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European Journal of Heart Failure 2005 7(4):520-524; doi:10.1016/j.ejheart.2004.07.011
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© 2005 European Society of Cardiology

Tissue Doppler velocities of mitral annulus and NT-proBNP in patients with heart failure

Martin Tretjaka,*, Franc Verovnika, Davorin Benkoa and Mirta Kozeljb

a Department of Cardiology, General Hospital Slovenj Gradec Gosposvetska 1, 2380 Slovenj Gradec, Slovenia
b Department of Cardiology, University Medical Centre Ljubljana Zaloska 7, 1000 Ljubljana, Slovenia

* Corresponding author. Tel.: +386 2 8823 400; Fax: +386 2 8823 505. E-mail address: martin.tretjak{at}siol.net


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: It has been shown that pulsed wave tissue Doppler velocities of mitral annulus correlate well with left ventricular (LV) diastolic and systolic functions. It is not yet clear whether these velocities can be used to estimate left ventricular dysfunction in an unselected population of patients with clinical signs and symptoms of heart failure (HF).

Aim: To determine whether LV mitral annulus velocities measured by tissue Doppler imaging (TDI) correlate with plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with HF.

Methods and results: Early diastolic (Em) and systolic (Sm) TDI velocities of septal and lateral mitral annulus were measured in 50 patients with HF together with other conventional echocardiographic parameters, and compared with plasma NT-proBNP levels. Significant correlations were found between NT-proBNP level and Em velocity (r=–0.79), Sm velocity (r=–0.43), early transmitral to Em velocity ratio (r=0.38), LV end diastolic diameter (r=0.29), LV ejection fraction (r=–0.44) and tricuspid regurgitant velocity (r=0.31). In multiple regression model (R2=0.733), the Em velocity was the most important predictor of NT-proBNP level.

Conclusions: Early diastolic mitral annulus velocity measured by TDI correlates strongly with plasma NT-proBNP levels, and provides a simple, accurate and reproducible echocardiographic index of heart failure.

Key Words: Tissue Doppler imaging • Heart failure • NT-proBNP

Received May 4, 2004; Revised June 17, 2004; Accepted July 21, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Pulsed wave tissue Doppler imaging (TDI) is used to measure myocardial velocities. Motion of the mitral annulus results from contraction of the left ventricle (LV) along its longitudinal axis. Early diastolic (Em) velocity of the mitral annulus has been shown to be a good predictor of diastolic LV function that is relatively preload-independent [1–4]. It is useful in the detection of impaired LV relaxation, even in patients with atrial fibrillation (AF) [5]. Systolic (Sm) velocity correlates well with LV ejection fraction (LVEF) assessed by other modalities [6–8]. In patients with heart failure (HF), both velocities are reduced even in the presence of significant mitral regurgitation (MR) [9]. A correlation between TDI-derived velocities and the degree of heart failure has not yet been confirmed.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a 76 amino acid peptide with no known biological function. It is a remnant from cleavage of pro-brain natriuretic peptide to brain natriuretic peptide (BNP), which is a biologically active peptide with vasodilator and natriuretic properties secreted mainly by ventricular myocytes [10,11]. In HF patients, plasma levels of NT-proBNP and BNP are elevated and correlate strongly with NYHA functional status [12,13]. NT-proBNP appears to be a more discerning marker of early cardiac dysfunction than BNP [14,15].

The purpose of this study was to asses the correlation between TDI-derived velocities and plasma levels of NT-proBNP in HF patients, who were included in the study irrespective of their systolic function, heart rhythm and presence of significant MR.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
We studied 50 consecutive patients, 27 men, aged 50±10 years, who were admitted to the Department of Cardiology, General hospital Slovenj Gradec for echocardiographic evaluation of symptomatic HF (New York Heart Association classes II to IV) due to various causes. The diagnosis of HF was made by an experienced cardiologist on the basis of clinical signs and symptoms, X-ray data and elevated plasma levels of NT-proBNP.

