Ann Thorac Surg 1997;63:1095-1100
© 1997 The Society of Thoracic Surgeons
Original Article: Cardiovascular
Significance of Raised Natriuretic Peptides After Bicaval and Standard Cardiac Transplantation
Ahmed El Gamel, FRCS,
Nizar A. Yonan, FRCS,
Brian Keevil, MRCPath,
Raymond Warbuton, PhD,
John Kakadellis, MD,
Ashley Woodcock, FRCP,
Colin S. Campbell, FRCS,
Ali N. Rahman, FRCS,
Abdul K. Deiraniya, FRCS
Cardiothoracic Transplant Unit, Biochemistry Department, and North West Lung Centre, Wythenshawe Hospital, Manchester, England
Accepted for publication November 4, 1996.
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Abstract
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Background. High levels of plasma atrial natriuretic peptide (ANP) and ventricular natriuretic peptide (BNP) have been identified after standard orthotopic cardiac transplantation. It has been postulated that the high ANP levels are a result of persistent secretion from the large residual atrial mass after transplantation. This study was undertaken to investigate the significance of raised ANP and BNP levels after standard and bicaval orthotopic heart transplantation.
Methods. Plasma ANP and BNP levels were measured in 40 ambulatory, randomly selected cardiac transplant patients (group A, n = 20 had bicaval transplantation; group B, n = 20 had standard transplantation) and 10 healthy volunteers (group C). Cardiac transplant patients underwent endomyocardial biopsy and hemodynamic evaluation.
Results. Plasma levels of ANP and BNP were elevated in the transplant recipients in comparison with normal volunteers (p = 0.0001 and p < 0.0001, respectively). There was no significant difference in the ANP levels between group A and group B, whereas BNP levels were higher in group B compared with group A (p = 0.03). Linear regression analysis showed that a faster heart rate, high mean pulmonary artery pressure, high pulmonary capillary wedge pressure, and high transpulmonary gradient were associated with higher levels of BNP (p < 0.05). Lower mean systemic pressure was associated with higher levels of ANP (p < 0.05).
Conclusions. High levels of ANP and BNP are synthesized and secreted by the transplanted denervated human heart regardless of the surgical technique. The level of BNP correlates with ventricular performance and afterload. The bicaval technique seems to be associated with better left ventricular and right ventricular diastolic performance.
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Introduction
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Natriuretic peptides are hormones that play an important role in the cardiovascular homeostasis of both mammalian and nonmammalian vertebrates [1]. All natriuretic peptides have shown a high degree of sequence homology. The major stimulus for atrial natriuretic peptide (ANP) release is atrial stretch, and elevated values are observed in volume overload states such as congestive cardiac failure [2]. The present data also suggest that peripheral plasma (BNP) and ANP levels are useful noninvasive indices of cardiac performance and ventricular hypertrophy in the nontransplant physiology [3–5].
Sustained high levels of ANP have been observed after heart transplantation [6]. This is thought to be the result of the pretransplantation heart failure inducing cellular adaptations favoring accelerated and sustained ANP synthesis and secretion. It has been postulated that the large remnant of recipient atrial tissue after standard orthotopic heart transplantation continues to actively secrete ANP [7]. We [8] have previously described the Wythenshawe bicaval orthotopic heart transplantation technique, which has the advantage of maintaining the normal size and shape of the left atrium and an intact donor right atrium with much smaller atrial mass in comparison with the standard technique, and with only an extra bridge of tissue between the pulmonary veins different from total heart transplantation. Donor tissues can also be responsible for natriuretic peptide secretion. High levels of BNP in donor ventricular tissue samples have been identified after transplantation [9]. Although it has been postulated that the high ANP levels are a result of persistent secretion from the large residual atrial mass after transplantation [7], the significance of high levels of BNP after cardiac transplantation is less apparent [9].
Orthotopic cardiac transplantation results in the loss of afferent information from cardiac mechanoreceptors. Thus, transplantation possibly results in exaggerated neuroendocrine responses when patients are physically active. Plasma renin activity and ANP level were elevated at rest in heart transplant recipients. Relative changes in plasma norepinephrine, vasopressin, and ANP levels and plasma renin activity were greater in heart transplant recipients during exercise than in normal controls [10].
