Narrow true lumen favors future complication even in small diameter of type B aortic dissection

Introduction

The annual incidence of acute aortic dissection per 100,000 people is around 2.9–4.4 cases (1,2), and the number of cases reported from Japan ranges from 3 to 10 (3,4). Although surgical treatment has been established for acute Stanford type A aortic dissection, conservative treatment is the first choice for uncomplicated Stanford type B aortic dissection (TBAD). This is because the mortality rate at 14 days for antihypertensive treatment alone is about 2.4–6.3%, which is equivalent to the outcome of surgical treatment (5-7).

The survival rate of uncomplicated TBAD is acceptable (6), but the rate of invasive treatment in the chronic phase was 45% in 3 years, and 50% in 5 years (8). Recently, a treatment option called preemptive thoracic endovascular aortic repair (TEVAR) has shown a better outcome than optimal medical management, according to a 5-year randomized controlled trial, suggesting that it may become the preferred treatment for TBAD (9). However, there are still no ideal predicting factors for those patients who need surgical intervention.

In recent years, technological advances have made it possible to measure areas more accurately with three-dimensional computed tomography (3DCT), which can be performed in a shorter time, making it a useful diagnostic tool in clinical practice (10).

In this retrospective study, we aimed to verify the value of known predicting factors and to explore whether it is possible to identify the imaging parameters which were strongly associated with the factors involved in the development of late aorta-related complications during treatment of uncomplicated TBAD in the TEVAR era. The novelties of this study lie in its focus on changes in the true and false lumens, and its demonstration that quantitative evaluation can provide valid information to predict the need for preemptive TEVAR, ultimately improving the outcome of TBAD. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-864/rc).

Methods

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Approval was granted from the Yamagata University Hospital Ethical Committee (No. 2018-245) and the ethical board of Nihonkai General Hospital (No. 006-3-5) and written consent were waived because of the retrospective nature of the study.

Study design and patients

A retrospective study was conducted using prospectively collected electronic medical records from Yamagata University Hospital between July 2004 and October 2019, and Nihonkai General Hospital between February 2016 and May 2019. Acute uncomplicated TBAD was defined as the absence of refractory pain, uncontrollable hypertension, malperfusion (both dynamic obstruction, which is improved by false lumen decompression, and static obstruction, which is not improved) or signs of early disease progression (11), such as retrograde type A dissection presenting within 14 days of symptom onset. The time course of aortic dissection was divided into acute (<14 days), sub-acute (15–90 days), and chronic (>90 days) phases (11).

Data collection and CT image re-analysis

Clinical data were extracted from the electronic medical record systems of two hospitals. These data included the following: demographic characteristics (such as age, sex, body mass index, etc.), medical conditions [diagnosis, in-hospital management, including intensive care unit (ICU) or high care unit (HCU) management, discharge medication, follow-up observation, etc.], and survival information. Survival was assessed through systematic follow-up outpatient clinics, electronic record vital status, or confirmation via a phone call. Information was collected by three people to prevent observer bias.

In-hospital management

Successful medical management in the acute phase was defined as control of hypertension and remission of general symptoms. That protocol was developed using Japanese guidelines as a reference (3). The outcome “aorta-related complication” includes enlargement of the aortic diameter (≥55 mm and/or ≥5 mm in 6 months), malperfusion and aortic rupture (3,11).

Imaging techniques

Contrast computed tomography (CT) scanning data at emergency admission, at the 1st and 7th days after admission, at hospital discharge, at 3, 6 and 12 months and annually thereafter, were recollected from hospital medical record systems (12). Image analysis was performed on a SYNAPSE VINCENT system (FUJIFILM Holding Corporation, Tokyo, Japan) with a dedicated 3D image analyzer. For CT angiography measurements, the midline of the aorta was first drawn, and multiplanar reconstruction (MPR) images in the axial plane perpendicular to it were created for measurement (Figure S1A). The aortic centerline was created by the VINCENT system software, which uses a 3D algorithm that performs MPR centered on the contrasted aortic lumen. The primary entry in the most proximal portion of the descending aorta was defined as an entry tear (12). This was measured using MPR on the cross section where the tear has the largest diameter. The location of entry tear in the descending aorta was examined and classified into distal arch, tracheal bifurcation level, diaphragm level, celiac artery level, and abdominal aorta.

