We tested the hypothesis that the disproportionate increase of body surface area in obesity may lead to the overestimation of aortic stenosis (AS) severity when the aortic valve area (AVA) is indexed (AVAI) for body surface area in 1,524 patients enrolled in the Simvastatin and Ezetimibe in AS study. Obesity was defined as a body mass index of ≥30 kg/m 2 . Peak aortic jet velocity, mean aortic gradient, AVA, and energy loss (EL) did not differ, although AVAI and EL indexed (ELI) for body surface area were significantly smaller in the obese group (n = 321) compared with the nonobese (n = 1,203) group (both p <0.05). Severe AS by AVAI (<0.6 cm 2 /m 2 ) but nonsevere by AVA (>1.0 cm 2 ; AVAI/AVA discordance) was found in 15% of the patients, whereas severe AS by ELI (<0.6 cm 2 /m 2 ) but nonsevere by EL (>1.0 cm 2 ; ELI/EL discordance) was found in 9% of the patients. Obesity was associated with a 2.4-fold higher prevalence of AVAI/AVA discordance and a 1.6-fold higher prevalence of ELI/EL discordance. Discordant grading was also associated with male gender, larger body size, higher mean aortic gradient, and stroke volume (all p <0.05). During a median follow-up of 4.3 years, 419 patients were referred for aortic valve replacement and 177 patients died or were hospitalized because of heart failure. In the Cox regression analyses, AVAI/AVA discordance was associated with a 28% higher rate of aortic valve replacement (p <0.05) but did not predict the rate of combined death and hospitalization for heart failure. In conclusion, using AVAI and ELI for the grading of stenosis in patients with obesity may lead to overestimation of true AS severity.
In aortic stenosis (AS), therapeutic decisions are based on the status of symptoms and hemodynamic severity and left ventricular function estimated by echocardiography. Accurate assessment of AS severity is of major importance for diagnosis, management, and prognosis of the disease. Current guidelines recommend a variety of Doppler echocardiographic measures for assessing AS severity, including peak aortic jet velocity, mean aortic gradient, aortic valve area (AVA), and AVA indexed (AVAI) for body surface area. In milder degrees of AS, adjusting for pressure recovery in calculation of valve area gives a more accurate estimate of the disease severity and prognosis. The indexation of valve area for body surface area is recommended to avoid overestimation of AS, particularly in subjects with small body size. We hypothesized that the disproportionate increase of body surface area in obesity may lead to the overestimation of AS severity when the indexed valve area is used in patients with obesity.
Methods
A total of 1,873 patients aged 45 to 85 years with asymptomatic AS (peak aortic valve velocity ≥2.5 and ≤4.0 m/s) were recruited in the Simvastatin Ezetimibe in AS study, a prospective, multicenter, randomized, double-blind study on the effect of combined simvastatin and ezetimibe or placebo on AS progression and associated cardiovascular events during a median of 4.3 years. The primary study end point was combined aortic valve replacement (AVR), hospitalization for heart failure due to progression of AS, cardiovascular death, coronary revascularization, nonhemorrhagic stroke, myocardial infarction, and hospitalization for unstable angina pectoris. Total mortality was a tertiary study end point. All end points were adjudicated by an independent committee. For the present analysis, 1,561 patients with complete baseline echocardiographic data allowing assessment of AVA, AVAI, energy loss (EL), and EL index (ELI) were eligible. Thirteen patients with body mass index <18.5 kg/m 2 , 15 patients with AVA <1.0 cm 2 but AVAI >0.6 cm 2 /m 2 , and 9 patients with EL <1.0 cm 2 and ELI >0.6 cm 2 /m 2 were excluded for statistical reasons because of the low numbers, leaving 1,524 patients for the present prespecified analysis.
Echocardiography was done in 173 study centers following a standardized protocol. Blinded, off-line analysis was done at the Core Laboratory at the Haukeland University Hospital, Bergen, Norway. Quantitative assessment of the left ventricle and the aortic valve was performed following the joint European Association of Echocardiography and American Society of Echocardiography guidelines. Stroke volume was calculated from Teichholz-derived left ventricular volumes. The AVA was calculated by the continuity equation with Doppler time velocity integrals and indexed for body size (AVAI). EL was calculated as (AVA × Aa)/(Aa − AVA) and indexed for body size (ELI), where Aa is the aortic area at the sinotubuluar junction. Severe AS was defined as AVA or EL <1.0 cm 2 and AVAI or ELI <0.6 cm 2 /m 2 , respectively. We defined the AVAI/AVA discordance as severe AS by AVAI but nonsevere by AVA and ELI/EL discordance as severe AS by ELI but nonsevere by EL.
All data management and analyses were performed by IBM SPSS 21.0 (IBM Corporation, Armonk, New York). The study population was divided into obese (body mass index ≥30 kg/m 2 ) and nonobese groups. Continuous variables are presented as mean ± SD and categorical variables as percentages. Comparisons between the groups were done with t and chi-square tests as appropriate. Covariates of AVAI/AVA and ELI/EL discordance were identified in logistic regression analyses. End point incidences were calculated by Kaplan-Maier analysis. The association of AVAI/AVA and ELI/EL discordances with incident AVR and combined death from any cause and hospitalization for heart failure due to progression of AS was tested in Cox regression analyses. Two-tailed p <0.05 was considered significant in all analyses.
