Morphogenesis of the Mitral Valve

As with the anatomy, it is convenient to consider development of the mitral valve in terms of its leaflets, tendinous cords, and papillary muscles. We now know from studies investigating the lineage of the constituents of developing atrioventricular valves that the leaflets have never had a myocardial heritage. They are derived from the cushions that, initially, are formed within the atrioventricular canal. When first seen, only two such cushions are present, located superiorly and inferiorly within the atrioventricular canal. The canal, at this early stage of development, opens exclusively into the developing left ventricle, with the right ventricle supporting the entirety of the outflow tract (see also Chapter 3 ). The myocardium of the atrioventricular canal produces continuity between the developing atrial and ventricular chambers throughout the circumference of the canal ( Fig. 34.1 ).

Initial appearances of the atrioventricular cushions formed within the atrioventricular canal of the developing heart. These images are taken from a dataset prepared from a mouse embryo sacrificed at embryologic day 10.5. Left, “Four-chamber” section. Right, Long-axis section across the canal. At this initial stage, the canal empties exclusively into the developing left ventricle. Note the canal myocardium surrounding the cushions, which are positioned superiorly and inferiorly within the canal.

With ongoing development, there is expansion of the canal such that the cavity of the right atrium is brought into continuity with the developing cavity of the right ventricle. By embryologic day (E) 12.5 in the developing mouse heart, it becomes possible to recognize two additional cushions at the margins of the atrioventricular canal ( Fig. 34.2 ).

Images from an episcopic dataset prepared from a mouse embryo sacrificed at E12.5. Note the presence of two additional cushions formed laterally at the sides of the atrioventricular junction. Although the junction (shown in B) remains a common entity, it now empties directly into both ventricles (shown in A). The aortic root, however, still retains its initial location above the developing right ventricle.

At the stage shown in Fig. 34.2 , the major cushions, located superiorly and inferiorly, have yet to fuse one to the other. This process takes place during the latter part of E12.5 in the mouse heart so that, by E13.5, the common junction has been divided into separate orifices for the right and left ventricles. By this stage, the primary atrial septum has also fused to the atrial aspect of the cushions, thus producing separate right and left atrioventricular junctions. The aortic root, however, still retains its location above the developing right ventricle ( Fig. 34.3 ).

These images, taken in the frontal (left) and short-axis (right) planes, are comparable to those shown in Fig. 34.11 but were obtained using an episcopic dataset prepared from a mouse embryo sacrificed at embryologic day 13.5. Left, The atrial septum has fused with the atrial surface of the major atrioventricular cushions to produce separate right and left atrioventricular junctions. Right, The cushions have also fused with each other. As seen in the short-axis view, however, the junction still remains ovoid, with the aortic root retaining its location above the developing right ventricle. Note also that the right atrioventricular orifice has expanded inferiorly across the developing muscular ventricular septum.

The key feature in the separation and development of the atrioventricular valves is the transfer of the aortic root into the left ventricle, which is necessary to permit closure of the embryonic interventricular communication. In the mouse, this process takes place during E13.5, so that, by E14.5, the ventricular septum has been closed by the formation of the “tubercles” from the right ventricular surfaces of the fused atrioventricular cushions ( Fig. 34.4 ).

Images taken from an episcopic dataset prepared from a mouse embryo sacrificed at embryologic day 14.5. Left, Frontal section showing that the aortic root has now been transferred to the left ventricle, with the embryonic interventricular communication closed by the “tubercles” formed at the rightward ends of the major atrioventricular cushions. Right, The aortic root is now interposed between the developing mitral valve and the septum. The fused major cushions now form the potential aortic leaflet of the mitral valve, with the left lateral cushion expanding to form the mural leaflet.

