At present, the optimal treatment strategy for heart failure patients and moderate-to-severe (3+) or severe (4+) mitral regurgitation with a class IIa recommendation for CRT is uncertain.Whether these patents should also be treated for functional mitral regurgitation or with CRT also remains unclear. We therefore propose a randomized 2x2 factorial design in this patient population to understand the the impact of both CRT and transcatheter mitral valve repair with the MitraClip on their functional status and quality of life.

Inclusion Criteria:

1. Symptomatic moderate-to-severe (3+) or severe (4+) functional mitral regurgitation due to cardiomyopathy of either ischemic or non-ischemic etiology as determined by transthoracic echocardiogram (TTE), and confirmed by the Echocardiography Core Lab (ECL);

2. Symptomatic heart failure as defined by New York Heart Association (NYHA) class II, III or ambulatory IV;

3. Treatment and compliance with optimal medical therapy for heart failure for at least 30 days; Optimal medical therapy is defined by: Maximum tolerated beta-blocker, angiotensin converting enzyme inhibitor (ACE) or angiotensin receptor blocker (ARB), and aldosterone antagonist (as per the ACCF/AHA Guidelines as judged by the HF specialist investigator on site and confirmed by the Clinical Eligibility Committee).

4. Left ventricular ejection fraction ≤ 35%, as assessed by any one of the following methods: echocardiography, contrast left ventriculography, gated blood pool scan or cardiac magnetic resonance imaging (MRI);

5. Class IIa indication for cardiac resynchronization therapy:

   1. Left bundle branch block (LBBB) and QRS duration of 120-149 ms;
   2. Right bundle branch block (RBBB) and QRS ≥ 150 ms.

6. Clinical agreement amongst local investigators that the patient will not be offered surgical intervention;

7. The primary regurgitant jet, in the opinion of the MitraClip implanting investigator, can successfully be treated by the MitraClip. Treatment of commissural mitral regurgitation may be treated at the discretion of the operator. All major jets contributing the secondary MR will be treated with the MitraClip;

8. Ability to perform a six-minute walk test (6MWT) without substantial physical limitations and without use of a walker or wheelchair and distance walked in 6 minutes of ≤ 450m;

9. Ability and willingness to give written informed consent and to comply with the requirements of the study.

Exclusion Criteria:

1. Life expectancy less than 12 months due to noncardiac conditions;

2. ACC/AHA Stage D Heart Failure;

3. Left ventricular ejection fraction ≤ 15%;

4. Hypotension (systolic pressure <90 mm Hg) or requirement for inotropic support or mechanical hemodynamic support;

5. United Network for Organ Sharing (UNOS) status 1 heart transplantation or prior orthotopic heart transplantation;

6. Untreated clinically significant coronary artery disease requiring revascularization;

7. CABG within prior 30 days;

8. Percutaneous coronary intervention within prior 30 days;

9. Severe Chronic Obstructive Pulmonary Disease (COPD) requiring continuous daytime home oxygen or chronic oral corticosteroid therapy;

10. Previous surgical mitral valve bioprosthesis, mitral annuloplasty, or transcatheter mitral valve procedure;

11. Positive pregnancy test, or woman of child bearing potential not using highly effective methods of contraception;

12. Mitral valve area <4.0 cm2 as assessed by planimetry of the mitral valve;

13. Subjects in whom trans-esophageal echocardiography is contraindicated or high risk;

14. Mitral leaflet anatomy which may preclude MitraClip implantation:

    1. Perforated mitral leaflets or clefts, lack of primary or secondary chordal support;
    2. Severe calcification in the grasping area;
    3. Rheumatic valve disease.

15. Previously implanted Cardiac Resynchronization Therapy and Defibrillator (CRT-D) system;

16. Stroke or transient ischemic event within 30 days before randomization;

17. Modified Rankin Scale >4 disability;

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

19. Severe renal impairment defined as an Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula;

20. Severe anemia requiring transfusional support or therapy with erythropoietin;

21. Physical evidence of right-sided congestive heart failure with echocardiographic evidence of moderate or severe right ventricular dysfunction;

22. Aortic valve disease requiring surgery or transcatheter intervention;

23. Significant tricuspid valve disease requiring surgical intervention or very severe tricuspid regurgitation;

24. Active infection requiring antibiotic therapy;

25. Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease;

26. Echocardiographic evidence of intracardiac mass, thrombus or vegetation;

27. Any condition making it unlikely the patient will be able to complete all protocol procedures (including compliance with guideline directed medical therapy) and follow-up visits;

28. Presence of any of the following:

    1. Pulmonary artery systolic pressure (PASP) > 70 mm Hg confirmed by right heart catheterization;
    2. Infiltrative cardiomyopathies.

29. Any other condition(s) that would compromise the safety of the patient as judged by the site principal investigator.