Annuloplasty

Transcatheter ring implantation technologies can be divided into direct and indirect annuloplasty, depending on the type of interaction with the native annulus11Colli A, Fiocco A, Nadali M, Besola L, Pradegan N, Folino G et al. Transcatheter mitral valve therapies for degenerative and functional mitral regurgitation. 2020. In Emerging Technologies for Heart Diseases (pp. 417-461).. Academic Press.. Indirect annuloplasty devices are typically implanted into the coronary sinus and potentially are simpler for deployment, but can perform a lower grade of reduction in terms of native annular dimensions, compared to direct annuloplasty. Direct approaches can mimic a surgical annuloplasty in a more effective fashion, thus allowing for better annular stabilization and leaflet coaptation restoring.
Currently, clinical experience on transapical technologies is very limited, being Valcare Amend the only successfully implanted device in humans9.

Valcare Amend

The AMEND (Valcare Medical, Herzliya Pituach, Israel) is a transcatheter-implanting solution for direct mitral annuloplasty (Figure 1). The device is intended to deliver a complete semirigid D-shaped ring to the LA, to anchor it to the annulus and stabilize it, resulting in reduced antero-posterior dimensions and improved leaflet coaptation. Three ring sizes are available (34, 40 and 46 mm), allowing to treat a wide range of patients, by fitting a diseased annulus ranging from 29 to 50 mm. Currently the Company developed both transapical and transseptal delivery options, through a 24F and 28F catheter, respectively.22Mangieri A, Laricchia A, Giannini F, Gallo F, Kargoli F, Ladanyi A et al … & Latib, A. Emerging Technologies for Percutaneous Mitral Valve Repair. Frontiers in Cardiovascular Medicine. 2019; 6.
The first-in-human successful implantation was performed and described in 2016 by our Group 33Gerosa G, Besola L, Manzan E et al. First-in-Human of Catheter-Delivered Annuloplasty Ring to Treat Functional Mitral Regurgitation. JACC Cardiovasc Interv. 2016 Nov 14;9(21):e211-e213.. Transapical implantation is performed in a hybrid operating room, under general anesthesia, using a conventional left anterior mini-thoracotomy. The entire procedure is guided by transesophageal echocardiography (2D and 3D TEE) and fluoroscopy. After introduction into the LV, the 28-F AMEND system is navigated over a wire through the mitral valve into the LA. Once unsheated, the ring adoptes its closed D shape and can be appropriately oriented by the use of multiple adjustment tools of the delivery system. Once the desired position is confirmed by fluoroscopic guidance, a two-step anchoring procedure is performed. First, multiple anchors are deployed on the posterior segment of the ring, allowing for a secure fixation of the device to the posterior annulus. During the second step, the sheath is steered anteriorly toward the aortomitral continuity and once good contact is achieved, the anterior anchors are deployed, resulting in both complete fixation and antero-posterior diameter reduction. The device is finally released and the delivery system is retracted from the heart.
Current clinical experience includes a total of 14 implanted patients10. Eight of them were treated for FMR as a single annuloplasty therapy, while 2 patients were implanted to treat DMR as a single therapy. In 4 other patients, AMEND ring implantation was performed in a combination procedure, with MitraClip (3 patients) and NeoChord (1 patient), thus representing a solid foundation for stand-alone or combined repair, to improve both leaflet and chordal repair procedures10,44Meerkin D. The AMEND Mitral Repair System: Technology and Clinical Updates. Presentation CRT 2019. Chicago, IL 2019.. Post-procedural MR was ≤ 2+ in all performed implantations. In treated patients (n=14), 20% mean reduction of AP diameter was achieved, no residual pulmonary flow reversal in all cases was reported, mean reduction of the jet area was 74%10,12.
The AMENDTM trial (NCT02602613, Annuloplasty Ring Applied in a Transcatheter Method) is currently recruiting to evaluate the efficacy and safety of the device, with a target sample size of 40 patients10.