The aortic root is transferred into the left ventricle, so that it becomes positioned between the left ventricular components of the fused major atrioventricular cushions and the ventricular septum. These fused major cushions form what will become the aortic leaflet of the mitral valve. When initially transferred into the left ventricle, however, the aortic root retains a completely muscular infundibulum. The left lateral cushion has expanded concomitant with the transfer of the aortic root, such that the newly formed left atrioventricular orifice is obliquely situated within the short axis of the left ventricle ( Fig. 34.4 , right ). Subsequent to transfer of the aortic root to form the outflow tract of the left ventricle, there is major proliferation of the compact part of the ventricular wall. At the same time, the initial trabecular component diminishes markedly in size, but the trabeculations retain their connections with the distal edges of the cushions. The trabeculations coalesce to form the tension apparatus of the developing valve; this is initially myocardial to the margins of the cushions, which are being transformed to form the valvar leaflets ( Fig. 34.5 ).

Images taken in the long axis of the left ventricle showing the transformation of the coalescing trabecular layer of the ventricular wall to form the tension apparatus of the valve. (A) Initially, at embryologic day (E) 14.5, the aortic root retains its muscular infundibulum (star). The leaflets can be recognized between the myocardial components of the developing valvar apparatus (arrows) . With ongoing maturation through E16.5 (B) and E18.5 (C), the cushions become transformed into the valvar leaflets, with the trabeculations forming the papillary muscles and subsequently the tendinous cords.

The sequence of features now known to appear during normal development permit explanations to be offered for the various lesions afflicting the mitral valve, with the maturation of the trabeculations to produce both the tendinous cords and papillary muscles providing an understanding of why, on occasion, the muscles can extend to form the arcade along the leaflets. The changes observed in the cushions as the initially common atrioventricular junction is divided into the separate right and left atrioventricular junctions shows how the “isolated” cleft of the mitral valve represents failure of fusion of the major atrioventricular cushions. Comparison with the arrangement seen in the setting of a common atrioventricular junction, however, shows why the “cleft” is different anatomically but comparable developmentally, with the zone of apposition between the bridging leaflets as seen in hearts with deficient atrioventricular septation ( Fig. 34.6 ).

Images showing the differences in anatomic terms between the cleft aortic leaflet of the mitral valve (left) and the zone of apposition between the bridging leaflets of a heart with deficient atrioventricular septation (right) . Both lesions were observed in mice bred subsequent to perturbation of the Furin enzyme and sacrificed at embryologic day 14.5, by which time the ventricular septum is normally closed. The difference is the presence of separate atrioventricular junctions in the heart shown (left) as opposed to a common atrioventricular junction (right) . The “building blocks” are comparable, but their anatomy is fundamentally different. VSD, Ventricular septal defect.

Morphology

The leaflets are hinged from the annulus ( Fig. 34.7 ), but this is far from a constant structure. As far as we are aware, furthermore, there are no specific congenital lesions that afflict only the annulus. There are significant differences in the arrangement of the hinges of the aortic and mural leaflets. In this regard, we prefer to describe the leaflets as being “aortic” and “mural,” since this accounts for their morphology irrespective of their specific location in space. In hearts with concordant ventriculoarterial connections, the aortic leaflet is hinged along the area of fibrous continuity with the leaflets of the aortic valve; hence our use of the descriptive term. The two ends of the region of fibrous continuity between the leaflets of the two valves are thickened as the right and left fibrous trigones. It is the anchorage of these trigones to the basal surface of the ventricular mass that secures the aortic-mitral unit within the left ventricle. This part of the mitral valvar circumference, therefore, is strong. It is much less likely to dilate under abnormal circumstances than is the part supporting the mural or posterior leaflet. This leaflet is anchored along the parietal part of the left atrioventricular junction. Marked variation is found in normal hearts in the specific arrangement of the mural annulus. In some places, it is a firm fibrous cord. In others, the cord is replaced by a longer fibrous sheet, or else the fibrous tissue becomes deficient, with the atrial and ventricular musculatures separated by fibroadipose tissue rather than a true annulus. This part of the valvar circumference dilates in the setting of valve disease.

Long-axis section through the left ventricle showing the parasternal echocardiographic view and illustrating the components of the mitral valvar complex. All components work in harmony when the valve is normal. The specimen was prepared subsequent to injection of fixative under pressure in the left ventricle, maintaining the systolic configuration of the leaflets.

