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Ann Thorac Surg 2007;83:1338-1344
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Natural History of Ascending Aortic Aneurysms in the Setting of an Unreplaced Bicuspid Aortic Valve

^a Section of Cardiothoracic Surgery, Yale University School of Medicine, New Haven, Connecticut
^b Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York
^c Landmark Medical Center/Beth Israel Deaconess Medical Center, Woonsocket, Rhode Island

Accepted for publication October 27, 2006.

^_* Address correspondence to Dr Coady, Cardiac Surgery, Landmark Medical Center, 206 Cass Ave, Woonsocket, RI 02895 (Email: macoady{at}gmail.com).

Presented at the Poster Session of the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background: Patients with bicuspid aortic valve (BAV) are at risk for valvular disease and ascending aortic aneurysms and dissections. Although others have investigated the need for concomitant repair, the natural history of aortic disease has not been addressed.

Methods: A review of our institutional clinical database identified 514 patients (326 male, 188 female) with unrepaired ascending aortic aneurysms followed from 1985 to 2005. Seventy patients (13.4%) diagnosed with BAV form group A; the remaining 445 patients form group B. Growth rates and risk factors for complications were assessed.

Results: Patients in group A had a lower incidence of hypertension (p = 0.0185), carotid artery disease, and stroke (p = 0.0184), and presented at an earlier age (49.0 versus 64.2 years, p < 0.0001). Group A also had a higher rate of aortic growth (0.19 versus 0.13 cm/year, p = 0.0102). The incidence of rupture and dissection were similar. Overall survival was better among patients with BAV (p < 0.0001). Among patients with BAV, those with aortic stenosis had a higher risk of rupture, dissection, or death before operative repair than did those with normally functioning valves (odds ratio 10.475, 95% confidence interval: 1.153 to 95.155).

Conclusions: Aortic stenosis presents a significant added risk for patients with aneurysmal disease in the face of BAV. Despite faster rates of growth, however, patients with BAV have similar rates of aortic rupture, dissection, and death and improved long-term survival. Contributing to this finding may be the lower incidence of comorbidities, the younger age at presentation, and the more attentive follow-up with earlier operative repair.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Bicuspid aortic valve (BAV) is the most common congenital heart defect, occurring in 1% to 2% of the general population [1]. Given the high incidence of sequelae, including aortic valve calcification and dysfunction [2–5], congenital aortic malformations [6, 7], and aortic dilatation and dissection [1, 8, 9], it may account for more morbidity and mortality than all other congenital malformations combined [10]. Both genetic and acquired causes of the aortic pathology associated with BAV have been postulated, but neither the pathophysiology nor the natural history of aortic disease in the setting of BAV has been well-defined.

We have previously reported that the natural history of patients with Marfan syndrome argues for earlier repair of aortic aneurysms in these patients [11]. Other authors have identified size criteria for resection of aortic aneurysms during surgery for valve disease in BAV [12]. However, indications for aortic surgery alone (in the absence of valvular criteria for cardiac surgery) have not been well established. If, as has been postulated, the aortic root dilation in BAV can be attributed in part to a collagen vascular disorders, as in Marfan syndrome [10], optimal treatment of these patients may involve surgery at smaller aortic sizes than the general population with aortic disease. The present study was undertaken to evaluate the natural history of aortic disease in the setting of an unreplaced bicuspid aortic valve and to estimate risk factors for adverse outcomes.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patient Population
Our institutional database contains information on 1,504 patients with thoracic aortic disease followed at the Yale Center for Thoracic Aortic Disease between 1985 and 2005. The Yale Institutional Review Board has approved this database and this study; informed consent was obtained when possible, and—with the permission of the Institutional Review Board—the consent requirement was waived when consent could not be obtained. Exclusion criteria for this study included a diagnosis of Marfan syndrome, the presence of a dissection at presentation (because dissection was an endpoint of the study), and a history of previous cardiac surgery. The date of presentation is the date that the patient first presented with thoracic aortic disease (either aneurysm or dissection). Of the included patients, 514 (326 males, 188 females) had unrepaired ascending aortic aneurysms (defined as ascending aortic size measurement greater than 3.5 cm in maximal dimension). Of this cohort, 70 (13.4%) were found to have BAV (group A), with the 445 patients remaining as group B. Valve leaflet number was identified either by echocardiogram or intraoperatively. Functional abnormalities of the valve were recovered from echocardiogram reports and included in the analysis.

