ABSTRACT
Background
No medical therapy has been proven to prevent the progression of aortic dilatation in bicuspid aortic valve (BAV) disease, and prophylactic aortic surgery remains the mainstay of treatment.
Hypothesis
Among patients with BAV disease who are referred for surgery, preoperative statin use is associated with decreased odds of ascending aortic dilatation.
Methods
We reviewed all BAV patients who underwent aortic valve and/or aortic surgery at our center between April 2004 and December 2013. Aortic diameter (AD), defined as the maximum ascending aortic dimension, was determined by magnetic resonance imaging, computed tomography, or echocardiography. Patients were divided into 2 groups: maximal AD <4.5 cm or ≥4.5 cm. The association between preoperative statin use and aortic dilatation was assessed using multivariable logistic regression modeling.
Results
Of 680 consecutive patients, 405 (60%) had AD <4.5 cm (mean age, 60 ± 14 years; 45% on statins), whereas 275 (40%) had AD ≥4.5 cm (mean age, 54 ± 13 years; 35% on statins) at the time of surgery. After adjusting for age, body surface area, sex, hypertension, aortic stenosis, severity of aortic regurgitation, and use of angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and β‐blockers, patients with AD ≥4.5 cm had 0.66× lower odds (95% confidence interval: 0.45‐0.96) of being on preoperative statins compared with those with AD <4.5 cm (P = 0.029).
Conclusions
In a retrospective study of BAV patients referred for surgery, preoperative statin use was associated with lower odds of clinically significant ascending aortic dilatation.
Introduction
Although aortic stenosis (AS) and aortic regurgitation (AR) represent the most common complications in bicuspid aortic valve (BAV) disease, >50% of patients with BAV develop ascending aortic dilatation, placing them at 8‐ to 12‐fold increased risk of aortic dissection compared with the general population.1, 2, 3, 4 Prophylactic aortic surgery is indicated in BAV patients with dilated aortas to prevent aortic catastrophes. In BAV patients undergoing aortic valve replacement for severe AS or AR, consensus guidelines state that aneurysm repair is reasonable if the ascending aorta exceeds 4.5 cm.5, 6
Patients with BAV have intrinsic abnormalities of the aortic media, including accelerated smooth‐muscle‐cell apoptosis, elastic fiber degeneration, and increased matrix metalloproteinase (MMP) expression.1, 4, 7, 8 Factors associated with aortic dilatation in patients with BAV include age, sex, race, body surface area (BSA), hypertension, aortic valve leaflet fusion pattern, and severity of AS and/or AR.9, 10, 11, 12 No pharmacologic intervention has been shown to slow the progression of aortic dilatation in BAV disease, and strategies for medical management are extrapolated from Marfan syndrome.12, 13 Statins are thought to limit the progression of abdominal aortic aneurysms (AAAs) by reducing MMP expression.14, 15, 16 Recent studies have suggested that statin therapy might also be associated with reduced ascending aortic dilatation in BAV disease.12, 17 In this study, we characterized the association between preoperative statin use and aortic dilatation in a surgical cohort of BAV patients.
Methods
Data for this project were obtained from the Cardiovascular Research Database (CARD) of the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital. This database is approved by the institutional review board at Northwestern University. The CARD was queried for patients with BAV who underwent aortic valve and/or aortic surgery at our center between April 2004 and December 2013. Patients with a history of transcatheter aortic valve implants, ventricular assist devices, cardiac transplants, or trauma were not included in the analysis. Preoperative variables were retrieved from the database and chart review, and data were de‐identified before analysis. All investigations were in accordance with the Declaration of Helsinki.
Current practice at our institution is to perform preoperative magnetic resonance (MR) or computed tomography (CT) imaging for patients with suspected BAV. In the group with aortic diameter (AD) <4.5 cm, 44% had a preoperative MR or CT performed at our institution, compared with 43% of patients in the AD ≥4.5 cm group (P = 0.8.) Echocardiographic data were used only when MR or CT measurements were not available, and were verified by a board‐certified cardiologist to help minimize potential measurement errors. Based on the preoperative AD, defined as the maximum ascending aortic dimension on MR, CT, or echocardiography, patients were divided into 2 groups, AD <4.5 cm and AD ≥4.5 cm.
