Percutaneous Edge-to-Edge Repair of Mitral Regurgitation: echocardiographic road map for patient selection and timing for intervention

Abstract

This review focuses on the selection criteria and timing of percutaneous edge-to-edge mitral valve repair in patients with functional or degenerative mitral valve regurgitation. Echocardiographic imaging is the first-line approach for the evaluation of mitral valve patients, providing crucial information on the severity and functional anatomy of regurgitant valve lesions considered for percutaneous repair. In particular, we report the echocardiographic parameters and clinical variables for patient selection before MitraClip Therapy.

Riassunto

Questa revisione analizza i criteri per le indicazioni e la selezione del tempo ottimale per l’intervento di riparazione percutanea in pazienti con insufficienza mitralica funzionale o degenerativa. L’ imaging ecocardiografico è l’ approccio di prima linea per valutare i pazienti con patologia valvolare mitralica perchè fornisce informazioni cruciali riguardanti l’entità e l’anatomia funzionale del rigurgito valvolare per selezionare le lesioni suscettibili di riparazione percutanea. In particolare, vengono analizzati i parametri ecocardiografici e le variabili cliniche per la selezione dei pazienti che possono beneficiare della terapia con MitraClip.

Introduction

Mitral regurgitation (MR) is an important cause of morbidity/mortality with relevant and progressive epidemiologic incidence after the seventh decade of life [1].

Traditional surgery is the consolidated approach to eliminate symptoms, and improve the life expectancy of patients with MR [2].

Recently, the introduction of Percutaneous Valve Repair (PVR) techniques has opened new frontiers in MR therapy, eliminating the need for thoracotomy and extracorporeal circulation 2, 3.

PVR techniques may correct MR through the direct or indirect reduction of mitral annular dilatation, or by intervening on the primary or secondary abnormalities of the mitral leaflets.

In analogy with the surgical approach, the efficacy and feasibility of PVR depend on patient clinical selection, and on an accurate evaluation of the mechanism and severity of MR through the integrated use of Doppler echocardiography [4].

Echocardiography evaluates MR severity, making use of parameters related to the sampling of the regurgitant jet and parameters independent from the regurgitant jet [5] (Tab. I). These methods are imperfect, and require multi-parametric integrated evaluation.

For an accurate evaluation of MR severity indexes, an adequate and complete sampling of the regurgitant jet in all its components is necessary: convergence region (expression of the site and width of the regurgitant lesion), vena contracta (point of maximum conversion of the potential energy to kinetic energy), jet extension in left atrium (correlated to jet kinetic energy during impact in the receiving chamber).

The convergence region is defined by an isovelocity surface (PISA Proximal Isovelocity Surface Area) due to acceleration of the flow velocity convergence towards the regurgitant orifice.

The convergence region can be calculated, as it maintains hemispherical morphology, by multiplying the radius of the hemisphere and the maximum velocity employed to sample the flow direction (velocity aliasing).

Based on the continuity equation, the product of the area and the flow velocity is constant at every point according to PISA formula (rx2x2πxValiasing)/ERO x regurgitant jet velocity.

Consequently, it is possible to estimate ERO (PISA/regurgitation velocity) and the regurgitant volume RV (EROxregurgitant flow velocity integral).

The PISA method is widely used for MR evaluation, but it may present some limitations if the convergence region has a non-hemispheric geometry, and in the presence of eccentric multiple jets.

The Vena contracta (VC), measured according to anterior-posterior dimension, perpendicular to the intercommissural line, is the parameter of most immediate application used to differentiate between severe (VC >7 mm) and mild regurgitation (VC < 3 mm). The VC is not affected by loading conditions and may be applied in eccentric geometry jet, while it can be limited by the coexistence of multiple jets.

The distribution of the regurgitant jet velocity in the left atrium, though immediately useful to evaluate the presence and entity of MR, should not be used alone as it is limited by numerous instrumental and pathophysiological variables, as it is an expression of the velocity entity and not of the regurgitant volume.

