http://informahealthcare.com/ceh ISSN: 1064-1963 (print), 1525-6006 (electronic) Clin Exp Hypertens, 2015; 37(2): 148–154 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/10641963.2014.913611
ORIGINAL ARTICLE
Association of N-terminal pro-brain natriuretic peptide and hemodynamic parameters measured by impedance cardiography in patients with essential hypertension Paweł Krzesin´ski1, Grzegorz Gielerak1, Adam Stan´czyk1, Katarzyna Piotrowicz1, Wiesław Piechota2, and Andrzej Skrobowski1 1
Department of Cardiology and Internal Diseases, Military Institute of Medicine, Warsaw, Poland and 2Department of Laboratory Diagnostics, Military Institute of Medicine, Warsaw, Poland Abstract
Keywords
The aim of this study was to evaluate the association of NT-proBNP with clinical and hemodynamic assessment in 156 patients with arterial hypertension. NT-proBNP correlated positively with, i.e. age (r ¼ 0.310, p ¼ 0.00008), mean blood pressure (MBP; r ¼ 0.199, p ¼ 0.0136), Heather index (HI; r ¼ 0.375, p50.00001) and negatively with thoracic fluid content (TFC; r ¼ 0.300, p ¼ 0.0002). The patients with higher NT-proBNP were older (46.1 versus 40.6 years, p ¼ 0.001), with higher MBP (102.6 versus 98.5 mm Hg, p ¼ 0.0043), HI (14.54 versus 11.93 Ohm s2, p ¼ 0.009) and lower TFC (27.5 versus 29.4 1/kOhm, p ¼ 0.0032). The independent predictors of higher NT-proBNP were: age, MBP and HI.
Amino-terminal pro-brain natriuretic peptide, cardiovascular system, hemodynamics, hypertension, impedance cardiography
Introduction Natriuretic peptides (NP) are cardiac neurohormones released from the heart chambers in response to ventricular expansion and pressure overload. N-terminal pro-brain natriuretic peptide (NT-proBNP) is aminoterminal fragment of brain natriuretic peptide (BNP), more useful in laboratory testing because of longer half-life (1,2). The elevation of serum concentration of NP has been observed both in patients with impaired and preserved left ventricular systolic function, especially those with heart failure (HF) (3). High NT-proBNP confirmed to be related not only to preload but also to increased afterload, especially high blood pressure (BP) and arterial stiffness (4). Therefore, NT-proBNP was also tested in patients with arterial hypertension (AH) revealing to be a marker of impaired diastolic function and left ventricular hypertrophy (4,5). In some studies, NT-proBNP was also identified as cardiovascular risk factor in hypertensive population (6,7). Most studies on patients on AH concentrated on relationship between NP and echocardiographic measurements, especially left ventricular mass index (LVMI), and markers of diastolic dysfunction derived from mitral flow analysis and tissue Doppler imaging (TDI) (5,8), confirmed
Correspondence: Paweł Krzesin´ski, Department of Cardiology and Internal Diseases, Military Institute of Medicine, Szasero´w Street 128, 04-141 Warsaw 44, Poland. Tel: +48226816389. Mob: + 48606939390. Fax: +48228108089. E-mail: [email protected]
History Received 21 February 2014 Revised 18 March 2014 Accepted 23 March 2014 Published online 30 April 2014
in magnetic resonance imaging (9,10). However, these techniques have limitations in the assessment of ventricularvascular interactions. The current guidelines for HF management indicate the value of NT-proBNP5125 pg/ml as cut-off point for the exclusion of HF (3). However, it does not mean that lower values of NT-proBNP are accidental and do not have any clinical significance. NT-proBNP seems to present potency of explaining the complex pathophysiology of left ventricle (LV) overload, especially in hypertensive patients. Since NT-proBNP revealed to be diagnostic in pre-hypertension as well as in assessing the risk of diastolic HF (5), even its relatively low serum concentration may bring valuable pathophysiological information. In order to explore this scientific subject, NT-proBNP should be confronted with complex assessment providing data on preload, afterload, ventricular outflow and aortic compliance. Therefore, impedance cardiography (ICG), a non-invasive method of hemodynamic evaluation, was used in this study. This simple method has recently proved to be useful in diagnosis and treatment of patients with HF and AH (11,12). Potency of ICG to estimate, i.e. thoracic fluid content (TFC), stroke volume, systemic vascular resistance, ejection blood flow parameters and aortic compliance justified stating the hypothesis that its confrontation with NT-proBNP can result in interesting conclusions. The aim of the retrospective analysis presented in this article was to evaluate association of NT-proBNP with hemodynamic parameters measured by ICG.
NT-proBNP and hemodynamics in hypertension
DOI: 10.3109/10641963.2014.913611
Methods Study population This study included 156 patients (115 men; mean age 43.3 ± 10.5 years) with at least 3-month history of mild or moderate AH defined according to European Society of Cardiology guidelines (13). Exclusion criteria comprised: (i) confirmed secondary AH, (ii) improperly controlled AH with three or more medicines, (iii) heart failure, (iv) cardiomyopathy, (v) significant heart rhythm disorders, (vi) significant valvular disease, (vii) kidney failure, (viii) chronic obstructive pulmonary disease, (ix) diabetes, (x) polyneuropathy, (xi) peripheral vascular disease and (xii) age518 years and465 years. The group selected to the analysis comprised patients with AH from two clinical studies performed in the Department of Cardiology and Internal Diseases of Military Institute of Medicine from March 2008 to May 2012. Both studies were conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki, with the approval of local ethics committee (no 3/WIM/2008 and no 44/WIM/2010). Each patient provided written informed consent to participate in the study. Demographic and clinical characteristics of the study group are shown in Table 1. Clinical examination Clinical examination was performed with special consideration of familiar history of AH, cardiovascular risk factors and symptoms indicating secondary cause of AH. Office blood pressure measurement (Omron M4 Plus, Japan) was performed by technique compliant with European Society of Cardiology guidelines (13). Laboratory tests included, i.e. evaluation of renal function (creatinine, glomerular filtration rate) and metabolic disturbances. Echocardiography Two-dimensional echocardiography was performed using standard parasternal, apical and subcostal views (VIVID S6 Medical System, 2.5 MHz transducer). The left ventricular hypertrophy was diagnosed according to the ASE-recommended formula for estimation of LV mass from 2D linear LV
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measurements and indexed to body surface area (cut-off values for men LVMI4115 g/m2, for women495 g/m2). The assessment of diastolic dysfunction was performed according to current guidelines (14,15). Impedance cardiography All ICG measurements were performed using the NiccomoÔ device (Medis, Ilmenau, Germany) after 10 min of rest in a supine position. Data were recorded during a 10-min assessment and exported to a dedicated software (Niccomo Software, Ilmenau, Germany). The final analysis included mean values of hemodynamic parameters from each 10-min recording such as: systolic blood pressure (SBP, [mm Hg]); diastolic blood pressure (DBP, [mm Hg]); mean blood pressure (MBP [mm Hg]); pulse pressure (PP, [mm Hg]), calculated as PP ¼ SBP DBP; heart rate (HR, [bpm]; left ventricular ejection time (LVET, ms), the interval between opening and closing of the aortic valve; stroke index (SI, [ml m2]); calculated using the Sramek and Bernstein formula SI ¼ VEPT dZmax Z01 LVET BSA1, accounting for weight, height and gender (variable VEPT), the amplitude of the systolic wave of the ICG (dZmax), LVET and body surface area (BSA); cardiac index (CI, [ml m2 min1]), calculated as CI ¼ SI HR; end diastolic index (EDI, [ml m2]); acceleration time index (ACI, [100 s2]), stating for maximum acceleration of blood flow between aortic valve opening and C-point of ICG wave – ACI ¼ 100 dZmax dt1; velocity index (VI, [1000 s1]): VI ¼ 1000 dZmax Z01; Heather index (HI, [Ohm s2]), a derivate of TRC, the time interval between the R-peak of the ECG and the time of dZmax, called C-point of ICG wave HI ¼ dZmax TRC, characterizing the maximum contraction force of the left ventricle and corresponding to cardiac inotropism; TFC (1 kOhm1), calculated from basic impedance (Z0) as its converse: TFC ¼ 1000 Z01; systemic vascular resistance index (SVRI, [dyn s cm5 m2]); SVRI ¼ 80 [MBP CVP] CI1, where CVP is central venous pressure (assumed value 6 mm Hg); total arterial compliance (TAC, ml/mm Hg), TAC ¼ SV PP1. NT-proBNP (N-terminal pro-brain natriuretic peptide) NT-proBNP was estimated with Roche Diagnostics ElecsysÕ proBNP Assay (Mannheim, Germany). Only patients with NT-proBNP5125 pg/ml were considered to the analysis.
