A. Mitral valve anatomy (Fig. 5.1). The mitral valve (MV) consists of two leaflets—the anterior and posterior leaflets.

1. The anterior leaflet is triangular in shape and larger and thicker than the posterior leaflet, accounting for most of the closing surface area of the mitral orifice. Its broad surface is divided into anterior and posterior areas. The anterior leaflet attaches at its base to the mitral annulus in continuity with the aortic valve through the fibrous aortic-mitral curtain.

2. The posterior leaflet is crescent shaped and has a longer attachment to the mitral annulus, compared to the anterior leaflet. It is segmented into three scallops that are separated by clefts: segment 1 is anterolateral, segment 2 is in the middle, and segment 3 is posteromedial.

3. The anterior and posterior leaflets meet at two commissures: the posteromedial and anterolateral commissures. The mitral annulus is a C-shaped fibromuscular ring at the base of the left ventricle (LV) to which the MV leaflets attach. It has a three-dimensional (3D) saddle shape with its “lowest points” at the level of both commissures.

4. The chordae tendineae are thin fibrous structures that attach the leaflets to the two papillary muscles in the LV. Normal chordae vary widely in number and appearance, and are designated according to their insertion site on the leaflet.

a. Primary chordae (marginal chordae) insert on the free margins of the leaflets. They play a major role in leaflet coaptation and prevent prolapse.

b. Secondary chordae (basal or strut chordae) insert on the leaflets’ ventricular surface, providing structural support and preventing leaflet billowing.

c. Tertiary chordae insert on the mitral annulus and posterior leaflet base and also contribute to leaflet structural support.

d. Of note, there are also commissural chordae (distinct from the leaflet chordae), which insert into the free margins of the two commissures.

5. The papillary muscles (anterolateral and posteromedial) originate from the LV free wall between the apex and middle third of the ventricular cavity. The anterolateral papillary muscle has usually two heads, anterior and posterior, whereas the posteromedial papillary muscle usually has three heads, anterior, intermediate, and posterior.

Anatomic variations in papillary muscle anatomy, including their origin, shape, and number of heads, have important pathologic consequences. For instance, anterior displacement of the papillary muscles may cause leaflet slack and increased residual leaflet length, which may have an impact on the production of systolic anterior motion.

The posteromedial papillary muscle has a single blood supply usually from the posterior descending artery, whereas the anterolateral papillary muscle is supplied by both the left anterior descending artery and left circumflex artery. Because of differences in blood supply, the posteromedial papillary muscle is more vulnerable to rupture than the anterolateral papillary muscle in the setting of myocardial infarction.

B. Surgical classification. A segmental anatomy of the mitral leaflets proposed by Carpentier helps with the description of the localization of specific MV lesions. Because the posterior leaflet is naturally segmented by clefts at the free edge into three scallops, the Carpentier classification divides the posterior leaflet into three corresponding segments (P1, P2, and P3) from lateral to medial (P1 is the most lateral and P3 is the most medial). The anterior leaflet (devoid of clefts) is then also divided into three segments (A1, A2, and A3) that are opposing each of the corresponding posterior scallops (the segment opposing P1 is A1, the segment opposing P2 is A2, and the segment opposing P3 is A3)—see Figure 5.2.

In most cases, transthoracic echocardiography (TTE) is sufficient to visualize all three segments and the commissures; however, in some instances, advanced echocardiographic techniques (3D echocardiography [3D echo] and transesophageal echocardiography [TEE]) are required for a better understanding of the MV anatomy, especially when surgery is contemplated.

A. Pathoanatomy (Fig. 5.3). The pathologic causes of mitral regurgitation (MR) can be classified anatomically as follows:

1. Leaflet abnormalities, which in turn may be subclassified into:

a. Annular dilation from left atrium (LA) or LV enlargement with resultant loss of adequate leaflet coaptation.

b. Mitral annular calcifications causing restricted motion of the annulus and loss of its sphincter activity.

a. Chordal elongation and in severe forms chordal rupture (flail) due to myxomatous degeneration as seen in MVP.

b. Chordal fibrosis and calcification as may occur in rheumatic heart disease.

a. Displacement and hypertrophy of the papillary muscles, contributing to systolic anterior motion in hypertrophic cardiomyopathy.

b. Rupture as may occur in the setting of myocardial infarction.

c. Dysfunction, usually from an ischemic insult.

