Pathophysiology of Mitral Valve Disease

	THE NORMAL MITRAL VALVE

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The mitral annulus is a pliable junctional zone of fibrous and muscular tissue joining the left atrium and ventricle that anchors the hinge portion of the anterior and posterior mitral leaflets.^1–11 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 atrioventricular membranous septum, the mitral and tricuspid valves, and the aortic root; and (2) the left fibrous trigone at the junction of the mitral valve and left coronary cusp of the aortic valve (Fig. 36-1). The anterior mitral leaflet spans the distance between the commissures (including the trigones) and is in direct fibrous continuity with most of the left and noncoronary aortic valve cusps. Fine tendon-like collagen bundles, the fila of Henle, extend out circumferentially from each fibrous trigone a variable distance towards the corresponding side of the mitral orifice. The posterior one half to two thirds of the annulus, which subtends the posterior leaflet, is primarily muscular with little or no fibrous tissue.¹⁰ This muscle is arranged mainly perpendicularly to the annulus, but a less prominent group of muscle fibers is arranged parallel to the annulus.

View larger version (51K): [in this window] [in a new window]   FIGURE 36-1 Diagram from a pathological perspective with division of the septum illustrating the fibrous continuity between the mitral and aortic valves. (Reproduced with permission from Anderson RH, Wilcox BR: The anatomy of the mitral valve, in Wells FC, Shapiro LM (eds): Mitral Valve Disease. Oxford, England, Butterworth-Heinemann, 1996; p 4.)

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 covers the atrial aspect 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.¹⁰ 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; it is confined mostly to the anterior leaflet and is densely packed with elastin. The fibroelastic layers become thickened with advanced age due to elaboration of more elastin and collagen formation; similar accelerated changes also accompany the progression of myxomatous (or degenerative or "floppy") mitral valvular disease. In addition to these complex connective tissue structures, the mitral leaflets contain myocardium, smooth muscle, contractile interstitial cells, and blood vessels, as well as both adrenergic and cholinergic afferent and efferent nerves.^13–19 Leaflet contractile tissue is neurally controlled and may play a role in mitral valve function.^6,16–25 The atrial surface of the anterior leaflet exhibits a depolarizing spike shortly before the onset of the QRS complex, and the resulting contraction of leaflet muscle, along with contraction of smooth muscle and 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.^{16–19,24,26–29} Mitral leaflet stretch of 10% or more also leads to an action potential that initiates leaflet muscle contraction.²⁸

Annular Size, Shape, and Dynamics

The average mitral annulus cross-sectional area ranges from 5.0 to 11.4 cm² in normal human hearts (average is 7.6 cm²).³⁰ The annular perimeter of the posterior leaflet is longer than that subtending the anterior leaflet by a 2:1 ratio; i.e., the posterior annulus circumscribes about two thirds of the mitral annulus.¹² Annular area varies during the cardiac cycle and is influenced directly by both left atrial and LV size and pressure.^4,31 The magnitude of change in mitral annular area is in the 20% to 40% range.^{4,8,9,31–38} 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.^{4,8,33,35,36,39} Importantly, one half to two thirds of the total decrease in annular area may occur during atrial contraction (thereby actually being presystolic); this component of annular area change is smaller when the PR interval is short, and is completely abolished when atrial fibrillation is present or ventricular pacing is employed. Annular area decreases further (if LV end-diastolic volume is not abnormally elevated) to a minimum in early to mid systole.^4,7,8,31,33

The human mitral annulus is roughly elliptical (or D- or kidney-shaped), with greater eccentricity (i.e., being less circular) in systole than in diastole.^{3,4,8,30,31,35,37,40} In its most elliptical configuration, the ratio of minor to major diameters is approximately 0.75. In three-dimensional space, the annulus is somewhat saddle-shaped (or, more precisely, a hyperbolic paraboloid), with the highest point (i.e., farthest from the LV apex) located anteriorly; this point is termed the "fibrosa" or the "saddle horn" in the echocardiography literature, is located in the middle of the anterior annulus, and is readily identified in echocardiographic images due to the common surface it shares with the aortic valve. The low points are located posteromedially and anterolaterally near the commissures, and another less prominent high point is located directly posterior.^4,41,42 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 from (during diastole) the relatively immobile anterior annulus.^4,37 Certain annular segments located near the left fibrous trigone (or area of aortic-mitral continuity), however, may actually lengthen slightly during LV ejection, at least in canine and ovine hearts.⁴³

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 left atrial filling and emptying.^{4,8,33,36,44,45} The annulus moves little 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 thus 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 subsequently aids left atrial 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.^{4,8,35,36,44–50} Subsequently, the annulus moves very little during isovolumic relaxation but then exhibits rapid recoil back toward the left atrium in early diastole. This recoiling increases the net velocity of mitral inflow by as much as 20%.^9,36

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.^12,44 Regions of both leaflets are concave toward the left ventricle during systole,^51–53 but leaflet shape is complex and some regional anterior leaflet curvature may actually be convex to the left ventricle during systole.^39,41,42 Leaflet opening does not start with the free margin but rather in the center of the leaflet; leaflet curvature initially flattens and then becomes reversed (making the leaflet convex toward the left ventricle) while the edges are still approximated.^39,52,53 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 milliseconds later.^53–55 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 (since the anterior leaflet is opened more widely than the posterior leaflet at the onset of ventricular systole).⁵⁵ 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.^52,53

Mitral valve closure is completed 10 to 40 milliseconds after the initial systolic rise of LV pressure, but, surprisingly, leaflet opening motion may actually precede the diastolic pressure crossover point by up to 60 milliseconds.^53,56,57 While the onset of mitral valve closure at the end of diastole appears to be initiated by atrial contraction, competent leaflet closure requires an increase in ventricular pressure above that in the atrium (irrespective of whether or not a normal atrial electrical and mechanical sequence is present) and a proper valve annular size to permit apposition of the valve leaflets at the onset of and during ventricular ejection.^16,31,55

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.^11,58 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.¹² A loop from the papillary muscles to the mitral annulus is completed by the chordae tendineae continuing into the mitral leaflets, which are then attached to the annular ring. The distance from the tip of the human papillary muscle to its corresponding mitral annulus averages 23.5 mm from the tip of the anterolateral papillary muscle to the left trigone, and 23.2 mm to the point between the anterior and middle scallops of the posterior leaflet.⁵⁹ The distance from the tip of the posteromedial papillary muscle to the right trigone is 23.5 mm and to the annular point between the middle and posteromedial scallops of the posterior leaflet is 23.5 mm. The posteromedial papillary muscle is usually supplied by the right coronary artery (or a dominant left circumflex artery in 10% of cases); the anterolateral papillary muscle is supplied by both the left anterior descending and circumflex coronary arteries .^11,60,61

The posteromedial and anterolateral papillary muscles give rise to chordae tendineae going to both leaflets (Fig. 36-2).¹² The chordae are classically and functionally divided into three groups.^11,62 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^12,62; they insert on the ventricular surface of the leaflets at the junction of the rough and clear zones, which is demarcated by a ridge corresponding to the line of leaflet coaptation. The second-order chordae (including the strut chordae) serve to anchor the valve and are more prominent on the anterior leaflet; second-order chordae may also arborize from large chordae that go to the leaflet free edge (first-order chordae). The third-order chordae, also called tertiary or basal chordae, originate directly from the trabeculae carnae of the ventricular wall, attach to the posterior leaflet near the annulus, and can be identified by their fan-shaped patterns.⁶² Additionally, distinct commissural chordae and cleft chordae exist in the commissures. Chordae contain nerve fibers, and some chordae, considered to be immature forms, may contain muscle tissue.¹⁷ 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 leaflets⁶²; on the other end, over 100 smaller individual chordae attach to the leaflets.

View larger version (36K): [in this window] [in a new window]   FIGURE 36-2 Mitral valve and subvalvular apparatus. Anterolateral papillary muscle (ALPM); posteromedial papillary muscle (PMPM); aortic leaflet (AoL); anterior commissural leaflet (Ant.Com.L.); posterior commissural leaflet (Post.Com.L.); anterior scallop (Ant.Scal.); middle scallop (Mid.Scal.); height of leaflet (h); length of attachment of leaflet (l) l posterior scallop (Post.Scal.); right fibrous trigone (Rt.Trigone); left fibrous trigone (Lt.Trigone); anterior main chorda (1); posterior main chorda (2); anterior paramedial chorda (3); posterior paramedial chorda (4); anterior paracommissural chorda (5); posterior paracommissural chorda (6); anterior commissural chorda (7); posterior commissural chorda (8); anterior cleft chorda (9); and posterior cleft chorda (10). (Reproduced with permission from Sakai T, Okita Y, Ueda Y, et al: Distance between mitral annulus and papillary muscles: anatomic study in normal human hearts. J Thorac Cardiovasc Surg 1999; 118: 636.)

