Ten Future Challenges in the Field of Transcatheter Mitral Valve Edge-to-Edge Repair.

Mitral valve transcatheter edge-to-edge repair (M-TEER) and replacement (TMVR) have evolved as guideline-recommended treatment approaches for mitral regurgitation (MR). Even though they are supported by a growing body of evidence from either randomized trials or large registries, there are still several unsolved challenges in the field of interventional MR treatment. In the present review, we discuss the ten most important open questions regarding M-TEER and TMVR.

Multiphoton In Vivo Microscopy of Embryonic Thrombopoiesis Reveals the Generation of Platelets through Budding.

Platelets are generated by specialized cells called megakaryocytes (MKs). However, MK's origin and platelet release mode have remained incompletely understood. Here, we established direct visualization of embryonic thrombopoiesis in vivo by combining multiphoton intravital microscopy (MP-IVM) with a fluorescence switch reporter mouse model under control of the platelet factor 4 promoter (Pf4CreRosa26mTmG). Using this microscopy tool, we discovered that fetal liver MKs provide higher thrombopoietic activity than yolk sac MKs. Mechanistically, fetal platelets were released from MKs either by membrane buds or the formation of proplatelets, with the former constituting the key process. In E14.5 c-Myb-deficient embryos that lack definitive hematopoiesis, MK and platelet numbers were similar to wild-type embryos, indicating the independence of embryonic thrombopoiesis from definitive hematopoiesis at this stage of development. In summary, our novel MP-IVM protocol allows the characterization of thrombopoiesis with high spatio-temporal resolution in the mouse embryo and has identified membrane budding as the main mechanism of fetal platelet production.

Cardio-hepatic syndrome in patients undergoing mitral valve transcatheter edge-to-edge repair.

AIMS: The impact of the cardio-hepatic syndrome (CHS) on outcomes in patients undergoing mitral valve transcatheter edge-to-edge repair (M-TEER) for relevant mitral regurgitation (MR) is unknown. The objectives of this study were three-fold: (i) to characterize the pattern of hepatic impairment, (ii) to investigate the prognostic value of CHS, and (iii) to evaluate the changes in hepatic function after M-TEER. METHODS AND RESULTS: Hepatic impairment was quantified by laboratory parameters of liver function. In accordance with existing literature, two types of CHS were distinguished: ischaemic type I CHS (elevation of both transaminases) and cholestatic type II CHS (elevation of two out of three parameters of hepatic cholestasis). The impact of CHS on 2-year mortality was evaluated using a Cox model. The change in hepatic function after M-TEER was assessed by laboratory testing at follow-up. We analysed 1083 patients who underwent M-TEER for relevant primary or secondary MR at four European centres between 2008 and 2019. Ischaemic type I and cholestatic type II CHS were observed in 11.1% and 23.0% of patients, respectively. Predictors for 2-year all-cause mortality differed by MR aetiology. While in primary MR cholestatic type II CHS was independently associated with 2-year mortality, ischaemic CHS type I was an independent mortality predictor in secondary MR patients. At follow-up, patients with MR reduction ≤2+ (obtained in 90.7% of patients) presented with improved parameters of hepatic function (median reduction of 0.2 mg/dl, 0.2 U/L and 21 U/L for bilirubin, alanine aminotransferase and gamma-glutamyl transferase, respectively, p < 0.01). CONCLUSIONS: The CHS is frequently observed in patients undergoing M-TEER and significantly impairs 2-year survival. Successful M-TEER may have beneficial effects on CHS.

Transcatheter mitral valve replacement or repair for secondary mitral regurgitation: a propensity score-matched analysis.