Statistical Analysis
Baseline characteristics were compared between groups using 2‐sample t tests or the Wilcoxon rank sum test, and a multivariable logistic regression model was used to quantify risk factors for AD ≥4.5 cm. To avoid overfitting, the model was internally validated using leave‐one‐out cross‐validation, and the comparisons criterion for overfitting was the area under the receiver operating characteristic curve. Body surface area‐ and height‐indexed maximum AD were also modeled using linear regression for normally distributed outcomes, using the same explanatory variables as those described for the logistic‐regression model. Statistical significance was established at the 2‐sided 5% α level, and there were no adjustments for multiplicity.
Results
A total of 680 patients met inclusion criteria, of whom 405 (60%) had AD <4.5 cm and 275 (40%) had AD ≥4.5 cm at the time of surgery. Baseline characteristics are shown in Table 1. Both groups were predominantly male and Caucasian. The prevalence of most comorbidities, including diabetes mellitus, hypertension, and smoking, did not differ significantly. Congestive heart failure, coronary artery disease (CAD), and a diagnosis of dyslipidemia were less common in the AD ≥4.5 cm group. Patients with AD ≥4.5 cm were younger, had more family history of aortic dissection, larger BSA, and greater body mass index. Surgical indication was not captured in our database. We infer that AS and/or AR was the surgical indication for most patients in the AD <4.5 cm group, whereas aortic aneurysm with or without AS and/or AR was the indication for most patients in the AD ≥4.5 cm group (Table 1). More than 99% of patients underwent aortic valve surgery, with only 9 patients receiving primary aortic resection.
Table 1.
Baseline Clinical, Demographic, and Imaging Characteristics According to AD Group
| Variable | AD <4.5 cm (n = 405) | AD ≥4.5 cm (n = 275) | P Valuea |
|---|---|---|---|
| Age | 60 ± 14 | 54 ± 13 | <0.001 |
| Female sex | 125 (31) | 42 (15) | <0.001 |
| L‐R cusp fusion | 258 (64) | 183 (67) | 0.72 |
| Caucasian race | 331 (84) | 235 (88) | 0.25 |
| BSA | 2.0 ± 0.3 | 2.1 ± 0.3 | <0.001 |
| BMI | 27.8 ± 5.6 | 28.6 ± 5.0 | 0.06 |
| Family history of aortic dissection | 1 (0.2) | 6 (2) | 0.014 |
| DM | 51 (13) | 23 (8) | 0.08 |
| HTN | 229 (57) | 144 (52) | 0.28 |
| PVD | 14 (3) | 7 (3) | 0.50 |
| CVD | 34 (8) | 19 (7) | 0.48 |
| CLD | 43 (11) | 20 (7) | 0.14 |
| Former smoker | 68 (17) | 47 (17) | 0.92 |
| CHF | 107 (26) | 43 (16) | <0.001 |
| CAD | 118 (31) | 47 (18) | <0.001 |
| Dyslipidemia | 231 (57) | 126 (46) | 0.004 |
| LDL‐C, mg/dL | 75 ± 36 | 82 ± 38 | 0.08 |
| TC, mg/dLb | 131 ± 51 | 140 ± 50 | 0.12 |
| AV mean gradient, mm Hg | 47 ± 17 | 34 ± 18 | <0.001 |
| AV area, cm2 | 0.8 ± 0.3 | 1.0 ± 0.4 | <0.001 |
| AV peak jet velocity, m/s | 4.4 ± 0.8 | 3.8 ± 1.0 | <0.001 |
| AS | 317 (78) | 152 (56) | <0.001 |
| Severe ASc | 295 (93) | 117 (77) | <0.001 |
| AR | 265 (65) | 197 (71) | 0.019 |
| Medications | |||
| ACEI | 102 (25) | 67 (24) | 0.81 |
| ARB | 51 (13) | 32 (12) | 0.71 |
| CCB | 45 (11) | 28 (10) | 0.71 |
| Antiarrhythmics | 14 (3) | 5 (2) | 0.20 |
| Aspirin | 73 (18) | 41 (15) | 0.29 |
| Steroids | 10 (2) | 8 (3) | 0.73 |
| Statins | 183 (45) | 95 (35) | 0.006 |
| High‐potency statind | 99 (54) | 55 (58) | 0.55 |
| β‐Blocker | 153 (38) | 125 (45) | 0.046 |
| Procedures | |||
| CABG | 89 (22) | 33 (12) | <0.001 |
| AV replacement | 393 (97) | 265 (96) | 0.63 |
| AV repair | 9 (2) | 4 (1) | 0.47 |
| Aneurysm repair surgery | 49 (12) | 260 (95) | <0.001e |
| AR only | 54 (13) | 2 (1) | — |
