Chapter 40. Pathophysiology of Mitral Valve Disease

Anatomy

The mitral annulus is a pliable junctional zone of discontinuous fibrous and muscular tissue that joins the left atrium and left ventricle and anchors the hinge portions of the anterior and posterior mitral leaflets.1–8 The annulus has two major collagenous structures: (1) the right fibrous trigone, which is part of the central fibrous body and is located at the intersection of the membranous septum, the tricuspid annulus, and the aortic annulus; and (2) the left fibrous trigone, which is located near the aortic annulus under the left aortic cusp (Fig. 40-1). The anterior mitral leaflet spans the distance between the commissures (including the trigones) and is in direct fibrous continuity with the aortic annulus under the left and noncoronary aortic valve cusps, including the fibrous triangle between the left and noncoronary aortic valve cusps. The posterior half to two-thirds of the annulus, which subtends the posterior leaflet, is primarily muscular with little or no fibrous tissue.4

The mitral valve has two major leaflets, the larger anterior (or aortic or septal) leaflet and the smaller posterior (or mural) leaflet; the latter usually contains three or more scallops separated by fetal clefts or subcommissures, which are developed to variable degrees in different individuals.9 The three posterior leaflet scallops are anatomically termed anterolateral (P1), middle (P2), and posteromedial (P3) scallops (Fig. 40-2). The portions of the leaflets near the free margin on the atrial surface are called the rough zone, with the remainder of the leaflet surface closer to the annulus being termed the smooth (or bare or membranous) zone. The ratio of the height of the rough zone to the height of the clear zone is 0.6 for the anterior leaflet and 1.4 for the posterior leaflet because the clear zone on the posterior scallops occupies only about 2 mm.9 The two leaflets are separated by the posteromedial and anterolateral commissures, which usually are distinctly developed but occasionally are incomplete.

The histologic structure of the leaflets includes three layers: (1) the fibrosa, the solid collagenous core that is continuous with the chordae tendineae; (2) the spongiosa, which is on the atrial surface and forms the leaflet leading edge (it consists of few collagen fibers but has abundant proteoglycans, elastin, and mixed connective tissue cells); and (3) a thin fibroelastic covering of most of the leaflets.4 On the atrial aspect of both leaflets, this surface (the atrialis) is rich in elastin. The ventricular side of the fibroelastic cover (the ventricularis) is much thicker, confined mostly to the anterior leaflet, and densely packed with elastin. The fibroelastic layers become thickened with advancing age as a result of elaboration of more elastin and more collagen formation; accelerated similar changes also accompany the progression of myxomatous (degenerative or “floppy”) mitral valvular disease in young patients with the Barlow syndrome. In addition to these complex connective tissue structures, the mitral leaflets contain myocardium, smooth muscle, contractile valvular interstitial cells, and blood vessels, as well as both adrenergic and cholinergic afferent and efferent nerves.10–24 Leaflet contractile tissue is neurally controlled and plays a role in mitral valve function.8,11–14,25–32 The atrial surface of the anterior leaflet exhibits a depolarizing electrocardiogram spike shortly before the onset of the QRS complex, and the resulting contraction of leaflet muscle (which can be abolished by beta-blockade), along with contraction of smooth muscle and valvular interstitial cells, possibly aids leaflet coaptation before the onset of systole, as well as stiffens the leaflet in response to rising left ventricular (LV) pressure.11–14,29,31,33,34–38 Mitral leaflet stretch of 10% or more also leads to an action potential that initiates leaflet muscle contraction.34,39

Annular Size, Shape, and Dynamics

The average mitral annular cross-sectional area ranges from 5.0 to 11.4 cm2 in normal human hearts (average is 7.6 cm2).40 The annular perimeter of the posterior leaflet is longer than that subtending the anterior leaflet by a ratio of 2:1; ie, the posterior annulus circumscribes approximately two-thirds of the mitral annulus.12 Annular area varies during the cardiac cycle and is influenced directly by both left atrial (LA) and LV contraction, size, and pressure.41,42 The mitral annular area changes by 20 to 40% during the cardiac cycle.6,41–47 Annular size increases beginning in late systole and continues through isovolumic relaxation and into diastole; maximal annular area occurs in late diastole around the time of the P wave on the electrocardiogram.6,41,43,46,48 Importantly, half to two-thirds of the total decrease in annular area occurs during atrial contraction (or presystolic); this component of annular area change is smaller when the PR interval is short and is abolished completely when atrial fibrillation or ventricular pacing is present. Annular area decreases further (if LV end-diastolic volume is not abnormally elevated) to a minimum in early to midsystole.5,6,41–43

The normal human mitral annulus is roughly elliptical (or kidney-shaped), with greater eccentricity (ie, being less circular) in systole than in diastole.3,6,40–42,45,47,49 In its most elliptical configuration, the ratio of minor to major diameters is approximately 0.75. In three-dimensional space, the annulus is saddle shaped (or more precisely, a hyperbolic paraboloid), with the highest point (farthest from the LV apex) located anteriorly in the middle of the anterior leaflet; this point is termed the fibrosa in the echocardiography literature and the saddle horn by surgeons, and is readily identified in echocardiographic images owing to the common junction with the aortic valve. The low points are located posteromedially and anterolaterally in the commissures, and another less prominent high point is located directly posterior.41,50,51 During the cardiac cycle, annular regions adjacent to the posterior leaflet (where the leaflet attaches directly to the atrial and ventricular endocardium) move toward (during systole) and away (during diastole) from the relatively immobile anterior annulus.41,47

The mitral annulus moves upward into the left atrium in diastole and toward the LV apex during systole; the duration, average rate, and magnitude of annular displacement correlate with (and perhaps influence) the rate of LA filling and emptying.6,41,43,46,52,53 The annulus moves slightly during late diastole (2 to 4 mm toward the left atrium during atrial systole). This movement does not occur in the presence of atrial fibrillation and may be an atriogenic contractile property.The annulus moves a greater distance (3 to 16 mm toward the LV apex) during isovolumic contraction and ventricular ejection. This systolic motion, which aids subsequent LA filling, occurs in the presence or absence of atrial fibrillation and is related to the extent of ventricular emptying; thus, it is likely driven by LV contraction.6,41,45,46,52–55 Subsequently, the annulus moves very little during isovolumic relaxation but then exhibits rapid recoil toward the left atrium in early diastole. This recoiling increases the net velocity of mitral inflow by as much as 20%.46,56 Annular motion can be responsible for up to 20% of LV filling and ejection.57

Dynamic Leaflet Motion

The posterior mitral leaflet is attached to thinner chordae tendineae than the anterior leaflet, and its motion is restrained by chordae during both systole and diastole.9,52 Regions of both leaflets are concave toward the left ventricle during systole,58–60 but leaflet shape is complex, and anterior leaflet curvature near the annulus is convex to the left ventricle during systole, thus resulting in a sigmoid shape.48,50,51,61 Leaflet opening does not start with the free margin but rather in the center of the leaflet; leaflet curvature flattens initially and then becomes reversed (making the leaflet convex toward the left ventricle) while the edges are still approximated.48,59,60 The leading edge then moves into the left ventricle (like a traveling wave), and the leaflet straightens. The leaflet edges in the middle of the valve appear to separate before those portions closer to the commissures, and posterior leaflet opening occurs approximately 8 to 40 ms later.60–63 Early leaflet opening (e wave) is very rapid; once reaching maximum opening, the edges exhibit a slow to-and-fro movement (like a flag flapping in a breeze) until another less forceful opening impulse occurs, associated with the a wave. During late diastole, the leaflets move gradually away from the LV wall.

Valve closure starts with the leaflet bulging toward the atrium at its attachment point to the annulus. The closure rate of the anterior leaflet is almost twice that of the posterior leaflet, thereby ensuring arrival of both cusps at their closed positions simultaneously (because the anterior leaflet is opened more widely than the posterior leaflet at the onset of ventricular systole).63 The anterior leaflet actually arrives at the plane of the annulus in a bulged shape (concave to the ventricle), but as the closing movement proceeds and the leaflet ascends toward the atrium, this curvature appears to run through the whole leaflet, from the annulus toward the edge, in a rolling manner. The leaflet edge is the last part of the leaflet to approach the annular plane. Leaflet curvature is more pronounced with the onset of systolic ejection.59,60

Chordae Tendineae and Papillary Muscles

Epicardial fibers in the left ventricle descend from the base of the heart and proceed inward at the apex to form the two papillary muscles, which are characterized by vertically oriented myocardial fibers.64,65 The anterolateral papillary muscle usually has one major head and is a more prominent structure; the posteromedial papillary muscle can have two or more subheads and is flatter.9 A loop from the papillary muscles to the mitral annulus is completed by the chordae tendineae continuing into the mitral leaflets, which then are attached to the annulus. The posteromedial papillary muscle usually is supplied by the right coronary artery (or a dominant left circumflex artery in 10% of patients); the anterolateral papillary muscle is supplied by blood flow from both the left anterior descending and circumflex coronary arteries.7,64,66,67

The posteromedial and anterolateral papillary muscles give rise to chordae tendineae going to both leaflets9 (Fig. 40-3). Classically, the chordae are divided functionally into three groups.64,68 First-order chordae originate near the papillary muscle tips, divide progressively, and insert on the leading edge of the leaflets; these primary chordae prevent valve-edge prolapse during systole. The second-order chordae (including two or more larger and less branched “strut” chordae) originate from the same location and tend to be thicker and fewer in number;9,68 they insert on the ventricular surface of the leaflets at the junction of the rough and clear zones, which is demarcated by a subtle ridge on the leaflet corresponding to the line of leaflet coaptation. The second-order chordae (including the strut chordae) serve to anchor the valve, are more prominent on the anterior leaflet, and are important for optimal ventricular systolic function. Second-order chordae also may arborize from large chordae that also give rise to first-order chordae. The third-order chordae, also called tertiary or basal chordae, originate directly from the trabeculae carneae of the ventricular wall, attach to the posterior leaflet near the annulus, and can be identified by their fan-shaped patterns.68 Additionally, distinct commissural chordae and cleft chordae exist in the commissures. In total, about 25 major chordal trunks (range 15 to 32) arise from the papillary muscles in humans, equally divided between those going to the anterior and posterior leaflets; on the other end, greater than 100 smaller individual chordae attach to the leaflets.68 Studies of porcine mitral valves demonstrate that the chordae have different microstructures based on chordal type.69 The presence of blood vessels characterizes the chordae as complex living components that work in coordination with the other elements of the valvular and subvalvular apparatus.

During diastole, the papillary muscles form an inflow tract. During systole, they create an outflow tract that later becomes obliterated owing to systolic thickening of the papillary muscles, thereby augmenting LV ejection by volume displacement.65 The contribution of the papillary muscles to LV chamber volume is 5 to 8% during diastole but 15 to 30% during systole.65,70 The anterolateral and posteromedial papillary muscles contract simultaneously and are innervated by both sympathetic and parasympathetic (vagal) nerves.71,72

Studies of papillary muscle function during the cardiac cycle have yielded discordant results.71,73–76 Although the papillary muscles shorten at some point during systole (by more than one-fourth their maximum length), this contraction may be isometric or substantially less than that of the LV free wall fibers.73–75,77–80 In addition, there is no consensus as to the exact timing of papillary muscle contraction and elongation during the cardiac cycle.71–73,75,76,78,79 Some studies suggest that the papillary muscles contract before the LV free wall so that the mitral valve leaflets are supported during early LV ejection;76 others, however, show that papillary muscles lengthen during isovolumic contraction and shorten during ejection, as well as during isovolumic relaxation.72,75 From the standpoint of electromechanics, although papillary muscle excitation occurs simultaneously with the rest of the endocardial surface of the ventricle, the papillary muscles may contract just after the onset of LV contraction.71,78 Papillary muscle shortening throughout isovolumic relaxation may play a role in opening the mitral valve, and elongation in late diastole may be necessary to permit proper valve closure.78

Experimentally, both papillary muscles closely mimic general LV dynamics; ie, the papillary muscles shorten during ejection, lengthen during diastole, and change length minimally during the isovolumic periods73 (Fig. 40-4). These findings suggest that earlier studies suggesting that papillary muscle lengthens during isovolumic contraction and shortens during isovolumic relaxation may have been confounded by some form of myocardial injury or surgical trauma during instrumentation.73

Etiology

Mitral stenosis generally is the result of rheumatic heart disease.81–88 Nonrheumatic causes of mitral stenosis or LV inflow obstruction include severe mitral annular and/or leaflet calcification in elderly people, congenital mitral valve deformities, malignant carcinoid syndrome, neoplasm, LA thrombus, endocarditic vegetations, certain inherited metabolic diseases, and those cases related to previous commissurotomy or an implanted prosthesis.84–90 A definite history of rheumatic fever can be obtained in only about 50 to 60% of patients; women are affected more often than men by a 2:1 to 3:1 ratio. Nearly always acquired before age 20, rheumatic valvular disease becomes clinically evident one to three decades later.

Approximately 20 million cases of rheumatic fever occur in developing countries annually.91 In the United States, Western Europe, and other developed countries, the prevalence of mitral stenosis has decreased markedly. The etiologic agent for acute rheumatic fever is group A beta-hemolytic streptococcus, but the specific immunologic and inflammatory mechanisms leading to the valvulitis are less clear.91–94 Streptococcal antigens cross-react with human tissues, known as molecular mimicry, and may stimulate immunologic responses. Components implicated in the organism's virulence include the hyaluronic acid capsule and the antigenic streptococcal M protein and its peptides.91–93 Mimicry between streptococcal antigens and heart tissue proteins, combined with high inflammatory cytokine and low interleukin-4 production, leads to the development of autoimmune reactions and cardiac tissue damage.92,93

In addition to affecting the cardiac valves, rheumatic heart disease is a pancarditis affecting to various degrees the endocardium, myocardium, and pericardium81–83,87 (Fig. 40-5). In rheumatic valvulitis, mitral valve involvement is the most common (isolated mitral stenosis is found in 40% of patients), followed by combined aortic and mitral valve disease, and least frequently, isolated aortic valve disease, with or without tricuspid involvement. Pathoanatomical characteristics of mitral valvulitis include commissural fusion, leaflet fibrosis with stiffening and retraction, and chordal fusion and shortening (Fig. 40-6).82,88 Leaflet stiffening and fibrosis can be exacerbated over time by increased flow turbulence. Valvular regurgitation can develop as a result of chordal fusion and shortening. The chordae tendineae may become so retracted that the leaflets appear to insert directly into the papillary muscles. The degree of calcification varies. It is more common and of greater severity in men, older patients, and those with a higher transvalvular gradient.83 In some cases, rheumatic myocarditis results in left ventricular dilatation caused by a cardiomyopathic process and progressive heart failure.

