Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC z983yWJsXtxSqK6rkyBP4Wz S0066-782X2020000701004 S0066-782X2020005005202 abc.20190201 10.36660/abc.20190201 Artigo Original Doença Arterial Coronariana Anatômica Associada à Quimioterapia em Pacientes com Câncer de Pulmão Avaliada pelo Escore Angiográfico SYNTAX Yang Qian 1 Chen Yundai 1 Gao Hai 2 Zhang Jianzhong 3 Zhang Juan 4 Zhang Mingjie 1 Jing Jing 1 Zhu Pingjun 1 Zhou Hao 1 0000-0002-8738-7417 Hu Shunying 1 Chinese PLA General Hospital Department of Cardiology First Medical Center Beijing China Chinese PLA General Hospital - Department of Cardiology, First Medical Center, Beijing - China Beijing An Zhen Hospital Department of Cardiology, Chaoyang-qu Beijing China Beijing An Zhen Hospital - Department of Cardiology, Chaoyang-qu, Beijing - China Unimed Scientific Inc. Wuxi China Unimed Scientific Inc., Wuxi - China Chinese PLA General Hospital Department of Oncology First Medical Center Beijing China Chinese PLA General Hospital - Department of Oncology - First Medical Center, Beijing – China Correspondência: Shunying Hu • Department of Cardiology, Chinese PLA General Hospital - 28 Fuxing Road Beijing 100853 – China E-mail: hsylily@163.com

Contribuição dos autores

Concepção e desenho da pesquisa: Chen Y, Hu S; Obtenção de dados: Yang Q, Gao H, Zhang M, Jing J, Zhu P; Análise e interpretação dos dados: Yang Q, Gao H, Zhang J, Zhou H, Hu S; Análise estatística: Zhang J, Zhou H, Hu S; Obtenção de financiamento: Hu S; Redação do manuscrito: Zhang J, Hu S; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Yang Q, Chen Y, Hu S.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 30 03 2020 06 2020 114 6 1004 1012 07 02 2019 03 06 2019 23 06 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 doença arterial coronariana (DAC) associada à quimioterapia está se tornando um tema emergente na prática clínica. Contudo, o mecanismo subjacente da quimioterapia associada à DAC permanence incerto.

 Objetivos

O estudo investigou a associação entre a quimioterapia e as anomalias anatômicas ateroscleróticas das artérias coronárias dentre pacientes com cancer de pulmão.

 Métodos

Foram incluídos pacientes submetidos à angiografia coronária (AGC), entre 2010 e 2017, com câncer de pulmão prévio. Os fatores de risco associados à DAC e os dados sobre o câncer de pulmão foram avaliados. Avaliamos as anomalias das artérias coronárias de acordo com o escore SYNTAX (SXescore) calculado à AGC. Na análise de regressão logística, o escore SYNTAX foi classificado como alto (SXescoreALTO) se ≥22. Os dados foram analisados através de estatística descritiva e análise de regressão.

 Resultados

Ao todo, 94 pacientes foram incluídos no estudo. O SXescore foi mais alto no grupo com quimioterapia quando comparado com o grupo sem quimioterapia (25,25, IIQ [4,50–30,00] versus 16,50, IIQ [5,00–22,00]; p = 0,0195). A taxa do SXescoreALTO foi maior no grupo com quimioterapia do que no no grupo sem quimioterapia (58,33% versus 25,86; p = 0,0016). Tanto a análise de regressão logística univariada (OR: 4,013; 95% IC:1,655–9,731) quanto a multivariada (OR: 5,868; 95% IC:1,778–19,367) revelaram que a quimioterapia aumentou o risco de uma maior taxa do SXescoreALTO. A análise multivariada de regressão logística Stepwise mostrou que o risco para DAC anatômica mais grave aumenta com a quimioterapia como um todo em 5.323 vezes (95% IC: 2,002–14,152), e com o regime à base de platina em 5,850 vezes (95% IC: 2,027–16,879).

 Conclusões

A quimioterapia está associada com a complexidade e gravidade anatômica da DAC, o que pode explicar, em parte, o maior risco de DAC associada à quimioterapia dentre pacientes com câncer de pulmão. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

 Doença da Artéria Coronariana/fisiopatologia Neoplasias Pulmonares/tratamento farmacológico Pontuação de Propensão Syntax Escore Angioplastia/métodos Fatores de Risco National Natural Science Foundation of China 81770237 Fontes de financiamento. O presente estudo foi financiado pelo National Natural Science Foundation of China, número 81770237. Introdução

As estratégias de tratameto modernas levaram à melhora nas chances de sobrevivência ao diagnóstico de câncer. Entretanto, esses ganhos têm um custo.1 A toxicidade cardiovascular é uma potencial complicação a curto ou longo prazo de várias terapias anticâncer e está se tornando uma das maiores preocupações no que diz respeito aos efeitos colaterais desse tipo de tratamento.2 As doenças do coração que podem ser induzidas por agentes quimioterápicos anticâncer incluem a disfunção cardíaca, a isquemia cardíaca, a arritmia, o AVC e a hipertensão arterial pulmonar.1,3,4 A doença arterial coronariana (DAC) associada à quimioterapia está se tornando um problema clínico emergente, o qual é difícil de administrar, devido as suas várias manifestações clínicas e ao complicado mecanismo fisiopatológico envolvido.5-7 Eventos coronarianos induzidos pela quimioterapia que ocorreram logo após a administração dos agentes quimioterápicos, possivelmente em decorrência de trombose aguda ou vasoespasmo, já foram relatados.3,8 Entretanto, a patogênese da DAC crônica associada à quimioterapia ainda não é conhecida.

O câncer de pulmão é o câncer incidental mais comum, e a principal causa de morte por câncer.9 A quimioterapia é um tratamento importante contra o câncer de pulmão.10,11Sabe-se que os agentes quimioterápicos para o câncer de pulmão, inclusive taxanos, cisplatina, carboplatina, bevacizumabe, sorafenibe e erlotinibe,3,10,12 causam infarto agudo do miocárdio. Desse modo, faz-se necessário investigar o efeito a longo prazo da quimioterapia sobre as alterações anatômicas da artéria coronária nos pacientes com câncer de pulmão.

A complexidade e características das lesões coronárias são preditores conhecidos de complicações periprocedimentais e de mortalidade a longo prazo.13-15 O escore SYNTAX (SXescore) foi desenvolvido para caracterizar prospectivamente a vasculatura coronariana por números de lesões e seus impactos funcionais, localização e complexidade.16-18 É uma ferramenta importante para classificar a complexidade da DAC e para a estratificação de risco de pacientes que estão sendo considerados para revascularização, e vem demonstrando valor satisfatório como um preditor de eventos cardíacos adversos significativos, incluindo a morte cardíaca. Os SXescores mais altos, indicativos de doenças mais complexas, hipoteticamente representam um desafio terapêutico maior, além de apresentarem prognósticos cardíacos potencialmente piores.16,17,19-21

Estudos recentes utilizaram o SXescore para quantificar a gravidade da DAC dentre pacientes com câncer, buscando examinar principalmente o efeito da radioterapia sobre a DAC.20,21 No presente estudo, utilizamos o SXescore para avaliar a complexidade e gravidade da DAC dentre pacientes com câncer de pulmão, a fim de investigar a relação entre a quimioterapia e a DAC. Também observamos o efeito da radioterapia e de outros fatores de risco sobre a gravidade anatômica das artérias coronárias dentre esses pacientes.

