Transcatheter Aortic Valve Implantation With Balloon-Expandable Valve Prostheses in Patients With Pure Native Non- or Mildly Calcified Aortic Regurgitation: A Case-Series and Literature Review

Abstract

Objective. Transcatheter aortic valve implantation (TAVI) is an off-label procedure for selected patients at high surgical risk with native non- or mildly calcified aortic regurgitation (AR). Traditionally, self-expanding transcatheter heart valves (THV) have been favored over balloon-expandable THV’s probably due to assumed better device fixation. We report a series of patients with native severe AR successfully treated with a balloon-expandable THV. Methods. Between 2019 and 2022, 8 consecutive patients (5 male, 82 (interquartile range 80-85) years old, STS PROM 4.0% (interquartile range 2.9-6.0), EuroSCORE II 5.5% (IQR 4.1-7.0) with non- or mildly calcified pure AR were treated with a balloon-expandable THV. All procedures were performed after heart team discussion and standardized diagnostic workup. Clinical endpoints were collected prospectively and included device success, procedural complications (according to VARC-2 definitions) and 1-month survival. Results. Device success was 100% with no device embolization or migration. Two perprocedural nonfatal complications were reported (one access site complication that required stent implantation and one pericardial tamponade). Two patients required permanent pacemaker implantation for complete AV block. At discharge and at 30-day follow-up all patients were alive and no patient showed more than minimal AR. Conclusion. This series documents that treatment of native non- or mildly calcified AR with balloon-expandable THV is feasible, safe and offers favorable short-term clinical outcomes. Hence, TAVI with balloon-expandable THVs may offer a valuable treatment option in patients with native AR at high surgical risk.

J INVASIVE CARDIOL 2023;35(5):E254-E264.

Key words: aortic regurgitation, transcatheter aortic valve implantation, transcatheter aortic valve replacement, transcatheter heart valves, native non- or mildly calcified aortic regurgitation, balloon-expandable valve prostheses

Introduction

Severe native aortic valve regurgitation (AR) is a common valvular disease that can lead to deterioration of left ventricular (LV) function due to diastolic aortic blood backflow through the leaking valve into the left ventricle. This volume overload raises LV preload and afterload, increases ventricular wall stress, and results in poor prognosis if left untreated. Current guidelines recommend surgical valve replacement for severe AR as soon as it becomes symptomatic and/or if certain echocardiographic parameters are met. ¹ However, many patients with symptomatic severe native AR are denied surgery due to high surgical risk. Transcatheter aortic valve implantation (TAVI) might represent a valuable treatment alternative in such patients. The major concern of performing TAVI in native uncalcified valves in the setting of severe AR are anatomical considerations, including large aortic valve annuli (exceeding the size of currently available transcatheter heart valves [THVs]), difficulties in valve fixation and in precise device positioning due to high-flow situation with increased catheter movement and the lack of valvular calcification for secure THV fixation. Traditionally, self-expandable THVs have been preferred in pure AR probably due to the possibility of recapturing and repositioning, potentially resulting in a more predictable procedural outcome. However, balloon-expandable THVs have evolved considerably over the last two decades. Current, balloon-expandable THVs are associated with excellent procedural outcomes, very low rates of paravalvular regurgitation, and permanent pacemaker implantation (PPI) in aortic stenosis patients.^2-4  Nevertheless, in AR, THV fixation has been considered to be a major limitation and therefore, very few cases of TAVI with balloon-expandable THVs have been described. ^5-9 In the current manuscript, we report our single-center experience of TAVI with a balloon-expandable THV in consecutive patients with native AR at high surgical risk.

Methods

Study population and preprocedural evaluation. From 2019 until 2022, we included all consecutive patients who underwent TAVI for native AR with a balloon-expandable THV at our institution. The indication for TAVI and the choice of THV was discussed by an interdisciplinary heart valve team consisting of cardiologists, cardiovascular surgeons, and cardiac anesthesiologists on the basis of routinely performed pre-procedural diagnostics including imaging with an ECG-gated computed tomography angiography, transthoracic (and occasionally transesophageal) echocardiography, and coronary angiography with right heart catheterization. All patients were entered into a prospective national TAVI registry (Swiss TAVI registry, clinicaltrials.gov NCT01368250). The study protocol of the Swiss TAVI Registry was approved by the local cantonal ethics committee and all patients gave written informed consent prior to enrollment.

