Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension. To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes. Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups. NEP-I increased plasma ANP (Htx, 20.6 +/- 2.3 to 33.2 +/- 5.9 pmol/L, P < 0.01; controls, 7.7 +/- 1.2 to 10.6 +/- 2.6 pmol/L) and cGMP, but not BNP. Renin decreased similarly in both groups, whereas aldosterone decreased significantly only in Htx. Enhanced urinary sodium (1650 +/- 370% versus 450 +/- 150%, P = 0.01), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects. Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (6.9 +/- 2.0% versus 7.4 +/- 2.8% in controls and Htx). Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx. These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation.

J Thorac Cardiovasc Surg 1999;117:391-2

Brain natriuretic peptide (BNP), a recently discovered cardiac hormone, is secreted mainly by the cardiac ventricles and has potent diuretic, natriuretic, and vasorelaxant properties. Circulating BNP levels are increased in patients with heart failure in proportion to the severity of the disease and may have important compensatory renal, cardiovascular, and endocrinologic actions. Cardiac transplantation, a recognized treatment for end-stage heart failure, normalizes the neuroendocrine balance, but atrial natriuretic peptide and BNP levels remain elevated in heart-transplant recipients.1Buckley MG Sethi D Markandu ND Sagnella A Singer DRJ MacGregor GA. Plasma concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac transplant recipients and patients with dialysis-independent or dialysis-dependant chronic renal failure.Clin Sci. 1992; 83: 437-444Crossref PubMed Scopus (106) Google Scholar Contrasting with the numerous studies focused on atrial natriuretic peptide in heart transplantation2Geny B, Piquard F, Follénius M, Thiranos JCL, Charpentier A, Epailly E, et al. Endothelin participates in increased circulating atrial natriuretic peptide early after human heart transplantation. J Heart Lung Transplant. In press.Google Scholar and despite the greater potential beneficial effects of BNP, few data are available concerning the BNP level response to cardiac transplantation.3Ationu A Burch M Singer D Littleton P Carter N. Cardiac transplantation affects ventricular expression of brain natriuretic peptide.Cardiovasc Res. 1993; 27: 188-191Crossref PubMed Scopus (50) Google Scholar, 4El Gamel A Campbell C Yonan N Keevil B Warburton R Woodcock A et al.Atrial natriuretic peptide release after cardiac transplantation.J Thorac Cardiovasc Surg. 1996; 112: 1128-1129Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Method and results. Plasma BNP levels were determined by radioimmunoassay with kits from Peninsula Laboratories (Belmont, Calif.) after extraction by Sep Pak C18 cartridges (Waters Chromatography, Milford, Mass.) in 25 patients just before and daily during the first week after either heart transplantation (n = 15) or coronary artery bypass grafting (CABG, n = 10). Patients undergoing CABG served as a control group to differentiate any hormonal effects of cardiac surgery per se from specific effects of transplantation. Cardiovascular hemodynamics, plasma creatinine level (used as an index of renal function), endothelin level, and medications were measured simultaneously. The study was approved by the institutional review board, and each patient gave informed consent. Fig. 1 shows that plasma BNP level tended to decrease partially and transiently after transplantation, in opposition to the increase observed after CABG. Table I presents the beneficial hemodynamic effects of heart transplantation. Table ITime course of hemodynamic parameters before and after heart transplantationBeforePOD IPOD 4POD 8pValuesPAP (mm Hg)48 ± 534 ± 2*31 ± 3*—0.002PCWP (mm Hg)24 ± 310 ± 1*13 ± 1*—<0.0001sSBP (mm Hg)120 ± 3124 ± 5133 ± 5131 ± 40.06HR (beats/min)81 ± 4128 ± 3*109 ± 2*91 ± 3<0.0001Data are mean ± standard error of the mean. Differences between groups were obtained by one-way ANOVA with repeated measures on time. When probability was lower than 0.05, pairwise comparisons with before value were assessed by Tukey's test. POD, Postoperative day; sPAP, systolic pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; sSBP, systolic systemic blood pressure; HR, heart rate.*p < 0.01. Open table in a new tab CABG transiently increased the heart rate but did not modify the systemic blood pressure; right ventricular hemodynamics were not determined. Serum creatinine level, not modified after CABG, tended to increase after transplantation. As previously reported, endothelin level increased progressively after operation.2Geny B, Piquard F, Follénius M, Thiranos JCL, Charpentier A, Epailly E, et al. Endothelin participates in increased circulating atrial natriuretic peptide early after human heart transplantation. J Heart Lung Transplant. In press.Google Scholar Positive correlations were observed between systolic, diastolic, and mean pulmonary artery pressures and BNP level (r = 0.57, p = 0.01; r = 0.45, p = 0.04; and r = 0.47, p = 0.04, respectively) and capillary wedge pressure and