In aortic stenosis (AS), the increased afterload results in progressive structural and functional changes that precede the development of symptoms. We hypothesized that the detection of abnormalities in left ventricular long-axis function could identify patients with asymptomatic AS at increased risk of events. We prospectively examined the outcome of 126 patients with asymptomatic AS who underwent a comprehensive echocardiographic examination, including tissue Doppler imaging. B-type natriuretic peptide (BNP) was measured in all patients. During a median follow-up period of 20.3 ± 17.8 months, 6 patients died, 8 developed symptoms but did not undergo surgery, and 48 underwent aortic valve replacement. On multivariate Cox regression analysis, the parameters associated with the predefined outcome were gender (p = 0.048), left atrial area index (p = 0.011), systolic annular velocity (p = 0.016), E/Ea ratio (p = 0.024), late diastolic annular velocity (p = 0.023), and BNP (p = 0.012). Using receiver operating characteristics curve analysis, a left atrial area index of ≥12.4 cm 2 /m 2 , systolic annular velocity of ≤4.5 cm/s, E/Ea ratio >13.8, late diastolic annular velocity of ≤9 cm/s, and BNP of ≥61 pg/ml were identified as the best cutoff values to predict events. In conclusion, in asymptomatic AS, tissue Doppler imaging and BNP measurements provide prognostic information beyond that from clinical and conventional echocardiographic parameters.
Aortic valve stenosis (AS) is the most common valvular disease and has become the most common cardiovascular disease, after coronary artery disease and hypertension, in developed countries. AS is characterized by a long asymptomatic phase, lasting several decades, during which outflow obstruction progressively develops. Aortic valve replacement is the sole effective therapy for symptomatic patients. In contrast, the management of asymptomatic AS remains controversial. In these patients, the chronically increased afterload results in progressive left ventricular (LV) myocardial hypertrophy and interstitial fibrosis, diastolic dysfunction, elevated left atrial pressures, dilation of the left atrium, and, eventually, intrinsic myocardial dysfunction. These structural and functional changes precede symptom development, predict changes in clinical status, and trigger B-type natriuretic peptide (BNP) release. In AS, the BNP level correlates with the valve area, diastolic function, functional status, and symptomatic deterioration and might improve risk stratification. Tissue Doppler measurement of mitral annular velocities is a sensitive method for the detection of early abnormalities in LV long-axis function and improves the assessment of LV diastolic function. In asymptomatic AS, the incremental prognostic value of tissue Doppler imaging and BNP measurement compared with validated parameters has never been investigated. The present study was undertaken to prospectively assess the comparative usefulness in predicting the clinical outcomes of long-axis function and BNP level in a series of patients with asymptomatic severe AS.
Methods
Asymptomatic patients with severe AS were prospectively screened from our echocardiographic laboratory for inclusion in the present study. All the patients met the following criteria: (1) moderate to severe AS, as defined by an aortic valve area of ≤1.2 cm 2 ; (2) no symptoms according to a careful history taken by the referring physician; (3) normal LV ejection fraction (≥55%), as calculated by 2-dimensional echocardiography; (4) no more than mild associated cardiac valve lesions; (5) sinus rhythm; and (6) serum creatinine <16 mg/L. A total of 126 patients met these criteria. The relevant institutional review boards approved the protocol, and all patients gave written informed consent.
A comprehensive Doppler echocardiographic study, including M-mode, 2-dimensional echocardiography, color Doppler, and pulsed-wave and continuous-wave Doppler measurements was performed, in all patients using a VIVID 7 ultrasound machine (General Electric Healthcare, Little Chalfont, United Kingdom). The images were stored on a dedicated workstation for off-line analysis. For each measurement, ≥2 cardiac cycles were averaged. Continuous-wave Doppler was used to measure the aortic transvalvular maximal velocities; the peak and mean gradients were calculated using the simplified Bernoulli equation. The aortic valve area was calculated from the continuity equation. The LV end-diastolic and end-systolic volumes and ejection fraction were measured using the bi-apical Simpson disk method. The left atrial area was obtained by planimetry in 2 end-systolic frames of the apical 4-chamber view. Color tissue Doppler imaging was performed in the apical views (2 and 4 chamber) to assess longitudinal myocardial function (frame rate ≥115/s). Off-line peak systolic velocities obtained at the level of the septal, lateral, inferior, and anterior mitral annulus were measured separately and then averaged. An effort was made to align each of the LV walls as near to 0° as possible to the long-axis motion. For diastolic function, the peak velocities of early (E) and late (A) diastolic filling, E/A ratio, deceleration time, and isovolumic relaxation time were derived from Doppler recordings of LV inflow. Using pulsed-wave tissue Doppler, the peak velocities during early (Ea) and late (Aa) diastole obtained at the level of the septal and lateral mitral annulus were measured separately and then averaged. The E/Ea ratio was then calculated.