Procedural details of TAVI for AR. TAVI was performed in a hybrid operation room under general anesthesia and using intraprocedural transesophageal echocardiography fusion imaging technique (Figure 1). The technique allows the overlaying of 2D- and 3D-echocardiography on fluoroscopy and provides an ECG-gated 3D model of the heart as well. The model of the aortic valve is merged and superimposed on the fluoroscopic images, helping in defining the optimal fluoroscopic projection for the implantation as well as for the precise placement of the aortic prosthesis at the level of the annulus.¹⁰ In the absence of valve calcification (typically used as an anatomical landmark during TAVI in aortic valve stenosis), the model facilitates the correct positioning of the valve prosthesis within the annulus. The implantation itself does not differ much from the usual TAVI procedure for aortic stenosis, while the landing zone is typically high. In all patients, an Edwards SAPIEN-3 THV (Edwards LifeSciences) was used with at least 10% oversizing based on CT measurements to ensure adequate annular fixation. All procedures were performed under general anesthesia with periprocedural transesophageal echocardiography. Arterial access via the femoral artery using fluoroscopic-guided puncture and Seldinger technique was used for all cases. Rapid pacing was applied in all patients for stable and precise valve release. This was done over the left ventricular guidewire (Safari², Boston Scientific) in all patients in order to additionally prevent the implantation of a transvenous temporary pacemaker and its possible associated complications.

Data collection and study endpoints. The study protocol of the Swiss TAVI registry includes baseline clinical, laboratory, echocardiographic and CT data as well as procedural data and clinical follow-up at pre-specified time points (1, 3, 6 and 12 months and yearly thereafter). Referral cardiologists, general practitioners, and patients were contacted whenever necessary for further information. Clinical events are prospectively collected within the Swiss TAVI Registry and adjudicated by a dedicated clinical event committee according to the standardized criteria of the Valve Academic Research Consortium VARC-2 Criteria.¹¹ All data were anonymized and centrally collected.

The main study endpoints of this patients series were device success and mortality immediately after the procedure and at 30 days according to VARC-2 definitions. Additionally, periprocedural complications (bleeding, stroke, acute kidney injury, vascular access site complications, etc.) are reported according to the VARC-2 criteria. Functional capacity before and 30 days after the procedure was assessed with the New York Heart Association (NYHA) functional class. Systematic echocardiography assessment at baseline and one month after the procedure was available for 7 of 8 (87.5%) patients and allowed comparison of LV ejection fraction and volumes.

CT images analysis.  Data from CT angiography was analyzed using commercially available software (3mensio Medical Imaging). Aortic annular dimensions (diameter, perimeter, and area) were measured using electronic calipers and/or manually placed segmentation points with cubic spline interpolation as previously described.¹² Eccentricity index is a measure of the circularity of the aortic annulus using a simple formula derived from measurements on the double oblique projections: (1−minimal diameter/maximal diameter) — hence the closer the number is to 0, the more circular the annulus is. The perimeter and area oversizing indexes were defined as: (device nominal perimeter or area)/(annulus perimeter or area measured) x 100, respectively. Quantification of aortic valve calcification from contrast-enhanced CT was performed using a modified individual threshold technique as previously described by Eberhard et al.¹³ In brief, the average CT density of contrast in the aortic root and their standard deviation (SD) (at the level of the sino-tubular junction) was measured, and an individual threshold for calcification was set (in Hounsfield units): average aortic root density + 5*SD. The calcifications (all pixels with densities above the predefined threshold) were then semi-automatically segmented including aortic valve, aortic root, and annular calcifications ranging from the tip of the aortic valve cusps to 2 mm below the annulus (carefully excluding extensive subannular calcifications lower than 2 mm into the LV outflow tract). The volume of calcification is given in mm³.

Statistical analysis. Statistical analysis was performed using Microsoft Excel. Numerical data were given as median values with their respective interquartile range (IQR) unless otherwise stated. Categorical data was expressed as proportions or percentages.

