Syndrome of mitral valve prolapse: Current perspectives

Syndrome of Mitral

Valve ProIapse: Current Perspectives Azam

Ansari

T

HE SYNDROME OF mitral valve prolapse (SMVP) is perhaps the most common cardiac valvular disorder, affecting a variable percentage of the general population irrespective of age, caste, creed, nationality, or sex& is probably not a new syndrome. Because of protean and subtle manifestations it may have masqueraded for at least a century under such terms as irritable heart syndrome, DaCosta syndrome, neurocirculatory asthenia, anxiety neurosis, and soldier’s heart, until Reid’ in 1961 postulated and Barlow et al2 in 1963 convincingly demonstrated by tine left ventriculography that mitral valve prolapse (MVP) can be a definite cause of mitral regurgitation (MR). It appears astonishing as to why the master clinicians of the past did not recognize the distinctive physical findings (both cardiac and noncardiac) of SMVP which are so commonly known to all of us now. One possible explanation is that the auscultatory findings of the so-called “click-murmur,” which is the clinical hallmark and correlate of MVP by echocardiography, were inappropriately attributed to extracardiac causes. In addition, rheumatic heart disease, which was more prevalent in the late 19th and early 20th century, was incorrectly thought to be the cause of all cases of isolated mitral regurgitation (IMR). The spectrum of SMVP varies from an isolated nonejection systolic click with or without late systolic murmur and no mitral insufficiency to severe mitral insufficiency with a holosystolic murmur with a whoop or honk and no systolic click. Phenomenal progress in the clinical and laboratory elucidation of SMVP has taken place during the past 27 years to the extent that it is now possible not only to define but also to synthesize a meaningful concept of SMVP including its etiology, pathology, pathogenesis, pathophysiology, clinical, ECG, phonocardiographic, echocardiographic, angiographic, and prognostic features. However, the high prevalence of MVP in an otherwise healthy population has led some to question whether it is in fact a true disease entity or merely a disease in search of or created by its definition.3 Overdiagnosis and underdiagnosis of MVP either by clinical or echocardiographic criteria, and its variable presentation in Progress

in Cardiovascular

Diseases,

Vol XXXII,

No 1 (July/August),

different individuals or in the same individual on different occasions, have not only perplexed but also frustrated clinicians and echocardiographers alike. The purpose of this article is to develop a current perspective of SMVP based on the worldwide knowledge gained during the past 27 years (1961 to 1988) and the personal experience and observations of the author at an active cardiac center in the midwestern United States. Its main objective is to present a clear, concise, yet comprehensive concept of SMVP emphasizing recent observations in its etiology, pathology, pathogenesis, pathophysiology, diagnosis, management, and prognosis with an emphasis upon how to avoid pitfalls and improve the accuracy of diagnosis in clinical practice. Such an undertaking is inherently difficult because SMVP is a heterogeneous entity with an extremely broad and variable clinical spectrum. SMVP can best be understood by defining its two most important components and then combining them together with reference to the mitral valve. A syndrome is the concurrent existence of a set of symptoms and signs encountered in a pathologic or disease state. Prolapse is the displacement of an organ or part of an organ from its normal position through an opening into a cavity. Thus SMVP can now be defined as the concurrent existence of palpitation, skeletal abnormalities (tall, slender build, scoliosis, pectus excavatum, etc), hypomastia (in women), low normal BP, click-murmur or late systolic murmur, and various recurrent cardiac arrhythmias noted in patients in whom the mitral valve frequently displaces through the left atrioventricular (AV) ring into the left atria1 cavity. When the mitral valve displaces into the left atria1 cavity, ie, when MVP is present but there are no accompanying symptoms and signs, then by definition SMVP is absent. Such an occurrence is not From the Department of Medicine (Section Cardiology), Metropolitan Medical Center (now Metropolitan-Mount Siani), Minneapolis. Address reprint requests to Azam Ansari, MD, FACC, Suite 444,825 South Eighth St, Minnepolis. MN 55404. o 1989 by W.B. Saunders Company. 0033-0620/89/3201-0002$5.00/O

1989:

pp 3 i-72

31

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uncommon in certain physiologic states, eg, reduced left ventricular cavity size, young children, adolescent growth, and a hyperdynamic circulatory state. This distinction between SMVP and MVP is of importance. It should therefore be clear that diagnosis of SMVP is the responsibility of clinicians rather than echocardiographic or cardiac catheterization laboratory reports, because at best these reports deal with only one variable component of the entire syndrome. HISTORICAL

PERSPECTIVES

Wooley, in a painstaking historical survey, has traced lineage from irritable heart to SMVP in four publications.4-7 Bedford traced the theme of palpitation and nervous heart to the mid- 1~OOS.~ However, it was not until 1836 that Williams published his classic text Practical Observation on Nervous and Sympathetic Palpitations of the Heart, as distinguished from the palpitation resulting from organic heart disease.’ DaCosta” published his preliminary reports about irritable heart as a result of studies conducted in a US Army Hospital for injuries and diseases of the nervous system. DaCosta’s definitive and classic work on irritable heart, published in 1871, was soon widely recognized. DaCosta thought that his observations were similar to those described as “soldier’s heart” among British troops in India and in the Crimean War. MacLean” had confirmed in 1867 that the irritable heart was similar and widely referred to as soldier’s heart in the British Army. Thus, the lineage of SMVP may be traced to British and US military medicine during the 1860s.’ Mackenzie I2 lectured on the soldier’s heart and war neurosis at the St Andrew’s Clinical Institute in 1920 and presented a broadbased appraisal that dealt not only with the cardiac signs and symptoms but also the role of the neuropsychiatric symptoms and the mechanism of radiation of chest pain, concepts that are still in the process of deliberation several decades later.6 Allbuttr3 criticized some of Mackenzie’s observations. In particular, he emphasized that mitral and tricuspid murmurs in patients diagnosed to have soldier’s heart probably indicated valve disorder with a potential for progression. He also was of the opinion that the symptom complex in this disorder was too uniform to be fictitious.6

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In 1913 Gallivardin I4 described pericardial adhesions in four autopsy cases in whom systolic clicks had been heard during life. Lesch15 considered the observations of Gallivardin to be the first step in the clinical evolution of SMVP. Based on his observation and following the reports of Johnston,‘6 who found that midsystolic click and murmurs changed markedly with postural changes and respiration, the theory of extracardisc origin of systolic click and midsystolic murmurs was born. An exception to these observations was White,17 who in 1931 suggested that midsystolic clicks sometimes arose from abnormally long chordae tendineae. However, other leading cardiologists of the time continued to report and reemphasize that midsystolic click and late systolic murmurs were benign, that they were not associated with rheumatic heart disease, and that their main importance was that they could be mistaken for diastolic gallop sounds. In 1965 Ronan et al,‘* using intracardiac phonocardiography, documented the origin of nonejection systolic clicks and late systolic murmurs to the mitral valve in a patient with hemodynamic evidence of IMR. Before this observation recording of both of these acoustical events within the left atria1 chamber had not been described. In 1966, Criley et ali9 documented an excellent correlation between the clinical and tine left ventriculographic findings of MVP. With these two crucial documentations the previous observations of Gallivardin and Johnston that midsystolic clicks and murmurs were due to the presence of pericardial thickening were disproved. The concept of SMVP developed rapidly with the introduction of echocardiography into clinical practice. This first occurred when Shah and Gramiak2’ described the M-mode echocardiographic (M-echo) criteria of MVP in 1970 and 6 years later Sahn et al” defined the two-dimensional echocardiographic (2D echo) criteria. As the historical thread runs through the various descriptive treatises defining a loo-year cycle from DaCosta’s syndrome to SMVP, patients’ complaints, signs, symptoms have changed very little; only the interpretations of these signs and symptoms have changed considerably.’ The clinician’s understanding has been significantly enhanced by clinical, echocardiographic, and angiocardiographic correlations. The historical

SYNDROME

OF MITRAL

VALVE

33

PROLAPSE

and clinical evolution of SMVP is summarized in Table 1. RECOMMENDED

GLOSSARY

OF TERMS

SMVP during the past 27 years has been given various descriptive names, such as systolic clickmurmur syndrome, midsystolic click-late systolic murmur syndrome, Barlow’s syndrome, ReidBarlow’s syndrome, billowing mitral valve leaflet syndrome, ballooning mitral cusp syndrome, redundant mitral cusp syndrome, hooded mitral valve syndrome, and floppy mitral valve synTable

1. Historic

and Mitral

Clinical Valve

Evolution Prolapse

(1636)’

of

Milestone

Authors

Williams

of Syndrome

Pointed

out nervous

under in

females, hysteria with morbid susceptibility to ordinary impression, usually in the Young between the ages of 15 to 25 Years. Such palpitations were “often attended with other symptoms-pains in the heart and the lung, the patient may complain of dull aching sensation

(1867)”

DaCostal (187 1)‘c Paul C Wood (1941)

Reid

11961)’

situated in these parts or referable to the heart itself.” Described irritable heart syndrome. Soldier’s heart and effort syndrome. Lumped irritable heart, soldier’s heart and neurocirculatory asthenia into one entity, ie, anxietY Described and recorded

neurosis. midsystolic

click by extracardiac phocardiography. He postulated that it represented a taut snapping of chordae tendineae during the late high pressure phase

of ventricular

which, when incompetence, murmur. Barlow

et al (1963)’

Ronan

et al (1966)”

Criley

et al (1 966)19

Shah and Gramiak (1970)” Sahn et al (1976)”

resulting resulted

systole in mitral in a systolic

Demonstrated angiographically the systolic prolapse of the mitral valve as a cause of mitral regurgitation. Recorded midsystolic click and late systolic murmurs by intracardiac phonocardiographic technique and documented their mitral valve origin. Correlated the clinical and tine angiographic findings of MVP. Described M-mode echocardiographic criteria of MVP. Described 2-D echocardiographic criteria

of MVP

Redundant Mitral Valve, Floppy Mitral Valve

These terms should best be restricted for the anatomic description of the mitral valve, either by pathologists, echocardiographers, or angiographers. Myxomatous Mitral

palpitation

some well-marked constitutional characteristic of temperament

Maclean

drome. This varied and fanciful, but nonunanimous terminology probably emanates from the indiscriminate use of different terms coined by clinicians, pathologists, angiographers, and echocardiographers as they each perceived SMVP during its evolution. Each one emphasized a narrow aspect of SMVP. The following is an attempt to deal with this excessive and redundant terminology:

in children.

Valve

Its use should be restricted to pathologists who are describing histologic changes. Use of this term in the clinical setting in a live patient would be inappropriate because myxomatous degeneration cannot be diagnosed by clinicians, angiographers, or echocardiographers. Click Murmur Syndrome or Midsystolic Click and Late Systolic Murmur Syndrome

These terms should only be used by clinicians because they are based on ascultatory findings. The use of these terms would be inappropriate for pathologists, angiographers, or echocardiographers. Conversely, clinicians should not presume that all patients with click-murmur syndrome are due to MVP unless the latter has been demonstrated by echocardiography or left ventriculography. Mitral Valve Prolapse

This is a dynamic condition in living patients which can be best assessed by echocardiography and/or angiocardiography; as such its use should be limited to echocardiographers and angiocardiographers. They should follow specific criteria (see sections on echocardiography and angiocardiography) as much, as possible: It may or may not be associated with any symptoms or signs of cardiac disease. Syndrome of Mitral

Valve Prolapse

This term should be used only by clinicians who have documented MVP either by echocardiography- or tine left ventriculography in those

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patients who also have abnormal anthropometry, skeletal abnormalities, palpitations, postural hypotension in the presence of midsystolic click, and/or systolic click and murmur. Hypomastia in women is an additional component. PREVALENCE

According to various estimates, MVP occurs in from 1% to 20% of the world’s population. This wide range can be explained in part by differences in the diagnostic criteria and the populations screened. Using auscultatory findings to document click-murmur syndrome, the incidence is lower than when MVP is detected by echocardiography in an adult population. For this reason there is an imperfect correlation between auscultatory and echocardiographic evidence of MVP both in children and adults. Approximately 5% of a healthy pediatric population have auscultatory evidence of MVP as indicated by a recent study of 3,100 consecutive pediatric patients 1 month to 18 years old. 22 In the Framingham study, clicks were heard in only 11% and murmurs were heard in only 7% of 264 subjects found to have MVP on echocardiographic screening.23 More recently it has been indicated that MVP occurs in about 5% to 21% of the seemingly healthy population. 24This increased incidence of prevalence of MVP may be misleading because the majority of these studies used M-mode-echo for the confirmation of diagnosis. However, technical limitations of this one-dimensional method permit ambiguity and the M-mode-echo criteria used to determine the prevalence of MVP have become suspect. Two-dimensional echo allows simultaneous visualization of the mitral valve and its annulus and thereby provides the most accurate means of assessing mitral leaflet position in systole. With this method the generally accepted definition of MVP is a motion of the mitral valve leaflet superior to the annulus during systole. Using this definition, Warth et a125found a 13% incidence of MVP in normal children and the incidence increased to 35% in the 10 to 18-year age group. There was no statistical difference between male and female children at any age. However, the prevalence of superior systolic motion decreased markedly (1%) when consideration was given to its presence in more than one echocardiographic view or to displacement of the coaptation point of mitral valve

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leaflet (0.5%). The author suggested that superior systolic motion occurs with increased frequency in normal children and therefore calls into question the reliability of these criteria of MVP as a standard for the diagnosis of MVP. More restrictive diagnostic criteria that would consider the degree of leaflet displacement or its presence in multiple echocardiographic views may be necessary to identify those subjects whose mitral valve closure patterns fall outside the range of normal. When such restrictive criteria are used it is obvious that the incidence of MVP will be much lower, perhaps in the range of 2% to 5%. The true incidence of SMVP, however, remains uncertain at this time because it is not known how many of these 2% to 5% of the MVP population indeed have other characteristics of SMVP. ETIOLOGY

SMVP is recognized in all age groups. It is more common among young women than men; however, this difference decreases with increasing age in women but remains constant in men. Levy and Savage26 indicate that irrespective of the diagnostic criteria used to define SMVP, there is a 2:l female to male ratio. Familial occurrence has been described.27 Its etiology is diverse; however, a distinct subset of patients is now recognized in whom no apparent cause exists for MVP and no associated cardiovascular disease can be identified. The term idiopathic mitral valve prolapse (IMVP) has been aptly applied to this particular subset. However, it should be pointed out that this conclusion can be arrived at only after a number of common diseases associated with MVP, such as Marfan’s syndrome, Ehlers-Danlos syndrome, rheumatic valvular heart disease, and coronary artery disease, have been looked for and appropriately excluded. The various causes and conditions associated with SMVP are given in Table 2. Patients with SMVP and hyperthyroidism often have common symptoms the most outstanding of which is recurrent palpitation. To determine whether or not common symptoms contributed to the reported association between these two conditions, Zullo et a128evaluated 220 patients with SMVP and 216 first degree relatives in 72 families; 65 relatives with MVP and 151 relatives without MVP, all older than 16

SYNDROME

Table

OF MITRAL

2.