Table 1. Basic clinical characteristics. Study group (n ¼ 156) Men, n (%) Age (years), mean ± SD BMI (kg/m), mean ± SD Office SBP (mm Hg), mean ± SD Office DBP (mm Hg), mean ± SD HR (1/min), mean ± SD Metabolic syndrome, n (%) Smoking, n (%) Family history of AH, n (%) Left ventricular hypertrophy, n (%) Impaired relaxation of left ventricle, n (%) Creatinine (mg/dl), mean ± SD GFR (ml/min 1.73 m2), mean ± SD
115 (73.7) 43.3 ± 10.5 29.1 ± 4.1 146.5 ± 14.0 93.8 ± 8.6 70.5 ± 10.4 96 (61.5) 35 (22.4) 93 (59.6) 30 (19.2) 35 (22.4) 0.855 ± 0.140 99.4 ± 18.5
AH, arterial hypertension; BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; SD, standard deviation.
Statistical analysis The statistical analysis of the results was performed using Statistica 7.0 (StatSoft, Inc., Tulsa, OK). The distribution and normality of data were assessed by visual inspection and using the Shapiro–Wilk test. Continuous variables were presented as means ± SDs and categorical variables as absolute and relative frequencies (percentages). Assessment of relations between NT-proBNP and other parameters was performed using univariate linear regression. Then the most correlated and representative variables were included in multivariate linear regression model. In second part of the analysis, between-group comparisons were performed using t-Student’s test for normally distributed data and
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non-parametric tests for data that did not show a normal distribution. Then the most representative variables were included in logistic regression model. A p value of50.05 was taken to indicate statistical significance.
Multivariate linear regression The most correlated and representative variables (age, gender, creatinine, MBP, HI and TFC) were included in multivariate linear regression model. The analysis revealed that age, MBP
Results Univariate linear regression The mean value of NT-proBNP in study group was 38.3 pg/ml (range: 5.0–103.2 pg/ml). An univariate linear regression analysis demonstrated that NT-proBNP correlated positively with age, SBP, MBP, SI, CI, ACI, VI, HI, LVET, EDI, creatinine and negatively with TFC – Table 2 and Figures 1–4. No significant relation with BMI, DBP, PP, HR, SVRI, TAC and GFR was observed.
Table 2. Correlations between NT-proBNP and other parameters.
NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP
versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus
age BMI SBP DBP MBP PP HR SI CI SVRI ACI VI HI LVET TFC EDI TAC creatinine GFR
R
p
0.310 0.119 0.210 0.121 0.199 0.131 0.019 0.218 0.196 0.079 0.225 0.248 0.375 0.197 0.300 0.183 0.006 0.203 0.075
0.00008 NS 0.0093 NS 0.0136 NS NS 0.0065 0.0151 NS 0.0051 0.0020 0.000002 NS 0.00018 0.0228 NS 0.015 NS
Figure 2. Correlation between NT-proBNP and MBP.
ACI, acceleration time index; CI, cardiac index; DBP, diastolic blood pressure; EDI, end diastolic index; HI, Heather index; HR, heart rate; LVET, left ventricular ejection time; MBP, mean blood pressure; NS, non-significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; PP, pulse pressure; SBP, systolic blood pressure; SI, stroke index; SVRI, systemic vascular resistance index; TAC, total arterial compliance; TFC, thoracic fluid content; VI, velocity index.
Figure 3. Correlation between NT-proBNP and TFC.
Figure 1. Correlation between NT-proBNP and age.
Figure 4. Correlation between NT-proBNP and HI.
NT-proBNP and hemodynamics in hypertension
DOI: 10.3109/10641963.2014.913611
and HI independently correlated to NT-proBNP. The multiple regression model (R squared value of 0.227) with these explanatory variables was: ½NT-proBNP ¼ 0:74 ½age þ 1:83 ½HI þ 0:48 ½MBP 65:55 Therefore, in the above model, the most pronounced influence on NT-proBNP was observed for unitary change in HI, less – in MBP and age (change of 1 Ohm s2 equals to 3.81 mm Hg and 2.47 years). However, the analysis of contribution power of these variables has to consider different data distribution, order of magnitude and range of potential change (for HI: mean 13.3 ± 4.9, 95% CI: 12.5–14.0, range: 4.7–32.6 Ohm s2; for MBP: mean 100.6 ± 8.8, 95% CI: 99.2–102.0, range: 81–127 mm Hg; for age: mean 43.3 ± 10.5, 95% CI: 41.7– 45.0, range: 19–65 years). Subgroup comparison based on NT-proBNP In further analysis, basing on the value of median NT-proBNP (31.8 pg/ml), the study group was divided into two subgroups: (1) ‘‘low normal’’ NT-proBNP – LN_NTproBNP (531.8 pg/ ml) and (2) ‘‘high normal’’ NT-proBNP – HN_NTproBNP (431.8 pg/ml). These comparative analysis confirmed significant differences in hemodynamic parameters between patients with lower and higher normal values of NT-proBNP – Table 3. Logistic regression The most representative variables (age, gender, creatinine, MBP, HI and TFC) were included in logistic regression model with NT_proBNP category as dependent binary variable (LN_NTproBNP and HN_NTproBNP) that revealed three
independent predictors of ‘‘high’’ NT-proBNP (2 ¼ 36.37, p50.00005): age (OR 1.05, 95% CI: 1.01–1.09, p ¼ 0.02), MBP (OR 1.06, 95% CI: 1.01–1.11, p ¼ 0.0096), HI (OR 1.14, 95% CI: 1.04–1.26, p ¼ 0.005). Those results were compatible with multivariate linear regression model presented above.
Discussion Presented results revealed that even in range of low values the level of NT-proBNP is not just a case of accidental distribution. In our study, we consciously included only patients with NT-proBNP5125 pg/ml to avoid potential bias of subclinical HF. Therefore, the mean value (38.3 pg/ml) and median (31.8 pg/ml) in the study group was rather low. Nonetheless, it discriminated patients with different hemodynamic profiles. The accuracy of low values of NP to detect abnormalities in morphology and hemodynamic function of heart muscle was confirmed in some studies. Mueller et al. (16) defined NT-proBNP level of 39 pg/ml as high sensitive (90%) in detection of cardiac structural diseases in echocardiography. Lubien et al. (8) used a cut-off value of BNP 62 pg/ml to discriminate patients with diastolic dysfunction with sensitivity of 85% and specificity of 83%. Karaca et al. (17) observed even better accuracy of cut-off value of 37 pg/ml (respectively 80% and 100%). Wei et al. (18) reported high diagnostic value of BNP440 pg/ml in the assessment of left ventricular end diastolic diameter (LVEDD). However, in our study we aimed to confront NT-proBNP with multiparametric noninvasive hemodynamic assessment by ICG that revealed to be complementary tool in evaluation of subtle pathophysiology of LV overload in hypertensive patients. It confirmed some previous observations and revealed new interesting interactions.