Results

Baseline characteristics. All 8 consecutive patients (3 female, 5 male, aged 82.4 [IQR 80.0–85.2] years) had symptomatic moderate to severe or severe AR and were considered moderate- or high-risk for cardiac surgery after interdisciplinary discussion. The STS PROM was 4.0 % (IQR 2.9–6.0), the EuroSCORE II to 5.5 % (IQR 4.1–7.0). In three patients the implantation was planned electively whereby the other patients were admitted to hospital due to acute heart failure requiring urgent intervention. All patients had tricuspid aortic valves and AR due to either degenerative valve disease and/or concomitant aortic disease (ie, dilatation of aortic sinus). Further details on the etiology are shown in Figure 2. The remainder of clinical baseline characteristics is given in Table 1.

CT image analysis. Details of CT image analysis are given for every individual patient in Table 2. As expected for AR, aortic annuli tended to be large (median diameter 26.4 mm) with considerable eccentricity (eccentricity index ranging from 0.15 to 0.38) and only minimal or mild calcifications. Median calculated volume of calcification was 20.5 mm³ (IQR 5.5–67.3) and in 5 of 8 (63%) patients the amount of calcifications was clinically negligible (<25 mm³). An example of non-calcified aortic valve apparatus with significant eccentricity is shown in Figure 3. The median perimeter oversizing index was 7.5% (IQR 3.0 – 11.0) and the median area oversizing indexes was 21.4% (IQR 15.0–28.3).

Periprocedural data and procedural outcome. Implantation was successful in all patients.  Implanted THVs were Edwards SAPIEN-3 29 mm in 6 (75%) patients, SAPIEN-3 Ultra 26 mm in 1 (12.5%), and SAPIEN-3 Ultra 23 mm in 1 (12.5%) patient. No pre- or post-dilatation was performed. Periprocedural echocardiography showed device success in all patients. Time of radiation exposure was 10 minute 40 seconds (IQR 6 minute 30 seconds – 13 minute 50 seconds) with a dose-area product of 487 cGyxcm² (IQR 327.5-857.5) and 70ml (IQR 57.5–82) of Ultravist-370 contrast agent (Bayer) was used. No procedure-related death, device embolization, coronary obstruction, aortic root injury or conversion to conventional surgery were reported. One patient had an access site complication requiring implantation of a covered stent due to laceration of the common femoral artery. One patient developed pericardial tamponade at day 1 requiring pericardiocentesis and substitution of 2 erythrocyte concentrates. After exclusion of other possible causes by means of transesophageal echocardiography and CT angiography, the etiology was thought to be inadvertent left ventricular wire perforation. Two patients developed a third-degree atrioventricular (AV) block requiring PPI. One patient fell, leading to a fractured humerus that required surgery. Three patients needed a red blood cell transfusion. Acute kidney injury occurred in one patient without the need of continuous renal replacement therapy. Length of stay on intensive and/or intermediate care unit and length of hospital stay were 5.0 days (IQR 2.8–7.0) and 11.5 days (IQR 8.75–27.0), respectively.

Clinical follow-up. At 30 days, all-cause mortality was 0% and device success was 100%. Early safety at 30 days was 87.5% (7/8, due to the one case of pericardial hematoma mentioned above). Echocardiographic follow-up is described in Table 3. Functional capacity at 30 days measured by NYHA class was ≤ II in all but one patient. One patient died 4 months after the index procedure due to an urosepsis. In this patient no routine follow-up at 30 days had been performed. Echocardiographic and clinical follow-up is provided for two patients at 12-month of follow-up and for two patients at 6-months of follow-up where device success was still 100%. One other patient had cardiac resynchronization therapy defibrillator implantation for heart failure, and later on developed pacemaker endocarditis that was successfully treated with antibiotics.

