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Role of B-Type Natriuretic Peptide and Effect of Nesiritide After Total Cardiac Replacement With the AbioCor Total Artificial Heart
Role of B-Type Natriuretic Peptide and Effect of Nesiritide After Total Cardiac Replacement With the AbioCor Total Artificial Heart Reynolds Delgado III, MD,a Yasmin Wadia, MD,b Biswajit Kar, MD,a Whitson Ethridge, MD,c Aly Zewail, MD,a Toni Pool, RN,b Timothy J. Myers, MD,b Nancy Scroggins, RN,b and O. H. Frazier, MDd Endogenous B-type natriuretic peptide (BNP) is thought to be produced in the cardiac ventricles. After sub-total cardiectomy and implantation of a total artificial heart (TAH), the abrupt withdrawal of BNP impairs renal function despite normal hemodynamic variables. We hypothesized that abrupt withdrawal of endogenous BNP may impair renal function and volume homeostasis and BNP may have a direct renal influence unrelated to its cardiovascular effect. Nesiritide infusion should be supplemented in the interim and weaned slowly until BNP levels normalize, which suggests that BNP is produced in tissues other than the cardiac ventricles. J Heart Lung Transplant 2005; 24:1166 –70. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
The heart is an endocrine organ that releases atrial natriuretic peptide (ANP) from the atria and B-type natriuretic peptide (BNP) from the ventricles.1,2 These endogenous hormones counteract the effects of heart failure by causing vasodilation, increased renal perfusion, and possibly decreased neurohormonal activation.3,4 A third hormone, C-type natriuretic peptide (CNP), is similar to BNP in structure and is thought to be produced by the vascular endothelium.5,6 The natriuretic peptides are released from intracellular vacuoles in response to mechanical stretching.7 There is a great degree of homology between the different types of peptides, but their release from the aforementioned tissues has been verified by tissue analysis and immunostaining techniques.8,9 In congestive heart failure (CHF) resulting from either diastolic or systolic dysfunction, elevated left atrial pressure and left ventricular diastolic pressure lead to increased ANP and BNP levels, respectively; when measured in the serum, these hormones correlate with various indicators of the clinical severity of CHF. Most recently, BNP has been used to determine the volume status and the prognosis of heart failure patients.2,10 The effect of BNP, whether exogenous or endogenous,
From the Departments of aCardiology and bCardiopulmonary Transplantation and Assist Device Research, Texas Heart Institute, Houston, Texas; cDepartment of Nephrology, St. Luke’s Episcopal Hospital, Houston, Texas; and dDepartment of Cardiopulmonary Transplantation, Texas Heart Institute, Houston, Texas. Submitted January 29, 2004; revised September 14, 2004; accepted October 11, 2004. Reprint requests: Yasmin Wadia, MD, Department of Cardiopulmonary Transplantation and Assist Devices, Texas Heart Institute, MC2114A, P.O. Box 20345, Houston, TX 77225-0345. Telephone: 713-8577294. Fax: 832-355-9004. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.10.008
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on renal function is poorly understood and may be due to direct renal influences or improved overall hemodynamics. The patient with a total artificial heart (TAH) presents a unique situation in which heart failure has been eliminated, normal hemodynamic values restored, and the tissue responsible for BNP production surgically removed. We describe 3 patients who underwent complete excision of the ventricles and placement of the AbioCor TAH (AbioMed, Danvers, MA). The renal effects of exogenous BNP administration were examined during the early post-operative period. After exogenous BNP was withdrawn, we measured endogenous BNP levels to determine whether tissues other than the ventricular myocardium were responsible for producing this hormone. The ABIOCOR Total Artificial Heart The AbioCor TAH is a totally implantable mechanical cardiac replacement device that provides complete leftand right-side pulsatile circulatory support. It is implanted in the chest orthotopically after the native ventricles have been completely excised. Comprised of titanium and polyurethane, the AbioCor consists of 2 artificial ventricles, 4 tri-leaflet valves and a motordriven hydraulic pumping system, and utilizes a transcutaneous energy transmission system. Measuring Plasma BNP Concentration A BNP assay was used, which is based on the Shionogi antibody in an automated platform format that is applicable to hospital clinical laboratories (Bayer Diagnostics, Tarrytown, NJ). This assay demonstrated the smallest coefficient of analytic variation, just below 2%. Using optimal cutoff thresholds, the specificity of the assays for dyspnea due to heart failure was found to be 70% to 89%, and sensitivity ranged from 80% to 94%.30 –32
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related to chronic CHF and pulmonary disease. One week before TAH implantation, despite the presence of euvolemia, the patient’s BNP level was 666 pg/ml, indicating severe heart failure. Nesiritide infusion was started empirically on Day 2 post-operatively after the patient failed to respond to conventional intravenous diuretic therapy with multiple diuretics in escalating doses. On post-operative day (POD) 5, nesiritide therapy was discontinued in an attempt to wean, and forced diuresis was initiated. Yet the patient developed clinical volume overload and renal failure. One day later, nesiritide was re-started and, within minutes, resulted in an increase in urine output but also a rise in the blood urea nitrogen (BUN) and serum creatinine levels, which necessitated continuous veno-venous hemodialysis (CVVHD) up to POD 18. Nesiritide infusion was continued to POD 10 when it was weaned successfully. By POD 22, the patient’s serum creatinine level was 1.3 mg/dl. During TAH support, the patient had no heartfailure symptoms and had normal hemodynamic values except for an elevated pulmonary artery pressure.
