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European Journal of Heart Failure 2005 7(4):512-519; doi:10.1016/j.ejheart.2004.07.014
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© 2005 European Society of Cardiology

Reduced myocardial velocities of left ventricular long-axis contraction identify both systolic and diastolic heart failure—a comparison with brain natriuretic peptide

Dragos Vinereanu, Pitt O. Lim, Michael P. Frenneaux and Alan G. Fraser*

Wales Heart Research Institute, University of Wales College of Medicine Cardiff CF14 4XN, UK

* Corresponding author. Tel.: +44 29 20 74 3489; Fax: +44 29 20 74 3500. E-mail address: fraserag{at}cf.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Echocardiographic diagnosis of radial fractional shortening or global ejection fraction fails to diagnose all patients with heart failure; about 40%, with apparently normal global systolic function, will have elevated brain natriuretic peptide (BNP) concentrations and "pure" diastolic dysfunction. Screening methods do not include assessment of left ventricular (LV) longitudinal function, however, which is a more sensitive marker of subclinical disease.

Aims: We investigated the diagnostic potential of assessment of LV longitudinal function in suspected heart failure, in a comparison against BNP.

Methods: Fifty consecutive subjects (aged 65±12 years; 30 men) referred to a heart failure clinic with unexplained breathlessness were examined by echocardiography and had plasma BNP measured by fluorescence immunoassay.

Results: Global systolic function (ejection fraction) correlated moderately with log-transformed BNP (r=–0.54), as did global diastolic function (r=0.55 for estimated LV filling pressure, and r=–0.51 for transmitral flow propagation velocity), and radial systolic function (r=–0.60) (all p<0.001). The echocardiographic parameter that correlated best with BNP, however, was LV longitudinal systolic function (r=–0.78, p<0.001). By stepwise multiple regression analysis, BNP was predicted by longitudinal systolic velocity, in association with LV mass index and radial systolic velocity (r=0.81, r2=0.66, p<0.0001). The sensitivity and specificity of a longitudinal systolic velocity of ≤5.5 cm/s (mean of 4 basal segments) to diagnose heart failure (defined as an elevated BNP) were 94% and 85%, respectively; the negative predictive value was 97%.

Conclusion: Non-invasive diagnosis or exclusion of suspected heart failure, whether systolic or diastolic, can be performed accurately by echocardiographic measurement of LV longitudinal systolic function.

Key Words: Natriuretic peptides • Heart failure • Echocardiography

Received February 4, 2004; Revised July 5, 2004; Accepted July 15, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Non-invasive diagnosis of left ventricular (LV) dysfunction by echocardiography is most often based on the assessment of ejection fraction [1]. This may be measured accurately by planimetry of left ventricular end-diastolic and end-systolic areas, which reflect global function, or it may be estimated from radial fractional shortening using the Teichholz formula [2] although it is inaccurate. Neither method performs optimally when compared with brain natriuretic peptide (BNP), a cardiac neurohormone secreted by the ventricles in response to volume expansion and pressure overload [1]. BNP is highly accurate in diagnosing heart failure since blood concentrations correlate with LV diastolic pressure and New York Heart Association (NYHA) functional class [3,4]. Conventional echocardiographic tests of systolic function are normal in some patients who have elevated BNP, giving false negative results in patients who may then be diagnosed to have diastolic heart failure [5].

Changes in longitudinal shortening of the LV, which is determined particularly by the function of the subendocardial fibres [6], are more sensitive markers of early systolic dysfunction associated with ageing [7] or caused by subclinical disease [8,9]. We therefore investigated the diagnostic potential of measuring longitudinal function in suspected heart failure, in a comparison against BNP.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study groups
In a cross-sectional study, we investigated 50 patients (65±12 years, 30 men) referred to a specialist heart failure clinic for assessment of breathlessness. All patients were in sinus rhythm, and none had a history of myocardial infarction. Subjects with moderate or severe valvar disease were excluded.

The diagnosis made by clinical, ECG, and echocardiographic criteria, was hypertensive heart disease in 15 patients, ischemic heart disease in 17 patients, and dilated cardiomyopathy (probably non-ischemic) in six patients. In 12 patients, breathlessness was diagnosed to be non-cardiac (asthma in two cases, and hyperventilation in 10 cases); all these 12 patients had normal clinical examination of the cardiovascular system, a normal resting 12-lead ECG, and normal transthoracic echocardiography. Seventeen patients were taking an angiotensin converting enzyme inhibitor, 29 a diuretic, 4 a beta-blocker, 11 a statin, and 5 a calcium-antagonist. The investigation conformed with the principles outlined in the Declaration of Helsinki. The protocol was approved by the Local Research Ethics Committee, and each patient gave informed consent.

