Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC bLf69LhCPZQbNkYDyPgNcTn S0066-782X2021000100048 abc.20190476 10.36660/abc.20190476 Artigo Original A Associação da Relação Proteína C-Reativa/Albumina em Pacientes com Ectasia da Artéria Coronária Isolada Sercelik Alper 1 Tanrıverdi Okan 2 0000-0001-7768-2562 Askin Lutfu 2 Turkmen Serdar 2 Sanko University Faculty of Medicine Gaziantep Turquia Sanko University Faculty of Medicine,Gaziantep - Turquia Adiyaman University Education and Research Hospital Adıyaman Century Turquia Adiyaman University Education and Research Hospital - Cardiology,Adıyaman, Century - Turquia Correspondência: Lutfu Askin • Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Cardiology - Adıyaman Eğitim Ve Araştırma Hastanesi Kardiyoloji Bölümü Adıyaman Centry, 2230 – Turquia E-mail: lutfuaskin23@gmail.com

Contribuição dos Autores

Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados, Análise estatística and Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Sercelik A, Askin L, Turkmen S, Tanriverdi O; Redação do manuscrito: Askin L.

Potencial conflito de interesses

Os autores declaram não haver conflito de interesses pertinentes.

 16 12 2020 01 2021 116 1 48 54 17 07 2019 09 09 2019 23 10 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Resumo Fundamento

A ectasia da artéria coronária (EAC) é definida como a dilatação difusa ou localizada do lúmen da artéria coronária com diâmetro de 1,5 a 2,0 vezes o diâmetro da artéria coronária normal adjacente. A relação proteína C-reativa/albumina (CAR, sigla em inglês) é um marcador inflamatório útil que tem sido documentado em doença arterial coronariana.

 Objetivo

Analisar a associação entre a EAC e a CAR.

 Métodos

Um protocolo caso-controle foi utilizado neste estudo. Foram incluídos 102 pacientesconsecutivos com EAC isolada sem estenose (56 homens e 46 mulheres; idade média de 60,4 ± 8,8 anos). O grupo controle era constituido pelo mesmo número de pacientes pareados por sexo e idade com artérias coronárias normais (55 homens e 47 mulheres; idade média de 61,2 ± 9,1 anos). Características clínicas, achados laboratoriais e histórico de uso de medicamentos foram registrados. Foram realizados teste t de Student, teste U de Mann-Whitney, teste do qui-quadrado, análise de regressão linear e logística. Foi considerado estatisticamente significativo p bilateral < 0,05.

 Resultados

A CAR estava aumentada nos pacientes com EAC em comparação com os controles (32 e 16; p < 0,001). Além disso, foi verificado que a CAR era um preditor independente da EAC (razão de chances = 2,202; intervalo de confiança 95%, 1,184 – 5,365; p < 0,001).

 Conclusão

No presente estudo, determinamos que os níveis da CAR estavam significativamente mais altos no grupo EAC que no grupo controle e a CAR estava significativamente correlacionada com a EAC. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

 Proteína C-Reativa Albuminas Doença da Artéria Coronariana Inflamação Aneurisma Coronário Dilatação Patológica (ectasia Introdução

A ectasia da artéria coronária (EAC) é definida como a dilatação difusa ou localizada do lúmen da artéria coronária com diâmetro de 1,5 a 2,0 vezes o diâmetro da artéria coronária normal adjacente. Os aneurismas coronários são definidos como a dilatação luminal com um aumento > 2,0 vezes.1 Com o rápido aumento nas aplicações de angiografia coronária (AC), um número crescente de EAC tem sido detectado. Tem sido demonstrado que a EAC é um preditor de mortalidade. As taxas de mortalidade de pacientes com EAC são semelhantes às de pacientes com doença aneurismática não obstrutiva ou doença de três vasos.2 A etiopatogênese dessa entidade clínica não é totalmente compreendida. A causa mais comum da EAC na população ocidental é a doença arterial coronariana (DAC) aterosclerótica. As anomalias congênitas são a segunda causa etiológica mais comum. Doença de Kawasaki, doenças do tecido colágeno e doenças do tecido conjuntivo são outras causas comuns da EAC. Os procedimentos invasivos coronários percutâneos e o trauma raramente levam à EAC.3 , 4 A dor precordial é geralmente o sintoma primário da EAC. No entanto, arritmia, síndrome coronariana aguda e morte cardíaca súbita são outras condições clínicas observadas na EAC.5 , 6

Estudos anteriores demonstraram que a inflamação pode desempenhar um papel na EAC.7 A PCR e a albumina têm sido associadas à gravidade da DAC e à presença de complicações cardiovasculares.8 A PCR, que é um dos biomarcadores inflamatórios mais amplamente usados, está associada à disfunção endotelial, estado protrombótico, remodelamento e desestabilização das placas ateroscleróticas. Além disso, tem sido verificado que os níveis elevados de PCR em pacientes com carga aterosclerótica estão associados a eventos cardiovasculares significativos.11 De outra forma, a inflamação causa a hipoalbuminemia com interrupção do equilíbrio síntese-catabolismo da albumina. A albumina sérica é a proteína sérica mais importante, com funções vitais no corpo humano e possui propriedades antiaterogênicas, incluindo atividades antioxidantes, inibição da ativação plaquetária e modulação e agregação do metabolismo do ácido araquidônico.15 Vários estudos anteriores relataram que a hipoalbuminemia está associada ao infarto do miocárdio mais frequente e ao aumento da mortalidade em pacientes com síndrome coronariana aguda.10 , 16 , 17 Em comparação com a PCR ou a albumina isoladamente, a relação PCR/albumina (CAR, sigla em inglês), um novo índice de risco baseado na inflamação, demonstrou refletir melhor o prognóstico em pacientes com doença aguda e malignidade.18 No entanto, a relação entre a CAR e a EAC ainda não é conhecida. A EAC é uma doença inflamatória; portanto, formulamos a hipótese de que o CAR poderia estar associado ao EAC. Nosso objetivo foi o de investigar a associação entre a EAC e a CAR.

 Métodos

Foi realizado um estudo caso-controle aprovado pelo Comitê de Ética do Hospital Universitário de Sanko. Foram incluídos pacientes com suspeita de isquemia coronária e dor precordial típica após resultados positivos ou equivalentes de testes isquêmicos não invasivos. Todos os pacientes foram submetidos à AC. Durante a AC, os dados digitais de todos os pacientes foram analisados e foram realizadas medidas coronárias quantitativas. O diâmetro do cateter foi utilizado como referência para determinar o diâmetro real do lúmen da artéria coronária. A definição do segmento ectático foi determinada pela realização de pelo menos duas medições nos segmentos proximal, médio e distal das artérias coronárias em pacientes com AC normal e em pacientes que foram considerados como tendo um segmento coronário ectático. A EAC foi definida como a dilatação difusa ou localizada do lúmen da artéria coronária com diâmetro 1,5 a 2,0 vezes o diâmetro da artéria coronária normal adjacente e esses pacientes foram incluídos no grupo EAC isolada. Os pacientes sem placa coronariana ou ectasia foram incluídos no grupo coronária normal.

O histórico médico da população do estudo foi obtido de prontuários e registrado em formulários elaborados para cada paciente. A hipertensão (HT) foi diagnosticada quando a PAS era > 140 mmHg e/ou quando a PAD era > 90 mmHg, ou pelo uso de medicamentos anti-hipertensivos. Diabetes mellitus (DM) foi diagnosticada quando a glicemia de jejum era ≥ 126 mg/dL ou pelo uso de medicamentos antidiabéticos. A hiperlipidemia (HL) foi definida como colesterol total > 200 mg/dL, histórico de dislipidemia e/ou uso de medicamentos antilipidêmicos. Os pacientes que fumavam durante 1 ano ou mais foram definidos como fumantes. O IMC foi determinado usando a fórmula padrão. A FEVE foi calculada automaticamente de acordo com o método de Simpson modificado, com auxílio de um software do aparelho de ecocardiografia.20

Medições laboratoriais

Os níveis de glicose no sangue, creatinina, albumina e PCR foram determinados conforme descrito. A proteína total sérica e a albumina foram medidas por bromine cresol technique usando um analisador C8000 (Abbott Laboratories, IL, EUA). A PCR foi medida por nefelometria (BN ProSpec System, Siemens). A taxa de filtração glomerular estimada foi determinada utilizando a equação Cockcroft-Gault.