Chordal Repair

Transcatheter chordal repair technologies are primarily intended to treat DMR. Although the disease can involve multiple components of the MV apparatus, rupture of native chordae represents one of the leading mechanisms.
In the past decades, surgical practice introduced chordal replacement by polytetrafluorethylene (PTFE) sutures implantation55Zussa C, Frater RW, Polesel E, et al. Artificial mitral valve chordae: experimental and clinical experience. Ann Thorac Surg 1990;50:367-73., alone or together with the positioning of a ring, demonstrating excellent results in terms of long-term clinical outcomes. Further validation of the chordal therapy was later achieved, after the introduction of the “respect rather than resect” principle66Carpentier A. Cardiac valve surgery–the ”French correction”. J Thorac Cardiovasc Surg. 1983 Sep;86(3):323-37.,77Frater RW1, Vetter HO, Zussa C, Dahm M. Chordal replacement in mitral valve repair. Circulation. 1990 Nov;82(5 Suppl):IV125-30.,88Adams DH1, Rosenhek R, Falk V. Degenerative mitral valve regurgitation: best practice revolution.Eur Heart J. 2010 Aug;31(16):1958-66., becoming a mainstay in open heart MVRe techniques.
Several years later, the expanding field of Transcatheter Mitral Valve Repair (TMVRe) technologies has embraced the chordal repair philosophy.
Mostly by beating-heart transapical approach99Noack T, Borger MA. Chordal replacement: future surgical gold standard or first-line option as bridge to definitive therapy in primary mitral regurgitation? Ann Cardiothorac Surg 2020. doi: 10.21037/acs-2020-mv-22, this technique stresses the concept of micro-invasiveness and is currently the only one in clinical practice to allow a real-time heart-beating assessment of residual MR during the chordal tensioning phase, with a filled left ventricle through live three-dimensional intraoperative trasesophageal echocardiography . It has become a feasible, safe and reproducible option in selected patients with non-complex primary MR and can be potentially adopted in combined procedure, together with other-targeting transcatheter technologies, covering in that way the wide spectrum of MV lesions. In the scenario of transapical chordal repair systems, we focus on currently available devices in clinical practice: Neochord DS 1000 and Harpoon Mitral Valve Repair System (MVRS).

Neochord DS 1000:

The Neochord DS 1000 device (Neochord Inc, St. Louis Park, MN) is a transapical off-pump MVRe system based on expanded polytetrafluorethylene (ePTFE) chordal implantation. Currently more than 1,200 patients have been already treated with Neochord in the world1010Fiocco A, Nadali M, Speziali G, Colli A. Transcatheter mitral valve chordal repair: current indications and future perspectives. Front Cardiovasc Med. 2019;6:128. https://doi.org/10.3389/fcvm.2019.00128..
In December 2012, the results reported by the TACT Trial (Transapical Artificial Chordae Tendinae - NCT01777815) allowed this technology to gain CE mark approval1111Seeburger, J., Rinaldi, M., Nielsen, S. L., Salizzoni, S., Lange, R., Schoenburg, M., … & Aidietis, A. (2014). Off-pump transapical implantation of artificial neo-chordae to correct mitral regurgitation: the TACT Trial (Transapical Artificial Chordae Tendinae) proof of concept. Journal of the American College of Cardiology, 63(9), 914-919. 1212https://www.clinicaltrials.gov/ct2/show/NCT01777815, being the first transcatheter chordal repair device available on the market. In the US it received the investigational device exemption (IDE) approval from the United States Food and Drug Administration (FDA), and early clinical experience has been recently reported in Asian countries, mainly represented by China.1313Wang, L. H., Pu, Z. X., Kong, M. J., Jiang, J. B., Ren, K. D., Gao, F., … & Liu, X. B. (2019). The first four cases of successful NeoChord procedure in mainland China. World journal of emergency medicine, 10(3), 133. Preoperative anatomic and echocardiographic selection criteria as well as progressive technique refinement, contributed to create a solid procedural framework, thus the procedure evolved into a reproducible and safe technique, with good results in selected patients.