2.2. Echocardiography
Patients were studied using a Vingmed System 5 echocardiographic machine (GE Vingmed, Horten, Norway), with a 1.5–2.5 MHz transducer. Digital echocardiographic data were acquired and transferred to a Macintosh computer.

M-mode tracings from the parasternal long-axis view were used to measure septal thickness, LV diameter, and posterior wall thickness, and LV mass index was calculated (method of Devereux with the application of the Penn convention). Cross-sectional images were recorded from the apex in apical four-chamber and two-chamber planes, and end-diastolic and end-systolic areas were measured for the calculation of ejection fraction (modified biplane Simpson's method). Pulsed-wave Doppler of transmitral flow was used to assess global diastolic function, with the sample volume placed at the tips of the mitral leaflets in the apical four-chamber view. The following Doppler indices were measured: peak early velocity (E), peak atrial velocity (A), E-wave deceleration time, and atrial wave duration. Mitral E/A ratio was calculated. Isovolumic relaxation time was measured on the pulsed-wave Doppler trace recorded with the sample volume placed between mitral inflow and aortic outflow. Pulmonary venous flow recordings were obtained from the apical four-chamber view, with the sample volume placed 1 cm into the right upper pulmonary vein, and the following parameters were measured: peak systolic velocity (S), peak diastolic velocity (D), peak atrial velocity (A), and atrial wave duration. Left ventricular inflow was recorded by colour M-mode echocardiography and flow propagation velocity was measured [10].

Off-line tissue Doppler measurements were made, of radial function from the basal posterior wall (parasternal long-axis view), and of longitudinal function from the velocities of basal septal and basal lateral segments (apical four-chamber view) and basal anterior and basal inferior segments (apical two-chamber view). Peak myocardial velocities in systole and early diastole were measured using customised software (Echopac TVI, GE Vingmed; mean of two consecutive beats), as previously described [11]. Velocities of the four segments imaged from the apex were averaged. LV diastolic filling pressure was estimated from the ratio of the mitral E wave, recorded by pulsed-wave Doppler, to the mitral annular early diastolic velocity (Ea wave) recorded by pulsed-wave tissue Doppler [12].

2.3. BNP plasma levels
Before the evaluation by echocardiography, a 5-ml blood sample was collected into a tube containing potassium EDTA. Plasma BNP was measured by fluorescence immunoassay with the Triage B-Type Natriuretic Peptide test (Biosite Diagnostics, San Diego, CA). The concentration of BNP is proportional to the fluorescence bound in the detection lane of the portable Triage meter, which measures levels between 1 and 1300 pg/ml, with a coefficient of variation between 10% and 16%. There is no significant cross-reactivity with endothelin-1, alfa-atrial natriuretic peptide, or aldosterone. The echocardiographer was unaware of the BNP levels.

2.4. Reproducibility
We have reported detailed studies of inter-observer agreement of tissue Doppler measurements in our laboratory [11]. Ten randomly selected studies were analysed by four observers, and each pooled standard deviation was divided by its corresponding mean value, to give a coefficient of variation (CV in %). Coefficients of variation were 8–13% for measurements of peak systolic velocity for the basal segments in the apical views.

2.5. Statistical analysis
Analysis was performed with SPSS software (version 11.0) (SPSS, Chicago, IL). Results are presented as mean value±standard deviation. BNP was log-transformed because its distribution was skew. Pearson's correlation was used to investigate relations between variables, and stepwise multiple regression to assess the influence of selected variables on BNP. Special software (comprhos.exe, courtesy of Professor Frank Dunstan, UWCM, Cardiff, UK) was used to compare pairs of correlation coefficients. The utility of longitudinal systolic velocity for the diagnosis of LV dysfunction was compared with BNP (normal range defined as mean±2SD of the subjects with non-cardiac cause of breathlessness) using receiver-operating characteristic (ROC) curves. Cut-off limits for myocardial velocities were determined, that gave as high a sensitivity as possible while accepting if necessary a lower specificity, in order to minimise false negatives. A p<0.05 for a two-tailed test was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
General characteristics of the patients are shown in Table 1. Six patients (12%) with breathlessness were judged clinically to be in NYHA class I. The others all had abnormal breathlessness, which was graded as follows: 23 in class IIa (46%), 11 in class IIb (22%), 5 in class III (10%) and 5 in class IV (10%). Fourteen patients had systolic dysfunction, defined as an ejection fraction ≤50% as recommended by Vasan and Levy [13]. Twenty-four patients with normal ejection fractions had one or more abnormal indices of diastolic function, according to the echocardiographic criteria published by the European Study Group on Diastolic Heart Failure [14]: 21 had a prolonged isovolumetric relaxation time for age, 11 had an increased velocity of pulmonary venous retrograde flow during atrial systole, and 6 had prolonged atrial retrograde flow (>30 ms longer than the duration of mitral flow during atrial systole). Twelve patients had normal systolic and normal diastolic function.


