Aortic Luminal Remodeling After Intravascular Stent Therapy for Coarctation of the Aorta: Intermediate Results

ABSTRACT

OBJECTIVE. Outcomes after adult coarctation of the aorta (CoA) stenting is scant. We explored predictors of aortic remodeling after stent implantation and report early- and intermediate-term clinical outcomes. METHODS. Adult patients who underwent stenting between July 2003 and December 2017 were included in this single-center retrospective study. We created a novel index of aortic volumetric and diameter changes using computed tomography (CT)/magnetic resonance (MR) images measured through TeraRecon and AngioQ. Predictors of aortic remodeling were explored using univariable linear regression analysis. RESULTS. One hundred and thirty-four patients (mean age 35.2 years, 58.2% men) underwent CoA stenting. Paired aortic diameter measurements were available in 20 patients, and 40 paired patients in volumetric measurements.  There was significant reduction in aortic diameter immediately proximal to the left carotid and subclavian arteries, and the aorta distal to the stenosis (P<.05) at follow-up. There was a significant volumetric reduction in the ascending aorta, aortic arch, and the aortic segment most proximal to the top of the stent (P<.05). Univariate predictors of aortic remodeling included sex, age, presence of previous surgical repair, aortic valve morphology, and the number of antihypertensive medications. Mean follow-up time was 4.0 ± 3.8 years, where 5% of patients underwent reintervention due to complications, 3% developed aneurysms, and 3% had stent fractures. CONCLUSIONS. This study is the first to examine the anatomical changes that occur in the aorta post stent repair through analysis of serial imaging. Patients with stent-repaired coarctation demonstrated negative remodeling in multiple areas of the aorta with regards to the aortic diameter and volumetric measurements.

INTRODUCTION

Coarctation of the aorta (CoA) is characterized by a narrowing at the aortic isthmus distal to the left subclavian artery causing obstruction, upstream hypertension, and reduced distal flow. The anatomical spectrum of the obstruction varies from a discrete stenosis to diffuse arch hypoplasia, with a varied expression between these extremes.¹ CoA can occur in isolation or coexist with other congenital defects, most commonly bicuspid aortic valve (BAV).²

Untreated CoA has a poor prognosis; between the 1930s and the 1960s, 25% of patients died before age 20. The mortality rate increased from 1.6% in the first 2 decades to 6.7% per annum in the sixth and later decades, exacerbated by the lack of comprehensive aortic imaging available.³ This, in conjunction with limited treatment of hypertension, resulted in predominantly severe phenotypes presented to health care providers.

The introduction of endovascular therapy has now become a first-line guideline-supported therapy.⁴ Due to improved access diagnosis and various treatment options, the survival rate has risen to 87.4% at a mean age of 40.⁵ The advancement of new medical technology has placed an emphasis on identifying postprocedural and late complications in stented CoA patients. Several studies indicated that despite relief of the initial obstruction, the risk of subsequent complications persists.^6-8 Current literature, however, is scant with regard to comprehensive follow-up imaging and long-term clinical outcomes; thus, in consequence, physiological responses or changes post CoA treatment have not been well-described. Cardiovascular pathologies such as hypertension have been previously suggested to exacerbate hypertrophic remodeling of large arteries.⁹ In addition, changes in the aortic diameter were seen after aortic valve replacement in BAV patients.¹⁰

In this regard, we aimed to elucidate the anatomical changes that occur in the aorta after stent placement in the adult CoA population through comparison of aortic dimensions before and after stent implantation and explore the predictors of arch remodeling and the early and intermediate clinical outcomes at follow-up.

METHODS

Study setting and population. This is a retrospective cohort study enrolling all adult patients who underwent implantation of an endovascular stent for CoA from July 2003 to December 2017 at the Toronto General Hospital (TGH). Using chart abstraction, all patients meeting this eligibility criteria were consecutively entered into an electronic clinical database. The study protocol has been approved by the ethics research board of the University Health Network. Patient consent requirement was waived due to the retrospective nature of the study.

Procedural and follow-up information. Patients underwent stent implantation under local anesthesia supplemented by brief deep propofol sedation at time of stent implantation. Intravenous heparin (100 IU/kg) was administered after femoral cannulation and activated clot time (ACT) was routinely monitored. A single dose of antibiotics was given to all patients at time of procedure. The majority of stent implantations were accessed through a simultaneous radial and femoral route and performed using the “rose petal” technique.

