The floppy, myxomatous mitral valve, mitral valve prolapse, and mitral regurgitation

The Floppy, Myxomatous Mitral Valve, Mitral and Mitral Regurgitation Charles

F. Wooley,

Peter B. Baker, Albert J. Kolibash, James W. Kilman, Harisios Boudoulas

T

HE MODERN HISTORY of valvular heart disease in general, and mitral valvular disease in particular, may be traced to the early 1800s. The mitral valvular regurgitation lineage is more complex than other forms of valvular heart disease, full of contradictions, reversals, and paradox. The earlier medical literature contained incisive insights into mitral regurgitation, observations that were lost and rediscovered, widely scattered in time and space. Doctrine without data prevailed for prolonged intervals with a notable absence of scientific inquiry. Certain biological and clinical concepts were prerequisites to appreciating the central role of the floppy, myxomatous mitral valve in the mitral valve prolapse-mitral valvular regurgitation story. We present data from multiple sources in a format emphasizing conceptual chronology rather than priority, for as will be seen, the story has many investigators and many sources. THE MEANING OF CARDIAC MURMURS THE 19TH CENTURY

IN

Cardiovascular physical diagnosis developed through multiple stages, from observation and inspection to palpation, percussion, and auscultation. Prior to the turn of the 19th century, mitral regurgitation and other forms of valvular heart disease were not diagnosable during life. Clinical diagnosis with autopsy correlation reached new levels in France during the 19th century (Fig 1). Corvisart, the teacher, refined and redefined Auenbrugger’s percussion method in 1808; this was followed shortly thereafter by his pupil Laennec’s 1819 description of the stethoscope and the revolutionary new form of cardiac auscultation. The potential for clinical diagnosis expanded along with the art and science of auscultation. Certain physiological principles-the timing and origin of the first and second heart sounds-had to be established before clinicians could accurately time murmurs. Laennec’s belief that the in Cardiovascular

Diseases,

Vol XXXIII,

No 6 (May/June),

Elizabeth

A. Sparks, and

first sound resulted from ventricular contraction and that contraction of the auricles caused the second heart sound led to a period of confusion. Studies during the 1830s by Rouanet, Bouillaud, Magendie, Hope, and C.J.B. Williams led to clarification of the heart sound sequence, ie, that the first heart sound was related to ventricular contraction with closure of mitral and tricuspid valves, and the second heart was related to aortic and pulmonic valve closure. Clinicians could now separate systole and diastale.’ Hope established the relationship of apical systolic thrills and murmurs with mitral regurgitation and described mitral regurgitation as a distinct lesion in 1831, initiating a debate, ie, apical systolic murmurs signified mitral regurgitation, that would last a century.‘Z2 In 1840, C.J.B. Williams provided that pathological correlation for a loud apical systolic murmur heard during life in a patient when the autopsy demonstrated ruptured mitral chordae. Austin Flint in the United States recognized and taught that mitral regurgitation could be long borne without serious inconvenience with a natural history quite distinct from other forms of valvular disease.3 This was a concept that was lost and then resurfaced again in the 20th century. The 19th century French auscultors recognized the holosystolic murmur of mitral regurgitation, but held that the apical mid-systolic and late-systolic murmurs were “nonorganic.” Two Americans challenged these assumptions at the turn of the century. Griffith’ thought it quite likely and logical in 1892 that apical mid-systolic

Concept: Mitral Regurgitation, a Discrete Lesion, Has Recognizable Clinical Findings

Progress

Valve Prolapse,

From the Divtiion of Cardiology, Departments of Internal Medicine, Pathology, and Sugery, The Ohio State University College of Medicine, Columbus, OH. Supported by rhe Overstreet Cardiovascular Teaching and Research Laboratory, Division of Cardiology, The Ohio State University College of Medicine. Address reprint requests to Charles F. Wooley, MD, Division of Cardiology, Depamnent of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, 43210. Copyright 0 1991 by W. B. Saunders Company 0033-0620/91/3306-0005$5.OOiO 1991:

pp 397-433

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I 1820

I 1800 Fig 1. auscultation,

Floppy mitral valve and murmur interpretation,

I 1840

mitral valvular regurgitation. The pathology, and mitral regurgitation.

and late-systolic murmurs were of mitral origin. Ha11,5agreeingwith Griffith, predicted pathogenesis when he concluded that a systolic murmur that began with a “sharp puff’ depended on some sudden change in the hydraulic conditions within the heart “as in a sudden yielding of a valve from inability to withstand pressure of contained blood.” At the end of the 19th century (Fig l), mitral regurgitation was recognized as a common if not the most common valvular lesion, and clinical diagnostic criteria for far advanced mitral regurgitation were widely appreciated.’ Information from the cardiovascular physiologists about mitral valve function was just beginning to have an impact in the clinical area. Apical systolic clicks and apical mid- and late-systolic murmurs were generally regarded as nonorganic or extracardisc in origin.6 A coherent approach to the pathophysiology and etiology of mitral regurgitation had not yet surfaced. THE 20TH CENTURY-THE SWINGS

I 1860

PENDULUM

Concept: Dogma Without Data About Mitral Regurgitation Inhibited Inquiry During the first half of the 20th century (Fig 2) the decline and nadir of mitral regurgitation paralleled certain developments in cardiology.