Table 3. Comparison between LN_NTproBNP and HN_NTproBNP subgroups. Parameters Age (years), mean ± SD Male (n, %) BMI (kg/m2), mean ± SD SBP (mm Hg), mean ± SD DBP (mm Hg), mean ± SD MBP (mm Hg), mean ± SD PP (mm Hg), mean ± SD HR (bpm), mean ± SD SI (ml m2), mean ± SD CI (ml m2 min1), mean ± SD SVRI (dyn s cm5 m2), mean ± SD ACI (100 s2), mean ± SD VI (1000 s1), mean ± SD HI (Ohm s2), mean ± SD LVET (ms), mean ± SD TFC (1 kOhm1), mean ± SD EDI (ml m2), mean ± SD TAC (ml/mm Hg), mean ± SD Left ventricular hypertrophy (n, %) Impaired relaxation of left ventricle (n, %) Creatinine (mg/dl), mean ± SD GFR (ml/min 1.73 m2), mean ± SD
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LN_NTproBNP (n ¼ 78)
HN_NTproBNP (n ¼ 78)
p
40.6 ± 11.5 70 (89.7) 29.6 ± 4.2 134.5 ± 10.4 87.0 ± 7.9 98.5 ± 8.3 47.5 ± 6.7 71.5 ± 11.4 46.0 ± 8.0 3.24 ± 0.53 2362.6 ± 476.1 65.1 ± 24.1 41.8 ± 12.8 11.93 ± 4.31 311.4 ± 38.0 29.4 ± 3.8 72.1 ± 10.4 2.06 ± 0.46 17 (21.8) 14 (18.0) 0.887 ± 0.118 100.9 ± 19.0
46.1 ± 8.7 45 (57.7) 28.7 ± 4.1 140.0 ± 13.6 89.3 ± 8.5 102.6 ± 8.8 50.2 ± 10.0 69.4 ± 9.2 50.1 ± 9.4 3.42 ± 0.51 2327.4 ± 463.1 71.9 ± 23.9 46.4 ± 12.6 14.54 ± 5.11 326.9 ± 35.2 27.5 ± 4.2 78.2 ± 13.7 2.05 ± 0.55 18 (23.1) 16 (20.5) 0.823 ± 0.154 97.9 ± 18.0
0.00096 0.00005 NS 0.0076 NS 0.0043 NS NS 0.0041 0.0317 NS 0.0377 0.0087 0.00034 0.007 0.0032 0.002 NS NS NS 0.014 NS
ACI, acceleration time index; CI, cardiac index; DBP, diastolic blood pressure; EDI, end diastolic index; HI, Heather index; HR, heart rate; LVET, left ventricular ejection time; MBP, mean blood pressure; NS, non-significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; PP, pulse pressure; SBP, systolic blood pressure; SI, stroke index; SVRI, systemic vascular resistance index; TAC, total arterial compliance; TFC, thoracic fluid content; VI, velocity index.
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NT-proBNP and afterload NT-proBNP correlated with parameters characterizing afterload (SBP, DBP and MBP). The positive relation with MBP suggests that resistance of small arteries had higher input to afterload than stiffness of large arteries (characterized by PP and TAC). These results are only partly consistent with observations of Huang et al. (19) that related positive correlation of impaired aortic elasticity with NT-proBNP. This discrepancy can be explained by different characteristics of patients in the area of age, lower office blood pressure and antihypertensive treatment influencing peripheral resistance (i.e. angiotensin converting enzyme inhibitors and calcium channel blockers). It probably reflects the different mechanism responsible for increased afterload depending on age. Among younger hypertensives large arteries are relatively compliant and increased afterload is mostly provoked by functional impairment of small resistance arteries. The arterial stiffness is more pronounced in older hypertensives (20). The association of age-related arterial stiffness with NP levels has also been observed in healthy men which confirms the influence of vascular remodeling on LV hemodynamics (20,21). NT-proBNP, preload and cardiac contractility The observation that NT-proBNP is related to parameters characterizing LV function as a blood pump seems especially valuable. The most convincing positive correlations were observed for HI, VI and ACI, parameters describing the rapidity of blood outflow from LV to the aorta. NT-proBNP was also higher in patients with longer LVET and higher SI (and consequently CI). Since some of these parameters have also its ‘‘volume’’ component (dZmax), this observation suggests that NT-proBNP increases in case of higher LV fluid overload and contractility. Higher EDI in HN_NTproBNP group suggests influence of relative LV volume overload on NT-proBNP. These observations confirm the well-known mechanism of NP release provoked by elevated LV diastolic pressure and myocitic stretch (22). Higher EDI and SI suggest that intravascular fluid overload does not impair LV ejection function in this group of patients. On the contrary, it contributes to higher LV outflow – the increase of SI seems to be a response of elastic LV to cardiac preload. This mechanism aims at maintaining normal left atrial (LA) pressure (22). However, it has to be underlined that such hemodynamic profile can evolve to defective active relaxation, increased LA pressure and pulmonary congestion. In the first stage of LV dysfunction, fluid overload can become ‘‘symptomatic’’ only during high exercise stress when LV pressures increase (23). Over time, such patients can present typical symptoms of HF (5). HF patients with significantly impaired systolic function and increased preload operate on the flat and descending portion of the Frank– Starling curve, when every increase in preload contributes to relevant increase in LVEDD and decrease of CI (24). NT-proBNP and chest fluid Negative correlation of NT-proBNP with TFC is not easy to interpret. Higher EDI in HN_NTproBNP subgroup provokes
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expectation that total fluid in the thorax should also be higher. However, this way of deduction assumes similar hemodynamic pattern for HF and uncomplicated AH that can be misleading. In fact, chronic elevation of LV pressures and its distension in HF patients provokes continuous release of NP. However, their compensatory action is insufficient and does not bring desirable hemodynamic effects. Velazquez-Cecena et al. (25) observed that HF patients with higher TFC and lower SI (the group at increased risk of decompensation) had higher BNP and LV end diastolic pressure. Likewise, Feliciano et al. (26) revealed positive correlation of NT-proBNP with TFC (r ¼ 0.649, p50.0001) and negative with SI (r ¼ 0.324, p ¼ 0.016) in group of 55 HF patients (mean EF 24.7%). Havelka et al. (27) observed positive relation of BNP and TFC (r ¼ 0.32, p ¼ 0.02) in patients presenting dyspnoea at emergency departments. Moreover, TFC revealed to be a powerful predictor of BNP level and outcome in patients with acute HF discharged from hospital (28). However, Banak et al. (29) indicated that relation of TFC and BNP depended on patient’s clinical status and volemia. Although correlation was significant for whole study group (r ¼ 0.57, p ¼ 0.001), after excluding patients with exacerbation of HF symptoms it revealed to be non-significant (r ¼ 0.24, p ¼ 0.22). Moreover, there was no such association in healthy controls (r ¼ 0.17, p ¼ 0.51). Thus, in HF patients NT-proBNP seems to be a marker of severely impaired hemodynamics (especially LV end-diastolic pressure and increased pulmonary wedge pressure), increasing along with fluid retention and deterioration of cardiac output. In contrary, the observations from our study are opposite – TFC was lower in HN_NTproBNP subgroup. This phenomenon can be explained by the physiological action of NP which effectively stimulates natriuresis, diuresis and vasodilatation in uncomplicated AH. Higher blood pressure and LV overload can trigger NP release that effects in compensatory mechanism, mostly fluid loss. Plasma BNP acts against vasoconstriction, sodium retention and antidiuretic effects of activated renin–angiotensin–aldosterone system (30). However, in case of higher resistance of small artery vessels intravascular bed remains limited. Therefore, the hemodynamic pattern reveals relatively lower extravascular fluid (component of TFC) than heart and vascular plasma volume (EDI and SI). NT-proBNP and other assessed parameters Our results confirmed previous relation of NT-proBNP to age and its higher concentration in women (31,32). CostelloBoerrigter et al. (33) observed that serum concentration of NT-proBNP is even three times greater in normal women than men and increases with age of 10–20 pg/ml per decade. However, opposite to some researchers, we did not observe the association with BMI (34). The correlation with creatinine was not reflected in glomerular filtration rate (GFR) which can be explained by older age of patients with higher NT-proBNP (GFR was calculated from MDRD formula). Exclusion criteria in our study limited the bias of other factors influencing NP levels, however, they must be considered in any clinical case (valvular heart disease, arrhythmia, ischemic heart disease, renal impairment, lung diseases and sepsis) (1,4).