 Métodos Desenho e pacientes do estudo

Foi utilizado um desenho de estudo transversal hospitalar. Os pacientes do estudo foram admitidos no Hospital Geral Chinês do PLA para se submeterem à angiografia coronária (AGC) devido à suspeita de angina de peito ou estenose da artéria coronária revelada pela angiotomografia computadorizada, entre 2010 e 2017. Além disso, os pacientes deveriam ter recebido anteriormente diagnóstico definitivo de câncer de pulmão. Os pacientes que haviam sido submetidos à intervenção coronária percutânea prévia foram excluídos.

Examinamos minuciosamente os registros médicos eletrônicos dos pacientes no que diz respeito à história do câncer de pulmão, incluindo o diagnóstico, a idade à época do diagnóstico, localização e histórico do tratamento (quimioterapia e radioterapia). Revisamos o sexo, a idade à epoca da AGC, o índice de massa corporal (IMC), o histórico familiar de doenças cardiovasculares (DCVs), o uso de tabaco, a hipertensão, o diabetes, a hiperlipidemia e o perfil lipídico. Esses dados foram extraídos utilizando a plataforma de dados de pesquisa clínica criada pela Xiliu Data. Algumas informações foram checadas via telephone com os próprios pacientes ou seus familiares.

 A angiografia coronária e o SXescore

A partir do angiograma diagnóstico basal, pontuamos separadamente cada estenose coronária ≥50% em vasos com diâmetro ≥1,5 mm. Em seguida, somamos os escores para obter o SXescore global, que havíamos calculado prospectivamente utilizando o algaritmo SXescore (já totalmente descrito na literatura).16,17,22 Todas as variávies angiográficas pertinentes ao cálculo do SXescore foram computadas “às cegas” por 2 cardiologistas intervencionistas experientes. Quando havia divergência entre os dois cardiologistas em relação ao cálculo do SXescore de algum paciente, os mesmos discutiam o angiograma e atribuíam um SXescore comum para o paciente. Os SXescores finais foram calculados por paciente e salvos em uma base de dados dedicada. A Figura 1 mostra dois exemplos representativos de SXescores, tendo como base a AGC.

– <italic>SXescore da artéria coronária à AGC. AGCs representativos de um paciente com SXbaixo (SXescore = 2; A–B) e um paciente com SXalto (SXescore = 38; C–D) .</italic>

No estudo, o Sxescore de 22 foi o tercil superior. Definimos os graus do SXescore como SXbaixo (<22) ou SXalto (≥22). Por meio de análise de regressão logística, definimos que o grau do SXescore seria alto se o SXescore ≥22.

 Análise estatística

As estatísticas descritivas basais estão apresentadas como frequências e percentuais para variáveis categóricas e como média ± desvio padrão (DP) e mediana (interval interquartil [IIQ]) para variáveis contínuas. Avaliamos a normalidade dos dados utilizando o teste de assimetria e curtose. As diferenças entre grupos de estudo foram avaliadas usando o teste Qui-quadrado ou o teste exato de Fisher para dados categóricos, e o teste T foi utilizado para dados contínuos. Utilizamos o teste T para comparar as médias entre os grupos quando as variáveis estavam distribuídas normalmente, e um teste não paramétrico quando as mesmas não estavam distribuídas normalmente. O Qui-quadrado ou o teste exato de Fisher foram utilizados para examinar as diferenças para medidas categóricas. Avaliamos as relações entre a quimioterapia e a complexidade da DAC por meio de análise de regressão logística, ajustando as covariáveis relacionadas, que incluíram: idade, gênero, IMC, tabagismo, histórico familiar de DACs, hipertensão, diabetes e hiperlipidemia. As razões de probabilidade (OR) e os intervalos de confiança [ICs] em 95% foram calculados. Todos os valores de p foram bicaudais, e o nível de significância estatística de 0,05 foi adotado. Todas as análises estatísticas foram realizadas utilizando o programa SAS, versão 9.3 (SAS Institute, Inc., Cary, Carolina do Norte, EUA).

 Resultados Características dos pacientes

Incluímos no estudo 94 pacientes com câncer de pulmão prévio, que haviam sido submetidos à AGC no Hospital Geral Chinês do PLA, entre 2010 e 2017. Ao todo, foram incluídos 73 homens e 21 mulheres (M:F = 3,48). Dentre os participantes, oitenta e cinco foram diagnosticados com câncer de pulmão de células não pequenas, e os outros 9 pacientes com câncer de pulmão de células pequenas. Trinta e seis pacientes tinham histórico de quimioterapia. Dentre os pacientes com quimioterapia, 28 pacientes receberam regimes à base de platina. A quimioterapia à base de platina, em combinação principalmente com gencitabina ou docetaxe (e outros agentes), foi utilizada em pacientes com câncer de pulmão em células não pequenas. Em pacientes com câncer de pulmão em células pequenas, foi utilizada uma combinação quimioterápica de compostos de platina e etoposido. Um paciente recebeu antraciclina (Farmorubicina) que reconhecidamente tem um efeito cardiotóxico. Cinco pacientes receberam inibidores da tirosina quinase. Três pacientes não posuíam informações detalhadas sobre os regimes de quimioterapia. Cinquenta e oito pacientes não receberam quimioterapia.

Não foram observadas diferenças significativas em relação aos fatores de risco convencionais de DAC (hipertensão, hiperlipidemia, diabetes ou histórico de tabagismo) entre os grupos com quimioterapia e sem quimioterapia. No grupo com quimioterapia, mais pacientes receberam radioterapia do que no grupo sem quimioterapia (p < 0,0001). A variação do tempo de intervalo entre o diagnóstico de câncer e a CAG foi discrepante entre os dois grupos. As características dos pacientes estão listadas na Tabela 1.

