Alexander A. Brescia and Gorav Ailawadi
Anatomy
The surgical anatomy of the mitral valve is discussed in Chapter 45 and should be reviewed including the spatial relationship between the mitral annulus, circumflex coronary artery and coronary sinus, AV node, and the left and non-coronary cusps of the aortic valve, which make up the aortomitral curtain. Particular attention should be paid to the septum and left ventricular outflow tract (LVOT) when considering transcatheter mitral interventions. Transcatheter mitral repair and replacement is more difficult than transcatheter aortic valve replacement (TAVR, Chapter 58) for several reasons, including: the overall larger size of the mitral valve, the potential for creating LVOT obstruction, the usual lack of calcium which can help anchor devices, predominant regurgitant pathology rather than stenosis as with aortic stenosis, and the relatively less well tolerated issue of mitral paravalvular leak (PVL) as compared with aortic valve PVL.
Epidemiology and Pathophysiology
Mitral valve regurgitation (MR) is defined as leakage of blood from the left ventricle (LV) to the left atrium (LA) during systole, and exists over a spectrum including: acute MR, chronic compensated MR, and chronic decompensated MR. Acute MR can be a consequence of chordal rupture/flail, papillary muscle rupture, acute MI, trauma, or even potentially COVID-19 infection and presents as acute, symptomatic, severe heart failure that often requires surgical intervention. In less acute MR, the LV remodels (LV hypertrophies and dilates) to preserve stroke volume in the presence of increased preload, resulting in chronic compensated MR. Eventually the LV will no longer be able to compensate for continued LV dilatation, and stroke volume will decrease resulting in decreased cardiac output and congestive heart failure – a state known as chronic decompensated MR.
MR is classified into primary and secondary MR. Primary MR is intrinsic to the mitral valve leaflets and chords includes etiologies such as myxomatous degeneration, rheumatic heart disease, radiation injury, endocarditis, and autoimmune disease. Secondary, or functional, MR occurs when the valve leaflets are structurally normal, but coaptation is restricted by abnormal structure and/or function of the LV or left atrium, as in chronic atrial fibrillation.
Diagnosis
Symptoms associated with MR can vary and depend on both the severity and chronicity of the disease. Common symptoms include heart failure symptoms, such as shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, fatigue, palpitations (atrial fibrillation), as well as symptoms of a low output state. On physical exam, the murmur of MR is best heard at the apex with the patient in the left lateral decubitus position. With severe MR, the murmur is holosystolic and radiates to the axilla. The murmur of MR can be accentuated by squatting, handgrip, and during exhalation, while it is decreased by standing or the valsalva maneuver. Chest x-ray may demonstrate cardiomegaly and/or LA enlargement. On EKG, LA enlargement (bifid P wave with >40ms between the two peaks) is usually present and/or atrial fibrillation may be seen.
Echocardiography is the gold standard for diagnosing MR, providing information on the mechanisms and severity of MR, LV function and size, LA size, degree of pulmonary hypertension, presence of associated valvular disease, as well as suitability for repair. While TTE may be effective for determining the degree of MR present, TEE is better for examining the mechanism of valve dysfunction due to the probe’s proximity to the MV. Echocardiographic assessment of MR is divided into quantitative and qualitative measures. Qualitative measures include visual assessment of severity. Semi-quantitative measures include vena contracta width (narrowest diameter of the jet flow) and jet area (% of LA), while quantitative measures include regurgitant volume (RV) and fraction (RF) as well as effective regurgitant orifice area (EROA).
| Severe MR | |
| Vena contracta width (VC) | ≥0.7 cm |
| Effective regurgitatant orifice area (EROA) | ≥0.4 cm2 |
| Regurgitant volume (RV) | ≥60 mL/beat |
| Regurgitant fraction (RF) | ≥50% |
| Jet area | >40% of LA area |
| Severe secondary/functional MR | |
| Regurgitant volume (RV) | >30 mL/beat |
| Regurgitant fraction (RF) | ≥50% |
| Effective regurgitatant orifice area (EROA) | ≥0.2 cm2 |
TEE is a class I indication (Level of Evidence B-NR) for diagnosis to determine suitability for a transcatheter mitral valve intervention in patients with chronic secondary MR with severe symptoms that are unresponsive to guideline-directed medical therapy (GDMT). Intra-procedural guidance with TEE is also recommended during transcatheter mitral interventions (class I indication, Level of Evidence C-EO).
