Pathophysiology of Mitral Valve Disease

LEARNING OBJECTIVES

Recognize abnormalities of the mitral valve that lead to a disease state.
Describe how abnormalities of the mitral valve cause pathology.
Predict the outcomes of patients with each mitral valve pathology.
Differentiate functional, primary, and mixed pathology.

INTRODUCTION

Understanding the normal structure and function of the components of the mitral apparatus is key in understanding the resultant pathophysiology when these components, or their interaction with one another, is disrupted. Therefore, we will review the normal physiologic function of the annulus, leaflets, chordae tendineae, and papillary muscles. We will then discuss the two broad categories of mitral valve pathophysiology: Mitral Valve Regurgitation and Mitral Valve Stenosis. Thereafter, we will discuss sequalae of mitral valve disease followed by special populations of mitral valve disease including pregnancy and congenital syndromes.

NORMAL MITRAL VALVE PHYSIOLOGIC FUNCTION

The mitral valve is a dynamic valve whose orifice and shape change during the cardiac cycle. The integrity and synchronized interaction of the components of the mitral valve apparatus: annulus, leaflets, chordae tendinea, and papillary muscles are necessary for normal function.

Annulus

Part of the cardiac skeleton, the annulus is a ring of fibrous tissue that anchors the mitral valve at the intersection of the left atrium (LA), left ventricle (LV), and the mitral leaflets. The anterior portion of the annulus, circumscribed by the left and right fibrous trigones, is contiguous with the left coronary and part of the non-coronary cusps of the aortic annulus, and correlates with the pommel in the saddle-shape analogy, making it the highest or most atrial portion of the annulus ( Fig. 2.1 ). This portion of the annulus is more fibrous and is connected to the aortic annulus by the aortic mitral curtain, or a rigid span of fibrous tissue, also known as the intertrigonal region. The anterior portion of the annulus is more fibrous compared to the more muscular posterior portion, making it less prone to dilatation. The lowest point of the annulus, or the seat of the saddle, is located just posterior to the commissures. The posterior portion of the annulus corresponding to the cantle is more loosely attached to the cardiac skeleton and may play a role in the shape-shifting that has been observed in recent studies using the 3D echocardiography.

During diastole, the mitral valve takes on a large, circular shape creating a negligible pressure gradient between the LA and LV facilitating passive left ventricular filling. Advanced imaging in recent studies of healthy subjects has revealed an average mitral annular area of ~10 cm ² , which is significantly larger than the widely accepted “normal” mitral annular area of 4 to 6 cm ² . During systole, the mitral valve must hold the gates against the contractile forces of the LV giving the left ventricular volume only one exit, maintaining forward stroke volume (SV) and cardiac output (CO). Valve closure and leaflet coaptation occurs in early-systole, during iso-volumetric contraction, due to anteroposterior contraction accentuating the saddle-shape.

Leaflets

A continuous sheet of tissue extending from the annulus, the mitral valve leaflets are divided into anterior, posterior, and commissural parts. The anterior and posterior commissures divide the valve into anterior and posterior leaflets. The anterior leaflet is dome-shaped, longer, and thicker than the crescent-shaped posterior leaflet which has a shorter radial length though encompasses a greater circumferential distance of the annulus, approximately 5 cm compared to 3 cm. Some degree of redundant leaflet tissue is necessary for effective coaptation. The normal ratio of the area within the annulus to the area of the leaflet tissue is 1.5 to 2.0. Both anterior and posterior leaflets are described as having three corresponding scallops progressing numerically from anterior to posterior, though only the posterior leaflet has physical demarcations.