5. Left ventricle abnormalities. The LV can contribute to MR through two major mechanisms:

MR burdens the LV with an excessive volume load that leads to a series of compensatory adjustments that vary during the course of the disease. The impact of MR is determined by the magnitude of the regurgitant volume (ReVol) and the time course of development of the regurgitation.

1. Acute mitral regurgitation. There is a sudden increase in preload (LV end-diastolic volume) because of the ReVol returning from the LA. The ventricle utilizes its preload reserve, and the Frank-Starling mechanism contributes to an increase in the total stroke volume. The normal LV compliance (the LV did not have time to accommodate) limits the increase in end-diastolic volume to a modest rise. Therefore, a significant increase in LV filling pressures occurs. LV afterload (wall stress) is decreased as most of the blood is ejected into the lower resistance LA. The increase in LV preload and the decrease in afterload result in increases in ejection fraction (EF) and total stroke volume. Forward cardiac output declines, however, because much of the flow is directed to the LA. The major burden and threat is to the pulmonary venous circulation and the lungs, leading to pulmonary edema. Although most patients require urgent surgery, some evolve into a chronic state.

2. Chronic mitral regurgitation. The natural history of chronic MR can be divided into three stages: an early compensated stage during which most patients remain free of symptoms, a transitional stage where there is progressive and adverse LV remodeling, and ultimately the decompensated stage marked by the development of symptoms. The progression may be insidious; thus, it is extremely important to identify deleterious LV changes and recommend surgical intervention prior to the development of irreversible LV damage.

a. Compensated stage. Chronic volume overload leads to progressive LV enlargement. Eccentric hypertrophy develops as new sarcomeres are added “in series.” Systolic wall stress is normalized as a consequence of the hypertrophy. During this compensated stage, both contractility and EF are normal, but total stroke volume is increased as a result of the increased end-diastolic volume.

b. Transitional stage. Structural and functional remodeling of the ventricle occurs and compensatory mechanisms start to fail. There is progressive increase in the ReVol and a decrease in LV contractile function with an increase in wall stress. EF starts declining below 60%, but usually remains above 50%. This phase is difficult to identify clinically because most patients are asymptomatic. In such cases, an elevated B-type natriuretic peptide or abnormal echocardiographic strain pattern may raise the concern for latent ventricular dysfunction. Surgical intervention at this point may lead to a “paradoxical” worsening of the EF because the low-resistance “pathway” to the LA is no longer available and the LV must eject all its blood against the higher resistance normal pathway (aorta).

c. Decompensated stage. There is substantial and progressive LV dilation leading to a depressed myocardial state (with increased LV diastolic pressures) and increased wall stress (increased afterload). As a consequence, there is a decline in the EF below 50%. At this stage, these deleterious changes often preclude an optimal result after surgical correction of the regurgitation.

The clinical manifestations of MR, symptoms, physical examination findings, and electrocardiographic or radiographic changes are mainly determined by the rapidity of MR development.

1. Signs and symptoms: Patients with acute severe MR usually present in cardiogenic shock with the sudden onset and rapid progression of pulmonary edema (leading quickly to dyspnea at rest and marked orthopnea) and hypotension (with signs of poor perfusion: peripheral vasoconstriction, pallor, and diaphoresis). It is frequently a cardiac emergency; patients are severely ill and require urgent medical and surgical treatment. The presentation may be less dramatic if acute MR is superimposed on chronic MR. In this case, patients will note a marked worsening of their symptoms with sudden increase in their shortness of breath, dyspnea on exertion, fatigue, and weakness.

2. Cardiac exam: The arterial pulse is usually rapid and of low amplitude (decreased forward output) with a hyperdynamic cardiac impulse. On auscultation, the systolic murmur is often short and soft owing to the rapid equilibration of pressures between the LV and LA. An S₃ is often present.

