Abstract
Background:
There is little evidence on managing the proximal aorta of 4.0-4.5 cm during aortic valve replacement (AVR) in bicuspid aortic valve (BAV) patients.
Methods:
A total of 431 patients between 1993-2019 underwent either an isolated AVR, AVR + concomitant ascending aorta replacement, or aortic root replacement. We divided patients into native root dilation [4.0-4.5 cm, n=121] vs. root control groups [<4.0 cm, n=238], native ascending dilation [4.0-4.5cm, n=50] vs. ascending control groups [<4.0 cm, n=166], or proximal dilation (root or ascending aorta 4.0-4.5 cm, n=160) and proximal control groups (both root and ascending aorta <4.0 cm, n=272).
Results:
Growth rate was similar between the root dilation and control groups, (both were 0.1 mm/year, p=0.56). The ascending dilation group had an aorta growth rate of 0.0 mm/year after AVR or root replacement, which was significantly different from the ascending control group (0.2 mm/year), p=0.01. Furthermore, growth rate was similar between the proximal dilation (combined root or ascending dilation) and control group (both were 0.1 mm/year, p=0.20). There were only two ascending aortic aneurysm repairs after AVR in the whole cohort. The long-term survival was similar between the root or ascending dilation groups vs. root or ascending control groups, and between the proximal dilation and control groups. Multivariable Cox regression confirmed aortic root or ascending dilation was not a significant risk factor of long-term mortality.
Conclusions:
Our findings supported not replacing a 4.0-4.5 cm proximal thoracic aorta, including aortic root and ascending aorta, at the time of AVR for BAV patients.
Keywords: Bicuspid aortic valve, thoracic aortic aneurysm, progression of aorta, long-term outcomes
Graphical Abstract
Current information on management of the proximal aorta during aortic valve replacement (AVR) in bicuspid valve (BAV) patients is contradictory. Some observational studies suggest radical replacement of all ascending aortas during AVR1, while others are more conservative based on aortic size2,3. Currently, surgical intervention is recommended for aortic diameter of >4.5cm during a concomitant AVR 4. On the other hand, routine monitoring using cardiovascular imaging studies such as echocardiogram, computed tomography (CT) or magnetic resonance imaging (MRI), is recommended when BAV patients have ascending aorta diameter between 4.0- 4.5 cm, irrespective of a planned AVR procedure4. However, some authors have reported a high risk of ascending aortic aneurysm or dissection in BAV patients who did not undergo prophylactic ascending aortic repair at the time of AVR1. Hence, this study was designed to evaluate the survival outcomes and rate of reoperation of the dilated proximal aorta of 4.0-4.5 cm in BAV patients after aortic valve replacement.
PATIENTS AND METHODS
This study was approved by the Institutional Review Board at Michigan Medicine (HUM001118517; September 26th, 2016) and a waiver of informed consent was obtained.
Data Collection
Data between 1993-2019 was retrieved through the Bicuspid Aortic Valve (BAV) registry at Michigan Medicine to identify BAV patients who underwent aortic valve replacement with or without a concomitant aortic root or ascending aorta procedure. The BAV registry at Michigan Medicine was designed to gather information on cardiac patients with bicuspid aortic valves in order to assess potential genetic variants of BAV diseases, patterns of aortic dilation, and responses to medical therapy based on serial imaging. Patients who were 18 years old and above and who had BAV disease were recruited for the registry. BAV patients with age <18 years old, thoracic aorta size greater than 4.5 cm, undocumented aorta size diameter, or patients who underwent simultaneous root and ascending aorta procedures were excluded from the study.
The data from the BAV registry was supplemented with data from the Society of Thoracic Surgeons (STS) Michigan Medicine Cardiac Surgery Data Warehouse. Preoperative, operative, and postoperative variables were obtained. Also, imaging studies including echocardiography, CT scans, and MRIs were reviewed, and maximum diameter measurements of the aortic root and tubular ascending aorta were directly extracted. The mean follow-up time for imaging was three years at our institution. A majority of the patients were recruited between 2010- 2019. This data was supplemented with a retrospective medical record review by the study team. Survival and reoperation data were collected by medical record review and supplemented with National Death Index data through December 31st, 20185. The end of the study period was on May 6th, 2020. Primary outcomes were defined as long-term survival and rate of reoperation. Secondary outcome was the rate of progression of the dilated proximal aorta diameter.
