Recently, an aortic valve area (AVA) index (AVAI) <0.6 cm 2 /m 2 was proposed as an indicator of severe aortic stenosis. The purpose of the present study was to clarify the prognostic value of the AVAI. We identified 103 consecutive asymptomatic patients (mean age 72 ± 11 years) with severe aortic stenosis, defined by an AVA of <1.0 cm 2 , who had not undergone aortic valve replacement on initial evaluation. During follow-up (median 36 ± 27 months), 31 aortic valve replacements and 20 cardiac deaths occurred. Multivariate analysis revealed that an AVAI <0.6 cm 2 /m 2 (hazard ratio 2.6, 95% confidence interval 1.1 to 6.3; p = 0.03) and peak aortic jet velocity (Vp) >4.0 m/s (hazard ratio 2.6, 95% confidence interval 1.2 to 5.8; p = 0.02) were associated with cardiac events but that an AVA <0.75 cm 2 was not. The event-free survival of patients with an AVAI of ≥0.6 cm 2 /m 2 was better than that for those with an AVAI <0.6 cm 2 /m 2 (86% vs 41% at 3 years, p <0.01). Furthermore, patients with an AVAI of ≥0.6 cm 2 /m 2 and Vp of ≤4.0 m/s showed an excellent prognosis, but those without these findings had poorer outcomes. In conclusion, AVAI is a powerful predictor of adverse events in asymptomatic patients with severe aortic stenosis. Furthermore, the combination of AVAI and Vp provides additional prognostic information. Watchful observations are required for timely aortic valve replacement in patients with an AVAI of <0.6 cm 2 /m 2 or a Vp >4.0 m/s.
Aortic valve area (AVA) is a widely used marker for aortic stenosis (AS) severity. It is considered more effective than the aortic valve pressure gradient for evaluating severity, because diagnosis using the pressure gradient leads to an underestimation of the severity of low-flow and/or low-gradient “severe” AS. However, some recent studies have demonstrated that the AVA is not necessarily related to mortality. In addition, most patients with an AVA of 0.75 to 1.0 cm 2 reportedly did not require intervention to the aortic valves, although an AVA of <1.0 cm 2 is classified as severe AS. Thus, whether the AVA is useful for prognostic prediction is controversial. Therefore, a definition with a strong relation to the clinical outcome is necessary. Recently, the American College of Cardiology, American Heart Association, and European Society of Cardiology have proposed an aortic valve area index (AVAI) of <0.6 cm 2 /m 2 as a new indicator for severe AS. However, the prognostic value of the AVAI is not well known. We assessed whether the AVAI is applicable to predicting the outcome in asymptomatic patients with severe AS.
Methods
From 2001 to 2007, asymptomatic patients who underwent transthoracic echocardiography and had severe AS, defined as an AVA of <1.0 cm 2 , were retrospectively identified for the present study if they had not undergone aortic valve replacement on initial evaluation. The exclusion criteria were a history of coronary artery disease (diagnosed by clinical, electrocardiographic, echocardiographic, and coronary angiographic evaluation), more than mild mitral valve regurgitation or stenosis, more than mild aortic regurgitation, and primary hypertrophic cardiomyopathy. The patients who planned to undergo aortic valve replacement at the initial evaluation and who had symptoms associated with AS were also excluded. Seven patients underwent cardiac catheterization because of suspicious findings for coronary artery disease before the entry and did not have significant lesions. Accordingly, they were included. A total of 103 patients (mean ± SD years, 72 ± 11 years; 46 men and 57 women; mean body surface area, calculated with the weight-height formula of DuBois and DuBois, 1.50 ± 0.15 m 2 ; mean AVA 0.82 ± 0.15 cm 2 ; mean AVAI 0.56 ± 0.11 cm 2 /m 2 ; and mean peak aortic jet velocity [Vp] 4.1 ± 0.9 m/s) were enrolled in the present study. The institutional review board of the Osaka City University Hospital approved the present study.
Baseline echocardiograms were obtained using commercially available ultrasound systems. All patients underwent comprehensive examination, including 2-dimensional echocardiography and continuous-wave, pulsed-wave, and color Doppler echocardiography conducted by experienced echocardiographers. Multiple transducer positions were used to record the Vp. The AVA was calculated using the continuity equation. The AVAI was obtained by dividing the AVA by the body surface area. The left ventricular (LV) ejection fraction was calculated using the disk method. The LV mass was calculated according to the American Society of Echocardiography criteria applied to the formula of Troy et al. The LV mass index was obtained by dividing the LV mass by the body surface area. According to American Society of Echocardiography, we calculated the E/e′ ratio as follows: the early diastolic velocities of mitral inflow (E) were obtained in the apical view using pulsed-wave Doppler, and the early diastolic mitral annular velocities (e′) was evaluated in the septal insertion site of the mitral leaflets. An E/e′ ratio >15 was considered to represent abnormal diastolic function.
