Study Population

A total of 1192 consecutive patients who were referred to our echocardiography laboratory for diastolic stress tests between September 2005 and March 2008 were enrolled. The evaluation of exertional dyspnea was the reason for performing diastolic stress echocardiography in 263 patients, and the assessment of LV functional reserve during exercise in patients with hypertension, diabetes mellitus, both diabetes and hypertension, hypertrophic cardiomyopathy or dilated cardiomyopathy, and end-stage renal disease was the reason in 613, 95, 81, 107, and 33 patients, respectively. Among them, 385 patients with abnormal relaxation on Doppler mitral inflow (E/A ratio < 0.75 or E-wave DT > 240 ms) were prospectively enrolled in this study. Patients who met the following criteria were excluded from participation: LV ejection fraction < 50%; significant valvular heart disease of more than a mild degree; any forms of cardiomyopathy, history, or diagnosis of ischemic heart disease by coronary angiography or exercise-induced new regional abnormality; and any conditions that cause volume expansion, such as chronic kidney disease (creatinine clearance < 60 mL/min), hypothyroidism, or liver cirrhosis. Ultimately, the remaining 154 patients constituted the study population. All antihypertensive medications were withheld from midnight the day before diastolic stress echocardiography to control the short-term effects of antihypertensive medications. Study approval was obtained from the institutional review board of Yonsei University College of Medicine.

Blood Test

To evaluate the effect of volume status, we measured blood creatinine levels and hemoglobin concentrations in all patients. In addition, creatinine clearance was calculated using the Cockcroft-Gault equation.

Conventional Echocardiography

Standard 2-dimensional measurements (LV diastolic and systolic dimensions, ventricular septum, posterior wall thickness, and LV mass index) were obtained with M-mode quantification. LV ejection fraction was calculated using the modified Quinones method. Left atrial volume index was measured by the prolated ellipsoidal method, and LV outflow tract diameter was measured from the parasternal long-axis view. Blood pressure was measured in the left arm using an oscillometric blood pressure monitoring device (Solar 8000; GE Medical Systems, Milwaukee, WI). End-systolic pressure was estimated as (2 × systolic pressure + diastolic pressure)/3. Stroke volume (SV) was calculated as 0.785 × (LV outflow tract diameter) × time-velocity integral at LV outflow tract, and this value was used to calculate cardiac output (SV × heart rate).

Preload Augmentation by Leg Raise and Diastolic Stress Echocardiography

After obtaining rest images from the standard parasternal and apical views, the patient’s legs were passively elevated using a hinged examination plinth until their femoral ischial joint was at a 60° angle. The legs were passively elevated for 3 minutes, and then all Doppler echocardiographic parameters and hemodynamic parameters were remeasured in the leg-raised state. After the raised leg was lowered, graded multistage symptom-limited supine bicycle exercise testing was performed with a variable-load bicycle ergometer (Medical Positioning, Inc, Kansas City, MO). Patients pedaled at a constant speed beginning with a workload of 25 W, increasing by an increment of 25 W every 3 minutes. During exercise, simultaneous respiratory gas analysis and blood pressure, heart rate, and electrocardiographic recordings (Solar 8000) were performed.

Echocardiography was performed using a Vivid 7 ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway) with a 2.5-MHz transducer during rest, each stage of exercise, and recovery in the sequence described as follows. From the apical window, a 2-mm pulsed Doppler sample volume was placed at the opened mitral valve tip, and mitral flow velocities from 5 to 10 cardiac cycles were recorded. The mitral inflow velocities were traced, and the following variables were obtained: peak velocity of early and late filling and DT of the E-wave velocity. Tricuspid regurgitant jet velocity was also obtained to estimate pulmonary artery systolic pressure using continuous-wave Doppler, if measurable. Mitral annular velocity was measured using Doppler tissue imaging in pulsed-wave Doppler mode. The filter was set to exclude high-frequency signals, and the Nyquist limit was adjusted to a range of 15 to 20 cm/s. The gain and sample volume were minimized to allow for a clear tissue signal with minimal background noise. Early and late diastolic (e′ and a′) and systolic (S′) velocities of the mitral annulus were measured from the apical 4-chamber view with a 5-mm sample volume placed at the septal corner of the mitral annulus. These measurements were performed at baseline and with the legs raised, at each stage of exercise, and during recovery in the same sequence.