BNP level (r = 0.49, p = 0.03) when considering the acute effect of transplantation (day 0 and day 1). Among the usual first-week chronotropic and inotropic drug support, only isoproterenol (INN: isoprenaline) and dopamine correlated with plasma BNP level in heart transplantation (r = 0.57, p < 0.0001, and r = 0.23, p < 0.02, respectively). No significant correlation was observed between BNP level and azathioprine, prednisolone, or cyclosporine (INN: ciclosporin), but BNP level was positively correlated with serum creatinine and endothelin levels (r = 0.60, p < 0.0001, and r = 0.55, p = 0.002, respectively). Data are mean ± standard error of the mean. Differences between groups were obtained by one-way ANOVA with repeated measures on time. When probability was lower than 0.05, pairwise comparisons with before value were assessed by Tukey's test. POD, Postoperative day; sPAP, systolic pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; sSBP, systolic systemic blood pressure; HR, heart rate. *p < 0.01. Discussion. This study confirms that plasma BNP levels are elevated in heart transplantation. It supports, for the first time, the contention that the hemodynamic improvement after cardiac transplantation may partially decrease circulating BNP levels early after the operation. Indeed, we observed positive correlations between BNP level and decreased pulmonary capillary wedge and pulmonary artery pressures in heart transplantation. Accordingly, the right ventricle has been shown to participate in BNP secretion after heart transplantation,3Ationu A Burch M Singer D Littleton P Carter N. Cardiac transplantation affects ventricular expression of brain natriuretic peptide.Cardiovasc Res. 1993; 27: 188-191Crossref PubMed Scopus (50) Google Scholar and increased plasma BNP levels were recently reported to be associated with increased right ventricular afterload in heart transplantation.4El Gamel A Campbell C Yonan N Keevil B Warburton R Woodcock A et al.Atrial natriuretic peptide release after cardiac transplantation.J Thorac Cardiovasc Surg. 1996; 112: 1128-1129Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Several factors acting on BNP clearance and secretion rates may explain why BNP level decreases only partially and transiently after transplantation. BNP is cleared by the kidney, and moderate renal failure, as inferred from increased creatinine level, may partially explain the secondary increase of the cardiac hormone. Endothelin may participate in BNP level elevation in heart transplantation, both through its deleterious renal effects and through direct stimulation of BNP secretion. BNP levels after cardiac transplantation may also reflect predominantly right and left ventricular diastolic function.4El Gamel A Campbell C Yonan N Keevil B Warburton R Woodcock A et al.Atrial natriuretic peptide release after cardiac transplantation.J Thorac Cardiovasc Surg. 1996; 112: 1128-1129Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Indeed, BNP level is elevated in patients with isolated diastolic dysfunction,5Lang CC Prasad N McAlpine HM Macleod C Lipworth BJ MacDonald TM et al.Increased plasma levels of brain natriuretic peptide in patients with isolated diastolic dysfunction.Am Heart J. 1994; 127: 1635-1636Abstract Full Text PDF PubMed Scopus (78) Google Scholar and it is well known that, in addition to normalizing systolic function, heart transplantation results in diastolic dysfunction. This may explain the need for drug support and the positive correlation observed between BNP level and isoproterenol. Although positive correlation between BNP level and trough cyclosporine levels has not consistently been reported,3Ationu A Burch M Singer D Littleton P Carter N. Cardiac transplantation affects ventricular expression of brain natriuretic peptide.Cardiovasc Res. 1993; 27: 188-191Crossref PubMed Scopus (50) Google Scholar, 4El Gamel A Campbell C Yonan N Keevil B Warburton R Woodcock A et al.Atrial natriuretic peptide release after cardiac transplantation.J Thorac Cardiovasc Surg. 1996; 112: 1128-1129Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar it is tempting to speculate that cyclosporine may participate in BNP level increase in our heart transplantation group, because BNP level increased when cyclosporine therapy was began (day 4). In this view, the lack of correlation between BNP level and cyclosporine in our heart transplantation group may rely on the fact that peak levels or local tissue concentrations of cyclosporine, rather than 12-hour trough level, may be better for cyclosporine effect assessment. In summary, an early determination of BNP level after transplantation allowed us to observe transient changes that might otherwise have been missed. The results suggest that hemodynamic improvement after heart transplantation reduces plasma BNP levels and that impaired renal function, increased endothelin level, and diastolic dysfunction increase the cardiac hormone early after heart transplantation. Systemic hypertension, occurring later after transplantation, may then increase diastolic dysfunction, thus enhancing BNP secretion in heart transplantation.