As there are variations in tissue characteristics between anterior and posterior leaflets, there are variations in tissue characteristics within each leaflet with the central portion being thinner and parachute-like, the clear zone. The free edges, or coaptation region, are thicker, hydrophilic, protein-rich, and deemed the rough zone and are the primary area of chordae attachment. The area of leaflet attachment to the annulus is termed the basal zone. Mitral valve leaflets are composed of four histologic layers: (1) atrialis –atrial surface primarily aligned elastic/collagen fibers; (2) spongiosa –next layer, predominates in clear zone, extracellular matrix of proteoglycans, glycosaminoglycans, and elastic fibers; (3) fibrosa –strength layer composed of aligned collagen fibers forming central structural collagenous core; and (4) ventricularis –ventricular surface layer of contiguous endothelial cells with elastic and collagen fibers. Both leaflets contain muscle tissue near the annulus which resembles atrial myocardial cells. This tissue is excitable from the atrial side and may contract prior to LV contraction. It has been postulated that this early “leaflet” contraction may be crucial in preventing regurgitation during iso-volumetric contraction of the LV.

Chordae Tendineae

Chordae tendineae arise from the anterolateral (AL) and posteromedial (PM) papillary muscles and insert onto the leaflets. ^, They are divided into three types defined by their area of attachment. Primary chords attach to the rough zone, or the coaptation region, of both leaflets and are responsible for leaflet apposition. Secondary chords attach throughout the body of the leaflet and are said to contribute to normal ventricular geometry. Strut chords are the largest and strongest and attach the tip of each papillary muscle to the body of the anterior leaflet. Tertiary chords connect the base of the posterior leaflet directly to the ventricular wall.

The function of the chordae has been controversial. Flail, inversion of the leaflet edge into the atrium, is prevented by the thinner, less elastic, primary chords, also known as marginal chords. Secondary chords, or basal chordae, are larger and more elastic, and serve to transfer loads to the leaflets while protecting the primary chords from this load bearing.

Papillary Muscles

There are typically two large papillary muscles arising from the apical one-third of the LV. The chords attach to these AL or PM papillary muscles. There is, however, considerable variation in papillary muscle anatomy, which explains numerous variations in the number of heads arising from each papillary muscle, as well as the blood supply to each described in the literature. ^, ^, The AL papillary muscle usually has a single head and a dual blood supply from the left circumflex and left anterior descending coronary arteries. The PM papillary muscle usually has two heads and a single blood supply from either the right or circumflex coronary artery.

Papillary muscles function synchronously with ventricular contraction and leaflet motion to maintain a relatively constant length of the chordae, or distance between the papillary muscles and the leaflets. During early systole, longitudinal ventricular contraction moves the entire papillary muscle closer to the annulus. At this same time, the mitral leaflets are moving atrially. Thus, the distance between the papillary muscles and leaflets remains relatively constant. Later during systole, isolated papillary muscle contraction increases the distance from the tip of the papillary muscle to the annulus and closing leaflets. This creates tension on both leaflets and holds them posteriorly, preventing systolic anterior motion (SAM) and left ventricular outflow tract (LVOT) obstruction. Maintaining the equestrian analogies, one might describe the function of the papillary muscles as that of a skilled rider’s arms maintaining the reins (chordae) at a constant length so as not to allow the reins to go slack and taught causing overdue and abrupt impact on the horse’s mouth. Using this analogy, one can imagine how discoordination of this complex interaction may result in chordal rupture as the slack chordae suddenly take on the force of LV contraction.

MITRAL REGURGITATION

Let us start by exploring Carpentier’s classification which will serve as a guide to describe the structural pathology that results in mitral regurgitation ( Fig. 2.2 ). The French cardiac surgeon, Alain Carpentier so eloquently and humbly described his functional classification at the 1983 meeting of the American Association of Thoracic Surgery (AATS). Per Carpentier, “there are only two functional anomalies: the opening and closing motions of each leaflet are either increased as with leaflet prolapse or diminished as with restricted leaflet motion ( Fig. 2.3 ).

Fig. 2.3, Carpentier’s Physiopathological Classification.

Carpentier Type I

The Carpentier classification focuses primarily on leaflet position relative to the mitral annular plane. In Carpentier Type I, leaflets have normal opening and closing motion. Primary mitral regurgitation, defined as deriving from the mitral valve apparatus, can occur due to leaflet perforation or cleft. Leaflet perforation can be iatrogenic from interventional procedures. Endocarditis of the mitral valve or direct extension of endocarditis of the aortic valve via their shared fibrous trigone can also result in leaflet perforation.