All data were stored digitally, and measurements were made at the completion of each study. Among the obtained Doppler beats, 3 clear and consecutive beats were measured, and their average values were used for further calculations. Two-dimensional echocardiographic images from apical views at rest and during exercise were acquired, digitized, recorded, and analyzed for wall motion analysis. LV diastolic function reserve and reserve index were calculated as Δe′ (change of e′ from rest to exercise) and resting e′ × Δe′, respectively, as in a previous study. As an index of exercise capacity, total exercise duration and V o ₂ max were used.

Statistical Analysis

Continuous variables are summarized as mean ± SD. Categorical variables are summarized as percentages of the group total. Comparisons of continuous variables between rest and leg raise were performed using paired-sample t tests. Comparisons of clinical characteristics, hemodynamic parameters, and Doppler echocardiographic indices between the subgroups were performed using analysis of variance with post hoc analysis using Tukey’s method and Fisher’s exact test for categorical variables. Comparisons of exercise-induced changes of hemodynamic parameters between subgroups were performed using repeated analysis of variance. Pearson’s correlation coefficients were used to assess correlations between normally distributed variables. Stepwise multiple linear regression analysis was performed to detect the independent determinants of exercise capacity. SPSS version 13.0 (SPSS, Inc, Chicago, IL) was used to compute all statistical analyses, and P values < .05 were considered statistically significant.

Baseline Characteristics

Baseline clinical and Doppler echocardiographic parameters are described in Table 1 .

Response to Preload Augmentation by Leg Raise

During passive leg raise, E velocity, A velocity, and the E/A ratio increased, and E-wave DT was significantly shortened; e′ velocity was also increased in response to passive leg raise. SV and cardiac output were also increased ( Table 2 ). The degree of E-velocity response to leg raise (ΔE _L ) significantly and inversely correlated with resting pulse pressure ( r = −0.261, P = .001), with a marginal correlation with age ( r = −0.140, P = .084). ΔE _L was significantly but weakly correlated with Δe′ _L ( r = 0.258, P < .001) and ΔS′ _L ( r = 0.159, P = .049). Resting e′ was not significantly correlated with ΔE/e′ _L ( r = −0.187, P = .372).

Subclassification According to Response to Leg Raise

Patients were divided into two groups according to resting E/e′ ratio: group I (E/e′ < 15 [n = 131]) and group II (E/e′ ≥ 15 [n = 23]). Group I subjects were further subdivided into group IA (persistent E/e′ < 15 after leg raise [n = 112]) and group IB (change in E/e′ ≥ 15 after leg raise [n = 19]) according to their responses to leg raise ( Figure 1 ). Group II had more women, older patients, and patients with lower S′ and a′ velocities than group IA, whereas there were no significant differences compared with group IB ( Tables 3 and 4 ). Group IB had more women and older patients compared with group IA ( Table 3 ). Group IB had lower resting e′ velocities than group IA ( Table 4 ). Group IB patients showed smaller increases in e′ velocity (0.13 ± 0.72 vs 1.19 ± 0.96 cm/s, P < .001) and higher increases in E velocity (22.4 ± 9.7 vs 15.0 ± 8.7 cm/s, P = .001) during leg raise compared with group IA patients ( Figure 2 ). Velocities of e′ during exercising (at 25 and 50 W) and the magnitude of e′-velocity changes during exercise were significantly lower in group IB compared with group IA. Diastolic functional reserve indices at 25 and 50 W in group IB were significantly lower than in group IA. Moreover, group IB patients had higher E/e′ ratios during exercise (at 25 and 50 W) than those in group IA, accompanied by lower exercise capacity compared with group IA. In a multivariate analysis, group IB was independently and significantly associated with lower V o ₂ max (β = −0.219, P = .010) and exercise duration (β = −0.198, P = .035), independent of age and gender ( Table 4 ). The change in E/e′ ratio with leg raise tended to be greater in older patients in group IB ( Table 5 ). Among group IB subjects (n = 19), 13 (68%) showed E/e′ ratios > 15 at any stage of exercising, but in group IA subjects (n = 112), only 11 (10%) showed E/e′ ratios > 15 at any exercise stage. Therefore, the sensitivity, specificity, positive predictive value, and negative predictive value of leg raise for the prediction of exercise-induced filling pressure elevation were 54%, 94%, 68%, and 90%, respectively.

