Determinação do Tecido Cicatricial do Miocárdio no Fenômeno de Fluxo Coronário Lento e a Relação entre a Quantidade de Tecido Cicatricial e o Nt-ProBNP

Mustafa Candemir; Asife Şahinarslan; Merve Yazol; Yusuf Ali Öner; Bülent Boyacı

doi:10.36660/abc.2018149

. 2020 Mar 20;114(3):540–551. [Article in Portuguese] doi: 10.36660/abc.2018149

View full-text in English

Determinação do Tecido Cicatricial do Miocárdio no Fenômeno de Fluxo Coronário Lento e a Relação entre a Quantidade de Tecido Cicatricial e o Nt-ProBNP

Mustafa Candemir ^1,², Asife Şahinarslan ², Merve Yazol ³, Yusuf Ali Öner ⁴, Bülent Boyacı ²

PMCID: PMC7792723 PMID: 32267328

Resumo

Fundamento

A fisiopatologia e o prognóstico não estão claramente determinados nos pacientes com fenômeno do fluxo coronário lento (FCL). Esses pacientes apresentam várias condições clínicas, que variam desde quadro assintomático até internação hospitalar com morte cardíaca súbita.

Objetivos

Nosso objetivo foi avaliar os achados da ressonância magnética cardíaca (RMC) com o realce tardio pelo gadolínio (RTG), como um indicador de fibrose miocárdica. Também buscamos determinar a relação entre a presença de fibrose miocárdica e os níveis de NT-proBNP em pacientes com FCL na artéria coronária descendente anterior esquerda (DAE).

Métodos

Ao todo, 35 pacientes, entre 31 e 75 anos de idade, foram incluídos. Os pacientes estudados (n=19) apresentaram artérias coronárias epicárdicas normais na angiografia, mas tinham FCL na DAE. O grupo controle de pacientes (n=16) apresentou artérias coronárias epicárdicas normais e níveis de escore TIMI normais na angiografia. Em ambos os grupos, os pacientes foram examinados com RMC para a detecção de presença de fibrose miocárdica. Além disso, níveis plasmáticos de NT-proBNP foram medidos. Valores de p < 0,05 foram considerados significativos.

Resultados

A taxa de fibrose miocárdica foi significativamente maior na RMC para os pacientes com FCL (p=0.018). Uma quantidade variável de tecido cicatricial foi detectada no ápice ventricular esquerdo em 7 pacientes e nas regiões inferior e inferolateral em 3 pacientes. Não foram observadas diferenças nos níveis de NT-proBNP nos pacientes com FCL. Entretanto, os níveis de NT-proBNP foram maiores nos pacientes com FCL, que apresentaram fibrose miocárdica na RMC (p=0.022).

Conclusões

Em suma, o RTG na RMC mostrou que a cicatriz miocárdica isquêmica pode estar presente nos pacientes com FCL. Esses resultados indicam que o FCL pode nem sempre ser inofensivo. (Arq Bras Cardiol. 2020; 114(3):540-551)

Keywords: Insuficiência Cardiaca, Reserva Fracionada de Fluxo Miocárdico, Cicatriz Hipertrófica, Prognóstico, Peptídeo Natriurético Tipo C, Fibrose Endomiocárdica, Espectroscopia de Ressonância Magnética/métodos

Introdução

Há pouca informação na literatura em relação ao prognóstico do fenômeno do fluxo coronário lento (FCL). Dados preexistentes indicam que a isquemia miocárdica relacionada ao fluxo lento pode causar angina e o prognóstico é pior nesses pacientes. ¹ Também relatou-se uma associação entre infarto agudo do miocárdio, ² morte cardíaca súbita e arritmia ventricular maligna e o FCL. ³ A ocorrência de episódios recorrentes de dor torácica ou dor torácica em repouso, bem como elevadas taxas de internações de emergência e hospitalizações, foram relatadas. ^4
,
5 Desse modo, esse fenômeno não é tão inofensivo como parece mas, ao contrário, possui potencial para causar séria deterioração na qualidade de vida. Não se sabe ao certo atualmente se há lesões orgânicas nesses pacientes, devido à ausência de investigações e resultados mais aprofundados.

Os níveis de N-terminal do pró-hormônio do peptídeo natriurético do tipo B (NT-proBNP) aumentaram após o exercício nos pacientes com fluxo coronário lento. ⁶ Há uma correlação entre a isquemia ou o tamanho do infarto na ressonância magnética (RMI), e essa correlação também pode ser observada nos níveis de NT-proBNP nos pacientes com síndrome coronariana aguda. ⁷ Com os avanços na ressonância magnética cardíaca (RMC), a isquemia microvascular e a fibrose cardíaca podem ser demonstradas através dessa técnica. ^8
,
9 A relação entre a extensão da fibrose e os níveis de NT-proBNP nesses pacientes já foi revelada em vários exames de RMI realizados em pacientes com síndrome aguda coronariana. ^10
,
11 Entretanto, não há estudos na literatura que tenham avaliado pacientes com FCL para detecção da presença de fibrose no tecido do miocárdio, de acordo com os resultados do realce tardio pelo gadolínio (RTG) na RMC. O objetivo deste estudo foi investigar a presença de fibrose miocárdica em pacientes com fluxo lento na artéria coronária descendente anterior esquerda por meio da técnica do realce tardio pelo gadolínio na RMC, bem como avaliar a relação entre a fibrose miocárdica e os níveis de NT-proBNP.

Materiais e Métodos

População do Estudo

Dentre os pacientes que foram admitidos no nosso departamento entre janeiro de 2015 e agosto de 2016, e submetidos à angiografia coronária devido a dores torácicas, 19 pacientes com o fenômeno do fluxo coronário lento na DAE foram incluídos neste estudo de coorte prospectivo. O grupo controle incluiu dezesseis pacientes cujas artérias epicárdicas estavam completamente normais com fluxo coronário normal.

Este estudo foi aprovado pelo Comitê de Ética do Hospital Universitário de Gazi e conduzido em conformidade com os princípios da declaração de Helsinki.

Critérios de Exclusão

Os seguintes pacientes foram excluídos do estudo: pacientes com ectasia de artéria coronariana ou lesões ateroscleróticas nas artérias coronárias esquerda e descendente anterior esquerda; pacientes submetidos à intervenção coronária percutânea; pacientes com intervenção da artéria coronária agendada; pacientes com estenose >50% em qualquer artéria coronária; pacientes com história prévia de IM; pacientes com função sistólica do ventrículo esquerdo <50%; pacientes com claustrofobia, insuficiência cardíaca ou disfunção valvar, extra-sístoles ventriculares ou anormalidades da condução atrioventricular e bloqueio de ramo ou fibrilação atrial; pacientes com teste de esforço positivo; pacientes com cardiomiopatias restritiva, hipertrófica ou dilatada; pacientes com doença sistêmica conhecida (hipertireoidismo, hipotireoidismo, malignidade, doença autoimune, infecção ou quaisquer distúrbios pulmonares, hepáticos, renais, hematológicos); pacientes com história prévia de miocardite, com TFG <80 ml/min, e pacientes que se recusaram a participar do estudo.