Previous analyses of papillary muscle function during the cardiac cycle yielded widely discordant results.^64,66–70 Although the papillary muscles shorten at some point during systole (by upwards of one fourth of their maximum length),^{66,69,71–74} some suggest that this contraction may be isometric or substantially less than that of the LV free wall fibers.^68,74 In addition, there is no consensus as to the exact timing of papillary muscle contraction and elongation during the cardiac cycle.^{64–67,69,70,72,73} Some suggest that papillary muscles contract before the LV free wall so that the mitral valve leaflets are supported during early LV ejection⁷⁰; others, however, report that papillary muscles lengthen during isovolumic contraction and shorten during ejection as well as during isovolumic relaxation.^65,67,69 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.^64,72 Maximal shortening and elongation of the papillary muscle may follow thickening and thinning of an adjacent LV free wall segment.^72,73 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.⁷²

In the experimental setting, it has been shown that both papillary muscles closely mimic general LV dynamics; i.e., the papillary muscles shorten during ejection, lengthen during diastole, and change length minimally during the isovolumic periods (Fig. 36-3). ⁶⁶ These findings suggest that earlier studies purporting papillary muscle lengthening during isovolumic contraction and shortening during isovolumic relaxation may have been confounded by some form of myocardial injury or surgical trauma.⁶⁶

View larger version (25K): [in this window] [in a new window]   FIGURE 36-3 Graphs showing typical dynamics of the left ventricle and papillary muscles from a control run (left panel) and 2 minutes after left circumflex coronary artery occlusion (right panel). In the left panel, papillary muscle lengths are temporally related closely to changes in LV volume (LV VOL). In the right panel, the dynamics of the ischemic posterior papillary muscle are markedly different and more closely track changes in LV pressure (LVP). ANT, anterior papillary muscle; POST, posterior papillary muscle. (Reproduced with permission from Rayhill SC, Daughters GT, Castro LJ, et al: Dynamics of normal and ischemic canine papillary muscles. Circ Res 1994; 74:1179.)

	MITRAL STENOSIS

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Mitral stenosis is generally the result of rheumatic heart disease.^75–81 Nonrheumatic causes of mitral stenosis or LV inflow obstruction include severe mitral annular and/or leaflet calcification, congenital mitral valve deformities, malignant carcinoid syndrome, neoplasm, left atrial thrombus, endocarditic vegetations, certain inherited metabolic diseases, and causes related to a previous commissurotomy or implanted prosthetic valve (Fig. 36-4).^79–83 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.

View larger version (34K): [in this window] [in a new window]   FIGURE 36-4 Diagrams demonstrating causes of mitral stenosis, including rheumatic heart disease, active infective endocarditis, massive mitral annular calcification, and congenital single papillary muscle syndrome. (Modified from Waller BF, Howard J, Fess S: Pathology of mitral valve stenosis and pure mitral regurgitation, part I. Clin Cardiol 17:330, 1994. Copyrighted and reprinted with the permission of Clinical Cardiology Publishing Company, Inc., and/or the Foundation for Advances in Medicine and Science, Inc., Mahwah, NJ 07430-0832, USA.)

In addition to affecting the cardiac valves, rheumatic heart disease is a pancarditis affecting to various degrees the endocardium, myocardium, and pericardium (Fig. 36-5).^75,77,78 In rheumatic valvulitis, mitral valve involvement is the most common (isolated mitral stenosis is found in 40% of cases), followed by combined aortic and mitral valve disease, and, least frequently, isolated aortic valve disease. Pathoanatomic changes characteristic of mitral valvulitis include commissural fusion, leaflet fibrosis with stiffening and retraction, and chordal fusion and shortening.⁷⁷ Leaflet stiffening and fibrosis can be exacerbated over time by increased flow turbulence. Valvular regurgitation can develop due to 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.⁷⁸ In some cases, rheumatic myocarditis results in cardiac dilation and progressive heart failure.

View larger version (153K): [in this window] [in a new window]   FIGURE 36-5 Intraoperative photograph of mitral stenosis as a result of rheumatic heart disease. The mitral leaflets are markedly restricted. The arrowheads point to the anterior leaflet near the anterolateral commissure.

Hemodynamics

In patients with mitral stenosis, an early, mid-, and late diastolic transvalvular gradient is present between the left atrium and ventricle, and as the degree of mitral stenosis worsens, a progressively higher gradient, especially late in diastole, occurs (Fig. 36-6).^79,85–87 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.^85,87 With exercise, the left atrial pressure and gradient rise substantially. LV end-diastolic pressure is usually normal.

View larger version (21K): [in this window] [in a new window]   FIGURE 36-6 Left ventricular and left atrial pressures in mitral stenosis. The higher left atrial pressure results in earlier opening and later closure of the mitral valve. The left ventricular diastolic pressure in mitral stenosis rises slowly because of the absence of a rapid filling wave. (Reproduced with permission from Schofield PM: Invasive investigation of the mitral valve, in Wells FC, Shapiro LM (eds): Mitral Valve Disease. Oxford, England, Butterworth-Heinemann, 1996; p 84.)

Because of effective atrial contraction, the mean left atrial pressure in patients with mitral stenosis and normal sinus rhythm is lower compared to that of patients in atrial fibrillation.^89,90 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.^75,89,90

Ventricular Adaptation

In patients with isolated mitral stenosis and restricted LV inflow, LV chamber size (end-diastolic volume) is normal or decreased, and the end-diastolic pressure is typically low.^79,91,92 The peak filling rate is reduced, as is stroke volume. Cardiac output is thus diminished as a result of inflow obstruction rather than LV pump failure.⁹³ LV mass is normal or slightly subnormal in the majority of these patients.⁹¹ During exercise, the ejection fraction may increase slightly; however, LV filling is compromised by the shorter diastolic 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.⁹²

Approximately 25% to 50% of patients with severe mitral stenosis have LV systolic dysfunction as a consequence of associated diseases (e.g., mitral regurgitation, aortic valve disease, ischemic heart disease, rheumatic myocarditis or pancarditis, and myocardial fibrosis).^78,87,92 In these patients, LV end-systolic and end-diastolic volumes may be larger than normal. Also, because right ventricular afterload increases as pulmonary hypertension develops in these patients, right ventricular systolic performance deteriorates.^79,94 Clinically, however, increased right ventricular afterload as a result of mitral stenosis is usually associated with normal right ventricular contractility.⁷⁹

Atrial Adaptation

In patients with mitral stenosis who are in normal sinus rhythm, the left atrial pressure tracing is characterized by an elevated mean left atrial pressure with a prominent a wave, which is followed by a gradual pressure decline.^75,90 The a wave pressure largely reflects the kinetic energy dissipated in overcoming the resistance across the valve. Because of the stenotic valve, coordinated left atrial contraction is important in maintaining transvalvular flow.⁹⁰ The high left atrial pressure gradually leads to left atrial hypertrophy and dilation, atrial fibrillation, and atrial mural thrombi formation.^78,92,95 The degree of left atrial 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.⁹² Disorganization of atrial muscle fibers is associated with abnormal conduction velocities and inhomogeneous refractory periods. Premature atrial activation due to increased automaticity or reentry eventually may lead to atrial fibrillation, which is present in over one half of patients with either pure mitral stenosis or mixed mitral stenosis and regurgitation.^95,96 Major determinants of atrial fibrillation in patients with rheumatic heart disease include older age and larger left atrial diameter.⁹⁵

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.⁸⁵ 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 elevates impedance to right ventricular emptying and produces high right ventricular end-diastolic and right atrial pressures.

Left atrial hypertension produces pulmonary vasoconstriction, which exacerbates the elevated pulmonary vascular resistance.^78,94 As the mean left atrial 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 left atrial 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 progressively worsens, leading to right-sided heart failure, tricuspid insufficiency, and occasionally pulmonic valve insufficiency.^79,94 Severe mitral stenosis ultimately causes irreversible pulmonary vascular changes; cardiac output is low at rest and remains subnormal during exercise.⁸⁵

Clinical Evaluation

Because of the gradual development of mitral stenosis, patients may remain asymptomatic for many years.^75,85,96 Characteristic symptoms of mitral stenosis eventually develop and are associated primarily with pulmonary venous congestion or low cardiac output, e.g., dyspnea on exertion, orthopnea, or paroxysmal nocturnal dyspnea and fatigue. Dyspnea is often precipitated by events that elevate left atrial pressure, such as physical or emotional stress or atrial fibrillation. In patients with mild mitral stenosis, symptoms usually occur only with extreme exertion. 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, edema, and ascites can be found.

As a result of high left atrial pressure and increased pulmonary blood volume in the early phases of the disease, hemoptysis may develop secondary to rupture of dilated bronchial veins (or submucosal varices).^75,94 Over time, pulmonary vascular resistance increases 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 due to rupture of alveolar capillaries.

