- Email: [email protected]
Low plasma levels of brain natriuretic peptide in severe acute heart failure: Merely a case?
International Journal of Cardiology 122 (2007) e18 – e20 www.elsevier.com/locate/ijcard
Letter to the Editor
Low plasma levels of brain natriuretic peptide in severe acute heart failure: Merely a case? Loretta Brentana ⁎, Pier Luigi Temporelli, Ugo Corrà, Marinella Gattone, Massimo Pistono, Alessandro Imparato, Marco Gnemmi, Pantaleo Giannuzzi Division of Cardiology, “Salvatore Maugeri” Foundation, IRCCS, Medical Center of Rehabilitation, Veruno (NO), Italy Received 31 August 2006; accepted 11 November 2006 Available online 26 March 2007
Abstract Brain natriuretic peptide (BNP) is commonly used for diagnosis and prognosis of patients with congestive heart failure (HF). High levels of BNP are associated with high probability of cardiogenic dyspnea and higher risk of subsequent cardiovascular events. We describe a case of acute HF (worsening chronic HF) in a 74-year-old male with low plasma BNP levels on admission, in whom a rapid and consistent increase in the marker's concentration occurred after administration of diuretics and vasodilators, despite a prompt clinical and hemodynamic improvement. Reports of cardiogenic dyspnea with moderate increase or normal plasma levels of BNP have been recently published: does this signify a pitfall for BNP as a useful diagnostic and prognostic tool? Clinical implications of our observation are discussed, and we conclude that neurohumoral biomarkers do not obviate the need for a careful physical and instrumental examination of patient. © 2007 Published by Elsevier Ireland Ltd. Keywords: Brain natriuretic peptide; Acute heart failure; Aortic stenosis
Despite the improvement obtained with neurohumoral antagonists, natural history of left ventricular dysfunction and heart failure (HF) remains progressive and many patients develop decompensated HF. Normalization of the left ventricular (LV) filling pressures is known to be associated with a favorable prognosis and is therefore accepted as a major therapeutic goal [1]. Unfortunately, clinical signs have a low accuracy in detecting hemodynamic changes in patients with acute HF, and the benefit of Swan-Ganz catheterization is still uncertain as it was demonstrated in a recent randomized controlled trial [2]. Accordingly, noninvasive Doppler echocardiographic indexes have been validated to monitor hemodynamic variables in HF patients [3]. In the clinical setting, however, a well established method which is both reproducible and easy to perform for monitoring filling pressures in acute HF is not yet available. ⁎ Corresponding author. Divisione di Cardiologia, Fondazione “Salvatore Maugeri”, IRCCS,Via Revislate, 13- 28010 Veruno (NO), Italy. Tel.: +39 0322 884711; fax: +39 0322 884966. E-mail address: [email protected] (L. Brentana). 0167-5273/$ - see front matter © 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.ijcard.2006.11.085
The assay of plasma brain natriuretic peptide (BNP) appears to meet these latter requirements. In the aetiological diagnosis of dyspnea, BNP can distinguish cardiogenic dyspnea with high accuracy. Maisel et al. [4] have demonstrated that BNP correlates with the New York Heart Association (NYHA) classification of symptoms and LV function. Data on short term changes of BNP after hemodynamic improvement are however discordant. Kazanegra [5] reported a good relation between pulmonary capillary wedge pressure and BNP. On the other hand, O'Neill [6] demonstrated no correlation between BNP and any hemodynamically derived variables. 1. Case report A 74-year-old male was admitted to our Cardiology Department for dyspnea, asthenia and orthopnea (NYHA class IV). The patient had a history of diabetes mellitus, arterial hypertension, dyslipidemia, chronic atrial fibrillation and had been submitted to surgical coronary revascularization for severe three vessels artery disease ten years before. A recent
L. Brentana et al. / International Journal of Cardiology 122 (2007) e18–e20
e19
dysfunction (ejection fraction 29%) with asynergy at the anterior, septal and inferior walls without fibrosis, high pulmonary arterial systolic hypertension (70 mm Hg), severe mitral regurgitation for leaflets diffuse calcification, and tricuspid aortic valve stenosis (underestimated mean gradient 30 mm Hg, maximum gradient 49 mm Hg). On admission, BNP was 201 pg/ml and NT-proBNP was 1586 pg/ml. The patient was treated with furosemide (bolus 100 mg and infusion 10 mg/h for 48 h) and with low dose nitrates (5 gamma/kg/die for 48 h). After 24 h of infusion, BNP and NT-proBNP slightly decreased to 162 pg/ml and 1033 pg/ml, respectively. In the following days, clinical conditions improved (NYHA class from IV to II) and at chest X-ray there was reduction of infiltrates (Fig. 1, bottom). Moreover, a reduction of pulmonary arterial hypertension (from 70 to 40 mm Hg) and of mitral regurgitation (mild vs moderate to severe) was evident at Doppler echocardiography. Despite this clinical and hemodynamic improvement, on day 7 BNP and NT-proBNP plasma levels increased to 340 pg/ml and 2285 pg/ml, respectively, without significant worsening of renal function (creatinine and creatinine clearance were stable respect to the admission). On day 13, conditions were stable with no signs of congestion or peripheral hypoperfusion but BNP plasma levels further increased (BNP: 360 pg/ml; NTproBNP: 2386 pg/ml) (Fig. 2).