The regurgitation fraction represents an important parameter in MR evaluation independently from the regurgitant jet and requires an accurate evaluation of left ventricle (LV) stroke volume and LV ejection volume.

The regurgitation fraction can be particularly useful in the case of limited applicability of parameters relevant to the regurgitant jet.

Analysis of the inversion or reduction of the systolic pulmonary flow gives important information regarding the hemodynamic impact of MR.

Characterization of the anatomo-functional mechanism of MR, and the feasibility analysis of PVR techniques use the classification introduced by Carpentier for surgical repair (Fig. 1):

• Type I: Loss of leaflet systolic coaptation with normal systo-diastolic mobility. With this mechanism the leaflets, despite normal apposition at annular surface level, do not coapt during systole due to annular dilatation.

  Valvular regurgitation is characterized by single jet or multiple central jets, with variable intercommissural width according to the extension of leaflet coaptation abnormalities at annular surface level.

• Type II: Loss of leaflet coaptation due to excessive mobility (prolapse, chordal rupture). Characteristically, the regurgitant jet moves away from the prolapsing segment of the leaflet.

  In patients with bi-leaflet prolapse, the regurgitant jet may be central (symmetric distance from annular plane) or moving away from the dominant prolapsing leaflet.

• Type III: Leaflet apposition abnormality due to systo-diastolic reduced mobility (intrinsic alterations) (Type IIIa) or to reduced systolic mobility and preserved diastolic mobility (Type IIIb) (functional malapposition from left ventricular remodeling). Systolic coaptation of the leaflets may be incomplete or absent.

Regurgitant jet geometry may differ as regards and direction, being central or eccentric according to the distribution of the functional abnormalities of the leaflets and the commissures. In the presence of asymmetrical lesions, the regurgitant jet moves away from the leaflet with the highest coaptation point compared to the contralateral leaflet, thus simulating a pseudo-prolapse.

PVR techniques that simulate surgical annuloplasty are suitable only for patients with Type I MR, while those simulating surgical techniques of primary leaflet correction can be rationally applied to patients with Types II and III MR.

In the field of PVR techniques, the MitraClip system, which is able to reproduce the edge-to-edge surgical technique introduced by Alfieri, is the only percutaneous therapeutic approach that, at the present time, has a validated clinical application, while the remaining procedures still have to be considered in an experimental phase.

We herein analyze the clinical-echocardiographic criteria for the selection of patients with functional/ischemic or degenerative MR, who might benefit from MitraClip therapy.

The rationale of echocardiographic selection is to identify the valvular lesion (target lesion) for capture, and the subsequent release of the MitraClip device without provoking mechanical lesions of the mitral apparatus.

The capture of the target lesion has to involve both leaflets in a complete and symmetrical way, creating a double orifice valve without residual mitral regurgitation or stenosis.

This aim can be facilitated by an appropriate relationship between the anatomical characteristics of the target lesion (leaflet length, intercommissural width of the target lesion) and MitraClip capture capabilities (length and width of the arms, respectively 7 and 4 mm). Fig. 2a reports a step-by-step transesophageal echographic monitoring of MitraClip implantation targeting effective double mitral valve orifice in the site of regurgitation without residual stenosis.

Excessive redundancy (Barlow Syndrome) or fibro-calcific restriction of the leaflets (fibroelastic deficiency, rheumatic disease) may represent, owing to clip fixed dimensions, anatomical conditions for potential leaflet capture mismatch (tissue hypoplasia or clip inadequacy for the capture of reduntant valvular tissue) with the consequent risk of early or late detachment.

The MitraClip PVR system, although simulating the edge-to-edge technique, presents, when compared to the surgical procedure, the important limit of prosthetic anulus omission.

Isolated or dominant annular dilation, with the complete loss of leaflet coaptation, is another unfavorable anatomo-functional condition for complete and long lasting capture and implantation of the MitraClip system.