AIMS: This study aimed to compare outcomes after transcatheter mitral valve replacement (TMVR) and mitral valve transcatheter edge-to-edge repair (M-TEER) for the treatment of secondary mitral regurgitation (SMR). METHODS AND RESULTS: The CHOICE-MI registry included 262 patients with SMR treated with TMVR between 2014 and 2022. The EuroSMR registry included 1065 patients with SMR treated with M-TEER between 2014 and 2019. Propensity score (PS) matching was performed for 12 demographic, clinical and echocardiographic parameters. Echocardiographic, functional and clinical outcomes out to 1 year were compared in the matched cohorts. After PS matching, 235 TMVR patients (75.5 years [70.0, 80.0], 60.2% male, EuroSCORE II 6.3% [interquartile range 3.8, 12.4]) were compared to 411 M-TEER patients (76.7 years [70.1, 80.5], 59.0% male, EuroSCORE II 6.7% [3.9, 12.4]). All-cause mortality was 6.8% after TMVR and 3.8% after M-TEER at 30 days (p = 0.11), and 25.8% after TMVR and 18.9% after M-TEER at 1 year (p = 0.056). No differences in mortality after 1 year were found between both groups in a 30-day landmark analysis (TMVR: 20.4%, M-TEER: 15.8%, p = 0.21). Compared to M-TEER, TMVR resulted in more effective mitral regurgitation (MR) reduction (residual MR ≤1+ at discharge for TMVR vs. M-TEER: 95.8% vs. 68.8%, p < 0.001), and superior symptomatic improvement (New York Heart Association class ≤II at 1 year: 77.8% vs. 64.3%, p = 0.015). CONCLUSION: In this PS-matched comparison between TMVR and M-TEER in patients with severe SMR, TMVR was associated with superior reduction of MR and superior symptomatic improvement. While post-procedural mortality tended to be higher after TMVR, no significant differences in mortality were found beyond 30 days.

Transcatheter edge-to-edge repair for secondary mitral regurgitation with third-generation devices in heart failure patients - results from the Global EXPAND Post-Market study.

AIMS: Mitral valve transcatheter edge-to-edge repair is a guideline-recommended treatment option for patients with secondary mitral regurgitation (SMR). The purpose of this analysis was to report contemporary real-world outcomes in SMR patients treated with third-generation MitraClip systems. METHODS AND RESULTS: EXPAND is a prospective, multicentre, international, single-arm study with 1041 patients treated for mitral regurgitation (MR) with MitraClip NTR/XTR, with 30-day and 1-year follow-up. All echocardiograms were analysed by an independent echocardiographic core lab. Study outcomes included procedural outcomes, durability of MR reduction, and major adverse events including all-cause mortality and heart failure hospitalizations (HFH). A subgroup of 413 symptomatic patients (age 74.7 ± 10.1 years, 58% male) with severe SMR were included. MR reduction to MR ≤ 1+ and MR ≤ 2+ was achieved in 93.0% and 98.5% of patients, respectively, which was sustained at 1-year follow-up. All-cause mortality was 17.7% at 1-year- follow-up, and the combined endpoint of all-cause mortality or first HFH occurred in 34% of patients. This combined endpoint was significantly less frequently observed in MR ≤ 1+ patients (Kaplan-Maier estimates: 29.7% vs. 69.6% for MR ≤ 1+ vs. MR ≥ 2 +; p < 0.0001). New York Heart Association (NYHA) functional class improved significantly from baseline (NYHA ≤ II: 17%) to 1-year follow-up (NYHA ≤ II: 78%) (p < 0.0001). While MR reduction was comparable between NTR-only vs. XTR-only treated patients, less XTR clips were required for achieving MR reduction. CONCLUSIONS: Under real-world conditions, optimal sustained MR reduction to MR ≤ 1+ was achieved in a high percentage of patients with third-generation MitraClip, which translated into symptomatic improvement and low event rates. These results appear to be comparable with recent randomized clinical trials.

Staging Heart Failure Patients With Secondary Mitral Regurgitation Undergoing Transcatheter Edge-to-Edge Repair.

