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Current Status and Challenges of Valvular Heart Disease Interventional Therapy

Zhang, Yi; Xiong, Tianyuan; Feng, Yuan

Editor(s): Xu, Tianyu; Fu, Xaoxia

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doi: 10.1097/CD9.0000000000000049
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Valvular heart diseases (VHD) comprise diseases of the aortic valve, mitral valve, tricuspid valve, and pulmonary valve, which are prevalent in aging populations. In a population-based study in the USA, the prevalence of VHD was reported in 13.2% of people aged >75 years, with degenerative lesions being dominant.[1] In the United Kingdom, moderate or severe VHD prevalence in patients aged >65 years exceeded 11%.[2] An epidemiological study suggested that the prevalence of VHD in the Hubei Province of China was approximately 2.05% in people aged >60 years.[3] Although rheumatic valvular diseases accounted for the majority of VHD in China, the prevalence of degenerative valvular diseases has also noticeably increased due to significant improvements in social economics and aging of the Chinese population.

The main treatment options for VHD include conservative medical treatment, interventional therapy, and surgery. As conservative treatment is unable to efficiently improve prognosis, surgical valve replacement or repair is one of the standard treatments for various VHD. However, a large number of patients cannot receive surgery due to contraindications, advanced age, poor cardiac function, or comorbidities. Therefore, interventional therapy techniques for valvular diseases have emerged, bringing novel treatment options to the aforementioned patients. This review aimed to summarize the current state of VHD transcatheter treatment and related possible challenges in the future.

Transcatheter aortic valve replacement (TAVR)

Epidemiology of aortic valvular disease

The prevalence of moderate or severe aortic diseases approaches 4% in patients aged >75 years in the USA.[4] In addition, there are more than 2 million patients with aortic valvular disease aged >75 years in China, of which more than 400,000 are in urgent need of surgery or intervention.[5] According to the dominant anatomic and functional consequences of aortic failure, aortic valvular diseases can be divided into aortic stenosis (AS) and aortic regurgitation (AR). The European Valvular Heart Disease Survey showed that AS and AR comprised 24.4% and 7.5%, respectively, in cases of VHD without history of interventional therapy.[6] In China, AR is more prevalent than AS, especially in patients aged >75 years (2.85% vs. 0.89%).[7] According to the European Valvular Heart Disease Survey results, up to 33% of patients with VHD could not undergo surgery, and this rate is even higher in China. The 2-year mortality rate of patients with symptomaptic severe AS is as high as 50% if no surgery was performed. Considering the unmet needs to treat AS and AR, TAVR is a considerable option.

Development history of TAVR

Global history of TAVR

The first TAVR was performed in 2002 by Cribier et al[8] in France using a balloon-expandable Cribier-Edwards valve. Subsequently, TAVR has developed rapidly with a series of randomized controlled trials (RCTs) being carried out successively since 2007, including a total of about 15,000 patients, supporting the corresponding guidelines [Table 1].[9–21] The earliest RCT on TAVR was the landmark study—the Placement of Aortic Transcatheter Valves (PARTNER) trial, which included patients with severe AS who were unable to undergo surgery and suggested that TAVR with a balloon-expandable valve had lower rates of all-cause mortality at a 2-year follow-up than standard medical therapy (43.3% vs. 68.0%, P< 0.001).[10,22] Moreover, TAVR was comparable to surgical aortic valve replacement (SAVR) in terms of mortality (33.9% vs. 35.0%, P = 0.78), symptom remission, and hemodynamic improvement at a 2-year follow-up in patients at high risk of surgery.[9,23] Therefore, the 2012 European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines and 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for VHD management suggested TAVR as a recommended treatment option for patients with severe AS who are unable to undergo surgery with a level of recommendation (L-R) I and level of evidence (L-E) B and as an alternative treatment option for surgically high-risk patients (L-R IIa, L-E B).[24,25] Subsequently, as confirmed by a series of researches, the 2017 ACC/AHA guidelines for VHD management increased the recommendation strength of TAVR for patients unable to undergo surgery and high-risk patients (L-R I, L-E A). Furthermore, as the 2-year follow-up results of the PARTNER 2 RCT suggested that TAVR and SAVR showed similar incidence of death or disabling stroke for intermediate-risk patients with severe AS (P= 0.25), the 2017 ACC/AHA guidelines for VHD management listed intermediate-risk patients as the indicated population for TAVR (L-R IIa, L-E B-R),[14,26] while the 2017 ESC/EACTS guidelines for VHD management further included patients with frailty, porcelain aorta, or chest radiation sequelae (L-R I, L-E B).[27] This recommendation was supported by multiple clinical studies, including the PARTNER 1 trial, U.S. Corevalve High Risk trial, Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trial, PARTNER 2 trial, and Nordic Aortic Valve Intervention (NOTION) trial.[11–13,15,21] In 2019, the Evolut Low Risk trial, which included surgically low-risk patients treated by TAVR with the self-expanding valve, suggested that the composite endpoint of death or disabling stroke after TAVR was not inferior to that after SAVR at a 2-year follow-up (P > 0.999).[19] In addition, the PARTNER 3 trial that included the balloon-expandable valve suggested that the composite endpoint rate was significantly lower in the TAVR cohort than in the SAVR cohort at a 1-year follow-up (8.5% vs. 15.1%, P < 0.001).[18] Therefore, the 2020 ACC/AHA guidelines for VHD management recommended TAVR over SAVR for all-comer patients aged >80 years with a life expectancy of < 10 years (L-R I, L-E A), making a tradeoff for all patients aged between 65 and 80 years (L-R I, L-E A).[28] It is anticipated that the next version of the ESC/EACTS guidelines for VHD management will broaden the indications for TAVR in surgically low-risk patients.