Systemic thromboembolism, occurring in approximately 20% of cases, may be the first symptom of mitral stenosis; recurrent embolization occurs in 25% of patients.^75,97,98 The incidence of thromboembolic events is higher in patients with mitral stenosis or mixed mitral stenosis–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.^75,99 Embolization to coronary arteries may lead to angina, arrhythmias, or myocardial infarction; renal embolization can result in hypertension.⁷⁵ Factors that increase the risk of thromboembolic events include low cardiac output, left atrial dilation, atrial fibrillation, left atrial thrombus, absence of tricuspid or aortic regurgitation, and the presence of echocardiographic "smoke," an indicator of stagnant flow. Patients with these risk factors should be anticoagulated.^75,97–99 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 long-standing low cardiac output, congestive heart failure, and inanition.⁷⁵ The peripheral arterial pulse is generally normal, except in patients with a decreased LV stroke volume, in which case the pulse amplitude is diminished. Heart size is usually 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, an increased first sound, an opening snap, and an apical diastolic rumble.^75,100–102 The presystolic murmur, which occurs due to closing of the anterior mitral leaflet, is a consistent finding and begins earlier in those in sinus rhythm compared with patients in atrial fibrillation.¹⁰² The first heart sound (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.¹⁰³ 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 due to sudden tensing of the pliable leaflets during valve opening and is absent when the leaflets are rigid or immobile.^75,100,101 In mild mitral stenosis, the diastolic murmur is soft and of short duration; a long or holo-diastolic 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.¹⁰²

On chest radiography, left atrial 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 mainstem bronchus.^76,85,104 The overall cardiac size is often normal. Prominence of the pulmonary arteries coupled with left atrial 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 distension 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 in normal sinus rhythm, left atrial enlargement is the earliest change (a wide notched P wave in lead II and a biphasic P wave in lead V₁).^85,105 Atrial arrhythmias are more 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.¹⁰⁵ 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 dilation and hypertrophy, however, also can mask the changes indicative of LV hypertrophy on the electrocardiographic tracing in patients with multivalvular disease.¹⁰⁵

Echocardiography has become the primary noninvasive technique for assessing mitral valve pathology and pathophysiology.^76,106–109 Cross-sectional valve area and left atrial and ventricular dimensions can be quantified using two-dimensional echocardiography. Best appreciated in the parasternal long-axis view, the features of rheumatic mitral stenosis include reduced diastolic excursion of the leaflets and thickening or calcification of the valvular and subvalvular apparatus (Figs. 36-7 and 36-8). 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.^75,107 To estimate mitral valve area, the pressure half-time (time required for the initial diastolic gradient to decline by 50%) is employed; the more prolonged the half-time, the more severe is the reduction in orifice area.¹⁰⁷ 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 has generally fallen out of popularity. In patients with combined aortic regurgitation and mitral stenosis, the pressure half-time method may be unreliable because the regurgitant jet may interfere with the valve area calculation.¹⁰⁷

View larger version (99K): [in this window] [in a new window]   FIGURE 36-7 Echocardiogram (long axis) of a patient with severe mitral stenosis due to rheumatic heart disease. A thickened, stenotic valve separates an enlarged left atrium (right) and the left ventricle (left) and outflow tract (above).

View larger version (105K): [in this window] [in a new window]   FIGURE 36-8 Echocardiogram (long axis) of a patient with severe mitral stenosis due to mitral annular calcification.

Cardiac catheterization is not necessary to establish the diagnosis of mitral stenosis; however, it can provide valuable data regarding associated coronary artery disease.^76,104 Left ventriculography permits assessment of the mitral valve and LV contractility and calculation of ejection fraction, but today its role has been 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. Therefore, the only real need for cardiac catheterization in these patients currently is to study coronary arteries or, rarely, to evaluate the reversibility of severe pulmonary hypertension using pharmacological interventions.

Postoperative Outcome

Whereas indexes of LV systolic function are used to determine the natural history and surgical prognosis of patients with other valvular lesions, there are few data linking LV function to outcome in those with mitral stenosis. Not surprisingly, the best indicator is related to the degree of clinical impairment. Surgical intervention (open mitral commissurotomy or mitral valve replacement) substantially improves the functional capacity and long-term survival of patients with mitral stenosis; 67% to 90% of patients are alive at 10 years.^{105,111–113} However, patients who received an open commissurotomy have a higher rate of reoperation at 10 years compared to those who underwent mitral valve replacement (42% versus 4%).¹¹³

Generally, a valve area of 1 cm² is considered critical mitral stenosis and is associated with significant symptoms and morbidity. In physically active or larger patients, somewhat larger valve areas (1.2 cm²) may produce symptoms.⁷⁹ The LV cavity may become foreshortened and more globular; these morphologic changes, however, rarely dictate operative timing and do not influence surgical outcome. Despite a higher operative risk in those with severe pulmonary hypertension and right-sided heart failure, these patients usually improve postoperatively with a reduction in pulmonary vascular pressures.^79,114

Summary

Mitral stenosis is generally due to rheumatic heart disease. In rheumatic valvulitis, the mitral valve is most commonly involved, followed by combined aortic and mitral valve disease. With worsening mitral stenosis, a progressively higher transvalvular pressure gradient occurs. 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. In mild to moderate mitral stenosis, pulmonary vascular resistance may not be elevated, and pulmonary arterial pressure may be normal at rest and rise only with exertion or increased heart rate. In severe mitral stenosis with elevated pulmonary vascular resistance, pulmonary arterial pressure is usually high at rest. Characteristic symptoms of mitral stenosis are primarily associated with pulmonary venous congestion or low cardiac output. Echocardiography remains the best noninvasive technique for assessing mitral valve pathology and pathophysiology. Surgical intervention can substantially improve the functional capacity and long-term survival of patients with mitral stenosis.

	MITRAL REGURGITATION

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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.^{11,60,115,116} Normal LV geometry and alignment of papillary muscles and chordae tendineae permit leaflet coaptation and prevent leaflet prolapse during ventricular systole. Dysfunction of any one or more components of this valvular-ventricular complex can lead to mitral regurgitation. Regurgitation can also occur in diastole. Diastolic regurgitation results from delayed ventricular contraction, but this phenomenon appears to have few clinical implications.¹¹⁷

The most common etiology of systolic mitral regurgitation in patients undergoing surgical evaluation is myxomatous degeneration, also termed "flail leaflet," floppy mitral valve, or mitral valve prolapse (29% to 70% of cases); other causes include ischemic heart disease with ischemic mitral regurgitation (IMR), dilated cardiomyopathy (in which the term "functional mitral regurgitation" [FMR] is used), rheumatic valve disease, mitral annular calcification, infective endocarditis, idiopathic chordal rupture (usually associated with fibroelastic deficiency), congenital anomalies, endocardial fibrosis, and collagen-vascular disorders (Fig. 36-9). ^{76,80,81,104,116,118–122} IMR is a specific subset of FMR, but both are usually associated with morphologically normal mitral leaflets.

View larger version (46K): [in this window] [in a new window]   FIGURE 36-9 Diagram demonstrating causes of pure mitral regurgitation, including infective endocarditis, floppy mitral valve, floppy mitral valve with ruptured chordae, rheumatic heart disease, papillary muscle dysfunction, hypertrophic cardiomyopathy, dilated cardiomyopathy, endocardial disorders, and annular calcification. (Modified from Waller BF, Howard J, Fess S: Pathology of mitral valve stenosis and pure mitral regurgitation, part II. Clin Cardiol 17:395, 1994. Copyrighted and reprinted with the permission of Clinical Cardiology Publishing Company, Inc., and/or the Foundation for Advances in Medicine and Science, Inc., Mahwah, NJ 07430-0832, USA.)

View larger version (10K): [in this window] [in a new window]   FIGURE 36-10 Carpentier's functional classification of the types of leaflet and chordal motion associated with mitral regurgitation. In type I, the leaflet motion is normal. Type II mitral regurgitation is due to leaflet prolapse or excessive motion. Type III (restricted leaflet motion) is subdivided into restriction during diastole ("a") or systole ("b"). Type IIIb is typically seen in patients with ischemic mitral regurgitation. The course of the leaflets during the cardiac cycle is represented by the dotted lines. (Modified with permission from Carpentier A: Cardiac valve surgery: the "French correction." J Thorac Cardiovasc Surg 86: 323, 1983.)

Myxomatous degeneration (floppy mitral valve or mitral valve prolapse) is the most common cause of mitral regurgitation in the United States.^{11,118,119,127} The cause of mitral valve prolapse is most likely congenital with defective fibroelastic connective tissue in the leaflets, chordae, and annulus (Fig. 36-11).^78,128–130 Some degree of mitral valve prolapse is seen echocardiographically in 5% to 6% of the normal female population^128,129,131; it can be familial and is associated with hypertension. Although mitral valve prolapse appears to be more widespread in women, severe mitral regurgitation due to mitral valve prolapse is more common in men. 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. The risk of endocarditis is increased only if valvular regurgitation is present and accompanied by a murmur. The syndrome of mitral valve prolapse includes palpitations, chest pain, syncope or dyspnea, and a mid-systolic click (with or without a late systolic murmur of mitral regurgitation).^128,129 These latter findings are typically seen in patients with Barlow's syndrome, where extensive hooding and billowing of both leaflets are the rule.

