A bicuspid aortic valve (BAV) is often associated with dilation or aneurysm of the ascending aorta (AA) despite of absence of significant valve dysfunction. Bicuspid aortopathy and consequent aortic stiffness may adversely affect left ventricular (LV) diastolic function. This study aimed to investigate the impact of global and regional aortic mechanical function on LV diastolic function in subjects with BAV. Fifty-six subjects with BAV (45 men, mean age 52 ± 13 years) without significant valve dysfunction and 56 age- and gender-matched controls with tricuspid aortic valve were studied. The aortic phenotypes were classified into 3 groups: normal shape, predominant dilatation of the sinus of Valsalva, and predominant dilatation of the AA. Structural and functional parameters of the AA and LV were measured using 2-dimensional echocardiography. Global aortic mechanical function was assessed by radial artery tonometry. The subjects with BAV showed a higher incidence of a predominant AA phenotype (53.6% vs 17.9%, p <0.001), larger indexed aortic diameters, increased augmentation index, lower pulse pressure amplification, lower early diastolic mitral annular (e’) velocity, and higher E/e’ than those with tricuspid aortic valve . The e’ velocity and E/e’ varied with different aortic phenotypes in subjects with BAV. Correlations between e’ velocity and parameters of aortic stiffness were stronger in subjects with BAV than those in controls. Multiple regression analysis revealed that augmentation index normalized for a heart rate of 75 beats/min was an independent determinant of e’ velocity (β = −0.24, p = 0.044) and E/e’ (β = 0.30, p = 0.018) in subjects with BAV even after controlling for confounding factors. LV diastolic function is closely related to aortic phenotype and mechanical alteration in subjects with BAV.
A bicuspid aortic valve (BAV) is not a localized disease just to the aortic valve but is associated with abnormalities of the thoracic aorta including dilatation, aneurysm formation, coarctation, and dissection. Valvular dysfunction may play a role in the development of aortic dilatation, but aortic dilatation often appears out of proportion to the degree of valve dysfunction. Moreover, increased aortic wall stiffness has been reported in subjects with normally functioning or mildly dysfunctional BAV, and abnormal aortic elastic properties are not based solely on aortic size, suggesting an intrinsic aortic tissue abnormality in subjects with BAV. Left ventricular (LV) diastolic dysfunction is associated with an unfavorable outcomes and is considered to be one of the major contributors of heart failure. Previous studies have reported that increased aortic stiffness is related to LV diastolic dysfunction in various cardiac conditions. A few previous studies have demonstrated LV remodeling and dysfunction in subjects with BAV, but the relation between aortic mechanical function and LV diastolic function is still uncertain. Theoretically, on the basis of the intrinsic abnormalities of the aortic wall in subjects with BAV, consequent aortic stiffness may affect LV diastolic function, which is substrate for future development of heart failure. Accordingly, our aims in the present study were (1) to evaluate differences in LV diastolic function in subjects with BAV compared to subjects with tricuspid aortic valve (TAV) and (2) to explore the mechanistic linkage of global and regional mechanical aortic function to LV diastolic function in subjects with BAV.
Methods
Fifty-six subjects with BAVs (45 men, 11 women; mean age 52 ± 13 years) who had been diagnosed with isolated BAV without aortic valve dysfunction (defined as less than mild aortic stenosis or regurgitation) were enrolled in study. The control group, matched for age and gender, comprised 56 subjects who were referred for an echocardiography to evaluate cardiac function. All subjects in both groups were in sinus rhythm and had normal 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; coarctation of the aorta; cardiomyopathies; peripheral systolic blood pressure (BP) >140 mm Hg; or renal insufficiency (serum creatinine level ≥1.4 mg/dl). The Institutional Review Board of Yonsei University College of Medicine approved the study protocol, and informed consent was obtained from all study subjects.
