Abstract

Today, it is almost 22 years since the first transcatheter aortic valve implant (TAVI) and 11 years since the first transcatheter mitral valve implantation (TMVI) was implanted. TMVI never escalated like TAVI. So far, only one transcatheter mitral valve (TMV) has Conformité Européenne approval and none has Food and Drug Administration approval. This means that no TMV is commercial in the United States. There are several TMVs in clinical studies, but because of anatomical limitations, inclusion is slow. This editorial focuses on the challenges and opportunities in TMVI.

Introduction

The mortality rate for untreated severe mitral regurgitation (MR) is up to 50% at a 5-year duration⁽¹⁾, and the incidence in the Western world of such patients is 1-2%, with a prevalence of 10% for patients >75 years⁽²⁾.

Today, it is almost 22 years since A. Cribier performed the “first-in-man” (FIM) transcatheter aortic valve implant (TAVI) procedure April 16, 2002⁽³⁾ and 20 years since “FIM” Mitraclip (Abbott Vascular, Abbott park, IL, United States) was performed in Venezuela 2003 by Dr. Condado and his team (Abbott home page) and received the Conformité Européenne (CE) mark 2008. Almost 10 years later, in 2012, the first transcatheter mitral valve implantation (TMVI) was performed by Søndergaard et al.⁽⁴⁾ using the CardiAQ valve (Edwards Lifesciences, Irvine, United States). TMVI never escalated like TAVI.

Over the last decade, it has become clear that treating the mitral valve represents a much more complex endeavor than TAVI, given the complex saddle-shaped and noncalcified mitral annulus and potential interactions with the left ventricular outflow tract (LVOT). MR is a heterogeneous disease. Repair is generally the preferred surgical treatment option although it is highly dependent on the experience of the center. The question is whether the same strategy should be used for catheter treatment. Additional pathologies are common in patients with mitral valve disease, such as aortic stenosis, tricuspid regurgitation, left ventricular dyssynchrony, atrial fibrillation, and heart failure. These must be addressed, in addition to replacement or repair, most often before the mitral procedure, with the exception of tricuspid regurgitation. The durability of bioprosthesis in the mitral position is questionable.

Several TMVI systems are in clinical studies for human implants with different properties and designs. Only one system has CE approval, the Tendyne™ valve from Abbott⁽⁵⁾, and none has Food and Drug Administration approval, which means that there is no commercially available transcatheter mitral valve (TMV) in the US.

For current issues with TMVI, please see Figure 1 for a summary.

To date, TMVI has largely been reserved for patients who are poor candidates for surgery and for whom transcatheter mitral valve repair is unlikely to provide durable MR reduction. The first clinical consideration is whether the patient can tolerate a transapical intervention and how the patient functions in daily life. To decide between replacement or repair, anatomical suitability and patient frailty should be considered. A frail patient may benefit from the less invasive method even though the result may not be perfect. For patients with restricted leaflets, small annuli, and/or many clefts, replacement may provide the best result.

Patients with HF should receive optimal HF treatment before the procedure, including cardiac rhythm management devices such as implantable cardioverter defibrillatorand cardiac resynchronization therapy, if indicated. Other comorbidities to consider are right heart failure, tricuspid regurgitation, aortic stenosis or regurgitation, coronary artery disease, chronic obstructive pulmonary disease, and the ability to tolerate oral anticoagulation.

⦁ Prosthesis sizing, see below regarding the challenges in sizing.

⦁ Calcium in the annulus, mitral annular calcification (MAC), evaluation⁽⁶⁾.

⦁ Evaluation of neo LVOT (aorto-mitral angle, septal bulge, anterior leaflet)⁽⁷⁾.

⦁ Thickness of the myocardium and papillary muscle anatomy.

⦁ Implantation angles for the best coaxiality.

⦁ Chest access.

Several computed tomography (CT) softwares can be used for CT reconstruction: 3Mensio (Pie Medical Imaging, Maastrict, Netherland), Materialize (Loeven, Belgium), and circle CVI (Cadiovascular Imaging Inc., Calgary, Canada). In some cases, CT scan is used for 3D printing. It is of great importance that the CT scan is performed for the entire heart cyclus, is electrocardiography gated, and with thin slices. Multislice CT derived mitral intercommisural dimension and left ventricular endsystolic diameter are easily performed measures that are effective predictors of anatomical suitability or screen failure for TMVI devices⁽⁸⁾.

Figure 2 summarizes preprocedural planning.

