Transcatheter mitral valve intervention in advanced heart failure

Abstract

See Related Article, page 1353 See Related Article, page 1353 Unlike the taxonomy of cardiac valves based on location (pulmonary or aortic) or leaflet number (tricuspid), the mitral valve designation is an iconic one. Vesalius recognized the sheer complexity of this valve apparatus and chose to brand it after a bishop's headgear, the mitre, owing to its likeness.1Ho SY Anatomy of the mitral valve.Heart. 2002; 88: iv5-i10PubMed Google Scholar Characteristically, the physiologic competence of the mitral valve is dependent on the competitive intersection of 5 distinct factors. These include an interplay among (1) left atrial size (and less importantly, function); (2) left ventricular dilation and contractile performance; (3) chordal tendons and papillary muscle alignment, integrity, and function; (4) mitral annular shape, size, and function; and finally (5) the anterior and posterior valvular leaflets and their scallops.2Perloff JK Roberts WC The mitral apparatus. Functional anatomy of mitral regurgitation.Circulation. 1972; 46: 227-239Crossref PubMed Scopus (309) Google Scholar A cardiomyopathic phenotype that leads to the clinical syndrome of advanced heart failure habitually produces distortion in all the elements necessary to cause mitral valvular incompetence without a direct pathology within the valve itself and is therefore referred to as secondary or functional mitral regurgitation. The mechanisms diversely include the reduced contractile force that leads to sub-optimal closing of the leaflets; a spherical shape of the dilated ventricle that adversely alters the orientation, length, and consequent tension on the chordal-papillary muscle structure; the dilation of the mitral annulus (but more importantly the inability of the annulus to contract during systole) that causes reduced leaflet alignment; and finally the dilation of the posterior wall of the left atrium that increases the tensile draw on the posterior leaflet of the valve.2Perloff JK Roberts WC The mitral apparatus. Functional anatomy of mitral regurgitation.Circulation. 1972; 46: 227-239Crossref PubMed Scopus (309) Google Scholar As mitral regurgitation ensues, it contributes to the worsening of these compound abnormalities and increases in severity over time. This worsening in the regurgitant volume leads to progression in the clinical and functional aspects of advanced heart failure and adversely influences prognosis.3Chehab O Roberts-Thomson R Ng Yin Ling C et al.Secondary mitral regurgitation: pathophysiology, proportionality and prognosis.Heart. 2020; 106: 716-723Crossref PubMed Scopus (10) Google Scholar Interrupting this vicious cycle is therefore of critical importance as a therapeutic target in advanced heart failure. Pharmacologic therapy that targets neurohormonal pathways and results in myocardial recovery or remission is associated with an improvement in mitral regurgitation.4Almarzooq Z Pareek M Sinnenberg L Vaduganathan M Mehra MR Nine contemporary therapeutic directions in heart failure.Heart Asia. 2019; 11e011150Crossref PubMed Scopus (3) Google Scholar,5Kang DH Park SJ Shin SH et al.Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation.Circulation. 2019; 139: 1354-1365Crossref PubMed Scopus (154) Google Scholar Cardiac resynchronization therapy is additive in improving the prognosis and also reducing mitral regurgitation (during rest and exercise), a factor that may be crucial in determining the clinical response to such therapy.6Madaric J Vanderheyden M Van Laethem C et al.Early and late effects of cardiac resynchronization therapy on exercise-induced mitral regurgitation: relationship with left ventricular dyssynchrony, remodelling and cardiopulmonary performance.Eur Heart J. 2007; 28: 2134-2141Crossref PubMed Scopus (54) Google Scholar However, in some patients, secondary mitral regurgitation remains unabetted and continues to drive the clinical syndrome of heart failure despite optimal medical therapy. In others, the biologic process of left ventricular failure progresses relentlessly, and such patients become intolerant to pharmacologic therapy and may not respond to cardiac resynchronization therapy with consequent worsening in mitral regurgitation. These represent 2 distinct pathophysiologic states with varied responses to directing treatment to the mitral valve. In the former situation, there may be a clinical benefit because mitral regurgitation is a residual driver of prognosis, whereas in the latter (and more common situation), it is less helpful to directly tackle the valve when severe ventricular dysfunction should instead be the primary therapeutic target.7Carabello BA MitraClip and tertiary mitral regurgitation-mitral regurgitation gets curiouser and curiouser.JAMA Cardiol. 