All patients were recruited and followed (after informed consent was obtained) at our institution, a major referral center for southern New England. Patients underwent aortic repair based on previously defined criteria [11, 13, 14]. Hospital chart review was conducted on each identified patient and the data entered into a computerized database (MS Access 2003; Microsoft, Redmond, Washington). Long-term follow-up was conducted through clinic visits, telephone interviews, and hospital admissions. Data recovered from hospital records and computer files were cross-referenced with hospital discharge abstract data monitored by the Connecticut Hospital Association and the Connecticut State Mortality Records as well as Social Security Death Index (available at: http://sssdi.rootsweb.com). The patient database is maintained as part of ongoing studies at our institution.

Serial aortic size measurements were obtained through several diagnostic-imaging modalities, including computed tomographic scanning, magnetic resonance imaging, and echocardiography. Growth rates were calculated using the first and last measured sizes regardless of modality. Where available these size measurements were corrected for body surface area, as previously described [13]. Aortic valve function (including presence and severity of aortic regurgitation and stenosis, aortic valve area, and number of leaflets) was assessed and recorded at each echocardiogram using both transthoracic and transesophageal two-dimensional Doppler echocardiography.

Statistical Methods
Statistical methods were used to identify and estimate risk factors for the following outcomes: annual growth rates of aneurysms, cumulative incidence of major negative events (rupture, dissection and death before operative repair), survival free from major negative events, and overall long-term survival (both before operative repair and independent of operative repair). When analyzing smoking history, hypertension, and the presence of cardiac, pulmonary or renal disease, patients were stratified according to established criteria of risk for complications from vascular disease [15], and the analysis was performed both with the stratified severity levels and with a dichotomous variable indicating the presence of disease of any severity. Results are not shown for the analysis with stratified levels because they did not provide any additional information.

The methods of statistical analysis included ² test for comparisons of dichotomous risk factors (history of coronary artery disease, congestive heart failure, abdominal aortic aneurysms, and so forth) with negative outcomes (rupture, dissection, death), Mantel-Haenszel ² test for comparisons taking into consideration disease severity (cardiac disease, pulmonary disease, progressively larger aneurysms, and so forth), and the Student t test for comparisons of continuous variables with negative outcomes (p < 0.05). Kaplan-Meir survival estimates were calculated with the log-rank test for difference between strata. Cox regression models were used to identify the most predictive variables. Variables were entered into multivariate models in a stepwise manner, and the threshold for entry was p less than 0.10. All statistics were performed using SAS 9.13 for Windows (SAS Institute, Cary, North Carolina).

Aneurysm Growth Rates
Once patients underwent surgical repair of the aorta, subsequent measurements were excluded from analysis. Growth rate estimates were obtained by means of a multivariable regression analysis; this statistical method was previously described in detail by our team [16]. The p values reported for growth rates indicate that that risk factor was statistically significant in the regression analysis used to estimate the annual rate of growth; p less than 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
Patient Demographics
Baseline patient demographics are displayed in Table 1. Patients in group A presented at a younger age, with smaller initial aortic diameters, and with fewer baseline comorbidites (Table 1). However, group A patients had significantly more functional abnormalities of the aortic valve (Table 2). Among patients with either aortic stenosis or regurgitation, the severity of either stenosis or regurgitation and the measured aortic valve area did not differ significantly between groups (data not shown).

Follow-Up
The mean duration of follow-up, both long term independent of operative repair (65.1 versus 63.8 months, p = 0.8525) and before operative repair (43.3 versus 42.3 months, p = 0.8900) did not vary between groups. The mean interval between imaging studies before operative aortic repair was also similar between group A (161.0 days) and group B (138.9 days, p = 0.6052).