Table 1 - Overview of important RCTs associated with TAVR.
Study Size (TAVR/ SAVR or Others, number of patients) Mean age (years)/ STS-PROM (%) Trial arms Outomes
PARTNER 1A [9,12] (NCT00530894) 348/351 84.1/11.7 (high risk) TAVR (Sapien) vs. SAVR 1. At 30 days:• All-cause mortality: 3.4% vs. 6.5% (P = 0.07).• Major strokes: 3.8% vs. 2.1% (P = 0.20).• Major vascular complications: 11.0% vs. 3.2% (P < 0.001).• Major bleeding: 9.3% vs. 19.5% (P < 0.001).• New-onset atrial fibrillation: 8.6% vs. 16.0% (P = 0.006).• TAVR demonstrated more improvement in symptoms.2. At 1 years:• All-cause mortality: 24.2% vs. 26.8% (P = 0.44).• Major stroke: 5.1% vs. 2.4% (P = 0.07).• Similar in symptoms improvement.3. At 2 years:• All-cause mortality: 33.9% vs. 35.0% (P = 0.78).• Similae all strokes (P = 0.52) and improvement in valve areas.• TAVR had more PVL (P < 0.001).4. At 5 years:• All-cause mortality: 67.8% vs. 62.4% (P = 0.76).• No SVD requiring surgical valve replacement in either group.• Moderate or severe AR: 14% vs. 1% (P < 0.0001).
PARTNER 1B [10] (NCT00530894) 179/179 83/11.6 (extremly high risk) TAVR (Sapien) vs. standard medical therapy 1. At 30 days:• Major strokes: 5.0% vs. 1.1% (P = 0.06).• Major vascular complications: 16.2% vs. 1.1% (P < 0.001).• No deterioration in the functioning of the bioprosthetic valve in TAVR.2. At 1 year:• All-cause mortality: 30.7% vs. 50.7% (P < 0.001).• All-cause death or re-hospitalization: 42.5% vs. 71.6% (P < 0.001).• NYHA class III/IV: 25.2% vs. 58.0% (P < 0.001).3. At 2 years:• All-cause mortality: 43.3% vs. 68.0% (P < 0.001).• Stroke: 13.8% vs. 5.5% (P = 0.01).• Rehospitalization: 35.0% vs. 72.5% (P < 0.001).• TAVR was associated with improved functional status (P < 0.001), a sustained increase in aortic-valve area and a decrease in aortic-valve gradient, with no worsening of PVL.
CoreValve U.S.Pivotal High Risk [11,21] (NCT01240902) 391/359 83/7.4 (high risk) TAVI (Edward CoreValve) vs. SAVR 1. At 1 year:• All-cause mortality: 14.2% vs. 19.1% (P = 0.04).• Similar in valve stenosis, functional status, quality of life.• TAVR had a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke.2. At 3 years:• Death or stroke: 37.3% vs. 46.7% (P = 0.006).3. At 5 years:• All-cause mortality: 55.3% vs. 55.4%.• Major stroke: 12.3% vs. 13.2%.• No clinically significant valve thrombosis in TAVR.• Freedom from severe SVD: 99.2% vs. 98.3% (P = 0.32).• Freedom from valve reintervention: 97.0% vs. 98.9% (P = 0.04).• Permanent pacemaker: 33.0% vs. 19.8%.
PARTNER 2 [14,16] (NCT01314313) 1011/1021 82/5.8(intermediate risk) TAVI (Sapien XT) vs. SAVR 1. At 2 years:• All-cause death or disabling stroke: 19.3% vs. 21.1% (P = 0.25).• In transfemoral-access cohort: TAVR resulted in a lower rate of death or disabling stroke than surgery (HR = 0.79; 95% CI: 0.62–1.00; P = 0.05).• In transthoracic-access cohort: similar rates of death or disabling stroke.• TAVR resulted in larger aortic-valve areas and lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; whereas more major vascular complications and PVL.2. At 5 year:
• Death from any cause or disabling stroke: 47.9% and 43.4% (P = 0.21); In the transfemoral-access cohort: 44.5% vs. 42.0%; In the transthoracic-access cohort: 59.3% vs. 48.3%.• At least mild paravalvular AR: 33.3% vs. 6.3%.• Repeat hospitalizations: 33.3% vs. 25.2%.• Aortic-valve reinterventions: 3.2% vs. 0.8%.• Similar improvement in health status.
SURTAVI [15] (NCT01586910) 863/794 79.8/4.5 (intermediate risk) TAVI(CoreValve/Evolut R) vs. SAVR At 2 years:• All-cause death or disabling stroke: 12.6% vs. 14.0% (P > 0.999).• TAVR was associated with lower rates of acute kidney injury, atrial fibrillation, and transfusion requirements, as well as lower mean gradients and larger aortic-valve areas, whereas higher rates of residual AR and need for pacemaker implantation.• SVD did not occur in either group.
PARTNER 3 [18,20] (NCT02675114) 503/497 73/1.9(low risk) TAVI(Sapien 3) vs. SAVR 1. At 30 days:• Stroke: 0.6% vs. 2.4% (P = 0.02).• Death or stroke: 1.0% vs. 3.3% (P = 0.01).• New-onset atrial fibrillation: 5.0% vs. 39.5% (P < 0.001).• Length of index hospitalization: 3.0 days vs. 7.0 days (P < 0.001).• Death, KCCQ score of 45, or decrease from baseline in KCCQ score of ≥10 points: 3.9% vs. 30.6% (P < 0.001).• No difference in the major vascular complications, new permanent pacemaker insertions, or moderate or severe PVL.2. At 1 year:• Death, stroke or rehospitalization: 8.5% vs. 15.1% (P < 0.001).3. At 2 year:• Cause, all stroke, or cardiovascular rehospitalization: 11.5% vs. 17.4% (P = 0.007).• Death: 2.4% vs. 3.2% (P = 0.47).• Stroke: 2.4% vs. 3.6% (P = 0.28).• Valve thrombosis 2.6% vs. 0.7% (P = 0.02).• Disease-specific health status continued to be better after TAVR.• Similar in hemodynamic valve deterioration and bioprosthetic valve failure.
Evolut Low Risk [19] (NCT02701283) 734/734 74/1.9 (low risk) TAVI(CoreValve, Evolut R/Pro) vs. SAVR 1. At 30 days:• Disabling stroke: 0.5% vs. 1.7%.• Life-threatening or disabling bleeding: 2.4% vs. 7.5%.• Acute kidney injury stage 2 or 3: 0.9% vs. 2.8%.• Atrial fibrillation: 7.7% vs. 35.4%.• Moderate/severe AR: 3.5% vs. 0.5%.• Pacemaker implantation: 17.4% vs. 6.1%.2. At 1 year:• Aortic-valve gradients: 8.6 mmHg vs. 11.2 mmHg.• Effective orifice areas: 2.3 cm2 vs. 2.0 cm2.3. At 2 years:• Death or disabling stroke: 5.3% vs. 6.7%.
NOTION [13,17] (NCT01057173) 145/135 79.1/3(all comer) TAVI (CoreValve) vs. SAVR 1. At 1 years:• Similar in the composite rate of death from any cause, stroke, or MI.2. At 5 years:• All-cause mortality, stroke, or MI: 38.0% vs. 36.3% (P = 0.86).• Prosthetic valve area: 1.7 cm2 vs. 1.2 cm2 (P < 0.001).• Mean transprosthetic gradient: 8.2 mmHg vs. 13.7 mmHg (P < 0.001).• Moderate/severe AR: 8.2% vs. 0 (P < 0.001).• New pacemaker: 43.7% vs. 8.7% (P < 0.001).3. At 6 years:• All-cause mortality: 42.5% vs. 37.7% (P = 0.58).• SVD: 4.8% vs. 24.0% (P < 0.001).• Bioprosthetic valvular failure: 7.5% vs. 6.7% (P = 0.89).
AR: Aortic regurgitation; CI: Confidence interval; HR: Hazard ratio; KCCQ: Kansas City Cardiomyopathy Questionnaire; MI: Myocardial infarction; NYHA: New York Heart Association Classification; PVL: Peri-valvular leakage; RCT: Randomized controlled trial; SAVR: Surgical aortic valve replacement; STS-PROM: Society of Thoracic Surgeons - predicted risk of mortality; SVD: Structural valve deterioration; TAVI: Transcatheter aortic valve implantation; TAVR: Transcatheter aortic valve replacement.
Comparations were always made by TAVR vs. SAVR standard medical therapy.

TAVR in China

TAVR was promoted in China relatively later than in Western countries. In October 2010, Junbo Ge successfully performed the first-in-man (FIM) TAVR domestically. Since then, a number of domestic hospitals have successfully performed TAVR using imported prostheses for research purposes due to the lack of market-approved devices. In September 2012, the Fuwai Hospital was the first to successfully perform TAVR using the domestic Venus-A valve (Venus Medtech Co., Hangzhou, China) and initiated the clinical registry of Venus-A valve, marking the arrival of the domestic TAVR device era. An early single-center clinical study in China has shown that the Venus-A valve had similar 2-year survival outcomes to the CoreValve in patients unable to undergo surgery and surgically high-risk patients (11.1% vs. 7.4%, P = 0.64)[29] and similar 1-year survival outcomes to the Sapien valve and J-Valve (P = 0.850),[30] providing early evidence to support the application of the Venus-A valve.