| AS only | 214 (53) | 8 (3) | — |
| AS and AR | 78 (19) | 3 (1) | — |
| No AS nor AR | 10 (2) | 2 (1) | — |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AD, aortic diameter; AS, aortic stenosis; AR, aortic regurgitation; ARB, angiotensin receptor blocker; AV, aortic valve; BMI, body mass index; BSA, body surface area; CAD, coronary artery disease; CCB, calcium channel blocker; CHF, congestive heart failure; CLD, chronic lung disease; CVD, cerebrovascular disease; DM, diabetes mellitus; HTN, hypertension; L‐R cusp fusion, left‐right coronary cusp fusion; LDL‐C, low‐density lipoprotein cholesterol; PVD, peripheral vascular disease; TC, total cholesterol.
Data are presented as n (%) or mean ± SD.
P values are 2‐sided with α = 0.05.
Perioperative lipid data were available in only 52% of patients.
The denominator for severe AS represents all patients with a diagnosis of AS.
High‐potency statin refers to atorvastatin or rosuvastatin.
P value reflects overall difference between groups for aneurysm repair, AR only, AS only, AS and AR, and no AS nor AR.
Valvular function was different between groups. Aortic regurgitation of any severity was more common with AD ≥4.5 cm compared with AD <4.5 cm, whereas AS of any severity was less common among patients with AD ≥4.5 cm. Aortic valve fusion patterns were similar.
Preoperative medications were similar for angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers. Patients with AD ≥4.5 cm had higher rates of β‐blocker use (45% vs 38%; P = 0.046), whereas statin use was lower with AD ≥4.5 cm (35% vs 45%; P = 0.006). Statin potency did not differ between groups. Statins were initiated based on the referring cardiologist's preference, and the indication for statin therapy was not captured in our database. Perioperative lipid values were available for 52% of patients in our database. Total cholesterol and low‐density lipoprotein cholesterol (LDL‐C) levels did not differ significantly.
After adjusting for age, BSA, female sex, hypertension, β‐blockers, ACEIs, ARBs, AS, and severity of AR, patients with AD ≥4.5 cm had 0.66× lower odds (95% confidence interval [CI]: 0.45‐0.96) of being on preoperative statins compared with those with AD <4.5 cm (P = 0.029; Figure 1, Table 2.)
Figure 1.
Forest plot with 95% Wald confidence limits showing multivariable logistic regression analysis, modeling odds of having AD ≥ 4.5 cm vs AD <4.5 cm. Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; AD, aortic diameter; AR, aortic regurgitation; ARB, angiotensin receptor blocker; BSA, body surface area; mod/sev, moderate/severe.
Table 2.
Multivariable Logistic Regression With Stepwise Variable Selection, Modeling Odds of Having AD ≥4.5 cm vs AD <4.5 cm
| Effect | OR | 95% CI | P Value |
|---|---|---|---|
| Age | 0.98 | 0.97‐0.99 | 0.026 |
| BSA | 3.55 | 1.65‐7.65 | 0.001 |
| Female sex | 0.64 | 0.40‐1.03 | 0.068 |
| HTN | 0.99 | 0.67‐1.46 | 0.96 |
| Preop medications | |||
| β‐Blocker | 1.25 | 0.88‐1.78 | 0.22 |
| Statin | 0.66 | 0.45‐0.96 | 0.029 |
| ACEI | 1.02 | 0.68‐1.54 | 0.92 |
| ARB | 0.96 | 0.56‐1.68 | 0.90 |
| AS | 0.39 | 0.26‐0.59 | <0.001 |
| AR | |||
| Severe vs none | 0.49 | 0.28‐0.85 | 0.011 |
| Mod/sev vs none | 0.83 | 0.34‐2.01 | 0.68 |
| Moderate vs none | 1.36 | 0.84‐2.18 | 0.21 |
| Mild vs none | 1.00 | 0.64‐1.58 | 0.99 |
Abbreviations: ACEI, angiotensin converting enzyme inhibitor; AD, aortic diameter; AR, aortic regurgitation; ARB, angiotensin receptor blocker; AS, aortic stenosis; BSA, body surface area; CI, confidence interval; HTN, hypertension; Mod/sev, moderate/severe; OR, odds ratio; Preop, preoperative.