All subjects underwent comprehensive transthoracic echocardiography using commercially available equipment. Standard 2-dimensional and Doppler measurements were performed per the recommendations of the American Society of Echocardiography guidelines. Mitral inflow velocities were obtained by pulse-wave Doppler in the apical 4-chamber view. Early diastolic mitral inflow (E) velocity and the deceleration time of the E velocity were measured. Early diastolic mitral annular (e’) velocity was measured from the septal mitral annulus, and the E/e’ ratio, a measure of LV filling pressure, was calculated. For each quantitative parameter, 3 consecutive beats were averaged. Echocardiographic data were gathered and analyzed by 2 independent investigators who were unaware of the subjects’ clinical data.
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 2 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 3 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.
All measurements of the aorta were performed according to recommendations and on the QRS complex of the electrocardiogram. The dimension of the Valsalva sinuses was measured perpendicular to the right and left (or non) aortic sinuses. The sinotubular junction was measured in which the aortic sinuses meet the tubular aorta. The ascending aorta (AA) was measured approximately 2 cm distal to the sinotubular junction. AA dimensions were normalized to the body surface area. Three aortic phenotypes were defined for all groups, as previously reported : (1) normal shape (Valsalva sinuses <37 mm and AA < Valsalva); (2) predominant dilatation of the Valsalva sinuses (Valsalva ≥37 mm and Valsalva > AA); and (3) predominant dilatation of the AA (AA ≥37 mm and AA > Valsalva).
Regional aortic mechanical properties were assessed using systolic and diastolic aortic diameters (which were measured 3 cm above the aortic valve) and combined systolic and diastolic BP, as previously reported. The diastolic aortic diameter was obtained at the peak of the R wave simultaneously with the recorded electrocardiogram, while the systolic aortic diameter was measured at the maximal anterior motion of the anterior aortic wall. The following indexes of aortic mechanical properties were calculated: aortic strain (%) = 100 [(systolic aortic diameter) − (diastolic aortic diameter)]/(diastolic aortic diameter); aortic stiffness index = ln (systolic BP/diastolic BP)/aortic strain; and aortic distensibility index (cm −2 ·dyn −1 ·10 6 ) = 2 × aortic strain/(systolic BP − diastolic BP).
Central hemodynamics and parameters of aortic stiffness were assessed by pulse-wave analysis of the radial artery using a commercially available radial artery tonometry system (SphygmoCor; AtCor Medical, Sydney, Australia). Pulse-wave analyses were performed by independent investigators who were unaware of the subjects’ clinical and echocardiographic data. Measurements were taken with subjects in the supine position after ≥5 minutes 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, Texas). 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 augmentation index (AIx) were derived by pulse waveform analysis. 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 the first systolic (ejection wave) peaks. 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 was calculated as the ratio of the peripheral to the central PP. Pulse wave velocity (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 minutes of rest in the laboratory using the validated Omron HEM-705 CP oscillometric sphygmomanometer (Omron Corporation, Kyoto, Japan).
Data are expressed as mean ± standard deviation for continuous variables and the number of subjects and as percentages for categorical variables. Pairwise comparisons between subjects with BAV and controls were performed using standard chi-square tests for categorical variables and paired t tests for continuous variables. To compare continuous variables related to aortic mechanical properties and LV diastolic function in different aortic phenotypes, an analysis of variance was performed. To determine independent correlates of e’ and E/e’, 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 models. Subgroup analysis was performed using unpaired t tests in subjects with TAV with normal-shaped aorta and subjects with BAV with 3 different aortic phenotypes. p Values <0.05 were considered statistically significant.
All analyses were conducted using SPSS Statistics (version 18.0.0, IBM Corp., Armonk, NY).