– Características dos pacientes estratificados por histórico de quimioterapia
Características Grupo com quimioterapia (n = 36) Grupo sem quimioterapia (n = 58) Valor de p
Gênero 0,6257
Masculino 27 (75,00%) 46 (79,31%)
Feminino 9 (25,00%) 12 (20,69%)
Idade à AGC (anos) 0,077
<60 3 (8,33%) 13 (22,41%)
≥60 33 (91,67%) 45 (77,59%)
Tempo de intervalo entre o diagnóstico de câncer e a AGC (anos) 0,000
≤2 17 (47,22%) 48 (82,76%)
>2 19 (52,78%) 10 (17,24%)
Tipos de câncer de pulmão 0,081
Câncer de pulmão de células não pequenas 30 (83,33%) 55 (94,83%)
Câncer de pulmão de células pequenas 6 (16,67%) 3 (5,17%)
Regimes de quimioterapia NA
Platina + 28 (77,78%) --
Inibidores de tirosina quinase apenas 5 (13,89%) --
Regimes não verificados 3(8,33%) --
Radioterapia <0,0001
Não 19 (52,78%) 54 (93,10%)
Sim 17 (47,22%) 4 (6,90%)
IMC 24,81 ± 2,89 25,32 ± 2,79 0,3944
Hipertensão 0,2455
Não 12 (34,29%) 27 (46,55%)
Sim 23 (65,71%) 31 (53,45%)
Diabetes 0,9343
Não 28 (80,00%) 46 (80,70%)
Sim 7 (20,00%) 11 (19,30%)
Hiperlipidemia 0,5157
Não 29 (82,86%) 50 (87,72%)
Sim 6 (17,14%) 7 (12,28%)
Tabagismo 0,8938
Não 18 (51,43%) 29 (50,00%)
Sim 17 (48,57%) 29 (50,00%)
Consumo de álcool 0,1640
Não 45 (73,77%) 56 (62,92%)
Sim 16 (26,23%) 33 (37,08%)
Colesterol 4,15 ± 1,08 4,25 ± 1,10 0,6896
Trigliceríde 1,38 ± 0,71 1,49 ± 0,99 0,7905
Colesterol de lipoproteínas de baixa densidade 2,58 ± 0,96 2,48 ± 0,88 0,6999
Colesterol de lipoproteínas de alta densidade 1,17 ± 0,34 1,33 ± 0,87 0,8345

AGC: angiografia coronária; IMC: índice de massa corporal.

Análise da associação entre a quimioterapia e o SXescoreALTO

Os pacientes que foram submetidos à quimioterapia desenvolveram DAC anatômica mais grave em relação àqueles que não foram submetidos à quimioterapia. O SXescore foi significativamente mais alto no grupo com quimioterapia em relação ao grupo sem quimioterapia (25,25, IIQ [4,50–30,00] versus 16,50, IIQ [5,00–22,00]; p = 0,0195). De acordo com a definicão de graus do SXescore, o percentual do SXalto foi significamente maior no grupo com quimioterapia do que no grupo sem quimioterapia (58,33% versus 25,86%; p = 0,0016). Os detalhes estão listados na Tabela 2.

– SXescore e graus do SXescore nos pacientes com câncer de pulmão estratificados por quimioterapia ou radioterapia
Variáveis Variável estatística Estratificação por quimioterapia Estratificação por radioterapia
Grupo com quimioterapia (n = 36) Grupo sem quimioterapia (n = 36) Valor de p Grupo com radioterapia Grupo sem radioterapia Valor de p
SXescore 0,3045
Média ± DP 20,00 ± 12,70 14,96 ± 10,47 0,0195 18,67 ± 12,58 16,38 ± 11,31
Mediana 25,25 16,50 22,00 19,00
Q1–Q3 4,50–30,00 5,00–22,00 5,00–30,00 5,00–25,00
Mín–máx 0,00–38,00 0,00–38,00 1,00–35,50 0,00–38,00
Grau do SXescore 0,0016 0,1319
SXbaixo (<22) N (%) 15 (41,67%) 43 (74,14%) 10 (47,62%) 48 (65,75%)
SXalto (≥22) N (%) 21 (58,33%) 15 (25,86%) 11 (52,38%) 25 (34,25%)

A radioterapia é outro tratamento importante contra o câncer de pulmão. No nosso estudo, o SXescore foi mais alto no grupo com radioterapia do que no grupo sem radioterapia (22,00, IIQ [5,00–30,00] versus 19,00, IIQ [5,00–25,00]; p = 0,3045). O percentual do SXalto foi maior no grupo com radioterapia do que no grupo sem radioterapia (52,38% versus 34,25%; p = 0,1319). Entretanto, não houve diferenças significativas tanto para o SXescore quanto para a taxa do SXalto entre os grupos com radioterapia e sem radioterapia. Comparada com a radioterapia, a quimioterapia mostrou efeitos piores sobre as anomalias das artérias coronárias dentre os pacientes com câncer de pulmão. Os resultados estão apresentados na Tabela 2.

A análise de regressão logística univariada mostrou que a quimioterapia aumentou significativamente a taxa do SXalto em 4,013 vezes (95% IC: 1,655–9,731). A OR da radioterapia para o SXalto foi 2,112 (95% IC: 0,790–5,646), o que não mostrou significância estatística evidente. O tabagismo, como um fator de risco cardiovascular convencional, aumentou significativamente a taxa do SXalto em 3,182 vezes (95% IC: 1,327–7,628). A OR de outros fatores de risco cardiovasculares para o SXalto foram >1, mas não mostraram significância estatística evidente. Na análise de regressão logística multivariada, a quimioterapia aumentou o risco de DAC com anomalias anatômicas mais graves em 5,868 vezes (95% IC: 1,778-19,367). As ORs da radioterapia e do tabagismo para o SXalto foram 1,124 (95% IC: 0,286–4,416) e 3,035 (95% IC: 1,036–8,893), respectivamente. Os resultados estão apresentados na Tabela 3.

– Análise de regressão logística pela gravidade anatômica da artéria coronária nos pacientes com câncer de pulmão
Variáveis Modelo univariado Modelo multivariado
OR (95% IC) p OR (95% IC) p
Idade (anos) 0,9427 0,642
<60 Ref Ref
≥60 1,042 (0,343–3,161) 0,723 (0,184–2,840)
Gênero 0,1278 0,362
Feminino Ref Ref
Masculino 2,326 (0,781–7,140) 1,856 (0,490–7,021)
IMC 0,4538 0,428
<25 Ref Ref
≥25 1,376 (0,597–3,168) 1,528 (0,536–4,355)
Tabagismo 0,0095 0,043
Não Ref Ref
Sim 3,182 (1,327–7,628) 3,035 (1,036–8,893)
Histórico familiar de DAC 0,2467 0,659
Não Ref Ref
Sim 2,011 (0,617–6,563) 1,379 (0,331–5,754)
Hipertensão 0,9667 0,748
Não Ref Ref
Sim 1,018 (0,437–2,372) 1,180 (0,431–3,234)
Diabetes tipo 2 0,5338 0,501
Não Ref Ref
Sim 1,393 (0,491–3,953) 1,561 (0,426–5,721)
Hiperlipidemia 0,9732 0,616
Não Ref Ref
Sim 1,021 (0,306–3,410) 0,677 (0,147–3,118)
Intervalo de tempo entre o diagnóstico de câncer e a ACG (anos) 0,2914 0,899
≤2 Ref Ref
>2 1,484 (0,609–3,617) 1,075 (0,350–3,301)
Radioterapia 0,136 0,867
Não Ref Ref
Sim 2,112 (0,790–5,646) 1,124 (0,286–4,416)
Quimioterapia 0,0021 0,004
Não Ref Ref
Sim 4,013 (1,655–9,731) 5,868 (1,778–19,367)

IMC: índice de massa corpora; DAC: doença arterial coronariana; ACG: angiografia coronária.