Patient selection
Between 1993-2019, a total of 431 BAV patients at our institution underwent either an isolated aortic valve replacement (AVR, n= 164), AVR + concomitant ascending aorta replacement (n=200), or aortic root replacement (n=67). Patients were divided into two pairs of groups based on the size of their native aortic root or ascending aorta at the time of the AVR: root control (root <40 mm, n= 238) vs. root dilation (root between 40-45 mm, n= 121) groups, and ascending control (ascending <40 mm, n=166) vs. ascending dilation (ascending size between 40-45 mm, n=50) (Figure 1). In the root control and dilation groups, all patients had native root preserved after AVR with or without ascending replacement. In the ascending control and dilation groups, all patients had native ascending aorta preserved after aortic valve or root replacement. Since current guidelines do not separate root and ascending aneurysm, we combined root or ascending groups into proximal dilation (root or ascending aorta 40-45 mm) and proximal control groups (root and ascending aorta <40mm). Twenty patients did not have either an aortic root diameter (n=5) or ascending aorta diameter (n=15) recorded at initial cardiovascular imaging prior to initial isolated AVR and were excluded from the study.
Figure 1:
Consort diagram of selection and distribution of study population.
There were 16 patients who had aortic root (n=14) or ascending aorta (n=2) diameter between 4.5-4.8 cm from preoperative studies, which were not replaced by the surgeons during the initial AVR procedure by the surgeon’s discretion.
Statistical Analysis
Data were presented as median (25%, 75%) for continuous data and n (%) for categorical data. Univariate comparisons between the groups were performed using Wilcoxon rank-sum tests for continuous data and chi-square tests for categorical data. Generalized linear mixed effect models were used to analyze longitudinal data for the proximal thoracic aorta, including root and ascending aorta size over time. These data over time were treated as repeated measurements. The rate of change of proximal thoracic aorta size over time is not impacted by age, sex, proximal dilation, aortic insufficiency, or aortic stenosis, given the insignificant interaction terms between time and these factors. The Kaplan-Meier method with log-rank testing was used to describe survival over time. Cox proportional hazard regression models were used to calculate the hazard ratio of enlarged proximal thoracic aorta for long-term mortality adjusting age, sex, proximal dilation, aortic insufficiency and aortic stenosis. All variables passed the proportional hazard assumptions. Statistical calculations were performed using SAS 9.4 (SAS Institute, Cary, NC).
RESULTS
Root dilation vs Root control group
Characteristics at initial operation of aortic valve with or without ascending aorta replacement.
Compared to the root control, the root dilation group had significantly higher proportions of male patients (92% vs 60%), moderate aortic insufficiency (23% vs 14%) but had lower proportion of patients with diabetes (5.8% vs 16%), aortic valve stenosis (68% vs 85%), and who were current smokers (5.0% vs 13%). Otherwise, there was no difference between groups for all other important perioperative data. (Table 1)
Table 1:
Demographics and pre-existing conditions of the sample population
| Root control (n=238) | Root dilation (n=121) | p-value | Ascending control (n=166) | Ascending dilation (n=50) | p-value | |
|---|---|---|---|---|---|---|
| Sex (male) | 143(60) | 111(92) | <.0001 | 108(65) | 41(82) | 0.02 |
| Age | 59(51, 66) | 59(50, 66) | 1.0 | 60(50, 67) | 56(50, 64) | 0.51 |
| BSA | 2.1(1.8, 2.3) | 2.1(2.0, 2.3) | 0.03 | 2.0(1.9, 2.2) | 2.1(1.9, 2.3) | 0.42 |
