Methods

Our analysis was performed as a substudy of the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. The SEAS study randomized 1,873 women and men aged 45 to 85 years with asymptomatic mild to moderate AS to a 4-year, multicenter, double-blind, placebo-controlled treatment with a combination of simvastatin and ezetimibe or placebo to evaluate the effect on AS progression and cardiovascular morbidity and mortality. The eligible patients had asymptomatic AS, defined as aortic valve thickening accompanied by a peak transaortic velocity of ≥2.5 and ≤4.0 m/s. Study organization, design, patient recruitment, and the main results have been previously published.

Patients with diabetes mellitus, renal impairment, a history of coronary heart disease, systolic heart failure, previous stroke, peripheral arterial disease, rheumatic valvular disease, prosthetic valves, more than mild aortic or mitral regurgitation or other significant valvular disease, or any other condition requiring lipid-lowering therapy were not included in the SEAS study. The ethics committees in each country approved the SEAS study, and all patients provided written informed consent. The Echocardiography Core Laboratory at Haukeland University Hospital, Bergen, Norway, received 1,777 baseline studies. It was possible to determine the LV geometry on 1,719 baseline echocardiograms. The patient population was divided into BMI classes: underweight, BMI <18.5 kg/m ² ; normal weight, BMI 18.5 to 24.9 kg/m ² ; overweight, BMI 25 to 29.9 kg/m ² ; and obese, BMI ≥30 kg/m ² . The 16 patients with a BMI of <18.5 kg/m ² were excluded for statistical reasons. Thus, the present study population included 1,703 patients. Hypertension was defined as a history of hypertension as reported by the patient’s attending physician.

Baseline echocardiography was performed by specially trained physicians and echocardiographers at 173 study centers in Norway, Denmark, Sweden, Finland, Germany, Ireland and the United Kingdom, according to a previously published, standardized procedure. The echocardiographic protocol included parasternal long- and short-axis views and apical 2-, 3-, 4-, and 5-chamber views. LV filling and subaortic blood velocity were recorded using pulsed Doppler echocardiography. Continuous-wave Doppler recorded from multiple windows, with imaging and nonimaging transducers, was used to obtain the peak transaortic blood velocity. All images were recorded on VHS tapes, CD, or MO disks and sent for central, blinded interpretation at the SEAS Echocardiography Core Laboratory. All echocardiography examinations were first read by a junior member of the staff and proofread by the senior investigator (EG). The reading was performed using off-line digital workstations with Image Arena (TomTec Imaging Systems GmbH, Unterschleissheim, Germany) software.

The LV dimensions and wall thickness were measured on 2-dimensional images according to the American Society of Echocardiography guidelines. The end-diastolic LV dimensions were used to calculate the LV mass by an anatomically validated equation. LV hypertrophy was defined as the LV mass indexed for height ^2.7 >46.7 g/m ^2.7 in women and >49.2 g/m ^2.7 in men. The relative wall thickness was calculated as 2 × the posterior wall thickness/LV internal diameter at end-diastole and considered increased if ≥0.43. LV geometry was assessed from the LV mass/height ^2.7 combined with the relative wall thickness, grouping patients with normal LV mass/height ^2.7 into normal geometry or concentric remodeling patterns, and patients with elevated LV mass/height ^2.7 into eccentric or concentric LV hypertrophy patterns. The LV endocardial systolic function was calculated as the LV ejection fraction using the Teichholz formula and considered low if <0.50. LV myocardial systolic function was assessed by stress-corrected mid-wall shortening (actual/predicted mid-wall shortening ratio for actual circumferential end-systolic stress) and considered low if <87% in men and <90% in women. The effective aortic valve area was calculated using the continuity equation with velocity time integrals and inner aortic annular diameter and indexed for the body surface area. Aortic and mitral valve regurgitation were graded using color Doppler imaging.

Statistical Package for Social Sciences, version 15.0, software (SPSS, Chicago, Illinois) was used for data management and analysis. Data are expressed as the mean ± SD for continuous variables and as percentages for categorical variables. The study population was divided into 3 BMI classes (BMI <25, 25.0 to 29.9, and ≥30 kg/m ² ). The chi-square test, analysis of variance with Scheffe’s post hoc test, and general linear model with Sidak’s post hoc test was used to compare the categorical and continuous variables between BMI classes, as appropriate. Univariate correlations were assessed using Pearson’s correlation coefficient. The effect of BMI on LV hypertrophy was assessed using multiple logistic regression analysis, including LV hypertrophy as the dependent variable and BMI, age, gender, known hypertension, systolic blood pressure, LV ejection fraction, peak transaortic velocity, and mitral regurgitation as the independent variables. Two-tailed p values of ≤0.05 were considered significant on both univariate and multivariate analyses.