Dados dos Pacientes

Foram medidos a altura, o peso e o índice de massa corporal (IMC) dos pacientes do estudo. A idade, o gênero, os fatores de risco cardiovascular (hipertensão, diabetes, dislipidemia, tabagismo e histórico familiar), características demográficas e comorbidades foram registrados. Foi obtido eletrocardiograma (ECG) de todos os pacientes e todos eles apresentaram ritmo sinusal. Todos os pacientes do estudo foram examinados na posição decúbito lateral direita, utilizando um sistema de ultrassom Vivid 7-Pro (GE Vingmed, Horten, Noruega), equipado com um transdutor de 2,5 MHz, através do registro simultâneo pelo ECG de 1 derivação. Medições em modo-M e Doppler foram realizadas em conformidade com as recomendações da Associação Americana de Ecocardiografia. ¹²

O teste de esforço foi realizado em média 3 dias antes da angiografia em todos os pacientes (GE medical system, Milwaukee, EUA), de acordo com o protocolo padrão de Bruce, sendo o ECG convencional, além das medições da pressão arterial e da frequência cardíaca realizadas em períodos de tempo pré-definidos, conforme dizetrizes relevantes. ¹³

Foram coletadas amostras de sangue para dosagem de NT-proBNP, através da bainha vascular, imediatamente antes da sua retirada. Após a coleta, elas foram centrifugadas por 10 minutos a 4500 RPM e armazenadas a -20 ºC até a realização dos testes sorológicos. No dia da análise, após as amostras atingirem a temperatura ambiente, um imunoensaio eletroquimioluminescente foi realizado com o Analisador Cobas e 411 (Roche Diagnostics GmbH, Mannheim, Alemanha). Os resultados foram apresentados em picogramas por ml (pg/ml). O coeficiente de variação do NT-proBNP, através desse método, foi inferior a 5%.

Angiografia Coronária e Contagem de Quadros TIMI

A angiografia coronária foi realizada utilizando-se a técnica padrão de Judkins com acesso femoral e a 30 imagens por segundo, através do sistema de angiografia Infinix (Toshiba Corporation, Tochigi, Japão). A iopromida (Ultravist-370; Bayer Pharma AG, Berlim, Alemanha) foi utilizada como agente de contraste durante a angiografia coronária. Uma média de 6 a 8 ml do agente de contraste foi injetada manualmente para cada exposição. As artérias coronárias foram visualizadas em projeção oblíqua esquerda e direita no ângulo cranial-caudal apropriado. A velocidade do fluxo na DAE foi avaliada nas projeções oblíquas anterior direita e esquerda, frequentemente com ângulo caudal. As imagens foram avaliadas por dois especialistas clínicos cegos em relação às condições clínicas dos pacientes.

A avaliação quantitativa do fluxo coronário foi realizada de acordo com o estudo TIMI-4, através da contagem de quadros angiográficos, a partir do momento da administração do agente de contraste, até a sua chegada a um determinado ponto distal. ¹⁴ A metodologia da contagem de quadros foi padronizada para cada vaso epicárdico. A contagem de quadros TIMI começou com o primeiro quadro no qual o contraste preencheu completamente a artéria. O preenchimento completo da artéria foi determinado pelo cumprimento dos três critérios a seguir: (1) Uma coluna de contraste total ou quase totalmente concentrado deve se estender ao longo de toda a origem da artéria coronária; (2) O contraste toca ambas as bordas de origem da artéria coronária; e (3) Deve haver um um fluxo anterógrado de contraste. O último quadro a ser contado foi aquele no qual o contraste preencheu inicialmente o ramo distal da artéria alvo. A opacificação completa do segmento distal não foi necessária.

O escore TIMI para a DAE foi 1,7 vez mais elevado do que a contagem média da ACD e da ACx. Consequentemente, a contagem do escore TIMI para a DAE foi dividida por 1,7 para calcular a contagem quadro a quadro TIMI corrigida (CTFC).

No nosso estudo, o fluxo coronário para a DAE foi considerado normal se a contagem do escore TIMI <23 e foi definida como lenta se a contagem do escore TIMI ≥ 23. ^15
,
16

Técnica da Ressonância Magnética

A RMC foi realizada após uma mediana de 8 dias (0-21 dias) após a angiografia coronária. Sequências padronizadas de estudos sobre perfusão pela RMC foram utilizadas em todos os pacientes. A veia antecubital esquerda foi usada para injeção do contraste intravenoso. Os dados de RM dos pacientes foram adquiridos utilizando um sistema de IRM 3T (Siemens MAGNETOM® Verio, Erlangen, Alemanha) equipado com gradiente de potência de 45 mT/m. Uma bobina de 6 canais foi colocada na parede torácica frontal enquanto o paciente estava deitado em decúbito dorsal com as almofadas de ECG posicionadas corretamente. Foram obtidas aquisições multiplanares com uma sequência turbo-FLASH de inversão-recuperação sensível à fase (PSIR) em múltiplas apneias expiratórias. As imagens padrão do coração de eixo longo, 2 câmaras, 4 câmaras e eixo curto foram obtidas alinhando a válvula mitral e o ápice. Os parâmetros de imagem foram: TR (tempo de repetição): 800; TE (tempo de eco) 6,66 ms; espessura das fatias: 8 mm; matriz: 128x256; FOV (campo de visão): 400 mm. Imagens ponderadas em T1 e T2 acompanhadas de sequência de pulsos “inversão-recuperação” para atenuação de sinais de sangue (sangue escuro) e de sequência-SPIN ECO foram adquiridas para avaliar a morfologia do miocárdio (TR/TE/ espessura/ matriz/ FOV: 698/6,6/ 8 mm/ 128x256, 360 mm). Foram adquiridas imagens de perfusão miocárdica dinâmica de primeira passagem uilizando-se a sequência de pulso SR Turbo FLASH (TfI), após administração de uma dose de 0,025 mmol/kg de Gd-DTPA intravenoso (Magnevist; Bayer Healthcare, Wayne NJ, EUA). Em intervalos de oito minutos de repouso, uma série de imagens de “gradiente-eco” (cine-RM) no plano de eixo curto foram adquiridas para avaliação funcional dos ventrículos ao longo do ciclo cardíaco, utilizando-se a apneia (TR/TE/ espessura/ matriz/ FOV: 40.24/ TE/ 8 mm/128x256/ 360 mm). Imagens ponderadas em T1, de eixo curto e 4 câmaras, foram obtidas na sequência PSIR, aproximadamente 8 minutos após a administração do contraste (TR/TE/ espessura/ matriz/ FOV: 756/ TE: 1,15/ 6 mm/ 128x256/360 mm). O tempo total de duração do exame foi de 35 minutos em média.

Os custos da RMC e da dosagem plasmática do NT-proBNP foram cobertos pela Unidade de Projetos de Pesquisa Científica da Universidade de Gazi.

Análise de Imagem por Ressonância Magnética

Todas as imagens da RMC foram transferidas para a estação de trabalho para análise (Siemens, Leonardo multimodality workplace, Siemens Healthcare). Todas as avaliações foram realizadas visualmente. Os exames de RMC foram avaliados retrospectivamente por um radiologista com mais de 15 anos de experiência em imagem cardíaca, de forma cega aos resultados da ecocardiografia e da angiografia coronária. Ao se observar quaisquer defeitos de perfusão ou realce tardio durante essas avaliações, os mesmos eram registrados de forma precisa. O realce do contraste nas sequências de perfusão foi definido como o cumprimento de todas as 5 fases após a obtenção da intensidade de sinal mais alta no ventrículo esquerdo. Os resultados da RMC foram então comparados com os resultados da ecocardiografia e da angiografia coronária dos pacientes.