Figure 1. (A) Patient 1. Early urine output and serum creatinine levels during nesiritide infusion after AbioCor implantation. (B) Patient 2. Correlation between nesiritide dose and urine output during AbioCor support. U/O, urine output. (C) Patient 3. Fluctuation in serum creatinine levels and urine output in response to nesiritide therapy after AbioCor implantation. BNP, B-type natriuretic peptide; post OP, post-operative.
CASE REPORTS Case 1 A 68-year-old man with a history of coronary artery disease and severe CHF underwent implantation of an AbioCor after an episode of acute cardiac decompensation placed him at high risk for death within 1 month (Figure 1A). Before TAH implantation, he had mild renal and hepatic dysfunction with a serum creatinine level of 1.1 mg/dl and a serum total bilirubin level of 2.6 mg/dl. In addition, he had fixed and elevated pulmonary vascular resistance
Case 2 A 68-year-old man was admitted for inotrope-dependent end-stage ischemic cardiomyopathy with chronic renal insufficiency and peripheral vascular disease (Figure 1B). Like Patient 1, he had acute decompensated chronic heart failure and a high probability of death within 1 month. Pre-operatively, he had a BNP level of 1,010 pg/ml, a BUN level of 45 mg/dl and a serum creatinine level of 1.8 mg/dl. After TAH implantation, CVVHD was started in the operating room for volume overload and renal failure. This modality was discontinued on POD 4. On POD 15, nesiritide infusion was started at 0.005 g/kg/min initially, then increased to 0.01 g/kg/min. The patient’s urine output increased, and serum creatinine levels decreased to normal on titration of the nesiritide dose to a maximum of 0.03 g/kg/min. On POD 48, the nesiritide was titrated off and the patient was placed on diuretic therapy. Afterward, his serum BNP levels remained between 100 and 200 pg/ml. Case 3 A 64-year-old man was admitted for ischemic end-stage CHF (Figure 1C). Seven years earlier, he had undergone coronary artery bypass grafting. Six months before the present admission, he was diagnosed with right renal carcinoma and underwent a radical nephrectomy. At the current admission, he had severe cachexia, acutely imposed on chronic bi-ventricular failure and chronic renal insufficiency. He was not considered a suitable candidate for heart transplantation because of his history of recent malignancy. Again, his risk score indicated a high risk of mortality within 1 month. Preoperatively, he had a BNP level of ⬎3,000 pg/ml and a
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serum creatinine level of 1.8 mg/dl. Nesiritide therapy was initiated pre-operatively and continued after TAH implantation. Post-operatively, the serum creatinine level returned to normal, and the urine output could be titrated by increasing or decreasing the nesiritide dose. RESULTS One week before TAH implantation, all 3 of our patients had elevated BNP levels (666, 1,010 and ⬎3,000 pg/ml, respectively), indicating severe heart failure. In the early post-operative period, exogenous nesiritide infusion correlated with urine output, serum creatinine and BUN levels. At nesiritide doses of 0.006 to 0.040 g/kg/min, the correlation coefficient between urinary output and the nesiritide dose was 0.81 (p ⫽ 0.004) in Patient 1 (Figure 1A), 0.86 (p ⫽ 0.027) in Patient 2 (Figures 1B) and 0.79 (p ⬍ 0.001) in Patient 3 (Figure 1C). Similar correlations were seen between the nesiritide dose and BUN and creatinine levels. After withdrawal of nesiritide, the BNP levels were low but did not fall to zero, even weeks later. Three to 4 weeks after weaning from nesiritide, the endogenous BNP levels were 93, 200 and 54 pg/ml in Patients 1, 2 and 3, respectively (normal value ⬍100 pg/ml). DISCUSSION In healthy subjects, plasma BNP levels are very low (⬍100 pg/ml). The major stimulus for BNP release appears to be ventricular volume and/or pressure overload,12 as in CHF. High plasma levels of vasodilatory neurohormonal factors, such as ANP and BNP, are also increased in proportion to the severity of CHF.20 –22 The biologic receptors of natriuretic peptides may be downregulated in patients with severe CHF,23–25 and the compensatory activity of these endogenous peptides may be attenuated. The presence of natriuretic peptide binding sites in the heart suggests a paracrine function. A relevant localization of natriuretic peptide receptors has been found in cardiac regions that are particularly suitable for monitoring blood volume and pressure oscillations, such as the inflow and outflow tracts.19 The TAH recipient is unique for studying the actions and production of BNP. Our small group showed evidence that BNP comes from tissues other than the cardiac ventricles. During implantation of a TAH, a portion of the atria is left intact. After TAH placement, the atrial pressures in our patients were directly measured and were normal, so the atria would not likely be a source of significant amounts of BNP. This finding indicates that there is some production of the hormone in non-cardiac tissues. We found a significant correlation between administration of exogenous BNP and the parameters of renal function, indicating that this hormone may directly affect the kidney.