DOI: 10.3109/10641963.2014.913611
NT-proBNP as a marker of hemodynamic profile The composite analysis of hemodynamics and NT-proBNP in patients with AH revealed very interesting observations. In young- and middle-aged hypertensives, higher NT-proBNP seems to respond both to the increased afterload and preload. However, it also corresponds with heart muscle contractility and effects in lower total fluid accumulation in the chest. It may suggest that in this group of patients NT-proBNP is a marker of compensatory mechanism that works quite effectively against LV overload. In patients with AH, the NP levels should be interpreted with awareness of its physiological role. Our results suggest that NT-proBNP level should be concerned in view of patients’ clinical state. It can suggest HF in case of dyspnea, but in AH without HF symptoms it can just be a marker of specific hemodynamic profile and activated neurohormonal response to LV overload. In such cases, ICG can be a valuable diagnostic support. The unique value of our study is that by including patients with untreated AH we avoided significant bias of hypotensive therapy which can influence NT-proBNP levels (4). Practical implications of regression models Our multivariate regression model only in low percentage (27.8%) explains NT-proBNP values, which indicates more complex mechanism of its release. However, it suggests that in coincidence with older age, higher MBP and HI, the value of NT-proBNP can even exceed 125 pg/ml (cut-off point for HF exclusion). On the other hand, ‘‘high normal’’ NT-proBNP with low MBP, low HI and younger age should provoke more detailed diagnostics aimed at detecting other potential causes of increased NT-proBNP. Also, logistic regression model confirmed independence of age, MBP and HI as predictors of ‘‘high normal’’ NT-proBNP. However, the interpretation of these results should be very cautious because of some obvious limitations. Being aware that our model is limited to specific population we suggest further studies aimed at creating models of higher predictive values. Limitations The authors are aware that the small sample size and the retrospective design limit the study. The most relevant statistical limitation is interdependence of some ICG parameters caused by formulas for their calculation that include the same variables (i.e. Z0 and dZmax). Therefore, the variables selection to multivariate models is restricted and must be carefully considered. Also, for this reason, we do not present correlations between these parameters to avoid potential mathematical bias. Lack of difference between subgroups in the area of LV hypertrophy and impaired relaxation do not exclude the potential association of NT-proBNP with detailed echocardiographic parameters that characterize LV morphology and hemodynamics. Such assessment was not the object of this study and should be further explored.
Conclusions In patients with AH, ICG and NT-proBNP revealed to be complementary methods in the assessment of hemodynamic coupling between left ventricle and vascular bed.
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The performed analysis revealed interesting relations describing complex pathomechanism connected with hemodynamic disturbances in AH. In patients with AH, serum concentration of NT-proBNP and ICG measurements can complete patient’s evaluation providing additional important clinical information.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. The study was supported by Military Institute of Medicine, Warsaw, Poland (grant no 69/WIM).
References 1. McCullough PA, Neyou A. Comprehensive review of the relative clinical utility of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide assays in cardiovascular disease. Open Heart Fail J 2009;2:6–17. 2. Ceyhan C, Unal S, Yenisey C, et al. The role of N terminal probrain natriuretic peptide in the evaluation of left ventricular diastolic dysfunction: correlation with echocardiographic indexes in hypertensive patients. Int J Cardiovasc Imaging 2008;24:253–9. 3. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69. 4. Bricca G, Lantelme P. Natriuretic peptides: ready for prime-time in hypertension? Arch Cardiovasc Dis 2011;104:403–9. 5. Parekh N, Maisel AS. Utility of B-natriuretic peptide in the evaluation of left ventricular diastolic function and diastolic heart failure. Curr Opin Cardiol 2009;24:155–60. 6. Pedersen F, Raymond I, Kistorp C, et al. N-terminal pro-brain natriuretic peptide in arterial hypertension: a valuable prognostic marker of cardiovascular events. J Card Fail 2005; 11(5 Suppl):S70–5. 7. Olsen MH, Wachtell K, Tuxen C, et al. N-terminal pro-brain natriuretic peptide predicts cardiovascular events in patients with hypertension and left ventricular hypertrophy: a LIFE study. J Hypertens 2004;22:1597–604. 8. Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595–601. 9. Hildebrandt P, Boesen M, Olsen M, et al. N-terminal pro brain natriuretic peptide in arterial hypertension – a marker for left ventricular dimensions and prognosis. Eur J Heart Fail 2004;6: 313–17. 10. Morillas P, Castillo J, Quiles J, et al. Usefulness of NT-proBNP level for diagnosing left ventricular hypertrophy in hypertensive patients. A cardiac magnetic resonance study. Rev Esp Cardiol 2008;61:972–5. 11. Packer M, Abraham WT, Mehra MR, et al. Utility of impedance cardiography for the identification of short-term risk of clinical decompensation in stable patients with chronic heart failure. J Am Coll Cardiol 2006;47:2245–52. 12. Krzesin´ski P, Gielerak GG, Kowal JJ. A ‘‘patient-tailored’’ treatment of hypertension with use of impedance cardiography: a randomized, prospective and controlled trial. Med Sci Monit 2013; 19:242–50. 13. Mancia G, De Backer G, Dominiczak A, et al. The task force for the management of arterial hypertension of the european society of hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. 14. Lang RM, Bierig M, Devereux RB, et al. American Society of Echocardiography’s Nomenclature and Standards Committee, Task Force on Chamber Quantification, American College of Cardiology Echocardiography Committee, American Heart Association, European Association of Echocardiography, European Society of Cardiology Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108.
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P. Krzesin´ski et al.
15. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165–93. 16. Mueller T, Gegenhuber A, Dieplinger B, et al. Capability of B-type natriuretic peptide (BNP) and amino-terminal proBNP as indicators of cardiac structural disease in asymptomatic patients with systemic arterial hypertension. Clin Chem 2005;51:2245–51. 17. Karaca I, Gu¨lcu¨ E, Yavuzkir M, et al. B-type natriuretic peptide level in the diagnosis of asymptomatic diastolic dysfunction. Anadolu Kardiyol Derg 2007;7:262–7. 18. Wei T, Zeng C, Chen L, et al. Bedside tests of B-type natriuretic peptide in the diagnosis of left ventricular diastolic dysfunction in hypertensive patients. Eur J Heart Fail 2005;7:75–9. 19. Huang Y, Song Y, Mai W, et al. Association of N-terminal pro brain natriuretic peptide and impaired aortic elastic property in hypertensive patients. Clin Chim Acta 2011;412:2272–6. 20. Kass DA. Ventricular arterial stiffening: integrating the pathophysiology. Hypertension 2005;46:185–93. 21. Yambe M, Tomiyama H, Koji Y, et al. B-type natriuretic peptide and arterial stiffness in healthy Japanese men. Am J Hypertens 2006;19:443–7. 22. Dokainish H. Combining tissue Doppler echocardiography and B-type natriuretic peptide in the evaluation of left ventricular filling pressures: review of the literature and clinical recommendations. Can J Cardiol 2007;23:983–9. 23. Ambrosi P, Oddoze C, Habib G. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation, 2002;106:e70. 24. Fukuta H, Little WC. The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin 2008;4:1–11. 25. Velazquez-Cecena JL, Sharma S, Nagajothi N, et al. Left ventricular end diastolic pressure and serum brain natriuretic
Clin Exp Hypertens, 2015; 37(2): 148–154
26.
27. 28.
29. 30. 31.
32. 33.
34.
peptide levels in patients with abnormal impedance cardiography parameters. Arch Med Res 2008;39:408–11. Feliciano J, Soares R, Silva S, et al. NT-proBNP levels and resting hemodynamic parameters assessed by bioimpedance in patients with chronic heart failure. Rev Port Cardiol 2007;26: 1021–8. Havelka EG, Rzechula KH, Bryant TO, et al. Correlation between impedance cardiography and B-type natriuretic peptide levels in dyspneic patients. J Emerg Med 2011;40:146–50. Pimenta J, Paulo C, Mascarenhas J, et al. BNP at discharge in acute heart failure patients: is it all about volemia? A study using impedance cardiography to assess fluid and hemodynamic status. Int J Cardiol 2010;145:209–14. Balak W, Sinkiewicz W, Gilewski W, et al. Relationship between thoracic fluid content and natriuretic peptide type B in patients with systolic heart failure. Kardiol Pol 2009;67:1220–5. Palazzuoli A, Gallotta M, Quatrini I, Nuti R. Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure. Vasc Health Risk Manag 2010;6:411–18. Goetze JP, Mogelvang R, Maage L, et al. Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction. Eur Heart J 2006; 27:3004–10. Freitag MH, Larson MG, Levy D, et al. Plasma brain natriuretic peptide levels and blood pressure tracking in the Framingham Heart Study. Hypertension 2003;41:978–83. Costello-Boerrigter LC, Boerrigter G, Redfield MM, et al. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 2006;47: 345–53. Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004;109:594–600.