The determination of plasma and whole blood free amino acid concentrations in arterial and portal venous blood during post prandial state in the rat was used to estimate the role of the erythrocytes in amino acid exchanges. The erythrocyte contents were calculated from plasma, whole blood concentrations and the hematocrit. The veno-arterial concentration differences in plasma were significant for all amino acids except a-aminobutyrate and ornithine whereas in the erythrocytes only 8 amino acids exhibit significant differences (ASP, ALA, VAL, MET, ILE, LEU, TYR, PHE). For 6 amino acids, a significant correlation between the plasma and the erythrocyte concentration has been found (VAL, ILE, LEU, TYR, PHE, HIS). These data suggest that in vivo during the time of contact between blood and organ tissues, some amino acids but not all are significantly taken up by the erythrocytes. Thus, it may be concluded that erythrocyte amino acid blood transport in arterio-venous portal exchanges, concerns particularly tyrosine and essential amino acids. The erythrocyte amino acid transport represents quantitatively about 20 per cent of the total blood transport.

BACKGROUND:Hemodynamic improvement after heart transplantation is expected to normalize the neuroendocrine balance, but circulating atrial natriuretic peptide (ANP) remains elevated. Endothelin stimulates ANP secretion and its concentration increases after heart transplantation, suggesting a role for this peptide in the cardiovascular adaptative response to heart transplantation.METHODS:To investigate whether endothelin may induce ANP increase in heart transplant recipients, we monitored daily ANP, endothelin, and related hormonal, biologic, and hemodynamic parameters before and during the first week after either heart transplantation (n = 15) or coronary artery bypass grafting (n = 10).RESULTS:Surgery induced a transient secretory peak of arginine vasopressin and endothelin in both groups at day 1. Bypass grafting did not modify normal ANP (11.8 +/- 2.1 pmol/L), endothelin (2.4 +/- 0.3 pmol/L), renin activity (0.11 +/- 0.04 pmol/L/sec), or aldosterone (492 +/- 122 pmol/L) values. Heart transplantation normalized the renin-aldosterone axis, but the early decrease observed for ANP (from 27.2 +/- 4.8 to 21.14 +/- 1.4 pmol/L) was only partial and transient. Endothelin further increased (from 4.4 +/- 0.8 to 9.14 +/- 1.8 pmol/L; p < 0.01) after transplantation. Positive correlations were observed between endothelin, isoproterenol dose, creatinine, right atrial pressure, and ANP, but multiple correlation analysis showed the important role of endothelin (r = 0.69, p < 0.001). Cyclic guanosine monophosphate correlated with ANP (r = 0.65, p < 0.001).CONCLUSIONS:Elevated endothelin, suggesting vascular dysfunction, likely contributes to the ANP increase observed early after heart transplantation. Furthermore, ANP, through a cardiac endothelium feedback, may act in the maintenance of circulatory homeostasis in heart transplant recipients.