The selection of the patients suitable to undergo PVR therapy requires a different clinical-instrumental approach in patients with functional/ischemic MR to those with degenerative MR. Transthoracic echocardiography is the first line diagnostic approach for patient exclusion from the procedure in the presence of evident valve calcification or extensive multiple mechanisms of MR. Transesophageal evaluation is necessary to establish not only the suitability but also the complexity of the MitraClip procedure.

Mitral valve continence, in the absence of structural abnormalities, is conditioned by the equilibrium between tethering and coaptation forces respectively generated by the degree of cavity dilation and by the force and synchrony of left ventricular wall contraction [6].

Functional/ischemic MR is produced by reduced leaflet systolic apposition with subannular displacement of the coaptation point, consequent to the tethering of valvular tissue not compensated by coaptation forces.

Leaflet malapposition (measured as leaflet tenting area, TA) and coaptation point displacement (measured as coaptation depth from the annulus, CD), are the determinants of functional mitral regurgitation development, which is strictly correlated, in terms of site and entity, to the interaction between remodeling type/grade and entity/asynchrony of LV coaptation forces.

Leaflet malapposition can be asymmetric or symmetric as a consequence of LV regional or global remodeling.

Symmetric malapposition with systolic coaptation preservation (longitudinal extension at least 2 mm), but without excessive displacement from the annular plane (CD lower than 10 mm) represents, according to the EVEREST study [7], a feasible valvular lesion for the MitraClip PVR system.

Systolic coaptation preservation in the presence of symmetric malapposition, facilitating complete leaflet capture, can be considered an important element to define the feasibility and efficacy of MitraClip therapy (Fig. 2b). Vice versa, the loss of systolic leaflet coaptation, an expression of advanced LV remodeling or predominant annular dilation, may represent an unfavorable condition for MitraClip implantation, with the risk of intra-procedural mechanical complications or potential late displacement of the clip (Fig. 3).

Echo-Doppler mapping of the site and intercommissural extension of the regurgitant lesion is essential to predict the site of clip implantation, the need for an additional clip, and the relevant risk of post-procedural residual stenosis.

However, being dynamic functional MR is affected by loading manipulations that might condition the degree of remodeling and LV contraction forces.

MitraClip therapy feasibility consequently requires an integrated approach considering all the variables underlying a certain degree of valve lesion and its potential reversibility.

Optimization of medical therapy and the identification of the so-called ‘recoverable left ventricle’ through the correction of asynchrony of contraction and of ischemic or tachycardia-dependent myocardial dysfunction are essential to define PVR feasibility and efficacy in each patient.

The evaluation of functional MR severity represents a diagnostic challenge when considering the dynamic nature of the valve lesion.

Doppler-Echocardiography is an accurate method to define MR entity. However, it requires an integrated approach to consider the pathophysiological determinants underlying the valve lesion, and the potentially misleading evidence regarding its fluctuation.

Functional MR is indeed determined by the systolic malcoaptation of the leaflets and by left atrial-LV pressure gradient resulting from LV force and synchrony of contraction and from the degree of left atrial camera compliance receiving the regurgitant volume.

The regurgitant valvular lesion presents a proto-systolic peak (caused by inertial forces of apposition of the leaflet tissue consequent to deficit and/or LV contractile asynchrony) and a characteristic mesosystolic reduction due to a transitory prevalence of coaptation forces (tending towards leaflet tethering reduction) (Fig. 4).

From the interaction between valvular malcoaptation and atrial-ventricular gradient, derives a characteristic intra-beat fluctuation of functional MR with a proto-systolic peak, a mesosystolic reduction and a subsequent late increase during telesystole.

The use of conventional MR severity parameters based on regurgitant jet analysis (effective regurgitation area calculated with PISA method, vena contracta, jet extension in left atrium) has to consider the potential pitfalls of measurement underestimation during mesosystole.

The use of parameters independent from the regurgitant jet, such as regurgitation fraction (deriving from the ratio of LV ejection volume and effective systolic output) has to be considered as a useful parameter for an accurate evaluation of functional MR with significant intra-beat fluctuation and the presence of multiple jets.