 Angiografia coronária

Foi realizada a AC pelo método de Judkins, via femoral, utilizando os ângulos cranial e caudal nos planos inclinados direito e esquerdo a 30 fps. As imagens de AC dos pacientes foram analisadas por cardiologistas intervencionistas cegos ao estudo. A EAC já foi definida por Falsetti e Carroll;21 o nosso estudo utilizou o mesmo método. Os segmentos normais foram definidos como a ausência de estenose ou ectasia determinada pela AC. Os casos de EAC com estenose coronariana foram excluídos do estudo.

 Análise estatística

A análise estatística foi realizada utilizando SPSS v25 (SPSS Inc., EUA). A normalidade das variáveis contínuas foi testada pelo teste de Kolmogorov-Smirnov e apresentada como média e desvio padrão ou mediana e intervalo interquartil, de acordo com a normalidade dos dados. As variáveis contínuas com distribuição normal foram comparadas pelo teste t de Student e o teste U de Mann-Whitney foi usado para aquelas com distribuição não normal. Foi utilizado o teste t de Student para valores não pareados. Os dados categóricos foram comparados usando o teste do qui-quadrado. Na análise de regressão linear univariada, as variáveis com nível de significância p < 0,25 foram definidas como potenciais marcadores de risco e incluídas como variáveis comuns em todo o modelo de variável. A análise de regressão logística foi realizada para obter determinantes independentes da EAC. Foi considerado estatisticamente significativo p bilateral < 0,05.

 Resultados

Dos 226 pacientes, 8 foram excluídos por causa de infarto do miocárdio e disfunção ventricular esquerda; 5 foram excluídos por hipertrofia ventricular esquerda e doença valvar cardíaca e 6 foram excluídos por HT e insuficiência renal (n = 6). Além disso, 3 pacientes foram excluídos por outros motivos, como doença cerebrovascular, disfunção hepática, doença autoimune, doença neoplásica e osteoporose (n = 3). Após essas exclusões, 204 pacientes foram inscritos. Foram incluídos 102 pacientes com EAC isolada sem estenose da artéria coronária (56 homens e 46 mulheres; idade média 60,4 ± 8,8 anos) no grupo paciente; o grupo controle foi constituído pelo mesmo número de indivíduos consecutivos com artérias coronárias angiograficamente normais (55 homens e 47 mulheres; idade média 61,2 ± 9,1 anos).

A Tabela 1 mostra os dados dos pacientes. As características demográficas mostraram grupos pareados por idade e sexo. Fatores de risco de DAC como DM também foram semelhantes, mas outros fatores de risco (tabagismo, HT, HL e histórico familiar) foram significativamente maiores no grupo EAC do que no grupo controle (p < 0,001, p < 0,001, p = 0,006 e p = 0,022, respectivamente). Nenhuma mudança foi observada em termos de regimes de tratamento.

– Características de linha de base da população do estudo
Variáveis Grupo EAC (n = 102) Grupo controle (n = 102) Valor p
Idade, anos 60,4 ± 8,8 61,2 ± 9,1 0,422
Sexo (masculino), n, (% ) 56 (54,9) 55 (53,9) 0,740
IMC (kg/m2) 27,4±3,1 25,2± 3,2 0,317
Diabetes mellitus, n (%) 15 (14,7) 12 (11,7) 0,422
Tabagismo, n, (%) 40 (39,2) 18 (17,6) < 0,001
Hipertensão, n (%) 38 (37,2) 27 (26,4) < 0,001
Hiperlipidemia, n (%) 22 (21,5 ) 10 (9,8) 0,006
Histórico familiar, n, (%) 15 (14,7) 8 (7,8) 0,022
Medicamentos prévios, n, (%)
Ácido acetilsalicílico 20 (19,6) 16 (15,6) 0,224
Betabloqueadores 22 (21,5) 17 (16,6) 0,314
IECA/BRA 17 (16,6) 13 (12,7) 0,509
Estatinas 10 (9,8) 7 (7,1) 0,356
FEVE, (%) 60,2±3,4 61,3±3,9 0,533
PAS (mmHg) 122,0±9,1 118,6±7,5 0,424
PAD (mmHg) 88,0±7,2 85,6±4,1 0,358
Frequência cardíaca (batidas/m) 75,2±9 73,8±7 0,411
Hemoglobina, g/dL 13,1+1,8 12,7+1,7 0,388
Contagem de leucócitos, 103/mL 8,6±2,9 8,4±2,2 0,758
Contagem de plaquetas, 103/mL 232,7±77,4 244,8±75,2 0,554
Glicemia de jejum (mg/dL) 127,1±42,8 123,1±45,2 0,146
Creatinina, mg/dL 0,86 (0,75-0,99) 0,85 (0,75-0,97) 0,785
TFGe, mL/min 92,3 (68,9-105,6) 93,8 (74,9-107,9) 0,656
Colesterol total, mg/dL 168,0±36,0 158,2±39,8 0,411
HDL (mg/dL) 33,6±7,0 39,8±8,0 0,012
LDL (mg/dL) 123,2±32,6 98,4±29,4 < 0,001
Triglicerídeos, mg/dL 129 + 61 122 + 58 0,188
Proteína C-reativa, mg/dL 1,25 (0,50-2,84) 0,62 (0,27-1,16) < 0,001
Albumina, g/dL 3,76 + 0,42 4,02 + 0,32 < 0,001
CAR, *100 32 (12-68) 16 (6-30) < 0,001

BRA: bloqueadores dos receptores da angiotensina; CAR: relação proteína C-reativa/albumina; FEVE: fração de ejeção do ventrículo esquerdo; HDL: lipoproteína de alta densidade; IECA: inibidores da enzima conversora de angiotensina; IMC: índice de massa corporal; LDL: lipoproteína de baixa densidade; PAD: pressão arterial diastólica; PAS: pressão arterial sistólica; TFGe: taxa de filtração glomerular estimada.

A avaliação de IMC, PAS, PAD, FEVE, frequência cardíaca e glicemia de jejum não revelou diferenças significativas. Os parâmetros do painel lipídico, triglicerídeos e grupos de colesterol total foram semelhantes; o HDL foi mais alto nos controles (p = 0,012) e o LDL foi maior nos pacientes com EAC (p < 0,001). A PCR, a albumina e a CAR diferiram significativamente entre os grupos (p < 0,001). Houve semelhança entre os grupos em relação aos outros parâmetros laboratoriais.

Aplicando um modelo de regressão logística univariada, DM, tabagismo, HT e CAR correlacionaram-se com a EAC. A análise de regressão revelou que tabagismo, HT e CAR foram preditores independentes de EAC (tabagismo: razão de chances [RC] 1,812 [IC 95% 1,124 – 2,655; p = 0,024], HT: RC 2,175 [IC 95% 1,156 – 4,227; p < 0,001], CAR: RC 2,202 [IC 95% 1,184 – 5,365; p < 0,001]) ( Tabela 2 ).

– Fatores associados com a ectasia da artéria coronária
Análise de regressão linear Análise de regressão logística
Coeficientes IC 95% Valor p RC IC 95% Valor p
Idade, anos 0,052 0,013-0,107
FEVE 0,002 −0,018-0,026
IMC (kg/m2) 0,030 0,010-0,073
Diabetes mellitus 0,168 0,011- 0,524 0,024* 1,277 0,811-1,613 0,102
Tabagismo 0,322 0,010-1,114 0,007* 1,812 1,124-2,655 0,024*
Hipertensão 0,533 0,017-1,010 0,003* 2,175 1,156-4,227 < 0,001*
Hiperlipidemia 0,025 −0,020-0,056
PAS (mmHg) 0,068 −0,017-0,122
PAD (mmHg) 0,024 −0,002-0,048
Frequência cardíaca (batidas/m) 0,074 −0,024-0,172
CAR, *100 0,618 0,119-1,496 < 0,001* 2,202 1,184-5,365 < 0,001*
HDL (mg/dL) −0,076 −0,312-0,025
LDL (mg/dL) 0,009 −0,057-0,020

*Valor p < 0,05. As variáveis com p < 0,25 na regressão univariada foram incluídas na regressão multivariada. CAR: relação proteína C-reativa/albumina; FEVE: fração de ejeção do ventrículo esquerdo; HDL: lipoproteína de alta densidade; IMC: índice de massa corporal; LDL: lipoproteína de baixa densidade; PAD: pressão arterial diastólica; PAS: pressão arterial sistólica.