Leaflet Perforation

Leaflet perforation may be iatrogenic, secondary to trauma, or occur due to infective endocarditis, inflammation of the endocardial lining secondary to infection. Endothelial damage, most commonly affecting the valve leaflets, is followed by thrombotic vegetations which then provide a substrate for bacterial colonization similar to a petri dish. Invasion, usually starting from the coaptive surface, damages leaflet and chordal tissue, and among its many detrimental effects are aneurysm formation and leaflet perforation.

Libman-Sacks endocarditis refers to the sterile fibrin-platelet thrombi vegetations and inflammatory valvular changes which are one of the cardiac manifestations of systemic lupus erythematosus (SLE). It is sometimes also referred to as non-bacterial thrombotic endocarditis (NBTE) or “marantic” endocarditis, and in addition to SLE is associated with malignancy, most commonly adenocarcinoma. The latter term comes from the associated wasting, or cachexia, that can be seen in these patients. Libman-Sacks most commonly affects the mitral valve, followed by the aortic valve. Vegetations differ from the mobile, narrow base of their infectious counterpart in that they are characteristically immobile and sessile. This condition is usually not of hemodynamic significance; however, may manifest as acute or chronic mitral regurgitation (MR). It has also been associated with cerebrovascular and peripheral arterial embolism, cognitive dysfunction, superimposed infective endocarditis, and need for high-risk valvular surgery. Libman-Sacks endocarditis is included here as it has been implicated in several reported cases of leaflet perforation.

Mitral Valve Clefts

Mitral valve clefts are deep, congenital indentations in the leaflet extending to the annulus. They are a rare cause of MR which prior to three-dimensional echocardiography (3DE) were almost always found in association with congenital heart disease. The anterior mitral leaflet is formed by the fusion of the superior and inferior atrioventricular (endocardial) cushions. It makes sense then that cleft mitral valves have been most often associated with endocardial cushion defects such as atrioventricular (AV) canals and ostium primum atrial septal defects (ASDs). , Mitral valve clefts may also occur in the posterior leaflet not associated with other congenital defects.

Annular Dilatation

Secondary mitral regurgitation in Carpentier Type I occurs due to an increased annular area or annular deformation resulting in a larger, flatter annulus, and loss of its saddle-shape configuration. The annulus of the mitral valve is dynamic with left atrial contraction reducing presystolic area, facilitating early leaflet motion and adequate coaptation. When this atriogenic contraction is non-functional, equivalent reduction of annular area is possible via ventricular contraction; however, this is delayed and results in increased MR. Conditions which lead to an increase in mitral annular area include: left atrial dilation and non-ischemic/dilated cardiomyopathy. Atrial fibrillation alone usually results in mild MR due to isolated annular dilation, but can cause more severe MR depending on the degree of left atrial dilation. In patients with atrial fibrillation, severe tricuspid regurgitation is more common than severe MR due to the more robust fibrous skeleton of the mitral annulus better resisting significant dilation. Interestingly, Gertz et al. found that successful ablation led to decreased LA and annular dimensions with associated decrease in MR. However, in patients with recurrent atrial fibrillation, there was no significant change in annular dimensions despite decreased LA size, suggesting a primary annular association. Secondary MR is derived not from the mitral apparatus, but from the LV or LA.

Diastolic Mitral Regurgitation

Diastolic MR is a rare form of functional MR which can be observed with or without structural heart disease. There is normally a negative pressure gradient which promotes forward flow through the mitral valve during diastole. After atrial contraction, LV pressure usually exceeds LA pressure pushing the mitral valve leaflets to approximate. Full closure of the mitral valve requires additional pressure generated by LV contraction. Diastolic MR occurs due to incomplete closure of the mitral valve when this pressure gradient is reversed. Various mechanisms can result in reversal of this pressure gradient including: asynchronous atrial and ventricular contraction, “overdue” LV systole, significant elevation in LV end-diastolic pressure such as occurs with severe aortic insufficiency, and significant LV dysfunction. ^, The most common mechanism is “overdue” LV systole commonly due to atrioventricular block or rapid atrial arrhythmia with long intermission.