Classification
Alain Carpentier is a French surgeon who established many modern techniques of mitral valve repair as well as a classification system of MR, published in his famous paper from 1983 titled “Cardiac valve surgery – the ‘French connection.’” Carpentier’s classification classifies MR according to the movements of the mitral leaflet, and is used to help guide surgical approach.
- Type I. Normal leaflet motion. MR secondary to annular dilation (dilated or ischemic cardiomyopathy ± significant LV dysfunction) or leaflet perforation (infective endocarditis).
- Type II. Increased leaflet motion (leaflet prolapse or flail). MR secondary to chordal elongation or more commonly rupture (myxomatous or degenerative disease) or papillary muscle rupture (ischemic cardiomyopathy).
- Type IIIa. Restricted leaflet motion/opening in systole and diastole. MR secondary to leaflet calcification (degenerative) or chordal thickening, shortening, or fusion/commissural fusion (rheumatic heart disease).
- Type IIIb. Restricted leaflet motion/closing in systole. MR secondary to papillary muscle displacement or leaflet tethering (ischemic MR) or LV dilatation (dilated cardiomyopathy)
Indications for Intervention
The 2020 American College of Cardiology/American Heart Association Valve Guidelines include the following recommendations for transcatheter edge-to-edge repair (TEER) of mitral valve pathology:
Chronic Primary MR
Class IIa recommendations:
- Based on data from the EVEREST II trial and High-Risk REALISM Registry, TEER with MitraClip is reasonable in severely symptomatic patients (NYHA class III or IV) with primary severe MR and high or prohibitive surgical risk, if mitral valve anatomy is favorable for the repair procedure and patient life expectancy is at least 1 year. – Level of Evidence B-NR
Chronic Secondary MR
Class IIa recommendations:
- In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent symptoms (NYHA class II, III, or IV) while on optimal GDMT for HF (Stage D), TEER with MitraClip is reasonable in patients with appropriate anatomy as defined on TEE and with LVEF between 20% and 50%, LVESD ≤70 mm, and pulmonary artery systolic pressure ≤70 mm Hg. – Level of Evidence B-R
Transcatheter Mitral Valve Interventions
Recently, percutaneous and minimal incision transcatheter MV (TMV) techniques have been developed for both MV repair and replacement, with acceptable clinical outcomes and avoidance of the morbidity associated with open surgery. Newly-developed devices target leaflet repair, modification of LV geometry, chordal replacement, and complete valve replacement.
Transcatheter Mitral Valve Repair
Transcatheter repair devices and techniques can be divided into three categories: leaflet repair, indirect annuloplasty, and direct annuloplasty.
Leaflet Repair
The most widely used percutaneous device is the MitraClip (Abbott Vascular, Santa Clara, California), which was first used in 2003 and is a cloth-covered cobalt-chromium clip that affixes the anterior and posterior leaflets, resembling a surgical Alfieri stitch. The EVEREST (Endovascular Valve Edge-to-Edge Repair Study) trial compared surgical mitral repair with MitraClip and found that despite similar mortality, the surgical group had higher perioperative morbidity (driven by blood transfusions), while the MitraClip group underwent more reinterventions. The high-risk REALISM registry arm of the EVEREST trial demonstrated safety and efficacy compared to a historical medically treated patients leading to approval in primary MR patients at prohibitive surgical risk.
More recently, use of the MitraClip device in patients with severe secondary MR was studied in the MITRA-FR (Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients with Severe Secondary Mitral Regurgitation) and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) randomized controlled trials. The French MITRA-FR trial found no difference in the composite outcome of all-cause mortality or unplanned heart failure hospitalization at 12 months between groups receiving MitraClip plus GDMT versus GDMT alone. In contrast, the concurrent COAPT trial found a significant advantage in the MitraClip arm for all primary and secondary end points, including heart failure hospitalizations and all-cause mortality at 2-years. The MitraClip was approved for commercial use in 2013 to treat severe symptomatic degenerative MR based on European data and the EVEREST II trial and in March 2019 added an expanded indication for secondary MR based on the COAPT trial. Most recently, the REPAIR MR trial began enrolling a target 500 intermediate surgical risk patients randomized to undergo surgical mitral repair versus MitraClip.