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  		Table 1 General characteristics of the study group, and the correlations (r) with log-transformed brain natriuretic peptide

 
Plasma BNP levels ranged from 1 to 1016 pg/ml (median=150 pg/ml). The upper limit of the normal distribution, taken as 2 standard deviations above the mean concentration of BNP in the 12 patients with a non-cardiac cause of breathlessness, was 88 pg/ml; this was used to define the cut-off limit between patients with a non-cardiac cause of breathlessness and patients with a diagnosis of heart failure.

3.1. Left ventricular systolic function and BNP
The echocardiographic tests were analysed for their relationship with BNP concentration, using univariate correlations. Global LV systolic function, measured as ejection fraction using the biplane Simpson's formula, correlated inversely with log-BNP (r=–0.54, p<0.001). Radial or short-axis LV systolic function, measured by tissue Doppler as the peak systolic velocity of the myocardium in the basal posterior segment, also correlated inversely with log-BNP (r=–0.60, p<0.001). The echocardiographic parameter that correlated most strongly with log-BNP (Table 1), however, was the mean systolic velocity of LV longitudinal shortening (r=–0.78, p<0.001) (Fig. 1).


Figure 1
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  		Fig. 1 Relationship between 4-site mean longitudinal systolic velocity and log-transformed brain natriuretic peptide.

 
Of the 14 patients with a low ejection fraction, 10 had an elevated BNP concentration. There were four patients with a low ejection fraction (37±10%) who had a normal BNP concentration; all four of these patients were receiving an angiotensin converting enzyme inhibitor, a beta blocker, and oral diuretics.

3.2. Left ventricular diastolic function and BNP
LV filling pressure, estimated non-invasively as the E/Ea ratio, correlated with BNP (r=0.55, p<0.001). Left ventricular relaxation measured as the propagation velocity of early diastolic filling through the mitral valve, correlated inversely (r=–0.51, p<0.001). There were less strong inverse correlations between radial and longitudinal myocardial velocities during early diastolic relaxation and BNP (Table 1).

There were 24 patients with breathlessness who had a normal global ejection fraction (>50%) and at least one abnormal diastolic test. These patients therefore fulfilled the criteria for diastolic heart failure, but only 7 of them had an elevated BNP concentration (mean 203±94 pg/ml). These patients would get false negative diagnoses of normality according to global systolic function. Using tissue Doppler echocardiography, however, these seven patients had significantly lower longitudinal myocardial systolic velocities than did the 17 patients with normal ejection fraction and diastolic abnormalities on detailed Doppler echocardiography but normal BNP (32±24 pg/ml): the respective mean velocities were 4.9±0.8 cm/s compared with 6.7±1.1 cm/s (p<0.01).

3.3. Echocardiographic diagnosis of suspected heart failure
The performance of different echocardiographic tests for the diagnosis of heart failure (defined as BNP>88 pg/ml) is summarised in Table 2. Receiver operating characteristic (ROC) curves for selected parameters are displayed in Fig. 2. The diagnostic sensitivity of the conventional echocardiographic criterion of an ejection fraction ≤50%, was only 59%; using an optimal cut-point for ejection fraction of ≤59%, identified from the ROC curve, gave a sensitivity of 76%, a specificity of 61%, and positive and negative predictive values of 50% and 83% respectively.


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  		Table 2 Diagnostic performance of echocardiographic tests to detect patients with a brain natriuretic peptide concentration >88 pg/ml

 


Figure 2
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  		Fig. 2 Receiver-operating characteristic curves showing comparative diagnostic performance of mean longitudinal systolic velocity (p<0.0001), radial systolic velocity (p<0.0001), and ejection fraction (p<0.01), to detect patients with a brain natriuretic peptide concentration >88 pg/ml. The cut-points selected for optimal sensitivity and specificity are indicated on each curve.

 
The criterion with the highest overall diagnostic performance, assessed as the area under the ROC curve (AUC; also called the C statistic), was longitudinal mean systolic velocity (AUC 0.94). The optimal cut-point of ≤5.5 cm/s gave very high sensitivity (94%) and negative predictive value (97%) for diagnosing or excluding a BNP concentration >88 pg/ml (Table 2). In comparison, radial systolic velocity had high sensitivity but much lower specificity, and an AUC of 0.85. The AUC for ejection fraction was 0.74.

