Mitral valve prolapse: A cardiomyopathic state?

Mitral

Valve

Prolapse: Michael

H. Crawford

A Cardiomyopathic and

M

ITRAL VALVE prolapse is a descriptive term that can be applied to several cardiac physiologic and disease states in which the mitral valve leaflets protrude into the left atrium during systole. The medical history and clinical findings in patients with this condition vary with the underlying etiology. The causes of mitral valve prolapse can be roughly grouped under three categories that are not necessarily exclusive (Table 1). In the first category a specific primary alteration of the valve leaflet structure can be found. The normal mitral valve leaflet consists of two histologic layers; the fibrosa on the left ventricular aspect, where the chordae tendineae insert and the spongiosa on the atria1 side. The spongiosa, which normally contains acid mucopolysaccharide, is increased in patients with mitral valve prolapse. This increase in acid mucopolysaccharides has lead to the term “myxomatous degeneration,” but there is actually no evidence that the increased valvular tissue is degenerated.’ These pathologic changes of the mitral valve are similar to those seen in Marfan’s Syndrome and other related connective tissue diseases.2*3 Although these redundant leaflets in themselves may have considerable propensity to prolapse during systole, controversy has occurred concerning whether certain alterations in left ventricular contraction patterns observed on cineangiography are a result of the leaflet prolapse or the cause of the leaflet deformity. Whether or not primary mitral valve prolapse represents a primary cardiac myopathic condition or not is the subject of this article. Before addressing this issue it is useful to consider the other causes of mitral valve prolapse and the role the left ventricular myocardium plays in these conditions. The second general category of causes of mitral valve prolapse is various diseases that produce dysfunction of the mitral apparatus allowing an otherwise normal, or at least not redundant, mitral valve to prolapse during systole. The mitral apparatus is a complex structure comprised of the left atrium, annulus, leaflets, chordae, papillary muscles, and left ventricular wall. Diseases that involve any one or combina-

Progress

in Cardiovascular

Diseases, Vol. XXVII,

No. 2 (September/October),

Robert

State?

A. O’Rourke

tion of these components may result in prolapse of the mitral leaflets during systole, with or without disruption of structural continuity. Some patients with rheumatic mitral valve disease have had evidence of mitral valve prolapse and patients with spontaneous chordal rupture have severe prolapse of the mitral leaflets involved (flail leaflet). More pertinent to this discussion is the patient with coronary artery disease and papillary muscle dysfunction who has auscultatory and angiographic evidence of mitral valve prolapse.435 These patients may have a normal mitral valve echogram, because the leaflets are not redun dant, and thus, the amount of prolapse may be subtle. Occasionally, a patient with dilated congestive cardiomyopathy will show some mild posterior sagging of the mitral valve leaflets on echocardiogram associated with the frequent finding of mitral regurgitation in these patients. It is believed that this is due to inadequate contraction of the papillary muscles and dilata-, tion of the mitral annulus. However, the typical nonejection systolic click is usually not present. in these cases. In summary, any disease that produces papillary muscle dysfunction could produce this type of secondary mitral valve prolapse. The third general category of conditions that can cause mitral valve prolapse is associated with a decrease in left ventricular volume. If left ventricular size becomes sufficiently small during systole, a normal mitral valve may be disproportionately large compared with the ventricle during systole, which would permit it to prolapse into the left atrium. In such conditions the prolapse is usually detected only by echocardiogram; the usual auscultatory features being absent or overshadowed by the primary disease process. For example, the patient with hypertrophic From the Division of Cardiology, Department of Meditine. University of Texas tfealrh Science Center, San Anlonio. Tex. Address reprint requesls to Robert A. O’Rourke, MD, Division of Cardiology, Department of Medicine, Universily of Texas Health Science Cenier, San Antonio. TX. 01984 by Gram & Straiton. Inc. 0033-0620/84/2702-0004$03.00/0

