Ascending aortic dilation commonly occurs in patients with bicuspid aortic valve (BAV). Statins have been shown to reduce the expression of matrix metalloproteinases and slow the progression of abdominal aortic aneurysms. The role of statins in slowing ascending aortic dilation in patients with BAV is unknown. We sought to compare the ascending aortic dimensions in patients with BAV stenosis treated with versus without a statin. From our catheterization laboratory database, all patients undergoing preoperative coronary angiography before aortic valve with or without ascending aorta replacement for bicuspid aortic stenosis (AS) from 2004 to 2007 were identified. The ascending aortic size was measured on their preoperative transesophageal echocardiogram. Data on statin use were obtained from chart review, and the ascending aortic size was compared between patients taking and not taking a statin. The study sample included 147 patients, of whom 76 were treated with statins (mean age 62 ± 9 years, 72% men) and 71 were not (mean age 59 ± 12 years, 68% men). The total and low-density lipoprotein cholesterol and triglyceride levels were significantly lower in the statin group. The ascending aorta size was significantly lower in the statin subgroup of the pure severe AS group (3.6 ± 0.7 cm vs 3.9 ± 0.6 cm, p <0.01) but not in the mixed severe AS and severe aortic regurgitation group. In the pure severe AS group, significantly fewer patients taking a statin had an ascending aorta ≥4 cm (29% vs 52%, p <0.02). On multivariate analysis, statin use was the only independent predictor of aortic size and was associated with a 0.33-cm reduction in aortic size (95% confidence interval 0.06 to 0.59, p <0.01). In conclusion, patients with statin-treated BAV stenosis have a smaller ascending aortic size than patients with BAV untreated with statins.
Ascending aortic dilation (AAD) commonly occurs in patients with a bicuspid aortic valve (BAV) and can lead to aneurysm formation, dissection, or rupture. No medical intervention has been proved to slow the progression of AAD in patients with BAV. The current guidelines recommend using β blockers (class IIa recommendation) in patients with BAV with an aortic root >4.0 cm; however, this recommendation is based on data from patients with Marfan syndrome and not patients with BAV. Histologically, the aortic wall in most patients with BAV is characterized by degeneration and a loss of elastic fibers. Increased expression and activity of matrix metalloproteinases has been observed in patients with BAV and aortic aneurysms. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have been shown to reduce the expression of matrix metalloproteinase and thereby slow the progression of abdominal aortic aneurysms. The role of statins in AAD in patients with BAV is unknown. We sought to compare the aortic sizes in patients with BAV stenosis treated with a statin to those not treated with a statin.
Methods
All patients undergoing preoperative diagnostic coronary angiography before aortic valve with or without ascending aorta replacement surgery for severe BAV stenosis at our hospital from 2004 to 2007 were identified from our cardiac catheterization database. The clinical characteristics, including the presence of hypertension (blood pressure ≥140/90 mm Hg or treatment with an antihypertensive drug), hyperlipidemia (total cholesterol ≥200 mg/dl or treatment with a lipid-lowering agent), diabetes mellitus (fasting plasma glucose ≥126 mg/dl or treatment with an oral hypoglycemic agent or insulin), smoking history, peripheral arterial disease, body mass index, and laboratory values (lipid profile and creatinine) were obtained from chart review. Echocardiographic measurements, including the severity of valve dysfunction and left ventricular ejection fraction, were obtained from chart review. The aortic dimensions were measured on the preoperative transesophageal echocardiogram at the following levels: aortic annulus, aortic sinus, sinotubular junction, and mid-ascending aorta at the level of the pulmonary artery. Data on statin use was obtained by chart review. Hyperlipidemia was the indication for statin use in patients in the statin group. Patients with previous aortic or aortic valve replacement were excluded. The ascending aortic size was compared in patients treated with and without a statin. In addition, these patients were divided into those with pure severe aortic stenosis (AS) and those with concomitant severe AS and severe aortic regurgitation (AR), and the ascending aortic size was compared in those treated with and without a statin. The institutional review board waived the requirements for informed consent.
The continuous variables are presented as the mean ± SD. Student’s t test and the chi-square or Mann-Whitney U test were used to compare the mean values for the continuous and categorical variables, respectively. Multivariate analysis models were developed to predict AAD using age, gender, height, weight, hypertension, diabetes, smoking history, total cholesterol, low-density lipoprotein, and high-density lipoprotein, medication (statin, β blocker, and angiotensin-converting enzyme inhibitor), severe aortic regurgitation, aortic valve area, and the left ventricular ejection fraction as predictors. All tests were 2-tailed, and p values were considered statistically significant when <0.05. Stata, version 10.0 (StataCorp, College Station, Texas) was used for statistical analysis.