All the parameters listed in Table 1 were included in a multivariate analysis. BNP was predicted by mean longitudinal systolic velocity (β standardised coefficient 0.35) in association with LV mass index (β standardised coefficient 0.39) and radial systolic velocity (β standardised coefficient 0.28) (r=0.81, r2=0.66, p<0.0001).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
We have demonstrated that the echocardiographic diagnosis or exclusion of suspected heart failure, whether systolic or diastolic, should be performed using measurements of LV longitudinal systolic function, since mean longitudinal myocardial systolic velocity is the echocardiographic parameter that correlates most closely with blood concentrations of brain natriuretic peptide. Correlations between conventional diagnostic indicators such as ejection fraction and radial systolic function, and BNP, are less strong.

4.1. BNP as a marker of LV dysfunction
BNP is a 32 amino-acid polypeptide secreted by the ventricles in response to increases in filling pressure, and in proportion to wall stress [15,16]. BNP is elevated in patients with asymptomatic LV dysfunction, whether systolic due to ischemic heart disease, or predominantly diastolic due to left ventricular hypertrophy secondary to hypertension [17,18]. In comparisons against conventional echocardiography, BNP had a sensitivity of 86–97% and a specificity of 84–98% to detect an LV ejection fraction <50% [3,19]. In a community study of 3177 participants, the performance of BNP to detect LV systolic dysfunction was suboptimal (AUC<0.75), but echocardiographic LV ejection fraction was only assessed visually [1]. Using accurate measurements of ejection fraction by magnetic resonance imaging, the sensitivity of N-terminal pro-BNP to detect an abnormal ejection fraction was 84% and the specificity was 85% [4].

Since BNP is a good marker of LV dysfunction, it is an appropriate independent standard against which echocardiographic parameters of systolic and diastolic function can be tested for their ability to diagnose suspected heart failure, as was performed in our study. Normal upper limits of BNP vary according to the population that is studied (for example, whether symptomatic or asymptomatic, of which etiologies, and using which definitions of LV dysfunction) and depending on the assay [1]. We defined a cut-off limit of 88 pg/ml, from the mean+2SD of the BNP concentration in patients with a non-cardiac cause of breathlessness; this value is similar to the levels defined in previous studies using the same immunoassay, which were 75, 76 and 80 pg/ml [3,19,20]. Furthermore, in the recent large ‘Breathing Not Properly— Multinational Study of 1586 patients presenting to the emergency department with breathlessness, a BNP threshold of ≥100 pg/ml was very accurate (AUC=0.90) in separating out those patients with heart failure, whether systolic or diastolic, from those with non-cardiac pathologies [21].

4.2. Diagnosis of heart failure by echocardiography
In this study, we observed as expected that reduced systolic function as measured in standard echocardiographic protocols in patients with suspected heart failure, was related to increasing concentrations of BNP, but the correlations were only moderate. Classifying patients by these traditional echocardiographic criteria alone, without reference to BNP concentration, would have given many false negative and false positive results.

Ejection fraction is considered to be a very useful test, but of course it fails to diagnose patients with diastolic heart failure. Ejection fraction is maintained with age [22] and so it is insensitive to the reduction of left ventricular longitudinal systolic function that can be observed with echocardiographic techniques that measure regional function [7]. Estimation of global systolic function from M-mode echocardiographic studies of radial function in a parasternal long-axis image of the left ventricle, is still applied using the Teichholz formula, but this is a considerable simplification in which ventricular volumes are obtained by cubing a single short-axis diameter (D): [7/(2.4+D)]xD3 [2]. Its application in patients with abnormal left ventricular geometry is inaccurate.

Left ventricular longitudinal function can now be measured accurately and reproducibly using tissue Doppler echocardiography [11]. Not only has this technique revealed aging of longitudinal systolic function in normal subjects [7], but it has also demonstrated that long-axis systolic and diastolic function are closely matched [23]. These observations seriously question if there is really a clinical condition of "pure" diastolic heart failure. Tissue Doppler echocardiographic studies in patients with diabetes mellitus have also demonstrated a possible reason for the suboptimal diagnostic performance of measurements of radial systolic function: in patients with subclinical disease and reduced longitudinal function, radial systolic function was increased, perhaps as a compensatory response [24].