I

I 1880 19th century chronology See text for further detail.

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l

1900 of important

concepts

linking

British cardiologists-initially Graham Steel1 and James Mackenzie, and later Thomas Lewis and John Parkinson-downplayed the diagnostic significance of apical systolic murmurs. Mackenzie’s original intent was to overcome the “tyranny of the stethoscope” and to spare a host of individuals from invalidism and cardiac neurosis.7 Later, during World War I, the concept was expanded on a grand scale so that medical officers could deal specifically with the large numbers of young men with apical systolic murmurs, soldier’s heart, and the effort syndrome who presented extraordinary diagnostic, disposition, and pension problems during World War I. The doctrine that the apical systolic murmur should be disregarded when not accompanied by other signs of heart disease was developed and implemented under the wartime manpower pressures. Large numbers of medical officers were exposed to this doctrine. This approach became policy first in Great Britain and then in the United States military as the war progressed. Intended to provide medical officers with guidelines about fitness for military service, the net result of setting dogma without data was the inhibition of inquiry for several decades.78-1’ Twentieth century-thought about mitral regur-

FLOPPY

I 1900

MITRAL

VALVE,

MVP,

MITRAL

I 1910

Fig 2. Floppy mitral valve and mitral important concepts about cardiovascular and the existence of mitral regurgitation,

REGURGITATION

I 1920

I 1940

I 1999

valvular regurgitation. Shows disorders of connective tissue and the pathological definition

gitation reached its nadir in 1926 in the United States. Richard Cabot attacked the basic concept of mitral regurgitation as a clinical entity in his text, Facts on the Heart,” and stated that mitral regurgitation was a lesion almost never verified at postmortem. Cabot stated that physicians were in error when diagnosing mitral regurgitation on the basis of loud apical systolic murmurs that he thought were extraordinarily common in all sorts of noncardiac disease as in health. He dated this pernicious habit to the World War I wartime experience noted above “ . . . fortunately the mistake was discovered and the rule put into effect that no man should be rejected from military service on account of a systolic murmur no matter how loud it might be.” He expressed doubts that mitral regurgitation could be diagnosed in life but did grant that it might exist as a great rarity. It is not “a clinical entity, for it cannot, so far as I can see, be recognized in life. Mackenzie has told us how he gradually came to recognize that no one ever died of mitral regurgitation.” These were powerful statements from highly respected sources. Recall Mackenzie’s role in the development of British cardiology, whereas

I 1959

the first half of the 29th century. Chronology origin, controversy about the meaning of systolic of floppy mitral valves. See text for further detail.

of certain murmurs

in the United States Cabot was widely recognized for his emphasis on autopsy correlations and his contributions to medical progress with the case history method of teaching. These influential figures had a significant and negative impact on the mitral regurgitation debate that lasted for several decades. Although Thomas Lewis13 continued to teach “the diagnosis of mitral regurgitation has a very limited importance” as late as 1933, clinical cardiologists such as Paul Dudley White and Samuel Levine in Boston realized that Cabot’s position was too radical and developed a more reasonable approach to the apical systolic murmur-mitral regurgitation association in the early 1930s (Fig 2). However, the preoccupation with rheumatic fever as the cause for most forms of valvular disease remained a pervasive influence in cardiac pathology and clinical cardiology. Modern concepts of normal mitral valve morphology and function with clarification of the etiology, pathophysiology, and natural course of mitral valvular regurgitation began with the mid-20th century cardiovascular diagnostic and surgical era that provided a powerful impetus to the study of normal mitral valve function and

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mitral regurgitation. The “closed” mitral commissurotomy procedure gave best results in patients with “pure” mitral stenosis, and patients with varying degrees of mitral regurgitation were excluded from the procedure. This type of surgery stimulated development of methods for detecting and quantitating mitral regurgitation in patients with rheumatic mitral valve disease. In time, “pure” mitral regurgitation came into its own and an entirely new chapter in cardiology was written. At mid-century, Paul Wood in England realized that the pendulum had swung much too far during the early years of the century and expressed the view that “mitral regurgitation could now be seen in its proper perspective.“14 NONRHEUMATIC EXISTS

MITRAL REGURGITATION AND IS COMMON

Concept: Stretch Differs From Scar in the Pathogenesisof Mitral Valvular Regurgitation