BACKGROUND: Secondary mitral regurgitation (SMR) is a progressive disease with characteristic pathophysiological changes that may influence prognosis. Although the staging of SMR patients suffering from heart failure with reduced ejection fraction (HFrEF) according to extramitral cardiac involvement has prognostic value in medically treated patients, such data are so far lacking for edge-to-edge mitral valve repair (M-TEER). OBJECTIVES: This study sought to classify M-TEER patients into disease stages based on the phenotype of extramitral cardiac involvement and to assess its impact on symptomatic and survival outcomes. METHODS: Based on echocardiographic and clinical assessment, patients were assigned to 1 of the following HFrEF-SMR groups: left ventricular involvement (Stage 1), left atrial involvement (Stage 2), right ventricular volume/pressure overload (Stage 3), or biventricular failure (Stage 4). A Cox regression model was implemented to investigate the impact of HFrEF-SMR stages on 2-year all-cause mortality. The symptomatic outcome was assessed with New York Heart Association functional class at follow-up. RESULTS: Among a total of 849 eligible patients who underwent M-TEER for relevant SMR from 2008 until 2019, 9.5% (n = 81) presented with left ventricular involvement, 46% (n = 393) with left atrial involvement, 15% (n = 129) with right ventricular pressure/volume overload, and 29% (n = 246) with biventricular failure. An increase in HFrEF-SMR stage was associated with increased 2-year all-cause mortality after M-TEER (HR: 1.39; CI: 1.23-1.58; P < 0.01). Furthermore, higher HFrEF-SMR stages were associated with significantly less symptomatic improvement at follow-up. CONCLUSIONS: The classification of M-TEER patients into HFrEF-SMR stages according to extramitral cardiac involvement provides prognostic value in terms of postinterventional survival and symptomatic improvement.

Transcatheter edge-to-edge mitral valve repair in mitral regurgitation: current status and future prospects.

INTRODUCTION: Mitral regurgitation (MR) is associated with substantial morbidity and mortality. Within the past 15 years, mitral valve edge-to-edge repair (M-TEER) has developed from an experimental approach to a guideline-recommended, safe, and effective treatment option for patients with severe primary or secondary mitral regurgitation. AREAS COVERED: This review covered relevant publications of M-TEER and summarizes the development of M-TEER devices within the last 15 years. It outlines anatomical challenges which drove the evolution of M-TEER devices, provides an overview about the current state of clinical application and research, and offers an outlook into the future of transcatheter mitral valve treatment. EXPERT OPINION: The development and refinement of new M-TEER device generations offer the possibility to treat a wide range of mitral valve anatomies. Choosing the best device for the individual anatomic properties of the patients and considering comorbidities is the key to maximized MR reduction, minimalized complication rates, and thus optimized postinterventional prognosis. Independent from prognostic implications, quality of life has become an important patient-centered outcome that can be improved by M-TEER in virtually all patients treated.

Sex-specific impact of anthropometric parameters on outcomes after transcatheter edge-to-edge repair for secondary mitral regurgitation.

BACKGROUND: Body surface area (BSA) has been reported to be the stronger predictor for prognosis than body mass index in heart failure (HF) patients. The sex-specific association of BSA with mortality has been unclear. METHODS: EuroSMR, a European multicenter registry, included patients who underwent edge-to-edge repair (TEER) for secondary mitral regurgitation (SMR). The outcome was two-year all-cause mortality. RESULTS: The present cohort included 1594 HF patients (age, 74 ± 10 years; male, 66%). Association of calculated BSA with two-year all-cause mortality was evaluated. Patients were classified into three BSA groups: the lowest 10% (S), the highest 10% (L), and intermediate between S and L (M). Mean BSA was 1.87 ± 0.21 m2 (male, 1.94 ± 0.18 m2; female, 1.73 ± 0.18 m2). The association of BSA with the endpoint in females showed a U-shaped curve, indicating worse prognosis for both S and L. The association in males followed a linear regression, demonstrating better prognosis for L. Hazard ratio (HR) of L to S in males was 0.43 (95% confidence interval [CI], 0.25-0.74; p = 0.002), whereas HR of L to M in females was 1.76 (95% CI, 1.11-2.78; p = 0.016) (p for interaction = 0.003). CONCLUSIONS: Sex-specific association patterns demonstrate the complex influence of anthropomorphic factors in HF patients scheduled for TEER. Further investigation beyond simple evaluation of weight and height is needed for better comprehension of the obesity paradox and better prediction of the results of transcatheter therapy in HF patients.