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Effect of BNP on Renal Hemodynamics and Tubular Function B-type natriuretic peptide is known to have natriuretic, diuretic and vasorelaxant properties and may have antagonistic effects on the renin–angiotensin–aldosterone system.26,27 In 1998, Jensen and co-workers27 undertook a dose-response study in 48 healthy male volunteers to observe the effects of continuous BNP infusion for 60 minutes. The infusion increased urine flow rate and sodium excretion in a dose-dependent way while decreasing the renal plasma flow and increasing the glomerular filtration rate, also in a dose-dependent fashion. The blood pressure, heart rate, angiotensin II levels and aldosterone levels were unaffected by the BNP infusion, but renin secretion was directly inhibited. Severe heart failure characterized by sodium retention and fluid overload entails elevated plasma levels of natriuretic peptides and neuroendocrine activation of hormones of the renin–angiotensin–aldosterone system. The long-term elevation of natriuretic peptides is postulated to result in receptor downregulation, as the new balance between the natriuretic peptides and the sodium-retaining hormones favors sodium retention. A unique situation develops when the heart is explanted and replaced with a TAH. First, the main source of BNP is removed and not replaced. Second, the downregulated natriuretic receptors in the kidney are suddenly faced with much lower levels of BNP. In the immediate post-operative period, our 3 patients had a precipitous decline in urine output that was unresponsive to escalating diuretic therapy. The patients responded quickly, within minutes, to exogenous BNP infusion, which was dose-responsive. They remained dependent on BNP infusion for approximately 2 to 3 weeks, after which we were gradually able to wean them from nesiritide. Three weeks after weaning, the plasma BNP levels remained between 50 and 200 pg/ml, and the patients became responsive to diuretic therapy. On the basis of these 3 cases, we hypothesize that the altered milieu present in severe CHF and the compensatory downregulation of natriuretic receptors take approximately 3 weeks to normalize. Extracardiac sources of BNP secretion, such as the brain, adrenal glands, thyroid gland, and spleen, may supply BNP after withdrawal of nesiritide. Other possible sources include the atrial tissue left at the time of surgery and the vascular endothelium, and transcripts of BNP have been localized to the central nervous system, lung, thyroid, adrenal glands, kidney, spleen, small intestine, ovary, uterus and striated muscle.11 The first patient had pulmonary hypertension, so the pulmonary vasculature may have been a source. The
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pulmonary endothelium is known to be a possible source of BNP.11 Other possible sources include the atrial tissue left at the time of surgery, the vascular endothelium, and the other sites mentioned earlier in this discussion.13,14 A limitation of the study is that BNP levels were not measured post-operatively before nesiritide was administered. Nesiritide was used peri-operatively in 2 patients and the second and third patients had chronic renal insufficiency pre-operatively. After removal of the native ventricles, BNP levels were assumed to be low and empirical replacement with exogenous BNP restored renal responsiveness within minutes of administration. The patient cohort was inhomogeneous and there was no protocol on the basis of which nesiritide was administered. Investigators have shown that BNP induces a significant increase in effective renal plasma flow (paraaminohippurate clearance), glomerular filtration rate (creatinine clearance), urine flow rate and sodium excretion.15–18 In our first patient, a significant deterioration in renal function coincided with the sudden decrease in high plasma BNP levels, post-operative decrease in his high endogenous BNP levels, and later withdrawal of exogenous BNP. This finding suggests that the high plasma BNP levels are important for renal function in CHF patients. Nesiritide has been shown to induce balanced vasodilation and to stimulate excretion of salt and water by the kidneys18; therefore, given our observations, it is possible that BNP has a direct renal mechanism in patients with volume overload related to renal failure or CHF. In adult heart transplant recipients, raised BNP levels have been found to correlate with non-cellular allograft rejection, and declining values conversely reflect a response to therapy.28 Elevation of plasma BNP levels immediately after orthotopic heart transplantation in children is not associated with allograft rejection and changes in left ventricular function or dimension, and these levels usually return to normal by 14 weeks.29 In conclusion, in our 3 TAH patients, BNP levels were normal or slightly elevated approximately 1 month after implantation of the TAH. Because the native cardiac ventricles and endogenous source were surgically removed and exogenous BNP infusion weaned off, significant production of the hormone may occur at sites other than the ventricular myocardium. In addition, BNP may help regulate renal function, and TAH recipients may develop renal dysfunction after abrupt withdrawal of endogenous BNP, so supplementation may be necessary during the early post-operative period. This evidence that BNP has a direct effect on renal function should be studied further. The unique scenario presented by CHF patients who receive a TAH provides insight into the role of BNP in human heart failure.