Results
Patients with obesity (n = 321) had higher fasting serum glucose and more dyslipidemia and included more patients with hypertension than the patients without obesity ( Table 1 ). AS severity did not differ between the obese and nonobese groups when assessed by peak aortic jet velocity, mean aortic gradient, AVA, or EL. In contrast, AVAI and ELI were significantly smaller in the obese group ( Table 2 ).
| Variables | Nonobese (n = 1,203) | Obese (n = 321) | p Value |
|---|---|---|---|
| Women | 35 | 48 | <0.001 |
| Age (yrs) | 67.4 ± 9.9 | 67.3 ± 8.7 | 0.951 |
| Height (m) | 1.71 ± 0.09 | 1.68 ± 0.10 | <0.001 |
| Weight (kg) | 74.8 ± 11.1 | 94.6 ± 12.9 | |
| BMI (kg/m 2 ) | 25.4 ± 2.5 | 33.3 ± 3.4 | |
| Body surface area (m 2 ) | 1.87 ± 0.18 | 2.04 ± 0.19 | <0.001 |
| Systolic blood pressure (mm Hg) | 144 ± 20 | 147 ± 19 | 0.003 |
| Diastolic blood pressure (mm Hg) | 82 ± 10 | 84 ± 11 | <0.001 |
| Hypertension | 84 | 96 | <0.001 |
| Serum creatinine (μmol/L) | 94 ± 15 | 93 ± 17 | 0.012 |
| Glucose (mmol/L) | 5.2 ± 0.7 | 5.7 ± 1.1 | <0.001 |
| Total cholesterol (mmol/L) (mg/dl) | 5.8 ± 1.0224.3 ± 38.7 | 5.6 ± 1.0216.6 ± 38.7 | 0.016 |
| HDL cholesterol (mmol/L) | 1.5 ± 0.4 | 1.3 ± 0.4 | <0.001 |
| (mg/dl) | 58.0 ± 15.5 | 50.3 ± 15.5 | |
| LDL cholesterol (mmol/L) | 3.6 ± 0.9 | 3.5 ± 0.9 | 0.008 |
| (mg/dl) | 139.2 ± 34.8 | 135.4 ± 34.8 | |
| Triglycerides (mmol/L) | 1.4 ± 0.7 | 1.7 ± 0.8 | <0.001 |
| (mg/dl) | 54.1 ± 27.1 | 65.7 ± 30.1 |
| Variables | Nonobese (n = 1,203) | Obese (n = 321) | p Value |
|---|---|---|---|
| LV end-diastolic diameter (cm) | 5.0 ± 0.6 | 5.2 ± 0.6 | <0.001 |
| LV end-systolic diameter (cm) | 3.2 ± 0.6 | 3.3 ± 0.6 | <0.001 |
| LV ejection fraction | 66 ± 8 | 65 ± 8 | 0.010 |
| Endocardial fractional shortening | 37 ± 6 | 36 ± 6 | 0.013 |
| LV mass (g) | 191 ± 63 | 220 ± 78 | <0.001 |
| Stroke volume (ml) | 80 ± 22 | 84 ± 23 | 0.008 |
| Cardiac output (L/min) | 5.2 ± 1.5 | 5.6 ± 1.7 | <0.001 |
| Sinotubular junction diameter (cm) | 2.8 ± 0.4 | 2.8 ± 0.4 | 0.587 |
| Sinus of valsalva diameter (cm) | 3.6 ± 0.5 | 3.6 ± 0.5 | 0.993 |
| Peak aortic velocity (m/s) | 3.1 ± 0.5 | 3.1 ± 0.6 | 0.133 |
| Mean aortic gradient (mm Hg) | 23 ± 9 | 23 ± 9 | 0.135 |
| AVA (cm 2 ) | 1.28 ± 0.46 | 1.28 ± 0.44 | 0.962 |
| AVAI (cm 2 /m 2 ) | 0.68 ± 0.24 | 0.62 ± 0.21 | <0.001 |
| Pressure recovery (mm Hg) | 5.8 ± 2.2 | 6.2 ± 2.5 | 0.011 |
| EL (cm 2 ) | 1.72 ± 0.93 | 1.74 ± 0.90 | 0.666 |
| ELI (cm 2 /m 2 ) | 0.92 ± 0.48 | 0.85 ± 0.43 | 0.025 |
The AVAI/AVA discordance was found in 15% of the patients, and ELI/EL discordance was found in 9% of the patients in the total study population, and both were significantly more common among patients with obesity (23% and 13% vs 13% and 9%, respectively, both p <0.05; Table 3 ; Figure 1 ). In multivariate analyses, obesity was associated with 2.4-fold higher prevalence of AVAI/AVA discordance and 1.6-fold higher prevalence of ELI/EL discordance ( Table 4 ).
| AVAI/AVA Discordance | ELI/EL Discordance | |||
|---|---|---|---|---|
| Yes (n = 225) | No (n = 1,299) | Yes (n = 144) | No (n = 1,380) | |
| Male gender | 84 ∗ | 59 | 79 † | 61 |
| Body surface area (m 2 ) | 2.04 ± 0.16 ∗ | 1.88 ± 0.19 | 2.01 ± 0.14 † | 1.89 ± 0.19 |
| Obesity | 32 ∗ | 19 | 29 † | 20 |
| Aortic sinus diameter (cm) | 3.7 ± 0.5 ∗ | 3.6 ± 0.5 | 3.8 ± 0.5 † | 3.6 ± 0.5 |
| Left ventricular mass (g) | 214 ± 70 ∗ | 193 ± 67 | 220 ± 69 † | 194 ± 67 |
| Stroke volume (ml) | 85 ± 21 ∗ | 80 ± 23 | 84 ± 22 | 81 ± 23 |
| Mean aortic gradient (mm Hg) | 25 ± 8 ∗ | 22 ± 9 | 26 ± 8 † | 22 ± 9 |
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