Leave‐one‐out cross‐validation indicates that the area under the receiver operating characteristic curve did not differ significantly between the full‐data and cross‐validated models (Figure 2). This finding demonstrates that the model does not overfit the data and can be used for prediction on external data.
Figure 2.
The ROC curve for leave‐one‐out cross‐validation analysis. The area under the ROC curve did not differ significantly between the full‐data (blue line) and cross‐validated (red line) models. The AUC with 95% CIs is shown for each model. Abbreviations: AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic.
Patients taking preoperative statins had a significantly smaller BSA‐indexed maximum AD (coefficient: −0.11, SE: 0.04, P = 0.005). Statins were not associated with a significantly smaller height‐indexed maximum AD (coefficient: −0.0007, SE: 0.0004, P = 0.085), despite the trend (see Supporting Information, Tables 3 & 4, in the online version of this article).
To further test the robustness of our model, we modeled the odds of being on preoperative statin therapy and maximum AD as a continuous variable. Patients taking preoperative statins had 0.98× lower odds (odds ratio [OR]: 0.98, 95% CI: 0.96‐0.99) of increased maximum AD compared with those not taking statins (P = 0.038). We also performed sensitivity analyses in patients with and without CAD. In both groups, statin use was associated nonsignificantly with lower odds of AD ≥4.5 cm (OR: 0.74 for AD ≥4.5 cm in CAD patients, 95% CI: 0.29‐1.86, P = 0.515; OR: 0.79 for AD ≥4.5 cm in non‐CAD patients, 95% CI: 0.51‐1.22, P = 0.284 (see Supporting Information, Tables 1 & 2, in the online version of this article).
Discussion
Aortic dilatation in BAV disease likely arises from a combination of hemodynamics and genetics, with intrinsic abnormalities of the aortic media and overexpression of MMPs playing a central role.7, 18 Given their ability to suppress MMPs and limit AAA progression,14, 19, 20 it is believed that statins may also be useful in BAV disease. Preoperative statin therapy was independently associated with smaller aortic size in our cohort of surgical patients with BAV disease.
Our result corroborates the findings of Yuan et al, who report an association between statin therapy and decreased dimensions of the aortic root, sinotubular junction, and ascending aorta in a cohort of BAV patients referred for surgery.17 Similarly, our observations are concordant with a report showing that statin therapy is associated with smaller aortic size among BAV patients with severe AS.12 By contrast, a small study of BAV patients with aortic roots ≤4.5 cm found that statin therapy did not significantly affect aortic root diameter over a mean follow‐up of 6.2 ± 2 years after AVR.21 At 680 patients, our cohort is larger and more extensively characterized than these 3 studies that have addressed the role of statins in BAV disease. Our comparison of AD <4.5 cm to AD ≥4.5 cm may be more clinically relevant than the cutoff of >4.0 cm used by Goel et al, in light of consensus guidelines using 4.5 cm as the lowest threshold for surgical intervention.5, 6
Statins have lipid‐independent effects on the immune system and vascular endothelial function.13, 22, 23, 24, 25, 26, 27 They decrease reactive oxygen species formation in vitro, limit MMP release, and preserve or increase expression of tissue inhibitor of MMPs.14, 16, 20, 22, 27, 28, 29 Previous studies have shown that statins limit AAA growth by decreasing MMP expression.19, 20 MMP activity is upregulated in the BAV aorta, suggesting that statins may work through a similar mechanism to limit thoracic aortic aneurysm formation.4, 7, 8, 18
Increased age, severe AR, and the presence of AS were each associated with smaller aortic dimensions. Our observation of an association between age and smaller aortic size is at odds with previous studies identifying age as a risk factor for larger aortic size.10, 30 In our cohort, providers may have been more proactive in referring older patients for surgery at lower ADs. Also, the higher prevalence of CAD in the AD <4.5 cm group may confound the effect of age, as it is possible that atherosclerosis creates stiffer aortas that dilate less. Alternatively, there is increasing recognition that BAV disease is composed of heterogeneous phenotypes,31 and it is conceivable that BAV patients with CAD could have less severe aortic involvement.