Análise Estatística

Utilizou-se o programa estatístico SPSS (versão 21.0, SPSS Inc., Chicago, Illinois, EUA) para a análise de dados do estudo. Foram utilizados métodos visuais (histogramas, gráficos de probabilidade) e analíticos (teste Kolmogorov-Smirnov) para determinar a normalidade das variáveis. Nas análises descritivas, as variáveis distribuídas normalmente foram apresentadas como valor e desvio padrão, enquanto que as não normais foram apresentadas como mediana (intervalo interquartil). As variáveis categóricas foram apresentadas como percentuais. Amostras independentes do Teste-t e Mann-Whitney U foram usadas para comparar as variáveis numéricas. A análise do qui-quadrado de Pearson foi utilizada para comparar os dados categóricos, mas o teste exato de Fisher foi realizado quando dois dos valores esperados ficavam abaixo de 5 ou um dos valores esperados fosse menor que 2. Valores de p <0,05 foram considerados estatisticamente significativos.

Resultados

Ao todo, 35 pacientes foram incluídos no estudo. Os pacientes foram divididos em 2 grupos: o grupo de pacientes e o grupo controle. Dezenove pacientes foram incluídos no grupo com fluxo lento na DAE, e 16 pacientes com fluxo coronário normal foram incluídos no grupo controle ( Figura 1 ). Os pacientes do grupo controle foram comparados, quanto aos fatores de risco, aos indivíduos dos grupos de pacientes. A idade média dos pacientes era de 50,3 ± 10,7, e 6 dos 35 pacientes (17%) eram mulheres. Onze pacientes (31%) eram diabéticos, 9 pacientes (25%) eram hipertensos, 5 pacientes (14%) eram dislipidêmicos, 18 pacientes (51%) eram tabagistas e 8 pacientes (22%) tinham histórico familiar positivo ( Tabela 1 ).

Tabela 1. – Comparação das características clínicas de ambos os grupos.

Parâmetros	Total (N=35)	Fluxo Lento (N= 19)	Controle (N= 16)	Valor de p
Idade, média (DP), anos	50,3 ± 10,7	51,3 ± 8,2	49,44 ± 12,8	0,62
Sexo (Masculino), n (%)	29 (82)	15 (78,9)	14 (87,5)	0,50
Hipertensão, n (%)	9 (25)	6 (31,6)	3 (18,8)	0,38
Diabetes mellitus, n (%)	11 (31)	6 (31,6)	5 (31,3)	0,98
Tabagista, n (%)	18 (51)	9 (47,4)	9 (56,3)	0,60
Histórico familiar, n (%)	8 (22)	4 (21,1)	4 (25)	0,78
Dislipidemia, n (%)	5 (14)	3 (15,8)	2 (12,5)	0,78
IMC, média (DP) (kg/m ² )	27,7 ± 2,3	28,1 ± 2,5	27,3 ± 2	0,39
NT-proBNP (pg/ml)	29,5 (17,7-66,2)	47,8 (22,6-121,5)	26,0 (10,9-58,1)	0,246
cTFC (quadro/segundo)	34,6 ± 16,2	28,0 ± 8,6	13,1 ± 1,2	<0,001
METs, mL/kg/dk	10,38 ± 1,91	9,74 ± 2,05	11,15 ± 1,43	0,027
Resultados positivos da IMR n (%)	10 (28)	10 (52,6)	0 (0)	0,001

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IMC: índice de massa corporal; cTFC: TIMI corrigido; METs: equivalentes metabólicos; RMI: ressonância magnética por imagem.

A principal queixa de todos os pacientes era dor torácica. O ECG de todos os pacientes mostrou ritmo sinusal. A frequência cardíaca variou entre 64 e 92 bpm. A frequência cardíaca média foi 74 bpm. Além disso, não houve sinal de isquemia, hipertrofia ou arritmia ao ECG. A fração de ejeção do ventrículo esquerdo e outros achados ecocardiográficos dos pacientes estavam normais. Adicionalmente, os testes de esforço de todos os pacientes foram negativos. A troponina de alta sensibilidade foi medida antes e depois da angiografia coronária em todos os pacientes. Todos os valores ficaram abaixo do valor limite e não houve aumento nos valores de troponina após a angiografia.

O tempo de intervalo entre os exames de RMC e a angiografia coronária dos pacientes não deveria ser superior a 21 dias.

Quando os pacientes com fluxo lento foram comparados com o grupo controle, nenhuma diferença significativa foi observada nos valores de NT-proBNP (p=0,247). Os resultados positivos da RMC foram significativamente mais comuns nos pacientes com fluxo lento (p=0,001) (Table 1). Tecido cicatricial foi observado em níveis variáveis no ápice cardíaco de 7 pacientes ( Figuras 2 e 5 ) e nas regiões inferior e inferolateral em 3 pacientes ( Figures 3 , 4 , 6 , 7 and 8 ). Nenhum tecido cicatricial foi observado em 9 pacientes ( Figure 9 ).

As características demográficas e os graus de fluxo TIMI não foram diferentes no grupo positivo à RCM quando comparado com o grupo negativo à RMI. ( Tabela 2 ). Os níveis de NT-proBNP foram estatisticamente significativos nos pacientes com fluxo lento e tecido cicatricial à RMC (p=0,022) ( Tabela 2 ).

Tabela 2. – Características clínicas dos pacientes com fluxo lento.

Parâmetros	Fluxo Lento (N= 19)

	RMI cardíaca (+) (N=10)	RMI cardíaca (-) (N= 9)	Valor de p
Idade, média (DP), anos	54,1 ± 9,6	49,4 ± 7,1	0,29
Sexo (Masculino), n (%)	6 (60)	9 (100)	0,08
Hipertensão, n (%)	4 (40)	2 (22,2)	0,62
Diabetes mellitus, n (%)	3 (30)	3 (33,3)	1,0
Tabagista, n (%)	6 (60)	3 (33,3)	0,37
Histórico familiar, n (%)	1 (10)	3 (33,3)	0,30
Dislipidemia, n (%)	3 (30)	0 (0)	0,21
IMC, média (DP) (kg/m ² )	28,2 ± 3,0	28,0 ± 2,4	0,81
NT-proBNP (pg/ml)	147,10	28,0 (21,5-56,2)	0,03
cTFC (quadro/segundo)	(41,57-734,57)	26,4 (22,9-35,0)	0,67
METs, mL/kg/dk	24,1 (23,8-28,9)	10,26 ± 1,92	0,304

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IMC: índice de massa corporal; cTFC: TIMI corrigido; METs: equivalentes metabólicos; RMI: ressonância magnética por imagem.

Todos os indivíduos completaram o teste ergométrico usando o protocolo Bruce. Todos os pacientes apresentaram capacidade aeróbica acima de 7 METs. Os testes de esforço foram encerrados a pedido dos próprios pacientes. Não foram observadas alterações significativas de segmento ST (≥1 mm) ou de onda T em nenhum teste de esforço. Os valores do equivalente metabólico (METS) foram diferentes nos grupos controle, fluxo lento, e positivo à RMI (11,15 ± 1,43; 9,74 ± 2,05; 9,27 ± 2,15, respectivamente; p=0,027 para o grupo controle versus o grupo fluxo lento; p=0,013 para o grupo controle versus o grupo positivo à RM). Não houve diferenças de valores de MET entre o grupo controle e o grupo negativo à RM (11,15 ± 1,43 vs 9,74 ± 2,05; p=0,201) ( Tabela 3 ).

Tabela 3. – Resultados dos testes de esforço por grupos.