The areas of the true and false lumens were measured, respectively. Measurements were taken in the orthogonal cross section at the location of maximum aortic diameter. (Figure S1B,S1C). The area with the largest aortic diameter with the primary entry was statistically treated as the “maximum aortic diameter”. The maximum aortic diameter was compared between images obtained at the beginning of the subacute phase and images during the chronic phase. True lumen area ratio (TLAR: true lumen area to true and false lumen area) and false lumen area ratio (FLAR: false lumen area to true and false lumen area) were examined based on the findings of the CT scan at the time of initial diagnosis.

The status of the false lumen on imaging was classified as patent if flow was present in the absence of a thrombus (13). “Partial thrombosis” was evaluated at a later phase when an enhanced CT scan was performed.

Intramural hematomas and penetrating aortic ulcers were not included in this study. All thrombosed false lumen types have intimal tears confirmed by CT.

Statistical analysis

Clinical characteristics and CT imaging parameters of patients at emergency admission and during follow-up were summarized. Categorical measures were presented as percentages. Continuous measures were presented as medians and interquartile ranges. Outcomes were assessed with unadjusted and multivariable models. Aorta-related complication-free rates were calculated using Kaplan-Meier curves and tested by the log-rank test. Factors that are associated with aorta-related complication were investigated with the use of Cox proportional hazards regression model. All model-based results are presented with 95% confidence intervals (CIs). All statistical analyses were performed with R-4.2.0 software.

Results

A total of 296 patients were admitted to two hospitals with a diagnosis of TBAD. In all patients, the time of onset of acute TBAD could be identified. Patients were excluded if they developed acute complications in two weeks (58 patients) or if they had traumatic acute TBAD (21 patients). The remaining 213 patients that were treated medically for two weeks were enrolled in this study (Figure S2). All were Japanese, and 149 (70.0%) were male. The mean (range) age of all patients was 69.9 (62.0–79.0) years (Table 1). The mean observation period was 54±45 months. During follow-up, patients were divided into two groups: those with aorta-related complications [group A, n=53 (25%)] and those without [group U, n=160 (75%)].

The most common aorta-related complication was aortic enlargement [23.5% (n=50)]. The incidence of aortic rupture was 2.3% (n=5). Malperfusion was seen in only one patient (0.5%) and required surgical management (Figure S2). Five patients died from aorta-related complication (2.8%). During follow-up, patients who had an aorta-related complication, despite medical management, underwent an aortic intervention. An 84-year-old man died of aortobronchial fistulation 2 months after onset. He was unable to stand on his own due to dementia, and his family did not request surgical intervention. A 77-year-old man died of infection 3 months after onset of symptoms following TEVAR for aortoesophageal fistula followed by esophagectomy and planned reconstructive surgery with a graft replacement. Another three patients died of aortic rupture, two of whom died after graft replacement. Aortic interventions were needed in 39 patients (18%), and these included 13 with graft replacement, 27 with endovascular repair, 2 with hybrid (open repair and endovascular) repair and 1 with an extra-anatomical bypass. Two patients who developed Stanford type A aortic dissection during the follow-up period underwent graft replacement, and both survived. One case was after TEVAR, but the primary entry was in the ascending aorta, so the relationship to TEVAR was unclear. The survival rate after surgical intervention was 90% (35 of 39). None of the 27 cases of preemptive TEVAR performed in the subacute or early chronic phase were uncomplicated, and the 1- and 5-year aortic-related death-free rates for 100%/92%, respectively. Overall survival at 1 year after surgery was 96% vs. 97% (group A vs. group U) and at 5 years was 71% vs. 90% (group A vs. group U) (Figure 1). The 1-, 5-, and 10-year aorta-related complication-free rates for 213 patients were 76%, 72%, and 72%, respectively (Figure S3).

Figure 1 Freedom from all-cause death following conservative treatment for acute uncomplicated type B dissection. Survival rates are displayed in 30-month intervals. The group with aorta-related complications is group A, and those without is group U. The 95% CI is shown in color. CI, confidence interval.

There were no differences in patient’s characteristics between the two groups (Table 1). Marfan syndrome was present in 4 patients overall, and those patients were excluded from the analysis.

At the time of hospital discharge, no association of drug treatment with subsequent prognosis was observed (Table 1). From the CT findings of early subacute phase, significant differences between groups were found in the maximum aortic diameter (group A: 40±7 mm vs. group U: 37±6 mm, P=0.02), false lumen area (group A: 899±655 mm²vs. group U: 535±313 mm², P<0.001), and incidence of patent false lumen [group A: 64% (32 of 50) vs. group U: 34% (55 of 160), P<0.001].