Discussion

AR is a common valvular disease that can lead to deterioration of cardiac function due to backflow of blood from the aorta into the left ventricle during diastole. In contrast to aortic stenosis, AR is characterized by chronic volume overload leading to chamber enlargement and eccentric hypertrophy associated with left ventricular cavity structural modifications and progressive left-ventricular dysfunction. When myocardial dysfunction becomes irreversible, recovery after correction is challenging. Likely because of irreversible left ventricular remodeling such as increased interstitial fibrosis and fiber hypertrophy. ¹⁴ The 2021 European Society of Cardiology valvular guidelines recommend treatment of severe AR as soon as it becomes symptomatic or if echocardiographic signs of left ventricular deterioration are detected. Furthermore they state that TAVI may be considered in experienced centers for selected patients that are ineligible for surgical aortic valve replacement (SAVR).¹ A number of studies confirm that undertreatment of patients with symptomatic severe AR is prevalent: The EURO Observational VHD II survey showed that of 279 patients with severe AR, which met indication for valve replacement, only 33% received treatment. ¹⁵ Thourani et al demonstrated that surgical aortic valve replacement (SAVR) saves lives in patients with severe AR irrespective of left ventricular function, and that untreated patients have high 1-year mortality rates (24% vs 9% in the SAVR-group), which translated into a 2.7-fold increased risk of mortality in patients who failed to undergo surgery. They highlighted that only 25.7% of patients with symptomatic severe AR received SAVR within 1 year of diagnosis.¹⁶ These data suggest that there is an unmet clinical need for treatment, which could be addressed by transcatheter valve replacement.

The currently available THVs are designed for the treatment of calcified stenosis, relying on the fixation within an extensively calcified aortic valve annulus and cusps. In contrast in native AR, where disease often extends to structures other than the aortic valve alone and often calcification is rare, TAVI is not a common procedure. Presently, the only THV with CE approval for pure AR is the JenaValve. Overall, most TAVI cases of pure AR performed used self-expandable THVs. We are reporting our single center experience in consecutive patients with severe AR in native non or mildly-calcified valves treated with balloon-expandable Edwards Sapien-3 prosthesis. This is, to our knowledge, the largest case-series of patients with non or mildly calcified AR treated with the Edwards Sapien-3 valve. Upon adequate patient selection and consideration of the anatomical aspects of the annulus, good clinical outcome can be achieved. Even though implantation can be technically difficult due to missing anatomical landmarks, TAVI for pure AR is feasible with favorable clinical outcome in high-risk patients deemed inoperable. The use of fusion echocardiographic imaging technique, allowing the overlaying of 2D and 3D echocardiography on fluoroscopy in real time and providing an ECG-gated 3D model of the aortic valve may potentially help in defining the optimal position for device implantation in absence of calcium. This is reflected in the relative small amount of contrast agent used in this collective of patients. In our limited series, successful implantation was achieved in all patients with no device embolization or migration. Complications appear not to differ from the ones typically seen in percutaneous treatment of severe AS using the same device and includes vascular access complication as well as the need of pacemaker implantation due to high-degree AV block.

Challenges for successful THV positioning and deployment in pure AR are the lack of calcifications of aortic annulus and cusps for the anchoring of the prosthesis, absence of fluoroscopic calcific landmarks, increased stroke volume, high back-and-forth flow status through the valve, aortic root dilatations, and annular eccentricity. Migration into the left ventricle or embolization into the aorta can occur up to several hours after implantation.¹⁷

Balloon-expandable or self-expandable valve? TAVI for non-calcified AR is being performed more and more frequently in many centers around the world.^18,5,19 If one refers to the literature, by far more self-expandable valves have been used, probably due to the possibility of recapturing and repositioning of the valve that gives it a more predictable behavior. Whether the different fixation mechanisms, for example, the continuous radial forces of self-expandable valves have a decisive benefit in these patients can only be speculated. To date, with the available published data in a very heterogenous patient collective and the lack of comparative studies, it cannot be conclusively said which heart valve is best suited for which anatomy. This is why we believe that a discussion of every case in a heart team is of great importance to find the best option for each individual patient.    