Na regressão logística multivariada Stepwise ajustada para fatores de risco relacionados à DAC (idade, gênero, IMC, tabagismo, histórico familiar de DCVs, hipertensão, diabetes e hiperlipidemia), e para fatores de risco relacionados ao câncer de pulmão (histórico de radioterapia e quimioterapia), a quimioterapia como um todo e o tabagismo aumentaram significativamente a taxa do SXalto em 5.323 vezes (95% IC: 2,002–14,152) e 3.646 vezes (95% IC:1,374–9,678), respectivamente. Além disso, detectamos que, no que diz respeito aos efeitos do regime à base de platina sobre a DAC anatômica, os resultados foram semelhantes, sendo que a OR do regime à base de platina foi 5,850 (95% IC: 2,027–16,879) e a OR do tabagismo foi 3,670 (95% IC: 1,303–10,339). Os resultados estão apresentados na Tabela 4.

– Modelo de regressão logística multivariada Stepwise para gravidade anatômica da artéria coronária dentre pacientes com câncer de pulmão
Variáveis OR 95% IC Valor de p
Total de pacientes (n=94)
Tabagismo 3,646 1,374-9,678 0,009
Quimioterapia 5,323 2,002-14,152 0,001
Pacientes, exceto com ITQ ou RNV (n=86)
Tabagismo 3,670 1,303-10,339 0,14
Quimioterapia 5,850 2,027-16,879 0,007

ITQ: inibidores da tirosina-quinase; RNV: regimes não verificados.

Discussão

Até onde temos conhecimento, este estudo é o primeiro a demonstrar quantitativamente que a quimioterapia está relacionada com a complexidade anatômica e a gravidade da DAC dentre os pacientes com câncer de pulmão, usando o SXescore com base nos angiogramas coronários.

A terapia antineoplásica é frequentemente dificultada pelo desenvolvimento de complicações cardiovasculares, tais como insuficiência cardíaca, infarto do miocárdio, hipertensão, tromboembolismo, prolongação do QT e bradicardia.23 Até o momento, as doenças do coração induzidas por quimioterapia relatadas com mais frequência são a disfunção e a insuficiência cardíaca, conforme avaliado à ecocardiografia.1,24,25 Os eventos da artéria coronária relacionados à quimioterapia estão se tornando problemas clínicos importantes dentre a população com câncer submetidas à quimioterapia.5-7 Eventos agudos da artéria coronária que ocorreram logo após a administração de agentes quimioterápicos foram relatados.3,8 Haugnes et al.,26mostraram um risco 5,7 vezes maior de DAC, e um risco de infarto do miocárdio 3,1 vezes maior, nos regimes à base de cisplatina, quando comparados com a cirurgia isolada, em um tempo médio de observação de 19 anos.26 O presente estudo investigou a associação entre a quimioterapia e as anomalias anatômicas das artérias coronárias dentre pacientes com câncer de pulmão.

O câncer de pulmão é o câncer incidental mais comum e é a principal causa de morte por câncer.9 O estudo avaliou as anomalias anatômicas das artérias coronárias através do SXescore e investigou a relação entre a quimioterapia e a complexidade anatômica da DAC dentre pacientes com câncer de pulmão. Os resultados mostraram que tanto a taxa do SXescore quanto a do SXalto foram significativamente maiores nos pacientes que foram submetidos à quimioterapia, quando comparados com pacientes que não foram. A análise de regressão logística multivariada Stepwise mostrou que o risco de CAD anatômica mais grave aumenta devido à quimioterapia como um todo em 5,323 vezes, e com os regimes à base de platina, em 5,850 vezes. Os resultados indicam que a quimioterapia está associada com a complexidade anatômica e a gravidade da DAC, o que pode, ao menos em parte, explicar a morbidade mais elevada a longo prazo da DAC associada à quimioterapia, inclusive o infarto do miocárdio.26 Até onde sabemos, nenhum outro estudo semelhante de grande porte detectou quantitativamente a associação entre a quimioterapia e a gravidade e complexidade anatômica da DAC dentre pacientes com câncer de pulmão.

Embora a DAC associada à quimioterapia esteja se tornando uma questão emergente, o mecanismo subjacente da DAC associada à quimioterapia permanence desconhecido. Os eventos agudos da artéria coronária que ocorreram logo após a administração de agentes quimioterápicos foram decorrentes possivelmente de trombose aguda ou vasoespasmo.3,8 Nosso estudo indicou que os eventos coronários a longo prazo associados à quimiterapia podem ser decorrentes de anomalias anatômicas mais graves induzidas por agentes quimioterápicos. No presente estudo, cerca de 90% dos pacientes tinham câncer de pulmão em células não pequenas, e os outros pacientes tinham câncer de pulmão em células pequenas. A maioria dos regimes de quimioterapia dos pacientes do estudo envolvia mais de um agente quimioterápico, a maioria dos quais contêm platina. A platina foi a base da quimioterapia para a maioria dos pacientes. Cinco pacientes receberam gefitinibe. No estudo, um paciente recebeu antraciclina, que é conhecida por seu efeito cardiotóxico. É razoável determinar que as células endoteliais desempenham um papel importante durante a patogênse da DAC anatômica crônica, e a lesão endotelial induzida por agentes quimioterápicos pode ser a causa central da DAC associada à quimioterapia. Cada paciente do estudo recebeu vários agentes quimioterápicos. Desse modo, foi difícil deduzir qual deles desempenhou o papel mais importante no desenvolvimento da DAC associada à quimioterapia. Já que a platina é o agente mais utilizado, talvez ela seja um dos agentes mais importantes que precisam de estudos adicionais para ilustrar o mecanismo subjacente da DAC associada à quimioterapia.

A radioterapia desempenha um papel fundamental no tratamento do câncer de pulmão.27 Estudos anteriores demonstraram o efeito da radiação sobre as doenças do coração.20,28-30 No presente estudo, ambos o SXescore e o percentual do SXalto foram mais altos no grupo com radioterapia do que no grupo sem radioterapia, mas não houve diferenças significativas entre os dois grupos. Na análise de regressão logística, a OR da radioterapia para o SXalto foi 2,112 (95% IC, 0,790–5,646), o que indica a probabilidade de a radioterapia aumentar a complexidade das artérias corronárias. Porém, os resultados não mostraram diferenças significantes. Os dados ambíguos podem ser o resultado da menor amostra de pacientes que receberam radioterapia dentre a população estudada. Com base nos resultados já mencionados, talvez possamos afirmar que a quimioterapia pode desempenhar um papel mais importante do que se pensa atualmente no que diz respeito à DAC. Entretanto, nós não podemos afirmar que a quimioterapia é pior que a radiografia em termos de DAC, principalmente devido à pequena amostra, sem dados individuais suficientes para cada agente quimioterápico. Acreditamos que os resultados são interessantes e merecem estudos futuros.

A doença cardíaca que se manifesta após o câncer pode ser decorrente de vários mecanismos: riscos cardiovasculares compartilhados entre o câncer e a doença cardiovascular, estados inflamatórios associados com malignidades e/ou efeitos cardiotóxicos do tratamento do câncer. A idade, o gênero, o uso de tabaco, o histórico familiar de DAC, a hipertensão, o diabetes tipo 2 e a hiperlipidemia são fatores de risco bastante conhecidos de DAC.31-35 O tabagismo é um fator de risco bem conhecido e comum tanto de DAC quanto de câncer de pulmão. No nosso estudo, metade dos pacientes com câncer de pulmão eram tabagistas, o que é consistente com os dados nacionais, mostrando que cerca de 57% dos pacientes diagnósticados com câncer de pulmão são fumantes ou ex-fumantes.36 No nosso estudo, outros fatores de risco cardiovascular também aumentaram a gravidade da DAC, mas aqueles fatores de risco não demonstraram significância estatística evidente para o aumento do SXescore. Por outro lado, o tabagismo mostrou mais efeitos significativos sobre o aumento do risco para SXalto em 3.646 vezes.

