabetes	148 (45.0)	39 (35.8)	109 (49.5)	0.018
Dyslipidemia	181 (60.7)	48 (48.5)	133 (66.8)	0.002
Glucose	124.0 (103.0 – 175.0)	121.0 (103.0 – 163.0)	128.0 (104.0 – 180.0)	0.381
Triacylglycerol	126.0 (97.0 – 183.0)	151.0 (97.0 – 201.0)	122.0 (93.5 – 174.0)	0.080
Total Cholesterol	170.0 (139.0 – 204.0)	185.0 (157.5 – 215.3)	161.0 (134.0 – 196.0)	0.002
HDL- Cholesterol	39.0 (32.0 – 46.5)	36.0 (32.0 – 45.0)	41.0 (33.0 – 47.2)	0.065
LDL- Cholesterol	99.0 (77.0 – 124.3)	114.0 (89.0 – 134.0)	93.0 (72.0 – 118.0)	0.0004
Netrin-1	44.8 (34.8 – 62.8)	44.8 (33.8 – 65.8)	44.8 (34.7 – 65.0)	0.861
IL-1β	13.8 (7.1 – 29.7)	15.5 (7.9 – 49.7)	13.4 (7.1 – 24.1)	0.037

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Values are median (interquartile interval) or n (%). ACS: acute coronary syndrome. BMI: body mass index in kg/m². HDL: high-density lipoprotein. IL-1β: Interleukin - 1beta. LDL: low-density lipoprotein. NSTEMI: non-STsegment elevation Myocardial Infarction. STEMI: ST-segment elevation Myocardial Infarction. UA: unstable angina. Data of plasma glucose, triacylglycerol, total cholesterol, HDL and LDL are presented as mg/dL. Netrin-1 and IL-1β are presented as pg/mL. Mann-Whitney test or chi-square test.

At admission, women presented similar values of BMI, serum concentrations of glucose, triacylglycerol, and HDL cholesterol regardless in both age groups. The frequency of important risk factors such as hypertension, dyslipidemia and diabetes were higher in older women. However, levels of LDL cholesterol were lower in older ones. Current smokers were more frequent in younger women while more than 50% of the older women never smoked (Table 2). We did not find differences in the median of Netrin-1 between age groups. However, the median of IL-1β was higher in the younger group.

Associations between low and high Netrin-1 or IL1- β and the outcomes, according to the age range were presented in Table 3 and Table 4, respectively. The number of death of all-cause was very low (3 death) in the women younger than 60 years and only 6 cases of the combined outcome, avoiding reliable analyzes in this group. However, in the older (>60 years) group, we found associations between the highest level of Netrin-1 and deaths from all causes and cardiovascular causes. An association between high IL-1β and death for CVD as also found among older women (p = 0.034).

Table 3. – Outcomes according to the Netrin-1 in females.

	Female - Total			< 60 years			> 60 years
2 years follow-up	Low Netrin-1	High Netrin-1	p	Low Netrin-1	High Netrin-1	p	Low Netrin-1	High Netrin-1	p
All-cause mortality	18 (36.0)	32 (64.0)	0.021	2 (66.7)	1 (33.3)	0.612	16 (34.0)	31 (66.0)	0.011
Cardiovascular mortality	12 (35.3)	22 (64.7)	0.052	2 (66.7)	1 (33.3)	0.612	10 (32.3)	21 (67.7)	0.029
Fatal or new non-fatal MI	11 (39.3)	17 (60.7)	0.193	4 (66.7)	2 (33.3)	0.467	7 (31.8)	15 (68.2)	0.066

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Values are n (%). MI: myocardial infarction. Chi-square test.

Table 4. – Outcomes according to the IL-1β in females.

	Female - Total			< 60 years			> 60 years
2 years follow-up	Low IL-1β	High IL-1β	p	Low IL-1β	High IL-1β	p	Low IL-1β	High IL-1β	p
All-cause mortality	21 (42.0)	29 (58.0)	0.221	0 (0.0)	3 (100.0)	0.118	19 (40.4)	28 (59.6)	0.140
Cardiovascular mortality	12 (35.3)	22 (64.7)	0.071	0 (0.0)	3 (100.0)	0.118	10 (32.3)	21 (67.7)	0.034
Fatal or new non-fatal MI	10 (35.7)	18 (64.3)	0.117	2 (33.3)	4 (66.7)	0.438	7 (31.8)	15 (68.2)	0.075

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Values are n (%). IL-1β: Interleukin - 1beta. MI: myocardial infarction. Chi-square test.

These data showing a worse prognostic in older females with high levels of Netrin-1 and IL-1β at admission were confirmed by Kaplan-Meier curves. High levels of Netrin-1 showed a lower rate of survival when considering all-cause mortality (p = 0.011, Figure 1A) and also considering only cardiovascular deaths (p = 0.024, Figure 1B). The marker only tended to be associated with fatal MI or new non-fatal MI (p = 0.067, Figure 1C). High levels of IL-1β also showed a lower rate of survival when considering cardiovascular deaths (p = 0.031, Figure 1E) and tended to be associated with fatal MI or new non-fatal MI (p = 0.064, Figure 1F).