Mitral annular calcification may progress to mitral sclerosis and eventually stenosis in elderly people or those who are dialysis dependent.88,90 The anterior leaflet can become thick and immobile; LV inflow obstruction also results from calcification of the posterior mitral valve leaflet. Calcific protrusions into the ventricle and extension of the calcium into the leaflets further narrow the valve orifice, resulting in mitral stenosis.88,90 In these cases, the left ventricle typically is small, hypertrophied, and noncompliant.

Hemodynamics

In patients with mitral stenosis, an early, middle, and late diastolic transvalvular gradient is present between the left atrium and ventricle; as the degree of mitral stenosis worsens, a progressively higher gradient occurs, especially late in diastole.84,95–97 The average left atrial pressure in patients with severe mitral stenosis may be in the range of 15 to 20 mm Hg at rest, with a mean transvalvular gradient of 10 to 15 mm Hg.95,97 With exercise, the LA pressure and gradient rise substantially.

Another physiologic measurement in patients with mitral stenosis is the (derived) cross-sectional valve area, which is calculated from the mean transvalvular pressure gradient and cardiac output. The transvalvular pressure gradient is a function of the square of the transvalvular flow rate; eg, doubling the flow quadruples the gradient. Mitral transvalvular flow depends on cardiac output and heart rate. An increase in heart rate decreases the duration of transvalvular LV filling during diastole; the transvalvular mean gradient increases, and consequently, so does LA pressure.96,98 A high transvalvular gradient may be associated with a normal cardiac output. Conversely, if cardiac output is low, only a modest transvalvular gradient may be present.

Because of effective atrial contraction, the mean LA pressure in patients with mitral stenosis and normal sinus rhythm is lower than that in patients with atrial fibrillation.99,100 Sinus rhythm further augments flow through the stenotic valve, thereby helping to maintain adequate forward cardiac output. The development of atrial fibrillation decreases cardiac output by 20% or more; atrial fibrillation with a rapid ventricular response can lead to acute dyspnea and pulmonary edema.81,99

Ventricular Adaptation

In patients with isolated mitral stenosis and restricted LV inflow, LV chamber size (end-diastolic volume) is normal or smaller than normal, and the end-diastolic pressure typically is low.84,101,102 The peak filling rate is reduced, as is stroke volume. Cardiac output thus is diminished as a result of inflow obstruction leading to underfilling of the ventricle rather than LV pump failure.103 During exercise, the LV ejection fraction may increase slightly; however, LV filling is compromised by the shorter diastolic filling periods at higher heart rates, resulting in a smaller end-diastolic volume (or LV preload). Therefore, stroke volume and a blunted increase (or even decrease) in cardiac output can occur.102

Approximately 25 to 50% of patients with severe mitral stenosis have LV systolic dysfunction as a consequence of associated problems (eg, mitral regurgitation, aortic valve disease, ischemic heart disease, rheumatic myocarditis or pancarditis, and myocardial fibrosis) or internal constraint of a rigid mitral valve, reduced preload, and reflex increase in afterload.83,88,97,102 In these patients, LV end-systolic and -diastolic volumes may be larger than normal. Diastolic dysfunction and abnormal chamber compliance are sometimes evident.88 Also, because right ventricular afterload increases as pulmonary hypertension develops in these patients, right ventricular systolic performance deteriorates.84,104

Atrial Adaptation

In patients with mitral stenosis who are in normal sinus rhythm, the LA pressure tracing is characterized by an elevated mean LA pressure with a prominent a wave, which is followed by a gradual pressure decline.81,100 Because of the stenotic valve, coordinated LA contraction is important in maintaining adequate transvalvular flow.100 The high LA pressure gradually leads to LA hypertrophy and dilatation, atrial fibrillation, and atrial thrombus formation.83,102,105 The degree of LA enlargement and fibrosis does not correlate with the severity of the valvular stenosis partly because of the marked variation in duration of the stenotic lesion and atrial involvement by the underlying rheumatic inflammatory process.102 Disorganization of atrial muscle fibers is associated with abnormal conduction velocities and inhomogeneous refractory periods. Premature atrial activation owing to increased automaticity or reentry eventually may lead to atrial fibrillation, which is present in more than half of patients with either pure mitral stenosis or mixed mitral stenosis and regurgitation.105 Major determinants of atrial fibrillation in patients with rheumatic heart disease include older age and larger LA diameter.105

Pulmonary Changes

In patients with mild to moderate mitral stenosis, pulmonary vascular resistance is not increased, and pulmonary arterial pressure may remain normal at rest, rising only with exertion or increased heart rate.95 In severe chronic mitral stenosis with elevated pulmonary vascular resistance, pulmonary arterial pressure is elevated at rest and can approach systemic pressure with exercise. A pulmonary arterial systolic pressure greater than 60 mm Hg significantly increases impedance to right ventricular emptying and produces high right ventricular end-diastolic and right atrial pressures.

LA hypertension produces pulmonary vasoconstriction, which exacerbates the elevated pulmonary vascular resistance.83,104 As the mean LA pressure exceeds 30 mm Hg above oncotic pressure, transudation of fluid into the pulmonary interstitium occurs, leading to reduced lung compliance. Pulmonary hypertension develops as a result of passive transmission of high LA pressure, pulmonary venous hypertension, pulmonary arteriolar constriction, and eventually, pulmonary vascular obliterative changes. Early changes in the pulmonary vascular bed may be considered protective in that the elevated pulmonary vascular resistance protects the pulmonary capillary bed from excessively high pressures. However, the pulmonary hypertension worsens progressively, leading to right-sided heart failure, tricuspid insufficiency, and occasionally, pulmonic valve insufficiency.84,104

Clinical Evaluation

Because of the gradual development of mitral stenosis, patients may remain asymptomatic for many years.81,88,95 Characteristic symptoms of mitral stenosis eventually develop and are associated primarily with pulmonary venous congestion or low cardiac output, eg, dyspnea on exertion, orthopnea, or paroxysmal nocturnal dyspnea and fatigue. With progressive stenosis (valve area between 1 and 2 cm2), patients become symptomatic with less effort. When mitral valve area decreases to about 1 cm2, symptoms become more pronounced. As pulmonary hypertension and right-sided heart failure subsequently develop, signs of tricuspid regurgitation, hepatomegaly, peripheral edema, and ascites can be found.

As a result of high LA pressure and increased pulmonary blood volume, hemoptysis may develop secondary to rupture of dilated bronchial veins (or submucosal varices).81,88,104 Over time, pulmonary vascular resistance becomes higher, and the likelihood of hemoptysis decreases. Hemoptysis also may result from pulmonary infarction, which is a late complication of chronic heart failure. Acute pulmonary edema with pink frothy sputum can occur as a result of alveolar capillary rupture.

Systemic thromboembolism, occurring in approximately 20% of patients, may be the first symptom of mitral stenosis; recurrent embolization occurs in 25% of patients.81,106 The incidence of thromboembolic events is higher in patients with mitral stenosis or mixed mitral stenosis–mitral regurgitation than in those with pure mitral regurgitation. At least 40% of all clinically important embolic events involve the cerebral circulation, approximately 15% involve the visceral vessels, and 15% affect the lower extremities.81,107 Embolization to coronary arteries may lead to angina, arrhythmias, or myocardial infarction; renal embolization can result in hypertension.81 Factors that increase the risk of thromboembolic events include low cardiac output, LA dilatation, atrial fibrillation, left atrial thrombus, absence of tricuspid or aortic regurgitation, and the presence of echocardiographic “smoke” in the atrium, an indicator of stagnant flow. Patients with these risk factors should be anticoagulated.81,106,107 If an episode of systemic embolization occurs in patients in sinus rhythm, infective endocarditis, which is more common in mild than in severe mitral stenosis, should be considered.

Patients with chronic mitral stenosis are often thin and frail (cardiac cachexia), indicative of longstanding low cardiac output, congestive heart failure, and inanition.81 The peripheral arterial pulse generally is normal, except in patients with a decreased LV stroke volume, in which case the pulse amplitude is diminished. Heart size usually is normal, with a normal apical impulse on chest palpation. An apical diastolic thrill may be present. In patients with pulmonary hypertension, a right ventricular lift can be felt in the left parasternal region. Auscultatory findings include a presystolic murmur, a loud S₁, an opening snap, and an apical diastolic rumble.81,88,108–110 The presystolic murmur, which occurs because of closing of the anterior mitral leaflet, is a consistent finding and begins earlier in those in sinus rhythm than in those in atrial fibrillation.110 S₁ is accentuated in mitral stenosis when the leaflets are pliable but diminished in later phases of the disease when the leaflets are thickened or calcified. As pulmonary artery pressure becomes elevated, S₂ becomes prominent.111 With progressive pulmonary hypertension, the normal splitting of S₂ narrows because of reduced pulmonary vascular compliance. Other signs of pulmonary hypertension include a murmur of tricuspid and/or pulmonic regurgitation and an S₄ originating from the right ventricle. Best heard at the apex, the early diastolic mitral opening snap is caused by sudden tensing of the pliable leaflets during valve opening and is absent when the leaflets are rigid or immobile.81,108,109 In mild mitral stenosis, the diastolic rumble is soft and of short duration; a long or holodiastolic murmur indicates severe mitral stenosis. The intensity of the murmur does not necessarily correlate with the severity of the stenosis; indeed, no diastolic murmur may be detectable in patients with severe stenosis, calcified leaflets, or low cardiac output.110 Coagulation abnormalities common in mitral stenosis include changes in platelet and fibrinolytic activity and increased concentration of fibrinopeptide A, thrombin-antithrombin III complex, and d-dimer.88

On chest radiography, LA enlargement is the earliest change found in patients with mitral stenosis; it is suggested by posterior bulging of the left atrium seen on the lateral view, a double contour of the right heart border seen on the posteroanterior film, and elevation of the left main stem bronchus.95 The overall cardiac size often is normal. Prominence of the pulmonary arteries coupled with LA enlargement may obliterate the normal concavity between the aorta and left ventricle to produce a straight left heart border. In the lung fields, pulmonary congestion may be recognized as distention of the pulmonary arteries and veins in the upper lung fields and pleural effusions. If mitral stenosis is severe, engorged pulmonary lymphatics are seen as distinct horizontal linear opacities in the lower lung fields (Kerley B lines).

The electrocardiogram is not accurate in assessing the severity of mitral stenosis and in many cases may be completely normal. In patients with severe mitral stenosis and normal sinus rhythm, LA enlargement is the earliest change (a wide notched P wave in lead II and a biphasic P wave in lead V1).88,95,112 Atrial arrhythmias are common in patients with advanced degrees of mitral stenosis. In those with pulmonary hypertension, right ventricular hypertrophy may develop and is associated with right-axis deviation, a tall R wave in V₁, and secondary ST-T-wave changes; however, the electrocardiogram is not a sensitive indicator of right ventricular hypertrophy or the degree of pulmonary hypertension.112 Because multivalvular disease may be present in patients with rheumatic heart disease, signs of left and right ventricular hypertrophy can be identified on the electrocardiogram in cases of combined mitral and aortic stenosis. Right atrial enlargement and right ventricular dilatation and hypertrophy, however, also can mask the changes indicative of LV hypertrophy on the electrocardiographic tracing in patients with multivalvular disease.112

Echocardiography has become the primary diagnostic method for assessing mitral valve pathology and pathophysiology.7,88,113–116 Cross-sectional valve area and LA and LV dimensions can be quantified using two-dimensional transthoracic echocardiography (TTE). Best appreciated in the parasternal long-axis view, features of rheumatic mitral stenosis include reduced diastolic excursion of the leaflets (Carpentier type IIIa leaflet motion) and thickening or calcification of the valvular and subvalvular apparatus (Fig. 40-7). M-mode findings include thickening, reduced motion, and parallel movement of the anterior and posterior leaflets during diastole. The mitral valve area can be planimetered directly in the short-axis view, but this measurement has limited clinical value. Doppler echocardiography accurately determines peak and mean transvalvular mitral pressure gradients that correlate closely with cardiac catheterization measurements.81,113 To estimate mitral valve area, the pressure half-time (time required for the initial diastolic gradient to decline by 50%) has been employed; the more prolonged the half-time, the more severe is the reduction in orifice area.113 Using the pressure half-time determination, mitral valve area is equal to 220 (an empirical value) divided by the pressure half-time. Deriving mitral valve area using the pressure half-time method, however, generally has fallen out of favor. The mean mitral gradient at rest and with bicycle or supine exercise measured using Doppler echocardiography is more useful clinically than estimating mitral valve area; the simultaneous increase in right ventricular systolic pressure (estimated from continuous-wave or pulse-wave Doppler envelopes of the tricuspid regurgitation signal) during exercise is also revealing. The mitral separation index, which is the average of the maximum separation of the mitral leaflet tips in diastole in parasternal and apical four-chamber views, shows good correlation with mitral valve area measured by planimetry and pressure half-time and may be able to discriminate between hemodynamically significant and insignificant mitral stenosis.117 TEE can provide more information in the evaluation of mitral stenosis; although rarely needed, it is better than the transthoracic approach for visualizing details of valvular pathology, such as valve mobility and thickness, subvalvular apparatus involvement, and extent of leaflet or commissural calcification.88,113,114

Three-dimensional (3D) echocardiography facilitates spatial recognition of intracardiac structures and can evaluate cardiac valvular and congenital heart disease using both real-time three-dimensional TTE and TEE images.116,118,119 The addition of color-flow Doppler to 3D echocardiography provides better visualization of regurgitant lesions and promises to improve quantitative assessment of such lesions. Measurements of LV volume using 3D echocardiography correlate tightly with measurements obtained using both contrast ventriculography and magnetic resonance imaging (MRI). Cardiac MRI technology continues to be refined but remains inferior to echocardiography for depiction of valvular morphology and motion.120,121 Multidetector computed tomography (CT) may emerge as a technique that can evaluate both cardiac structure and function. Experience with gated multidetector CT has yielded good visualization of valve leaflet hinges, commissures, and the mitral annulus.122 Main limitations of this technology include image noise, the time required for postprocessing, and the radiation dose.