Discussão

Este relato mostra que a CAR foi significativamente mais alta no grupo EAC do que no grupo controle. Até onde sabemos, somos os primeiros a mostrar que a CAR está intimamente associada à EAC.

Ainda não está claro quais fatores locais ou globais estão envolvidos na patogênese da EAC. Foi relatado que a EAC é causada pela anormalidade generalizada na parede vascular contendo vários segmentos e que representa ectasia sacular em vez de ectasia fusiforme.22 Um estudo relativamente limitado sobre o prognóstico foi realizado para pacientes com EAC. Trinta anos atrás, o maior estudo de coorte de EAC descobriu que os pacientes aneurismáticos tinham uma taxa de mortalidade em 5 anos de 26%.23 Kajinami et al.,26 examinaram a autópsia de um paciente com EAC e hipercolesterolemia familiar, que morreu no século XX devido a um infarto agudo do miocárdio. O exame microscópico revelou uma grande quantidade de células plasmáticas, macrófagos e infiltração de linfócitos nas camadas íntima/média das artérias coronárias. Durante o exame patológico da EAC, foram observadas evidências de reações ateroscleróticas, como hialinização comum típica, calcificação focal e fibrose, acúmulo de lipídios, dano intimal e medial, colesterol, hemorragia e corpo estranho de células gigantes.

Outro fator potencial que leva ao desenvolvimento da EAC é o óxido nítrico (ON), que pode causar dilatação coronária devido à hiperestimulação do endotélio. Muitos pacientes têm recebido o trinitrato de gliceril crônico para angina, que pode piorar a ectasia por meio da estimulação do ON. Esses pacientes podem ter DAC e a aterosclerose demonstrou causar liberação inadequada de ON endotelial.25 Quyyumi et al.,26 demonstraram a relação entre o ON e a aterosclerose relatando que a dilatação vascular coronária foi causada pelo aumento do ON, devido à acetilcolina sem aterosclerose angiograficamente comprovada.

O mecanismo patológico subjacente da EAC ainda não está totalmente compreendido. Embora não tenha sido confirmada uma relação definitiva entre a aterosclerose e a EAC, a EAC é considerada uma variante de DAC e a principal causa de EAC é a aterosclerose.23 , 27 O papel da inflamação no processo da aterosclerose é bem documentado.28 A aterosclerose está associada à formação de aneurisma que se estende até a túnica média durante um processo inflamatório, que termina com a degeneração da média cística. 31 Estudos anteriores demonstraram que marcadores inflamatórios, como moléculas de adesão solúveis no plasma, leucócitos, adiponectina, fosfolipase-A2 associada à lipoproteína, PCR, inibidor do ativador do plasminogênio-1, IL-1, TNF-alfa e IL-10 foram significativamente aumentados em pacients com EAC.32

Vários estudos anteriores mostraram que a CAR está associada à aterosclerose e sugeriram que deveria ser considerada um marcador de risco cardiovascular. Este estudo verificou que a CAR foi significativamente mais alta em pacientes com EAC do que no grupo controle e apoia a hipótese de que a aterosclerose causa EAC.

As células isquêmicas ou necróticas danificadas causam uma resposta inflamatória sistêmica ao liberar agentes pró-inflamatórios no tecido e no plasma. O prognóstico da doença pode mudar com a velocidade da inflamação.33 Tem sido demonstrado que a aterosclerose demonstrou está fortemente correlacionada com o aumento da PCR sérica.34 Além disso, tem sido mostrado que a PCR está associada com disfunção coronária endotelial dependente e independente em pacientes com DAC,35 sugerindo que o aumento da PCR pode predizer a disfunção em pacientes com STEMI e pode ser um forte preditor do fenômeno de não refluxo ( no-reflow ).36 Em nosso estudo, os níveis elevados da PCR demonstrarm uma forte associação entre a EAC e a PCR.

A hipoalbuminemia não é apenas um fator de risco; também indica mau prognóstico em pacientes com STEMI.37 , 38 Foi documentado que o aumento da inflamação contribui para a síntese e a degradação da albumina.39 A hipoalbuminemia leva a muitas complicações, incluindo a disfunção endotelial, bem como a agregação plaquetária e a estenose da artéria coronária induzida por disfunção plaquetária.40 Em um estudo de 1.303 indivíduos com síndrome coronariana aguda, foi verificado que os níveis séricos de albumina estavam associadas à gravidade da DAC.10 Em nosso estudo, houve uma correlação negativa entre o nível sérico de albumina level e a EAC.

Acredita-se que a CAR, conforme originalmente descrita por Fairclough et al.,42 seja melhor do que a PCR e a albumina isoladamente para predizer complicações médicas.42 A inflamação é uma das características da aterogênese e a CAR demonstra as condições inflamatórias.

A CAR foi recentemente investigada como um biomarcador potencial para prever as consequências de eventos cardiovasculares adversos.43 Cagdas et al.,44 mostraram que a CAR e a gravidade da DAC estavam associadas. Em pacientes com câncer maligno, a CAR previu o prognóstico e a progressão da doença.45 , 46 Por isso, a CAR é um biomarcador mais confiável para a previsão da gravidade da doença. Relatórios anteriores que avaliaram a CAR na DAC mostraram resultados promissores. Um estudo de STEMI mostrou que a contagem de leucócitos, a relação neutrófilos/linfócitos e a CAR se correlacionaram com o fenômeno de não refluxo.43

Os resultados do nosso estudo mostraram que a associação da CAR com a EAC foi significativa. Este é o primeiro estudo a mostrar uma associação entre a EAC e os níveis mais elevados da CAR. O aumento da CAR foi um marcador prognóstico da EAC. Os resultados de um estudo sobre a relação entre a hipercolesterolemia familiar e a EAC mostraram que a dislipidemia foi uma das causas da EAC.47 Em nosso estudo, foram observados níveis elevados de LDL e baixos de HDL em pacientes com EAC. Nenhuma mudança significativa foi encontrada nos níveis de triglicerídeos em pacientes com EAC em comparação com os controles. Uma forte relação foi demonstrada entre HT e EAC.48 Em nosso estudo, a prevalência de HT foi maior entre pacientes com EAC e a HT foi independentemente associada com a EAC.

Observamos que a CAR foi mais alta nos pacientes do que no grupo controle. Supomos que a CAR elevada pode predizer o risco de aterosclerose em pacientes com EAC. Uma revisão da literatura mostra que a EAC não é uma condição clínica inocente e que estudos maiores serão necessários no futuro para criar a melhor estratégia de tratamento e gerenciamento de risco.

Limitações do estudo

Estudos mais abrangentes e multicêntricos são necessários para melhor explicar a variabilidade dos marcadores inflamatórios e o papel preditor dos níveis séricos da CAR. A significância prognóstica da CAR não foi avaliada e deverá ser estabelecida em investigações futuras. Este foi um estudo caso-controle e, portanto, não foi possível obter dados de mortalidade. Embora a CAR seja aceita como um novo marcador miocárdico sensível, sua especificidade na determinação da presença de EAC tem sido questionada, porque muitas outras condições, especialmente outras infecções, também podem aumentar os níveis da CAR. Os níveis da CAR podem ser afetados por outros fatores importantes, como idade, sexo e raça. Finalmente, em vez de usar métodos quantitativos, como ultrassom intravascular, a avaliação visual foi o único método usado para diagnosticar e excluir pacientes.