Parâmetro	Controle (N= 16) (1)	RM Cardíaca (+) (N=10) (2)	RM Cardíaca (-) (N= 9) (3)	Valor de p (1-2)	Valor de p (1-3)
METs, mL/kg/dk	11,15 ± 1,43	9,27 ± 2,15	10,26 ± 1,92	0,013	0,201

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METs: equivalentes metabólicos; RM: ressonância magnética

Discussão

O principal achado deste estudo foi a detecção de tecido cicatricial à RMC em pacientes com fluxo lento na DAE. Os valores de NT-proBNP foram mais altos nos pacientes com fluxo lento e tecido cicatricial à RMC. Além disso, a capacidade aeróbica desses pacientes foi inferior quando comparada com a do grupo controle. Na literatura, os pacientes com fluxo coronário lento não haviam sido previamente avaliados por meio de RMC para detecção de presença de fibrose miocárdica. No nosso estudo, detectamos tecido cicatricial miocárdico na região da DAE em aproximadamente metade dos pacientes com o fenômeno do FCL na DAE. Esse achado foi estatística e clinicamente significativo quando comparado com o grupo controle. Entretanto, nós não avaliamos os pacientes com exames seriados de RMI ou medições seriadas de NT-proBNP. A ausência de tecido cicatricial nos pacientes restantes pode ser explicada pela limitação do nosso estudo. O desenvolvimento de tecido cicatricial no miocárdio requer a existência de um processo progressivo decorrente de danos contínuos durante anos. Assim sendo, a ausência de tecido cicatricial poderia ser o resultado do momento da avaliação. Como bem se sabe, o processo de formação de placa ateromatosa demora muitos anos, dependendo da presença de fatores de risco cardiovasculares, condições ambientais, fatores genéticos, e período de tempo. Os mesmos fatores podem também se aplicar ao fluxo coronário lento. Demonstramos com este estudo que o FLC não é de forma alguma inofensivo e que ele pode levar à cicatrização do tecido miocárdico ao final do respectivo processo patológico. O papel do NT-proBNP na fisiopatologia do FCL não está claro. Demonstrou-se que o peptídeo natriurético do tipo B é secretado dos cardiomiócitos em resposta à isquemia, e que essa secreção pode também ser independente do estresse da parede ventricular esquerda. ^17
-
20 Adicionalmente, além dos miócitos cardíacos, os fibroblastos podem secretar BNP e causar fibrose por indução das metaloproteinases de matriz através da liberação de BNP. ²¹ No nosso estudo, os níveis de NT-proBNP não foram significativamente altos nos pacientes com fluxo lento. Entretanto, eles foram considerados altos nos pacientes com fluxo lento, nos quais as cicatrizes foram detectadas na RMC. Pode-se sugerir que os níveis de NT-proBNP foram elevados apenas na presença de fibrose suficiente em resposta ao fluxo coronário lento, que levou ao desenvolvimento de tecido cicatricial do miocárdio. A etiologia do FCL não foi claramente compreendida desde que foi descrita pela primeira vez. Embora o FCL possa ser uma consequência de alterações microvasculares, o aumento da resistência microvascular e a aterosclerose generalizada em estágio inicial também demonstraram desempenhar um papel na etiologia. ^22
,
23 Além disso, tentou-se lançar mão das alterações histológicas e patológicas nas artérias coronárias para elucidar a etiologia. Em um estudo conduzido em pacientes com FCL, Mangieri et al., ¹⁷ encontraram mudanças, tais como edema celular, hiperplasia fibromuscular, hipertrofia medial, proliferação miointimal, fibrose irregular, lesão capilar e redução do lúmen capilar, resultantes da biópsia do miocárdio, tendo alegado que essas alterações patológicas tornavam o fluxo sanguíneo mais lento através do aumento da resistência vascular. ^22
,
23 Ademais, no FCL, a ultrassonografia intravascular (USIV) revelou espessamento intimal difuso e calcificação generalizada, e a angigrafia coronária mostrou placas ateromatosas que não causam irregularidade luminal. ²⁴

Embora tenha-se relatada associação do fluxo coronário lento com muitas condições patológicas, ele parece desencadear uma doença aterosclerótica generalizada que é coincidente com uma doença microvascular na qual a disfunção endotelial encontra-se em primeiro plano. Pode-se considerer que a fibrose e a isquemia microvascular se desenvolvem no tecido miocárdico de pacientes com FCL, como consequência das alterações que ocorrem no nível microvascular, e nosso estudo corrobora esse ponto de vista.

A função microvascular coronária deteriorada no FCL demonstrou uma relação com o aumento do risco de eventos cardiovasculares. ^25
-
27 Além disso, foi relatado que, nos pacientes com disfunção microvascular, o prognóstico é semelhante àquele observado na doença arterial coronariana obstrutiva, e que essa disfunção não é tão benigna quanto se pensava. ^28
-
30 As manifestações clínicas dessa patologia também estão associadas a achados significativos. Dor torácia atípica, ^16
,
31 dor torácia típica ³² e dor torácica em repouso, que requerem intervenção urgente, ^4
,
33 frequentemente ocorrem em pacientes com fluxo coronário lento. Do mesmo modo, pacientes com FCL mostraram ser mais sintomáticos e suas internações hospitalares mais frequentes. ³⁴ Com base nisso, a RMC pode ser considerada uma boa escolha para investigar se o tecido miocárdico foi ou não afetado, além de oferecer uma opção favorável para avaliar a extensão da lesão, nos pacientes com FCL. A RMC de realce tardio possui alta resolução espacial. Com esse método, a fronteira entre o tecido infartado na parede do VE e o miocárdio viavél pode ser identificada através do exame da área do fluxo coronário lento. Além disso, a expansão transmural da área infartada pode ser determinada através desse método. Também é possível distinguir entre a isquemia vascular e não vascular em função da difusão do gadolínio.8 Na cardiomiopatia não isquêmica, o envolvimento do gadolínio é independente da perfusão vascular e ocorre na região subendocárdica. O envolvimento do gadolínio está diretamente associada à alimentação vascular na cardiomiopatia isquêmica. Além disso, esse envolvimento está localizado na região subendocárdica ou transmural. ³⁵

Panting et al.,31 demonstraram a hipoperfusão subendocárdica usando a RMC em pacientes com síndrome X, que acredita-se estar associada à disfunção microvascular. ³⁶ Do mesmo modo, Lanza et al.,32 detectaram defeitos de perfusão na região da DAE do miocárdio nos pacientes com síndrome X. ³⁷ Demonstrou-se também que há uma importante relação entre a reserva de perfusão miocárdica, que é examinada através da RMC, e a disfunção microvascular coronariana, a qual é um precursor da aterosclerose precoce . ³⁸

O NT-proBNP deve ser considerado após teste de esforço em pacientes com fluxo coronário lento. Ele pode fornecer informações sobre a fibrose cardíaca, embora ela possa ser afetada por diversas condições. Entretanto, não é possível realizar a RMC em todos os pacientes com contagem baixa de quadros TIMI devido à relação custo-benefício. A RMC pode ser considerada nos casos de pacientes com fluxo coronário lento em grau severo, dor torácica severa e valores elevados do biomarcador após o exercício. Devido ao pequeno número de pacientes do nosso estudo, não podemos fazer nenhuma recomendação em termos de tratamento, RMC ou controle do biomarcador. Todavia, este estudo poderá lançar luz sobre outros estudos, tanto no tocante ao tratamento (drogas antifibróticas) quanto aos exames (RMC, nível de NT-ProBNP, dentre outros).

Limitações do Estudo

Nosso estudo teve algumas limitações. Primeiramente, o número de pacientes foi pequeno. Em segundo lugar, as angiografias coronarianas foram realizadas por médicos diferentes e, embora as imagens angiográficas sejam padronizadas, houve diferenças pouco significativas entre as projeções. Finalmente, a técnica de ultrassom intravascular (USIV), capaz de mostrar a estrutura e as funções das artérias coronárias em detalhes, as medições da reserva de fluxo fracionada (RFF) e da pressão intracoronária ( pressure wire ), e os testes de acetilcolina não foram realizados no nosso estudo. Entretanto, a realização desses testes invasivos, com o seu potential de complicações, em pacientes sem estenose epicárdica não é apropriado por razões éticas.