Etiology Syndrome

VALVE

35

PROLAPSE

and Conditions of Mitral Valve

Associated Prolapse

With

Congenital Idiopathic MVP Marfan’s syndrome Ehlers-Danlos syndrome Osteogenesis imperfecta Dochenne’s muscular dystrophy Myotonic dystrophy Wolff-Parkinson-White syndrome Pseudoxanthoma Turner’s syndrome Noonan’s Congenital

elasticurn

syndrome heart disease

(with

ventricular septal defect, von Wilebrand’s disease Glycogen storage disease

atrial

Ebstein

septal

defect,

anomaly)

Fabry’s disease Sandhoff’s disease Straight back syndrome Neuro-ecto-mesodermal Congenital prolonged Keratoconus Acquired Rheumatic Occlusive Coronary Congestive

endocarditis coronary artery

disease

spasm cardiomyopathy

Myocarditis Previous mitral Trauma Relapsing Systemic

dysplasia OT syndrome

valve

surgery

polychondritis lupus erythematosus

Polymyositis Rheumatoid arthritis Polyarteritis nodosa Hyperthyroidism Athlete’s heart Migraine

headache

years of age. They found that the age and sex adjusted prevalence rate of hyperthyroidism was significantly higher in probands with MVP than in family members without MVP (3.5% v O%, P value = .03), while an intermediate prevalence of hyperthyroidism (2.2%) was observed in family members with MVP. Thus, it appears that the prevalence of hyperthyroidism is increased among patients with SMVP as compared to family members without MVP, but the prevalence of hyperthyroidism is similar among family members with or without MVP. Inheritance

MVP appears to be the most common autosoma1 dominant cardiovascular abnormality in humans. To ascertain inheritance patterns, De-

vereux et a12’ studied 45 probands and 179 first degree relatives. Echocardiographic MVP was present in 54 of 179 first degree relatives (30%); at least one first degree relative was affected in 29 families including members of two generations in 23 families. The familial prevalence of MVP was similar whether or not the proband had characteristic symptoms, auscultatory abnormalities, ECG findings, thoracic bony abnormalities, or coexisting heart disease. MVP occurred in 39 of 90 women (41%) but 17 of 89 (19%, P < .005) and in 51 of 143 adults (35%) and only three of 36 children age 1 to 15 (P < .005). The authors concluded that MVP is an inherited autosomal dominant disorder irrespective of clinical findings, and the MVP gene shows age and sex dependent expression. Swindle et a13’ observed MVP in 26 of 92 animals in a harem breeding colony of rhesus monkeys (Macaca Mulatta). Analysis of the breeding record suggested that MVP was a dominant genetic trait with an approximate birth incidence of 16% to 20% in the colony. The existence of MVP in nonhuman primate species not only provides a unique opportunity to study the disease in an experimental animal but also both the incidence and mode of inheritance are almost identical to what has been recorded in human beings. PATHOLOGY

During the past 27 years it has become clear that while the pathologic abnormality in MVP is usually localized to the mitral valve leaflets, these abnormalities often extend to the mitral valve apparatus (MVA). The latter is a complex but well-designed structure. Its proper function depends on the extremely delicate and wellcoordinated effort between its six components, ie, the left atrium, the mitral valve annulus, mitral valve leaflets, the chordae tendineae, the papillary muscles, and the adjacent endomyocardium of the left ventricle supporting the base of the papillary muscle. Abnormality of any one of these six components of the MVA may cause MVP. Histologically, normal mitral leaflets are composed of essentially three layers. (1) The layer at the closing aspect, the atrialis, is comprised of fibroelastic connective tissue; (2) the middle layer, known as spongiosa, is composed of loose

36

myxomatous connective tissue; and (3) the third layer comprises the noncontact aspect and is known as fibrosa-as the name implies, this layer is formed by a sheet of dense collagen. The chordae tendineae, which are also densely collagenous, insert into the fibrosa, the layer that supplies the essential strength to the substance of the mitral leaflets.3’ Gross

The mitral valve leaflets, both anterior and posterior, are large, voluminous, redundant and have a ballooning, hooding, or hemorrhoidal appearance to the naked eye. This type of gross appearance of the mitral valve is best appreciated when the left atrium is open and the mitral valve is looked at from above (Fig 1).32 The annular circumference of the mitral valve ring (Fig 2)33 is invariably increased (normal 9.0 to 11.0 cm). The mitral valve leaflets often appear to be deformed and the chordae tendineae appear to be elongated, focally thickened, but generally thin. Because of loss of tensile strength they may break easily on individual handling. While both leaflets of the mitral valve are often involved, it is not uncommon to have findings confined to either the posterior or the anterior mitral leaflet, most commonly the former. The commissures of both leaflets are easily definable, and do not show any fusion, a point worth emphasizing, to differentiate the mitral valve abnormality resulting from rheumatic heart disease. Not uncommonly, friction lesions (fibrotic lesions) are found on the surface mural endocardium of the left ventricle. They are believed to result from the friction of the chordae tendineae against the surface endocardium during left ventricular systole. Longstanding fibrotic lesions tend to calcify and entrap the chordae tendineae, thereby causing effective shortening of the involved chordae.31

Histologically, the primary pathologic abnormality in MVP appears to be an increased amount of tissue composing the middle layer of spongiosa, with intermittent encroachment of this layer into the fibrosa. The increase in spongiosa is mostly due to the excessive accumulation of mucopolysaccharides resulting from myxomatous degeneration34 secondary to a fundamental

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abnormality in collagen metabolism.35a This abnormality, which may not appear prominent with hematoxylin-eosin staining (Fig 3A) of the sections of mitral valve leaflets, can be strikingly demonstrated by special stains such as toluidine blue (Fig 3B). The myxomatous change, when it encroaches into the continuity of fibrosa, leads to its intrinsic weakness and thereby causes prolapse of the involved mitral valve leaflet towards the left atrium. As indicated above, the process, however, does not necessarily involve both leaflets uniformly: the posterior leaflet is most commonly involved, especially in its central third. When the anterior mitral leaflet is involved its posterior medial half is more apt to be affected than the anterolateral half. In mild cases, the valvular myxomatous stroma is enlarged on histologic examination, but the leaflets appear normal grossly. However, with increasing quantities of myxomatous degeneration the leaflets become thick, redundant, and thereby prolapse. The gross and microscopic changes described above need not necessarily be limited to the mitral valve leaflets because the mitral valve annulus and chordae tendineae may also be affected by the same pathologic process. King et a135bstudied the morphology and histologic characteristics of MVP with severe MR and compared them with normal mitral valve. Increased surface area, increased diameter, and decreased density were noted on gross morphology, whereas thinning, fragmentation, and loss of fiber orientation were noted on histologic specimens. Similar changes were also present in the chordae tendineae. In addition, myxomatous proliferation is not restricted to the mitral valve apparatus because it has been noted to occur in the other cardiac valves, particularly in those patients who have Marfan’s syndrome. Histologic evidence of a left ventricular myocardial abnormality has been described on biopsy. 36 A reduced ability of cardiac tissue to metabolize norepinephrine by monamine oxidase has also been reported.37 Considerable confusion surrounds the concept of myxomatous degeneration of the cardiac valve and its relation to various diseases. However, general agreement exists about the histologic pattern of myxomatous degeneration as described by Sherman et a1.38Myxomatous degeneration is pathologically characterized by destruc-

SYNDROME

OF MITRAL

VALVE PROLAPSE

37

Fig. 1. (A) Gross appearance of normal MV, as viewed from LA at autopsy of a noncardisc patient. (6) Gross appearance of the MVP of both anterior and posterior mitral leaflets as viewed from the LA. The leaflets are thickened, redundant, and have prolapsed into the LA above the MA. LA, left atrium; MV, mitral valve; LAA, left atrial appendage: MA, mitral annulus; C, Chordae. (Reprinted with permission.“)

tion and loss of normal valvular architecture accompanied by an increase in the ground substance without any accompanying inflammatory reaction. Biochemical studies have shown that the abnormally increased ground substance involved in myxomatous degeneration is an acid

mucopolysaccharide. Numerous conditions, ineluding aging, rheumatic heart disease and Marfan’s syndrome have been associated with secondary myxomatous degeneration of cardiac valves. Primary myxomatous degeneration, however, remains distinguishable from these entities because

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Fig. 2. Gross appearance of an opened mitral valve excised from a patient with MVP. In addition to the redundance of both anterior (A) and posterior (PI leaflets of the mitral valve there is an increased (normal 9.0 to 11.0 cm) annular circumference. (Reprinted with permission.“)

of the lack of associated abnormalities. Electron microscopy has shown haphazard arrangement, disruption and fragmentation of collagen fibrils. PATHOGENESIS

Just as the etiology and clinical manifestations of SMVP are diverse, so is its pathogenesis. Several interesting and pertinent observations have been made in this respect since 1963, as discussed below. Decreased Production of Type III Collagen

This is a characteristic biochemical abnormality in patients with Type IV Ehlers-Danlos syndrome which consistently produces MVP. Normal mitral valve tissue contains all three types of collagen, ie, Type I, II, III, and A-B. Jaffe et aP9 studied production of Type III collagen by using cultured skin fibroblast from the family members of a proband with classic Type IV Ehlers-Danlos syndrome. Production of Type III collagen was 21.53 f 2.0% of the total production in eight control subjects and was reduced to 12.08% + 3.7% in patients with MVP. They found that the biochemical abnormalities in the production of Type III collagen and echocardiographic findings of MVP were completely concordant. All patients with abnormal production of Type III collagen had MVP and all subjects with normal production of Type III collagen had entirely normal echocardiograms. Because of this consistent and concordant association of abnormal production of Type III collagen and MVP the authors suggested that this abnormality of collagen may play a pathogenetic role in the development of MVP. Therefore, it appears that skin analysis may prove to be a practical and sensitive method to evaluate the abnormal production of Type III collagen in the pathogenesis of MVP.

Fig. 3. (A) Microscopic section of the mitral vafve from a patient who had SMVP. There is evidence of extensive myxomatous degeneration in the center and absence of collagen fibers and inflammatory reaction (hematoxylineoein stain; original magnification x40). (B) Same section stained with toluidina blue: original magnification x40. The purple-reddish areas of staining signify myxomatous daganeration with absent collagen fibers. The blue stained areas indicate absence of myxomatous degeneration and presence of collagen fibers.

However, further studies of a large number of patients are necessary to test this hypothesis and the possibility that MVP may represent a forme fruste of Type IV Ehlers-Danlos syndrome. A reduction of Type III A and B collagen has also been found in patients with MVP without EhlersDanlos syndrome,40 and even the family members of SMVP patients may have decreased production of Type III collagen. Dysjunction of the Mitral Annulus Fibrosis

Hutchins et a141recently described dysjunction of the mitral annulus fibrosis in 92% of patients

SYNDROME

OF MITRAL

VALVE

PROLAPSE

who had a typical floppy mitral valve morphologically at autopsy. They define the dysjunction as detachment between the atria1 wall-mitral valve junction and the left ventricular free wall. The same process was noted in only 5% of hearts of patients without floppy mitral valves. Based on these results they concluded that the finding of a floppy mitral valve is significantly associated with dysjunction of the mitral annulus fibrosis (P < .OOl). They hypothesize that floppy mitral valve develops from hypermobility of the mitral valve apparatus and that the hypermotility is usually secondary to the dysjunction of the mitral annulus fibrosis, an anatomic variation in the morphology of the annulus. Normally the left atria1 wall joins the mitral valve annulus and then is attached by connective tissue to the left ventricular free wall (Fig 4A).41b When dysjunction of the annulus fibrosis occurs, the connective tissue attachment between the left atrial-mitral valve with the left ventricle free wall is either absent or markedly displaced upwards (Fig 4B). However, it remains to be proved whether dysjunction of the mitral annulus fibrosis is the cause or the result of MVP. Most recently, the findings of Hutchins et al have been questioned. Angelini et a14’ found that dysjunction of the mitral valve annulus occurs in both control subjects and patients with MVP, and that this finding is actually an anatomic variant of normal morphologic characteristics of the left atrioventricular junction and its connection. However, this study

Fig. 4. Severe dysjunction (between the arrowheads of the mitral annulus fibrosis) complicated by rupture of the connective tissues of the ennulus (hematosylin-eosin, original magnification of A x3, of B x5). (Reprinted by permission of the New England Journal of Medicine, vol 314, pp 535-540, 1 986.4’)

39

was comparatively very small and until supported in its conclusion by a larger study, its findings cannot negate the important observations of Hutchins et al. Abnormal

Chordai Architecture

Van Der Bel-Kahn et a143studied ten patients with an average age of 58 years who underwent mitral valve replacement because of IMVP with severe regurgitation. None of these patients had evidence of Marfan’s syndrome, Ehlers-Danlos syndrome, or other systemic diseases that would indicate an underlying connective tissue disorder as the cause of MVP. They studied the morphology of the resected mitral valve specimens and found that there was marked variation in the chordal branching and the pattern of anchoring in each of the ten cases, rendering the most prolapsed part of the leaflet less well supported. Microscopically, the dominant pathologic change was myxomatous degeneration within the affected leaflet and chordae with secondary changes in both atria1 and ventricular surfaces. Based on their findings, the authors suggested that insufficient chordal support may have been responsible for the development of MVP through a process of chronic stress on the MVA, particularly in the subset of aged patients. Similar observations were made earlier by Becker and DeWit43b when they described a spectrum of normality of the mitral valve apparatus including the chordae tendineae relevant to the pathogenesis of MVP

40

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Further observations are needed before this hypothesis can be accepted as a significant pathogenetic factor in the development of MVP. Cardiomyopathy

Considering that the majority of the patients with SMVP have ST segment depression, T wave abnormalities, and cardiac arrhythmia at some point in their clinical course, it has been suggested that SMVP may be a form of left ventricular disease, possibly a localized form of cardiomyopathy. Ehlers et a144 were the first to recognize an unusual left ventricular contour in six women with SMVP. These authors noted a marked posterior-inferior bulging which encroached on the left ventricular cavity during systole. Later Gulotta et a14* described 26 patients with click-murmur and prolapsed mitral valve leaflets in whom contractility was quantitatively determined angiographically and was found to be markedly impaired in 13 patients with marked hypokinesia of the anterolateral wall of the left ventricle. Although the etiology of this localized form of cardiomyopathy is not known and resting global left ventricular function was found to be normal in the majority of cases, recent reports have emphasized abnormal performance of the left ventricle during isometric exercise.46 It is difficult to comprehend that MVP is responsible for the impaired regional ventricular contractility. On the other hand, it is likely that the latter may be responsible in some cases for both the MVP and the resulting MR. Crawford and O’Rourke47 recently reexamined the issue whether MVP is a cardiomyopathic state. They were of the opinion that the abnormal contraction pattern is a consequence of abnormal leaflet tissue motion during systole creating abnormal stress on the papillary muscle and supporting left ventricular wall and that there is insufficient evidence at present to attribute any histologic, metabolic, or angiographic abnormality described so far in SMVP to a primary cardiomyopathic state. Myocardial

Ischemia

Myocardial ischemia, causing papillary muscle dysfunction and thereby MR has been well known since its early description by Burch et a1.48 MR in such instances results from incomplete