This study was undertaken to determine whether elevated plasma ANP and BNP levels observed after cardiac transplantation are related to a large atrial mass, the severity of rejection, cardiac functions, or hemodynamics. To evaluate these questions we compared the ANP and BNP concentrations found in two groups of patients. One group underwent standard cardiac transplantation and the other bicaval cardiac transplantation.
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Patients and Methods
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Patients
We have randomly selected 40 ambulatory patients from two groups of recipients (the bicaval group and the standard group) in our follow-up program 6 months to 1 year after cardiac transplantation. Group A (n = 20) had bicaval transplantation (small atrial mass), group B (n = 20) had standard transplantation (large atrial mass), and group C (n = 10) were normal volunteers between 1993 and 1994. Only patients in sinus rhythm were included in the random table (to exclude dysrhythmia as a cause for myocardial dysfunction). Demographic data and primary pathology are summarized in Table 1
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Endomyocardial Biopsies
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Endomyocardial biopsies were performed via the right internal jugular vein in all patients. Intracardiac pressures were measured by introducing a multipurpose Cordis 7F vascular catheter (Cordis Corporation, Miami, FL) in all patients at the time of biopsy.
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Echocardiography
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Transthoracic echocardiography was performed to assess the systolic function (ejection fraction) in both groups A and B after the biopsy.
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ANP and BNP Assay
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All patients were in the supine position while 10 mL of of peripheral venous blood [11] was collected in lithium heparin-coated glass tubes with aprotinin to inactivate protease from all the three groups. All transplant recipients received 10 mg of temazepam as a premedication, and sampling was only performed when the heart rate settled to the resting rate for each recipient. Samples were taken before the performance of endomyocardial biopsy to avoid stressful stimulation. Then samples were transported at 4°C to the laboratory. Samples were centrifuged (2,000 rpm for 5 minutes) to separate the plasma, which was stored at -70°C. All plasma was extracted through a Sep-Pak C18 cartridge by acid alcohol to remove any possible contaminants. Specific human ANP and BNP radioimmunoassay techniques (Peninsula Laboratory, CA) were used to measure simultaneously plasma levels of ANP and BNP. Concentrations are expressed in picograms per milliliter after correction for the dilution.
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Cyclosporine Assay
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Blood for the determination of specific cyclosporine levels was drawn 1 hour before the morning dose of the drug (trough levels). Cyclosporine blood levels were analyzed using the EMIT assay [12] (Syva Diagnostic) on a COBAS MIRAS analyzer. Renal function was assessed by measurement of serum creatinine levels.
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Histologic Examination
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At the time of cardiac biopsy, four tissue samples were obtained, immediately fixed in formalin, and processed routinely on the same day. All biopsy specimens were graded according to the Working Formulation of the International Society for Heart and Lung Transplantation [13].
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Statistics
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Data were analyzed using Statview SE+ graphics software (Abacus Concepts, Berkeley, CA). All data were expressed as mean values and standard errors or median and range. Data were compared using nonparameteric tests, the Mann-Whitney and Kruskal-Wallis test for continuous variables, simple, multiple regression analysis, and Spearman correlation coefficient to establish correlation. Values of p less than 0.05 were accepted as statistically significant.
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Results
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There were no significant differences in age, sex distribution, primary pathology, preoperative transpulmonary gradient, or pulmonary vascular resistance between groups A and B and the whole of the transplant population (see Table 1
). The control group C was younger, but this was not statistically significant compared with the transplantation groups (see Table 1). The ANP levels of groups A and B were almost twice the values of the control group (p = 0.0001) (Table 2). There were no significant difference in ANP levels between groups A and B (see Table 2).
Levels of BNP were seven to ten times the control group values (p = 0.0001) (see Table 2). Group B had significantly higher BNP levels than group A (p = 0.04) (see Table 2).
The serum creatinine level was significantly higher in group B compared with group A (p = 0.002). The right ventricular pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, and the incidence of mitral incompetence were significantly higher in group B compared with group A (Table 3). The right atrial pressure, mean systemic arterial pressure, ejection fraction, and heart rate were not significantly different in the two groups (see Table 3). There were no significant differences between group A and group B in trough cyclosporine levels, serum electrolytes, or blood urea level. Data from both groups were compiled for simple and multiple linear regression analysis and to establish correlation with different variables and both ANP and BNP. Atrial natriuretic peptide level showed a negative correlation with the mean blood pressure (p = 0.0001) (Fig 1). Multiple regression analysis showed that ANP, captopril, and furosemide are the only factors that have a significant effect on mean arterial pressure (Table 4). The level of BNP correlated positively with higher transpulmonary gradient (p = 0.001) (Fig 2) and faster heart rate (Fig 3).