| Co-morbidities | ||||||
| Hypertension | 121(51) | 59(48) | 0.90 | 73(44) | 29(58) | 0.15 |
| Diabetes | 39(16) | 7(5.8) | 0.01 | 24(14) | 5(10) | 0.20 |
| Smokers | ||||||
| Former | 83(35) | 41(34) | 0.85 | 62(37) | 17(34) | 0.67 |
| Current | 32(13) | 6(5.0) | 0.01 | 14(8.4) | 8(16) | 0.12 |
| BAV Type | ||||||
| 0 | 19(8.0) | 7(5.8) | 0.45 | 14(8.4) | 5(10) | 0.78 |
| 1 | 181(76) | 93(77) | 0.87 | 123(74) | 36(72) | 0.77 |
| 2 | 18(7.6) | 12(9.9) | 0.45 | 7(4.2) | 4(8.0) | 0.28 |
| Prior AVR | 1(0.4) | 1(0.8) | 1.0 | 1(0.6) | 1(2.0) | 0.41 |
| Not reported | 19(8.0) | 8(6.6) | 0.64 | 21(13) | 4(8.0) | 0.37 |
| Aortic Stenosis | 204(85) | 83(68) | 0.002 | 138(83) | 41(82) | 0.85 |
| Aortic Insufficiency | 173(73) | 95(79) | 0.20 | 129(78) | 39(78) | 0.88 |
| Trace | 48(20) | 11(9.2) | 0.008 | 28(17) | 7(14) | 0.62 |
| Mild | 71(30) | 39(32) | 0.74 | 42(25) | 16(32) | 0.36 |
| Moderate | 32(14) | 28(23) | 0.02 | 29(18) | 9(18) | 0.95 |
| Severe | 22(9.3) | 18(15) | 0.11 | 30(18) | 7(14) | 0.49 |
| Endocarditis | 3(1.3) | 2(1.6) | 1.0 | 8(4.8) | 1(2.0) | 0.69 |
| Initial operations: | ||||||
| AVR | 127(53) | 32(26) | <.0001 | 111(67) | 39(78) | 0.13 |
| Root replacement | 0(0) | 0(0) | 55(33) | 11(22) | 0.13 | |
| AVR + ascending replacement | 111(47) | 89(74) | <.0001 | 0(0) | 0(0) | 1.0 |
| Late Re-Operations | 0(0) | 0(0) | 1.0 | 0(0) | 2(4.0) | 0.05 |
| Aortic Root Aneurysm | 0(0) | 0(0) | 1.0 | 0(0) | 0(0) | 1.0 |
| Ascending aneurysm | 0(0) | 0(0) | 1.0 | 0(0) | 2(4.0) | 0.05 |
Data presented as median (25%, 75%) for continuous data and proportion (%) for categorical data.
Abbreviations: BSA=body surface area
P-value <0.05 indicates statistically significant difference between control vs dilation group.
Imaging and survival follow-up
The mean follow-up imaging (Echocardiogram, CT, MRI) time was three years. The average amount of imaging for patients was 4.0 scans for the root control group, 4.4 scans for the root dilation group, 3.4 scans for the ascending control group, and 3.5 scans for the ascending aorta dilation group. The mean follow-up of long-term survival was 5 years. The completeness of follow up for long-term survival was 87%.
Aortic root size and Growth rate
The median aortic root size was 35.0 mm (interquartile range: 32.1- 37.0 mm) in the root control group, vs median root size of 42.0 mm (interquartile range: 41.0- 43.3 mm) in the root dilatation group (Table 2). There was no difference between the rate of growth of the aortic root between the root dilation and control groups, p=0.56 (Figure 2A). However, the rate of growth of the aortic root was significant in both groups compared to baseline, i.e., aortic root size increased by 0.1mm/year in both groups, (p=0.03). In addition, though the growth rate was not different between groups, the difference in aortic root diameter between the two groups was 6.6mm, p<.0001 (Figure 2A).
Table 2:
Aortic root and ascending aorta diameter at initial operation of aortic valve or root replacement.
| # of obs | Mean (SD) | Min- Max | Median (25-75 percentile) | |
|---|---|---|---|---|
| Aortic root size (mm) | ||||
| Control | 238 | 34.5 (3.5) | 24.9- 39.9 | 35.0 (32.1- 37.0) |
| Root dilatation group | 121 | 42.4 (1.9) | 40.0- 48.0a | 42.0 (41.0- 43.3) |
| Ascending aorta size (mm) | ||||
| Control | 166 | 34.7 (3.2) | 26.0- 39.8 | 35.0 (32.4- 37.8) |
| Ascending dilatation | 50 | 41.7 (1.4) | 40.0- 47.0b | 41.7 (41.0- 42.4) |
Abbreviations: Obs= Observations
: 14 patients had aortic root size between 4.5-4.8 cm from preoperative studies that was not replaced at the discretion of the surgeon. None of these patients required reoperation for root aneurysm during the study period.