Compared to Western TAVR candidates, Chinese TAVR candidates (1) are more often presenting with bicuspid aortic valves (BAVs)[31]; (2) have more severe aortic valve calcifica- tion[31]; (3) present more prevalent AR[7]; (4) have smaller average diameter of the femoral artery[31]; and (5) comprise a higher prevalence of rheumatic valvular disease than that of degenerative lesions.[6]

According to the characteristics of Chinese candidate patients, researchers have proposed many solutions as follows: (1) for patients with severe calcification, “supra-annular sizing” using a comprehensive assessment of the supra-annular structure is proposed to optimize valve size selection[32]; (2) for patients with BAV lesions, “balloon sizing” is used to assist valve size selection[33]; (3) for patients with AS and no severely calcified leaflets, “direct valve implantation” is used to reduce the damage to the integrity of landing zone caused by pre-dilatation and improve the device success rate.[34] The 5-year results of the Venus-A valve registry have shown promising long-term results, with an all-cause mortality of 20.8%; the Venus-A valve has occupied the largest proportion of transcatheter aortic prostheses used in the domestic market.[35] More than 4000 cases of TAVR have been completed successfully by the end of 2019 in approximately 200 hospitals from over 20 Chinese provinces or cities.[36]

Devices for TAVR

International devices for TAVR

According to their development timeline, aortic valve prosthe- ses can be divided into early- and new-generation valves. Early-generation transcatheter aortic valves mainly comprised the CoreValve (Medtronic, Minneapolis, Minnesota, USA) and the Sapien/Sapien XT (Edwards Lifesciences LLC, Irvine, California, USA) valves. Such valves usually include a relatively large delivery system profile, no anti-leakage design, and no retrievable function. With improvements, the new-generation transcatheter aortic valves have been developed with antileakage design such as outer skirt, retrievable function, and a low delivery system profile. According to different valve expansion mechanisms, prostheses are generally divided into balloon-expandable and self-expanding valve [Table 2] [Figure 1].

Table 2 - Comparative overview of devices for TAVR.
Devices Photo Design Size (mm) CE/FDA/NMPA mark (year) Characteristics
Sapien 3 Figure 1A Bovine pericardiumCobalt-chromiumBalloon-expandable 23, 26, 29 2014 CE2015 FDA2020 NMPA External skirt to reduce PVL.Upcoming RCT data in low risk population.
Sapien 3 Ultra Figure 1B Bovine pericardiumCobalt-chromiumBalloon-expandable 20, 23, 26, 29 2018 CE2019 FDA Higher sealing skirt with a textured structure to promote endothelization.Upcoming RCT data in low risk population.
Evolut R Figure 1C Porcine pericardiumNitinolSelf-expanding 23, 26, 29, 34 2013 CE2015 FDA Resheathable up to 80% deployment.Upcoming RCT data in low risk population.
Evolut Pro Figure 1D Porcine pericardiumNitinolSelf-expanding 23, 26, 29 2017 CE2017 FDA Resheathable up to 80% deployment.Double layer skirt.Upcoming RCT data in low risk population.
Accurate neo Figure 1E Porcine pericardium NitinolSelf-expanding S (23), M (25), L (27) TF 2014 CETA 2017 CE Low PPM requirement.A supra-annular design. A unique “top-down” deployment.Expandable introducer.
Accurate neo 2 Figure 1F Porcine pericardiumNitinolSelf-expanding S (23), M (25), L (27) 2020 CE Added with modified anti-PVL skirt.
Portico Figure 1G Bovine pericardiumNitinolSelf-expanding 23, 25, 27, 29 2012 CE2021 FDA Resheathable up to 85% deployment.
Venus-A Figure 1H Porcine pericardiumNitinolSelf-expanding 23, 26, 29, 32 2017 NMPA Experience in bicuspid valve population in China.Reduced cost.Strong radial force.
Venus-A Plus Figure 1I Porcine pericardiumNitinolSelf-expanding 23, 26, 29, 32 2020 NMPA Added with resheathable function.
Vitaflow Figure 1J Bovine pericardiumNitinolSelf-expanding 21, 24, 27, 30 2019 NMPA Strong radial force.Double-layer skirt.
Vitaflow 2 Figure 1K Bovine pericardiumNitinolSelf-expanding 21, 24, 27, 30 Await Added with resheathable function.
TaurusOne Figure 1L Bovine pericardiumNitinolSelf-expanding 23, 26, 29, 31 2021 NMPA Strong radial force.External skirt to reduce PVL.
TaurusElite Figure 1M Bovine pericardiumNitinolSelf-expanding 23, 26, 29, 31 2021 NMPA Resheathable function.
J-Valve Figure 1N Porcine pericardiumNitinol Self-expanding 21, 23, 25, 27 2017 NMPA Active fixation for use in AR.Short stent.Mainly used by transapical approach.
AR: Aortic regurgitation; CE: Conformite europeene; FDA: Food and Drug Administration of the USA; L: Large; M: Medium; NMPA: National Medical Product Administration; PPM: Permanent pacemaker implantation; PVL: Peri-valvular leakage; RCT: Randomized controlled trial; S: Small; TA: Transapical access; TAVR: Transcatheter aortic valve replacement; TF: Transfemoral access.

Figure 1:
Photos of devices for transcatheter aortic valve replacement. (A) Sapien 3; (B) Sapien 3 Ultra; (C) Evolut R; (D) Evolut Pro; (E) Accurate neo; (F) Accurate neo 2; (G) Portico; (H) Venus-A; (I) Venus-A Plus; (J) Vitaflow; (K) Vitaflow 2; (L) TaurusOne; (M) TaurusElite; (N) J-Valve.

Balloon-expandable valves

Currently, balloon-expandable valves mainly come from Edwards Lifesciences Limited Liability Company (Irvine, California, USA), which developed the Sapien, Sapien XT, and new generation of Sapien 3 and Sapien 3 Ultra valve systems. These balloon-expandable valves are all used for transfemoral access, retrograding to the aorta, and anchoring by balloon inflation in the designated position. Compared to early-generation valves, new-generation valves can reduce peri-valvular leakage (PVL), advance the delivery system easily, and avoid left ventricular damage ulteriorly. The serials of the PARTNER trials,[9,10,12,14,16,18,20] which used Sapien, Sapein XT, and Sapien 3 valves for TAVR in high-, intermediate-, and low-risk patients, demonstrated that patients with AS treated by TAVR had outcomes not inferior to those treated by SAVR, thus validating the safety and effectiveness of these valves. According to a clinical study, TAVR using the CoreValve was associated with a higher risk of PVL (15.5% vs. 8.3%, P < 0.0001) and higher in-hospital (5.6% vs. 4.2%, P= 0.01) and 2-year (29.8% vs. 26.6%, P= 0.003) mortality than that using Sapien XT or Sapien 3 valves.[37] Accordingly, the balloon-expandable TAVR technology represented by the Sapien valves occupies an important position in the global market and is the most widespread balloon-expandable valve worldwide. So far, there are more than 450,000 patients who have underwent the implantation of serials of the Sapien valves worldwide. In addition, the Sapien 3 and Sapien 3 Ultra valves have been approved by the Food and Drug Administration (FDA) of the USA and gained the conformite europeene (CE) mark from the European Union in 2019 to be used in surgically low-risk patients with severe AS. In June 2020, the Sapien 3 valve clinical trial had been completed in China with supporting results, and the valve has been approved for marketing domestically.

Self-expanding valves

Unlike balloon-expandable valves, self-expanding valves are designed to anchor by progressively being released and do not require balloon assistance during their deployment. The Medtronic company (Minneapolis, Minnesota, USA), whose main valves include the CoreValve and new-generation Evolut R/Pro valve, is the first company to develop and promote transcatheter self-expanding aortic valves. The new-generation valves incorporate a design such as outer-skirt that reduce PVL and have retrievable function, a simpler delivery system, and a more consistent radial force, which have shown favorable rates of all-cause mortality and complications in the Evolut Low Risk trials.[19] Accordingly, the Evolut R/PRO valve has been approved by the FDA and gained the CE mark in 2019 to be used in low-risk patients with severe AS.

