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European Journal of Heart Failure 2008 10(11):1094-1101; doi:10.1016/j.ejheart.2008.07.011
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© 2008 European Society of Cardiology

Stratification of impaired relaxation filling patterns by passive leg lifting in patients with preserved left ventricular ejection fraction

Tomoko Ishizua, Yoshihiro Seoa,*, Satoru Kawanoa, Shigeyuki Watanabea, Toshiyuki Ishimitsub and Kazutaka Aonumaa

a Cardiovascular Division, Institute of Clinical Medicine, Graduate School of Comprehensive Human Science, University of Tsukuba 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan
b Ibaraki Medical Center Japan

* Corresponding author. Tel.: +81 29 853 3142; fax: +81 29 853 3143. E-mail address: yo-seo{at}md.tsukuba.ac.jp (Y. Seo)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Methods: We evaluated diastolic functional reserve in 108 patients with normal left ventricular ejection fraction (LVEF) ≥ 50% but abnormal relaxation (ratio of transmitral peak velocity of early and late diastolic flow (E/A)<1) using passive leg lifting. We calculated the pulmonary venous systolic to diastolic flow ratio (S/D) as a marker of left atrial reservoir function, and the time difference between the duration of pulmonary venous retrograde flow (PVAd) and the duration of the mitral A wave (PVAd-Ad) as a marker of left ventricular end-diastolic pressure (LVEDP).

Results: During leg lifting, the E/A was ≥ 1 in 39 patients (the inverted group); the remaining 69 patients comprised the stable group. Comparing the inverted group with the stable group at baseline, S/D was smaller (1.5±0.4 vs. 1.8±0.5, P=0.002) and PVAd-Ad greater (11±23 ms vs. –23±28 ms, P<0.001).Multiple logistic regression analysis revealed that PVAd-Ad and S/D predicted E/A inversion with leg lifting after adjustment for age, LV wall thickness, LV dimension, LVEF, deceleration time of E, and E/E'.

Conclusion: In patients with preserved LVEF but early diastolic dysfunction, passive leg lifting may identify patients having a less compliant left ventricle and impaired left atrial reservoir function.

Key Words: Left ventricular dysfunction • Diastolic heart failure • Echocardiography • Diastolic functional reserve

Received November 23, 2007; Revised May 20, 2008; Accepted July 21, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Normal aging is accompanied by a reduction in the E and augmentation of the A of transmitral flow, and E/A becomes less than 1. The changes in these diastolic indices have been attributed to slower LV pressure decay or, as Hees et al. [1] have recently reported, to a reduction in mean left atrial pressure. Community-based studies have shown that isolated LV diastolic dysfunction is common in the elderly [2-4], and even mild diastolic dysfunction, as evidenced by an abnormal relaxation pattern, is associated with marked increases in all-cause mortality [2,3,5]. In addition to abnormal relaxation, some patients may have a concealed LV compliance abnormality. Patients with reduced LV compliance and abnormal LV relaxation pattern may be at high risk of developing diastolic heart failure [6]. In such a pathologic state, although the left atrial pressure is within the normal range, the LVEDP is increased [7-9]. Hadano et al. [8] evaluated the discrepancy between LVEDP and pulmonary capillary wedge pressure in patients with heart failure and showed that these parameters could be separately estimated non-invasively by Doppler echocardiography. LVEDP was estimated by PVAd-Ad [10,11], and pulmonary capillary wedge pressure was estimated by E/E' [12]. Estimation of LVEDP requires measurement of PVAd by transthoracic echo, but good quality images of pulmonary retrograde flow cannot always be acquired in the clinical setting. However, transmitral flow is easily recorded [13] in the majority of patients. In patients with severe LV systolic dysfunction, transmitral flow changes during passive leg lifting have been reported to stratify patients into subgroups with poor or good prognosis [14]. Transmitral flow changes during the leg-lifting manoeuvre may be associated with reduced LV compliance. Therefore, identification of subgroups of patients with abnormal LV relaxation and different levels of risk has important implications in the choice of interventional strategies to prevent diastolic heart failure. The present study was performed to test the hypothesis that in patients with preserved LVEF and an abnormal LV relaxation pattern, passive leg lifting could identify patients with reduced LV compliance but normal mean LV filling pressure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patient characteristics
We studied patients referred for routine echocardiographic evaluation of LV function. Patients with a LVEF≥50% and an abnormal transmitral flow relaxation pattern were eligible for inclusion. An abnormal transmitral flow relaxation pattern was defined as an E/A ratio <1. Patients with atrial fibrillation or flutter, regional LV wall motion abnormality, ischaemic heart disease, dilated cardiomyopathy, or severe mitral valve disease were excluded, as were patients with insufficient echocardiographic image quality for analysis. Informed verbal consent was obtained from all patients after a detailed explanation of the study was provided.