Our standard follow-up protocol includes computed tomography (CT) aortogram approximately 2 to 3 months after the procedure, a cardiac catheterization at 12 months after the implant, and subsequent focused CT or magnetic resonance (MR) scans every 3 to 5 years. Cerebral imaging was performed at least once to exclude possible cerebral aneurysms.

Data collection. We reviewed data from both electronic and paper forms of the medical charts. A detailed data dictionary was developed for chart abstraction, which included data on baseline demographics (eg, age, sex), type of stenosis (native vs recurrent), associated congenital heart defects, hypertension (severity, medication use), procedural characteristics and outcomes (eg, stent type, procedural complications), clinical outcomes recorded at follow-up visits, and diagnostic imaging (see details below). Whenever available, we relied on 24-hour ambulatory blood pressure measurements to rule out masked hypertension, white coat hypertension, and determine the mean daytime blood pressure.

Imaging data during baseline and routine follow-up (eg, cardiac catheterization and CT or MR scans) were also examined. Only contrast-enhanced CT images were reviewed, with electrocardiogram (ECG)-gated cardiac CT images at 75% (diastole) preferred over non-gated cardiac CT and thoracic CT. Volumetric aortic measurements were obtained from CT or MR images using the medical imaging program iNtuition (TeraRecon), and aortic diameters were obtained from the magnification corrected cardiac catheterization angiograms. Clinically successful stent implantations were defined as freedom from a significant gradient (< 5 mm Hg) across the coarctation site without the presence of major vascular adverse events requiring immediate surgical or percutaneous reintervention.

Measuring aortic diameter and volume. The study's primary outcome was anatomical changes in arch morphology evaluated as the difference between aortic dimensions before stent implantation and after stent implantation at 1-year follow-up. We first investigated the primary outcome through aortic diameter measurements using catheterization images at baseline and at the 1-year angiogram follow-up (Figure A in Supplemental material). An in situ 10 mm interval marker catheter was used for magnification correction.  However, due to noncompatible angiographic angulations between studies, a number of paired acquisitions could not be used (Figure 1). Accordingly, to decrease the measurement error, aortic volumes, or the sum of cross-sectional disks obtained from non-invasive imaging (CT scans or MRI studies), were used.

Volumetric measurements were taken from baseline and follow-up CT/MR studies with the 3D volume navigation function using the iNtuition program with 5 segments of interest (Figure B in Supplemental material).

Both diameter and volumetric aortic measurements were indexed to patient body surface area (BSA) values (ie, each measurement was divided by patient baseline BSA). Hypertensive stages were defined in accordance with the 2018 American Hypertension Clinical Practice Guidelines.¹¹

Statistical analysis. Baseline characteristics and clinical outcomes were reported for the full sample as well as separately by sex for exploratory purposes. Continuous variables were described using mean and standard deviation (SD) and analyzed using paired sample t-tests. Categorical variables were described using counts and percentages and compared using a chi-square test or Fisher’s exact test when appropriate. Univariate linear regression analysis was used to explore the predictors of aortic remodeling using a preselected list of variables including sex, age, presence of previous surgical repair, aortic valve morphology, and the number of antihypertensive medications. All analyses were performed using R statistical software (version 3.6.0).¹² A two-sided P value <.05 was considered significant for all comparisons.

RESULTS

Between July 2003 and December 2017, 134 patients were referred to the Structural Heart Disease Program at TGH for percutaneous CoA stent repair. The selection of the study sample for aortic diameter and volume analysis is presented in Figure 1. Although all patients received an interventional catheterization and a 1-year follow-up catheterization, 69 patients were excluded from the study due to missing preprocedural catheterization images or postprocedural follow-up catheterization images. A further 46 patients were excluded due to incompatible angiographic catheterization angles, leaving 20 patients in the final sample for diameter analysis. Fifty patients (37.3%) had paired pre- and post-implantation cardiac CT or MR imaging. Of these, 12 patients were excluded due to substandard image quality or corrupted data files, leaving 38 patients as the final sample for analysis of aortic volumes.

Baseline characteristics. The characteristics of the study population are presented in Table 1. The mean age of the population was 35.2 years (SD = 12.9 years, range: 17-72), 58.2% male. Of patients for whom aortic valve morphology was available (n =120), 49.2% (n = 59) had a BAV (all Sievers Type I), 50.0% (n = 60) had a tricuspid aortic valve (TAV), and 0.8% (n = 1) had a prosthetic valve. The majority of patients had a native coarctation (n = 91, 67.9%). Systemic hypertension was present in 85.8% (n = 109), and 17.1% (n = 23) had concomitant congenital heart defects (CHD). Males had a higher BSA (P<.001), and a significantly higher proportion were taking antihypertensive medications (P<.05). Eighty-three patients (65.4%) had a covered Cheatham-Platinum (CP) stent (NuMED Inc.), 35 (27.6%) had a bare metal Palmaz stent (Cordis), and 3 each (2.4%) had a bare metal CP stent, covered Advanta V12 stent (Atrium Medical Corp), and a bare metal Andrastent XL stent (Andramed Medical Devices). Procedural characteristics of the stents are further described in Supplemental material, Table A.

