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How to differentiate functional from degenerative mitral regurgitation

La Canna, Giovanni; Scarfo’, Iside; Caso, Ilaria

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Journal of Cardiovascular Medicine: February 2018 - Volume 19 - Issue - p e75-e79
doi: 10.2459/JCM.0000000000000579
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Introduction

Mitral regurgitation is an important cause of morbidity and mortality, its incidence increasing with age, with a peak over the seventh decade of life.1 The pathophysiology of the condition includes primary forms (due to dominant primary pathological conditions of the mitral valve apparatus), and secondary forms [secondary to dynamic valvular conditions deriving from left ventricular (LV) disorder, thus the expression of a dominant myocardial condition]. The differentiation between these two forms of mitral regurgitation is essential for an accurate therapeutic planning. The clinical evaluation is very helpful in the differential diagnosis, but imaging assessment is necessary for precise pathophysiologic definition of mitral regurgitation.

Echocardiography is the first-line imaging test for the assessment of the morphology and pathophysiology of the valvular apparatus in patients with mitral regurgitation. Selected patients may benefit from second-line imaging (computed tomography, NMR), particularly when complex therapeutic strategies are considered.2,3

Pathophysiology and clinical assessment of mitral regurgitation

Mitral valvular competence is dependent on the leaflet reaching the annular plane (leaflet apposition) before the systolic coaptation, which occurs symmetrically and should maintain an appropriate length along the intercommissural surface of the leaflets. According to the apposition and coaptation phases, it is possible to define different pathophysiologic mechanisms of mitral regurgitation.

The apposition anomalies are defined by the inability of the leaflets to reach the annular plane, and occur for pathological conditions affecting primary valvular structures, or for functional tethering of structurally normal leaflets, secondary to remodeling or asynchrony of the LV.

The coaptation anomalies are consequence of excessive motion of the valve leaflets (prolapse or flail after chordae rupture), or are secondary to annular dilation exceeding the coaptation surface of the leaflets. More infrequently, mitral regurgitation can occur despite a normal apposition and systolic coaptation of the leaflets (perforation, agenesis, congenital fissure). Carpentier popularized a pathophysiological classification of mitral regurgitation (Fig. 1), which includes three types of mitral regurgitation according to leaflets motion: Type I (coaptation anomalies with normal leaflets motion); Type II (coaptation anomalies with excessive leaflets motion); Type III (apposition anomalies with restricted leaflets motion). Type III could be further divided into Type IIIa (restricted both systolic and diastolic leaflet motion from organic leaflets problems) and Type IIIb (restricted only systolic motion from functional chordae tethering and LV remodeling).

Fig. 1
Fig. 1:
Carpentier classification of mitral regurgitation according to leaflets apposition and coaptation. Read text for explanation.

Primary mitral regurgitation with organic problems of the mitral valve apparatus could lead to coaptation anomalies for excess leaflets motion (Type II), or malapposition for restricted systolic and diastolic motion (Type IIIa). On the other hand, functional mitral regurgitation follows coaptation anomalies with annular dilation and normal leaflets motion (Type I), or leaflets malapposition and restricted systolic motion with LV remodeling (Type IIIb).

The most common histology of primary mitral regurgitation is degenerative, including myxomatous degeneration and fibroelastic deficiency (FED).4

Disorder and immunohistochemical studies revealed specific characteristics of myxomatous degeneration and FED, capable of differentiating the two conditions, associated with different clinical phenotypes and therapeutic strategies. In particular, myxomatous degeneration is characterized by a diffuse thickening of the leaflets, with fragmentation of the elastin, and increased cellular proliferation with an elevated enzymatic proteolytic activity. Conversely, FED displays a focal thickening of the leaflets with elastin accumulation, a decrease of the collagen of the valvular apparatus, and an increase component of myofibroblasts and up-regulation of transforming growth factor beta.5

The advanced forms of myxomatous degeneration with the involvement of the entire valvular tissue and disconnection of the posterior leaflet from the mitral annulus characterize Barlow's disease.

Table 1 outlines the main clinical and morphologic characteristics of degenerative mitral regurgitation.

Table 1
Table 1:
Clinical characteristics and therapeutics implications of myxomatous vs. fibroelastic deficiency mitral regurgitation

Patients with myxomatous degeneration usually have a prolonged medical history characterized by a variable systolic murmur according to the underlying mechanism and amount of regurgitation. The valvular disorder could involve one or both leaflets and be associated with meso-tele systolic or holosystolic regurgitation chronology enhanced by Valsalva maneuver. In Barlow's disease, the murmur is anticipated by a nonejection click. When mitral prolapse is complicated by chordae rupture, the murmur becomes holosystolic, decreases in tele-systole and during Valsalva maneuver.