The Accurate neo valve, developed by Boston Scientific (Natick, Massachusetts, USA), is a special-releasing self-expanding valve with a supra-annular design. During release, the distal end is released firstly to anchor, and the valve stent is subsequently pushed to the native aortic annulus; the proximal end of the stent is released after automatic positioning. The new- generation Accurate neo 2 valve is mainly improved with the skirt against PVL. The Accurate neo valve is associated with higher rates of residual AR than the Sapien 3 valve.[38] However, its supra-annular design with low residual gradients may be advantageous in patients with a small anatomy or mild calcification or those undergoing valve-in-valve treatment.[39,40]

The self-expanding Portico valve, developed by Abbott Vascular (Santa Clara, California, USA), allows valve retraction in a low-leaflet position within the large-cell stent to reduce left ventricular outflow tract protrusion and provide easy access for future coronary interventions. The 1-year outcomes of the trial named International Long-Term Follow-Up Study of Patients Implanted with a PorticoTM Valve (PORTICO-I, NCT01802788), which involved 941 patients with an average Society of Thoracic Surgeons-predicted risk of mortality (STS- PROM) of 5.8%, demonstrated rates of all-cause death, cardiovascular death, disabling stroke, and myocardial infarction of 12.1%, 6.6%, 2.2%, and 2.5%, respectively, in addition to favorable hemodynamic results of low transvalvular pressure gradient and incidence of significant PVL.[41]

Domestic devices for TAVR

The first transcatheter aortic valve used in China is the self-expanding Venus-A valve (Venus MedTech, Hangzhou, China), which has a strong radial force to be fully deployed in patients with severely calcified AS. Between September 2012 and January 2015, 101 patients were enrolled into the Venus-A clinical trial. At the 1-year follow-up of this trial, the all-cause mortality was only 6.1%, and cardiac function significantly improved in all patients. This valve was finally approved by the National Medical Product Administration (NMPA) for marketing in China on April 25, 2017. The second-generation product of this valve is the Venus-A plus valve, which is upgraded with retrievable and relocatable function to effectively improve the success and safety of TAVR. The Venus-A plus clinical trial showed that this valve system was safer than the first-generation valve and had a low incidence of composite endpoint events at 30-day follow-up (16.13% vs. 27.7%).[35] In November 2020, this valve was approved for marketing and became the first domestically retrievable TAVR system in China.

The VitaFlow valve system (MicroPort Scientific Corporation, Shanghai, China) is a self-expanding valve, with an innovative double-layer skirt, strong radial force, and large-cell stent design. A multicenter, single-arm study involving 110 symptomatic patients with AS with an average STS-PROM of 8.84% reported 1-year rate of all-cause death, major stroke, major vascular complication, coronary artery obstruction, and new pacemaker implantation 2.7%, 2.7%, 2.7%, 1.8%, and 19.1%, respectively, without moderate or severe PVL.[42] In July 2019, this valve system passed its clinical trial and was marketed in China, becoming the first local self-expandable valve made by bovine pericardial tissue. The second-generation VitaFlow II valve system (MicroPort Scientific Corporation, Shanghai, China) has retrievable function and an anti-PVL structure, and the clinical trial for this valve started in 2018 and is ongoing at the time of writing this study.

The TaurusOne valve is a self-expanding valve from the Peijia Medical Limited Corporation (Suzhou, Jiangsu Province, China), and the clinical trial for this valve is ongoing at the time of writing this study. The second-generation product, TaurusElite valve, has been upgraded with retrievable function; the pre-market clinical trial for this valve began in December 2019 and is ongoing at the time of writing this study. The J-Valve (JieCheng Medical Technology Co., Ltd., Suzhou, Jiangsu Province, China), another transapical second-generation expandable valve, has 3 graspers for fixation on the periphery of the stent connected by active strings, facilitating anchoring, especially in patients with AR with rare severe calcification. This valve could capture leaflets and reduce displacement risk after valve releasing. The J-Valve registry included 107 AS or AR patients, with an average age of 74.4 years and a EuroScore of 27.5 points. The 30-day and 2-year cardiac mortality rate was 2.8% and 4.7%, respectively.[43] In May 2017, the J-Valve became the first transapical transcatheter aortic valve to be marketed in China.

Challenges in future TAVR technology

Bicuspid aortic valve

In China, the proportion of candidate patients for TAVR with BAV is approximately 40%, significantly exceeding that in Europe and the USA, in which valves for BAV cases comprising <10% of commercially used valves for TAVR.[31] BAVs have unfavorable anatomic characteristics for TAVR, such as a noncircular and oversized annulus, severe and unevenly distributed calcification on leaflets, and concomitant ascending aorta dilation, which were all previously considered as relative contraindications to TAVR. However, an exploration study including a population of severe AS with BAV using the Sapien 3 and Evolut R/Pro valves showed favorable results with 30-day, 1-year, and 2-year mortality rates of 2.0%, 6.7%, and 12.5%, respectively.[44] With continuous successful TAVRs in patients with BAV, domestic hospitals have accumulated experience in the application of TAVR in such patients, especially using the Venus- A valve,[45–47] indicating that TAVR is feasible and safe for candidate patients with BAV. Therefore, BAV is regarded as a relative indication for TAVR by the consensus of Chinese experts.

Young patients requiring TAVR

The latest 2020 ACC/AHA guidelines for VHD management suggested that all-comer patients aged between 65 and 80 years may be potential candidates for TAVR following a corresponding discretion by the heart team, leading to an increasing number of young patients undergoing TAVR. Therefore, the long-term durability of valves already becomes a problem which was faced by the patients and physicians. The long-term durability outcomes of the first-generation valves presented at the 2016 EuroPCR conference suggested that TAVR devices may be comparable to SAVR devices if the same definition of structural valve degeneration is used, with a time from operation to valve deterioration and re-intervention ranging between 7 and 11 years postoperatively.[48] However, some studies have indicated that young patients who received TAVR might have a worse prognosis than old patients.[49,50] The NOTION II RCT planned to include surgically low-risk patients aged <75 years and compare the long-term follow-up outcomes for 5 to 10 years between patients who underwent TAVR and those who underwent SAVR, which is expected to provide more data on TAVR use in young patients.

Transcatheter valve-in-valve intervention

According to the Society of Thoracic Surgeons (STS) National Database, of 15,397 patients who underwent SAVR alone in 2006, 64.9% were aged >65 years, indicating a high risk of reoperation because they will be aged >80 years at the time of valve deterioration.[51] An international multicenter registry showed that transcatheter valve-in-valve implantation is safe and feasible for patients with surgical bioprosthetic valve deterioration.[52] In addition, the 2020 ACC/AHA guidelines and 2017 ESC/EACTS guidelines for VHD management proposed that transcatheter valve-in-valve implantation is a reasonable alternative to reoperation in surgical high-risk patients or those unable to undergo surgery with surgical bioprosthetic failure and limited valve expansion because of inability to use original surgical prostheses, leading to a risk of patient-prosthesis mismatch. Bioprosthetic valve fractures may potentially solve this issue.[53] Considering the high risk of patient-prosthesis mismatch and poor prognosis of the aforementioned patients, surgeons are advised to carefully balance the advantages and disadvantages during index surgery and select a bioprosthesis with a larger size, if possible.