Além disso, o tempo de duração do câncer de pulmão pode desempenhar um papel na progressão da DAC. No estudo, coletamos dados do tempo de intervalo entre o diagnóstico do câncer e a AGC. Embora o tempo de intervalo entre o diagnóstico do câncer e a AGC tenha sido discrepante entre os dois grupos (possivelmente por se tratar de um estudo retrospectivo de pequeno porte), o modelo logístico multivariado com ajuste adicional para a variável tempo de intervalo ainda mostrou diferenças significativas na gravidade da DAC entre os pacientes com quimioterapia e aqueles sem quimioterapia.

Nosso estudo tem várias limitações. Em primeiro lugar, trata-se de um estudo unicêntrico com uma amostra pequena, realizado com uma população específica de pacientes que haviam tido câncer de pulmão e necessitado de AGC devido à suspeita de DAC grave. Um número menor de pacientes recebeu radioterapia. Dentre os 94 pacientes do estudo, 21 pacientes costumavam receber radioterapia. Em particular, apenas 4 pacientes (6,9%) tinham histórico de radioterapia no grupo sem quimioterapia. Os resultados da amostra da população de pacientes, por ser pequena e específica, podem ser desviantes. Em segundo lugar, este foi um estudo retrospectivo, que pode carecer de algumas informações valiosas acerca dos pacientes. Seria útil saber o estágio do câncer de pulmão na apresentação inicial. Aqueles que receberam quimioterapia podem ter tido uma doença mais avançada e, consequentemente, mais inflamação, por um período mais longo de tempo, o que pode causar aterosclerose e contribuir para os resultados observados neste estudo. Entretanto, nós não recebemos dados tão amplos sobre os pacientes. Em terceiro lugar, nós não investigamos se SXescore estava associado com eventos cardiovasculares a longo prazo nos pacientes do estudo. Estudos clínicos adicionais prospectivos e em larga escala podem ser necessários para verificar o efeito da quimioterapia sobre a anomalia anatômica da DAC e o mecanismo subjacente da DAC associada à quimioterapia.

 Conclusões

Em resumo, o presente estudo demonstra que a quimioterapia está associada à gravidade e complexidade anatômica da DAC a longo prazo. Os resultados podem explicar em parte o fato de pacientes com câncer e histórico de quimioterapia apresentarem um risco mais elevado de eventos da artéria coronária, quando comparados com pacientes sem histórico de quimioterapia. Entretanto, devido às limitações, um estudo prospectivo de larga escala, bem como pesquisas futuras fisiopatológicas e moleculares, serão necessários para melhor ilustrar a associação entre a quimioterapia e a DAC, e o mecanismo subjacente da CAD associada à quimioterapia.

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Vinculação acadêmica

Este artigo é parte de dissertação de Mestrado de Qian Yang pela Chinese PLA general hospital.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética do Chinese PLA General Hospital sob o número de protocolo 52019-223-02. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013.

Fontes de financiamento. O presente estudo foi financiado pelo National Natural Science Foundation of China, número 81770237.

 Original Article Chemotherapy-Related Anatomical Coronary-Artery Disease in Lung Cancer Patients Evaluated by Coronary-Angiography SYNTAX Score Yang Qian 1 Chen Yundai 1 Gao Hai 2 Zhang Jianzhong 3 Zhang Juan 4 Zhang Mingjie 1 Jing Jing 1 Zhu Pingjun 1 Zhou Hao 1 0000-0002-8738-7417 Hu Shunying 1 China Chinese PLA General Hospital - Department of Cardiology, First Medical Center, Beijing - China China Beijing An Zhen Hospital - Department of Cardiology, Chaoyang-qu, Beijing - China China Unimed Scientific Inc., Wuxi - China China Chinese PLA General Hospital - Department of Oncology - First Medical Center, Beijing – China Mailing Address: Shunying Hu • Department of Cardiology, Chinese PLA General Hospital - 28 Fuxing Road Beijing 100853 – China E-mail: hsylily@163.com

Author contributions

Conception and design of the research: Chen Y, Hu S; Acquisition of data: Yang Q, Gao H, Zhang M, Jing J, Zhu P; Analysis and interpretation of the data: Yang Q, Gao H, Zhang J, Zhou H, Hu S; Statistical analysis: Zhang J, Zhou H, Hu S; Obtaining financing: Hu S; Writing of the manuscript: Zhang J, Hu S; Critical revision of the manuscript for intellectual content: Yang Q, Chen Y, Hu S.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Abstract Background

Chemotherapy-related coronary artery disease (CAD) is becoming an emerging issue in clinic. However, the underlying mechanism of chemotherapy-related CAD remains unclear.

 Objective

The study investigated the association between chemotherapy and atherosclerotic anatomical abnormalities of coronary arteries among lung cancer patients.

 Methods

Patients undergoing coronary angiography (CAG) between 2010 and 2017, who previously had lung cancer, were examined. Risk factors associated with CAD and information about lung cancer were evaluated. We assessed coronary-artery abnormalities by SYNTAX score (SXscore) based on CAG. In logistic-regression analysis, we defined high SXscore (SXhigh) grade as positive if ≥22. Data were analyzed through descriptive statistics and regression analysis.

 Results

A total of 94 patients were included in the study. The SXscore was higher in the chemotherapy group than in the non-chemotherapy group (25.25, IQR [4.50–30.00] vs. 16.50, IQR [ 5.00–22.00], p = 0.0195). The SXhigh rate was greater in the chemotherapy group than in the non-chemotherapy group (58.33% vs. 25.86; p = 0.0016). Both univariate (OR:4.013; 95% CI:1.655–9.731) and multivariate (OR:5.868; 95% CI:1.778–19.367) logistic-regression analysis revealed that chemotherapy increased the risk of greater SXhigh rates. Multivariate stepwise logistic-regression analysis showed the risk of more severe anatomical CAD is increased by chemotherapy as a whole by 5.323 times (95% CI: 2.002–14.152), and by platinum-based regimens by 5.850 times (95% CI: 2.027–16.879).

 Conclusions

Chemotherapy is associated with anatomical complexity and severity of CAD, which might partly account for the higher risk of chemotherapy-related CAD among lung cancer patients. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

 Coronary Artery Disease/physiopathology Lung Neoplasms/drug therapy Lung Neoplasms/complications Propensity Score Score Syntax Angioplasty/methods Risk Factors Introduction

Modern treatment strategies have led to an improvement in the chances of surviving a diagnosis of cancer. However, these gains can come at a cost.1 Cardiovascular toxicity is a potential short- or long-term complication of various anticancer therapies and is becoming one of the most concerning side effects of anti-cancer therapy.2 Heart conditions that may be induced by anticancer chemotherapeutic agents include cardiac dysfunction, cardiac ischemia, arrhythmia, stroke and pulmonary-artery hypertension.1,3,4Chemotherapy-related coronary artery disease (CAD) is becoming an emerging clinical problem difficult to manage due to various clinical manifestation and complicated pathophysiological mechanisms.5-7 Chemotherapy-induced coronary-artery events that occurred shortly after administration of chemotherapeutic agents, possibly due to acute thrombosis or vasospasm, have been reported.3,8 However, the pathogenesis of chronic chemotherapy-related CAD remains unclear.