Carpentier Type II

Carpentier Type II is defined as excessive leaflet motion, the free edge of the leaflet traveling greater than 2 mm beyond its normal coaptation point at the annulus during systole. In his initial article, Carpentier, using Barlow’s description, states that this must be clearly delineated from billowing, in which excess leaflet tissue protrudes into the LA during systole while the free edge remains in apposition below the annulus. Fig. 2.4 depicts the difference between prolapse and billowing, and the conglomeration thereof. While the terminology may be confusing and inconsistent in the literature, all mitral valve prolapse (MVP) fails under Carpentier Type II, and is the most frequent cause of MR in developed countries, affecting 2% to 5% of the population. The spectrum of myxomatous degeneration, from fibroelastic deficiency (FED), to myxomatous disease, and finally Barlow’s disease (BD; diffuse myxomatous degeneration) encompasses many of the etiologies of MVP. MVP may result from primary autosomal dominant disorder of variable penetrance or associated with other inherited disorders such as Marfan syndrome or Ehlers-Danlos syndrome. ^, Table 2.1 provides a more complete list of syndromic causes of myxomatous degeneration.

Fig. 2.4, Carpentier’s Depiction of Billowing Versus Prolapse.

TABLE 2.1

Syndromic Causes of Myxomatous Degeneration

Syndrome	Associated Genetic Mutation(s)	Estimated Prevalence of MVP
Marfan	FBN1	25%–45%
Ehlers-Danlos	COL5A1, COL5A2	6%
Loeys-Dietz	TGFBR1, TGFBR2	21%
Aneurysms-osteoarthritis	SMAD3	45%
Hypertrophic cardiomyopathy	MYN7, MYBPC3, TNNT2, TNNI3	3%
Osteogenesis imperfecta	COL1A1, COL1A2	Unknown
Pseudoxanthoma elasticum	ABCC6	Unknown

MVP, Mitral valve prolapse.

(Adapted from Fishbein GA, Fishbein MC. Mitral valve pathology. Curr Cardiol Rep. 2019;21(7):61.)

Fibroelastic Deficiency

FED is on the low end of the spectrum of myxomatous degeneration leading to MVP. It is characterized by the redundancy and thickening of one mitral valve segment in an otherwise thin and translucent valve. Histopathologically, these valves tend to be deficient in collagen, elastin, and proteoglycans. FED typically presents around the sixth decade with ruptured chord and flail leaflet due to acute loss of mechanical integrity. This acute mechanism of failure largely accounts for it being the most common primary mitral valve disease requiring surgical repair. Acute MR and pulmonary edema may result from rupture of the chordae. The pathophysiology of acute MR is described after the classification of MR as there are numerous etiologies that may result in acute MR.

Myxomatous Degeneration

Prolapse from myxomatous mitral valve disease results from abnormally large, usually posterior leaflet comprised of loose myxomatous tissue, rather than dense collagen and elastin. Leaflet histopathology reveals fragmented collagen, increased extracellular proteoglycans, and fibrosis. This results in elongated, stretched out leaflets and attenuated chordae prone to rupture. The valve may have an overall thickened, gelatinous, scalloped appearance. The prolapse caused by myxomatous degeneration is usually asymptomatic and may have resultant MR; however, in more severe cases, annular enlargement and elongated chordae can cause more profound MR. In rare cases, patients may experience symptoms from atrial or ventricular arrhythmias, thromboembolic events, and infective endocarditis.

