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The Acute Effect of Metoprolol upon NT-proBNP Level in Patients with Congestive Heart Failure D. ZDRENGHEA, DANA POP, MARIA ILEA, G. BODISZ, ADINA MĂLAI, M. ZDRENGHEA Deptartment of Cardiology, Rehabilitation
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The Acute Effect of Metoprolol upon NT-proBNP Level in Patients with Congestive Heart Failure D. ZDRENGHEA, DANA POP, MARIA ILEA, G. BODISZ, ADINA MĂLAI, M. ZDRENGHEA Deptartment of Cardiology, Rehabilitation Hospital, Cluj-Napoca, Romania Brain natriuretic peptide (BNP) is a sensitive and specific marker of left ventricular (LV) function. The acute effect of β blockers upon plasma BNP levels in CHF patients has been less studied but it is important because of the initial possible depressing effect upon LV function. Purpose. To investigate the acute effect of oral Metoprolol upon plasma probnp levels in CHF patients. Methods. There were included 56 patients with congestive heart failure, 38 with ischemic heart disease and 18 with idiopathic dilated cardiomyopathy, 40 males and 16 females, aged between 25 and 65 years, who were compared with 19 healthy individuals, 12 males and 7 females, of the same age. All patients were free of beta blockers treatment. Plasma Nt-proBNP was determined in fasting state using ELISA method (NV 250 fmol/ml). After this, every patient received 50 mg Metoprolol succinate and at three hours (considered as peak plasmatic concentration) venous blood samples were again obtained and Nt-proBNP determined. Results. NT-pro BNP was increased (1400±130 fmol/ml) in heart failure patients and normal (187±17.2 fmol/ml) in healthy controls. After Metoprolol the plasmatic level of NT-proBNP was not significantly different in both healthy controls (162±13.3 fmol/ml) and heart failure patients (1419±133 fmol/ml) in comparison with baseline values. After Metoprolol NT-proBNP decreased (from 1266±121 to 1120±107, p 0.05) in III NYHA class patients and increased (from 1457±142 to 1530±150, p 0.05) in IV NYHA class patients. It remained unchanged in patients with LVEF 30% (1384±140 vs 1389±129 fmol/ml) and increased (from 1480±134 to 1690±161 fmol/ml, p 0.05) in patients with LVEF 30%; it was not significantly modified in patients with atrial fibrillation in comparison with those in sinus rhythm (1348±132 vs 1516±168 fmol/ml). Conclusion. Beta blockers do not have a severe depressant effect on left ventricular performance in all patients with systolic heart failure. A LVEF 30% suggests, but the lack of modification of NT-proBNP levels after administration of 50 mg Metoprolol confirm, that the beta blocking treatment can be initiated with higher doses than those recommended until now. Key words: brain natriuretic peptide, beta-blockers, congestive heart failure. Brain natriuretic peptide (BNP) represents a quick and sensitive marker for the changes of left ventricular performance, increasing at rest and during exercise in patients with congestive heart failure [1][2]. BNP also increases in acute heart failure, representing a useful diagnostic tool and, at the same time, is used in the follow-up and proving the efficacy of the applied emergency treatment [1][3]. The effect of beta blockers upon plasmatic level of BNP was studied during short and long time treatment, the first one increasing cardiac peptides and the second one decreasing them in relationship with improvement of left ventricular performance [4][5]. Cardiac peptides increase during exercise in heart failure patients, but also in healthy people [1 3]. This seems to support the idea that in heart failure patients the treatment with beta blockers has to be initiated with very small doses. On the other hand, in clinical practice, mainly in patients with atrial fibrillation, it is often necessary to administrate higher doses of beta blockers, doses as high as mg Metoprolol/ day being recommended [6]. Thus, the aim of the present study is to investigate the acute effect of beta blockers upon BNP in heart failure patients, a subject that was less studied until now, even if it has important clinical implications, because of the initial possible depressant effect upon left ventricular function. MATERIAL AND METHOD In the present study there were included 56 patients with congestive heart failure, 38 with ROM. J. INTERN. MED., 2009, 47, 1, 35 40 36 D. Zdrenghea et al. 2 ischemic heart disease and 18 with idiopathic dilated cardiomyopathy, 40 males and 16 females, aged between 25 and 65 years, who were compared with 19 healthy individuals, 12 males and 7 females of the same age. The diagnosis was sustained on a clinical and echocardiographic (2D) basis, with LVEF 40%, which was also the inclusion criteria in the heart failure group. All patients were free of beta blockers treatment during the last month before the study and they received no treatment on the examination day. Plasma NT-proBNP was determined