Patients with FED have a limited valvular lesion, and prolapse is frequently complicated by chordae rupture, more often of the posterior leaflet. The murmur is often holosystolic when chordae are ruptured, is detected after symptoms onset, and the patients are older. Patients with myxomatous degeneration could remain asymptomatic for a long time; conversely, symptoms appear ambiguously and with ‘flash’ episodes in patients with FED. Patients with Barlow's disease could manifest malignant ventricular arrhythmias, regardless of the degree of LV volume overload, and be at risk for sudden cardiac death, which could represent the initial symptom of the condition and persist after successful surgical repair.

The general clinical examination is helpful in identifying systemic diseases associated with mitral regurgitation and myxomatous degeneration (e.g. Marfan syndrome).

Functional mitral regurgitation can occur in patients with ischemic LV dysfunction, or with electromechanic asynchrony, or with tachyarrhythmia-related dysfunction and hypokinetic primary cardiomyopathy. Clinical identification of functional mitral regurgitation could be challenging as, at times, the murmur could be absent with a low LV-atrial gradient, or variable in relationship with the different pathogenic aspects of the valvular lesions determining fluctuation of the regurgitant volume and of the associated murmur. Accordingly, imaging tests are warranted in patients with suspected functional mitral regurgitation, even when no murmur could be detected, particularly in patients with ‘flash’ symptoms or with recurrent heart failure, often brought about by a fluctuation of the degree of mitral regurgitation.

Echocardiographic evaluation of degenerative mitral regurgitation

Transthoracic or transesophageal echocardiography is the first-line imaging for the anatomical and functional definition of degenerative mitral regurgitation.

Myxomatous degeneration is characterized by redundant valvular tissue with echogenicity similar to myocardium (lower than pericardium), with characteristic systolic thinning, secondary to the flaccidity of the valvular tissue.6

FED, on the other hand, is characterized by thinning of the valvular tissue without systolic–diastolic variations (‘poor’ mitral valve). In the contest of a FED, segmental myxomatous valve degeneration could coexist.

Annular calcification, with leaflet involvement, is relatively common in myxomatous degeneration.

Patients with Barlow's disease and significant leaflet redundancy with detachment of the posterior leaflet from the annulus could present early calcification of the valvular apparatus also at young age.

Echocardiography is essential in the definition of the functional anatomy leading to mitral regurgitation, such as prolapse and chordae rupture ‘flail’ (Type II Carpentier lesions).

Prolapse could be defined by the dislocation of the coaptation point of the leaflets more than 2 mm from the annular plane, with eversion of the free margin when chordae rupture occurs.

Tridimensional echo analysis allows an accurate definition of the prolapsing segments on the anteroposterior axis of the annulus, which is the standard reference plane for definition of coaptation geometry of the saddle-shaped annulus.7 The analysis of the degree of dislocation of the systolic coaptation point on the anteroposterior plane allows a quantitative estimation of the prolapsing lesions, separating dominant (>5 mm) from secondary (>2 and <5 mm) lesions.8 Secondary lesions, at variance from primary lesions, could be difficult to identify at surgery, and become problematic if not included in the surgical repair. Furthermore, secondary lesions could represent evolution of primary lesions after remodeling of the LV. Ventricular reverse remodeling due to correction of concomitant cardiac disorder or pharmacological unloading could unmask primary lesions.

Chordae rupture simplifies the pathophysiology of the prolapsing lesions, limiting the impact of the LV remodeling in the assessment.

Three-dimensional echocardiography is useful in mapping the valvular lesions, and in differentiating single from multisegment lesions (more than one segment in a single leaflet), either ‘facing’ or ‘nonfacing’, as well as dominant and secondary lesions.8

Echo imaging is also invaluable in grading of mitral regurgitation and matching the site of the lesion with the regurgitation.

The differentiation between myxomatous degeneration and FED in patients with mitral regurgitation has important implication in the choice of the repair strategy, either surgical or percutaneous.

The redundant valvular tissue characterizing myxomatous degeneration could determine complex regurgitant lesions necessitation of advanced surgical techniques. On the other hand, FED usually leads to limited lesions amenable to standard surgical approach. Nonetheless, the redundant valvular tissue of myxomatous degeneration could provide a valuable substrate for redo surgery, which is not available in patients with FED.

Patients with myxomatous degeneration and significant annular dilation present with an altered geometry of coaptation of the prolapsing segments, limiting the feasibility of percutaneous chordae implant. This situation also is less than optimal for percutaneous MitraClip repair.

Annular calcification with leaflet involvement is not uncommon in myxomatous degeneration. In particular, patients with Barlow's disease could present early calcification of the valvular apparatus, thus limiting the results of repair techniques.

Echocardiographic evaluation of functional mitral regurgitation

Functional mitral regurgitation could be viewed as a syndrome characterized by altered mitral valve function without structural organic lesions of the valvular apparatus.9

Functional mitral regurgitation follows a LV disorder with regional or global remodeling. Mitral regurgitation is the result of tethering of the leaflets below the annular plane, which is not compensated by the wall and annular contractions determining systolic coaptation. The normal work of the papillary muscles is instrumental in the transmission of the tethering forces to the mitral valve apparatus and for the development of functional mitral regurgitation. When the papillary muscle is ischemic or necrotic, mitral regurgitation is eliminated or does not develop at all. An important aspect of functional mitral regurgitation is the variability of the underlying pathogenic mechanism, which stems from the balance between tethering and coaptation forces generated by the LV.10

The asynchronous contraction resulting from delayed electrical activation of the left bundle branch block could lead to a delayed protosystolic apposition of the mitral leaflets (loitering effect) and valvular regurgitation with a protosystolic peak and a presystolic component.