Fig. 1. Top. Chest X-ray of the patient at admission for acute decompensation of chronic heart failure. Bottom. Chest X-ray of the patient after intravenous diuretics and vasodilators.
angiography had excluded significant graft stenosis. Patient was on treatment with furosemide 25 mg/die, potassium canreonate 25 mg/die, and ramipril 7.5 mg/die and had shown a gradual worsening of symptoms in the 2 weeks leading up to admission. On admission, systemic blood pressure was 105/ 60 mm Hg, heart rate 120 b/min in atrial fibrillation; there was no fever. Physical examination revealed bibasilar rales, systolic murmur and third heart sound. Peripheral congestion, hepatomegaly and hepato-jugular reflux were present. Electrocardiogram showed no signs of ischemia. Haemoglobin, leukocytes, C-reactive protein, D-dimer, renal (creatinine 1.08 mg/dl) and hepatic function, serum electrolytes (sodium 146 mEq/l, potassium 3.9 mEq/l), creatine kinase-MB and troponins were within normal range. Chest-X rays showed interstitial infiltrates with pleural effusion at the right lung (Fig. 1, top). Transthoracic echocardiogram showed LV hypertrophy (interventricular septum 16 mm), normal LV volumes (LV end diastolic volume 65 ml/m2), severe LV
Fig. 2. Serial changes in BNP and NT-proBNP plasma levels during hospitalization.
e20
L. Brentana et al. / International Journal of Cardiology 122 (2007) e18–e20
Patient was then submitted to replacement of aortic valve with biological prosthesis, after dobutamine echocardiography that evidenced myocardial contractile reserve, increase in valve gradient with no change in valve area. At six months clinical conditions of patient are stable (NYHA II) and ejection fraction at echocardiogram is 40%. 2. Discussion This patient had the typical characteristics of patients enrolled in clinical studies on acute HF (male sex, mean age 70 years) and promptly responded to medications, but paradoxically his BNP trend showed a strange and unusual behavior: BNP and NT-proBNP were lower during the phase of decompensation of HF and increased after hemodynamic and clinical improvement. A decrease in BNP in patients with end-stage HF has already been described [7,8], possibly reflecting an exhaustion of the ability of cardiomyocytes to synthesize and secrete a sufficient amount of natriuretic peptides and/or their increased degradation and/or clearance. In our patient, however, there was LV hypertrophy and there was no extensive myocardial fibrosis nor significant LV enlargement. A possible explanation that support our findings is the high body mass index of the patient (32 kg/ m2). In fact, in obese patients low BNP levels (median value 332 pg/ml) have been reported in the course of decompensated HF that continue to maintain a relation with symptoms and hemodynamic status [9], a correlation not present in our case. The decompensation of chronic HF in our case was related also to the coexistence of moderate aortic stenosis due to significative calcifications of cuspids, associated with possible subendocardial ischemia. It is known that in patients with aortic stenosis BNP correlates with disease severity and with symptoms [10]. In our patient, despite the coexistence of underestimated aortic stenosis, severe LV systolic dysfunction, left atriomegaly (27 cm2) and chronic atrial fibrillation, BNP was low and paradoxically increased after unloading therapy and after improvement in hemodynamic and symptoms. In conclusion, in line with recent sporadic data [7,8], our case report warns against the indiscriminate use of BNP and