The procedure is performed, under general anesthesia, selective lung intubation and real-time 2D/3D TEE guidance. Through an antero-lateral left mini-thoracotomy in the fifth-intercostal space, the pericardium is opened and suspended, and the left lung is selectively excluded, exposing the left ventricle (LV) apex. The ideal entry side is identified about 2 cm–4 cm postero-lateral from the real apex 1414Colli, A., Bizzotto, E., Manzan, E., Besola, L., Pradegan, N., Bellu, R., … & Gerosa, G. (2017). Patient-specific ventricular access site selection for the NeoChord mitral valve repair procedure. The Annals of Thoracic Surgery, 104(2), e199-e202.and confirmed with a gentle digital palpation under 2D-TEE imaging. Two pledgeted round purse-string are sutured around the identified entry-site which is then scalpeled with an 11 inch blade, performing a trans-wall ventriculotomy. The device is first gently introduced inside the LV and then carefully navigated trough the LV avoiding papillary muscles damage and interference with subvalvular apparatus of anterior mitral leaflet (AML). Ventricular navigation is real-time guided through TEE X-plane view. Once the valve is crossed, a 3D imaging assessment allows for a precise positioning of the tip on the targeted scallop which is grasped by closing the jaws of the device. A fiberoptic display gives a feedback on the secured leaflet capture, before grasping. The grasped leaflet is then pierced at its edge, allowing for the deployment of a single pair of chords (Figure 2). The device is subsequently opened and gently retrieved from the ventricle, leading outside the chordal loop. The two ends of the suture are then passed in the loop, forming a girth hitch knot that is advanced till the free edge of the scallop. The procedure is repeated for each pair of chords deployed. Finally under 2D and 3D TEE control, the chords are tensioned, until adequate leaflet coaptation is achieved and all the chordal free ends are then secured to the LV wall 1515Colli, A., Adams, D., Fiocco, A., Pradegan, N., Longinotti, L., Nadali, M., … & Gerosa, G. (2018). Transapical NeoChord mitral valve repair. Annals of cardiothoracic surgery, 7(6), 812. on a Teflon felt.
The learning curve needed to perform optimally NC procedure, combining procedure standardization, technical refinements and adequate patient-selection, has been analyzed in a single center study.1616Colli A, Bagozzi L, Banchelli F, Besola L, Bizzotto E, Pradegan N, et al. Learning curve analysis of transapical NeoChord mitral valve repair. Eur J Cardiothorac Surg. (2018) 54:273–80. doi: 10.1093/ejcts/ezy046 In the CUSUM analysis performed by Colli et.al, the procedure demonstrates to be safe and effective. Threshold, beyond which the number of deaths or ineffective procedures would be unacceptable, was never reached, showing a good surgical performance even at the beginning of the experience. The study estimates a need for 50 cases per surgeon to standardize the technique and reach the “good performance period”. The Authors underline that most of the early failures were linked to technical errors during MV crossing phase, which were subsequently avoided with the improvement of the intraventricular navigation technique and adoption of different imaging views to cross the MV. To reduce the learning curve effect, acting on the technical refinement and procedure standardization, a dedicated preclinical training program was introduced, by the use of proctored highly realistic simulation on ex-vivo pulsatile models.1717Leopaldi AM, Wrobel K, Speziali G, van Tuijl S, Drasutiene A, Chitwood WR Jr. The dynamic cardiac biosimulator: a method for training physicians in beating-heart mitral valve repair procedures. J Thorac Cardiovasc Surg. (2018) 155:147–55. doi: 10.1016/j.jtcvs.2017.09.011