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These findings may also relate, to lesser extent, to patients who undergo abrupt ventricular unloading with a left ventricular assist device. Further larger studies are needed to delineate the important effects of BNP on the kidneys and other end organs in patients with end-stage heart disease. REFERENCES 1. Horky K, Widimsky J, Jr. Role of the heart as an endocrine organ. Cor Vasa 1991;33:441–50. 2. Maisel A. B-type natriuretic peptide levels: diagnostic and therapeutic potential. Cardiovasc Toxicol 2001;1:159 – 64. 3. Johnson W, Omland T, Hall C, et al. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. JAMA 2002;39:1623–9. 4. Chen HH, Burnett JC. Natriuretic peptides in the pathophysiology of congestive heart failure. Curr Cardiol Rep 2000;2:198 –205. 5. Dhingra H, Roongsritong C, Kurtzman NA. Brain natriuretic peptide: role in cardiovascular and volume homeostasis. Semin Nephrol 2002;22:423–37. 6. Matsuo H. Discovery of a natriuretic peptide family and their clinical application. Can J Physiol Pharmacol 2001; 79:736 – 40. 7. Cho Y, Somer BG, Amatya A. Natriuretic peptides and their therapeutic potential. Heart Dis 1999;1:305–28. 8. Yoshimura M, Yasue H, Ogawa H. Pathophysiological significance and clinical application of ANP and BNP in patients with heart failure. Can J Physiol Pharmacol 2001;79:730 –5. 9. Wiedemann K, Jahn H, Kellner M. Effects of natriuretic peptides upon hypothalamo–pituitary–adrenocortical system activity and anxiety behavior. Exp Clin Endocrinol Diabetes 2000;108:5–13. 10. Cowie MR, Mendez GF. BNP and congestive heart failure. Progr Cardiovasc Dis 2002;44:293–321. 11. Gerbes AL, Dagnino L, Nguyen T, Nemer M. Transcription of brain natriuretic peptide and atrial natriuretic peptide genes in human tissues. J Clin Endocrinol Metab 1994;78: 1307–11. 12. Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464 –9. 13. Perhonen M, Takala TE, Vuolteenaho O, et al. Induction of cardiac natriuretic peptide gene expression in rats trained in hypobaric hypoxic conditions. Am J Physiol 1997;273:R344 –52. 14. Durocher D, Grepin C, Nemer M. Regulation of gene expression in the endocrine heart. Recent Progr Horm Res 1998;53:7–23. 15. La Villa G, Fronzaroli C, Lazzeri C, et al. Cardiovascular and renal effects of low dose brain natriuretic peptide infusion in man. J Clin Endocrinol Metab 1994;78: 1166 –71. 16. Beltowski J, Wojcicka G. Regulation of renal tubular sodium transport by cardiac natriuretic peptides: two decades of research. Med Sci Monit 2002;8:RA39 –52.
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17. Elkayam U, Akhter MW, Tummala P, Khan S, Singh H. Nesiritide: a new drug for the treatment of decompensated heart failure. J Cardiovasc Pharmacol Ther 2002;7:181–94. 18. Schreiner GF, Protter AA. B-type natriuretic peptide for the treatment of congestive heart failure. Curr Opin Pharmacol 2002;2:142–7. 19. Cerra MC. Cardiac distribution of the binding sites for natriuretic peptides in vertebrates. Cardioscience 1994;5: 215–24. 20. Rodeheffer RJ, Tanaka I, Imada T, Hollister AS, Robertson D, Inagami T. Atrial pressure and secretion of atrial natriuretic factor into the human central circulation. JAMA 1986;8: 18 –26. 21. Raine AEG, Phil D, Erne P, et al. Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure. N Engl J Med 1986;315:533–7. 22. Tsutamoto T, Bito K, Kinoshita M. Plasma atrial natriuretic polypeptide as an index of left ventricular end-diastolic pressure in patients with chronic left-sided heart failure. Am Heart J 1989;117:599 – 606. 23. Tsutamoto T, Kanamori T, Wada A, Kinoshita M. Uncoupling of atrial natriuretic peptide extraction and cyclic guanosine monophosphate production in the pulmonary circulation in patients with severe heart failure. JAMA 1992;20:541– 6. 24. Tsutamoto T, Kanamori T, Morigami N, Sugimoto Y, Yamaoka O, Kinoshita M. Possibility of down regulation of atrial natriuretic peptide receptor coupled to guanylate cyclase in peripheral vascular beds of patients with chronic severe heart failure. Circulation 1993;87:70 –5.