tendency to underestimate the clinical evaluation of patients presenting with dyspnea, and highlights the need for larger studies on the role of BNP in acute HF patients with concomitant pathologic conditions like obesity and diabetes mellitus. References [1] Stevenson LW, Tillisch JH, Hamilton M, et al. Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol 1990;66:1348–54. [2] Binanay C, Califf RM, Hasselblad V, et al. ESCAPE Investigators and ESCAPE Study Coordinators. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005;294:1625–33. [3] Temporelli PL, Scapellato F, Corrà U, et al. Chronic mitral regurgitation and Doppler estimation of left ventricular filling pressures in patients with heart failure. J Am Soc Echocardiogr 2001;14:1094–9. [4] Maisel AS, Krishnaswamy P, Nowak RM, et al. Breathing Not Properly Multinational Study Investigators. Rapid measurement of Btype natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. [5] Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 2001;7:21–9. [6] O'Neill JO, Bott-Silvermann CE, McRae AT, et al. B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure. Am Heart J 2005;149:363–9. [7] Packer M. Should B-type natriuretic peptide be measured routinely to guide the diagnosis and management of chronic heart failure? Focused perspective. Circulation 2003;108:2950–295. [8] Miller WL, Burnett Jr JC, Hartman KA, Henle MP, Burritt MF, Jaffe AS. Lower rather than higher levels of B-type natriuretic peptides (NTproBNP and BNP) predict short-term mortality in end-stage heart failure patients treated with nesiritide. Am J Cardiol 2005;96:837–41. [9] Horwich TB, Hamilton MA, Fonarow GC. B-type natriuretic peptide levels in obese patients with advanced heart failure. J Am Coll Cardiol 2006;47:85–90. [10] Gerber IL, Stewart RA, Legget ME, et al. Increased plasma natriuretic peptide reflect symptom onset in aortic stenosis. Circulation 2003;107:1884–90.
Letter to the Editor
Low plasma levels of brain natriuretic peptide in severe acute heart failure: Merely a case? Loretta Brentana ⁎, Pier Luigi Temporelli, Ugo Corrà, Marinella Gattone, Massimo Pistono, Alessandro Imparato, Marco Gnemmi, Pantaleo Giannuzzi Division of Cardiology, “Salvatore Maugeri” Foundation, IRCCS, Medical Center of Rehabilitation, Veruno (NO), Italy Received 31 August 2006; accepted 11 November 2006 Available online 26 March 2007
Abstract Brain natriuretic peptide (BNP) is commonly used for diagnosis and prognosis of patients with congestive heart failure (HF). High levels of BNP are associated with high probability of cardiogenic dyspnea and higher risk of subsequent cardiovascular events. We describe a case of acute HF (worsening chronic HF) in a 74-year-old male with low plasma BNP levels on admission, in whom a rapid and consistent increase in the marker's concentration occurred after administration of diuretics and vasodilators, despite a prompt clinical and hemodynamic improvement. Reports of cardiogenic dyspnea with moderate increase or normal plasma levels of BNP have been recently published: does this signify a pitfall for BNP as a useful diagnostic and prognostic tool? Clinical implications of our observation are discussed, and we conclude that neurohumoral biomarkers do not obviate the need for a careful physical and instrumental examination of patient. © 2007 Published by Elsevier Ireland Ltd. Keywords: Brain natriuretic peptide; Acute heart failure; Aortic stenosis
Despite the improvement obtained with neurohumoral antagonists, natural history of left ventricular dysfunction and heart failure (HF) remains progressive and many patients develop decompensated HF. Normalization of the left ventricular (LV) filling pressures is known to be associated with a favorable prognosis and is therefore accepted as a major therapeutic goal [1]. Unfortunately, clinical signs have a low accuracy in detecting hemodynamic changes in patients with acute HF, and the benefit of Swan-Ganz catheterization is still uncertain as it was demonstrated in a recent randomized controlled trial [2]. Accordingly, noninvasive Doppler echocardiographic indexes have been validated to monitor hemodynamic variables in HF patients [3]. In the clinical setting, however, a well established method which is both reproducible and easy to perform for monitoring filling pressures in acute HF is not yet available. ⁎ Corresponding author. Divisione di Cardiologia, Fondazione “Salvatore Maugeri”, IRCCS,Via Revislate, 13- 28010 Veruno (NO), Italy. Tel.: +39 0322 884711; fax: +39 0322 884966. E-mail address: [email protected] (L. Brentana). 0167-5273/$ - see front matter © 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.ijcard.2006.11.085