1984

133

CRAWFORD

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Table

1. Classification Primary

of Mitral

Leaflet

Valve

Prolapse

Abnormality

Familial NonfamilIal Marfan’s

syndrome

Other

connectwe

Secondary

Prolapse

Rheumatic

valve

Coronary

artery

Ruptured

chordae

tissue

disorders

disease disease

Cardiomyopathles Functional Decreased Enhanced

Prolapse left ventricular left ventricular

volume contractility

obstructive cardiomyopathy almost always has a small left ventricular cavity size and occasionally demonstrates systolic prolapse of the posterior mitral valve leaflet in addition to the anterior motion of the anterior mitral valve leaflet on the echocardiogram. However, mid-systolic clicks are not appreciated in this condition. Prolapse also has been described on echocardiograms from patients without obstruction and systolic anterior mitral valve motion.’ The role altered papillary muscle alignment plays in the prolapse seen in hypertrophic diseases is unknown. Another example is the frequent association of mitral valve prolapse with secundum atrial septal defect on the echocardiogram with and without the characteristic physical findings of prolapse.x At t$e time of surgery when the mitral valve is inspected, often it has been found to be normal. Also, after closure of the defect, the prolapse often dis’appears on the echocardiogram.’ However, t-here may be an increased incidence of the primary valve disorder in patients with atrial septal defects as well.’ Also, it has been observed that when normal individuals are given a potent vasodilator such as the inhalation of amyl nitrite, during the time of rapid tachycardia and reduced left ventricular volume, mitral valve prolapse can be demonstrated by echocardiography. In addition, typical physical findings of mitral valve prolapse have been observed transiently in patients with decreased blood volume, from causes such as gastrointestinal bleeding, and a hypercontractile state induced by hyperthyroidism.” Therefore, it would appear that a disproportionately small left ventricle from any cause may result in echocardiographic, and sometimes auscultatory, evidence of mitral valve prolapse. It is clear that mitral valve prolapse secondary to other primary cardiac diseases as discussed

AND

O’ROURKE

above can be a result of myocardial dysfunction. Since primary mitral leaflet abnormalities with prolapse are believed to be a relatively common entity, especially in females, there is considerable likelihood that patients with primary prolapse may also acquire other cardiac diseases that could lead to secondary mitral valve prolapse. Thus, the frequent occurrence of primary mitral valve prolapse and one of the diseases mentioned above has lead to some confusion regarding the etiology and the role of the myocardium in the former. However, carefully performed studies in certain patients in whom other cardiac diseases have been excluded have continued to show contraction abnormalities of the left ventricle in ;)I least some of the patients with primary mitral valve prolapse. We will discuss the significance of these findings in regard to the etiology 01 primary mitral valve prolapse. Several features of the mitral valve prolapse syndrome have led to the speculation that the disease has a prominent myocardial component (Table 2). First. some patients with mitral valve prolapse have had abnormalities of the resting electrocardiogram (ECG). The most common ECG changes have been ST-T wave abnormalities in the inferior leads (II, II!. AVF). I.e?;s common findings are prominent U waves, peaked T waves, prolonged Q-T interval and other conduction disturbances.” Second, ventricular arrhythmias are a frequent finding in patients with mitral valve prolapse, ranging from a 40% to 70% incidence in some studies.” ” However. high grade ventricular dysrhythmias arc infrequent and occur most commonly in those with the characteristic ST-T wave changes.” Third, abnormal hemodynamic measurements have been found at the time of cardiac catheterization in some patients. but especially those with considerable mitral regurgitation.” Finally, left ventricular cineangiography has demonstrated abnormal contraction patterns which have been attributed to a cardiomyopathic condition.” (Fig 1). Various types of abnormalities have been described on left ventricular cineangiography, Table

2.

Factors

Supportive

Abnormal

resting

of a Cardiomyopathy ECG

Ventricular

arrhythmias

Abnormal

hemodynamics

LV contraction

abnormalmes

MITRAL

VALVE

PROLAPSE

MYOPATHY

Fig 1. Cineangiogram frame near end-systole from a left ventricular contrast injection in the right anterior oblique projection. Note the posterior protrusion of a voluminous mitral valve accompanied by a hypercontractile appearance of the inferior wall and cavity obliteration of the apex.