Right ventricular function in transcatheter mitral and tricuspid valve edge-to-edge repair.

Since transcatheter edge-to-edge repair (TEER) has become a valuable therapy in the treatment of both, mitral (MR) and tricuspid regurgitation (TR), the question of optimized patient selection has gained growing importance. After years of attributing rather little attention to the right ventricle (RV) and its function in the setting of valvular heart failure, this neglect has recently changed. The present review sought to summarize anatomy and function of the RV in a clinical context and aimed at presenting the current knowledge on how the RV influences outcomes after TEER for atrioventricular regurgitation. The anatomy of the RV is determined by its unique shape, which necessitates to use three-dimensional imaging methods for detailed and comprehensive characterization. Complex parameters such as RV to pulmonary artery coupling (RVPAc) have been developed to combine information of RV function and afterload which is primary determined by the pulmonary vasculature and LV filling pressure. Beyond that, TR, which is closely related to RV function also plays an important role in the setting of TEER. While mitral valve transcatheter edge-to-edge repair (M-TEER) leads to reduction of concomitant TR in some patients, the prognostic value of TR in the setting of M-TEER remains unclear. Overall, this review summarizes the current state of knowledge of the outstanding role of RV function and associated TR in the setting of TEER and outlines the unsolved questions associated with right-sided heart failure.

Right ventricular dysfunction predicts outcome after transcatheter mitral valve repair for primary mitral valve regurgitation.

AIMS: Right ventricular dysfunction (RVD), as expressed by right ventricular to pulmonary artery coupling, has recently been identified as a strong outcome predictor in patients undergoing mitral valve edge-to-edge repair (M-TEER) for secondary mitral regurgitation (MR). The aim of this study was to define RVD in patients undergoing M-TEER for primary MR (PMR) and to evaluate its impact on procedural MR reduction, symptomatic development and 2-year all-cause mortality. METHODS AND RESULTS: This multicentre study included patients undergoing M-TEER for symptomatic PMR at nine international centres. The study cohort was divided into a derivation (DC) and validation cohort (VC) for calculation and validation of the best discriminatory value for RVD. A total of 648 PMR patients were included in the study. DC and VC were comparable regarding procedural success and outcomes at follow-up. Sensitivity analysis identified RVD as an independent predictor for 2-year mortality in the DC (hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.47-3.81, p < 0.001), which was confirmed in the VC (HR 2.06, 95% CI 1.36-3.13, p < 0.001). Procedural success (MR ≤2+) and symptomatic improvement at follow-up (New York Heart Association [NYHA] class ≤II) were lower in PMR patients with RVD (MR ≤2+: 82% vs. 93%, p = 0.002; NYHA class ≤II: 57.3% vs. 66.5%, p = 0.09 for with vs. without RVD). In all PMR patients, the presence of RVD significantly impaired 2-year survival after M-TEER (HR 2.23, 95% CI 1.63-3.05, p < 0.001). CONCLUSIONS: Mitral valve edge-to-edge repair is an effective treatment option for PMR patients. The presence of RVD is associated with less MR reduction, less symptomatic improvement and increased 2-year mortality. Accordingly, RVD might be included into pre-procedural prognostic considerations.

Guideline-directed medical therapy in patients undergoing transcatheter edge-to-edge repair for secondary mitral regurgitation.