The assay of plasma brain natriuretic peptide (BNP) appears to meet these latter requirements. In the aetiological diagnosis of dyspnea, BNP can distinguish cardiogenic dyspnea with high accuracy. Maisel et al. [4] have demonstrated that BNP correlates with the New York Heart Association (NYHA) classification of symptoms and LV function. Data on short term changes of BNP after hemodynamic improvement are however discordant. Kazanegra [5] reported a good relation between pulmonary capillary wedge pressure and BNP. On the other hand, O'Neill [6] demonstrated no correlation between BNP and any hemodynamically derived variables. 1. Case report A 74-year-old male was admitted to our Cardiology Department for dyspnea, asthenia and orthopnea (NYHA class IV). The patient had a history of diabetes mellitus, arterial hypertension, dyslipidemia, chronic atrial fibrillation and had been submitted to surgical coronary revascularization for severe three vessels artery disease ten years before. A recent
L. Brentana et al. / International Journal of Cardiology 122 (2007) e18–e20
e19
dysfunction (ejection fraction 29%) with asynergy at the anterior, septal and inferior walls without fibrosis, high pulmonary arterial systolic hypertension (70 mm Hg), severe mitral regurgitation for leaflets diffuse calcification, and tricuspid aortic valve stenosis (underestimated mean gradient 30 mm Hg, maximum gradient 49 mm Hg). On admission, BNP was 201 pg/ml and NT-proBNP was 1586 pg/ml. The patient was treated with furosemide (bolus 100 mg and infusion 10 mg/h for 48 h) and with low dose nitrates (5 gamma/kg/die for 48 h). After 24 h of infusion, BNP and NT-proBNP slightly decreased to 162 pg/ml and 1033 pg/ml, respectively. In the following days, clinical conditions improved (NYHA class from IV to II) and at chest X-ray there was reduction of infiltrates (Fig. 1, bottom). Moreover, a reduction of pulmonary arterial hypertension (from 70 to 40 mm Hg) and of mitral regurgitation (mild vs moderate to severe) was evident at Doppler echocardiography. Despite this clinical and hemodynamic improvement, on day 7 BNP and NT-proBNP plasma levels increased to 340 pg/ml and 2285 pg/ml, respectively, without significant worsening of renal function (creatinine and creatinine clearance were stable respect to the admission). On day 13, conditions were stable with no signs of congestion or peripheral hypoperfusion but BNP plasma levels further increased (BNP: 360 pg/ml; NTproBNP: 2386 pg/ml) (Fig. 2).
Fig. 1. Top. Chest X-ray of the patient at admission for acute decompensation of chronic heart failure. Bottom. Chest X-ray of the patient after intravenous diuretics and vasodilators.
angiography had excluded significant graft stenosis. Patient was on treatment with furosemide 25 mg/die, potassium canreonate 25 mg/die, and ramipril 7.5 mg/die and had shown a gradual worsening of symptoms in the 2 weeks leading up to admission. On admission, systemic blood pressure was 105/ 60 mm Hg, heart rate 120 b/min in atrial fibrillation; there was no fever. Physical examination revealed bibasilar rales, systolic murmur and third heart sound. Peripheral congestion, hepatomegaly and hepato-jugular reflux were present. Electrocardiogram showed no signs of ischemia. Haemoglobin, leukocytes, C-reactive protein, D-dimer, renal (creatinine 1.08 mg/dl) and hepatic function, serum electrolytes (sodium 146 mEq/l, potassium 3.9 mEq/l), creatine kinase-MB and troponins were within normal range. Chest-X rays showed interstitial infiltrates with pleural effusion at the right lung (Fig. 1, top). Transthoracic echocardiogram showed LV hypertrophy (interventricular septum 16 mm), normal LV volumes (LV end diastolic volume 65 ml/m2), severe LV
Fig. 2. Serial changes in BNP and NT-proBNP plasma levels during hospitalization.
