Ceramidas Plasmáticas na Estratificação de Risco das Doenças Cardiovasculares

Débora L M Junqueira; Alline Stach; Adriano Caixeta; Juliana Sallum; Erika Yasaki; Jeane Tsutsui; Edgar Rizatti; Carlos E Rochitte; Ching-Jianhong; Jean-Paul Kovalik; José E Krieger; A Mark Richards; Mark Y Chan; Leonardo P de Carvalho

doi:10.36660/abc.20201165

. 2022 Apr 7;118(4):768–777. [Article in Portuguese] doi: 10.36660/abc.20201165

View full-text in English

Ceramidas Plasmáticas na Estratificação de Risco das Doenças Cardiovasculares

Débora L M Junqueira ^1,², Alline Stach ², Adriano Caixeta ¹, Juliana Sallum ¹, Erika Yasaki ¹, Jeane Tsutsui ^3,⁴, Edgar Rizatti ³, Carlos E Rochitte ^2,⁴, Ching-Jianhong ⁵, Jean-Paul Kovalik ⁵, José E Krieger ⁴, A Mark Richards ⁶, Mark Y Chan ⁶, Leonardo P de Carvalho ^1,^2,³

PMCID: PMC9007014 PMID: 35508055

Resumo

A produção de ceramida ocorre em todo o corpo e desempenha um papel importante na manutenção da fisiologia normal. No entanto, os níveis de ceramidas são alterados em estados de doença, principalmente durante o desenvolvimento de diabetes e dislipidemia. A produção de ceramidas também está associada à instabilidade das placas ateroscleróticas. Estudos recentes revelam que pacientes com doença arterial coronariana instável apresentam níveis plasmáticos aumentados de ceramidas (principalmente C16, C18 e C24:1). Atualmente, são consideradas biomarcadores emergentes nas doenças cardiovasculares, sendo utilizadas na predição de instabilidade da placa aterosclerótica e eventos cardiovasculares adversos de forma independente aos fatores de risco tradicionais. Com o objetivo de descrever e discutir o papel das ceramidas na estratificação das doenças cardiovasculares, o desenvolvimento desta revisão narrativa contextualiza a importância desse biomarcador no cenário atual da cardiologia.

Keywords: Doenças Cardiovasculares, Doença da Arterial Coronariana, Ceramidas/uso terapêutico, Glicoesfingolipideos Neutros/uso terapêutico, Estratificação das Doenças, Diabetes Mellitus, Dislipidemias, Biomarcadores

Introdução

Dados da Organização Mundial da Saúde (OMS) demonstram que as doenças cardiovasculares (DCV) foram responsáveis por uma grande porcentagem dos 50 milhões de óbitos ocorridos na última década: cerca de 17 milhões de pessoas.¹ Essa mortalidade é especialmente alta na fase aguda após um infarto agudo do miocárdio (IAM), com 10-15% de recorrência de eventos isquêmicos em 1 ano e taxas cumulativas de até 50% após 10 anos.²

Aproximadamente 50% dos pacientes submetidos a intervenção coronária percutânea primária (ICP) possuem doença multivascular que, de forma geral, apresenta-se como uma doença crônica progressiva e com altas taxas de mortalidade. Atualmente, não podemos prevenir com precisão a recorrência de eventos isquêmicos agudos, claramente demonstrando a grande necessidade de biomarcadores que possam prever a instabilidade da placa aterosclerótica coronariana.³

Estudos recentes têm destacado o papel fisiopatológico de outras classes lipídicas além do colesterol de lipoproteína de baixa densidade (low density lipoprotein, LDL) na aterosclerose e no IAM, incluindo ceramidas, esfingomielina, fosfatidilcolinas e ésteres de colesterol.^4,5 As ceramidas participam de múltiplas vias envolvidas na sinalização de danos celulares, causando a liberação de citocinas pró-inflamatórias que modulam diretamente a apoptose por meio da expressão gênica de proteínas pró-apoptóticas.⁶

Nosso grupo tem trabalhado no desenvolvimento de biomarcadores lipídicos por meio de espectrometria de massa, entre outras técnicas de biologia molecular, para o desenvolvimento de um biomarcador plasmático capaz de diagnosticar a instabilidade da placa aterosclerótica e prever reinfartos cardíacos e a progressão para insuficiência cardíaca (IC) em pacientes com síndrome coronariana aguda (SCA).

A ceramida é um biomarcador lipídico com papel emergente no diagnóstico precoce e na estratificação de risco, atuando como biomarcador de eventos cardiovasculares (CVs) primários e secundários em pacientes com aterosclerose clínica e subclínica suscetíveis ao desenvolvimento de eventos isquêmicos agudos.^5,7

Ceramida: uma breve revisão da fisiologia desse novo biomarcador lipídico.

As ceramidas e o colesterol LDL são lipídios estruturais da membrana que mantêm sua fluidez e integridade por meio da formação de poros seletivos, modulando a movimentação de compostos entre os espaços intra e extracelulares. A ceramida é um esfingolipídio formado pela associação de uma esfingosina com um ácido graxo, sendo um componente-chave na formação das membranas celulares8 e atuando como um importante intermediário na sinalização de processos que regulam a homeostase celular, tais como inflamação, apoptose e a resposta celular ao estresse.⁹

As ceramidas se acumulam na placa de ateroma coronariana¹⁰ e em suas formas glicosiladas: as glicosilceramidas e as lactosilceramidas (Figura 1), que são abundantes na placa em desenvolvimento.^11,12 Além disso, dados do nosso grupo mostraram que o próprio tecido miocárdico pode produzir ceramidas diretamente em resposta à isquemia e reperfusão.¹³

A ceramidase é uma enzima que quebra os ácidos graxos da ceramida para produzir esfingosina, a qual, por sua vez, é fosforilada pela esfingosina-1-fosfatase para formar esfingosina-1-fosfato. A síntese das ceramidas pode ocorrer através da hidrólise da esfingomielina (degradação), através da via de recuperação (reciclagem) na qual a esfingosina é fosforilada ou através de uma via de novo, na qual as diidroceramidas são dessaturadas.⁹

Ceramidas: uma ligação entre aterosclerose, diabetes e dislipidemia

As ceramidas constituem aproximadamente 30% do colesterol LDL circulante. O aumento da concentração de ceramida altera a permeabilidade da membrana celular, facilitando o acúmulo de colesterol LDL na parede do vaso. Esse acúmulo amplifica o processo inflamatório da parede do vaso e promove a apoptose das células musculares lisas vasculares e a disfunção endotelial, ocasionando a instabilidade da placa aterosclerótica e sua ruptura¹⁴ (Figura 2).

Além da placa aterosclerótica, o acúmulo de colesterol também ocorre na musculatura lisa esquelética, interferindo na expressão do transportador de glicose tipo 4, o que ocasiona defeito no transporte muscular de glicose e prejudica sua capacidade de síntese de glicogênio.¹⁵ As ceramidas também estimulam a apoptose das células β pancreáticas, reduzindo diretamente a produção de insulina.¹⁶ Major et al.,¹⁷ demonstraram que as ceramidas podem mimetizar os efeitos citotóxicos do fator de necrose tumoral, da interleucina 1 beta e do interferon-gama nas células β pancreáticas, desencadeando inflamação e apoptose.¹⁷ O acúmulo de ceramida nos tecidos resulta na disfunção metabólica de múltiplos órgãos e no desenvolvimento de complicações do diabetes. A Figura 3 demonstra os principais tecidos afetados pelas ceramidas.^18,19

Portanto, além de determinar o grau de dislipidemia e o risco de aterosclerose através do valor do colesterol LDL, a dosagem da ceramida também auxilia o médico a determinar a resistência insulínica e a apoptose de células beta pancreáticas.

A implicação clínica da ceramida levou à patente desse biomarcador nos EUA e na Europa, estando atualmente disponível para uso clínico em hospitais de referência, como a Mayo Clinic.²⁰

Os exames de rastreamento são necessários para o acompanhamento da aterosclerose subclínica?

