Table of Contents
Year : 2020  |  Volume : 5  |  Issue : 2  |  Page : 62-70

Transcatheter treatment of mitral regurgitation: Current status and future prospects

Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai, China

Date of Submission11-May-2020
Date of Acceptance19-Jun-2020
Date of Web Publication30-Jun-2020

Correspondence Address:
Da-Xin Zhou
Department of Cardiology, Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cp.cp_13_20

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In recent years, transcatheter treatment of mitral regurgitation (MR) has been extensively explored and has shown promising results. After transcatheter mitral valve repair (TMVr) with MitraClip has become a routine strategy in patients with symptomatic degenerate MR at prohibitive surgical risk, the benefits of TMVr are now being examined in patients with functional MR (FMR). However, the contradictory observations in COAPT and MITRA-FR clinical trials so far have suggested that only patients with severe FMR disproportionate to left ventricular disorder may benefit from this interventional therapy. Nevertheless, more evidence is required to support this hypothesis. In addition, various new devices have been developed, including two original designs from China Mainland, which have displayed excellent performance. Several percutaneous (femoral vein.transseptal) valves used in transcatheter mitral valve replacement have been developed and have also shown good feasibility. Furthermore, hybrid techniques in MR therapies have been emerging, which may reduce residual MR and improve the treatment effects.

Keywords: Mitral regurgitation, mitral insufficiency, regurgitant lesion, valve therapy, percutaneous valve therapy

How to cite this article:
Long YL, Pan WZ, Zhou DX, Ge JB. Transcatheter treatment of mitral regurgitation: Current status and future prospects. Cardiol Plus 2020;5:62-70

How to cite this URL:
Long YL, Pan WZ, Zhou DX, Ge JB. Transcatheter treatment of mitral regurgitation: Current status and future prospects. Cardiol Plus [serial online] 2020 [cited 2020 Sep 26];5:62-70. Available from:

  Introduction Top

Mitral regurgitation (MR) is a valvular heart disease with a high incidence in the population and the community.[1],[2] The incidence rate increases with age, and the estimated prevalence is 1 in 10 people in those who are 75 years and older.[1],[3],[4] Moderate-to-severe MR is associated with frequent heart failure and significant morbidity.[2] Formerly, due to impaired left ventricular (LV) function, older age, and comorbidities, majority of patients with MR recommended for mitral surgery were not able to receive this life-saving procedure.[2],[5] However, transcatheter mitral valve repair (TMVr) using MitraClip, as a nonsurgical, less invasive alternative, has revolutionized the management of MR and has become the standard of care for patients with symptomatic degenerate (primary) MR (DMR) at prohibitive surgical risk.[6],[7] It has also become a promising treatment for patients with functional (secondary) MR (FMR).[8],[9] The development of newer generations of transcatheter mitral valve (MV) treatment techniques,[10],[11],[12] careful patient selection,[4],[8],[13],[14],[15],[16] and precise assessment[17],[18] have driven stepwise improvements in reducing mortality and improving prognosis. However, the questions on the causal relationship between FMR and LV dysfunction,[19] the evaluation and judgment of an optimal treatment for patients with chronic heart failure with FMR, the remote cardiac function improvement after transcatheter MV replacement (TMVR), the timing of transcatheter treatment of asymptomatic severe MR, and complications such as significant residual MR, device disengagement or migration, embolization, LV outflow tract (LVOT) obstruction, and paravalvular leak remain unanswered. In this context, we reviewed the state-of-the-art transcatheter treatment for MR to provide a current perspective on recent and ongoing trials, the current and future devices, expert consensus and strategies to further reduce the complication rates, and future prospects of transcatheter treatment of MR.