Negative Event Rates
Cumulative rates of negative events are shown in Table 3. Mortality rates (both before operative repair and long term, whether operative repair occurred or not) were significantly lower among patients in group A. Otherwise, event rates were similar (Table 3). The time to negative events (whether rupture, dissection, or the combined endpoint of rupture or dissection) was similar between groups (data not shown). Survival before operative repair of the aorta is shown in Figure 1.

View larger version (6K): [in this window] [in a new window]   Fig 1. Kaplan-Meier cumulative survival before operative repair. Five-year survival rate before operative repair is given as a function of valve type. Bicuspid aortic valves (BAV [group A; black line]) are associated with a lower preoperative mortality rate (p = 0.0006). (Gray line = group B, all others; error bars = standard error of the survival estimate; p = 0.0001.)

Long-Term Survival
Overall long-term survival is shown in Figure 2. The 1-, 3-, and 5-year survival was higher among patients in group A (98.4%, 96.4%, and 90.6%, respectively) than in group B (93.8%, 83.9%, and 73.6%, respectively). There was a trend toward decreased event-free survival among patients in group B who also had aortic stenosis (Fig 3); a significantly decreased event-free survival was evident among patients in group A with aortic stenosis when compared with those without stenotic valves (Fig 4).

View larger version (6K): [in this window] [in a new window]   Fig 2. Kaplan-Meier cumulative survival. Five-year survival is given as a function of valve type. Bicuspid aortic valves (BAV [group A, black line]) are associated with a lower mortality rate (p = 0.0001). (Gray line = group B, all others; error bars = standard error of the survival estimate; p < 0.0001.)

View larger version (7K): [in this window] [in a new window]   Fig 3. Freedom from negative event (dissection, rupture, or death) for patients in group B (all others). Five-year event-free survival is given as a function of valve stenosis. (Black line = stenotic valve; gray line = nonstenotic valve; error bars = standard error of the freedom from negative events; p = 0.7319.)

View larger version (6K): [in this window] [in a new window]   Fig 4. Freedom from negative event (dissection, rupture, or death) in patients in group A (bicuspid aortic valves). Five-year event-free survival is given as a function of valve stenosis. (Black line = stenotic valve; gray line = nonstenotic valve; error bars = standard error of the freedom from negative events; p = 0.0096.)

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

Although the first hypothesis has the advantage of relative simplicity, several studies suggest that hemodynamic alterations alone cannot be responsible for aortic dilatation in these patients. Although the incidence of valvular dysfunction was high in our group of patients with BAV, approximately half of the patients did not have any evidence of aortic stenosis on echocardiography. These results are consistent with several studies which demonstrate the presence of aortic dilatation in patients with normally functioning bicuspid valves [8, 17–19] Furthermore, Yasuda and coworkers [20] have demonstrated that aortic valve replacement alone does not prevent aortic dilatation in patients with BAV.

However, the presence of aortic valve dysfunction is not without consequence to the proximal aorta. In all patients, aortic stenosis increased the growth rate of the proximal ascending aorta. While our study does not address the mechanism for this effect, one might postulate that the altered hemodynamics resulting from a high pressure aortic ejection jet may place a greater burden on an already dilated proximal aorta. These data appear to differ from those of Keane and colleagues [19], and the molecular work of Catrufo and colleagues [21]. Both of these groups identified significant aortic dilatation among patients with BAV and aortic regurgitation. In both cases, however, the analysis was focused primarily on the proximal aorta, either proximal to or immediately superior to the sinotubular junction. In contrast, our size measurements were derived from the largest diameter of the ascending aorta or proximal aortic arch [19, 21], suggesting that while regurgitation is associated with proximal aortic dilatation, the hemodynamic effects of stenosis may result in aortic disease more distally. This observation supports the suggestion of Cotrufo and associates [21], that dilatation in the setting of regurgitant valve disease may be a different entity from that occurring in the setting of stenosis, and further studies should analyze these groups separately.