 Conclusão

Nosso estudo demostra que os níveis da CAR são mais altos nos pacientes com EAC em comparação aos pacientes com artérias coronárias normais. Os níveis altos da CAR podem suportar a hipótese de que a CAR possa estar relacionada ao desenvolvimento da EAC. Em nosso estudo, os altos níveis da CAR estavam significativamente correlacionados com a EAC.

 Referências 1. Aktürk E, Aşkın L, Nacar H, Taşolar MH, Türkmen S, Çetin M, et al. Association of serum prolidase activity in patients with isolated coronary artery ectasia. Anatol J Cardiol. 2018;19(2):110-6. Aktürk E Aşkın L Nacar H Taşolar MH Türkmen S Çetin M et al Association of serum prolidase activity in patients with isolated coronary artery ectasia Anatol J Cardiol 2018 19 2 110 116 2. Baman TS, Cole JH, Devireddy CM, Sperling LS. Risk factors and outcomes in patients with coronary artery aneurysms. Am J Cardiol. 2004;93(12):1549-51. Baman TS Cole JH Devireddy CM Sperling LS Risk factors and outcomes in patients with coronary artery aneurysms Am J Cardiol 2004 93 12 1549 1551 3. Sayin T, Döven O, Berkalp B, Akyürek O, Güleç S, Oral D. Exercise induced myocardial ischemia in patients with coronary artery ectasia without obstructive coronary artery disease. Int J Cardiol. 2001;78(2):143-9. Sayin T Döven O Berkalp B Akyürek O Güleç S Oral D Exercise induced myocardial ischemia in patients with coronary artery ectasia without obstructive coronary artery disease Int J Cardiol 2001 78 2 143 149 4. Maehara A, Mintz GS, Ahmed JM, Fuchs S, Castagna MT, Pichard AD, et al. An intravascular ultrasound classification of angiographic coronary artery aneurysms. Am J Cardiol. 2001;88(4):365-70. Maehara A Mintz GS Ahmed JM Fuchs S Castagna MT Pichard AD et al An intravascular ultrasound classification of angiographic coronary artery aneurysms Am J Cardiol 2001 88 4 365 370 5. Mrdovic I, Jozic T, Asanin M, Perunicic J, Ostojic M. Myocardial reinfarction in a patient with coronary ectasia. Cardiology. 2004;102(1):32-4. Mrdovic I Jozic T Asanin M Perunicic J Ostojic M Myocardial reinfarction in a patient with coronary ectasia Cardiology 2004 102 1 32 34 6. Rosenberg VD, Nepomnyashchikh LM. Pathomorphological peculiarities of coronary artery ectasias and their role in the pathogenesis of sudden cardiac death. Bull Exp Biol Med. 2004;138(5):515-21. Rosenberg VD Nepomnyashchikh LM Pathomorphological peculiarities of coronary artery ectasias and their role in the pathogenesis of sudden cardiac death Bull Exp Biol Med 2004 138 5 515 521 7. Ozcan OU, Gulec S. Coronary artery ectasia. Cor Vasa. 2013;55(3):242-7. Ozcan OU Gulec S Coronary artery ectasia Cor Vasa 2013 55 3 242 247 8. Bisoendial RJ, Boekholdt SM, Vergeer M, Stroes ES, Kastelein JJ. C-reactive protein is a mediator of cardiovascular disease. Eur Heart J. 2010;31(17):2087-91. Bisoendial RJ Boekholdt SM Vergeer M Stroes ES Kastelein JJ C-reactive protein is a mediator of cardiovascular disease Eur Heart J 2010 31 17 2087 2091 9. Karadeniz M, Duran M, Akyel A, Yarlıoğlueş M, Öcek AH, Çelik İE, et al. High sensitive CRP level is associated with intermediate and high SYNTAX score in patients with acute coronary syndrome. Int Heart J. 2015;56(4):377-80. Karadeniz M Duran M Akyel A Yarlıoğlueş M Öcek AH Çelik İE et al High sensitive CRP level is associated with intermediate and high SYNTAX score in patients with acute coronary syndrome Int Heart J 2015 56 4 377 380 10. Kurtul A, Murat SN, Yarlioglues M, Duran M, Ocek AH, Koseoglu C, et al. Usefulness of serum albumin concentration to predict high coronary SYNTAX score and in-hospital mortality in patients with acute coronary syndrome. Angiology. 2016;67(1):34-40. Kurtul A Murat SN Yarlioglues M Duran M Ocek AH Koseoglu C et al Usefulness of serum albumin concentration to predict high coronary SYNTAX score and in-hospital mortality in patients with acute coronary syndrome Angiology 2016 67 1 34 40 11. Bisoendial RJ, Kastelein JJ, Peters SL, Levels JH, Birjmohun R, Rotmans JI, et al. Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects. J Lipid Res. 2007;48(4):952–60. Bisoendial RJ Kastelein JJ Peters SL Levels JH Birjmohun R Rotmans JI et al Effects of CRP infusion on endothelial function and coagulation in normocholesterolemic and hypercholesterolemic subjects J Lipid Res 2007 48 4 952 960 12. Devaraj S, Kumaresan PR, Jialal I. Effect of C-reactive protein on chemokine expression in human aortic endothelial cells. J Mol Cell Cardiol. 2004;36(3):405–10. Devaraj S Kumaresan PR Jialal I Effect of C-reactive protein on chemokine expression in human aortic endothelial cells J Mol Cell Cardiol 2004 36 3 405 410 13. Taniguchi H, Momiyama Y, Ohmori R, Yonemura A, Yamashita T, Tamai S, et al. Associations of plasma C-reactive protein levels with the presence and extent of coronary stenosis in patients with stable coronary artery disease. Atherosclerosis. 2005;178(1):173–7. Taniguchi H Momiyama Y Ohmori R Yonemura A Yamashita T Tamai S et al Associations of plasma C-reactive protein levels with the presence and extent of coronary stenosis in patients with stable coronary artery disease Atherosclerosis 2005 178 1 173 177 14. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997;349(9050):462–6. Haverkate F Thompson SG Pyke SD Gallimore JR Pepys MB Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group Lancet 1997 349 9050 462 466 15. Purdon AD, Rao AK. Interaction of albumin, arachidonic acid and prostanoids in platelets. Prostaglandins, Leukot Essent Fat Acids. 1989;35(4):213–8. Purdon AD Rao AK Interaction of albumin, arachidonic acid and prostanoids in platelets Prostaglandins, Leukot Essent Fat Acids 1989 35 4 213 218 16. Nelson JJ, Liao D, Sharrett AR, Folsom AR, Chambless LE, Shahar E, et al. Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 2000;151(5):468–77. Nelson JJ Liao D Sharrett AR Folsom AR Chambless LE Shahar E et al Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study Am J Epidemiol 2000 151 5 468 477 17. Oduncu V, Erkol A, Karabay CY, Kurt M, Akgun T, Bulut M, et al. The prognostic value of serum albumin levels on admission in patients with acute ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention. Coron Artery Dis. 2013;24(2):88–94. Oduncu V Erkol A Karabay CY Kurt M Akgun T Bulut M et al The prognostic value of serum albumin levels on admission in patients with acute ST-segment elevation myocardial infarction undergoing a primary percutaneous coronary intervention Coron Artery Dis 2013 24 2 88 94 18. Fairclough E, Cairns E, Hamilton J, Kelly C. Evaluation of a modified early warning system for acute medical admissions and comparison with C-reactive protein/albümin ratio as a predictor of patient outcome. Clin Med (Lond). 2009;9(1):30–3. Fairclough E Cairns E Hamilton J Kelly C Evaluation of a modified early warning system for acute medical admissions and comparison with C-reactive protein/albümin ratio as a predictor of patient outcome Clin Med Lond 2009 9 1 30 33 19. Kinoshita A, Onoda H, Imai N, Iwaku A, Oishi M, Tanaka K, et al. The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma. Ann Surg Oncol. 2015;22(33):803–10. Kinoshita A Onoda H Imai N Iwaku A Oishi M Tanaka K et al The C-reactive protein/albumin ratio, a novel inflammation-based prognostic score, predicts outcomes in patients with hepatocellular carcinoma Ann Surg Oncol 2015 22 33 803 810 20. Schiller NB, Acquatella H, Ports TA, Drew D, Goerke J, Ringertz H, et al. Left ventricular volume from paired biplane two-dimensional echocardiography. Circulation. 1979; 60(3):547-55. Schiller NB Acquatella H Ports TA Drew D Goerke J Ringertz H et al Left ventricular volume from paired biplane two-dimensional echocardiography Circulation 1979 60 3 547 555 21. Falsetti HL, Carroll RJ. Coronary artery aneurysm: a review of the literature with a report of 11 new cases. Chest. 1976; 69(5):630-6. Falsetti HL Carroll RJ Coronary artery aneurysm: a review of the literature with a report of 11 new cases Chest 1976 69 5 630 636 22. Williams MJ, Stewart RA. Coronary artery ectasia: local pathology or diffuse disease? Cathet Cardiovasc Diagn. 1994; 33(2):116-9. Williams MJ Stewart RA Coronary artery ectasia: local pathology or diffuse disease? Cathet Cardiovasc Diagn 1994 33 2 116 119 23. Swaye PS, Fisher LD, Litwin P, Vignola PA, Judkins MP, Kemp HG, et al. Aneurysmal coronary artery disease. Circulation. 1983;67(1):134-8. Swaye PS Fisher LD Litwin P Vignola PA Judkins MP Kemp HG et al Aneurysmal coronary artery disease Circulation 1983 67 1 134 138 24. Kajinami K, Kasashima S, Oda Y, Koizumi J, Katskuda S, Mabuchi H. Coronary ectasia in familial hypercholesterolemia: histopathologic study regarding matrix metalloproteinases. Mod Pathol. 1999; 12(12):1174-80. Kajinami K Kasashima S Oda Y Koizumi J Katskuda S Mabuchi H Coronary ectasia in familial hypercholesterolemia: histopathologic study regarding matrix metalloproteinases Mod Pathol 1999 12 12 1174 1180 25. Kahraman F, Karabacak M, Türker Y. Serum nitric oxide level in patients with coronary artery ectasia. Anatol J Cardiol. 