View larger version (147K): [in this window] [in a new window]   FIGURE 36-11 Intraoperative photograph of mitral regurgitation due to floppy mitral valve.

Only 5% to 10% of patients with mitral valve prolapse progress to severe mitral regurgitation, and the majority remain asymptomatic.^76,128,129 Mechanisms accounting for severe mitral regurgitation in persons with mitral valve prolapse include annular dilation and rupture or elongation of the first-order chordae (58%), annular dilation without chordal rupture (19%), and chordal rupture without annular dilation (19%).¹³⁰ Chordal rupture is probably related to defective collagen, underlying papillary muscle fibrosis or dysfunction, or bacterial endocarditis.^{11,60,78,80,81,119,121,132–134} Elongation without rupture of other first-order as well as many second-order chordae frequently accompanies chordal rupture. Chordal rupture is typically the culprit when mitral regurgitation develops acutely in patients without any previous symptoms of heart disease and in those with known mitral valve prolapse.^76,80,121 Chordal rupture was evident in 14% to 23% of surgically excised purely regurgitant valve specimens; in 73% to 93% of these cases, the underlying pathology was degenerative or floppy mitral valve syndrome.^80,81,121 Posterior chordal rupture was the most frequent finding, followed by anterior chordal rupture and then combined anterior and posterior chordal rupture.^{80,81,119,121}

FUNCTIONAL AND ISCHEMIC MITRAL REGURGITATION

Functional mitral regurgitation (FMR), or regurgitation in the setting of structurally normal valve leaflets, is due to incomplete mitral leaflet coaptation in patients with LV dysfunction and dilation (e.g., dilated cardiomyopathy and ischemic heart disease).^135–138 Often clinically silent, FMR or IMR portends a poor prognosis. Similar degrees of LV systolic dysfunction and dilation may also be associated with long-standing severe mitral regurgitation simply due to the chronic volume overload of the ventricle.

In patients with acute myocardial infarction, IMR occurs in about 15% of cases of anterior wall involvement but is present in up to 40% of patients with an inferior infarct.^80,81 The severity of mitral regurgitation is generally related to the size of the area of LV akinesia or dyskinesia. Experimentally, the papillary-annular distances remain relatively constant in the normal heart throughout the cardiac cycle.¹³⁶ In acute ischemia, however, the papillary-annular distances differ from the nonischemic state, suggesting a repositioning of the papillary muscle tips relative to the mitral annulus. These papillary tip displacements can tether or "tent" the leaflets apically during systole, e.g., Carpentier "type IIIb" restricted systolic leaflet motion.^123,136 Furthermore, during acute ischemia, alterations in mitral apparatus geometry are seen not only in late or end systole, but in early systole as well.¹³⁹ Systolic mitral annular dilation and shape change and altered posterior papillary muscle position and motion may be the primary mechanisms for incomplete mitral leaflet coaptation causing acute IMR during acute inferior or posterolateral ischemia.

Chronic ischemic heart disease results in LV dilation, regional LV systolic wall motion abnormalities, and occasionally papillary muscle fibrosis and shortening, which can lead to papillary muscle malalignment and mitral regurgitation. Mechanisms implicated in chronic IMR include simple annular dilation from LV enlargement, which causes incomplete mitral leaflet coaptation and is associated with normal leaflet motion (Carpentier type I); local LV remodeling with papillary muscle displacement producing apical tethering or tenting of the leaflets (Carpentier type IIIb restricted leaflet motion); or both mechanisms.^123,135 Experimentally, IMR increases over time as the left ventricle dilates and changes shape due to ischemia and previous infarction.^137,138 Geometric changes associated with LV remodeling include an increased distance over which the mitral leaflets are tethered from the papillary muscles (usually the posterior papillary muscle) to the middle of the anterior annulus (or "fibrosa," an easily identified echocardiographic landmark), as well as an increased mitral annular diameter.^137,138 The leaflets cannot coapt normally during systole due to apical leaflet tenting (Fig. 36-12).

View larger version (45K): [in this window] [in a new window]   FIGURE 36-12 Drawing of balance of forces in mitral apparatus in the left panel. In the right panel, potential effect of papillary muscle displacement to restrain leaflet closure, causing mitral regurgitation. (Reproduced with permission from Liel-Cohen N, Guerrero JL, Otsuji Y, et al: Design of a new surgical approach for ventricular remodeling to relieve ischemic mitral regurgitation. Circulation 2000; 101: 2756.)

Myocardial infarction leading to papillary muscle dysfunction occurs more frequently when the blood supply to the papillary muscle is provided by one vessel, as is more frequently the case with the posteromedial papillary muscle after an inferior myocardial infarction. Also, coronary artery disease involving both the right and circumflex coronary arteries (as opposed to single-vessel disease) can cause posteromedial papillary muscle dysfunction.¹⁴¹ Although papillary muscle necrosis frequently complicates myocardial infarction, frank rupture of a papillary muscle is rare. Total papillary muscle rupture is usually fatal due to the resulting severe mitral regurgitation and LV pump failure; survival is possible with rupture of one or two of the subheads of a papillary muscle, which is associated with a lesser degree of 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.^142,143

RHEUMATIC DISEASE

Although the incidence is decreasing in the United States, rheumatic fever remains a common cause of mitral regurgitation around the world.^{11,80,81,116,120–122} It is unknown why rheumatic fever leads to valvular stenosis in some patients and pure regurgitation in others. The pathoanatomic changes of the purely regurgitant rheumatic valve differ from those in a stenotic valve. Regurgitant rheumatic valves have diffuse fibrous thickening of leaflets with minimal calcific deposits and relatively nonfused commissures; chordae tendineae are usually not extremely thickened nor fused.^80,81 There also may be shortening of the chordae tendineae, infiltration of the papillary muscle, and asymmetric annular dilation that develops primarily in the posteromedial portions.

MITRAL ANNULAR CALCIFICATION

Mitral annular calcification is a degenerative disease that is essentially limited to the elderly.^11,76,83 Most patients are older than 60 years of age, and women are affected more often than men. The pathogenesis of mitral annular calcification is not known, but it appears to be a stress-induced phenomenon; annular calcification is associated with systemic hypertension, hypertrophic cardiomyopathy, and aortic stenosis. 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 rigid bars up to 2 cm in thickness.^76,83 Initially, calcification begins at the mid portion of the posterior annulus; as the process progresses, the leaflets become upwardly deformed, stretching the chordae tendineae, and a rigid curved bar surrounding the entire posterior annulus or even a complete ring of calcium may encircle the entire mitral orifice. Invasion of the calcific spurs into the myocardium and impingement on the conduction system can result in atrioventricular and/or intraventricular conduction defects. Annular calcification causes mitral regurgitation by displacing the mitral leaflets, immobilizing the peripheral portion of the mitral leaflets (thereby preventing their normal systolic coaptation), or impairing the presystolic sphincteric action of the annulus.^76,83 As the degree of mitral regurgitation gets worse over time, LV volume overload can lead to heart failure. Systemic embolization can occur if annular calcific debris is extensive and friable.

Hemodynamics

The pathophysiology of acute mitral regurgitation markedly differs from that of chronic mitral regurgitation. Acute regurgitation may result from spontaneous chordal rupture, myocardial ischemia, infective endocarditis, or chest trauma.^{11,60,133,142,143} The clinical impact of acute mitral incompetence is largely modulated by the compliance of the left atrium. In a normal left atrium with a relatively low compliance, acute mitral regurgitation results in high left atrial pressure, which can rapidly lead to pulmonary edema. Such is not the situation in patients with chronic mitral regurgitation, in whom compensatory changes over time increase left atrial and pulmonary venous compliance so that the symptoms of pulmonary congestion can be negligible for several years.

In mitral regurgitation, the impedance to LV emptying is decreased because the mitral orifice is in parallel with the LV outflow tract.^11,87,144 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 (termed "ERO").^11,145,146 Regurgitation into the left atrium increases left atrial pressure and reduces forward systemic flow. Left atrial pressure rises significantly during ventricular systole, followed by an abrupt decline in early diastole. At end-diastole, left atrial pressure may remain elevated with a transient 5- to 10-mm Hg transvalvular gradient, representing a flow gradient associated with the increased diastolic flow rate.

If the mitral annulus is not rigid, various diagnostic and therapeutic interventions can alter the size of the ERO. Altered loading conditions (elevated preload and afterload) and decreased contractility result in progressive LV dilation and a larger ERO.¹⁴⁷ When LV size is reduced by medical management (e.g., digoxin, diuretics, and most importantly vasodilators), the ERO and regurgitant volume are reduced.^148,149 Importantly, stress echocardiography using an inotropic drug like dobutamine usually decreases the ERO and degree of mitral regurgitation in patients with FMR and IMR because the LV chamber is smaller and the viable LV walls are thickening and contracting better.