Conclusão

Neste estudo, que foi conduzido para demonstrar o tecido cicatricial relacionado com o fenômeno do FLC, a RMC pela técnica do realce tardio apresentou resultados positivos. A RMC revelou tecido cicatricial nos pacientes com fluxo lento. Esses resultados sugerem que o fenômeno do fluxo lento pode acarretar alterações irreversíveis no tecido do miocárdio. As prováveis consequências dessas alterações devem ser investigadas em pesquisas futuras.

Vinculação Acadêmica

Este artigo é parte de tese de Doutorado de Mustafa Candemir pela Gazi University.

Aprovação Ética e Consentimento Informado

Este estudo foi aprovado pelo Comitê de Ética do Gazi University sob o número de protocolo 83. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013. O consentimento informado foi obtido de todos os participantes incluídos no estudo.

Fontes de Financiamento. O presente estudo foi financiado pelo Gazi University Scentific Research Projects.

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Arq Bras Cardiol. 2020 Mar 20;114(3):540–551. [Article in English]

Determination of Myocardial Scar Tissue in Coronary Slow Flow Phenomenon and The Relationship Between Amount of Scar Tissue and Nt-ProBNP

Mustafa Candemir ^1,², Asife Şahinarslan ², Merve Yazol ³, Yusuf Ali Öner ⁴, Bülent Boyacı ²

Abstract

Background

Pathophysiology and prognosis are not clearly determined in patients with the coronary slow flow phenomenon (CSFP). These patients present with various clinical conditions ranging from being asymptomatic to being admitted with sudden cardiac death.

Objectives

We aimed at assessing the findings of late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging (CMR) as an indicator of myocardial fibrosis. We also aimed at determining the relationship between the presence of myocardial fibrosis and NT-proBNP levels in patients with CSFP in the left anterior descending coronary artery (LAD).

Methods

A total of 35 patients were enrolled within an age range of 31-75. The study patients (n=19) had normal epicardial coronary arteries at angiography, but they presented with CSFP in the LAD. The control group patients (n=16) had normal epicardial coronary arteries and TIMI scores at normal levels in angiography. In both groups, the patients were examined with CMR for the presence of myocardial fibrosis. In addition, plasma NT-proBNP levels were measured. A p-value < 0.05 was considered significant.

Results

The rate of myocardial fibrosis was significantly higher in CMR in the patients with CSFP (p=0.018). A variable amount of myocardial scar tissue was detected at the left ventricular apex in 7 patients and at the inferior and inferolateral regions in 3 patients. There was no difference in the level of NT-proBNP in patients with CSFP. However, the NT-proBNP levels were higher in patients with CSFP, who had scar tissue in CMR (p=0.022).

Conclusions

In conclusion, LGE in CMR showed that ischemic myocardial scarring may exist in patients with CSFP. These results indicate that CSFP may not always be innocent. (Arq Bras Cardiol. 2020; 114(3):540-551)

Keywords: Heart Failure; Fractional Flow Reserve, Myocardial; Cicatrix, Hypertrophic; Prognosis; Natriuretic-Peptide, C-Type; Endomyocardial Fibrosis, Magnetic Resonance Spectroscopy

Introduction

There is limited information in the literature regarding the prognosis of slow coronary flow phenomenon (CSFP). The preexisting data indicates that slow flow-related myocardial ischemia may cause angina and the prognosis is worse in these patients. ¹ Acute myocardial infarction, ² sudden cardiac death and malignant ventricular arrhythmia were also reported to be associated with CSFP. ³ The occurrence of recurrent episodes of chest pain or chest pain developing at rest, as well as high rates of emergency admissions, and hospitalizations are reported. ^4
,
5 Thus, this phenomenon is not as innocent as it appears to be, bearing a potential to cause serious deterioration in the quality of life. It is not clearly known today whether organic injuries exist in these patients, due to the lack of further investigation and findings.

The level of N-terminal proB-type natriuretic peptide (NT-proBNP) has been shown to increase after exercise in patients with slow coronary artery flow. ⁶ There is a correlation between ischemia or infarct size on magnetic resonance imaging (MRI) and this correlation can be observed in the NT-proBNP levels in patients with acute coronary syndrome as well. ⁷ As a result of the advances in cardiac magnetic resonance imaging (CMR), microvascular ischemia and cardiac fibrosis can be demonstrated using this technique. ^8
,
9 The relation between the extent of fibrosis and NT-proBNP levels in these patients has been revealed by several MRI studies performed in patients with acute coronary syndrome. ^10
,
11 However, there are no studies in the literature evaluating patients with CSFP for the presence of fibrosis in the myocardial tissue according to the findings of late gadolinium enhancement in CMR. This study aimed at investigating the presence of myocardial fibrosis in patients with slow flow in the left anterior descending coronary artery by using the late gadolinium enhancement technique in CMR. In addition, it aimed at evaluating the relationship between myocardial fibrosis and NT-proBNP levels.

Materials and Methods

Study Population

Among the patients who were admitted to our department between January 2015 - August 2016 and who underwent coronary angiography for chest pain, 19 patients with the coronary slow flow phenomenon in LAD were included in this prospective cohort study. The control group included sixteen patients whose epicardial arteries were entirely normal with a normal coronary flow.

This study was approved by the ethics committee of the Gazi University Hospital and was conducted in accordance with the principles of the Helsinki declaration.

Exclusion Criteria

The following patients were excluded from the study: patients with coronary artery ectasia or atherosclerotic lesions in left main and left anterior descending coronary arteries; patients who underwent percutaneous coronary intervention; patients scheduled to undergo coronary artery intervention; patients with >50% stenosis in any coronary artery; patients with a prior history of MI; patients with <50% left ventricular systolic function; patients with claustrophobia, heart failure or valve dysfunction, ventricular extrasystoles or atrioventricular conduction abnormalities, and branch block or atrial fibrillation; patients with positive treadmill test; patients with restrictive, hypertrophic or dilated cardiomyopathies; patients with known systemic disease (hyperthyroidism, hypothyroidism, malignancy, autoimmune disease, infection or any of the pulmonary, hepatic, renal, hematologic disorders); patients with a history of myocarditis, whose GFRs are <80 ml / min and patients who refused to participate in the study.

Patient Data

The study patients were measured for height, weight, and body mass index (BMI). Patients’ age, gender, cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking and family history), demographic characteristics and comorbid diseases were recorded. Electrocardiography (ECG) was obtained for all patients and all of them demonstrated a sinus rhythm. All study patients were examined on the right lateral decubitus position with a Vivid 7-Pro Ultrasound system (Vingmed Electronic, GE, Horten, Norway), equipped with a 2.5 MHz probe, through simultaneous one-lead ECG recording. M-mode and Doppler measurements were performed in accordance with the recommendations of the American Echocardiography Association. ¹²

Exercise test was performed at an average of 3 days before angiography in all patients (GE medical system, Milwaukee, USA), according to the standard Bruce protocol test, with standard ECG, blood pressure and heart rate measurements performed at prespecified time points, as per relevant guidelines. ¹³

Blood samples for the quantification of NT-proBNP were collected through the angiography sheath immediately before its removal. After the collection, they were centrifuged for 10 min at 4500 rpm and stored at -20 ºC until the time when the isolated serum was analyzed. On the day of the analysis, after the samples reached room temperature, an electrochemiluminescence immunoassay was performed with the Roche Cobas e 411 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The results were presented in picograms per ml (pg/ml). The coefficent of variation value for the NT-proBNP was found below 5% via this method.