Dysplastic Valves

The three main pathologic subgroups usually described are more benchmarks on a continuous spectrum than totally separated groups.

Papillary Muscle to Commissure Fusion, Arcade or Hammock Mitral Valve

Papillary muscle to commissure fusion is the most common feature found in dysplastic mitral valves. Rarely isolated, it is most often associated with either of the two following lesions. Again, a large spectrum of lesions can be seen with short and thin but present cords on one end and totally absent cords with large, bulky, and obstructive papillary muscle on the other end.

In the most severe form, the muscles come together on the leading edge of the aortic leaflet, forming the muscular arcade observed by the pathologist ( Figs. 34.8 and 34.9 ).

Rare example of pure papillary muscle–to-commissure fusion with a thin leaflet. The two papillary muscles are evenly developed and spaced. Chordae on the inferoseptal papillary muscle are very short and absent on the superolateral one. Accessory papillary muscles dedicated to the posterior leaflet are present.

Papillary muscles supporting the leaflets fuse along the leading edge of the aortic leaflet, producing a muscular arcade (left) . Note also the obliteration of the interchordal spaces, which would have rendered the valve stenotic (arrow) .

( Right, From Séguéla P-E, Houyel L, Acar P. Congenital malformations of the mitral valve. Arch Cardiovasc Dis. 2011;104[8–9]:465–479.)

When viewed from the atrial aspect, with the valve intact as seen by the surgeon, the intermixing of cords attached to the enlarged papillary muscle gives the appearance of a hammock. The abnormal attachments produce mitral valvar insufficiency, but the morphologic appearance suggests that the valve would also be stenotic.

Parachute Mitral Valve

Anomalies of the papillary muscles produce the lesion most usually described as the “parachute” lesion. In this regard, it should be remembered that, although usually described as being “anteromedial” and “posterolateral,” the papillary muscles of the mitral valve are located inferoseptally and superolaterally when viewed with the heart in an attitudinally appropriate position (see Chapter 2 ). A parachute mitral valve exceptionally corresponds to the two muscles fused to produce a solitary myocardial mass ( Fig. 34.10 , right ). Commonly, a predominant papillary muscle—usually the anteromedial (or inferoseptal)—is sided with a diminutive posterolateral (or superolateral) papillary muscle. The latter can be connected to a patent commissure or to the undersurface of an imperforated commissure. The functional lesion of a parachute mitral valve can be either regurgitating or stenotic according to the size of the orifice and to the mobility of the leaflets and suspension apparatus combination. It is very often associated with papillary-muscle-to-commissure fusion.

Two lesions described as producing the so-called parachute mitral valve. Left, Absence of the superolateral papillary muscle, so that all the tendinous cords converge on the inferoseptal muscle. Right, Abnormal mitral valve that was removed at surgery. The papillary muscles are fused and the tendinous cords are thickened.

Mitral Cleft

The cleft mitral valve is often isolated and can be easily differentiated from a left atrioventricular valve in a partial atrioventricular septal defect. It is an actual cleft with no suspension apparatus on the edges of the defect. The cleft is centered on the aortic commissure between the noncoronary and left coronary cusps. Each half of the anterior leaflet at the midportion bears the attachment of the strut chordae, whereas the papillary muscles have a normal appearance and function. This is well explained on the basis of failure of fusion between the left ventricular components of the superior and inferior atrioventricular cushions, but in the setting of separate right and left atrioventricular junctions (see later), the space between the cleft components of the leaflet creates the substrate for valvar incompetence. With time, the cleft mitral valve’s regurgitation will generate secondary lesions at the edges of the cleft, such as thickening, rolling in, and retraction. The defect is never stenotic and may generate no or only little regurgitation for a long time ( Fig. 34.11 ).

These images show congenital clefts in the aortic leaflet of the mitral valve. (A) Heart with an intact ventricular septum. Note that both parts of the cleft leaflet are dysplastic and there is thickening of the tendinous cords. (B) Heart with an associated perimembranous ventricular septum defect. The cleft is supported by tendinous cords that attach to the crest of the deficient muscular ventricular septum, but the cleft is directed toward the aortic root (arrow) .

A very rare cleft of the posterior leaflet can be found. Morphologically it could be defined as a cleft of the posterior leaflet or hypoplasia or aplasia of the middle scallop.

Dual-Orifice Mitral Valves

Mitral valves with dual orifices are very rare as opposed to dual orifices found in the left atrioventricular valves of complete or partial atrioventricular septal defects. The two orifices are produced by the presence of a tongue of valvar tissue, which joins together the facing edges of the mural and aortic leaflets, with each orifice supported by one of the papillary muscles ( Fig. 34.12 ).

Tongue of valvar tissue joining together the aortic and mural leaflets of the mitral valve, producing dual valvar orifices (stars) . Note that each orifice is supported by one of the paired papillary muscles of the valve.

Accessory Mitral Valve Tissue

The intercordal spaces are filled with a dense network of immature valve tissue ( Fig. 34.13 ). When there is continuity between the anterior and posterior leaflets, the accessory valvar tissue may generate a gradient directly related to the size of the perforations in the accessory tissue. When the accessory valve tissue is entrapped in the left ventricular outflow tract, the mitral valve may become regurgitant because of the traction exerted by the accessory valvar tissue on the anterior leaflet, which results in the opening of the valve in midsystole ; however, in that case the left ventricular outflow tract obstruction is the predominant hemodynamic lesion and is usually responsible for the diagnosis. Often, the accessory mitral valve tissue does not generate a significant gradient or insufficiency.

Macroscopic view of accessory mitral valve tissue after surgical resection.

Supravalvar Mitral Ring

Often considered a congenital anomaly of the mitral valve, the supravalvar mitral ring is a fibrous construction attached to the posterior annulus of the mitral valve; it runs across both commissures and to the middle height of the anterior leaflet. The lesion is stenotic, often to a greater extent than might be suggested by the extension of the ring. This is more a result of the limitation of the opening of the anterior leaflet than of the actual diaphragm effect of the ring ( Fig. 34.14 ). The supravalvar mitral ring is an acquired lesion resulting from turbulent flow across the mitral valve. The primary lesion of the mitral valve responsible for the turbulent flow can be obvious, stenotic, and regurgitant or it can be discrete or mild and difficult to identify. It may even be only flow related in the context of a left-to-right shunt. It can be related to a prominent coronary sinus, as found in a persistent left superior vena cava draining into the coronary sinus. Perhaps for these reasons the supravalvar mitral ring is prone to recur after surgical resection unless the underlying anatomic anomaly has been identified and corrected.

Anatomic appearance of supravalvar stenosing ring (A, arrows ) and a surgical view of a typical supravalvar ring (B). Both panels demonstrate the membrane attached to the atrial surface of the mural leaflet of the valve, close to the mitral annulus, and the extension toward the mid-height of the anterior (aortic) leaflet.

Strictly attached to the mitral valve annulus, the supravalvar mitral ring must be differentiated from the cor triatriatum, which is not acquired and can be found in the antenatal and neonatal scans. Extremely rarely, fibrous construction can be found in the vestibule of the left atrium, producing true supravalvar rings.

Anomalies of the Mitral Valve in Hypoplastic Left Heart Syndrome

The mitral valve is always set within a severely hypoplastic annulus. Most valves have two recognizable papillary muscles. The leaflet tissue is most often severely thickened and dysplastic; occasionally the leaflet tissue has a normal aspect and the valve is a miniature version of the standard one ( Fig. 34.15 ). On that spectrum, an isolated relative hypoplasia of the mitral valve without hypoplasia of the left ventricle can also be encountered.

(A) Absence of the left atrioventricular connections. (B) How the leaflets of the mitral valve can be fused to form an imperforate shelf. Both lesions are seen most frequently in combination with aortic atresia, when they are an integral part of the hypoplastic left ventricle syndrome (see Chapter 69 ). In the heart shown in (B), however, the imperforate valve is found in the setting of a patent aortic root and deficient ventricular septation.

