Impact of Left Ventricular Outflow Tract Calcification on Pacemaker Implantation After Transcatheter Aortic Valve Implantation With Second-Generation Devices

Abstract: Objectives. To evaluate the impact of left ventricular outflow tract calcification (LVOT-CA) localization and extension on permanent pacemaker implantation (PPI) rates after transcatheter aortic valve implantation (TAVI) with second-generation devices. Methods. This single-center retrospective study included all consecutive patients who underwent transfemoral TAVI with second-generation devices at San Raffaele Hospital in Milan, Italy from January 2014 to June 2017. The localization and extension of LVOT-CA were evaluated using computed tomography imaging; LVOT regions were categorized according to the overlying coronary cusps. Results. The study population consisted of 377 patients, of which LVOT-CA was present in 133 patients (35.3%). Patients with LVOT-CA had significantly a higher rate of post-TAVI PPI (32.0% vs 19.2% in patients with no LVOT-CA; P<.01). Multivariable analysis demonstrated LVOT-CA in the non-coronary cusp, as well as preprocedural right bundle-branch block, age, body mass index, and mechanically expanded prosthesis implantation, to be strong independent predictors of PPI. Conclusions. LVOT-CA in the non-coronary cusp is a strong independent predictor of PPI after TAVI with second-generation devices. Further studies are needed to confirm these data in a larger, multicenter population. 

J INVASIVE CARDIOL 2020;32(5):180-185. Epub 2020 February 11.

Key words: calcification, left ventricular outflow tract, TAVI

In the last decade, transcatheter aortic valve implantation (TAVI) has become a less-invasive alternative to surgery in patients with symptomatic, severe aortic stenosis who are deemed at increased surgical risk.^1,2 Despite significant advances in TAVI technology (eg, device profile, maneuverability, sealing skirt, etc), two known procedure-related issues still deserve rightful attention: the occurrence of significant paravalvular leakage (PVL); and acquired conduction abnormalities requiring permanent pacemaker implantation (PPI).^3,4 The incidence of these complications is known to be related to both patient-specific and procedure-related factors (eg, prosthesis over-sizing, depth of valve implantation, and choice of the device).⁵ Left ventricular outflow tract (LVOT) calcification (CA) is a chronic degenerative process of the subvalvular aortic apparatus, with a prevalence of 30%-40% among patients with severe aortic stenosis.^6-8 Aortic valve complex calcification and LVOT-CA have been associated with higher rates of PVL after TAVI procedures with first-generation devices.⁹ Moderate or greater LVOT-CA has recently been associated with reduced survival after TAVI at mid-term follow-up.¹⁰ Furthermore, LVOT-CA has been reported as a predictor of PPI after TAVI with the new-generation Sapien 3 valve (Edwards Lifesciences).⁷ However, the impact of LVOT-CA on periprocedural outcomes after TAVI with new-generation devices remains poorly defined. The aim of our study was to evaluate the impact of LVOT-CA localization and extension on PPI after TAVI with current-generation TAVI devices. 

Methods 

Study population. Analyses were based on a retrospective, single-center, dedicated TAVI registry of 657 patients who underwent TAVI at San Raffaele Hospital in Milan, Italy, between January 2014 and June 2017. 

All patients with a native tricuspid aortic valve who underwent transfemoral TAVI with new-generation devices (the balloon-expandable Sapien 3; the mechanically expandable Lotus [Boston Scientific]; and the self-expandable Evolut R [Medtronic], Portico [Abbott Structural Heart], and Acurate neo [Boston Scientific]) were included in the study. 

Included patients had not undergone previous surgery involving the LVOT, aortic valve complex, ascending aorta (with the exception of coronary artery bypass graft surgery), or a previous TAVI. Data were prospectively recorded in our dedicated TAVI registry, but retrospectively analyzed. All subjects gave informed consent for data collection and analysis. Procedural outcomes were evaluated according to the Valve Academic Research Consortium (VARC)-2 consensus definition.¹¹