2.2. Echocardiographic procedure
A Toshiba SSA 390A echocardiographic system (Toshiba Medical Systems Corp., Tokyo, Japan) with a 3.5-MHz probe was used to perform Doppler and two-dimensional echocardiographic examinations, which were obtained with the patients lying in a supine or slightly left lateral decubitus position. The transmitral flow was recorded and E, A, E/A, the deceleration time of E, and A duration were measured (Fig. 1A). Systolic, early diastolic, and late diastolic mitral annulus velocities were measured by pulsed Doppler imaging with a 4-mm sample volume placed at the lateral corner of the mitral annulus from the apical window. Right upper pulmonary venous flow was recorded by Doppler, and the second peak systolic and diastolic forward flow peak velocities and of late diastolic retrograde flow duration were measured. In case of suboptimal pulmonary venous Doppler imaging quality, contrast enhancement was performed with Levovist [15] (Schering, Berlin, Germany). Measurements were repeated during a passive leg-lifting manoeuvre (legs elevated to 45° from the horizontal position), after haemodynamic conditions had been stabilized. E/E' was calculated as an index of left atrial pressure, PVAd-Ad as an index of LVEDP, and S/D as an index of left atrial reservoir function [16].


Figure 01
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  		Fig. 1 Measurements of transmitral flow velocities (A), pulmonary venous flow velocities (B), and mitral annulus velocities (C) in a 78-year-old man with hypertension from the inverted group. The E/A changed from 0.7 to 1.1 during leg lifting. The PVAd-Ad changed from 43 to 57 ms. E, peak velocity of early transmitral flow; A, peak velocity of late transmitral flow; DT, deceleration time of early transmitral flow; Ad, duration of late mitral flow; E', peak early diastolic velocity of mitral annulus; S, peak systolic velocity of pulmonary venous flow; D, peak diastolic forward velocity of pulmonary venous flow; PVAd, duration of retrograde pulmonary venous flow.

 
2.3. Statistical analysis
Results are expressed as number or mean±SD. Baseline characteristics and echocardiographic data at rest were compared with Student's t test for continuous variables and chi-squared and Fisher's exact test for categorical variables. Comparison between echocardiographic variables at rest and those during leg lifting was performed with a Wilcoxon signed-rank test. Differences were considered significant when the P value was <0.05. Multivariate logistic regression analysis was performed to identify independent predictors for an abnormal transmitral flow response during leg lifting. To examine possible confounding-adjusted correlations between echocardiographic measurements and an abnormal response of transmitral flow, age, sex, and other clinically important variables were entered in a multivariate logistic regression analysis as independent variables. Collinearity was controlled by checking whether standard error increased largely or the adjusted R2 decreased when the new variables were included. Receiver-operating characteristic (ROC) curves were constructed for the individual Doppler variables for the prediction of E/A inversion during leg lifting. All calculations were performed with the SPSS statistical program (Version 11.0, Chicago, Ill).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
A total of 108 patients (69 men, 39 women; age: 66±10 years) were enrolled in this study. Passive leg lifting was performed without any patient effort and was well tolerated in all patients. During passive leg lifting, changes in blood pressure and heart rate were not significantly different from baseline measurements. Thirty nine patients with an E/A≥1 during leg lifting were included in the inverted group (Fig. 1). The remaining 69 patients with an E/A<1 during leg lifting comprised the stable group. Patients in the inverted group were significantly younger than patients in the stable group (Table 1). The underlying disease or indication for echocardiography was hypertension in 27 patients, ECG abnormality in 22 patients, chest pain in 20 patients, LV hypertrophy in 11 patients, shortness of breath in 10 patients, diabetes in 8 patients, systolic murmur in 7 patients, and cerebrovascular disease in 7 patients (Table 1).


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  		Table 1 Clinical characteristics of the two patient groups

 
At baseline, the LV diastolic dimension was larger (Table 2), A was lower, E/A was larger, deceleration time of E was shorter, mitral A duration was shorter, systolic mitral annular velocity was lower, and duration of pulmonary venous late diastolic reversal flow was longer in patients in the inverted group than those in the stable group (Table 3). Other echocardiographic variables, including left atrial dimension, LVEF, LV wall thickness, early diastolic annular velocity, and E/E' were similar between the groups. During passive leg lifting, E, E/A (Fig. 2), and E/E' (Fig. 3) increased significantly in both groups, indicating that LV preload increased significantly with this manoeuvre. In the stable group, A increased significantly during leg lifting. In contrast, in the inverted group, A decreased significantly during leg lifting (Fig. 2).