Cardiac catheterization is not necessary to establish the diagnosis of mitral stenosis; however, it provides information regarding coronary artery status.123 Historically, left ventriculography permits assessment of the mitral valve and LV contractility and calculation of ejection fraction, but its role has been totally replaced by echocardiography. Left-sided heart catheterization allows determination of LV end-diastolic pressure; right-sided heart catheterization is performed to measure cardiac index and the degree of pulmonary hypertension. Rarely, cardiac catheterization is used to evaluate the reversibility of severe pulmonary hypertension using pharmacologic interventions, including inhaled nitric oxide when indicated.

Postprocedure Outcome

Whereas LV systolic function is used to predict the natural history and postprocedure prognosis of patients with other valvular lesions, there are few data linking LV function to outcome in patients with mitral stenosis. Not surprisingly, the best indicator is related to the degree of clinical impairment. Untreated mitral stenosis is associated with a poor prognosis once severe symptoms occur.88 Percutaneous balloon valvuloplasty is the mainstay of treatment of mitral stenosis provided the anatomy is favorable (Fig. 40-8).88 Generally, the technique immediately doubles mitral valve area and decreases the gradient substantially in properly selected patients with rheumatic mitral stenosis. Approximately 90% of patients improve clinically if a valve area greater than 1.5 cm2 without significant regurgitation can be achieved.124 Surgical intervention (eg, open mitral commissurotomy or mitral valve replacement) substantially improves functional capacity and long-term survival of patients with mitral stenosis; 67 to 90% of patients are alive at 10 years.112,125–127 Despite a higher operative risk for patients with severe pulmonary hypertension and right-sided heart failure, these individuals usually improve postoperatively with a reduction in pulmonary vascular pressures.84,128 If there is not excessive scarring of the subvalvular mitral apparatus, mitral valve replacement using chordal-sparing techniques can be performed in patients with rheumatic mitral valve disease, particularly those with mixed stenotic and regurgitant lesions; this results in a reduction in LV end-systolic and end-diastolic volumes and preservation of LV systolic pump performance.129,130 Alternatively, the valve and the entire subvalvular apparatus have to be resected during mitral valve replacement when the disease process is very advanced and all structures are densely calcified and extremely scarred, which frequently is the case in older patients.

Summary

Mitral stenosis generally is caused by rheumatic heart disease. With worsening mitral stenosis, a progressively higher transvalvular pressure gradient develops. Mitral transvalvular flow depends on cardiac output and heart rate; an increase in heart rate decreases the duration of transvalvular filling during diastole and reduces forward cardiac output, causing symptoms. In mild to moderate mitral stenosis, pulmonary vascular resistance may not be elevated; pulmonary arterial pressure may be normal at rest and rise only with exercise or increased heart rate. In patients with severe mitral stenosis with elevated pulmonary vascular resistance, the pulmonary arterial pressure usually is high at rest. Characteristic symptoms of mitral stenosis are associated with pulmonary venous congestion and/or low cardiac output. Echocardiography remains the best technique for assessing mitral valve pathology. Percutaneous or surgical intervention can improve functional capacity and long-term survival of patients with mitral stenosis.

Etiology

The functional competence of the mitral valve relies on proper, coordinated interaction of the mitral annulus and leaflets, chordae tendineae, papillary muscles, left atrium, and left ventricle, what we refer to as the valvular-ventricular complex.64,66,131–134 Normal LV geometry and alignment of the papillary muscles and chordae tendineae permit leaflet coaptation and prevent prolapse during ventricular systole. Dysfunction of any one or more of the components of this valvular–ventricular complex can lead to mitral regurgitation. Regurgitation also can occur in diastole (<i>presystolic mitral regurgitation</i>) as a result of delayed ventricular contraction or permanent ventricular pacing, but this phenomenon appears to have few clinical implications.135

Important causes of systolic mitral regurgitation include ischemic heart disease with ischemic mitral regurgitation (IMR), dilated cardiomyopathy [for which the general term functional mitral regurgitation (FMR) is used], myxomatous degeneration, rheumatic valve disease, mitral annular calcification, infective endocarditis, congenital anomalies, endocardial fibrosis, myocarditis and collagen-vascular disorders.83,86,87,136–138 IMR is considered a specific subset of FMR. Acute mitral regurgitation also may be the result of ventricular dysfunction from rapidly developing cardiomyopathy, such as Takotsubo cardiomyopathy, in which the mitral regurgitation is caused by left ventricular outflow tract obstruction and systolic anterior motion of the mitral valve from apical ballooning.139

In general, four types of structural changes of the mitral valve apparatus may produce regurgitation: Leaflet retraction from fibrosis and calcification, annular dilatation, chordal abnormalities (including rupture, elongation, or shortening), and LV dysfunction with or without papillary muscle involvement.64,66,140–146 Carpentier classified mitral regurgitation into three main pathoanatomic types based on leaflet motion: normal leaflet motion (type I), leaflet prolapse or excessive motion (type II), and restricted leaflet motion (type III).140,141 Type III is further subdivided into types IIIa and IIIb based on leaflet restriction during diastole (type IIIa), as seen in rheumatic disease, or during systole (type IIIb), which is typically seen in IMR (Fig. 40-9). Mitral regurgitation with normal leaflet motion can be the result of annular dilatation, which is often secondary to LV dilatation, eg, patients with dilated cardiomyopathy or ischemic cardiomyopathy. Normal leaflet motion also includes patients with leaflet perforation secondary to endocarditis. Leaflet prolapse typically results from a floppy mitral valve with chordal elongation and/or rupture, but rarely also can be seen in patients with coronary artery disease who have papillary muscle elongation or rupture. Mitral regurgitation caused by restricted leaflet motion is associated with rheumatic valve disease (types IIIa and IIIb), ischemic heart disease (IMR with type IIIb restricted systolic leaflet motion secondary to apical tethering or tenting), and dilated cardiomyopathy (type IIIb).141,142

Functional and Ischemic Mitral Regurgitation

Functional mitral regurgitation (FMR) is the result of incomplete mitral leaflet coaptation in the setting of LV dysfunction and dilatation with or without annular dilatation (eg, dilated cardiomyopathy or ischemic cardiomyopathy).143–146 LV systolic dysfunction and dilatation also may be associated with longstanding mitral regurgitation caused by severe chronic LV volume overload. Most commonly, the etiology of nonischemic cardiomyopathy is unknown or idiopathic; the second most common cause is advanced valvular disease. FMR occurs in 40% of patients with heart failure caused by dilated cardiomyopathy.146 In the past, the leaflet morphology in patients with FMR was considered normal, but further analyses have shown the leaflets to be biochemically different, with extracellular matrix changes associated with altered cardiac dimensions.147,148 In recipient hearts obtained at time of transplantation, mitral leaflets have up to 78% more deoxyribonucleic acid, 59% more glycosaminoglycans, 15% more collagen, but 7% less water than autopsy control leaflets.147,148 Radially and circumferentially oriented anterior mitral leaflet strips from failing hearts are 50 to 61% stiffer and less viscous.148 Experimentally, in tachycardia-induced cardiomyopathy, there is significant heterogeneous remodeling with increased collagen and elastic fiber turnover and myofibroblast phenotype of the mitral valve leaflet.149 Thus, the mitral leaflets in heart failure have altered intrinsic structural properties, suggesting that the permanently distended and fibrotic tissue is unable to stretch sufficiently to cover the valve orifice and that mitral regurgitation in these patients is not purely functional.147–149

IMR, a subset of FMR, is becoming more widely appreciated as the population ages and more patients survive acute myocardial infarction. In those with acute infarction, IMR occurs in approximately 15% of patients with anterior wall involvement and up to 40% of patients with an inferior infarct.85,86,150 Generally, the severity of mitral regurgitation is related to the size of the area of LV akinesia or dyskinesia. The pathophysiology of IMR can be attributed to changes in global and regional LV function or geometry, alterations in mitral annular geometry, abnormal leaflet motion and malcoaptation, increased interpapillary distance, and papillary muscle malalignment leading to apical tethering of the leaflets with restricted systolic leaflet motion (type IIIb) (Fig. 40-10).140,143,144,150–163 Because of the interdependence of the elements constituting the valvular–ventricular complex in IMR, perturbation of any component, such as LV systolic function and geometry, annular geometry, leaflet motion and morphology, and papillary and chordal relationship, may result in mitral regurgitation.

Left Ventricular Systolic Function and Geometry

Although LV dilatation and dysfunction are less pronounced in the setting of inferior myocardial infarction than that affecting the anterior wall, the incidence and severity of mitral regurgitation are greater in patients with inferior infarctions.85,86,150,152,155 Over time, as the left ventricle dilates and changes shape after the ischemic event (postinfarction remodeling), the degree of IMR progresses.145,155,164 Geometric changes associated with ventricular remodeling, such as posteromedial papillary muscle dislocation in the lateral axis, may lead to leaflet tenting, as reflected by a larger distance from the middle of the anterior annulus (saddle horn on echocardiography) to the posteromedial papillary muscle tip, and increased annular diameter.145,156,157,164 At the ventricular level, myocardial infarction associated with chronic IMR is associated with greater adverse perturbations in LV systolic torsion and diastolic recoil than myocardial infarction without chronic IMR.165 These abnormalities may be linked to more LV dilatation, which possibly reduces the effectiveness of fiber shortening on torsion generation. Altered LV torsion and recoil may contribute to the “ventricular disease” component of chronic IMR, with increased gradients of myocardial oxygen consumption adversely affecting cardiac efficiency and impaired early diastolic filling.165 Additionally, in a subacute model of IMR (less than 7 weeks), there is an equivalent increase in LV end-diastolic volume in those with mild mitral regurgitation compared to those with more severe mitral regurgitation, coupled with unchanged end-diastolic and -systolic remodeling strains, including systolic circumferential, longitudinal, and radial strains; these findings in aggregate argue against an intracellular (cardiomyocyte) mechanism for the LV dysfunction.166 Instead, differences in subepicardial shear strains suggest a causal role of altered interfiber interactions, and the mechanical impairment may be in extracellular matrix between the fibers and the microtubules in the cytoskeleton that couple cardiomyocyte shortening to LV wall thickening.166

Annular Geometry

In IMR, there may be increased mitral annular area, annular stretching (involving both anterior and posterior components of the annulus), increased septal-lateral annular dimension (also termed the anteroposterior axis), which is perpendicular to the line of leaflet coaptation), lateral displacement of posteromedial papillary muscle, and apically tethered posterior leaflet with restricted closing motion, all of which contribute to leaflet malcoaptation152,153,156,157 (Fig. 40-11). The septal-lateral annular dilatation and diminished LV systolic function determine mitral systolic tenting area, which in turn is predictive of the severity of the IMR.152 LV dilatation and larger annular dimensions after inferior myocardial infarction require the mitral leaflets to cover more area during closing, exceeding their normal redundancy or “reserve,” which is exacerbated by restricted leaflet closure (type IIIb motion) owing to apical leaflet tenting. Additionally, the distinctive saddle shape of the normal annulus, which becomes accentuated during systole, is eliminated, suggesting an association between maintaining the saddle shape and valvular competence.152,167–169 Furthermore, in patients with IMR, the anterior and posterior annular perimeters and annular orifice area (9.1 cm2 compared with 5.7 cm2 normally) are increased accompanied by an increase in the intertrigonal (anterior) annular distance and restriction of annular motion.157

Leaflet Motion and Morphology

Acute IMR from proximal left circumflex artery occlusion experimentally results in delayed valve closure in early systole (termed <i>leaflet</i> loitering) and increased leaflet edge separation throughout ejection in three leaflet coaptation sites across the valve, specifically near the anterior commissure, the valve center, and near the posterior commissure.151,153 In addition, there is lateral displacement of the central scallop of the posterior leaflet, suggesting that interscallop malcoaptation, which is mechanistically owing to septal-lateral annular dilatation, can contribute to IMR in certain circumstances.163 Clinically, chronic IMR is associated with apical systolic restriction of the posterior leaflet, thereby effectively preventing competent valve closure. Chronic IMR is also associated with posterior leaflet displacement in the posterior direction and lateral displacement of both leaflets. When the position of each leaflet edge is assessed independently, the anterior leaflet is not displaced apically after inferior infarction, although with more time and further remodeling, apical restriction of this leaflet may occur.156 A strong echocardiographic determinant of leaflet tenting height is the distance from the tips of the papillary muscles to the saddle horn of the anterior annulus; LV end-diastolic volume is only weakly correlated with tenting height.170 Recent startling human observations have revealed that in some patients with IMR/FMR, there is growth or elongation of the leaflets associated with leaflet thickening that compensates for the larger orifice area and minimizes the amount of mitral regurgitation. In others, however, the leaflets do not become larger and cannot coapt normally across the large orifice, which causes more leaks.171