A major step in understanding the etiology of mitral valvular regurgitation was the recognition that stretch, redundant or excessive valvular tissue, was an entirely different pathogenetic process in valvular heart disease than postinflammatory scar. This was part of the gradual realization that multiple, nonrheumatic forms of mitral regurgitation existed and, in fact, were quite common. Inflammatory disorders occupied a dominant role in clinical thought about the etiology of valvular heart disease for a prolonged period of time. The few exceptions were termed “wear and tear” or “degenerative” processes. In general, pathologists attributed the appearances of thickened valves to previous rheumatism. As a result, the stretch versus scar etiologic concept developed slowly. Pathological reports that presented exceptions to the rheumatic and atherosclerotic doctrine appeared first, followed by descriptions of the clinical course of patients with enlarged floppy mitral valves, initially from retrospective analysis of autopsy-based studies. Clinical correlations with surgical pathology, angiographic morphology, echocardiographic, and other imaging techniques followed. Hallmark papers by Bailey and Hickam in 194415 and Brigden and Leatham in 195316were not immediately recognized as such, and trans-

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lation into the clinical realm required another two decades. The 1944 Bailey and Hickam paper,15 based on autopsy studies, appeared under the inappropriate and incomplete title of “Rupture of Mitral Chordae Tendineae,” and when subsequently referred to, salient features of the study were overlooked or underemphasized. Bailey and Hickam made the association of severe mitral regurgitation with rupture of elongated, thin mitral chordae not related to infectious endocarditis. Voluminous mitral cusps showed “fibrosis without stenosis” and ballooned or bulged upward into the left atrium. Dilatation of the mitral annulus was a consistent finding. Histological study showed valvular connective tissue changes without inflammation. This gross histological profile led the investigators to exclude a rheumatic etiology. As Bailey commented, “We realized that the cases did not well fit the prevailing rheumatic dogma and in our own minds we left a big question mark on etiology.” The illustrations in the article establish the paper as a fundamental floppy mitral valve study. The Brigden and Leatham article16 described “pure” mitral incompetence in males without a rheumatic history. A long natural history, susceptibility to bacterial endocarditis, and the late onset of rapidly progressive congestive heart failure were clinical features. The study serves as a forerunner to the natural history studies of patients with floppy mitral valves published later in the century. Recognition and awareness of the stretch versus scar pathogenesis came from a new group of cardiac morphological pathologists who introduced description terms as mucoid degeneration (Fernex and Fernex, 1958),” billowing sail deformity (Oka and Angrist, 1961),l” or floppy, myxomatous, mutinous, hooded, or balloon mitral valves (Fig 3). The Fernex article dealt with two older patients with mitral regurgitation, cardiomegaly, and mitral valves with multiple domes and augmentation of the valve surface without evidence of the Marfan syndrome. This was one of the key articles introducing the concept of connective tissue etiology for floppy mitral valves, since the gross morphologi-

FLOPPY

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I 1950

MVP,

MITRAL

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I 1960

401

I 1970

I 1960

Fig 3. Floppy mitral valve and mitral valvular regurgitation. mitral regurgitation, and mitral valve prolapse. Contributions See text for further detail.

Shows the second half of the of the pathologists, morphologists,

cal descriptions and illustrations were supplemented by special stain histological techniques. Paradoxically, the use of diverse terms by the pathologists hindered the recognition of the frequency and importance of floppy mitral valves, a pattern that would be repeated shortly by the clinicians and angiographers. THE MYXOMATOUS,

FLOPPY

MITRAL

I 1990

VALVE

Concept: Recognition of Floppy Mitral Valves Was a Multidisciplina~ Activity Current concepts regarding the gross and histological characteristics of floppy mitral valves developed during the past 40 years and are based on the cumulative observations of many investigators (Fig 3). The primary focus of each morphological study on floppy mitral valves generally involved one of the following areas: (1) valvular abnormalities in patients with a generalized connective tissue disorder, particularly the Marfan syndrome, (2) spontaneous rupture of “normal” chordae tendineae, and (3)

20th century. surgeons,

2000 Floppy clinicians,

mitral valves, and imagers.

the floppy mitral valve as a primary and distinctive pathological process. Mitral valve abnormalities were recognized in patients with the Marfan syndrome as early as 1905.19 Although published descriptions and photographs of these abnormal mitral valves were typical for floppy mitral valves,2o-22the association between the mitral valve abnormalities and valvular dysfunction was not well defined. Later reports clearly associated floppy mitral valve abnormalities with valvular insufficiency in patients with the Marfan syndrome.23.25 Rupture of chordae tendineae in the absence of infective endocarditis was recognized as a pathological process in the 1940s. The chordae tendineae were often described as normal, and the distinctive morphological features of floppy mitral valves were either not recognized or not emphasized.26.27 Bailey and Hickam” made the important observation that the valve cusps were abnormal and not typical of chronic rheumatic valvular disease. Another important concept,

