Background
Inconsistencies between gradients and aortic valve area are frequent in the echocardiographic evaluation of aortic stenosis (AS). Assessing AS severity is essential for the correct management of the disease. The aim of this study was to evaluate whether ejection dynamics, particularly acceleration time (AT) and the ratio of AT to ejection time (ET), could be diagnostic parameters in patients with AS.
Methods
Patients with AS (aortic peak velocity > 2 m/sec) were prospectively enrolled. Quantitative echocardiographic Doppler parameters including ejection dynamics (AT, ET, and AT/ET ratio) as well as conventional and clinical parameters were analyzed. AT, ET, and AT/ET ratio were calculated in different stages of AS. A receiver operating characteristic curve was plotted to determine the best cutoff value to identify severe AS.
Results
Two hundred sixty-two patients were included (mean age, 75 ± 8 years; 54% women), of whom 109 (42%) had severe AS, 99 (38%) had moderate AS, 22 (8%) had mild AS, 24 (9%) had classical low-flow, low-gradient severe AS, and eight (3%) had paradoxical low-flow, low-gradient severe AS. AT was higher in patients with higher levels of severity of AS (65 ± 16 vs 82 ± 19 vs 109 ± 23 msec, P < .001) as well as AT/ET ratios (0.22 ± 0.05 vs 0.29 ± 0.07 vs 0.37 ± 0.06, P < .001). Using a cutoff of 94 msec, AT had sensitivity of 71% and specificity of 81% for severe AS; using a cutoff of 0.35, the AT/ET ratio had sensitivity of 59% and specificity of 86%. On multivariate analysis, AT was associated with effective orifice area ( B = −0.64, P < .001) and ET with heart rate ( B = −0.62, P < .001) and age ( B = 0.30, P = .04).
Conclusions
Ejection dynamics parameters, such as AT and AT/ET, can help evaluate AS severity.
Highlights
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As the aortic stenosis became more severe, the AT and the AT/ET were higher.
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With a cutoff point of 94 ms, AT had a sensitivity of 71% and a specificity of 81% for severe aortic stenosis.
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Using a cutoff of 0.35, the AT/ET ratio had a sensitivity of 59% and a specificity of 86% for severe aortic stenosis.
Patients with AT/ET ratio values higher than 0.35 showed more cardiovascular events in our cohort
Aortic stenosis (AS) was the most frequent valve disease referred for surgical treatment in developed countries. The approach to the management of the disease depends on accurate diagnosis of the etiology and stage of AS severity. Echocardiography is the mainstay of assessment, and three parameters are recommended for AS severity evaluation: effective orifice area (EOA) by the continuity equation, mean aortic gradient, and peak jet velocity.
However, peak velocity and mean gradient are flow dependent and may be unrepresentative of the grade of AS at extremes of physiologic flow. EOA estimated by continuity equation may be limited when left ventricular systolic function is severely impaired ; in addition, the measurement of left ventricular tract outflow diameter is the greatest potential source of error in the continuity equation.
Guidelines suggest that the aortic waveform shape may be helpful. Nevertheless, few studies have evaluated ejection dynamics parameters in native aortic valve disease. Our group showed a good correlation between acceleration time (AT)/ejection time (ET) ratio and symptomatic status in patients with AS.
Our aim was to evaluate AT and the AT/ET ratio as diagnostic parameters in AS and to analyze the defining characteristics of the aortic waveform.
Methods
Patient Population
We prospectively included 262 patients between September 2012 and December 2015 with valvular native AS (peak velocity > 2 m/s). The exclusion criteria were age < 18 years, suboptimal acoustic window, concomitant moderate or severe aortic regurgitation, moderate or severe mitral or tricuspid valvular disease, subvalvular or supravalvular AS (defined as velocity > 1.5 m/s), and ascending thoracic aorta diameter < 25 mm. Seven patients were excluded because of suboptimal acoustic window. We also enrolled prospectively 69 patients between January 2016 and September 2016 to create a validation group.
The study protocol was approved by the ethics committee of our center. All participants gave their consent to participate in the study.
Echocardiographic Examination
Two-dimensional transthoracic echocardiographic and Doppler studies were performed using clinical ultrasound machines equipped with 2.5- to 3.5-MHz transducers (iE33; Phillips Medical Systems, Best, The Netherlands). All tests were conducted by one experienced sonographer. Blood pressure was measured at the time of the echocardiographic evaluation.