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valve leaflet coaptation either because of an abnormal spatial relationship between the papillary muscle and mitral valve leaflet or by MVP resulting from the failure of ischemic or fibrotic papillary muscles to shorten during ventricular contraction. Tei et a14’ studied the pathogenesis of MVP in short-term experimental coronary occlusion in 12 closed-chest dogs. Two-dimensional echo was used to assess left ventricular function, the mitral valve complex and left atria1 size. Presence of MR was assessed by left ventricular contrast echocardiography. Thirty-seven coronary occlusions of up to ten minutes in duration were carried out in a proximal and distal location in the left anterior descending and the right circumflex arteries. MR as judged by a rise in the pulmonary artery wedge pressure was observed in 15 of 37 brief coronary occlusion experiments. MVP was noted in all 15 experiments as well as in four additional studies in which MR was not seen. The development of experimental MVP was explained by measurements that demonstrated a relative displacement of the papillary muscle tip towards the mitral orifice. The authors concluded that MVP is a common sequela of short-term coronary occlusion and is often associated with MR. Relative displacement of an ischemic papillary muscle towards the mitral orifice appears to be the likely mechanism of acute ischemic MVP. While this hypothesis cannot explain the pathogenesis of MVP in all patients, it has important implications in those who have ischemic heart disease as the underlying etiology for MVP. Neuroendocrine-Cardiovascular

Considerations

The anxiety, tachycardia, dysrhythmia, atypical chest pain, postural hypotension, and ECG abnormalities in patients with SMVP suggest a metabolic abnormality consistent with a hyperadrenergic state. The possibility of a neuroendocrine-cardiovascular disorder as the underlying pathogenetic mechanism for SMVP was studied by Boudoulas et a?’ in 20 symptomatic patients with auscultatory and echocardiographic confirmation of MVP. Serum T,, T,, and plasma cortisol were normal in all patients. Patients with MVP also had normal responses but higher glucose levels than controls in response to oral glucose administration. Twenty-four-hour urinary epinephrine and norephrine excretions were

SYNDROME

OF MITRAL

VALVE

PROLAPSE

greater than normal. A shortened electromechanical systole corrected for heart rate (QT,) was also present. Frequent ventricular premature contractions with couplets and triplets were found in 14 patients. Increased catecholamine excretion and frequency of PVCs were correlated during the day and both parameters decreased at night. The catecholamine increase in response to exercise was greater in patients in whom the number of PVCs increased to more than ten per minute compared with patients in whom the PVCs remained relatively unchanged. Based on these results the authors concluded that patients with SMVP have high adrenergic tone that might contribute to their multiple symptoms. Pasternac et al” studied total plasma catecholamine levels, plasma norepinephrine levels, heart rate, and systolic and diastolic pressure in 15 patients with SMVP and 19 control subjects in the supine and standing position. In all 15 symptomatic patients, total plasma catecholamine levels and plasma norepinephrine levels were significantly elevated in both the supine and standing position and heart rate was slower than in normal subjects in the supine position but returned to normal in the upright position. In addition to the above abnormalities, the authors associated supine bradycardia with increased parasympathetic tone and postulated dual autonomic dysfunction in patients with SMVP. However, Chesler et a152failed to find any significant difference between plasma norepinephrine levels, heart rate, and BP before, during, and after tilt in six men and five women who had MVP compared with 11 control subjects matched by age and sex. These authors concluded that a hyperadrenergic state was not an integral component of SMVP. They did, however, acknowledge that the symptoms resulting from anxiety are probably adrenergically mediated, but this probably represents a coincidence of two common conditions encountered in medical practice. Davies et a153studied nine women with SMVP whose symptoms and signs suggested P-adrenergic hypersensitivity and seven normal volunteer women. They found that quiet standing (five minutes) increased both heart rate and plasma norepinephrine (P < .05) in patients with SMVP but not in normal control subjects. The dose of isoproterenol required either to increase heart rate 25 beats per minute or to decrease mean

41

arterial pressure by 20 mmHg was significantly less in patients with SMVP than in normal controls. SMVP patients were desensitized by a four-hour isoproterenol infusion whereas sensitivity in normal control subjects did not change. The authors also found that in patients with SMVP baseline ,f3-adrenergic receptor coupling was elevated compared to that in the control subjects. Isoproterenol infusion desensitized and induced uncoupling of these patients but did not alter coupling in normal volunteers. They concluded that there was evidence both of physiologic and pharmacologic ,8-adrenergic hypersensitivity in vivo directly corresponding to biochemical supercoupling in a subset of patients with SMVP. PATHOPHYSIOLOGY

Chest Pain It has been ascribed to various causes including compression of the left circumflex coronary artery in the atrioventricular groove by the prolapsing leaflet, interference with papillary muscle blood supply, arteriosclerotic coronary artery disease, and psychologic factors. Most recently, LeWinter et a154 postulated that chest pain in SMVP may be related to a discrepancy between myocardial oxygen demand and supply within the MVA. To test this hypothesis, they selectively increased afterload by means of an infusion of phenylephrine in patients with clickmurmur syndrome with or without a history of antecedent chest pain. Of nine patients with a history of antecedent chest pain, eight had precordial pain during infusion of phenylephrine. Of 12 patients with no previous history of precordial pain, only one had pain with infusion of phenylephrine. These investigators were able to document that the presence of pain during infusion and disappearance of pain after discontinuation of infusion occurred at similar levels of systolic arterial pressure. In patients with SMVP the pain began to diminish at almost precisely the point at which it had appeared, and completely dissipated with further decline of systolic pressure. In view of their findings, they proposed the following mechanism to explain the pathogenesis of precordial chest pain in SMVP. The areas at the base of the papillary muscle are subject to the greatest amount of tension during systole in comparison with other areas of the left ventricle.

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As the mitral valve leaflet prolapses into the left atrium during systole, it is likely that myocardial wall tension in the area of the papillary muscle increases. As a result of this regional alteration in wall tension, a localized discrepancy between myocardial oxygen supply and demand occurs within the MVA. An agent that selectively increases myocardial wall tension by increasing afterload would accentuate this discrepancy and therefore induce transient chest pain. This effect would be expected to be particularly pronounced in patients with a clinical history of atypical chest pain if such discomfort is indeed the result of an imbalance between myocardial oxygen supply and demand. Thus it appears that spontaneous variation in systemic arterial pressure produces a discrepancy between myocardial oxygen supply and demand and may cause precordial chest pain in ambulatory patients with SMVP. Natarajan et a15’ performed atria1 pacing in 23 patients undergoing cardiac catheterization for MVP. Seven of these patients demonstrated lactate production or less than 10% lactate extraction during pacing tachycardia and two showed these abnormalities at rest. Only five patients developed chest pain during pacing and only two had associated ST depression. Since none of these patients had epicardial coronary artery disease on coronary angiography, the findings were attributed to a defect in myocardial lactate metabolism.

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tion originating in the mitral valve leaflet could propagate into the left atria1 wall. These findings suggest that the mitral valve and adjacent left atria1 wall could act as a site of ectopic impulse initiation. Even though it has been conclusively demonstrated that muscle fibers normally exist in mitral valve leaflets in man, it remains to be determined if they are capable of developing spontaneous diastolic depolarization and automatic impulse formation. Zeilenga and Criley” are of the opinion that there is a functional and anatomic basis for the dysrhythmias frequently encountered in SMVP. They postulate two mechanisms by which mitral valve dysfunction and ectopic impulse formation may be related: (1) mechanical stimulation of the left ventricle or left atrium by excessive movement of the prolapsing valve leaflet and (2) ectopic impulse formation in the myocardium from stretching of the valve leaflet. It appears doubtful if a single pathophysiologic mechanism can explain the various cardiac arrhythmias in patients with SMVP. The mechanism at best is multifactorial, and one possibility that has received very little attention in man is initiation of the ectopic impulse formation within the mitral valve stoma itself. One clinical observation that partially supports this possibility is the not infrequent cessation of arrhythmia after mitral valve replacement. Mitral

Cardiac Arrhythmias

The exact pathophysiologic mechanism of the arrhythmias in SMVP is not well understood. It has been variably attributed to neuroendocrine cardiovascular imbalance (see Pathogenesis), a high incidence of accessory bypass tracts (see Electrocardiography in Diagnosis), mitral valve abnormalities, and/or a regional ischemic process. 56 Wit et als7 performed microelectrode studies on isolated canine anteromedial left atria1 wall preparations with the anterior mitral valve leaflet attached. Muscle fibers in the mitral valve leaflets were capable of developing spontaneous diastolic depolarization which resulted in automatic pulse initiation when they were exposed to epinephrine or when they were stretched. Spontaneous diastolic depolarization and automaticity also occurred without pharmacologic and other experimental intervention. Spontaneous activa-

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Regurgitation

Roberts et als9 studied 83 patients (age 26 to 79, mean 60)-26 women (31%) and 57 men (69%)-with SMVP severe enough to warrant mitral valve replacement. They found two major mechanisms for severe MR: (1) dilatation of the mitral annulus with or without rupture of chordae tendinae and (2) rupture of chordae tendinae with or without dilatation of the mitral annulus. In three patients the mechanism of MR was uncertain. Regional Left Ventricular

Dysfunction

Nutter et a16’ after studying a group of 26 patients (2 1 females, five males with mean age of 46 years) with respect to left ventricular structure, function, and the coronary circulation proposed a pathophysiologic mechanism (Fig 5)60 to explain the clinical and angiographic findings of SMVP. Three major patterns of ventricular con-

SYNDROME

OF MITRAL

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PROLAPSE

a negative interference with this balance occurs, causing an increased traction on the papillary muscle and a concomitant dilatation of the annular ring, thereby leading to further MVP and regionallwleft ventricular dysfunction. DIAGNOSIS

/

.

FOCAL PAPILLARY OR SUBJACENT VENTRICULAR DYSFUNCllON - ISCHEMIA 1 1 t REGlOtuL Pm+ mNo~AL “ENTRICULAR ARRHYTHMllS DILATATION B YENTRCULAR DrFUNCTlON VECTOR CONTwcllON caNcJRM*LITIE* n3ond.. cdormltm.“~

Fig. 5. A MVP (Reprinted

proposed pathophysiologic with permission.W)

mechanism

of

traction were identified: (1) normal in 7; (2) abnormal, usually an inferior deformity and/or anterior asynergy in 8, and (3) hyperkinetic in 11. Normal resting left ventricular function as assessed by an ejection fraction of >55% was present in 7/25 (68%). Selective coronary angiography was essentially normal in all 2.5 patients studied, and an ischemic ECG response was detected during maximal exercise testing in only l/12 and in none of the ten atria1 pacing stress tests. Myocardial lactate extraction did not change significantly during atria1 pacing in six patients. The authors concluded that cardiomyopathy does not appear to be a primary pathogenetic mechanism of IMVP. No abnormalities of the coronary circulation or of myocardial metabolism were demonstrated. They proposed that in some patients with SMVP the basic process may progress to significant mitral regurgitation, ventricular dilatation, and dysfunction of the papillary muscle. They felt that the characteristic ventriculographic deformity, ischemic ECG, and many of the sometimes life-threatening, recurrent ventricular arrhythmias are the result of regional ventricular dysfunction related to abnormalities in the papillary muscle rather than a diffuse cardiomyopathy or some generalized disorder of the coronary circulation or myocardial metabolism. Bryhn and Girding 61 developed a dynamic model to explain some of the clinical and morphologic findings in IMVP. The authors explain that in normaI patients the mitral leaflets, annular ring, chordae tendineae, and papillary muscle represent a functional entity balanced by pressure forces from the left ventricle acting upon the leaflets. When the leaflets are larger, as in MVP,

The diagnosis of SMVP can be either easy or extremely difficult because its manifestations can be subtle and extremely diverse. Both under- and overdiagnosis have been nagging problems to most practicing physicians, because of a potential significant impact on employment, securing life insurance, and most of all the physical and psychic health of any given individual. By observing the following sequence of clinical and laboratory evidence it is possible to arrive at the proper diagnosis in the majority of patients. Symptoms They are often nonspecific and range between no symptoms to sudden unexpected death. It is estimated that only 20% of patients with MVP are asymptomatic. 62 Palpitation, light-headedness, dizziness, atypical chest discomfort, and panic attacks occur in 80% of patients with SMVP. However, none of these symptoms is entirely specific for SMVP, and considerable discrepancy as to the prevalence of symptoms exists between controlled, improperly controlled clinical series, and population-based studies due to selection bias. For example, Savage et alz3 in their Framingham Heart Study experience reported that chest pain, dyspnea, or syncope were not specifically associated with MVP. Devereux et al63 most recently reported that in adult patients with SMVP palpitations were more frequent than among control subjects, whereas no difference existed in the prevalence of chest pain, dyspnea, or anxiety related symptoms. However, Arfken et a164 in a study of 591 children (age 9 to 14 years) found no difference in the prevalence of fatigue, palpitations, dizziness, or dyspnea on exertion among 31 children with SMVP and those without it. Increased excretion of epinephrine and norepinephrine, presumably secondary to increased sympathetic tone, have been considered responsible for the development of at least some of these symptoms. When MR is severe or supervenes acutely due to ruptured chordae tendineae, then dyspnea on

44

minimal exertion, paroxysmal nocturnal dyspnea, and congestive heart failure supervene. Similarly, when SMVP is secondarily associated with other forms of heart disease, eg, atria1 septal defect or Marfan’s syndrome, symptoms produced by the primary disease may predominate. Signs

These are many and varied and can be grouped under two categories, noncardiac and cardiac. Noncardiac. Patients with SMVP have some common anthropometric characteristics. Schutte et al65 studied the height, anterior-posterior (AP) diameter of the chest, and long arm span in 60 patients with MVP, 21 first degree relatives and a control group of 57 normal women. They found that women with MVP as well as their first degree relatives usually tend to be taller, thinner, have a narrow AP diameter of the chest and long arm span. We have made similar observations in men. The association of SMVP with these skeletal abnormalities may represent a forme fruste of Marfan’s syndrome. Patients with MVP also have a high incidence of straight back and pectus excavatum. In a recent series of 50 patients with straight back syndrome, 64% had MVP whereas only 17.5% of age- and sex-matched controls demonstrated similar pathology on echocardiogram. Accentuated kyphosis and thin ribs are also common. Recently, Rosenberg et a16’ detected hypomastia in 61% of patients with echocardiographically proven MVP as compared with 24% of the controls. The association between MVP and the various musculoskeletal abnormalities and the hypomastia can be explained by the fact that the mitral valve undergoes embryologic differentiation at the sixth week of fetal life about the same time the vertebral column and thoracic cage develop their shape and form through chondrification.68*69 The breasts, which in large part are of mesenchymal origin, undergo prirnordial development during the same time. Cardiac. The jugular venous pulsation and peripheral arterial pulsation are usually normal. However, when arrhythmias are present, frequent extrasystoles will be noted in the arterial pulse. Orthostatic hypotension is common and may be the unappreciated mechanism responsible for some of the nonspecific symptoms of SMVP such as light-headedness, dizziness, or