Há uma lacuna significativa na detecção da doença aterosclerótica subclínica e na triagem e no acompanhamento custo-efetivos dessa condição, com muitos testes não invasivos sendo solicitados rotineiramente em populações com diferentes níveis de risco CV. Isso ocorre em todo o mundo e, apesar do avanço crescente dos testes não invasivos para a detecção da doença aterosclerótica, a estratificação de risco permanece imperfeita.²¹ Considerando os custos crescentes com os cuidados de saúde, essa prática médica estereotipada deve, portanto, ser reavaliada.

A associação de dados clínicos e de imagem no apoio ao desenvolvimento de protocolos que incorporem escores de risco clássicos, como os escores de Framingham e INTERHEART, tem sido testada com o intuito de aprimorar a estratificação de risco CV. No entanto, esses métodos, quando aplicados à população em geral sem uma etapa de triagem, têm capacidade limitada na avaliação do risco CV por razões logísticas e de custo.²²

O Multi-Ethnic Study of Atherosclerosis (MESA), um dos estudos mais relevantes na área, trouxe contribuições importantes para a compreensão do desenvolvimento e da progressão da DCV do estágio subclínico ao clínico. Em uma subanálise do MESA, um grande painel de biomarcadores de proteínas foi avaliado para encontrar marcadores preditivos de progressão de DCV. Em comparação aos fatores de risco CV clássicos, biomarcadores de proteína com vários painéis específicos de inflamação, resistência à insulina, lipídios, hemostasia, fibrinólise, dano oxidativo, estresse endotelial, entre outros, foram testados e apresentaram apenas um valor preditivo incremental limítrofe para eventos adversos CVs em longo prazo (AUC: 0,768 vs. 0,776, p = 0,003) e não apresentaram valor incremental na predição de eventos CVs adversos em médio prazo (AUC: 0,795 vs. 0,796, p = 0,627). Portanto, devido aos valores semelhantes da curva característica de operação do receptor (receiver operating characteristic, ROC), novos métodos de rastreamento e estratificação de risco são necessários para melhorar a detecção precoce da instabilidade da placa.²³

O desenvolvimento desse biomarcador possibilitaria a intervenção na progressão inicial da placa aterosclerótica, sendo, portanto, essencial para evitar o enorme custo adicional imposto pela fase sintomática da doença aterosclerótica. Essas considerações são importantes e devem ser avaliadas no desenvolvimento de plataformas de rastreamento de saúde populacional, objetivando uma boa relação de custo-efetividade.

Devemos dosar as ceramidas e o colesterol LDL?

A aterosclerose subclínica antecede a maioria dos eventos CVs e sua detecção pode melhorar a estratificação de risco CV.^11,12 No entanto, uma incompatibilidade tem sido relatada entre perfis de fatores de risco convencionais aparentemente benignos e a presença de aterosclerose subclínica detectada por calcificação da artéria coronária ou medição da espessura da íntima no ultrassom de carótidas.^13,14

Estudos identificaram a presença de aterosclerose subclínica em quase 60% dos indivíduos de meia-idade classificados como de baixo risco CV de acordo com os escores de risco tradicionais; em 41% desses indivíduos, observaram-se múltiplos locais vasculares afetados.¹⁵ Esses achados sugerem que outras variáveis além dos fatores de risco CV convencionais podem desempenhar um papel relevante na aterogênese.

Os pacientes com doença aterosclerótica são uma população muito heterogênea, com estratificação de risco complexa, sendo errôneo considerar todos esses pacientes com risco semelhante de eventos agudos. Atualmente, o uso de escores de risco CV é indicado pelas diretrizes como uma ferramenta de estratificação; no entanto, devido às limitações na precisão preditiva, principalmente em pacientes com alto risco CV, a otimização das ferramentas de risco por meio da recalibração de escores ou da associação com biomarcadores é frequentemente necessária para uma maior acurácia preditiva em diferentes populações.

O colesterol LDL é um fator de risco diretamente envolvido no desenvolvimento da placa aterosclerótica e, portanto, um importante alvo terapêutico na prática clínica. Dieta, mudanças no estilo de vida e medicamentos podem resultar em reduções significativas e sustentadas do colesterol LDL plasmático. No entanto, apesar disso, as DCVs continuam sendo uma das principais causas de morte em todo o mundo,²⁴ sugerindo que o controle convencional do colesterol LDL não é suficiente. A detecção e a prevenção precoces da instabilidade da placa aterosclerótica podem abrir caminhos para reduzir significativamente a progressão da doença.

As diretrizes atuais endossam o controle do colesterol LDL e a medição de marcadores inflamatórios inespecíficos, como a proteína C reativa, para a estratificação de risco CV. No entanto, a fisiopatologia da aterosclerose envolve a interseção complexa de dislipidemia, inflamação, disfunção endotelial e ativação plaquetária, entre outros fatores.²⁵ Dados recentes demonstram possíveis associações entre cada uma dessas vias com os níveis plasmáticos das ceramidas, indicando associação e causalidade plausíveis desse biomarcador em DCV aguda e instabilidade da placa aterosclerótica.

Além disso, o colesterol LDL plasmático não prediz com precisão eventos cardíacos adversos maiores e eventos cerebrovasculares (major adverse cardiac and cerebrovascular events, MACCE), exigindo, na prática clínica, avaliação médica criteriosa e uma série de testes não invasivos para acompanhar a progressão da placa aterosclerótica.26 Por outro lado, as concentrações plasmáticas de ceramidas são elevadas em várias condições relacionadas às doenças cardíacas, além do papel bioquímico na progressão da aterosclerose, também estudado por nosso grupo anteriormente. Observamos em estudos preliminares a liberação incremental de ceramidas na fase aguda do IAM e em placas humanas instáveis, correlacionando esses achados com dados pré-clínicos que mostraram a suprarregulação de enzimas produtoras de ceramidas no miocárdio, com aumento dos níveis plasmáticos nas primeiras 24 horas após um evento isquêmico agudo.⁵

As ceramidas também estão associadas a um maior risco de evolução em pacientes com IC. Em 423 pacientes com IC aguda, as concentrações plasmáticas de ceramidas foram independentemente associadas à morte e à piora da função ventricular esquerda durante a hospitalização.²⁷

A busca por evidências: ceramidas e predição de risco CV

Prevenção primária:

O estudo FINRISK incluiu pacientes sem eventos cardiovasculares prévios e mostrou que os níveis circulantes de ceramidas específicas (16:0, 18:0 e 24:1) estão significativamente associados a eventos cardiovasculares maiores subsequentes quando comparados a indivíduos que permaneceram assintomáticos. As associações univariadas significativas entre ceramidas e eventos fatais sugerem que elas desempenham um papel fundamental na ruptura das placas ateroscleróticas nessa população.⁷

Além disso, Petterson et al.,²⁸ demonstraram, ainda no contexto da prevenção primária, que a proporção de ceramidas C24:0/C16:0 e a concentração plasmática de ceramida C24:0 estão inversamente associadas a fatores de risco coronariano, como idade e tabagismo, e inversamente associadas ao desenvolvimento de DAC e IC.²⁸

Doença arterial coronária:

Em uma análise post-hoc do Systolic Blood Pressure Intervention Trial (N = 9.631), Nguyen et al.,³¹ demonstraram que os níveis plasmáticos de colesterol LDL não estavam associados ao desfecho composto primário (infarto do miocárdio, acidente vascular cerebral, insuficiência cardíaca descompensada aguda e morte por causas CVs).²⁹ Além disso, avaliando os pacientes em prevenção secundária de eventos CVs (N = 1.562), observou-se que o colesterol LDL foi apenas marginalmente associado à incidência de eventos CVs: taxa de risco ajustada: 1,005 (intervalo de confiança de 95% [IC95%] = 1,002-1,009; p = 0,005 [aumento de 1 mg/dL]), com baixa capacidade de discriminação de eventos cardiovasculares adversos maiores (MACE) (área ROC de 0,54; p = 0,087).²⁹

Embora estudos com inibidores de PCSK9, como o Odyssey Outcomes e Fourier,³⁰ reforcem o princípio “quanto menor, melhor”, significando que há uma associação entre níveis baixos de colesterol LDL e baixo risco de aterosclerose clínica, não há uma correlação de risco perfeita. Para preencher essa lacuna, o uso de métodos de medição de metabólitos por técnicas metabolômicas tem sido cada vez mais utilizado, pois esses métodos apresentam vantagens sobre os métodos clássicos devido à análise mais abrangente dos metabólitos e à capacidade de obtenção do perfil metabólico do tecido-alvo da doença de interesse.