2017; 17(4):341. Kahraman F Karabacak M Türker Y Serum nitric oxide level in patients with coronary artery ectasia Anatol J Cardiol 2017 17 4 341 26. Quyyumi AA, Dakak N, Andrews NP, Husain S, Arora S, Gilligan DM, et al. Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis. J Clin Invest. 1995; 95(4): 1747-55. Quyyumi AA Dakak N Andrews NP Husain S Arora S Gilligan DM et al Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis J Clin Invest 1995 95 4 1747 1755 27. Cohen P, O’Gara PT. Coronary artery aneurysms: a review of the natural history, pathophysiology, and management. Cardiol Rev. 2008;16(6):301-4. Cohen P O’Gara PT Coronary artery aneurysms: a review of the natural history, pathophysiology, and management Cardiol Rev 2008 16 6 301 304 28. Ozde C, Korkmaz A, Kundi H, Oflar E, Ungan I, Xankisi V, et al. Relationship between plasma levels of soluble CD40 ligand and the presence and severity of isolated coronary artery ectasia. Clin Appl Thromb Hemost. 2018;24(2):379-86. Ozde C Korkmaz A Kundi H Oflar E Ungan I Xankisi V et al Relationship between plasma levels of soluble CD40 ligand and the presence and severity of isolated coronary artery ectasia Clin Appl Thromb Hemost 2018 24 2 379 386 29. Xu Y, Yu Q, Yang J, Yuan F, Zhong Y, Zhou Z, et al. Acute hemodynamic effects of remote ischemic preconditioning on coronary perfusion pressure and coronary collateral blood flow in coronary heart disease. Acta Cardiol Sin. 2018;34(4):299-306. Xu Y Yu Q Yang J Yuan F Zhong Y Zhou Z et al Acute hemodynamic effects of remote ischemic preconditioning on coronary perfusion pressure and coronary collateral blood flow in coronary heart disease Acta Cardiol Sin 2018 34 4 299 306 30. Zhao ZW, Ren YG, Liu J. Low serum adropin levels are associated with coronary slow flow phenomenon. Acta Cardiol Sin. 2018;34(4):307-12. Zhao ZW Ren YG Liu J Low serum adropin levels are associated with coronary slow flow phenomenon Acta Cardiol Sin 2018 34 4 307 312 31. Nichols L, Lagana S, Parwani A. Coronary artery aneurysm: a review and hypothesis regarding etiology. Arch Pathology Lab Med 2008;132(5):823-8. Nichols L Lagana S Parwani A Coronary artery aneurysm: a review and hypothesis regarding etiology Arch Pathology Lab Med 2008 132 5 823 828 32. Turhan H, Erbay AR, Yasar AS, Askoy Y, Bicer A, Yetkin G, et al. Plasma soluble adhesion molecules; intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin levels in patients with isolated coronary artery ectasia. Coron Artery Dis. 2005;16(1):45-50 Turhan H Erbay AR Yasar AS Askoy Y Bicer A Yetkin G et al Plasma soluble adhesion molecules; intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin levels in patients with isolated coronary artery ectasia Coron Artery Dis 2005 16 1 45 50 33. Kottoor SJ, Arora RR. The utility of anti-inflammatory agents in cardiovascular disease: a novel perspective on the treatment of atherosclerosis. J Cardiovasc Pharmacol Ther. 2018: 23(6):483-493. Kottoor SJ Arora RR The utility of anti-inflammatory agents in cardiovascular disease: a novel perspective on the treatment of atherosclerosis J Cardiovasc Pharmacol Ther 2018 23 6 483 493 34. Yousuf O, Mohanty BD, Martin SS, Joshi PH, Blaha MJ, Nasir K, et al. High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol. 2013;62(5):397-408. Yousuf O Mohanty BD Martin SS Joshi PH Blaha MJ Nasir K et al High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? J Am Coll Cardiol 2013 62 5 397 408 35. Tomai F, Ribichini F, Ghini AS, Ferrero V, Andò G, Vassanelli C, et al. Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease. Eur Heart J. 2005; 26(20):2099-105. Tomai F Ribichini F Ghini AS Ferrero V Andò G Vassanelli C et al Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease Eur Heart J 2005 26 20 2099 2105 36. Huet F, Akodad M, Kuster N, Kovacsik H, Leclercq F, Dupuy AM, et al. An hs-TNT second peak associated with high CRP at day 2 appears as potential biomarkers of micro-vascular occlusion on magnetic resonance imaging after reperfused ST-segment elevation myocardial infarction. Cardiology. 2018;140(4):227-36. Huet F Akodad M Kuster N Kovacsik H Leclercq F Dupuy AM et al An hs-TNT second peak associated with high CRP at day 2 appears as potential biomarkers of micro-vascular occlusion on magnetic resonance imaging after reperfused ST-segment elevation myocardial infarction Cardiology 2018 140 4 227 236 37. Oduncu V, Erkol A, Karabay CY, Kurt M, Akgun T, Bulut M, et al. The prognostic value of serum albumin levels on admission in patients with acute STsegment elevation myocardial infarction undergoing a primary percutaneous coronary intervention. Coron Artery Dis. 2013; 24(2):88-94. Oduncu V Erkol A Karabay CY Kurt M Akgun T Bulut M et al The prognostic value of serum albumin levels on admission in patients with acute STsegment elevation myocardial infarction undergoing a primary percutaneous coronary intervention Coron Artery Dis 2013 24 2 88 94 38. Nelson J, Liao D, Sharrett AR, Folsom AR, Chambless LE, Shahar E, et al. Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 2000; 151(5):468-77. Nelson J Liao D Sharrett AR Folsom AR Chambless LE Shahar E et al Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study Am J Epidemiol 2000 151 5 468 477 39. Don BR, Kaysen GA. Serum albumin: relationship to inflammation and nutrition. Semin Dial. 2004;17(6):432-7. Don BR Kaysen GA Serum albumin: relationship to inflammation and nutrition Semin Dial 2004 17 6 432 437 40. Joles JA, Willekes-Koolschijn N, Koomans HA. Hypoalbuminemia causes high blood viscosity by increasing red cell lysophosphatidylcholine. Kidney Int. 1997;52(3):761-70. Joles JA Willekes-Koolschijn N Koomans HA Hypoalbuminemia causes high blood viscosity by increasing red cell lysophosphatidylcholine Kidney Int 1997 52 3 761 770 41. Mikhailidis DP, Ganotakis ES. Plasma albumin and platelet function: relevance to atherogenesis and thrombosis. Platelets. 1996; 7(3):125-37. Mikhailidis DP Ganotakis ES Plasma albumin and platelet function: relevance to atherogenesis and thrombosis Platelets 1996 7 3 125 137 42. Fairclough E, Cairns E, Hamilton J, Kelly C. Evaluation of a modified early warning system for acute medical admissions and comparison with C-reactive protein/albumin ratio as a predictor of patient outcome. Clin Med. 2009;9(1):30-3. Fairclough E Cairns E Hamilton J Kelly C Evaluation of a modified early warning system for acute medical admissions and comparison with C-reactive protein/albumin ratio as a predictor of patient outcome Clin Med 2009 9 1 30 33 43. Duman H, Çinier G, Bakırcı EM, et al. Relationship Between C-Reactive Protein to Albumin Ratio and Thrombus Burden in Patients With Acute Coronary Syndrome. Clin Appl Thromb Hemost 2019;25:1076029618824418. doi: 10.1177/1076029618824418. Duman H Çinier G Bakırcı EM et al Relationship Between C-Reactive Protein to Albumin Ratio and Thrombus Burden in Patients With Acute Coronary Syndrome Clin Appl Thromb Hemost 2019 25 1076029618824418 10.1177/1076029618824418. 44. Çağdaş M, Rencüzoğullari I, Karakoyun S, Karabag Y, Yesin M, Artaç I, et al. Assessment of Relationship Between C-Reactive Protein to Albumin Ratio and Coronary Artery Disease Severity in Patients With Acute Coronary Syndrome. Angiology. 2019;70(4):361-8. Çağdaş M Rencüzoğullari I Karakoyun S Karabag Y Yesin M Artaç I et al Assessment of Relationship Between C-Reactive Protein to Albumin Ratio and Coronary Artery Disease Severity in Patients With Acute Coronary Syndrome Angiology 2019 70 4 361 368 45. Yoshida N, Baba H. The C-reactive protein/albumin ratio may predict the long-term outcome in patients with malignant pleural mesothelioma. Ann Surg Oncol. 2018;25(6): 1471-2. Yoshida N Baba H The C-reactive protein/albumin ratio may predict the long-term outcome in patients with malignant pleural mesothelioma Ann Surg Oncol 2018 25 6 1471 1472 46. Chen Z, Shao Y, Fan M, Zhuang Q, Wang K, Cao W, et al. Prognostic significance of preoperative C-reactive protein: albumin ratio in patients with clear cell renal cell carcinoma. Int J Clin Exp Pathol. 2015;8(11):14893-900. Chen Z Shao Y Fan M Zhuang Q Wang K Cao W et al Prognostic significance of preoperative C-reactive protein: albumin ratio in patients with clear cell renal cell carcinoma Int J Clin Exp Pathol 2015 8 11 14893 14900 47. Takajashi K, Ohyanagi M, Ikeoka K, Tateishi J, Iwasaki T. Clinical course of patients with coronary ectasia. Cardiology 1999; 91(3):145-9. Takajashi K Ohyanagi M Ikeoka K Tateishi J Iwasaki T Clinical course of patients with coronary ectasia Cardiology 1999 91 3 145 149 48. Yilmaz H, Sayar N, Yilmaz M, Tangürek B, Cakmak N, Gürkan U, et al. Coronary artery ectasia: clinical and angiographical evaluation. Turk Kardiyol Dern Ars 2008; 36(8):530-5. Yilmaz H Sayar N Yilmaz M Tangürek B Cakmak N Gürkan U et al Coronary artery ectasia: clinical and angiographical evaluation Turk Kardiyol Dern Ars 2008 36 8 530 535