Most studies have reported a direct relationship between AR severity and aortic dilatation in BAV patients.10, 30, 32 Increased stroke volume in AR increases aortic wall shear stress, which may drive progressive dilatation in the setting of intrinsic connective‐tissue abnormalities in the BAV aorta.10, 13, 33 By contrast, we found an association between severe AR and decreased AD. Referral bias likely contributes to an overrepresentation of patients with severe AR in our smaller aorta cohort, given that severe AR or AS is an indication for surgery regardless of aortic size.6
The presence of AS was protective against dilatation in our study. The relationship between AS and aortic size remains unsettled in the literature.30, 32 As with AR, referral bias likely contributes to an overrepresentation of patients with AS in our AD <4.5 cm cohort. Of note, a recent Mendelian randomization study found that a genetic predisposition to elevated LDL‐C was associated with aortic‐valve calcification and the incidence of AS, providing evidence supporting a causal relationship between LDL‐C and AS.34 This observation may explain the increased incidence of both AS and dyslipidemia in our AD <4.5 cm group.
Increased BSA was independently associated with greater odds of aortic dilatation in our logistic‐regression model and has been described in other cohorts of BAV patients.10 It is worth noting that statin use remained significantly associated with smaller BSA‐indexed maximum AD in our study. Aortic dissection can occur at absolute aortic sizes below current surgical thresholds, particularly in women, leading others to propose using indexed cutoffs for surgical intervention.35, 36 However, current American Heart Association/American College of Cardiology guidelines do not recommend adjusting AD for body size.6
Study Limitations
Our study has limitations, including those inherent to a retrospective, single‐center study. Our findings may not apply to BAV patients who do not meet surgical indications. Most patients in our study were Caucasian, and results could differ in other ethnicities. Although most comorbidities, including hypertension, were similarly represented, the AD <4.5 cm group had a higher prevalence of congestive heart failure, CAD, and dyslipidemia. This likely reflects differences in age between the 2 groups, as well as referral bias to tertiary‐care institutions. The association of statins with decreased AD lost statistical significance in sensitivity analyses of patients with and without CAD, although the direction and magnitude of the observations remained relatively unchanged. Decreased statistical power from sample‐size reduction likely contributes to this loss of significance. The imaging modality used to determine maximal AD was not recorded in our database, although our data show that similar proportions of patients in each group received preoperative MR or CT. Moreover, others have observed that a protective effect of statins might not extend to all ascending aortic sites,17, 24 and our use of maximal AD renders us unable to confirm this finding. Because many patients were referred and did not have their medical records transferred to our system, we were unable to calculate the rate of progression of aortic dilatation or document the duration of statin therapy.
Conclusion
Statins may have a protective effect against aortic dilatation in BAV patients who meet surgical indications. Additional research is needed to clarify the pathogenesis of BAV disease to help define strategies for pharmacotherapy. Randomized controlled trials of statins in BAV patients would help further elucidate their role in the medical management of this disease.
Supporting information
Supplemental Table 1: logistic regression for modeling odds of having a maximal aortic diameter (AD) ≥ 4.5 cm (vs. < 4.5 cm) among CAD patients only
Supplemental Figure 1A: Odds ratios corresponding to Supplemental Table 1
Supplemental Figure 1B: Cross‐validated Receiver's Operating Characteristics (ROC) Curves Associated with Supplemental Table 1
Supplemental Figure 2A: Odds ratios corresponding to Supplemental Table 2
Supplemental Figure 2B: Cross‐validated Receiver's Operating Characteristics (ROC) Curves Associated with Supplemental Table 2
Acknowledgments
The authors thank the support staff in the Division of Cardiac Surgery at Northwestern University and the Bluhm Cardiovascular Institute, including Jane Kruse and Anna Huskin, and Christopher Mitchell of the Northwestern Enterprise Data Warehouse.