The analysis of the hazard ratios (Table 5) showed an increased risk of death from all causes for the high Netrin-1 group that remained significant in the adjusted model. The same results were seen for risk of death from cardiovascular causes.

Table 5. – Hazard Ratios for high Netrin-1 and IL-1β and all-cause mortality, cardiovascular mortality and fatal or new non-fatal MI in older (>60 years) females.

	All-cause mortality		Cardiovascular mortality		Fatal or new non-fatal MI
	HR (95% CI)	p	HR (95% CI)	p	HR (95% CI)	p
	Netrin-1
Crude	2.15 (1.17 – 3.93)	0.013	2.31 (1.09 – 4.92)	0.029	2.25 (0.92 – 5.54)	0.075
Adjusted *	2.08 (1.04 – 4.16)	0.038	2.68 (1.06 – 6.74)	0.036	1.82 (0.65 – 5.07)	0.247
	IL-1β
Crude	1.57 (0.87 – 2.81)	0.127	2.23 (1.05 – 4.75)	0.036	2.27 (0.92 – 5.58)	0.073
Adjusted *	2.03 (1.06 – 3.89)	0.031	3.01 (1.26 – 7.17)	0.013	3.05 (1.12 – 8.32)	0.029

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CI: confidence interval. HR: hazard ratio. IL-1β: Interleukin - 1beta. MI: myocardial infarction. * Adjusted for age, type of Acute Coronary Syndrome, diabetes, hypertension and dyslipidemia.

Considering the high levels of IL-1β, we did not find significant HR in the crude model for all-cause mortality and fatal or new non-fatal MI (Table 5). However, significant HR for all-cause mortality and fatal or new non-fatal MI were observed in the adjusted model. We also observed an increased risk of death from cardiovascular causes for the high IL-1β group even after model adjustment.

Discussion

This work is the pioneer in evaluating the prognostic value of Netrin-1 in ACS and presents new information about the prognostic value of IL-1β in this condition.

In our study, we observed an association between the highest levels of Netrin-1 and worse prognosis when all-cause mortality and cardiovascular mortality were analyzed, in elderly females.

Plasma Netrin-1 is a diagnostic biomarker of many cancer types.^17-19It was verified that the higher gene expression or concentration of Netrin-1 in these tissues was associated with a worse prognosis, probably related to the anti-apoptotic and angiogenic effects of Netrin-1. However, the role of Netrin-1 in atherosclerosis and cardiac remodeling after MI is still controversial. It has been described that netrin-1 could promote or protect against atherosclerosis, in the dependency of environmental conditions.²⁰ Reduced endogenous levels of Netrin-1 can also lead to deleterious effects since pro-atherogenic factors can reduce the expression of this molecule.²⁰ In models of MI, netrin-1 administration reduced the severity of myocardium lesion when compared to the non-supplemented controls.^21,22

In our study, it is possible that the "High Netrin-1" group is composed of patients who had a more severe ACS event. Our hypothesis is that the level of Netrin-1 increases in more severe cases of ACS. This hypothesis is based on studies that indicate that the expression of Netrin-1 is induced after cellular injury and can be used as a biomarker for organ damage or disease²³ as seen in the cardiac surgery.²⁴ Moreover, hypoxia, a condition closely linked to atherosclerosis and ACS is also an inducer of Netrin-1 expression.²⁵ Moreover, Van Gils et al.⁶ observed increased expression of the molecule in cholesterol-loaded macrophages promoting the retention of these cells in vitro, which could contribute to a more rapid evolution of the atherosclerotic plaque and consequently increase the chance of thrombus formation and occurrence of infarction.

These factors lead us to believe that the highest number of unfavorable outcomes, as well as the higher risk of death from all causes and from cardiovascular causes observed in women over 60 years of age with higher Netrin-1 levels are associated with the severity of event and the higher degree of inflammation (as suggested by the high levels of IL-1β) which may have contributed to a worse prognosis.

Regarding IL-1β, high levels of this one and other pro-inflammatory cytokines have already been identified in patients with ACS.²⁶ Nonetheless, few studies were addressed to the prognostic value of this cytokine.^27,28 In agreement with our results, these studies suggest that higher levels of IL-1β were seen in patients with ACS who underwent new events during follow-up.

IL-1β is capable of increasing the expression of molecules that contribute to plaque rupture and thrombus formation, culminating in the occurrence of ACS.^10,29 Thus, higher levels of serum IL-1β could reflect exacerbated inflammation, favoring the occurrence of cardiovascular complications.