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syncope. 7oCoghlan et al” studied heart rate and BP response to a standardized valsalva maneuver and postural test in 44 untreated patients with proven MVP and 1.5 healthy subjects of similar age who served as controls. The directional changes of BP and heart rate were similar in control subjects and patients in both tests, but patients with SMVP differed from the controls by their widely oscillating heart rate during upright posture, their exaggerated and prolonged bradycardia during the recovery phase of the valsalva maneuver, and following their return to recumbency in the postural test. The patients also showed a greater respiratory variation of R-R interval which became especially marked during adjustment to changes of posture. The authors postulated an abnormal central modulation of baro-reflexes as the best explanation of the dysautonomic responses of patients with SMVP. Palpation of the chest may show an active left ventricular impulse mostly due to an asthenic build. A hyperdynamic left ventricular heave suggesting MR is rare unless significant MR is present. The first and second heart sounds are usually normal; however, a loud mitral component of S, at the apex in patients with nonrheumatic mitral regurgitation suggests the possibility of holosystolic MVP.72 The intensity of the heart sound was reduced in patients who have acute MR due to flail mitral leaflets, but the intensity of the first sound did not differ in controls and in patients with mid to late systolic prolapse. The auscultatory hallmark of SMVP is a nonejection midsystolic click or series of clicks beginning usually 0.14 second after S,. In some patients it has a scratchy quality and in others it may mimic the sound of a prosthetic valve. It is most commonly audible along the lower left sternal border. Although most commonly noted to occur at midsystole, the click has been noted to occur in both early and late systole, depending upon the timing of the MVP. The origin of the click probably lies in the tensing or snapping of the chordae rather than the prolapsing leaflet because it does not always correlate with the onset of prolapse on echocardiogram. The click is often, though not invariably, followed by a mid to late crescendo systolic murmur that continues up to A,. This

SYNDROME

OF MITRAL

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PROLAPSE

murmur is similar to that produced by papillary muscle dysfunction. In general, the duration of the murmur is a function of the severity of MR; however, when the murmur is confined to late systole, MR is usually not severe. As the MR becomes more severe, the murmur commences earlier and becomes holosystolic.73 Another unusual sound associated with MVP is the precordial honk or whoop. It is an intermittent, loud, resonant sound usually heard at the apex late in systole and it is frequently preceded by a midsystolic click. It has been shown by intracardiac phonocardiography that the whoop arises from the mitral valve and represents MR. Pansystolic murmurs occur in 10% of patients with SMVP. Most of these patients have holosystolic MVP on echocardiogram. In the auscultatory diagnosis of SMVP it should be emphasized that the timing of the click, the murmur, or both is important rather than the intensity of either. MR can be present without an audible murmur but demonstrable by echo-Doppler studies. One peculiar feature of the above described auscultatory findings in patients with SMVP is their variability not only from one patient to another but also in the same patient on different occasions. For example, some patients with SMVP exhibit both midsystolic click and mid and late systolic murmur; others present with one or the other of these two common findings; still others have only a click on one occasion and only a murmur on the other and both on a third examination, and no auscultatory abnormality at all on a fourth.73 Rarely, MVP can also cause an early diastolic sound or a murmur best heard at the apex or left sternal border approximately 70 to 100 ms following A,, at a time when the prolapsed mitral leaflet is returning from its journey in the left atrium.74 The auscultatory and phonocardiographic findings of SMVP are sensitive to physiologic75 and pharmacologic intervention and recognition of the changes induced by these interventions is of value in the diagnosis of SMVP. As a rule, any maneuver that decreases left ventricular volume such as standing, reduction of impedance to left ventricular outflow, reduction in venous return, and augmentation of contractility will result in an earlier occurrence of prolapse during systole. As a consequence, the onset of the click-murmur

45

will move closer to S,. Conversely, when the prolapse is severe or left ventricular size is markedly reduced or both, prolapse may begin with the onset of systole and as a consequence the click may not be audible and the murmur may be holosystolic. 73 On the other hand, when left ventricular volume is increased such as during squatting, increasing venous return by leg raising in the supine position, reduction of myocardial contractility, bradycardia, or an increase in impedance to the left ventricular emptying, the onset of both the click and murmur will be delayed (Fig 6).76 Indeed, if the left ventricle becomes extremely large, prolapse may not occur at all and abnormal auscultatory features may disappear entirely. Psychological stress may also increase the intensity of the click and exacerbate arrhythmia in MVP, a finding that may explain the intermittency of auscultatory findings and arrhythmias in patients with SMVP.” Because of the side effects and cost involved in administering them, pharmacologic maneuvers have been replaced by physiologic maneuvers in eliciting auscultatory findings of MVP in difficult cases. The most useful and simple physiologic maneuver at the bedside is auscultation in the supine, sitting, and standing positions with or without isometric hand grip.

Fig. 6. External phonocardiogram recorded at the fourth intercostal space on the left sternal border end apex show that as the patient moves from supine to the standing position, the systolic click and late systolic murmur migrate towards first heart sound (S,) coincident with decreased ventricular volume. earlier MVP, and more prolonged MR. In addition, heart rate increases when the patient stands. Upon squatting the patient’s heart rate slows; ventricular volume increases: MVP and MR occur later; and the click murmur becomes late systolic. SC, systolic click: SM. systolic murmur. (Reprinted with permission.)

46

ECG The major ECG abnormalities associated with SMVP are partially or totally inverted T waves in leads II, III, and AVF, with or without ST segment depression, occasionally involving the left precordial leads and rarely the right precordial leads.78 Some authors have attributed these changes to strain or ischemia of the papillary muscles and endocardium secondary ‘to prolapse of the mitral valve leaflet.7g Pocock and Barlow” advanced a similar- explanation and considered that forceful contraction of the papillary muscle might occlude or thrombose its rather tenuous vascular supply. There is some similarity between the ECG changes of SMVP with those seen in patients with neurocirculatory asthenia and/or hyperventilation syndrome. To study this problem, Abinader” studied ST-T ECG changes in 35 patients following oral administration of 40 mg of propranolol. Twenty-eight patients showed improvement. The author argued against a systemic etiology in these patients and suggested the possibility of sympathetic overactivity and autonomic imbalance as the basis for the ECG changes of SMVP. Our observation has been similar (Fig 7). Other common ECG features seen in patients with SMVP range from rare supraventricular or ventricular premature contractions to recurrent life-threatening supraventricular and ventricular tachyarrhythmia as well as conduction abnormal-

Resting ECG in a 26-year-old woman with Fig. 7. SMVP. The ST-T wave changes seen in inferior leads at rest became more prominent in the standing position when sinus tachycardia developed. These changes were corrected after 40 mg of propranolol. The improvements suggest blockade of excess sympathetic-neuroendocrine activity, particularly in the standing posture.

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ities. Such cardiac arrhythmias constitute an important component of the SMVP.** Although almost all types of cardiac arrhythmia have been noted in patients with SMVP, the most common are supraventricular and ventricular premature contractions and supraventricular and ventricular tachycardias. Indeed, it has been said that SMVP should be considered in any patient with otherwise unexplained recurrent supraventricular and ventricular tachyarrhythmia. However, bradycardia due to sinus node dysfunction and varying degrees of atrioventricular (AV) block have also been observed.83*84The mechanism and pathogenesis of cardiac arrhythmias are not clear but some relevant experimental and clinical observations have been made (see Pathophysiology). Serious ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation are significantly more common in patients who also have repolarization abnormalities with prolongation of the QT interval corrected for heart rate (QT,.). Occurrence of sudden cardiac death in patients with SMVP is rare and occurs in only approximately 1% of those patients who have recurrent ventricular arrhythmias.85 There is high incidence of Wolff-ParkinsonWhite syndrome (WPW) in patients who have SMVP. However, the absence of ECG evidence of WPW should not be taken as evidence against the existence of accessory bypass tracks in patients with SMVP who suffer recurrent attacks of supraventricular tachyarrhythmia. It is estimated that in the general population approximately 20% of patients with paroxysmal supraventricular tachycardia have an accessory bypass track whereas the incidence in patients with SMVP is three times as great. Often such bypass tracks are located on the left side. These and other considerations suggest that patients with SMVP who develop recurrent supraventricular tachycardia should be considered for electrophysiologic investigation. However, the clinical significance of inducible ventricular arrhythmias in patients with SMVP is uncertain.s6 Ware et als7 performed electrophysiologic studies in 60 patients with SMVP, 49 of whom had documented bradyarrhythmias while 28 had syncope. They found sinus node dysfunction in 8, prolonged HV interval in 10, intra-Hisian delay in 9, and functional bundle branch block in 15. Dual

SYNDROME

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PROLAPSE

AV nodal pathways were demonstrated in 24 patients. Comparison with 101 similarly symptomatic patients without SMVP revealed a greater prevalence of dual AV nodal pathways in MVP patients. The two laboratory tests that have been most frequently used in detecting and managing cardiac arrhythmia in patients with SMVP are the multistage exercise test and the 24-hour ambulatory ECG monitor. Both are extremely sensitive in detecting arrhythmias and should be considered complementary rather than exclusive of each other. However, one shortcoming of these tests is their variable reproducibility because of day-to-day variation of such arrhythmias in patients with SMVP. Kramer et al** questioned the previously selfevident tenet that patients with SMVP are remarkably prone to both supraventrictdar and ventricular arrhythmias. The authors compared ambulatory arrhythmias in 63 patients with SMVP and 28 symptom-matched control subjects. All patients were in normal sinus rhythm. Only small differences in the frequency and severity of supraventricular and ventricular premature contractions were noted between the two groups. The authors concluded that compared with similarly symptomatic controls, patients with SMVP do not have as high an excess prevalence of arrhythmia as previously described. However, when the results of the Framingham Study*’ were combined with the study of Kramer et al described above, the difference among SMVP and normals achieved statistical significance (28% v 17% P < .02). Phonocardiogram

Extracardiac and intracardiac phonocardiography, have been used extensively to study the click-murmur component of SMVP. However, as newer modalities, eg, echocardiography, were introduced, use of extracardiac phonocardiography for the confirmation of the clinical diagnosis of click-murmur component of SMVP has become less common. Chest Roentgenogram

In the majority of the patients with SMVP the chest roentgenogram shows no abnormalities of the cardiac silhouette, although left atria1 and left ventricular enlargement may be evident if

resulting mitral regurgitation is severe and longstanding. Calcification of the mitral valve or annulus is unusual in young patients with SMVP, although it could be present in the elderly. A high incidence of abnormalities of the bony thorax has been reported in patients with SMVP, including pectus excavatum (Fig 8), scoliosis (Fig 9) and straight back syndrome (Fig lo), or a combination thereof.g05g1 Echocardiogram

The echocardiogram has been the single most useful laboratory test for confirming the clinical diagnosis of SMVP. Shah and Gramiak” first reported the M-mode echocardiographic criteria for MVP. They described two distinctive echocardiographic patterns in 30 selected patients who were felt to have SMVP on clinical grounds. One was an abrupt posterior displacement in mid and late systole (Fig 11)g2 and the other was a hammock-like pansystolic displacement (Fig 12) in the mitral valve echogram of these patients. They concluded that M-mode echocardiography is a “useful diagnostic and investigative tool . . . in patients with MVP.” Since then it has been accepted that when posterior displacement exceeds 2 to 3 mm below the mitral closure line (CD), MVP is present. It should be noted that this 2 to 3 mm posterior displacement is entirely arbitrary and subject to a number of vagaries; thus, while helpful it is not completely reliable. However, when it is associated with other Mmode criteria described for echocardiographic diagnosis of MVP, ie, thickened mitral leaflets and increased diastolic excursion,g3 the diagnostic accuracy increases. When abnormal diastolic motion of the posterior mitral leaflet, coarse chaotic diastolic flutter of the mitral leaflet, and systolic fluttering of the leaflet and appearance of echoes in the left atrium during systole are noted, then the possibility of flail mitral leaflet due to a ruptured chordae should be considered. When two or more of these findings are present in the same patient they are often diagnostic of a ruptured chordae. Approximately 10% to 20% of patients with auscultatory evidence of MVP have a false negative M-mode echocardiogram. Pharmacologic maneuvers do not significantly improve the sensitivity. In such patients sensitivity can be improved (20%) by performing the M-mode

48

Fig. 8. Chest x-ray prominence of the heart view. PA, posterior-anterior.

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PA (A) and right lateral (B) in a patient with SMVP and pectus excavatum. Notice the left-sided on the PA chest x-ray due to the compression from the pectus excavatum (arrow) in the right lateral

echocardiogram in the standing position as well as the supine position94 (Fig 13). This echocardiographic phenomenon appears to be analogous to the absence of the systolic click or murmur in the supine position which becomes apparent in the standing position. Alternatively, a 2D echo can be used to confirm the diagnosis of MVP in those patients who have false negative and/or a nondi-

agnostic supine echo in the presence of a systolic click-murmur. With the advent of the 2D echo the echocardiographic diagnosis of MVP became more accurate because the plane of the mitral annulus is clearly visible as a reference point. Both parasternal long axis and apical four-chamber views appear to have equal sensitivity in detecting MVP. The

Fig. 9. (A) PA chest x-ray showing scoliosis of the lower thoracic spine (arrow) in a young woman with SMVP. (81 Lateral chest x-ray of the same patient demonstrating normal antero-posterior diameter.

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Fig. 10. Chest x-ray with PA (A) and right lateral (B) in a patient with BMVP associated with straight back. Notice that the cardiac silhouette is normal but there is marked narrowing of the anterior-posterior diameter of the chest due to straightening of the upper dorsal spine posteriorly.

most important 2D echo characteristics of MVP are systolic displacement of either the anterior or posterior leaflets into the left atrium beyond the mitral annular plane (Fig 14A), thickening of the mitral valve leaflets due to redundancy, dilatation of the mitral annulus, and coexistence of prolapse of the other cardiac valves. Other not uncommon accompanying echocardiographic findings in patients with SMVP are dilatation of the aortic root, probably related to myxomatous degeneration and aneurysm of the interatrial septum, probably related to left atria1 hypertension resulting from MR. The commonest accompaniment is tricuspid valve prolapse (Fig 14B). EKG

.,ii

The specificity of these criteria increases when regurgitation across the prolapsing valves (Fig 15A and B) can be demonstrated by color Doppler flow mapping (cDfm). Paradoxical motion of the posterior wall of the left ventricle during upright posture has been recorded in patients who did not show this abnormality in the supine position. g5 Flail mitral leaflet on 2D echo is diagnosed usually by the absence of leaflet coaptation (Fig 16) and a sudden whipping motion of the leaflet from the left ventricle into the left atrium. If resulting MR is acute in onset left atria1 size may be normal, but the left ventricle is often dilated due to volume overload. Vegetations superimposed on a prolapsing mitral leaflet usually appear as a focal echogenic density which does not involve the entire length of the leaflet. It EKG

:RV,

Fig. 11. M-mode echocardiogram in a 3%year-old woman with SMVP secondary to Ehlers-Danlos syndrome Type Ill. These is 4 to 5 mm posterior buckling in mid and late systole (arrow). (RV, right ventricle; IVS, interventricular septum: LPW, left ventricular posterior wall; AML. anterior mitral leaflet: PML, posterior mitral leaflet: CD. mitral valve closure line. (Reprinted with permission.“)

Fig. 12. M-mode echocardiogram in a 27-year-old young male with SMVP. Marked thickening of the anterior mitral leaflet due to redundancy and hammock-like pansystolic displacement of the mitral valve (arrows) are obvious.

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SUPINE M-mode echocardiogram Fig. 13. became apparent only in the standing

in an 18-year-old position.

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STANDING young

is often mobile and seen in both systole and diastole (Fig 17A and B). When performing an echocardiographic study, it is important to direct the echo beam to the junction of the mitral annulus and the posterior wall of the left atrium and ventricle in order to visualize the posterior leaflet adequately. Since it is possible to establish a false-positive diagnosis from tracings obtained only from the body of the leaflets, care must be taken to identify the mitral annular plane as a reference point and keep the transducer perpendicular to the chest wall during

male

in supine

and

standing

positions.

