Is there a role for human B-type natriuretic peptide in cardiac surgery?

Hong Liu, MD
University of California Davis Health System
Sacramento, CA

Natriuretic peptide hormones, a family of vasoactive peptides with many favorable physiological properties, have emerged as important candidates for development of diagnostic and therapeutic agents in cardiovascular diseases. Three types of natriuretic peptides have been identified, atrial natriuretic peptide (ANP), brain (B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP is synthesized in the atrial tissue, and despite the name, the primary site of BNP synthesis is the ventricular myocardium.1 CNP is structurally different from ANP and BNP; it is expressed mainly in CNS and vascular tissues. The stimulus for ANP and BNP release is myocyte stretch, not transmural pressure load.2 Three natriuretic peptide receptors have also been identified: NPR-A, NPR-B, and NPR-C. Binding to A and B receptors couples to generate cyclic guanosine monophosphate as the second messenger that mediates most of their biological effects.3 ANP and BNP are cleared by binding to NPR-C on cell surfaces with endocytosis and lysosomal degradation; they are also inactivated by proteolysis from neutral endopeptidase,4 and direct renal filtration.

ANP and BNP seem to have identical physiological actions which include: blocking cardiac sympathetic nervous system activity, inhibiting the renin-angiotension-aldosterone system, a direct lusitropic action in the myocardium, and antiproliferative and antifibrotic effects in the vascular tissue.5 Natriuretic peptides have been used as cardiac biomarkers for heart failure, asympotomatic left-ventricular systolic and diastolic dysfunctions, right-ventricular disorders, and predicting the risks in adult open-heart surgery,6,7 pediatric open-heart surgery,8 and heart transplantation surgery.9

Nesiritide (Natrecor, Scios, Sunnyvale, CA), is a recombinant human BNP that has been shown to be effective in treating decompensated heart failure.10 Nesiritide shares the same physiological activities with the endogenous BNP. The biological duration of nesiritide seems to be longer than its pharmacokinetic half-life.11 It achieves 90% of its peak effects within 30 minutes after an intravenous bolus dose and the actions are maintained for at least 24 hours. The mean initial elimination phase is approximately two minutes, and the mean terminal elimination half-life is 18-20 minutes. Even though it is partly eliminated via renal filtration, dosage adjustment is not required for patients with renal insufficiency.

Although there are no large published clinical studies, the currently available data on the use of nesiritide shows promising results in treating acute cardiac failure in both adult and pediatric open-heart surgery patients who presented with post-op pump failure. Natriuretic peptide treatments decreased pulmonary capillary wedge pressure, right atrial pressure, pulmonary artery pressure, and systemic vascular resistance. Improved left ventricular compliance, cardiac index, and diuresis were also observed 8, 12-14. The Natrecor Administrated Peri-Anesthesia in Patient undergoing CABG (NAPA) trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial has been launched to investigate the intra-operative administration of nesiritide in 250 patients with NYHA class II-IV CHF, especially with pulmonary hypertension and EFs <40% who are undergoing on-pump CABG procedures +/- MVR. The endpoints of primary interest are changes in serum creatinine and pulmonary artery pressure pre-op through hospitalization. This study will also assess the impact of Natrecor on post-op neurohumoral expression, i.e. endothelin-1, BNP, NT-pro BNP, IL-6, TNFa, C-reactive protien, Troponin-T, and the need for medical interventions including use of inotropes and vasodilators. Results are expected to be available by 2005.

In summary, despite the availability of nesiritide for clinical use, its clinical role in combination or in lieu of other agents such as milrinone, nitroglycerin and nitroprusside remains unclear. From the data available, either BNP or ANP, may be useful in patients with heart failure who undergo cardiac surgery and continue to show evidence of failure in the postoperative period.

References:

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