Amended and merged with AHEAD-EU study

The study will test the safety and performance of the Cardiovalve transfemoral mitral valve replacement system in treating patients with severe mitral regurgitation who are at high risk for open chest surgery. The system is comprised of comprised of: 1) an Implant; 2) a Delivery System (DS); and 3) Accessories that are required for the implantation procedure. the procedure is performed under general anesthesia.

The study will test the safety and performance of the Cardiovalve transfemoral mitral valve replacement system in treating patients with severe mitral regurgitation who are at high risk for open chest surgery. The system is comprised of comprised of: 1) an Implant; 2) a Delivery System (DS); and 3) Accessories that are required for the implantation procedure. The implant procedure is performed under general anesthesia, and the participants will be followed-up at discharge, 1- 3-, 6-, 12- and 24-months post-procedure, in order to check the system functionality and effect on their cardiology status.

General Inclusion Criteria:

2. NYHA functional II, III or ambulatory IV 3. Severe mitral regurgitation (MR grade 3-4+) with pronounced secondary MR etiology 4. Subject is on optimal guideline-directed medical therapy for heart failure for at least 30 days or CRT if indicated.

5. Elevated risk for conventional open mitral valve repair or replacement surgery in the consideration of the site Heart Team (including a cardiac surgeon, a cardiologist and imaging specialist as a minimum) based on STS/Euro Score II (per MVARC Part 1), frailty and co-morbidities.

6. Able to undergo Transesophageal Echocardiography (TEE). 7. Subject understands the study requirements and the treatment procedures and provides written Informed Consent before any study-specific tests or procedures are performed.

8. The subject commits to return for the scheduled post-operative follow-up visits at the hospital.

Anatomical Inclusion Criteria 9. Suitable for femoral access procedure and trans septal catheterization 10. Native mitral valve geometry and size and LV outflow tract characteristics compatible with the Cardiovalve (as assessed by the independent Screening Committee)

Exclusion Criteria:

Cardiovascular Exclusion Criteria

1. Prior stroke or TIA within 3 months or Modified Rankin Scale ≥4 disability

2. Acute myocardial infarction within the previous 30 days

3. Any prior heart valve surgery or transcatheter mitral intervention

4. Any percutaneous cardiovascular intervention, cardiovascular surgery, or carotid surgery within 30 days

5. Rheumatic heart disease or endocarditis within the previous 3 months

6. Hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or any other structural heart disease causing heart failure other than dilated cardiomyopathy of either ischemic or non-ischemic etiology

7. Existence of inferior vena cava filter or atrial septal device (contraindicating femoral access and transseptal catheterization)

8. Untreated clinically significant coronary artery disease requiring revascularization

9. Tricuspid valve disease requiring surgery or severe tricuspid regurgitation

10. Aortic or pulmonic valve disease requiring surgery

11. CRT/ICD implant within 30 days Anatomical Exclusion Criteria (assessed by pre-procedural imaging)

12. Left Ventricular Ejection Fraction (LVEF) <30%

13. LV end diastolic diameter > 70mm

14. Significant abnormalities of the mitral valve and sub-valvular apparatus.

15. Severe mitral annular or leaflets calcification

16. Left atrial or LV thrombus or vegetation

17. Severe right ventricular dysfunction

18. Severe tricuspid or aortic valve disease

    General Exclusion Criteria

19. Subject who is currently participating in an investigational study, other than this study

20. Hemodynamic instability defined as systolic pressure < 90mmHg or the need for inotropic support or intra-aortic balloon pump or other hemodynamic support device, or any mechanical heart assistance

21. Subject has contrast agent hypersensitivity that cannot be adequately pre-medicated, has an allergy to Nitinol alloys (nickel and titanium), or has intolerance to antiplatelet, anticoagulant, or thrombolytic medications

22. Bleeding diathesis or hypercoagulable state

23. Active peptic ulcer or active gastrointestinal bleeding

24. Pulmonary artery systolic pressure >70 mmHg

25. Patients with renal insufficiency (creatinine > 2.5 mg/dL)

26. Need for emergent or urgent surgery for any reason or any planned cardiac Surgery within the next 12 months

27. Subject with hepatic insufficiency

28. Subject has a co-morbid illness that may result in a life expectancy of less than one year

29. Active infection that requires antibiotic therapy

30. Subject is pregnant, breastfeeding or intend to become pregnant within one year