: 2 patients had ascending aorta size between 4.5-4.7 cm from preoperative studies that was not replaced at the discretion of the surgeon. Only 1 patient, who had 4.5 cm ascending aneurysm but active aortic valve endocarditis, in this group had reoperation for ascending aortic aneurysm during the study period.
Figure 2:
There was no difference between the rate of growth of the native aortic root between the root dilation and control groups, p=0.56. However, the rate of growth of the aortic root over time was significant in both groups, 0.1 mm/year, p=0.03. The difference in diameter between the two groups was 6.6 mm, p<.0001 (A). The growth rate was 0.0 mm/year in the ascending dilation group but 0.2 mm/year in the control group, p= 0.01. Lastly, at 10 years of follow-up, the difference in diameter between the two groups was significant (4.5 mm), p <.0001 (B). There was no difference in rate of growth of the proximal thoracic aorta between the proximal dilation and proximal control groups, p= 0.20. However, the rate of growth of the proximal aorta was significant in both groups compared to baseline, 0.1 mm/year, p= 0.0004. The difference in diameter between the two groups was 5.9 mm, p<.0001 (C).
Reoperation and Survival
There were no reoperations for aortic root aneurysm identified during the 17-year study period. There was no significant difference in long-term survival between the root dilation and root control groups, p=0.16 (Figure 3A). 10-year survival was 89% (95% Confidence interval (CI): 79%, 94%) in the root control group and 98.0% (95% CI: 91.5%, 99.5%) in the root dilation group (Figure 3A).
Figure 3:
Kaplan-Meier analysis showed the long-term survival was not significantly different between aortic root dilation and control groups; 10-year survival: 98% (95% confidence interval (CI): 91.5%, 99.5%) vs. 89% (95% CI: 79%, 94%) (A), ascending aorta dilation and control groups; 10-year survival: 97% (95% CI: 81%, 99.6%) vs 94% (95% CI: 86%, 98%) (B), or the proximal aorta dilation and control groups; 10-year survival: 98.3% (95% CI: 93.5%, 99.6%) vs 91.2% (95% CI: 84.2%, 95.2%) (C).
Ascending Dilation vs Ascending Control Group
Characteristics at initial operation of aortic valve with or without root replacement.
Compared to the ascending aorta control, the ascending aorta dilation group had significantly higher proportion of males (82% vs 65%). There was no difference between groups for all other perioperative data (Table 1).
Ascending aorta size and Growth rate
The median ascending aorta diameter was 35.0 mm (interquartile range: 32.4- 37.8 mm) in the ascending aorta control group, vs 41.7 mm (interquartile range: 41.0- 42.4 mm) in the ascending aorta dilatation group (Table 2). The growth rate (0.0mm/year) in the ascending dilation group was significantly smaller than in the ascending control group (0.2mm/year), p= 0.01 (Figure 2B). Compared to baseline diameter in each group, the growth rate per year was not significant in the ascending dilation group (p= 0.97) over time but was significant in the control group (p<0.0001). Lastly, at 10 years of follow-up, the difference in ascending aorta diameter between the two groups was 4.5mm, p <.0001 (Figure 2B).
Reoperation and Survival in Ascending Aorta cohorts
Only 2 patients underwent reoperation for an ascending aorta aneurysm repair after one and two years respectively (Table 3). There was no significant difference of long-term survival between the ascending aorta dilation and ascending aorta control groups, p= 0.93 (Figure 3B). The 10-year survival was 94% (95% CI: 86%, 98%) in the ascending control group and 97% (95% CI: 81%, 99.6%) in the ascending dilation group (Figure 3B).
Table 3:
Patients who underwent re-operation for aneurysm after index AVR replacement procedures
| Pt | Aortic root (mm) | Ascending aorta (mm) | Time span (year) | Aortic root at redo (mm) | Ascending aorta at redo (mm) | Indication | Procedure |
|---|---|---|---|---|---|---|---|
| 1* | 34 | 45 | 1 | 34 | 51 | Ascending aneurysm | Ascending and hemiarch replacement |
| 2* | 41 | 40 | 2 | 40 | 53 | Ascending aneurysm | Ascending replacement |
Abbreviations: AVR= Aortic valve replacement
Case #1 had active endocarditis; surgeon chose not to replace the ascending aortic aneurysm. Case #2 had fast growing ascending aortic aneurysm due to giant cell aortitis after aortic valve replacement.