2019; 4: 307-308Crossref PubMed Scopus (15) Google Scholar This prediction has been laid bare in clinical trials that have tested transcatheter mitral valve interventions for the amelioration of mitral regurgitation in heart failure. In 1998, a surgical operation that consists of anchoring the free edge of 1 leaflet to the corresponding free edge of the facing leaflet of the mitral valve was introduced.8Maisano F Torracca L Oppizzi M et al.The edge-to-edge technique: a simplified method to correct mitral insufficiency.Eur J Cardiothorac Surg. 1998; 13: 240-246Crossref PubMed Scopus (322) Google Scholar In the past decade, this surgical technique was adapted to a transcatheter method using a trans-septal approach to clip the free edges of the mitral leaflets together using a device called MitraClip (Abbott, Chicago, IL), which is now commercially available. The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial that enrolled mild to moderate patients with heart failure with residual significant mitral regurgitation, a procedurally favorable anatomy and exposure to maximally tolerated medical therapy demonstrated an improved survival, reduced morbidity, and better quality of life.9Stone GW Lindenfeld J Abraham WT et al.Transcatheter mitral-valve repair in patients with heart failure.N Engl J Med. 2018; 379: 2307-2318Crossref PubMed Scopus (1331) Google Scholar The Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) study that enrolled patients with lesser mitral regurgitation in the setting of greater left ventricular dilation and failure than COAPT was unable to demonstrate a benefit of applying the MitraClip procedure in its population with heart failure.10Iung B Armoiry X Vahanian A et al.Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years.Eur J Heart Fail. 2019; 21: 1619-1627Crossref PubMed Scopus (118) Google Scholar Generally, these findings have been debated and interpreted to prematurely conclude that it may be wise to avoid transcatheter mitral valve intervention in patients with advanced heart failure with more severely dilated left ventricles because in these individuals, heart failure is too advanced for a clinically meaningful benefit to occur. In this issue of the journal, Godino et al11Godino C Munafo A Scotti A et al.MitraClip in secondary mitral regurgitation as a bridge to heart transplantation: 1-year outcomes from the International MitraBridge Registry.J Heart Lung Transplant. 2020; 39: 1353-1362Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar provide a registry series of 119 patients with advanced heart failure who were either actively listed for heart transplantation, awaiting listing, or being evaluated as possible candidates for transplantation only if concomitant relative contraindications such as renal insufficiency, obesity, or pulmonary vascular hypertension could be reconciled. This study, which did not receive any external funding, was conducted at 17 international centers across Europe and Canada in 5 countries. Patients with advanced heart failure were carefully selected by individual participating centers to undergo a MitraClip procedure and followed up for at least 1 year. Intriguingly, the procedure was shown to be feasible and safe in the short term with no 30-day mortality. MitraClip use in this registry population resulted in improvements in post-procedure hospitalizations and functional capacity when compared with pre-procedural patient profiles. The median follow-up in this cohort was nearly 18 months, and in this timeframe, nearly 40% of patients either died or underwent a durable left ventricular assist device (LVAD) or a high-urgency transplantation for clinical worsening. Thus, on the surface, one could conclude that these patients likely did not benefit substantially even in the absence of a control group comparison. However, a closer examination of the outcomes points to a glimmer of hope wherein nearly 25% of the patients improved clinically to no longer require transplantation, and a significant number were able to overcome the relative contraindications of an increased pulmonary vascular resistance or renal insufficiency to enable listing for heart transplantation. In an era where donor organs for transplantation are scarce and largely allocated to the sickest hospitalized patients, and alternative support strategies such as LVADs are associated with an increased morbidity and cost of care, strategies that may serve as an additional intermediate bridge are attractive.12Cogswell R John R Estep JD et al.An early investigation of outcomes with the new 2018 donor heart allocation system in the United States.J Heart Lung Transplant. 2020; 39: 1-4Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar,13Goldstein DJ Naka Y Horstmanshof D et al.Association of clinical outcomes With left ventricular assist device use by bridge to transplant or destination therapy intent: the Multicenter Study of MagLev Technology in patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) randomized clinical trial.JAMA Cardiol. 2020; 5: 411-419Crossref PubMed Scopus (53) Google Scholar The challenge lies in defining those patients with advanced heart failure who may benefit from such a bridge strategy while reserving more advanced but effective strategies such as a LVAD bridge for those predicted to not benefit.14Kanwar MK Rajagopal K Itoh A et al.Impact of left ventricular assist device implantation on mitral regurgitation: an analysis from the MOMENTUM 3 trial.J Heart Lung Transplant. 