Papillary Muscle and Chordal Relationships

The papillary-annular distances in the LV long axis remain relatively constant in normal hearts throughout the cardiac cycle.144 During acute ischemia, however, these distances change, which reflects repositioning or dislocation of the papillary muscle tips with respect to the mitral annulus. This can also contribute to apical tenting of the leaflets during systole.140,144,156,159 With proximal circumflex artery occlusion and resulting IMR in an ovine model, the interpapillary distance and LV end-diastolic volume both increase. There is also increased mitral annular area and displacement of both (but predominantly the posteromedial) papillary muscle tips away from the septal annulus throughout ejection and at end-systole.156,159 Posteromedial papillary muscle tip displacement probably results from failure of the ischemic papillary muscle to shorten during systole, lengthening of the ischemic papillary muscle over time, and dyskinesia of the ischemic LV wall subtending the papillary muscle. Since posterior papillary muscle displacement in the apical and posterior directions also occurs in sheep that did not develop substantial degrees of IMR, the additional posteromedial papillary muscle displacement in the lateral direction is a dominant factor in the development of IMR.156 In the setting of posterolateral ischemia, a larger distance from the papillary muscle tips to the midseptal annulus is an important determinant of mitral regurgitant jet area and volume.150,156 The nonischemic anterolateral papillary muscle also may play a role in apical leaflet restriction because this papillary muscle is displaced apically at end-systole relative to baseline. In sheep with mitral regurgitation, posteromedial papillary muscle tethering distance, papillary muscle depth, and papillary muscle angle are unchanged, and the anterolateral papillary muscle depth and papillary muscle angle decrease with decreasing ejection fraction.159 Reduced systolic shortening of either papillary muscle in isolation, on the other hand, does not result in mitral regurgitation; thus, the previous notion that papillary muscle dysfunction by itself is responsible for IMR is not correct. In fact, papillary muscle dysfunction paradoxically can decrease mitral regurgitation resulting from inferobasal ischemia by reducing leaflet tethering, which improves leaflet coaptation.172 Further insult to the LV wall underlying the papillary muscles is likely needed before valvular incompetence occurs. Finally, acute IMR from experimental posterior LV ischemia is associated with chordal and leaflet tethering at the nonischemic commissural portion of the mitral valve and a paradoxical decrease of the chordal forces and relative prolapse at the ischemic commissural site.160 Thus a combination of systolic annular dilatation and shape change and altered posteromedial (and possibly anterolateral) papillary muscle position and motion contributes to incomplete leaflet coaptation and IMR during acute inferior or posterolateral ischemia.

Papillary Muscle Ischemia

Papillary muscle dysfunction in patients with ischemic heart disease has been thought to contribute to mitral regurgitation, although the significance of its role in IMR remains in question.64,66,67,85,86,144,156,159,172 The papillary muscles are particularly susceptible to ischemia, more so the posteromedial papillary muscle (supplied only by the posterior descending artery in 63% of cases) than the anterolateral papillary muscle (supplied by both the left anterior descending and the circumflex arteries in 71% of cases).64,66,67 Hence, myocardial infarction leading to papillary muscle dysfunction occurs more frequently with the posteromedial papillary muscle after an inferior myocardial infarction. Although papillary muscle necrosis can complicate myocardial infarction, frank rupture of a papillary muscle is rare. Total papillary muscle rupture usually is fatal as a result of severe mitral regurgitation and LV pump failure; survival long enough to reach the operating room in reasonable condition is possible with rupture of one or two of the subheads of a papillary muscle, which is associated with a lesser degree of acute mitral regurgitation. Papillary muscle rupture usually occurs 2 to 7 days after myocardial infarction; without urgent surgery, approximately 50 to 75% of such patients may die within 24 hours.173,174

Myxomatous Degeneration

Myxomatous degeneration of the mitral valve, also known as floppy mitral valve or mitral valve prolapse, is the most common cause of mitral regurgitation in patients undergoing surgical evaluation in the United States.64,175–178 The etiology of mitral valve prolapse is both acquired (fibroelastic deficiency in older patients) and congenital or heritable, with excess spongy, weak fibroelastic connective tissue constituting the leaflets and chordae tendineae (Barlow's valve in younger patients)83,179–182 (Fig. 40-12). Frequently associated with connective tissue disorders, such as Marfan syndrome, Ehlers-Danlos and osteogenesis imperfecta, mitral valve prolapse at a young age can be sporadic or familial with autosomal dominant and X-linked inheritance.182,183 Although three different loci on chromosomes 16, 11, and 13 (autosomal dominant) are linked to mitral valve prolapse, no specific gene has yet been incriminated.182,183 Also, a locus on chromosome X cosegregates with a rare form of mitral valve prolapse called X-linked myxomatous mitral valve dystrophy.183 Some degree of mitral valve prolapse is seen echocardiographically in 5 to 6% of the female population.179,184 The risk of endocarditis is increased only if valvular regurgitation is present and accompanied by a murmur. Mitral valve prolapse appears to be more widespread in women, but severe mitral regurgitation resulting from mitral valve prolapse is more common in men. Subtle signs of heart failure, usually manifest as declining stamina and fatigue, may be the presenting complaint in 25 to 40% of symptomatic patients with mitral valve prolapse. As strictly defined originally by John Barlow, Barlow's syndrome includes prolapse of the posterior leaflet and chest pain, and occasionally palpitations, syncope, and dyspnea; in younger patients, the initial clinical sign is a midsystolic nonejection click, which later evolves into a click followed by a late systolic murmur.179 This latter scenario is seen typically in young patients with Barlow's valves, in which large amounts of excessive leaflet tissue and marked annular dilatation are coupled with extensive hooding and billowing of both leaflets.

Pathologically, the atrial aspect of the prolapsing mitral leaflet often is thickened focally, whereas the changes on the ventricular surface of the leaflet consist of connective tissue thickening primarily on the interchordal segments with fibrous proliferation into adjacent chordae and onto the ventricular endocardium.83,179,181 Histologically, elastic fiber and collagen fragmentation and disorganization are present, and acid mucopolysaccharide material accumulates in the leaflets. Myxomatous degeneration commonly involves the annulus, resulting in annular thickening and dilatation. All these changes are pronounced in young patients with Barlow's valves but can be minimal in older subjects with fibroelastic deficiency, in whom the noninvolved posterior leaflet scallops and anterior leaflet are normal and thin (termed pellucid by Carpentier). It is important to recognize that these two distinct varieties of mitral valve prolapse exist and can be segregated on clinical grounds, even if pathologists have difficulty discriminating between the two, because the repair techniques differ in major ways. The main visual and pathologic difference is the extent and degree of degenerative changes. Many centers like the Mayo Clinic encounter mainly elderly patients with coronary artery disease and fibroelastic deficiency (78% of their surgical “flail” leaflet surgical population were greater than 60 years old and/or required concomitant coronary artery bypass grafting), in whom the valvular pathology is limited, and simple repair techniques, such as the small McGoon triangular excision of the middle scallop of the posterior leaflet, are applicable and work well.185 In contrast, other institutions attract younger patients who have Barlow's valves or severely myxomatous mitral valves, circumstances that demand much more extensive repair techniques and different expertise.

Only 5 to 10% of patients with mitral valve prolapse progress to develop severe mitral regurgitation, and they can surprisingly remain relatively asymptomatic until very late.179,180 Mechanisms accounting for severe mitral regurgitation in those with mitral valve prolapse include annular dilatation and rupture or elongation of the first-order chordae (58%), annular dilatation without chordal rupture (19%), and chordal rupture without annular dilatation (19%).181 Chordal rupture, probably related to defective collagen, underlying papillary muscle fibrosis or dysfunction, or bacterial endocarditis, typically is the culprit when mitral regurgitation develops acutely in patients without any previous symptoms of heart disease or suddenly becomes worse in those with known mitral valve prolapse.64,66,83,85,86,137,186 Chordal rupture is typically found in older patients with prolapse owing to fibroelastic degeneration without much accompanying leaflet pathology. Chordal rupture is evident in 14 to 23% of surgically excised purely regurgitant valve specimens; in 73 to 93% of these patients, the underlying pathology is degenerative or floppy mitral valves.85,86,137 Posterior chordal rupture, usually subtending just the middle scallop, is the most frequent finding, followed by anterior chordal rupture and then combined anterior and posterior chordal rupture.85,86,137

Rheumatic Disease

With decreasing incidence in the United States, rheumatic fever remains a common cause of mitral regurgitation in developing countries.64,85–87,136–138,187 It is unknown why rheumatic fever leads to valvular stenosis in some patients and pure regurgitation in others. The pathoanatomical changes of the purely regurgitant rheumatic valve differ from those in a stenotic valve. In chronic rheumatic mitral regurgitation, the valves have diffuse fibrous thickening of the leaflets with minimal calcific deposits and relatively nonfused commissures; chordae tendineae usually are not extremely thickened or fused.85–87 There also may be shortening of the chordae tendineae, fibrous infiltration of the papillary muscle, and asymmetric annular dilatation primarily in the posteromedial portion. During the first episodes of rheumatic fever (average age is 9 years), patients may develop acute mitral regurgitation, which is more frequently related to annular dilatation and prolapse of the anterior or posterior mitral valve leaflet.87,187 Those with anterior leaflet prolapse tend to improve with medical management; however, those with prolapse of the posterior leaflet have a less favorable outcome and often require early surgical repair.187

Mitral Annular Calcification

Mitral annular calcification is a degenerative disorder that usually is confined to elderly individuals; most patients are older than 60 years of age, and women are affected more often than men.64,90 The pathogenesis of mitral annular calcification is not known, but it appears to be a stress-induced phenomenon; annular calcification also can be associated with systemic hypertension, hypertrophic cardiomyopathy, aortic stenosis, and occasionally, advanced Barlow's disease. Other predisposing conditions include chronic renal failure and diabetes mellitus. Aortic valve calcification is an associated finding in 50% of patients with severe mitral annular calcification.

The gross appearance of mitral annular calcification may vary from small, localized calcified spicules to massive, rigid bars up to 2 cm in thickness in the annulus and leaflets.90 Initially, calcification begins at the midportion of the posterior annulus; as the process progresses, the leaflets become upwardly deformed, stretching the chordae tendineae, and a rigid curved bar of calcium surrounding the entire posterior annulus in a horseshoe shape or even a complete ring of calcium may encircle the entire mitral orifice. The calcific deposit spurs extend into the LV myocardium and the conduction system, which can result in atrioventricular and/or intraventricular conduction defects. Annular calcification causes mitral regurgitation by displacing and immobilizing the mitral leaflets (thereby preventing their normal systolic coaptation) or impairing the presystolic sphincteric action of the annulus.90 As the degree of mitral regurgitation worsens over time, LV volume overload can lead to heart failure. Systemic embolization can occur if the annular calcific debris is extensive and friable.

Hemodynamics

The pathophysiology of acute mitral regurgitation differs from that of chronic mitral regurgitation. Acute regurgitation may result from spontaneous chordal rupture, myocardial ischemia or infarction, infective endocarditis, or chest trauma.64,66,173,174,186 The clinical impact of acute mitral incompetence is modulated largely by the compliance of the left atrium and the pulmonary vasculature. In a normal left atrium with a relatively low compliance, acute mitral regurgitation results in high LA pressure, which can lead rapidly to pulmonary edema. Such is not the situation in patients with chronic mitral regurgitation, in whom compensatory changes over time increase LA and pulmonary bed venous compliance so that symptoms of pulmonary congestion may not occur for many years.

With mitral regurgitation, the impedance to LV emptying is lowered because the mitral orifice is in parallel with the LV outflow tract.64,97,188 The volume of mitral regurgitation depends on the square root of the systolic pressure gradient between the left ventricle and the atrium, the time duration of regurgitation, and the effective regurgitant orifice (ERO).64,170,189,190 The ERO is determined echocardiographically using two-dimensional color Doppler imaging to measure the cross-sectional area of the vena contracta (narrowest width of the regurgitant jet) and the proximal isovelocity surface area (PISA), or continuous-wave Doppler measuring the ratio of regurgitant volume to regurgitant time-velocity integral.170,191 Regurgitation into the left atrium increases LA pressure and reduces forward cardiac output. LA pressure even may remain elevated at end-diastole (transient 5- to 10-mm Hg transvalvular gradient), representing a functional gradient associated with the increased diastolic LV filling rate.