AIMS: Guideline-directed medical therapy (GDMT), based on the combination of beta-blockers (BB), renin-angiotensin system inhibitors (RASI), and mineralocorticoid receptor antagonists (MRA), is known to have a major impact on the outcome of patients with heart failure with reduced ejection fraction (HFrEF). Although GDMT is recommended prior to mitral valve transcatheter edge-to-edge repair (M-TEER), not all patients tolerate it. We studied the association of GDMT prescription with survival in HFrEF patients undergoing M-TEER for secondary mitral regurgitation (SMR). METHODS AND RESULTS: EuroSMR, a European multicentre registry, included SMR patients with left ventricular ejection fraction <50%. The outcome was 2-year all-cause mortality. Of 1344 patients, BB, RASI, and MRA were prescribed in 1169 (87%), 1012 (75%), and 765 (57%) patients at the time of M-TEER, respectively. Triple GDMT prescription was associated with a lower 2-year all-cause mortality compared to non-triple GDMT (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.60-0.91). The association persisted in patients with glomerular filtration rate <30 ml/min, ischaemic aetiology, or right ventricular dysfunction. Further, a positive impact of triple GDMT prescription on survival was observed in patients with residual mitral regurgitation of ≥2+ (HR 0.62; 95% CI 0.44-0.86), but not in patients with residual mitral regurgitation of ≤1+ (HR 0.83; 95% CI 0.64-1.08). CONCLUSION: Triple GDMT prescription is associated with higher 2-year survival after M-TEER in HFrEF patients with SMR. This association was consistent also in patients with major comorbidities or non-optimal results after M-TEER.

Transcatheter Mitral Valve Repair in Patients With Atrial Functional Mitral Regurgitation.

BACKGROUND: Among patients with severe functional mitral regurgitation (FMR), atrial functional mitral regurgitation (aFMR) represents an underrecognized entity. Data regarding outcomes after mitral valve transcatheter edge-to-edge repair (M-TEER) in aFMR remain scarce. OBJECTIVES: The objective of this study was to analyze the outcome of aFMR patients undergoing M-TEER. METHODS: Using patients from the international EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry undergoing M-TEER for FMR, the authors analyzed baseline characteristics and 2-year outcomes in aFMR in comparison to non-aFMR and ventricular FMR. Additionally, the impact of right ventricular dysfunction (RVD) (defined as right ventricular to pulmonary artery uncoupling) on outcome after M-TEER was assessed. RESULTS: Among 1,608 FMR patients treated by M-TEER, 126 (7.8%) were categorized as aFMR. All 126 aFMR patients had preserved left ventricular function without regional wall motion abnormalities, left arterial dilatation and Carpentier leaflet motion type I. Procedural success (defined as mitral regurgitation ≤2+ at discharge) was 87.2% (P < 0.001) and New York Heart Association (NYHA) functional class significantly improved during follow-up (NYHA functional class III/IV: 86.5% at baseline to 36.6% at follow-up; P < 0.001). The estimated 2-year survival rate in aFMR patients was 70.4%. Two-year survival did not differ significantly between aFMR, non-aFMR, and ventricular FMR. Besides NYHA functional class IV, RVD was identified as a strong independent predictor for 2-year survival (HR: 2.82 [95% CI: 1.24-6.45]; P = 0.014). CONCLUSIONS: aFMR is a frequent cause of FMR and can be effectively treated with M-TEER to improve symptoms at follow-up. Advanced heart failure symptoms and RVD were identified as important risk factors for survival in aFMR patients.

Left atrial volume index and outcome after transcatheter edge-to-edge valve repair for secondary mitral regurgitation.

AIMS: To investigate the role of left atrial volume index (LAVi) in patients with secondary mitral regurgitation (SMR) undergoing transcatheter edge-to-edge mitral valve repair (TEER). METHODS AND RESULTS: Outcomes were evaluated in SMR patients of a European multicentre registry according to baseline LAVi. Main analysis was performed for all-cause mortality; residual mitral regurgitation (MR) and New York Heart Association (NYHA) class improvement were analysed for patients available. A total of 1074 patients were included with a median LAVi (interquartile range) of 58 ml/m2 (46-73). Postprocedural reduction of MR grade to ≤2+ was similar across LAVi quintiles, ranging 91%-96% (p = 0.26). Symptomatic benefit (≥1 NYHA class improvement) also did not differ by LAVi quintiles (61%-68% of patients) (p = 0.66). The risk of mortality increased by 23%-42% in the four upper quintiles compared to the bottom quintile (LAVi <42 ml/m2 ). The hazard ratio (HR) of mortality was 1.35 (95% confidence interval [CI] 1.02-1.78, p = 0.035) associated with a LAVi >42 ml/m2 , which was attenuated after multivariable adjustment (HR 1.18, 95% CI 0.83-1.67, p = 0.36). A significant interaction was found for MR severity and pulmonary hypertension, with an increased risk of death associated with enlarged LAVi in patients with inframedian effective regurgitant orifice area (HR 1.99, 95% CI 1.06-3.74, p = 0.032) and in patients with systolic pulmonary pressure ≤50 mmHg (HR 1.67, 95% CI 1.02-2.75, p = 0.042) in multivariable analysis. CONCLUSION: Procedural success and symptomatic benefit were high throughout the whole range of LAVi. The prognostic impact of left atrial enlargement was relevant in patients with less severe SMR and without pulmonary hypertension, reinforcing the need to identify patients in the early course of backward congestion to achieve good long-term outcome after TEER.