Aortic diameter measurements. Average time from the procedure to first follow-up cardiac catheterization was 1.9 years (SD = 1.4 years). Twenty paired cardiac catheterizations were used to compare aortic diameters (paired pre- and post-operative catheterization image seen in Supplemental material, Figure C). No significant differences were found in baseline characteristics when comparing these 20 patients to the total sample (Supplemental material, Table B). Table 2 reports aortic diameter measurements of paired cardiac catheterizations normalized to BSA (cm/m²). A significant decrease in mean aortic diameter was observed in the aortic arch immediately proximal to the left carotid artery (LCA) origin (P=.024), the widest dilated area distal to the stenosis (P<.001), and a significant increase at the area of tightest stenosis (P<.001). A spaghetti plot of all paired aortic diameter changes for all 20 patients is shown in Figure 2.

Aortic volumetric measurements. Average time from the procedure to first follow-up CT/MR was 1.0 years (SD=1.5 years). A total of 38 paired CT/MR scans were used to obtain aortic volumetric measurements (paired pre- and post-operative CT image seen in Supplemental material, Figure D). No significant differences were found in baseline characteristics when comparing these 20 patients to the total sample other than proportion of patients with BAV (P<.05), as seen in Supplemental material, Table C. A significant reduction in aortic volume was seen along the ascending aorta, the aortic arch, and the area immediately proximal to the stent (P=.009, P=.001, P=.002, respectively) exhibited in Table 3. All stent lumen volumetric measurements were also found to be significantly reduced from baseline. The segment of aorta with the largest volume was the ascending aorta, followed by the aortic arch and the proximal descending aorta (descending aorta 1). All 38 patients with paired CT/MR scans were plotted in a spaghetti plot to show the difference in postprocedural and baseline aortic volume (Figure 3.)

Predictors of aortic remodeling. Univariable analyses were conducted to explore the potential predictors of aortic remodeling. Full details of the predictors of changes in aortic diameter measurements are reported in Supplemental material, Table D. Univariable analyses to detect baseline predictors of aortic volumetric remodeling parameters are presented in Table 4. Results revealed that neither sex nor age were significantly associated with volumetric remodeling (P>.05). Previous surgery was shown to be significantly associated with aortic volume remodeling in the ascending aorta and segment proximal to the stent, where there was less volume regression seen in patients who have had previous surgical repair (P<.05). Compared to patients with BAV, having a TAV was associated with less volume regression in the 1st, 2nd, and last segment of descending aorta (P<.001, P<.01, and P<.05, respectively). Lastly, the number of antihypertensive medications was associated with less volume regression in the last segment of the descending aorta (P<.05).

Clinical outcomes. A total of 14 (10.4%) patients had complications, with 2 in-hospital complications (1.5%) and 12 intermediate complications (9.0%) (Table 5). No procedural complications were observed. There was 1 case of an in-hospital stroke and 1 case of an aneurysm formation prior to discharge. The former occurred in the right middle cerebral artery upon awakening from the procedure thought to be related to air embolism from the injector. The patient with the aneurysm was initially planted with a 50 mm bare metal Palmaz stent and a 50 mm covered CP stent during reintervention. The mean follow-up for obtaining intermediate clinical outcomes was 4.0 years (SD = 3.8). During follow-up, 4 additional patients developed an arch aneurysm, 6 had stent fractures, and 2 had stent recoil. Further details of the complications are reported in Supplemental material, Table E. Of the 15 patients with a complication, 66.7% (n = 10) were men, 53.3% (n = 8) had an implantation of Palmaz stent, 26.7% (n = 4) had a CP stent, 13.3% (n = 2) had a covered Atrium Advanta V12 stent, and 6.7% (n = 1) had a bare metal XL AndraStent.

