The European Journal of Heart Failure 6 (2004) 313–317
N-terminal pro brain natriuretic peptide in arterial hypertension— a marker for left ventricular dimensions and prognosis Per Hildebrandta,*, Mikael Boesenb, Michael Olsenc, Kristian Wachtellc, Bjoern Groenninga a
Department of Cardiology and Endocrinology, Frederiksberg University Hospital, 57 Nordre Fasanvej, DK–2000, Frederiksberg, Denmark b Danish Research Centre of Magnetic Resonance, Hvidovre University Hospital, Denmark c Department of Cardiology, Glostrup University Hospital, Denmark Received 22 December 2003; accepted 8 January 2004
In arterial hypertension risk factor evaluation, including LV mass measurements, and risk stratification using risk charts or programs, is generally recommended. In heart failure NT-proBNP has been shown to be a marker of LV dimensions and of prognosis. If the same diagnostic and prognostic value is present in arterial hypertension, risk factor evaluation would be easier. In 36 patients with arterial hypertension, electrocardiographic LV hypertrophy and preserved left ventricular function, NT-proBNP was eight-fold higher than in healthy subjects. The log NT-proBNP correlated with LV mass index (Rs0.47, Ps0.0002) measured by magnetic resonance imaging. In other subjects with arterial hypertension a significant but weak correlation to diastolic properties has been demonstrated. As for prognosis, a recent study in patients with hypertension, electrocardiographic left ventricular hypertrophy and preserved LV function demonstrated that NT-proBNP was a very strong prognostic marker, especially combined with a history of cardiovascular disease. Patients with high NT-proBNP and known cardiovascular disease had a seven-fold increase in CV events compared to patients with low NT-proBNP and no CV disease, while patients with either high NT-proBNP or CV disease had a three–four-fold increased risk. In conclusion NT-proBNP predicts LV mass in hypertensive patients and is a very strong prognostic marker in these patients. This could indicate a use of NT-proBNP in the future for risk stratification and perhaps monitoring of treatment in patients with arterial hypertension. 䊚 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Keywords: Arterial hypertension; Cardiovascular disease; Natriuretic peptides; Magnetic resonance imaging
1. Introduction Arterial hypertension is a major health problem, affecting approximately 25% of the adult population, and an increasing economic burden for the health care system due to cardiovascular complications and due to the growing use of antihypertensive drugs; 2–3 drugs are necessary in most patients to control blood pressure w1 x . The cardiovascular risk in hypertensive patients is not only dependent on the magnitude of the elevation in blood pressure, but also on other risk factors, such as age, sex, smoking, cholesterol level, diabetes, etc. The global risk for the individual patient can be estimated *Corresponding author. Tel.: q45-3816-4360; fax: q45-38164369. E-mail address:
[email protected] (P. Hildebrandt).
using risk charts or computer programmes w2x. In high risk patients intensive treatment including rigorous blood pressure control is warranted, while a less aggressive approach may be taken for the management of low risk patients. A single powerful risk marker for use in clinical practice, alone or in combination with other means of risk stratification, would make assessment of these patients much easier. Brain natriuretic peptide (BNP) and its split product N-terminal pro BNP (NT-proBNP) are closely related to left ventricular (LV) dimensions, function and mass w3x, and a valuable diagnostic w4x and prognostic tool w5x in patients with heart failure. These peptides are also strong prognostic markers in unselected populations w6x, but the significance of the natriuretic peptides in patients with hypertension and preserved LV systolic function is largely unknown.