Proximal Dilation vs Proximal Control group
We combined the root and ascending aorta dilation groups into a proximal dilation group (Supplemental table 1). The median proximal aorta size was 35.6 mm (interquartile range: 33.0- 38.0 mm) in the proximal control group vs median aorta size of 42.0 mm (interquartile range: 41.0- 43.0 mm) in the proximal dilation group (Supplemental Table 2). There was no difference between the rate of growth of the proximal thoracic aorta between the dilation and control groups, p= 0.20 (Figure 2C). However, the rate of growth of the proximal aorta was significant in both groups compared to baseline, i.e., proximal aorta size increased by 0.1mm/year in both groups, p= 0.0004. Multivariable regression analysis showed that the growth rate of the proximal thoracic aorta was not significantly impacted by risk factors such as age, sex, proximal dilation, aortic insufficiency and aortic stenosis (all p-values >0.05).
There was no significant difference of long-term survival between the proximal dilation and proximal control groups, p= 0.20 (Figure 3C). The 10-year survival was 98.3% (95% CI: 93.5%, 99.6%) in the proximal dilation group and 91.2% (95% CI: 84.2%, 95.2%) in the proximal control group (Figure 3C). Multivariable Cox proportional hazard regression analysis showed that age, sex, proximal dilation, or preoperative aortic stenosis or aortic insufficiency were not significant risk factors for long-term survival (Table 4).
Table 4:
Multivariable Cox proportional hazard regression of risk factors of long-term survival
| Variable | Hazard Ratio | Confidence Interval | p-value |
|---|---|---|---|
| Proximal Dilation group | 0.53 | 0.16-1.71 | 0.29 |
| Age | 1.02 | 0.97-1.07 | 0.55 |
| Sex | 1.15 | 0.41-3.24 | 0.79 |
| Aortic Insufficiency | 0.50 | 0.17-1.49 | 0.21 |
| Aortic Stenosis | 1.11 | 0.36-3.43 | 0.86 |
All variables passed proportional hazard assumption.
COMMENT
In this study, we identified that the dilated proximal thoracic aorta i.e., aortic root and ascending aorta of 4.0- 4.5 cm, in bicuspid aortic valve disease patients had similar long-term survival, reoperation rate, and growth rate over time compared to the control group with diameter <4.0 cm. Aortic root or ascending dilation were not significant risk factors for long-term mortality. The reoperation for aortic root or ascending aneurysm was exceedingly low. These findings were summarized in the supplementary video.
In the 1990’s and 2000’s, observational and genetic studies showed an increased risk of acute complications, such as aortic dissection, in bicuspid valve aortopathy compared to the general population. This led to a more aggressive surgical approach to mild aortic dilation in bicuspid aortic valve disease patients compared to tricuspid aortic valve patients6,7. However, recent histological and benchtop biomechanical data shows higher tensile strength in resected thoracic aortas of bicuspid aortic valve disease patients compared to tricuspid aortic valve patients, particularly in longitudinal and circumferential directions8,9.
The current American Association of Thoracic Surgery (AATS) guidelines recommend that the dilated aortic root and ascending aorta in bicuspid aortic valve disease patients be replaced when their size exceeds 4.5 cm during a concomitant aortic valve replacement procedure4. The rationale for this recommendation is based on findings that the incidence of aortic complications such as aortic dissection or rupture is low post-AVR in BAV patients10, and the incidence of root dilation post-AVR is similar to that in patients with tricuspid aortic valve disease11. However, managing the dilated aorta with diameter of 4-4.5 cm remains controversial. There is no direct evidence to show the progression of the mildly dilated aorta.