In addition, Keane and colleagues [19] looked at size at a single timepoint where the present study examines rate of growth over time. One might speculate that this indicates that while proximal aortic dilatation results in regurgitation (or occurs at the same time as the regurgitation), in stenotic BAV patients, altered hemodynamics result in more rapid aortic dilatation. Detailed longitudinal data starting with normally functioning BAV in the setting of a nondilated aorta would likely be required to fully elucidate these relationships.

Consistent with this hypothesis, however, we have demonstrated that among patients with BAV, there is a significantly increased risk of rupture or dissection in the setting of aortic stenosis. Clinically, this argues for earlier replacement of stenotic aortic valves in patients with BAV. However, further studies including detailed analysis of the hemodynamics of the proximal aorta are required to understand the mechanism of this effect and develop clear guidelines for valve replacement. As to why a similar effect was not observed in group B, two possible explanations present themselves: (1) the decreased use of echocardiograms in this population may result in an underreporting of aortic stenosis and consequent selection bias, or (2) the proximal aorta of patients with BAV in the setting of ascending aortic aneurysms may respond differently to the altered hemodynamics.

The other hypothesis for the high incidence of aortic disease in this population—an inborn congenital defect in aortic wall structure—appears more compelling. Several authors have presented histologic evidence of structural abnormalities in the proximal aortic media in patients with BAV [10, 22, 23]. As with familial thoracic aortic aneurysms and dissections, an autosomal dominant inheritance with reduced penetrance is evident in at least some families with bicuspid valves [24, 25]. Also, BAV has been associated with alterations in the vascular matrix of the proximal aorta resulting in decreased levels of fibrillin-1 [26].

If defects in fibrillin or other connective tissue proteins account for the initiation of aortic dilatation in these patients, it may be warranted to repair the aorta at a smaller size than in patients with normal valves. For example, in patients with Marfan syndrome, we have previously demonstrated an increased propensity toward rupture, resulting in a lower threshold for operative intervention at 5.0 cm rather than 5.5 cm in the ascending aorta [11]. In the current study, we were not able to find a similarly increased risk of complications, and negative events appear to have occurred at similar sizes in both groups. While earlier selection of patients with bicuspid valves for surgical repair may have hidden a true difference, we cannot recommend repair at a smaller size based on these data. However, we can recommend that patients with BAV—particularly those with aortic valve stenosis—be followed at frequent intervals given their higher rate of growth and significant complication rate.

Overall, the outcomes for patients with aortic aneurysms in the setting of unreplaced bicuspid valves were excellent. Several mechanisms likely account for this. The younger age and lower incidence of comorbidities mean that these patients have better postoperative outcomes after aortic repair. In addition, given that no patients died before operative repair (despite the incidence of both rupture and dissection), their younger age and better health status may allow them to survive these events long enough to reach definitive repair.

Several limitations of these data should be enumerated. Small sample sizes inevitably limit the statistical power of our analysis particularly when looking only at patients with bicuspid valves. Although valve leaflets were assessed for the majority of the patients in group B, we cannot know for certain that all of those patients had tricuspid valves; the inclusion of patients with undiagnosed bicuspid valves in group B may decrease the significance of our findings. Finally, this study does not attempt to identify pathophysiologic mechanisms for any of the findings described here; rather, we describe clinical outcomes and make relevant recommendations for clinical practice. Future studies will be required to define the mechanisms underlying several of our findings, particularly the higher growth rates associated with BAV, as well as the influence of aortic stenosis on outcomes in this population.

These data permit the following conclusions: (1) patients with ascending aortic aneurysms in the setting of an unreplaced aortic valve present with aortic disease at younger ages and with fewer comorbities; (2) despite higher growth rates in these patients, negative events occur at similar rates and at similar aortic diameter; and (3) the presence of aortic stenosis and BAV results in high negative event rates. We recommend that patients with BAV be followed closely with frequent assessment of both aortic diameter and aortic valve disease.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Ryan R. Davies Divakar Mandapati Donald M. Botta, Jr John A. Elefteriades Michael A. Coady Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Davies, R. R. Articles by Coady, M. A. Search for Related Content PubMed PubMed Citation Articles by Davies, R. R. Articles by Coady, M. A. Related Collections Great vessels