1388-9842/04/$ - see front matter 䊚 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejheart.2004.01.001
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Abstract
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Table 1 Baseline values for LIFE patients and normal volunteers
Sex (% men) Mean (range) age (years) Mean (S.D.) height (cm) Mean (S.D.) weight (kg) Mean (S.D.) BSA (m2) Mean (S.D.) LVEDVI (mlym2) Mean (S.D.) LVESVI (mlym2) Mean (S.D.) LVMI (gym2) Mean (S.D.) LVEF (fraction) NT-proBNP (pgyml)*
Normal volunteers (ns20)
LIFE study (ns38)
P Value
90 60.6 (54–79) 176 (5.66) 79.7 (12.4) 1.97 (0.15) 54.6 (12.8) 16.9 (4.89) 90.0 (14.8) 0.69 (0.06) 16.2 (2.10)
71 63.8 (56 – 81) 172 (9.14) 81.9 (13.7) 1.95 (0.20) 61.5 (13.1) 22.6 (9.69) 106 (19.5) 0.64 (0.12) 158 (2.95)
0.10 0.20 0.07 0.55 0.73 0.06 0.02 0.003 0.09 -0.0001
BSAsbody surface area; LIFEsLosartan intervention for endpoint reduction in hypertension; LVEDVIsleft ventricular end-diastolic volume index; LVEFsleft ventricular ejection fraction; LVESVIsleft ventricular end-systolic volume index; NT-proBNPsN-terminal pro brain natriuretic peptide; S.D.sstandard deviation. *Log analysis.
2.1. Patients
2.3. Blood sampling
The study population comprised of 18 male and two female normal volunteers with no history or evidence of hypertension or cardiac disease, and 27 male and nine female patients with hypertension, electrocardiographic evidence of LV hypertrophy and preserved LV systolic function by echocardiography, included in the Losartan Intervention for endpoint reduction in hypertension (LIFE) study. For demographics see Table 1.
Blood was taken at baseline, centrifuged immediately and plasma frozen at y80 8C. After thawing, the plasma was analyzed for NT-proBNP using the commercially available Elecsys proBNP sandwich immunoassay on an Elecsys 2010 (Roche Diagnostics, Mannheim).
2.2. MRI examination The patients were investigated at baseline, when they were free of antihypertensive treatment. LV end-diastolic (LVEDV) and end-systolic (LVESV) volumes were measured using MR cinematographic (CINE) short axis
2.4. Results Demographic data for patients and normal controls are given in Table 1, LV dimensions and their relation to NT-proBNP are given in Table 2, and the association between LVMI and NT-proBNP is shown in Fig. 1. NTproBNP was significantly higher in the LIFE patients than in the normal volunteers. There were no significant correlations between log NT-proBNP and any of the LV
Table 2 Associations between log NT-proBNP and left-ventricular dimensions and ejection fraction in the LIFE patients and the normal volunteers Correlations with log NT-proBNP
Normal volunteers (ns20)
LVEDVI (r (P) values) LVESVI (r (P) values) LVMI (r (P) values) LVEF (r (P) values)
0.22 0.24 0.38 y0.05
(0.35) (0.31) (0.10) (0.85)
LIFE study (ns38) 0.07 0.20 0.47 y0.15
(0.69) (0.23) (0.003) (0.36)
All (ns58) 0.18 0.32 0.47 y0.25
(0.18) (0.02) (0.0002) (0.06)
LIFEsLosartan intervention for endpoint reduction in hypertension; LVEDVIsleft ventricular end-diastolic volume index; LVEFsleft ventricular ejection fraction; LVESVIsleft ventricular end-systolic volume index; NT-proBNPsN-terminal pro brain natriuretic peptide.
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As BNP primarily reflects myocyte stretch w7x it is possible that LV hypertrophy induces an increase in NTproBNP. We investigated the relationship between NTproBNP and cardiac structure and function evaluated using cardiac magnetic resonance imaging (MRI), which is a substantially more accurate and reproducible method than echocardiography w8x.
imaging. From this LV ejection fraction (LVEF) was calculated using the formula: LVEFs LVEDV%LVESVyLVEDV. LV mass was measured from the stack of end-diastolic CINE short-axis slices covering the left ventricle as the area enclosed by the epicardial and endocardial borders of the myocardium multiplied by a density factor of 1.05. LV mass index (LVMI) was calculated using body surface area calculated from height and weight w9x.
2. Evaluation of cardiac structure and function
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hypertension. The study demonstrated a four-fold higher BNP level in renovascular hypertension compared to patients with essential hypertension, while no difference was demonstrated between moderate and severe essential hypertension. The study was hampered by different blood pressure levels and different drug treatments in the three groups. Clarification of the diagnostic potential of BNPyNT-proBNP in renovascular hypertension awaits further studies. 3. Screening hypertrophy
measures among the normal volunteers. In the LIFE patients, log NT-proBNP was significantly associated with LVMI (rs0.47, Ps0.003), but not with any other LV measures. Overall, log NT-proBNP correlated with LVMI (rs0.47, Ps0.0002), LVESVI (rs0.32, Ps 0.02), and LVEF (rsy0.25, Ps0.06). 2.5. Other studies In a study using echocardiographic measurements Luchner et al. w10x demonstrated the value of NTproBNP as a marker for LV mass, but with a large scatter of data. In the same study, BNP was significantly better than atrial natriuretic peptide (ANP) in predicting LV mass. In another LIFE sub-study of 180 patients a similar relationship between LV mass and NT-proBNP was demonstrated using echocardiography w11x, but with a wider data scatter than our MRI sub-study found, probably due to a less accurate method for LV measurements. In the same study significant, but weak correlations were found between NT-proBNP and early systolic dysfunction as judged by midwall fractional shortening, and with some (EyA ratio, left atrial size) but not all (IVRT, deceleration time) echocardiographic surrogate measures of diastolic function. Regarding the mechanism for the increase in BNPy NT-proBNP in patients with LV hypertrophy, it has been demonstrated that atrium-derived BNP is a significant predictor of LV mass index in patients with LV hypertrophy. The atriumderived component contributes significantly to the elevation of plasma BNPyNT-proBNP, levels, probably reflecting atrial pressure and volume overload in LV hypertrophy, even in the absence of systolic dysfunction w12x. In a small study, Mussalo et al. w13x investigated BNP levels in patients with moderate renovascular hypertension and in patients with moderate and severe essential
hypertensionyleft
ventricular
In population studies, patients with hypertension have a slightly or moderately elevated NT-proBNP plasma level compared with age- and sex matched volunteers without hypertension. In a recent report from the Framingham study w14x NT-proBNP appeared a useful method for screening for LV hypertrophy in the general population, but at a too high cost, due to a low prevalence of the disorder. In another report from the Framingham study, baseline BNP values in normotensive subjects did not predict development of hypertension four years later, and was only weakly associated with the risk of blood pressure progression w15x. 4. Prognostic marker in hypertension Information exists on the prognostic value of BNP or NT-proBNP in the general population, in patients with heart failure and in patients with acute coronary syndromes, while information on the prognostic value in other patient groups is generally sparse. In one small study Suzuki et al. w16x demonstrated a strong correlation between BNP and future cardiovascular events in patients with hypertension with and without LV hypertrophy. In another LIFE trial sub-study of 183 patients with known hypertension and echocardiographic LV hypertrophy, we demonstrated that NT-proBNP was a strong prognostic marker for the composite endpoint of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction w17x. We divided the patients into four groups according to plasma NT-proBNP above or below median value (185 pgyml), and with or without known cardiovascular disease (CVD) (defined as ischaemic heart disease, peripheral vascular disease, cerebrovascular disease, diabetes or heart failure). In these subgroups the following five-year event rates were demonstrated: Low NT-proBNP and no known CVD: 4.3%; High NT-proBNP and no known CVD: 14.8%; Low NT-proBNP and known CVD: 18.2%; and High NT-proBNP and known CVD: 26.3%. The differences between the groups were highly significant. Using NT-proBNP we were accordingly able
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Fig. 1. Association between the plasma level of NT-proBNP and LVMI in the normal volunteers and in the LIFE patients. LVMIsleft ventricular mass index; NT-proBNPsN-terminal pro brain natriuretic peptide.
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5. Influence of treatment and treatment monitoring For evaluation of a potential role for NT-proBNP in treatment monitoring, it is important to know the influence of different antihypertensive drugs on the plasma levels of the natriuretic peptides. As demonstrated in heart failure the Angiotensin II receptor blocker valsartan reduced the plasma level of BNP w18x, and in the LIFE study the cardio-selective beta-blocker atenolol moderately increased the plasma NT-proBNP level. Studies in patients with heart failure have demonstrated similar changes during beta-blockade as well as a reduction in BNPyNT-proBNP levels during angiotensin converting enzyme (ACE) -inhibitor treatment w19,20x. No studies have been carried out to assess BNPyNTproBNP as potential markers for treatment monitoring in patients with hypertension. The finding that NT-proBNP even after one year of treatment was a strong prognostic marker suggests a role for NT-proBNP for monitoring even during aggressive treatment, but this clearly needs confirmation from prospective studies. 6. Conclusion We have demonstrated that the plasma level of NTproBNP is significantly increased in patients with essential hypertension and preserved LV systolic function compared to age- and sex matched normal volunteers. The plasma level of NT-proBNP partially reflects LV myocardial mass suggesting a potential role as a marker for LV hypertrophy in the evaluation of patients with essential hypertension.
References w1x Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351(9118):1755 –62. w2x De Backer G, Ambrosioni E, Broch-Johnsen K, et al. Europeean guidelines on cardiovascular disease prevention i clinical practise. Third joint task force of European and other Societies on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24:1601 –10. w3x Groenning BA, Nilsson JC, Sondergaard L, et al. Detection of left ventricular enlargement and impaired systolic function with plasma N-terminal pro brain natriuretic peptide concentrations. Am Heart J 2002;143(5):023 –9. w4x Gustafsson F, Badskjær J, Hansen FS, Paulsen AH, Hildebrandt P. Value of N-terminal proBNP in the diagnosis of left ventricular systolic dysfunction in primary care patients referred for echocardiography. Heart Drug 2003;3:141 –6. ¨ w5x Gardner RS, Ozalp F, Murday AJ, Robb SD, McDonagh TA. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J 2003;24:1735 –43. w6x McDonagh TA, Cunningham AD, Morrison CE, et al. Left ventricular dysfunction, natriuretic peptides, and mortality in an urban population. Heart 2001;86(1):21 –6. w7x Nakao K, Ogawa Y, Suga S-I, Imura H. Molecular biology and biochemistry of the natriuretic peptide system. I: natriuretic peptides. J Hypertens 1992;10:907 –12. w8x Bellenger NG, Burgess MI, Ray SG, et al. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? Eur Heart J 2000;21:1387 –96. w9x Alfakih K, Plein S, Thiele H, Jones T, Ridgway JP, Sivananthan MU. Normal human left and right ventricular dimensions for MRI as assessed by turbo gradient echo and steady-state free precession imaging sequences. J Magn Reson Imaging 2003;17:323 –9. w10x Luchner A, Burnett JC, Jougasaki M, et al. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens 2000;18:1121 – 8. w11x Wachtell K, Olsen MH, Hall C. Is NT-pro brain natriuretic peptide related to systolic and diastolic left ventricular function at baseline and during antihypertensive treatment. (abstract, ACC 2003), Circ 2003. w12x Murakami Y, Shimada T, Inoue S, et al. New insights into mechanism of the elevation of plasma brain natriuretic polypeptide levels in patients with left ventricular hypertrophy. Can J Cardiol 2002;18(12):1294 –300. w13x Mussalo H, Vanninen E, Ikaheimo ¨ R, Hartikainen J. NTproANP and BNP in renovascular and in severe and mild essentila hypertension. Kidney Blood Press R 2003;26:34 –41. w14x Vasan RS, Benjamin EJ, Larson MG, et al. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction. J Am Med Assoc 2002;288:1252 –9. w15x 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. w16x Suzuki M, Hamada M, Yamamoto K, Kazatani Y, Hiwada K. Brain natriuretic peptide as a risk marker for incident hypertensive cardiovascular events. Hypertens Res 2002;25(5):669 – 76.
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to identify a low-risk group of approximately 1y3 of the patients in this otherwise high-risk group of patients with hypertension and electrocardiographic LV hypertrophy. Patients with an elevated NT-proBNP or known CVD had an approximately four-fold increase in event rate, while patients with a high plasma NT-proBNP as well as known CVD had a seven-fold increased risk. The strong prognostic value was still present with NTproBNP measured after one year of treatment based on either a beta-receptor-blocker or an angiotensin-II receptor antagonist. In addition, the prognostic value of NT-proBNP has been confirmed in another yet unpublished study. In a group of more than 200 unselected hypertensive patients with normal echocardiograms and without severe cardiovascular disease or diabetes, 3-year event rates were 2% and 11% in patients with NT-proBNP below or above the median value of 163 pgyml, respectively. In conclusion, available data suggest a strong prognostic value of NT-proBNP in patients with arterial hypertension.
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