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ORIGINAL ARTICLE
Association of N-terminal pro-brain natriuretic peptide and hemodynamic parameters measured by impedance cardiography in patients with essential hypertension Paweł Krzesin´ski1, Grzegorz Gielerak1, Adam Stan´czyk1, Katarzyna Piotrowicz1, Wiesław Piechota2, and Andrzej Skrobowski1 1
Department of Cardiology and Internal Diseases, Military Institute of Medicine, Warsaw, Poland and 2Department of Laboratory Diagnostics, Military Institute of Medicine, Warsaw, Poland Abstract
Keywords
The aim of this study was to evaluate the association of NT-proBNP with clinical and hemodynamic assessment in 156 patients with arterial hypertension. NT-proBNP correlated positively with, i.e. age (r ¼ 0.310, p ¼ 0.00008), mean blood pressure (MBP; r ¼ 0.199, p ¼ 0.0136), Heather index (HI; r ¼ 0.375, p50.00001) and negatively with thoracic fluid content (TFC; r ¼ 0.300, p ¼ 0.0002). The patients with higher NT-proBNP were older (46.1 versus 40.6 years, p ¼ 0.001), with higher MBP (102.6 versus 98.5 mm Hg, p ¼ 0.0043), HI (14.54 versus 11.93 Ohm s2, p ¼ 0.009) and lower TFC (27.5 versus 29.4 1/kOhm, p ¼ 0.0032). The independent predictors of higher NT-proBNP were: age, MBP and HI.
Amino-terminal pro-brain natriuretic peptide, cardiovascular system, hemodynamics, hypertension, impedance cardiography
Introduction Natriuretic peptides (NP) are cardiac neurohormones released from the heart chambers in response to ventricular expansion and pressure overload. N-terminal pro-brain natriuretic peptide (NT-proBNP) is aminoterminal fragment of brain natriuretic peptide (BNP), more useful in laboratory testing because of longer half-life (1,2). The elevation of serum concentration of NP has been observed both in patients with impaired and preserved left ventricular systolic function, especially those with heart failure (HF) (3). High NT-proBNP confirmed to be related not only to preload but also to increased afterload, especially high blood pressure (BP) and arterial stiffness (4). Therefore, NT-proBNP was also tested in patients with arterial hypertension (AH) revealing to be a marker of impaired diastolic function and left ventricular hypertrophy (4,5). In some studies, NT-proBNP was also identified as cardiovascular risk factor in hypertensive population (6,7). Most studies on patients on AH concentrated on relationship between NP and echocardiographic measurements, especially left ventricular mass index (LVMI), and markers of diastolic dysfunction derived from mitral flow analysis and tissue Doppler imaging (TDI) (5,8), confirmed
Correspondence: Paweł Krzesin´ski, Department of Cardiology and Internal Diseases, Military Institute of Medicine, Szasero´w Street 128, 04-141 Warsaw 44, Poland. Tel: +48226816389. Mob: + 48606939390. Fax: +48228108089. E-mail: [email protected]
History Received 21 February 2014 Revised 18 March 2014 Accepted 23 March 2014 Published online 30 April 2014
in magnetic resonance imaging (9,10). However, these techniques have limitations in the assessment of ventricularvascular interactions. The current guidelines for HF management indicate the value of NT-proBNP5125 pg/ml as cut-off point for the exclusion of HF (3). However, it does not mean that lower values of NT-proBNP are accidental and do not have any clinical significance. NT-proBNP seems to present potency of explaining the complex pathophysiology of left ventricle (LV) overload, especially in hypertensive patients. Since NT-proBNP revealed to be diagnostic in pre-hypertension as well as in assessing the risk of diastolic HF (5), even its relatively low serum concentration may bring valuable pathophysiological information. In order to explore this scientific subject, NT-proBNP should be confronted with complex assessment providing data on preload, afterload, ventricular outflow and aortic compliance. Therefore, impedance cardiography (ICG), a non-invasive method of hemodynamic evaluation, was used in this study. This simple method has recently proved to be useful in diagnosis and treatment of patients with HF and AH (11,12). Potency of ICG to estimate, i.e. thoracic fluid content (TFC), stroke volume, systemic vascular resistance, ejection blood flow parameters and aortic compliance justified stating the hypothesis that its confrontation with NT-proBNP can result in interesting conclusions. The aim of the retrospective analysis presented in this article was to evaluate association of NT-proBNP with hemodynamic parameters measured by ICG.
NT-proBNP and hemodynamics in hypertension
DOI: 10.3109/10641963.2014.913611
Methods Study population This study included 156 patients (115 men; mean age 43.3 ± 10.5 years) with at least 3-month history of mild or moderate AH defined according to European Society of Cardiology guidelines (13). Exclusion criteria comprised: (i) confirmed secondary AH, (ii) improperly controlled AH with three or more medicines, (iii) heart failure, (iv) cardiomyopathy, (v) significant heart rhythm disorders, (vi) significant valvular disease, (vii) kidney failure, (viii) chronic obstructive pulmonary disease, (ix) diabetes, (x) polyneuropathy, (xi) peripheral vascular disease and (xii) age518 years and465 years. The group selected to the analysis comprised patients with AH from two clinical studies performed in the Department of Cardiology and Internal Diseases of Military Institute of Medicine from March 2008 to May 2012. Both studies were conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki, with the approval of local ethics committee (no 3/WIM/2008 and no 44/WIM/2010). Each patient provided written informed consent to participate in the study. Demographic and clinical characteristics of the study group are shown in Table 1. Clinical examination Clinical examination was performed with special consideration of familiar history of AH, cardiovascular risk factors and symptoms indicating secondary cause of AH. Office blood pressure measurement (Omron M4 Plus, Japan) was performed by technique compliant with European Society of Cardiology guidelines (13). Laboratory tests included, i.e. evaluation of renal function (creatinine, glomerular filtration rate) and metabolic disturbances. Echocardiography Two-dimensional echocardiography was performed using standard parasternal, apical and subcostal views (VIVID S6 Medical System, 2.5 MHz transducer). The left ventricular hypertrophy was diagnosed according to the ASE-recommended formula for estimation of LV mass from 2D linear LV
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measurements and indexed to body surface area (cut-off values for men LVMI4115 g/m2, for women495 g/m2). The assessment of diastolic dysfunction was performed according to current guidelines (14,15). Impedance cardiography All ICG measurements were performed using the NiccomoÔ device (Medis, Ilmenau, Germany) after 10 min of rest in a supine position. Data were recorded during a 10-min assessment and exported to a dedicated software (Niccomo Software, Ilmenau, Germany). The final analysis included mean values of hemodynamic parameters from each 10-min recording such as: systolic blood pressure (SBP, [mm Hg]); diastolic blood pressure (DBP, [mm Hg]); mean blood pressure (MBP [mm Hg]); pulse pressure (PP, [mm Hg]), calculated as PP ¼ SBP DBP; heart rate (HR, [bpm]; left ventricular ejection time (LVET, ms), the interval between opening and closing of the aortic valve; stroke index (SI, [ml m2]); calculated using the Sramek and Bernstein formula SI ¼ VEPT dZmax Z01 LVET BSA1, accounting for weight, height and gender (variable VEPT), the amplitude of the systolic wave of the ICG (dZmax), LVET and body surface area (BSA); cardiac index (CI, [ml m2 min1]), calculated as CI ¼ SI HR; end diastolic index (EDI, [ml m2]); acceleration time index (ACI, [100 s2]), stating for maximum acceleration of blood flow between aortic valve opening and C-point of ICG wave – ACI ¼ 100 dZmax dt1; velocity index (VI, [1000 s1]): VI ¼ 1000 dZmax Z01; Heather index (HI, [Ohm s2]), a derivate of TRC, the time interval between the R-peak of the ECG and the time of dZmax, called C-point of ICG wave HI ¼ dZmax TRC, characterizing the maximum contraction force of the left ventricle and corresponding to cardiac inotropism; TFC (1 kOhm1), calculated from basic impedance (Z0) as its converse: TFC ¼ 1000 Z01; systemic vascular resistance index (SVRI, [dyn s cm5 m2]); SVRI ¼ 80 [MBP CVP] CI1, where CVP is central venous pressure (assumed value 6 mm Hg); total arterial compliance (TAC, ml/mm Hg), TAC ¼ SV PP1. NT-proBNP (N-terminal pro-brain natriuretic peptide) NT-proBNP was estimated with Roche Diagnostics ElecsysÕ proBNP Assay (Mannheim, Germany). Only patients with NT-proBNP5125 pg/ml were considered to the analysis.