Ventricular Adaptation

The loading conditions in mitral regurgitation are favorable to LV ejection because LV preload is increased whereas LV afterload is normal or decreased. 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.^11,144 Because this increased 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.¹⁴⁴ Simultaneous reductions in developed tension due to lower LV systolic wall stress (or afterload) associated with mitral regurgitation allow 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 substantial increase in preload (LV end-diastolic volume or, more precisely, LV end-diastolic wall stress) allows the heart to compensate for the chronic mitral regurgitation for long periods of time before severe symptoms occur.^11,150,151 A fundamental response of the ventricle to augmented preload is to increase stroke volume and stroke work, although effective forward stroke volume may be normal or actually subnormal. High LV preload eventually leads to LV dilation and shape changes of the ventricle, i.e., more spherical remodeling, due to replication of sarcomeres in series as a consequence of chronic elevation of LV end-diastolic wall stress.^150,151 This 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 (and unlike the situation in patients with LV pressure overload), the degree of hypertrophy correlates with the amount of chamber dilation so that the ratio of LV mass to end-diastolic volume remains in the normal range.^152–154 The contractile dysfunction that ultimately evolves is accompanied by increased myocyte length as well as reduced myofibril content.^151,152 The basic changes thus are a combination of myofibrillar loss and the absence of significant hypertrophy in response to the progressive decrease in ventricular pump function; experimental work indicates that the defect is intrinsic to the myocyte per se.¹⁵⁵ Conversely, in acute mitral regurgitation, the ratio of LV mass to end-diastolic volume is reduced because chamber dilation can occur rapidly and the LV wall becomes acutely thinned; this increase in LV end-diastolic volume is associated with sarcomere lengthening along the length-tension curve.¹⁵¹

After the initial compensatory phase, LV systolic contractility becomes progressively more impaired with chronic mitral regurgitation.^153–156 Because of the low impedance during systole, however, clinical indexes of myocardial systolic function, such as ejection fraction and fractional circumferential fiber shortening (%FSc), can still be normal even if severely depressed LV systolic contractility is present.^155,157,158 An ejection fraction of less than 40% to 50% or %FSc under 28% indicates an advanced degree of myocardial dysfunction in the presence of severe mitral regurgitation. The commonly used ejection-phase indexes of LV performance, e.g., ejection fraction, %FSc, cardiac output, stroke volume, stroke work, etc., are all affected by changes in LV preload and afterload that accompany all forms of valvular heart disease. End-systolic dimension or LV end-systolic volume (LVESV) is less dependent on preload than is ejection fraction and can be used as a better measure of left ventricular systolic contractile function.¹⁵⁹

To avoid the pitfalls imposed by abnormal LV loading conditions, load-independent indexes of LV contractility (e.g., end-systolic elastance derived from the end-systolic pressure-volume relationship [ESPVR]) are preferable to measure LV systolic functional mechanics in the face of mitral regurgitation.^{153,154,159–161} In hypertrophied and dilated hearts, as seen in chronic mitral regurgitation, however, the utility of end-systolic elastance may be limited due to the geometric changes and hypertrophy that occur; using the end-systolic stress-volume relationship in these circumstances yields more precise estimates. One other problem inherent in the use of end-systolic elastance or stress-volume data is that end systole and end ejection are dissociated in patients with mitral regurgitation; end ejection is defined as minimum LV volume, and end systole is defined as the instant when LV elastance reaches its maximal value. Because of this dissociation of end systole from minimal ventricular volume, end ejection pressure-volume relations do not correlate with maximal elastance values derived using isochronal methods.¹⁶⁰

Using load-independent indexes of LV contractility in an experimental mitral regurgitation preparation, Yun et al demonstrated that the normalized end-systolic pressure-volume relationships decreased by 36% and end-systolic stress-volume relationships declined by 21% after 3 months of mitral regurgitation (Fig. 36-13).¹⁵³ There was a 26% reduction in LV preload-recruitable stroke work (the relation of stroke work to LV end-diastolic volume) and a 14% drop in preload-recruitable pressure-volume area (the relation of stroke work to LV pressure-volume area). The efficiency of energy transfer from pressure-volume area to external pressure-volume work at matched LV end-diastolic volume decreased by 25%. Furthermore, there was deterioration in ventriculoarterial coupling over time; i.e., a mismatch developed between the ventricle and the total (forward and regurgitant) vascular load. Although the overall (systemic plus left atrial) effective arterial elastance decreased, there was a proportionally greater reduction in LV end-systolic elastance. Thus LV systolic mechanics were impaired, global LV energetics and efficiency deteriorated, and a mismatch in coupling between the left ventricle and arterial bed emerged.¹⁵³ Further analysis demonstrated that progression from acute to chronic mitral regurgitation at 3 months was associated with a decrease in maximum torsional deformation from 6.3 degrees to 4.7 degrees and a decrease in early diastolic recoil from +3.8 degrees to –1.5 degrees (Fig. 36-14).¹⁶²

View larger version (24K): [in this window] [in a new window]   FIGURE 36-13 Pressure-volume (top panel) and stress-volume (bottom panel) loops obtained during caval occlusion at 1 week (squares) and 3 months (triangles) after surgically creating mitral regurgitation in dogs along with the corresponding end-systolic pressure-volume (ESPV) relationship (top) and end-systolic stress-volume (ESSV) relationship (bottom). In each animal, there was a rightward and downward shift of the ESPV and ESSV relationships along with a decline in their slopes at 3 months. (Reproduced with permission from Yun KL, Rayhill SC, Niczyporuk MA, et al: Left ventricular mechanics and energetics in the dilated canine heart: acute versus chronic mitral regurgitation. J Thorac Cardiovasc Surg 1992; 104:26.)

View larger version (28K): [in this window] [in a new window]   FIGURE 36-14 Torsional deformation versus fractional ejection with acute (top) and chronic (bottom) mitral regurgitation in a representative animal. With acute mitral regurgitation, systole (solid line) is characterized by a slight clockwise rotation followed be counterclockwise torsion that peaks at end ejection. Early diastole (dashed line) shows steeper torsional recoil than mid-to-late diastole (dotted line). With chronic mitral regurgitation, the initial clockwise torsion is larger, the maximum positive torsion is decreased, and less recoil occurs during early diastole. (Reproduced with permission from Tibayan FA, Yun KL, Lai DTM, et al: Torsional dynamics in the evolution from acute to chronic mitral regurgitation. J Heart Valve Dis 2002; 11:39.)

Clinically, LVESV accurately reflects changes in LV systolic function; it is independent of preload and varies directly and linearly with afterload (Fig. 36-15).^{159,163–166} The larger the LVESV becomes, the worse the LV systolic function or contractility. Correcting LVESV for afterload (i.e., end-systolic wall stress [ESS]) and body size (LV end-systolic volume index [LVESVI]) provides an excellent index of LV systolic function that is less influenced by loading conditions and variation in patient size. ^163,164 Preoperative LVESV or LVESVI has been shown to be a better predictor of postoperative outcome in terms of postoperative LV systolic performance and cardiac death than is ejection fraction, LV end-diastolic volume, or LV end-diastolic pressure.¹⁶⁶

View larger version (31K): [in this window] [in a new window]   FIGURE 36-15 Pathophysiologic stages of mitral regurgitation. Panel A shows the transition from normal physiology to acute mitral regurgitation (AMR). The volume overload of acute regurgitation increases preload sarcomere length (SL) so that end-diastolic volume (EDV) increases from 150 to 170 mL. Ejection of blood into the left atrium (LA) reduces afterload [or end-systolic stress (ESS)], and therefore end-systolic volume (ESV) is reduced from 50 to 30 mL. Ejection fraction (EF) increases acutely, but because 50% of the stroke volume is regurgitated into the left atrium (regurgitant fraction of 0.50), forward stroke volume (FSV) is reduced from 100 to 70 mL. Increased left atrial volume raises left atrial pressure from normal to 25 mm Hg. Panel B shows the transition from acute mitral regurgitation to chronic compensated mitral regurgitation (CCMR). Development of eccentric hypertrophy has increased end-diastolic volume from 170 to 240 mL. The larger ventricle has an increased afterload because the radius applied in the Laplace equation for stress is larger. In turn, end-systolic volume is returned to normal. The presence of eccentric hypertrophy, however, allows for increase in total stroke volume and forward stroke volume. Left atrial enlargement allows the left atrial volume overload to be accommodated at a lower filling pressure (15 mm Hg). The LV ejection fraction is supernormal. Panel C shows the transition to chronic decompensated mitral regurgitation (CDMR). The now weakened ventricle can no longer contract well, and LV end-systolic volume increases from 50 to 110 mL. Forward stroke volume is reduced, and cardiac dilation leads to an increased mitral regurgitant fraction. These favorable loading conditions, however, still permit the ejection fraction to remain normal (0.58). CF: contractile function; N: normal; downward arrow: depressed. (Modified with permission from Carabello BA: Mitral regurgitation, pt.1: basic pathophysiological principles. Mod Concepts Cardiovasc Dis 1998; 57:53.)

