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Cardiac transplantation is an important treatment option for those patients with end stage heart failure who have failed to respond to disease modifying treatment. However, cardiac transplantation is not without risk, with the one year mortality around 19%,1 and identifying patients at the highest risk of death is notoriously difficult.
Brain natriuretic peptide (BNP) and the N-terminal portion of pro-brain natriuretic peptide (NT-proBNP) are now well established diagnostic and adverse prognostic markers in all stages of congestive heart failure. Indeed, we have shown that NT-proBNP is predictive of death before cardiac transplantation.2 Studies have also shown that increasing BNP concentrations precede cardiac allograft rejection and are associated with poor survival late after transplantation.3 However, the prognostic ability of NT-proBNP immediately after cardiac transplantation has not been evaluated. The goal of this study was therefore to assess the short term prognostic ability of NT-proBNP in patients after cardiac transplantation.
We prospectively studied 26 consecutive patients undergoing orthotopic cardiac transplantation in the Scottish Cardiopulmonary Transplant Unit between September 2001 and September 2003. The primary end point was all cause mortality. The median follow up was 477 days (range 20–922 days). No patients were lost to follow up.
Blood for NT-proBNP was collected in EDTA containing tubes before each routine right ventricular endomyocardial biopsy. The samples were then spun at 3000 rpm for 10 minutes at 0°C. Plasma was extracted and frozen in aliquots at −70°C until analysis. NT-proBNP was measured by chemiluminescent immunoassay kits (Roche Diagnostics) on an Elecsys 2010 analyser. The clinicians caring for the patients were blinded to the neurohormone concentrations obtained. The local research ethics committee approved the study protocol and all patients gave written informed consent. The study complies with the Declaration of Helsinki.
All data were analysed by SPSS version 11.5 software (SPSS Inc, Chicago, Illinois, USA). Normally distributed continuous data, unless otherwise stated, are expressed as mean (SD). Non-normally distributed continuous data are expressed as median (25th to 75th centiles). The mean values of clinical variables were compared by the use of independent t tests, and median values by the Mann-Whitney U test. Cox proportional hazards analysis was used and variables achieving p < 0.10 on univariate analysis were then tested in a stepwise (forward) multiple Cox regression survival model to determine the independent predictors of mortality. A probability value of p < 0.05 was considered significant.
Table 1 describes the mean and median values of various clinical parameters for survivors and those who died, both at listing and one week after cardiac transplantation. The population was predominantly male (84.6%), with a mean age of 49.3 years. Of the 26 patients, five reached the primary end point of death (19.2% one year mortality). The causes of death were right heart dilatation in two, multiorgan failure in two, and respiratory syncytial virus infection in one.
The median NT-proBNP concentration one week after cardiac transplantation was 12 184 (6464–25 485) pg/ml. However, the median NT-proBNP concentration in patients who died was 32 930 (18 260–69 935) pg/ml compared with that of survivors of 10 713 (6029–18 646) pg/ml (p = 0.008); all five patients who died had an NT-proBNP concentration above the median. The other univariate markers of outcome one week after cardiac transplantation were troponin T and C reactive protein above their median concentrations and diastolic blood pressure below its median value. Haemofiltration, days in the intensive treatment unit, and prolonged need for inotropes were not correlated with outcome.
Figure 1 depicts the change in NT-proBNP concentration in all 26 patients. NT-proBNP concentrations were much higher one week after cardiac transplantation than on listing and, unlike patients who survived, in those who died these concentrations failed to fall. Multiple Cox proportional hazards regression analysis of the above univariate predictors was repeated to force ischaemia time, donor age, and postoperative creatinine into the model. NT-proBNP remained the only independent predictor of all cause mortality (χ2 = 6.9, p = 0.009).
This study first of all highlights the fact that cardiac transplantation is not a benign procedure and confirms the significant one year mortality after cardiac transplantation found from registry data of about 19%.1 In keeping with these registry data, univariate markers of outcome in this study included trends both for ischaemia time and donor age; however, we found no significant difference in recipient age or pulmonary vascular resistance preceding cardiac transplantation in patients who died. Significant univariate markers in this study not discussed in the aforementioned registry were diastolic blood pressure, C reactive protein, and NT-proBNP measured at the time of the first endomyocardial biopsy. Indeed, in this study, NT-proBNP was found to be the only independent predictor of mortality one week after transplantation.
Although small, this study extends the prognostic properties of NT-proBNP into the post-cardiac transplantation arena. It should be noted that this reflects the relatively small numbers of cardiac transplants carried out in most centres around the world: 77% of reporting centres averaged fewer than 20 procedures a year (and 45% fewer than 10 a year).1
Previous research has shown that an increased BNP or NT-proBNP concentration is associated with a poorer survival rate in all stages of congestive heart failure. The B-type natriuretic peptides have also been studied in patients after cardiac transplantation. BNP has been shown to be slightly higher in patients with treatable allograft rejection.4 Work by Mehra et al3 has shown that BNP is independently predictive of survival of patients long after cardiac transplantation. A recent study has also shown that administration of nesiritide (recombinant BNP) can improve haemodynamic function, as well as renal function, immediately after cardiac transplantation in patients with increased filling pressures.5
Why NT-proBNP should be predictive of death in this population is uncertain, particularly given the heterogeneous modes of death. However, patients who died had greatly raised NT-proBNP concentrations that failed to fall before death. A raised NT-proBNP concentration may indicate left or right ventricular dysfunction secondary to myocardial insult, renal dysfunction, or multiorgan failure. Larger studies are therefore needed to determine where this test can fit in clinically and whether methods now used in heart failure studies to “drive down” BNP and NT-proBNP concentrations would alter the subsequent prognosis.
In summary, this study has shown that a single measurement of NT-proBNP one week after cardiac transplantation can help to identify patients at the highest risk of death. Patients at the highest risk of death were shown to have persistently increased concentrations of NT-proBNP. As the natriuretic peptides, in particular BNP and NT-proBNP, are coming into clinical usage for the diagnosis and prognosis of heart failure and rapid assays are now available, it is tantalising to think that we now may well have another potential use for this simple, non-invasive marker.
We acknowledge the help and support of the patients and staff of the Scottish Cardiopulmonary Transplant Unit. We also acknowledge the financial assistance of the British Heart Foundation.
Source of support: British Heart Foundation