Late

systolic

prolapse

recording or derive the M-Mode tracing under 2D echo direction. Alpert et a196studied the sensitivity and specificity of various previously described 2D echo criteria of MVP in 70 patients with MVP and compared them with 100 normal control subjects. Specificity of individual criteria was uniformly high, ranging from 88% for excessive motion of the posterior mitral ring to 100% for several signs including systolic arching in the parasternal long axis view, excessive posterior coaptation, and diastolic doming of the anterior

Fig. 14. (A) Two-dimensional echocardiogram (apical four-chamber mitral leaflets above the annulus .plane% The dotted line represents tricuspid valve prolapse. The dotted lines represent the plane of mitral

viewj demonstrating the plane of mitral and tricuspid annuli.

thickening and prolapse of both annulus. (8) Coexisting mitraland RA, right atrium; LV. left ventricle.

SYNDROME

OF MITRAL

Fig. 15. Two-dimensional moder ‘ate MR jet (white (white and black arrows)

VALVE

arrow) in the

51

PROLAPSE

echocardiogram (apical four-chamber in the LA (A) and moderate tricuspid RA (B).

mitra .l leaflet. Sensitivity of individual criteria, howe ver, was low to moderate, ranging from 1% for a whipping motion of both mitral leaflets to 70% for excessive posterior coaptation of the

view) with regurgitation

color Doppler flow as demonstrated

mapping by two

showing independent

single jets

mitral leaflets in an apical four-chamber view. The highest sensitivity (87%) was associated with the presence of systolic arching of one or both mitral leaflets in the parasternal long axis

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Fig. 16. Two-dimensional echocardiogram iapical fourchamber view) of a 54-year-old Caucasian man who had acute MR due to ruptured ohordae tandineae. There is lack of coaptation of both mitral leaflets (arrow) and the coaptation point is displaced posteriorly due to a flail posterior mitral leaflet. The LA is normal whereas the LV is dilated due to volume overload.

view, systolic bowing of one or both mitral leaflets in the apical four-chamber view, excessive posterior coaptation of the mitral leaflets, or any combination of these findings. This increase in sensitivity was achieved without sacrificing specificity (97%). Thus, individual 2D echo signs tested possessed uniformly high specificity but only low to moderate sensitivity; however, sensitivity can be markedly enhanced without sacrificing specificity by using a selected combination of echocardiographic criteria and the requisite that they be present in at least two different views.

Systolic Fig. 17. MVP demonstrating

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Morganroth et a197aproposed 2D echo as the best available standard for detection of MVP. They considered the presence of mitral leaflets above the level of the mitral valve annulus to be the hallmark of MVP because this criterion was absent in 24 patients who were also lacking auscultatory and angiographic evidence of MVP. However, this finding may vary in severity not only in different patients but also in the same patient on different occasions or even in two different cardiac cycles (Fig 18A and B). Considerable argument has resulted as to which view of the 2D echo has the best sensitivity of detecting MVP. Both parasternal long axis and apical four chamber views are now considered equally sensitive. In our experience all views are equally important because each one may demonstrate a different specific feature; eg, diastolic doming of the anterior mitral leaflet is best seen in the short axis view and superior systolic motion is best appreciated in an apical fourchamber view. The echocardiographic diagnosis of MVP becomes firm when it is documented in three out of four views. Levine and Weyman3 while pondering the question can MVP be separated from normal mitral valve closure, concluded that it is unlikely that the question of normality or abnormality will ever be answered unless a well-controlled study of a representative population is performed to determine whether any specific pattern of leaflet closure, size, or other feature correlates with a state of illness or conveys a prognosis

(A) and diastolic (B) frame of a 2-D echocardiogram (apical four-chamber a focal mobile echogenic density on the AML (arrows), suggesting infective

view) in a patient known to have endocarditis. VEG. vegetation.

SYNDROME

OF MITRAL

VALVE

The systolic frames Fig. 18. (A and B) representing two different cardiac cycles during a 2D-echo study (apical fourchamber view) illustrate the variable degree of the prolapse of the AML (arrow) in the same patient.

53

PROLAPSE

r l

*

*I

Icp

A

worse than those pertaining in their absence, ie, those that are operationally abnormal. It should be emphasized that 2D echo at the present time is not only a diagnostic but also an investigative tool for further study of the SMVP. The echocardiographic findings of MVP have also been reported to occur in a large number of first degree relatives of patients with established MVP but the diagnostic significance of this observation remains uncertain. However, 2D echo should not be used as a definitive test that can independently establish the diagnosis of MVP because no true gold standard is available against which the accuracy of the sensitivity and specificity of the various echocardiographic criteria of MVP can be measured with certainty. At the present time the clinical significance of mild systolic arching and bowing of the mitral leaflets into the left atrium in patients with no MR or symptoms and signs associated with SMVP remains undetermined. Levine et a1g7b in their retrospective study of 3 12 patients selected for the absence of forms of heart disease other than MVP found that there was a lack of association between leaflet displacement isolated to the apical four chamber view and independent echocardiographic evidence of abnormality, eg, left atria1 enlargement, leaflet thickness and MR. They concluded that MV displacement limited only to the apical four chamber view is, in general, a normal geometric finding probably related to systolic annulus non-polarity and is unassociated with other echocardiographic evidence of patho-

B logic significance. Thus it can best be said that while 2D echo can be used to confirm the clinical diagnosis of SMVP or to demonstrate and exclude other conditions that clinically mimic MVP, eg, hypertrophic obstructive cardiomyopathy (HOCM), aneurysm of the interatrial septum, etc, it probably should not be used as a definitive test that can independently establish the diagnosis of SMVP. Correlation with clinical findings, particularly auscultation in different postures should be emphasized to reduce the incidence of false positive and negative diagnoses of SMVP.” Panidis et al” performed pulse Doppler echocardiography (pDe) in 80 consecutive patients (22 men, 58 women age 38 f 16 years) who had MVP diagnosed by 2D echo and found that MR as assessed by pDe was common (69%) in patients with MVP but was usually mild and not always associated with an audible murmur. Significant MR (Fig 19) was rare (10%) and usually occurred in men with MVP who were more than 50 years old. Mild mitral regurgitation was noted in 59%. Come et al”“’ studied the prevalence of mitral, aortic, tricuspid, and pulmonary valvular regurgitation detected by pDe in 80 consecutive patients with MVP and also in 85 normal control subjects with similar age and sex distribution. Regurgitation was noted to involve any of the four cardiac valves and was clinically silent in the majority of patients. The prevalence of mitral and aortic regurgitation was significantly higher in patients with MVP than in normal subjects, suggesting that alterations in

54

Fig. 19. Pulsed Doppler echocardiogram of a patient known to have SMVP demonstrates the presence of moderate Ml? in the LA. Interrogation of the LA in an apical four-chamber view by a pulsed Doppler beam (vertical dotted line) detected the regurgitation jet up to the mid-left atrium. Because the regurgitation jet was going away from the transducer, its velocity is depicted below the zero line.

the underlying valve structure in the syndrome of valve prolapse may indeed be responsible for this regurgitation. While tricuspid regurgitation was more frequent in patients with prolapse (19%) than in normal control subjects (1 l%), this difference was not statistically significant. A Doppler signal of isolated late systolic tricuspid regurgitation, however, was detected only in patients with SMVP who had echocardiographic signs of tricuspid valve prolapse. The prevalence of a Doppler signal compatible with pulmonary regurgitation did not differ in patients with MVP and in normal subjects. However, it should be pointed out that interrogation of the right ventricular outflow tract was performed in all subjects just below the pulmonic valve; therefore the validity of this conclusion remains questionable.“’ Konicek et al”* studied 21 subjects with pDe before and after the subjects donated 550 mL of blood. Two subjects demonstrated minimal prolapse postphlebotomy but in only one echocardiographic view and without mitral regurgitation by pDe. The authors concluded there was no evidence that a pathologic degree of MVP can be produced in normal subjects by reduction in the blood volume. Abbasi et allo studied the comparative value of M-mode, 2D echo, and pDe diagnosis of MVP in 125 consecutive patients with or without a late systolic murmur. M-mode had a sensitivity of

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50% (62/125), 2D echo a sensitivity of 68% (85/125), and pDe a sensitivity of 72% (90/ 125). However, when all three techniques were combined, the echocardiographic sensitivity improved to 93% (116/125). Experience at our institution has been similar and we consider all three techniques for the detection of MVP as complementary. Accordingly, when MVP is the indication for the echocardiographic study, the technicians should be instructed to perform all three components unless otherwise specified by the attending physician. Such an approach is not only valid but justifiable when one realizes that echocardiographic features of MVP have a variable spectrum. Now that cDfm is being used more often in all echocardiographic laboratories it is probable that addition of cDfm will further increase the sensitivity of detecting MR in patients with MVP by 2D echo criteria but in whom pDe failed to reveal MR because of an extremely eccentric location of the regurgitant jet. Hemodynamics

Hemodynamic measurements are normal in the majority of patients with SMVP with absent or mild chronic MR. Observed abnormalities of increased left atria1 pressures, prominent and tall V waves in left atria1 or pulmonary capillary wedge pressure recordings are present in those patients who have acute MR due to ruptured chordae tendineae or superimposed infective endocarditis. Sometimes the V waves are so large that they can be detected in the pulmonary artery tracing itself. In the setting of left atria1 enlargement seen with chronic progressive MR due to MVP, however, V waves may be dampened and of normal or only slightly increase in amplitude because of increase compliance of the enlarged left atrium.lo4 Angiocardiography

Left ventricular tine angiocardiography provided the earliest evidence that abnormal superior systolic displacement of the mitral leaflets were responsible for the click and the late systolic murmur. Angiography still remains a source of diagnostic information but has rapidly given way to echocardiography because of the cost and invasive nature of the procedure. Not uncommonly, neither clinical nor echocardiographic examination will confirm all cases of MVP. Left ventricular tine angiography in such cases has

SYNDROME

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been helpful. The appearance of end systolic bulging of one or both mitral leaflets into the left atrium is considered diagnostic of MVP. The right anterior oblique projection is most useful for defining prolapse of the posterior mitral leaflet (Fig 20A) and the left anterior oblique projection for defining prolapse of the anterior mitral leaflet”’ (Fig 20B). Recent studies, however, have noted an inordinately high prevalence of angiographic evidence of MVP in a variety of cardiac disorders, reflecting a significant discrepancy between clinical and angiographic findings of MVP. Engle et al lo6 believed that this discrepancy results because some degree of systolic motion of the mitral leaflet towards the left atrium occurs even in normal individuals, particularly in the right anterior oblique projection. It is generally acknowledged that the difference between systolic mitral motion in the normal and in MVP patient is essentially a matter of degree. Only by accurate identification of the site of attachment of the posterior mitral leaflet to the mitral annulus and by measurement of the actual

distance of protrusion of the posterior mitral leaflet can MVP be diagnosed with certainty (Fig 21).‘06 Systolic protrusion of mitral leaflets >l 1 mm beyond a line between the fulcrum and long axis of the ventricle was not found in any normal subject but was present in 75% of patients whose physical examination and echocardiographic evaluation indicated MVP. This finding may be considered a quantitative angiographic criterion for the diagnosis of MVP. Angiographic appearance of the triscalloped structure of the posterior mitral leaflet in patients with MVP has also been described. to7 Barlow and Bosman108 emphasized the importance of the disappearance in diastole of the posterior mitral leaflet protrusion seen on the right anterior oblique view of the left ventricular tine angiogram as an important criterion for the angiographic diagnosis of MVP. In our experience the observation of this criterion is of the utmost importance to avoid a false positive diagnosis of MVP by angiocardiography. Other abnormalities noted on angiocardiography in patients with MVP include dilatation and calcification of the mitral annulus and poor

Fig. 20. (A) Systolic frame of a right anterior oblique left ventriculogram leaflet prolapse showing a triscalloped bulge (arrows). (B) End systolic demonstrating anterior leaflet prolapse. (Reprinted with permission.‘06)

from a patient with isolated frame of LAO left ventriculogram

posterior mitral in a patient

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etiologies. However, the ejection fraction at rest determined by radionuclide angiography tends to be normal in patients with MVP without significant MR. A small subset of patients do not exhibit a normal increase in ejection fraction during exercise, suggesting reduced cardiac reserve.log When there is involvement of both papillary muscles there may be indentation of the anterior as well as inferior wall of the left ventricle, giving the cardiac silhouette an hourglass appearance. It has been suggested that the left ventricular contraction abnormalities seen on angiocardiography may be primary but the bulk of the available evidence suggests that this is most likely secondary to redundancy of the mitral valve leaflets and transmission of abnormal tension of these leaflets to the papillary muscle and underlying left ventricle. Marked interobserver variability in angiographic assessment of MVP was pointed out by DeMaria et al”’ in 1977. Left ventricular tine angiograms were reviewed by 20 observers and in no instance was there complete agreement regarding the presence or absence of MVP, even in patients in whom the clinical assessment was unequivocal. Kennett et al”’ also showed marked intraobserver variability, particularly in defining which leaflet prolapsed. Cohen et a1112rightly pointed out that most of the angiographic studies of MVP have been carried out without knowledge of the precise anatomic correlation of various angiographic patterns and that the range of normal has not been well defined by this technique thus accounting for the intraobserver and interobserver variability. Fig. 21. (A) Early diastolic (top) and end systolic (bottom) frames from the right anterior oblique left ventriculogram, in a subject without MVP. The schematic diagrams at the right illustrate the technique used in identifying the posterior mitral fulcrum (f) and measuring the degree of MVP (d). Stippled area represents the inflow of nonopacified blood from the LA to the LV. (B) In a subject with MVP, the corresponding schematic diagram illustrates measurement as in A. D, maximum mitral protrusion behind and above L; F. mitral fulcrum: L. perpendicular from F to LA: LA, long axis LV; LOT, LV outflow tract. (Reprinted with permission from the American College of Cardiology, J Am Coll Cardiol. ~013, pp 1085-l 088. 1884.‘06)

contraction of the basal portion of the left ventricle. An increased rate of circumferential fiber shortening has been observed in the presence of significant MR as in patients with MR of other

Newer

Guidelines

Perloff et al1r3 in an effort to resolve the classical dilemma posed by the gray zone between normal and MVP recently proposed major and minor criteria analogous to the Jones’ criteria for rheumatic fever. Their sole objective was to provide clinicians with a more secure basis for diagnosis so that healthy, asymptomatic young persons will not be assigned an inappropriate diagnosis of heart disease. With that aim the authors assigned certain weights to various criteria, the sum of which was then used to argue for or against the diagnosis of MVP with a variable degree of probability. Symptoms were considered nonspecific because most if not all of the

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symptoms noted in MVP occur in other disease settings or in normal persons and because their causal relationship to MVP remains unsettled. These major and minor criteria are given in Table 3. Clinical Spectrum

In 1976 Lesch” pointed out that MVP has a variable clinical spectrum. Devereux et alli in order to determine the true spectrum of SMVP studied the relationship between clinical features of SMVP and echocardiographically documented MVP. They studied the clinical findings in 88 patients with echocardiographic MVP and compared them with those of 81 of their adult first degree relatives with MVP and in two control groups without MVP: 172 first degree relatives and 60 spouses. Comparison of the relatives with and without MVP demonstrated true associations between MVP and systolic click or murTable

Major

3.

