Edmo Atique Gabriel and Sthefano Atique Gabriel (eds.)Inflammatory Response in Cardiovascular Surgery201310.1007/978-1-4471-4429-8_47© Springer-Verlag London 2013
47. Role of BNP in Pediatric Heart Transplantation
(1)
Pediatric Cardiothoracic Surgery Unit, Heart Institute (InCor), University of Sao Paulo Medical School, Av. Eneas de Carvalho Aguiar, 44, 2nd Floor – Block 2, Room 5, 05403-000 Sao Paulo, Brazil
(2)
Pediatric Cardiology and Adult Congenital Heart Disease Unit, Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
Abstract
The role of hormonal changes and biomarkers has been studied after heart transplantation; they include B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP), adrenomedullin (ADM), cardiac troponin T (cTnT), C-reactive protein (CRP), endothelial growth factor, glycoprotein 130, and cytokines, such as tumor necrosis factor α (TNF), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) [1].
Introduction
The role of hormonal changes and biomarkers has been studied after heart transplantation; they include B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP), adrenomedullin (ADM), cardiac troponin T (cTnT), C-reactive protein (CRP), endothelial growth factor, glycoprotein 130, and cytokines, such as tumor necrosis factor α (TNF), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) [1].
Studies with electron microscopy of atrial and ventricular muscle cells made by Kisch in 1963 [2] and Jamieson and Palade in 1964 [3] marked the beginning of the research on polypeptide hormones called natriuretic factors and the atrial natriuretic factor (ANF). In 1981, Bold [4] experimentally tested the actions of these polypeptides. They had a characteristically high biological natriuretic response, drop in blood pressure, and increased hematocrit values [4–7].
Natriuretic peptides are a family that consists of three main components: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), in addition to urodilatin, a peptide found in the urine [4–7].
In 1983, de Bold and Flynn [8], after isolating and sequencing BNP, started their studies on the correlation between serum levels of circulating BNP and the diagnosis and treatment of heart failure.
Brain natriuretic peptide (BNP) is homologous to ANP hormone (neurohormone released by atrial myocytes and to a lesser extent in the ventricles), and the physiologically active portion consists of 32 amino acids [9].
It has been identified in the brain and subsequently in the heart, mainly in the myocytes of the ventricle. Studies have shown low plasma concentrations under physiological settings, with a significant increase in pathological situations, such as ventricular hypertrophy and heart failure [9].
It has been shown that the concentration of BNP is less than 20 % of the levels of ANP in normal individuals, but can equal or exceed these levels in patients with congestive heart failure [10].
NT pro-BNP is an inactive metabolite of the pro-BNP peptide, and it has been described to be useful for the evaluation of heart failure and the prognostic outcome of heart transplant candidates [11] because of its greater serum stability and not being metabolized by neuropeptidase. Furthermore, it seems to have a longer half-life than BNP [7].
A study conducted in healthy subjects showed increased levels of BNP with age and in females. The authors concluded that 90 % of healthy young adults present BNP values smaller than 25 pg/ml and NT pro-BNP smaller than or equal to 70 pg/ml [7].
In 2006, Soldin et al. evaluated 808 persons for –21 years, with a significant number of subjects in each age group, showing high levels of BNP in neonates (1,585 pg/ml) and in children up to 6 months (263 pg/ml), with little variation in the other age groups. In this study, no difference was observed between genders, and the 95th percentile was around 100 pg/ml [12].
The secretion of BNP is regulated by the myocardial wall tension, and its plasma levels are elevated in systolic and/or diastolic heart failure and in cases of volume overload, providing a predictor of the development of heart failure and cardiovascular mortality [13–19].
Elevated serum levels of BNP (greater than 200 pg/ml) showed 100 % sensitivity and specificity of 97.1 %, a positive predictive value of 97.3 %, and a negative predictive value of 100 % for diagnosing decompensated heart failure in adult patients, and 80 % sensitivity and specificity of 86 % as a predictor of mortality. In some studies, BNP is related to increased central venous pressure and pulmonary capillary wedge pressure [20–22].
BNP and Heart Transplantation
Heart transplantation has been a therapeutic option in patients with heart failure refractory to conventional therapy and in patients with complex congenital heart disease [27, 28].
The first heart transplant in humans was performed by Barnard et al. in 1967, and Kantrovitz et al. performed the first transplantation in a newborn in the same year [29, 30].
The absence of immunosuppressive drugs effective in the prophylaxis, treatment of rejection, and the difficulty in diagnosis resulted in a decrease in the number of procedures before 1980. The introduction of cyclosporine as an immunosuppressive drug in the 1980s [31] as well as increased survival has led many centers to re-initiate their programs.
Despite the significant improvement in survival, rejection [hyperacute, acute humoral (vascular), acute cellular, and chronic (allograft vasculopathy)] has been described up to 70 % of deaths within 5–10 years after transplant [1].
Hyperacute rejection is less frequent and may occur immediately after extracorporeal circulation. It is caused by antibodies to the ABO system and to histocompatibility antigens (HLA). This is a serious event that can lead to graft loss [1].
Acute rejection is observed, especially in the first 6 months post-transplant. It is mediated by T cells. The patient may be asymptomatic or have nonspecific symptoms to low cardiac output due to graft failure. Endomyocardial biopsy is the gold standard for the diagnosis and determines the intensity and distribution of the cellular infiltrate in the myocardium as well as whether myocardial necrosis is present [1].
The humoral or vascular rejection is mediated by antibodies against the T cells and antibodies directed against the HLA antigens and endothelial cells of the donor. It is more common in already sensitized patients who have received blood products prior to transplantation or have a history of pregnancy or use of mechanical ventricular assist support before transplantation. These patients may present with severe hemodynamic compromise related to ventricular dysfunction due to diffuse ischemia [1].
Some biological markers such as BNP have been compared with the findings of endomyocardial biopsy in the diagnosis of cellular rejection; however, the results are still controversial, especially in pediatric patients [32].
The blood level of BNP has been shown to be a factor indicative of rejection and appears to be related to ventricular remodeling after orthotopic cardiac transplantation. In multivariate analysis, independent predictors of elevated BNP were changes in the diastolic function and/or systolic echocardiogram, elevated pulmonary capillary wedge pressure, reduction of the cardiac index score, and presence of symptoms of fatigue and dyspnea [33].
Ationu et al. [34] studied the gene expression of ventricular and atrial natriuretic peptide in patients undergoing heart transplantation and found that these peptides may be involved in ventricular remodeling after transplantation.
Studies evaluating blood levels of BNP and endomyocardial biopsy showed accuracy in the detection of rejection episodes, increasing according to the degree of rejection, with values ranging from 101 to 194 pg/ml in rejection grade 0–3 A and levels of 1,144–1,843 pg/ml in more severe degrees of rejection, negative predictive value of 98 %, and a cutoff value of 130 pg/ml [35].
In the adult population, studies show that blood levels of BNP remain high in the first 2 months after transplantation, preventing the diagnosis of rejection, with its levels reducing progressively over a 6-month period, at which point correlation with the histological rejection can be observed [36].
Martinez et al. evaluated BNP levels measured consecutively 9–12 months after transplantation in relation to the following events: death, late rejection (after first year), and graft dysfunction. The authors found a higher number of events in the group with BNP levels that had increased by more than 20 % [36].
Lan et al. [37] reported a study conducted in 44 children who underwent orthotopic heart transplantation. The peptide levels remained high after the transplants, with decreased levels to lower values of 100 pg/ml at 14 weeks in a follow-up period of 171 months.
< div class='tao-gold-member'>
Only gold members can continue reading. Log In or Register to continue
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