Systolic or diastolic CT image acquisition for transcatheter aortic valve replacement - An outcome analysis.

BACKGROUND: Computed tomography (CT) imaging is the standard of care before transcatheter aortic valve replacement (TAVR). The aortic annulus undergoes conformational changes during the heart cycle. Therefore, the image acquisition time point can impact prosthesis sizing and fit. Clinical outcome data are lacking. The aim of this study was to compare systolic and diastolic cardiac CT data acquisition with regard to procedural and clinical outcomes in patients undergoing TAVR for severe aortic stenosis (AS). METHODS: Preprocedural high-pitch helical CT datasets were analyzed in 1954 patients undergoing TAVR between 2013 and 2018 â€‹at our center. Patients were stratified into two groups according to the acquisition heart phase (979 systolic and 975 diastolic). The study was approved by the local ethics committee. RESULTS: Median age was 81.6 [interquartile range 77.5-85.8] years and 964 (49.3%) patients were male. No significant difference was found for the Valve Academic Research Consortium-3 (VARC-3) endpoints of technical failure (systolic, 5.1% vs. diastolic, 5.2%, p â€‹= â€‹0.94) or device failure (systolic, 13.7% vs. diastolic, 13.5%, p â€‹= â€‹0.92). There was no difference in paravalvular regurgitation. All-cause 30-day mortality was comparable (systolic, 3.6% [95% confidence interval, 2.4-4.7%] vs. diastolic, 3.6% [2.4-4.8%], p â€‹= â€‹1.00), while 3-year mortality rates were higher in the diastolic group (Society of Thoracic Surgeons score adjusted hazard ratio, 1.25 [1.07-1.46], p â€‹< â€‹0.01). CONCLUSIONS: While the 30-day technical and clinical outcomes after TAVR are comparable between systolic and diastolic CT imaging, diastolic imaging was associated with higher long-term mortality. Therefore, the data support the guideline recommendation of systolic imaging.

Propofol versus midazolam sedation in patients with cardiogenic shock - an observational propensity-matched study.

PURPOSE: Benzodiazepines are recommended as first line sedative agent in ventilated cardiogenic shock patients, although data regarding the optimal sedation strategy are sparse. The aim of this study was to investigate the hemodynamic effects of propofol versus midazolam sedation in our cardiogenic shock registry. MATERIALS AND METHODS: Mechanically ventilated patients suffering from cardiogenic shock were retrospectively enrolled from the cardiogenic shock registry of the university hospital of Munich. 174 patients treated predominantly with propofol were matched by propensity-score to 174 patients treated predominantly with midazolam. RESULTS: Catecholamine doses were similar on admission but significantly lower in the propofol group on days 1-4 of ICU stay. Mortality rate was 38% in the propofol and 52% in the midazolam group after 30 days (p = 0.002). Rate of ≥BARC3 bleeding was significantly lower in the propofol group compared to the midazolam group (p = 0.008). Sedation with midazolam was significantly associated with ICU mortality. CONCLUSION: In this observational cohort study, sedation with propofol in comparison to midazolam was linked to a reduced dose of catecholamines, decreased mortality and bleeding rates for patients with cardiogenic shock. Based on this study and in contrast to current recommendations, propofol should be given consideration for sedation in cardiogenic shock patients.