Study Subjects

We prospectively identified 50 subjects with BAVs (mean age, 52 ± 14 years) without aortic valve dysfunction, defined as less than mild aortic stenosis or regurgitation, who underwent echocardiography at Severance Cardiovascular Hospital (Seoul, Korea) between June 1, 2009, and May 31, 2010. The control group, matched for sex and age, comprised 50 subjects who were referred for echocardiography to evaluate cardiac function. All subjects in both groups were in sinus rhythm and had normal left ventricular (LV) ejection fractions (≥55%). Subjects were excluded if they had significant mitral, aortic, or tricuspid valvular dysfunction; Marfan syndrome or other connective tissue diseases; peripheral artery disease; cardiomyopathies; peripheral systolic blood pressure (BP) > 140 mm Hg; or renal insufficiency (serum creatinine level ≥ 1.4 mg/dL). This study was approved by the institutional review board of our institution, and informed consent was obtained from all study subjects.

Echocardiography

Comprehensive transthoracic echocardiography was performed using commercially available equipment (Vivid 7, GE Vingmed Ultrasound AS, Horten, Norway; or Sonos 5500, Philips Medical Systems, Andover, MA). Aortic valve morphology was evaluated in the parasternal long-axis and short-axis views, and only those subjects with clearly identified aortic valve orifices and leaflets were included. A congenital BAV was diagnosed when only two cusps were unequivocally identified in systole and diastole in the short-axis view, with a clear “fish mouth” appearance during systole. We classified BAV phenotypes into three types according to raphe orientation in relation to the sinuses and cusp fusion pattern: (1) fusion of the left coronary and right coronary cusps, (2) fusion of the right coronary and noncoronary cusps, and (3) fusion of the left coronary and noncoronary cusps. The presence and severity of aortic regurgitation were assessed using an integrated approach. Color Doppler imaging was performed to measure the proximal jet width or cross-sectional area obtained from the long-axis view immediately below the aortic valve (within 1 cm of the valve), and the ratio of the proximal jet width to the LV outflow tract diameter was calculated. Other specific and supportive signs of severity were also assessed. Peak aortic velocity was assessed by continuous-wave Doppler, and aortic stenosis was considered to be present when the peak aortic velocity was > 2.5 m/sec. Measurements of the four aortic segments, including the aortic annulus, sinus of Valsalva, sinotubular junction, and proximal ascending aorta 1 cm above the sinotubular junction, were obtained at end-diastole by two-dimensional echocardiography. A dilated ascending aorta was defined as an aorta with a diameter ≥ 40 mm. Aortic dimensions were normalized to body surface area.

LV internal diameter, septal thickness, and LV posterior wall thickness were measured at end-diastole. LV mass was calculated using the formula developed by Devereux et al. and indexed to body surface area. Left atrial volume was calculated from the parasternal long-axis view and apical four-chamber view using the prolate ellipse method and indexed to body surface area. Mitral inflow velocities were obtained by pulsed-wave Doppler in the apical four-chamber view. Mitral early diastolic velocity (E) and the deceleration time of the E velocity were measured. Peak early diastolic mitral annular velocity (Ea) was measured from the septal mitral annulus, and the E/Ea ratio, a measure of LV filling pressure, was calculated. For each quantitative parameter, three consecutive beats were averaged. Echocardiographic data were gathered and analyzed by two independent investigators who were unaware of subjects’ clinical data.

Measurement of Central Hemodynamics

Central hemodynamics and parameters of arterial stiffness were assessed by pulse-wave analysis of the radial artery using a commercially available radial artery tonometry system (SphygmoCor; AtCor Medical, Sydney, Australia). Measurements were taken with subjects in the supine position after ≥5 min of rest immediately before echocardiography. As reported previously, peripheral pressure waveforms were recorded from the radial artery at the wrist using applanation tonometry with a high-fidelity micromanometer (Millar Instruments, Houston, TX). After 20 sequential waveforms were acquired, a validated generalized transfer function was used to generate the corresponding central aortic pressures and pressure waveforms. Central systolic and diastolic BP, pulse pressure (PP), augmentation pressure, and the AIx were derived by pulse waveform analysis ( Figure 1 ). PP was calculated as the difference between the respective systolic and diastolic pressures. Augmentation pressure was calculated as the difference between the second (reflected wave) and first systolic (ejection wave) peaks, and AIx was defined as the ratio of the augmentation pressure to the aortic PP and is expressed as a percentage. In addition, given that AIx is influenced by heart rate, an index normalized for a heart rate of 75 beats/min (AIx@75) was used in accordance with Wilkinson et al. PP amplification (PPA) was calculated as the ratio of the peripheral to the central PP. PWV was assessed using the quotient of the carotid-femoral path length and carotid-femoral pressure pulse transit time. High-quality recordings, which were defined as those with in-device quality indexes > 90%, were derived from an algorithm that included average pulse height, pulse height variation, diastolic variation, and the maximum rate of rise of the peripheral waveform. Peripheral BP was measured with subjects in the supine position at the brachial artery of the dominant arm after 15 min of rest in the laboratory using the validated Omron HEM-705 CP oscillometric sphygmomanometer (Omron Corporation, Kyoto, Japan). These hemodynamic data were measured and analyzed by an independent investigator who was unaware of subjects’ clinical data.

A central aortic pressure waveform and parameters from radial artery tonometry.

Statistical Analysis

Data are expressed as mean ± SD for continuous variables. Pairwise comparisons between patients with BAVs and controls were performed using standard χ ² tests for categorical variables and paired t tests for continuous variables.

To compare continuous variables related to central aortic stiffness in different BAV phenotypes, analysis of variance was performed. To determine independent correlates of AIx@75 and PPA, linear relations were verified using simple linear regression analysis. Variables that were statistically significant in the univariate analysis were included in the multiple linear regression model. Subgroup analysis was performed using unpaired t tests among controls and those with aortic diameter values above and below the median for subjects with BAVs. P values < .05 were considered statistically significant.