Pure AR

SAVR is currently a standard treatment for pure AR, but a number of patients with contraindications or high surgical risk cannot receive surgery. Such patients may benefit from TAVR using the minimally invasive technique. However, anatomical challenges, such as the coexisting aortic root or ascending aorta dilation and large size of the aortic annulus, still exist. Moreover, lesions in patients with pure AR often lack clarification, possibly making it difficult for transcatheter valves to anchor stably and consequently increasing post-operative migration or PVL risk. The JenaValve and domestic J-Valve, with special three U-shaped graspers to fix on leaflets, may be suitable for such patients, even if the transapical approach is used. Because of the high prevalence of domestic AR, several researches have shown successful deployment of the J-Valve in patients with pure AR, indicating the feasibility and safety of TAVR procedure.[43,54,55]

Coronary occlusion

Coronary occlusion is a devastating complication that requires adequate preoperative assessment such as computed tomography assessing to reduce its risk, especially in patients with BAV, severe valvular calcification, low coronary ostium, or history of coronary artery disease. The bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction during TAVR (BASILICA) technique, coronary protection, and chimney stent strategy may help reduce the incidence of coronary occlusion, but there are risks of associated complications and treatment failure.[56–58] The difficulty of coronary angiography and percutaneous coronary intervention greatly increases after TAVR, which is also a matter that requires full consideration and might be solved by improving the valve structure in the future.

Transcatheter mitral valve intervention

Mitral valve disease epidemiology

The prevalence of moderate or severe mitral valve disease in patients aged >75 years in the USA might approach 10%.[1] According to different hemodynamics, mitral diseases can be divided into mitral stenosis and mitral regurgitation (MR). Mitral stenosis is prevalent in developing countries, with similar treatment results of surgery and percutaneous balloon valvuloplasty for this population.[59] MR is the most common VHD, with an incidence reaching 10% in the population aged >75 years in the Western countries.[1] According to different pathogenesis processes, MR can be divided into primary or organic lesions and secondary or functional lesions. Approximately more than 18.1 million people worldwide were diagnosed with primary MR in 2017, resulting in 35,700 deaths, while secondary MR accounted for 65% of moderate or severe MR cases and affacted up to 24% of patients with systolic heart failure.[60–62] The spectrum of mitral disease in China is different from that in developed countries, with rheumatic lesions being the most prevalent and the incidence of degenerative lesions increasing in recent years. Researches have estimated that there are approximately 10 million patients with MR (≥grade III) requiring treatment in China.[63,64] However, these patients are often refused by surgeons because of contraindications. In the meantime, conservative medical therapies are associated with poor prognosis, suggesting that there is still a considerable need for MR treatment. Therefore, transcatheter mitral valve intervention has been gradually adopted by physicians and patients due to its advantages of minimal invasiveness and short hospital stay. According to different modalities, transcatheter mitral valve intervention can be divided into transcatheter mitral valve repair and transcatheter mitral valve implantation (TMVI) [Table 3] [Figure 2].

Table 3 - Comparative overview of devices for transcatheter mitral valve intervention.
Devices Photo Usage CE/FDA/NMPA mark (years) Characteristics
Mitralclip Figure 2A Transcatheter edge-to-edge repair 2008 CE2019 FDA2020 NMPA Great experiences and can be used for treating TR. But anatomical limitations.
PASCAL Figure 2B Transcatheter edge-to-edge repair 2019 CE for MV2020 CE for TV Individual capture and fixation of leaflets and can be used for treating TR
DragonFly Figure 2C Transcatheter edge-to-edge repair Await Individual capture and fixation of leaflets.Adjustable angle when clipping.
ValveClamp Figure 2D Transcatheter edge-to-edge repair Await Bi-leaflets capturing simultaneously, but transapical approach.
Carillon Figure 2E Indirect transcatheter annuloplasty 2011 CE Simpler technique through coronary sinus but with indirect effect. Possible harm of LCX.
Cardioband Figure 2F Direct transcatheter annuloplasty 2015 CE for MV, 2018 CE for TV May serve as a platform for TMVR and can be used for treating TR, but only posterior mitral annulus cinching.Inapposite for mitral annulus calcification.Possible harm of LCX.
Mitralign Figure 2G Direct transcatheter annuloplasty 2016 CE May improve leaflet coaptation and can be used for treating TR, but by transapical approach of higher risk (bleeding and chordae injury).Only posterior mitral annulus cinching.
NeoChord Figure 2H Transcatheter artificial chordae implantation 2012 CE Beating heart in contrast to the surgical approach, but complications if inappropriate length.
Mitralstitch Figure 2I Transcatheter artificial chordal implantation and edge-to-edge repair Await Achieve artificial tendon implantation and edge-to-edge repair simultaneously.
Tendyne Figure 2J Transcatheter mitral valve implantation 2020 CE,2020 FDA Porcine leaflet, retrievable, but by transapical approach.
Intrepid Figure 2K Transcatheter mitral valve implantation Await Bovine leaflets, nitinol stent, size of 43#, 46#, 50#, and variable outer stent to accommodate native mitral annulus.But by transapical approach.
Mi-thos Figure 2L Transcatheter mitral valve implantation Await Double-deck brocket, but by transapical approach.
HighLife Figure 2M Transcatheter mitral valve implantation Await Based on concept of “valve-in-ring” to implant prosthesis via transseptal access
CE: Conformite europeene; FDA: Food and Drug Administration of the USA; LCX: Left circumflex artery; MV: Mitral valve; NMPA: National Medical Product Administration; TMVR: Transcatheter mitral valve repair; TR: Tricuspid regurgitation; TV: Tricuspid valve.

Figure 2:
Photos of devices for transcatheter mitral valve intervention. (A) Mitralclip; (B) PASCAL; (C) DragonFly; (D) ValveClamp; (E) Carillon; (F) Cardioband; (G) Mitralign; (H) NeoChord; (I) Mitralstitch; (J) Tendyne; (K) Intrepid; (L) Mi-thos; (M) HighLife.

Transcatheter mitral valve repair

Transcatheter edge-to-edge repair

Transcatheter edge-to-edge repair is based on surgical edge-to- edge mitral valve repair, which uses special mitral clippers for puncturing the atrial septum via the femoral vein to clamp the mitral valve and reduce the regurgitation orifice area. This special mitral clipper was first developed by Tec Deldman's team in 1999 and was named MitraClip (Abbott Vascular, Menlo Park, California, USA). The early results of the Endovascular Valve Edge-to-Edge Repair study (EVEREST II, NCT00209274) showed that intervention using MitraClip was slightly inferior to conventional surgery in reducing MR but had similar clinical improvements and superior safety.[65] Therefore, the 2012 ESC/ EACTS guidelines for VHD management recommended surgical high-risk patients with severe primary MR and patients unable to undergo surgery as candidates for MitraClip therapy (L-R IIb, L-E C). According to the favorable long-term 5-year follow-up results of the EVEREST II study, MitraClip was approved by FDA to be used for treating surgical high-risk patients and patients with degenerative MR in 2013 after gaining the CE mark in 2008.[66] For functional MR treatment, there were some differences in the results of 2 important studies. The Percutaneous Repair with the Mitraclip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR, NCT01920698) trial suggested that MitraClip did not improve the rate of mortality or heart failure rehospitalization, despite optimization using guideline-directed management therapy in patients with functional MR. However, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial showed opposite results.[67] In March 2019, the FDA approved MitraClip to be used for the treatment of functional MR based on the results of the COAPT trial, which has been more rigorously designed and conducted and adopted by the 2020 ACC/AHA guidelines for VHD management as well. The long-term follow-up results of the MITRA-FR and COAPT trials still had completely different conclusions, making the use of MitraClip for treating functional MR controversial. But the treatment benefit of population enrolled according to COAPT criteria has established the potential feasibility of Mitraclip usage in functioanl MR patients. MitraClip is currently the most widely used transcatheter mitral repair device in the market and was updated to its fourth generation, MitraClip G4, which has 4 types of clips; MitraClip G4 was successively approved by FDA and gained the CE mark in September 2019 and September 2020, respectively. Compared with TAVR, the development of MitraClip is relatively lagging in China. In 2012, the first MitraClip procedure for MR treatment was completed in China, and continuous other successful corresponding procedures have been performed in other domestic centers. In 2020, MitraClip obtained Chinese NMPA approval.