For noncalcified MR, prosthesis sizing and annular support are crucial. Most valves are in 2-3 sizes and are circular. The Tendyne™ valve is produced in 13 different sizes with a standard profile and low profile frame. It is also oval like the mitral annulus. All prostheses must be somewhat oversized to sit in place and avoid paravalvular leakage (PVL). One must take into account that for the circular prostheses, the transmission of the mitral annulus from an oval shape to a circular shape will change the area.

For patients with MAC, the annulus may be too small for the mitral prosthesis.

LVOT is the anatomical region of the left ventricle between the anterior mitral leaflet and the left ventricular septum where blood flows before reaching the aorta through the aortic valve. With the large prosthesis sizes of most TMVI systems, in addition to being anatomically close to the LVOT, LVOT obstruction is a large design hurdle to overcome. To avoid LVOT obstruction, many factors need to be considered:

⦁ Protrusion of the TMVI into the left ventricle.

⦁ Flaring of the prosthesis created by the anchoring method may extend to the LVOT.

⦁ The angle between the aortic and mitral planes, the aortomitral annular angle, determines the protrusion of the prosthesis into the LVOT and may affect blood flow dynamics.

⦁ Septal bulging can create narrowing of the LVOT in systole.

⦁ Length of the anterior leaflet and potential for obstruction due to systolic anterior motion (SAM). CT reconstruction is performed to calculate the new LVOT area after valve implantation, and an area of 200-250 mm² is recommended as a cut-off⁽⁹⁾. To reduce the septal bulge, it is possible to perform septal ablation, preferably in advance⁽¹⁰⁾.

Several techniques have been developed to cut the anterior leaflet to avoid LVOT obstruction by a long leaflet:

⦁ Lampoon procedure⁽¹¹⁾.

⦁ Direct by endoscopic scissors.

⦁ Shortcut device (Pi Cardia)⁽¹²⁾.

⦁ Placing neochord.

For transapical TMVI, the Shortcut device or just cutting with endoscopic scissors seems to be less complicated.

The TMVI prosthesis frame must be able to be crimped down and conform to a low-profile delivery system, and on expanding from the delivery system, the frame “remembers” its shape before crimping. The valve must withstand the dynamic pressure and flow conditions prevailing within the left ventricle during systole and diastole. The design must additionally have an anchoring system that maintains the valve in place throughout these dynamic conditions after final placement.

Minimizing outflow tract obstruction and allowing for the maximum amount of blood flow through the LVOT is vital for the patient’s heart function.

Proper blood flow washout to avoid flow stagnation is important to prevent thrombosis, especially for mitral prostheses that are larger, resulting in more synthetic material implanted, and partially reside in the atrium with low flow velocities. Proper conformation with optimal sealing prevents PVL and resultant turbulent flow, which can cause thrombus formation or hemolysis. Close matching of the natural shape of the mitral annulus can improve valve performance and reduce PVL. A design that allows the valve to be fully positionable and retrieved during the initial implant procedure allows for optimal valve placement and can mitigate outflow tract obstruction.

Many transcatheter mitral prostheses have an outer (for anchoring) and an inner (housing the valve) frame.

The mitral annulus is D-shaped, and during regurgitation, there is little calcium for support. Fixation of the prosthesis may therefore be challenging. Before tissue ingrowth, the prosthesis may dislocate or migrate because of high pressure during the systolic phase when the valve is closed. The prosthesis generally needs to be seated within noncalcified tissue that is both dynamic and D-shaped in one plane and saddle shaped in three dimensions. In some cases, MAC is present and presents distinct challenges due to the heterogeneous mechanical properties and geometry of the annulus. In addition, it may be narrow, and large noncompliant balloons are not available for predilatation.The anchoring systems used by current TMVI systems include the following:

⦁ A tether and epicardial pad to achieve coordination axial forces, Tendyne™ valve (Abbott)⁽¹³⁾.

⦁ Atrial and ventricular flanges to grasp the mitral annulus and leaflets, CardiAQ⁽⁴⁾.

⦁ Native leaflet grasping to fixate the prosthesis in place of the Tiara valve⁽¹⁴⁾.

⦁ Docking systems to allow sufficient radial forces to anchor the valve, High life (Highlife Medical, Irvine, California)⁽¹⁴⁾ and Sapien M3 (Edwards Lifesciences, Irvine, California)⁽¹⁵⁾.

⦁ Subannular hooks that pierce the native mitral valve tissue/annular winglets, NaviGate (NaviGate Cardiac structures, Lake Forest, California)⁽¹⁴⁾.

⦁ Cork-like effects that produce radial forces to aid the anchoring of the prosthesis, Intrepid valve (Medtroic)⁽¹⁴⁾.