Table 1. Basic clinical characteristics. Study group (n ¼ 156) Men, n (%) Age (years), mean ± SD BMI (kg/m), mean ± SD Office SBP (mm Hg), mean ± SD Office DBP (mm Hg), mean ± SD HR (1/min), mean ± SD Metabolic syndrome, n (%) Smoking, n (%) Family history of AH, n (%) Left ventricular hypertrophy, n (%) Impaired relaxation of left ventricle, n (%) Creatinine (mg/dl), mean ± SD GFR (ml/min 1.73 m2), mean ± SD
115 (73.7) 43.3 ± 10.5 29.1 ± 4.1 146.5 ± 14.0 93.8 ± 8.6 70.5 ± 10.4 96 (61.5) 35 (22.4) 93 (59.6) 30 (19.2) 35 (22.4) 0.855 ± 0.140 99.4 ± 18.5
AH, arterial hypertension; BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; SD, standard deviation.
Statistical analysis The statistical analysis of the results was performed using Statistica 7.0 (StatSoft, Inc., Tulsa, OK). The distribution and normality of data were assessed by visual inspection and using the Shapiro–Wilk test. Continuous variables were presented as means ± SDs and categorical variables as absolute and relative frequencies (percentages). Assessment of relations between NT-proBNP and other parameters was performed using univariate linear regression. Then the most correlated and representative variables were included in multivariate linear regression model. In second part of the analysis, between-group comparisons were performed using t-Student’s test for normally distributed data and
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non-parametric tests for data that did not show a normal distribution. Then the most representative variables were included in logistic regression model. A p value of50.05 was taken to indicate statistical significance.
Multivariate linear regression The most correlated and representative variables (age, gender, creatinine, MBP, HI and TFC) were included in multivariate linear regression model. The analysis revealed that age, MBP
Results Univariate linear regression The mean value of NT-proBNP in study group was 38.3 pg/ml (range: 5.0–103.2 pg/ml). An univariate linear regression analysis demonstrated that NT-proBNP correlated positively with age, SBP, MBP, SI, CI, ACI, VI, HI, LVET, EDI, creatinine and negatively with TFC – Table 2 and Figures 1–4. No significant relation with BMI, DBP, PP, HR, SVRI, TAC and GFR was observed.
Table 2. Correlations between NT-proBNP and other parameters.
NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP NTpro-BNP
versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus versus
age BMI SBP DBP MBP PP HR SI CI SVRI ACI VI HI LVET TFC EDI TAC creatinine GFR
R
p
0.310 0.119 0.210 0.121 0.199 0.131 0.019 0.218 0.196 0.079 0.225 0.248 0.375 0.197 0.300 0.183 0.006 0.203 0.075
0.00008 NS 0.0093 NS 0.0136 NS NS 0.0065 0.0151 NS 0.0051 0.0020 0.000002 NS 0.00018 0.0228 NS 0.015 NS
Figure 2. Correlation between NT-proBNP and MBP.
ACI, acceleration time index; CI, cardiac index; DBP, diastolic blood pressure; EDI, end diastolic index; HI, Heather index; HR, heart rate; LVET, left ventricular ejection time; MBP, mean blood pressure; NS, non-significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; PP, pulse pressure; SBP, systolic blood pressure; SI, stroke index; SVRI, systemic vascular resistance index; TAC, total arterial compliance; TFC, thoracic fluid content; VI, velocity index.
Figure 3. Correlation between NT-proBNP and TFC.
Figure 1. Correlation between NT-proBNP and age.
Figure 4. Correlation between NT-proBNP and HI.
NT-proBNP and hemodynamics in hypertension
DOI: 10.3109/10641963.2014.913611
and HI independently correlated to NT-proBNP. The multiple regression model (R squared value of 0.227) with these explanatory variables was: ½NT-proBNP ¼ 0:74 ½age þ 1:83 ½HI þ 0:48 ½MBP 65:55 Therefore, in the above model, the most pronounced influence on NT-proBNP was observed for unitary change in HI, less – in MBP and age (change of 1 Ohm s2 equals to 3.81 mm Hg and 2.47 years). However, the analysis of contribution power of these variables has to consider different data distribution, order of magnitude and range of potential change (for HI: mean 13.3 ± 4.9, 95% CI: 12.5–14.0, range: 4.7–32.6 Ohm s2; for MBP: mean 100.6 ± 8.8, 95% CI: 99.2–102.0, range: 81–127 mm Hg; for age: mean 43.3 ± 10.5, 95% CI: 41.7– 45.0, range: 19–65 years). Subgroup comparison based on NT-proBNP In further analysis, basing on the value of median NT-proBNP (31.8 pg/ml), the study group was divided into two subgroups: (1) ‘‘low normal’’ NT-proBNP – LN_NTproBNP (531.8 pg/ ml) and (2) ‘‘high normal’’ NT-proBNP – HN_NTproBNP (431.8 pg/ml). These comparative analysis confirmed significant differences in hemodynamic parameters between patients with lower and higher normal values of NT-proBNP – Table 3. Logistic regression The most representative variables (age, gender, creatinine, MBP, HI and TFC) were included in logistic regression model with NT_proBNP category as dependent binary variable (LN_NTproBNP and HN_NTproBNP) that revealed three
independent predictors of ‘‘high’’ NT-proBNP (2 ¼ 36.37, p50.00005): age (OR 1.05, 95% CI: 1.01–1.09, p ¼ 0.02), MBP (OR 1.06, 95% CI: 1.01–1.11, p ¼ 0.0096), HI (OR 1.14, 95% CI: 1.04–1.26, p ¼ 0.005). Those results were compatible with multivariate linear regression model presented above.
Discussion Presented results revealed that even in range of low values the level of NT-proBNP is not just a case of accidental distribution. In our study, we consciously included only patients with NT-proBNP5125 pg/ml to avoid potential bias of subclinical HF. Therefore, the mean value (38.3 pg/ml) and median (31.8 pg/ml) in the study group was rather low. Nonetheless, it discriminated patients with different hemodynamic profiles. The accuracy of low values of NP to detect abnormalities in morphology and hemodynamic function of heart muscle was confirmed in some studies. Mueller et al. (16) defined NT-proBNP level of 39 pg/ml as high sensitive (90%) in detection of cardiac structural diseases in echocardiography. Lubien et al. (8) used a cut-off value of BNP 62 pg/ml to discriminate patients with diastolic dysfunction with sensitivity of 85% and specificity of 83%. Karaca et al. (17) observed even better accuracy of cut-off value of 37 pg/ml (respectively 80% and 100%). Wei et al. (18) reported high diagnostic value of BNP440 pg/ml in the assessment of left ventricular end diastolic diameter (LVEDD). However, in our study we aimed to confront NT-proBNP with multiparametric noninvasive hemodynamic assessment by ICG that revealed to be complementary tool in evaluation of subtle pathophysiology of LV overload in hypertensive patients. It confirmed some previous observations and revealed new interesting interactions.
