Oliveira Marcela Silva, Carmona Fabio, Vicente Walter V A, Manso Paulo H, Mata Karina M, Celes Mara Rúbia, Campos Erica C, Ramos Simone G
Departments of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.
Departments of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Pediatr Cardiol. 2017 Apr;38(4):734-745. doi: 10.1007/s00246-017-1573-1. Epub 2017 Feb 18.
Surgeries to correct congenital heart diseases are increasing in Brazil and worldwide. However, even with the advances in surgical techniques and perfusion, some cases, especially the more complex ones, can develop heart failure and death. A retrospective study of patients who underwent surgery for correction of congenital heart diseases with cardiopulmonary bypass (CPB) in a university tertiary-care hospital that died, showed infarction in different stages of evolution and scattered microcalcifications in the myocardium, even without coronary obstruction. CPB is a process routinely used during cardiac surgery for congenital heart disease. However, CPB has been related to increased endogenous catecholamines that can lead to major injuries in cardiomyocytes. The mechanisms involved are not completely understood. The aim of this study was to evaluate the alterations induced in the β-adrenergic receptors and GRK-2 present in atrial cardiomyocytes of infants with congenital heart disease undergoing surgical repair with CPB and correlate the alterations with functional and biochemical markers of ischemia/myocardial injury. The study consisted of right atrial biopsies of infants undergoing surgical correction in HC-FMRPUSP. Thirty-three cases were selected. Atrial biopsies were obtained at the beginning of CPB (group G1) and at the end of CPB (group G2). Real-time PCR, Western blotting, and immunofluorescence analysis were conducted to evaluate the expression of β, β-adrenergic receptors, and GRK-2 in atrial myocardium. Cardiac function was evaluated by echocardiography and biochemical analysis (N-terminal pro-brain natriuretic peptide (NT-ProBNP), lactate, and cardiac troponin I). We observed an increase in serum lactate, NT-proBNP, and troponin I at the end of CPB indicating tissue hypoxia/ischemia. Even without major clinical consequences in cardiac function, these alterations were followed by a significant increase in gene expression of β and β receptors and GRK-2, suggesting that this is one of the mechanisms responsible for the exacerbated response of cardiomyocytes to circulating catecholamines. These alterations could explain the irreversible myocardial damage and lipid peroxidation of membranes classically attributed to catecholamine excess, observed in some infants who develop heart failure and postoperative death. Although other factors may be involved, this study confirms that CPB acts as a potent inducer of increased gene expression of β- adrenergic receptors and GRK-2, making the myocardium of these infants more susceptible to the effects of circulating endogenous catecholamines, which may contribute to the development of irreversible myocardial damage and death.
在巴西乃至全球范围内，用于矫正先天性心脏病的手术数量都在不断增加。然而，即便手术技术和灌注技术有所进步，一些病例，尤其是较为复杂的病例，仍可能发展为心力衰竭甚至死亡。一项针对在某大学三级护理医院接受先天性心脏病矫正手术且使用体外循环（CPB）后死亡患者的回顾性研究显示，即便没有冠状动脉阻塞，心肌仍存在不同演变阶段的梗死以及散在的微钙化。CPB是先天性心脏病心脏手术中常规使用的一个过程。然而，CPB与内源性儿茶酚胺增加有关，这可能导致心肌细胞受到严重损伤。其中涉及的机制尚未完全明确。本研究的目的是评估接受CPB手术修复的先天性心脏病婴儿心房心肌细胞中β - 肾上腺素能受体和GRK - 2的变化，并将这些变化与缺血/心肌损伤的功能和生化标志物相关联。该研究包括对在HC - FMRPUSP接受手术矫正的婴儿进行右心房活检。共选取了33例病例。在CPB开始时（G1组）和CPB结束时（G2组）获取心房活检样本。通过实时PCR、蛋白质印迹法和免疫荧光分析来评估心房心肌中β、β - 肾上腺素能受体和GRK - 2的表达。通过超声心动图和生化分析（N端前脑钠肽（NT - ProBNP）、乳酸和心肌肌钙蛋白I）评估心脏功能。我们观察到CPB结束时血清乳酸、NT - proBNP和肌钙蛋白I升高，表明组织存在缺氧/缺血。即便对心脏功能没有重大临床影响，这些变化之后β和β受体以及GRK - 2的基因表达也显著增加，这表明这是心肌细胞对循环儿茶酚胺反应加剧的机制之一。这些变化可以解释在一些出现心力衰竭和术后死亡的婴儿中经典归因于儿茶酚胺过量的不可逆心肌损伤和膜脂质过氧化现象。尽管可能涉及其他因素，但本研究证实CPB是β - 肾上腺素能受体和GRK - 2基因表达增加的有力诱导因素，使这些婴儿的心肌更容易受到循环内源性儿茶酚胺的影响，这可能导致不可逆心肌损伤和死亡的发生。