Our study showed that dilation of the proximal aorta was a very slow process in BAV patients with mild dilation of aortic root or ascending aorta (4.0 – 4.5 cm) and was not significantly different from dilation of proximal aorta <4 cm (Figure 2). Valvuloaortopathy such as aortic stenosis, aortic insufficiency, and proximal dilation did not significantly impact growth of the proximal thoracic aorta (4.0 – 4.5 cm) in BAV patients after AVR. Aortic root growth was significant in both dilated root and control groups (0.1 mm/year). The ascending aorta growth (0.2 mm/year), however, was only significant in the ascending aorta < 4 cm compared to the dilated ascending group, confirming heterogeneity of the BAV patient population. Della Corte et.al showed that the mean growth rate of the aortic sinuses in BAV patients is 0.3mm/year while the growth rate at the ascending aorta is 0.6 mm/year12. Most patients in their study had a root diameter between 3.0 cm- 4.2 cm, an ascending aorta diameter between 3.4 cm- 5.2 cm, and dilation was defined as aorta size >3.7cm. Our findings supported that the mildly dilated proximal thoracic aorta (4.0 – 4.5 cm) can be left alone during aortic valve or root replacement, in BAV patients as a concomitant surgery to AVR.
In this study, only two patients underwent reoperation- both for an ascending aortic aneurysm repair after one and two years of follow-up. The first patient had an ascending aorta size of 4.5 cm based on intra-operative TEE that was not replaced intraoperatively during index AVR due to active aortic valve endocarditis. The ascending aneurysm was resected at 5.1 cm two years later, which could probably be observed. The pathology of resected aorta showed myxoid degeneration. The second patient had an ascending aorta size of 4.0 cm during index AVR but the aorta diameter surprisingly became aneurysmal to 5.3 cm after 2 years of surveillance. The pathology of resected aorta in this patient showed giant cell aortitis which could explain the fast-growing aneurysm. None of the two patients had connective tissue diseases. This low rate of complications was consistent with other studies which show that only about 20%-30% of BAV patients will develop worsening aortic aneurysm after a follow-up of 9 to 25 years13,14. In addition, less than 0.55% will develop aortic dissection 15 years after AVR15. However, this observation highlights that although it was rare, some BAV patients could develop proximal aortic aneurysm in a short period of time. Close surveillance is needed especially in the first few years.
The overall 5- and 10-year survival estimates of the dilated proximal aorta group were greater than 98.0%, which was not significantly different from the long-term survival in the control group (Figure 2). Similar findings were reported by Kaneko et.al. who observed that the rate of reoperation and mortality outcomes were similar and low in BAV patients who underwent isolated aortic valve replacement versus concurrent repair of dilated thoracic aorta16, though their study included patients with thoracic aorta size of 3.5 cm-5.9 cm in the isolated AVR cohort and 4.0-5.9 cm in the AVR plus concurrent aorta repair cohort.
In summary, after we left the 4-4.5 cm proximal aorta i.e., aortic root or ascending aorta, alone in BAV patients during AVR, those patients had similar long-term survival, reoperation rate, and aorta growth rate compared to patients with proximal thoracic aorta <4 cm. Our results support the AATS guidelines: no resection of aortic root or ascending aorta of 4-4.5 cm at the time of aortic valve replacement.
This study has several limitations of a single center retrospective research study. The sample size was relatively small, and the follow-up time for imaging studies was relatively short for good portion of patients. Our follow-up data of reoperation and survival, however, were adequate. Patients may require reoperation for aortic root and ascending aortic aneurysm 20-30 years after the initial aortic valve operation as we had seen in individual cases. Longitudinal follow-up of twenty years for BAV patients is needed to make a definitive recommendation of how to manage BAV patients with aortic root or ascending dilation of 4-4.5 cm. Lastly, most patients had initial operations at the University of Michigan, but some were operated at other hospitals. There could be some variation of the operative technique for initial operation.
In conclusion, our study supports the current AATS guideline that the aortic root or ascending aorta diameter of 4.0- 4.5cm in bicuspid aortic valve disease patients can be left alone during an aortic valve replacement surgery. However, long-term studies are still needed to make a definitive recommendation. Surveillance with cardiovascular imaging such as CT angiogram, MRI, or echocardiography, is adequate.
Supplementary Material
GLOSSARY OF ABBREVIATIONS
- AVR
Aortic valve replacement
- BAV
Bicuspid aortic valve
- CT
Computed tomography
- MRI
Magnetic resonance imaging
- STS
Society of Thoracic Surgeons
- SAS
Statistical analysis system
- AATS
American Association of Thoracic Surgery
- BSA
Body surface area
- AS
Aortic Stenosis
- AI
Aortic Insufficiency
Footnotes
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