Criteria Mitral

for Clinical Diagnosis Valve Prolapse

of

murs or both (67 v 9%, P < .OOl), thoracic bony abnormalities (41 v 16%, P < .OOl), systolic BP ~120 mmHg (53 v 31%, P < .OOl), body weight 90% or less of ideal (3 1 v 14%, P < .005) and palpitation (40 v 24%, P < .Ol). In contrast, relatives with MVP showed no significant increase over normal relatives or spouses without MVP in prevalence of chest pain, dyspnea, panic attacks, anxiety, or repolarization abnormalities, but these features were all more common in women than in men (P < .Ol). Thus the authors concluded that the basic spectrum of SMVP comprises low body weight, thoracic bony abnormalities, low BP, palpitation, midsystolic clicks, and late systolic murmurs. Other suggested clinical features including atypical chest pain, dyspnea, panic attacks, and ECG abnormalities appear to be associated with MVP because of bias and an erroneous classification of differences between men and women as being due to MVP. Having defined the basic spectrum of SMVP an expanded clinical spectrum of SMVP is presented (Table 4).

Criteria

DIFFERENTIAL

Auscultation Mid- to late systolic clicks and late systolic murmur or whoop alone or in combination at the cardiac apex Two-dimensional echocardiogram Marked superior systolic displacement with coaptation point at or superior Mild to moderate superior leaflets with Chordal rupture

of mitral to annular displacement

of mitral

Doppler MR Annular dilatation Echocardiogram plus auscultation Mild to moderate superior systolic

displacement

of mitral

leaflets

HOCM

leaflets plane

systolic

with

Prominent mid- to late systolic apex Apical late systolic or holosystolic

clicks

at the cardiac

murmur

in the

vow7 Late systolic whoop Minor Criteria Auscultation Loud first heart sound with

an apical

holosystolic

murmur

Two-dimensional echocardiogram Isolated mild to moderate superior systolic displacement the posterior mitral leaflet Moderate superior systolic displacement of both mitral leaflets Echocardiogram plus history Mild to moderate superior leaflets with Focal

neurologic

young First-degree Reprinted

with

relatives

of

Mid systolic clicks and late systolic murmurs have been reported in HOCM. The systolic murmur changes in intensity and duration with various postures, such as standing (increase) and squatting (decrease). The Valsalva maneuver is also another helpful bedside technique to differentiate between the two. While the systolic murmur of HOCM increases in intensity during Valsalva’s maneuver, the systolic murmur of MVP does not increase in intensity but may increase in duration. Pharmacologic maneuvers have also been described to differentiate between the two disorders. Following amyl nitrate inhalation the systolic murmur of HOCM becomes louder, whereas that of MVP either does not change or actually decreases. Similarly, following a premature beat the murmur of HOCM increases in intensity and duration, whereas that of MVP usually remains unchanged or decreases. Atria1 Myxoma

systolic

attacks

permission.“3

DIAGNOSIS

displacement

or amaurosis with

major

criteria

of mitral fugax

in the

Mobile, pedunculated left atria1 myxoma may prolapse to variable degrees and cross the mitral valve orifice, causing either obstruction to mitral inflow or mitral regurgitation. The resultant symptoms and signs often mimic those of mitral

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Table

Grade

4.

Clinical Mitral

0

Spectrum of Syndrome Valve Prolapse

Symptoms cardiac

Grade

I

Symptoms cardiac

be differentiated because each entity has its own characteristic findings.

of

and clinical features (both and noncardiac) absent but

echocardiogram other indications

performed positive

Aneurysm of the Interatrial Interventricular Septum

for for MVP.

II

Symptoms cardiac benign exercise, for MVP

Grade

pulsed Symptoms

Ill

and clinical features (both and noncardiac) present, cardiac arrhythmia at rest or positive echocardiogram and mild regurgitation Doppler. and clinical

features

by (both

cardiac and noncardiac) present, recurrent cardiac arrhythmia, positive echocardiogram for MVP with moderate MR by pulsed Doppler, left atrial enlargement but Grade

no left ventricular dilatation. Symptoms and clinical features (both cardiac and noncardiac) present,

IV

Coronary

echocardiogram positive for MVP, recurrent complex arrhythmia, progressive chronic atrial and ventricular Grade

V

MR with left enlargement.

Symptoms and clinical features (both cardiac and noncardiac) present, acute paroxysmal nocturnal dyspnea, due to acute MR (normal left atrium) resulting from flail mitral leaflet or ruptured chordae

Grade

tendineae infective Symptoms

VI

or superimposed endocarditis. and clinical features

cardiac and noncardiac) echocardiogram positive MR by Doppler, arrhythmia with or sudden The clinical

spectrum

described

(both

present, for MVP,

and complex recurrent syncope

death. above

is based

on the state

or

Both lesions have been reported to produce a midsystolic click and systolic murmur.1’5 Atria1 septal aneurysm as the only congenital problem rarely occurs in an otherwise normal heart. Most reports associate interatrial septal aneurysm with increased atria1 pressure and bulging of the interatrial septum into a low-pressure site. In rare occasions aneurysm of the interatrial septum and MVP have been noted to occur in the same patient. Aneurysm of the interventricular septum may develop during and following spontaneous closure of a ventricular septal defect but its association with MVP is rare. At the present time echocardiography and/or angiocardiography are the only means of establishing a definitive diagnosis in these situations.

and clinical features (both and noncardiac) present

and echocardiogram positive for MVP but absent MR by pulsed Doppler. No cardiac arrhythmia. Grade

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of

our current knowledge about SMVP. It is meant to serve as a guideline rather than a doctrine. It will obviously require periodic modification as concepts relative to SMVP evolve.

Artery Disease

Two common manifestations of coronary artery disease, ie, chest pain and ECG abnormalities, are also quite common in SMVP. However, in patients with SMVP the chest pain is often atypical, fleeting, and nonexertional in nature. Both coronary arteriography and exercise myocardial scintigraphy using thallium-201 are helpful in differentiating the two conditions. When thallium-201 imaging does not demonstrate regional myocardial ischemia, the diagnosis of SMVP unrelated to coronary artery disease is most likely. ‘16 However, when myocardial scintigraphy is abnormal, the possibility of MVP with or without associated coronary artery disease cannot be excluded because exercise induced myocardial perfusion defects have been described in patients with SMVP.“7 COMPLICATIONS

valve disease. Like SMVP, the symptoms of left atria1 myxoma are often nonspecific and variable, and the auscultatory findings change with body posture. Loud S,, particularly when split and accompanied by systolic murmur which is loudest at the apex, can mimic the click murmur component of SMVP. An early diastolic sound termed a “plop” if not properly timed may also become a source of confusion. Echocardiography is a reliable means by which the two diseases can

Even though the course and prognosis of SMVP is generally favorable and life expectancy often normal, complications nevertheless can occur in 10% to 30% of patients. These are discussed below in order of their frequency. Progressive Mitral Regurgitation

It is now well recognized and accepted that SMVP is probably the most common cause of chronic IMR in developed countries that have

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witnessed a significant decline in rheumatic heart disease.iiga Progression of MR occurs in a small number (5% to 10%) of SMVP patients and the factors which predispose to such progression are age (>50), sex (greater in the male), progressive mechanical dysfunction of the MVA, and healed infective endocarditis, and possibly hypertension.“sb Wilken et al’lgc studied the question of severe MR requiring surgery in patients with MVP in New South Wales, Australia. They found that the risk of developing severe MR was age and sex related. The risk is minimal before age 50, rises sharply thereafter, particularly in men, and increases further with advancing age. Approximately 4% of men and 1.5% of women with MVP will require corrective mitral valve surgery before age 70. Infective Endocarditis

Until recently, the absence of definitive data concerning the prevalence of MVP in an otherwise healthy population had created substantial uncertainty about whether MVP is an important risk factor for infective endocarditis. Clemens et a11’9a evaluated this particular risk in a casecontrolled study of hospital in-patients who had undergone echocardiography and who lacked any known cardiovascular risk factors for endocarditis apart from MVP and isolated MR. Thirteen (25%) of 51 patients with endocarditis had MVP as compared with ten (7%) of 153 matched controls without endocarditis. For the 51 matched case-controlled subsets, the 8.2% odds ratio (95% confidence limit 2.4 to 28.4) indicated a substantially higher risk of endocarditis for people with MVP than for those without it. This association remained statistically significant when parenteral drug abuse and routine antibiotic prophylaxis preceding dental work and other forms of invasive instrumentation were taken into account. These findings support the contention that MVP is a significant risk factor for endocarditis particularly when associated with any degree of MR. Similar conclusions were reached in a recent publication from France.119b MacMahon et al”’ estimated that the risk of endocarditis in SMVP is three times greater in men than women, with the risk in persons above age 45 being greater particularly when associated with MR. The absolute risk of endocarditis in persons with echocardiographic evidence of MVP without clinical or Doppler evidence of

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MR is not perceptively different than the risk in the general population. Nolan et al’*’ compared clinical features, response to therapy and outcome of endocarditis in ten patients with MVP and 23 patients with endocarditis involving other types of left-sided valvular lesions. They found that signs of endocarditis were more subtle in patients with MVP; hence, diagnosis and treatment were often delayed. However, 9/10 of the patients with MVP and endocarditis responded optimally to antimicrobial therapy; only 5/23 patients with endocarditis without MVP responded similarly. Thus it appears that endocarditis in patients with MVP is more responsive to antimicrobial therapy even though the recognition of infection is often delayed. However, endocarditis superimposed on MVP is not a benign infection because progressive mitral regurgitation is a frequent sequel. Cerebral Thromboembolism

In a study of 1,138 patients (mean age 48 years) with MVP, Sandok and Guiliani’22 encountered a 3.5% incidence of focal cerebral ischemic events and suggested that a conservative estimate for the prevalence of cerebral infarction and/or transient ischemic attack (TIA) in patients with MVP was four times greater than the rate expected in the normal population. They postulated that the thrombi originating on or near the mitral valve were responsible for these episodes. Barnett et a1’23 studied the incidence of cerebroischemic events in two groups of patients. The older group consisted of 144 patients over 45 years of age (mean 64.7 years) who had a TIA or partial stroke. MVP was found in only eight (5.7%) of these patients and in ten (7.1%) of 41 age-matched controls without similar symptoms. The second group consisted of 60 patients who had a TIA or partial stroke but were under 45 years of age (mean 33.9 years). MVP was detected in 24 patients (40%) but in only five (6.8%) of 60 age-matched (mean age 33.7 years) controls. The authors calculated the odds ratio, 9.33, was highly significant (P > .OOl) and suggested that MVP plays a role in cerebral ischemia and/or infarction, particularly in younger patients. However, more recently, Hart and Easton estimated that the incidence of CVA or TTA in young patients with SMVP is 0.02%, and in older patients SMVP is likely to account for only 1% of all strokes.

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What pathologic evidence exists for the occurrence of antemortem thromboemboli on the mitral valve? The evidence at this time is entirely derived from the autopsy studies of patients who had MVP and suffered a cerebrovascular accident or whose valves were excised at surgery. Thrombi consisting of platelets and a fibrin mesh, quite capable of producing vascular occlusion, have been demonstrated in the angle between the atria1 surface of the mitral valve and the left atria1 wall. Elam et a1’25 examined a group of former oral contraceptive users who had experienced cerebrovascular insufficiency for the presence of hypercoagulable states. They found that hypercoagulability in the form of decreased plasma antithrombin III activity, increased platelet aggregation activity and elevated plasma-B thromboglobulin level were noted in addition to increased cigarette smoking, vascular headaches, hyperlipidemia, and MVP in such patients. The authors hypothesize that a preexistent hypercoagulable state in such a subset of MVP patients will magnify the risk of oral contraceptive related cerebrovascular morbidity. Zuppiroli et a1’26 studied platelet function and coagulation studies in 28 consecutive patients with MVP, seven of whom had previously showed a cerebrovascular disorder. The platelet aggregation rate was found to be abnormal and in addition there was a significant rise of Factor VIII and WF:Ag and fibrinopeptide A. Six of the seven patients with cerebrovascular disorders had high levels of both of these factors, suggesting the existence of a particular subset of patients with MVP with a higher risk of thromboembolic episodes. Rupture

of Chordae Tendineae

Jeresaty et a1’27 found a 2% incidence of spontaneous rupture of chordae tendineae in their first 100 patients over a 13-year follow-up. Considering this low incidence in the light of increased prevalence of MVP that affects 5% of the general population, the risk of any patient with MVP having spontaneous rupture of the chordae tendineae is relatively small. However, there is no doubt that MVP appears to be the most frequent cause of spontaneous rupture of the chordae tendineae (Fig 22A and B) as indicated by the fact that it was the only underlying morphologic abnormality in 20/22 patients

Fig. 22. (A) Longitudinal section of the LA and LV in a 50-year-old Caucasian woman who died of acute MR due to ruptured chordae tendineae. The mitral valve is thickened and redundant, but note that the chordae tendineae have different degrees of thickness. Multiple ruptured chordae tendineae (arrows) can be noted and the portion of the mitral leaflets that were supported by these ruptured chordae tendineae has prolapsed into the LA above the mitral annular plane. The papillary muscles are intact. (5) Same specimen as viewed from above in the open LA. PLAW, posterior left atrial wall: MV, mitral valve; PM, papillary muscle; RCT, ruptured chordee tendineae; MA, mitral annulus: ALAW, anterior left atrial well; PPML. prolapsed posterior mitral leaflet.

SYNDROME

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VALVE

PROLAPSE

(88%) when 25 consecutive surgically proved cases with a ruptured chordae were examined histologically. Rupture of chordae tendineae usually manifests either as acute onset severe MR or else sudden worsening of the chronic MR in patients with MVP. This predilection is particularly striking for men over age 50. Sudden Death

Sudden death is an uncommon complication of SMVP, occurring only in a very small number of SMVP patients. In 1972 Gooch et a1,iz8 after reviewing 16 studies, reported an overall incidence of 1% to 2% of patients dying of sudden death (SD) due to SMVP. While there is some clinical evidence that the cause of SD is ventricular arrhythmia, this evidence is tenuous and has not been adequately documented. Ambulatory ECG monitoring demonstrated frequent ventricular premature contractions in up to 85% of such patients before death; however, the cause and effect relationship remains uncertain. Chesler et a1129found 39 reported cases of SD attributable to SMVP. However, in only 19 of the reported cases were autopsies performed but even among these cases the information was in many instances so sparse that other pathologic conditions could not be excluded. They described the clinical and pathologic features of 14 cases of SMVP with SD, presumably attributable to ventricular dysrhythmia. These patients were 14 to 59 years old (mean age 29 * 11 years), 11 were female and three were male. None of the seven ECGs available before sudden death showed prolongation of the QT interval, but two had minor repolarization changes. Various degrees of MVP, endocardial friction lesions, and thrombi located between the posterior mitral leaflet and the left atria1 wall containing fibrin and platelets were present. The authors postulated that these abnormalities may be important in the pathogenesis of ventricular dysrhythmia, a factor that continues to remain a prime suspect as a cause of SD in patients with SMVP. Davies et a113’ studied 13 cases of unexpected SD at autopsy in patients with SMVP during a 5-year period. More than two thirds of these cases had evidence of significant MR caused by rupture of the chordae tendineae. Recognition of a subset of SMVP patients at risk for SD is important, but unfortunately we do not yet have convincing markers to identify such a group. Moderate MR

61

and cardiac arrhythmias are at present the two markers commonly thought to be the precursors of SD, but the sensitivity, specificity, and predictability of these markers as yet are undetermined. Other possible mechanisms for SD in patients with SMVP could be sinus bradycardia and sinus arrest. Leichtman et a1131 have noted a high prevalence of bradyarrhythmias in patients with MVP. In their study of 11 members of a family with a high prevalence of MVP, seven were found to have documented sinus bradycardia. The authors postulated that one possible mechanism of SD in patients with MVP can be prolonged sinus arrest without junctional or ventricular escape. Clinical Markers

Recently, Devereux et a1,132in order to determine various factors influencing the strength of association between SMVP and MR, rupture of chordae tendineae and endocarditis, studied the prevalence of SMVP in patients with disease and compared it with both clinical and populationbased control groups. The prevalence of MVP was 4% in the control group population and was significantly higher in patients with endocarditis (16%) MR (55%) and rupture of chordae tendineae (63%). Odds ratios for complications in persons with MVP ranged from 4.6% for endocarditis to 41.4% for rupture of chordae tendineae in overall analysis and 6.8% for endocarditis to 53.0% for rupture of chordae tendineae based on age-and-sex-matched case control groups (P < .OOl for each). All complications occurred disproportionately in men with MVP, in whom the odds ratio ranged from 2.7 to 7.4% compared with an additional control group of unselected subjects with MVP. Compared with this control group, patients with MVP and endocarditis were slightly more likely to have a previously known heart murmur (odds ratio 3.2%) and significantly more likely to have murmurs at the time of evaluation (odds ratio 8.5%). Patients with SMVP and MR and rupture of chordae tendineae were also significantly older than unselected subjects with MVP. The concentration of risk of endocarditis in men with MVP and patients with antecedent murmurs suggest that infective endocarditis prophylaxis is warranted in these groups.

