The Journal of International Medical Research 2005; 33: 454 – 459

Brain Natriuretic Peptide and the Severity of Aortic Regurgitation: Is There Any Correlation? M OZKAN, O BAYSAN, K ERINC, C KOZ, M YOKUSOGLU, M UZUN, C SAG, C GENC, H KARAEREN AND E ISIK Faculty of Medicine, Department of Cardiology, Gulhane Military Medical Academy, Ankara, Turkey We aimed to evaluate the correlation between aortic regurgitation severity and brain natriuretic (BNP) levels as a marker for left ventricular dysfunction. Sixty consecutive male patients (mean age 22 ± 3 years) with isolated chronic aortic regurgitation were enrolled in the study together with a control group of 30 agematched healthy volunteers (group A). Patients were classified with regard to aortic regurgitation vena contracta width KEY WORDS: BRAIN

as follows: group B, < 3 mm, mild (n = 16); group C, ≥ 3 and < 6 mm, moderate (n = 26); group D, ≥ 6 mm, severe (n = 18). BNP measurements were performed with a fluorescence immunoassay kit. BNP levels were increased in patients with aortic regurgitation, and severity of regurgitation had a significant influence on BNP levels. This effect can be explained by the volume loading effect of aortic regurgitation.

NATRIURETIC PEPTIDE;

AORTIC REGURGITATION; VENA FLUORESCENCE IMMUNOASSAY

Introduction

CONTRACTA WIDTH;

have rarely been studied, however.11 We

The heart mainly secretes two natriuretic peptides: atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). ANP is released into the circulation even with minor stimuli such as posture and fluid loading.1,2 Contrary to rapid fluctuations in plasma ANP concentration, BNP concentration shows minor oscillations,3 and its secretion is directly related to ventricular volume and pressure overload.4,5 Of these two peptides, BNP is a more sensitive marker for left ventricular dysfunction and emerges as a congestive heart failure diagnostic tool.6 – 10 BNP plasma levels in aortic regurgitation

evaluated plasma natriuretic peptide levels in young male patients with various aortic regurgitation severities.

Patients and methods PATIENTS Between November 2002 and May 2004, consecutive male patients with isolated chronic aortic regurgitation (New York Heart Association [NYHA] Class II) were enrolled in the study. Patients with concomitant diseases that may affect BNP measurement such as mitral regurgitation greater than to a mild degree, mitral stenosis in any degree, aortic

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M Ozkan, O Baysan, K Erinc et al. Brain natriuretic peptide and aortic regurgitation stenosis (mean gradient > 25 mmHg) and respiratory or renal disease were excluded. Patients with multiple or diffuse aortic regurgitant jets on colour Doppler echocardiography were also excluded. Age-matched healthy male subjects without clinical symptoms or signs of cardiopulmonary or renal disease were used as controls (group A). The study protocol was approved by the regional ethics committee and all patients gave written informed consent.

ECHOCARDIOGRAPHIC EXAMINATION Data were obtained using Hewlett Packard Sonos 2500® echocardiographic equipment. All patients underwent comprehensive examination, including M-mode, two-dimensional and Doppler echocardiography. Colour Doppler imaging was performed with standard colour encoding and Nyquist limit between 50 and 60 cm/s. The gain was adjusted to the maximal colour gain without signal outside flow areas. The colour Doppler images of the vena contracta were obtained from parasternal long-axis views. Transducer position was optimized to visualize the flow convergence region and regurgitant flow jet. With a zoom of the region of interest, meticulous care was taken to visualize the vena contracta (VC), defined as the narrowest neck of regurgitant flow immediately downstream from the flow convergence region. Measurement of vena contracta width (VCW) was performed as previously described.12 Patients with aortic regurgitation were further stratified into three subgroups according to VCW as recommended by the American Society of Echocardiography:13 16 patients had mild aortic regurgitation (VCW < 3 mm, group B); 26 patients had moderate aortic regurgitation (VCW ≥ 3 and < 6 mm, group C); and 18 patients had severe aortic regurgitation (VCW ≥ 6 mm, group D).

During the echocardiograpic examination the following parameters were also measured: left ventricular internal diameter diastolic (LVIDd); left ventricular internal diameter systolic (LVIDs); ejection fraction (EF); fractional shortening (FS); end diastolic volume (EDV); end systolic volume (ESV); interventricular septum diastolic (IVSd); and posterior wall diastolic (PWd).

BRAIN NATRIURETIC PEPTIDE MEASUREMENT Immediately before echocardiographic examination, 2 cc venous whole blood samples taken from every patient were collected into a tube containing potassium ethylenediamine tetra-acetic acid. BNP was measured immediately with the Triage® BNP Test (Biosite Diagnostics, La Jolla, CA, USA), which uses the fluorescence immunoassay method. The method has previously been described and measurement of plasma BNP levels has been validated in other studies.14 – 16

STATISTICAL ANALYSIS One-way analysis of variance (ANOVA) with post hoc test (least significant difference) and Pearson’s correlation were used in 0.05 was considered comparisons. P statistically significant.