All patients underwent standard echocardiographic examination performed in the left lateral decubitus position. An ATL HDI 5000 phased-array system equipped with TDI technology was used. The LVEF was calculated from apical four- and two-chamber views using the modified Simpson's method. Patients with LVEF >45% and normal LV end diastolic diameter (LVEDD) were defined as having diastolic heart failure. LVEDD was measured from parasternal long axis view at the tip of the mitral valve and maximal left atrial (LA) area from apical four-chamber view. Pulsed-wave Doppler was used to measure transmitral early diastolic velocity (E) and early deceleration time (DT). The peak regurgitant velocity at the tricuspid valve (TRV) was measured by continuous Doppler. The presence of significant mitral regurgitation was assessed according to published criteria [9]. Pulsed-wave TDI velocities were measured at the septal and lateral corners of the mitral annulus in the apical four-chamber position, with the mitral annulus motion being aligned with the sample volume line. A 5-mm sample volume was used. The main systolic velocity (defined as the major systolic positive wave) and the early diastolic velocity (defined as the first negative wave following T wave in simultaneous ECG tracing) were measured on-line at a sweep speed of 50 mm/s. During normal breathing three consecutive beats for patients in sinus rhythm and five for patients in atrial fibrillation were averaged. A mean value measured from the septal and lateral sites was calculated. All measurements were performed by an experienced echocardiographer blinded to the NT-proBNP levels.

NT-proBNP levels were measured in blood samples collected by venipuncture into EDTA tubes, up to 4 h before echocardiography. The automated electrochemiluminescence immunoassay (Roche-Elecsys 2010, ref. value 0–26.6 pmol/l) was used.

Continuous data are presented as mean±S.D. and categorical data as numbers (%). Natural log transformation was used for NT-proBNP levels because of logarithmic distribution. Student's t-test of unpaired samples was used to compare Doppler data and NT-proBNP levels in different subgroups of patients. Linear regression was used to determine correlations between continuous variables. The relationship of NT-proBNP level with age and different echocardiographic parameters (except E/Em ratio, a derived variable) was examined with a multiple linear regression model. Data were analysed using the standard statistical software (SPSS version 11.0; SPSS, Chicago, Illinois). A P value of <0.05 was considered significant.

The inter-observer variability was tested by two investigators in five patients, as described in previous studies [1,7]. The established error level was low: 6±4% for systolic velocity and 7±4% for early diastolic velocity.

The study was approved by the national medical ethics committee. All subjects gave a written informed consent to participate in the study.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The basic clinical and echocardiographic data of the patients studied are listed in Table 1. The causes of HF included: ischemic heart disease in 20 (40%) cases, systemic hypertension in 14 (28%), dilated cardiomyopathy in 4 (8%) and valvular dysfunction in 4 (8%) patients. In 8 (16%) patients, the cause of HF was not defined. Mitral annular velocities from TDI were recordable at both sites in all 50 patients. Table 2 shows Doppler and TDI data for all patients and patient subgroups. The mitral annular velocities from TDI in all patients were lower than in previously published studies of normal subjects [7]. There were significant differences in Em velocities and DT between patients with sinus rhythm and those with atrial fibrillation (AF). Significant differences were found in Em and Sm velocities and DT between patients with systolic and those with diastolic heart failure and in E and E/Em ratio between patients with and those without significant MR.


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  		Table 1 Basic clinical and echocardiographic data

 


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  		Table 2 Doppler and annular tissue Doppler data for all patients and different subgroups of patients

 
A strong and highly significant correlation (r=–0.79, P<0.001) between Em velocity and log NT-proBNP level was found in all patients (Fig. 1). The correlation between Sm velocity and log NT-proBNP level was weaker, but still highly statistically significant (r=–0.43, P=0.002). Additionally, log NT-proBNP levels correlated significantly with E/Em ratio (r=0,38, P=0.007), LVEF (r=–0.44, P=0.001), LVEDD (r=–0.28, P=0.044) and TRV (r=0.31, P=0.027), but not with E, DT or LA area (Table 3). Analysis with a multiple linear regression model revealed log NT-proBNP levels to be independently related to age, LVEF, LA area, Em velocity and Sm velocity (R2=0.73, P<0.001). The relation to Em was the strongest (β=–0.76).


Figure 1
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  		Fig. 1 Scatter plots showing the correlation between natural log of plasma NT-proBNP level and (A) early diastolic mitral annular velocity (Em); (B) systolic mitral annular velocity (Sm); (C) ratio of early transmitral to early mitral annular velocity (E/Em).

 


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  		Table 3 Relation of natural log NT-proBNP levels to age and echocardiographic indexes

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
To our knowledge, this is the first study to examine the correlation between the mitral annulus TDI velocities and NT-proBNP levels in unselected HF patients. In contrast to previous studies comparing TDI data and BNP levels [16–18] more than half of the patients in our study had AF. The patients were unselected, the prevalence of AF being only slightly higher than previously reported for patients with HF in our country [19].