The parasternal long-axis view with zoom was used to measure aortic annular diameter in early systole. Using pulsed Doppler in the left ventricular outflow tract, placing the sample volume 1 cm below the aortic valve, the time-velocity integral was obtained. Stroke volume was then calculated assuming a circular shape of the left ventricular outflow tract. Continuous-wave Doppler recording of flow through the valve was performed from the five-chamber and right parasternal windows to record maximal instantaneous and mean pressure gradients across the aortic valve.
EOA was calculated using the continuity equation. An indexed EOA was estimated as EOA/body surface area. Mean transvalvular pressure gradient was obtained using the modified Bernoulli equation. A Doppler velocity index, a simplification of the continuity equation, was calculated as the time-velocity integral of the left ventricular outflow tract divided by the time-velocity integral of the aortic jet. We also estimated systolic work loss as (100 × aortic mean gradient)/(aortic mean gradient + systolic blood pressure).
All measurements represent averages of three cardiac cycles for patients in sinus rhythm and at least six cycles if the patient was in a rhythm other than sinus. In any case, estimation of extrasystolic beat was always avoided. Doppler recordings were performed at a sweep speed of 150 mm/sec.
Dobutamine stress echocardiography was performed when EOA calculated by the continuity equation was <1.0 cm 2 , aortic transvalvular mean gradient <40 mm Hg, and left ventricular ejection fraction <40%. A low-dose dobutamine infusion was begun after the baseline study at 5 μg/kg body weight/min up to 20 μg/kg/min, titrated upward in steps of 5 μg/kg/min every 5 min. Doppler spectrograms of the left ventricular outflow tract and AS jet velocity were obtained within the last 2 min of each dose. Blood pressure was monitored using automatic sphygmomanometry. Beta-blocker therapy was suspended 24 hours before the index examination.
In patients with left ventricular ejection fractions > 50%, mild AS was defined as EOA > 1.5 cm 2 , moderate AS as EOA between 1.0 and 1.5 cm 2 , and severe AS as EOA < 1.0 cm 2 . In patients with left ventricular dysfunction, “classical” low-flow, low-gradient severe AS was defined by an AS jet > 4 m/sec or a mean gradient > 40 mm Hg and an aortic valve area ≤ 1.0 cm 2 during stress echocardiography. “Paradoxical” low-flow, low-gradient severe AS was defined as EOA < 1.0 cm 2 , mean gradient < 40 mm Hg, left ventricular ejection fraction > 50%, and stroke volume index ≤ 35 mL/m 2 . Low flow in the latter group is not due to systolic function, unlike classical low-flow, low-gradient AS.
In patients with severe AS, discordance was defined as EOA < 1 cm 2 and mean gradient < 40 mm Hg, which includes patients with classical low-flow, low-gradient severe AS and paradoxical low-flow, low-gradient severe AS.
Systolic Time Intervals
The systolic time intervals of flow through the aortic valve were measured using the velocity curve from the continuous-wave Doppler recording ( Figure 1 ) in the apical view. ET was measured as the time from onset to end of systolic flow. AT was defined as the time interval between the beginning of systolic flow to its peak velocity. The AT/ET ratio was then calculated.
Outcomes
Clinical follow-up was performed in those patients diagnosed between 2012 and 2014. We decided to study those patients to achieve a longer follow-up period. A composite end point was defined as cardiac death or aortic valve replacement. We also recorded cardiac death and percutaneous and surgical aortic valve replacement. Cardiac death included death resulting from sudden cardiac death, heart failure, stroke, or cardiovascular procedures. Clinical follow-up was performed by hospital database or death certificate review or telephone call.
Interobserver Variability
To assess the intraobserver variability of systolic time intervals, a total of 20 studies (five with mild, five with moderate, and five with severe AS and five in which the peak velocity was obtained in the right parasternal view) were evaluated by the same observer on two different occasions (not necessarily the same beats). To quantify interobserver variability, these 20 studies were evaluated by a second experienced cardiologist, unaware of the findings of the first physician, who carried out the study of the severity of AS. For the study of variability, the intraclass correlation coefficient was used.
Statistical Analysis
Continuous variables are presented as mean ± SD and were compared using the unpaired t test. Categorical variables are expressed as percentages and were compared using χ 2 analysis or the Fisher exact test. The comparison between ejection dynamics parameters (AT and AT/ET ratio) and other echocardiographic parameters was calculated using Pearson correlation. Analysis of variance was used to compare AT, ET, and AT/ET values in different stages of AS.
We prospectively enrolled patients with AS diagnosed in our echocardiography laboratory during 2016, which forms the validation group. Patients diagnosed between 2012 and 2015 constituted the derivation group.