  Current Perspective on Transcatheter Treatment of Functional Mitral Regurgitation Top

It is widely accepted that FMR is induced by the annular dilatation and leaflet tethering from LV remodeling, which is mainly caused by ischemic or dilated cardiomyopathy but without lesions of the valve structure. FMR is more common in hospitals and community,[4] especially in patients with severe LV dysfunction and heart failure. It is also a strong predictor of worse prognosis.[19],[20] Surgical treatment has proved to be unable to reduce hospitalization or death in patients with FMR.[21] Some studies indicated that the transcatheter correction of FMR could reduce LV volume and improve the adverse clinical outcomes, but the evidence is still limited.[19],[22] Therefore, before the 3-year data of COAPT trial and 2-year data of MITRA-FR trial were published in 2019, only guideline-directed medical therapy (GDMT) and cardiac resynchronization therapy (CRT) (if appropriate) were recommend for FMR management.[6],[7]

COAPT and MITRA-FR are two multicenter clinical randomized controlled parallel trials. Both trials were aimed to evaluate the benefits of transcatheter intervention on chronic heart failure with LV dysfunction and severe FMR in nonresponders to GDMT and CRT (if appropriate), but their results were diametrically opposite.[23],[24]

The COAPT trial was conducted in the United States and Canada and involved 614 patients with heart failure and moderate (grade 3+) to severe (grade 4+) FMR, defined as an effective regurgitant orifice area (EROA) >30 mm2 or regurgitant volume (RV) >45 mL/beat, and LV ejection fraction (LVEF) ≥20%, who still had the symptoms of heart failure after treatment with maximum tolerated dose of GDMT. Those patients were randomly assigned to either the intervention groups (312 patients received TMVr with MitraClip plus GDMT) or the control group (302 patients received only GDMT).[23] The primary end point was all hospitalizations for heart failure. The 3-year follow-up results of the COAPT study were presented at the Transcatheter Cardiovascular Therapeutics (TCT) Congress 2019. Intention-to-treat (ITT) analysis indicated that in the 3-year follow-up period, the composite rate of all-cause death and hospitalization rate of heart failure in MitraClip + GDMT group were significantly lower than that observed in GDMT group alone (58.8% vs. 88.1%, P < 0.001). During the follow-up, 58 patients in the GDMT group received strategy conversion: 5 patients received rescued MitraClip implantation within 2 years, while 53 patients received rescued MitraClip implantation within 24–36 months. Compared to the patients in the GDMT group, those 58 patients still benefited from TMVr treatment, and all-cause mortality and hospitalization rate of heart failure were significantly reduced.

The MITRA-FR trial was conducted at 37 centers in France and enrolled 304 patients with symptomatic heart failure and severe FMR (using the definition of 2017 European Society of Cardiology [ESC] guidelines: EROA >20 mm2 or RV >30 ml/beat and LVEF between 15% and 40%).[24],[25] Those patients were randomly assigned, in a 1:1 ratio, to either the intervention groups (152 patients received TMVr with MitraClip plus GDMT) or the control group (152 patients received only GDMT). The primary end point was the incidence of death within 12 months or first unplanned hospitalization for heart failure. The extended follow-up data were presented at the ESC Congress 2019. The results for primary end point at 2 years did not significantly differ between the control and the intervention group (68.6% vs. 64.2%).[25] In addition, there was no significant difference in the results for secondary end points in the two groups (all-cause mortality [33.9% vs. 35%, hazard ratio (HR) 0.99], cardiovascular mortality [31.2% vs. 32.4%, HR 0.99], rehospitalization for unplanned heart failure [58.7% vs. 63.5%, HR 1.03], and major cardiovascular adverse events [66.1% vs. 68.6%, HR 1.09]).[25] Compared with the 1st-year data of MITRA-FR trial,[24] there was still no visible benefit of TMVr in those patients with severe FMR. However, it is worth mentioning that a lower rate of first hospitalization for heart failure was observed for the first time in the intervention group.[26] Therefore, the researchers contemplated that the primary end point of MITRA-FR trial might meet the COAPT trial at 5 years of follow-up, and a sustainable decrease in rehospitalization rate might be observed.[26] Even though the negative outcomes have been shown in MITRA-FR trial, the benefits of TMVr in patients with heart failure and FMR cannot be denied.