which can be roughly grouped into several categories. First, increased contraction has been described especially of the inferior mid-wall, the entire mid-wall, and occasionally, the entire ventricle is hypercontractile.‘8 Second, hypokinesis has been observed involving the long axis, the high posterior wall and occasionally, the anterior wall, and rarely, more diffusely.‘9 The third abnormality that has been described is early relaxation of the anterior wall prior to mitral valve opening.20~2’Finally, inadequate mitral annulus contraction or actual expansion of the annulus has been described.12In some patients this may be due to a connective tissue disease involving the annulus. These left ventricular contraction abnormalities have been relatively frequent in patients referred for cardiac catheterization. The most common abnormalities observed are increasedcontraction of the inferior mid-wall with early relaxation of the anterior free wall. It has been noted that patients with abnormal contraction patterns tend to be older, have more mitral regurgitation, and often have the characteristic ST-T wave changes.*’ Whether these findings would be as prevalent in an asymptomatic younger population without significant mitral regurgitation has not been investigated;

135

however, it is noteworthy that echocardiographic studies have rarely described any wall-motion abnormalities. Thus, these cineangiographic studies may be addressing a more severe end of the spectrum of this disease,which raisesserious questionsabout the etiologic significance of these findings. intracardiac pressuresand cardiac output are usually normal in patients with mitral valve prolapse. However, these measurements may become progressively abnormal as mitral regurgitation becomes more severe. Patients with marked mitral regurgitation demonstrate the usual findings consisting of elevated left ventricular end-diastolic, left atria], pulmonary artery wedge pressures and occasionally pulmonary artery and right ventricular hypertension. In severe cases cardiac output may be reduced.23 Also, in one study evidence of reduced left ventricular compliance was detected by atria1 pacing and appeared to be unrelated to the degree of regurgitation.14 Global left ventricular performance as determined by cineangiography is usually normal or super-normal in the studies reported, with a few patients showing abnormal ejection fraction when moderate to severe mitral regurgitation is present. Also, a few patients have been reported to have enlarged left ventricular volumes in the absenceof severe mitral regurgitation.‘8 In addition, somepatients have been described with left ventricular hypertrophy and increased left ventricular mass,‘8~‘9However, despite the prevalence of abnormal contraction patterns, the function of the left ventricle is not usually impaired. The interpretation of these heterogeneousand disparate findings on cardiac catheterization is both difficult and controversial. Several hypotheses have been advanced to explain the findings, but none completely encompassesall of the abnormalities that have been described (Table 3). One problem in putting together a cohesive Table

3.

Possible

Explanations Abnormalities

of Contraction

LV dysfunction due to mitral regurgitation Primary cardiomyopathic condition Abnormal tension on papillary muscles leaflet prolapse abnormal myocardial contraction passive deformity of ventricle Early afterload decrease from prolapse Autonomic

dysfunction

with

excess

from

catecholamines

136

thesis for the role of the left ventricular myocardium in mitral valve prolapse is the problem of dealing with secondary changes induced by mitral regurgitation itself. It is classically taught that “mitral regurgitation begets mitral regurgitation”; implying that the regurgitation of blood from the left ventricle into the left atrium leads to secondary changes in these two chambers and the mitral apparatus that encourages the development of more severe regurgitation. Progressive dilatation of the left ventricle due to a chronic volume load has several deleterious consequences which may adversely effect mitral apparatus function. Simple mechanical problems occur due to dilatation alone such as papillary muscle malalignment, mitral annular dilatation and left atria1 enlargement, which augment mitral regurgitation. A more serious problem is the sarcomere slippage and resultant fibrosis that ultimately decreases the ability of the left ventricle to compensate for the volume load by an enhanced contractile effort. The myocardial dysfunction leads to more dilatation and more mitral regurgitation. Mitral valve prolapse can thus progress to the point where mitral regurgitation has induced changes in left ventricular performance that are irrelevant to the pathophysiology of the basic disease process. How many of the angiographic findings that have been described are related to this development is unknown. Clearly, some patients with prolapse but no mitral regurgitation have had abnormalities of left ventricular contraction or performance described. However, as stated above, the majority of patients with severe left ventricular contraction abnormalities and left ventricular dysfunction have mitral regurgitation. This difficulty is certainly not resolved and represents one of the uncertainties in this curious syndrome. The most controversial hypothesis that has been advanced to explain this syndrome is that the entire disease entity is due to a cardiomyopathic condition.25 This hypothesis states that there is a primary congenital or acquired disease of the myocardium that leads to hypercontraction in some areas, hypocontraction in others, and early relaxation in still others; and that these changes disrupt the mitral apparatus such that the mitral leaflets are allowed to prolapse toward the left atrium during systole. This disruption of orderly myocardial contraction produces abnor-