Venous blood samples for BNP measurement were drawn before echocardiography, after 10 minutes of supine rest. Chilled ethylenediaminetetraacetic acid tubes were centrifuged immediately at 4,000 rpm (4°C) for 15 minutes. Separated plasma samples were processed by immunofluorescence assay (Biosite, Beckman Coulter, San Diego, California). The inter- and intra-assay variation was 5% and 4%, respectively. The assay detection limit was 1 pg/ml.
Symptom-limited graded bicycle exercise tests were performed at inclusion for all patients. After an initial workload of 25 W maintained for 2 minutes, the load was increased by steps of 25 W every 2 minutes. The exercise test was interrupted when the age-related maximum heart rate was reached or if symptoms, hypotension, or significant ventricular arrhythmias developed. The test was considered abnormal if the patient presented with ≥1 of the following criteria: (1) angina, (2) evidence of dyspnea, (3) dizziness, (4) syncope or near-syncope, (5) and increase in systolic blood pressure during exercise of <20 mm Hg or a decrease in blood pressure, and (6) ventricular tachycardia or >4 premature ventricular complexes in a row. Because the present study was conducted before the official recommendations of 2007, the results of the exercise test, even when abnormal, did not affect patient treatment.
Follow-up information was obtained from interviews with the patients, their relatives, or their physicians every 6 to 12 months, according to the guidelines. Particular care was taken to obtain information regarding the development of symptoms, eventual aortic valve replacement, and death. The clinical management was determined independently by the patient’s personal physician using all information available. The combined end point included the onset of symptoms (angina, dyspnea, syncope, heart failure), cardiac-related death, and the need for aortic valve replacement.
Continuous variables are expressed as the mean ± SD, unless otherwise specified. Group comparisons for categorical variables were obtained using the chi-square test and for continuous variables with 1-way analysis of variance. Analysis was performed by censoring follow-up data at cardiac surgery, if eventually performed. To detect independent predictors of events, a multivariate Cox proportional hazards regression procedure was used to compare the patients who remained asymptomatic during follow-up and those who experienced an event (STATISTICA, version 7, Statsoft, France). All clinically relevant variables with p <0.10 were included in the multivariate model. p Values <0.05 were considered significant. Receiver operating characteristic curve analysis was performed to determine the cutoff values that best distinguished the issue (area under the curve). Survival curves were established using the Kaplan-Meier method, and statistical significance was determined using the log-rank test.
Results
The mean patient age was 67 ± 10 years (range 41 to 84). From the patient history and echocardiographic analysis findings, the suspected origin of AS was calcification of a trileaflet (n = 104), bicuspid (n = 15), rheumatic disease (commissural fusion and calcification most prominent along the edges of the cusps on echocardiography; n = 5), and undetermined (n = 2). The aortic valve area range was 0.38 to 1.2 cm 2 (mean 0.82 ± 0.15), and the peak aortic pressure gradient was 77 ± 21 mm Hg. The mean aortic pressure gradient was 26 to 86 mm Hg (mean 45 ± 14). The mean LV ejection fraction was 67 ± 7% (range 55% to 84%), and the mean peak annular systolic velocity was 4.5 ± 1.5 cm/s (range 0.84 to 9). The mean BNP level was 102 ± 178 pg/ml (range 5 to 1,500). At inclusion, the exercise test findings were abnormal (dyspnea in 20, decrease or increase in systolic blood pressure during exercise of <20 mm Hg in 6, and combined parameters in 6) in 32 patients (25%). During a median follow-up period of 20.3 ± 18.7 months (interquartile range 9 to 22), the predefined end point occurred in 62 patients. Of the 62 patients, 6 patients died from cardiovascular causes: 3 suddenly and 3 from progressive heart failure. Aortic valve replacement was required for the development of symptoms in 34 patients, new-onset atrial fibrillation in 1, newly positive exercise test findings in 7, and equivocal symptoms in 6. Finally, 8 patients developed symptoms but refused to undergo surgery.
