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Letters to the Editor |
Departments of1
Internal Medicine, and 2
Laboratory Medicine, Konventhospital Barmherzige Brueder Linz, A-4021 Linz, Austria
3 Department of Applied System Sciences, and Statistics, University of Linz, A-4040 Linz, Austria
aAuthor for correspondence. Fax 43-732-7897-2299; e-mail meinhard.haltmayer{at}bblinz.at.
To the Editor:
The short-term infusion of levosimendan (SimdaxTM), a calcium sensitizer, improves the hemodynamic function in patients with decompensated heart failure (1)(2)(3). Blood concentrations of B-type natriuretic peptide (BNP) and the amino-terminal fragment of its precursor hormone (NT-proBNP) have been reported to reflect the severity of heart failure (4), and BNP concentrations have been shown to decrease with improving hemodynamic function during tailored intravenous treatment of decompensated heart failure (5). Because of the shorter biological half-life of BNP compared with NT-proBNP (6), we hypothesized that BNP would show a faster response to hemodynamic improvement during intravenous levosimendan therapy. This could be of relevance considering the possible role of natriuretic peptides for guiding therapy in acutely decompensated heart failure.
The present observational study, carried out prospectively at the Division of Internal Medicine, St. John of God Hospital (Linz, Austria), was approved by the local ethics committee in accordance to the Helsinki Declaration. Eligible patients were those admitted with acute decompensation of chronic heart failure who were judged to require hemodynamic monitoring and intravenous treatment. Inclusion criteria were defined as follows, based on a previous report (1): documented left ventricular ejection fraction 
30% by echocardiogram and a pulmonary artery catheter placed for clinical purposes that demonstrated a pulmonary capillary wedge pressure (PCWP) 
15 mmHg along with a cardiac index (CI) 2.5 L · min-1 · m-2. Exclusion criteria were angina-limited exercise; unstable angina or acute myocardial infarction with urgent need for invasive procedure; obstructive cardiomyopathy; uncorrected primary stenotic valve; history of ventricular flutter, fibrillation, or symptomatic ventricular tachycardia; symptomatic primary pulmonary disease; supine systolic blood pressure <85 or >200 mmHg; resting heart rate >120 beats/min; serum creatinine >25 mg/L; liver transaminases >2 times the upper limit of the reference interval; and uncorrected hypo- or hyperkalemia (serum potassium <3.5 or >5.5 mmol/L). Between January and July 2003, we recruited 11 consecutive patients after obtaining informed written consent.
In all study participants, levosimendan (Simdax) was initiated with an intravenous bolus of 24 µg/kg of body weight (delivered over 10 min) followed by a continuous infusion of 0.1 µg · (kg body weight)-1 · min-1 for the next 50 min. Thereafter, the continuous infusion rate was increased in all patients to 0.2 µg · (kg body weight)-1 · min-1 for the next 23 h. None of the following dose-limiting events occurred: symptomatic hypotension with a systolic blood pressure <75 mmHg; tachycardia with a heart rate >140 beats/min for at least 10 min or increased by >25 beats/min; need for rescue therapy with intravenous positive inotropic or vasodilator drugs; or any adverse event that, in the opinion of the investigators, required dose modification. During infusion, the dose of concomitant oral medications (i.e., angiotensin-converting enzyme inhibitors, beta-blockers, digitalis glycosides, amiodarone) was held constant, but diuretics were stopped.
Hemodynamic measurements were made by means of a pulmonary artery catheter and included PCWP, pulmonary artery pressure, right atrial pressure, and cardiac output (thermodilution). Heart rate was determined from the electrocardiogram, and blood pressure was determined by intraarterial monitoring. CI, stroke volume, systemic vascular resistance, and pulmonary vascular resistance were calculated by standard equations. Hemodynamic measurements were recorded at baseline (before start of levosimendan administration), at 10 min (at the end of initial bolus), at 60 min (at the end of first infusion period), at 120 min (2 h after initiation of infusion), at 6 h (6 h after initiation of infusion), and at 24 h (the end of levosimendan infusion). Blood samples were drawn at those same time points for determination of BNP and NT-proBNP. Plasma BNP was assayed on an ADVIA Centaur analyzer (Bayer Diagnostics), and serum NT-proBNP was assayed on an Elecsys 2010 analyzer (Roche Diagnostics), both according to the manufacturers’ recommendations.