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that chordae rupture was due to connective tissue dissolution, was described by Caulfield.% Additional reports, still focusing primarily on chordal rupture, identified the gross characteristics of floppy mitral valves including voluminous cusps, elongated chordae tendineae, and annular dilation.29*30 Marchand et alz9 suggested that minor congenital abnormalities led to the valvular changes, whereas Singh et a13’ suggested that the valvular changes were secondary to valvular insufficiency. However, the floppy mitral valve did not receive emphasis as a primary pathological entity of connective tissue origin in these studies. That most cases of chordal rupture occur in floppy mitral valves was not clear until many years after the pathology of the floppy valve had been characterized. Two separate studies in 198531,32established a strong association between ruptured chordae tendineae and floppy mitral valves. A recent systematic study of chordae tendineae in normal, floppy, and control regurgitant (but not floppy) mitral valves documented moderate to severe myxomatous chordal changes almost exclusively in floppy mitral valves and implicated myxomatous changes in the pathogenesis of chordal rupture.33 The 1958 Fernex and Fernex paperI incorporated recognition that the morphological changes of floppy mitral valves constituted a distinctive, primary, pathological process in patients without an obvious systemic connective tissue disorder. Several fundamental features were described, including enlargement and hooding of the cusps and myxomatous or mucoid degeneraTable First Author

Fernex” Oka’* Pomerance” Pomerance” McKay6O Guthies’ Davies’” Lucas? Kings2 Van der Bel Kahn= Baker””

Year of Publication

No. of Valves Hooding

2

1. Floppy

tion. The valvular abnormalities were recognized to be a cause of mitral valvular insufficiency. Three years later, Oka and Angrist” used the term “billowing-sail” distortion to describe the mitral valve cusp deformity in aging dogs and also noted disorganization of collagen fibers. A link to vahular pathoIogy and mitral insufficiency in aged humans was suggested. Beginning in the mid and late 1960s many reports were published that described the morphology of floppy mitral valves.3447Table 1 lists 11 studies that provided new observations and definitive information pertinent to the morphological definition of floppy mitral valves. Pomerance initially published a brief description of “ballooning deformity” of the mitral valve in 1967.4s A landmark study followed in 196949 and detailed most of the gross pathological features and morphological valvular complications of floppy mitral valves. Working with knowledge that clinical reports had drawn attention to “a type of mitral incompetence associated with a peculiar deformity of the mitral valve,” Pomerance reported severe ballooning deformities of the mitral valve in 1% of necropsies. There were 35 patients, 23 men and 12 women, ranging from 51 to 98 years old. A spectrum of pathological change was described, from enlargement of the posterior mitral cusp only to involvement of the tricuspid valve was well as both mitral cusps. Cusp fibrosa was replaced by metachromatically staining loose myxomatous material; fibroelastic thickening of adjacent endocardium was noted; fibrinous endocardial changes were common; bacterial endocarditis and ruptured chordae without enMiiral

Valve

Leaflets Expansion

Pathology

Chordaa

Fibrin

Myxomatous

1958 1961

?

x X

X X

X X

1967 1969 1973 1976 1978

? 35 38 ? 147

X X X X x

X x X X

X X

1982 1982

171 12

x X

X x x

1985 1988

10 8

X x

x X

x

X X X

ET AL

Elongation

Tsndineae

Rupture

AllllUlUS

Myxomatous

Enlargement

X

x x

X X

X X X X

x

X X

X

Endocarditis

NP

X X X

X

Calcification

X X X X X

X X

X

X

X

X

X

X X

X X

X

x

x

X X

X X x x

x x

X X

FLOPPY

MITRAL

VALVE,

MVP,

MITRAL

REGURGITATION

docarditis were documented. Clinical relevance and stratification were also considered. Most of the 35 patients had pathological evidence of mitral regurgitation; however, 16 apparently had no symptoms related to their cardiac pathology. Similar pathological changes were present in 4.5% of elderly patients with systolic murmurs noted during life. Pomerance defined most of the floppy mitral valve morphological features that were rediscovered during the imaging era. An excellent illustration of a “ballooning,” mitral valve with generalized thickening of the posterior mitral cusp was accompanied by the following succinct observations: The (mitral) cusps become thickened, opaque, and voluminous . . the chordae tendineae become attenuated and may rupture. Histologically, there is metachromatic degeneration involving mainly the distal half of the valve fibrosa. The severity of this condition varies from localized areas of ballooning, usually in the center of the posterior cusp, to gross ectasia, with prolapse of the voluminous cusps into the atrium in systole, resulting in mitral incompetence. Such severe degrees were not common and appeared unrelated to age, but lesser degrees were frequent, and the incidence of these rose with age up to 64 years in the male and 74 years in the female with little further change with increasing years.