CRAWFORD

AND

O’ROURKE

mal tension on the mitral leaflets and secondarily leads to increases in myxomatous tissue in the spongiosa layer of the valve leaflet, elongation of the chordae tendineae and all the other pathologic abnormalities that have been described.‘” These changes in the mitral apparatus eventually lead to mitral regurgitation, which progresses with time producing new left ventricular abnormalities. Although this is an interesting hypothesis, there is very little evidence to support it in its entirety, since most patients with mitral valve prolapse have normal left ventricular function. The principle evidence for this theory is from the angiographic studies mentioned above that usually are performed on patients at the most severe end of the spectrum. There are few angiographic studies available on patients with milder forms of the disease or children with auscultatory findings of mitral valve prolapse. What feu autopsy studies have been performed on young individuals with the syndrome have shown abnormalities of the leaflet tissue and no discernable histologic changes in the myocardium.‘.2h Of course, this does not rule out an abnormality of the contraction of the left ventricle unassociated with histological changes. Thus, more work needs to be done in order to prove this hypothcsis. The hypothesis that is most consistent with the clinical and pathological information available is that these contraction abnormalities on left ventricular cineangiography represent the consequence of prolapse of the mitral valve leaflets. According to this theory, prolapse of the mitral leaflets puts excessive stress on the chordae tendineae, which in turn puts excess stress on the papillary muscles. This leads to a hypercontractile effort of the papillary muscles resulting in the abnormal contraction patterns on the angiogram. The abnormally contracting papillary muscles may stress other regions of the myocardium and make them appear hypocontractile or result in early relaxation of other segments. The hyperkinetic ventricles observed in some patients may be due to the prolapse itself unloading the ventricle in early systole by allowing a more vigorous contraction than would otherwise be present. Any ventricle showing diffuse hypokinesis would probably be the result of prolonged mitral regurgitation or some other cardiac disease process. Also, it is not entirely clear whether the deformi-

MITRAL

VALVE

PROLAPSE

MYOPATHY

ties during systole are solely the result of hypercontractility or whether or not they represent passive traction on the left ventricular wall by the chordal and papillary muscles that are moving with the leaflets towards the left atrium (Fig 2). However, the ventricle with supernormal function certainly represents enhanced contraction. No matter which is the exact mechanism producing abnormalities of the systolic silhouette on angiography, the major thesis of this explanation is that any deformities are due to the primary abnormality of the leaflets, which are redundant and billowing and tend to prolapse back into the left atrium during systole. In support of this theory, cases have been described where patients have had mitral valve replacement for refractory ventricular tachycardia or for severe mitral regurgitation due to mitral valve prolapse. Cineangiograms performed after operation have shown a disappearance of the contraction abnormalities typical of

Fig 2. Anatomic drawings of the left heart structures and the corresponding cineangiographic silhouettes are illustrated. (A) Normal. Ant, anterior mitral valve leaflet; Ao, aorta; LA. left atrium: LV, left ventricle: MVA. mitral valve annulus: Post, posterior mitral valve leaflet. (El Partial prolapse of the posterior leaflet resulting in mitral regurgitation fM.R.J and deformity of the inferior wall (arrow). (C) Prolapse of the entire posterior leaflet with deformity of the anterior wall, also. (Reprinted with permission).”

137

Table

4.