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25. Tsutamoto T, Wada A, Maedo K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure. Prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509–16. 26. Lang CC, Coutie WJ, Khong TK, Choy AM, Struthers AD. Dietary sodium loading increases plasma brain natriuretic peptide levels in man. J Hypertens 1991;9:779 – 82. 27. Jensen KT, Carstens J, Pedersen EB. Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans. Am J Physiol 1998;274:F63–F72. 28. Park MH, Scott RL, Uber PA, Mehra MR. Bedside B-type natriuretic peptide and acute non-cellular cardiac allograft rejection. J Heart Lung Transplant 2002;21:613– 4. 29. Lan YT, Chang RK, Alejos JC, et al. B-type natriuretic peptide in children after cardiac transplantation. J Heart Lung Transplant 2004;23:558 – 63. 30. Lainchbury JG, Campbell E, Frampton CM, Yandle TG, Nicholls G, Richards AM. Brain natriuretic peptide and N-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath. JAMA 2003;42:728 –35. 31. Wu AHB, Smith A, Wieczorek S, et al. Biological variation for N-terminal pro-and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure. Am J Cardiol 2003;92:628 –31. 32. Rodeheffer RJ. Measuring plasma B-type natriuretic peptide in heart failure. Good to go in 2004? JAMA 2004;44: 740 –9.
The heart is an endocrine organ that releases atrial natriuretic peptide (ANP) from the atria and B-type natriuretic peptide (BNP) from the ventricles.1,2 These endogenous hormones counteract the effects of heart failure by causing vasodilation, increased renal perfusion, and possibly decreased neurohormonal activation.3,4 A third hormone, C-type natriuretic peptide (CNP), is similar to BNP in structure and is thought to be produced by the vascular endothelium.5,6 The natriuretic peptides are released from intracellular vacuoles in response to mechanical stretching.7 There is a great degree of homology between the different types of peptides, but their release from the aforementioned tissues has been verified by tissue analysis and immunostaining techniques.8,9 In congestive heart failure (CHF) resulting from either diastolic or systolic dysfunction, elevated left atrial pressure and left ventricular diastolic pressure lead to increased ANP and BNP levels, respectively; when measured in the serum, these hormones correlate with various indicators of the clinical severity of CHF. Most recently, BNP has been used to determine the volume status and the prognosis of heart failure patients.2,10 The effect of BNP, whether exogenous or endogenous,
From the Departments of aCardiology and bCardiopulmonary Transplantation and Assist Device Research, Texas Heart Institute, Houston, Texas; cDepartment of Nephrology, St. Luke’s Episcopal Hospital, Houston, Texas; and dDepartment of Cardiopulmonary Transplantation, Texas Heart Institute, Houston, Texas. Submitted January 29, 2004; revised September 14, 2004; accepted October 11, 2004. Reprint requests: Yasmin Wadia, MD, Department of Cardiopulmonary Transplantation and Assist Devices, Texas Heart Institute, MC2114A, P.O. Box 20345, Houston, TX 77225-0345. Telephone: 713-8577294. Fax: 832-355-9004. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.10.008
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on renal function is poorly understood and may be due to direct renal influences or improved overall hemodynamics. The patient with a total artificial heart (TAH) presents a unique situation in which heart failure has been eliminated, normal hemodynamic values restored, and the tissue responsible for BNP production surgically removed. We describe 3 patients who underwent complete excision of the ventricles and placement of the AbioCor TAH (AbioMed, Danvers, MA). The renal effects of exogenous BNP administration were examined during the early post-operative period. After exogenous BNP was withdrawn, we measured endogenous BNP levels to determine whether tissues other than the ventricular myocardium were responsible for producing this hormone. The ABIOCOR Total Artificial Heart The AbioCor TAH is a totally implantable mechanical cardiac replacement device that provides complete leftand right-side pulsatile circulatory support. It is implanted in the chest orthotopically after the native ventricles have been completely excised. Comprised of titanium and polyurethane, the AbioCor consists of 2 artificial ventricles, 4 tri-leaflet valves and a motordriven hydraulic pumping system, and utilizes a transcutaneous energy transmission system. Measuring Plasma BNP Concentration A BNP assay was used, which is based on the Shionogi antibody in an automated platform format that is applicable to hospital clinical laboratories (Bayer Diagnostics, Tarrytown, NJ). This assay demonstrated the smallest coefficient of analytic variation, just below 2%. Using optimal cutoff thresholds, the specificity of the assays for dyspnea due to heart failure was found to be 70% to 89%, and sensitivity ranged from 80% to 94%.30 –32