Ideal candidates for MitraClip include patients with central 2/3 valve MR jet, mitral valve area >4 cm2, posterior leaflet mobile length >10mm, flail gap (coaptation gap) <10 mm, flail width (coaptation gap width) <15mm, and no calcification at the grasping zone, although real-world use is broader. Contraindications to transcatheter mitral valve repair include active infective endocarditis, rheumatic heart disease of the MV, prohibitively small MVA (<3.5cm2), severe calcification with mitral stenosis or restricted leaflet motion, multiple regurgitant jets, short or restricted posterior mitral leaflet (<5mm in the intended grasping location), intracardiac thrombus, caval interruption (transhepatic has been performed but is rare), and the presence of large atrial septal occluder devices.
The PASCAL (Paddle, Spacer, Clasps, Alfieri stitch) device (Edwards Lifesciences, Irvine, California), another TEER device, was initially launched in 2016 and delivered through a transfemoral, transseptal approach. It involves a spacer placed between mitral leaflets which catches them independently and clasps them together. The PASCAL underwent feasibility trials in Europe and the CLASP IID/IIF trial randomized patients to PASCAL or MitraClip and is currently ongoing.
Indirect Annuloplasty
Other transcatheter repair devices provide an indirect annuloplasty. The Carillon Mitral Contour System (Cardiac Dimensions, Kirkland, Washington) modifies the mitral annulus indirectly by reshaping the adjacent coronary sinus. Through a transjugular approach, a septal lateral reduction is performed to improve coaptation and the device is planted with two anchors connected by a curved bridge, with the circumflex artery always checked for patency after implantation, with recapturing and repositioning possible. The AMADEUS and TITAN studies have examined the Carilion device in patients with secondary MR and advanced heart failure and found decreases in MR, improvement in symptoms, better quality of life, and significant reduction in LV diameter and volume in the short term, with more than 1000 devices having been implanted thus far. The CARILLON pivotal trial comparing the device to GDMT alone is currently underway.
The ARTO system (MVRx, Inc., San Mateo, California) is delivered through a transjugular, transseptal approach with 2 magnetic-tipped catheters placed in the coronary sinus and the second into the left atrium, which then meet near P3 and secure the first anchor through first passing a crossing wire. The wire is replaced with a septal bridge from the coronary sinus side and secured using a 2-disc atrial septal defect closure device near the interatrial septum. With tension applied to the bridge, the septo-lateral annular dimension shortens. The MAVERIC (MitrAl ValvE RepaIr Clinical) trial is a single arm feasibility study evaluating the ARTO system, with preliminary findings indicating a reduction in MR, LV and LA volume, heart failure symptoms, and hospitalizations at 2 years.
Direct Annuloplasty
The Cardioband device (Edwards Lifesciences) is a C-shaped polyester sleeve implanted through a transfemoral, transseptal approach under TEE guidance with between 12 and 17 steel screw-anchors to secure the device in place segmentally from trigone to trigone, mimicking a surgical partial annuloplasty. Early feasibility trials were successful in 2015 with technical success and reduction of MR, associated with an improved quality of life. The partial annuloplasty Cardioband can also have future interventions performed to complement it, including TEER and transcatheter mitral replacement, if indicated. Similarly, the AccuCinch (Ancora Heart, Santa Clara, California) is delivered transfemoral retrograde and inserts 12 to 16 self-expanding nitinol anchors into the subannular LV myocardium of the mitral annulus, with the cinching mechanism utilized to reduce LV and annular size. A series of separate CorCinch feasibility studies are underway in the U.S. and Europe for patients with secondary MR, severe heart failure, and previous mitral interventions.
Whereas these devices mimic a surgical partial annuloplasty, other devices provide near-complete or complete annuloplasty rings which may better address secondary MR. The AMEND (Valcare Medical, Israel) device is a semi-rigid, D-shaped annuloplasty ring surrounded by polyethylene terephthalate fabric and delivered transapically into the left atrium, secured with 4 zones of anchors in the native annulus. The first-in-human transseptal implant was recently performed in Israel, with enrollment for the AMEND Plus pilot clinical study to begin soon. The Millipede IRIS (Boston Scientific, Boston, Massachusetts) is a transcatheter complete, semirigid annuloplasty ring with eight helical stainless-steel anchors placed directly into the annulus. It is delivered through a transfemoral, transseptal approach, the first transcatheter implant was performed in April 2017, and the 21-patient feasibility trial just completed enrollment.