e20
L. Brentana et al. / International Journal of Cardiology 122 (2007) e18–e20
Patient was then submitted to replacement of aortic valve with biological prosthesis, after dobutamine echocardiography that evidenced myocardial contractile reserve, increase in valve gradient with no change in valve area. At six months clinical conditions of patient are stable (NYHA II) and ejection fraction at echocardiogram is 40%. 2. Discussion This patient had the typical characteristics of patients enrolled in clinical studies on acute HF (male sex, mean age 70 years) and promptly responded to medications, but paradoxically his BNP trend showed a strange and unusual behavior: BNP and NT-proBNP were lower during the phase of decompensation of HF and increased after hemodynamic and clinical improvement. A decrease in BNP in patients with end-stage HF has already been described [7,8], possibly reflecting an exhaustion of the ability of cardiomyocytes to synthesize and secrete a sufficient amount of natriuretic peptides and/or their increased degradation and/or clearance. In our patient, however, there was LV hypertrophy and there was no extensive myocardial fibrosis nor significant LV enlargement. A possible explanation that support our findings is the high body mass index of the patient (32 kg/ m2). In fact, in obese patients low BNP levels (median value 332 pg/ml) have been reported in the course of decompensated HF that continue to maintain a relation with symptoms and hemodynamic status [9], a correlation not present in our case. The decompensation of chronic HF in our case was related also to the coexistence of moderate aortic stenosis due to significative calcifications of cuspids, associated with possible subendocardial ischemia. It is known that in patients with aortic stenosis BNP correlates with disease severity and with symptoms [10]. In our patient, despite the coexistence of underestimated aortic stenosis, severe LV systolic dysfunction, left atriomegaly (27 cm2) and chronic atrial fibrillation, BNP was low and paradoxically increased after unloading therapy and after improvement in hemodynamic and symptoms. In conclusion, in line with recent sporadic data [7,8], our case report warns against the indiscriminate use of BNP and
tendency to underestimate the clinical evaluation of patients presenting with dyspnea, and highlights the need for larger studies on the role of BNP in acute HF patients with concomitant pathologic conditions like obesity and diabetes mellitus. References [1] Stevenson LW, Tillisch JH, Hamilton M, et al. Importance of hemodynamic response to therapy in predicting survival with ejection fraction less than or equal to 20% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol 1990;66:1348–54. [2] Binanay C, Califf RM, Hasselblad V, et al. ESCAPE Investigators and ESCAPE Study Coordinators. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA 2005;294:1625–33. [3] Temporelli PL, Scapellato F, Corrà U, et al. Chronic mitral regurgitation and Doppler estimation of left ventricular filling pressures in patients with heart failure. J Am Soc Echocardiogr 2001;14:1094–9. [4] Maisel AS, Krishnaswamy P, Nowak RM, et al. Breathing Not Properly Multinational Study Investigators. Rapid measurement of Btype natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. [5] Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 2001;7:21–9. [6] O'Neill JO, Bott-Silvermann CE, McRae AT, et al. B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure. Am Heart J 2005;149:363–9. [7] Packer M. Should B-type natriuretic peptide be measured routinely to guide the diagnosis and management of chronic heart failure? Focused perspective. Circulation 2003;108:2950–295. [8] Miller WL, Burnett Jr JC, Hartman KA, Henle MP, Burritt MF, Jaffe AS. Lower rather than higher levels of B-type natriuretic peptides (NTproBNP and BNP) predict short-term mortality in end-stage heart failure patients treated with nesiritide. Am J Cardiol 2005;96:837–41. [9] Horwich TB, Hamilton MA, Fonarow GC. B-type natriuretic peptide levels in obese patients with advanced heart failure. J Am Coll Cardiol 2006;47:85–90. [10] Gerber IL, Stewart RA, Legget ME, et al. Increased plasma natriuretic peptide reflect symptom onset in aortic stenosis. Circulation 2003;107:1884–90.