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related to chronic CHF and pulmonary disease. One week before TAH implantation, despite the presence of euvolemia, the patient’s BNP level was 666 pg/ml, indicating severe heart failure. Nesiritide infusion was started empirically on Day 2 post-operatively after the patient failed to respond to conventional intravenous diuretic therapy with multiple diuretics in escalating doses. On post-operative day (POD) 5, nesiritide therapy was discontinued in an attempt to wean, and forced diuresis was initiated. Yet the patient developed clinical volume overload and renal failure. One day later, nesiritide was re-started and, within minutes, resulted in an increase in urine output but also a rise in the blood urea nitrogen (BUN) and serum creatinine levels, which necessitated continuous veno-venous hemodialysis (CVVHD) up to POD 18. Nesiritide infusion was continued to POD 10 when it was weaned successfully. By POD 22, the patient’s serum creatinine level was 1.3 mg/dl. During TAH support, the patient had no heartfailure symptoms and had normal hemodynamic values except for an elevated pulmonary artery pressure.
Figure 1. (A) Patient 1. Early urine output and serum creatinine levels during nesiritide infusion after AbioCor implantation. (B) Patient 2. Correlation between nesiritide dose and urine output during AbioCor support. U/O, urine output. (C) Patient 3. Fluctuation in serum creatinine levels and urine output in response to nesiritide therapy after AbioCor implantation. BNP, B-type natriuretic peptide; post OP, post-operative.
CASE REPORTS Case 1 A 68-year-old man with a history of coronary artery disease and severe CHF underwent implantation of an AbioCor after an episode of acute cardiac decompensation placed him at high risk for death within 1 month (Figure 1A). Before TAH implantation, he had mild renal and hepatic dysfunction with a serum creatinine level of 1.1 mg/dl and a serum total bilirubin level of 2.6 mg/dl. In addition, he had fixed and elevated pulmonary vascular resistance
Case 2 A 68-year-old man was admitted for inotrope-dependent end-stage ischemic cardiomyopathy with chronic renal insufficiency and peripheral vascular disease (Figure 1B). Like Patient 1, he had acute decompensated chronic heart failure and a high probability of death within 1 month. Pre-operatively, he had a BNP level of 1,010 pg/ml, a BUN level of 45 mg/dl and a serum creatinine level of 1.8 mg/dl. After TAH implantation, CVVHD was started in the operating room for volume overload and renal failure. This modality was discontinued on POD 4. On POD 15, nesiritide infusion was started at 0.005 g/kg/min initially, then increased to 0.01 g/kg/min. The patient’s urine output increased, and serum creatinine levels decreased to normal on titration of the nesiritide dose to a maximum of 0.03 g/kg/min. On POD 48, the nesiritide was titrated off and the patient was placed on diuretic therapy. Afterward, his serum BNP levels remained between 100 and 200 pg/ml. Case 3 A 64-year-old man was admitted for ischemic end-stage CHF (Figure 1C). Seven years earlier, he had undergone coronary artery bypass grafting. Six months before the present admission, he was diagnosed with right renal carcinoma and underwent a radical nephrectomy. At the current admission, he had severe cachexia, acutely imposed on chronic bi-ventricular failure and chronic renal insufficiency. He was not considered a suitable candidate for heart transplantation because of his history of recent malignancy. Again, his risk score indicated a high risk of mortality within 1 month. Preoperatively, he had a BNP level of ⬎3,000 pg/ml and a
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serum creatinine level of 1.8 mg/dl. Nesiritide therapy was initiated pre-operatively and continued after TAH implantation. Post-operatively, the serum creatinine level returned to normal, and the urine output could be titrated by increasing or decreasing the nesiritide dose. RESULTS One week before TAH implantation, all 3 of our patients had elevated BNP levels (666, 1,010 and ⬎3,000 pg/ml, respectively), indicating severe heart failure. In the early post-operative period, exogenous nesiritide infusion correlated with urine output, serum creatinine and BUN levels. At nesiritide doses of 0.006 to 0.040 g/kg/min, the correlation coefficient between urinary output and the nesiritide dose was 0.81 (p ⫽ 0.004) in Patient 1 (Figure 1A), 0.86 (p ⫽ 0.027) in Patient 2 (Figures 1B) and 0.79 (p ⬍ 0.001) in Patient 3 (Figure 1C). Similar correlations were seen between the nesiritide dose and BUN and creatinine levels. After withdrawal of nesiritide, the BNP levels were low but did not fall to zero, even weeks later. Three to 4 weeks after weaning from nesiritide, the endogenous BNP levels