Background: The breakdown of blood pressure and body fluid homeostasis observed in heart transplant (Htx) recipients may partly be due, as in heart failure, to a blunted renal response to elevated atrial natriuretic peptide (ANP).Method: This possibility was addressed through determination of the relationship between ANP, the urinary cyclic guanosine monophosphate (cGMP), a biologic marker of ANP renal activity, and the early renal responses to 10 mL/kg isotonic saline infusion over 30 minutes in 8 control subjects and 8 matched Htx recipients.Results: Urine flow, natriuresis, and urinary cGMP excretion increased similarly in both groups, resulting in elimination of, respectively, 1/2 and 2/3 of the sodium and the water load during the experiment that lasted 4 hours and 30 minutes. Plasma renin and aldosterone decreases were similar in both groups. Elevated ANP further increased in Htx after saline infusion (from 19.5 +/- 3.7 to 33.8 +/- 5.6 pmol/L, P < .001). Plasma cGMP paralleled ANP in both groups (r = 0.81; P < .001). Significant correlations were observed between plasma ANP and urinary cGMP excretion (r = 0.48, P < .025 and r = 0.43, P < .05 in Htx recipients and control subjects) and between plasma ANP and urinary sodium excretion (r = 0.64, P < .001 in Htx recipients).Conclusion: In spite. of a relative renal hyporesponsiveness to the cardiac hormone, with higher plasma ANP being not associated with increased renal excretions in Htx recipients, ANP is likely to participate in the appropriate short-term renal response to acute volume expansion in Htx recipients.

Background Contrast echocardiography is a useful tool for assessing repeatedly patients with coronary artery disease, Nevertheless, elevated pulmonary artery and systemic blood pressures likely to be associated with cardiac ischemia may limit the left Ventricular opacification (LVO) because of the microspheres' sensitivity to pressure.Objective To determine the effects of systemic and pulmonary artery blood pressures on LVO.Methods We performed 55 intravenous injections (0.08 and 0.22 ml/kg) of a new transpulmonary contrast agent (Albunex), during two separated exposures, into 20 cardiac ischemic patients while monitoring invasively their cardiac indexes, and intracardiac, systemic, and pulmonary artery blood pressures. LVO was graded qualitatively from faint to full.Results A logistic model with the grade of LVO as the dependent variable and a selection from among the dose, exposure, right and left atrial blood pressures, systolic systemic and pulmonary artery blood pressures (ranges 94-208 and 14-45 mmHg, respectively), cardiac index, stroke index, and pulmonary and systemic vascular resistances as the explanatory variables demonstrated that increasing the dose gives an increasing probability of LVO (P = 0.02) and that increasing the pulmonary artery pressure reduces that probability (P = 0.006), A decreased cardiac index tended also to be associated with decreased LVO, The systemic blood pressure and the pulmonary and systemic vascular resistances had no statistically significant effect on the grade of LVO.Conclusions LVO after intravenous administration of Albunex is dose-dependent and limited by an elevated pulmonary artery pressure, These data suggest that one should use higher doses for cardiac ischemic patients with elevated pulmonary artery pressures and that use of Albunex has the potential to detect pulmonary hypertension in patients.

Background and hypothesis: Multiple contrast-enhanced echocardiographic studies are to be expected in patients with cardiac ischemic disease, but the sonication process used to produce the echocontrast agent Albunex(R) may result in new epitopes that could cause an immunogenic response.Methods: Repeated exposures to intravenous Albunex over a period of time long enough to allow development of an eventual immune reaction were performed in 12 patients while monitoring for lymphocyte transformation, microsphere specific IgE and IgG antibodies, and systemic, pulmonary artery, capillary wedge, and right atrial pressures, as well as cardiac output, left ventricular fractional shortening, and blood gases.Results: No significant H-3-thymidine incorporation and thus no specific blastic transformation of the patients' lymphocytes were observed either for high or low Albunex concentrations, corresponding to the expected hepatic and plasma concentrations of microspheres. No formation of microsphere-specific IgE and IgG antibodies was observed after the first or second Albunex exposure. Furthermore, no clinically significant hemodynamic or respiratory adverse reactions were observed in any patient.Conclusion: These results suggest that repeated exposures to intravenous Albunex induce no adverse effect on the cellular and humoral immune systems and on left and right heart hemodynamics in patients.