The histological changes in floppy mitral valves were subsequently studied in more detail. Kern and TuckelSO recognized that myxomatous change was nonspecific and occurred in several forms of valvular pathology. A clear, detailed description of the histological morphology was presented by Guthrie and Edwards in 1976,51 who observed that the normalvalve cusp connective tissue layers were recognizable but distorted. The concept of collagen “dissolution or disruption” as the primary defect in floppy mitral valves was emphasized by King et a15’in a quantitative study comparing floppy and normal mitral valves. Although control valves demonstrated varying degrees of myxomatous degeneration, elastin dissolution, and mucopolysaccharide infiltration, only floppy mitral valves had dissolution of collagen involving the valve cusp fibrosa and chordae tendineae. A major study by Davies et al was published in 1978.53 The incidence and severity of floppy mitral valves was determined in a prospective study of 1,984 consecutive autopsies in London hospitals using a standardized approach to mi-

403

tral valve inspection, morphology, classification, function, and clinical significance. The incidence of clinically significant floppy mitral valves was 3.9% in the men and 5.2% in the women. Prolapse was limited to the mural leaflet in about 67% of hearts studied, affected the aortic leaflet in lo%, and involved both leaflets in 23%. Severely floppy halves were not apparent until age 40 and the incidence of severely floppy valves increased with age. The meticulous, thoughtful analysis of necropsy, surgical, and forensic material in this comprehensive study helped place the redundant, floppy mitral in its clinical perspective. With the introduction of morphological grading came recognition that minor morphological abnormalities were not clinically significant in terms of recognizable complications, whereas more severe valvular abnormalities were associated with serious complications. Lucas and Edwards presented an extensive autopsy-based morphological and natural history analysis from Minnesota.54 They developed another grading system and distinguished the minor hooding of cusps in normal mitral valves from abnormal mitral valve hooding. Consecutive autopsies of 1,376 patients who died in a city community hospital yielded 102 patients who met the authors’ strict pathological criteria for floppy mitral valves, an incidence of 7.4% (62 males and 40 females). A registry series of 69 hearts from necropsy studies at referral hospitals provided subgroups of patients with complications. Precise gross and histological criteria were presented, along with a clear, concise consideration of primary features of floppy mitral valves, secondary effects, and complications. The floppy valve was a relatively infrequent cause of death in the community hospital patients, and the age at death was similar to the community hospital control autopsy group. In contrast to the Davies study, the average severity of the floppy valve did not increase as patients grew older. To better define the natural history of complications and lesions associated with floppy mitral valves, 90 cases from the registry specimens and the community hospital series were analyzed to provide a better approximation of the natural

404

history of these subgroups. The cumulative mortality from the group with specific complications or associated conditions emphasized the significant morbidity and mortality in these subgroups, just as the community hospital series showed the uncomplicated floppy mitral valve appeared to be a benign condition. Other floppy mitral valve abnormalities with possible implications for pathogenesis included abnormalities in arrangement of chordae tendineae causing localized deficiencies in valve cusp support.55,56 Disjunction of the mitral valve and mitral annulus fibrosus, a condition characterized by separation of the left atria1 wall-mitral valve junction and the most superior aspect of the left ventricular free wall was described by Hutchins et al.57 Angelini et al’* were unable to confirm the high incidence of valvular disjunction in floppy mitral valves. The transition from the autopsy-based 19th century and the early 20th century studies, with limited clinical correlations, to the mid to late 20th century cardiovascular diagnostic, surgical, and pathological era was reflected in a series of surgical pathology studies that appeared in the 1960s and 1970s (Fig 3). The surgical-pathological studies of this era included “Symptomatic Valvular Myxomatous Transformation (The Floppy Valve Syndrome)”

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a fundamental study by Read et al in 1965 in the United States34; “Reconstructive Surgery for Mitral Valvular Regurgitation,” by Carpentier et al in the 1960s in France”; “Clinical and Pathological Findings in Patients With ‘Floppy’ Valves Treated Surgically,” by McKay and Yacoub in 1973 in England@‘; and Further Use of Meticulous Morphological Observations as the Basis for Plastic and Reconstructive Mitral Valve Surgery, by Carpentier et al in 1976.59 Precise morphological definition of myxomatous, floppy mitral valves (Figs 4-7) became important when the surgical approach to floppy mitral valve repair, reconstruction, or replacement became feasible. A broad spectrum of quantitative changes has been described. The surface area of both leaflets was increased (Figs 7, 8) in one quantitative study of floppy valves removed at surgery for severe mitral regurgitation.” The usual 2:l ratio of anterior leaflet to posterior leaflet surface area (anterior greater than posterior) was altered by virtue of enlargement of all or portions of the posterior leaflet. Mitral annulus size was increased in this study. Chordae, frequently thin and elongated, had major deviations in the pattern of chordal branching and anchorage. Dimensional changes in this floppy mitral valve study included significant increases in

Fig 4. Floppy mitral valve, atrial (inflow) surface. Prominent ballooning toward the left atrial chamber involves large areas of the posterior leaflet (lower half of the photograph). Smaller areasof ballooning are noted along the free margin of the anterior leaflet. Both leaflets are thickened.