Coronary Angiography and Timi Frame Count

Coronary angiography was performed using the standard Judkins technique with a femoral approach and at 30 frames per second, using Toshiba Infinix cardiac angiography (Toshiba Corporation, Tochigi, Japan). Iopromide (Ultravist-370; Bayer Pharma AG, Berlin, Germany) was used as contrast agent during coronary angiography. An average of 6 to 8 ml of contrast agent was injected manually for each exposure. Coronary arteries were visualized through left and right oblique views with appropiate cranial or caudal angles. The speed of flow at LAD was assessed in right or left anterior oblique views often with caudal angle. The images were evaluated by two clinical specialists who were blind to the clinical findings of the patients.

Quantitative evaluation of coronary flow was performed in accordance with the TIMI-4 study, by counting cine frames, starting from the time of contrast agent administration, until it reached to a certain distal point. ¹⁴ The methodology of frame count was standardized for each epicardial vessel. TIMI frame counting started with the first frame in which the dye completely filled in the artery. The complete filling of the artery was determined by meeting the following three criteria: (1) A column of almost or fully concentrated dye should extend across the entire width of the origin of the artery; (2) The dye should touch both borders of the origin of the artery; and (3) there should be an antegrade motion of the dye. The last frame counted was the one in which the dye first enterered the end-point branch of the target artery. A complete opacification was not required at the distal segment.

LAD and TIMI frame counts were 1.7 times longer than the mean of the RCA and CX counts. Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC).

In our study, coronary flow for LAD was accepted to be normal when the TIMI frame count was <23 and it was accepted as slow when the TIMI frame count was ≥ 23. ^15
,
16

Magnetic Resonance Imaging Technique

CMR was performed after a median of 8 days (range 0-21 days) after coronary angiography. Standard sequences of cardiac MR perfusion studies were used in all patients. The left antecubital vein was used for intravenous contrast injection. MRI scans of patients were obtained using a 3 Tesla MRI device (Siemens MAGNETOM ^® Verio, Erlangen, Germany) with a gradient power of 45 mT/m. A 6-channel body coil was placed on the front chest wall while the patient was lying in the supine position with ECG pads placed properly. Multiplanar scout images were obtained with the phase-sensitive inversion-recovery (PSIR) turbo FLASH sequence using a repeated breath-hold MRI-technique. Standart long-axis, 2-chamber, 4-chamber and short- axis images of heart were obtained by aligning the mitral valve and the apex. Imaging parameters were: repetition time (TR) = 800ms; echo time (TE) = 6.66ms; slice thickness = 8 mm; matrix = 128x256 and field of view (FOV) = 400 mm. T1, T2 weighted images accompanied by ‘inversion recovery’ pulse for the suppression of blood signals (dark blood) and the turbo spin echo sequence were obtained in order to evaluate the myocardial morphology (TR/TE/ thickness/ matrix/ FOV: 698/6.6/ 8 mm/ 128x256, 360 mm).

Dynamic first-pass myocardial perfusion imaging with SR Turbo FLASH (TfI) pulse sequence was acquired after 0.025 mmol/kg Gd-DTPA (Magnevist; Bayer Healthcare, Wayne NJ, USA) was administered intravenously. In eight-minute resting intervals, cine short axis gradient echo sequences for functional imaging of the ventricles were obtained throughout cardiac cycle using the breath-hold technique (TR/TE/ thickness/ matrix/ FOV: 40,24/ TE/ 8 mm/128x256/ 360 mm). Short-axis and 4-chamber images were obtained with T1-weighted PSIR technique, approximately in the 8th minute after the contrast was applied (TR/TE/ thickness/ matrix/ FOV: 756/ TE: 1,15/ 6 mm/ 128x256/360 mm). Total imaging duration lasted 35 minutes on average.

The cost of CMR and plasma NT-proBNP testing were covered by the Scientific Research Projects Unit of the Gazi University.

Magnetic Resonance Image Analysis

All CMR images were transferred to the work station for analysis (Siemens multimodality workplace, Leonardo, Siemens Healthcare). All evaluations were performed visually. CMR studies were retrospectively evaluated by a radiologist experienced for more than 15 years in cardiac imaging, who was blind to the results of echocardiography and coronary angiography examinations. When any perfusion defects or late enhancement were observed during these examinations, they were precisely recorded. Contrast enhancement in perfusion sequences was defined as accomplishing all of the 5 phases after obtaining the highest signal intensity in the left ventricle. CMR results were then compared with the patients’ echocardiography and coronary angiography results.

Statistical Analysis

The study data were analyzed by using the SPSS (SPSS Inc., Chicago, version 21.0) program. The variables were examined using visual (histograms, probability plots) and analytical methods (the Kolmogorov-Simirnov test) to determine whether or not they were normally distributed. Descriptive analyses were presented with the values and standard deviations for the normally distributed variables, and with the median (interquartile range), for the non-normally distributed variables. Categorical variables were presented using percentages. Independent samples t-test and the Mann-Whitney U test were used to compare the numerical variables. Pearson’s Chi-square analysis was used to compare the categorical data, but Fisher’s exact test was performed when two of the expected values were below 5 or one of the expected value was below 2. A difference with a p-value <0.05 was considered statistically significant.

Results

A total of 35 patients were included in the study. Patients were divided into 2 groups as the patient group and the control group. Nineteen patients were identified comprising the group with slow flow in LAD, and 16 patients with normal coronary flow were included in the control group ( Figure 1 ). The patients in the control group were matched for their risk factors to the individuals in the patient group. The mean age of the patients was 50.3 ± 10.7, and 6 out of 35 patients (17%) were females. Eleven patients (31%) were diabetic, 9 patients (25%) were hypertensive, 5 patients (14%) were dyslipidemic, 18 patients (51%) were smokers and 8 patients (22%) had a positive family history ( Table 1 ).

Table 1. – Comparison of Clinical Characteristics between both Groups.

Parameters	Total (N=35)	Slow Flow (N= 19)	Control (N= 16)	p value
Age, mean (SD), years	50.3 ± 10.7	51.3 ± 8.2	49.44 ± 12.8	0.62
Sex (Male), n (%)	29 (82)	15 (78.9)	14 (87.5)	0.50
Hypertension, n (%)	9 (25)	6 (31.6)	3 (18.8)	0.38
Diabetes mellitus, n (%)	11 (31)	6 (31.6)	5 (31.3)	0.98
Smoker, n (%)	18 (51)	9 (47.4)	9 (56.3)	0.60
Family history, n (%)	8 (22)	4 (21.1)	4 (25)	0.78
Dyslipidaemia, n (%)	5 (14)	3 (15.8)	2 (12.5)	0.78
BMI, mean (SD) (kg/m ² )	27.7 ± 2.3	28.1 ± 2.5	27.3 ± 2	0.39
NT-proBNP (pg/ml)	29,5 (17.7-66.2)	47.8 (22.6-121.5)	26.0 (10.9-58.1)	0.246
cTIMI flow (frame/second)	34.6 ± 16.2	28.0 ± 8.6	13.1 ± 1.2	<0.001
METs, mL/kg/dk	10.38 ± 1.91	9.74 ± 2.05	11.15 ± 1.43	0.027
Positive results of MRI n (%)	10 (28)	10 (52.6)	0 (0)	0.001

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BMI: body mass index ; cTIMI: corrected Thrombolysis in Myocardial Infarction; METs: metabolic equivalents; MRI: magnetic resonance imaging.