Multidetector computed tomography (MDCT) scan. All included subjects had undergone MDCT for procedural planning. All MDCT exams were performed using an electrocardiogram-gate, 64-slice CT system (LightSpeed VCT-XTE scanner; GE Healthcare). Images were acquired during the infusion of iodixanol 320 contrast agent, and retrospectively gated scans of the thorax and abdomen were performed. Images were analyzed with OsiriX DICOM software, with three-dimensional and multiplanar sections. Aortic annulus measurements were performed in systole (20% of the RR interval).¹² Aortic valve calcification (AVC) was classified and graded using a semiquantitative scoring system with a 4-degree scale, as previously described.¹³

Definitions. Aortic angulation was defined as previously described.¹⁴ Mitral annular calcification (MAC) was defined by presence of dense calcium deposits at the base of mitral leaflets between the left atrium and ventricle. Circumferential and vertical MAC extensions were classified and graded using a semiquantitative scoring system with a 4-degree scale, as previously described.¹⁵ Ascending aorta dilation was defined if the ascending aorta was >40 mm.¹⁶ Regions of the aortic valve complex were separated into aortic valve leaflet and LVOT regions corresponding to the overlying coronary cusps, as previously reported.⁶ Vertical LVOT-CA extension was defined as the maximal vertical length of the calcium nodule measured from the virtual basal ring to its maximal extension inside the LVOT (seen in a plane perpendicular to the plane identified by the virtual basal ring). Horizontal LVOT-CA protrusion was defined as the maximal thickness of the calcium nodule seen in a plane parallel to the plane identified by the virtual basal ring. Circumferential extension was defined as the percentage of the perimeter of LVOT cross-section covered by the calcium nodule. Each one of these three LVOT-CA parameters was graded as absent, non-severe, or severe. Severe calcification was defined as the presence of a calcific nodule with vertical extension >5 mm, horizontal protrusion >3 mm, and circumferential extension >10% (Figure 1). 

Statistical analysis.  Continuous variables are presented as mean ± standard deviation, and differences between groups were compared with the unpaired Student’s t-test. Categorical variables are presented as numbers and percentages and tested by the Chi-square test or Fisher’s exact test.  Binary logistic regression analysis using purposeful selection of covariates was performed to assess the predictors of PPI. Candidate variables included covariates associated at univariate analysis with PPI (all with a P-value <.10) as well as variables considered to be relevant according to the investigators’ judgment and previously published literature.  The results are reported as adjusted odds ratio (OR) with associated 95% confidence interval (CI). Goodness-of-fit of the logistic regression model was assessed with the Hosmer-Lemeshow statistic; discrimination of the logistic regression model was assessed with the C-statistic. All reported P-values were two-sided, and a P<.05 was considered statistically significant. All analyses were performed using SPSS software, version 20.0 (SPSS, Inc).

Results

During the study period, a total of 657 patients underwent TAVI at our institution. After exclusion of 280 patients (62 non-transfemoral access, 69 valve-in-valve or previous aortic interventions, 34 bicuspid aortic valves, 24 preoperative MDCT scans not acquired at our institution or not available for analysis, and 91 implanted with devices not fulfilling study criteria), a total of 377 patients were included in the final analysis. LVOT-CA was present in 133 patients (35.3%), while 244 patients (64.7%) had no LVOT-CA.

Baseline characteristics. The baseline clinical characteristics of included patients are shown in Table 1. The mean age of the study population was 81.5 ± 7.18 years, and 58.1% were women. There were no significant differences in multiple baseline variables between the non-LVOT-CA group and the LVOT-CA group. Patients with no LVOT-CA were more likely to have had a previous percutaneous coronary intervention or coronary artery bypass graft surgery, whereas LVOT-CA patients had severe aortic regurgitation at baseline more frequently than non-LVOT-CA patients. 

LVOT-CA description and anatomical characteristics. A descriptive analysis of LVOT-CA extension according to LVOT region involved is shown in Table 2. Anatomical characteristics as obtained by preprocedural MDCT are shown in Table 1. LVOT-CA patients had a higher prevalence of AVC grades 3-4 (66.2% vs 48.8% in non-LVOT-CA patients; P<.01), overall MAC (64.7% vs 43.4% in non-LVOT-CA patients; P<.001), and severe circumferential MAC (27.3% vs 14.3% in non-LVOT-CA patients; P<.01). 