PASCAL (Edwards Lifesciences, Irvine, California, USA) is similar to MitraClip, despite its rhomboid folding clip structure. The force of clipping and leaflet fixation is based on elastic preformed metal retraction, without additional kinetic work. The PASCAL multicenter FIM study showed a high rate of procedural success and good post-operative MR reduction.[68] The multicenter single-arm clinical Edwards PASCAL Transcatheter Mitral Valve Repair System study (CLASP) suggested that the overall safety of this device was satisfactory.[69] In February 2019, PASCAL received the CE mark, together with the large-scale RCT CLASP IID/IIF approved by FDA.

In China, there are mainly 2 domestic devices for transcatheter edge-to-edge repair. DragonFly (Valgen Medtech Co., Hangzhou, China) is the first transfemoral mitral repair device in China, which has the independent ability for each clip to capture a leaflet and the unique clamp design allowing the clamp arm to clip with low tension. The 2020 Catheter Interventions in Congenital, Structural and Valvular Heart Disease (CSI) Webinar conference reported that the first 10 DragonFly cases in China had been completed with a device success rate of 100%, and all patients had an MR ≤ grade 2 before discharge. More follow-up outcomes will be collected continuously, and the clinical registry of DragonFly approved by the Chinese NMPA is about to be carried out. Another device is ValveClamp (Hanyu Medtech Co., Shanghai, China), the third transcatheter edge-to-edge repair device introduced internationally. ValveClamp can be advanced either via the peripheral arteries or the apex with a mean device time of 28.5 minutes. The 12 FIM cases of ValveClamp had a procedural success rate of approximately 100%, with no major adverse cardiovascular events. Moreover, the obviously reduced maximal regurgitant orifice area was maintained at 1- and 3-month follow-ups according to a report on the 2019 China Interventional Therapeutics (CIT) conference. At present, the premarketing multi-center trial of ValveClamp (CLAMP-2, NCT03869164) is conducted in 10 cardiovascular centers nationwide. The second-generation product of ValveClamp, which is inserted via the femoral artery, will soon be used in clinical practice.

Transcatheter mitral annuloplasty

Indirect transcatheter annuloplasty implants a special device in the coronary sinus to reduce the annulus size, thereby reducing the mitral valve orifice area and regurgitation. The representative device is Carillon (Cardiac Dimension Inc., Kirkland, Washington, USA). Although the initial clinical study Mitral Annuloplasty Device European Union Study has been completed and has gained the CE mark, Carillon was not progressed to be used in clinical practice due to its low procedural success rate and coronary artery occlusion risk. The device may compress the coronary circumflex branch when deployed, resulting in secondary myocardial ischemia and even myocardial infarction. Nevertheless, this device remains the only CE-approved indirect transcatheter mitral annuloplasty device.

Direct transcatheter annuloplasty can reduce mitral annulus size by placing an adjustable prosthetic annulus through a catheter. The representative devices are Cardioband (Edwards Lifesciences, Irvine, California, USA) and Mitralign (Mitralign Inc, Tewksbury, Massachusetts, USA). Cardioband is inserted by puncturing the atrial septum through the venous approach, with an annular contraction ratio reaching approximately 25% to 30%, which is suitable for patients with secondary MR. Researches have shown that the proportion of patients with MR ≥ grade 3 decreased from 77.4% preoperatively to 10.7% 1 month postoperatively and remained at 13.6% at a 7-month follow-up.[70] Preoperative screening requires special attention to the anatomy of the circumflex artery to avoid complications, and significant mitral annulus calcification may limit the screening efficiency. Unlike Cardioband, the Mitralign system shrinks the annulus size by tightening a string between the pledgets anchored to the annulus through artery approach. The FIM study of Mitralign showed that the device success rate was 70.4%; MR was reduced in 50% of patients, and there was significant cardiac functional improvement at a 6-month follow-up.[71]

Transcatheter artificial chordae implantation

Transcatheter artificial chordae implantation originated from a surgery for fixing prolapsed leaflets using an artificial chordae in patients who have long or ruptured mitral chordae tendineae, and the representative device is NeoChord (NeoChord, Minneapolis, Minnesota, USA), which is suitable for patients with mitral valve prolapse/flail. Subsequent study data showed that NeoChord had good efficacy and safety and a low incidence of corresponding complications[72,73] The aforementioned NeoChord studies only included surgical low-risk patients, and the safety and efficacy of this device in surgical high-risk patients need to be confirmed in the future.

Other types of transcatheter mitral valve repair

Given the complexity of the mitral valve anatomy and the pathogenesis of related diseases, combined transcatheter procedures may be necessary. Accordingly, the transcatheter COMBO mitral valve therapy has been proposed.[74] Moreover, in China, MitralStitch (Valgen Medtech, Hangzhou, China) is a representative device for combined procedures as it can achieve not only artificial chordal implantation but also complete mitral edge-to- edge repair using the transapical approach in a broader range of candidate patients. The first MitralStitch procedure was completed in 2018, and the single-center study related to this device achieved promising results.[75] In April 2019, a prospective, multicenter, single group assignment study for evaluating the safety and effectiveness of MitralStitch mitral valve repair system in patients with moderate to severe and severe mitral regurgitation (MIRACLE II, NCT04080362) was initiated and is currently ongoing at the time of writing this study.

Transcatheter mitral valve implantation

Due to the complex anatomy of the mitral valve, MR may have various etiologies with great heterogeneity, which are difficult for one device to repair. Therefore, TMVI may be a potential technical solution. TMVI can be divided into valve-in-mitral annular calcification (valve-in-mac), valve-in-native mitral valve (valve-in-valve), and valve-in-degenerated surgical bioprostheses or rings (valve-in-ring), with valve-in-valve having the best performance. Since the FIM TMVI was successfully performed in Denmark using the Cardi AQ valve (Edwards Lifesciences, Irvine, California, USA) in 2012, new devices have been continuously emerging, including the Tendyne device (Tendyne Holdings, LLC, a subsidiary of Abbott Vascular, Roseville, Minnesota, USA), Intrepid System (Medtronic, Minneapolis, Minnesota, USA), Neovasc Tiara Device (Neovasc, Richmond, British Columbia, Canada), Fortis System (Edwards Lifesciences, Irvine, California, USA), HighLife Device (Peijia Medical Limited Corporation, Suzhou, Jiangsu Province, China), Caisson System (Maple Grove, Minneapolis, Minnesota, USA), MValve Device (Herzliya, Tel Aviv, Israel), and NCS NaviGate System (NaviGate Cardiac Structures, LakeFore St, California, USA), with the first 2 valves being the most commonly used in clinical practice. The Tendyne valve is a D-shaped retrievable TMVI device with an atrial rim to avoid PVL and the ability to perform apical string fixation to avoid displacement. In 2019, the 1-year follow-up results of the first 100 patients receiving the Tendyne valve showed a device success rate of 97%, none or trace MR rate of 98.7% at 30 days and 1-year all-cause mortality of 27.6%.[76,77] The ongoing global multicenter clinical trial to evaluate the safety and effectiveness of using the Tendyne mitral valve system for the treatment of symptomatic mitral regurgitation (SUMMIT, NCT03433274) will further verify the safety and efficacy of the Tendyne valve. The Intrepid valve is another TMVI valve that is similar to the Tendyne valve. The FIM study of the Intrepid valve included 50 patients and showed a device success rate of 98%, with significantly decreased MR, increased cardiac function, and a 30-day mortality of 14%.[78] The transcatheter mitral valve replacement (TMVR) with the Medtronic IntrepidTM system in patients with severe symptomatic mitral regurgitation (APOLLO, NCT03242642) RCT reported at the 2019 Transcatheter Valve Therapies (TVT) conference that the 30-day mortality rate related to this device was only 2%. Simultaneously, the optimization and iterative updates of the Intrepid transcatheter mitral valve repair system in 2019 made it possible to implant the valve through peripheral venous approach, with a lower risk of myocardial injury and the avoidance of chest incision. Mi-thos (NewMed Medical, Shanghai, China) is a domestic TMVI system that is implanted using the transapical approach. This device was reportedly successfully used in a patient with a degenerated bioprosthetic mitral valve and severe MR and was preliminarily effective.[79] HighLife (Peijia Medical Limited Corporation, Suzhou, Jiangsu Province, China) is a self-expanding valve used for TMVR via transseptal access based on mechanism of “valve-in-ring”. The implantation procedure of HighLife valve consists of 2 steps plus 2 accesses, which includes placing loop and positioned subannular implant around the subannular structure via femoral artery access and valve implantation via transseptal access. The first two cases with severe functional MR who received HighLife valve implantation achieved safe and excellent early hemodynamic performance.[80]