The main complaint was chest pain in all study patients. ECG of all patients was sinus rhythm. Heart rates were between 64/min - 92/min. The average heart rate was 74/min. In addition, there was no sign of ischemia, hypertrophy or arrhythmia in the ECG. Left ventricular ejection fraction and other echocardiography findings of the patients were normal. In addition, all patients’ treadmill tests were negative. High sensitivity troponin was measured before and after coronary angiography in all patients. All values were below the threshold and there was no increase in troponin values after angiography.

The time interval between the CMR examinations and catheter coronary angiography of the patients was scheduled not to be longer than 21 days.

When patients with slow flow were compared with the control group, no significant differences were found in NT-proBNP values (p=0.247). The positive CMR results were significantly more common in the patients with the slow flow (p=0.001) ( Table 1 ). Scar tissue was found at varying levels in the cardiac apex of 7 patients (Figures 2 and 5) and at the inferior and inferolateral regions in 3 patients (Figures 3,4,6,7 and 8). No scar tissues were found in 9 patients ( Figure 9 ).

Demographic characteristics and TIMI grade flow were not different in the CMR positive group compared to the MRI negative group ( Table 2 ). NT-proBNP levels were statistically significant in patients with slow flow and scar tissue in CMR (p=0.022) ( Table 2 ).

Table 2. – Clinical characteristics in patients with slow flow.

Parameters	Slow Flow (N= 19)

	Cardiac MRI (+) (N=10)	Cardiac MRI (-) (N= 9)	p value
Age, mean (SD), years	54.1 ± 9.6	49.4 ± 7.1	0.29
Sex (Male), n (%)	6 (60)	9 (100)	0.08
Hypertension, n (%)	4 (40)	2 (22.2)	0.62
Diabetes mellitus, n (%)	3 (30)	3 (33.3)	1.0
Smoker, n (%)	6 (60)	3 (33.3)	0.37
Family history, n (%)	1 (10)	3 (33.3)	0.30
Dyslipidaemia, n (%)	3 (30)	0 (0)	0.21
BMI, mean (SD) (kg/m ² )	28.2 ± 3.0	28.0 ± 2.4	0.81
NT-proBNP (pg/ml)	147.10	28.0 (21.5-56.2)	0.03
cTIMI flow (frame/second)	(41.57-734.57)	26.4 (22.9-35.0)	0.67
METs, mL/kg/dk	24.1 (23.8-28.9)	10.26 ± 1.92	0.304

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BMI: body mass index ; cTIMI: corrected Thrombolysis in Myocardial Infarction; METs: metabolic equivalents; MRI: magnetic resonance imaging.

All subjects completed treadmill exercise testing using the Bruce protocol. All patients had exercise capacity over 7 mets. Treadmill tests were terminated on the patients’ own request. There was no significant ST depression (≥1 mm) or T negativity in any exercise test. Metabolic equivalent (MET) values were different in the control, slow flow, and MR positive groups (11.15 ± 1.43; 9.74 ± 2.05; 9.27 ± 2.15, respectively; p=0.027 for the control group vs. the slow flow group; p=0.013 for the group control vs. the MR positive group). There were no differences in MET values between the control group and the MR negative group (11.15 ± 1.43 vs 9.74 ± 2.05; p=0.201) ( Table 3 ).

Table 3. – Exercise test results for groups.

Parameter	Control (N= 16) (1)	Cardiac MRI (+) (N=10) (2)	Cardiac MRI (-) (N= 9) (3)	p value (1-2)	p value (1-3)
METs, mL/kg/dk	11.15 ± 1.43	9.27 ± 2.15	10.26 ± 1.92	0.013	0.201

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METs: metabolic equivalents; MRI: magnetic resonance imaging.

Discussion

The main finding of this study was the detection of scar tissue in CMR in the patients with slow flow in the LAD. NT-proBNP values were higher in patients with slow flow and scar tissue in CMR. In addition, the exercise capacity of these patients was lower compared to the control group. Coronary slow flow patients have not previously been evaluated with CMR to detect any presence of myocardial fibrosis in the literature. In our study, we detected scar tissue in the myocardium in the LAD field in about half of patients with CSFP in the LAD. This finding was statistically and clinically significant when compared to the control group. However, we did not evaluate the patients with serial MRI examinations or serial NT-proBNP measurements. The absence of scar tissue in the remaining patients may be explained by this limitation of our study. The development of scar tissue in the myocardium requires a progressive process occurring as a result of continuous damage over years. Thus, the absence of scar tissue might have been due to timing of the assessment. As it is very well known, the process of atheromatous plaque formation takes many years, depending on the presence of cardiovascular risk factors, environmental conditions, genetic factors and the time period. The same factors may also apply to coronary slow flow. We have shown with this study that the CSFP is not harmless at all and that it can lead to scarring in the myocardial tissue at the end of the respective pathological process.

The role of NT-proBNP in the pathophysiology of CSFP is not clear. It has been shown that B-type natriuretic peptide is secreted from cardiomyocytes in response to ischemia and that its secretion can also be independent of left ventricular wall stress. ^17
-
20 Also, in addition to cardiac myocytes, fibroblasts can secrete BNP and cause fibrosis by induction of matrix metalloproteinases by releasing BNP. ²¹ In our study, the levels of NT-proBNP were not significantly high in patients with slow flow. However, they were found to be high in patients with slow flow, in whom scars were detected in CMR. It may be suggested that NT-proBNP levels are elevated only in the presence of sufficient fibrosis in response to coronary slow flow, which has led to the development of myocardial scar tissue. The etiology of CSFP has not been clearly understood since it was first described. Although CSFP may be the result of microvascular alterations, increased microvascular resistance and early stage widespread atherosclerosis have also been shown to play a role in the etiology. ^22
,
23 In addition, histological and pathological changes in the coronary arteries have been tried to be used for elucidating the etiology. In a study conducted in patients with CSFP, Mangieri et al. ¹⁷ found changes such as cellular edema, fibromuscular hyperplasia, medial hypertrophy, myointimal proliferation, irregular fibrosis, capillary damage and decreased capillary lumen, as a result of myocardial biopsy, and claimed that these pathological changes slowed blood flow by increasing vascular resistance. ^22
,
23 Moreover, in CSFP, intravascular ultrasonography (IVUS) has shown diffuse intimal thickening and widespread calcification, and coronary angiography has shown atheromatous plaques that do not cause luminal irregularity. ²⁴

Although coronary slow flow has been reported to be associated with many pathologic conditions, it appears to be the onset of a widespread atherosclerotic disease that is coincidental with a microvascular disease in which endothelial dysfunction is in the forefront. It can be considered that microvascular ischemia and fibrosis may develop in the myocardial tissue in patients with CSFP as a result of changes that take place at the microvascular level and our study supports this view.