This work was partially supported by the Northwestern University Clinical and Translational Sciences (NUCATS) grant UL1TR000150. Dr. McCarthy receives royalties from Edwards Lifesciences and serves as a paid consultant for Edwards Lifesciences, Abbott, and MiCardia. Dr. Thomas receives an honorarium from Edwards Lifesciences.
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
References
- 1. Braverman AC, Guven H, Beardslee MA, et al. The bicuspid aortic valve. Curr Probl Cardiol. 2005;30:470–522. [DOI] [PubMed] [Google Scholar]
- 2. Michelena HI, Khanna AD, Mahoney D, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104–1112. [DOI] [PubMed] [Google Scholar]
- 3. Vallely MP, Semsarian C, Bannon PG. Management of the ascending aorta in patients with bicuspid aortic valve disease. Heart Lung Circ. 2008;17:357–363. [DOI] [PubMed] [Google Scholar]
- 4. Fedak PW, Verma S, David TE, et al. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation. 2002;106:900–904. [DOI] [PubMed] [Google Scholar]
- 5. Vahanian A, Alfieri O, Andreotti F, et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology, European Association for Cardio‐Thoracic Surgery. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33:2451–2496.22922415 [Google Scholar]
- 6. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published correction appears in J Am Coll Cardiol. 2014;63:2489]. J Am Coll Cardiol. 2014;63:2438–2488. [DOI] [PubMed] [Google Scholar]
- 7. Fedak PW, de Sa MP, Verma S, et al. Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J Thorac Cardiovasc Surg. 2003;126:797–806. [DOI] [PubMed] [Google Scholar]
- 8. Nataatmadja M, West M, West J, et al. Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm. Circulation. 2003;108(suppl 1):II329–II334. [DOI] [PubMed] [Google Scholar]
- 9. Della Corte A, Bancone C, Quarto C, et al. Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression. Eur J Cardiothorac Surg. 2007;31:397–404. [DOI] [PubMed] [Google Scholar]
- 10. Thanassoulis G, Yip JW, Filion K, et al. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med. 2008;5:821–828. [DOI] [PubMed] [Google Scholar]
- 11. Chandra S, Lang RM, Nicolarsen J, et al. Bicuspid aortic valve: inter‐racial difference in frequency and aortic dimensions. JACC Cardiovasc Imaging. 2012;5:981–989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Goel SS, Tuzcu EM, Agarwal S, et al. Comparison of ascending aortic size in patients with severe bicuspid aortic valve stenosis treated with versus without a statin drug. Am J Cardiol. 2011;108:1458–1462. [DOI] [PubMed] [Google Scholar]
- 13. Tadros TM, Klein MD, Shapira OM. Ascending aortic dilatation associated with bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications. Circulation. 2009;119:880–890. [DOI] [PubMed] [Google Scholar]
- 14. Luan Z, Chase AJ, Newby AC. Statins inhibit secretion of metalloproteinases‐1, ‐2, ‐3, and ‐9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol. 2003;23:769–775. [DOI] [PubMed] [Google Scholar]
- 15. Schmoker JD, McPartland KJ, Fellinger EK, et al. Matrix metalloproteinase and tissue inhibitor expression in atherosclerotic and nonatherosclerotic thoracic aortic aneurysms. J Thorac Cardiovasc Surg. 2007;133:155–161. [DOI] [PubMed] [Google Scholar]
- 16. Danyi P, Elefteriades JA, Jovin IS. Medical therapy of thoracic aortic aneurysms: are we there yet? Circulation. 2011;124:1469–1476. [DOI] [PubMed] [Google Scholar]
- 17. Yuan SM, Jing H, Lavee J. The bicuspid aortic valve and its relation to aortic dilation. Clinics (Sao Paulo). 2010;65:497–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Verma S, Siu SC. Aortic dilatation in patients with bicuspid aortic valve. N Engl J Med. 2014;370:1920–1929. [DOI] [PubMed] [Google Scholar]
- 19. Shiraya S, Miyake T, Aoki M, et al. Inhibition of development of experimental aortic abdominal aneurysm in rat model by atorvastatin through inhibition of macrophage migration. Atherosclerosis. 2009;202:34–40. [DOI] [PubMed] [Google Scholar]