Barlow’s Disease (Diffuse Myxomatous Degeneration)

Barlow first associated MR with the characteristic midsystolic click and following systolic murmur in the 1960s. As previously mentioned, it was Carpentier who distinguished BD from MVP. Per Carpentier, BD is defined as: bileaflet prolapse greater than 2 mm, a billowing valve with excessively thickened leaflets greater than 3 mm, and severe annular dilation. There are, in fact, pathologic features which differentiate BD from other mitral regurgitant pathologies including significantly thicker leaflets, which are histologically explained by a larger spongiosa layer with infiltration into the fibrosa layer. The larger spongiosa layer is due to accumulation of mucopolysaccharides, which disrupt normal collagen bundles leading to larger billowing leaflet. BD usually results in chronic, rather than acute, MR; however, it is associated with poor outcomes, arrhythmias, and sudden cardiac death.

Malignant Mitral Valve Prolapse

Dating back to the early 1980s, there have been reports of sudden death in young otherwise healthy patients with MVP. These sudden deaths occurred in the absence of severe MR or coexistent coronary artery disease, leading to the notion that there is a malignant form of this usually benign condition. This malignant MVP has also been associated with bileaflet disease (Barlow’s), ventricular arrhythmias, and idiopathic LV systolic dysfunction. A recent study by Garbi et al. showed a mean age of 38, a slight male predominance (51.7%), and extensive bileaflet prolapse with annular dilatation. Thickened, elongated chords with thickened ballooning leaflets characteristic of BD were present in all cases. Myocardial fibrosis has also been implicated in cases of sudden cardiac death related to MVP. Recent studies present strong evidence of an associated cardiomyopathy with malignant MVP with myocardial and papillary muscle fibrosis seen on pathology and cardiac MRI, abnormal myocardial contraction pattern, and Pickelhaube Sign on tissue doppler correlating with high strain. These findings have also been associated with complex ventricular arrhythmias. Some studies have correlated QT dispersion and sudden cardiac death (SCD) with leaflet thickness and the degree of MVP. ^, This makes sense as the larger, billowing leaflet would generate more tension or strain on the associated papillary muscle and myocardium. This may explain the localized abnormal myocardial contraction and hypertrophy compensating for the greater strain created by the enlarged leaflet. However, malignant MVP seems to be unrelated to MR severity. Recent studies have implicated mitral annular disjunction (MAD) in malignant MVP. MAD is defined as detachment of the roots of the mitral annulus from the ventricular myocardium with atrial displacement of the leaflet hinge point, and has been associated with malignant ventricular arrhythmias, MVP, and ventricular fibrosis.

While sudden cardiac death is rare in MVP, the risk is double that in the normal population. This explains the flurry of research in this area as we strive to identify those patients at greatest risk of sudden cardiac death and determine the best management. There is still much that remains controversial, and further study needs to be done in this area.

Traumatic/Iatrogenic Mitral Regurgitation

Traumatic MR is exceedingly rare, but should be considered in blunt cardiac trauma especially with new onset heart failure. MR from blunt cardiac trauma may occur immediately, usually associated with a damaged papillary muscle, or days to months later depending upon the injured component of the valve apparatus. Penetrating cardiac injuries may also result in MR, hopefully with more innate heightened suspicion given the mechanism.

There are various mechanisms by which iatrogenic MR has occurred. These include percutaneous interventions, surgical interventions, and intracardiac left ventricular assist devices. Transcatheter procedures that involve entering the LV, such as transcatheter aortic valve replacement (TAVR), or insertion of an axial flow left ventricular assist device should be very carefully monitored by echocardiography to avoid irreversible damage to the mitral valve. Pigtail catheters and curved guidewires which are used partially to avoid iatrogenic perforation can wrap around chordae becoming stuck and result in significant MR.

Flail

Flail leaflet may result from any of the subtypes of Type II MR and is distinguished from prolapse by loss of normal attachment to the ventricular myocardium to the extent that the leaflet tip points upward toward atrium. Leaflet detachment may affect only one scallop or a smaller portion of a leaflet, in which case, it is deemed a partial flail. The classic flail leaflet refers to the detachment of the majority of the anterior, or posterior, leaflet from its papillary muscle as may occur with chordal rupture or papillary muscle rupture such as in the setting of acute MI.

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