If the mitral annulus is not rigid, various diagnostic and therapeutic interventions can alter ERO. Altered loading conditions (elevated preload and afterload) and decreased contractility result in progressive LV dilatation and a larger ERO.192 When LV size is reduced by medical management (eg, digoxin, diuretics, and most importantly, arteriolar vasodilators), ERO, and regurgitant volume fall.193,194 Stress echocardiography using an inotropic drug, such as dobutamine, usually decreases ERO and the degree of mitral regurgitation in patients with FMR and IMR because the LV chamber is smaller at the beginning of systole (end-diastole) and throughout systole secondary to enhanced LV contractility.195

Ventricular Adaptation

The loading conditions induced by mitral regurgitation promote more LV ejection because ventricular preload is increased and afterload is normal or decreased secondary to backward flow across the mitral valve. In terms of cardiac energetics, reduced LV impedance in patients with mitral regurgitation allows a greater proportion of contractile energy to be expended in myocardial fiber shortening than in tension development.64,188 Because increased fiber shortening is less of a determinant of myocardial oxygen consumption than other components, such as tension (or pressure) development and heart rate, mitral regurgitation causes only small increases in myocardial oxygen consumption.188 Reduction in developed tension as a result of lower LV systolic wall stress (LV afterload) permits the ventricle to adapt to the substantial regurgitant volume by increasing LV end-diastolic volume to maintain adequate forward output. Along with lower afterload, this increase in preload (LV end-diastolic volume or, more precisely, LV end-diastolic wall stress) allows the heart to compensate for chronic mitral regurgitation for a long time before symptoms occur.64,196,197 A fundamental response to increased preload is augmented stroke volume and stroke work, although effective forward stroke volume may be normal or subnormal. High LV preload eventually leads to LV dilatation and shape change, ie, more spherical remodeling, owing to replication of sarcomeres in series as a consequence of chronic elevation of LV end-diastolic wall stress.196,197 This process is in contrast to LV hypertrophy secondary to chronic pressure overload (elevated systolic wall stress), which leads to sarcomere replication in parallel. In chronic mitral regurgitation, LV mass also increases; however, the degree of hypertrophy correlates with the amount of chamber dilatation so that the ratio of LV mass to end-diastolic volume remains in the normal range (unlike the situation in patients with LV pressure overload).198–200 The contractile dysfunction that evolves due to chronic LV volume overload is accompanied by increased myocyte length as well as reduced myofibril content.197,198 The basic changes thus are a combination of myofibrillar loss and the absence of significant hypertrophy in response to the progressive decrease in left ventricular pump function. The defect is intrinsic to the myocyte per se, but changes in the extracellular matrix also play a role.166,201 Conversely, in acute mitral regurgitation, the ratio of LV mass to end-diastolic volume is reduced because chamber dilatation occurs suddenly, and the LV wall becomes acutely thinned; this increase in LV end-diastolic volume is associated with sarcomere lengthening along the length-tension curve.197

After the initial compensatory phase, LV systolic contractility becomes progressively impaired as mitral regurgitation progresses chronically.199–202 Because of the low impedance during systole, however, ejection-phase indexes of LV systolic function, such as ejection fraction, stroke volume, and fractional circumferential fiber shortening (%FSc), still can be normal even if the contractility is severely depressed.201,203,204 An ejection fraction of less than 55 to 60% or %FSc less than 28% in the presence of severe mitral regurgitation indicates an advanced degree of myocardial dysfunction. The ejection-phase indexes commonly used clinically to estimate LV pump performance, eg, ejection fraction, %FSc, cardiac output, stroke volume, stroke work, etc. are all affected by changes in LV preload and afterload.

Because of abnormal LV loading conditions in the setting of mitral regurgitation, load-independent indexes of LV contractility (eg, end-systolic elastance derived from the end-systolic pressure–volume relationship [ESPVR]) or preload recruitable stroke work (PRSW, also termed linearized Frank-Starling relationship) are preferred to measure LV systolic function and mechanics.199,200,202,205,206 In hypertrophied and dilated hearts, as seen in chronic mitral regurgitation, however, the utility of end-systolic elastance may be limited because of LV chamber shape and size changes. It is necessary to use the end-systolic stress-volume relationship in these circumstances. One other problem inherent in the use of end-systolic elastance or stress-volume data is that end-systole and -ejection are dissociated in patients with mitral regurgitation. End-ejection is defined as minimum LV volume and end-systole as the instant when LV elastance reaches its maximal value. Because of this temporal dissociation of end-systole from minimal ventricular volume, end-ejection pressure–volume relations do not correlate with maximal elastance values derived using isochronal methods.205 End-systolic dimension or LV end-systolic volume (LVESV) is less dependent on LV loading conditions than is ejection fraction, and therefore is a better measure of LV systolic contractile function. LVESV varies directly and linearly with afterload, and inversely with contractile state.202,207–209 The larger the LVESV becomes, the worse LV contractility. Correcting LVESV for chamber geometry, wall thickness and afterload [ie, end-systolic wall stress (ESS)], and body size (LV end-systolic volume index [LVESVI]) provides good indexes of LV systolic function that are less influenced by loading conditions and variation in patient size.207,208 Thus, preoperative LVESV or LVESVI is a better predictor of outcome in terms of postoperative LV systolic performance and cardiac death than is ejection fraction, end-diastolic volume, or end-diastolic pressure.209

Based on load-independent indexes of LV contractility in experimental mitral regurgitation, the normalized end-systolic pressure–volume and end-systolic stress-volume relationships decline after 3 months of mitral regurgitation.199 PRSW (the relation of stroke work to LV end-diastolic volume) and preload-recruitable pressure–volume area (the relation of stroke work to LV pressure–volume area) also fall, along with a decrease in efficiency of energy transfer from pressure–volume area to external pressure–volume work at matched LV end-diastolic volume. Furthermore, there is deterioration in ventriculoarterial coupling over time; ie, a mismatch develops between the ventricle and the total (forward and regurgitant) vascular load.199 Although the overall (systemic plus LA) effective arterial elastance is decreased, there is a proportionally greater reduction in LV end-systolic elastance. Thus, LV systolic mechanics become impaired along with deterioration in global LV energetics and efficiency, and a mismatch develops in coupling between the left ventricle and the arterial bed.199 Additionally, progression from acute to chronic mitral regurgitation (at 3 months) is associated with a decrease in maximum LV systolic torsional deformation from 6.3 to 4.7 degrees and a decrease in early diastolic LV recoil from +3.8 to –1.5 degrees210 (Fig. 40-13). Because torsion is a mechanism by which the left ventricle equalizes transmural gradients of fiber strain and oxygen demand, a decrease in systolic torsion in chronic mitral regurgitation may play a role in the inexorable and progressive decline of LV performance.210 The left ventricle responds to decreased forward cardiac output resulting from mitral regurgitation by dilating; such dilatation equalizes the lengths of the endocardial and epicardial radii and thereby decreases systolic LV torsion. In assessing transmural 3D myocardial deformations in an ovine model of isolated mitral regurgitation, early changes in LV function at 12 weeks was evidenced by alterations in transmural strain (which may be detected before the onset of global LV dysfunction), but not by changes in B-type natriuretic peptide or PRSW.211 The associated increase in transmural gradient of fiber strain and oxygen supply–demand imbalance results in a further decrease in forward cardiac output, leading to more LV dilatation and continuing the vicious cycle.

Diastolic inflow into the ventricle must increase as total stroke volume increases during the evolution of mitral regurgitation and ventricular dilatation.212–215 Acute mitral regurgitation enhances LV diastolic function by increasing the early diastolic filling rate and decreasing chamber stiffness. Flow across the mitral valve during early diastole is determined by the LA-LV pressure gradient, even though other factors, such as diastolic restoring forces and LV diastolic recoil (creating LV suction) during isovolumic relaxation also influence early LV filling.212 In middle and late diastole, the lower LV chamber stiffness in patients with acute mitral regurgitation (evidenced by a shift of the LV diastolic pressure dimension or pressure–volume relationship to the right) allows the LV mean and LV end-diastolic pressures (and stresses) to remain in the normal range. In patients with chronic mitral regurgitation and preserved ejection fraction, LV chamber stiffness is also lower, similar to that during acute mitral regurgitation. Conversely, in those with impaired LV systolic function, chamber stiffness usually is normal.214 In general, chronic mitral regurgitation causes a decrease in LV systolic contractile function but an increase in early diastolic function (as evidenced by an increase in early diastolic filling rate and a decrease in chamber stiffness).215,216 The reduced chamber stiffness may be the result of altered ventricular geometry (more spherical or less eccentric shape); this shape change can exacerbate the degree of mitral regurgitation by distorting annular dimensions and dislocating the papillary muscles.214,217 Although the LV chamber stiffness is less owing to the change in geometry, the LV myocardium may be stiffer as a result of myocyte hypertrophy and interstitial fibrosis.214,215

Regarding the impact of mitral regurgitation on right ventricular contractility, reduction in right ventricular systolic function is associated with a worse prognosis, emphasizing the adverse impact of pulmonary hypertension in this disease.218 Patients with a right ventricular ejection fraction of less than 30% are at risk for a suboptimal outcome.

Atrial Adaptation

Regurgitant flow into the left atrium leads to progressive atrial enlargement, the degree of which does not correspond directly with the severity of mitral regurgitation.101,188 Also, the LA v wave in mitral regurgitation does not correlate with LA volume. Compared with patients with mitral stenosis, LA size can be larger in patients with longstanding mitral regurgitation, but thrombus formation and systemic thromboembolization occur less frequently because of the absence of atrial stasis.101,104 Atrial fibrillation occurs less often in those with mitral regurgitation than in individuals with mitral stenosis.104

LA compliance is an important component of the patient's overall hemodynamic status if mitral regurgitation is present.64,186,188,219 With sudden development of mitral regurgitation from chordal rupture, papillary muscle infarction, or leaflet perforation, LA compliance is normal or reduced. The left atrium is not enlarged, but the mean LA pressure and v wave are high. Gradually, the left atrial myocardium becomes hypertrophied, proliferative changes develop in the pulmonary vasculature, and pulmonary vascular resistance rises. As the mitral regurgitation becomes chronic and more severe, the left atrium becomes markedly enlarged, atrial compliance is increased, the atrial wall is fibrotic, but LA pressure remains normal or only slightly elevated.219 In this situation, pulmonary artery pressure and pulmonary vascular resistance usually are still in the normal range or are elevated only modestly.

Pulmonary Changes

Because chronic mitral regurgitation is associated with LA enlargement and only mild elevations in LA pressure, pronounced increases in pulmonary vascular resistance usually do not develop. In patients with acute mitral regurgitation with normal or reduced LA compliance, a sudden increase in LA pressure initially elevates pulmonary vascular resistance, and occasionally acute right-sided heart failure occurs.64,186 Pulmonary edema is seen less frequently in patients with chronic mitral regurgitation than in those with mitral stenosis because elevated LA pressure is uncommon. In patients with IMR and heart failure, however, acute pulmonary edema is associated with the dynamic changes in IMR and the resulting increase in pulmonary vascular pressure.220 Exercise-induced changes in ERO, tricuspid regurgitant pressure gradient (estimate of systolic pulmonary artery pressure), and LV ejection fraction are independently associated with the development of pulmonary edema.220 From the standpoint of pulmonary parenchymal function and respiratory mechanics in patients with chronic mitral regurgitation, there is a decline in vital capacity, total lung capacity, forced expiratory volume, and maximal expiratory flow at 50% vital capacity.74 These patients also may have a positive response to methacholine challenge; this bronchial hyperresponsiveness may result from increased vagal tone owing to longstanding pulmonary congestion.

Clinical Evaluation

Patients with mild to moderate mitral regurgitation may remain asymptomatic for many years as the left ventricle adapts to the increased workload and maintains normal forward cardiac output. Gradually, symptoms reflecting decreased cardiac output with physical activity and/or pulmonary congestion develop insidiously, such as weakness, fatigue, palpitations, and dyspnea on exertion. If right-sided heart failure appears late in the course of the disease, hepatomegaly, peripheral edema, and ascites occur and can be associated with rapid clinical deterioration.106,221 Conversely, acute mitral regurgitation usually is associated with marked sudden pulmonary congestion and pulmonary edema. Patients with coronary artery disease can present with myocardial ischemia or infarction and associated mitral regurgitation. Acute papillary muscle rupture may clinically mimic the presentation of a patient with a postinfarction ventricular septal defect.222

On physical examination, the cardiac impulse in patients with mitral regurgitation is hyperdynamic and displaced laterally; the forcefulness of the apical impulse is indicative of the degree of LV enlargement. In patients with chronic mitral regurgitation, S₁ usually is diminished. S₂ may be single, closely split, normally split, or even widely split as a consequence of the reduced resistance to LV ejection; a common finding is a widely split S₂ that results from shortening of LV systole and early closure of the aortic valve.223 An S₃ gallop may be appreciated from the increased transmitral diastolic flow rate during the rapid filling phase. The apical systolic murmur of mitral regurgitation can be blowing, moderately harsh, or even soft and usually radiates to the axilla and left or right sternal border and occasionally to the neck or the vertebral column.223 The murmur is best appreciated in early systole in patients with FMR or IMR. With rupture of the posterior leaflet first-order chordae, the mitral regurgitation jet is directed superiorly and impinges on the atrial septum near the base of the aorta, which can produce a murmur heard best along the right sternal border and radiating to the neck.223,224 In cases of ruptured anterior leaflet first-order chordae, the leakage is aimed laterally and toward the posterior LA wall; the murmur may be transmitted posteriorly. Although there is no correlation between the intensity of the systolic murmur and the hemodynamic severity of the mitral regurgitation, a holosystolic murmur is characteristic of more regurgitant flow.223 In younger patients with Barlow's valves (severe bileaflet mitral billowing with prolapse), early in the disease process, a characteristic midsystolic click is heard, followed by a late systolic murmur; as the annulus and left ventricle dilate, the murmur over time becomes holosystolic, and the midsystolic click may become inaudible.

On chest radiography, cardiomegaly indicative of LV and LA enlargement is found commonly in patients with longstanding moderate to severe mitral regurgitation.123 Acute mitral regurgitation often is not associated with an enlarged heart shadow. Chest x-ray findings of congested lung fields are less prominent in patients with mitral regurgitation than in those with mitral stenosis, but interstitial edema is seen frequently in individuals with acute mitral regurgitation and those with progressive LV failure secondary to chronic mitral regurgitation.

Changes on the electrocardiogram are not particularly useful and depend on the etiology, severity, and duration of the mitral regurgitation.112,223 Atrial fibrillation can occur late in the natural history of the disease and usually causes sudden exacerbation of symptoms. In cases of chronic mitral regurgitation, LV volume overload leads to LA and LV dilatation, and eventually to LV hypertrophy. Electrocardiographic evidence of LV enlargement or hypertrophy occurs in half of patients, 15% have right ventricular hypertrophy owing to increased pulmonary vascular resistance, and 5% have combined left and right ventricular hypertrophy.112 Ventricular arrhythmias may be noted on ambulatory ECG recording or event monitors, especially in patients with LV systolic dysfunction. In those with acute mitral regurgitation, LA and/or LV dilatation may not be evident, and the electrocardiogram may be normal or show only nonspecific findings, including sinus tachycardia or ST-T-wave alterations.112 Findings of myocardial ischemia or infarction, more commonly noted in the inferior leads, may be present when acute mitral regurgitation is related to acute inferior myocardial infarction or myocardial ischemia; in these cases, first-degree AV block is a common coexisting finding.