Uma análise metabolômica não direcionada identificou três ceramidas plasmáticas significativamente associadas à mortalidade cardiovascular em uma coorte com DAC confirmada por angiografia. As ceramidas associadas à alta mortalidade cardiovascular nesse estudo foram: C16:0, C18:0 e C24:1. A associação ocorreu independentemente de idade, índice de massa corporal, tabagismo, uso de estatinas, triglicerídeos, LDL e colesterol total.¹⁴

Kaasenbrood et al.,³¹ tentaram melhorar a predição de eventos agudos nesse grupo de pacientes através do escore de risco SMART (manifestações secundárias de doença arterial).³¹ Esse escore de risco compreende variáveis clínicas e laboratoriais (colesterol total, colesterol HDL, taxa de filtração glomerular estimada, proteína C reativa) e foi testado em várias coortes. Com base nos resultados obtidos, os autores sugeriram novos algoritmos de estimativa de risco CV para estratificar essa população individualmente e com maior precisão, demonstrando a capacidade de aprimoramento dos escores de risco pela incorporação de biomarcadores.³¹

No Mediterranean Diet Prevention (PREDIMED), um estudo de coorte prospectivo em pacientes com alto risco CV, ceramidas C24:0, C22:0 e C16:0 foram associadas a DCV.4 A razão de chance (odds ratio, OR) comparando os quartis extremos das concentrações plasmáticas de ceramidas C16: 0, C22: 0, C24: 0 e C24: 1 foram de 2,39 (1,49-3,83; p < 0,001), 1,91 (1,21-3,01; p = 0,003), 1,97 (1,21-3,01; p = 0,004) e 1,73 (1,09-2,74; p = 0,011), respectivamente. Em um estudo prospectivo de aproximadamente 500 pacientes submetidos a angiografia coronária eletiva, Meeusen et al. relataram que os níveis plasmáticos de C16:0, C18:0 e C24:1 foram independentemente associados a um risco aumentado de MACCE em um acompanhamento médio de 4 anos.³² O risco associado às ceramidas foi novamente independente dos fatores de risco tradicionais, incluindo idade, sexo, índice de massa corporal, tabagismo e colesterol. Além disso, o valor preditivo permaneceu significativo após ajustes adicionais para glicose sérica e história familiar de DAC. Esses resultados sugerem que, quando as ceramidas plasmáticas estão altas em pacientes com ou sem estenose significativa da artéria coronária, o risco de morte é alto em ambos os grupos.³²

Outro escore de risco envolvendo ceramidas é o CERT2, que foi desenvolvido no estudo The Western Norway Coronary Angiography Cohort (WECAC) e validado nos estudos Intervenção a Longo Prazo com Pravastatina em Doença Isquêmica (LIPID) e Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung (KAROLA).³³ Os resultados mostraram que a ferramenta de estimativa de risco CV desenvolvida com a incorporação da medição de ceramidas pode estratificar os MACE de forma confiável em pacientes com DAC estável. Evidências adicionais obtidas nos estudos WECAC e LIPID demonstraram que esses biomarcadores isoladamente estratificam de forma acurada o risco CV primário em pacientes com e sem diabetes; em indivíduos com diabetes, os únicos preditores com valor significativo no estudo WECAC foram o escore CERT2 e a troponina altamente sensível.

SCA

No estudo European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis – Intravascular Ultrasound (N = 600 pacientes), Cheng et al. demonstraram que os níveis plasmáticos de C16:0, C18:0 e C24:1 foram significativamente associados à morfologia vulnerável da placa coronária em indivíduos com SCA. Além disso, os níveis plasmáticos mais elevados dessas ceramidas também foram significativamente associados a uma maior gravidade angiográfica de estenose coronariana,^14,34 bem como a uma menor perfusão da parede miocárdica pós-estresse em pacientes com DAC estabelecida ou suspeita que realizaram cintilografia de perfusão miocárdica.^35,36 Esses achados sugerem causalidade entre a elevação das ceramidas na placa aterosclerótica e sua instabilidade ou gravidade.

Recentemente, Pan, Dong, Sun et al. utilizando tomografia de coerência óptica (optical coherence tomography, OCT) em pacientes com STEMI e ruptura de placa, observaram níveis plasmáticos elevados de C16:0, C18:0 e C24:0 em comparação a indivíduos sem doença coronariana e pacientes com DAC estável (p < 0,001, p < 0,001, p < 0,001, p < 0,001, respectivamente). Esse foi o primeiro estudo utilizando OCT que provou uma associação positiva e independente entre as concentrações plasmáticas de ceramidas e a presença de ruptura de placa, sugerindo que as concentrações plasmáticas de ceramidas podem atuar como potenciais biomarcadores para a ruptura de placa.³⁷

Mais evidências dessa associação foram obtidas no estudo de Laaksonen et al.,⁵ Em uma coorte prospectiva de pacientes com DAC estável, 81 dos 1.580 pacientes (Tabela 1) apresentaram elevação de ceramida sérica e, posteriormente, apresentaram MACE ao longo de 4,6 anos de acompanhamento. Essa proporção foi mantida mesmo após o ajuste para o tratamento com estatinas. As ceramidas foram preditivas em ambos os casos, com OR praticamente igual em pacientes com ou sem estatinas: 1,68 (1,31-2,15) vs. 1,7 (1,33-2,17), respectivamente. Nesse estudo, o nível plasmático de colesterol LDL não foi significativamente preditivo de MACE.⁵

Tabela 1. – Escore de risco relativo envolvendo ceramidas em diferentes coortes.

Escore	Categoria	BECAC (Risco 5 anos)⁵			SPUM-ACS (Risco 1 ano)⁵

		Morte (n)	%	Risco Relativo	Morte (n)	%	Risco Relativo
0-2	Baixo	15/549	2,7%	1,0	9/575	1,6%	1,0
3-6	Moderado	29/601	4,8%	1,8	16/611	2,6%	1,7
7-9	Alto	20/288	6,9%	2,5	9/270	3,3%	2,1
10-12	Muito alto	17/149	11,4%	4,2	17/181	9,4%	6,0

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Fonte: adaptado da Mayo Clinic. https://www.mayoclinic.org/

Laaksonen et al.,⁵ também analisaram o estudo SPUM-SCA (N = 1.637), realizado em pacientes com SCA, em que as ceramidas foram novamente preditoras de MACE independentemente do risco CV. Em 51 pacientes que morreram em até um ano após um evento cardíaco, as ceramidas plasmáticas mensuradas apresentaram níveis significativamente maiores em comparação aos pacientes que sobreviveram durante o acompanhamento.⁵

Finalmente, De Carvalho et al.,¹³ avaliaram pacientes com IAM em duas coortes de pacientes submetidos a estratificação invasiva, comparando as taxas de sobrevida livre de MACCE em pacientes de alto risco definidas pelo escore Global Registry of Acute Coronary Events (GRACE) ajustado para a população local. Nesse estudo, evidenciou-se que o escore GRACE apresentou menor capacidade de predição de sobrevida livre de eventos quando comparado ao desempenho preditivo de uma associação de 12 ceramidas plasmáticas medidas na fase aguda do IAM.¹³ Esse estudo incluiu chineses, malaios e indianos, etnias que representam uma grande proporção da população mundial. Ainda, foi realizada revalidação externa do valor preditivo desses biomarcadores em uma população de caucasianos da Nova Zelândia, demonstrando o desenvolvimento de um biomarcador com potencial uso universal. Esses dados foram ainda corroborados com análise de biologia molecular de biópsias de placas ateroscleróticas de pacientes submetidos a cirurgia cardíaca com e sem infarto recentes, confirmando o aumento da produção de ceramidas em pacientes com placa aterosclerótica instável.