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.^91,144 Also, the left atrial v wave in mitral regurgitation does not correlate with left atrial volume. Compared to patients with mitral stenosis, left atrial size can be larger in patients with long-standing mitral regurgitation; conversely, thrombus formation and systemic thromboembolization occur less frequently because of the absence of atrial stasis.^91,94 Also, atrial fibrillation occurs less often in those with mitral regurgitation and does not affect the clinical course as dramatically as in individuals with mitral stenosis.⁹⁴

Left atrial compliance is an important component of the patient's overall hemodynamic status with mitral regurgitation.^{11,133,144,176,177} With sudden development of mitral regurgitation due to chordal rupture, papillary muscle infarction, or leaflet perforation, left atrial compliance is normal or reduced. The left atrium is not enlarged, but the mean left atrial pressure (and the v wave) is elevated. 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, left atrial compliance increases and left atrial enlargement occurs. In patients with severe, long-standing mitral regurgitation, the left atrium is markedly enlarged, atrial compliance is increased, the atrial wall is fibrotic, but left atrial pressure is normal or only slightly above normal.¹⁷⁶ In this situation, pulmonary artery pressure and pulmonary vascular resistance usually still remain in the normal range or are only modestly elevated. Atrial fibrillation and a low cardiac output, however, can be present.

Pulmonary Changes

Because chronic mitral regurgitation is associated with left atrial enlargement and mild elevation in left atrial pressure, pronounced increases in pulmonary vascular resistance usually do not develop. In patients with acute mitral regurgitation with normal or reduced left atrial compliance, a sudden increase in left atrial pressure initially may modulate an elevation in pulmonary vascular resistance and acute right-sided heart failure.^11,133 Acute pulmonary edema occurs less frequently in patients with chronic mitral regurgitation than in those with mitral stenosis because a sudden increase in left atrial pressure is uncommon. Pulmonary vascular resistance is increased more often in patients with mitral stenosis than in those with mitral regurgitation due to the chronically high left atrial pressure. 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.¹⁷⁸ These patients also may have a positive response to methacholine challenge; this bronchial hyperresponsiveness may result from increased vagal tone due to chronic 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. Gradually, symptoms reflective of decreased cardiac output with physical activity and/or pulmonary congestion develop, such as weakness, fatigue, palpitations, and dyspnea on exertion. If right-sided heart failure appears, hepatomegaly, peripheral edema, and ascites occur and can be associated with rapid clinical deterioration.^96,98 With acute mitral regurgitation, pulmonary congestion and pulmonary edema are prominent. Clinically, acute papillary muscle rupture may mimic the presentation of a patient with a postinfarction ventricular septal defect.¹⁷⁹

On physical examination, the cardiac impulse in patients with mitral regurgitation is hyperdynamic and displaced to the left; the forcefulness of the apical impulse is indicative of the degree of LV enlargement. In patients with chronic mitral regurgitation, S₁ is usually 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.¹⁸⁰ An S₃ may be appreciated due to the increased transmitral diastolic flow rate during the rapid filling phase. The apical systolic murmur is blowing, moderately harsh, and radiates to the axilla and the inferior angle of the scapula, left sternal border, occasionally to the neck, and to the vertebral column.¹⁸⁰ With rupture of posterior leaflet first-order chordae, the mitral regurgitation jet is directed anteriorly and impinges on the atrial septum near the base of the aorta, which can produce a murmur prominent in the aortic area radiating to the neck.^180,181 In ruptured anterior leaflet first-order chordae, the leakage is aimed toward the posterior left atrial wall, and the murmur may be transmitted posteriorly. Although there is little 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.^180,182 Because of the relatively noncompliant left atrium in acute mitral regurgitation, the murmur is often early and mid-systolic.¹¹ In patients with the Barlow syndrome (severe bileaflet mitral billowing and/or prolapse) and mitral regurgitation, a characteristic mid-systolic click is heard followed by a late systolic murmur.

On chest radiography, cardiomegaly indicative of LV and left atrial enlargement is commonly found in patients with long-standing moderate to severe mitral regurgitation.^180,183 Acute mitral regurgitation often is not associated with an enlarged heart shadow and may produce only mild left atrial enlargement, despite an elevated left atrial pressure. Chest x-ray findings of congestive changes in the lung fields are less prominent in patients with mitral regurgitation compared with those with mitral stenosis, but interstitial edema is frequently seen in individuals with acute mitral regurgitation or those with progressive LV failure secondary to chronic mitral regurgitation.

Changes on the electrocardiogram are generally not reliable and depend on the etiology, severity, and duration of the mitral regurgitation.^105,180 Atrial fibrillation is a common finding late in the natural history of the disease. In cases of chronic mitral regurgitation, LV volume overload leads to left atrial and ventricular dilation and, eventually, some degree of LV hypertrophy. Evidence of LV enlargement or hypertrophy occurs in one half of patients; 15% have right ventricular hypertrophy due to increased pulmonary vascular resistance, and 5% have combined left and right ventricular hypertrophy.¹⁰⁵ Complex ventricular arrhythmias may be noted on ambulatory electrocardiogram recordings, especially in patients with LV systolic dysfunction. In acute mitral regurgitation, left atrial and/or LV dilation may not be evident, and the electrocardiogram may be normal or show only nonspecific findings, including sinus tachycardia or ST-T wave alterations.¹⁰⁵ Findings of myocardial ischemia or infarction, more commonly noted in the inferior leads, may be present when acute mitral regurgitation is related to ischemic heart disease; 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.^105,131,184 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.^128,131 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.¹³¹ Complex atrial arrhythmias may be present in upwards of 14% of patients, and complex ventricular arrhythmias are present in 30% of patients.¹²⁴ Age correlates with the incidence of complex atrial arrhythmias; female gender and anterior mitral valve thickening are predictors of complex ventricular arrhythmias.¹²⁴

Transthoracic echocardiography is used to follow accurately the progression of left atrial and LV dilation in patients with chronic mitral regurgitation.^{11,106,108,185,186} Echocardiography confirms enlargement of the chamber, and color flow Doppler examination of the mitral valve establishes the pattern, direction, and magnitude of regurgitant flow. Two-dimensional echocardiography identifies abnormalities of leaflet and chordal morphology and function, including myxomatous degeneration with or without leaflet prolapse, restricted leaflet motion and lack of adequate coaptation from rheumatic valvulitis (fused leaflets), ischemic heart disease, and leaflet destruction by endocarditis (Fig. 36-16). ^{11,107,126,187} Chordal rupture causing a flail leaflet is characterized by excessive motion of the leaflet tip beyond the normal coaptation point and mitral annular level into the left atrium. Papillary muscle rupture following myocardial infarction and annular dilation also can be visualized by echocardiography (Fig. 36-17).¹⁰⁷ Pulsed wave or continuous wave Doppler echocardiography tends to overestimate the severity of mitral regurgitation in patients with depressed LV ejection fraction and low cardiac output; it is extremely sensitive and specific in diagnosing mild or severe mitral regurgitation, but not as accurate in assessing moderate degrees of regurgitation.¹¹ The most commonly used method to assess the degree of regurgitation is echocardiographic Doppler color-flow mapping, which permits visualization of the origin, extent, direction, duration, and velocity of disturbed flow (regurgitant jet) within the left atrium.^107,185,186 In patients with LV dysfunction and FMR, apical leaflet tenting, leaflet tenting area, tenting height, and estimated ERO can be quantitatively measured.^145,146 Tenting is characterized by restriction of normal leaflet displacement towards the annulus during systole, with resultant mitral regurgitation (Fig. 36-18). The degree of systolic leaflet tenting is determined by apical and posterior papillary muscle displacement. Further, the degree of mitral regurgitation can be quantitatively measured by calculating mitral and aortic stroke volumes; regurgitant volume is the difference between these two stroke volumes. The ERO area is the ratio of regurgitant volume to regurgitant time-velocity integral. Additionally, examination of the proximal isovelocity surface area analyzes the proximal flow convergence below the valve leaflets as the blood accelerates towards the leaking site, and ERO is calculated as the ratio of regurgitant flow to regurgitant velocity.¹⁴⁵

View larger version (96K): [in this window] [in a new window]   FIGURE 36-16 Echocardiogram (long axis) of a patient with mitral regurgitation due to floppy mitral valve. The leaflets billow back into the left atrium during systole.

View larger version (110K): [in this window] [in a new window]   FIGURE 36-17 Echocardiogram (two-chamber view) of a patient with mitral regurgitation due to ruptured papillary muscle.

View larger version (89K): [in this window] [in a new window]   FIGURE 36-18 Echocardiogram of a patient with ischemic mitral regurgitation and apical systolic leaflet tenting.

Three-dimensional echocardiography continues to evolve and shows some promise in the assessment of congenital and acquired heart disease.¹¹⁰ This technique facilitates spatial recognition of intracardiac structures and has been validated experimentally. In patients with mitral regurgitation, three-dimensional echocardiography has been shown to be fairly accurate in elucidating the dynamic mechanisms of the mitral regurgitation leaks, but only offers qualitative information.