Results
The baseline characteristics of the patients with BAV stenosis treated with and without statins are listed in Table 1 . The mean age was 62 ± 9 years in the statin group and 59 ± 12 years in the nonstatin group (p = 0.1). The prevalence of hypertension, hyperlipidemia, and diabetes mellitus was significantly greater in the statin group. The statin group had significantly lower total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels compared to the nonstatin group. The measures of body size, including height and body mass index, were similar in the 2 groups. The baseline characteristics of the patients with predominant severe AS and concomitant severe AS and severe AR are also listed in Table 1 .
| Variable | All Bicuspid AS | Predominant Severe AS | Severe AS and Severe AR | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Statin Therapy | Statin Therapy | Statin Therapy | |||||||
| Yes (n = 76) | No (n = 71) | p Value | Yes (n = 65) | No (n = 62) | p Value | Yes (n = 11) | No (n = 9) | p Value | |
| Age (years) | 62 ± 9 | 59 ± 12 | 0.1 | 62 ± 10 | 60 ± 12 | 0.3 | 61 ± 8 | 53 ± 11 | 0.06 |
| Men | 55 (72%) | 48 (68%) | 0.52 | 49 (75%) | 40 (65%) | 0.18 | 6 (55%) | 8 (89%) | 0.09 |
| Hypertension | 51 (68%) | 28 (40%) | 0.001 | 46 (72%) | 27 (44%) | 0.001 | 5 (45%) | 1 (11%) | 0.09 |
| Diabetes mellitus | 14 (19%) | 5 (7%) | 0.03 | 13 (20%) | 5 (8%) | 0.04 | 1 (9%) | 0 (0%) | 0.35 |
| Hyperlipidemia | 74 (99%) | 26 (37%) | 0.0001 | 65 (100%) | 23 (37%) | 0.001 | 10 (91%) | 3 (33%) | 0.007 |
| Smoker | 36 (51%) | 27 (42%) | 0.28 | 33 (55%) | 24 (42%) | 0.16 | 3 (27%) | 3 (38%) | 0.63 |
| Peripheral arterial disease | 3 (4%) | 1 (1%) | 0.35 | 3 (5%) | 1 (2%) | 0.34 | 0 (0%) | 0 (0%) | — |
| Height (m) | 1.59 ± 0.48 | 1.51 ± 0.59 | 0.33 | 1.58 ± 0.5 | 1.50 ± 0.59 | 0.46 | 1.72 ± 0.1 | 1.56 ± 0.6 | 0.4 |
| Body mass index (kg/m 2 ) | 27 ± 10 | 24 ± 11 | 0.09 | 27 ± 10 | 24 ± 11 | 0.2 | 28 ± 6 | 23 ± 9 | 0.2 |
| Creatinine (mg/dl) | 1.0 ± 0.5 | 1.0 ± 0.3 | 0.9 | 2.0 ± 0.6 | 1.0 ± 0.3 | 0.8 | 0.9 ± 0.2 | 1.0 ± 0.2 | 0.3 |
| Total cholesterol (mg/dl) | 170 ± 36 | 193 ± 39 | 0.0002 | 170 ± 35 | 192 ± 38 | 0.001 | 172 ± 43 | 206 ± 48 | 0.12 |
| Low-density lipoprotein cholesterol (mg/dl) | 91 ± 29 | 108 ± 32 | 0.001 | 90 ± 28 | 108 ± 32 | 0.001 | 94 ± 32 | 104 ± 39 | 0.6 |
| High-density lipoprotein cholesterol (mg/dl) | 56 ± 15 | 58 ± 24 | 0.46 | 55 ± 15 | 59 ± 25 | 0.36 | 57 ± 20 | 54 ± 15 | 0.7 |
| Triglycerides (mg/dl) | 121 ± 56 | 154 ± 108 | 0.022 | 125 ± 59 | 142 ± 82 | 0.2 | 102 ± 29 | 248 ± 208 | 0.03 |
| β Blocker | 33 (44%) | 18 (28%) | 0.05 | 30 (47%) | 16 (29%) | 0.04 | 3 (27%) | 2 (25%) | 0.91 |
| Angiotensin-converting enzyme inhibitor | 30 (40%) | 16 (25%) | 0.06 | 27 (42%) | 14 (25%) | 0.05 | 3 (27%) | 2 (25%) | 0.91 |
| Calcium channel blocker | 6 (8%) | 2 (3%) | 0.17 | 5 (8%) | 2 (3%) | 0.27 | 1 (9%) | 0 (0%) | 0.35 |
| Angiotensin receptor blocker | 4 (5%) | 1 (1%) | 0.19 | 4 (6%) | 1 (2%) | 0.18 | 0 (0%) | 0 (0%) | — |
The patients in both groups had a similar severity of AS, as assessed by the aortic valve area (by continuity equation) and peak and mean gradients ( Table 2 ). The prevalence of severe AR, defined as ≥3+ was similar in the 2 groups (14% vs 13%, p = 0.75). The echocardiographic characteristics of those with pure severe AS versus severe AS and severe AR are also listed in Table 2 . The ascending aortic diameter was significantly smaller in the statin group than in the nonstatin group in those with pure severe AS (3.6 ± 0.7 cm vs 3.9 ± 0.6 cm, p <0.01) but not in the statin-treated patients with concomitant severe AS and severe AR ( Figure 1 ). No difference in size was found at other sites in the ascending aorta, including the aortic annulus, aortic sinus, and sinotubular junction, between the statin and nonstatin groups. An ascending aortic size >4 cm was present in 29% of the patients with statin-treated pure severe AS compared to 52% in the statin untreated patients (p <0.01; Figure 2 ). No difference was found in the prevalence of ascending aortic size >4 cm in the statin-treated patients with severe AS and severe AR compared to those with pure severe AS. A very significant heterogeneity was present in the type and dose of statin used. No differences were found in the ascending aortic diameters in the patients receiving a submaximal versus maximal statin dose (3.6 ± 0.7 vs 3.7 ± 1.0 cm, p = 0.6) or in those receiving a starting statin dose versus a higher than starting dose (3.7 ± 0.7 vs 3.6 ± 0.7 cm, p = 0.7).