Table 3. Comparison between LN_NTproBNP and HN_NTproBNP subgroups. Parameters Age (years), mean ± SD Male (n, %) BMI (kg/m2), mean ± SD SBP (mm Hg), mean ± SD DBP (mm Hg), mean ± SD MBP (mm Hg), mean ± SD PP (mm Hg), mean ± SD HR (bpm), mean ± SD SI (ml m2), mean ± SD CI (ml m2 min1), mean ± SD SVRI (dyn s cm5 m2), mean ± SD ACI (100 s2), mean ± SD VI (1000 s1), mean ± SD HI (Ohm s2), mean ± SD LVET (ms), mean ± SD TFC (1 kOhm1), mean ± SD EDI (ml m2), mean ± SD TAC (ml/mm Hg), mean ± SD Left ventricular hypertrophy (n, %) Impaired relaxation of left ventricle (n, %) Creatinine (mg/dl), mean ± SD GFR (ml/min 1.73 m2), mean ± SD
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LN_NTproBNP (n ¼ 78)
HN_NTproBNP (n ¼ 78)
p
40.6 ± 11.5 70 (89.7) 29.6 ± 4.2 134.5 ± 10.4 87.0 ± 7.9 98.5 ± 8.3 47.5 ± 6.7 71.5 ± 11.4 46.0 ± 8.0 3.24 ± 0.53 2362.6 ± 476.1 65.1 ± 24.1 41.8 ± 12.8 11.93 ± 4.31 311.4 ± 38.0 29.4 ± 3.8 72.1 ± 10.4 2.06 ± 0.46 17 (21.8) 14 (18.0) 0.887 ± 0.118 100.9 ± 19.0
46.1 ± 8.7 45 (57.7) 28.7 ± 4.1 140.0 ± 13.6 89.3 ± 8.5 102.6 ± 8.8 50.2 ± 10.0 69.4 ± 9.2 50.1 ± 9.4 3.42 ± 0.51 2327.4 ± 463.1 71.9 ± 23.9 46.4 ± 12.6 14.54 ± 5.11 326.9 ± 35.2 27.5 ± 4.2 78.2 ± 13.7 2.05 ± 0.55 18 (23.1) 16 (20.5) 0.823 ± 0.154 97.9 ± 18.0
0.00096 0.00005 NS 0.0076 NS 0.0043 NS NS 0.0041 0.0317 NS 0.0377 0.0087 0.00034 0.007 0.0032 0.002 NS NS NS 0.014 NS
ACI, acceleration time index; CI, cardiac index; DBP, diastolic blood pressure; EDI, end diastolic index; HI, Heather index; HR, heart rate; LVET, left ventricular ejection time; MBP, mean blood pressure; NS, non-significant; NT-proBNP, N-terminal pro-brain natriuretic peptide; PP, pulse pressure; SBP, systolic blood pressure; SI, stroke index; SVRI, systemic vascular resistance index; TAC, total arterial compliance; TFC, thoracic fluid content; VI, velocity index.
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NT-proBNP and afterload NT-proBNP correlated with parameters characterizing afterload (SBP, DBP and MBP). The positive relation with MBP suggests that resistance of small arteries had higher input to afterload than stiffness of large arteries (characterized by PP and TAC). These results are only partly consistent with observations of Huang et al. (19) that related positive correlation of impaired aortic elasticity with NT-proBNP. This discrepancy can be explained by different characteristics of patients in the area of age, lower office blood pressure and antihypertensive treatment influencing peripheral resistance (i.e. angiotensin converting enzyme inhibitors and calcium channel blockers). It probably reflects the different mechanism responsible for increased afterload depending on age. Among younger hypertensives large arteries are relatively compliant and increased afterload is mostly provoked by functional impairment of small resistance arteries. The arterial stiffness is more pronounced in older hypertensives (20). The association of age-related arterial stiffness with NP levels has also been observed in healthy men which confirms the influence of vascular remodeling on LV hemodynamics (20,21). NT-proBNP, preload and cardiac contractility The observation that NT-proBNP is related to parameters characterizing LV function as a blood pump seems especially valuable. The most convincing positive correlations were observed for HI, VI and ACI, parameters describing the rapidity of blood outflow from LV to the aorta. NT-proBNP was also higher in patients with longer LVET and higher SI (and consequently CI). Since some of these parameters have also its ‘‘volume’’ component (dZmax), this observation suggests that NT-proBNP increases in case of higher LV fluid overload and contractility. Higher EDI in HN_NTproBNP group suggests influence of relative LV volume overload on NT-proBNP. These observations confirm the well-known mechanism of NP release provoked by elevated LV diastolic pressure and myocitic stretch (22). Higher EDI and SI suggest that intravascular fluid overload does not impair LV ejection function in this group of patients. On the contrary, it contributes to higher LV outflow – the increase of SI seems to be a response of elastic LV to cardiac preload. This mechanism aims at maintaining normal left atrial (LA) pressure (22). However, it has to be underlined that such hemodynamic profile can evolve to defective active relaxation, increased LA pressure and pulmonary congestion. In the first stage of LV dysfunction, fluid overload can become ‘‘symptomatic’’ only during high exercise stress when LV pressures increase (23). Over time, such patients can present typical symptoms of HF (5). HF patients with significantly impaired systolic function and increased preload operate on the flat and descending portion of the Frank– Starling curve, when every increase in preload contributes to relevant increase in LVEDD and decrease of CI (24). NT-proBNP and chest fluid Negative correlation of NT-proBNP with TFC is not easy to interpret. Higher EDI in HN_NTproBNP subgroup provokes
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expectation that total fluid in the thorax should also be higher. However, this way of deduction assumes similar hemodynamic pattern for HF and uncomplicated AH that can be misleading. In fact, chronic elevation of LV pressures and its distension in HF patients provokes continuous release of NP. However, their compensatory action is insufficient and does not bring desirable hemodynamic effects. Velazquez-Cecena et al. (25) observed that HF patients with higher TFC and lower SI (the group at increased risk of decompensation) had higher BNP and LV end diastolic pressure. Likewise, Feliciano et al. (26) revealed positive correlation of NT-proBNP with TFC (r ¼ 0.649, p50.0001) and negative with SI (r ¼ 0.324, p ¼ 0.016) in group of 55 HF patients (mean EF 24.7%). Havelka et al. (27) observed positive relation of BNP and TFC (r ¼ 0.32, p ¼ 0.02) in patients presenting dyspnoea at emergency departments. Moreover, TFC revealed to be a powerful predictor of BNP level and outcome in patients with acute HF discharged from hospital (28). However, Banak et al. (29) indicated that relation of TFC and BNP depended on patient’s clinical status and volemia. Although correlation was significant for whole study group (r ¼ 0.57, p ¼ 0.001), after excluding patients with exacerbation of HF symptoms it revealed to be non-significant (r ¼ 0.24, p ¼ 0.22). Moreover, there was no such association in healthy controls (r ¼ 0.17, p ¼ 0.51). Thus, in HF patients NT-proBNP seems to be a marker of severely impaired hemodynamics (especially LV end-diastolic pressure and increased pulmonary wedge pressure), increasing along with fluid retention and deterioration of cardiac output. In contrary, the observations from our study are opposite – TFC was lower in HN_NTproBNP subgroup. This phenomenon can be explained by the physiological action of NP which effectively stimulates natriuresis, diuresis and vasodilatation in uncomplicated AH. Higher blood pressure and LV overload can trigger NP release that effects in compensatory mechanism, mostly fluid loss. Plasma BNP acts against vasoconstriction, sodium retention and antidiuretic effects of activated renin–angiotensin–aldosterone system (30). However, in case of higher resistance of small artery vessels intravascular bed remains limited. Therefore, the hemodynamic pattern reveals relatively lower extravascular fluid (component of TFC) than heart and vascular plasma volume (EDI and SI). NT-proBNP and other assessed parameters Our results confirmed previous relation of NT-proBNP to age and its higher concentration in women (31,32). CostelloBoerrigter et al. (33) observed that serum concentration of NT-proBNP is even three times greater in normal women than men and increases with age of 10–20 pg/ml per decade. However, opposite to some researchers, we did not observe the association with BMI (34). The correlation with creatinine was not reflected in glomerular filtration rate (GFR) which can be explained by older age of patients with higher NT-proBNP (GFR was calculated from MDRD formula). Exclusion criteria in our study limited the bias of other factors influencing NP levels, however, they must be considered in any clinical case (valvular heart disease, arrhythmia, ischemic heart disease, renal impairment, lung diseases and sepsis) (1,4).