Results

The total study population included 39% women, the mean clinic blood pressure was 145/82 ± 20/10 mm Hg, age 67 ± 10 years, BMI 26.9 ± 4.3 kg/m ² , and peak transaortic velocity 3.1 ± 0.5 m/s. With increasing BMI class, the prevalence of hypertension and the use of antihypertensive medication increased ( Table 1 ). In particular, the use of angiotensin-converting enzyme inhibitors increased with increasing BMI (p <0.05). However, no significant difference was found in the use of angiotensin II receptor blockers among the 3 groups.

The LV mass/height ^2.7 and prevalence of LV hypertrophy increased with increasing BMI class, and LV systolic function and the prevalence of mitral regurgitation decreased ( Table 2 ). LV systolic dysfunction, measured as low stress-corrected mid-wall shortening (p = 0.06), and low ejection fraction (p = 0.13) tended to be more prevalent with increasing obesity ( Table 2 ). The transaortic peak velocity did not differ among the 3 groups, and the aortic valve area was significantly smaller in the normal weight class ( Table 2 ). The LV geometry differed significantly among the BMI classes, and obesity was particularly associated with eccentric LV hypertrophy ( Figure 1 ). On multiple logistic regression analysis, a greater BMI predicted the presence of LV hypertrophy (odds ratio 1.15 per unit of increased BMI, 95% confidence interval 1.12 to 1.18, p <0.001) independent of AS severity and systolic blood pressure in the total study population ( Table 3 ), as well as in the hypertensive and normotensive subpopulations (data not shown). In an alternative model, including aortic regurgitation among the covariates, the results did not change. Substituting stress-corrected mid-wall shortening for ejection fraction in the model yielded similar results. In a model substituting antihypertensive treatment for a history of hypertension, a greater BMI predicted the presence of LV hypertrophy (odds ratio 1.15 per unit of increased BMI, 95% confidence interval 1.11 to 1.18, p <0.001), independent of antihypertensive drug use (odds ratio 1.37, 95% confidence interval 1.09 to 1.72, p <0.01).

Table 2

Echocardiographic findings

Variable	BMI (kg/m 2 )
	<25 (n = 605, 35%)	25–29.9 (n = 752, 44%)	≥30 (n = 346, 20%)
Left ventricular end-diastolic diameter (cm)	4.88 ± 0.60	5.11 ± 0.62 ⁎	5.19 ± 0.64 ⁎
Left ventricular end-systolic diameter (cm)	3.06 ± 0.53	3.25 ± 0.56 ⁎	3.32 ± 0.58 ⁎
Septum diameter end-diastolic (cm)	1.09 ± 0.25	1.18 ± 0.28 ⁎	1.23 ± 0.28 ⁎
Posterior wall thickness end-diastolic (cm)	0.85 ± 0.17	0.90 ± 0.19 ⁎	0.93 ± 0.20 ⁎
Mid-wall shortening	17.5 ± 3.2	16.9 ± 3.4 ⁎	16.6 ± 3.2 ⁎
Stress-corrected midwall shortening	106 ± 21%	103 ± 22% †	102 ± 21% ⁎
Low stress-corrected midwall shortening	142 (24%)	209 (28%)	104 (30%)
Left ventricular ejection fraction	0.67 ± 0.08	0.65 ± 0.08 ⁎	0.65 ± 0.08 ⁎
Low ejection fraction	11 (1.8%)	26 (3.5%)	13 (3.8%)
Relative wall thickness	0.35 ± 0.09	0.36 ± 0.09	0.37 ± 0.09
Left ventricular mass index/height 2.7	40.5 ± 11.7	46.7 ± 13.9 ⁎	53.3 ± 16.7 ⁎
Left ventricular hypertrophy	130 (22%)	282 (38%) †	187 (54%) †
Transaortic peak velocity (m/sec)	3.12 ± 0.53	3.06 ± 0.55	3.11 ± 0.56
Aortic valve area (cm 2 )	1.19 ± 0.42	1.33 ± 0.49 ⁎	1.31 ± 0.50 ⁎
Aortic annulus diameter (cm)	2.15 ± 0.26	2.21 ± 0.26 ⁎	2.20 ± 0.27
Aortic regurgitation	362 (61%)	458 (63%)	190 (57%)
Mitral regurgitation	314 (53%)	357 (50%) †	128 (40%) †

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