FLOPPY

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VALVE,

MVP,

MITRAL

REGURGITATION

405

Fig 5. Floppy mitral valve. The leaflets are thickened w&th prominent hooding of the posterior leaflet noted at the left. Annular length is markedly increased. The thick, fibrotic chordae tendineae are focally fused to the adjacent endocardium (arrow).

commissural length, commisural diameter, longest and shortest diameter, and length of line of coaptation. The weight of myxomatous floppy mitral valves was significantly greater than control valves (Fig 9), and varying degrees of thickness occurred in the floppy valves. Floppy valve morphological definition improved the understanding of mechanisms of valvular dysfunction, and stimulated design of surgical reconstructive procedures. Roberts discussed mitral valve prolapse (a

term he prefers to the floppy mitral valve) on many occasions, frequently within the context of “Cardiovascular Abnormalities Usually Silent Until Adulthood.“45 He and his coinvestigators have been particularly concerned with the interface between valve morphology and clinical expression in terms of auscultatory phenomena, electrocardiographic and echocardiographic representation, and surgical correlates. Analysis of operatively excised valves demonstrated two mechanisms for severe mitral regurgitation-

Fig 6. Floppy mitral valve with ruptured chordae. The ruptured end (arrow) is ragged. Histology showed adherent fibrin and speckled calcifications. The chorda is attached to the anterior leaflet. Scale is in centimeters.

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Fig 7. Comparison’ of floppy mitral valve (top) and normal mitral valve (bottom). Viewed from the atrial (inflow) surfaces, the floppy valve has a much larger annular length and leaflet surface area. The floppy valve leaflets are thickened and show evidence of ballooning, especially in the posterior leaflet. The posterior leaflet scalloping is accentuated in the floppy valve compared with the normal valve. AL, anterior leaflet; PL, posterior leaflet; PCS, posterior commissural scallop; MS, middle scallop; ACS, anterior commissural scallop. (Reprinted with permission.“‘)

dilatation of the mitral annulus with or without chordal rupture, or ruptured chordae with or without dilatation of the mitral annulus. Universal acceptance of the widespread existence of, and morphological basis for, floppy mitral valves, and development of gross and histological characteristics that distinguished these valves from rheumatic fever sequelae took about 40 years. Although the absence of acute and chronic inflammatory changes in early histological studies helped to dispel an infectious or rheumatic cause, curiosity about the essential tissue changes remained at a relatively low level.

The pathological studies and surgical-pathological observations provided the bases for floppy mitral valve definition. Gross morphological and histological characteristics existed and formed the basis for this definition. A spectrum of floppy mitral valve pathology was demonstrated. Longevity was not influenced by the mere presence of a floppy mitral valve. Degrees of redundancy, prolapse, and valvular dysfunction occurred. Certain complications, such as progressive mitral regurgitation, ruptured chordae tendineae, infectious endocarditis, and congestive heart failure, affected survival. Mameiter (mm)

Fig 8. Floppy mitral valve. Graphic presentation of morphological characteristics of a normal mitral valve and a floppy mitral valve associated with severe mitral regurgitation. Valve diameter [mm), valve surface area (mm2). and chordae length (cm) are presented.

FLOPPY

MITRAL

VALVE,

MVP,

MITRAL

REGURGITATION

407

0.0

WMIht km)

1.0

3.0

3.0

4.0

5.0

5.0

7.0 30.0

lltral Valve Fig 9. Floppy mitral valve. Graphic presentation of physical characteristics. Normal mitral valve compared with floppy mitral valve with severe mitral regurgitation. Weight (gm), valve area (cm*), and volume (ccl.

THE CLINICIANS-FROM AUSCULTATION TO PHONOCARDIOGRAPHY, ANGIOGRAPHY, AND CARDIOVASCULAR IMAGING Concept: Dynamic Auscultatoly Changes Reflected a Dynamic Valvular Process