Echocardiography is essential in identifying the LV disorder responsible for functional mitral regurgitation. The clinical–pathologic spectrum spans from two extremes: global and regional remodeling (Fig. 2).

Fig. 2
Fig. 2:
Schematic representation of functional mitral valve regurgitation in patients with regional remodeling (asymmetric leaflet malapposition) and global remodeling (symmetric leaflet malapposition) of the left ventricle.

Regional remodeling is due to single-vessel coronary disease with a billowing zone tethering the papillary muscle and the valvular tissue, with asymmetric malapposition below the annular plane and preserved mobility of the opposite leaflet (the regurgitant jet will pull away from the leaflet with higher coaptation point simulating a pseudoprolapse of the anterior leaflet).

Global remodeling of the LV is secondary to multivessels coronary artery disease or primary dilatative cardiomyopathy, and is characterized by symmetric malapposition of the leaflets below the annular plane, with subannular tethering and apical dislocation of the coaptation point, leading to functional regurgitation. In this situation, echo imaging will show a central regurgitation with intercommissural extension varying according to the geometric displacement and loss of systolic coaptation of the leaflets. Both symmetric and asymmetric malapposition are characterized by reduced systolic motion of the valvular tissue (Carpentier Type III). When, instead, the dominant mechanism of mitral regurgitation is annular dilation, the leaflets’ motion is preserved, with prevalent coaptation deficit and minimal or absent malapposition (Carpentier Type I).

The lesion responsible for functional mitral regurgitation is variable (intervenient ischemia, with spontaneous or postrevascularization recovery of akinetic segments, use of positive or negative inotropic drugs, loading changes of the LV), and determine surprising and unexpected changes of the degree of mitral regurgitation.10

Echocardiography provides a geometric assessment of the malapposition/mal-coaptation of the leaflets, thus allowing an estimation of the feasibility of the surgical or percutaneous repair techniques (Table 2). The most relevant parameters assessing the type of valvular lesion are the tethering area; the depth or the loss of coaptation; the tethering angle of the leaflets; annular dilation, which, along with the mapping of the site of regurgitation, can guide the planning for surgical or percutaneous repair procedures. Lastly, the identification of asynchrony in patients with conduction delay is important in selecting patients with functional mitral regurgitation likely to benefit from resynchronization therapy.

Table 2
Table 2:
Echo-Doppler parameters for surgical or percutaneous repair planning in functional mitral regurgitation

The mitral valve apparatus, albeit defined as normal in patients with functional mitral regurgitation, in patients with LV remodeling, could undergo a process of adaptation characterized by reactivation of embryonic genetic expression with production of cellular and extracellular matrix. This process could lead to an increased valvular surface but with more leaflets rigidity. The mitral regurgitation is then a consequence of the mal-adaptation of the valvular tissue, with insufficient leaflet area and increased rigidity to provide complete systolic coaptation.11,12

Three-dimensional echo assessment can provide important information for a better understanding of the mitral valve adaptation to LV remodeling. This information could guide therapeutic strategies aiming at preventing morphostructural mismatch responsible for the development of functional mitral regurgitation.

Patients with advanced ventricular remodeling can display significant morphologic anomalies of the valvular apparatus such that a reliable distinction between primary mitral regurgitation with LV dysfunction, and primary LV dysfunction with functional mitral regurgitation is almost impossible. The contractile reserve test can unmask degenerative mitral regurgitation with reduced prolapse for the extreme ventricular and annular dilation. Furthermore, the correction of ventricular asynchrony could favorably affect ventricular remodeling, thus revealing a previously hidden prolapse.

Conclusion

The accurate definition of the valvular lesion responsible for mitral regurgitation is paramount in planning an appropriate clinical-therapeutic strategy. Clinical evaluation can be very helpful in identifying the cause of degenerative mitral regurgitation, although could be inadequate for patients with functional mitral regurgitation, due to the ambiguity of the murmur and the frequent fluctuation of the degree of the regurgitation, requiring a systematic and dynamic imaging assessment. Echocardiography is the first-line imaging test to define the functional anatomy of patients with mitral regurgitation, providing the elements for a differential diagnosis between degenerative and functional cause, and can guide the surgical or percutaneous correction strategies. An integrated clinical-imaging evaluation is necessary to identify the pathophysiology underlying the often significant fluctuation of the regurgitation in patients with functional mitral regurgitation, thus providing a guide to their treatment.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

degenerative mitral regurgitation; echocardiography; functional mitral regurgitation

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