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Fig 1. . Relationship between atrial natriuretic peptide (ANP) level and mean systemic blood pressure (BP). Spearman correlation coefficient was used to calculate the p value.
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Table 4. . Output From Multiple Regression of Mean Arterial Blood Pressure Against Atrial Natriuretic Peptide, Cyclosporine Trough Levels, Captopril Dose, Furosemide Dose, Serum Creatinine and Serum Sodium
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Fig 2. . Transpulmonary gradient (TPG) and brain natriuretic peptide (BNP) after transplantation. Spearman correlation coefficient was used to calculate the p value.
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Fig 3. . Correlation between heart rate (HR) and brain natriuretic peptide (BNP) levels after transplantation. Spearman correlation coefficient was used to calculate the p value.
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We found no correlation between either peptide and ischemic time, bypass time, ejection fraction, right atrial pressure, serum electrolytes, serum creatinine level, furosemide dose, or captopril dose.
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Comment
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Function of Natriuretic Peptides
Since they were first discovered in the early 1980s, the role of natriuretic peptides (ANP, BNP) in the control of fluid and electrolyte balance, systemic blood pressure, and cardiac function has been extensively studied in both health and disease. Atrial natriuretic peptide can affect systemic blood pressure by several mechanisms, including modification of renal function and vascular tone, counteraction of the renin-angiotensin-aldosterone system, and action on brain regulatory sites. A series of interrelated events may follow from very small changes in the plasma levels of ANP to correct changes in blood volume or blood pressure [14]. It has also been found that the decrease in the intravascular fluid volume induced by furosemide administration resulted in the reduction of ANP concentration in plasma [15]. It has been shown that a change of body position from upright to supine results in an increase in the ANP concentration in plasma [15]. Atrial natriuretic peptide exhibits a favorable pathophysiologic profile in heart failure. It reduces preload and afterload by its natriuretic and vasodilatory actions. Furthermore, it reduces the activity of the renin aldosterone system [16]. However no direct relationship has been observed between plasma ANP level and left ventricular and right ventricular functional indices [17]. The major stimulus for ANP release is atrial stretch, and increased values are observed in volume overload states such as chronic renal failure.
Ventricular natriuretic peptide is a cardiac hormone secreted predominantly from the ventricle. Plasma levels of BNP increase in proportion to the severity of congestive heart failure [18]. High concentrations of plasma BNP may be another useful indicator of left ventricular dysfunction [4]. The plasma BNP level in normal subjects is approximately one sixth of the plasma ANP level. Plasma BNP levels are markedly increased in heart failure, renal failure, and hypertension. Augmentation of BNP secretion is much larger than that of ANP secretion. In addition, clearance of BNP from the circulation is slower than that of ANP (t
= 18.9 minutes) [19]. Ventricular natriuretic peptide is secreted more rapidly than ANP in acute heart failure [20].
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Natriuretic Peptides and Cardiac Transplantation
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Sustained elevated levels of ANP have been observed after heart transplantation [3, 7]. This may be because the pretransplantation cardiac failure induces cellular adaptations promoting accelerated ANP synthesis and secretion. Secretion of ANP is reduced by right atrial appendectomy, as proven clinically in human beings and experimentally in animals [21, 22]. It has therefore been postulated that the large remnant of recipient atrial tissue (when the standard orthotopic cardiac transplantation technique is performed) continues to be active in secreting high levels of ANP. The surgical technique itself has been addressed as one factor responsible for the increased ANP plasma levels after transplantation [7].
Our results question this hypothesis, as we have shown that there is no difference between the levels of ANP detected in patients who had received bicaval transplantation (small atrial mass) in comparison with patients who had received standard transplantation (large atrial remnants), as both groups secrete high levels of ANP 6 to 12 months after transplantation.
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ANP and Systemic Blood Pressure After Transplantation
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Cyclosporine-associated hypertension may be mediated in part by sodium and volume retention [23]. Both are described as a strong stimulus for the secretion of ANP to protect against the rise in blood pressure.