Clinical recognition of patients with mitral valve prolapse associated with a floppy mitral valve came about in a slow, protracted fashion that extended over at least 150 years. Numerous references in the 19th to 20th century medical literature dealt with cardiac auscultation and the clinical significance of systolic clicks, systolic gallops, and apical mid- and late-systolic murmurs.* Nineteenth century investigators related the apical systolic murmur to mitral regurgitation, extended their observations to include ruptured mitral chordae with autopsy correlation a few years later, and published their results in appropriate journals or textbooks. That 100 years would pass before matters were again seen as clearly says much about the ways clinicians learn. Although dynamic forms of mitral regurgitation had been postulated at the turn of the 20th century, another 60 years elapsed before dynamic mitral regurgitation reentered clinical consciousness. Much as the mid 20th century virology had “viruses in search of disease,” cardiology had floppy mitral valves in search of clinical definition. The clinicians resolved these matters in several stages (Fig 3). Phonocardiography was used to separate systolic ejection clicks arising in the great vessels from the nonejection systolic clicks

of mitral and tricuspid origin. Interventional phonocardiography was used to show that apical late systolic murmurs behaved as mitral regurgitant murmurs. Cineangiography identified mild mitral regurgitation and prolapse of the mitral valve in individuals with apical midand late-systolic murmurs with or without accompanying nonejection systolic clicks. Intracardiac phonocardiography localized the nonejection clicks and apical late systolic murmurs to the left heart. This “peculiar form” of mitral regurgitation was consistently associated with specific deformations of the mitral valve apparatus. John Barlow recalled this era when the firmly established theory of extracardiac origin for the apical systolic clicks and late systolic murmurs was challenged.61 Barlow’s interest in these auscultatory phenomena was stimulated while in London in the late 1950s and he carried the question with him to South Africa. John Reid,” also in South Africa, revived the postulate that these clicks and late systolic murmurs were of mitral valvular origin, and suggested that the clicks arose from the chordae and were “chordal snaps.” This was in 1961. Barlow and coinvestigators observed (1963) mitral regurgitation with left ventricular cineangiography in four patients with murmurs confined to late systole on phonocardiography.63 Late systolic murmurs recorded and analyzed using interventional phonocardiography responded to vasoactive maneuvers in a manner compatible with the behavior of a mitral regur-

408

gitant murmur.” Systolic click behavior was also compatible with an intracardiac origin that led to introduction of the term “nonejection” systolic click to distinguish the sound from aortic and pulmonic ejection clicks. This was a time of great intellectual ferment in diagnostic cardiology, and an entirely new approach to the interpretation of clinical auscultation developed as auscultatory-phonocardiographic data was interpreted in terms of the new hemodynamic, angiographic, and surgical observations. Criley had already clarified the dynamic cineangiographic anatomy of the mitral valve and phonocardiographic heart sound relations in normal individuals and was particularly adept in correlating and interpreting the auscultatory events of mitral stenosis and mitral regurgitation in terms of the new hemodynamic-angiographic information. Criley and coinvestigators introduced the concept and terminology of mitral valve “prolapse” in 1966,65 along with the angiographic timing of the auscultatory phenomena. However, unanimity about the angio-

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graphic definition of, and diagnostic criteria for, the floppy mitral valve would require another decade. Intracardiac phonocardiography was used to localize the systolic click and the apical late systolic murmur to the left heart (Fig 10) in close proximity to the mitral apparatus.65-68 Intracardiac phonocardiographic studies at four separate institutionrP8 were remarkably coherent. Mid- and late-apical systolic clicks, apical mid- and late-systolic murmurs, and apical systolic whoops were localized to the left atrium and shown to originate from the mitral valve apparatus. Murmur responses to pharmacological interventions were consistent with mitral valvular regurgitation, and left ventricular cineangiographic studies in these patients demonstrated mitral regurgitation. Criley et aP provided cineradiographic definition of the floppy mitral valve morphology and correlated the cardiovascular sound phenomena with the floppy mitral valve dynamics. Leighton et a16’noted the discrepancy between murmur configuration as recorded on the chest wall and the earlier onset,

Fig 10. (A) External and left atrial intracardiac phonocardiograms before and during phenylephrine infusion. External phonocardiogram at the apex (top line), a low intensity pansystolic murmur shows some late systolic accentuation with the drug. In the left atrium (bottom line) the accentuation of late systolic murmur components during phenylephrine administration is more obvious. The left atrial pressure pulse, recorded at full scale 20 mm Hg, shows an increase in the 7” wave amplitude with drug effect. (B) External and left atrial intracardiac phonocardiograms. The left atrial pressure is recorded at full scale 20 mm Hg. At the apex. a pansystolic murmur with late accentuation is recorded in both panels. In the first panel with the phonocatheter tip in the mitral valve area, an intense pansystolic murmur is recorded. In the second panel, the phonocatheter has been withdrawn to a slightly high level in the left atrium. The murmur at this site is less intense and more clearly shows late systolic accentuation. IC, intracardiac phono; S,, first heart sound; S,, second heart sound; SM. systolic murmur; LA, left atrium. (Reprinted with permission.@‘)

