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Postoperative organ dysfunction signatures of cardic surgery
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A cirurgia cardíaca sofreu uma transformação e crescimento impressionantes nas últimas décadas, permitindo que o foco da investigação seja atualmente colocado na perturbação da homeostasia peri-operatória. A cirurgia cardíaca induz perturbações homeostáticas importantes, principalmente como consequência da síndrome de resposta inflamatória sistémica (SIRS), sendo responsável pela ocorrência de disfunção de órgão pós-operatória.
Múltiplos sistemas biológicos e processos contribuem para a perturbação da homeostasia observada, especialmente o sistema imunitário e a ocorrência de inflamação. Recentemente, a cirurgia cardíaca entrou no seu período molecular e diversos estudos foram publicados caracterizando a inflamação pós-operatória. Compreender como os órgãos e sistemas são afetados pela inflamação e como ocorre a disrupção da homeostasia é essencial para prevenir e gerir de forma mais eficiente a disfunção de órgão pós-operatória.
Nesta tese apresentamos diversas linhas de evidência que demonstram a importância da disfunção de órgão no pós-operatório de cirurgia cardíaca. Começamos por recolher, de forma abrangente, evidência sobre as alterações observadas no sistema imunitário na cirurgia cardíaca, e como esta afeta cada órgão e sistema. Avaliamos num estudo inicial o impacto da circulação extracorporal na lesão de órgão pós-operatória, mostrando como períodos de hipotensão durante a circulação corporal originam lesão renal aguda pós-operatória. Avaliamos o grau de disfunção de cada sistema no pós-operatório imediato, caracterizando a assinatura específica de disfunção de órgão da cirurgia cardíaca. Apresentamos também uma correlação entre a disfunção de órgão pós-operatória imediata e sobrevida a longo prazo.
Numa tentativa de compreender melhor os eventos ocorridos no pós-operatório cardíaco, decidimos também explorar a influência do metabolismo na disfunção de órgão. Para tal, utilizamos uma análise metabolómica, uma tecnologia recente e inovadora, para caracterizar as alterações metabólicas induzidas pela cirurgia. Estabelecemos também uma correlação entre a perturbação da via do metabolismo dos ácidos gordos ómega-6 e a hemorragia pós-operatória. A perturbação do metabolismo do ácido araquidónico parece ser uma especificidade da cirurgia cardíaca, e é responsável pelo aumento de hemorragia significativa no pós-operatório e pela maior necessidade de transfusões alogénicas.
Em conjunto, demonstramos a importância da disfunção de órgão no pós-operatório de cirurgia cardíaca, e como afeta o prognóstico a longo prazo. Adicionalmente, a cirurgia cardíaca induz uma transição do metabolismo da glucose e ácidos gordos para o catabolismo das proteínas, com perturbação de vias específicas como a via do ácido araquidónico, com impacto significativo na morbilidade pós-operatória.
Cardiac surgery has undergone a remarkable growth and expansion in the past decades, allowing research to focus on perioperative homeostatic disruption. Cardiac surgery always causes a substantial perturbation of homeostasis, in relation to the associated postoperative systemic inflammatory response syndrome (SIRS) which may lead to postoperative organ dysfunction. Several biological systems and processes contribute to this homeostasis disruption, especially the immune and inflammatory responses. Recently, the consequences of cardiac surgery have begun to be analyzed at the molecular level. Numerous studies have found a contribution of inflammation to the pathophysiology of cardiac surgery. Understanding how organs and systems are affected by inflammation and homeostatic perturbation is essential to prevent and manage postoperative organ dysfunction. This thesis presents several lines of evidence that underscore the importance of organ dysfunction after cardiac surgery. We began by comprehensively gather evidence on how the immune system shapes cardiac surgery, and how each of the systems and organs react to the surgery. We then performed a study to explore how cardiac surgery with cardiopulmonary bypass can be a source of organ dysfunction. We show how hypotensive periods during cardiopulmonary bypass increase the risk of acute kidney injury. We have also evaluated the degree of postoperative organ dysfunction, specifying the organs and systems affected and providing a state-of-the-art postoperative organ dysfunction signature. A correlation between early postoperative organ dysfunction and long-term follow-up is also explored. We have then hypothesized that metabolic changes induced by cardiac surgery may play a role in postoperative organ dysfunction. To explore that possibility, we have used a state-of-the-art metabolomic approach to illustrate the occurrence of an altered metabolic program after cardiac surgery. We next explored the importance of metabolic perturbations in postoperative hemorrhage. Mechanistically, we found that the perturbation of arachidonic acid metabolism is a feature of cardiac surgery and it may be responsible for the increased postoperative bleeding risk and use of allogenic transfusions. Together, we demonstrate the importance of postoperative organ dysfunction in cardiac surgery and how it may affect long-term prognosis. Moreover, we show that cardiac surgery is associated with a metabolic shift from fatty acid and glucose to protein catabolism, with specific pathways, such as the arachidonic acid pathway, playing essential roles in postoperative morbidity.
Cardiac surgery has undergone a remarkable growth and expansion in the past decades, allowing research to focus on perioperative homeostatic disruption. Cardiac surgery always causes a substantial perturbation of homeostasis, in relation to the associated postoperative systemic inflammatory response syndrome (SIRS) which may lead to postoperative organ dysfunction. Several biological systems and processes contribute to this homeostasis disruption, especially the immune and inflammatory responses. Recently, the consequences of cardiac surgery have begun to be analyzed at the molecular level. Numerous studies have found a contribution of inflammation to the pathophysiology of cardiac surgery. Understanding how organs and systems are affected by inflammation and homeostatic perturbation is essential to prevent and manage postoperative organ dysfunction. This thesis presents several lines of evidence that underscore the importance of organ dysfunction after cardiac surgery. We began by comprehensively gather evidence on how the immune system shapes cardiac surgery, and how each of the systems and organs react to the surgery. We then performed a study to explore how cardiac surgery with cardiopulmonary bypass can be a source of organ dysfunction. We show how hypotensive periods during cardiopulmonary bypass increase the risk of acute kidney injury. We have also evaluated the degree of postoperative organ dysfunction, specifying the organs and systems affected and providing a state-of-the-art postoperative organ dysfunction signature. A correlation between early postoperative organ dysfunction and long-term follow-up is also explored. We have then hypothesized that metabolic changes induced by cardiac surgery may play a role in postoperative organ dysfunction. To explore that possibility, we have used a state-of-the-art metabolomic approach to illustrate the occurrence of an altered metabolic program after cardiac surgery. We next explored the importance of metabolic perturbations in postoperative hemorrhage. Mechanistically, we found that the perturbation of arachidonic acid metabolism is a feature of cardiac surgery and it may be responsible for the increased postoperative bleeding risk and use of allogenic transfusions. Together, we demonstrate the importance of postoperative organ dysfunction in cardiac surgery and how it may affect long-term prognosis. Moreover, we show that cardiac surgery is associated with a metabolic shift from fatty acid and glucose to protein catabolism, with specific pathways, such as the arachidonic acid pathway, playing essential roles in postoperative morbidity.
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Palavras-chave
cirurgia cardíaca disfunção órgão pós-operatória inflamação metabolismo metabolómica plaquetas hemorragia pós-operatória cardiac surgery postoperative organ dysfunction inflammation metabolism metabolomics platelet postoperative bleeding