Of the several indicators for AS severity proposed by the Guidelines of American College of Cardiology, American Heart Association, and European Society of Cardiology, we used only an AVA <1.0 cm 2 as the definition for severe AS. Therefore, the study population included patients with a Vp of ≤4.0 m/s and a mean aortic pressure gradient of ≤40 mm Hg, who were classified as having less than severe AS according to the guidelines.
Patients were followed up once a year or more after initial examination. Follow-up information was obtained from the medical records and interviews with the patients, their relatives, and their physicians. Aortic valve replacement was considered indicated when patients first presented with symptoms related to AS or patients presented with reduced LV function, which was defined by a LV ejection fraction <50%, even if they did not have symptoms. However, the surgical decision-making was performed by the attending physician. To assess the outcomes, the end point of the present study was aortic valve events, including aortic valve replacement and death from any cardiovascular cause.
The data are presented as the mean ± SD, counts, or proportions (%). Continuous data were compared using Student’s t test, irrespective of multiple testing procedures. The Kaplan-Meier method was used to assess event-free survival, with the differences evaluated using the log-rank test. Variables with p values <0.05 on univariate analysis were incorporated into a Cox proportional hazards model to estimate the hazard ratio for event-free survival. A p value of <0.05 was considered statistically significant.
Results
The mean duration of follow-up was 36 ± 27 months. Of the study group, 37 patients had an AVAI of ≥0.6 cm 2 /m 2 , and 66 patients had an AVAI of <0.6 cm 2 /m 2 . Compared to patients with AVAI of ≥0.6 cm 2 /m 2 , those with an AVAI <0.6 cm 2 /m 2 did not significantly differ in age, gender, LV ejection fraction, co-morbidities, C-reactive protein, or serum creatinine but exhibited a smaller AVA, higher Vp, greater peak and mean aortic pressure gradient, and larger body surface area. The baseline patient characteristics are listed in Table 1 .
| Variable | All (n = 103) | AVAI <0.6 cm 2 /m 2 (n = 66) | AVAI ≥0.6 cm 2 /m 2 (n = 37) | p Value |
|---|---|---|---|---|
| Age (years) | 72 ± 11 | 72 ± 11 | 73 ± 11 | 0.58 |
| Women | 57 (55%) | 35 (53%) | 22 (59%) | 0.53 |
| Body surface area (m 2 ) | 1.50 ± 0.15 | 1.53 ± 0.15 | 1.43 ± 0.12 | <0.01 |
| Heart rate (beats/min) | 74 ± 12 | 73 ± 11 | 75 ± 13 | 0.47 |
| Systolic blood pressure (mm Hg) | 133 ± 18 | 133 ± 19 | 135 ± 14 | 0.67 |
| Diastolic blood pressure (mm Hg) | 71 ± 11 | 72 ± 10 | 71 ± 13 | 0.72 |
| Hypertension | 57 (55%) | 35 (53%) | 22 (59%) | 0.53 |
| Dyslipidemia | 28 (27%) | 18 (27%) | 10 (27%) | 0.98 |
| Diabetes mellitus | 12 (12%) | 8 (12%) | 4 (11%) | 0.84 |
| Hemodialysis | 9 (8%) | 5 (8%) | 4 (11%) | 0.58 |
| Atrial fibrillation | 13 (13%) | 11 (17%) | 2 (5%) | 0.10 |
| Aortic valve area (cm 2 ) | 0.82 ± 0.15 | 0.75 ± 0.14 | 0.96 ± 0.06 | <0.01 |
| Aortic valve area index (cm 2 /m 2 ) | 0.56 ± 0.11 | 0.49 ± 0.08 | 0.68 ± 0.05 | <0.01 |
| Peak aortic jet velocity (m/s) | 4.1 ± 0.9 | 4.5 ± 0.8 | 3.5 ± 0.6 | <0.01 |
