Based on data from VIVID and TVT registries, where MViV was performed via a trans-septal approach in 18.5% and 49% of patients, respectively, the 30-day mortality was approximately 8–9%. Later, the MITRAL trial, which relied exclusively on a trans-septal technique, was able to further decrease the 30-day mortality to 3.3% ^[1][36]. However, this cohort was a highly selected population of patients with extremely experienced operators. To determine whether this lower mortality could be reproduced in the real world, especially on longer follow-up times, Whisenant et al. evaluated more contemporary outcomes with the Sapien 3 valve from the TVT registry. In 1529 patients hospitalized between 2015 and 2019 for MViV (1326 trans-septal and 203 transapical), procedural success was high (96.8%), with an all-cause mortality of 5.4% at 30 days and 16.7% at 1 year ^[2][37]. Though no differences were observed in the technical success rate of either approach, the trans-septal approach was associated with a lower mortality at 1 year (15.8% vs. 21.7%) with a hazard ratio of 0.67, thus, highlighting the importance of choosing the trans-septal approach in patients with a favorable anatomy ^[2][37]. MViV also led to early, sustained and clinically meaningful improvements in heart failure symptoms, as well as valve performance. In comparison, for the MITRAL trial, the mortality at 1 year was 3.3% (unchanged from 30-day outcomes) and 6.7% at 2 and 3 years ^[1][36]. Based on the available data, MViV was, thus, FDA approved for high-risk patients in June 2017 ^[3][38], but is actively being investigated in the ongoing PARTNER 3 trial for intermediate-surgical-risk patients, which consists of a prospective registry of 50 patients at 16 sites in the United States and Canada that recently completed enrollment in 2021 ^[4][39].

From an imaging standpoint, it is important to note that in 60–80% of patients treated successfully with MViV for a failed surgical bioprosthesis, abnormally increased residual transvalvular gradients were measured in transthoracic echocardiography before discharge or at 30 days, despite being within normal limits in a routine periprocedural transoesophageal echo. A few in vitro studies reported a substantial impact in actual MViV frame geometry (such as eccentricity, a nonround shape and underexpansion) on the altered transvalvular flow characteristics, and a large field-of-view intravascular ultrasound (IVUS) offers a unique tomographic perspective for a direct periprocedural measure of the MViV stent frame and leaflet geometry ^[5][6][40,41]. It is the actual three-dimensional expansion of the MViV stent frame that determines the pattern of the restored blood flow and the long-term outcomes of valve-in-valve deployment, and actual MViV expansion may differ significantly from the nominal, and there is no valid periprocedural measure to date. The periprocedural use of a large field-of-view IVUS may offer accurate and online measurements of the actual expansion of MViV deployed ^[5][6][40,41].

Based on the VIVID and TVT registries, early experiences with MViR patients had higher 30-day mortality of approximately 11–13%. In the MITRAL trial, which switched from a transapical to exclusively trans-septal approach, the 30-day mortality was significantly reduced to 6.7% ^[7][42]. The 1-year mortality of 23.3% was lower than predicted by the STS score of 7.6% ^[7][42] and similar to that of patients who were treated with MitraClip in the US based on the TVT registry ^[8][15], which was a favorable result, given the very well-established track record of transcatheter edge-to-edge repair. At 2 years, the mortality rate was 43.3%, which was similar to devices designed for the mitral valve, such as Tendyne, discussed in a later section. Patients receiving smaller-sized THVs with rigid rings were noted to have higher gradients. A subsequent analysis of contemporary data from a TVT database with Sapien 3 MViR found that the 30-day all-cause mortality decreased dramatically over time from approximately 11% in 2015–2016 to 6% in 2020, reproducing better outcomes with mortality rates similar to the MITRAL trial. The access route was also switched from being mainly transapical to transeptal. Based on these data, the FDA approved MViR for high-risk patients in May 2021 ^[3][38].