were 93, 200 and 54 pg/ml in Patients 1, 2 and 3, respectively (normal value ⬍100 pg/ml). DISCUSSION In healthy subjects, plasma BNP levels are very low (⬍100 pg/ml). The major stimulus for BNP release appears to be ventricular volume and/or pressure overload,12 as in CHF. High plasma levels of vasodilatory neurohormonal factors, such as ANP and BNP, are also increased in proportion to the severity of CHF.20 –22 The biologic receptors of natriuretic peptides may be downregulated in patients with severe CHF,23–25 and the compensatory activity of these endogenous peptides may be attenuated. The presence of natriuretic peptide binding sites in the heart suggests a paracrine function. A relevant localization of natriuretic peptide receptors has been found in cardiac regions that are particularly suitable for monitoring blood volume and pressure oscillations, such as the inflow and outflow tracts.19 The TAH recipient is unique for studying the actions and production of BNP. Our small group showed evidence that BNP comes from tissues other than the cardiac ventricles. During implantation of a TAH, a portion of the atria is left intact. After TAH placement, the atrial pressures in our patients were directly measured and were normal, so the atria would not likely be a source of significant amounts of BNP. This finding indicates that there is some production of the hormone in non-cardiac tissues. We found a significant correlation between administration of exogenous BNP and the parameters of renal function, indicating that this hormone may directly affect the kidney.
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Effect of BNP on Renal Hemodynamics and Tubular Function B-type natriuretic peptide is known to have natriuretic, diuretic and vasorelaxant properties and may have antagonistic effects on the renin–angiotensin–aldosterone system.26,27 In 1998, Jensen and co-workers27 undertook a dose-response study in 48 healthy male volunteers to observe the effects of continuous BNP infusion for 60 minutes. The infusion increased urine flow rate and sodium excretion in a dose-dependent way while decreasing the renal plasma flow and increasing the glomerular filtration rate, also in a dose-dependent fashion. The blood pressure, heart rate, angiotensin II levels and aldosterone levels were unaffected by the BNP infusion, but renin secretion was directly inhibited. Severe heart failure characterized by sodium retention and fluid overload entails elevated plasma levels of natriuretic peptides and neuroendocrine activation of hormones of the renin–angiotensin–aldosterone system. The long-term elevation of natriuretic peptides is postulated to result in receptor downregulation, as the new balance between the natriuretic peptides and the sodium-retaining hormones favors sodium retention. A unique situation develops when the heart is explanted and replaced with a TAH. First, the main source of BNP is removed and not replaced. Second, the downregulated natriuretic receptors in the kidney are suddenly faced with much lower levels of BNP. In the immediate post-operative period, our 3 patients had a precipitous decline in urine output that was unresponsive to escalating diuretic therapy. The patients responded quickly, within minutes, to exogenous BNP infusion, which was dose-responsive. They remained dependent on BNP infusion for approximately 2 to 3 weeks, after which we were gradually able to wean them from nesiritide. Three weeks after weaning, the plasma BNP levels remained between 50 and 200 pg/ml, and the patients became responsive to diuretic therapy. On the basis of these 3 cases, we hypothesize that the altered milieu present in severe CHF and the compensatory downregulation of natriuretic receptors take approximately 3 weeks to normalize. Extracardiac sources of BNP secretion, such as the brain, adrenal glands, thyroid gland, and spleen, may supply BNP after withdrawal of nesiritide. Other possible sources include the atrial tissue left at the time of surgery and the vascular endothelium, and transcripts of BNP have been localized to the central nervous system, lung, thyroid, adrenal glands, kidney, spleen, small intestine, ovary, uterus and striated muscle.11 The first patient had pulmonary hypertension, so the pulmonary vasculature may have been a source. The