Cardiac catheterization and left ventriculography have been important in the assessment of mitral regurgitation in the past,^{11,103,150,183,191} but echocardiography has basically replaced the need for left-heart catheterization in the vast majority of patients. It usually is indicated only to determine coronary artery anatomy in older patients. The severity of mitral regurgitation can be estimated during left ventriculography by the degree of opacification of the left atrium and pulmonary veins (Table 36-1),¹⁹¹ but this is far inferior to echocardiographic imaging methods. Other techniques, such as calculating mitral regurgitant fraction, have many limitations (regurgitant volume is determined as the difference between total LV angiographic stroke volume and the effective forward stroke volume measured by the Fick principle). By measuring rest and (supine bicycle) exercise pulmonary artery pressures and cardiac outputs, left- and right-sided heart catheterization can occasionally be useful to identify patients with primary myocardial disease who present with LV dilation and relatively mild degrees of mitral regurgitation (who therefore may not have a high likelihood of benefiting from mitral valve surgery).

Postoperative Changes in Left Ventricular Function

Mitral regurgitation due to flail leaflet is frequently asymptomatic yet is associated with a risk of progressive LV dysfunction and a suboptimal natural history if not treated surgically. Treated medically, mitral regurgitation due to flail leaflet is associated with high annual mortality (6.3%) and morbidity rates.^195,196 In these patients, the strategy of early surgery after diagnosis is associated with improved long-term rates of survival and morbidity after diagnosis.

Successful mitral valve repair or replacement is generally associated with clinical improvement, augmented forward stroke volume with lower total stroke volume, smaller LV end-diastolic volume, and regression of LV hypertrophy.^197,198 Surgical correction of chronic mitral regurgitation can preserve LV contractility, particularly in patients with a normal preoperative ejection fraction who have minimal ventricular dilation. On the other hand, in patients with impaired preoperative LV contractile function, improvement in LV function may not necessarily occur after operation.¹⁹⁹ An LVESVI exceeding 30 mL/m² is associated with decreased postoperative LV function, which is proportional to the degree of elevated preoperative LVESVI.^166,199 Patients with chronic mitral regurgitation should be referred for mitral valve surgery when LVESVI is no higher than 40 to 50 mL/m²; when LVESVI exceeds 60 mL/m², a poor outcome is likely.¹⁶⁶ 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 predictor of LV systolic function and an accurate predictor of surgical outcome in patients with mitral regurgitation.^163,164 Specifically, an ESS/LVESVI less than 2.6 portends a poor medium-term prognosis; conversely, a normal or high ESS/LVESVI ratio is associated with a favorable outcome, suggesting that LV contractile function had been relatively normal preoperatively.¹⁶⁴ Other predictors of increased operative risk include older age, higher 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.^{140,166,197,199–210}

Regarding long-term outcome, identified 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 left atrial size, decreased LV wall thickness/cavity dimension at end systole, and associated coronary artery disease.^{166,202,207–209,211,212} Although coronary artery disease portends a higher incidence of late death, simultaneous coronary revascularization improves this prognosis.²⁰²

Mitral valve repair for patients with myxomatous mitral regurgitation is feasible in the large majority of patients and offers excellent early and late functional results.^{119,213–215} Because fewer complications and a lower operative mortality rate are associated with valve repair compared with valve replacement, operation should be considered earlier in the natural history of the disease if the pathological anatomy is judged favorable for valve repair.^{116,118,124,195,196,202,213,216–218} When preoperative LVESVI indicates the presence of advanced 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) at time of valve replacement.^116,219

IMR is associated with higher operative risk (9% to 30%) than nonischemic forms of chronic mitral regurgitation.^{140,197,198,200,201,220,221} This higher mortality rate reflects concomitant adverse consequences of previous myocardial infarction and ischemia on LV function. Valve repair should be considered in these patients when feasible because it can potentially reduce complications and improve long-term survival.^{140,200,220,222} In the Brigham and Women's Hospital experience, patients with IMR and annular dilation or restricted leaflet motion (not chordal or papillary muscle rupture) who underwent valve repair, however, had a worse long-term outcome than those who underwent valve replacement.²²¹ Therefore, the pathophysiology of the IMR was a strong determinant (more so than the type of valve procedure) of long-term survival. The NYU group showed higher complication-free survival rates of 64% at 5 years for patients undergoing mitral valve repair compared to 47% at 5 years for those undergoing valve replacement.²²² The analysis of the early mortality rates of patients undergoing mitral valve repair and those undergoing valve replacement for IMR was confounded by the variables of functional class and presence of angina. Excluding these two variables, further analysis showed that the early mortality rate was lower for patients undergoing valve repair compared to that of patients undergoing valve replacement.²²² In the Cleveland Clinic experience, in the "better-risk" group of patients with IMR, there was a survival advantage of the mitral valve repair group (58% at 5 years) compared to those who underwent valve replacement (36% at 5 years); however, in the most complex, high-risk cases, late survival rates after valve repair and valve replacement were similarly poor.²²³

In a recent Mayo Clinic report, the group of medically managed patients who developed IMR in the chronic phase after myocardial infarction had a considerably higher mortality rate (62% at 5 years) compared to those who sustained myocardial infarctions and did not develop IMR (39% at 5 years).¹⁴⁶ Medium-term survival for patients with IMR and LV dysfunction was inversely related to the ERO and regurgitant volume. At 5 years, the survival rate was 47% for patients with ERO less than 20 mm² and 29% for those with ERO 20 mm² or higher (Fig. 36-19). Survival rates at 5 years were 35% when the regurgitant volume was 30 mL or higher compared to 44% for regurgitant volume less than 30 mL.¹⁴⁶ The risk ratio of cardiac death for patients with IMR was 1.56 for patients with ERO less than 20 mm² and 2.38 for those with ERO higher than 20 mm².¹⁴⁶ Comparatively, in patients with organic mitral regurgitation, ERO higher than 40 mm² has been considered severe, presumably the result of different LV and left atrial function and compliance compared to those with IMR.²²⁴

View larger version (15K): [in this window] [in a new window]   FIGURE 36-19 Survival after diagnosis according to degree of mitral regurgitation as graded by effective regurgitant orifice (ERO) being 20 mm2 or higher, or less than 20 mm2. Numbers at bottom indicate patients at risk for each interval. (Reproduced with permission from Grigioni F, Enriquez-Sarano M, Zehr KJ, et al: Ischemic mitral regurgitation: long term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001; 103:1759.)

Even after mitral valve surgery, some patients continue to be limited by heart failure symptoms and have a less than optimal long-term postoperative course. The incidence of congestive heart failure in patients who survived surgery (combined series of valve repair and valve replacement) for pure mitral regurgitation was 23%, 33%, and 37% at 5, 10, and 14 years in the Mayo Clinic experience.²²⁵ Valve repair (vs. replacement) was not an independent predictor of a decreased incidence of congestive heart failure; however, using a combined end point of congestive heart failure and death, valve repair compared to replacement in patients with organic mitral regurgitation appeared to confer a survival advantage. Patient survival after the first episode of congestive heart failure was dismal, being only 44% at 5 years. Causes of congestive heart failure include LV dysfunction in two thirds of the patients and valvular dysfunction in the other third. Predictors of postoperative heart failure were preoperative ejection fraction, coronary artery disease, and functional class.²²⁵ Importantly, preoperative functional class III/IV symptoms are associated with markedly decreased postoperative medium- and long-term survival independent of all baseline characteristics.²²⁶ Because mitral regurgitation in these patients was associated with late manifestation of advanced LV dysfunction, it historically was thought that mitral valve surgery could not help those with pronounced LV dilation and severe global systolic dysfunction. On the other hand, Bolling et al reported favorable medium-term results after mitral valve repair using an undersized flexible annuloplasty ring with resultant decreased LV volume and sphericity and increased ejection fraction and cardiac output in a challenging patient population who had dilated or ischemic cardiomyopathy and congestive heart failure.²²⁷

The decline in ejection fraction after mitral valve replacement for chronic mitral regurgitation is believed to be a result of postoperative increase in afterload, which historically was thought to be secondary to closure of the low resistance "pop-off" into the left atrium. A spherical mathematical model of the left ventricle has been used to define the relations between LV end-diastolic dimension, systolic wall stress, and ejection fraction (Fig. 36-20).²²⁸ In patients undergoing mitral valve replacement, concordant echocardiographic data and mathematical model results indicate that postoperative changes in systolic stress are directly related to changes in chamber size and that LV afterload may actually decrease if chordal preservation mitral valve replacement techniques are used. In terms of exercise performance after mitral valve surgery for nonischemic mitral regurgitation, it has been shown that although the patients are symptomatically improved, cardiopulmonary exercise testing at 7 months actually was not better.²²⁹ Furthermore, abnormal neurohumoral activation (norepinephrine, plasma renin activity, aldosterone, atrial natriuretic peptide, and endothelin-1) persisted at 7 months postoperatively (Table 36-2). Plasma renin activity, aldosterone, and ANP decreased somewhat after surgery but were still elevated compared to control. Neurohumoral activation may contribute to the impairment of exercise performance in patients with heart failure by limiting exercise-induced vasodilation or by contributing to maldistribution of peripheral blood flow.²²⁹ The persistence of abnormal neurohumoral activation probably reflects incomplete recovery of LV contractility 7 months after surgery; whether or not this pathological state with exercise will thereafter return to normal is unknown.