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  		Table 2 Echocardiographic measurements of left ventricular and left atrial structural variables from the two patient groups

 


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  		Table 3 Echocardiographic measurements of left ventricular systolic and diastolic variables from the two patient groups

 


Figure 02
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  		Fig. 2 Early (E) and late (A) transmitral flow peak velocity and E/A at baseline and during leg lifting in both groups. In the stable group, E and A are significantly increased during leg lifting. In the inverted group, E increased, but A decreased during leg lifting.

 


Figure 03
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  		Fig. 3 Ratio of early transmitral flow velocity to mitral annular velocity (E/E') in the supine position and during leg lifting. The E/E' increased during leg lifting in both groups. No significant difference between the two groups was observed at baseline or during the manoeuvre, indicating that leg lifting was an effective manoeuvre to increase preload in the study subjects.

 
With respect to Doppler pulmonary venous flow measurements (Fig. 4), PVAd-Ad was significantly longer (11±23 ms vs. –23±28 ms, P<0.001), and S/D was significantly smaller (1.5±0.4 vs. 1.8±0.5, P=0.002) in the inverted group than in the stable group. These two parameters were still significantly different between the two groups in a multivariate logistic regression model after adjusting for age, LVDd, LV wall thickness, EF, DT, and E/E' (Odds ratio 4.8 for each 1SD(31 ms) increment of PVAd-Ad, P<0.001, Odds ratio 0.39 for 1SD(0.5) of S/D, P=0.003, respectively, R2=0.41).The sensitivity to detect an abnormal PVAd-Ad (>0) by an E/A ratio ≥1 during leg lifting was 70%, the specificity was 87%, positive predictive value was 78%, and negative predictive value was 81%.


Figure 04
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  		Fig. 4 Doppler pulmonary venous flow in the 2 groups. At baseline, the ratio of pulmonary venous flow during systole and diastole (S/D), which is a marker of left atrial compliance, was significantly smaller in the inverted group than in the stable group. PVAd-Ad, which is a marker of left ventricular end-diastolic pressure, was higher in the inverted group than in the stable group.

 
The ROC curve analysis predicting E/A inversion during leg lifting for PVAd-Ad and E/A is shown in Fig. 5. The largest area was 0.82, P<0.001 for PVAd-Ad compared with 0.76, P<0.001 for E/A ratio, 0.64, P=0.005 for deceleration time of E. Area under the curve for E/E' was not significant (P=0.16).


Figure 05
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  		Fig. 5 ROC curve for prediction of E/A inversion during leg lifting using PVAd-Ad and baseline E/A. Area under the curve 0.82 (PVAd-Ad) and 0.76 (E/A).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The present study shows, that in a subset of patients with preserved LVEF and abnormal relaxation, the E/A ratio increased to ≥1 during passive leg lifting. In these patients with an increased E/A ratio, the baseline PVAd-Ad was greater than in the other patients, which suggests that these patients have an elevated LVEDP despite having a normal left atrial pressure. Therefore, E/A changes induced by passive leg lifting, used as a volume loading manoeuvre, may indicate that transmitral flow changes from a mildly abnormal pattern to a more severely abnormal pattern, namely pseudonormalization [17].

Although there is growing recognition that heart failure caused by a predominant abnormality in diastolic function, i.e., diastolic heart failure, is both common and causes significant morbidity and mortality, its diagnostic criteria based on Doppler echocardiography are still controversial [6,18]. Because a large proportion of elderly patients show an abnormal relaxation pattern, an E/A<1 at rest alone may not be sufficient to produce symptomatic diastolic heart failure [19]. Therefore, it is important to detect LVEDP elevation in patients with an LVEF≥50% and an E/A<1. The present study showed that passive leg lifting is a useful manoeuvre to identify patients with PVAd-Ad>0. PVAd-Ad has been reported to correlate with an increase in LVEDP [10,11]. The main limitation in using PVAd-Ad to assess an increase in LVEDP is the difficulty of accurately recording reversal of atrial flow [20]. We measured PVAd using contrast-enhanced Doppler echocardiography, because previous reports have shown that contrast enhancement improves the pulmonary venous flow Doppler signal [15].