4.3. Tissue Doppler diagnosis of subclinical LV dysfunction
The predominant orientation of myocardial fibers varies across the wall of the left ventricle. Echocardiographic tests of radial or short-axis function assess the mid-wall fibres of the LV which are orientated around the circumference of the ventricle; in this study, radial function was measured as the velocities of the basal posterior myocardial segment assessed from a parasternal window. Long-axis function of the LV is controlled by the subendocardial fibres since they are aligned longitudinally [6]; in this study, long-axis function was measured as the velocities of motion of basal myocardial segments assessed from apical imaging planes. Tissue Doppler measurements were made only from the basal segments because these have the best feasibility and reproducibility [11], which may be especially relevant in patients with heart failure and low velocities. Motion in the basal segments also represents the sum of all long-axis function in that ‘wall— of the left ventricle.

Since the subendocardium is most sensitive to ischemia and interstitial fibrosis [25], longitudinal velocities are decreased in the subclinical stages of heart failure; this has been shown in volume and pressure overload [8,9] as well as in ischemic heart disease [26]. We therefore tested, and indeed confirmed, the hypothesis that echocardiographic measurements of longitudinal function will best identify patients with raised BNP.

The precise hemodynamic trigger and mechanism of release of BNP from ventricular myocardium is not certain, but it has been demonstrated in the failing human heart that natriuretic peptides are differentially expressed across the ventricular wall with levels of BNP being upregulated predominantly in the subendocardium [27]. Thus altered subendocardial function might trigger BNP release before left ventricular dysfunction has progressed to involve all myocardial layers and to be manifest as systolic as well as diastolic dysfunction. Support for these concepts comes from studies of the effects of aging: long-axis systolic function declines with age [7] and there is also a small but significant increase in BNP concentration in normal subjects with age [28].

We observed significant correlations between both longitudinal and radial myocardial diastolic velocities and BNP concentrations, but these correlations were less strong than those demonstrated for systolic function. A major reason may be that myocardial diastolic velocities are affected by changes in preload [29].

4.4. Study limitations
There are no agreed criteria for the diagnosis of LV dysfunction by BNP, and so we applied a limit based on the BNP values obtained in the 12 subjects who had a normal clinical examination, a normal electrocardiogram, and normal systolic and diastolic function on detailed echocardiographic examination. This limitation, however, is shared by several previous studies [3,19–21].

Patients were receiving their usual treatment at the time of this study, so confounding effects of drug treatment cannot be excluded. For example, the small number of subjects with reduced ejection fraction who had normal BNP levels were all receiving beta blockade, which reduces myocardial tissue Doppler velocities [30]. It is also possible, however, that these patients had normal BNP levels because they were being successfully treated so that at the time of the study their left ventricular diastolic filling pressures were not significantly elevated [31].

The patients recruited for this study did not include any subjects who had had a myocardial infarction or who had a regional wall motion abnormality. Mean longitudinal systolic velocity is a less accurate indicator of global function in patients after myocardial infarction [32], but our results suggest that it might still be a closer correlate of BNP. Further studies in larger numbers of subjects, including patients with regional left ventricular dysfunction or with atrial fibrillation, would be helpful. It would also be interesting to study the relationships between BNP release and myocardial strain or strain rate; these newer tissue Doppler indices of regional contractile function are less influenced by tethering effects, and they are helpful as diagnostic markers of diastolic heart failure, as shown for example in a recent study of amyloid heart disease [33].

The argument could be advanced that new and more precise echocardiographic tests of heart failure are not needed, because plasma BNP concentration is now accepted as a definitive test. In the Framingham population study, however, it was shown that BNP was not very accurate for detecting heart failure [1]. A new echocardiographic test such as reduced long-axis systolic function compared with large normal populations would be very helpful.

Another possible limitation of using a cut-off limit of the longitudinal mean systolic velocity in order to diagnose suspected left ventricular dysfunction is the relatively moderate reproducibility of these measurements. However, reproducibility of acquiring and measuring myocardial velocities is better than for the previous echocardiographic methods, already used for the assessment of left ventricular function in routine clinical practice, such as measurements of left ventricular dimensions and ejection fraction (by Simpson's rule) [34]. Furthermore, a coefficient of variation of 10% would imply that two measurements can be confidently taken to be different when the value changes by 28% [11].


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The echocardiographic diagnosis of subclinical or early left ventricular dysfunction in suspected heart failure, especially in patients with normal global systolic function, should include assessment of longitudinal systolic function by tissue Doppler echocardiography. In studies of the diagnostic value of BNP, it should be compared with LV longitudinal systolic function, instead of the less sensitive parameter of ejection fraction.


   Acknowledgements
 
Dr Dragos Vinereanu was supported by a grant from the Heart Research Fund for Wales.


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

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