Os principais estudos que avaliaram a associação entre as ceramidas e o risco de eventos CV agudos estão demonstrados na Tabela 2.

Tabela 2. – Principais estudos que avaliaram a associação entre as ceramidas e o risco de eventos cardiovasculares agudos (publicação ordenada por ano).

Autor/referência	Característica do estudo	Desfecho primário	Ajuste	Resultado principal
Laaksonen et al.⁵ European Heart Journal 2016;37, 1967-1976	Estudo de coorte prospectivo com N = 1580 adultos (62 anos; 59% homem; IMC 25 kg/m2; LDL 2,8 mmol/L, triglicerídeos 1,4 mmol/L; 62,6% utilizando estatina) submetidos a angiografia coronária eletiva devido a DAC estável e recrutados no Hospital da Universidade de Haukeland, em Bergen (estudo BECAC). Seguimento de 4,6 anos em associação a 1.637 pacientes (63 anos; 78% sexo masculino, IMC 26 kg/m2, LDL 2,6 mmol/L, triglicerídeos 1 mmol/L, 27,2% em uso de estatina) com diagnóstico de SCA submetidos a tratamento invasivo em quatro hospitais universitários suíços (estudo SPUM-ACS), com seguimento de 1 ano.	Morte cardiovascular	Colesterol total, triglicerídeos, colesterol HDL, colesterol LDL, idade, sexo, tabagismo, infarto agudo do miocárdio prévio, diabetes, hipertensão e acidente vascular cerebral prévio.	Cer (d18: 1/16: 0) e Cer (d18: 1/24: 1) foram associadas a um risco aumentado de morte cardiovascular em todas as coortes. OR Cer (d18:1/16:0)/Cer(d18:1/24:0) foi de 4,49 (IC95%, 2,24-8,98), 1,64 (1,29-2,08) e 1,77 (1,41-2,23) para Corogene, SPUM-ACS e estudo BECAC, respectivamente.
Havulinna et al.⁷ Arteriosclerer Thromb Vasc Biol 2016;36: 2424-2430	Estudo de coorte populacional com N = 8.101 pacientes saudáveis (idade 48 anos; 47% homens, IMC 26 kg/m2, colesterol LDL 3,3 mmol/L, triglicerídeos 1,3 mmol/L) do FINRISK 2002.	MACCE	Colesterol total, colesterol HDL, pressão arterial, diabetes melito e tabagismo.	Cer (d18: 1/16: 0), Cer (d18: 1/18: 0) e Cer (d18: 1/24: 1) foram significativamente maiores em pacientes com evolução cardiovascular adversa quando comparados a indivíduos assintomáticos. As concentrações séricas das ceramidas de alto risco que previam morte cardiovascular em pacientes com DAC também foram maiores nos casos do FINRISK MACE em comparação a indivíduos assintomáticos da seguinte forma: Cer (d18: 1/16: 0), Cer (d18: 1/18: 0) e Cer (d18: 1/24: 1) 11,4%, 21,3% e 17,0% (p < 0,001 para todos).
Wang et al.⁴ Circulation 2017; 135: 2028-2040	Estudo de coorte aninhado no estudo randomizado Mediterranean Diet Prevention, com N = 980 participantes (68 anos; 45% homens, IMC 30 kg/m2, colesterol LDL 3,4 mmol/L, triglicerídeos 1,6 mmol/L), incluindo 230 casos de DCV e 787 participantes selecionados aleatoriamente. A subcoorte incluiu 37 casos sobrepostos de DCV. Foram excluídos dois participantes com concentrações indetectáveis de ceramida no plasma. Acompanhamento: 4,5 anos.	MACE	Idade, sexo, IMC, histórico familiar de doença arterial coronariana precoce, tabagismo, história de hipertensão, dislipidemia e diabetes tipo II.	Entre as ceramidas de alto risco identificadas, os últimos quartis dos níveis plasmáticos de Cer (d18: 1/16: 0), Cer (d18: 1/22: 0), Cer (d18: 1/24: 0) e Cer (d18: 1/24: 1) foram associados a um desfecho cardiovascular adverso. A RR multivariável comparando os quartis extremos das concentrações plasmáticas de C:16, C22:0, C24:0 e C24:1 foi de 2,39 (1,49-3,83, p < 0,001), 1,91 (1,21-3,01, p = 0,003), 1,97 (1,21-3,01, p = 0,004), e 1,73 (1,09-2,74, p = 0,011), respectivamente.
De Carvalho et al.¹³ JACC Basic Transl Sci 2018;3:163-175	Estudo prospectivo e longitudinal com N = 327 pacientes de coorte primária (57 anos; 90% sexo masculino; IMC 26 kg/m2; colesterol LDL 3,1 mmol/L; triglicerídeos 1,2 mmol/L) e 119 pacientes na coorte de validação (66 anos; 72% sexo masculino; IMC 29 kg/m2; colesterol LDL 3,2 mmol/L) com SCA submetidos a estratificação invasiva com mensurações plasmáticas realizadas em dois momentos (antes e após a estratificação invasiva) com seguimento de 1 ano.	MACCE	GRACE	Entre as ceramidas de alto risco previamente identificadas, os níveis plasmáticos de Cer (d18: 1/16: 0), Cer (d18: 1/18: 0) e Cer (d18: 1/24: 1) foram associados a eventos cardiovasculares adversos.
Meeusen et al.³² Arterioscler Thromb Vasc Biol. 2018; 38: 1933-1939	Estudo transversal: 495 participantes (60 anos; 62% sexo masculino; IMC 28 kg/m2; colesterol LDL 3,1 mmol/L; triglicerídeos 1,7 mmol/L; uso de estatina 28,5%) antes da angiografia coronária não urgente. Acompanhamento: 4 anos.	MACE (infarto do miocárdio, intervenção percutânea, cirurgia de revascularização miocárdica, acidente vascular cerebral ou morte)	Idade, sexo, IMC, hipertensão, tabagismo, colesterol LDL, colesterol HDL, triglicerídeos, glicemia, histórico familiar de doença arterial coronariana	Entre as ceramidas de alto risco identificadas anteriormente, os níveis plasmáticos de Cer (d18: 1/16: 0), Cer (d18: 1/18: 0) e Cer (d18: 1/24: 1) foram associados a eventos cardiovasculares adversos. As RRs ajustadas para o desvio padrão (IC95%) foram 1,50 (1,16-1,93) para Cer (16: 0), 1,42 (1,11-1,83) para Cer (18: 0) e 1,43 (1,08-1,89) para Cer (24: 1)
Peterson et al.²⁸ J Am Heart Assoc. 2018;7: e007931	Estudo baseado na comunidade: 2.642 participantes do Framingham Heart Study (66 anos; 46% homens; IMC 28 kg/m2, colesterol LDL 2,7 mmol/L, triglicerídeos 1,3 mmol/L, 42,7% estatina) e 3.134 participantes do Estudo de Saúde na Pomerânia (idade 54 anos; 48% homens; IMC 28 kg/m2; colesterol LDL 5,5 mmol/L; triglicerídeos 1,8 mmol/L; 14,5% em uso de estatina) foram seguidos por 6 e 8 anos, respectivamente.	MACE (i.e., eventos cardiovasculares fatais e não fatais).	Idade, sexo, índice de massa corporal, hipertensão, diabetes melito, tabagismo, anti-hipertensivos, proporção de colesterol total/HDL, triglicerídeos e medicamentos hipolipemiantes.	Entre as ceramidas de alto risco identificadas previamente, apenas as Cer (d18: 1/24: 0) foram associadas a desfechos cardiovasculares adversos. Na metanálise das duas coortes e após o ajuste dos fatores de risco para DAC, as proporções de ceramida C24: 0/C16: 0 foram inversamente associadas a DAC (RR por incremento médio do DP: 0,79; IC95%, 0,71-0,89; P < 0,0001) e inversamente associado a IC (RR: 0,78; IC95%, 0,61-1,00; P = 0,046).
Hilvo et al.³³ European Heart Journal 2019, in press	Estudo longitudinal: três grandes estudos de coorte com 3.789 pacientes (62 anos; 72% sexo masculino; colesterol LDL 2,9 mmol/L; triglicerídeos 1,5 mmol/L; 72,6% uso de estatina) da WECAC; 5.991 pacientes (65 anos; 83% homens; colesterol LDL 3,9 mmol/L; triglicerídeos 1,6 mmol/L; 49,9% em uso de estatina) do estudo LIPID; e 1.023 pacientes (idade 62 anos; homens 84%; colesterol LDL 3 mmol/L; triglicerídeos 1,6 mmol/L; uso de estatina 75,6%) do KAROLA. Acompanhamento: 6 anos.	MACE (por exemplo, desfecho composto de morte por CV, IM e acidente vascular cerebral)	Idade, sexo, tratamento com estatinas (WECAC, KAROLA), diabetes melito, hipertensão, tabagismo atual, IM prévio, acidente vascular cerebral prévio, estratificado por intervenção com vitamina B (WECAC) e grupo de tratamento (LIPID).	Um escore de risco simples, com base nas ceramidas e fosfatidilcolinas que apresentam as melhores características prognósticas, foi desenvolvido no estudo WECAC e validado nas outras duas coortes. Essa pontuação foi altamente significativa na previsão da mortalidade por DCV [As RRs multiajustadas (IC95%) pelo DP foram 1,44 (1,28-1,63) no WECAC, 1,47 (1,34-1,61) no estudo LIPID e 1,69 (1,31- 2,17) no KAROLA. Além disso, uma combinação do escore de risco com a troponina T de alta sensibilidade aumentou as RRs para 1,63 (1,44-1,85) e 2,04 (1,57-2,64) nas coortes WECAC e KAROLA, respectivamente.