The result of our study show that in patients with HF there are significant correlations between NT-proBNP levels and TDI-derived mitral annulus velocities, the correlation being the strongest for Em velocity. E/Em ratio, which is known to be an echocardiographic marker of LV filling pressure [1,5], was also related to NT-proBNP levels, but the correlation was weaker. A weak but still significant correlation with NT-proBNP levels was also found for LVEDD and TRV being a measure of right ventricular afterload. We found no correlation between DT and NT-proBNP. In a multiple regression model, Em velocity was the best single predictor of NT-proBNP levels. Mitral valve early/late diastolic velocity ratio and pulmonary vein reverse A wave duration were not analysed because the subgroup of patients with sinus rhythm was too small.

Our results are in contrast with the study by Mottram and coworkers [16] that examined the relationship between BNP plasma levels and the new echocardiographic indices of systolic and diastolic function in a group of highly selected patients. Their results showed a moderate degree of correlation between BNP and late diastolic mitral annular velocity, but no relationship between BNP and Em velocity. This difference in results can probably be explained by the selection of patients in their study, all patients had hypertension, sinus rhythm, normal LVEF and exertional dyspnea (New York Heart Association class II). BNP levels were increased with a narrower range and according to E/Em the majority of patients had normal LV filing pressure.

A recent study by Troughton et al. [17], on the other hand, examined the relation of BNP to newer echocardiographic diastolic indexes in patients with systolic heart failure in NYHA classes II–IV. They found a significant relationship between BNP levels and LV diastolic function measured by Em velocity and an even stronger correlation for DT and E/Em ratio. The results are comparable with the results of our study, bearing in mind that only 4 out of 106 patients had AF and that patients with severe MR were excluded. We showed, that significant MR has an important influence on E/Em because of higher E velocities, whereas Em velocity is not affected as demonstrated by Alam et al. [9]. In patients with atrial fibrillation, Em has been shown to correlate strongly with the time constant of relaxation ({tau}), whereas E/Em correlated well with left ventricular filling pressure [5]. Our observation that Em velocity correlates better with NT-proBNP levels than E/Em ratio can also be partially explained by the recently published study by Dokainish et al. [18]. They found that in patients with cardiac disease for PCWP>15 mm Hg, E/Em ratio appears more accurate than BNP, so it seems that BNP does not correlate with LV filling pressure that well. Em velocity is known to correlate strongly with the time constant of relaxation ({tau}), determined by cardiac catheterisation in all subjects irrespective of their LV filling pressure as demonstrated by Oki et al. [20]. We can speculate that in an unselected population of patients with HF Em velocity—as a measure of myocardial relaxation—is the main determinant for NT-proBNP secretion.

On the other hand, Sm velocity correlates strongly with global LV function determined by M-mode echocardiographic mitral annular displacement [7,8]. Our results confirmed a strong correlation (r=0.85, P<0.001) between Sm velocity and LVEF assessed by 2D echocardiography using Simpson's method. We studied patients with isolated diastolic LV dysfunction who had a preserved or mildly reduced LVEF (>45%) and high Sm velocities. The subjects with isolated LV dysfunction were found to have significantly higher Sm velocities. Consequently, the correlation between Sm velocity and NT-proBNP level was almost the same as between LVEF and NT-proBNP. Both were weaker then the correlation between Em and NT-proBNP, illustrating the importance of diastolic dysfunction in patients with systolic heart failure, as shown by other authors [21].

NT-proBNP levels have been used to guide HF therapy with some success. Some authors propose that echocardiographic findings may be important in determining the individual target level [17]. Our findings suggest that monitoring of HF treatment using serial Em measurements would be very simple and highly reproducible. Since Em velocity is relatively preload-independent, reducing preload with diuretics would have no significant impact on Em, and an increase would actually indicate improvement in LV function. Further studies are needed to clarify the possibility of TDI guided therapy of HF.

All studies hitherto mentioned were concerned only with the velocities along the long ventricular axis, taking no account of the function in the minor axis. We measured mitral annular velocities from only two corners of the mitral annulus. In the presence of regional wall motion abnormalities, the results may not reflect global LV function. We believe, however, that the effect of wall motion abnormalities was not important, because we have found a good correlation between Sm velocity and LVEF, comparable to the published values. Blood samples for NT-proBNP concentration measurements were not collected at the time of echocardiographic examination. Since elevated plasma NT-proBNP concentration was used as an inclusion criterion, we needed a time interval of up to 4 h for completion of the assay. In our opinion, the delay was not significant because the patient's functional status did not change significantly during this time, and because it has been shown that changes in plasma NT-proBNP levels require several days to become evident [22].

In conclusion, early diastolic mitral annulus velocity (Em) measured by pulsed wave tissue Doppler imaging (TDI) represents a simple, accurate and highly reproducible echocardiographic index of heart failure, and should therefore be incorporated into echocardiographic evaluation of LV function of patients with HF.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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