Procedural outcomes. Procedural outcomes are shown in Table 3. Predilation was performed more frequently among patients with LVOT-CA (60.9% vs 48.9% in non-LVOT-CA patients; P=.02), whereas the rate of postdilation was only numerically higher in the LVOT-CA group (26.3% vs 19.3% in non-LVOT-CA patients; P=.11).

There were 3 periprocedural deaths, including 1 LVOT-CA patient who had aortic dissection after Lotus implantation, 1 LVOT-CA patient who had a major vascular complication, and 1 non-LVOT-CA patient who had cardiac tamponade just after temporary PM positioning (before TAVI implantation); the transcatheter procedure was aborted and he received emergent surgery with an unfavorable periprocedural outcome. 

LVOT-CA patients had a higher rate of new PPI after the procedure (32.0% vs 19.2% in non-LVOT-CA patients; P<.01). The device success rate was 88.5% in the overall population, and was significantly higher among patients with no LVOT-CA compared with those with LVOT-CA (90.5% vs 82.7%, respectively; P=.02). This difference was mainly driven by a numerically higher rate of significant PVLs in the LVOT-CA group.  

Predictors of PPI after TAVI. Of the 377 patients included in the study, a total of 21 had previous PPI before TAVI and were therefore excluded from the analysis. After TAVI, a total of 84 patients (23.6%) required PPI. Patients with new PPI were older, had slightly higher body mass index and STS score, and presented more frequently with LVOT-CA (47.6% vs 31.5% in patients without new PPI; P<.01) and ascending aorta dilation (Table 4). The incidence of new PPI varied significantly accordingly to the prosthesis implanted (15.4% in the Sapien 3 group, 23.3% in the Evolut R group, 35.1% in the Lotus group, 32.6% in the Portico group, and 7.1% in the Acurate neo group). 

LVOT-CA in the region of the non-coronary cusp (NCC) was more frequent among patients with new PPI (31.0% vs 15.2% in patients without new PPI; P<.01). On univariable analysis (Table 4), age, ascending aorta dilation, any LVOT-CA, LVOT-CA in the NCC region, severe LVOT-CA protrusion, mechanically expanded valve implantation (compared with balloon-expandable valves), preprocedural right bundle-branch block, and preprocedural first-degree atrioventricular block were predictors of new PPI after TAVI. Multivariable analysis demonstrated that LVOT-CA in the NCC region was independently associated with new PPI (adjusted OR, 2.45; 95% CI, 1.19-5.07; P=.02); other independent predictors of new PPI were age, body mass index, mechanically expanded valve implantation (compared with balloon-expandable valves), and preprocedural right bundle-branch block. The C-statistic for the propensity-score model was 0.76, indicating good discrimination of the multivariable model; the Hosmer-Lemeshow goodness-of-fit test P-value was .13, indicating good calibration of the multivariable model.

Discussion

The main findings of the present study are as follows: (1) the prevalence of LVOT-CA in a transfemoral TAVI cohort treated with current-generation devices was 35.3% and was more commonly distributed in the left coronary cusp and NCC; and (2) LVOT-CA in the NCC appears to be an independent predictor of new PPI after TAVI.

Maeno et al⁷ have previously shown LVOT-CA in the NCC together with preoperative right bundle-branch block to be the most important predictors of PPI after TAVI. Furthermore, right bundle-branch block has also been shown to be a predictor of late PPI after TAVI.¹⁷ However, only balloon-expandable prostheses were evaluated in this series. We found that LVOT-CA in the NCC and preoperative right bundle-branch block were the strongest independent predictors even in a larger population of patients (n = 356) who received five different prosthesis types (Sapien 3, Evolut R, Lotus, Portico, and Acurate neo). This finding suggests a strong correlation between LVOT-CA in the NCC and PPI, which is to some extent maintained even using different TAVI device types. This could be explained by the proximity of the NCC to the conductive system of the heart, particularly the atrioventricular node and the left bundle branch.

During valve deployment, the nodules of calcium interposed between the prosthesis and the LVOT wall are pushed against the interventricular septum and can cause damage to conductive fibers passing within it. What is still unclear is how the presence, entity, and localization of LVOT-CA should interact with the different types of prosthesis. 

