Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure.

BACKGROUND: Brain natriuretic peptide (BNP) is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin-aldosterone-inhibiting and lusitropic properties. We have demonstrated that acute subcutaneous (SQ) administration of BNP in experimental congestive heart failure results in elevation of plasma BNP and its second messenger 3',5'-cyclic guanosine monophosphate (cGMP) with natriuresis and reduction in cardiac filling pressures. Furthermore, chronic subcutaneous BNP in experimental congestive heart failure also resulted in increases in cardiac output and decreases in pulmonary capillary wedge pressure and systemic vascular resistance. METHODS: The objective of the current study was to assess the safety and efficacy of repeated doses of subcutaneous human BNP, nesiritide, a recombinant form of human BNP (Scios Inc, Fremont, CA) in human subjects with New York Heart Association class II-III congestive heart failure. We defined the cardiorenal and humoral responses to subcutaneous BNP (nesiritide) administered every 12 hours with a total of 5 doses over 72 hours in a single-blind placebo-controlled design (n=8). The mean dose of nesiritide was 10 microg/kg every 12 hours. RESULTS: Initial saline placebo resulted in no change in any measured parameters (P<.05 versus baseline). With the first dose of BNP (nesiritide), cardiac output increased (4.8+/-0.4 to 6.4+/-0.5 L/min) and systolic blood pressure decreased (125+/-5 to 104+/-3 mm Hg) without a change in heart rate. Plasma BNP (167+/-115 to 830+/-470 pg/mL), cGMP (4+/-2 to 14+/-4 pmol/mL), and urinary cGMP excretion (3900+/-930 to 10,600+/-5000 pmol/min) increased with natriuresis and diuresis. Both plasma renin activity and plasma aldosterone decreased. These favorable biologic responses were observed with the fifth dose 72 hours after the initial dose. All the subjects tolerated the study well without any adverse events except for 1 subject who had a vasovagal episode during micturition after receiving the fifth dose on day 3. CONCLUSION: We conclude that subcutaneous administration of BNP (nesiritide) represents a novel and efficacious therapeutic strategy in human congestive heart failure to deliver BNP, a cardiac hormone which possesses unique cardiorenal and neurohumoral properties.

Ventricular adrenomedullin is associated with myocyte hypertrophy in human transplanted heart.

Adrenomedullin (ADM) is a vasoactive and natriuretic peptide. While it is known that ADM is increased in failing human ventricles, the expression of ADM in human ventricular allografts remains unknown. The present study was designed to investigate tissue localization and intensity of ADM expression in ventricular biopsy specimens and to characterize ventricular ADM in human cardiac allografts. Thirty-three post-transplant endomyocardial biopsy specimens were examined immunohistochemically. The average score (range: 0-4) of ADM immunoreactivity (IR) was 2.4+/-0.9 (mean+/-standard deviation). Right ventricular (RV) systolic pressure was significantly increased with high ADM-IR (p=0.048) and the ADM-IR positively associated with myocyte size (r(2)=0.23, p=0.010). In contrast, ADM-IR was not associated with systemic blood pressure, serum creatinine, cyclosporine concentration, cardiac fibrosis, or allograft rejection. The present study shows that ADM-IR is present in human ventricular endomyocardium after transplantation, and ADM-IR is associated with the magnitude of RV pressure and myocyte size, suggesting an important role for ventricular ADM in the counteraction against overload as well as in the progress of myocyte hypertrophy after heart transplantation.