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Este estudo foi aprovado pelo Comitê de Ética do Sanko University Clinical Research sob o número de protocolo 2019/06. 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

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 Original Article Association of C-Reactive Protein to Albumin Ratio in Patients with Isolated Coronary Artery Ectasia Sercelik Alper 1 Tanrıverdi Okan 2 0000-0001-7768-2562 Askin Lutfu 2 Turkmen Serdar 2 Turkey Sanko University Faculty of Medicine, Cardiology, Gaziantep - Turkey Turkey Adiyaman University Education and Research Hospital - Cardiology, Adiyaman - Turkey Mailing Address: Lutfu Askin • Adiyaman Universitesi Egitim ve Arastirma Hastanesi – Cardiology - Adıyaman Eğitim Ve Araştırma Hastanesi Kardiyoloji Bölümü Adıyaman Centry, 2230 – Turkey E-mail: lutfuaskin23@gmail.com

Author Contributions

Conception and design of the research, Acquisition of data, Analysis and interpretation of the data, Statistical analysis and Critical revision of the manuscript for intellectual content: Sercelik A, Askin L, Turkmen S, Tanriverdi O; Writing of the manuscript: Askin L.

Potential Conflict of Interest

The authors report no conflict of interest concerning the materials and methods used in this study or the findings specified in this paper.

 Abstract Background

Coronary artery ectasia (CAE) is defined as diffuse or localized dilatation of coronary artery lumen with a diameter of 1.5 to 2.0 times the adjacent normal coronary artery. The C-reactive protein to albumin ratio (CAR) is a useful inflammatory marker, which has been documented in coronary artery disease.

 Objective

To analyze the association of CAE and CAR.

 Methods

A case-control protocol was used in this study. We included 102 consecutive patients with isolated CAE without stenosis (56 men and 46 women; mean age 60.4 ± 8.8 years). The control subjects consisted of an equal number of sex and age matched patients with normal coronary arteries (55 men and 47 women; mean age 61.2 ± 9.1 years). Clinical features, laboratory findings, and medication use history were recorded. Student’s t test, Mann-Whitney U test, chi-square test, and linear and logistic regression analysis were performed. A 2-sided p < 0.05 was statistically considered significant.

 Results

The CAR was increased in patients with CAE compared to the controls (32 and 16; p < 0.001). In addition, the CAR was found to be an independent predictor of CAE (OR = 2.202; 95% CI 1.184 – 5.365; p < 0.001).

 Conclusion

In the present study, we determined that CAR levels were significantly higher in the CAE group than in the control group, and the CAR was significantly correlated with CAE. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

 C-Reactie Protein Albumins Coronary Artery Disease/complications Inflammation Coronary Aneurysm Dilatation, Pathologic (ectasig Introduction

Coronary artery ectasia (CAE) is defined as diffuse or localized dilatation of coronary artery lumen with a diameter 1.5 to 2.0 times the adjacent normal coronary artery. Coronary aneurysms are defined as luminal dilatation with a > 2.0 fold increase.1 With the rapid increase in applications of coronary angiography (CA), an increasing number of CAE have been detected. CAE has been shown to be a predictor of mortality. The mortality rates of patients with CAE are similar to those of patients with non-obstructive aneurysmal or 3-vessel disease.2 The etiopathogenesis of this clinical entity is not fully understood. The most common cause of CAE in the Western population is atherosclerotic coronary artery disease (CAD). Kawasaki disease, collagen tissue diseases, and connective tissue diseases are the other causes of CAE. Percutaneous coronary invasive procedures and trauma rarely lead to CAE.3 - 4 Chest pain is usually the primary symptom of CAE. However, arrhythmia, acute coronary syndrome, and sudden cardiac death are other observed clinical conditions of CAE.5 , 6

Previous studies have shown that inflammation may play a role in CAE.7 CRP and albumin have been linked to CAD severity and to the presence of cardiovascular complications.8 - 10 CRP, which is one of the most commonly used inflammatory biomarkers, is associated with endothelial dysfunction, prothrombotic status, remodeling, and destabilization of atherosclerotic plaques. Furthermore, elevated CRP levels in patients with atherosclerotic burden have been found to be associated with significant cardiovascular events.11 - 14 On the other hand, inflammation causes hypoalbuminemia with disruption of albumin synthesis-catabolism balance. Serum albumin is the most important serum protein with vital functions in the human body, and it has anti-atherogenic properties, including antioxidant activities, inhibition of platelet activation, and modulation and aggregation of arachidonic acid metabolism.15 Several previous studies have reported that hypoalbuminemia is associated with more frequent myocardial infarction and increased mortality in patients with acute coronary syndrome.10 , 16 , 17 In comparison with CRP or albumin alone, the CRP to albumin ratio (CAR), a new inflammation-based risk index, has been shown to better reflect prognosis in patients with acute medical condition and malignancy.18 , 19 However, the relationship between the CAR and CAE is not yet known. CAE is an inflammatory disease; thus, we hypothesized that the CAR could be associated with CAE. Our aim was to investigate the association between CAE and the CAR.