We have found ANP levels in both groups correlate negatively with the mean arterial pressure. This may be easily explained as result of the vasodilator potential of ANP. The increase in ANP level may be a counterregulatory mechanism aimed to compensate the cyclosporine-mediated activation of the renin-angiotensin-aldosterone system. Cyclosporine therapy tends to increase sympathetic activity, and this may contribute to posttransplantation pulmonary and systemic hypertension increasing the afterload, combined with salt and water retention due to the stimulation of the renin-angiotensin-aldosterone system [24]. There is experimental evidence that the administration of ANP to rats that have been exposed to acute or chronic cyclosporine treatment is able to reverse the harmful effect of cyclosporine on renal function [25]. The current evidence shows that both peptides suppress the renin-angiotensin-aldosterone system (approximately one-third decrease in renin activity and plasma aldosterone) [19].
Orthotopic cardiac transplantation results in the loss of afferent information from cardiac mechanoreceptors. Thus, transplantation possibly results in exaggerated neuroendocrine responses with activation of the renin-angiotensin-aldosterone system, which may also contribute to the increase in levels of natriuretic peptides after transplantation [10], so cyclosporine and cardiac denervation may both contribute the stimulation of natriuretic peptides secretion.
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BNP and Ventricular Function
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We have confirmed, like others [26, 27] that high levels of BNP are synthesized and secreted by the transplanted human heart. The transplanted ventricle is the main source of circulating BNP [9]. We found higher levels of BNP in the patients who had standard orthotopic cardiac transplantation. This may be the result of an increase in the right ventricular afterload presenting as a raised transpulmonary gradient and increased incidence of mitral incompetence, which might have contributed to the raised pulmonary capillary wedge pressure without overt ventricular failure in this group, compared with the bicaval group. This may indicate the presence of right and left ventricular diastolic dysfunction in the standard group in comparison with the bicaval group. Because there was no correlation between left ventricular systolic function (ejection fraction) and BNP levels, we can assume that BNP levels after transplantation reflect predominantly right ventricular and left ventricular diastolic function. Posttransplantation tachycardia has been associated with poor cardiac function and increased sympathetic tone. We have demonstrated a positive correlation between the BNP levels and heart rate, which may be another marker for graft dysfunction. Our findings correlate well with current understanding of BNP physiology; that is, plasma levels of BNP mainly reflect the degree of ventricular overload or hypertrophy [3, 28–30].
We found no correlation between ischemic time and natriuretic peptides, as others have identified [26], in both groups. We have also found no correlation between ANP and BNP levels and histologic grade of rejection.
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Conclusions
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Our data suggest that the increased production of ANP after cardiac transplantation is a normal physiologic response to the hypertension and increased water and salt retention. Atrial natriuretic peptide seems to play its natural role as a functional antagonist to vasopressin and the renin-angiotensin-aldosterone system, which is stimulated by cardiac denervation and cyclosporine administration.
Plasma BNP level may be another useful indicator of diastolic ventricular dysfunction after transplantation. Atrial preservation techniques may overcome the cardiac allograft diastolic dysfunction observed after transplantation. Others have reported the decline of ANP levels at a longer follow-up after transplantation (3 to 5 years). We hope to follow up our patients to determine long-term changes in levels of natriuretic peptides.
We have critically reviewed our data. We are aware of our limitations in the number we have studied and interpretation of correlation data. A better understanding of the multiple actions of ANP and BNP on the cardiovascular system and establishing a cause-and-effect relationship after transplantation need further studies. The potential of therapeutic interventions depending on these findings is promising.
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Acknowledgments
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Supported by a grant from the North West Lung Centre Research Funds.
We thank Mrs Ann Morris, Department of Medical Statistics Withington Hospital Manchester University, for her statistical advice and analysis, and Mr Geoffrey Corner, Information Officer, Heart and Lung Division, Wythenshawe Hospital, for providing us with the electronic records of the patients. We also wish to acknowledge the Department of Medical Illustration at Manchester Royal Infirmary for their help in producing the figures.
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Footnotes
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Presented at the Sixteenth Annual Meeting of the International Society for Heart and Lung Transplantation, New York, NY, Mar 15-18, 1996.
Address reprint requests to Mr Yonan, Cardiothoracic Transplant Unit, Wythenshawe Hospital, Southmoor Rd, Manchester M23 9LT, UK.
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Abstract
Introduction