- 20. Steinmetz EF, Buckley C, Shames ML, et al. Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice. Ann Surg. 2005;241:92–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Dayan V, Cura L, Muñoz L, et al. Risk of subsequent aortic dilatation is low in patients with bicuspid aortic valve and normal aortic root diameter at the time of aortic valve replacement. Interact Cardiovasc Thorac Surg. 2010;10:535–538. [DOI] [PubMed] [Google Scholar]
- 22. Nagashima H, Aoka Y, Sakomura Y, et al. A 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase‐9 in human abdominal aortic aneurysm wall. J Vasc Surg. 2002;36:158–163. [DOI] [PubMed] [Google Scholar]
- 23. Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol. 2002;54:395–399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Stein LH, Berger J, Tranquilli M, et al. Effect of statin drugs on thoracic aortic aneurysms. Am J Cardiol. 2013;112:1240–1245. [DOI] [PubMed] [Google Scholar]
- 25. Takagi H, Matsui M, Umemoto T. A meta‐analysis of clinical studies of statins for prevention of abdominal aortic aneurysm expansion. J Vasc Surg. 2010;52:1675–1681. [DOI] [PubMed] [Google Scholar]
- 26. Verma S, Szmitko PE, Fedak PW, et al. Can statin therapy alter the natural history of bicuspid aortic valves? Am J Physiol Heart Circ Physiol. 2005;288:H2547–H2549. [DOI] [PubMed] [Google Scholar]
- 27. Gazzerro P, Proto MC, Gangemi G, et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 2012;64:102–146. [DOI] [PubMed] [Google Scholar]
- 28. Ejiri J, Inoue N, Tsukube T, et al. Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res. 2003;59:988–996. [DOI] [PubMed] [Google Scholar]
- 29. Alvarez E, Rodiño‐Janeiro BK, Ucieda‐Somoza R, et al. Pravastatin counteracts angiotensin II‐induced upregulation and activation of NADPH oxidase at plasma membrane of human endothelial cells. J Cardiovasc Pharmacol. 2010;55:203–212. [DOI] [PubMed] [Google Scholar]
- 30. Keane MG, Wiegers SE, Plappert T, et al. Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation. 2000;102(19 suppl 3):III35–III39. [DOI] [PubMed] [Google Scholar]
- 31. Kang JW, Song HG, Yang DH, et al. Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction and bicuspid aortopathy: comprehensive evaluation using MDCT and echocardiography. JACC Cardiovasc Imaging. 2013;6:150–161. [DOI] [PubMed] [Google Scholar]
- 32. Novaro GM, Tiong IY, Pearce GL, et al. Features and predictors of ascending aortic dilatation in association with a congenital bicuspid aortic valve. Am J Cardiol. 2003;92:99–101. [DOI] [PubMed] [Google Scholar]
- 33. Tzemos N, Therrien J, Yip J, et al. Outcomes in adults with bicuspid aortic valves. JAMA. 2008;300:1317–1325. [DOI] [PubMed] [Google Scholar]
- 34. Smith JG, Luk K, Schulz CA, et al. Association of low‐density lipoprotein cholesterol–related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA. 2014;312:1764–1771. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. McDonald ML, Smedira NG, Blackstone EH, et al. Reduced survival in women after valve surgery for aortic regurgitation: effect of aortic enlargement and late aortic rupture. J Thorac Cardiovasc Surg. 2000;119:1205–1212. [DOI] [PubMed] [Google Scholar]
- 36. Roman MJ, Devereux RB, Kramer‐Fox R, et al. Two‐dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol. 1989;64:507–512. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Table 1: logistic regression for modeling odds of having a maximal aortic diameter (AD) ≥ 4.5 cm (vs. < 4.5 cm) among CAD patients only
Supplemental Figure 1A: Odds ratios corresponding to Supplemental Table 1
Supplemental Figure 1B: Cross‐validated Receiver's Operating Characteristics (ROC) Curves Associated with Supplemental Table 1
Supplemental Figure 2A: Odds ratios corresponding to Supplemental Table 2
Supplemental Figure 2B: Cross‐validated Receiver's Operating Characteristics (ROC) Curves Associated with Supplemental Table 2