A receiver operating characteristic curve was plotted in the derivation group to determine the best AT, ET, and AT/ET cutoff values for identifying severe AS. This cutoff was determined as the value providing a balance between sensitivity and specificity. The area under the ROC curve was calculated. The calculated cutoff was then tested in the validation cohort.
Cumulative probability of survival to the composite end point was estimated using the Kaplan-Meier method and compared between groups using a log-rank test.
Multiple linear regression models were developed to study the relationship between systolic time intervals (AT and ET) and the following variables: EOA, heart rate, left ventricular ejection fraction, stroke volume index, systolic arterial pressure, peak velocity, indexed left ventricular mass, and age. Baseline variables entered into the multivariate regression were those that have demonstrated their role in dynamics of ejection.
Differences were considered significant at P values < .05. For data analysis, the statistical program SPSS version 20.0 (SPSS, Chicago, Illinois) was used.
Results
A final sample of 262 patients were enrolled, of whom 22 (8%) had mild AS, 99 (38%) had moderate AS, 109 (42%) had severe AS, 24 (9%) had classical low-flow, low-gradient severe AS, and eight (3%) had “paradoxical” low-flow, low-gradient severe AS. The mean age was 75 ± 8 years, with 53% women and a mean body mass index of 29.6 ± 5.4 kg/m 2 . Degenerative calcification was the most common cause of AS (95%), followed by bicuspid aortic valve (3%) and rheumatic disease (2%).
We included 29 patients (11%) with left ventricular dysfunction (left ventricular ejection fraction < 50%), of whom 24 had low-flow, low-gradient severe AS (after dobutamine stress echocardiography) and five had moderate AS (three with pseudosevere AS after stress echocardiography and two with aortic valve area > 1.0 cm 2 on the basal study). In addition, eight patients with paradoxical low-flow, low-gradient AS were also included. Thus, we enrolled 32 patients (12%) with severe AS who had discordance between EOA and gradients.
Basal patient characteristics are summarized in Table 1 . The validation group was composed of 11 patients (16%) with mild AS, 31 (45%) with moderate AS, 25 (36%) with severe AS, and two (3%) with classical low-flow, low-gradient severe AS. There were no significant differences in clinical basal characteristics with the derivation group.
Variable | Mild AS ( n = 22) | Moderate AS ( n = 99) | Severe AS ( n = 109) | LFLG AS ( n = 24) | Paradoxical LFLG AS ( n = 8) | P |
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Women | 6 (27%) | 57 (58%) | 67 (61%) | 6 (26%) | 3 (37%) | .003 |
Age (y) | 69 ± 9 | 76 ± 8 | 76 ± 8 | 78 ± 7 | 76 ± 9 | .01 |
BMI (kg/m 2 ) | 29.7 ± 3.7 | 30.5 ± 5.4 | 28.9 ± 5.4 | 28.3 ± 5.2 | 30.6 ± 8.0 | .32 |
Hypertension | 18 (86%) | 86 (87%) | 72 (75%) | 16 (68%) | 8 (100%) | .03 |
Diabetes | 8 (38%) | 60 (61%) | 47 (49%) | 13 (54%) | 3 (37%) | .23 |
Dyslipidemia | 14 (67%) | 46 (47%) | 47 (49%) | 8 (32%) | 3 (37%) | .21 |
Degenerative | 20 (96%) | 93 (94%) | 102 (94%) | 24 (100%) | 8 (100%) | .71 |
Dialysis | 0 (0%) | 2 (2%) | 6 (5%) | 1 (6%) | 0 (0%) | .34 |
LVEF (%) | 65 ± 4 | 63 ± 8 | 61 ± 7 | 33 ± 3 | 66 ± 2 | <.001 |
Peak velocity | 2.7 ± 0.2 | 3.4 ± 0.4 | 4.5 ± 0.4 | 3.9 ± 0.4 | 3.7 ± 0.2 | <.001 |
Mean gradient | 19 ± 4 | 29 ± 8 | 52 ± 11 | 37 ± 8 | 37 ± 2 | <.001 |
Valve area (cm 2 ) | 1.72 ± 0.27 | 1.10 ± 0.23 | 0.70 ± 0.16 | 0.71 ± 0.14 | 0.62 ± 0.04 | <.001 |
Indexed area | 0.91 ± 0.14 | 0.63 ± 0.12 | 0.41 ± 0.09 | 0.39 ± 0.08 | 0.35 ± 0.09 | <.001 |
Systolic Time Intervals
Ejection dynamics parameters (AT, ET, and AT/ET ratio) are presented in Figure 2 . AT was higher in patients with more severe AS (65 ± 16 vs 82 ± 19 vs 109 ± 23 msec, P < .001), as was AT/ET ratio (0.22 ± 0.05 vs 0.29 ± 0.07 vs 0.37 ± 0.06, P < .001). Both measures were also high in patients with classical low-flow, low-gradient AS and those with paradoxical low-flow, low-gradient severe AS: AT was 116 ± 24 and 103 ± 15 msec, respectively, and AT/ET ratio was 0.41 ± 0.04 and 0.35 ± 0.06, respectively. Nevertheless, we failed to find differences in ET between the different stages of AS (292 ± 28 vs 301 ± 32 vs 304 ± 34 vs 301 ± 27 vs 301 ± 15 msec, P = .76).