Transcatheter Mitral Valve Replacement
Transcatheter mitral valve replacement has been attempted for nearly a decade. The anatomy of the MV creates a challenge for transcatheter interventions since the MV apparatus is dynamic and includes the annulus, leaflets, cords, papillary muscles, and the left ventricle. In addition, patients with severe MR may not tolerate a transapical procedure as well as a ventricle subject to severe AS which is usually substantially thicker. In addition, special attention must be paid to the septum and LVOT in order to prevent LVOT obstruction resulting from an implanted TMVR device. Accordingly, more than 50% of patients are screened out of being eligible for TMVR trials due to unsuitable anatomy. Within the context of these challenges, several transcatheter mitral replacement devices have been developed, with both minimal-incision surgical transapical or percutaneous transseptal approaches available. There has recently been a shift from transapical to transfemoral approaches, which should prompt trainees to learn the transseptal technique for exposing the mitral valve.
The first transcatheter MVR valve introduced was the CardiAQ (Edwards) in 2012, which is a trileaflet bovine self-expanding valve on a nitinol frame. The initial device was discontinued due to valve thrombosis and an updated design was renamed EVOQUE in 2015. It is lower profile, comes in 2 sizes, and was found to be technically successful (92%) in compassionate use in Europe, but exhibited a 45% 30-day mortality in this setting. The EVOQUE Eos MISCEND early feasibility study targeting a 58-patient enrollment is underway in the United States.
The CardioValve (Cardiovalve Ltd., Israel) has 2 nitinol frames, 24 grasping legs, and a bovine pericardium valve. The initial experience in 5 patients included technical success in all 5 but 30-day mortality in 3 of the 5. The AHEAD European feasibility study is currently enrolling patients. The Intrepid (Medtronic) is a bovine tri-leaflet self-expanding valve with a smaller ventricular component and large reverse umbrella atrial profile, designed to minimize ventricular footprint. The first transapical implant was in 2014 and a 50-patient feasibility study had 98% technical success and 30-day mortality of 14%, with all patients having <1+ MR at 30 days post-procedure. The multicenter, non-randomized APOLLO study is ongoing with a target enrollment of up to 1,150 participants to receive the device, including separate primary (stratified primary and secondary MR) and mitral annular calcification (MAC) cohorts. Early feasibility studies for a transseptal approach are underway. The SAPIEN M3 system (Edwards) uses a modified SAPIEN S3 in conjunction with a nitinol docking system and sealing skirt, available in a 29-millimeter valve and implanted through a transseptal approach. In addition, 1,529 high-risk patients have undergone a SAPIEN 3 mitral valve-in-valve procedure for failed bioprosthetic valves, with technical success was achieved in 96.8% and all-cause mortality was 5.4% at 30 days and 16.7% at 1 year.
The Tendyne (Abbott) device is implanted trans-apically and is a porcine tri-leaflet self-expanding valve which anchors in the mitral annulus, is secured in the LV apex, and is totally retrievable and repositionable. The valve was initially implanted in 2014 and technical success was achieved in 97% of the first 100 patients, with trace to mild MR in 99%, a 30-day mortality rate of 6%, and 1-year survival 72%. The SUMMIT trial is underway and has a randomized, non-randomized, and MAC cohort, with the randomized arm comparing the Tendyne to the MitraClip.
Each of these devices have undergone observational studies to demonstrate feasibility and improvement in heart failure symptoms but require further evaluation.
Conclusion
Transcatheter mitral valve repair and replacement procedures are rapidly emerging to complement and compete with established surgical techniques and address patient populations in whom surgical approaches are not preferred or safe. The most successful transcatheter techniques to address primary or secondary MR will replicate outcomes achieved through surgical intervention. Whether a transcatheter or surgical approach mitral valve therapy is pursued, the most important determinant of success is avoidance of residual and recurrent MR.
Suggested Readings
- Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021;143(5):e72-e227.
- Donatelle M and Ailawadi G. Transcatheter Mitral Valve Repair and Replacement: What’s on the Horizon? Semin Thoracic Surg. 2020:S1043-0679(20)30291-4.
- Chancellor WZ, Mehaffey JH, Clark SA, et al. Outcomes of surgical mitral valve replacement: A benchmark to assess transcatheter technologies. J Card Surg. 2021;36(1):69-73.
- Obadia J-F, Messika-Zeitoun D, Leurent G, et al. Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. N Engl J Med. 2018;379(24):2297-2306.
- Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018;379(24):2307-2318.