View larger version (15K): [in this window] [in a new window]   FIGURE 36-20 Illustration using the preload reserve-afterload mismatch concept of John Ross, Jr., of the potential responses of the left ventricle after surgical correction of chronic mitral regurgitation by mitral valve replacement (MVR) with or without chordal preservation. Left ventricular end-systolic stress (LV afterload) is plotted on the vertical axis and LV end-diastolic dimension (LV preload) is on the horizontal axis. The curves relate ejection fraction (EF) to both LV preload and afterload: the lower curve represents a ventricle with a normal EF and the upper curve indicates one with a decreased EF. The average preoperative and postoperative values of end-diastolic dimension, end-systolic stress, and EF are plotted for two different patient groups who underwent MVR: group I (end-diastolic dimension declined after MVR, a salutary response) and group II (no postoperative reduction in end-diastolic dimension, an undesired response). Group I consisted of two subgroups: group Ia (MVR with chordal preservation) and Ib (MVR with chordal division). The optimal postoperative response—a decrease in chamber size, lower afterload, and preserved EF—occurred only in group Ia (closed circles), where some or all of the chordae to one or both mitral leaflets were preserved. Group Ib (MVR with chordal division) also had smaller ventricles postoperatively (open squares), but experienced no decline in LV afterload; therefore, the LV systolic pump performance deteriorated (moving to the lower EF curve postoperatively). Finally, LV chamber size did not change and LV end-systolic stress actually increased postoperatively in group II (MVR with chordal division), indicative of impaired LV ejection performance (lower EF). The salutary response in group Ia was due in part to chordal preservation during MVR; additionally, it is possible that these patients could have been referred earlier in the natural history of their disease. The less favorable response seen in group Ib could potentially have been prevented if the chordae had been preserved during MVR, or if the valve could have been repaired. Finally, the most deleterious post-MVR response observed in group II was due to chordal severing during MVR, very late surgical referral (after irreversible myocardial dysfunction had occurred), or both. Data are shown as mean ± 1 standard error. (Clinical data were extracted from Rozich JD, Carabello BA, Usher BW, et al: Mitral valve replacement with and without chordal preservation in chronic mitral regurgitation. Circulation 1992; 86:1718. Reproduced with permission from Goldfine H, Aurigemma GP, Zile MR, et al: Left ventricular length-force-shortening relations before and after surgical correction of chronic mitral regurgitation. J Am Coll Cardiol 1998; 31:180.)

Since the concept was originally proposed by Lillehei et al in 1964, the mitral subvalvular apparatus is recognized as an important functional component of LV systolic and diastolic performance.^{153,154,230–248} The subvalvular apparatus, including normal chordal and papillary muscle function, is necessary to maintain optimal postoperative LV geometry and optimize postoperative LV systolic pump function. After conventional mitral valve replacement with total chordal excision, a significant decline in LV performance occurs with depression of regional and global elastance, dysynergy of contraction, and dyskinesia at the papillary muscle insertion sites; conversely, after valve replacement with (total or partial) chordal preservation, LV contractile function is preserved.^{172,236–240,242,248} Differences in LV systolic function between patients undergoing mitral valve repair and those having valve replacement without chordal preservation are attributed to disruption of the subvalvular apparatus. In a porcine experiment, severing either the anterior or the posterior leaflet chordae was detrimental to global LV systolic function (reduced maximal elastance), but function returned to normal after chordal reattachment.²³⁹ The contributions of the chordae subtending the anterior mitral leaflet are slightly greater than (but additive to) the contributions of the posterior leaflet chordae.²³⁸

In a canine experimental model of chronic mitral regurgitation, Yun et al demonstrated that mitral valve replacement with chordal preservation optimizes postoperative LV energetics and ventriculo-vascular coupling in addition to enhancing systolic performance.¹⁵⁴ After chordal interruption, global LV end-systolic elastance and the end-systolic stress-volume relationship fell by 46% and 33%, respectively. In terms of myocardial energetics, the slopes of the LV stroke work–end-diastolic volume and pressure-volume area–end-diastolic volume relations declined significantly by 20% and 11% (indicating reduced external stroke work and mechanical energy generated at any given level of preload) after valve replacement with chordal excision. Chordal severing in dilated canine hearts (secondary to chronic mitral regurgitation) after valve replacement resulted in impaired LV systolic mechanics and decreased LV energetics and efficiency due to an exacerbated mismatch in ventriculo-vascular coupling between the left ventricle and the systemic arterial bed.¹⁵⁴

Mitral valve replacement with chordal division results in a decline in segmental LV systolic function, not only in the areas subtending papillary muscle insertion but also in remote LV regions.²³² Clinically, valve replacement with chordal transection is associated with reduced rest and exercise ejection fraction due in part to an increase in ESS.²⁴⁷ Mitral valve repair improves rest and exercise ejection indexes, primarily due to a marked reduction in ESS and maintenance of a more ellipsoidal chamber geometry. Additionally, mitral valve replacement with complete chordal transection caused no postoperative change in LV end-diastolic volume, an increase in LVESV, an increase in ESS (89 to 111 g/m²), and a decrease in ejection fraction (from 60% to 36%).²⁴⁶ Conversely, patients in whom the chordae tendineae were preserved during valve replacement had a smaller LV end-diastolic volume and LVESV, decreased ESS (from 95 to 66 g/m²), and unchanged ejection fraction (63% and 61%). These findings suggest that reduced chamber size, reduced systolic afterload, and preservation of ventricular contractile function act in concert to maintain ejection performance after chordal-sparing valve replacement procedures. Conversely, increased LV chamber size, increased systolic afterload, and probable reduction in chamber contractile function combine to reduce ejection performance after mitral valve replacement with chordal transection.²⁴⁶

The loss of ventricular function after mitral valve replacement with chordal division may be due to heterogeneity of regional LV wall stress, and not to local depression of regional contractile function.²⁴⁹ After valve replacement with chordal transection in an experimental canine preparation, outward displacement of the ventricular wall and transverse shearing deformation were observed in the LV region of papillary muscle insertion during isovolumic contraction.²⁴⁹ Circumferential and radial strains during ejection were maintained at the basal LV site and enhanced on the apical LV site. Chordal transection induced an unloading effect on the myocardium at the papillary muscle insertion site; the resulting heterogeneity of regional systolic function was felt to be the mechanism for reduced global LV function and slowed ventricular relaxation. Anterior chordal transection with mitral valve replacement impaired not only regional LV function, but also regional right ventricular function.²⁵⁰ Using radionuclide angiography before and after mitral valve repair, LV ejection fraction did not change and right ventricular ejection fraction improved. In contrast, LV ejection fraction decreased after valve replacement with anterior chordal transection, and right ventricular ejection fraction was unchanged. In the region of the anterior papillary muscle insertion, local LV contractile function was impaired after valve replacement; additionally, the right ventricular apicoseptal region was impaired.²⁵⁰

Summary

The functional competence of the mitral valve relies on the interaction of the mitral annulus and leaflets, the subvalvular apparatus, the left atrium, and the left ventricle. The etiology of pure mitral regurgitation is variable, including myxomatous degeneration or floppy mitral valve, FMR or IMR, and rheumatic valve disease. Reduced LV impedance in patients with mitral regurgitation allows a greater proportion of contractile energy to be expended in myocardial fiber shortening rather than in tension development. Because increased shortening is a smaller determinant of myocardial oxygen consumption than the other components, mitral regurgitation causes only small increases in myocardial oxygen consumption. The augmented preload in chronic mitral regurgitation eventually leads to LV dilation. After the initial compensatory phase, LV systolic contractility becomes progressively more depressed as chronic mitral regurgitation evolves. Preoperative LVESV or LVESVI is a good predictor of postoperative outcome in terms of LV systolic performance. Operation for symptomatic patients should be performed before severe, irreversible LV systolic dysfunction develops, especially if the pathological anatomy appears to favor valve repair.

The mitral subvalvular apparatus is recognized as an important component of LV ejection performance; an intact mitral subvalvular apparatus, including chordae to both leaflets, is necessary to maintain optimal postoperative LV geometry and optimize LV systolic pump function. After mitral valve replacement with chordal transection, which hopefully is not performed commonly today, a decline in LV systolic performance occurs with depression of regional and global LV myocardial elastance, dysynergy of contraction, and dyskinesia at the papillary muscle insertion sites. A large cascade of 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 if chordal-sparing valve replacement techniques are carried out.