In patients with left ventricular dysfunction, we also found significant differences in AT and AT/ET ratio between moderate AS and left ventricular dysfunction, and classical low-flow, low-gradient severe AS: 99 ± 3 vs 117 ± 24 msec ( P < .001) and 0.33 ± 0.01 vs 0.42 ± 0.03 ( P < .001), respectively, but not in ET (299 ± 10 vs 301 ± 27 ms, P = .91).
Ejection dynamics parameters were compared between patients with severe AS and those with “discordant” severe AS: AT (109 ± 22 vs 115 ± 20 msec, P = .32) and ET (304 ± 34 vs 298 ± 26 msec, P = .54) were similar, but AT/ET ratio was higher in the “discordant” group (0.37 ± 0.06 vs 0.40 ± 0.05, P = .01).
AT and AT/ET ratio were higher in patients with severe AS with discordance than those with moderate AS (115 ± 20 vs 82 ± 19 ms [ P < .001] and 0.40 ± 0.05 vs 0.29 ± 0.07 [ P < .001]) but ET was similar (298 ± 26 vs 301 ± 32 ms, P = .76).
Of the 141 patients with severe AS, peak velocity was obtained in the apical view in 117 (83%) and in the right parasternal view in 24 (17%). AT and AT/ET ratio were significantly lower in the latter group (112 ± 21 vs 97 ± 16 ms [ P = .003] and 0.38 ± 0.06 vs 0.33 ± 0.05 [ P = .017]), while there were no differences in ET (297 ± 27 vs 300 ± 34 ms, P = .75).
Receiver operating characteristic analysis ( Figure 3 ) showed that AT and AT/ET ratio could discriminate severe AS, whereas ET could not. The largest area under the curve for systolic time intervals was for AT/ET ratio (0.88), followed by AT (0.86). Table 2 summarizes the best cutoff values for systolic time intervals, balancing sensitivity and specificity for severe AS as well as those cutoff values with 100% specificity for severe AS in the derivation group. In the validation group, using a cutoff of 94 msec, AT had sensitivity of 71%, specificity of 81%, positive predictive value of 78%, and negative predictive value of 74% for severe AS; at a cutoff of 0.35, AT/ET ratio had sensitivity of 59%, specificity of 86%, positive predictive value of 74%, and negative predictive value of 71%.
Variable | AUC | Optimal cutoff | Sensitivity (%) | Specificity (%) | Accuracy (%) | PPV (%) | NPV (%) | Cutoff for 100% specificity |
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AT (msec) | 0.86 | 94 | 79 | 80 | 77 | 75 | 84 | 153 |
AT/ET | 0.88 | 0.35 | 71 | 84 | 77 | 83 | 73 | 0.49 |
Correlation between ejection dynamics parameters (AT and AT/ET ratio) and other parameters recommended for the evaluation of AS severity are summarized in Tables 3 and 4 . We found good correlations between both ejection parameters (AT and AT/ET ratio) and all the usual echocardiographic methods for assessing AS ( Figures 4 and 5 ).
Variable | Pearson coefficient ( r ) | P |
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Peak velocity | 0.65 | <.001 |
Mean gradient | 0.68 | <.001 |
Valve area | −0.69 | <.001 |
Indexed area | −0.70 | <.001 |
Systolic work loss | 0.60 | <.001 |
Indexed ventricular mass | 0.43 | <.001 |
Doppler velocity index | −0.61 | <.001 |
Indexed stroke volume | −0.37 | .01 |
Age | 0.03 | .76 |
BMI | −0.07 | .42 |
LVEF | −0.31 | <.001 |
Heart rate | −0.19 | .12 |
ET | 0.36 | <.001 |