Anomalies of the Mitral Valve in the Setting of Anomaly of the Ventricular Arterial Connection and Ventricular Septal Defect

Essentially Double-Outlet Ventriculoarterial Connections Together With Anterosuperior Interventricular Muscular Communication

Often the heart has unbalanced ventricles and the anatomy does not affect the surgical treatment. Straddling, when one papillary muscle (usually the anterosuperior one or a lesser head of the latter), is located in the morphologic right ventricle is more common than overriding, where part of the mitral valve annulus is located beyond the morphologic right side of the interventricular septum and above an outlet VSD ( Fig. 34.16 ).

Heart with double-outlet right ventricle and subpulmonary interventricular communication, the so-called Taussig-Bing malformation. There is straddling and overriding of the superoanterior end of the zone of apposition between the aortic and mural leaflets. In this instance, the leaflets retain their location within the left ventricle, with straddling of the tendinous cords to attach to a papillary muscle located in the right ventricle.

Incidence and Etiology

Congenital deformities of the mitral valve are rare if those involving the left valve in hearts with common atrioventricular junction are excluded. Congenital mitral incompetence is even rarer. The prevalence of congenital mitral or tricuspid valve disease was of 0.04 per 1000 children in a general population study. Most male-to-female ratios from recent surgical series of mitral valve repair or replacement vary from 0.74 to 0.89. Congenital mitral valvar anomalies are rarely isolated. The fully developed syndrome of the so-called Shone complex, for example, includes four obstructions within the left heart, namely the valvar lesion itself, supravalvar mitral ring, subaortic stenosis, and aortic coarctation. Any of these obstructions may coexist with any congenital lesion affecting the mitral valve, particularly coarctation. In a clinical series of patients with congenital mitral stenosis and excluding hypoplasia of the left heart, almost three-quarters had additional anomalies. It is tempting to imagine that the development of one abnormality upstream may, during morphogenesis, result in a series of more distal abnormalities owing to disturbance in the patterns of flow. Annular hypoplasia of the mitral valve is almost always associated with hypoplasia of the left ventricle and aortic stenosis or atresia. VSD is quite common in this setting, and double-outlet right ventricle and tetralogy of Fallot occasionally occur. When the mitral valve is imperforate, left ventricular hypoplasia is inevitable unless there is an associated VSD.

Pathophysiology

The pathophysiology is very closely linked to the age of the patient and the presence or absence of associated lesions that will allow the heart to maintain systemic output and to offload the pulmonary circulation. Mitral stenosis or regurgitation results in elevation of the left atrial pressure. Coexistence of an atrial septal defect decompresses the left atrium due to the left-to-right shunt favored by a better right ventricular compliance, as in partial atrioventricular septal defect with left atrioventricular valve regurgitation and primum atrial septal defect (see Chapter 29 ). This may be so profound as to obscure or eliminate the mitral gradient. By contrast, excessive flow through the mitral valve, as may result from an associated VSD, will exaggerate the mitral gradient. Elevation of the left atrial pressure usually results in pulmonary hypertension. In the presence of associated patency of the arterial duct or a VSD, this can result in right-to-left shunting, which will be how the individual maintains systemic output in the neonatal period, whereas in the septated heart, the pulmonary arterial systolic pressure may exceed systemic pressure. Later in life, the rise in pulmonary vascular resistance and consequent fall in pulmonary blood flow will generate a fall in the gradient; right heart failure may ensue. By contrast, severe pulmonary stenosis in the setting of a VSD may entirely mask the effects of the valvar obstruction by reducing the flow of blood to the lungs. In fully septated hearts, when moderate-to-severe mitral regurgitation is left to evolve during childhood, the systemic output is usually maintained until the end of the first decade, with preservation of the systolic function despite a considerable regurgitation fraction. This adaptation occurs via extensive dialation of the left atrium and an increase of the left ventricular end-diastolic diameter. There is hardly any left atrial or pulmonary hypertension. Patients with chronic isolated mitral valve stenosis become symptomatic when the pulmonary vascular resistances increase (acutely during viral illnesses) or when the evolution of the interventricular interrelation modifies the diastolic function of the left ventricle. Associated obstructive lesions downstream obviously increase the severity of the mitral regurgitation.