DISCUSSION

With the advancement of medical technology leading to longer survival after coarctation repair, there is now an emphasis on elucidating postprocedural aortic remodeling and its potential impact on outcomes. Our study is one of the largest series reported to date on stent implantation for CoA and the first to examine the physiological remodeling of the aorta post repair using serial imaging. We reviewed 134 patients with intravascular stent therapy for CoA and observed a significant reduction in aortic diameter in the aortic arch proximal to the LCA bifurcation, the region of the tightest stenosis, and in the dilated area distal to the stenosis. From an aortic volume perspective, significant reductions were seen in the ascending aorta, aortic arch, and the aortic segment proximal to the stent. Potential predictors of aortic volume remodeling included previous surgical repair, valve morphology, and the number of hypertension medications.

Study population. Our center specializes solely in adult CHD; therefore, the average age of our cohort (35.2 years) was above the mean of 15.8 to 26.6 years seen in earlier studies.^8,13 Due to this, we observed a higher prevalence of preprocedural hypertension at baseline (85.8%) than reported in other studies at 61% to 77%.^7,13 The distribution of patients by prior treatment and valve morphology, however, was similar as observed in other studies.^6,13 Although gender differences have been reported in past studies in patients with CHD¹⁴, in this cohort of predominantly male CoA population, our exploratory analysis by sex did not reveal any statistically or clinically meaningful differences in baseline characteristics or outcomes. Next, our cohort was composed of 67.9% of patients undergoing percutaneous treatment with native coarctation. Similarly, Butera et al reported 102/143 (71%) with native-form coarctation.¹⁵ Lastly, regarding valve morphology, 49.2% of our cohort possessed BAV. This was also in accordance with previous studies, where Holzer et al demonstrated 41% of patients with BAV, and Ringel et al with 55% of patients with BAV.^6,13

To describe the anatomical changes in the aorta post stent implantation, we evaluated the diameter and volumetric changes using paired cardiac catheterization and CT/MR scans. We first reported a significant reduction in both aortic diameter at the level of the LCA bifurcation and aortic volume in the proximal segment to the stenosis. A possible explanation for this is a larger ascending aortic baseline size seen in CoA patients, as previous studies have demonstrated a correlation to ascending aortic dilatation, predisposed with the presence of BAV.^10,16 Although the causation of ascending aortic dilation has not been fully elucidated, one  hypothesis has been suggested to be congenital aortic fragility where individuals with BAV may possess an accelerated degeneration of the aortic medial layer, further worsened by the high hemodynamic stresses on the anterolateral portion of the ascending aorta.^17-19 Removal of the hemodynamic stressor post stenting may have alleviated the hemodynamic stress on the aortic walls, leading to a reduction in size.

We also reported a significant reduction in aortic diameter at the level of the descending aortic dilation immediately distal to the stenosis. A 2007 study examined aortic dilation change using CT diameter measurements across different segments of the aorta in 100 patients with aortic dissection.²⁰ They found that the upper descending aorta was most susceptible to increasing aortic dilation in the presence of aortic injury; thus, we may also have noted the regression in descending aortic diameter in our study upon elimination of the increased stress and turbulent flow on the aortic walls downstream of the stenosis.

Although changes in the aortic diameter is an excellent technique in examining one specific point along the aorta for vascular remodeling, the approach is limited in investigating an overall change of segments along the vessel. The 2-dimensional nature of a catheterization image was a principal limitation when interpreting measurements. Three-dimensional volumetric techniques may provide additional spatial information that is markedly more difficult to obtain from a 2-dimensional image.²¹ In addition, the aorta has been reported in a previous 2016 study to express eccentric shapes of the lumen, particularly with the presence of aortic dilatation.²² With this important caveat, we postulated that using volumetric assessment would be a more appropriate method to evaluate overall change and provide a more exhaustive assessment of aortic remodeling.

Predictors of remodeling. Another first in our study was the exploration of predictors of aortic diameter remodeling. One of the potential predictors associated with aortic remodeling was the presence of previous surgical repair of CoA associated with less negative remodeling in the ascending aorta than their native counterpart. We also found that the number of antihypertensive medications was associated with negative remodeling on the dilated descending aorta immediately distal to the stenosis, and the descending aorta (P=.008 and P=.004, respectively). Patients with TAV also saw less negative remodeling across the descending aorta.

Clinical outcomes. Overall, 10.4% of our patients reported a complication at follow-up. No mortality was observed, and rates of in-hospital complications were low at 1.5%, similar to periprocedural outcomes reported in prior studies.^7,13 At intermediate follow-up, 3% of patients experienced post-stent aneurysm formation, which is within range of 1% to 3% reported in past studies.^7,8,23 All 4 patients were implanted with either Palmaz XL or Palmaz Genesis. We suspect this may be due to sustained arterial injury during balloon expansion of the stent. Furthermore, the sharp edges of Palmaz stents may have exacerbated injury to the aortic wall, increasing the risk of aneurysmal formation.²⁴

We reported a total of 6 patients (4.5%) who developed stent fractures. Forbes et al reviewed the 12-month outcomes of 144 patients post coarctation stenting and reported 6 patients (4.2%) with stent fractures.⁸ Of the 6 patients who reported stent fractures, 2 had Palmaz stents and the remaining 4 had CP stents implanted. In our study, also the majority (4/6) of stent fractures were seen in patients with a covered CP stent. This may be attributed to the physical characteristics of the stent itself, as CP stents have lower radial strength in comparison to other devices.