Concerning echocardiographic selection criteria, both the extension of prolapsing segments and the annular dimension demonstrated to have an impact in term of outcomes on Neochord repair procedure. The prolapse/flail anatomical aspects were classified based on growing complexity as “Type A” isolated central posterior leaflet prolapse/flail, “Type B” posterior multi-segment prolapse/flail, “Type C” anterior or bi-leaflet prolapse/flail, “Type D” para-commissural prolapse/flail or presence of significant leaflet/annular calcifications. Several studies underlined differences between these groups, reporting better results in terms of outcomes when posterior leaflet disease (A and B type) was treated, compared to more complex leaflet lesions (Type C-D). 1818Colli, A., Manzan, E., Rucinskas, K., Janusauskas, V., Zucchetta, F., Zakarkaitė, D., … & Gerosa, G. (2015). Acute safety and efficacy of the NeoChord procedure. Interactive cardiovascular and thoracic surgery, 20(5), 575-581 1919 Colli A, Manzan E, Besola L, et al. One-Year Outcomes After Transapical Echocardiography-Guided Mitral Valve Repair. Circulation 2018;138:843-5. 10.1161/CIRCULATIONAHA.118.033509  The leaflet-to-annulus index (LAI) was further introduced to improve the patient-selection process. LAI was calculated by the ratio between the sum of anterior and posterior leaflet length and the antero-posterior diameter. It represents the amount of overriding tissue that is potentially responsible of coaptation, considering annular dilatation in relation to the extension of the leaflets and not as an absolute concept. An excess of leaflet tissue of at least 20% (corresponding to LAI >1.2) has shown to be a positive predictor of MR ≤ mild at 1 year follow-up2020Colli A, Besola L, Montagner M, Azzolina D, Soriani N, Manzan E, et al. Prognostic impact of leaflet-to-annulus index in patients treated with transapical off-pump echo-guided mitral valve repair with NeoChord implantation. Int J Cardiol 2018;257:235–7.. Thus, LAI can be used to identify patients without leaflet-to-annulus mismatch, who could benefit from a ringless repair procedure such as Neochord.
Since its first in human application in 20102121Seeburger, J., Borger, M. A., Tschernich, H., Leontjev, S., Holzhey, D., Noack, T., … & Mohr, F. W. (2010). Transapical beating heart mitral valve repair. Circulation: Cardiovascular Interventions, 3(6), 611-612., the device demonstrated good outcomes in reducing mitral regurgitation along with safety feasibility in patients with DMR2222Rucinskas K, Janusauskas V, Zakarkaite D, et al. Off-pump transapical implantation of artificial chordae to correct mitral regurgitation: early results of a single-center experience. J Thorac Cardiovasc Surg 2014;147:95-9. 10.1016/j.jtcvs.2013.08.012. The TACT trial (Transapical Chordae Tendinae, NCT01777815) was the first prospective, multicenter, single arm study designed to evaluate the safety profile and efficacy of NeoChord DS 10002323Seeburger, J., Rinaldi, M., Nielsen, S. L., Salizzoni, S., Lange, R., Schoenburg, M., … & Aidietis, A. (2014). Off-pump transapical implantation of artificial neo-chordae to correct mitral regurgitation: the TACT Trial (Transapical Artificial Chordae Tendinae) proof of concept. Journal of the American College of Cardiology, 63(9), 914-919.. Thirty patients with severe MR due to isolated posterior prolapse scheduled for off-pump transapical implantation of neo-chordae were included between 2009 and 2014. Acute procedural success, defined as the placement of at least 1 neochord and reduction of MR from 3+ or 4+ to at least 2 grades was achieved in 86.7% of patients (26). The trial highlighted the link between improvement of results and increased experience, since durable reduction in MR to ≤2+ at 30 days was achieved in 5 of the first 15 patients and 12 of the last 14 patients. The procedure was technically safe and feasible and yields further potential for improvement of efficacy and durability31,2424https://www.clinicaltrials.gov/ct2/show/NCT01777815. Of 6 patients initially enrolled in the early experience of the TACT trial at Leipzig-Heart Center, 3 of them reach a 5 year follow up showing up to mild-to moderate MR and good clinical condition. In these patients a trend toward reverse remodeling of the left ventricle and no increase in mitral annular dilatation was observed2525Kiefer, P., Meier, S., Noack, T., Borger, M. A., Ender, J., Hoyer, A., … & Seeburger, J. (2018). Good 5-year durability of transapical beating heart off-pump mitral valve repair with neochordae. The Annals of thoracic surgery, 106(2), 440-445..