Particularly in group A, the false lumen area (group A: 1,096±772 mm²vs. group U: 386±287 mm², P<0.001) tended to expand from the first visit (Table 2).

Aortic diameter at early subacute phase is a useful prognostic factor, and receiver operating characteristic (ROC) curve analysis showed that the incidence of aorta-related complications increased with a diameter greater than 39.100 mm (95% CI: 0.517–0.702, sensitivity: 0.745, specificity: 0.472) (Figure 2). As a new independent prognostic factor, the area under the curve of TLAR was generated (Figure 3). If the TLAR was 52.9% or less at the site where the dissected aorta was at its greatest diameter, aorta-related complications may have occurred in the long-term period, with a sensitivity of 0.775 and a specificity of 0.939. This tendency is the same for false lumens, and later aorta-related complications are more likely to occur with a sensitivity of 0.920 and specificity of 0.617 if the false lumen is greater than 814.000 mm (Figure 4). In our previous study, we found that an aneurysm diameter greater than 40 mm at initial presentation increased the likelihood of future aorta-related complications (14). A comparison of patients with an initial aortic diameter greater than 40 mm and those with an initial aortic diameter less than 40 mm showed that aorta-related complications were significantly more common in the former group when the TLAR was less than 52.9% (P<0.001). Interestingly, a TLAR of 52.9% or less increased the risk of future aorta-related complications, even when the aortic diameter was smaller than 40 mm (P<0.001) (Figure 5). The 1-, 3-, and 5-year aorta-related complications-free rates were 90%/54%/54% vs. 94/92/92%, respectively, for patients with a TLAR of less than 52.9% vs. 52.9% or greater with an aortic diameter of 40 mm or less.

Figure 2 Patient of uncomplicated type B aortic dissection, aortic diameter in the early subacute phase. (A) ROC curve. Maximum aortic diameter of the early subacute CT findings. (B) Kaplan-Meier curve of the aorta-related complication-free rate. Patients with an initial aortic diameter of 40 mm or less (marked as 0) vs. more than 40 mm (marked as 1) were compared. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic; CT, computed tomography.

Figure 3 CT image finding. True lumen area ratio of maximum aortic diameter at the early subacute phase. (A) ROC curve. The true lumen area ratio was examined based on the CT findings of early subacute phase. The probability of an aorta-related complication occurring in the long-term period. (B) Kaplan-Meier curve of the aorta-related complication-free rate. Patients were divided into groups with true lumen ratio of 52.9% or less (marked as 0) and more than 52.9% (marked as 1). AUC, area under the curve; CI, confidence interval; CT, computer tomography; ROC, receiver operating characteristic.

Figure 4 False lumen area (mm²) of maximum aortic diameter during follow-up. ROC curve. During follow-up, the false lumen area was measured when the aortic diameter was at its maximum. The probability of occurrence of aorta-related complication was examined. Patients with a false lumen of equal to or less than 814 mm² (marked as 0) or greater than 814 mm² (marked as 1) were compared. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic.

Figure 5 Survival curve was adjusted for age, gender and HT. (A) Patients with an initial aortic diameter of 40 mm or less than 40 mm were compared between groups with a TLAR of 52.9% or less (marked as 0) and more than 52.9% (marked as 1). (B) The probability of occurrence of aorta-related complication in the long-term period. Patients with an initial aortic diameter more than 40 mm were compared between groups with a TLAR of 52.9% or less (marked as 0) and more than 52.9% (marked as 1). HT, hypertension; TLAR, true lumen area ratio.

A multivariate model was created to predict late aortic adverse events in patients with TBAD who were medically managed. Predictors of late aorta-related complications included TLAR of early subacute phase [hazard ratio (HR), 0.129; 95% CI: 0.044–0.377; P<0.001] and enlargement of false lumen area during follow-up (HR, 6.086; 95% CI: 2.223–16.660; P<0.001). The results of the Cox proportional hazards regression model are summarized in Table 3.

Discussion

Key findings of this study are summarized as follows: (I) aorta-related complication tended to occur, especially in cases with a low TLAR at the time of early subacute phase, and (II) an increase in the false lumen after the acute phase is a significant risk for the occurrence of aorta-related complication in the subacute or chronic phase. These new findings provide an important basis for determining whether preventive aortic intervention should be performed.