Lung cancer is the most common incident cancer and the leading cause of cancer death.9 Chemotherapy is an important treatment for this disease.10,11 Chemotherapeutic agents for lung cancer, including taxanes, cisplatin, carboplatin, bevacizumab, sorafenib and erlotinib3,10,12 are known to cause acute myocardial infarction (AMI). It is important to investigate the long term effect of chemotherapy on anatomical changes of coronary artery among lung cancer patients.

Complexity and lesion characteristics of the coronary artery are well-recognized predictors of periprocedural complications and long-term mortality.13-15 The SYNTAX score (SXscore) was developed to prospectively characterize the coronary vasculature by number of lesions and their functional impacts, locations and complexity.16-18 It is an important tool for grading complexity of coronary artery disease (CAD) and for risk-stratifying patients who are being considered for revascularization. In addition, it has demonstrated good value as a predictor of major adverse cardiac events, including cardiac death. Higher SXscores, indicative of more-complex diseases, are hypothesized to represent a greater therapeutic challenge and to pose potentially worse cardiac prognoses.16,17,19-21

Recent studies used SXscore to quantify the severity of CAD among cancer patients, which looked mostly at the effect of radiotherapy on CAD.20,21 In the present study, we used SXscore to evaluate the complexity and severity of CAD among lung cancer patients to investigate the relationship between chemotherapy and CAD. We also observed the effect of radiotherapy and other risk factors on anatomical severity of coronary arteries among those patients.

 Methods Study design and patients

We used a hospital-based cross-sectional study design. The study patients were admitted to Chinese PLA General Hospital to undergo coronary angiography (CAG) due to suspected angina pectoris or stenosed coronary artery, showed by computer tomography angiography, between 2010 and 2017. Furthermore, the patients should have previously received definite diagnoses of lung cancer. Patients who had previously undergone percutaneous coronary intervention were excluded.

We thoroughly examined the patients’ electronic medical records for history of lung cancer, including diagnosis, age at time of diagnosis, location and treatment history (chemotherapy and radiotherapy). We reviewed sex, age at time of CAG, body mass index (BMI), family history of cardiovascular diseases (CVDs), tobacco use, hypertension, diabetes, hyperlipidemia and lipid profile. These data were extracted using a clinical-research data platform created by Xiliu Data. Some data were checked by telephone with the patients themselves or their families.

 Coronary angiography and SXscore

From the baseline diagnostic angiogram, we separately scored each coronary lesion with stenosis ≥50% in a vessel ≥1.5 mm diameter. Next, we added the scores to provide the overall SXscore, which we had calculated prospectively using the SXscore algorithm (described in full elsewhere in the literature).16,17,22 All angiographic variables pertinent to SXscore calculation were computed by two blinded experienced interventional cardiologists. When the SXscore of each patient differed between the two cardiologists, they would discuss the angiogram and come up with a common SXscore for each patient. Final SXscores were calculated per patient and saved in a dedicated database. Two representative examples with SXscores based on CAG are shown in Figure 1.

– <italic>SXscore of coronary artery based on CAG. Representative CAGs of a patient with SXlow (SXscore = 2; A–B) and a patient with SXhigh (SXscore = 38; C–D).</italic>

In the study, a Sxscore of 22 was the upper tertile. We defined SXscore grades as SXlow (<22) or SXhigh (≥22). Through logistic-regression analysis, high SXscore grade was determined as positive if SXscore ≥22.

 Statistical analysis

Baseline descriptive statistics are presented as frequencies and percentages for categorical variables and mean ± standard deviation (SD) and median (interquartile range [IQR]) for continuous variables. The normality of data was assessed using the Skewness and Kurtosis normality test. Differences between the study groups were assessed by chi-square test or Fisher’s exact test for categorical data, and by student’s t test for continuous data. We used student’s t test to compare the groups’ means when variables were normally distributed, and a non-parametric test when they were not normally distributed. Chi-square or Fisher’s exact test were used to examine differences for categorical measures. We assessed the relationships between chemotherapy and CAD complexity by logistic-regression analysis, adjusting related covariates that included age, gender, BMI, smoking, family history of CVDs, hypertension, diabetes and hyperlipidemia. Odds ratios (ORs) and 95% confidence intervals [CIs] were calculated. P values were 2-tailed, and we set the level of significance at 0.05. All statistical analyses were performed using SAS software, version 9.3 (SAS Institute, Inc., Cary, North Carolina, USA).

 Results Patient characteristics

A total of 94 patients who had previously had lung cancer and who underwent CAG at Chinese PLA General Hospital, between 2010 and 2017, were included in the study. Out of these, 73 were males and 21 females (M:F = 3.48). Eighty-five patients were diagnosed with non-small cell lung cancer, and the other 9 patients with small cell lung cancer. Thirty-six patients had histories of chemotherapy. Among the patients with chemotherapy, 28 patients received platinum-based regimens. Platinum-based regimens combining gemcitabine or docetaxel, and other agents, were used in non-small cell lung cancer patients, and double-platinum chemotherapy combined with etoposide was used in small cell lung cancer patients. One patient received anthracycline (pharmorubicin), which is known to have cardiac toxicity. Five patients received tyrosine kinase inhibitors (gefitinib). Three patients lacked detailed information about chemotherapy regimens. Fifty-eight patients did not receive any chemotherapy.

There were no significant differences regarding conventional CAD risk factors (hypertension, hyperlipidemia, diabetes or smoking history) between the chemotherapy and non-chemotherapy groups. In the chemotherapy group, more patients took radiotherapy than in the non-chemotherapy group (p < 0.0001). The time interval range from cancer diagnosis to CAG was discrepant between the two groups. Patient characteristics are listed in Table 1.