A single-center experience (144 patients) reports early procedural success of 98.6% (142), early mortality of 1.4% (2) and patient success (endpoint composite by MR ≤ 2 and freedom from reoperation) of 89% at 1 year27. A multicenter European study published in 2018 enrolling 213 patients reported an excellent procedural success rate. Procedural success was achieved in 206 (96.7%) patients, at 1-year follow-up, overall survival was 98 ± 1% and composite end point was achieved in 84 ± 2.5% for the overall population.2626Colli, A., Manzan, E., Aidietis, A., Rucinskas, K., Bizzotto, E., Besola, L., … & Drasutiene, A. (2018). An early European experience with transapical off-pump mitral valve repair with NeoChord implantation. European Journal of Cardio-Thoracic Surgery, 54(3), 460-466.
As above mentioned, in the United States the NeoChord technology has received investigational device exemption (IDE) approval from FDA. Patients are being enrolled in a prospective, multicenter, randomized controlled clinical trial (ReChord trial NCT02803957) comparing traditional surgical repair with NeoChord repair with a 1:1 randomization2727https://clinicaltrials.gov/ct2/show/NCT02803957. Neochord technology was already employed in combined transcatheter MVRe procedures with a simultaneous two-step annuloplasty and chordal repair session2828Colli, A., Raanani, E., Cobiella, J., Wrobel, K., Nombela, L., Maroto, L., … & Meerkin, D. (2020). Transapical and transfemoral combined mitral valve repair with annular and leaflet therapies. The Annals of Thoracic Surgery. 2929Von Bardeleben, R. S., Colli, A., Schulz, E., Ruf, T., Wrobel, K., Vahl, C. F., … & Beiras-Fernandez, A. (2018). First in human transcatheter COMBO mitral valve repair with direct ring annuloplasty and neochord leaflet implantation to treat degenerative mitral regurgitation: feasibility of the simultaneous toolbox concept guided by 3D echo and computed tomography fusion imaging. European heart journal, 39(15), 1314-1315.. During the first step AMEND ring was implanted, obtaining annular stabilization, A-P dimension reduction and thus increasing the overriding of the flailing leaflets. In a second phase, deployment of artificial chords with Neochord procedure allowed for flail treatment and restored leaflet coaptation.
Anecdotal cases of non-conventional use of Neochord device have been recently reported.
In 2018 the first in human edge-to-edge MVRe with neochord technology was applied on a high-risk surgical patient rejected for MitraClip due to unfavorable anatomy3030Colli, A., Besola, L., Bizzotto, E., Peruzzo, P., Pittarello, D., & Gerosa, G. (2018). Edge-to-edge mitral valve repair with transapical neochord implantation.. Furthermore, a transcatheter mitral valve replacement (MVR) case, combined with neochord implantation was reported. In the presence of a long AML, the risk of neo left ventricular outflow tract obstruction was reduced by previous neochord deployment on the AML and subsequent artificial tethering of the leaflet3131Beiras-Fernandez A, Ruf, T. F, Obadia J. F. I., Münzel T, Kreidel F, & von Bardeleben R. S. Neochord anterior leaflet treatment to facilitate transcatheter mitral valve replacement with 3D real-time echocardiography. European Heart Journal. 2020.
An interesting case of MVRe through neochord implantation in a patient affected by dextrocardia and situs-inversus, reporting no significant issues during the procedure was also described 3232Bhatia, I., Chan, D. T. L., Lam, S. C. C., & Au, T. W. K. (2020). Feasibility of novel transapical off pump beating heart mitral valve repair in a patient with dextrocardia and situs inversus. European Journal of Cardio-Thoracic Surgery..