Results
The baseline characteristics of the subjects with BAV and TAV were largely comparable ( Table 1 ). Of the subjects with BAV, 36 subjects (64.3%) showed the phenotype of fusion of the left and right coronary cusps and 13 subjects (23.2%) showed the phenotype of fusion of the right and noncoronary cusps. There were no statistically significant differences in the distribution of cardiovascular risks and the use of cardiovascular medications.
| Variable | TAVs (n=56) | BAVs (n=56) | P value |
|---|---|---|---|
| Age (years) | 52 ± 13 | 52 ± 13 | 1.000 |
| Male | 45 (80.4%) | 45 (80.4%) | 1.000 |
| Height (cm) | 168 ± 8 | 167 ± 8 | 0.590 |
| Weight (kg) | 68.3 ± 11.3 | 66.8 ± 11.3 | 0.459 |
| Body mass index (kg/m 2 ) | 24.1 ± 2.8 | 23.9 ± 3.2 | 0.642 |
| Hypertension | 28 (51.9%) | 23 (41.1%) | 0.257 |
| Diabetes mellitus | 5 (9.3%) | 6 (10.7%) | 0.799 |
| Dyslipidemia | 14 (25.0%) | 11 (19.6%) | 0.496 |
| Smokers | 25 (46.3%) | 17(30.4%) | 0.116 |
| Coronary artery disease | 2 (3.6%) | 4 (7.1%) | 0.401 |
| BAV phenotypes | |||
| LC-RC fusion | 36 (64.3%) | ||
| RC-NC fusion | 13 (23.2%) | ||
| LC-NC fusion | 7 (12.5%) | ||
| Medications | |||
| CCBs | 16 (28.6%) | 11 (20.8%) | 0.345 |
| Beta-blockers | 6 (10.7%) | 12 (21.4%) | 0.197 |
| ACE inhibitors or ARB | 13 (24.5%) | 21 (37.5%) | 0.144 |
| Diuretics | 4 (7.5%) | 10 (17.9%) | 0.108 |
The subjects with BAV showed a significantly higher prevalence of abnormal aortic phenotypes than the controls with TAV. Most of the control subjects with TAV (75.0%) had a nondilated aorta with normal shape. In contrast, in the subjects with BAV, predominant dilatation of tubular AA was greater than those in the subjects with TAV ( Table 2 , Figure 1 ). Indexed aortic diameters were significantly larger in subjects with BAVs than in controls with TAV at the site of the annulus, sinus of Valsalva, sinotubular junction, and AA ( Table 2 ).
| TAVs (n=56) | BAVs (n=56) | P value | |
|---|---|---|---|
| Aortic phenotype | |||
| Normal shape | 42 (75.0%) | 17 (30.4%) | < 0.001 |
| Predominant Valsalva sinus | 4 (7.1%) | 9 (16.1%) | 0.140 |
| Predominant ascending aorta | 10 (17.9%) | 30 (53.6%) | < 0.001 |
| Indexed aortic diameters | |||
| Annulus (mm/m 2 ) | 12.1 ± 1.2 | 13.4 ± 2.3 | <0.001 |
| Valsalva sinus (mm/m 2 ) | 17.8 ± 2.4 | 20.2 ± 4.0 | <0.001 |
| Sinotubular junction (mm/m 2 ) | 16.8 ± 2.0 | 18.7 ± 3.5 | 0.001 |
| Ascending aorta (mm/m 2 ) | 17.9 ± 2.4 | 20.7 ± 4.1 | <0.001 |
| Aortic mechanical properties | |||
| Aortic strain (%) | 8.59 ± 4.95 | 6.82 ± 3.52 | 0.032 |
| Aortic distensibility (cm 2 ·dyne -1 ) | 4.91 ± 2.96 | 4.10 ± 2.15 | 0.101 |
| Aortic stiffness index | 3.15 ±0.67 | 3.30 ± 0.57 | 0.222 |
| Peripheral pulse pressure (mmHg) | 47.9 ± 9.3 | 46.2 ± 11.0 | 0.389 |
| Central pulse pressure (mmHg) | 36.4 ± 7.7 | 37.3 ± 10.8 | 0.640 |
| Augmentation pressure (mmHg) | 8.8 ± 5.6 | 11.6 ± 6.2 | 0.017 |
| Augmentation index @75 (%) | 18.8 ± 8.1 | 25.4 ± 8.8 | <0.001 |