Transcatheter reintervention was performed in 5 patients. In our study, we reported 2 cases of stent recoil, both of which required reintervention due to an increase in pressure gradient across the stenotic lesion. The mechanism of restenosis post surgical repair has been thought to be attributed to proliferation of an incomplete resection of the abnormal aortic tissue, a failure in growth of the anastomotic site during infancy, or intimal and medial hyperplasia at the suture line.^25-27 Rate of restenosis is especially high in coarctation treatment with balloon angioplasty, contrasted by the restenosis rate seen in stenting.^28,29

Limitations. Several limitations should be considered in the interpretation of our study. The first limitation was the calibration process of cardiac catheterization images where calibration was required to be completed manually in every image. We used 10 mm pigtail markers to reduce measurement error, although the sections of the pigtail marker may not represent a full indicated range due to image projection angle. Another limitation is the attrition rate of the patient population as, from 134 patients who underwent stenting, only 20 patients had paired cardiac catheterization and 38 patients paired CT/MR imaging available digitally for evaluation. The TGH is an academic, quaternary hospital with patients referred from wide geographical regions. Therefore, for the majority of patients, repeat imaging studies were not available digitally. Our comparison of characteristics of patients with and without paired imaging data, however, indicated that this limitation did not introduce a selection bias and the results are potentially generalizable to the whole sample.

Also, gated cardiac CT scans were not performed in all patients; thus, a portion of volumetric measurements were made from non-gated CT scans. However, cardiac pulsation artifact mainly affects the aortic root in non-gated CTA and has little effect on the ascending aorta, arch, and descending aorta.³⁰ In addition, the true lumen and the outer vessel wall was not seen throughout the stented reason due to blooming artifacts in CT scans. Due to this limitation of the imaging modality, we were unable to assess changes in true aortic lumen across the stented region post procedure. Another limitation was that the definition of vessel remodeling not only includes the change of lumen diameter but also the change in the medial to lumen ratio. In this study, solely the luminal diameter and volume were measured, with no knowledge of the medial-to-lumen ratio. Lastly, having a single observer conducting the aortic measurements was another limitation. While having a second observer could increase the accuracy of the measurements, this was a resource-intensive task and was not logistically possible at the time of the study.

CONCLUSION

In conclusion, the stent implantation for CoA appears to be a safe and efficacious treatment with a low rate of complications. The aorta was observed to negatively remodel along the aortic arch and descending aortic dilation distal to the stenosis as assessed by cardiac catheterization measurements and in the ascending aorta, aortic arch, segment proximal to the stent, and the entire stented region in CT/MR measurements. Longer term, prospective studies with repeat follow-up imaging are needed for a comprehensive evaluation of predictors of aortic remodeling.

Affiliations and Disclosures

This work is supported by the Peter Munk chair in Structural Heart Disease Intervention. Dr. Horlick is supported by the Peter Munk Chair in Structural Heart Disease Intervention.

¹ Faculty of Medicine, Institute of Medical Science, University of Toronto, Ontario, Canada, ² Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Ontario, Canada, ³ Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, Ontario, Canada, ⁴ Max Rady Faculty of Medicine, University of Manitoba Department of Internal Medicine, ⁵ Gleneagles Hospital Penang, Pulau Pinang, Malaysia, ⁶ Mexican Institution of Social Security, UMAE No. 1, Merida, Yucatan, Mexico, ⁷ Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Ontario, Canada, *These authors contributed equally to this work

Disclosure: Dr. Horlick is a consultant for Edwards, Medtronic, and Abbott. He has received research grants from Abbott. The Structural Heart Disease program at University Health Network receives educational support from Abbott, Edwards and Medtronic. Dr Osten is a consultant for Edwards and Medtronic. Dr. Benson is a consultant for Medtronic. Edwards, Medtronic and Abbott were not involved in planning or execution of this analysis and have not seen or reviewed this manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Address for Correspondence: Dr. Eric Horlick, Toronto General Hospital, Room 6E-249, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada, Email: Eric.horlick@uhn.ca

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