Safety and Efficacy of Transcatheter Edge-to-Edge Repair for Atrial Functional Mitral Regurgitation

Inclusion criteria

• Age 18 years or older
• Echocardiographic core laboratory criteria (all must be present):
• Atrial FMR (FMR must be atrial in etiology without ventricular leaflet tethering)
• Severe MR (3+ or 4+) defined as either 1) an effective regurgitant orifice area (EROA) ≥0.3 cm² or pulmonary-venous systolic flow reversal (PSVFR), or 2) in the absence of PSVFR, EROA measures 0.20-0.29 cm² with one or more of the following: regurgitant volume ≥45 mL/beat, regurgitant fraction ≥40%, or vena contracta width ≥0.5 cm.
• LV ejection fraction ≥40% without more than mild regional wall motion abnormalities
• No or mild LV dilatation (LV end-diastolic volume index \<79 mL/m2 \[male\] or \<71 mL/m² \[female\])
• Left atrial dilation (left atrial volume index ≥34 mL/m²)
• Mitral annulus dilatation (AP diameter \>35mm or AP diameter index ≥19mm/m²)
• The mechanism of the atrial FMR is likely either atrial fibrillation (persistent/permanent or paroxysmal \[documented\]) and/or HFpEF. If HFpEF, one or both of the following must also be present:
• TTE criteria of diastolic dysfunction i. Average E/e' ≥15, or ii. Average E/e' 9-14 plus both of the following:
• \. Septal e' \<7 cm/s or lateral e' \<10 cm/s 2. TR Vmax \>2.8 m/s (or PASP \>35 mmHg if TR jet is adequate) AND/OR b) Invasive hemodynamic evidence (measured prior to randomization) of elevated LV filling pressures (PCWP (or LVEDP) ≥15 mmHg at rest or ≥25 mmHg with exercise; Note: If PCWP is 12 to 15 mmHg, the patient may be given a 7-10 mL/kg (approximately 500 mL) rapid infusion (over 5-10 min) of normal saline; if PCWP rises to ≥18 mmHg, the subject may be randomized.
• \. NT-proBNP ≥300 pg/mL (or BNP ≥100 pg/mL) if at the time of the test the patient is in sinus rhythm or NT-proBNP ≥600 pg/mL (or BNP ≥200 pg/mL) if the patient is in atrial fibrillation 5. Subject remains symptomatic (NYHA class II, III or ambulatory IV) despite maximally tolerated doses of societal indicated class I GDMT for ≥2 months
• a) Diuretics as needed to treat pulmonary congestion and peripheral edema b) If atrial fibrillation: Rate control medication to ensure heart rate \<110 bpm c) If HFpEF: i. SGLT2i for at least 2 months (required) ii. MRAs, e.g., spironolactone or finerenone) and angiotensin receptor-neprilysin inhibitors (ARNIs, e.g., sacubitril/valsartan) may be used at the discretion of each center (but should not be changed after randomization) 6. SBP \<140 mmHg and HR \<100 bpm (\<110 bpm if in atrial fibrillation) 7. Atrial fibrillation ablation is determined by the local heart team. If ablation is deemed necessary, it will be performed prior to enrollment; if ablation is considered unsuitable, no ablation will be performed after enrollment.
• \. Anatomy suitable for TEER 9. The subject or legal guardian voluntarily agrees to comply with all provisions of this clinical trial, including the possibility of being randomly assigned to the control group, as well as participating in all necessary postoperative follow-ups and provides written informed consent.

Exclusion criteria

• Patient is clinically unstable or has been hospitalized within the prior 30 days.
• Primary degenerative or organic mitral valve disease such as prolapse, Barlow's disease, rheumatic heart valve disease causing leaflet thickening, leaflet clefts or perforation, endocarditis, etc. Note: A small amount of mitral leaflet thickening or other abnormality may be present, but it cannot be the primary cause of MR.
• Moderate or severe mitral annular calcification, or any degree of mitral annular calcification if it is the primary cause of the MR or would interfere with TEER.
• Mitral valve area (MVA) \<4.0 cm² or mean trans-mitral valve gradient \>4 mmHg.
• Intent to treat the patient with mitral valve surgery within the next 24 months if randomized to control
• Known cardiomyopathy such as amyloid, sarcoid or hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, or pericardial diseases such as constrictive pericarditis.
• Previous mitral valve surgery or transcatheter mitral valve intervention.
• Concomitant severe (4+ or 5+) tricuspid regurgitation.
• Concomitant severe disease of the pulmonary valve.
• Concomitant severe disease of the aortic valve.
• Moderate or severe right ventricular dysfunction, defined as TAPSE≤14mm or RVFAV≤30% on the baseline echo.
• Severe pulmonary hypertension defined as RVSP≥70mmHg on the baseline echo.
• AF ablation procedure within 2 months prior to enrollment.
• Any implantation of an intracardiac pressure monitoring system, baroreceptor activation therapy, cardiac contractility modulation within 2 months prior to enrollment or planned any time after enrollment.
• If taking a chronic oral anticoagulation: Inability to discontinue it or bridge it with heparin for several days prior to the procedure
• If not taking a chronic oral anticoagulation: Inability to tolerate aspirin or clopidogrel for 6 months
• Untreated clinically significant coronary artery disease requiring revascularization
• Coronary artery bypass grafting (CABG) within prior 30 days
• Percutaneous coronary intervention (PCI) within prior 30 days
• Acute cerebrovascular event within prior 30 days or any prior intracranial hemorrhage
• Allergic to heparin or any study drug that cannot be pre-medicated
• Any contraindication to transesophageal echocardiography
• IVC filter in place
• Any atrial septal pathology interfering with mitral TEER (e.g. atrial septal aneurysm, device in place across the atrial septum, etc.)
• Any major surgery within prior 30 days or anticipated within 24 months
• Non-cardiac disease with a life expectancy \<24 months