3. Electrocardiography: ECG findings are nonspecific; however, the ECG may reveal the etiology of the acute MR (myocardial infarction, for example).

4. Chest radiography: Typically, there is evidence of bilateral pulmonary edema with a normal cardiac silhouette.

1. Signs and symptoms: Patients may remain asymptomatic for years despite severe MR. Symptoms will develop with the occurrence of:

a. LV failure with progressive increments in the ReVol and chamber size. The LV compensatory mechanisms will ultimately fail with further increase in LV size and reduction in LV contractile function with resultant congestive heart failure. Exercise intolerance and dyspnea on exertion usually occur first, then as the MR progresses, further symptoms will manifest.

b. Atrial fibrillation due to the dilated LA. Paroxysmal or persistent atrial fibrillation is common and may be the initial presentation of chronic MR.

c. Pulmonary hypertension. The progressive chronic increase in LA pressure may affect the pulmonary circulation leading to secondary pulmonary hypertension with resultant right ventricular (RV) failure, manifesting with elevated jugular venous pressure, peripheral edema, and hepatomegaly.

a. The apical impulse is displaced to the left secondary to LV enlargement.

b. Heart sounds: S₁ is diminished (mitral leaflets do not close properly) and an S₃ is usually heard (LV enlargement and/or failure).

c. Murmur: Most commonly, the murmur is holosystolic, heard best at the apex and radiating to the axilla. Its characteristics (timing, duration, quality, intensity, location, and radiation) vary with the etiology of MR. It may be distinguished from other systolic murmurs by the following:

There is modest correlation between the grade of the murmur and the severity of regurgitation. This correlation is better in primary rather than secondary MR.

3. Electrocardiography: Although nonspecific, common features include LA enlargement, atrial fibrillation, LV hypertrophy, and, in the event of secondary RV failure, RV hypertrophy.

4. Chest radiography: Cardiomegaly (from LA and LV enlargement) is typically seen. Pulmonary edema may manifest with progressive LV failure.

A practical classification of the etiologies of MR is shown in Figure 5.4.

A. Acute MR. There are two major mechanisms of acute MR:

1. Nonischemic: affecting the leaflets and/or chordae.

a. Ruptured mitral chordae leading to a “flail” leaflet. This can occur spontaneously but also can be seen in patients with:

b. Leaflet perforation from infective endocarditis.

2. Ischemic: mainly affecting the papillary muscles

a. Papillary muscle rupture due to acute myocardial infarction (MI), with rupture of the posteromedial muscle being more common because of its single
blood supply. Of note, acute MI can also lead to chordal rupture, and there are described cases of papillary muscle rupture as a result of cardiac trauma.

b. Papillary muscle infarction in the setting of acute MI (without necessary rupture) can also lead to acute MR.

c. Acute ischemia can cause transient LV dysfunction/dilation with resultant papillary muscle displacement and subsequent MR. This is often termed “reversible IMR” because prompt correction of the ischemic substrate will typically correct the MR.

B. Chronic mitral regurgitation. In chronic MR, it is important to distinguish between primary and secondary MR.

1. Primary mitral regurgitation: Valve incompetence is caused by pathology of at least one of the components of the MV (leaflets, chordae tendineae, papillary muscles, annulus). Etiologies include:

a. Mitral valve prolapse: also called degenerative or myxomatous MV disease. It is recognized as the major cause of MR in developed countries.

b. Infective endocarditis: valvular insufficiency results from infection-induced valvular damage.

c. Mitral annular calcification: common finding in the elderly. Calcification of the mitral annulus increases with age and is often associated with mild-to-moderate MR. It is rarely the cause of severe MR.

d. Rheumatic heart disease: more common in developing countries. While it usually causes mitral stenosis in adults, rheumatic heart disease often causes MR in children.

e. Valvular involvement in connective tissue disorders (e.g., systemic lupus erythematosus). This often progresses over time as acute inflammation of the valve, with disease episodes leading to scarring, leaflet retraction, and impaired coaptation.

f. Congenital MR: due to a cleft valve, for example.

g. Drugs: mainly anorectics (especially the combination of fenfluramine and phentermine called fen/phen) but also ergot derivatives and drugs used in the treatment of Parkinson disease. The mechanism seems related to increased serotoninergic activity with resultant increase in fibrosis at the valvular level.