Although the short-term survival rate for acute TBAD with strict medical control is good (15), there might be a significant number of patients requiring surgical intervention during the chronic phase (8). The most common aorta-related complication is aortic enlargement, and a report from the International Registry of Acute Aortic Dissection showed aortic expansion in 73.3% of patients with TBAD who chose conservative treatment (16). The mechanism of aortic expansion in chronic aortic dissection remains unclear. Kelly et al. (17) explained that with aortic dissection, the aneurysm expanded during the chronic phase by losing the muscle layer barrier, which reduced the resistance of the wall to blood pressure and led to an increase in the diameter of the false lumen.

Predictors of aortic enlargement have been investigated in detail, including the number of vessels originating in the false lumen (18) and the number of intercostal arteries (19). Other well-known predictors of aortic events and mortality in patients with chronic TBAD include male (20), partial thrombosis of the false lumen (21), and aortic diameter >40 mm (14,22,23). However, these risk factors do not directly suggest indications for surgical intervention. Aortic diameter and future aneurysm occurrence at the onset of acute TBAD have been widely reported and are particularly important independent risk factors (24); it is highly likely that the diameter of the aneurysm will increase over the long term in patients with an aortic diameter >40 mm at the site of dissection at the initial examination (25). An aortic diameter of less than 40 mm is also a known factor that reduces future risk (3). In our study, a low TLAR at the time of initial presentation and an increased area of the false lumen after the acute phase appeared to be more significant prognostic factors than aortic diameter at early subacute phase. Although no clear answers have been obtained for risk factors and mechanisms, it has been reported that the diameter of the false lumen is associated with long-term prognosis (26,27); in addition, it has been reported that the prognosis is poor when the true lumen is elliptical in shape (20). Some previous reports suggested that a TLAR of less than 25–30% indicates a risk of aortic enlargement (12,28), but these reports were based on axial CT data, and 3DCT may be necessary to evaluate the aortic arch, which is the most susceptible to aneurysm formation. The result that aorta-related complications are more likely to occur when TLAR is low even with small aortic diameters is clinically important and may be useful as a decision-making tool for aggressive intervention in the future.

Recently, an increasing number of reports support preemptive TEVAR for subacute uncomplicated TBAD as prophylaxis (29-31). However, there are still no clear criteria for what constitutes a decision to proceed with surgical intervention in patients who are still receiving conservative treatment with few symptoms. Based on our results, we inform patients with a narrow true lumen area of the risk from the early subacute phase and share with them that preemptive TEVAR is a treatment option. The most important points to keep in mind are to prevent serious complications such as retrograde type A dissection and paraplegia, with special attention to (I) sufficient informed consent, (II) careful consideration of the indication for the procedure in the aortic arch, (III) avoiding oversizing, (IV) avoiding touch-up, (V) keeping a healthy landing on the proximal side, and so on. The mid-term outcome is good with no additional interventions, which will be reported separately in the future.

Our study is limited by its retrospective design, its relatively small number of patients, incomplete follow-up (9%), and varying number of CT scans among patients. Three cases of ulcer-like projection type were observed in the present study, all of which became patent false lumen type over time. Therefore, these three cases are classified as patent false lumen in this study.

In some cases, surgical intervention was performed when aneurysmal enlargement was observed at a rate equivalent to 5 mm/6 months before 6 months after onset, so we have included 0.83 mm/month as a criterion for aneurysmal enlargement.

Our findings highlight the potential role of the enlargement of the false lumen and a narrow true lumen as biomarkers for patients with TBAD who are at risk for late aorta-related complications. This work, however, is hypothesis generating and requires prospective validation in larger cohorts.

Conclusions

Enlargement of the false lumen area on follow-up may be related to the occurrence of aorta-related complications in the future. Narrow true lumen is associated with the occurrence of future aorta-related complications, even if the diameter of the aorta is small, further exploration of the relationship between the subacute and chronic outcomes after TBAD is warranted.

Acknowledgments

We thank JAM Post (www.jamp.com) for English language editing.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-864/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-864/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-864/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-864/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Yamagata University Hospital Ethical Committee (#2018-245) and ethical board of Nihonkai General Hospital (#006-3-5), and written consent was waived because of the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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