Patients with MAC represent the highest-risk population, even prior to their presentation with valvular dysfunction. Multimodality imaging incorporating echocardiography and cardiac computed tomography is being increasingly recognized as being key for the assessment and grading of MAC and associated valve dysfunction ^[9][43]. To improve the MAC evaluation, a novel computed-tomography-based MAC score has been shown to predict outcomes among 334 patients with mitral valve dysfunction undergoing mitral valve surgery ^[10][44]. From the Framingham Heart Study, which consisted of 1197 patients who had a transthoracic echo with an average follow-up of 16 years, these individuals were often older females with significant cardiovascular comorbidities, such as hypertension, atrial fibrillation, stroke, coronary and peripheral artery disease, that elevated their risk for mortality ^[11][45]. Coupled with the technical challenges during surgery and potential complications from calcium deposition (such as posterior LV wall rupture), these risk factors increase the mortality to >20%. Thus, this cohort of patients are often left untreated and have traditionally been understudied until recently. A second study found that among 24,414 patients who underwent a clinically indicated echo, MAC was present in 23% (n = 5502) of the population ^[12][46]. Patients with MAC and MV dysfunction had a higher prevalence of mitral stenosis (MS) compared to those with MV dysfunction without MAC (6.6% vs. <1%). From a mortality standpoint, isolated MAC without MV dysfunction already had compromised outcomes (similar to those with MV dysfunction without MAC) compared to those without MAC or mitral valve dysfunction; 1-year Kaplan–Meier survival was 86–87% vs. 92%, with an HR of 1.40 (95% CI 1.31–1.49, p < 0.001) ^[12][46]. However, when MAC was associated with MV dysfunction, the 1-year survival was even poorer at 76%, with an HR of 1.79 (95% CI 1.58–2.01, p < 0.001) ^[12][46]. From a further analysis of this same cohort, during a median follow-up of 3.2 years, patients with MAC and severe mitral valve dysfunction who received intervention had higher survival than those without intervention (90% vs. 72% at 1 year; 55% vs. 35% at 4 year). The MV intervention was, thus, found to be an independent predictor of lower mortality, with a hazard ratio of 0.66 ^[13][47]. Another study also found mitral valve interventions to be associated with improved prognosis after propensity score matching, and the key predictors of mortality being a higher Charlson comorbidity index and frailty ^[14][48].

However, outcomes from the early experience with ViMAC were not ideal. From the TMVR in a MAC global registry, which consisted of 116 MAC patients with high STS scores of 15.3%, the 30-day and 1-year mortalities were 25% and 53.7%, respectively ^[15][49]. Similarly, from the multicenter TMVR registry led by the Cedars Sinai team, which consisted of 58 MAC patients, the 30-day mortality was even higher at 34.5% ^[16][50]. This could be attributed to three main challenges/complications with ViMAC: paravalvular leak with associated hemolysis, valve embolization and LVOT obstruction, the latter two of which can be predicted and, thus, prevented with improved temporal outcomes. LVOT obstruction was readily established as the strongest independent predictor of 1-year mortality for TMVR with an adjusted hazard ratio of 2.63 ^[15][49]. The two main ways to prevent LVOT obstruction are septal reduction strategies and anterior leaflet strategies. Septal reduction strategies include alcohol septal ablation, a concept generated in the MITRAL trial ^[17][51], and radiofrequency septal ablation ^[18][52]. Anterior leaflet strategies include surgical resection (MITRAL and SITRAL trials) and percutaneous laceration (LAMPOON trial). From a multicenter registry experience of preemptive alcohol ablation to prevent LVOT obstruction, there was an incremental increase in the size of the LVOT space, where the baseline median Neo-LVOT was 85.1 mm², with a median increase of 111.2 mm^{2 [18]}[52]. In cases where ViMAC is high risk, if the Neo-LVOT < 200 m², the optimal strategy to prevent LVOT obstruction is determined by measuring the Skirt Neo-LVOT, whereby the septal reduction strategy is considered if <200 mm² vs. LAMPOON-facilitated transeptal ViMAC if >200 mm^{2 [19]}[53]. In the MITRAL trial using alcohol septal ablation, there was an improvement in patient outcomes, whereby in a population with an STS score of 8.6%, trans-septal ViMAC had a 30-day mortality of 6.7%, compared to 21.4% for transatrial access. The 1-year mortality of 33% was not dissimilar to the MitraClip TVT registry, especially for secondary MR (31.2%) ^[8][20][15,54], while the 2-year mortality of 39.9% was similar to the transcatheter aortic valve (TAVR) experience from the PARTNER 1 trial (43.3%) ^[21][55]; the 3-year survival was 50% in a high-risk population. Furthermore, the mean mitral valve gradient remained stable at 2 years. Given these encouraging trials, the MITRAL II Pivotal trial is being conducted for high-risk surgical patients with severe MAC MS (MV area ≤ 1.5 cm²) or ≥3+ MR with NYHA class II or greater symptoms. The two arms are ViMAC with 100% trans-septal access + preemptive LVOT obstruction, for those with favorable anatomy and a CT MAC score ≥ 7 (n = 110), vs. natural history (n = 100) for noncandidates for intervention. The primary endpoint of interest will be all-cause death and heart failure hospitalization at 1 year.