2. Secondary mitral regurgitation: This is also referred to as functional MR because the MV anatomy is usually grossly normal, though histologic and biochemical abnormalities have been reported. MR in that case is caused by annular enlargement secondary to LV dilation and/or papillary muscle displacement secondary to LV remodeling.

Secondary MR is the most common valve disease, with ischemic heart disease accounting for approximately one-third of cases. It can thus be divided into IMR and nonischemic MR (NIMR).

a. Ischemic mitral regurgitation includes a spectrum of disorders comprising chronic MR post MI, acute MR with acute MI, and reversible MR as a result of myocardial ischemia.

b. Nonischemic mitral regurgitation is the form of MR found in all types of nonischemic cardiomyopathy, including DCM, restrictive cardiomyopathy, and hypertrophic cardiomyopathy. NIMR can also be secondary to RV pacing and atrial fibrillation.

i. Dilated cardiomyopathy: MR is due to annular dilation with displacement of the papillary muscles, which migrate laterally as the LV becomes more spherical with remodeling. The MR will increase the load on the LV and lead to its further dilation, which will worsen the MR—thus the saying “MR begets MR.”

ii. Restrictive cardiomyopathy: The mechanism of MR depends on the etiology. For instance, in amyloidosis, the valve itself may be involved
by amyloid deposition. In addition, severe LA enlargement (frequent in amyloid heart disease) can lead to annular dilation. In contrast, MR in Loeffler endocarditis (hypereosinophilic syndrome) is due to scarring and fibrosis of the chordae tendineae.

iii. Hypertrophic cardiomyopathy: MR in this case is multifactorial: altered geometry of the LV, systolic anterior motion of the anterior leaflet, and anatomic abnormalities of the leaflets and chordae tendineae.

iv. Right ventricular pacing: RV pacing leads to dyssynchronous contraction of the left and right ventricles. This dyssynchrony may alter the optimal functioning of the papillary muscles and lead to MR that can be severe.

v. Atrial fibrillation: Although the most common scenario is MR leading to atrial enlargement with secondary atrial fibrillation, long-standing atrial fibrillation on its own may lead to MR. The proposed mechanism is the following: long-standing atrial fibrillation results in an enlarged LA with subsequent significant mitral annular dilation. The stretched mitral annulus prevents adequate leaflet coaptation, which results in functional MR. Restoration of sinus rhythm in these patients may lead to a reduction in atrial size and annular dilation with resultant improvement in the degree of regurgitation.

A. Epidemiology. MVP is the most common cause of chronic primary MR in developed countries, accounting for over 50% of cases. Its prevalence varies among studies depending on the criteria used for diagnosis. Using the currently accepted definition of MVP, the overall prevalence is 2.4%, with equal occurrence in men and women.

B. Definition. Prolapse of the MV is defined as an abnormal systolic displacement (systolic billowing) of one or both leaflets into the LA. Based on the current echocardiographic criteria, MVP is diagnosed when either or both leaflets are displaced 2 mm or more in systole above a line connecting the annular hinge points in a long-axis view (parasternal or apical long axis). A long-axis view is required because even normal leaflets may appear to break the annular plane in other imaging views, owing to the 3-D saddle-shaped anatomy of the MV.

C. Pathology. MVP results from myxomatous degeneration of the MV, which is characterized by abnormal accumulation of mucopolysaccharides, leading to excessive leaflet tissue with elongated chordae prone to rupture. A wide spectrum of pathologic changes are observed with two relatively distinct ends but considerable overlap.