Study limitations. The present study has several limitations. First, it was a single-center, retrospective study, and therefore has numerous caveats when interpreting results. Second, despite the apparently large number of patients included in the study and the diversity of devices used during the procedures, the number of cases for each device was not large enough to assess specific device-related outcomes. 

Conclusion

The present study reports a prevalence of LVOT-CA in 35.3% of patients undergoing transfemoral TAVI for severe aortic stenosis. Presence of LVOT-CA in the NCC was found to be an independent predictor for new PPI. Further studies are needed to confirm these data in a larger, multicenter population.

From the ¹Interventional Cardiology Unit, ²Echocardiography Unit, and ³Radiology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Montorfano reports proctor income from Edwards Lifesciences, Boston Scientific, and Abbott. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 31, 2019, final version accepted September 12, 2019.

Address for correspondence: Marco B. Ancona, MD, Interventional Cardiology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy. Email: ancona.marco@hsr.it

1. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-2198. 
2. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374:1609-1620. 
3. Jilaihawi H, Makkar RR. Prognostic impact of aortic regurgitation after transcatheter aortic valve implantation. EuroIntervention. 2012;8(Suppl Q):Q31-Q33. 
4. Généreux P, Head SJ, Hahn R, et al. Paravalvular leak after transcatheter aortic valve replacement: the new Achilles’ heel? A comprehensive review of the literature. J Am Coll Cardiol. 2013;61:1125-1136. 
5. Petronio AS, Giannini C, De Carlo M. Mechanisms and prediction of aortic regurgitation after TAVI. EuroIntervention. 2012;8(Suppl Q):Q18-Q20.
6. Maeno Y, Abramowitz Y, Jilaihawi H, et al. Optimal sizing for SAPIEN 3 transcatheter aortic valve replacement in patients with or without left ventricular outflow tract calcification. EuroIntervention. 2017;12:e2177-e2185. 
7. Maeno Y, Abramowitz Y, Kawamori H, et al. A highly predictive risk model for pacemaker implantation after TAVR. JACC Cardiovasc Imaging. 2017;10(10 Pt A):1139-1147. 
8. Maeno Y, Abramowitz Y, Kazuno Y, et al. Transcatheter aortic valve implantation with different valve designs for severe device landing zone calcification. Int Heart J. 2017;58:56-62. 
9. Seiffert M, Fujita B, Avanesov M, et al. Device landing zone calcification and its impact on residual regurgitation after transcatheter aortic valve implantation with different devices. Eur Heart J Cardiovasc Imaging. 2016;17:576-584. 
10. Maeno Y, Abramowitz Y, Yoon S-H, et al. Relationship between left ventricular outflow tract calcium and mortality following transcatheter aortic valve implantation. Am J Cardiol. 2017;120:2017-2024. 
11. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60:1438-1454. 
12. Schultz CJ, Moelker A, Piazza N, et al. Three dimensional evaluation of the aortic annulus using multislice computer tomography: are manufacturer’s guidelines for sizing for percutaneous aortic valve replacement helpful? Eur Heart J. 2010;31:849-856. 
13. John D, Buellesfeld L, Yuecel S, et al. Correlation of device landing zone calcification and acute procedural success in patients undergoing transcatheter aortic valve implantations with the self-expanding CoreValve prosthesis. JACC Cardiovasc Interv. 2010;3:233-243. 
14. Abramowitz Y, Maeno Y, Chakravarty T, et al. Aortic angulation attenuates procedural success following self-expandable but not balloon-expandable TAVR. JACC Cardiovasc Imaging. 2016;9:964-972. 
15. Ancona MB, Giannini F, Mangieri A, et al. Impact of mitral annular calcium on outcomes after transcatheter aortic valve implantation. Am J Cardiol. 2017;120:2233-2240. 
16. Ancona MB, Moroni F, Chieffo A, et al. Impact of ascending aorta dilation on mid-term outcome after transcatheter aortic valve implantation. J Invasive Cardiol. 2019;31:278-281. Epub 2019 Sep 15. 
17. Mangieri A, Lanzillo G, Bertoldi L, et al. Predictors of advanced conduction disturbances requiring a late (≥48 h) permanent pacemaker following transcatheter aortic valve replacement. JACC Cardiovasc Interv. 2018;11:1519-1526.