In the majority of individuals with mitral valve prolapse, particularly those who are asymptomatic, the resting electrocardiogram is normal.112,184 In symptomatic patients, a variety of ST-T-wave changes, including T-wave inversion and sometimes ST-segment depression, particularly in the inferior leads, can be found.179,184 QTc prolongation also may be seen. Arrhythmias may be observed on ambulatory electrocardiograms, including premature atrial contractions, supraventricular tachycardia, AV block, bradyarrhythmias, and premature ventricular contractions.184 Atrial arrhythmias may be present in upward of 14% of patients, and ventricular arrhythmias are present in 30% of patients.112,184

Transthoracic echocardiography (TTE) is the diagnostic mainstay in patients with valvular heart disease. In those with chronic mitral regurgitation, this modality is used to follow the progression of LA and LV dilatation and changes in the amount of mitral regurgitation and leaflet morphology.7,64,116,191,225–227 Echocardiography identifies abnormalities in leaflet and chordal morphology and function, including myxomatous degeneration with or without leaflet prolapse, restricted systolic leaflet motion (as in IMR) or diastolic opening motion (as in rheumatic valve disease), lack of adequate coaptation due to annular dilatation or rheumatic valvulitis (fused subvalvular apparatus), and leaflet destruction by endocarditis7,64,113,116,191,227 (Fig. 40-14). The degree of mitral regurgitation is assessed using 2D color Doppler echocardiography, which permits visualization of the origin, extent, direction, duration, and velocity of disturbed backward flow of the regurgitant leak.113,191,227 Chordal rupture or elongation causing a flail leaflet is characterized by excessive motion of the leaflet tip backward into the left atrium beyond the normal leaflet coaptation zone. Papillary muscle rupture after myocardial infarction and annular dilatation can be visualized (Fig. 40-15). In patients with IMR or FMR, apical systolic tethering of the leaflets, tenting area and height, and leaflet opening angles can be quantitated using echocardiography, including important pathoanatomic differences between ischemic cardiomyopathy and idiopathic dilated cardiomyopathy170,189,191,228 (Fig. 40-16). When the regurgitant leak is caused in part or totally by annular dilatation, usually in the septal-lateral dimension, the coaptation height of the anterior and posterior leaflets can be measured.

In mitral regurgitation, ERO and regurgitant volume can be estimated quantitatively in many but not all patients using 2D color Doppler echocardiography.170,190,191 ERO was an important predictor of outcome in a sample of Mayo Clinic patients with mitral regurgitation and has been proposed as an indicator of when to proceed with mitral repair in asymptomatic patients with prolapse.190 However, accurate quantification of the degree of mitral regurgitation using ERO and regurgitant volume is demanding, time consuming, and may not be available at all institutions. The hemodynamic magnitude or severity of the mitral regurgitation also can be estimated semiquantitatively by calculating mitral and aortic stroke volumes, with regurgitant volume being the difference between these two stroke volumes. Cardiac MRI is an accurate method to measure regurgitant volume and regurgitant fraction by comparing right- with left-sided flow.121,229,230

Interest in the timing of the regurgitant leak has helped clinicians discern subtle details about the mechanism(s) responsible for the mitral regurgitation, infer information about the overall hemodynamic burden imposed by the LV volume overload, and predict the likelihood of successful and durable mitral repair.170,189–191,228 IMR is primarily an early-systolic leak, FMR occurs during early and middle systole (can be a biphasic pattern), and prolapse is associated with late-systolic leaks. Although detected by pulse- and continuous-wave Doppler echocardiography for years, the timing of the mitral regurgitation has become more widely appreciated as a result of a resurgence of interest in color Doppler M-mode echocardiography, which has a much faster temporal resolution (sampling frequency) than does 2D color Doppler echocardiography. Cardiac surgeons should study these color Doppler M-mode images carefully because the timing of the regurgitant leak yields important information about the mechanisms responsible for the MR.

TTE is usually adequate to learn all that is necessary, but if high-quality TTE images cannot be obtained because of the patient's habitus or advanced emphysema, transesophageal echocardiography (TEE) provides superior image quality and can reveal additional anatomical and pathophysiologic information, including details of the valvular pathoanatomy and the mechanism, origin, direction, timing, and severity of the regurgitant leak.7,64,116,191,226,227,231 TEE can detect small mitral vegetations, ruptured chordae, leaflet perforations or clefts, calcification, and other inflammatory changes and can be useful in patients with annular or leaflet calcification. TEE also is useful in patients with a previously implanted aortic valve prosthesis that can interfere with TTE assessment of mitral regurgitation owing to acoustic shadowing. Although intraoperative TEE during mitral valve repair is essential, a major limitation must always be remembered. The vascular unloading effects (vasodilatation) of general anesthesia downgrade the severity of mitral regurgitation.232,233 The judgment about how much mitral regurgitation is present must be made on the basis of an awake TTE study when the patient has a normal ambulatory blood pressure. This concept is imperative in assessing the degree of mitral regurgitation in patients with IMR when deciding whether to add a mitral valve procedure at the time of coronary artery bypass grafting. For patients in whom the degree of mitral regurgitation has been minimized by the effects of anesthesia, intraoperative TEE provocative testing using vasoconstrictor drugs with or without volume infusion is mandatory to guide surgical decision making. Testing consists of reproducing the patient's normal awake or active ambulatory hemodynamic condition with preload challenge and afterload augmentation.232,233 Preload challenge is performed after aortic cannulation for cardiopulmonary bypass by rapidly infusing volume from the pump until the pulmonary capillary wedge pressure reaches 15 to 18 mm Hg. If severe mitral regurgitation is not produced, LV afterload is increased by intravenous boluses of phenylephrine until the arterial systolic pressure climbs to the 130- to 150-mm Hg range. In patients undergoing coronary artery bypass grafting, if both tests are negative, or regurgitation is induced but associated with new regional LV systolic wall motion abnormalities (ie, the regurgitation is caused by acute ischemia of viable myocardium), the valve may not require visual inspection because coronary revascularization usually is all that is necessary if the inferior wall myocardium is viable. If these tests confirm the presence of moderate to severe mitral regurgitation, the valve is inspected and usually is repaired at the time of coronary revascularization.

Real-time 3D echocardiography is helpful in the visual assessment of congenital and acquired valvular disease7,116,118,228,234,235 (Fig. 40-17). In patients with mitral regurgitation, this modality is fairly accurate in elucidating the dynamic mechanisms of the regurgitant leak(s). The addition of color-flow Doppler to 3D imaging provides improved visualization and may offer improved quantitative assessment of regurgitant valvular lesions.7,116,118 Additionally, 3D echocardiography may provide more insight into the geometric deformities of the mitral leaflets and annulus, maximum tenting site of the mitral leaflet, and quantitative measurements of mitral valve tenting and annular deformity in patients with IMR.7,116,118,228,235 Real-time 3D color Doppler echocardiographic imaging provides direct measurement of vena contracta area.7,234 The quantification of mitral regurgitant flow directly at the lesion using color Doppler echocardiography, however, has been prevented because of multiple aliasing from high flow velocities. De-aliasing of color Doppler flow at the vena contracta is feasible and appears promising for measuring severity of mitral regurgitation. This novel approach can be readily implemented in current systems to provide regurgitant flow volume and regurgitant fraction.7,234

Cardiac catheterization and coronary angiography are rarely needed in patients with mitral regurgitation when it is prudent to determine coronary artery anatomy in older patients with prolapse before repair and those with IMR.64,111,196 Other techniques, such as calculating mitral regurgitant fraction (regurgitant volume determined as the difference between total LV angiographic stroke volume and the effective forward stroke volume measured by the Fick method), are limited. By measuring rest and exercise (supine bicycle) pulmonary artery pressures and cardiac output, right-sided heart catheterization can be useful occasionally to identify patients with primary myocardial disease who present with LV dilatation and relatively mild degrees of mitral regurgitation (who may not have a high likelihood of benefiting from mitral valve surgery) and those with severe mitral regurgitation who deny symptoms to see if they develop pulmonary hypertension with exercise.

Cardiac MRI can be employed to assess the cardiovascular system, including cardiac structure and function.120,121,229,236,230 Specialized MRI techniques, such as moving-slice velocity mapping, the control-volume method, planimetry, or real-time color-flow MRI have been used to evaluate and quantify the degree of mitral regurgitation. The presence of valvular regurgitation can be determined, LV volumes and mitral regurgitant fraction estimated, and information obtained concerning mitral and coronary anatomy. Direct measurement by MRI is a promising method for assessment of the severity of mitral regurgitation; MRI planimetry of the anatomical mitral regurgitant lesion permits quantification of regurgitation with good agreement with cardiac catheterization and echocardiography.230 Constraints of MRI, such as pacemakers or implanted defibrillators, morbid obesity, and claustrophobia, hamper the wider use of cardiac MRI. Multidetector CT has emerged as an imaging technique that can fully evaluate both cardiac structure and function, including coronary artery anatomy; this technology has yielded good visualization of valve leaflets, commissures, and mitral annulus.122 Limitations still include image noise, requirement for a regular rhythm and a slow heart rate during imaging, time required for postprocessing data analysis, and radiation dose.

Postoperative LV Function and Surgical Outcomes

General

Successful mitral valve repair or replacement usually is associated with clinical improvement, augmented forward stroke volume with lower total stroke volume, smaller LV end-diastolic volume, and regression of LV hypertrophy.177,127,238–243 Correction of mitral regurgitation can preserve LV contractility, particularly in patients with a normal preoperative ejection fraction who have minimal ventricular dilatation and those without significant coronary artery disease. On the other hand, in patients with LV dysfunction preoperatively, improvement in LV systolic function may not necessarily occur after operation.209,237 An LVESVI exceeding 30 mL/m2 is associated with decreased postoperative LV function.209,237 Thus, patients with chronic mitral regurgitation should be referred for mitral valve surgery before LVESVI exceeds 40 to 50 mL/m2 or when LV end-systolic dimension reaches 4 cm, consistent with the 2006 American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines (Fig. 40-18).209,238 LVESVI corrected for LV wall stress, a single-point ratio of end-systolic wall stress to end-systolic volume index (or ESS:LVESVI) is a good index of LV systolic function and accurately predicts surgical outcome in patients with mitral regurgitation.207,208 Specifically, an ESS:LVESVI ratio of less than 2.6 portends a poor medium-term prognosis, whereas a normal or high ESS:LVESVI ratio is associated with a favorable outcome.208 Significant determinants of increased operative risk also include older age, higher New York Heart Association (NYHA) functional class, associated coronary artery disease, increased LV end-diastolic pressure, elevated LV end-diastolic volume index, elevated LV end-systolic dimension, reduced LV ESS index, depressed resting ejection fraction, decreased fractional shortening, reduced cardiac index, elevated capillary wedge or right ventricular end-diastolic pressure, concomitant operative procedures, and previous cardiac surgery.209,237,238,244–247 The abnormal LV diastolic properties (including early diastolic filling rate, myocardial relaxation, chamber stiffness, myocardial stiffness, and end-diastolic pressure) also may be reversible after mitral valve surgery.215 If surgical correction of mitral regurgitation is carried out before the volume-overload cardiomyopathy reaches an irreversible stage, LV diastolic filling characteristics and systolic contractile function return toward normal values. Furthermore, LV volume and the LV volume:mass ratio (or dimension:thickness ratio) usually normalize postoperatively, but mild LV hypertrophy may persist.215

The decline in ejection fraction after mitral valve replacement for chronic mitral regurgitation historically was thought to result from an increase in LV afterload as a result of closure of the low-resistance early-systolic “pop-off” into the left atrium and the surgical excision of the subvalvular apparatus. A spherical mathematical model defining the relations among LV end-diastolic dimension, systolic wall stress, and ejection fraction, demonstrated that postoperative changes in systolic stress are related directly to changes in chamber size, and LV afterload may decrease postoperatively if chordal-preservation valve replacement techniques are used.248 In terms of exercise performance after surgery for nonischemic mitral regurgitation, although patients generally report symptomatic improvement, cardiopulmonary exercise testing at 7 months is not better than preoperatively, and abnormal neurohumoral activation persists, probably reflective of incomplete recovery of LV contractility.249 Regarding long-term clinical outcome, risk factors portending postoperative cardiac deterioration include larger LV end-diastolic dimension, increased LV end-systolic dimension, increased LVESV, diminished fractional shortening, reduced LV ESS index, large LA size, decreased LV wall thickness/cavity dimension at end-systole, and associated coronary artery disease.209,246,250–252

Patients with mitral regurgitation from a flail leaflet usually are asymptomatic, yet this entity is associated with a risk of progressive LV dysfunction and a suboptimal prognosis if not treated surgically. If managed conservatively with medical therapy, mitral regurgitation from a flail leaflet is associated with high annual mortality risk (6.3%) and morbidity rates.178,253 In these patients, mitral valve repair is feasible in the large majority of patients in experienced centers and offers excellent early and late functional results.177,254,255 Because fewer complications and lower operative mortality risk are associated with valve repair compared with valve replacement in this patient population, operation should be considered earlier in the natural history of the disease if the pathologic anatomy is judged favorable for valve repair.141,177,178,250,253,254 When a large preoperative LVESVI or end-systolic dimension indicates the presence of LV systolic dysfunction, every effort should be made to repair the valve, or at least preserve all chordae tendineae (to both the anterior and posterior leaflets) if valve replacement is necessary.238 Importantly, these surgical technical details have been emphasized in the 2006 ACC/AHA practice guidelines (see Fig. 40-16). Furthermore, these guidelines state how important it is that patients be referred to surgical centers that have demonstrated track records of excellence for mitral repair, including long-term repair durability as assessed by serial echocardiography.238