UNLABELLED To define the respective roles of the periphery and central oxygen transport in the exercise limitation of heart transplanted patients (HTR), we compared 11 HTR (15.1 +/- 10.8 months after transplantation) to six age and weight matched normal controls (C), during an incremental exercise test (30 W/3 min steps; supine position), up to peak exercise level. The C stopped between 120 and 240 W (mean = 180 +/- 39 W), whereas the HTR all reached 90 W, with a significantly lower oxygen uptake (VO2), cardiac index (CI) and arterio-venous oxygen difference (AVO2D) values (respectively VO2: 16.6 +/- 2.6 vs 30.0 +/- 9.3 ml.min-1.kig-1 STPD; CI: 6.84 +/- 1.10 vs 10.55 +/- 2.86l.min-1.m-2; AVO2D: 94 +/- 13 vs 109 +/- 9 ml.l-1; all p < 0.05) but with similar lactate (LA) values (respectively 7.25 +/- 1.98 vs 7.71 +/- 1.55 mmol.l-1; p = NS). At the 90 W step which corresponds to the peak level that all the HTR reached, the C were close to their anaerobic threshold and showed similar parameters of oxygen transport (VO2: 17.4 +/- 2.0; CI: 7.50 +/- 0.41; AVO2D:90 +/- 10) but a lower lactate level (LA: 2.93 +/- 4.76; p < 0.002). At the same intermediate exercise levels VO2, CI and AVO2D were similar in both groups, while the closely matched LA and ventilation increased faster in HTR, reaching significantly higher levels as soon at the 30 W step. This evidence for an increased anaerobic exercise energy generation in HTR suggests that the periphery participates significantly in their exercise limitation, a phenomenon that might be improvable by retraining. VALUES means+/-standard deviation.

The increase in plasma concentration of atrial natriuretic factor in heart transplant patients has not been fully elucidated. Besides an eventual pressure or volume overload leading to passive atrial distension, the atrial tension developed during atrial systole, or atrial ejection force, which may be increased by the transplantation procedure, is an important determinant of atrial natriuretic factor release. We therefore determined the plasma concentration of atrial natriuretic factor and the maximal atrial ejection force in 15 heart transplant patients and 8 controls, matched for age and body mass. Atrial ejection force, as defined as the force exerted by the left atrium to accelerate blood into the left ventricle during atrial systole, was obtained using combined two-dimensional imaging and doppler echocardiography. Serum creatinin concentrations, heart rate [91.9 (SD 13.2) vs 71.8 (SD 10.9) beats.min-1], mean arterial blood pressure [103.9 (SD 9.8) vs 87.4 (SD 5.8) mmHg, 13.85 (SD 1.31) vs 11.65 (SD 0.77) kPa], left ventricular posterior wall thickness and interventricular septum thickness were higher in heart transplant patients compared to controls. Plasma concentration of atrial natriuretic factor was also elevated in heart transplant patients [63.9 (SD 18.1) vs 34.0 (SD 3.2) pg.ml-1; P < 0.001]. In contrast, although the left atrial area was greater in heart transplant patients [28.2 (SD 4.8) vs 15.8 (SD 2.5) cm2; P < 0.001], mitral area, transmitral Doppler A-wave maximal velocity and atrial ejection force were similar in transplant and in control patients [7.7 (SD 3.5) vs 8.9 (SD 2.8) kdyn, 77 (SD 35) vs 89 (SD 28)mN]. No significant correlation was observed between concentration of atrial natriuretic factor and atrial ejection force, either in heart transplant patients or in controls. Thus, the elevated plasma concentration of atrial natriuretic factor observed in these heart transplant patients was multifactorial in origin, and was considered to depend upon an hypersecretion rather than upon a decreased clearance rate. Moreover, it is suggested that the atrial ejection force was unlikely to have participated in this enhanced release of atrial natriuretic factor.

The persistent impaired exercise capacity exhibited by heart transplanted patients (HTR) 1 year after the operation is mainly linked to a predominant peripheral muscular limitation as shown by an early increase of arterial lactates whereas the cardiac output and the O 2 arteriovenous content differences increase normally as control subjects (C). We submitted seven HTR and three age matched C to a 6 week endurance training program following the Square-Wave-Endurance Exercise Test (SWEET) as described by Gimenez (1982) : 4 min Base level intensity (B) was fixed at the ventilatory threshold (SV) and 1 min Peak level intensity (P) at the maximal tolerated power previously measured during a maximal incremental test. The procedure consists to progressively increase the duration of the test from the 1st to the 3rd week, then gradually increase the B and P levels from the 4th to the 6th week. We observe in both groups a significant decrease of the following mean values measured at the 4th minute of each base level: cardiac frequency, ventilation, CO 2 excretion, arterial lactates and ammoniac, epinephrine and norepinephrine values. These preliminary results confirm the predominant peripheral limitation among these patients and the beneficial effects of a short term program.