| Peak aortic jet velocity >4.0 m/s | 58 (55%) | 48 (73%) | 10 (27%) | <0.01 |
| Peak aortic pressure gradient (mm Hg) | 71 ± 29 | 82 ± 29 | 51 ± 17 | <0.01 |
| Mean aortic pressure gradient (mm Hg) | 41 ± 18 | 47 ± 18 | 28 ± 10 | <0.01 |
| Left ventricular ejection fraction (%) | 60.0 ± 9.6 | 59.6 ± 9.9 | 60.7 ± 9.0 | 0.59 |
| Left ventricular mass index (g/m 2 ) | 128 ± 41 | 132 ± 42 | 119 ± 37 | 0.13 |
| E/e′ | 17 ± 10 | 17 ± 10 | 17 ± 10 | 0.98 |
| E/e′ >15 | 40 (39%) | 27 (41%) | 13 (35%) | 0.56 |
| Left ventricular outflow tract (cm) | 2.1 ± 3.7 | 2.2 ± 3.6 | 2.0 ± 3.5 | 0.03 |
| Serum creatinine (mg/dl) | 1.79 ± 2.6 | 1.63 ± 2.4 | 2.1 ± 3.0 | 0.46 |
| C-reactive protein (mg/dl) | 0.39 ± 0.62 | 0.46 ± 0.73 | 0.27 ± 0.34 | 0.22 |
During follow-up, 51 events were observed, including 31 aortic valve replacements and 20 cardiac deaths. The event-free survival rate for all patients was 81%, 74%, 58%, and 48% at 1, 2, 3, and 5 years, respectively. The 31 patients underwent aortic valve replacement after developing symptoms (n = 24) or decreased LV systolic function (n = 7). The 20 deaths were from cardiac causes (congestive heart failure in 14 and sudden death in 6). Although 4 patients developed symptoms before sudden death, aortic valve replacement was not performed in these patients because of old age or significant co-morbidities, including chronic obstructive pulmonary disease, cancer, and cerebral infarction.
The candidate variables examined by univariate and multivariate analyses are listed in Table 2 . Univariate analysis showed that an AVAI <0.6 cm 2 /m 2 , Vp >4.0 m/s, and AVA <0.75 cm 2 were significant predictors of subsequent cardiac events but the LV ejection fraction, LV mass index, female gender, age, and co-morbidities were not. When these significant predictors on univariate analysis were incorporated, multivariate analysis showed that an AVAI <0.6 cm 2 /m 2 (hazard ratio 2.6, 95% confidence interval 1.1 to 6.4; p = 0.03) and Vp >4.0 m/s (hazard ratio 2.6, 95% confidence interval 1.2 to 5.8; p = 0.02) were independent predictors of adverse cardiac events, but an AVA of <0.75 cm 2 was not.
| Variable | HR (95% CI) | p Value |
|---|---|---|
| Univariate analysis | ||
| Age (years) | 1.00 (0.98–1.03) | 0.84 |
| Women | 0.99 (0.57–1.72) | 0.96 |
| Aortic valve area index <0.6 cm 2 /m 2 | 4.99 (2.34–10.65) | <0.01 |
| Peak aortic jet velocity >4.0 m/s | 4.65 (2.26–9.54) | <0.01 |
| Aortic valve area <0.75 cm 2 | 3.41 (1.95–5.96) | <0.01 |
| Left ventricular ejection fraction (%) | 0.99 (0.96–1.02) | 0.68 |
| Left ventricular mass index (g/m 2 ) | 1.00 (1.00–1.01) | 0.28 |
| E/e′ >15 | 1.22 (0.70–2.15) | 0.48 |
| Heart rate | 1.01 (0.99–1.04) | 0.38 |
| Hypertension | 0.68 (0.390–1.18) | 0.24 |
| Dyslipidemia | 0.85 (0.46–1.58) | 0.61 |
| Diabetes mellitus | 1.70 (0.75–3.83) | 0.20 |
| Hemodialysis | 1.87 (0.79–4.40) | 0.15 |
| Serum creatinine (mg/dl) | 1.08 (0.97–1.20) | 0.18 |
| C-reactive protein (mg/dl) | 1.17 (0.65–2.11) | 0.60 |
| Multivariate analysis | ||
| Aortic valve area index <0.6 cm 2 /m 2 | 2.62 (1.09–6.33) | 0.03 |
| Peak aortic jet velocity >4.0 m/s | 2.58 (1.15–5.78) | 0.02 |
| Aortic valve area <0.75 cm 2 | 1.48 (0.79–2.79) | 0.22 |
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