Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed.
Pathogenesis of Ischemic Mitral Regurgitation
Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction that substantially worsens prognosis. It is believed to result from left ventricular (LV) remodeling that takes place during the chronic phase of infarction. As the left ventricle remodels, the papillary muscles (PMs) are displaced away from the annular plane. This exerts traction (a tethering force) on the chordae tendineae, causing leaflet effacement, loss of coaptation zone height and an increase in regurgitant orifice area ( Figure 1 ). Consequently, the otherwise negligible LV closing force required to shut the mitral valve becomes insufficient to maintain valve competence. Postinfarction LV remodeling also causes perturbations of mitral annular geometry and motion that interfere with leaflet coaptation and further promote MR.
Left atrial remodeling (enlargement) in patients with ischemic MR may reflect the effects of volume overload of the atrium, reduced LV compliance, or atrial fibrillation. It is here proposed that enlargement of the left atrium has the potential to increase mitral leaflet tethering and worsen MR through a mechanism unrelated to LV remodeling, that might aptly be termed atriogenic leaflet tethering .
Anatomically, the posterior mitral annulus separates the left atrium internally from the inlet of the left ventricle externally ( Figure 2 ). I would like to suggest that as the left atrium enlarges, the attached posterior mitral annulus must, of anatomic necessity, be displaced basally onto the crest of the LV inlet, as depicted by the curved arrow in Figure 2 . Such a geometric change could potentially increase annulopapillary distance, thereby augmenting posterior leaflet tethering ( Figure 3 ). Displacement of the posterior annulus might also reduce the effective height of the posterior mitral leaflet, such that its available coaptation surface becomes reduced. Finally, as the posterior annulus mounts the crest of the LV inlet, it might also exert torque on the anterior annulus at the aortomitral curtain, causing it to pivot basally across its intertrigonal axis. In so doing, the anterior annulus may be drawn away from the PMs, causing tethering of the anterior mitral leaflet. The extent of anterior annulus displacement would likely, however, be limited by virtue of its attachment to the fixed aorta. It is important to emphasize that the foregoing considerations are meant to be hypothesis generating and that validation of atriogenic leaflet tethering as a legitimate mechanism that contributes to and/or causes MR remains to be proven.
Adaptations to Ischemic Mitral Regurgitation
The left ventricle compensates for MR by dilating to preserve forward output using the Starling mechanism. LV dilatation, however, worsens MR by increasing leaflet tethering, leading to a vicious cycle in which MR begets more MR. Recent studies suggest that certain structural adaptations play a role in reducing ischemic MR, and in contrast to the compensatory effects of LV enlargement, these reduce, rather than increase its severity. These adaptations involve the mitral valve leaflets, the PMs, the mitral annulus, and the LV false tendons. In this review, I discuss the role each may play in reducing ischemic MR. Therapies which exploit these adaptations are also discussed.
Mitral Valve Leaflets
Maintaining mitral valve competence requires an adequate amount of apposing leaflet tissue overlap at the coaptation zone. The height of the coaptation zone, which can be measured echocardiographically ( Figure 4 ), is normally about 1 cm. Recent three-dimensional echocardiographic and marker fluoroscopic studies suggest that the size of the mitral valve does not remain static but that adaptive remodeling (increases in area), particularly in the region of the coaptation zone, takes place in response to increased leaflet tethering force.
This is thought to be mediated by epithelial (endothelial)–mesenchymal transition (EMT), an ancient biologic process that facilitates organogenesis, carcinogenesis, and the physiologic response to injury. Tethering-induced mitral valve remodeling is thought to represent an example of the latter. The observation that EMT also facilitates valvulogenesis in the endocardial cushions suggests that tethering-induced mitral valve remodeling represents a recapitulation of this embryologic process.
EMT promotes tethering-induced remodeling by means of several signaling pathways (e.g., transforming growth factor–β, Notch, and Erb-B). The process is initiated by signaling factors that trigger a specific subset of endothelial cells to shed their cell-to-cell connections, resulting in delamination from the valve’s surface. These cells also develop invasive and migratory properties that enable them to pass through the basement membrane into the valve’s interstitium. The stem cell–like properties of these cells facilitate differentiation into a number of mesenchymal cell phenotypes, including fibroblasts, myofibroblasts and smooth muscle cells ( Figure 5 ). As the interstitium becomes populated with these cells, extracellular matrix is elaborated and remodeling ensues, resulting in increased mitral valve area and thickness. A more detailed discussion of EMT is beyond the scope of this review, and the interested reader is referred to the articles cited herein.
PMs
The mitral valve complex—PMs, chordae, annulus, and leaflets—functions as an integrated unit. As the annulus descends toward the LV apex in systole, tension is maintained on the chordae by the simultaneous contraction of the PMs, thereby preventing the leaflets from prolapsing into the left atrium. As a result, annular descent is able to effectively contribute to the forward LV stroke without regurgitation into the atrium. Two-dimensional echocardiographic studies reveal that normal PMs shorten approximately 1.0 cm, resulting in a fractional shortening of about 33%, which offsets annular descent by a comparable amount (annulopapillary balance; Figure 6 ). After infarction, PM fractional shortening is reduced by about one half. This loss of contractility is a compensatory adaptation that attenuates the severity of ischemic MR by reducing leaflet tethering. Even more robust adaptive reductions in leaflet tethering and MR occur when the PMs undergo paradoxical systolic elongation ( Figure 7 ), thought to result from the tension exerted on them by mitral valve closure (transmitral pressure).