Early experience with TMVR in the United States using aortic THV, which started with the off-label use of aortic THV, was first highlighted by the TVT registry from 2013 to 2017. There was a significant difference in outcomes of patients cleared for MViV, who had the lowest in-hospital and 30-day mortality when compared with MViR and ViMAC ^[22][56]. Although various factors, including distinct patient populations and procedural techniques, could have explained the varied outcomes between these three groups, such differences persisted in multiple subsequent studies. In a single-center study of 91 patients in France, Urena et al. observed that ViMAC had the highest mortality at 1 year (41.7%) and 2 years (58.4%) when compared to MViV (13.2% at 1 year; 29.4% at 2 years) and MViR (12.7% at 1 year; 24.5% at 2 years) ^[23][57]. Based on Cedar Sinai’s multicenter TMVR registry of 521 patients, ViMAC also had the highest 1-year mortality (62.8%) compared to MViR (30.6%) and MViV (14.0%) individuals ^[16][50]. The MITRAL trial confirmed these trends, whereby the three-year survival was significantly better for MViV (93.3%) than MViR and MViV (<60%) patients.

There has been extensive ongoing research into the use of dedicated THVs for native noncalcified MV diseases. The most well-studied and only mitral THV approved in Europe is the Tendyne, which is a transapically deployed trileaflet porcine bioprosthetic valve with its outer frame contoured to mitral annulus and available in multiple sizes and profiles to address a broad range of patient anatomies. From an initial report of the first 100 patients from the Tendyne Global Feasibility Study, 90% of whom had secondary MR, with a mean STS score of 7.9% and EF of 46.6%, the intraprocedural mortality was 0% and 30-day mortality was 6%, which was the first time that a transcatheter mitral device resulted in a 30-day mortality lower than predicted by the STS score ^[24][58]. At 12 months, there was an impressive reduction in the degree of MR with 98.4% of individuals having none too trivial MR at 12 months and sustained significant improvement in symptoms ^[24][58]. The 1-year mortality of 26% was similar to MitraClip per the TVT registry (24.7% for degenerative MR and 31% for functional MR) and TAVR per the PARTNER 1A trial (24%) ^[24][58]. Due to the favorable outcomes of this device, it received approval on 30/1/2020 ^[25][59]. Furthermore, the 2-year mortality was 41.6%, with a continued sustained improvement in MR, clinical symptoms and quality of life, as well as a significant reduction in the heart failure hospitalization rate (0.51 events per patient-year postoperation vs. 1.30 events per patient-year pre-operation) ^[26][60].

Early experience with Tendyne in MAC also demonstrated promising results. Per Sarajja et al., the first nine patients who received Tendyne in MAC who had an STS score of 7.4%, had a 30-day mortality of 0% ^[27][61]. A subsequent analysis of the first 20 patients showed a 1-year all-cause mortality of 40%, which was almost identical to the 1-year mortality of 39.9% from the original MITRAL trial, despite a higher-risk patient population ^[28][62]. Currently, SUMMIT (Safety and Effectiveness of Using the Tendyne Mitral Valve System for the Treatment of Symptomatic Mitral Regurgitation) is an ongoing study recruiting patients with symptomatic grade III/IV MR or severe MAC, deemed by the heart team to be more suitable for the transcatheter treatment than surgery ^[29][63]. For those individuals with MV anatomy and indications appropriate for transcatheter repair, they were randomized 1:1 to receive Tendyne or MitraClip; otherwise, subjects were directly offered Tendyne.