Discoordinate Modulation of Natriuretic Peptides During Acute Cardiac Allograft Rejection in Humans

Abstract

Background-Increased circulating levels of the cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) may be observed after orthotopic cardiac transplantation. Both the hypertrophic and inflammatory processes in the allograft may contribute to this increase, but no mechanistic explanation has been suggested for this observation. Methods and Results-Plasma immunoreactive ANF and BNP determinations were performed in 10 consecutive transplant patients. These were correlated with degree of rejection as reflected by histopathological findings at serial endomyocardial biopsies. Three patients had associated hemodynamic measurements and blood samples 24 hours before and after transplantation. All rejection episodes that received treatment were accompanied by a marked increase in BNP plasma levels to ϾϷ400 pg/mL. Steadily increasing BNP levels preceded overt rejection as assessed by histopathological criteria. The increase in plasma BNP was not always accompanied by an increase in ANF, which suggests the specific upregulation of BNP gene expression during acute rejection episodes. Treatment of the acute rejection episodes led to a substantial decrease of BNP plasma levels. Conclusions-The significant selective increase in plasma BNP levels found in the present study has not been previously described. This finding provides a new insight into the mechanism of allograft rejection and the modulation of natriuretic peptide synthesis and release. Furthermore, although preliminary, the data suggest that BNP plasma levels could form the basis for a new, noninvasive screening test to predict acute cardiac allograft rejection. Because treatment with the antilymphocyte monoclonal antibody OKT3 (murine monoclonal antibody to the CD3 antigen of the human T-cell) decreased BNP plasma levels, cytokine production by T-cells may mediate the selective increase in circulating BNP. (Circulation. 1999;100:287-291.)Key Words: transplantation Ⅲ natriuretic peptides Ⅲ atrial natriuretic factor Ⅲ myocarditis Ⅲ pathology U nder certain pathophysiological conditions, synthesis and release of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are significantly augmented in both atrial and ventricular cardiocytes. Increased production of these hormones by the ventricle is a hallmark of cardiac hypertrophy, failure, 1,2 and inflammation. 3,4 The former increase reflects the reexpression of the cardiac fetal phenotype seen with chronic hemodynamic overload, but the basis for the increased production of NP in myocarditis has not yet been defined.We reported that after cardiac transplantation, ANF plasma concentrations remain elevated, reaching levels comparable to those found before transplantation despite the normalization of filling pressures and the renin-angiotensin-aldosterone system. 5 Elevated BNP plasma levels have also been found after cardiac transplantation. 6 -8 Because BNP is predominantly of ventricular origin, it would be expected that repla...

Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis

“…The elevation of plasma BNP levels found in EAM rats in the absence of changes in plasma ANF levels in these investigations is similar to that reported previously by our laboratory in episodes of acute cardiac allograft rejection in humans (15,18). Separate quantifications of heart chambers were carried because our laboratory has shown previously that changes in ANF and BNP gene expression may occur in a chamberspecific manner (26).…”

“…RNA from tissue samples (n ϭ 4, each chamber, each group) was extracted using TRIzol (GIBCO) following manufacturer's instructions. RT was performed with SuperScript II Reverse Transcriptase (Invitrogen) using oligo(dT) [12][13][14][15][16][17][18] (Invitrogen) according to the manufacturer's instruction. Real-time PCR was performed using a LightCycler FastStart DNA Master SYBR Green I (Roche) according to the manufacturer's instruction.…”

“…However, we previously found that during an acute cardiac allograft rejection episode in humans, plasma BNP may be elevated above prerejection levels independent of hemodynamic parameters, whereas plasma ANF levels did not change in unison with BNP. Successful treatment of the acute rejection episode reversed the increased circulating BNP, suggesting that cytokines released from activated T lymphocytes may stimulate BNP secretion from cardiocytes (15).…”

Ventricular natriuretic peptide (BNP) in heart transplantation: BNP correlation with endomyocardial biopsy, laboratory and hemodynamic measures

“…[28][29][30] The utility of BNP in the diagnosis of heart transplant rejection has not been thoroughly investigated to date; the studies were generally limited to few cases with a short follow-up duration and sometimes contradictory results. 31,32 In this context, the simple laboratory assessment of BNP could be very useful in selecting patients for subsequent invasive techniques such as biopsy.…”

Fetal Cardiac Natriuretic Peptide Expression and Cardiovascular Hemodynamics in Endotoxin-Induced Acute Cardiac Dysfunction in Mouse

“…This finding is in agreement with earlier studies revealing that wall stretch induces rapid activation of BNP gene expression within one hour in the left ventricle (12), whereas induction of ANP gene expression is seen within 1 d after the initiation of increased cardiac overload (13). Inflammation has been suggested to increase plasma concentrations of natriuretic peptides in adults with acute cardiac allograft rejection (14). In addition, Tomaru and co-workers (15)have shown LPS induced production of BNP in isolated neonatal cardiomyocytes in vitro.…”