Conditions Associated Leaflet Abnormality Tricuspic

valve

Pulmonic

and

Thoracic

skeletal

Secundum Other

Autonomic

the

Primary

prolapse aortic

atrial

prolapse

septal

defect

heart

diseases

and

pulmonary

nervous

Atrioventricular

valve

abnormalities

congenital

Emphysema

With

fibrosis

system

bypass

disorders

tracts

mitral valve prolapse observed preoperatively., Also, in some cases the ventricular dysrhythmias disappeared as well.” Of course, there are other possible explanations for these changes postsurgery, but this certainly lends credence to the theory that this is a mechanical disruption of the myocardium by the prolapsing leaflets. There also is evidence that this primary leaflet abnormality involves other connective tissue and neural tissue (Table 4). In fact, increased catecholamine levels have been associated with the propensity to arrhythmias in some patients with this syndrome, and this finding may explain the hypercontractility seen in other patients.‘x~29 Indeed, many of the subjective symptoms of patients with mitral valve prolapse may be related to autonomic dysfunction.30 Also, mitral valve prolapse has been described in Marfan’s Syndrome and other connective tissue disorders. Therefore, much evidence points to a basic connective tissue disease rather than a cardiomyopathy as the etiology of primary mitral valve prolapse3’ (Table 5). Other evidence relating to the controversy about the etiology of mitral valve prolapse comes from percutaneous right ventricular biopsy data. Mason et a13’ reported that eight of 14 patients with clinical and angiographic evidence of mitral valve prolapse had light microscopic endocardial and interstitial fibrosis and 11 had electron microscopic evidence of degenerative mitochondria. These changes exceeded those found in a control group of patients with arrhythmias who did not have mitral valve prolapse. Although this type of evidence might support the theory that Table

5.

Factors

Speciftc

Supportive leaflet

Associated Normal

connectwe ventricular

Disappearance mitral

of a Primary

pathologic

tissue function

of contraction valve

replacement

Leaflet

Disease

changes disorders in most

patients

abnormalities

after

CRAWFORD

138

this syndrome is a cardiomyopathy, it must be realized that these patients were undergoing cardiac catheterization because of severe symptoms and findings of severe mitral regurgitation, and thus, represent the far end of the spectrum of patients with this condition. Also, these changes on histology are nonspecific and could represent the coincidence of mitral valve prolapse with other disease entities. In addition, it is unclear how representative the right ventricular side of the septum is of the entire left ventricle. Finally, such degenerative changes would not explain the hypercontractility observed on angiography. Although intriguing, the study is thus not conclusive and more work needs to be done in this area. Evidence for a metabolic defect in the myocardium has been conflicting. Natarajan et a133performed atria1 pacing in 23 patients undergoing cardiac catheterization for mitral valve prolapse. Seven of these patients demonstrated lactate production or lessthan 10% lactate extraction during pacing, and two showed these abnormalities at rest. Only five patients developed chest pain during pacing, and only two had ST depression demonstrated on the electrocardiogram. Since none of these patients had epicardial coronary artery diseaseon selective cineangiography, this evidence of myocardial ischemia was attributed to a myocardial metabolic defect. Interestingly, there was a relationship between the lactate abnormalities and the symptoms. However, there

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O’ROURKE

was no control group in the study. Nutter et al,” studied 26 patients undergoing cardiac catheterization for mitral valve prolapse and found no abnormalities of lactate metabolism with pacing. Therefore, the occurrence and significance of any myocardial metabolic abnormalities in patients with mitral valve prolapse is uncertain. SUMMARY

Patients with diseases of the myocardium. structural abnormalities of the heart, and valvular diseasemay have mitral valve prolapse demonstrated as a consequenceof these diseaseentities. However, there appears to be a primary diseaseof the mitral leaflets in which left ventricular cineangiography has demonstrated abnormal contraction patterns of the left ventricle in some patients. The cause of these abnormal contraction patterns is controversial, but most of the evidence points to these abnormalities being a consequence of the abnormal leaflet tissue motion during systole creating abnormal stress on the papillary muscles and supporting left ventricle wall. Biopsy evidence of myocardial changesand abnormal cardiac metabolic studies in somepatients have suggestedthat myocardial function may not be entirely normal in every patient with mitral valve prolapse. However. there is not sufficient evidence currently to ascribe these histologic, metabolic and angiographic changes to a primary cardiomyopathic condition.

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PROLAPSE

MYOPATHY

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