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BECAC: Bergen Coronary Angiography Cohort; DAC: doença arterial coronariana; FINRISK: population-based risk factor survey ; IC95%: intervalo de confiança de 95%; KAROLA: Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung; LIPID: Intervenção a Longo Prazo com Pravastatina em Doença Isquêmica; MACCE: eventos adversos cardíacos e cerebrovasculares maiores; MACE: eventos adversos cardíacos maiores; RR: razão de risco; SPUM-ACS: Special Program University Medicine-Inflammation in Acute Coronary Syndromes ; WECAC: The Western Norway Coronary Angiography Cohort.

Conclusão

As ceramidas plasmáticas são elevadas em pacientes com MACCE, e estudos pré-clínicos e clínicos demonstram uma associação desses lipídios com o processo de instabilidade da placa aterosclerótica.

A aferição das ceramidas possui valor incremental para a estratificação de risco, além dos fatores de risco clássicos, tanto na prevenção CV primária quanto na secundária. Medições consecutivas podem apresentar um valor preditivo incremental maior do que outros biomarcadores para a previsão de eventos adversos futuros. No entanto, precisamos de mais evidências obtidas através de estudos randomizados para avaliar o impacto prognóstico e do escalonamento terapêutico guiado pelos níveis plasmáticos de ceramidas.

Footnotes

Vinculação acadêmica

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

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

Fontes de financiamento: O presente estudo não teve fontes de financiamento externas.

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Arq Bras Cardiol. 2022 Apr 7;118(4):768–777. [Article in English]

Plasma Ceramides in Cardiovascular Disease Risk Stratification

Abstract

Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.

Keywords: Cardiovascular Diseases, Coronary Artery Disease, Ceramides/therapeutic use, Diseases Stratification, Diabetes Mellitus Dyslipidemias, Biomarkers

Introduction

Data from the World Health Organization (WHO) show that, out of the 50 million deaths recorded in the last decade, cardiovascular diseases (CVD) were responsible for a significant percentage: around 17 million people.¹ This mortality is particularly high in the acute phase following an acute myocardial infarction (AMI), with a

10%–15% recurrence of ischemic events within a year and cumulative rates of up to 50% in 10 years.²

Approximately 50% of the patients who undergo primary percutaneous coronary intervention have multivessel disease, usually manifested as a progressive chronic condition with high mortality rates. Currently, it is not possible to precisely prevent the recurrence of acute ischemic events, clearly demonstrating the need for biomarkers that may predict coronary atherosclerotic plaque instability.³

Recent studies have highlighted the pathophysiological role of classes of lipids other than LDL-cholesterol in atherosclerosis and AMI, including ceramides, sphingomyelin, phosphatidylcholines, and cholesterol esters.^4,5 Ceramides participate in multiple pathways involved in cellular damage signaling, liberating proinflammatory cytokines that directly modulate apoptosis via the expression of proapoptotic proteins.⁶

Our group has worked, throught mass spectometry, among other molecular techniques, for developing a plasma biomarker capable of diagnosing atherosclerotic plaque instability and predicting reinfartion and progression to Heart Failure (HF) in patients with Acute Coronary Syndrome (ACS).

Ceramides are lipid biomarkers with an emerging role in early diagnosis and risk stratification, acting as marker of primary and secondary cardiovascular (CV) events in patients with clinical and subclinical atherosclerosis who are susceptible to acute ischemic events.^5,7

Ceramide: a brief review of the physiology of this new lipid biomarker

Ceramides and LDL-cholesterol are structural lipids that maintain membrane fluidity and integrity through the formation of selective pores, modulating the movement of compounds between intra and extracellular spaces. Ceramides are sphingolipids formed by a sphingosine molecule and a fatty acid, being key components in the formation of cellular membranes⁸ and acting as an

important signaling intermediate in processes that regulate cell homeostasis, such as inflammation, apoptosis, and cellular stress response.⁹

Ceramides accumulate in the coronary atheroma,¹⁰and their glycosylated forms glucosylceramides and lactosylceramides (Figure 1) are abundant in the developing plaque.^11,12 Moreover, data from our group showed that the myocardial tissue itself may produce ceramides in a direct response to ischemia and reperfusion.¹³

Ceramidase is an enzyme that cleaves fatty acids from ceramide for producing sphingosine, which is in turn phosphorylated by sphingosine-1-phosphatase for producing sphingosine-1-phosphate. Ceramide synthesis may occur through the hydrolysis of sphingomyelin (degradation), the salvage (recycling) pathway where sphingosine is phosphorylated, or the de novo pathway where dihydroceramides are desaturated.⁹

Ceramides: a link between atherosclerosis, diabetes, and dyslipidemia

Ceramides constitute approximately 30% of circulating LDL-cholesterol. An increase in ceramide concentration alters cell membrane permeability, enabling the accumulation of LDL-cholesterol on blood vessel walls. This build-up amplifies the inflammatory process on vessel walls, promoting the apoptosis of vascular smooth muscle cells and endothelial dysfunction, which leads to atherosclerotic plaque instability and rupture¹⁴ (Figure 2).

In addition to the atherosclerotic plaque, this build-up occurs in smooth and skeletal muscles, interfering with the expression of glucose transporter type 4 (GLUT4); this causes a defect in muscle glucose uptake and hinders glycogen synthesis.¹⁵ Ceramides also stimulate the

apoptosis of pancreatic β cells, directly reducing insulin production.¹⁶Major et al.¹⁷ demonstrated that ceramides can mimic the cytotoxic effects of TNF-α, IL-1β, and IFN-γ in pancreatic β-cells, triggering inflammation and apoptosis.¹⁷ Ceramide accumulation in tissues results in metabolic dysfunction in multiple organs and diabetes complications. Figure 3 shows the main tissues affected by ceramides.^18,19

Therefore, the measurement of these molecules helps the physician determine not only the degree of dyslipidemia and risk of atherosclerosis through LDL-cholesterol levels, but also insulin resistance and β-cell apoptosis through ceramide levels.

Clinical implications led to a patent of this biomarker in the United States and Europe, being currently available for clinical use at referral hospitals such as Mayo Clinic.²⁰

Are screening examinations necessary for the follow-up of subclinical atherosclerosis?