1. Classic MVP or Barlow disease: Commonly seen in younger patients, this is characterized by severe myxomatous degeneration. The leaflets are markedly thickened (≥5 mm) and diffusely redundant with prolapse of most of the segments. The chordae are elongated and thickened, and the annulus is typically dilated.

2. Nonclassic MVP or fibroelastic deficiency: Typically seen in older patients, this is characterized primarily by chordal rupture (from lack of connective tissue) with resultant leaflet displacement. Usually, only one segment (most commonly P2) is involved. The leaflets are thin and moderately redundant with a mildly enlarged annulus.

Note: There is a pseudo MVP form: Pseudo MVP is seen when there is a disproportion in the size of the valve leaflets to the LV cavity size. Thus, this may occur in conditions where the LV size is relatively small such as in atrial septal defect or may occur in adolescents with morphologic changes in growth. The leaflets are not thickened but may appear to prolapse in some views and often normalize over time.

D. Classification. MVP may be classified into sporadic MVP, familial MVP, and MVP associated with connective tissue disorders.

1. Sporadic: Many cases of MVP are sporadic with no other family member affected and no identifiable connective tissue disorder. It may be accompanied by myxomatous degeneration and prolapse of other valves, particularly the tricuspid valve.

2. Familial: In this form, the inheritance is considered to be autosomal dominant with variable penetrance. Three loci have been identified in extended families with multiple affected members, mapped to chromosomes 11, 13, and 16.

3. Associated with connective tissue disorder: MVP is common in patients with Marfan, Ehlers-Danlos, Loeys-Dietz, and osteogenesis imperfecta syndromes.

1. Symptoms: Most patients are asymptomatic. The diagnosis is usually suspected from cardiac auscultation and then confirmed by echocardiography. When MVP is complicated by significant MR, symptoms due to valve insufficiency are present. Atypical chest pain is common among patients with MVP, the mechanism of which is unknown. A constellation of other symptoms including fatigue, orthostatic hypotension, palpitations, syncope, panic attack, and anxiety were thought to occur more frequently in patients with MVP and were known as the “MVP syndrome.” However, newer studies using the current updated definition of MVP have suggested that these symptoms are no more common in true MVP than in the rest of the population.

2. Physical exam: The typical auscultatory features of MVP are the nonejection click and the murmur of MR.

a. The click is thought to result from stretching of the redundant leaflets and chordae. It is mid-systolic to late-systolic and dynamic.

b. The murmur is absent if prolapse does not lead to regurgitation. When MR is present, the murmur is typically late-systolic early in the course of the disease, and then becomes holosystolic with severe prolapse. Its maximal intensity and radiation vary with the direction of the jet: a posteriorly directed jet from anterior leaflet prolapse may be well appreciated at the back.

c. Effect of diagnostic maneuvers: Certain maneuvers can produce dynamic changes in the auscultatory findings of MVP.

i. Maneuvers that reduce venous return and decrease the LV volume, such as standing or the Valsalva maneuver, lead to earlier occurrence of the prolapse, causing the systolic click to occur earlier and the murmur to become longer in duration.

ii. On the other hand, maneuvers that increase venous return (leg raising or lying down) or afterload (squatting or isometric handgrip) delay the occurrence of the prolapse, causing the click to occur later and the murmur to be shorter in duration.

F. Complications. Although commonly a benign condition, MVP is associated with significant complications that are more likely to occur in men. These complications can be grouped into arrhythmic and nonarrhythmic.

a. Sudden cardiac death (SCD): MVP appears to be associated with a low but higher than average rate of SCD. It is presumably attributed to ventricular arrhythmias; however, some studies have suggested that it may be directly related to MR, rather than MVP itself. Risk factors include significant MR, more severe myxomatous changes in the valve tissue, and decreased LV function. Despite this, no specific recommendations for risk stratification have been defined, and the role for electrophysiologic testing in these patients has not been established.

b. ECG abnormalities: Multiple electrical abnormalities have been reported in MVP: flattening or inversion of the T wave, QT prolongation, and false-positive ST-segment depression in response to exercise. These findings, however, are not supported by all studies.