Challenges of transcatheter mitral valve intervention

Transcatheter mitral valve repair can largely reduce MR, but the low acceptance rate and high in-hospital mortality remain major drawbacks. In addition, transcatheter mitral valve repair mainly treats only one type of anatomical lesion at once, which could not achieve one-stop treatment as surgery. So far, the edge-to-edge repair technique is the only transcatheter treatment recommended by current guidelines for primary and secondary severe symptomatic MR. However, device durability remains controversial. Although TMVI achieved satisfactory performance with good valve function, low rate of PVL, and short-term complications, it is associated with several problems. High risks of acute coronary complications and sub-valvular structure damage during transcatheter mitral valve deployment need to be considered. Meanwhile, due to some anatomical features of the mitral valve, including asymmetric annulus, irregular geometric leaflet, excessive annular size, non-calcification tissue, and complex sub-valvular structures, the difficulty to locate and anchor the mitral valve prosthesis remains an intractable problem. Moreover, detailed problems still existed such as (1) manipulation in the asymmetric calcification-free mitral annulus with high hemodynamic pressure; (2) risk of obstruction by the anterior mitral valve in the left ventricular outflow tract; (3) residual PVL, which often leads to hemolysis; (3) thrombosis risk; (4) the need for a transapical approach with a relatively large sheath; (5) technical heterogeneity; and (6) durability under the mechanical stress induced by movement during the cardiac cycle.

Although there is still not much evidence for TMVI, new devices will be continuously innovated, and more researches will be published due to natural advantages of its design and improvements in theoretical understanding. We believed that TMVI may become the new paradigm for MR treatment in the near future for those patients who are not suitable for transcatheter mitral valve repair.

Transcatheter tricuspid valve intervention

Epidemiology and treatment-status of tricuspid valve disease

Tricuspid stenosis is rare, while tricuspid regurgitation (TR) is the most common tricuspid valve disease, with an incidence of approximately 200,000 and >300,000 patients per year in the USA and Europe, respectively.[81] Most TRs are secondary lesions often associated with left heart diseases or atrial fibrillation that have a poor prognosis. However, TR has not received enough clinical attention, and few patients undergo independent tricuspid valve surgery, which is associated with high in-hospital mortality. Current treatment options for TR are limited. Surgical tricuspid valve repair or replacement provides no significant benefit, and medical treatment effects are poor. Nevertheless, some studies have shown that left-sided valve surgery combined with tricuspid valve repair may improve the prognosis of patients with TR,[82] suggesting the necessity of timely treatment for TR. Recently, research has demonstrated that transcatheter tricuspid valve intervention is associated with better survival and reduced heart failure rehospitalization occurrence than conservative medical therapy alone, preliminarily confirming the effectiveness of interventional therapy [Figure 3].[83]

Figure 3:
Comparative overview of devices for transcatheter tricuspid valve intervention. (A–C) Transcatheter tricuspid annuloplasty: TriCinch, Trialign, MIA; (D) Transcatheter tricuspid edge-to-edge repair: Triclip; (E) Transcatheter tricuspid valve repairment by enhancing coaptation: FORMA; (F and G) Orthotopic transcatheter tricuspid valve implantation: Navigate, LuX-Valve; (H and I) Heterotopic transcatheter tricuspid valve implantation: TricValve, Tricento.

Transcatheter tricuspid valve repair

Transcatheter tricuspid annuloplasty

The TriCinch System (4TECH Cardio Ltd, Galway, Ireland) is a transcatheter tricuspid annuloplasty device used to reduce the annulus size using an anchored coil at the junction of the anterior-posterior tricuspid valve leaflets. The annular diameter and regurgitation degree reduced postoperatively when the system was first applied, and the quality of life improved at 6 months postoperatively.[84] The second-generation TriCinch Coil system had better stability than the first-generation device and successfully converted the severe TR to mild TR postoperatively.[85] The multicenter study percutaneous treatment of tricuspid valve regurgitation with the TriCinch system™ (PREVENT, NCT02098200), which aimed to investigate the safety and efficacy of the TriCinch Coil system, is ongoing at the time of writing this study. The mechanism of Trialign (Mitraling, Tewksbury, Massachusetts, USA) is similar to that of the TriCinch Coil system. Intraoperatively, the catheter can reach the joint of the posterior-anterior or posterior-septal leaflet through the jugular vein and tighten the sutures linked to pledgets to fold the posterior leaflet, whose tension provided by a stent in postcava, thereby reducing the diameter of the tricuspid annulus. The registry trial early feasibility of the mitralign percutaneous tricuspid valve annuloplasty system (PTVAS) for symptomatic chronic functional tricuspid regurgitation (SCOUT, NCT02574650) related to the Trialign system showed that all 15 included patients with moderate or severe TR successfully underwent operation. At 30 days postoperatively, 12 patients had reduced effective regurgitant orifice area and significantly improved cardiac function, while 3 patients suffered pledget detachment,[86] confirming the feasibility of the usage of Trialign for functional TR treatment. Moreover, the associated SCOUT-II study that is currently ongoing at the time of writing this study is focusing on patients with trivial to moderate TR. The MIA device (Micro Interventional Devices, Inc., Newton, Pennsylvania, USA) comprises multiple polymeric anchors positioned between the anteroposterior and posteroseptal commissures and has a high technical success rate and high rate of valve area reduction.[87]

The Mitralign system, which was originally designed for MR treatment, is now indicated for patients with functional TR. This system can convert the tricuspid valve into the bicuspid valve by suturing and folding the annulus of the septal leaflet through the trans-jugular approach. The preliminary results of the SCOUT study showed that patients who underwent Mitralign implantation had significantly reduced regurgitation at 30 days postoperatively.[86] Another mitral valvular device is the Cardioband system, which gained the CE mark for TR treatment. The latest tricuspid regurgitation repair with cardioband transcatheter system (TRI-REPAIR, NCT02981953) clinical trial related to the Cardioband system reported sustained reduced annular size and TR severity at 2-year follow-up.[88]

Transcatheter tricuspid edge-to-edge repair and other TR treatments

The TriClip system (Abbott Vascular, Menlo Park, California, USA) clamps the anterior and septal leaflet or the posterior and septal leaflet via the femoral vein, similar to MitraClip. The trial to evaluate treatment with Abbott transcatheter clip repair system in patients with moderate or greater tricuspid regurgitation (TRILUMINATE, NCT03227757), which included 85 patients with moderate to severe TR treated with the TriClip system, demonstrated that 86% of patients had decreased TR by at least 1 grade at a 30-day follow-up.[89] In April 2020, the TriClip system gained the CE mark, becoming the first approved transcatheter tricuspid valve repair device in the world.