Results The baseline characteristics of the overall study group, consisting of 90 patients, are shown in Table 1. Sixty consecutive male patients (mean age, 22 ± 3 years) with isolated chronic aortic regurgitation were enrolled; of these 57 were asymptomatic and three were symptomatic (all NYHA Class II). One-way analysis of variance revealed significant differences in BNP levels between all groups (P < 0.001; Table 2). BNP levels increased even in patients with mild aortic regurgitation. Levels of BNP were increased

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TABLE 1: Baseline characteristics of patients in this study which investigated brain natriuretic peptide (BNP) levels in patients with aortic regurgitation Group

A (n = 30)

B (n = 16)

C (n = 26)

D (n = 18)

22 ± 3

23 ± 4

23 ± 3

22 ± 3

0

0.28 ± 0.04

0.47 ± 0.06

0.9 ± 2.2

Left ventricular internal diameter diastolic (mm)

48 ± 3

48 ± 3

54 ± 5

64 ± 6

Left ventricular internal diameter systolic (mm)

30 ± 4

30 ± 3

35 ± 4

41 ± 4

Ejection fraction (%)

68 ± 7

68 ± 3

64 ± 5

65 ± 4

Fractional shortening (%)

37 ± 6

38 ± 3

35 ± 4

35 ± 3

End diastolic volume (ml)

110 ± 19

107 ± 17

149 ± 29

185 ± 82

End systolic volume (ml)

37 ± 12

33 ± 8

51 ± 14

67 ± 30

Interventricular septum diastolic (mm)

9.2 ± 1.7

9.7 ± 1.3

9 ± 1.1

10.1 ± 2.1

Posterior wall diastolic (mm)

7.9 ± 1.6

11 ± 0.8

10.8 ± 1.1

11.6 ± 1.6

Age (years) Vena contracta (mm)

Values are given as mean ± SD. A, control; B, mild aortic regurgitation; C, moderate aortic regurgitation; D, severe aortic regurgitation.

TABLE 2: Brain natriuretic peptide (BNP) levels in patients in this study which measured BNP levels in patients with aortic regurgitation Group

A (n = 30)

B (n = 16)

C (n = 26)

D (n = 18)

P-value

BNP (pg/ml) median 1.2 5.0 3.9 13.1 < 0.001 (mean, range) (1.1, 0.1 – 2.1) (5.1, 2.5 – 8) (7.3, 0.9 – 24.5) (31.06, 1.2 – 200) A, control; B, mild aortic regurgitation; C, moderate aortic regurgitation; D, severe aortic regurgitation.

in patients with aortic regurgitation, and severity of aortic regurgitation had significant influence on BNP levels (r = 0.603, P < 0.001). Pearson’s correlation showed that the difference in BNP levels between the groups was significant (P < 0.05) except for between group B and group C (Fig. 1).

Discussion This study shows that plasma BNP levels increase in patients with aortic regurgitation. Plasma BNP concentration

increases with various conditions, especially heart failure, and is secreted mainly from ventricular myocytes, exerting its effects via natriuretic peptide receptors.17,18 Although BNP measurement is the principle heart failure diagnostic tool, other factors including drugs, chronic pulmonary disease, systemic and pulmonary hypertension, renal failure, aortic stenosis, mitral stenosis, and some endocrine diseases can affect plasma BNP levels.19 – 24 The exact mechanisms responsible for BNP secretion are unclear;

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120 P = 0.001 P = 0.032 NS

100 P = 0.001

BNP (pg/ml)

80

P = 0.001 P = 0.009

60

40

20

0 30 control s

16 mild

26 moderate

18 severe

FIGURE 1: In this study investigating brain natriuretic peptide (BNP) levels in patients with aortic regurgitation, BNP levels in patients with mild (group B, n = 16), moderate (group C, n = 26), severe (group D, n = 18) and no aortic regurgitation (controls, group A, n = 30) were measured. BNP levels increased with aortic regurgitation severity, and the difference in BNP levels between the groups was significant (P < 0.05) except for between group B and group C. NS, not significant

however, increased wall tension, secondary to pressure or volume overload and stretch, seems to play an important role25,26 and has been demonstrated in other studies.27,28 Volume overload caused by mild aortic regurgitation could lead to higher wall stress. Gerber et al.11 previously reported that BNP levels were higher in asymptomatic patients with aortic regurgitation compared with control subjects. In our study, BNP levels were higher even in patients with mild aortic regurgitation, and there were no differences in left ventricular dimensions in this subgroup compared with the control group. BNP levels were not increased among

patients with severe aortic regurgitation, as expected, and left ventricular, particularly end diastolic volumes, were increased. We suggest that plasma BNP levels reached a plateau in patients with aortic regurgitation in response to chronic volume overload. Patients with severe aortic regurgitation, contrary to mild or moderate aortic regurgitation, had BNP levels above previously reported normal values for the same age group.16 This might imply improved diagnostic capability of BNP measurement in patients with severe aortic regurgitation. This study has some limitations, however:

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M Ozkan, O Baysan, K Erinc et al. Brain natriuretic peptide and aortic regurgitation selection of vena contracta for the severity of regurgitation may be inadequate;12,29 other severity measures – such as jet width, jet width/left ventricular outflow tract width, and jet cross-sectional area/left ventricular outflow tract cross-sectional area – could be implemented for better discrimination; left ventricular wall stress measurement could also be applied; the number of samples in this study was limited; and selecting patients with same gender (male) and age prevents extrapolation of the results to women and

other age groups. The effects of gender and age on plasma BNP levels were not considered.30 In conclusion, BNP levels increase in patients with aortic regurgitation. Further studies on the effect of the severity of aortic regurgitation on BNP levels are needed.

Conflicts of interest No conflicts of interest were declared in relation to this article.

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Address for correspondence Dr M Ozkan Gülhane Askeri Tip, Akademisi Kardiyoloji AD, Etlik/Ankara, 06018, Turkey. E-mail: [email protected]

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