There is a significant gap in the detection of subclinical atherosclerosis and the cost-effective triage and follow-up of this entity, with various noninvasive tests being routinely requested in populations at different levels of CV risk. This is a reality worldwide, and despite the increasing advances in noninvasive tests for detecting atherosclerosis, risk stratification remains imperfect.²¹ Considering the escalating costs of health care, this stereotyped medical practice should thus be reevaluated.

The association of clinical and imaging data for supporting the development of protocols that incorporate classical risk scores such as Framingham and Interheart has been proposed for improving CV risk stratification.

However, these methods, when applied to the general population without a triage step, have limited capacity for assessing CV risk due to aspects related to logistics and costs.²²

The Multi-Ethnic Study of Atherosclerosis (MESA) study, one of the most relevant in this area, brought important contributions for comprehending the development and progression of CVD from subclinical to clinical stage. In a sub analysis of the MESA study, a large protein biomarker panel was evaluated in the search for predictive markers of CVD progression. When compared to classical CV risk factors, protein biomarkers with various specific panels for inflammation, insulin resistance, lipids, hemostasia, fibrinolysis, oxidative damage, and endothelial stress, among others, had incremental predictive values for long-term adverse CV events that were only borderline (area under the receiver operating characteristic curve [AUC]: 0.768 vs 0.776, p = 0.003) and did not reach an incremental predictive value in the prediction of medium-term adverse CV events (AUC: 0.795 vs 0.796, p = 0.627). Considering these similar ROC curve values, new screening and risk stratification methods are thus required to improve early detection of plaque instability.²³

Once developed, such a biomarker would enable interventions at the beginning of atherosclerotic plaque progression, being essential for avoiding the large additional costs of atherosclerosis’ symptomatic stage. These considerations are important and should be evaluated when developing platforms for population health screening and seeking adequate cost-effectiveness.

Should we measure ceramides and LDL-cholesterol?

Subclinical atherosclerosis precedes most CV events, and its detection may improve CV risk stratification.^11,12 However, an incompatibility has been reported between apparently benign conventional risk factor profiles and subclinical atherosclerosis detected by coronary artery calcification (CAC) or intima thickness measured at the carotid ultrasound.^13,14

Studies have identified subclinical atherosclerosis in almost 60% of middle-aged individuals at low CV risk according to traditional risk scores, and multiple affected vessel sites were found in 41% of these individuals.¹⁵ These findings suggest that variables other than conventional CV risk factors may play relevant roles in atherogenesis.

Patients with atherosclerosis consist in a very heterogeneous population, with complex risk stratification, and should not be all considered as being at similar risk for acute events. The use of CV risk scores is currently recommended by guidelines as a stratification tool; however, due to limitations in predictive precision especially in patients at high CV risk, the optimization of risk tools by recalibrating scores or their association with biomarkers is frequently needed for a higher predictive accuracy in different populations.

LDL-cholesterol is a risk factor directly involved in the development of atherosclerotic plaque, therefore being an important therapeutic target in clinical practice. Dieting, lifestyle changes, and use of medications can result in significant and sustained reductions in plasma LDL-cholesterol levels. However, CVD are still one of the main causes of death worldwide,²⁴ suggesting that conventional LDL-cholesterol control is not enough; the early detection and prevention of atherosclerotic plaque instability may thus open the way for significantly reducing disease progression.

Current guidelines endorse LDL-cholesterol control and the measurement of nonspecific inflammatory markers such as C-reactive protein (CRP) in CV risk stratification. However, the pathophysiology of atherosclerosis involves the complex intersection of dyslipidemia, inflammation, endothelial dysfunction, platelet activation, and other factors.²⁵ Recent data demonstrate possible associations between each of these pathways and plasma ceramide levels, indicating an association and plausible causality of this biomarker in acute CVD and atherosclerotic plaque instability.

Moreover, plasma LDL-cholesterol does not precisely predict major adverse cardiac and cerebrovascular events (MACCE), requiring a thorough medical assessment and a series of noninvasive tests in clinical practice for following up on the progression of atherosclerotic plaques.²⁶ On the other hand, plasma ceramide concentrations are increased in various conditions related to cardiac diseases, in addition to their biochemical role in the progression of atherosclerosis, which has also been studied by our group. Preliminary studies have showed an increase in ceramides in the acute phase of AMI and in vulnerable plaques in humans, correlating these findings with pre-clinical data that showed the upregulation of ceramide-producing enzymes in the myocardium, with an increase in plasma ceramide levels within the first 24 hours of an acute ischemic event.⁵

Ceramides are also associated with a higher risk of disease progression in patients with HF. Among 423 patients with acute HF, plasma ceramide concentrations were independently associated with death and worsening of left ventricular function during hospitalization.²⁷

Searching for evidence: ceramides and CV risk prediction

Primary prevention:

The FINRISK study was performed in patients with no previous history of CV events and showed that circulating levels of specific ceramides (16:0, 18:0, and 24:1) were significantly associated with subsequent major CV events when compared to individuals who remained asymptomatic. Significant univariate associations between ceramides and fatal events suggest they play a fundamental role in atherosclerotic plaque rupture in this population.⁷

Still considering primary prevention, Petterson et al.²⁸demonstrated that the proportion of ceramides C24:0/C16:0 and the plasma concentration of ceramide C24:0 were inversely associated with coronary risk factors such as age and smoking habits, in addition to the development of CAD and HF.²⁸

CAD:

In a post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) study (N = 9631), Nguyen et al. demonstrated that plasma LDL-cholesterol levels were not associated with the primary composite outcome (myocardial infarction, stroke, acute decompensated HF, and CV death).²⁹ In addition, when evaluating patients in secondary prevention of CV events (N = 1562), they observed that LDL-cholesterol was only marginally associated with the incidence of CV events (adjusted hazard ratio 1.005 [95% confidence interval, CI = 1.002–1.009], p = 0.005 [1 mg/dl increase], with poor discrimination for MACE [AUC = 0.54, p = 0.087]).²⁹

Although studies with PCSK9 inhibitors such as Odyssey Outcomes and Fourier³⁰ reinforce the “the lower, the better” principle, meaning there is an association between low LDL-cholesterol levels and a low risk of clinical atherosclerosis, no perfect risk correlation is observed. In order to fill this gap, the measurement of metabolites with metabolomic techniques has been increasingly employed since it presents advantages over classical methods such as a more comprehensive analysis and the acquisition of a metabolic profile of the target tissue considering the disease of interest.

An undirected metabolomic analysis identified 3 plasma ceramides that were significantly associated with CV mortality in a cohort with angiography-confirmed CAD. Ceramides associated with high CV mortality in this study were C16:0, C18:0, and C24:1, and their association was independent from age, body mass index (BMI), smoking habits, use of statins, triglycerides, LDL-cholesterol, and total cholesterol.¹⁴

Kaasenbrood et al.,31 using the Secondary Manifestations of Arterial Disease (SMART) risk score, attempted to improve the prediction of acute events in this group of patients.³¹ This risk score comprehends clinical and laboratory variables (total cholesterol, HDL-cholesterol, estimated glomerular filtration rate [eGFR], CRP) and was tested in various cohorts; based on the obtained results, the authors suggested new algorithms for estimating CV risk in order to individually and more precisely stratify this population, demonstrating the possibility of improving risk scores by incorporating biomarkers.³¹

In the Prevención con Dieta Mediterránea (Mediterranean Diet Prevention, PREDIMED) study, a prospective cohort study with patients at high CV risk, ceramides C24:0, C22:0, and C16:0 were associated with CVD.4 The odds radios comparing the extreme quartiles of plasma ceramides C16:0, C22:0, C24:0, and C24:1 were 2.39 (1.49–3,83; p < 0.001), 1.91 (1.21–3.01; p = 0.003), 1.97 (1.21–3.01; p = 0.004), and 1.73 (1.09–2.74; p = 0.011), respectively. In another prospective study with approximately 500 patients who underwent elective coronary angiography, Meeusen et al. reported that plasma C16:0, C18:0, and C24:1 levels were independently associated with increased risk of MACCE in a mean follow-up of 4 years.32 The risk associated with ceramides was also independent from traditional risk factors, including age, sex, BMI, smoking habits, and cholesterol. Moreover, the predictive value remained significant after additional adjustments for serum glucose and family history of CAD. These results suggest that, when plasma ceramide levels are high in patients with or without significant stenosis of the coronary artery, the risk of death is high in both groups.³²

Another risk score involving ceramides is the Coronary Event Risk Test (CERT2), which was developed in the Western Norway Coronary Angiography Cohort (WECAC) study and validated by the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) and Langzeiterfolge der Kardiologischen Anschlussheilbehandlung (KAROLA) studies.³³ Results showed that the CV risk estimation tool incorporating ceramide measurement could reliably stratify MACE in patients with stable CAD. Additional evidence obtained by the WECAC and LIPID studies demonstrated that these biomarkers alone were able to accurately stratify primary CV risk in patients with and without diabetes; in individuals with diabetes, the only significant predictors in this study were the CERT2 score and high-sensitivity troponin.