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MANAGEMENT

Because the SMVP is a heterogeneous entity with a wide and varied clinical spectrum, considerable controversy exists regarding its appropriate management, particularly in those who have minimal symptoms and the very young and the old. During the past 27 years it has become increasingly evident that the management of SMVP is dictated by the presence or absence of symptoms and signs in any given patient. Asymptomatic Mitral Valve Prolapse

Those patients who have no symptoms and signs of SMVP and in whom MVP was detected incidentally on echocardiogram performed for unrelated reason, should be reassured about the favorable prognosis and have periodic cardiovascular follow-up every two to three years. Most practicing cardiologists will agree that such patients should not be considered cardiac patients just on the basis of MVP until evidence of other cardiac abnormalities surfaces during follow-up, either on auscultation or resting ECG or ambulatory ECG monitoring. Whether or not such patients should receive endocarditis prophylaxis is a debatable issue. The problem is compounded by the fact that with the advent of the pDe, some of these asymptomatic patients have been found to have unequivocal MR despite the absence of click-murmur on auscultation and the absence of enlargement of the left atrium on echocardiogram. At our institution, if MVP is definitely present on the 2D echo, screening interrogation of the left atrium by pDe is performed, and if definite MR is present then this finding is communicated as such to the attending physician. He then is considered responsible for the final decision regarding the institution of prophylaxis before dental, genitourinary, and gastrointestinal (GI) surgery. In our opinion, patients who have MVP and definite MR by pDe are at an increased but unknown risk of endocarditis even during benign dental manipulation such as dental flossing, and therefore should receive prophylaxis even if they were to be asymptomatic or do not demonstrate clinical features of SMVP. Besides, the clinical hallmark of midsystolic click and late systolic murmur could be transient, and if not heard at the time of initial auscultation it does not necessarily mean that MVP is clinically absent, because these features may be audible on other occasions. Therefore, it is advisable that

ANSARI

patients who have MVP as an incidental finding on echocardiogram should be examined more carefully for the auscultatory findings of MVP in the supine and standing position as well as following hand grip exercise. Conversely, those patients who are asymptomatic but have definite auscultatory evidence of midsystolic click and late systolic murmur and whose echocardiographic findings are equivocal for MVP should be considered as having a benign cardiac valvular abnormality, and in addition to reassurance should receive prophylaxis. Here also the responsibility for making the decision of instituting prophylaxis resides with the attending physician. It is a common misconception among practicing physicians who seek echocardiographic confirmation of MVP in their patients that echocardiographers should indicate in their report whether or not the patient should receive prophylaxis. It cannot be overemphasized that the decision of instituting a life-long prophylactic measure should be based on the entire evaluation of the patient rather than a single laboratory test which has a significant element of intraobserver and interobserver variability. While there is no controversy regarding prophylaxis in patients with click-murmur syndrome,133 opinion at this time is not unanimous regarding patients who have only a midsystolic click but no systolic murmur. In such cases it is advisable to perform an echocardiogram with special attention to the interatrial and interventricular septum, because a midsystolic click can be produced by aneurysm of the interatrial or interventricular septum in the absence of MVP. In such patients prophylaxis is not indicated. However, those patients who have only a midsystolic click and show equivocal echocardiographic features of MVP should receive prophylaxis when MR is detected by pDe despite the absence of a murmur. Symptomatic Mitral Valve Prolapse

Patients with SMVP with a history of palpitation, dyspnea on exertion, light-headedness, dizziness, syncope, transient ischemic attacks, chest pain, cardiac arrhythmia on resting ECG or 24-hour Holter monitoring or following exercise testing, will require either medical or surgical management in addition to prophylaxis in order to control their symptoms and lead a normal life.

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Medical Management

Propranolol is the drug of choice for control of chest pain and cardiac arrhythmia. Either propranolol or diphenylhydantoin is useful in patients who have ventricular arrhythmias in the presence of prolonged Q-T,. Propranolol could be started in small doses of 10 mg four times a day and then tailored either up or down until the desired effect is reached. Objective evidence can often be achieved in this respect either by repeat 24-hour ambulatory ECG monitoring or multistage exercise testing.‘34 Similarly, diphenylhydantoin can be started with an initial dose of 100 mg three times a day and the dose adjusted until the desired effect is reached. Mexiletine 150 mg three times a day may be tried for those patients who continue to experience repeated ventricular arrhythmia despite higher doses of propranolol or diphenylhydantoin. This drug has produced a striking reduction in frequency and the number of cardiac arrhythmias in patients with SMVP. Similar experience has been noted with aprindine.‘35 Propranolol is useful in the treatment of recurrent chest discomfort in patients with SMVP both in those who have associated coronary artery disease and those who do not. However, nitrates should be used with extreme caution because of their propensity to reduce both afterload and preload which in turn may intensify the underlying tendency of MVP and thereby cause paradoxical ischemia of the papillary muscles. Patients with SMVP who experience a TIA because of cerebral thromboembolism should be investigated for other causes of such manifestations. However, when no other etiology is apparent, antiplatelet drugs such as aspirin and dipyridamole should be given and progress carefully assessed. Often only one form of treatment, eg, antiplatelet drugs, is enough to control the patient’s symptoms. However, if symptoms recur while on antiplatelet agents, anticoagulation should be strongly considered. Women who have TIA due to MVP should avoid oral contraceptives. Surgical Management

Patients with ventricular failure be managed like different etiology. those who are not

MVP with symptoms of left due to progressive MR should other patients with MR of Those with progressive MR, responsive to medical manage-

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ment, or those who have acute onset MR due to rupture of chordae tendineae should be considered surgical candidates. Tresch et a113’j studied the clinical, hemodynamic, pathologic, and surgical findings in 30 patients who required mitral valve surgery for MVP. The most common indication for surgery was congestive heart failure (CHF) which was often abrupt in onset. Of those patients who required mitral valve replacement for CHF due to MVP, males predominated and most were over 50 years of age. Nineteen of 30 patients also demonstrated ruptured chordae tendineae at the time of surgery in addition to MVP. This was again confirmed in a recent study in which mitral valve excision for chronic regurgitation due to MVP was the most common cause between the ages of 50 and 80 years and involved men in 76% of the cases.137 Yacoub et a113’studied the question of repair v valve replacement in the surgical treatment of MR caused by MVP. They studied 132 patients who were operated on for MR due to rupture of chordae tendineae of the posterior cusp. Fortysix patients underwent valve replacement using inverted, fresh, unstented antibiotic sterilized aortic homografts and 86 patients underwent valve repair. More than 80% of patients in both groups were in New York Heart Association Functional Class III or IV at the time of surgery. Early mortality was 11% and late mortality was 32% in those patients who underwent mitral valve replacement and 5% and 7%, respectively, in those patients who underwent mitral valve repair. The actuarial survival rate at 5 years was 62% in those who underwent mitral valve replacement and 90% in those who had mitral valve repair. Sixty-one percent and 76% of patients, respectively, were in Functional Class I following surgery. The authors concluded that valve repair was and continued to be the method of choice for surgical treatment of patients with MR due to MVP and ruptured chordae tendineae. Similar observations have been made by Carpentier et a1.13’ from France. Left stellate ganglion block followed by thoracic sympathectomy and even mitral valve replacement have been proposed for surgical treatment of refractory ventricular arrhythmia in SMVP; however, experience at present is insufficient to evaluate the effectiveness of such therapies.

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General

SMVP usually has a benign prognosis, particularly in young adults. Hancock and KochIN in their study of the long-term prognosis in 40 patients with SMVP encountered only two patients with CHF. Mills et a1141 studied the natural history and long-term prognosis of SMVP in 53 patients who had a midsystolic click or late systolic murmur or both documented by phonocardiography and followed for a mean of 13.7 years. At the time of their report, 38 patients were alive without serious complications and seven had died of unrelated causes. In two patients SMVP was implicated in the cause of death. Ventricular fibrillation occurred in one patient and bacterial endocarditis in three. Progressive mitral regurgitation developed in five patients requiring mitral valve replacement in two. Thus, the cumulative complication rate was 15%. Complications were significantly associated with a late systolic murmur rather than isolated midsystolic clicks. The authors concluded that the diagnoses of SMVP should not be regarded as ominous; however, patients in- whom this diagnosis is associated with a late systolic murmur should be followed closely. Nishimura et a114* also determined the longterm prognosis of MVP documented by echocardiography by following 237 minimally symptomatic or asymptomatic patients for a mean duration of 6.2 years (range 1 to 10.4 years). Actuarial 8-year probability of survival was 88%, which is not significantly different from that of a matched controlled population. An initial left ventricular end diastolic dimension exceeding 60 mm was the best echocardiographic criteria that predicted the subsequent need for mitral valve replacement (17 patients). Of the 97 patients with redundant mitral valve leaflets identified echocardiographically, 10.3% experienced sudden deaths, endocarditis, or a cerebrovascular accident; in contrast in the 140 patients with nonredundant valves only one (0.7%) had such complications (P < .OOl). The authors concluded that most patients with echocardiographic evidence of MVP had a benign course, but subsets of high risk for the development of progressive MR, sudden death, cerebroembolic events, or endocarditis can be identified by serial echocardiography.

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Among patients older than 50 years, the percentage of men without need for a mitral valve operation after 5 years was 96% for those with an end-diastolic diameter of <60 mm and 25% for those with a diameter 160 mm. The corresponding figures for women older than 50 were 98% and 75%. Similar echocardiographic observations and predictive values for the left ventricular end-diastolic dimension had been reported by Devereux et a1’43 during a mean follow-up of 4.5 years. They found that complications were due to MR in six out of ten (60%) patients with MVP whose initial left ventricular dimensions were 60 mm or more as compared with one out of 77 (~1%) patients with smaller ventricles (P < .Ol). One serious drawback of these studies is that observations were based on M-mode echocardiography which is less sensitive and accurate then 2D echocardiography in the diagnosis of MVP. Therefore, before clinicians can infer from these observations that M-mode echocardiography may be helpful in identifying high risk patients, it is essential to determine whether left ventricular enlargement has independent predictive value by 2D echo and pDe because the presence or absence of MR may turn out to be the actual and most significant risk factor rather than the enddiastolic dimension of the left ventricle, which may in turn be just an aftereffect. More recently, Diiren et a1’44 reported longterm follow-up of 300 patients with IMVP diagnosed by clinical, cinegraphic, and echocardiographic criteria. There were 136 male and 164 female patients, ranging in age from 10 to 87 years (mean 42.4). Serious complications developed in 100 patients (30%), sudden death in 3, ventricular tachycardia in 56, endocarditis in 18, and progressive MR in 8. Twenty-eight percent had mitral valve surgery because of progressive regurgitation. Cerebrovascular accidents occurred in 11 patients. The incidence of complications is higher in this study than reported in the past, possibly related to prolonged follow-up (20 years) and to a referral bias because all patients followed had been referred to an academic cardiac center. The latter drawback of the study means that the results as presented may not necessarily represent the natural history of even IMVP in the general population, let alone those who have SMVP.

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SMVP in Children

Bisset et a1’45 studied 119 children with isolated MVP with a mean follow-up of 6.9 years and found an excellent prognosis during childhood and adolescence. Only two patients required antiarrhythmic medications for supraventricular tachycardia. No progression of MR was observed and there were no sudden deaths. Only one patient developed endocarditis and one had a cerebrovascular accident. The growth and development pattern as judged by clinical examination had been normal, and all patients were living normal lives without any restriction of activities. SMVP in Athletes

Because the prognosis of SMVP is generally favorable, a permissive attitude towards participation of patients with SMVP in competitive sports is probably warranted.146 However, it would appear reasonable to disqualify athletes with SMVP if there is (1) history of recurrent syncope; (2) complex ventricular arrhythmia, particularly if worsening is noted during graded exercise; (3) significant mitral regurgitation; (4) prolongation of the QT interval; (5) association with Marfan’s syndrome; and (6) intrafamilial history of sudden death. SMVP in the Elderly

MVP does not occur only in young and middleaged patients. As 2D echo and pDe have been used increasingly in clinical practice it has been realized that patients over the age of 60 may also have MVP. Tresch and Siege1147 in reviewing echocardiograms of 237 patients with the diagnosis of MVP found 40 patients (5.9%) over 60 years of age with unequivocal echocardiographic findings of MVP. The mean age of these 40 patients was 67.1 years (range 61 to 86). The spectrum of MVP in elderly patients is approximately the same as that in the young and middle-aged with the exception that IMR and CHF as initial manifestations are more common. The specific reason for the increased incidence of CHF in elderly patients with SMVP is unclear. Perhaps self-perpetuating minimal MR progresses over many years to severe MR with or without rupture of chordae tendineae, ie, mitral insufficiency begets mitral insufficiency. The diagnosis and management of SMVP in elderly patients do not differ significantly from that in young and middle-aged patients with the

exception that mitral valve repair or replacement should be considered early before the onset of irreversible impairment of left ventricular function. All practicing clinicians should be aware of the possibility of SMVP as the underlying cause of IMR in elderly patients to ensure prompt diagnosis and management. SMVP and Pregnancy

Because SMVP is common in women of reproductive age, questions are often asked by the patient or the family whether pregnancy will have any adverse effects. In general, pregnancy is not contraindicated in patients with SMVP unless it is associated with severe MR, left ventricular dysfunction or complex arrhythmia requiring multiple antiarrhythmic drugs whose teratogenic effects on the fetus are not fully known, or when SMVP is associated Marfan’s syndrome. It should be emphasized that both the clinical and the echocardiographic features of MVP may disappear during the second and third trimester of pregnancy because of increased blood volume, only to return following parturition. One would reflect that the intrapartum stress and strain may lead to rupture of chordae tendineae in such patients but curiously enough no such example has been reported to date. Endocarditis prophylaxis in SMVP patients who require either episiotomy, forceps application, or caesarean section for delivery cannot be overemphasized. SUMMARY