Statistical calculations were performed with the MedCalc (Ver. 7.2.0.2) software. The Kolmogorov–Smirnov test was used to assess gaussian distribution of all relevant data. Time-dependent changes in hemodynamics and the BNP and NT-proBNP values were evaluated by paired t-tests. Values are presented as the mean (SD). All probabilities were two-tailed, and P values <0.05 (not corrected for multiple comparisons) were regarded as statistically significant.
The mean age of the study population (10 males and 1 female) was 62 (16) years. All patients had New York Heart Association class III (n = 3) to IV (n = 8) heart failure of either ischemic (n = 7) or nonischemic origin (n = 4) with a CI 2.2 L · min-1 · m-2 and a PCWP >15 mmHg. Mean left ventricular ejection fraction as determined by echocardiography was 20 (4)%. Relevant hemodynamic measurements (i.e., CI and PCWP) and BNP and NT-proBNP values at baseline as well as absolute/relative changes to baseline during levosimendan administration are shown in Table 1
. Main finding was a different response of BNP and NT-proBNP to a standardized levosimendan therapy in decompensated heart failure. When comparing relative changes with baseline measurements, BNP concentrations significantly decreased within 60 min, whereas NT-proBNP showed a significant decrease not earlier than 24 h after initiation of levosimendan infusion. In contrast, hemodynamic indices (PCWP and CI) changed immediately after initiation of levosimendan administration.
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The faster response of BNP to therapy compared with NT-proBNP may be attributable to their different biological half-lives. Although there currently are data only on the half-life of NT-proBNP in sheep (7), the half-life of human NT-proBNP is considered to be 60–120 min (probably depending on renal function) (6), suggesting that meaningful changes in hemodynamics could be reflected by this test theoretically every 12 h, which is in good accordance with our observations. Thus, NT-proBNP concentrations lag behind the clinical picture, given its longer time for clearance. The half-life time of human BNP is 
20 min (8), and a previous study showed that BNP may be able to reflect changes in PCWP every 2 h during a tailored intravenous treatment (other than levosimendan) of decompensated heart failure (5). Our data showed a statistically significant decrease in BNP concentrations 60 min after the beginning of levosimendan therapy, which was also the time interval for a significant change in PCWP. However, one limitation of our study was that we were not able to make any conclusions concerning the optimum time interval for monitoring patients with decompensated heart failure on a routine clinical basis, given the recently reported considerable biological variations in BNP and NT-proBNP (9). Another limitation is the preponderance of males in the present study group.
Because BNP concentrations correlate to increased end-diastolic pressure and left ventricular wall tension and thus reflect the degree of ventricular overload, PCWP should be a hemodynamic index with a close correlation to BNP. Indeed, the responses of BNP and PCWP to levosimendan therapy seem to be similar, but because of the small number of patients and the limited statistical power of the present study, our findings cannot be used to determine whether there is a direct relationship between BNP and hemodynamic indices in time course and whether BNP concentrations can be used for classifying responders and nonresponders to levosimendan therapy. To address these important issues, it will be necessary to perform larger studies to clarify whether BNP and/or NT-proBNP can be used as surrogate markers for PCWP (or other hemodynamic measures) in individual patients.
Acknowledgments
This work was supported in part by a grant for scientific research from the Upper Austrian Government. We thank Roche Diagnostics (Vienna, Austria) and Bayer Diagnostics (Vienna, Austria) for technical assistance and providing reagents free of charge. Neither of these companies played a role in the design of the study; data collection, analysis, and interpretation; or preparation of the manuscript.
References
The following articles in journals at HighWire Press have cited this article:
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 A. Gegenhuber, T. Mueller, B. Dieplinger, K. Lenz, W. Poelz, and M. Haltmayers Plasma B-Type Natriuretic Peptide in Patients With Pleural Effusions: Preliminary Observations Chest, August 1, 2005; 128(2): 1003 - 1009. [Abstract] [Full Text] [PDF]
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H. G. Wahl, S. Graf, H. Renz, and W. Fassbinder Elimination of the Cardiac Natriuretic Peptides B-Type Natriuretic Peptide (BNP) and N-Terminal proBNP by Hemodialysis Clin. Chem., June 1, 2004; 50(6): 1071 - 1074. [Full Text] [PDF]
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