There are various possible reasons that can explain the differences between the two studies. First and most important, the inclusion criteria for MR severity, LV dilation and disorder of COAPT and MITRA-FR trials were different.[23],[24],[27],[28] Compared with patients in the MITRA-FR trial, those enrolled in the COAPT trial had substantially more severe MR (EROA: 31 ± 10 mm2 vs. 41 ± 15 mm2) but smaller LV dimensions (LV end-diastolic volume [LVEDV]: 135 ± 35 mL/m2 vs. 101 ± 34 mL/m2).[23],[24] According to Grayburn's new evaluation framework, which based on the ratio of EROA to LVEDV, FMR can be categorized into different subtypes: (1) severe MR proportionate to LVEDV, (2) severe MR disproportionate to LVEDV, and (3) nonsevere MR.[8] The patients enrolled in COAPT and MITRA-FR trials belonged to the disproportionate and proportionate subtypes, respectively.[8] In this context, FMR was the determining factor or the initiating reason for LV dysfunction and thus the principle reason for the poor outcomes in the COAPT trial,[8],[27] which exactly explained why TMVr was capable of changing the clinical course of the disease in the COAPT trial than in the MITRA-FR trial.[8] Similarly, FMR was not the predominant factor in patients of MITRA-FR trial; therefore, an intervention focused on the MV would not bring evident effects.[8] Another possibility might be that the characteristics of severe FMR disproportionate to LV disorder are very similar to those of DMR, and the patients in COAPT trial may had mixed MR (FMR combined with invisible or hard-to-diagnosed DMR due to limited imaging), and the effects of TMVr in the treatment of DMR have already been confirmed to be beneficial.[29]

Second, the patients in the COAPT trial may have received more rationale and aggressive medical treatment than those in the MITRA-FR trial. GDMT in the COAPT trial had a detailed protocol in which every patient was assessed by a team of heart specialists at every site, to ensure that every patient received maximal doses of GDMT, and those vulnerable to GDMT during the run-in phases were excluded.[23] Furthermore, the dose of beta-blocker in the intervention group of the COAPT trial was increased after MitraClip implantation because the reduced MR after implantation might increase the cardiac output and subsequently the blood pressure in the patients.[23] Increasing the dose of angiotensin receptor neprilysin inhibitor[30] or beta-blocker is helpful in controlling the blood pressure, reducing the cardiac afterload, improving LV remodeling, and thus improving the outcomes.

Third, the operators in the COAPT trial may be more experienced, since there were significant differences in the implantation success rate, device implantation proportion, and residual MR rate at 1-year follow-up between the two trials.

Besides, the follow-ups of both COAPT and MITRA-FR trials will continue until 5 years, and another trial namely RESHAPE HF2 that enrolled 420 patients with similar study design and end points is ongoing. These studies may provide further evidence.

Based on the positive results of the COAPT trial, in March 2019, TMVr with MitraClip was approved by the U.S. Food and Drug Administration (FDA) in patients with chronic heart failure with LV dysfunction and severe FMR in nonresponders to GDMT and CRT (if appropriate). In May 2019, after comprehensive analysis and evaluation of the results of MITRA-FR and COAPT study, TMVr was also recommended in high-risk patients with severe FMR (class IIb) by the ESC guidelines.

  Current and Future Techniques and Devices Top

Among four heart valves, the MV is the most complex and consists of a mitral annulus, two asymmetric leaflets, chordae tendineae, and papillary muscles. Furthermore, the mitral apparatus is anatomically very close to the aortic valve and LVOT, which makes the transcatheter treatment of MR challenging. The frequent device-related complications and high mortality rate obstructed the development of an interventional therapy for MR. However, in the last decade, with the increased understanding of MV structure, many new technologies based on diverse mechanisms have been established [Figure 1] and [Figure 2].
Figure 1: Representative TMVr technologies

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Figure 2: New transcatheter mitral valve replacement equipments

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Transcatheter edge-to-edge repair

In 1998, Maisano et al. initially used surgical MV edge-to-edge repair strategy in patients with complicated MV lesions who were not recommended the usual surgical MV repair at that time. This research group was also first to assume that it would be feasible to perform this type of repair through a catheter.[31] This study laid the basis for the development of many transcatheter edge-to-edge devices. The improvement to these devices subsequently led to the development of the MitraClip system, the PASCAL system, the ValveClamp system, and various other transcatheter edge-to-edge repair techniques which are still in the developmental stages.

The MitraClip system (Abbott Inc., Chicago, IL, USA)

The MitraClip system is the first widely available device for transcatheter edge-to-edge repair technique, which is also currently the only device approved by the U.S. FDA for the treatment of both DMR and FMR. TMVr using MitraClip was performed first in 2002 and currently has been used in more than 100,000 implantations globally. Feldman et al. first descripted the MitraClip system and explained its operation processes in 2005.[32] The core components of the clip included a U-shaped gripper matched with two arms, which was used to capture and stabilize the leaflets. The “gripper and arms” design is still used in the third-generation MitraClip XTR but is more flexible with wider acquisition range (a 3-mm longer gripper and arm than the MitraClip NTR).[33] It is worth mentioning that the newer fourth-generation MitraClip G4 has adopted the design comes in four sizes to improve further the ability to capture and reduce the chances of residual MR. The clip delivery system is covered by a 24-F sheathed catheter using a two-knob coaxial design that permits multidirectional steering as per the requirement.

MitraClip implantation has now become a routine therapy in Europe and America, and its performance has been widely tested in the clinical trials and the real world. Five-year data of the EVEREST II trial endorsed the safety and durability of TMVr with MitraClip in MR reduction, which was comparable to the conventional surgical correction, except for more common reinterventions due to MR recurrence in 1-year follow-up.[34] The data from the Society of Thoracic Surgery (STS)/American College of Cardiology also proved the long-term clinical benefits of commercial TMVr using MitraClip in the real world.[35] Unfortunately, until now, the MitraClip system is not commercially available in Mainland China.

MR caused by MV leaflet laceration belongs to the category of DMR, TMVr in which used to be an area of blank. Recently, a case report proved the feasibility of TMVr using two clips in patients with MV leaflet laceration.[36]

There are various limitations of the MitraClip system. First, the use of MitraClip system has been associated with postoperative residual MR. Although, in some situations, the implantation of more than one clip has been reported as a remedial measure for residual MR,[37] it has been proved ineffective as a means of prevention in the routine practice and could even increase the risk of stroke.[38] As observed with TMVr alone, TMVr combined with various techniques, such as transcatheter leaflet therapy plus annuloplasty, may help lower its incidence. Second, the procedure has a long learning curve[16] and is not user-friendly, especially to a new surgeon or specialist, although its design has improved in the third generation.[33]

The PASCAL system (Edwards Lifesciences, Irvine, CA, USA)

The PASCAL system is another transcatheter edge-to-edge repair technique, which design is similar to MitraClip but steps to addressing some limitations of the Mitraclip system by improving the operability of the delivery system, and the flexibility of grasping clip (allowed independent leaflet grasping, which is capable until the third generation of MitraClip). First in man (FIM) study was published in 2017,[11] which enrolled 23 patients with symptomatic, severe DMR, FMR, or mixed MR at high risk or inoperable. 22 of 23 (96%) patients had technical success, of which 11 (59%) patients received two implants. The clinical outcomes were acceptable: 17 (77%) had MR grade 1+, and all patients had MR grade 2+. During the follow-up, 3 (13%) patients died, and complications including ischemic event (9%) and significant residual MR (4%) were observed.[11] Early real-world data initially displayed the advantage of independent movement control of the clasps.[39] Further investigations and large clinical tests are required to define the safety and reliability of the PASCAL system in reducing MR.

The ValveClamp system (Hanyu Medical Technology, Shanghai, China)

The ValveClamp system is the first and currently the only transcatheter edge-to-edge repair technique designed and developed in Mainland China.[40] The design concept of the ValveClamp is obviously different from the MitraClip and PASCAL systems. The two matched V-shape clamping arms provide a wider capturing area; the transapical approach make the locating and clamping procedure easier-to-operate, which step usually can be finished in 10-20 minutes and the whole process is under the guidance of intraoperative echocardiography, without the X-ray; and the design of the spherical valve-crossing device, which is woven from nitinol wire can avoid the device be entangled in chordae tendinae.

FIM study of the ValveClamp was conducted in three main cardiac centers of China in 2019.[12] Twelve patients (age: 76.5 ± 6.3 years, mean STS score: 6.9% ± 1.9%) with symptomatic severe DMR at high surgical risk were enrolled. The device success rate was 100%. The mean procedure time was 82.3 ± 27.6 min, during which the mean catheterization time was 26.8 ± 10.3 min. At postoperative 90 days, most patients had MR grade 1+, and only one patient had MR grade 2+. No patient was implanted more than one clamp, and no adverse events such as death, MR recurrence, reintervention, and device displacement were reported.[12] Due to the excellent performance in FIM study, the ValveClamp system was approved to conduct the premarketing trial in China (NCT03869164).

Transcatheter annuloplasty

Transcatheter annuloplasty also derives from surgical annuloplasty, which corrects the FMR by reducing the dimensions of MV annulus through direct and indirect approaches. However, indirect annuloplasty constrains the mitral annulus via the coronary sinus since the coronary vein has an anatomical proximity to the mitral annulus. Thereby, indirect annuloplasty would be unavailable in patients with dilated LV due to the increased distance between the coronary vein and the mitral annulus. Furthermore, all direct and indirect annuloplasty products may face a limitation that there are no quantitative indicators of optimal cinching. All operators must make decisions based on their own experience. In this clinical context, the MiCardia EnCorSQ System (MiCardia Corp., Irvine, CA, USA), an adjustable mitral annuloplasty ring, may offer a potential solution.[41] Nevertheless, more data are required to evaluate the performance of this novel annuloplasty system. Recently, more than 10 kinds of annuloplasty technologies have been developed, with the representative products below.

The Cardioband system (Edwards Lifesciences, Irvine, CA, USA)

The core component of Cardioband system is a semicircular polyester sleeve which is delivered through transseptal approach and deployed on the MV annulus from the lateral commissure to the medial commissure. The whole procedure is under the guidance of 3D transesophageal echocardiography and X-ray fluoroscopy.

One-year results of Cardioband implantation have been published in 2018, and the clinical improvement was acceptable with 95% of patients having mild-to-moderate MR. However, Cardioband implantation is not a simple procedure and involves high risk of coronary artery lesion. The procedure success rate was 68% (41/60), among which two patients had the coronary artery complications, and during the follow-up, device disengagement was observed in 10 patients.[10] It is worth mentioning that the most adverse events were noted in the early stage, and in the midterm of the study, the design of the device was improved with longer anchor (from 4 to 6 mm) and stronger support in the conjunction part,[10] which enhanced the device safety. Ongoing randomized controlled trial ACTIVE (NCT03016975) will further evaluate the effects of GDMT combined with Cardioband implantation compared to GDMT alone.

The Mitralign system (Mitralign Inc., Tewksbury, MA, USA)

The Mitralign system uses pairs of polyester pledgets connected with sutures instead of a ring deployed on the MV annulus, which constrains the annulus by shortening the length of the suture between pledgets. Mitralign deployment is also challenging, and its FIM study demonstrated that the device was successfully deployed in only 50 (70.4%) patients. Fortunately, no device displacement was observed during the 6-month follow-up,[42],[43] which may result from penetration of the Mitralign system through the mitral annulus structure. Reduction of MR degree and LV dimensions, improvement in cardiac functions (increase in 6-min walk distance by 56.5 ± 92.0 m, and reduction in the patients in New York Cardiac Functional Class III/IV from 53.3% to 23.3%) were noted in 6-month follow-up period.

The ARTO system (MVRx Inc., Belmont, CA, USA)

The ARTO system consists of two anchors connected by a tether and is delivered through a two-vein access. The two anchors are deployed over the atrial septum and the lateral wall of the left atrium (LA), which constricts the mitral annuals by shortening the distance between the anchors via the tether.

Initial results of the FIM study (MAVERIC: NCT02302872) have been reported; among 11 patients implanted with the ARTO system, one case of displacement and one case of severe pericardial effusion were noted. At 30-day follow-up, significant MR reduction (RV from 45.4 ± 15.0 ml to 19.5 ± 10.2 ml), LV volume decrease (LVEDV index from 118.7 ± 28.6 ml/m2 to 103.9 ± 21.2 ml/m2), and improved New York cardiac function were observed.[44] In 2017, 2-year results of the MAVERIC study also confirmed the sustained benefits of ARTO implantation.[45] Further research and clinical trials are required to evaluate this novel technology.

Transcatheter chordae tendineae repair

DMR caused by MV leaflet prolapse can be corrected by the surgical implantation of polytetrafluoroethylene artificial cords. Recently, the implantation of artificial cords through catheter has become a new trend for DMR treatment. Emerging new devices such as the Harpoon TSD-5 device (Edwards Lifesciences, Irvine, CA, USA) have demonstrated outstanding safety, good controlling ability, and biocompatibility.[46],[47] The MitralStitch system (Dinova medtech Co., Hangzhou, China) is the first transcatheter chordae tendineae repair device being established in China, which is also currently the only technology capable of conducting both transcatheter edge-to-edge repair and chordae tendineae repair. 30-day results of MitralStitch FIM study were presented at TCT Congress 2018. Both the device and operation showed the success rate of 100% without any death or device-related complications. The average operation time was only 30.0 ± 9.3 min. At 30-day follow-up, all patients demonstrated a significant reduction in MR.

Transcatheter mitral valve replacement

At present, diverse technologies are required for MV repair due to the complexity of MV anatomy as well as the heterogeneity of MR pathology. Theoretically, the transcatheter MV replacement (TMVR) is capable of providing one-stop solution for MR with mixed pathogenesis and seems like an attractive option. The first TMVR was performed with a transcatheter heart valve (THV) designed for transcatheter aortic valve replacement (TAVR) in 2012, which encouraged the development of TMVR technologies.

Different from calcified aortic valve, natural MV annulus cannot provide a stable and regular anchor zone for TAVR valves. Therefore, dozens of diverse THVs have been designed and developed in the last decade, but until now, only a limited number of patients have received the therapy worldwide. Unlike TAVR, the development of TMVR has been challenging. The current solutions for THV fixation on natural MV structure mainly include:

  1. The use of self-expandable nitinol stents in majority of TMVR products,[48] which enables the application of THV to individual MV anatomy
  2. Increasing the area contacted with LA, which is a common design in many THVs, such as the CardioValve system (Edwards Lifesciences, Irvine, CA, USA), the Intrepid system (Medtronic, Inc., Redwood City, CA, USA),[49] and the FORTIS valve (Edwards Lifesciences, Irvine, CA, USA)
  3. Adopting a waist-tightened design, such as the HighLife system (HighLife, Paris, France)[50]
  4. Installation of special anchor devices, such as the Tiara system (Neovasc Inc., Richmond, BC, Canada) which uses a leaflet anchor;[51] the Intrepid system (Medtronic, Inc., Redwood City, CA, USA) attached by small cleats on the outer frame; the Tendyne system (Abbott Inc., Chicago, IL, USA) that fixes through a polyethylene tether anchored to the LV apex;[52] the CardiAQ system (Edwards Lifesciences, Irvine, CA, USA) that uses anchors below the valve; the Sapien M3 system (Edwards Lifesciences, Irvine, CA, USA) that uses a nitinol dock which encircles the native MV leaflets and chordae tendineae[53]
  5. Using a spherical-shaped structured device such as the AltaValve system (4C Medical Technologies, Minneapolis, Minnesota, USA) that has a spherical-shaped nitinol frame that fixes the valve inside the LA and can also prevent the LVOT obstruction.[54] However, in the meantime, this structure may restrict the constriction of LA and thus increase the risk of heart failure.

Contrarily, the high risk of LVOT obstruction (about 22%) also restricted the further development of TMVR. Recently, Helmy et al. successfully punctured the anterior leaflet, expanded the hole with the balloon, and finally positioned the THV “within” the leaflet in three patients with high risk of LVOT obstruction.[55] This may be considered as an alternative strategy for TMVR candidates with high risk of LVOT obstruction. Khan et al. published a clinical trial with small sample size, which also supported the feasibility of this operation strategy.[56]

Currently, TMVR techniques are far from mature. Except for TAVR THVs, the Intrepid system and the Tendyne system are two promising technologies. Currently both the two systems have finished hundreds of implantations with favorable early data [49,57], and under clinical trials (Apollo, Summit). The initial data of Apollo trail (NCT03242642) has published by Martin Leon on TCT congress 2019: the study has already enrolled 180 patients and the 30-day mortality of first 51 patients was only 2%. TMVR in China: In year 2019, Zhongshan hospital Fudan University successfully conducted the first implantation of a novel TMVR technology: the Mi-thos system (NewMed Medical, Shanghai, China).

  the Future Prospects of Transcatheter Treatment of Mitral Regurgitation Top

Establishing the functional mitral regurgitation evaluation system

The evaluation and judgement of an optimal treatment for patients with chronic heart failure with FMR is an urgent task for future investigation, and more need to learn from COAPT and MITRA-FR trial.

The evaluate framework proposed by Paul A. Gray burn firstly estimate the severity of FMR based on comprehensively analyzing of the proportion between MR degree and LV disorder [8,58], which consistent with FMR's main pathophysiological features and is also intuitive to apply in the patient selection for FMR transcatheter intervention: patients with severe MR disproportionately to LV disorder. While patients with proportionate MR could benefited from GDMT direct at reducing LV volumes.[58]

However, there are still some limitations in the evaluation system:First, the EROA measurement can be challenging because of the technical reasons and potential inappropriate measurements.[8],[28] Furthermore, the ratio of EROA to LVEDV is influenced by hemodynamic effects,[8] which leads to the existence of a gray zone (not accurate for all the patients). Second, the existence of severe FMR that is disproportionate to LV disorder also suggests that FMR is not just the consequence of LV disorder. Actually, not only the LV chamber size, but also left atrial diameter, the systolic pressure gradient between the LA, and LV have been associated with FMR.[4],[15],[59] All relative data must be taken into consideration.

In summary, continually refined studies are required in the future to establish a simple, intuitive, widely applicable, and highly reliable evaluation system.

Hybrid techniques to reduce residual mitral regurgitation

Significant residual MR (grade III/IV) significantly increased the mortality (10.2% vs. 2.7%; P<0.001), and long-term adverse events. [35,60] In patients with MR caused by heterogeneous pathology, the application of the hybrid techniques in MV therapy is apt to reduce residual MR and improve treatment effects.

Combined existing TMVr technologies

Since the edge-to-edge repair could not direct address annular dilatation and surgical edge-to-edge repair without annuloplasty has been identified with increased MR recurrence.[61] Furthermore, additional Cardioband implantation has been reported as a rescue procedure to reduce residual MR after MitraClip in patients with large annular.[62],[63]

In such context, in patients with mixed MR etiologies, considering transcatheter edge-to-edge repair combined with transcatheter annuloplasty, or other combinations among existing TMVr technologies, may help in reducing complications and adverse events. However, the increased operation-related risk should not be ignored.

Transcatheter edge-to-edge repair combined with Amplatzer Vascular Plug II

In patients with large annulus who received MitraClip implantation but the clip placement position was not A2-P2 site of the annulus, additional implantation of Amplatzer Vascular Plug II in MV annulus between the clip and mitral commissure could prevent severe residual MR.[64] More investigations are needed to establish its long-term efficacy and safety. Further research and clinical trials are also needed to understand this novel strategy for percutaneous MV repair.

Percutaneous (transseptal) TMVR

In the past few years, the TMVR devices, including the two most mature device, Intrepid system and the Tendyne system, were implanted via transapical access. The transapical method was still a bit invasive and may injury the left ventricular function, [65,66] making the technology still defective. What's more encouraging is that at present, several TMVR valves (Sapien M3, Cardiovalve, Cephea's, Cassion, Highlife, Evoque) have achieved percutaneous (femoral vein-transseptal) implantation, which is less invasive.

A small number of early human clinical results show the feasibility of these valves. Among these early products, Edward's M3 valve is the fastest growing one.[53] In 2019, TCT reported 45 cases, with a success rate of 88.9%.

  Conclusions Top

The causes and mechanisms of MR display considerable heterogeneity; therefore, the individual analysis and evaluation before making treatment decisions, especially for patients with FMR, are warranted. Nowadays, patients have wide range of options for interventional correction of MR than before. Novel transcatheter technologies covering almost every mechanism of MR have been developed, but more clinical evidence is required to support those technologies in becoming the routine strategies. Finally, the hybrid techniques as the new trend of MR interventional correction may improve treatment effects, but due to the potential additional risks, it is recommended to perform such treatments in the experienced centers.

Financial support and sponsorship

This work was supported by a Grant from Biomedical Support Project of Science and Technology of Shanghai (Grant No. 19441915800).

Conflicts of interest

There are no conflicts of interest.

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