in fasting state using ELISA method (NV 250 fmol/ml). After this, every patient received 50 mg Metoprolol succinate and at three hours (considered as peak plasmatic concentration) venous blood samples were again obtained and NT-proBNP determined. In all patients there were also considered NYHA class (33 patients in class III NYHA and 23 in class IV NYHA), LVEF ( 30% in 38 patients and 30% in 18 patients) and atrial fibrillation (noted in 30 patients). STATISTICAL ANALYSIS The data were analyzed using SPSS 8.0 for Windows. We calculated mean and standard deviation for normal distributed quantitative variables. Differences between quantitative variables were examined using Student test (independent-sample T test), and for qualitative variables we used χ 2 test. A p value less than 0.05 was considered significant from the statistical point of view. RESULTS At the initial determination (Fig. 1) NT-proBNP was increased in heart failure patients (1400± 130 fmol/ml) and normal in healthy controls (187± 17.2 fmol/ml).to prove the effect of Metoprolol, blood pressure and heart rate were measured before and three hours after Metoprolol administration. Blood pressure decreased insignificantly from 111±10.2 to 105±10.1 mmhg in heart failure patients and increased insignificantly from 128±1.7 to 130±12.2 mmhg in healthy controls. In turn, in heart failure patients was registered an important decrease of the heart rate from 98±8.7 to 72±6.2 bpm (p 0.01), the decreasing being much less in healthy controls (74±6.5 to 64±6.9 bpm, p 0.05). The decrease in heart rate proves, in the absence of the determination of the plasmatic concentration, that Metoprolol was efficient and the modification of the plasmatic concentration of NT-proBNP can be attributed to it. At three hours after Metoprolol administration in both, healthy controls and heart failure patients, the plasmatic concentration of NT-proBNP was not significantly different (162±13.3 fmol/ml in healthy controls and 1419±133 fmol/ml in heart failure patients) in comparison with the baseline values (p 0.05). p ±133 baseline after Metoprolol 1400± ± ±15.3 CHF HC Fig. 1. NT-proBNP levels in healthy controls versus heart failure patients. 3 Effect of Metoprolol on congestive heart failure 37 The individual analysis showed that NTproBNP values remained the same in three patients (3900±371 fmol/ml), increased in 32 patients (from 1236±112 fmol/ml to 1426±131 fmol/ml, p 0.03) and decreased in 21 patients (from 1418±120 fmol/ml to 858±79 fmol/ml, p 0.03). When we took into consideration the NYHA class, NT-proBNP decreased in NYHA III patients (from 1266±121 to 1120±107 fmol/ml, p 0.05) and increased (from 1457±142 to 1530±150 fmol/ml, p 0.05) in NYHA IV class patients. With respect to the relationship between NTproBNP and LVEF, in patients with LVEF 30%, NT-proBNP increased from 1480±134 to 1690± 161 fmol/ml, p 0.05, but remained unchanged in patients with LVEF 30% (1384±140 vs 1389± 129 fmol/ml). Finally, in atrial fibrillation patients NTproBNP increased insignificantly from 1265±124 to 1348±132 fmol/ml and decreased insignificantly in patients in sinus rhythm (from 1587±149 to 1516±168 fmol/ml, p 0.05). Also, after Metoprolol NT-proBNP values were significantly higher in patients with IV NYHA class, atrial fibrillation or LVEF 30% in comparison with III NYHA class patients, patients in sinus rhythm or LVEF 30% (Fig. 2). % variation of NT-pro BNP * 5 * 6.56 * % * p 0.05 NYHA III NYHA IV FiA - FiA + FE 30% FE 30% Fig. 2. NT-pro BNP levels percent variation after administration of Metoprolol in relationship with some severity parameters. DISCUSSION The increased mean plasmatic level of NTproBNP proves again its value for the diagnosis and evaluation of heart failure patients [7 9]. The plasmatic values of NT-proBNP, almost six times more than normal, can be attributed to the generally severe depression of the left ventricular systolic function in patients with dilated cardiomyopathy and to the fact that all patients were included in NYHA class III or IV. More important for the purpose of the present study is the acute effect of a mild dose of Metoprolol (50 mg) upon NT-proBNP plasmatic level. As we already showed, the highly significant decrease of heart rate in dilated cardiomyopathy patients proved, indirectly but strongly, that at three 38 D. Zdrenghea et al. 4 hours after administration, plasmatic Metoprolol concentration was in the therapeutic range. In turn, NT-proBNP levels were not significantly modified in both, heart failure patients and healthy controls, even if they slightly increased in heart failure patients and slightly decreased in healthy controls. The results support the idea that even such a high initial dose of Metoprolol as 50 mg does not impair the hemodynamic disturbances, intracardiac pressure and stretching in systolic heart failure patients [10 13]. This suggests that, if necessary (high resting heart rate, rapid rate