Higher IL-1β levels suggest an exacerbated inflammation that could impair cardiac remodeling. Adverse remodeling after MI is the structural basis for ischemic heart failure. Although adequate amounts of IL-1β and other inflammatory cytokines are essential in the initial phase of remodeling, the decrease of cytokine levels is needed to promote effective healing.³⁰ It has been described that elevated levels of IL-1β up to two months after infarction in patients with STEMI were strongly associated with a worsening of cardiac function after one year of follow-up.³¹ Furthermore, cytokine was a strong predictor of left ventricular hypertrophy, which is important in predicting cardiovascular morbidity and mortality.³¹

Several factors may help to understand the absence of association with worse prognosis found among men and younger women. Cardiac and vascular tissues are influenced by hormones such as estrogen and testosterone, varying according to sex and age.^32,33 Older women have a larger left ventricle mass than men, due to factors that indicate lower arterial capacity, such as reduced carotid wall thickness.³³

The relationship between inflammatory cytokines and gender has not yet been elucidated, although differences between concentrations are observed in the literature.³² Studies indicate that IL-β concentration is higher in males.^33,34 Furthermore, cytokine levels are inversely related to age, as seen in our work and literature.³⁵ The literature does not provide data on sex differences for Netrin-1. Since we did not observe statistical gender differences in the levels of the markers, our hypothesis is that in our female group the levels of these were higher than the normal. This possible increase may be related to the higher frequency of cardiovascular risk factors in this group in the present study, factors that may lead to an increase in levels of inflammatory markers.³⁶ However, even after adjusting for these factors, high levels of Netrin-1 and IL-1β remained associated with worse prognosis, demonstrating that these inflammatory markers are independently associated with worse prognosis, and may be related to the reduction of arterial capacity already observed in older women when compared to men.

We point out as limitations of the study its unicentric characteristic and the absence of a control group. Furthermore, we did not collect data from the pre-event period, which would allow us to determine the variation in marker concentration after ACS.

Conclusions

Higher levels of Netrin-1 and IL-1β are associated with worse prognosis in elderly females with ACS. The mechanism for such association can be related to maintenance of inflammation and adverse cardiac remodeling, propitiating further cardiovascular events.

Study Association

This article is part of the thesis of Doctoral submitted by Paola Leocádio, from Universidade Federal de Minas Gerais.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Hospital Universitário - USP under the protocol number CEP-HU/USP 866/08. 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 funded by Fundação de Amparo à Pesquisa do Estado de São Paulo and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior.

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PERMALINK

Níveis Elevados de Netrina-1 e IL-1β em Mulheres Idosas com SCA: Pior Prognóstico no Acompanhamento de Dois Anos

Paola Leocádio

Penélope Menta

Melissa Dias

Júlia Fraga

Alessandra Goulart

Itamar Santos

Paulo Lotufo

Isabela Bensenor

Jacqueline Alvarez-Leite

Resumo

Fundamento

Objetivo

Métodos

Resultados

Conclusão

Introdução

Métodos

Desenho experimental

Coleta de dados e desfechos

Análise estatística

Resultados

Tabela 1. – Características gerais na fase hospitalar em homens e mulheres.

Tabela 2. – Características gerais na fase hospitalar em mulheres jovens (< 60 anos) e idosas (> 60 anos).

Tabela 3. – Desfechos de acordo com os níveis de Netrina-1 em mulheres.

Tabela 4. – Desfechos de acordo com os níveis de IL-1β em mulheres.

Figura 1. – Curvas de Kaplan-Meier para Netrina-1 (A – C) e IL-1β (D – F) em mulheres idosas (> 60 anos) no acompanhamento de dois anos. IL-1β: Interleucina - 1beta; DCV: doença cardiovascular; IAM: infarto agudo do miocárdio.

Tabela 5. – Razão de risco (HR) para os níveis de Netrina-1 e IL-1β e óbito por todas as causas, óbito por doenças cardiovasculares e desfecho combinado de IAM fatal ou novo IAM não fatal em mulheres idosas (> 60 anos).

Discussão

Conclusão

Referências

High Serum Netrin-1 and IL-1β in Elderly Females with ACS: Worse Prognosis in 2-years Follow-up

Paola Leocádio

Penélope Menta

Melissa Dias

Júlia Fraga

Alessandra Goulart

Itamar Santos

Paulo Lotufo

Isabela Bensenor

Jacqueline Alvarez-Leite

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Methods

Study design

Data collection and outcomes

Statistical analysis

Results

Table 1. – General characteristics in the hospital phase in males and females.

Table 2. – General characteristics in the hospital phase in younger (<60 y) and older (>60 years) females.

Table 3. – Outcomes according to the Netrin-1 in females.

Table 4. – Outcomes according to the IL-1β in females.

Figure 1. – Kaplan-Meier curves for Netrin-1 (A – C) and IL-1Β (D – F) in older (>60 years) females considering a 2-year follow-up. IL-1β: Interleukin - 1beta. MI: myocardial infarction.

Table 5. – Hazard Ratios for high Netrin-1 and IL-1β and all-cause mortality, cardiovascular mortality and fatal or new non-fatal MI in older (>60 years) females.

Discussion

Conclusions

ACTIONS

PERMALINK

RESOURCES

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