MitraClip, an effective device for treating degenerative and functional MR, is increasingly used in transcatheter tricuspid valve intervention. The multicenter multi-device Trivalve registry is the largest study to validate the efficacy of severe TR interventions, with MitraClip comprising over 60% of devices. The preliminary results of this study published in the 2018 Transcatheter Cardiovascular Therapeutics (TCT) conference showed favorable procedural success rates, device durability, and clinical benefits, and similar results can also be found in the PASCAL system, which was also used for patients with MR initially, combining the design concept of FORMA (Edwards Lifesciences, Irvine, California, USA) and the MitraClip system in addition to a central spacer that fills the regurgitant area and 2 independently grasping arms. The FIM experience of PASCAL suggested that this device has high procedural success and acceptable safety and induces significant clinical improve- ment[90]; PASCAL later became approved for commercial use in patients with TR in Europe in May 2020.

The FORMA system enhances coaptation by placing a spacer at the regurgitant orifice while preserving the original leaflet. Research has shown that TR significantly decreased postopera- tively using this device.[91] The early feasibility study of this device is currently ongoing and will expectedly further evaluate its safety. However, this device is only suitable for patients with small regurgitant orifices.

Transcatheter tricuspid valve implantation

Orthotopic transcatheter tricuspid valve implantation

The representative valve for orthotopic transcatheter tricuspid valve implantation is NaviGate (NaviGate Cardiac Structures, Lake Forest, California, USA). The NaviGate valve consists of equine pericardial tissue and nitinol stents sized between 36 and 52 mm and is used in patients with severe TR using either the jugular vein or atrium approach. Thus far, this valve has been used in surgical high-risk patients with TR in multiple clinical centers. Results have shown that this device has effectively improved cardiac function and right heart remodeling in patients.[92,93] However, the problems of PVL and its non- retrievable design pose some challenges related to its usage. In the future, the optimal population for this valve and corresponding long-term outcomes should be studied.

The LuX-Valve (Jenscare Biotechnology, Ningbo, Zhejiang, China), a transcatheter tricuspid valve replacement device developed in China, consists of bovine pericardial tissue and nitinol stents in addition to a skirt to prevent PVL. The deployment of this device does not require radial force but fixed by a special anchoring structure. Of the 12 patients included in the FIM study of this device, only 1 patient died in the hospital due to myocardial infarction.[94]

Heterotopic transcatheter tricuspid valve implantation

Heterotopic transcatheter tricuspid valve implantation can reduce the load of right heart by preventing the blood reflux into the superior and inferior vena cava during systole. Lauten et al[95] first proposed the idea of prosthesis in the vena cava to reduce TR and relieve heart failure symptoms. The Edwards Sapien XT valve and TricValve (P & F Products & Features Vertriebs GmbH, Vienna, Austria), a self-expanding valve with 2 separate stents, were reported to be first used in humans in 2013 and 2014, respectively. The Edwards Sapien XT valve is effective for improving dyspnea but has a high in-hospital mortality rate.[96] Another bi-leaflet valve that has been used in humans is the Tricento valve (NVT GmbH, Hechingen, Germany). After implantation, TR and right atrial dilatation did not significantly improve in most patients, with 1 patient having alleviated symptoms postoperatively and another dying of end-stage renal failure after 4 months.[97,98] Consequently, such a device cannot fundamentally treat TR and may even cause further tricuspid annulus dilation, impeding the further usage of these devices.

Challenges of transcatheter tricuspid valve intervention

Although transcatheter valve intervention by an experienced surgeon in patients with left-sided heart valvular disease can provide references for interventional TR treatment, transcatheter tricuspid valve intervention still faces many challenges due to the particular anatomy of valves, including (1) the large tricuspid annulus proximal to the right coronary artery; (2) thin wall of the right ventricle, which has a high perforation risk; (3) frequent presence of pacemaker or defibrillator leads during manipulation; and (4) adjacent location of the valve to the sinoatrial node and His bundle, which causes a high risk of conduction disturbances. In addition, low blood flow velocity in the right heart increases thrombosis and endocarditis risks. Although exploration studies have preliminarily confirmed that interventional therapy for TR is partially safe and effective in some cases, most studies on interventional therapy for TR are observational and have small sample sizes. Currently, the indications for interventional therapy for TR are still unclear, and whether early intervention for patients with mild to moderate TR has any benefits remains to be further validated. However, there is no doubt that tricuspid valve disease will be an important topic in the field of transcatheter valvular therapy in the near future. More well-designed RCTs with larger populations are needed to provide evidence for transcatheter tricuspid valve intervention.

Transcatheter pulmonary valve implantation (TPVI)

History of TPVI

The earliest transcatheter valve implantation technique, TPVI, was performed in 2000[99]; this surgery is mainly performed to treat patients with pulmonary regurgitation (PR) after surgery for complex congenital heart diseases, such as tetralogy of Fallot. Severe PR may lead to significantly reduced exercise tolerance and even ventricular arrhythmias or sudden death in patients; therefore, these patients may require surgical valve replacement, which has a high risk of reoperation. TPVI has evolved to become an attractive alternative to surgery in such patients, as supported by the early results of corresponding studies.

Devices for TPVI

The main valves used in Europe and the USA are Melody (Medtronic, Minneapolis, Minnesota, USA) or serial Sapien valves. However, these 2 valves need additional pre-mounted stents in the right ventricular outflow tract before implantation and have a relatively limited size (Melody ≤ 24 mm, and Sapien ≤ 29 mm). More than 85% of patients who underwent surgery for tetralogy of Fallot in China have a pulmonary annulus diameter >30 mm postoperatively; therefore, the aforementioend 2 valves are not suitable for most Chinese patients.

The domestic Venus P-Valve system (Venus Medtech Co., Hangzhou, China) is the first transcatheter self-expanding valve in the world and is especially used for patients with PR in clinical settings; this device does not require a pre-mounted stent. The early clinical trial for this device showed that the success rate was 98.2%, and the all-cause mortality was 3.6% at 1-year follow- up.[100] In 2016 and 2019, the pre-CE mark trial and the Investigational Device Exemption study for FDA were officially initiated, respectively. Venus P-valve implantation has provided satisfactory results with a high success rates and low complication rates in an inherently challenging patient population globally.[101]

Challenges of TPVI

Future developments in the field of TPVI should aim to reduce the complication rate, increase the freedom of re-intervention, and most importantly, expand the indicated population. The TVPI-related infective endocarditis rate is relatively high; therefore, it is necessary to initiate more research on the management of postoperative infective endocarditis. TPVI devices should be further improved to include a low profile design, long durability, low opening resistance, rapid and reliable closure, and non-thrombogenic properties.


The development of transcatheter intervention for VHD provides alternative options for patients who are unable to undergo surgery or not benefit from conservative medical therapy, with superior clinical outcomes in selected population. There are multiple international valve conferences and workshops being organized, such as the serial of PCR conferences, CIT conference, TVT conferences, TCT conference, TAVI Workshop in Latin America, and so on, to provided lectures and updated information about interventional cardiology. With the accumulation of evidence and device improvements, the indications for heart valvular intervention have been gradually expanding. In China, there are many current remarkable achievements in the field of interventional therapy for VHD combined with cuttingedge novel innovations. Intervention therapy for VHD has been continuously popularized and promoted, which is anticipated to benefit an increasing number of patients in the future.



Conflicts of Interests

Yuan Feng is a consultant/proctor of Venus Medtech, MicroPort and Peijia Medical.


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Valvular heart disease; Interventional therapy; Transcatheter therapy

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