atrial fibrillation, arrhythmias), or even as a routine protocol, beta blocker treatment, mainly with Metoprolol, can be initiated using higher doses than those recommended until now, without any major detrimental effect upon the haemodynamic status of the patient [15 20]. Thus, it will be possible to reach earlier the effective and optimal therapeutic dose to control heart rate and to improve the evolution and survival of the patients during long term treatment [5][6][12][13 15]. At the same time, the individual analysis of the results showed that, if in about 46% of the patients, Metoprolol did not increase the NTproBNP plasmatic level, in 54% of them NTproBNP significantly increased, probably due to the depression of the left ventricular systolic function caused by the beta blockade. This hypothesis is sustained by the significant increase of the NT-proBNP level in NYHA IV patients in comparison with NYHA III patients in whom NT-proBNP slightly decreases after Metoprolol. Metoprolol did not significantly modify NTproBNP in the 39 patients with LVEF 30%, but increased it in the 19 of them with LVEF 30%. At a first view the above data are not sustained by the atrial fibrillation patients in whom the NT-proBNP plasmatic levels, before and after Metoprolol, are smaller than in patients in sinus rhythm. But it is necessary not to forget that atrial fibrillation increases mainly ANP synthesis and that lowering the heart rate in atrial fibrillation patients results in an improvement of cardiac performance [21 23]. Thus our data supports the recommendation of using high doses of beta blockers ( mg/day for Metoprolol) in rapid rate atrial fibrillation, even in heart failure patients, without a high risk to develop acute heart failure [1][5][24]. In fact, the results suggest that in systolic heart failure patients with moderate depressed systolic function (LVEF between 30 40%) it is possible to initiate beta blocker treatment with higher doses than recommended until now. As for the patients with LVEF less than 30%, the classical protocol has to be used [1][2][5][26][27]. In conclusion, beta blockers do not have a severe depressant effect on left ventricular performance in all patients with systolic heart failure. A LVEF 30% suggests, but the lack of modification of NT-proBNP levels after administration of 50 mg Metoprolol confirm, that the treatment with beta blockers can be initiated with higher doses than those recommended until now. BNP-ul este un marker sensibil şi specific al funcţiei ventriculare stângi (VS). Efectul acut al betablocantelor asupra nivelelor plasmatice ale BNP-ului la pacienţii cu insuficienţă cardiacă cronică (ICC) a fost mai puţin studiat, dar este important datorită posibilului efect depresor iniţial asupra funcţiei VS. Scop. De a studia efectul acut al Metoprololului administrat oral asupra nivelului plasmatic al BNP-ului la pacienţii cu ICC. Metoda. Au fost incluşi 56 de pacienţi cu ICC, 38 cu cardiopatie ischemică şi 18 cu cardiomiopatie dilatativă idiopatică, 40 bărbaţi şi 16 femei, cu vârste cuprinse între 25 şi 65 de ani, care au fost comparaţi cu 19 indivizi sănătoşi, 12 bărbaţi şi 7 femei, de aceeaşi vârstă. Niciun pacient nu era sub tratament cu betablocant. Nivelul plasmatic al NT-proBNP a fost determinat à jeun, folosind metoda ELISA (VN 250fmol/ml). Apoi, fiecare pacient a primit 50 mg Metoprolol succinat şi s-au redeterminat nivelele plasmatice ale NT-proBNP la 3 ore (acesta fiind considerat peak-ul concentraţiei plasmatice). Rezultate. NT-proBNP a fost crescut (1400±130 fmol/ml) la pacienţii cu ICC şi normal (187±17,2 fmol/ml) la subiecţii sănătoşi. După administrarea de 5 Effect of Metoprolol on congestive heart failure 39 Metoprolol nivelele plasmatice ale NT-proBNP nu au diferit semnificativ faţă de cele bazale, atât la pacienţii cu ICC (1419±133 fmol/ml), cât şi la subiecţii sănătoşi (162±13.3 fmol/ml). După Metoprolol NT-proBNP a scăzut (de la 1266±121 la 1120±107 fmol/ml, p 0,05) la pacienţii cu ICC NYHA III şi a crescut (de la 1457±142 la 1530±150 fmol/ml, p 0.05) la cei aflaţi în clasa NYHA IV. NT-proBNP a rămas nemodificat la pacienţii cu FEVS 30% (1384±140 vs 1389± 129 fmol/ml) şi a crescut (de la 1480±134 la 1690±161 fmol/ml, p 0.05) la cei cu FEVS 30%. De asemenea, nivelele NT-proBNP nu au fost semnificativ modificate la pacienţii cu fibrilaţie atrială (1348±132 vs 1516±168 fmol/ml) în comparaţie cu cei aflaţi în ritm sinusal. În concluzie. În administrare acută betablocantele nu au un efect puternic depresor asupra performanţei VS la pacienţii cu ICC. O FEVS 30% sugerează, dar lipsa modificării nivelelor de NT-proBNP după administrarea a 50 mg Metoprolol confirmă faptul că tratamentul betablocant poate fi iniţiat cu doze mai mari decât cele recomandate până acum. Corresponding author: D. Zdrenghea, MD, PhD Rehabilitation Hospital, 46 50, Viilor St., Cluj-Napoca REFERENCES 1. 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