title: Increased Atrial β-Adrenergic Receptors and GRK-2 Gene Expression Can Play a Fundamental Role in Heart Failure After Repair of Congenital Heart Disease with Cardiopulmonary Bypass.
abstract: 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 β1, β2-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 β1and β2receptors 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.
authors.affiliation: Departments of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil. marcelaoliveira9@hotmail.com.
authors.forename: Marcela Silva
authors.identifier: http://orcid.org/0000-0002-9352-3008
authors.initials: MS
authors.lastname: Oliveira
authors.affiliation: Departments of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Fabio
authors.initials: F
authors.lastname: Carmona
authors.affiliation: Departments of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão, Brazil.
authors.forename: Walter V A
authors.initials: WVA
authors.lastname: Vicente
authors.affiliation: Departments of Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Paulo H
authors.initials: PH
authors.lastname: Manso
authors.affiliation: Departments of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Karina M
authors.initials: KM
authors.lastname: Mata
authors.affiliation: Departments of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.|Institute of Tropical Pathology and Public Health, Federal University of Goias, Jataí, GO, Brazil.
authors.forename: Mara Rúbia
authors.initials: MR
authors.lastname: Celes
authors.affiliation: Departments of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.|Department of Physical Education and Physiotherapy, Clinical Hospital of Federal University of Uberlandia, Uberlandia, MG, Brazil.
authors.forename: Erica C
authors.initials: EC
authors.lastname: Campos
authors.affiliation: Departments of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Simone G
authors.initials: SG
authors.lastname: Ramos
mesh_terms: D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002395:Catecholamines / Q000378:metabolism; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006325:Heart Atria / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D006330:Heart Defects, Congenital / Q000601:surgery*; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: Cardiac surgery; Cardiopulmonary bypass; Congenital heart disease; GRK-2; Hypoxia; Infants; Ishemia; β-adrenergic receptors