PM lengthening due to scar formation after myocardial infarction, as depicted in Figure 8 , likely represents aborted PM rupture. Nevertheless, the increase in PM length may reduce leaflet tethering and MR severity by decreasing annulopapillary distance. Extreme increases in PM length, however, can worsen MR by causing the mitral leaflets to prolapse into the left atrium.
Mitral Annulus
The mitral annulus has a three-dimensional shape that can be likened to a saddle with its high points located anteriorly (at the aortomitral curtain) and posteriorly, and its low points located medially and laterally, at the commissures ( Figure 9 ). Histologically, the annulus is composed of fibrous and adipose tissue and therefore lacks intrinsic contractile properties. Its motion is, therefore, determined by that of the basal LV segments to which it is attached, although adjacent atrial musculature may also play a role. The annulus undergoes three types of motion during systole that can be quantified with three-dimensional echocardiographic imaging ( Figures 10 and 11 ): (1) sphincterlike contraction (reduction in area), (2) translation toward the LV apex, and (3) folding along its intercommissural axis (saddle deepening). Wall motion abnormalities involving those LV segments that subserve these motions may increase the severity of ischemic MR. Hence, reduced sphincterlike contraction promotes MR because the ability of the annulus to draw the mitral leaflets together is compromised. Decreased apical translation increases tethering and promotes MR because PM shortening is no longer sufficiently offset (loss of annulopapillary balance). Reduced annular folding (saddle deepening) increases tethering distance by attenuating the normal systolic apical motion of its intercommissural axis.
Postinfarction remodeling not only alters the motion of the annulus but also its geometry, rendering it larger in area and more nonplanar (flatter), as depicted in Figure 12 . It is worth noting that the relationship between annular area and MR severity is variable, reflecting, at least in part, individual differences in the ratio of mitral valve covering area to annular area. Hence, an increased ratio (increased coaptation zone reserve) reduces the likelihood that MR will occur when the annulus is enlarged. Conversely, a reduced ratio increases the likelihood of MR. Not only annular enlargement but flattening as well promotes MR. This results from the increased leaflet tethering produced by basal displacement of its intercommissural axis toward the left atrium.
Ischemic MR caused by posterior infarction usually worsens with exercise because of the increase in leaflet tethering that attends the rise in afterload. This may relate to the compliance of infarcted tissue, which renders it amenable to geometric distortion. Nevertheless, ischemic MR need not worsen during exercise, particularly when there is recruitable contractile reserve in the basal LV segments attached to the posterior mitral annulus ( Figure 13 ). This is likely attributable to these segments possessing a blood supply separate from or in addition to that of the infarct-related artery. Hence, a coronary artery distribution that helps preserve annular geometry and function may be regarded as a protective adaptation in patients with ischemic MR due to posterior myocardial infarction.
LV False Tendons
LV false tendons are chordlike structures within the left ventricle that attach to its free walls, to the interventricular septum, and to the PMs. They are found in approximately half of hearts examined at autopsy. These structures contain varying amounts of fibrous and myocardial tissue, as well as Purkinje fibers that are in continuity with the left bundle branch of the conduction system.
One study of patients with functional MR and dilated cardiomyopathy of both ischemic and nonischemic etiology found that grade 3 to 4+ MR was significantly less likely to occur in the presence of transverse midcavity false tendons than in their absence ( Figure 14 ). Subjects with such false tendons were found to have reductions in tenting area (a measure of leaflet effacement equal to the area delimited by the mitral annulus and leaflets), possibly because of the restraint they impose on PM displacement resulting from LV remodeling.
LV false tendons, particularly those that contain muscular elements, may help prevent LV remodeling and PM relocation, because these structures reinforce the fibromuscular continuity of the so-called ventricular-valvular loop (VVL; Figure 15 ). The VVL is a fibromuscular syncytium that may be arbitrarily designated as beginning at the insertion site of LV epicardial fibers to the aortic annulus. These fibers descend obliquely toward the LV apex, gradually assuming a subendocardial location, where they give rise to the PMs. The strut chords emerging from the PMs, in turn, attach to the anterior mitral leaflet that provides further fibrous continuity that terminates at the right and left fibrous trigones, thereby closing the VVL. It has been proposed that the VVL stores the tension imparted to the strut chords by the contraction of the PMs and by the closing of the mitral valve (transmitral pressure). This tension is made evident by the collapse of the PMs that occurs when the chordae are transected. It has been suggested that the tension stored in the VVL generates an (inward) restoring force, which counterbalances wall stress, an (outward) distending force, that acts on the LV walls. This may be clinically significant because increased wall stress is thought to stimulate molecular and cellular processes responsible for LV remodeling. It remains to be determined, however, if false tendons reinforce the fibromuscular integrity of the VVL sufficiently to reduce wall stress and attenuate LV remodeling.