Mitral inflow and annular velocities of each group at rest and during passive leg raise. (A) Patient with “stable” relaxation abnormality (RA) (group IA, resting E/e′ < 15, persistent E/e′ < 15 during leg raise). (B) Patient from group IB (resting E/e′ < 15, persistent E/e′ < 15 during leg raise). (C) Patient from group II (resting E/e′ > 15). FP , Filling pressure.

Table 4

Subgroups according to resting E/e′ and response of E/e′ to leg raise (Doppler echocardiographic parameters)

	E/e′ resting < 15		E/e′ resting ≥ 15
	Group IA (persistent E/e′ < 15 after leg raise)	Group IB (change to E/e′ ≥ 15 after leg raise)	Group II
Variable	(n = 112)	(n = 19)	(n = 23)	P
Geometry
LV ejection fraction (%)	67.7 ± 5.9	67.3 ± 6.3	67.9 ± 6.8	.958
LV mass index (g/m 2 )	98.4 ± 20.8	106.3 ± 28.0	103.9 ± 28.8	.279
LAVI (ml/m 2 )	22.6 ± 6.9	23.3 ± 7.2	23.3 ± 8.4	.865
Resting Doppler index
E velocity (cm/s)	52.2 ± 10.7	57.2 ± 11.3	67.5 ± 14.5 †‡	<.001
A velocity (cm/s)	75.7 ± 13.6	82.4 ± 14.4	91.8 ± 15.6 †	<.001
E/A	0.69 ± 0.12	0.70 ± 0.10	0.74 ± 0.11	.296
E-wave DT (ms)	234.3 ± 37.8	237.4 ± 41.9	239.0 ± 48.0	.853
e′ velocity (cm/s)	5.2 ± 1.1	4.7 ± 0.9 ∗	3.8 ± 0.8 †‡	<.001
a′ velocity (cm/s)	8.7 ± 1.7	8.0 ± 1.6	7.5 ± 1.6 ∗	.009
E/e′	10.4 ± 2.2	12.4 ± 1.7 †	18.0 ± 2.5 †§	<.001
S′ velocity (cm/s)	6.7 ± 1.2	6.4 ± 1.3	5.7 ± 1.2 †	.001
Doppler index during leg raise
E L velocity (cm/s)	67.2 ± 12.2	79.6 ± 14.5 †	81.2 ± 17.4 †	<.001
A L velocity (cm/s)	79.9 ± 15.1	88.6 ± 12.84 ∗	93.8 ± 15.0 †	<.001
E/A L ratio	0.86 ± 0.20	0.90 ± 0.16	0.87 ± 0.15	.671
e′ L velocity (cm/s)	6.4 ± 1.2	4.7 ± 0.9 †	3.8 ± 0.8 †	<.001
E/e′ L	10.8 ± 2.0	16.5 ± 1.3 †	16.8 ± 3.8 †	<.001
ΔE/e′ L	0.40 ± 1.74	4.16 ± 2.15 †	−1.20 ± 2.22 †§	<.001
S′ L velocity (cm/s)	6.7 ± 1.2	6.2 ± 1.1	6.0 ± 1.3	.018
ΔS′ L (cm/s)	0.02 ± 1.19	−0.21 ± 0.75	0.37 ± 0.83	.217

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