| Variable | All Bicuspid AS | Predominant Severe AS | Severe AS and Severe AR | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Statin Therapy | Statin Therapy | Statin Therapy | |||||||
| Yes (n = 76) | No (n = 71) | p Value | Yes (n = 65) | No (n = 62) | p Value | Yes (n = 11) | No (n = 9) | p Value | |
| Aortic valve area (cm 2 ) | 0.74 ± 0.1 | 0.75 ± 0.1 | 0.70 | 0.74 ± 0.1 | 0.74 ± 0.2 | 0.9 | 0.78 ± 0.1 | 0.84 ± 0.1 | 0.3 |
| Peak transvalvular gradient (mm Hg) | 76 ± 22 | 77 ± 24 | 0.76 | 76 ± 22 | 76 ± 24 | 0.9 | 77 ± 28 | 84 ± 25 | 0.55 |
| Mean transvalvular gradient (mm Hg) | 45 ± 14 | 45 ± 14 | 0.8 | 45 ± 14 | 45 ± 14 | 1.0 | 45 ± 16 | 48 ± 15 | 0.63 |
| Left ventricular ejection fraction (%) | 55 ± 9 | 56 ± 11 | 0.8 | 55 ± 9 | 56 ± 10 | 0.8 | 55 ± 9 | 55 ± 16 | 0.9 |
| Left coronary cusp–right coronary cusp fusion | 62 (82%) | 65 (92%) | 0.08 | 55 (85%) | 57 (92%) | 0.20 | 7 (64%) | 8 (89%) | 0.19 |
| Right coronary cusp–noncoronary cusp fusion | 14 (18%) | 6 (8%) | 0.08 | 10 (15%) | 5 (8%) | 0.20 | 4 (36%) | 1 (11%) | 0.19 |
| Ascending aorta diameter (cm) | 3.6 ± 0.7 | 3.9 ± 0.6 | 0.01 | 3.6 ± 0.7 | 3.9 ± 0.6 | 0.01 | 3.8 ± 0.8 | 4.2 ± 0.8 | 0.3 |
| Ascending aorta ≥4 cm | 26 (34%) | 38 (54%) | 0.01 | 19 (29%) | 32 (52%) | 0.01 | 7 (64%) | 6 (67%) | 0.9 |
| Ascending aorta diameter | 0.3 | ||||||||
| Median | 3.6 | 4.0 | 0.01 | 3.6 | 4.0 | 0.01 | 4.1 | 4.3 | |
| Interquartile range | 3.0–4.2 | 3.5–4.4 | 3.0–4.0 | 3.4–4.3 | 3.0–4.5 | 3.8–4.6 | |||
| Annulus (cm) | 2.4 ± 0.3 | 2.3 ± 0.3 | 0.53 | 2.4 ± 0.3 | 2.3 ± 0.4 | 0.5 | 2.3 ± 0.3 | 2.3 ± 0.2 | 0.9 |
| Sinus of Valsalva (cm) | 3.4 ± 0.5 | 3.5 ± 0.6 | 0.48 | 3.4 ± 0.5 | 3.5 ± 0.6 | 0.52 | 3.7 ± 0.5 | 3.6 ± 0.5 | 0.9 |
| Sinotubular junction (cm) | 3.1 ± 0.5 | 3.3 ± 0.6 | 0.25 | 3.1 ± 0.5 | 3.3 ± 0.7 | 0.2 | 3.4 ± 0.3 | 3.2 ± 0.2 | 0.2 |
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