 Methods

A case-control study approved by the Ethics Committee in Sanko University Hospital was performed. Patients with suspected coronary ischemia and typical chest pain following positive or equivalent results of noninvasive ischemic tests were included. All patients underwent CA. During CA, digital data of all patients were analyzed, and quantitative coronary measurements were performed. Catheter diameter was used as the reference to determine the actual coronary artery lumen diameter. Definition of the ectatic segment was determined by performing at least two measurements at the proximal, middle, and distal segments of the coronary arteries in patients with normal CA and in patients who were considered to have an ectatic coronary segment. CAE was defined as diffuse or localized dilatation of coronary artery lumen with a diameter 1.5 to 2.0 times the adjacent normal coronary artery, and these patients were included in the isolated CAE group. Patients without coronary plaque or ectasia were included in the normal coronary group.

The medical history of the study population was obtained from medical records and recorded in forms prepared for each patient. Hypertension (HT) was diagnosed when SBP was > 140 mmHg and/or when DBP > 90 mmHg, or by antihypertensive drug use. Diabetes mellitus (DM) was diagnosed when fasting blood glucose was ≥ 126 mg/dL or by antidiabetic drug use. Hyperlipidemia (HL) was defined as total cholesterol level > 200 mg/dL, history of dyslipidemia, and/or antilipidemic drug use. Patients who were smokers for 1 year or more were defined as smokers. BMI was determined using the standard formula. The LVEF was automatically calculated according to the modified Simpson’s method, with the help of software on the echocardiography device.20

Laboratory Measurements

Blood glucose, creatinine, albumin, and CRP levels were determined as described. Serum total protein and albumin were measured by bromine cresol technique using a C8000 analyzer (Abbott Laboratories, IL, USA). CRP was measured by nephelometry (BN ProSpec System, Siemens). The estimated glomerular filtration rate was determined using the Cockcroft-Gault equation.

 Coronary angiography

CA was performed using Judkins method, via femoral approach, using cranial and caudal angles in the right and the left inclined planes at 30 fps. Patients’ CA images were analyzed by interventional cardiologists who were blinded to the study. CAE was defined by Falsetti and Carroll;21 our study used the same method. Normal segments were defined as the absence of stenosis or ectasia determined by CA. Cases of CAE with coronary stenosis were excluded from the study.

 Statistical analysis

Statistical analysis was carried out using SPSS v25 (SPSS Inc., USA). The normality of continuous variables was tested by the Kolmogorov-Smirnov test and presented as mean and standard deviation or median and interquartile range, according to data normality. Normally distributed continuous variables were compared by Student’s t test, and Mann-Whitney U test was used for non-normal distribution. Student’s t test for unpaired values was used. Categorical data were compared using chi-square test. In univariate linear regression analysis, variables with a significance level p < 0.25 were defined as potential risk markers and included as common variables in the whole variable model. Logistic regression analysis was performed to obtain independent determinants of CAE. A 2-sided p < 0.05 was statistically considered significant.

 Results

Of 226 patients, 8 were excluded because of myocardial infarction and left ventricular dysfunction; 5 were excluded due to left ventricular hypertrophy and heart valve disease, and 6 were excluded due to HT and renal failure (n = 6). In addition, 3 patients were excluded because of other reasons such as cerebrovascular disease, liver dysfunction, autoimmune disease, neoplastic disease, and osteoporosis (n = 3). After these exclusions, 204 patients were enrolled. One hundred two patients with isolated CAE and no coronary artery stenosis (56 men and 46 women; mean age 60.4 ± 8.8 years) were enrolled as patient group, and the control group consisted of the same number of consecutive subjects with angiographically normal coronary arteries (55 men and 47 women; mean age 61.2 ± 9.1 years).

Patients’ data are shown in Table 1 . The demographic characteristics showed age and sex matched groups. CAD risk factors such as DM were also similar, but other risk factors (smoking, HT, HL, and family history) were significantly higher in the CAE group than in the control group (p < 0.001, p < 0.001, p = 0.006, and p = 0.022, respectively). No changes were observed in terms of treatment regimens.

– Baseline characteristics of the study population
Variables Patients with CAE (n = 102) Control group (n = 102) P value
Age, years 60.4 ± 8.8 61.2 ± 9.1 0.422
Sex (male), n, (% ) 56 (54.9) 55 (53.9) 0.740
BMI (kg/m2) 27.4±3.1 25.2± 3.2 0.317
Diabetes mellitus, n (%) 15 (14.7) 12 (11.7) 0.422
Smoking, n, (%) 40 (39.2) 18 (17.6) < 0.001
Hypertension, n (%) 38 (37.2) 27 (26.4) < 0.001
Hyperlipidemia, n (%) 22 (21.5 ) 10 (9.8) 0.006
Family history, n, (%) 15 (14.7) 8 (7.8) 0.022
Previous medications, n, (%)
Acetylsalicylic acid 20 (19.6) 16 (15.6) 0.224
Betablockers 22 (21.5) 17 (16.6) 0.314
ACEI/ARB 17 (16.6) 13 (12.7) 0.509
Statins 10 (9.8) 7 (7.1) 0.356
LVEF, (%) 60.2±3.4 61.3±3.9 0.533
SBP (mmHg) 122.0±9.1 118.6±7.5 0.424
DBP (mmHg) 88.0±7.2 85.6±4.1 0.358
Heart rate (beat/m) 75.2±9 73.8±7 0.411
Hemoglobin, g/dL 13.1+1.8 12.7+1.7 0.388
White blood cell, 103/mL 8.6±2.9 8.4±2.2 0.758
Platelet count, 103/mL 232.7±77.4 244.8±75.2 0.554
FPG (mg/dL) 127.1±42.8 123.1±45.2 0.146
Creatinine, mg/dL 0.86 (0.75-0.99) 0.85 (0.75-0.97) 0.785
eGFR, mL/min 92.3 (68.9-105.6) 93.8 (74.9-107.9) 0.656
Total cholesterol, mg/dL 168.0±36.0 158.2±39.8 0.411
HDL (mg/dL) 33.6±7.0 39.8±8.0 0.012
LDL (mg/dL) 123.2±32.6 98.4±29.4 < 0.001
Triglyceride, mg/dL 129 + 61 122 + 58 0.188
C-reactive protein, mg/dL 1.25 (0.50-2.84) 0.62 (0.27-1.16) < 0.001
Albumin, g/dL 3.76 + 0.42 4.02 + 0.32 < 0.001
CAR, *100 32 (12-68) 16 (6-30) < 0.001

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BMI: body mass index; CAR: C-reactive protein to albumin ratio; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; FPG: fasting plasma glucose; HDL: high density lipoprotein; LDL: low density lipoprotein; LVEF: left ventricular ejection fraction; SBP: systolic blood pressure

Assessment of BMI, SBP, DBP, LVEF, heart rate, and fasting plasma glucose did not show any significant differences. Lipid panel parameters, triglycerides, and total cholesterol groups were similar; HDL was higher in the controls (p = 0.012), and LDL was higher in patients with CAE (p < 0.001). CRP, albumin, and the CAR differed significantly between the groups (p < 0.001). There was a similarity between the groups in terms of other laboratory parameters.