| Pulse pressure amplification | 1.36 ± 0.17 | 1.27 ± 0.19 | 0.019 |
| Pulse wave velocity (m/s) | 7.4 ± 1.1 | 7.7 ± 1.4 | 0.138 |
For the assessment of regional aortic mechanical properties by transthoracic echocardiography, aortic strain was significantly lower in the subjects with BAV than in the controls with TAV (6.82 ± 3.52 vs 8.59 ± 4.95, p = 0.032). The aortic distensibility and aortic stiffness indexes were not statistically different between the 2 groups ( Table 2 ). In terms of global aortic properties assessed by radial artery tonometry, augmentation pressure and the AIx@75 were significantly greater in subjects with BAV than in controls with TAV (p = 0.017 and p <0.001, respectively). Moreover, the subjects with BAV showed a significantly lower PP amplification than those with TAV. Although the mean aortic PWV was greater in the subjects with BAV than in controls with TAV, the difference did not reach statistical significance. When the subjects with BAV were subdivided into 3 groups according to their aortic phenotype, the parameters reflecting aortic mechanical properties were different between the subgroups. The subjects with BAV with a predominant AA phenotype showed significantly larger indexed AA diameter, higher AIx@75, and lower aortic strain than subjects with a normal-shaped aortic phenotype ( Figure 2 ).
Table 3 lists the structural and functional echocardiographic parameters of the LV. The subjects with BAV showed a significantly larger LV end-diastolic dimension than those with TAV and a trend toward a larger LV end-systolic dimension and LV mass index. However, there were no significant differences between the groups with respect to LV ejection fraction and LA volume index. Compared to controls with TAV, the e’ velocity was significantly lower (6.7 ± 2.1 vs 8.4 ± 1.6, p <0.001), and E/e’ (11.0 ± 3.6 vs 9.3 ± 2.9, p = 0.010) was significantly greater in the subjects with BAV ( Table 3 ). On subgroup analysis according to the aortic phenotypes, the predominant AA dilatation group in subjects with BAV revealed a more decreased e’ velocity and elevated E/e’ than other groups ( Figure 3 ).
| Variable | TAVs (n=56) | BAVs (n=56) | P value |
|---|---|---|---|
| LVEDD (mm) | 48.8 ± 3.9 | 51.0 ± 4.3 | 0.006 |
| LVESD (mm) | 32.3 ± 4.7 | 34.0 ± 4.6 | 0.053 |
| LVEF (%) | 66.2 ± 7.3 | 65.6 ± 7.2 | 0.621 |
| Relative wall thickness | 0.39 ± 0.08 | 0.37 ± 0.06 | 0.237 |
| LV mass index (g/m 2 ) | 92.0 ± 25.5 | 101.3 ±24.8 | 0.054 |
| LA volume index (ml/m 2 ) | 24.6 ± 7.0 | 25.4 ± 9.1 | 0.581 |
| E velocity (cm/s) | 66.0 ± 15.9 | 69.9 ±18.2 | 0.239 |
| A velocity (cm/s) | 61.8 ± 18.3 | 66.3 ± 21.9 | 0.244 |
| Deceleration time (ms) | 196.2 ± 34.0 | 205.6 ± 48.2 | 0.237 |
| e’ velocity (cm/s) | 8.4 ± 1.6 | 6.7 ± 2.1 | <0.001 |
| A’ velocity (cm/s) | 7.3 ± 1.5 | 8.3 ± 1.9 | 0.004 |
| S′ velocity (cm/s) | 7.3 ± 2.2 | 6.7 ± 1.3 | 0.103 |
| E/e’ | 9.3 ± 2.9 | 11.0 ± 3.6 | 0.010 |