Reports of the use of balloon-expandable valves for AR are scarce, although there is no evidence that these perform worse in regard to procedural success and outcome.  One of the largest meta-analysis of patients who received TAVI for the treatment of AR by Takagi et al⁵ included a total of 911 patients from 11 studies where an overall device success of 80.4% was reported. Compared to TAVI in aortic stenosis, the number of complications was relatively high (conversion to open surgery in 3%, reintervention in 3.9%, and 30-day all-cause mortality of 9.5%). An Edwards Sapien-3 THV was implanted in only 54 of the 911 cases and another large meta-analysis by Abdulla Haddad et al, that included 638 patients from 12 studies, did not report any further cases.¹⁸ The largest and most detailed data on the implantation of the Edwards Sapien-3 THV were published in the multicenter registry study by Yoon et al. ⁷ They included 41 cases and further reported procedural outcomes according to the device type (CoreValve [n = 110], Evolut R [n = 50], JenaValve [n= 64], Direct Flow [n = 35] and Sapien-3 [n = 41]). Numerically, the Edwards Sapien-3 THV had the highest rate of device success at 85.4%, the lowest rate of post-procedural aortic regurgitation (0%), the lowest all-cause mortality at 30 days (4.9%), the lowest stroke rate (0%), the lowest bleeding rate (0%) and the second lowest rate of second valve implantation at 12.2% (9.4% in the JenaValve group).  Further case reports and case series on the successful implantation of the Edwards Sapien-3 THV in no or mildly calcified AR as well as complications such as device embolization have been reported. ^6,8,9,20 Even a successful implantation of a Edwards Sapien-3 THV for the treatment of a severe AR in a patient with a left ventricular assist device has been described.²¹

In conclusion, previous publications on the implantation of the Edwards Sapien-3 THV show an outcome that is comparable to the one of SEV. Our experience does confirm this finding. Furthermore, parameters that are associated with worse outcomes have been identified: Yoon et al showed that none or mild aortic valve calcification was associated with less frequent device success for all valves. Also, a larger annulus (>25.2 mm) was associated for all valve types with less frequent device success (70.2% vs 86%) and led to higher rates of second valve implantation (21.2% vs 8.4%) and more post procedural AR of ≥ moderate (8.7% vs 2.8%). When post interventional AR was ≥ moderate, patients had higher rates of all-cause death at 1 year and higher rates of re hospitalization on follow-up.⁷ Due to the lack of annular calcification, oversizing of 10%-20% has been recommended for successful valve implantation to facilitate anchoring. Yoon et al reported that device oversizing (≥ 15%) was associated with a reduction in post procedural AR rates when using SEV. De Backer et al found significant increase on the incidence of device embolization with relative THV under- or oversizing when compared with neutral sizing without finding any causal explanation for this phenomenon.⁸ To evaluate the optimal sizing, further studies are required. Specifically, for the Edwards Sapien-3 THV, Yoon et al reported an oversizing index of 13.6 ± 13.9%, and also Urena et al reported for its 3 cases oversizing ratios of 27%, 23%, and 16%.⁶

Limitations. The small sample size is a limitation of our study. The patients differed considerably in their characteristics, making generalization difficult. Of course, there is no comparison to surgical therapy in these patients, which would not be feasible due to the above-mentioned characteristics. Nevertheless, implantation of balloon-expandable valve in non-calcified aortic regurgitation is a rare procedure that is likely to increase in the future and the limited number of patients undergoing this procedure represent real-world practice.

Conclusions

The present case series documents feasibility, safety, and short-term effectiveness of a balloon-expandable THV (Edwards SAPIEN-3) for the treatment of non- or mildly calcified AR in patients at high surgical risk. With device success of 100%, no embolization or migration, and excellent device function with no relevant paravalvular leak or recurrent regurgitation at short-term follow-up, valve-specific outcome was excellent. Our results were comparable with previous studies, especially with respect to procedural results with self-expandable valves. The key for a successful procedure appears to be sufficient oversizing of the valve after detailed anatomical screening and use of modern imaging techniques, such as fusion imaging in our cases, has the potential to improve procedural success rate. Future trials with more dedicated valves (JenaValve Trilogy with mechanism to clip onto native leaflets forming a natural seal) are ongoing such as the JenaValve ALIGN-AR Pivotal Trial. Initial results from successful implantation are promising. Nevertheless, it will take time until these valves can be used everywhere; until then current valves, including balloon-expandable ones, are a feasible alternative.

Affiliations and Disclosures

From ¹Heart Clinic Hirslanden Zurich, Zurich, Switzerland; and ²Inselspital, Bern University Hospital, Bern, Switzerland.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Wenaweser reports consulting/proctoring for Edwards Lifesciences and Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted March 16, 2023.

Address for correspondence: Luca Oechslin, Heart Clinic Zurich, Witellikerstrasse 40, Zurich, Zurich 8032 Switzerland. Email: luca.oechslin@hirslanden.ch

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