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pulmonary endothelium is known to be a possible source of BNP.11 Other possible sources include the atrial tissue left at the time of surgery, the vascular endothelium, and the other sites mentioned earlier in this discussion.13,14 A limitation of the study is that BNP levels were not measured post-operatively before nesiritide was administered. Nesiritide was used peri-operatively in 2 patients and the second and third patients had chronic renal insufficiency pre-operatively. After removal of the native ventricles, BNP levels were assumed to be low and empirical replacement with exogenous BNP restored renal responsiveness within minutes of administration. The patient cohort was inhomogeneous and there was no protocol on the basis of which nesiritide was administered. Investigators have shown that BNP induces a significant increase in effective renal plasma flow (paraaminohippurate clearance), glomerular filtration rate (creatinine clearance), urine flow rate and sodium excretion.15–18 In our first patient, a significant deterioration in renal function coincided with the sudden decrease in high plasma BNP levels, post-operative decrease in his high endogenous BNP levels, and later withdrawal of exogenous BNP. This finding suggests that the high plasma BNP levels are important for renal function in CHF patients. Nesiritide has been shown to induce balanced vasodilation and to stimulate excretion of salt and water by the kidneys18; therefore, given our observations, it is possible that BNP has a direct renal mechanism in patients with volume overload related to renal failure or CHF. In adult heart transplant recipients, raised BNP levels have been found to correlate with non-cellular allograft rejection, and declining values conversely reflect a response to therapy.28 Elevation of plasma BNP levels immediately after orthotopic heart transplantation in children is not associated with allograft rejection and changes in left ventricular function or dimension, and these levels usually return to normal by 14 weeks.29 In conclusion, in our 3 TAH patients, BNP levels were normal or slightly elevated approximately 1 month after implantation of the TAH. Because the native cardiac ventricles and endogenous source were surgically removed and exogenous BNP infusion weaned off, significant production of the hormone may occur at sites other than the ventricular myocardium. In addition, BNP may help regulate renal function, and TAH recipients may develop renal dysfunction after abrupt withdrawal of endogenous BNP, so supplementation may be necessary during the early post-operative period. This evidence that BNP has a direct effect on renal function should be studied further. The unique scenario presented by CHF patients who receive a TAH provides insight into the role of BNP in human heart failure.
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These findings may also relate, to lesser extent, to patients who undergo abrupt ventricular unloading with a left ventricular assist device. Further larger studies are needed to delineate the important effects of BNP on the kidneys and other end organs in patients with end-stage heart disease. REFERENCES 1. Horky K, Widimsky J, Jr. Role of the heart as an endocrine organ. Cor Vasa 1991;33:441–50. 2. Maisel A. B-type natriuretic peptide levels: diagnostic and therapeutic potential. Cardiovasc Toxicol 2001;1:159 – 64. 3. Johnson W, Omland T, Hall C, et al. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. JAMA 2002;39:1623–9. 4. Chen HH, Burnett JC. Natriuretic peptides in the pathophysiology of congestive heart failure. Curr Cardiol Rep 2000;2:198 –205. 5. Dhingra H, Roongsritong C, Kurtzman NA. Brain natriuretic peptide: role in cardiovascular and volume homeostasis. Semin Nephrol 2002;22:423–37. 6. Matsuo H. Discovery of a natriuretic peptide family and their clinical application. Can J Physiol Pharmacol 2001; 79:736 – 40. 7. Cho Y, Somer BG, Amatya A. Natriuretic peptides and their therapeutic potential. Heart Dis 1999;1:305–28. 8. Yoshimura M, Yasue H, Ogawa H. Pathophysiological significance and clinical application of ANP and BNP in patients with heart failure. Can J Physiol Pharmacol 2001;79:730 –5. 9. Wiedemann K, Jahn H, Kellner M. Effects of natriuretic peptides upon hypothalamo–pituitary–adrenocortical system activity and anxiety behavior. Exp Clin Endocrinol Diabetes 2000;108:5–13. 10. Cowie MR, Mendez GF. BNP and congestive heart failure. Progr Cardiovasc Dis 2002;44:293–321. 11. Gerbes AL, Dagnino L, Nguyen T, Nemer M. Transcription of brain natriuretic peptide and atrial natriuretic peptide genes in human tissues. J Clin Endocrinol Metab 1994;78: 1307–11. 12. Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993;87:464 –9. 13. Perhonen M, Takala TE, Vuolteenaho O, et al. Induction of cardiac natriuretic peptide gene expression in rats trained in hypobaric hypoxic conditions. Am J Physiol 1997;273:R344 –52. 14. Durocher D, Grepin C, Nemer M. Regulation of gene expression in the endocrine heart. Recent Progr Horm Res 1998;53:7–23. 15. La Villa G, Fronzaroli C, Lazzeri C, et al. Cardiovascular and renal effects of low dose brain natriuretic peptide infusion in man. J Clin Endocrinol Metab 1994;78: 1166 –71. 16. Beltowski J, Wojcicka G. Regulation of renal tubular sodium transport by cardiac natriuretic peptides: two decades of research. Med Sci Monit 2002;8:RA39 –52.
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