The clinical and echocardiographic characteristics of the patients who remained asymptomatic or experienced an event are listed in Table 1 . No clinical data, except female gender, allowed the distinction between the 2 groups. Patients who experienced an end point had a smaller aortic valve area, lower tissue Doppler annular systolic and diastolic velocities, and a greater E/Ea ratio, left atrial area, and BNP level. The response to exercise was more often abnormal in these patients. On multivariate Cox regression analysis, the parameters independently associated with the predefined composite outcome were gender, left atrial area index, systolic annular velocity, E/Ea, late diastolic annular velocity (Aa), and BNP level ( Figure 1 , Table 2 ). Figure 2 shows the survival curves for categorical variables, and Figure 3 shows an example of a patient with impaired long-axis function. In the subgroup of patients with a normal response to exercise, except for the E/Ea, the other parameters remained independently associated with the outcome.
| Variable | No Events (n = 64, 51%) | Events (n = 62, 49%) | Univariate | Multivariate | |
|---|---|---|---|---|---|
| p Value | p Value | Hazard Ratio (95% CI) | |||
| Age (years) | 68 ± 10 | 67 ± 12 | 0.51 | — | — |
| Women | 16 (25%) | 35 (56%) | 0.00024 | 0.048 ⁎ | 0.53 (0.28–0.99) ⁎ |
| Hypertension | 29 (43%) | 32 (52%) | 0.51 | — | — |
| Diabetes mellitus | 12 (19%) | 12 (19%) | 0.97 | — | — |
| Hypercholesterolemia | 28 (44%) | 26 (42%) | 0.34 | — | — |
| Systolic arterial pressure (mm Hg) | 144 ± 18 | 141 ± 19 | 0.55 | — | — |
| B-type natriuretic peptide (pg/ml) | 39.9 ± 27.3 | 166 ± 237 | <0.0001 | 0.012 ⁎ | 1.001 (1–1.003) ⁎ |
| Serum creatinine (mg/l) | 8.2 ± 1.8 | 8.7 ± 1.7 | 0.14 | — | — |
| Abnormal response to exercise | 6 (9) | 26 (42) | 0.007 | 0.88 | 0.95 (0.49–1.8) |
| Aortic valve area (cm 2 ) | 0.86 ± 0.13 | 0.79 ± 0.16 | 0.05 | 0.80 | 1.49 (0.06–34) |
| Peak aortic velocity (m/s) | 4.03 ± 0.55 | 4.35 ± 0.58 | 0.0013 | 0.58 | 1.31 (0.5–3.4) |
| Aortic peak pressure gradient (mm Hg) | 69.7 ± 19.7 | 77 ± 21 | 0.01 | — | — |
| Aortic mean pressure gradient (mm Hg) | 42.4 ± 13.4 | 46.7 ± 13. | 0.046 | 0.32 | 1.02 (0.9–1.06) |
| Left ventricular mass (g) | 174 ± 86 | 169 ± 67 | 0.85 | — | — |
| Left ventricular end-diastolic volume (ml) | 92.8 ± 26.5 | 96.9 ± 30.3 | 0.94 | — | — |
| Left ventricular end-systolic volume (ml) | 32.2 ± 14.2 | 32.5 ± 13 | 0.91 | — | — |
| Left ventricular ejection fraction (%) | 65.8 ± 7.4 | 67.4 ± 7.5 | 0.52 | — | — |
| Left atrial area index (cm 2 /m 2 ) | 10.3 ± 2.1 | 14.8 ± 3.4 | <0.0001 | 0.011 ⁎ | 1.06 (1.01–1.11) ⁎ |
| Mitral early diastolic filling wave (cm/s) | 77 ± 24 | 83 ± 26 | 0.12 | — | — |
| Mitral late diastolic filling wave (cm/s) | 87 ± 29 | 89 ± 28 | 0.29 | — | — |
| Mitral early/late diastolic filling ratio | 0.92 ± 0.32 | 0.99 ± 0.48 | 0.53 | — | — |
| Mitral early diastolic filling wave deceleration time (ms) | 219 ± 78 | 237 ± 97 | 0.34 | — | — |
| Peak systolic velocity (cm/s) | 5.2 ± 0.9 | 3.6 ± 1.6 | <0.0001 | 0.016 ⁎ | 0.73 (0.57–0.94) ⁎ |
| Peak early diastolic annular velocity (cm/s) | 9.95 ± 1.7 | 7.9 ± 1.8 | 0.025 | 0.91 | 1.01 (0.84–1.2) |
| Peak late diastolic annular velocity (cm/s) | 8.7 ± 2 | 7.6 ± 2.1 | <0.0001 | 0.023 ⁎ | 0.81 (0.67–0.97) ⁎ |
| Early diastolic filling/annular velocity (average annuli) | 10 ± 3.3 | 13.5 ± 6.6 | 0.009 | 0.024 ⁎ | 0.94 (0.88–0.99) ⁎ |
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