In the present study, the left atrial dimension could not be used to identify a concealed abnormality of LV compliance. Increased left atrial size has been reported to be associated with adverse cardiovascular outcomes [21] and is a marker of both the severity and chronicity of diastolic dysfunction and the magnitude of increase in left atrial pressure [22]. There may be two possible explanations: first, that a single left atrial dimension does not reflect the true left atrial volume [23] or second, that abnormal LV and left atrial stiffness can precede left atrial morphologic changes in patients with a normal pulmonary capillary wedge pressure.

4.1. Possible underlying mechanisms
During leg lifting, E/E', a marker of left atrial pressure, increased to a similar extent in both groups in the present study. However, the manoeuvre produced different transmitral flow responses, these were an E/A≥1 or an E/A<1. These results may indicate that the increase in left atrial pressure resulting from this manoeuvre is similar in magnitude in both groups. The E and pulmonary venous diastolic forward velocities increased in both groups; however, the A velocity increased in the stable group and decreased in the inverted group during leg lifting. A previous experimental study using multigrade volume loading showed that the A velocity increased after small volume loading, whereas it decreased with further volume loading [24]. The left atrium may be on the descending part of its Starling curve at high pre-A pressures [25], which could further contribute to the increased flow during atrial systole in the stable group with normal LV compliance. In contrast, since left atrial afterload against forward ejection increases as the LVEDP increases, "afterload mismatch" of the left atrium [16,26] may be induced in the inverted group because of decreased LV compliance.

In the present study, the pulmonary S/D ratio, which is a marker of left atrial reservoir function, was smaller in the inverted group. The pulmonary venous S/D ratio is theoretically influenced by LV contraction through the descent of the ventricular base during systole and left atrial chamber stiffness [27]. Ascribing systolic mitral annular velocity as an indicator of LV contraction, the lower value for systolic mitral annular velocity in the inverted group in the present study may indicate diminished LV contraction, although LVEF was similar in both groups. Therefore, the smaller S/D ratio in the inverted group may be influenced by both abnormal left atrial stiffness and decreased LV contraction.

In summary, these observations may be explained by the following mechanism: the small amount of volume loading induced by the leg-lifting manoeuvre may shift the pressure-volume loop higher in patients with a less compliant LV and an elevated LVEDP at baseline (Fig. 6). Pozzoli et al. [14] have shown that leg lifting increases LV end-diastolic volume and that in some patients, an end-diastolic volume increase of similar extent was attained at the expense of a far greater rise in LVEDP. In a less compliant LV, the LVEDP is elevated or the heart is working at a higher point on the end-diastolic pressure-volume relationship [6].


Figure 06
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  		Fig. 6 Pressure-volume loops comparing a normal left ventricle with a normal end-diastolic pressure (A) and a stiff left ventricle with limited preload reserve (B). Solid line indicates baseline condition in the supine position; dotted line indicates leg lifting. EDPVR, end-diastolic pressure-volume relationship.

 
4.2. Clinical implications
Abnormal LV relaxation is common in elderly patients, who often report shortness of breath on exertion. It can be difficult to determine whether these symptoms are due to diastolic heart failure or merely to the reduced physiological function associated with normal aging. The present study revealed an abnormal response to passive leg lifting with associated Doppler echocardiographic findings consistent with an elevated LVEDP and reduced left atrial reservoir function. In such patients, excessive fluid infusion may aggravate heart failure. Therefore, using the leg-lifting manoeuvre to detect concealed diastolic dysfunction with reduced LV compliance may contribute to the prevention of acute worsening of diastolic heart failure.

4.3. Study limitations
There were several limitations to this study. First, there was no direct measurement of changes in LV pressure during leg lifting. However, previous investigations have shown that passive leg lifting results in effective volume loading in patients with severely impaired LV systolic function [14], and the results could be extrapolated to patients with preserved EF. Second, direct haemodynamic evidence of the concealed LV diastolic dysfunction has not been shown in the present study. Although the presence of a less compliant ventricle is supposed to indicate a poorer prognosis compared to that of an LV with normal compliance and reduced LVEF [28], no data concerning outcomes were obtained in the present study. Further haemodynamic and follow-up investigations should be performed to evaluate these important aspects.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Passive leg lifting is a technically feasible non-invasive manoeuvre for identifying a LV with reduced compliance and abnormal relaxation in patients with preserved LVEF. Therefore, this manoeuvre may be useful to identify patients at high risk for developing diastolic heart failure.


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

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