c. Arrhythmias: While arrhythmias may be more common in MVP patients who develop MR, it is unclear whether their incidence is higher in patients without valvular regurgitation.

a. Mitral regurgitation: Myxomatous degeneration of the leaflets and chordae leads to loss of MV competence with resultant MR. The majority of MVP patients have mild MR; significant MR occurs in approximately 2% to 7% of cases. However, once regurgitation occurs, it may be progressive over time and needs to be followed closely.

b. Infective endocarditis: Patients with MVP are at higher risk for infected endocarditis; however, the absolute risk is low and the new valvular guidelines no longer recommend antibiotic prophylaxis for patients with MVP either with or without MR unless the patient has suffered a previous bout of endocarditis. Risk factors for infected endocarditis include age (>45 years), male gender, presence of a systolic murmur, and more severe myxomatous changes in the valve tissue.

c. Cerebrovascular accident (CVA): Data are conflicting—it appears that the risk of CVA is increased in patients with complicated MVP (by MR and atrial fibrillation in particular) or those with comorbidities, but the risk is low in young people with uncomplicated MVP.

A. Definition. While MR can occur in the acute setting of myocardial ischemia/infarction as previously discussed, the term ischemic mitral regurgitation (IMR) is commonly used to describe chronic postinfarction MR. It is the most common form of secondary MR. It is considered secondary, or functional, because the mechanism of MR is largely ventricular rather than valvular.

B. Mechanism. Various processes have been implicated in the pathophysiology of IMR (Fig. 5.5) including LV remodeling with resultant papillary muscle displacement and mitral annular dilation, LV dyssynchrony including papillary muscle dyssynchrony, and impaired LV contractility leading to alteration in the forces required for appropriate
MV closure. The relative importance of each of these processes depends largely on the distribution of coronary artery disease:

1. In the setting of inferior MI, typically caused by right coronary or left circumflex artery disease, the resultant inferobasal wall motion abnormalities lead to tethering of the posteromedial papillary muscle. This causes a restricted motion of the posterior leaflet and subsequently a posteriorly directed jet of MR.

2. In the setting of anterior MI, typically caused by left anterior descending artery disease, alterations in LV geometry—mainly spherical remodeling—and decreased LV contractility lead to papillary muscle displacement and affect the tension exerted on the leaflets. This results in apical tenting of the MV leaflets with failure to close completely.

C. Dynamic nature of ischemic mitral regurgitation. The severity of IMR changes with varying loading/hemodynamic conditions: for instance, exercise, hypertensive crisis, and other stressors may induce dynamic changes in LV wall motion contractility and geometry, with resultant worsening of MR. Stress echocardiography may uncover more severe MR in these circumstances. Conversely, the severity of IMR may be underestimated in the operating room: sedation and anesthesia decrease LV afterload and inotropic medications increase LV contractility, both resulting in better mitral coaptation and less MR. Thus, IMR should be evaluated in the preoperative setting under normal loading conditions.

D. Prognosis. IMR portends a poor prognosis. It is associated with increased mortality (even a mild degree of MR in the setting of ischemic heart disease affects survival negatively) as well as increased risk of developing heart failure. In fact, studies have shown that patients who develop MR following MI had higher mortality. IMR was also an important predictor of the development of heart failure, even in patients with a normal LV ejection fraction (LVEF) at the time of the MI. It is unclear whether the MR by itself causes the poor outcome, as its surgical correction at the time of coronary artery bypass grafting has little effect on survival.

Outcome studies in IMR have shown poorer prognosis with effective regurgitant orifice (ERO) ≥20 mm². For this reason, the 2014 valvular guidelines adopted an ERO ≥20 mm² to define severe secondary MR as opposed to the cutoff of ERO ≥40 mm² used to define severe primary MR.

A. Introduction. NIMR in DCM is one of the most common forms of functional or secondary MR; some degree of functional MR is almost always present in patients with severe DCM, regardless of the etiology.

B. Pathophysiology. In functional MR, a primary ventricular pathology leads to development of regurgitation through an anatomically normal valve. The mechanisms involved are: