The Extent of Aortic Annulus Calcification is a Predictor of Postprocedural Eccentricity and Paravalvular Regurgitation: A Pre- and Postinterventional Cardiac Computed Tomography Angiography Study

Abstract: Purpose. To investigate if the extent of aortic valve calcification is associated with postprocedural prosthesis eccentricity and paravalvular regurgitation (PAR) in patients undergoing transcatheter aortic valve implantation (TAVI). Methods. Cardiac computed tomography angiography (CCTA) was performed before and 3 months after TAVI in 46 patients who received the self-expanding CoreValve and in 22 patients who underwent balloon-expandable Edwards Sapien XT implantation. Aortic annulus calcification was measured with CCTA prior to TAVI and prosthesis eccentricity was assessed with post-TAVI CCTA. Standard echocardiography was also performed in all patients at 3-month follow-up exam. Results. Annulus eccentricity was reduced during TAVI using both implantation systems (from 0.23 ± 0.06 to 0.18 ± 0.07 using CoreValve and from 0.20 ± 0.07 to 0.05 ± 0.03 using Edwards Sapien XT; P<.001 for both). With Edwards Sapien XT, eccentricity reduction at the level of the aortic annulus was significantly higher compared with CoreValve (P<.001). Annulus eccentricity after CoreValve use was significantly related to absolute valve calcification and to valve calcification indexed to body surface area (BSA) (r = 0.48 and 0.50, respectively; P<.001 for both). Furthermore, a significant association was observed between aortic valve calcification and PAR (P<.01 by ANOVA) in patients who received CoreValve. Using ROC analysis, a cut-off value over 913 mm² aortic valve calcification predicted the occurrence of moderate or severe PAR with a sensitivity of 92% and a specificity of 63% (area under the curve = 0.75). Furthermore, multivariable analysis showed that aortic valve calcification was a robust predictor of postprocedural eccentricity and PAR, independent of the aortic annulus size and native valve eccentricity and of CoreValve prosthesis size (adjusted r = 0.46 and 0.50, respectively; P<.01 for both). Such associations were not present with the Edwards Sapien XT system. Conclusion. The extent of native aortic annulus calcification is predictive for postprocedural prosthesis eccentricity and PAR, which is an important marker for long-term mortality in patients undergoing TAVI. This observation applies for the CoreValve, but not for the Edwards Sapien XT valve. 

J INVASIVE CARDIOL 2015;27(3):172-180

Key words: cardiac computed tomography angiography, severe aortic stenosis, aortic valve calcification, prosthesis eccentricity, paravalvular aortic regurgitation

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Transcatheter aortic valve implantation (TAVI) has evolved as an important treatment option for high-risk patients with severe aortic valve stenosis.^1,2 However, one of the inherent problems in this technique is the risk of paravalvular aortic regurgitation (PAR), mainly due to suboptimal sealing of the prosthesis in calcified annuli. As we know from various trials, registries and reviews, PAR is an independent predictor of morbidity and mortality after TAVI.^3-6 Thus, understanding the mechanisms and predictors of PAR is very important. The different technical concepts of TAVI underline this aspect even more, since these implantation techniques may differently address calcification, annulus geometry, and PAR. 

The two main concepts of TAVI are: (1) implantation with a self-expanding valve; and (2) implantation with a balloon-expandable valve. Radial forces during and after implantation, and adjustment to the annulus geometry, may vary between the two implantation techniques. While a balloon-expandable valve may build up larger radial force with little adjustment to the annulus, a self-expanding valve may not exert a large radial force, but may therefore better adjust to an eccentric annulus. Both concepts have specific advantages and disadvantages regarding postinterventional results, such as low PAR, and interventional major complications, such as annular rupture. 

In most centers, cardiac computed tomography angiography (CCTA) is used as the main tool for annulus measurement and characterization prior to TAVI. However, few CCTA data exist on postprocedural hearts with the implanted prosthesis.⁷ The aim of our study was therefore to analyze both pre- and postprocedural CCTA data of TAVI patients, in order to understand annulus-related and prosthesis-related factors that may contribute to postprocedural PAR. In this regard, we hypothesized that increased aortic valve calcium burden may cause incomplete adaptation of the prosthesis struts to the aortic wall, leading to increased prosthesis eccentricity after TAVI and consecutively to increased PAR.

Methods

Patient population and study protocol. Our patient population consisted of 70 patients with symptomatic severe aortic stenosis considered for TAVI. Patients with impaired renal function (creatinine clearance <50 mL/min by MDRD) or other contraindications to the administration of iodine contrast agents were excluded from the follow-up CCTA study (Figure 1). TAVI was performed via transfemoral approach using CoreValve (Medtronic, Inc) in 46 patients and Edwards Sapien XT (Edwards Lifesciences, Inc) in 22 patients, while 2 patients underwent conservative and surgical treatment, respectively, and were excluded from analysis. All 68 remaining patients underwent baseline CCTA prior to TAVI and at 3-month follow-up, standard transthoracic echocardiography 3 months after TAVI, and clinical data assessment at 6-month follow-up. The decision to implant either a CoreValve or Edwards prosthesis was based on annulus size (eg, all patients with annuli >27 mm received a 31 mm CoreValve), on coronary ostia distance (too-low coronaries were disqualified from Sapien XT), and on sheath requirements (eg, 6.0 mm access vessels would not qualify for a 29 mm Edwards valve). In patients who could receive either valve, the decision was randomly assigned. 

All procedures complied with the Declaration of Helsinki and were approved by our local ethics committee, and all patients gave written informed consent.

256-slice CT scans. CCTA scans were performed using a 256-slice Brilliance iCT scanner (Philips Healthcare) that features a gantry rotation time of 270 ms, resulting in a temporal resolution of 36-135 ms, depending on the heart rate of the patient and the performance of multisegment reconstruction algorithms, and an isotropic sub-millimeter spatial resolution.

For assessment of aortic valve calcification, native scans without contrast agent were performed using the following imaging parameters: tube voltage of 120 kV with an effective tube current-time product of 55 mAs per section, slice collimation 32 x 0.625 mm acquisition and a 0.33 s gantry rotation time. 

For CCTA, a bolus of 80-100 mL of contrast agent (Ultravist 370) was injected intravenously using an antecubital intravenous line. The contrast agent was injected at a flow of 5 mL/s followed by a saline flush (50 mL at a flow of 5 mL/s). The scan started automatically using a bolus tracking with a region of interest placed in the descending aorta and a threshold of 110 Hounsfield Units (HU). The entire volume of the heart was acquired during one breath-hold in 4-7 s with simultaneous electrocardiographic (ECG) recording. The detector collimation was 2 x 128 x 0.625 mm, with overlapping slices of 0.625 mm thickness for CCTA and 2.5 mm thickness for non-contrast scans and dynamic z-focal spot for both acquisitions.

No premedication with ß-blockers or nitrates was given due to severe aortic stenosis in all patients. The tube voltage was 100-120 kV and the gantry rotation time was 0.27 s. Depending of their heart rate, patients underwent either retrospectively gated CCTA (with heart rates ≥75 beats/min; tube voltage of 100 or 120 kV and tube current of 800-1050 mAs depending on patient habitus) or prospectively triggered CCTA (with heart rates <75 beats/min; tube voltage of 100 or 120kV and tube current of 100-210 mAs depending on patient habitus). Dose modulation was applied with retrospectively gated scans. For consistency, we used diastolic images (75% of the cardiac cycle) for assessment of aortic valvular structures in all retrospectively gated and prospectively triggered CCTA scans prior to and after TAVI.

CT image analysis. CT datasets were analyzed using commercially available software (Philips Extended Brilliance Workspace 4.5). For analysis of aortic valve calcification in non-contrast scans, calcium was automatically marked using a standard threshold of 130 HU. Calcification was measured separately in the right, left, and non-coronary aortic cusp using axial images. Hereby, care was taken during positioning of areas of interest in order to avoid calcification of the aortic root, of the right and left coronary ostia, and of the mitral annulus, by crosschecking for anatomy and calcium distribution in contrast-enhanced images.

Standard coronal and sagittal views were used for the initial orientation of the aortic valve for measurement of aortic valve structures. Multiple oblique cuts through the aortic root were then obtained by aligning three perpendicular analysis windows (axial, oblique sagittal, and oblique coronal), so that the most caudal attachments of all three aortic valve leaflets could be simultaneously depicted in one multiple oblique image.⁸ Subsequently, using the Philips Extended Brilliance Workspace 4.5 software, a freehand region of interest (ROI) was drawn by manual contouring of the aortic annulus on multiple oblique planes defined by the base (ie, most caudal attachments) and the following parameters were assessed: the diameter of the aortic annulus using two-dimensional coronal images (D_{annulus coronal}), the shortest diameter of the aortic annulus of the native leaflets (D_{annulus short}), the longest diameter of the aortic annulus on the same multiple oblique plane (D_{annulus long}), the perimeter of the aortic annulus, and the distances between the annulus and the left and right coronary ostium (D_{left ostium} and D_{right ostium}). Of notice, the mean annular diameter (D_{annulus mean}) is provided based on the length of this freehand contour and not on the effective diameter. Eccentricity was always measured at the level of the aortic annulus with CCTA prior to TAVI and either at the level of the native annulus or at the level of the valve leaflet coaptation zone with post-TAVI CCTA, and was defined as eccentricity = 1-(D_{annulus short}/D_{annulus long}).

Cardiac catheterization. Patients underwent invasive cardiac evaluation, including coronary angiography and hemodynamic assessment using right heart catheterization. Simultaneous peak-to-peak and mean transvalvular gradients were determined invasively in case of inconclusive non-invasive findings. In addition, selective angiography of the left and right coronary artery was performed according to the angiographic guidelines. 

TAVI procedures and angiographic evaluation of PAR. TAVI procedures were performed as previously described. In brief, first a regular 18 Fr delivery sheath (for CoreValve) or an expandable 16, 18, or 20 Fr sheath (for Edwards Sapien XT) was placed into the femoral artery, a transjugular pacemaker placed in the right ventricle, and balloon valvuloplasty performed under rapid pacing. Afterward, a CoreValve or Edwards Sapien prosthesis was implanted. Access site was closed using the Prostar XL 10 Fr system (Abbott Vascular). If possible, all procedures were performed under local anesthesia and light analgosedation, monitored by a cardiac anesthesiologist. A back-up cardiac surgeon and a cardiopulmonary bypass machine were available for all procedures. 

After implantation, PAR was evaluated by aortography using a semiquantitative grading (0-3 scale): 0 = absent or minimal; 1 = mild; 2 = moderate; and 3 = severe regurgitation. If adaptation to the annulus seemed insufficient, postdilation was performed to reduce PAR.

Echocardiography and clinical follow-up data. With echocardiographic examinations semiquantitative grading was performed (0-3 scale): 0 = absent or minimal; 1 = mild; 2 = moderate; and 3 = severe regurgitation, in order to assess the presence of postprocedural PAR 3 months after TAVI. Grading was performed analogue to the Valve Academic Research Consortium 2 consensus document and to the EAE/ASE recommendations for echocardiography use in transcatheter interventions for valvular disease.^9,10 Furthermore, periprocedural complications such as annulus rupture, valve dislocation, coronary ostium occlusion, shock due to peripheral bleeding, atrioventricular-block or new left bundle branch block requiring the implantation of a permanent pacemaker and clinical events during 12 months of follow-up (cardiac death, non-fatal myocardial infarction, repeat TAVI, cardiac surgery, and all-cause mortality) were documented.

Statistical analysis. Statistical analysis was performed using commercially available software MedCalc9.3 (MedCalc software). Continuous variables were expressed as mean ± standard deviation and categorical variables as proportions. Repeated-measures ANOVA with Bonferroni correction for multiple comparisons was used to compare continuous variables. Group differences between ordinal variables were tested using the exact Mann-Whitney test and differences between nominal variables were assessed using Fisher exact tests. All tests were 2-tailed. Linear regression was used to compare aortic valve calcification with annulus eccentricity before and after TAVI. Receiver operating characteristic (ROC) curves were used to determine the predictive value of aortic calcification for the occurrence of postprocedural aortic regurgitation. Hereby, cut-off values were determined using the methodology described by DeLong et al.¹¹ Intraobserver and interobserver variability for quantification of aortic annulus diameter and aortic valve calcification were calculated by repeated analysis of all CT parameters in 50 randomly selected cases. For the calculation of intraobserver variability, readings were separated by 8 weeks to minimize recall bias. Differences were considered statistically significant at P<.05.

Results

Clinical characteristics. Postinterventional CCTA data were prospectively collected in 46 patients who received the CoreValve system and in 22 patients who received the Edwards Sapien XT valve. Baseline and laboratory characteristics are illustrated in Table 1. The two groups did not show significant differences in terms of clinical characteristics and size and shape of the aortic annulus and pre-TAVI annular eccentricity.

Change in annulus shape during TAVI. Annulus eccentricity was reduced during TAVI using both implantation systems from 0.23 ± 0.06 to 0.18 ± 0.07 using CoreValve and from 0.20 ± 0.07 to 0.05 ± 0.03 using Edwards Sapien XT; P<.001 for both). Eccentricity reduction at the level of the aortic annulus was significantly lower with CoreValve compared with the Edwards Sapien XT valve (P<.001) (Figure 2A). Similar findings were observed at the coaptation level of the two systems (Figure 2B). 

No significant difference was present for prosthesis eccentricity between the annulus and coaptation level for Edwards Sapien XT valves (P=NS), whereas eccentricity of the coaptation level was significantly lower than at the annular level with CoreValve systems (P<.001).

Relation of aortic valve calcification to eccentricity after TAVI. The extent of native valve calcification was not related to eccentricity prior to TAVI (r = -0.09; P=NS). However, annulus eccentricity after CoreValve implantation was significantly related to the absolute valve calcification (r = 0.48; P<.001) and to valve calcification related to BSA (r = 0.50; P<.001) (Figures 3A and 3B). Annulus eccentricity after Edwards Sapien XT implantation, on the other hand, was not related to valve calcification (r = 0.15; P=NS).

In addition, a significant inverse correlation was found between calcification and annular eccentricity reduction with CoreValve systems (Figure 4).

Paravalvular aortic regurgitation (PAR). Transthoracic echocardiography after TAVI revealed PAR both in patients who underwent CoreValve and Edwards Sapien XT implantation. A trend for higher PAR was observed with CoreValve, albeit without reaching statistical significance (Figure 5) (P=.09). Nine patients (19.5%) who received CoreValve exhibited moderate (n = 8) or severe regurgitation (n = 1) compared with 1 patient (4.5%) with moderate regurgitation who received an Edwards Sapien XT system. Thus, 10 of 68 patients (14.7%) exhibited more than mild PAR.

No severe PAR was observed by angiographic criteria. Moderate PAR was present in 7 patients (15%) who received CoreValve versus 1 patient (4.5%) who received an Edwards Sapien XT system (overall, in 8 of 68 patients; 11.7%). Agreement between echocardiographic and angiographic PAR was good (90%; κ = 0.62).

Relation of annulus calcification to PAR. In patients who underwent CoreValve implantation, the extent of eccentricity after TAVI at the level of the native annulus and at the level of the CoreValve leaflet coaptation was significantly associated with PAR (P<.01 and P=.03 by ANOVA, respectively) (Figures 6A and B). Furthermore, a significant association was observed between aortic valve calcification and PAR (P<.01 by ANOVA) (Figure 6C). Using ROC, a cut-off value over 913 mm² aortic valve calcification predicted the occurrence of  moderate or severe prosthesis regurgitation, with sensitivity of 92% and specificity of 63% (AUC = 0.75) (Figure 6D).

Multivariable analysis with patients receiving CoreValve showed that aortic valve calcification was a predictor of postprocedural increased eccentricity and regurgitation, independent of the aortic annulus size, native valve eccentricity, and prosthesis size (Table 2). On the other hand, no association was observed between valve calcification and annulus eccentricity after TAVI with PAR in patients who underwent Edwards Sapien XT implantation (P=NS for both).

Images of a patient with high extent calcification (1037 mm²) of the aortic valve, resulting in increased eccentricity of 1.50 after CoreValve implantation and moderate PAR (red arrows), can be appreciated in Figures 7a-7d. On the other hand, a patient with similarly high extent of calcification (987 mm²), but more circular annulus shape (eccentricity index = 1.05) after Edwards implantation and minimal regurgitation (red arrow), is shown in Figures 7e-7h.

Clinical follow-up. During follow-up, 3 of 46 patients (6.5%) who underwent CoreValve implantation died (1 due to acute iliac artery bleeding during TAVI, and 2 due to septic shock 42 days and 9.5 months after TAVI, respectively). Of the 22 patients who underwent Edwards Sapien XT implantation, 1 patient (4.5%) died due to septic shock 10 days after TAVI.

Observer variability. Interobserver and intraobserver variability for assessment of annulus short axis, coronal and long axis diameter, eccentricity, distance between the aortic annulus and the right and left coronary ostium, and aortic valve calcification are shown in Table 3. 

Discussion

PAR is still a limiting factor in TAVI procedures, especially affecting mid-term and long-term outcomes. With broader use of TAVIs and fewer vascular complications, PAR will increase in importance when judging success and indication for TAVI. Thus, understanding the mechanisms of this complication and its relation to various valve types is crucial. 

Previous reports have demonstrated that the extent of native aortic annulus calcification is related to PAR in patients undergoing TAVI.^12-16 These studies show that extensive annular calcification leads to more PAR,¹² which applies to CoreValves,^13,16 transapical Edwards valves,¹⁴ and transfemoral Edwards valves.^15,17

In our study, we demonstrated that increased PAR in such patients with heavily calcified annuli is related to postproce-dural prosthesis eccentricity, possibly due to impaired adhesion of the prosthesis to the native annulus, providing the pathoanatomic substrate for PAR. By analyzing both self-expanding and balloon-expanding valves in the same setting, we found that this observation along with the underlying mechanism applies to the CoreValve and not to the Edwards Sapien XT system. With CoreValve, an inverse correlation was found between annulus calcification and eccentricity reduction. This means that eccentricity reduction with this system was possibly less effective in patients with severe aortic valve calcification, compared with patients who had less calcified valves, thus suggesting that calcification may lead to uneven expansion, failing to correct preexisting valve annular eccentricity. In fact, in 10 of 46 CoreValve patients, valve eccentricity increased after TAVI. This was not the case in any of the patients who received the Edwards Sapien XT system. Because preexisting valve annular eccentricity was similar in patients who received CoreValve and Edwards Sapien XT, we believe that uneven expansion due to severe calcification rather than preexisting eccentricity was the main factor causing postprocedural eccentricity and PAR. In the same line, preexisting eccentricity was not independently associated with either postprocedural eccentricity or PAR in our multivariable analysis. 

Our findings underscore the ability of CCTA prior to TAVI to predict an important postprocedural complication, which is an established marker for long-term mortality in patients undergoing TAVI.