SMVP is perhaps the most common cardiac valvular disorder today affecting a variable percentage of the general population. It is probably not a new syndrome because it might have masqueraded for over 100 years under such loose terminology as soldier’s heart, irritable heart syndrome, DaCosta syndrome, neurocirculatory asthenia, and anxiety neurosis, until it was convincingly postulated and documented that SMVP can be a clinicopathologic, angiographic, and echocardiographic entity. It is recognized in all age groups, both sexes, and is inherited as an autosomal dominant disorder. The MVP gene shows age and sex dependent expression. In some patients, SMVP occurs secondary to other disease processes, such as Marfan’s syndrome, rheumatic heart disease, coronary artery disease or Ehlers-Danlos syndrome; however, a distinct subset of the patients is recognized in

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whom no apparent cause for MVP exists and no other associated cardiovascular disease can be demonstrated. During the past 27 years it has become clear that while the pathologic abnormality in MVP is usually localized to the mitral valve, it is not necessarily limited to it because it often extends to the entire MVA. Grossly, the mitral valve leaflets, both anterior and posterior, are large, voluminous, redundant, and have a ballooning or hemorrhoidal appearance to the naked eye. While both leaflets of the mitral valve are often involved, it is not uncommon to have findings confined to either the posterior or the anterior mitral leaflet, most commonly the former. Commissures of both leaflets are easily definable and do not show any fusion. The mitral valve annulus is stretched. Histologically, the primary pathologic abnormality in MVP appears to be the myxomatous degeneration of the middle layer of the spongiosa with intermittent encroachment of this layer into the fibrosa. Myxomatous degeneration is characterized by the loss of normal valvular architecture accompanied by an increase in the ground substance with no accompanying inflammatory reaction. Biochemical studies have shown that the abnormally increased group substance involved in the myxomatous degeneration is an acid mucopolysaccharide. The pathogenesis of SMVP remains largely unknown. However, several interesting and pertinent observations such as decreased production in Type III collagen, dysjunction of the mitral valve annulus fibrosis, abnormal chordal architecture supporting the mitral valve leaflets, myocardial ischemia, cardiomyopathic state, and a neuroendocrine cardiovascular process have all been described with some supporting evidence in favor of each of these pathogenetic factors. The pathophysiology of some of the common manifestations of SMVP such as chest pain, cardiac arrhythmia, and regional left ventricular dysfunction, continues to elude all investigators. On the contrary, the pathophysiology of both acute and chronic MR in patients with SMVP is relatively well delineated and relates to the acute and chronic dysfunction of the MVA resulting from ruptured chordae tendineae and/or dilatation of the mitral annulus. Regional alterations in wall tension and localized discrepancies between myocardial oxygen supply and demand in the MVA, spontaneous diastolic depolarization

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and automaticity of the muscle fibers in mitral valve leaflets, and contraction abnormalities in the papillary muscle rather than some generalized disorder of the coronary circulation or myocardial metabolism have been postulated to explain the aforementioned symptoms but each explanation remains unproven. The diagnosis of SMVP can either be easy or difficult because its manifestations are subtle, variable, and extremely diverse. Both underdiagnosis and overdiagnosis have been nagging problems to most practicing physicians including cardiologists; however, by synthesizing clinical symptoms, signs, and laboratory evidence described above it is often possible to arrive at the proper diagnosis in the majority of the patients. The symptoms are often nonspecific and range from no symptoms at all to sudden unexpected cardiac death. Approximately 20% of patients with MVP are asymptomatic. Palpitations, lightheadedness, dizziness, atypical chest discomfort, dyspnea, or panic attacks occur in 80% of patients with SMVP, but these are nonspecific. The SMVP has both noncardiac and cardiac signs. The noncardiac signs are certain anthropometric characteristics such as a tall, thin appearance, narrow anterior-posterior diameter of the chest, long arm span both in men and women, and hypomastia in women. In addition, straight back, pectus excavatum, and accentuated scoliosis are seen in approximately 60% to 70% of the patients. The most common cardiac signs of SMVP are the midsystolic click and late systolic murmur; occasionally a precordial honk or whoop may be present instead of a click and murmur. A peculiar feature of these auscultatory findings is their variability not only from one patient to another but also to the same patient on different occasions. The auscultatory and extracardiac phonocardiographic findings of SMVP are explicitly sensitive to physiologic and pharmacologic intervention, and recognition of these changes can be of value in the diagnosis of SMVP. The basic spectrum of SMVP includes low body weight, classic skeletal abnormalities, hypomastia in women, low BP, palpitations, and a midsystolic click and/or late systolic murmur. There are no characteristic ECG abnormalities in patients with SMVP. Partial or total inversion of T waves in leads II, III and AVF with or without ST segment depression which sometimes involves the left precordial leads have

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been attributed to strain and/or ischemia of the papillary muscles or endocardium secondary to prolapsing mitral valve leaflets. Other common ECG features seen in patients with SMVP range from rare supraventricular and ventricular premature contractions to recurrent life-threatening supraventricular and ventricular tachyarrhythmia as well as conduction abnormalities due to both sinus node and AV node dysfunction. Such cardiac arrhythmia constitutes an important component of SMVP. There is also an inordinately high incidence of the WPW syndrome in patients who have SMVP. It is estimated that in the general population approximately 20% of patients with paroxysmal supraventricular tachycardia have accessory bypass tracts whereas the incidence in patients with SMVP is three times as great. Often such accessory bypass tracts are located on the left side. In the majority of patients with SMVP, chest roentgenograms show no abnormalities of the cardiac silhouette, although left atria1 and left ventricular enlargement may be evident if mitral regurgitation has been long-standing. A high incidence of thoracic cage abnormalities including pectus excavatum, scoliosis, straight back, or any combination thereof has been noted in patients with SMVP. Echocardiography has been the single most useful laboratory technique for confirming the clinical diagnosis of MVP. M-mode echo, 2D echo, pDe, and cDfm all have individual characteristic criteria for the confirmation of the clinical diagnosis. Sensitivity and specificity of the diagnosis improves when these techniques are used in combination. It is expected that 2D echo along with cDFm would probably become more popular for the diagnosis of MVP because together these two techniques provide both anatomic and physiologic information that one needs not only to correlate with the physical findings but also to assess their clinical significance. It should be emphasized that despite these rapid advances in echocardiography and refinement of criteria, there is a nagging problem of interobserver and intraobserver variability common to all echocardiographic laboratories. One reason for this variability is the gray area of normality or abnormality regarding motion of the mitral valve. This issue cannot be answered unless a well-controlled study of a representative population is carried out to determine whether a specific

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pattern of leaflet closure, size, or other features correlates ‘with the state of illness or conveys a prognosis worse than those pertaining to their absence. Not uncommonly, neither clinical nor echocardiographic examination will confirm all cases of MVP. Left ventricular tine angiography in such cases may prove very helpful, although one rarely resorts to this technique for diagnosis. Again, marked intraobserver and interobserver variability in angiographic assessment of MVP exist because most of the angiographic studies of MVP have been carried out without knowledge of precise anatomic correlation of various angiographic patterns. Also, the range of normal has not been well defined by this technique. In order to resolve the classical dilemma posed by the gray zone between normal and SMVP, certain major and minor criteria analogous to the Jones criteria for the diagnosis of rheumatic fever have been proposed with the sole objective that clinicians will be able to diagnose SMVP on a more secure basis and that healthy asymptomatic young persons will not be assigned an inappropriate diagnosis of cardiac disease. Whether or not this objective will prove as useful as the Jones criteria remains uncertain at this time because the spectrum of SMVP is extremely broad. Even though the diagnosis of SMVP can be straightforward, other diseases such as HOCM, atria1 myxoma, aneurysm of the interatrial and interventricular septum, and coronary artery disease can mimic SMVP but they can be easily differentiated by clinical and echocardiographic criteria unique to each entity. The course and prognosis of SMVP is generally favorable and life expectancy is often normal; nevertheless, complications occur in 15% to 30% of patients. The most common in order of their frequency are progressive MR, endocarditis, TIA, rupture of chordae tendineae, and SD, All complications occur disproportionately more often in middle-aged men than in control groups. Three independent prognostic echocardiographic markers that have been identified to underlie these complications are thickening of the mitral valve leaflet (endocarditis and TIA), MR (endocarditis, cardiac arrhythmia, SD), and initial left ventricular end diastolic dimension exceeding 60 mm (mitral valve repair or replacement).

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Because SMVP is a heterogeneous entity with a wide and varied clinical spectrum, considerable controversy exists regarding its management, particularly in those who have minimal symptoms and the very young or very old. During the past 27 years it has become clear that management of SMVP is dictated by the presence or absence of symptoms in any given patient. Patients who have no symptoms or signs of SMVP and in whom MVP was detected incidentally on echocardiogram performed for an unrelated reason should be reassured about the favorable prognosis and have a periodic cardiovascular follow-up every 2 to 3 years. Such patients should not be considered as cardiac patients until evidence for cardiac abnormalities begin to surface during follow-up. Whether or not such patients should receive endocarditis prophylaxis is a debatable issue. However, there is no controversy regarding such prophylaxis in patients who have the click-murmur component of SMVP or MR by Doppler echocardiography. Opinion is not unanimous regarding patients who have only a midsystolic click but no systolic murmur or MR. SMVP patients with a history of frequent palpitations, chest pain, dyspnea or exertion, light-headedness, dizziness, amaurosis fugax, syncope, or recurrent cardiac arrhythmia will require either medical or surgical management in addition to endocarditis prophylaxis in order to control their symptoms. Propranolol is the drug of choice for the control of chest pain and cardiac arrhythmia, and either propranolol or diphenylhydantoin is useful in patients who have ventricular arrhythmias in the presence of a prolonged QT, interval. New antiarrhythmic drugs such as mexiletine and aprindine have also proved useful in patients who had recurrent ventricular arrhythmia despite high doses of propranolol or diphenylhydantoin. Left stellate ganglion block followed by sympathectomy and even mitral valve replacement have been proposed for surgical management of ventricular tacharhythmias refractory to all antiarrhythmic drugs. Patients with SMVP who have TIA due to cerebral thromboembolism

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require antiplatelet drugs such as aspirin, dipyridamole, or anticoagulants. Patients with progressive MR or those with acute MR with symptoms of left ventricular failure require mitral valve replacement or mitral valve repair, the two most common procedures used in such patients. At the present time evidence favors mitral valve repair rather than mitral valve replacement as the optimum management strategy for these patients. Besides symptoms of left ventricular failure, end-diastolic internal dimension of the left ventricle measuring >60 mm has proven to be of predictive value in defining the need for surgical intervention in patients with progressive MR due to MVP. CONCLUDING

REMARKS

The explosive outpouring of information regarding SMVP in the past 27 years has been incredible; however, the current state of our knowledge regarding it remains incomplete and often controversial. While some authors have questioned the very existence*48 of SMVP and others have called it a fiasco,14’ an enigma,15’ or paranoia, 15’ there is little doubt in the minds of clinicians that SMVP does exist. Part of the confusion and controversy may have been due to the indiscriminate and inappropriate use of the same terminology in both normal and diseased populations. MVP cannot be considered synonymous with SMVP; it merely constitutes one component of it. Accordingly, healthy, asymptomatic individuals with MVP cannot be truly compared with those patients who have full-fledged SMVP. When diagnosing or managing SMVP, if we all adhere to uniform criteria, then controversy and prolapse mania or paranoia would lessen considerably. ACKNOWLEDGMENT The author wishes to acknowledge his sincere appreciation and thanks to Rebecca Nelson and Karleen Shepard for preparation of the manuscript; Drs John Popowich, Paul Larson, and Mona Grotte for the preparation of some anatomic and pathologic material; and Drs Mark Schmidt and Robert Schultz for granting permission to use Figs 16 and 17, respectively, in the illustrations.

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5. Wooley CF: From irritable heart to mitral valveprolapse: British Army medical reports, 1860-1870. Am J Cardiol SS:1107-1109,198S 6. Wooley CF: From irritable heart to mitral valve prolapse. World War I, the British experience and James Mackenzie. Am J Cardiol57:463-466, 1986 7. Wooley CF: Where are the diseases of yesteryear? DaCosta’s syndrome, soldier’s heart, the effort syndrome, neurocirculatory asthenia-and the mitral valve prolapse syndrome. Circulation S3:749-751, 1976 8. Bedford E: Library of Cardiology Catalog of Books, Pamphlets and Journals. London, Royal College of Physicians, 1977 p 196 9. Williams JC: Practical Observations on Nervous and Sympathetic Palpitation of the Heart. London, Longman, Reese, Orme, Browne, 1836 IO. DaCosta JM: On irritable heart; A clinical study of a form of functional cardiac disorder and its consequences. Am J Med Sci 61:17-52, 1871 11. MacLean WC: Disease of the heart in the British Army, the cause and the remedy. Br Med J 1:161-164, 1867 12. MacKenzie J: The soldier’s heart. Br Med J 1: 117-I 19, 1916 13. Allbutt TC: The investigation of the significance of disorders and diseases of the heart in soldiers. Br Med J 2:139-141, 1917 14. Gallivardin L: Pseudo dedoublement du deuxieme bruit de coeur simulant le dddoublement mitral por bruit extracardique telesystolique surojouite. Lyon Med 121: 409-422, 1913 15. Lesch M: Mitral valve prolapse: A clinical spectrum. NEnglJMed294:1117-1119,1976 16. Johnston FD: Extra sounds occurring in cardiac systole. Am Heart J lS:221-231, 1938 17. White PD: “Rheumatic” heart disease, in: Heart Disease (ed I). New York, MacMillan, 193 1 (chapter 13, pp 322-341) 18. Ronan JA, Perloff JK, Harvey WP: Systolic clicks and the late systolic murmur. Am Heart J 70:319-325, 1965 19. Criley JM, Lewis KB, Humphries JO, et al: Prolapse of the mitral valve: Clinical and tine-angiocardiographic findings. Br Heart J 28:488-496, 1966 20. Shah PM, Gramiak R: Echocardiographic recognition of mitral valve prolapse. Cir 42:111-45, 1970 (Suppl III, abstr) 21. Sahn DJ, Allen HD, Goldberg SJ, et al: Mitral valve prolapse in children-A problem defined by real-time crosssectional echocardiography. Circulation S3:651-657, 1976 22. Greenwood RD: Mitral valve prolapse in childhood. Hosp Pratt 21:41-44, 1986 23. Savage DD, Devereux RB, Garrison RJ, et al: Mitral valve prolapse in the general population. II. Clinical features: The Framingham Study. Am Heart J 106:577-581, 1983 24. Markiewicz W, Stoner J, London E, et al: Mitral valve prolapse in 100 presumably healthy young females. Circulation 53(3):464-473, 1976 25. Warth DC, King ME, Cohen JM, et al: Prevalence of mitral valve prolapse in normal children. J Am Co11Cardiol 5:1173-l 177,1985 26. Levy D, Savage DD: Prevalence and clinical features of mitral valve prolapse. Am Heart J 113:1281-1290, 1987

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