Applying a univariate logistic regression model, DM, smoking, HT, and the CAR correlated with CAE. Regression analysis revealed that smoking, HT, and the CAR were independent predictors of CAE (smoking: OR 1.812 [95% CI 1.124 – 2.655; p = 0.024], HT: OR 2.175 [95% CI 1.156 – 4.227; p < 0.001], CAR: OR 2.202 [95% CI 1.184 – 5.365; p < 0.001]) ( Table 2 ).

– Factors associated with coronary artery ectasia
Linear regression analysis Logistic regression analysis
Coefficients 95% CI P value OR 95% CI P value
Age, years 0.052 0.013-0.107
LVEF 0.002 −0.018-0.026
BMI (kg/m2) 0.030 0.010-0.073
Diabetes mellitus 0.168 0.011- 0.524 0.024* 1.277 0.811-1.613 0.102
Smoking 0.322 0.010-1.114 0.007* 1.812 1.124-2.655 0.024*
Hypertension 0.533 0.017-1.010 0.003* 2.175 1.156-4.227 < 0.001*
Hyperlipidemia 0.025 −0.020-0.056
SBP (mmHg) 0.068 −0.017-0.122
DBP (mmHg) 0.024 −0.002-0.048
Heart rate (beat/m) 0.074 −0.024-0.172
CAR, *100 0.618 0.119-1.496 < 0.001* 2.202 1.184-5.365 < 0.001*
HDL (mg/dL) −0.076 −0.312-0.025
LDL (mg/dL) 0.009 −0.057-0.020

*P value < 0.05. Variables with p < 0.25 in univariate regression were included into multivariate regression. BMI: body mass index; CAR: C-reactive protein to albumin ratio; DBP: diastolic blood pressure; HDL: high density lipoprotein; LDL: low density lipoprotein; LVEF: Left ventricular ejection fraction; SBP: systolic blood pressure.

Discussion

This reports shows that the CAR was significantly higher in the CAE group than in the control group. To our knowledge, we are the first to show that the CAR is closely associated with CAE.

It is not clear which local or global factors are involved in CAE pathogenesis. It is reported that CAE is caused by the widespread abnormality in the vascular wall holding multiple segments and that it represents saccular ectasia rather than fusiform ectasia.22 A relatively limited study on prognosis was performed for patients with CAE. Thirty years ago, the largest cohort study of CAE found that aneurysmal patients had a 5-year mortality rate of 26%.23 Kajinami et al.24 examined the autopsy of a patient with CAE and familial hypercholesterolemia, who died in the twentieth century due to acute myocardial infarction. Microscopic examination revealed a large amount of plasma cells, macrophages, and lymphocyte infiltration in the intimal/medial layers of the coronary arteries. Evidence of atherosclerotic reactions such as typical common hyalinization, focal calcification and fibrosis, lipid accumulation, intimal and medial damage, cholesterol, hemorrhage, and foreign body giant cell were observed during pathological examination of CAE.

Another potential factor leading to the development of CAE is nitric oxide (NO), which may cause coronary dilatation due to over-stimulation of the endothelium. Many patients have been given chronic glyceryl trinitrate for angina that may worsen ectasia via NO stimulation. These patients may have CAD, and atherosclerosis has been shown to cause inappropriate release of endothelial NO.25 Quyyumi et al.26 demonstrated the relationship between NO and atherosclerosis and reported that coronary vascular dilatation was caused by increased NO due to acetylcholine without angiographically proven atherosclerosis.

The underlying pathological mechanism of CAE is still not fully understood. Although a definite relationship between atherosclerosis and CAE has not been confirmed, CAE is considered to be a variant of CAD and the main cause of CAE is atherosclerosis.23 , 27 - 29 The role of inflammation in the process of atherosclerosis is well known.28 - 30 Atherosclerosis is associated with aneurysm formation that extends to tunica media during an inflammatory process, which eventually ends with degeneration of the cystic media.31 Previous studies have shown that inflammatory markers such as plasma soluble adhesion molecules, leukocytes, adiponectin, lipoprotein-associated phospholipase-A2, CRP, plasminogen activator inhibitor-1, IL-1, TNF-alpha, and IL-10 have been significantly increased in patients with CAE.32

Many previous studies have shown that the CAR is associated with atherosclerosis and suggested that it should be considered as a marker of cardiovascular risk. This study found that the CAR was significantly higher in patients with CAE than in the control group, and it supports the hypothesis that atherosclerosis causes CAE.

Damaged ischemic or necrotic cells cause a systemic inflammatory response by releasing pro-inflammatory agents in tissue and plasma. The prognosis of the disease can change with the speed of inflammation.33 Atherosclerosis has been shown to be strongly correlated with increased serum CRP.34 In addition, CRP has been shown to be associated with endothelial dependent/independent coronary dysfunction in patients with CAD,35 suggesting that increased CRP may predict dysfunction in STEMI patients and may be a strong predictor of no-reflow phenomenon.36 In our study, elevated CRP levels showed a strong association between CAE and CRP.

Hypoalbuminemia is not only a risk factor; it also indicates poor prognosis in patients with STEMI.37 , 38 Increased inflammation has been documented to contribute to albumin synthesis and breakdown.39 Hypoalbuminemia leads to many complications including endothelial dysfunction as well as platelet aggregation and coronary artery stenosis induced by platelet dysfunction.40 - 41 In a study of 1,303 subjects with acute coronary syndrome, serum albumin levels were shown to be associated with severity of CAD.10 In our study, there was a negative correlation between serum albumin level and CAE.

It is believed that the CAR, as originally described by Fairclough et al.,42 is better than CRP and albumin alone for prediction of medical complications.42 Inflammation is one of the main characteristics of atherogenesis, and the CAR and demonstrates inflammatory conditions.

The CAR has recently been investigated as a potential biomarker for predicting the consequences of adverse cardiovascular events.43 Cagdas et al.44 showed that the CAR and the severity of CAD were associated. In malignant cancer patients, the CAR predicted prognosis and disease progression.45 , 46 Therefore, the CAR is a more reliable biomarker for prediction of disease severity. Previous reports that evaluated the CAR in CAD showed promising outcomes. A study of STEMI showed that white blood cell count, neutrophil to lymphocyte ratio, and the CAR correlated with the no-reflow phenomenon.43

The results of our study showed that the association of the CAR with CAE was significant. This is the first study to show an association between CAE and higher CAR levels. Increased CAR was a prognostic marker of CAE. The results of a study on the relationship between familial hypercholesterolemia and CAE showed that dyslipidemia was one of the causes of CAE.47 In our study, high LDL and low HDL levels were observed in patients with CAE. No significant change was found in triglyceride levels in patients with CAE compared to controls. A strong relationship has been shown between HT and CAE.48 In our study, the prevalence of HT was higher in patients with CAE, and HT was independently associated with CAE.

We observed that the CAR was higher in patients than in control group. We assume that higher CAR may predict the risk of atherosclerosis in patients with CAE. A review of the literature shows that CAE is not an innocent clinical condition and that larger studies are needed in the future to create the best strategy for treatment and risk management.

Study limitations

More comprehensive and multicenter studies are needed to better explain the variability of inflammatory markers and the predictive role of serum CAR levels. The prognostic significance of the CAR was not evaluated, and it should be established in future investigations. This was a case-control study, and we were thus unable to obtain mortality data. Although the CAR is accepted as a new, sensitive myocardial marker, its specificity in determining the presence of CAE has been questioned, because many other conditions, especially other infections, may also increase CAR levels. CAR levels may be affected by other important factors, such as age, sex, and race. Finally, instead of using quantitative methods such as intravascular ultrasound, visual assessment was the only method used to diagnose and exclude patients.

 Conclusion

Our study shows that CAR levels are higher in patients with CAE compared to subjects with normal coronary arteries. The high levels of CAR may support the hypothesis that the CAR could be related to the development of CAE. In our study, high CAR levels were significantly correlated with CAE.

Study Association

This study is not associated with any thesis or dissertation.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Sanko University Clinical Research under the protocol number 2019/06. 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.There was no external funding source for this study.