In patients with discrepancies between a clinical history of heart failure and an apparently non-significant degree of MR, an Echo-Doppler exercise test can provide useful information regarding the etiopathogenetic role of MR in symptom development.

Table II and Figure 5 summarize the main points of the clinical-instrumental approach for the selection of patients with functional/ischemic MR that might benefit from percutaneous MitraClip therapy 7, 8, 9, 10, 11.

The selection of patients with degenerative MR requires a detailed echocardiographic evaluation of target valve lesion. According to EVEREST criteria, it is possible to consider valve lesions with the following characteristics susceptible to correction with MitraClip treatment:

• Displacement of free margin prolapsing segment (with or without chordal rupture) less than 10 mm from the annular plane or non-prolapsing surrounding mitral valve tissue (flail gap)

• Central localization with intercommissural extension of the prolapsing segment less than 12 mm

• Absence of calcification in corresponding target lesion

• Mitral valve area over 4 cm

The above-mentioned criteria set the optimal anatomy for repair with the MitraClip device. Team experience might facilitate, in very selected cases, the correction of lesions defined suboptimal according to EVEREST criteria. However, multilocalized prolapse has to be considered, above all in cases of extreme redundancy of the valve tissue (e.g. Barlow's disease), an inadequate anatomical condition for MitraClip repair due to capture difficulties, and the risk of device dislocation (mismatch tissue/device).

Three-dimensional Echo evaluation can provide important information for valve lesion characterization in preparation for PVR. In particular, mitral valve anatomic representation allows us to map the prolapsing lesions (localization, intercommissural extension) and to identify valve anatomies that deviate from the Carpentier classification [12].

Surgical repair has to be considered the standard therapy for prolapsing MR since it can prevent valve regurgitation without the risks of prosthetic valve malfunction or the need for anticoagulant therapy, with favorable impact on life expectancy and quality, not unlike that of the healthy population, especially when carried out before the onset of myocardial damage due to volume overload.

Table III summarizes the potential anatomo-functional mechanisms caused by degenerative MR, and the relative repair techniques for the correction of MR according to valve lesion complexity and to the surgical team's experience [13].

Percutaneous MitraClip therapy, which mimics the edge-to-edge surgical technique, can be applied to central lesions with poor intercommissural extension, a limited systolic coaptation gap and the absence of important annular dilatation.

Comparison between surgical repair (including diversified techniques) and MitraClip therapy (a single approach) can be justified only if performed in selected and randomized patients that are eligible for both the approaches, according to the regurgitation mechanism. Furthermore, the aim of PVR, above all if applied during the initial phase, is to neutralize valve lesions without residual or recurrent regurgitation.

Vice versa, the evaluation of therapy efficacy with MitraClip is based on the significant reduction of MR, with the acceptance of residual regurgitation grades that are generally considered suboptimal and predictive of long-term failure in surgical repair procedures.

Patient selection for percutaneous therapy has therefore to take this into account so as not to extend its application to those patients eligible for surgical repair with a low operative risk and the probability of optimal long-term results.

According to EVEREST data, MitraClip therapy, although proposed as an equivalent to the surgical approach and associated with a lower transfusion rate due to bleeding, has in reality produced unsatisfactory results in a significant number of patients, with the subsequent necessity for short-term surgery in 41 of them (23%) [3].

At the present time, MitraClip therapy cannot be considered equivalent to surgical repair in patients with degenerative MR in terms of applicability and results.

Moreover, analysis of randomization criteria does not specify whether the assignment to surgery includes those patients who are not considered eligible for percutaneous therapy.

However, it is important to underline that in clinical practice, notwithstanding guideline suggestions, a significant percentage of patients does not undergo surgery due to high operative risk based on age, LV dysfunction and comorbidities.

MitraClip PVR represents a promising alternative to the surgical approach in this subgroup of patients, although it is indicated only for patients with adequate target lesions.