– Patient characteristics stratified by history of chemotherapy
Characteristic Chemotherapy group (n = 36) Non-chemotherapy group (n = 58) p value
Gender 0.6257
Male 27 (75.00%) 46 (79.31%)
Female 9 (25.00%) 12 (20.69%)
Age at CAG (years) 0,077
<60 3 (8,33%) 13 (22,41%)
≥60 33 (91.67%) 45 (77,59%)
Interval time from cancer diagnosis to CAG (years) 0.000
≤2 17 (47.22%) 48 (82.76%)
>2 19 (52.78%) 10 (17.24%)
Types of lung cancer 0.081
Non-small cell lung cancer 30 (83.33%) 55 (94.83%)
Small cell lung cancer 6 (16.67%) 3 (5.17%)
Regimens of chemotherapy NA
Platinum + 28 (77.78%) --
Tyrosine kinase inhibitors only 5 (13.89%) --
Not-verified regimens 3(8.33%) --
Radiotherapy <0.0001
No 19 (52.78%) 54 (93.10%)
Yes 17 (47.22%) 4 (6.90%)
BMI 24.81 ± 2.89 25.32 ± 2.79 0.3944
Hypertension
No 12 (34.29%) 27 (46.55%)
Yes 23 (65.71%) 31 (53.45%)
Diabetes 0.9343
No 28 (80.00%) 46 (80.70%)
Yes 7 (20.00%) 11 (19.30%)
Hyperlipidemia 0.5157
No 29 (82.86%) 50 (87.72%)
Yes 6 (17.14%) 7 (12.28%)
Smoking 0.8938
No 18 (51.43%) 29 (50.00%)
Yes 17 (48.57%) 29 (50.00%)
Alcohol consumption 0.1640
No 45 (73.77%) 56 (62.92%)
Yes 16 (26.23%) 33 (37.08%)
Cholesterol 4.15 ± 1.08 4.25 ± 1.10 0.6896
Triglyceride 1.38 ± 0.71 1.49 ± 0.99 0.7905
Low-density lipoprotein cholesterol 2.58 ± 0.96 2.48 ± 0.88 0.6999
High-density lipoprotein cholesterol 1.17 ± 0.34 1.33 ± 0.87 0.8345

BMI: body mass index; CAG: coronary angiography.

Analysis of association between chemotherapy and high SXscore

Patients who underwent chemotherapy developed more-severe anatomical CAD than those who did not undergo chemotherapy. The SXscore was significantly higher in the chemotherapy group than in the non-chemotherapy group (25.25,IQR [4.50–30.00] vs. 16.50, IQR[5.00–22.00]; p = 0.0195). According to the SXscore grade definition, the percentage of SXhigh was significantly higher in the chemotherapy group than in the non-chemotherapy group (58.33% vs. 25.86%; p = 0.0016). Details are shown in Table 2.

– SXscore and SXscore grades in lung cancer patients stratified by chemotherapy or radiotherapy
Variables Statistical variable Chemotherapy stratification Radiotherapy stratification
Chemotherapy group Non-chemotherapy group (n = 58) p value Radiotherapy group (n = 21) Non-radiotherapy group (n = 73) p value
SXscore 0.3045
Mean ± SD 20.00 ± 12.70 14.96 ± 10.47 0.0195 18.67 ± 12.58 16.38 ± 11.31
Median 25.25 16.50 22.00 19.00
Q1–Q3 4.50–30.00 5.00–22.00 5.00–30.00 5.00–25.00
Min–max 0.00–38.00 0.00–38.00 1.00–35.50 0.00–38.00
SXscore grade 0.0016 0.1319
SXlow (<22) N (%) 15 (41.67%) 43 (74.14%) 10 (47.62%) 48 (65.75%)
SXhigh (≥22) N (%) 21 (58.33%) 15 (25.86%) 11 (52.38%) 25 (34.25%)

Radiotherapy is another important treatment for lung cancer. In our study, the SXscore was higher in the radiotherapy group than in the non-radiotherapy group (22.00, IQR[ 5.00–30.00] vs. 19.00, IQR[5.00–25.00]; p = 0.3045). The percentage of SXhigh was higher in the radiotherapy group than in the non-radiotherapy group (52.38% vs. 34.25%; p = 0.1319). However, there was no significant difference for either SXscore or SXhigh rates between the radiotherapy and non-radiotherapy groups. Compared with radiotherapy, chemotherapy showed worse effects on anatomical abnormalities of coronary arteries among lung cancer patients. Results are presented in Table 2.

Univariate logistic-regression analysis showed that chemotherapy significantly increased the SXhigh rate by 4.013 times (95% CI:1.655–9.731). The OR of radiotherapy for SXhigh was 2.112 (95% CI: 0.790–5.646), which showed no obvious statistical significance. Smoking as a conventional cardiovascular risk factor was shown to significantly increase the SXhigh rate by 3.182 times (95% CI:1.327–7.628). The ORs of other cardiovascular risk factors for SXhigh were >1, but showed no obvious statistical significance. In multivariate logistic-regression analysis, chemotherapy was shown to increase the risk of CAD with more-severe anatomical abnormalities by 5.868 times (95% CI: 1.778-19.367). The ORs of radiotherapy and smoking for SXhigh were 1.124 (95% CI: 0.286–4.416) and 3.035 (95% CI: 1.036–8.893), respectively. Results are shown in Table 3.

– Logistic-regression analysis for anatomical severity of the coronary artery in lung cancer patients
Variable Univariate model Multivariate model
OR (95% CI) p OR (95% CI) p
Age (years) 0.9427 0.642
<60 Ref Ref
≥60 1.042 (0.343–3.161) 0.723 (0.184–2.840)
Gender 0.1278 0.362
Female Ref Ref
Male 2.326 (0.781–7.140) 1.856 (0.490–7.021)
BMI 0.4538 0.428
<25 Ref Ref
≥25 1.376 (0.597–3.168) 1.528 (0.536–4.355)
Smoking 0.0095 0.043
No Ref Ref
Yes 3.182 (1.327–7.628) 3.035 (1.036–8.893)
Family history of CAD 0.2467 0.659
No Ref Ref
Yes 2.011 (0.617–6.563) 1.379 (0.331–5.754)
Hypertension 0.9667 0.748
No Ref Ref
Yes 1.018 (0.437–2.372) 1.180 (0.431–3.234)
Type II diabetes 0.5338 0.501
No Ref Ref
Yes 1.393 (0.491–3.953) 1.561 (0.426–5.721)
Hyperlipidemia 0.9732 0.616
No Ref Ref
Yes 1.021 (0.306–3.410) 0.677 (0.147–3.118)
Interval time from cancer diagnosis to CAG (years) 0.2914 0.899
≤2 Ref Ref
>2 1.484 (0.609–3.617) 1.075 (0.350–3.301)
Radiotherapy 0.136 0.867
No Ref Ref
Yes 2.112 (0.790–5.646) 1.124 (0.286–4.416)
Chemotherapy 0.0021 0.004
No Ref Ref
Yes 4.013 (1.655–9.731) 5.868 (1.778–19.367)

BMI: body mass index; CAD: coronary artery disease; CAG: coronary angiography.

In multivariate stepwise logistic regression adjusted for related CAD risk factors (age, gender, BMI, smoking, family history of CVDs, hypertension, diabetes and hyperlipidemia) and lung cancer–related risk factors (history of radiotherapy and chemotherapy), chemotherapy as a whole and smoking were shown to significantly increase the SXhigh rate by 5.323 times (95% CI: 2.002–14.152) and by 3.646 times (95% CI: 1.374–9.678), respectively. Moreover, we detected that the effects of platinum-based regimen on anatomical CAD were similar: the OR of platinum-based regimen was 5.850 (95% CI: 2.027–16.879), and the OR of smoking was 3.670 (95% CI: 1.303–10339). Results are shown in Table 4.