⦁ Atrial cage that uses the full anatomy of the left atrium to prevent valve migration, AltaValve, (4C Medical, Marple Grove, Minneapolis, Minnesota)⁽¹⁶⁾.

The design of the delivery systems depends on the access route. Till now, apical delivery has been used. The valves are large and difficult to fit in small sheets. The apical systems range from 32 to 36 Fr. To deliver transfemoral, transseptal sheats have to be in smaller dimensions.

The approved indications or clinical study eligibility criteria must be met for treatment with TMVI. Normally, these criteria include an ejection fraction >30% and left ventricular diastolic diameter <7.0 cm. The regurgitation should be more than 2+, and the patient should be symptomatic to motivate treatment. The advantage of TMVI is that both primary and secondary MR etiologies, including MAC, can be treated.

Echocardiographic evaluation of the severity of MR, length of anterior leaflet, and presence of SAM, resulting in hemodynamic challenges, should be reviewed when selecting patients for TMVI. The function of the non-mitral valves, heart rhythm, and ejection fraction also need to be addressed.

After the first TMVI was performed, several devices were constructed and put into studies. Some devices are mentioned in the section for anchoring, but only one, the Tendyne™ valve, is commercial. Ongoing studies:

1. Tendyne™ EFS trial is published with 2-year follow-up⁽¹⁷⁾ and the resolve MR includes the first patients after commercialization. The Summit trial is also going on in the US comparing Tendyne and MitraClip and has a specific arm for MAC (NCT04940390).

2. Evoque, the first human transseptal replacement, was first described by Webb et al.⁽¹⁸⁾ in 2020 for a series of 14 patients with technical success in 13 of the patients and 7.1% 30-day mortality. Further investigation has to be done, and now it seems like Edwards Lifesciences will further develop this valve for tricuspid implantation in the Triscend II Pivotal trial (NCT04482062)⁽¹⁹⁾.

3. The Encircle trial for the Sapien M3 from Edwards Lifesciences has started both in Europe and the US and plans to include 300 patients (NCT04153292), so far no publication but presented at TCT 2022 by D Daniels.

4. The first Apollo trial was performed transapically to investigate the Intrepid valve (NCT03242642). Later, the Apollo expansion trial started in the US and the Apollo EU trial just started enrolling for transfemoral access, and tricuspid implantation has also been investigated⁽²⁰⁾.

5. The Cephea EFS study is enrolling in the US and Canada introducing the Gen II valve, presented in TVT 2023 J F Granada.

MAC is a high risk of surgery, both for annular rupture and paravalvular leak. Some case reports and small studies have shown that TMVI may be beneficial in such situations⁽²¹⁾ and that dedicated transcatheter mitral valve replacement therapy may have a future role in these anatomically challenging high-risk patients. There is a specific CT-based MAC score to predict the severity of MAC; the range is from 1 to 10, summarizing the scores for calcium thickness, calcium distribution, trigone involvement, and leaflet involvement. A score of 7 or more indicates severe MAC⁽⁶⁾ (Figure 3). In the Summit and Apollo trials, there are specific arms for MAC patients, and the results will be published.

For surgical mitral valve replacement, a previous AVR or TAVI may cause difficulties. A series of 11 patients reported TMVI implanted in patients with pre-existing aortic valve replacement. The procedures were performed without complications and did not alter the function of either prosthesis⁽²²⁾, as shown in Figure 4.

Because of the large amount of foreign material and risk of blood stagnation and thrombus formation, anticoagulation after TMVI is recommended for at least 3-6 months, but may be lifelong⁽²³⁾.

With regard to surgical mitral valves, the durability of biological valves is an issue. Thus far, it is difficult to perform any valve-in-valve for degenerated TMVIs. Therefore, the expected lifetime of the patient must be considered before TMVI.

Optimizing heart failure treatment before the procedure is essential. Perioperative dialog between anesthetic and surgical teams is crucial. The patients should be observed in the surgical cardiac intensive care unit first 12-24 hours. Schwann-Ganz monitoring may be useful, particularly in patients with pulmonary hypertension and/or right heart failure. Inotrope support may be better than fluid to maintain acceptable mean arterial pressure. It is important to differentiate between a pure MR patient and a MAC patient regarding strategy⁽²³⁾.

To date, there are no publications on TMVI to postpone or bridge to transplant. MitraClip treatment may optimize patient condition and/or postpone heart transplantation. The MitraBridge registry concludes that MitraClip treatment optimizes patient status and provides eligibility for heart transplantation in one-third of patients and no more need for transplantation in 22.5%⁽²⁴⁾. In our center, we postponed heart transplantation in one patient for 8 years and in another 7 months by implanting Tendyne™.