In a Mayo Clinic study focusing on the management of asymptomatic patients with organic mitral regurgitation, 456 asymptomatic patients with at least mild holosystolic mitral regurgitation defined echocardiographically were enrolled prospectively from 1991 to 2000.190 At entry, baseline ejection fraction was 70%, LV end-systolic dimension was 3.4 ± 6 cm, LV end-diastolic dimension was 5.6 ± 8 cm, LVESVI was 33 ± 130 mL/m2, and regurgitant volume was 66 ± 40 mL/beat. Management was at the discretion of the primary physician, including when to proceed to surgical intervention. At 5 years, 54% of patients had been operated on after an average of 1.2 ± 2 years of medical treatment when symptoms occurred or when worrisome echocardiographic findings were detected (based on the older 1998 ACC/AHA practice guidelines). Among the 230 patients who underwent a mitral valve procedure, 91% received a valve repair; the operative mortality rate was low at 1%. The patients were stratified by degree of regurgitation; mild, moderate, and severe were defined as regurgitant volumes of less than 30, 30 to 59, and 60 or more mL/beat, and ERO was defined as less than 20, 20 to 39, and 40 or greater mm2, respectively. For the medically treated patients, 5-year survival compared with U.S. Census life tables was significantly inferior for those with moderate regurgitation (ERO of 20 to 39 mm2, 66% versus 84%) and severe regurgitation (ERO of 40 mm2 or more, 58% versus 78%).190 Independent risk factors for death in the medically treated patients were advancing age, diabetes mellitus, and larger ERO. Even when adjusted for age, gender, diabetes, atrial fibrillation, and ejection fraction, ERO still predicted survival. The influence of ERO also held true for predicting cardiac deaths and all cardiac events. The 5-year cardiac death rate was 36% for patients with an ERO of 40 mm2 or greater compared with 20% for those with an ERO of 20 to 39 mm2 and only 3% for those with an ERO of less than 20 mm2. Mitral valve operation was an independent determinant of fewer deaths, cardiac deaths, and cardiac events, especially in those with a larger ERO.190 This important study, which focuses on the predictive effects of the severity of the regurgitation instead of the response of the ventricle, has prompted a rethinking in the approach to asymptomatic patients with mitral regurgitation owing to prolapse. All asymptomatic patients with an ERO of 40 mm2 or greater—except elderly people, in whom only symptoms dictate timing of operation—should be referred for consideration of early surgical repair. Those with an ERO in the 20 to 39 mm2 range should be monitored closely using serial echocardiography. Finally, those with the smallest ERO (<20 mm2) can be followed more conservatively and are at low risk of developing cardiac complications while being managed medically. Despite the valuable information in this study, future larger prospective trials are necessary to validate these results; it should also be remembered that most of these Mayo Clinic patients were older and their prolapse was caused by fibroelastic degeneration, not younger individuals with Barlow's valves. Further, the critical ERO threshold for mitral regurgitation from degenerative disease and prolapse (40 mm2) in patients with preserved LV systolic function is twice the 20 mm2 critical value of ERO that predicts an adverse outcome in patients with LV systolic dysfunction and IMR or FMR.170,189 In other words, it only takes a regurgitant orifice one-half as large to portend an unfavorable outcome if one has impaired LV systolic function owing to ischemic or idiopathic cardiomyopathy.

Because many patients with substantial mitral regurgitation report no symptoms, and symptoms have been the mainstay of when to consider surgical repair, cardiopulmonary exercise testing has been used to evaluate asymptomatic patients with organic mitral regurgitation (owing to prolapse in 93% of cases).256 Of 134 asymptomatic patients with an average ejection fraction of 73%, 57% had severe mitral regurgitation with a regurgitant volume of 68 ± 24 mL/beat (range of 30 to 146 mL/beat) and an ERO of 35 ± 14 mm2 (range 14 to 83 mm2). Surprisingly, functional capacity was markedly reduced (defined as 84% or less than expected) in 19% of these “asymptomatic” patients. Those with impaired functional capacity were roughly equally distributed according to regurgitant volume of less than or greater than 60 mL/beat and ERO of less than or greater than 40 mm2. When patients with extraneous reasons for impaired functional capacity were excluded, 14% had a reduced functional capacity, and their regurgitant volume and ERO were larger than those with a normal functional capacity. Determinants of reduced functional capacity were impaired LV diastolic function, lower forward stroke volume, and atrial fibrillation; ERO had no significant influence on functional capacity.257 Thus, it was the consequences of chronic mitral regurgitation and not the magnitude of the leak that predicted impaired functional capacity. Follow-up at over 2 years revealed that 66% of patients with impaired functional capacity sustained some adverse event or required mitral surgery (versus 29% of those with normal functional capacity) after adjusting for age, ERO, gender, and ejection fraction. Thus, the evidence supports that asymptomatic patients with substantial mitral regurgitation should undergo periodic cardiopulmonary exercise testing to detect subclinical impairment in functional capacity, and that mitral valve repair should be recommended to those with impaired capacity.

Even after mitral valve surgery for chronic mitral regurgitation, some patients continue to be limited by heart failure symptoms and have suboptimal long-term postoperative outcomes. The incidence of congestive heart failure in patients who survive surgery (combined series of valve repair and valve replacement) for pure mitral regurgitation has been 23%, 33%, and 37% at 5, 10, and 14 years.258 Valve repair is not a predictor of decreased incidence of congestive heart failure; however, using a combined end point of congestive heart failure and death, valve repair compared with valve replacement in patients with mitral regurgitation appears to confer a survival advantage. Patient survival after the first episode of congestive heart failure is dismal, being only 44% at 5 years. Causes of congestive heart failure include LV dysfunction in two-thirds of patients and valvular problems in the remaining one-third. Predictors of postoperative heart failure are lower preoperative ejection fraction, coronary artery disease, and higher NYHA functional class.258 Importantly, preoperative functional class III/IV symptoms are associated with markedly decreased postoperative medium- and long-term survival independent of all other baseline characteristics.259

Ischemic Mitral Regurgitation

To risk stratify patients after myocardial infarction, detecting and quantifying IMR are essential.189,260–262 In a report from the Mayo Clinic, medically managed patients who developed IMR late after myocardial infarction had a very high mortality rate (62% at 5 years) compared with those with an infarction who did not develop IMR (39% at 5 years).189 Medium-term survival for patients with IMR and LV systolic dysfunction was inversely related to the ERO and regurgitant volume. After 5 years, the survival rate was 47% for patients with an ERO of less than 20 mm2 and 29% for those with an ERO of 20 mm2 or greater. Survival at 5 years was 35% when the regurgitant volume was 30 mL/beat or greater compared with 44% for those with a regurgitant volume of less than 30 mL/beat. The relative risk ratio for cardiac death for patients with IMR was 1.56 for patients with an ERO of less than 20 mm2 versus 2.38 for those with an ERO of greater than 20 mm2. It must be remembered this ERO threshold was twice as large (40 mm2 or greater) in patients with prolapse or flail leaflets.190 An ERO of more than 40 mm2 was considered to reflect severe regurgitation in either disease, but the compound injury of coexisting LV dysfunction made the prognostic impact of even a “mild” leak (ERO of about 20 mm2) very strong in patients with IMR.262 In patients with myocardial infarction, the incidences of congestive heart failure or cardiac death were high even in patients with no or minimal symptoms at baseline and even higher in patients with IMR.261 Determinants of congestive heart failure were ejection fraction, sodium plasma level, and presence and degree of IMR. At 5 years, the rate of congestive heart failure was 18% without IMR compared with 53% if IMR was present. If the ERO was less than 20 mm2, the incidence of congestive heart failure was 46% compared with 68% when the ERO was 20 mm2 or greater. The relative risk of congestive heart failure was 3.65 if IMR was present but 4.42 if ERO was 20 mm2 or greater. At 5 years, the rate of congestive heart failure or cardiac death was 52%; the relative risk of congestive heart failure or cardiac death was 2.97 if IMR was present and 4.4 if ERO was 20 mm2 or greater261 (Fig. 40-19). Moderate or severe IMR was associated with a relative risk of 3.44 for congestive heart failure and 1.55 for death among 30-day survivors independent of age, gender, ejection fraction, and Killip class.260

Mitral repair or replacement for patients with IMR has been associated with higher operative risk (4 to 30%) than for patients with nonischemic chronic mitral regurgitation, which reflects the concomitant adverse consequences of previous myocardial infarction and ischemia.241,242,263–268 Most investigators believe that coronary revascularization alone in the setting of moderate or severe IMR leaves many patients (up to 40%) with significant residual mitral regurgitation and heart failure symptoms.143,269–271 Immediately postoperatively, IMR is absent or mild in 73% and severe in 6%; on the other hand, by 6 weeks, only 40% of patients have absent or mild mitral regurgitation, and 22% have severe mitral regurgitation270 (Fig. 40-20). Postoperative residual or recurrent IMR is not associated with the preoperative extent of coronary artery disease or LV dysfunction. The 5-year survival rate of patients without IMR undergoing isolated coronary artery bypass grafting is 85% compared with 73% for patients with moderate IMR.270 Because moderate IMR does not reliably resolve with bypass grafting alone, valve repair (or even chordal-sparing valve replacement) should be considered in these patients because it potentially can reduce cardiac morbidity and may improve long-term survival.143,269–270 Others argue that patients with moderate IMR undergoing coronary revascularization and concomitant mitral annuloplasty have less postoperative IMR but no improvement in long-term survival.155,264,266,272,273 The Yale group postulated that isolated coronary grafting without valve repair is adequate in most patients with ischemic cardiomyopathy and mild to moderate mitral regurgitation, yielding survival rates of 88% at 1 year and 50% at 5 years; however, this study was small, and only a few patients had clinically important degrees of IMR.274 Others have shown that for patients with moderate or moderately severe IMR, isolated coronary surgery and coronary revascularization combined with mitral annuloplasty provide similar long-term outcome with survival rates of 82 to 92% at 1 year, 40 to 75% at 5 years, and 37 to 47% at 10 years264–266,273–275 (Fig. 40-21). Predictors of long-term mortality are older age, prior myocardial infarction, unstable angina, chronic renal failure, atrial fibrillation, absence of an internal mammary artery graft, lack of beta blocker use, lower ejection fraction, smaller left atrial size, global LV wall motion abnormalities, severe lateral wall motion abnormalities, ST segment elevation in the lateral leads, higher voltage sum, mitral leaflet restriction, and fewer bypass grafts.264,266,273 Combined mitral valve repair and coronary revascularization does not emerge as a predictor of long-term survival in these series. In order to elucidate preoperatively those that would more likely benefit from isolated coronary artery bypass grafting, the Prague group evaluated 135 patients with ischemic heart disease and moderate IMR undergoing isolated coronary artery bypass surgery; of these, 42% of the patients had no or mild mitral regurgitation postoperatively, whereas 47% failed to improve.276 Before surgery, the improvement group had significantly more viable myocardium and less dyssynchrony between papillary muscles than the failure group. Thus, reliable improvement in moderate IMR by isolated coronary artery bypass graft surgery is likely only in patients with concomitant presence of viable myocardium and absence of dyssynchrony between papillary muscles.276 In a pilot study of cardiac MRI in patients with ischemic mitral regurgitation and ischemic cardiomyopathy, extensive scarring and severe wall motion abnormalities in the region of posterior papillary muscle correlated with recurrent mitral regurgitation after coronary artery bypass grafting and mitral annuloplasty.277 Routinely assessing scar burden may identify patients for whom annuloplasty alone is insufficient to eliminate mitral regurgitation. Therefore, although some investigators report that annuloplasty can be added to coronary grafting in high-risk patients without increasing early mortality, the potential benefit with respect to late survival and functional status is not proved and may be limited because of the underlying ischemic cardiomyopathy.264–266,272

In the Brigham and Women's Hospital experience, patients with IMR and annular dilatation or type IIIb restricted systolic leaflet motion (not chordal or papillary muscle rupture) who underwent valve repair and coronary revascularization had a worse long-term outcome than those who underwent valve replacement and coronary revascularization.263 Notably, the pathophysiology or cause of the IMR was a stronger determinant of long-term survival than was the type of valve procedure. Conversely, the New York University group reported a higher complication-free survival rate (64% at 5 years) for patients undergoing mitral valve repair compared with 47% at 5 years for those in whom the valve had to be replaced.278 The analysis of the early mortality risk for patients with IMR undergoing mitral valve repair versus valve replacement was confounded by many other factors, including functional disability and degree of angina. Excluding these two variables, further analysis showed that the early mortality rate was lower for patients undergoing valve repair than for those undergoing valve replacement.278 Based on propensity-score analysis, the Cleveland Clinic group found that in the lower-risk quintiles of patients with IMR, valve repair conferred a survival advantage (58% at 5 years) over those who underwent valve replacement (36% at 5 years); however, in the highest-risk patients, late survival after valve repair and valve replacement was similarly poor, and valve replacement actually conferred a small survival advantage.279 In their experience, when patients with severe IMR underwent mitral valve surgery, undersized annuloplasty resulted in a durable repair in 70 to 85% of cases.280 Although mitral valve repair is the procedure of choice in the majority of patients having surgery for IMR, in the most severely ill patients and those with certain echocardiographic characteristics (eg, severe bileaflet tethering), complete chordal-sparing mitral valve replacement may be preferable to repair.280 At the Laval University in Quebec, 370 patients with IMR underwent mitral valve repair or mitral valve replacement.281 The operative mortality was lower in the repair group (10%) compared with the replacement group (17%), but 6-year survival estimates were similar at 73% and 67%, respectively (Fig. 40-22). The type of valve procedure did not emerge as a risk factor for a poor outcome. Therefore, in patients with IMR, mitral valve repair is not necessarily superior to replacement in terms of overall survival.281

Analysis of the etiology of the mitral regurgitation (degenerative versus ischemic) in patients with coronary artery disease after combined mitral valve repair and coronary revascularization showed that those with IMR had more extensive coronary disease, worse ventricular function, more comorbidities, and more preoperative symptoms.282 Unadjusted 5-year survival estimates were 64 and 82% for patients with IMR and degenerative mitral regurgitation, respectively; however, matched pairs had equivalent but poor 5-year survival rates (66 and 65%, respectively). Long-term survival varied widely among patients with degenerative mitral regurgitation and coronary artery disease, depending largely on ischemic burden and extent of LV dysfunction.282 Similarly, in the Duke experience, the survival discrepancy between patients with IMR and those with degenerative mitral regurgitation combined with coronary artery disease was attributed to patient-related differences.268 In 535 patients (26% with IMR, 74% with nonischemic etiology) undergoing mitral valve repair with or without coronary artery bypass grafting, the 30-day mortality was 4.3% for those with IMR and 1.3% for nonischemic group; the 5 year survival was 56% for IMR and 84% for those with nonischemic mitral regurgitation.268 Only the number of preoperative comorbidities and advanced age emerged as predictors of survival, whereas ischemic etiology, gender, ejection fraction, NYHA functional class, coronary artery disease, reoperation, and year of operation did not achieve statistical significance. Because survival was not different between patients with IMR and those with nonischemic mitral regurgitation after routine use of a rigid-ring annuloplasty during coronary artery grafting, long-term patient survival was more influenced by baseline patient characteristics and comorbidity than by the etiology of the mitral regurgitation per se268 (Fig. 40-23). Additionally, investigators at the Mayo Clinic concluded that the decision as to whether to repair or replace the valve should be based on patient condition and not on whether the mitral regurgitation results from ischemia.267 Older age, ejection fraction of 35% or less, three-vessel coronary disease, mitral valve replacement, and residual mitral regurgitation at discharge were risk factors for death. The cause of the mitral regurgitation, ischemic versus degenerative, was not a predictor of long-term survival, class III or IV congestive heart failure, or recurrent regurgitation.267 Thus, survival after mitral valve surgery and coronary artery bypass grafting was determined more by the extent of coronary disease and LV systolic dysfunction and the success of the valve procedure.267,268 These reports highlight the poor prognosis of patients with IMR and how the patient's clinical condition and LV functional status are more powerful determinants of outcome than type of operative procedure performed. The University of Virginia group proposed that despite the multiple comorbidities in patients with IMR, mitral valve repair for IMR and degenerative mitral regurgitation produced comparable and satisfactory outcomes.283 The operative mortality rate for the IMR group was impressively low at 1.9% (compared with 1.2% in the degenerative group). The 5-year survival rate for those undergoing mitral valve repair was higher than expected at 84%, but significantly less that the 94% survival rate for patients with the degenerative MR. At longer follow-up, however, the survival trend for the IMR group diminished rapidly consistent with previous reported data (Fig. 40-24).268,283 Recurrent mitral regurgitation and the 5-year rates of freedom from reoperation were similar between the IMR and degenerative groups in the Virginia experience.283 Thus, an aggressive approach to repair patients with IMR, including treatment of leaflet tethering, may lead to acceptable results.

A compelling explanation for the generally poor long-term outcome of patients who undergo mitral valve repair for IMR is the presence of residual and/or recurrent mitral regurgitation postoperatively.284–286 Persistence of IMR after mitral annuloplasty is due predominantly to augmented posterior leaflet apical tethering with no improvement in anterior leaflet tethering and no increase in coaptation length.286 In a Cleveland Clinic report of annuloplasty (95% with concomitant coronary artery bypass grafting) for IMR, the proportion of patients with 0 or 1+ mitral regurgitation decreased from 71% preoperatively to 41% postoperatively, but the proportion with 3+ or 4+ residual or recurrent IMR increased from 13 to 28% during the first 6 months after repair284 (Fig. 40-25). The temporal pattern of development of severe regurgitation was similar for those who received a Cosgrove partial, flexible band or a semirigid, complete Carpentier Edwards ring (25%), but it was substantially worse for those who received a strip of glutaraldehyde-preserved xenograft pericardium for annuloplasty (66%).284 Smaller annuloplasty ring size apparently did not influence postoperative mitral regurgitation. At the Montreal Heart Institute, 78 patients underwent mitral valve repair for IMR.287 The operative mortality was 12.3% and the 5-year survival was 68%.287 Recurrent moderate mitral regurgitation was 37% and severe regurgitation was present in 20% at mean follow-up of 28 months. Only age and less marked preoperative posterior tethering were predictive of recurrent mitral regurgitation. Patients with preoperative NYHA class greater than II and recurrent MR greater than 2+ had lower survival rates (Fig. 40-26). This finding again highlights the need for improved repair techniques, better patient selection, or possibly chordal-sparing mitral valve replacement in certain patients.283,284,287

Mitral Subvalvular Apparatus and LV Systolic Function

Originally proposed by Lillehei and colleagues in 1964, the mitral subvalvular apparatus (or valvular–ventricular complex), including chordal and papillary muscle function, is important for optimal postoperative LV geometry and systolic pump function.131–134,199,200,288–292 After mitral valve replacement with total chordal excision, LV performance declines along with depression of regional and global LV elastance, dyssynergy of contraction, and dyskinesia at the papillary muscle insertion sites. Conversely, valve replacement with total or partial chordal preservation maintains LV contractile function.131–133,216,292 Experimentally, severing either the anterior or the posterior leaflet chordae impairs global LV systolic function, as evidenced by reduced maximal elastance, but this is reversible if chordal reattachment is carried out.132 In a canine model of chronic mitral regurgitation, mitral valve replacement with chordal preservation (compared with chordal severing) optimized postoperative LV energetics and ventriculovascular coupling in addition to enhancing systolic performance.200 Chordal interruption decreased global LV end-systolic elastance and depressed the end-systolic stress–volume relationship. In terms of myocardial energetics, the slopes of the LV stroke work–end-diastolic volume (preload recruitable stroke work, or PRSW) and pressure–volume area–end-diastolic volume relations also declined, indicating a reduction in external stroke work and mechanical energy generated at any given level of preload.

Clinically, mitral valve replacement with chordal division is associated with reduced rest and exercise LV ejection fraction owing in part to an increase in LV end-systolic stress (ESS).291 Mitral valve repair does not perturb rest and exercise ejection indexes of LV function primarily as a consequence of reducing ESS and maintaining a more ellipsoidal chamber geometry. Mitral valve replacement with complete chordal transection results in no postoperative change in LV end-diastolic volume, an increase in LVESV, an increase in ESS, and a decrease in ejection fraction.290 Patients who undergo chordal-sparing valve replacement, on the other hand, have a smaller LV end-diastolic volume and LVESV, decreased ESS, and unchanged ejection fraction. These findings suggest that smaller chamber size, reduced systolic afterload, and preservation of ventricular contractile function act in concert to maintain ejection performance after chordal-sparing mitral valve replacement. In contrast, increased LV chamber size, increased systolic afterload, and probable reduction in LV contractile function leading to reduced ejection performance occur in patients who undergo valve replacement with chordal transaction.290 Indeed, the 2006 ACC/AHA valve practice guidelines stipulate that the subvalvular apparatus be preserved whenever possible when the mitral valve must be replaced in patients with MR, including chordae to both mitral leaflets.238

The loss of ventricular function after mitral valve replacement with chordal division may be caused by heterogeneity of regional LV wall stress and not local depression of regional contractile function.293 After valve replacement with chordal transection in an experimental model, outward displacement of the ventricular wall and transverse shearing deformation occurred in the LV region papillary muscle insertion during isovolumic contraction.293 Circumferential and radial strains during ejection were maintained at the basal LV site and enhanced in the apical LV site. Chordal transection augmented regional myocardial loading at the papillary muscle insertion site; the resulting heterogeneity of regional systolic function might be the mechanism for reduced global LV function and slowed ventricular relaxation. Anterior chordal transection with mitral valve replacement caused impaired regional LV function and also impaired regional right ventricular function,294 whereas radionuclide angiography before and after mitral valve repair showed that LV ejection fraction did not change and right ventricular ejection fraction improved. In the region of the anterolateral papillary muscle insertion, local LV contractile function deteriorated after valve replacement with chordal transection, and right ventricular apicoseptal region was similarly impaired.294

In patients with chronic IMR, surgical division of the second-order chordae subtending the infarcted wall (usually those originating from the posteromedial papillary muscle) has been proposed to treat IMR.295,296 It is postulated that if the apical systolic tethering is eliminated, the normal redundancy of the mitral leaflet area creates better coaptation with the intact first-order or marginal chordae preventing leaflet prolapse. Clinically, the Toronto group compared the outcomes of patients who underwent chordal-cutting mitral valve repair (n = 43) and those undergoing conventional mitral valve repair (n = 49) for ischemic mitral regurgitation.196 The reduction in tenting height before-to-after repair was similar in the two groups of patients, but those undergoing chordal cutting had a greater reduction in tenting area. The chordal-cutting group also had greater mobility of the anterior leaflet, as measured by a reduction in the distance between the free edge of the anterior mitral valve leaflet and the posterior left ventricular wall. Additionally, those undergoing conventional mitral valve repair had a higher incidence of recurrent mitral regurgitation during 2 years of follow-up.296 Chordal cutting did not adversely affect postoperative left ventricular ejection fraction (10% relative increase in EF compared with 11% in the control group). The authors proposed that chordal cutting improves mitral valve leaflet mobility and reduces mitral regurgitation recurrence in patients with ischemic mitral regurgitation, without any obvious deleterious effects on left ventricular function.296 It is known, however, that division of the chordae, especially the second-order or “strut” chordae, impairs LV systolic function.154,297,298 Dividing the second-order chordae in an acute ovine preparation is associated with regional LV systolic dysfunction near the chordal insertion sites and neither prevents nor decreases the severity of acute IMR, septal-lateral annular dilatation, leaflet tenting area, or leaflet tenting volume.154,297 Cutting the anterior mitral leaflet second-order chordae alters LV chamber long-axis and subvalvular geometry, remodels end-diastolic transmural myocardial architecture in the equatorial lateral LV region, perturbs systolic transmural LV wall-thickening mechanics (thereby decreasing subendocardial “microtorsion”) and wall thickening, changes systolic temporal dynamics with delayed ejection, and impairs global LV systolic function (decreased end-systolic elastance and PRSW).298 Because of the importance of the chordae for LV structure and function, we believe that caution is necessary when considering procedures that cut second-order chordae to treat patients with IMR because of the resulting compromise in LV systolic function in ventricles that are already impaired.154,297,298

Summary

The functional competence of the mitral valve relies on the interaction of the mitral annulus and leaflets, chordae tendineae, papillary muscles, left atrium, and left ventricle. Dysfunction of any one or more components of this valvuloventricular complex can lead to mitral regurgitation. Important causes of mitral regurgitation include ischemic heart disease with IMR, dilated cardiomyopathy leading to FMR, myxomatous degeneration and prolapse, rheumatic valve disease, mitral annular calcification, and infective endocarditis. Four structural changes of the mitral valve apparatus may produce regurgitation: leaflet retraction from fibrosis and calcification, annular dilatation, chordal abnormalities, and LV systolic dysfunction with or without papillary muscle involvement. In IMR, changes in global and regional LV function and geometry, alterations in mitral annular geometry, abnormal leaflet (type IIIb) motion, leaflet malcoaptation, increased interpapillary distance, and papillary muscle lateral displacement and malalignment all may result in apical tenting of the leaflets and mitral incompetence.

With mitral regurgitation, the impedance to LV emptying is lower because the mitral orifice is parallel with the LV outflow tract. Reduced LV impedance allows a greater proportion of contractile energy to be expended in myocardial fiber shortening than in tension development. After the initial compensatory phase, LV contractility becomes progressively more impaired with chronic mitral regurgitation and chronic LV volume overload. Importantly, because of the low impedance during systole, clinical indexes of systolic function, such as ejection fraction, can be normal even if depressed LV contractility is already present. LVESV is less dependent on preload than is ejection fraction and is a better measure of LV contractile reserve. Preoperative LVESV is a good predictor of postoperative outcome. Surgical mitral valve repair (or, if repair is judged not to be durable, mitral valve replacement with total chordal preservation) for chronic mitral regurgitation can preserve LV contractility, particularly in patients with a normal preoperative ejection fraction who have minimal ventricular dilatation and those without major coronary disease. In patients with impaired preoperative LV contractility, LV systolic function may not necessarily improve after ring annuloplasty and definitely will not improve if the subvalvular apparatus and chordae are divided during mitral valve replacement.

IMR is generally associated with a higher operative risk than is nonischemic chronic mitral regurgitation. In patients with ischemic cardiomyopathy and mild mitral regurgitation, isolated coronary artery bypass grafting may suffice if most of the ventricle is still viable. Other workers argue that coronary revascularization alone in the setting of moderate IMR leaves many patients with substantial residual mitral regurgitation, heart failure symptoms, and a grave prognosis. Because moderate IMR does not resolve reliably with coronary revascularization alone, valve repair (undersized mitral annuloplasty with or without other adjunctive techniques) should be considered because it can reduce complications and possibly may improve long-term survival. Survival after mitral valve surgery and coronary artery bypass grafting may be more determined by the extent of coronary artery disease and LV dysfunction than by the etiology of mitral regurgitation. IMR may be a manifestation rather than an important impetus for postinfarct LV remodeling.

The mitral subvalvular apparatus is a key component of LV ejection performance; an intact mitral subvalvular apparatus, including second-order chordae tendineae to both leaflets, is necessary to maintain optimal postoperative LV geometry and maximize postoperative systolic pump function. After mitral valve replacement with chordal transection, LV systolic performance declines (depressed regional and global LV elastance, dyssynergy of contraction, and dyskinesia at the papillary muscle insertion sites). Experimental and clinical findings suggests that reduced LV chamber size, reduced LV systolic afterload, and preservation of ventricular contractile function act in concert to maintain ejection performance after mitral valve repair or total chordal-sparing valve replacement.