2020; 39: 529-537Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In a secondary analysis of the Multicenter Study of MagLev Technology in Patient Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial, patients with advanced heart failure refractory to medical therapy and with moderate to severe mitral regurgitation at baseline had a 2-year survival of 80% with an LVAD implant. Such patients were mostly treated with IV inotropic therapy at baseline and once an LVAD was implanted, even residual mitral regurgitation (which occurred in fewer than 5% of patients implanted with the HeartMate 3 pump by 1 month of implant) did not modify the late outcome in an adverse manner.14Kanwar MK Rajagopal K Itoh A et al.Impact of left ventricular assist device implantation on mitral regurgitation: an analysis from the MOMENTUM 3 trial.J Heart Lung Transplant. 2020; 39: 529-537Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Such a population as evaluated in MOMENTUM 3 may not be suitable for a transcatheter approach to treating mitral regurgitation and may be better served by LVAD implantation. Empirical data as in the study by Godino et al11Godino C Munafo A Scotti A et al.MitraClip in secondary mitral regurgitation as a bridge to heart transplantation: 1-year outcomes from the International MitraBridge Registry.J Heart Lung Transplant. 2020; 39: 1353-1362Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar cannot be used to determine the clinical guidance for which patients should be considered for an intermediate mitral valve intervention strategy; however, some clues to guide further investigation are apparent. An a priori elimination of MitraClip as a therapeutic option for these patients may be unwise. Transplant-listed patients tend to be younger (in sharp contrast to those in the MITRA-FR study wherein 33% of patients were over 75 years old) and with fewer comorbid conditions (compared with MITRA-FR wherein the average glomerular filtration rate was 49 ml/min), and such patients who are not yet bound to continuous inotropic therapy and still tolerant of neurohormonal-directed therapy, may be reasonable candidates to be considered for mitral valve intervention provided they possess a suitable valve anatomy for this approach.10Iung B Armoiry X Vahanian A et al.Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years.Eur J Heart Fail. 2019; 21: 1619-1627Crossref PubMed Scopus (118) Google Scholar Furthermore, in such patients, the presence of preserved renal function as well as the absence of severe pulmonary hypertension or severe right-sided heart failure should be ascertained.15Tigges E Blankenberg S von Bardeleben RS et al.Implication of pulmonary hypertension in patients undergoing MitraClip therapy: results from the German transcatheter mitral valve interventions (TRAMI) registry.Eur J Heart Fail. 2018; 20: 585-594Crossref PubMed Scopus (42) Google Scholar,16Frea S Crimi G Gaemperli O et al.Improving selection of Mitraclip candidates in advanced chronic heart failure: look right to predict right.J Card Fail. 2019; 25: 312-313Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Even if only hypothesis is generating, these concepts may provide guidance for clinical trials specifically targeting patients listed for heart transplantation. The advent of transcatheter mitral valve intervention represents an important advance in heart failure therapeutics. Structural heart teams are currently capable of selecting an optimal anatomy for mitral valve intervention with the assistance of advanced imaging procedures. We now challenge them to open the dialog on the selective consideration of percutaneous mitral valve intervention in ambulatory patients with advanced heart failure, especially selected patients listed for heart transplantation who are young and with an acceptable morbidity burden. Such a specific candidate population may improve sufficiently to be able to defer or even avoid transplantation. This may be of particular benefit for the patients with advanced heart failure awaiting transplantation in a priority category where the timely identification of a suitable donor organ is unlikely. Rather than considering heart transplant candidates as too ill for the consideration of percutaneous mitral valve intervention, we call for additional studies in this growing patient population. Future studies should be strengthened by the precise quantitation of mitral regurgitation and consistency in patient selection across sites. In summary, we believe that transcatheter mitral valve intervention in advanced heart failure should not necessarily be considered a bridge too far.17Ryan C A bridge too far.1st ed. Simon & Schuster, New York1974Google Scholar M.R.M. reports receiving travel support and consulting fees, paid to Brigham and Women's Hospital, from Abbott; fees for serving on a steering committee from Medtronic and Janssen (Johnson & Johnson); fees for serving on a data and safety monitoring board from Mesoblast, consulting fees from Baim Institute of Clinical Research, Portola, Bayer and Triple Gene; and fees for serving as a scientific board member from Leviticus, NuPulseCV, and FineHeart. M.R.M. is also the editor of the Journal of Heart and Lung Transplantation, but this editorial does not represent the official stance of the journal or the society that it represents. M.R.C. reports research support from Abbott to the Advocate Heart Institute and she serves as a member of the Steering Committees for Abbott sponsored clinical trials. The authors appreciate the critical review of this editorial by Hasan K. Siddiqi, MD and Daniel R. Goldstein, MD (incoming editor-in-chief of the Journal).