– Multivariate stepwise logistic-regression model for anatomical severity of the coronary artery among lung cancer patients
Variables OR 95% CI p value
Total patients (n=94)
Smoking 3.646 1.374-9.678 0.009
Chemotherapy 5.323 2.002-14.152 0.001
Patients except with TKI or NVR (n=86)
Smoking 3.670 1.303-10.339 0.14
Chemotherapy 5.850 2.027-16.879 0.007

TKI: Tyrosine kinase inhibitors; NVR: Not verified regimens

Discussion

To the best of our knowledge, this study is the first to quantitatively demonstrate that chemotherapy is related to anatomical complexity and severity of CAD among lung cancer patients, using SXscore based on coronary angiograms.

Antineoplastic therapy is frequently hindered by the development of cardiovascular complications such as heart failure, myocardial infarction, hypertension, thromboembolism, QT prolongation and bradycardia.23 Until now, the most often reported chemotherapy-induced heart conditions have been cardiac dysfunction and heart failure, as evaluated by echocardiography.1,24,25 Chemotherapy-related coronary-artery events are becoming important clinical problems among the cancer population who received chemotherapy.5-7 Acute coronary-artery events that occurred shortly after administration of chemotherapeutic agents were reported.3,8 Haugnes et al.26 showed a 5.7-fold higher risk of CAD and a 3.1-fold higher risk of myocardial infarction with cisplatin-based regimens compared with surgery alone, in a median observation time of 19 years.26 The present study investigated the association between chemotherapy and anatomical abnormalities of coronary arteries among lung cancer patients.

Lung cancer is the most common incident cancer and the leading cause of cancer death.9 The study assessed anatomical abnormalities of coronary arteries by the SXscore and investigated the relationship between chemotherapy and anatomical complexity of CAD among lung cancer patients. Results showed that both SXscore and SXhigh rates were significantly greater in patients who underwent chemotherapy compared with patients who did not. Multivariate stepwise logistic-regression analysis showed that the risk of more severe anatomical CAD is increased by chemotherapy as a whole by 5.323 times, and by platinum-based regimens by 5.850 times. The results indicate that chemotherapy is associated with the anatomical complexity and severity of CAD, which may at least partly explain the long-term higher morbidity of chemotherapy-related CAD, including myocardial infarction.26 To our knowledge, no similar large study has quantitatively detected the association between chemotherapy and anatomical complexity and severity of CAD among lung cancer patients.

Although chemotherapy-related CAD is becoming an emerging issue, the underlying mechanism of chemotherapy-related CAD remains unclea. Acute coronary-artery events that occurred shortly after administration of chemotherapeutic agents were possibly due to acute thrombosis or vasospasm.3,8Our study indicated that long-term chemotherapy-related coronary events may be due to more severe anatomical abnormalities induced by chemotherapeutic agents. In the present study, about 90% of the study patients are non-small cell lung cancer patients, and the others are small cell lung cancer patients. Most of chemotherapy regimens for the study patients involved more than one chemotherapeutic agent, most of which contained platinum. In fact, platinum was the base of chemotherapy for most of the patients. In the study, five patients received gefitinib and one patient received anthracycline, which is known to have cardiac toxicity. It is reasonable to determine that endothelial cells play an important role during the pathogenesis of chronic anatomical CAD. Besides, chemotherapeutic agents-induced endothelial injuries might be the core cause of chemotherapy-related CAD. Each study patient took various chemotherapeutic agents. Thus, it was difficult to infer which played the most important role in the progress of chemotherapy-related CAD. Since platinum is the most used agent, it may be one of the most important agents to be further studied for illustrating the underlying mechanisms of chemotherapy-related CAD.

Radiotherapy plays a major role in the management of lung cancer.27 Previous studies have shown the effect of radiation on heart diseases.20,28-30 In the present study, both the SXscore and the SXhigh percentage were greater in the radiotherapy group in relation to the non-radiotherapy group. Nevertheless, no significant differences were observed between the two groups. In logistic-regression analysis, the OR of radiotherapy for the SXhigh was 2.112 (95% CI: 0.790–5.646), which means that radiotherapy is likely to increase the anatomical complexity of coronary arteries. However, the results could not show significant differences. The ambiguous results may be due to the smaller sample of patients receiving radiotherapy in the study population. Based on the results mentioned, we could say that chemotherapy may play a more important role than is currently thought in terms of CAD. However, it was not possible to determine that chemotherapy is worse than radiotherapy in terms of CAD, particularly due to the small sample and the lack of enough individual data for each chemotherapeutic agent. Still, we believe the results are interesting and deserve further study.

Heart disease manifesting after cancer may be due to several mechanisms: shared cardiovascular risks between cancer and cardiovascular disease, inflammatory states associated with malignancies and/or cardiotoxic effects of cancer therapy. Age, gender, tobacco use, family history of CAD, hypertension, type II diabetes and hyperlipidemia are the well-known risk factors for CAD.31-35 Smoking is a well-known common risk factor for both CAD and lung cancer. In our study, half of lung cancer patients were smokers, which is consistent with national data, showing that about 57% of lung cancer diagnosed patients were either current or former smokers.36 In the study, other cardiovascular risk factors have shown to be likely to increase the severity of CAD. However, those risk factors did not show obvious statistical significance for increasing the SXscore. On the other hand, smoking showed a more significant effect, by increasing the risk for SXhigh by 3.646 times.

Moreover, the length of time of lung cancer may play a role in the progression of CAD. In the study, we collected the data on the time interval between cancer diagnosis and CAG. Although the time interval between cancer diagnosis and CAG was discrepant between the two groups (possibly because this is a small retrospective study), the multivariate logistic analysis, adjusted for the time interval variable, showed a significant difference regarding CAD severity between patients with chemotherapy and those without chemotherapy.

Our study has several limitations. First, it was a small sample single-center study, performed among a specific population of patients, who had had lung cancers and who required CAG due to suspected severe CAD. A lower number of patients received radiotherapy: among the 94 study patients, 21 used to receive radiotherapy. In particular, only 4 patients (6.9%) had a history of radiotherapy in the non-chemotherapy group. Therefore, the results from this specific small sample may be deviant. Second, it was a retrospective study, thus some valuable information on the study patients might be lacking. For instance, it would be helpful to know the stage of lung cancer at initial presentation, since those who received chemotherapy could have had more advanced disease and, consequently, more inflammation for a longer period of time, which may promote atherosclerosis and contribute to the results observed. However, we were not able to obtain such comprehensive information on the patients. Third, we did not investigate whether the SXscore was associated with long-term cardiovascular events in the study patients. Additional prospective, large-scale clinical studies may be required to verify the effect of chemotherapy on the anatomical abnormality of CAD and the underlying mechanisms of chemotherapy-related CAD.

 Conclusions

In brief, the present study demonstrates that chemotherapy is associated with long-term anatomical complexity and CAD severity. The results could partly explain why cancer patients with a history of chemotherapy are at higher risk of suffering coronary events compared to those with no history of chemotherapy. However, due to the limitations mentioned, a large-scale prospective study, as well as further pathophysiological and molecular researches, are needed to further illustrate the association between chemotherapy and CAD, and the underlying mechanisms of chemotherapy-related CAD.

Study Association

This article is a part of the master dissertation of Qian Yang from Chinese PLA general hospital.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Chinese PLA General Hospital under the protocol number 52019-223-02. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013.

Sources of Funding. This study was funded by National Natural Science Foundation of China, number 81770237.