ACS

In the European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound (favor verificar se está correto.) (ATHEROREMO-IVUS) study (N = 600 patients), Cheng et al. demonstrated that plasma C16:0, C18:0, and C24:1 levels were significantly associated with vulnerable coronary plaque in individuals with ACS. Increased plasma levels of these ceramides were also significantly associated with higher angiographic severity of coronary stenosis,^14,34 as well as a lower perfusion of the myocardial wall after stress in patients with established or suspected CAD who underwent myocardial perfusion scintigraphy.^35,36 These findings suggest causality between increased ceramides in the atherosclerotic plaque and its instability or severity.

Using optical coherence tomography (OCT) in patients with ST‐segment–elevation myocardial infarction (STEMI), Bo Yu et al. recently observed increased plasma C16:0, C18:0, and C24:0 levels when compared to individuals with no coronary disease or with stable CAD (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively). This was the first study using OCT that proved a positive independent association between plasma ceramide concentrations and plaque rupture, suggesting that plasma ceramide concentrations may act as potential biomarkers of plaque rupture.³⁷

Additional evidence of this association was obtained by Laasksonen et al.⁵ in a prospective cohort of patients with stable CAD; increased serum ceramide levels were observed in 81 out of 1580 patients (Table 1), who later presented MACE in 4.6 years of follow-up. This proportion was maintained even after adjustment for treatment with statins. Ceramides were predictive in both cases, with comparable odds ratios (OR) in patients using statins or not: 1.68 (1.31–2.15) vs 1.7 (1.33–2.17). In this study, plasma LDL-cholesterol was not significantly predictive of MACE.⁵

Table 1. – Relative risk scores involving ceramides in different cohorts.

Score	Category	BECAC (5-year risk)⁵			SPUM-ACS (1-year risk)⁵

		Deaths (n)	%	Relative Risk	Morte (n)	%	Relative Risk
0-2	Low	15/549	2.7%	1.0	9/575	1.6%	1.0
3-6	Moderate	29/601	4.8%	1.8	16/611	2.6%	1.7
7-9	Increased	20/288	6.9%	2.5	9/270	3.3%	2.1
10-12	Higher	17/149	11.4%	4.2	17/181	9.4%	6.0

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Source: adapted from Mayo Clinic. https://www.mayoclinic.org/

Laasksonen et al.⁵ analyzed the Special Program University Medicine-Inflammation in Acute Coronary Syndromes (SPUM-ACS) study (N = 1637), performed with patients with ACS, where ceramides were also predictors of MACE regardless of CV risk. In 51 patients who died within a year of a cardiac event, plasma ceramides were found at significantly higher levels when compared to patients who survived during follow-up.⁵

Finally, De Carvalho et al.¹³ assessed patients with AMI in 2 cohorts of patients subjected to invasive stratification, comparing MACCE-free survival rates in high-risk patients as defined by the Global Registry of Acute Coronary Events (GRACE) score adjusted to the local population. In this study, the GRACE score was less capable of predicting event-free survival when compared to an association of 12 plasma ceramides measured in the acute phase of AMI.¹³ This study included Chinese, Malay, and Indian people, ethnicities that represent a considerable proportion of the global population; external revalidation of the predictive value of these biomarkers was performed in a Caucasian population in New Zealand, demonstrating the development of a potentially universal biomarker. These data were also corroborated by the molecular biology analysis of atherosclerotic plaque biopsies obtained from patients subjected to heart surgery who had experienced or not recent infarctions, confirming the increase in ceramide production in patients with vulnerable atherosclerotic plaque.

The main studies evaluating the association between ceramides and risk of acute CV events are demonstrated on Table 2.

Table 2. – Main studies evaluating the association between ceramides and risk of acute cardiovascular events (by year of publication).