The deteriorated coronary microvascular function in CSFP has been shown to be associated with increased risk of cardiovascular events. ^25
-
27 It has also been reported that, in patients with microvascular dysfunction, the prognosis is similar to that observed in obstructive coronary artery disease, and that this dysfunction is not as benign as it is thought to be. ^28
-
30 Clinical manifestations of this pathology are also associated with significant findings. Atypical chest pain, ^16
-
31 typical chest pain ³² and resting chest pain that require urgent intervention ^4
,
33 frequently occur in patients with coronary slow flow. Similarly, patients with CSFP were found to be more symptomatic and their hospital admissions were found to be more frequent. ³⁴ Based on this, CMR may be considered a good choice for investigating whether the myocardial tissue is affected or not, as well as providing a favorable option to evaluate the extent of the injury in patients with CSFP. Delayed contrast-enhanced CMR has high spatial resolution. With this method, the boundary between the infarcted tissue on the LV wall and the viable myocardium can be identified by examining the area of coronary slow flow. In addition, the transmural spread of the infarction area can be determined with this method. It is also possible to distinguish between vascular and non-vascular ischemia owing to the diffusion of gadolinium. ⁸ In non-ischemic cardiomyopathy, gadolinium involvement is independent of vascular perfusion and occurs in the subendocardial region. Gadolinium involvement is directly associated with vascular feeding in ischemic cardiomyopathy. In addition, this involvement is in the subendocardial or transmural region. ³⁵

Panting et al. ³¹ demonstrated subendocardial hypoperfusion with CMR in patients with syndrome X, which is believed to be associated with microvascular dysfunction. ³⁶ In the same way, Lanza et al. ³² detected perfusion defects in the LAD region of the myocardium in syndrome X patients. ³⁷ It is also shown that there is an important relationship between a myocardial perfusion reserve, which is examined with CMR and coronary microvascular dysfunction, and is a precursor of early atherosclerosis. ³⁸

NT-proBNP may be considered after an effort test in patients with coronary slow flow. It can give information about cardiac fibrosis, although it may be affected by several conditions. However, it is not possible to perform a CMR in all patients with low TIMI frame count due to cost effectiveness. CMR may be considered in patients with severe coronary slow flow degree, severe chest pain and high biomarker values after exercise. Because of the small number of patients in our study, we cannot make any recommendations about treatment, CMR or biomarker control. However, this study will shed light on studies on both treatment (anti-fibrotic drugs) and examination (CMR, NT-ProBNP, among others).

Study Limitations

Our study had a few limitations. First, the number of patients was low. Second, coronary angiographies were performed by different clinicians and, although angiographic images were standardized, there were negligible differences between the projections. Finally, the intravascular ultrasound (IVUS) technique, which can show the structure and functions of coronary arteries in detail, fractional flow reserve (FFR) and intracoronary pressure (pressure-wire) measurements, and acetylcholine testing were not performed in our study. However, performing these invasive tests, with their potential complications, in patients with no epicardial stenosis is not appropriate due to ethical reasons.

Conclusion

In this study, which was conducted to demonstrate scar tissue related to CSFP, CMR with delayed gadolinium enhancement technique has been found to yield valuable results. CMR showed scar tissue in patients with slow flow. These results suggest that the slow flow phenomenon may result in irreversible changes in myocardial tissue. The probable consequences of these changes should be investigated in further studies.

Study Association

This article is part of the thesis of Doctoral submitted by Mustafa Candemir, from Gazi University.

Ethics Approval and Consent to Participate

This study was approved by the Ethics Committee of the Gazi University under the protocol number 83. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

Sources of Funding. This study was funded by Gazi University Scentific Research Projects.

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PERMALINK

Determinação do Tecido Cicatricial do Miocárdio no Fenômeno de Fluxo Coronário Lento e a Relação entre a Quantidade de Tecido Cicatricial e o Nt-ProBNP

Mustafa Candemir

Asife Şahinarslan

Merve Yazol

Yusuf Ali Öner

Bülent Boyacı

Resumo

Fundamento

Objetivos

Métodos

Resultados

Conclusões

Introdução

Materiais e Métodos

População do Estudo

Critérios de Exclusão

Dados dos Pacientes

Angiografia Coronária e Contagem de Quadros TIMI

Técnica da Ressonância Magnética

Análise de Imagem por Ressonância Magnética

Análise Estatística

Resultados

Figura 1. – Seleção de pacientes. RMC: imagem por ressonância magnética cardíaca.

Tabela 1. – Comparação das características clínicas de ambos os grupos.

Figura 2. – Imagem no plano 4 câmaras, na sequência inversão-recuperação sensível à fase (PSIR) com realce tardio, revelando realce tardio subendocárdico circunferencial na região apical (setas) do ventrículo esquerdo.

Figura 5. – Lesão focal em imagem ponderada em T1 no plano 4 câmaras, na sequência PSIR, com realce tardio pelo gadolínio. Lesão focal localizada na região apical do ventrículo esquerdo, revelando realce tardio subendocárdico-miocárdico compatível com fibrose.

Figura 3. – Imagem de RMC na sequência PSIR com contraste tardio no eixo curto, revelando áreas e focos de realce tardio em regiões subendocárdicas (transmurais) e subepicárdicas, sobretudo nas paredes do ventrículo esquerdo inferior e inferolateral.

Figura 6. – Imagem de sequência PSIR, com realce tardio, no eixo curto, representando áreas de realce subendocárdicas, sobretudo na parede ventricular esquerda inferolateral. Tecido cicatrial abrangendo quase 25-50 % da espessura da parede.

Figura 8. – Imagem de RMC com sequência PSIR pela técnica do contraste tardio no eixo curto, revelando áreas de realce focal nas regiões subepicárdica e subendocárdica localizadas nas paredes inferior e inferolateral do VE.

Figura 9. – Essa imagem mostra a aparência de um miocárdio normal. Essa imagem em particular foi adquirida na sequência PSIR. Não há realce anormal.

Tabela 2. – Características clínicas dos pacientes com fluxo lento.

Tabela 3. – Resultados dos testes de esforço por grupos.

Discussão

Limitações do Estudo

Conclusão

Referências

Determination of Myocardial Scar Tissue in Coronary Slow Flow Phenomenon and The Relationship Between Amount of Scar Tissue and Nt-ProBNP

Mustafa Candemir

Asife Şahinarslan

Merve Yazol

Yusuf Ali Öner

Bülent Boyacı

Abstract

Background

Objectives

Methods

Results

Conclusions

Introduction

Materials and Methods

Study Population

Exclusion Criteria

Patient Data

Coronary Angiography and Timi Frame Count

Magnetic Resonance Imaging Technique

Magnetic Resonance Image Analysis

Statistical Analysis

Results

Figure 1. – Patient selection. CMR: cardiac magnetic resonance imaging.

Table 1. – Comparison of Clinical Characteristics between both Groups.

Figure 2. – Four-chamber delayed-enhancement Phase Sensitive Inversion Recovery (PSIR) image, showing delayed subendocardial circumferential enhancement in the apical region (arrows) of the left ventricle.

Figure 5. – There is a focal lesion in four-chamber PSIR prepared gadolinium-enhanced T1-weighted image. Focal lesion localized to the apical region of the left ventricle, showing late subendocardial- myocardial enhancement compatible with fibrosis.

Figure 3. – Short- axis delayed contrast-enhanced PSIR cardiac MR image, showing focal subendocardial transmural and subepicardial enhancement areas, mostly in the inferior and inferolateral left ventricular walls.

Figure 6. – Short-axis delayed contrast-enhanced PSIR image represents sub-endocardial enhancement areas, mostly in the inferorolateral left ventricular wall. Scar tissue spanning in nearly 25-50% of wall thickness.

Figure 7. – Short- axis delayed contrast-enhanced PSIR cardiac MR image, showing focal subendocardial transmural and subepicardial enhancement areas, mostly in the inferior and inferolateral left ventricular walls (arrows), indicating scar tissues in the distribution of the LAD.

Figure 8. – Short- axis delayed contrast-enhanced PSIR cardiac MR image, demonstrating focal subendocardial and subepicardial enhancement areas localized into the inferior and inferolateral left ventricular walls.

Figure 9. – This image shows the appearance of normal myocardium. This particular image was obtained using Phase Sensitive Inversion Recovery (PSIR). There is no abnormal enhancement.

Table 2. – Clinical characteristics in patients with slow flow.

Table 3. – Exercise test results for groups.

Discussion

Study Limitations

Conclusion

ACTIONS

PERMALINK

RESOURCES

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