In addition, we were able to show the distinctive differences of postimplantation geometry between CoreValve and Sapien XT. Importantly, the two implantation groups did not significantly differ in terms of clinical characteristics, size and shape of the aortic annulus, and annulus eccentricity prior to TAVI. Only the logistic EuroSCORE was significantly lower in the CoreValve group, which is most likely related to our relatively small sample size. This difference in the risk score was not apparent when analyzing the Society of Thoracic Surgeons (STS) score. From an anatomic viewpoint, the self-expanding valve conforms to the annulus, thus being significantly more eccentric than the balloon-expanding valve, which possibly more effectively circumvents uneven expansion of the prosthesis. From an anatomic perspective, the annulus is geometrically modulated to a significantly higher degree (losing eccentricity) with the balloon-expanding valve. The higher radial force of the Edwards valve during implantation and the stiffer frame after implantation leads to a low eccentricity independent of annulus calcification, very much in contrast to CoreValve, which is highly affected by strong calcification. This finding has two important implications. Thus, considering the trend toward higher PAR in CoreValve and the significant association of calcification, CoreValve eccentricity, and PAR, patients with extensive calcification may benefit from balloon-expanding valves. On the other hand, this specific characteristic probably influences implantation risks, such as annular rupture, due to the different abilities to conform to the annular geometry. A valve that changes the annulus geometry will more likely cause annular complications than a valve that influences geometry less and rather conforms to the annulus. Therefore, this study gives some unique new insights into the geometrical behavior of the two main TAVI prostheses, improving our knowledge about prosthesis-related and annulus-related aspects of PAR.    

From a technical point of view, CCTA represents a non-invasive imaging technique that allows the visualization of aortic valve structures with high sub-millimeter spatial resolution and quantitative assessment of annulus diameters and eccentricity with high reproducibility.⁸ Furthermore, CCTA is the only imaging modality that can assess aortic valve calcification in such a precise and quantitative way. Previous studies used contrast-enhanced aortography or echocardiography for the preprocedural evaluation of aortic valve structures including device sizing and placement.^18,19 However, the two-dimensional nature of these techniques may limit their ability to consistently assess the complex three-dimensional geometry of the aortic annulus. In agreement with these theoretical considerations, recent studies indicated that echocardiography systematically underestimates the diameter of the aortic annulus diameter (~2 mm) compared to CCTA.²⁰ Although echocardiography is a very practical imaging technique, we therefore chose to assess aortic valve structures using CCTA in our study. PAR, on the other hand, was assessed by standard echocardiography, which demonstrated good agreement with contrast-enhanced aortography. 

Study limitations. The main limitation of this work is related to the distribution of the two valves. Ideally, a randomized design with equal numbers of CoreValve and Sapien valves would have led to more robust data. Thus, a potential bias may be present in these data, especially since some patients had anatomies that prohibited implantations with Sapien XT. However, comparing both groups, we did not see any relevant differences. 

Conclusion

The extent of native aortic annulus calcification is predictive for postprocedural prosthesis eccentricity and PAR. CoreValve conforms more to the annulus, whereas Sapien XT mainly changes the annulus geometry. These findings may influence the decision process for the type of valve during TAVIs, aiming at optimal results with the fewest complications. 

Acknowledgments. We thank our technicians Kerstin Graf, Birgit Hörig, and Daniel Helm for their help with performing the high-quality cardiac CT examinations.

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From the ¹Department of Cardiology, University of Heidelberg, Heidelberg, Germany; and the ²Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kauczor reports grants from Siemens and Boehringer Ingelheim; personal fees from Siemens, Boehringer Ingelheim, Bayer, Novartis, Almirall, and GSK; non-financial support from Boehringer Ingelheim and Bayer. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 28, 2014, provisional acceptance given April 3, 2014, final version accepted July 23, 2014.

Address for correspondence: Grigorios Korosoglou, University of Heidelberg, Department of Cardiology, Im Neuenheimer Feld 410, Heidelberg, 69120, Germany. Email: gkorosoglou@hotmail.com