Author/reference	Study characteristics	Primary outcome	Adjustment	Main result
Laaksonen et al.⁵ European Heart Journal 2016;37, 1967-1976	Prospective cohort study with N = 1580 adults (62 years old; 59% male; BMI 25 kg/m2; LDL-cholesterol 2.8 mmol/l, triglycerides 1.4mmol/l; statin use 62.6%) who underwent elective coronary angiography due to stable CAD and were recruited at the Haukeland University Hospital in Bergen (BECAC study) with 4.6 years of follow-up, in addition to 1637 patients (63 years old; 78% male, BMI 26 kg/m2, LDL-cholesterol 2.6 mmol/l, triglycerides 1 mmol/l, statin use 27.2%) with an ACS diagnosis who underwent invasive treatment in 4 Swiss university hospitals (SPUM-ACS study), with 1-year follow-up	Cardiovascular death	Total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, age, sex, smoking habits, previous acute myocardial infarction, diabetes mellitus, hypertension, previous stroke	Cer (d18:1/16:0) and Cer (d18:1/24:1) were associated with an increased risk of cardiovascular death in all cohorts. OR Cer (d18:1/16:0)/Cer(d18:1/24:0) was 4.49 (95% CI, 2.24–8.98), 1.64 (1.29–2.08), and 1.77 (1.41–2.23) for Corogene, SPUM-ACS, and BECAC studies, respectively
Havulinna et al.⁷ Arteriosclerer Thromb Vasc Biol 2016;36: 2424-2430	Populational cohort study with N = 8101 healthy patients (48 years old; 47% male, BMI 26 kg/m2, LDL-cholesterol 3.3 mmol/l, triglycerides 1.3 mmol/l) from FINRISK 2002	Major cardiac and cerebrovascular adverse events	Total cholesterol, HDL-cholesterol, arterial pressure, diabetes mellitus, and smoking habits	Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) levels were significantly higher in patients with adverse cardiovascular progression when compared to asymptomatic individuals. Serum concentrations of high-risk ceramides predicting cardiovascular death in patients with CAD were also higher in FINRISK MACE cases when compared to asymptomatic individuals, as follows: Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) 11.4%, 21.3%, and 17.0%, respectively (p < 0.001 for all)
Wang et al.⁴ Circulation 2017; 135: 2028-2040	Cohort study nested in the PREDIMED randomized study with N = 980 participants (68 years old; 45% male, BMI 30 kg/m2, LDL-cholesterol 3.4 mmol/l, triglycerides 1.6 mmol/l), including 230 cases of CVD and 767 randomly selected participants. The sub cohort included 37 overlapping CVD cases. Two participants with undetectable plasma ceramide concentrations were excluded. Follow-up: 4.5 years	MACE	IAge, sex, BMI, family history of premature CAD, smoking habits, history of hypertension, dyslipidemia, and type 2 diabetes.	Among the high-risk ceramides identified, the upper quartiles of plasma Cer (d18:1/16:0), Cer (d18:1/22:0), Cer (d18:1/24:0), and Cer (d18:1/24:1) levels were associated with an adverse cardiovascular outcome. The multivariable hazard ratios comparing the extreme quartiles of plasma C:16, C22:0, C24:0, and C24:1 concentrations were 2.39 (1.49–3.83, p < 0.001), 1.91 (1.21–3.01, p = 0.003), 1.97 (1.21–3.01, p = 0.004), and 1.73 (1.09–2.74, p = 0.011), respectively.
De Carvalho et al.¹³ JACC Basic Transl Sci 2018;3:163-175	Prospective longitudinal study with N = 327 patients from a primary cohort (57 years old; 90% male, BMI 26 kg/m2, LDL-cholesterol 3.1 mmol/l, triglycerides 1.2 mmol/l) and 119 patients in the validation cohort (66 years old; 72% male, BMI 29 kg/m2, LDL-cholesterol 3.2 mmol/l) with ACS who underwent invasive stratification with plasma measurements performed before and after stratification; 1-year follow-up.	Major cardiac and cerebrovascular adverse events	GRACE	Among the high-risk ceramides previously identified, the plasma Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) levels were associated with adverse cardiovascular events
Meeusen et al.³² Arterioscler Thromb Vasc Biol. 2018; 38: 1933-1939	Cross-sectional study: 495 participants (60 years old; 62% male, BMI 28kg/m2, LDL-cholesterol 3.1 mmol/l, triglycerides 1.7 mmol/l, statin use 28.5%) before nonurgent coronary angiography. Follow-up: 4 years	MACE (myocardial infarction, percutaneous intervention, myocardial revascularization surgery, stroke, or death).	Age, sex, BMI, hypertension, smoking habits, LDL-cholesterol, HDL-cholesterol, triglycerides, glycemia, family history of CAD	Among the high-risk ceramides previously identified, plasma Cer (d18:1/16:0), Cer (d18:1/18:0), and Cer (d18:1/24:1) levels were associated with adverse cardiovascular events. Adjusted hazard ratios per standard deviation (95% CI) were 1.50 (1.16–1.93) for Cer (16:0), 1.42 (1.11–1.83) for Cer (18:0), and 1.43 (1.08–1.89) for Cer (24:1)
Peterson et al.²⁸ J Am Heart Assoc. 2018;7: e007931	Community-based study: 2642 participants from the Framingham Heart Study (FHS; 66 years old; 46% male, BMI 28 kg/m2, LDL-cholesterol 2.7 mmol/l, triglycerides 1.3 mmol/l, statin use 42.7%) and 3134 participants from the Study of Health in Pomerania (SHIP; 54 years old, 48% male, BMI 28 kg/m2, LDL-cholesterol 5.5 mmol/l, triglycerides 1.8 mmol/l, statin use 14.5%) were followed up for 6 and 8 years, respectively	MACE (fatal and non-fatal cardiovascular events)	Age, sex, BMI, hypertension, diabetes mellitus, smoking habits, anti-hypertensives, total cholesterol/HDL-cholesterol ratio, triglycerides, and lipid-lowering drugs	Among the high-risk ceramides previously identified, only Cer (d18:1/24:0) were associated with adverse cardiovascular outcomes. In the meta-analysis of both cohorts and after adjusting risk factors for CAD, C24:0/C16:0 ratios were inversely associated with CAD (hazard ratio per mean standard deviation increase, 0.79; 95% CI, 0.71–0.89; p < 0.0001) and inversely associated with HF (hazard ratio, 0.78; 95% CI, 0.61–1,00; p = 0.046).
Hilvo et al.³³ European Heart Journal 2019, in press	Longitudinal study; 3 large cohort studies: 3789 patients (62 years old; 72% male, LDL-cholesterol 2.9 mmol/l, triglycerides 1.5 mmol/l, statin use 72.6%) from the Western Norway Coronary Angiography Cohort (WECAC); 5991 patients (65 years old; 83% male, LDL-cholesterol 3.9 mmol/l, triglycerides 1.6 mmol/l, statin use 49.9%) from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study; and 1023 patients (62 years old; 84% male, LDL-cholesterol 3 mmol/l, triglycerides 1.6 mmol/l, statin use 75.6%) from the Langzeiterfolge der Kardiologischen Anschlussheilbehandlung (KAROLA) study. Follow-up: 6 years	MACE (composite endpoint including death due to CV events, MI, and stroke )	IAge, sex, treatment with statins (WECAC, KAROLA), diabetes mellitus, hypertension, current smoking habit, previous MI, previous stroke, stratified according to vitamin B intervention (WECAC) and treatment group (LIPID).	A simple risk score, based on ceramides and phosphatidylcholines with the best prognostic characteristics, was developed by the WECAC study and validated in the other 2 cohorts. This score was highly significant for predicting mortality due to CVD (multi-adjusted hazard ratios [95% CI] per standard deviation were 1.44 [1.28–1.63] at the WECAC, 1.47 [1.34–1.61] at the LIPID study, and 1.69 [1.31– 2.17] at the KAROLA study). Moreover, a combination of the risk score with high-sensitivity troponin T increased hazard ratios to 1.63 (1.44–1.85) and 2.04 (1.57–2.64) in the WECAC and KAROLA cohorts, respectively.

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Conclusion

Plasma ceramides are elevated in patients with MACCE, and pre-clinical and clinical studies demonstrate an association between these lipids and atherosclerotic plaque instability.

Their measurement has incremental value for risk stratification, in addition to the classic risk factors both in primary and secondary CV prevention; consecutive measurements may have higher incremental predictive value than other biomarkers considering future adverse events. However, we still need further evidence from randomized studies to assess the impact of this marker on prognosis and of treatment escalation guided by plasma ceramide levels.

Footnotes

Study Association

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

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Sources of Funding: There were no external funding sources for this study.

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PERMALINK

Ceramidas Plasmáticas na Estratificação de Risco das Doenças Cardiovasculares

Débora L M Junqueira

Alline Stach

Adriano Caixeta

Juliana Sallum

Erika Yasaki

Jeane Tsutsui

Edgar Rizatti

Carlos E Rochitte

Ching-Jianhong

Jean-Paul Kovalik

José E Krieger

A Mark Richards

Mark Y Chan

Leonardo P de Carvalho

Resumo

Introdução

Ceramida: uma breve revisão da fisiologia desse novo biomarcador lipídico.

Figura 1. – Vias do metabolismo de esfingolipídios.

Ceramidas: uma ligação entre aterosclerose, diabetes e dislipidemia

Figura 2. – Ceramidas plasmáticas e ruptura de placa. ECAM = eventos cardiovasculares adversos maiores. Fonte: coleção do autor.

Figura 3. – Ação das ceramidas em diferentes órgãos.

Os exames de rastreamento são necessários para o acompanhamento da aterosclerose subclínica?

Devemos dosar as ceramidas e o colesterol LDL?

A busca por evidências: ceramidas e predição de risco CV

Prevenção primária:

Doença arterial coronária:

SCA

Tabela 1. – Escore de risco relativo envolvendo ceramidas em diferentes coortes.

Tabela 2. – Principais estudos que avaliaram a associação entre as ceramidas e o risco de eventos cardiovasculares agudos (publicação ordenada por ano).

Conclusão

Footnotes

Referências

Plasma Ceramides in Cardiovascular Disease Risk Stratification

Débora L M Junqueira

Alline Stach

Adriano Caixeta

Juliana Sallum

Erika Yasaki

Jeane Tsutsui

Edgar Rizatti

Carlos E Rochitte

Ching-Jianhong

Jean-Paul Kovalik

José E Krieger

A Mark Richards

Mark Y Chan

Leonardo P de Carvalho

Abstract

Introduction

Ceramide: a brief review of the physiology of this new lipid biomarker

Figure 1. – Sphingolipid metabolic pathways.

Ceramides: a link between atherosclerosis, diabetes, and dyslipidemia

Figure 2. – Plasma ceramides and plaque rupture. Source: author’s collection.

Figure 3. – Effect of ceramides on different organs.

Are screening examinations necessary for the follow-up of subclinical atherosclerosis?

Should we measure ceramides and LDL-cholesterol?

Searching for evidence: ceramides and CV risk prediction

Primary prevention:

CAD:

ACS

Table 1. – Relative risk scores involving ceramides in different cohorts.

Table 2. – Main studies evaluating the association between ceramides and risk of acute cardiovascular events (by year of publication).

Conclusion

Footnotes

ACTIONS

PERMALINK

RESOURCES

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