DOI: 10.3109/10641963.2014.913611
NT-proBNP as a marker of hemodynamic profile The composite analysis of hemodynamics and NT-proBNP in patients with AH revealed very interesting observations. In young- and middle-aged hypertensives, higher NT-proBNP seems to respond both to the increased afterload and preload. However, it also corresponds with heart muscle contractility and effects in lower total fluid accumulation in the chest. It may suggest that in this group of patients NT-proBNP is a marker of compensatory mechanism that works quite effectively against LV overload. In patients with AH, the NP levels should be interpreted with awareness of its physiological role. Our results suggest that NT-proBNP level should be concerned in view of patients’ clinical state. It can suggest HF in case of dyspnea, but in AH without HF symptoms it can just be a marker of specific hemodynamic profile and activated neurohormonal response to LV overload. In such cases, ICG can be a valuable diagnostic support. The unique value of our study is that by including patients with untreated AH we avoided significant bias of hypotensive therapy which can influence NT-proBNP levels (4). Practical implications of regression models Our multivariate regression model only in low percentage (27.8%) explains NT-proBNP values, which indicates more complex mechanism of its release. However, it suggests that in coincidence with older age, higher MBP and HI, the value of NT-proBNP can even exceed 125 pg/ml (cut-off point for HF exclusion). On the other hand, ‘‘high normal’’ NT-proBNP with low MBP, low HI and younger age should provoke more detailed diagnostics aimed at detecting other potential causes of increased NT-proBNP. Also, logistic regression model confirmed independence of age, MBP and HI as predictors of ‘‘high normal’’ NT-proBNP. However, the interpretation of these results should be very cautious because of some obvious limitations. Being aware that our model is limited to specific population we suggest further studies aimed at creating models of higher predictive values. Limitations The authors are aware that the small sample size and the retrospective design limit the study. The most relevant statistical limitation is interdependence of some ICG parameters caused by formulas for their calculation that include the same variables (i.e. Z0 and dZmax). Therefore, the variables selection to multivariate models is restricted and must be carefully considered. Also, for this reason, we do not present correlations between these parameters to avoid potential mathematical bias. Lack of difference between subgroups in the area of LV hypertrophy and impaired relaxation do not exclude the potential association of NT-proBNP with detailed echocardiographic parameters that characterize LV morphology and hemodynamics. Such assessment was not the object of this study and should be further explored.
Conclusions In patients with AH, ICG and NT-proBNP revealed to be complementary methods in the assessment of hemodynamic coupling between left ventricle and vascular bed.
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The performed analysis revealed interesting relations describing complex pathomechanism connected with hemodynamic disturbances in AH. In patients with AH, serum concentration of NT-proBNP and ICG measurements can complete patient’s evaluation providing additional important clinical information.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article. The study was supported by Military Institute of Medicine, Warsaw, Poland (grant no 69/WIM).
References 1. McCullough PA, Neyou A. Comprehensive review of the relative clinical utility of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide assays in cardiovascular disease. Open Heart Fail J 2009;2:6–17. 2. Ceyhan C, Unal S, Yenisey C, et al. The role of N terminal probrain natriuretic peptide in the evaluation of left ventricular diastolic dysfunction: correlation with echocardiographic indexes in hypertensive patients. Int J Cardiovasc Imaging 2008;24:253–9. 3. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69. 4. Bricca G, Lantelme P. Natriuretic peptides: ready for prime-time in hypertension? Arch Cardiovasc Dis 2011;104:403–9. 5. Parekh N, Maisel AS. Utility of B-natriuretic peptide in the evaluation of left ventricular diastolic function and diastolic heart failure. Curr Opin Cardiol 2009;24:155–60. 6. Pedersen F, Raymond I, Kistorp C, et al. N-terminal pro-brain natriuretic peptide in arterial hypertension: a valuable prognostic marker of cardiovascular events. J Card Fail 2005; 11(5 Suppl):S70–5. 7. Olsen MH, Wachtell K, Tuxen C, et al. N-terminal pro-brain natriuretic peptide predicts cardiovascular events in patients with hypertension and left ventricular hypertrophy: a LIFE study. J Hypertens 2004;22:1597–604. 8. Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 2002;105:595–601. 9. Hildebrandt P, Boesen M, Olsen M, et al. N-terminal pro brain natriuretic peptide in arterial hypertension – a marker for left ventricular dimensions and prognosis. Eur J Heart Fail 2004;6: 313–17. 10. Morillas P, Castillo J, Quiles J, et al. Usefulness of NT-proBNP level for diagnosing left ventricular hypertrophy in hypertensive patients. A cardiac magnetic resonance study. Rev Esp Cardiol 2008;61:972–5. 11. Packer M, Abraham WT, Mehra MR, et al. Utility of impedance cardiography for the identification of short-term risk of clinical decompensation in stable patients with chronic heart failure. J Am Coll Cardiol 2006;47:2245–52. 12. Krzesin´ski P, Gielerak GG, Kowal JJ. A ‘‘patient-tailored’’ treatment of hypertension with use of impedance cardiography: a randomized, prospective and controlled trial. Med Sci Monit 2013; 19:242–50. 13. Mancia G, De Backer G, Dominiczak A, et al. The task force for the management of arterial hypertension of the european society of hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. 14. Lang RM, Bierig M, Devereux RB, et al. American Society of Echocardiography’s Nomenclature and Standards Committee, Task Force on Chamber Quantification, American College of Cardiology Echocardiography Committee, American Heart Association, European Association of Echocardiography, European Society of Cardiology Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108.
154
P. Krzesin´ski et al.
15. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10:165–93. 16. Mueller T, Gegenhuber A, Dieplinger B, et al. Capability of B-type natriuretic peptide (BNP) and amino-terminal proBNP as indicators of cardiac structural disease in asymptomatic patients with systemic arterial hypertension. Clin Chem 2005;51:2245–51. 17. Karaca I, Gu¨lcu¨ E, Yavuzkir M, et al. B-type natriuretic peptide level in the diagnosis of asymptomatic diastolic dysfunction. Anadolu Kardiyol Derg 2007;7:262–7. 18. Wei T, Zeng C, Chen L, et al. Bedside tests of B-type natriuretic peptide in the diagnosis of left ventricular diastolic dysfunction in hypertensive patients. Eur J Heart Fail 2005;7:75–9. 19. Huang Y, Song Y, Mai W, et al. Association of N-terminal pro brain natriuretic peptide and impaired aortic elastic property in hypertensive patients. Clin Chim Acta 2011;412:2272–6. 20. Kass DA. Ventricular arterial stiffening: integrating the pathophysiology. Hypertension 2005;46:185–93. 21. Yambe M, Tomiyama H, Koji Y, et al. B-type natriuretic peptide and arterial stiffness in healthy Japanese men. Am J Hypertens 2006;19:443–7. 22. Dokainish H. Combining tissue Doppler echocardiography and B-type natriuretic peptide in the evaluation of left ventricular filling pressures: review of the literature and clinical recommendations. Can J Cardiol 2007;23:983–9. 23. Ambrosi P, Oddoze C, Habib G. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation, 2002;106:e70. 24. Fukuta H, Little WC. The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin 2008;4:1–11. 25. Velazquez-Cecena JL, Sharma S, Nagajothi N, et al. Left ventricular end diastolic pressure and serum brain natriuretic
Clin Exp Hypertens, 2015; 37(2): 148–154
26.
27. 28.
29. 30. 31.
32. 33.
34.
peptide levels in patients with abnormal impedance cardiography parameters. Arch Med Res 2008;39:408–11. Feliciano J, Soares R, Silva S, et al. NT-proBNP levels and resting hemodynamic parameters assessed by bioimpedance in patients with chronic heart failure. Rev Port Cardiol 2007;26: 1021–8. Havelka EG, Rzechula KH, Bryant TO, et al. Correlation between impedance cardiography and B-type natriuretic peptide levels in dyspneic patients. J Emerg Med 2011;40:146–50. Pimenta J, Paulo C, Mascarenhas J, et al. BNP at discharge in acute heart failure patients: is it all about volemia? A study using impedance cardiography to assess fluid and hemodynamic status. Int J Cardiol 2010;145:209–14. Balak W, Sinkiewicz W, Gilewski W, et al. Relationship between thoracic fluid content and natriuretic peptide type B in patients with systolic heart failure. Kardiol Pol 2009;67:1220–5. Palazzuoli A, Gallotta M, Quatrini I, Nuti R. Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure. Vasc Health Risk Manag 2010;6:411–18. Goetze JP, Mogelvang R, Maage L, et al. Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertrophy and systolic dysfunction. Eur Heart J 2006; 27:3004–10. Freitag MH, Larson MG, Levy D, et al. Plasma brain natriuretic peptide levels and blood pressure tracking in the Framingham Heart Study. Hypertension 2003;41:978–83. Costello-Boerrigter LC, Boerrigter G, Redfield MM, et al. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 2006;47: 345–53. Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004;109:594–600.
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