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longer duration, and greater intensity of the mitral regurgitation murmur recorded in the left atrium; directional changes of the mitral regurgitation jet in relation to the chest wall were suggested as significant factors in determining the configuration and timing of the murmur heard and recorded on the anterior chest wall. The apical, nonejection systolic click or clicks and the mid-to-late apical systolic murmur became the auscultatory-phonocardiographic hallmarks (Figs 11, 12) for mild mitral regurgitation and the “systolic click-late systolic murmur syndrome” during this transition time to mitral valve prolapse.69 Postural auscultation confirmed by postural phonocardiography demonstrated reproducible, dynamic auscultatory changes. Mechanisms for the timing and movement of the systolic click and the mid-to-late systolic murmurs with changes in body posture, the use of vasoactive drugs and other hemodynamic maneuvers were analyzed. The dynamic changes in left ventricular volume and its determinants were the primary mediators in the variable timing and extent of mitral valvular prolapse and the onset of mitral regurgitation.69-71These auscultatory changes with interventions are summarized in Fig 12. The jinni was out of the bottle. Many investigators in the United States, Canada, Europe, South Africa, Australia, and Japan presented observations at the time of, and after, these papers, and expanded the scope and understanding of the role of the floppy mitral valve in mitral valve prolapse and mitral valvular regurgitation. Resp

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Fig 12. Auscultation-phonocardiography. Patient with floppy mitral vahre, mitral valve prolapse, end mitral regurgitation. Schematic representation of phonocardiogram in the recumbent position (left panel), standing position (middle panel) and with prompt squatting (right panel). From top to bottom: phonocardiogram (S,, first heart sound; C, systolic click; SM. systolic murmur; S,, second heart sound); figure indicates body posture; LV, left ventricle; Ao, aorta; and LA, left atrium; schematic with mitral valve leaflets prolapsing into the left atrium. The configuration of left ventricle, the timing, and degree of mitral valve prolapse change with changes in left ventricular volume. The euscultatory changes with standing are indicated in the mfddle panel along with changes in left ventricular volume (decrease); similar changes occur wlth exercise, emyl nitrite, isoproterenol. The panel on the right illustrates changes with prompt squatting when left ventricular volume increases. Similar auscultetory end dynamic changes occur with leg raising and propranolol. See text for further details.

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Fig 11. Auocultatlon-phonocardiography. External phonocardiogram from a young woman with floppy mitral vahre end mild mitral regurgitation. Top to bottom: Respirometer, downward reflection with inspiration; phonocardiogram, right sternal border (RSB), filter cut-off, 100 Hz; phonocardiogram at apex, filter cut-off, 100 Hz. S,, first heart sound; SC, nonejection systolic click; LSM, late systolic murmur; EKG, electrocardiogram.

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Phonocardiography, an objective form of quality control for clinical auscultation, was widely used during the 1950 to 1970 era with the electrocardiogram, direct and indirect cardiac pressure pulses, and the echocardiogram for timing heart sounds and murmurs and confirming their origin. Paradoxically, phonocardiography was summarily eclipsed during the 1970s and graphic records were no longer readily available or required to substantiate auscultatory impressions. The net result has been a trough in auscultatory skills and the widespread use of stethoscopy with limited auscultatory comprehension. Patients with multiple heart sounds-left ventricular fourth heart sound S, and S,; splitting of the mitral and tricuspid components of the first heart sound; S, and an ejection click, nonejection click, or both-have been poorly discriminated. Systolic clicks have been frequently described but rarely documented by a generation of physicians who have never seen a phonocardiogram. Clinical or cardiac imaging studies performed without careful phonocardiographic documentation of auscultatory events resulted in further confusion as mild mitral regurgitation and the “systolic click-late systolic murmur syndrome” merged into mitral valve prolapse. During the 1970s and 198Os, the application first of M-mode echocardiographic and later of two-dimensional echo and still later of echoDoppler studies had a further, remarkable impact on the diagnosis of the floppy mitral valve, mitral valve prolapse, and mitral valvular regurgitation. Like the clinicians, pathologists, and angiographers before them, the echocardiographers introduced their share of confusion into the story. Early M-mode echocardiographic images and diagnostic criteria lacked sensitivity, specificity, and appropriate clinical correlations. Basic floppy mitral valve morphology was frequently ignored. As emphasis shifted from angiographic definition of floppy mitral valve morphology and prolapse in patients with the well-defined auscultatory findings that had been the dignostic basis for the “systolic click-late systolic murmur syndrome,” the simplistic question “Does the valve prolapse?” replaced the traditional cardiovascular diagnostic process based on history, physical examination, and laboratory correla-

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tions. Clinical cardiologists lost control of the diagnostic process in this group of patients. Technological improvements in imaging equipment, stricter diagnostic criteria, and establishment of more rigid clinical correlates that were absent in the earlier echocardiography studies gradually produced greater coherence in diagnostic specificity and sensitivity.“76 In time, the addition of a spectrum of Doppler techniques, tine computed tomography, and magnetic resonance imaging tine to the imaging approaches produced remarkable diagnostic refinements (Fig 13 A-D). The development of imaging techniques for spatial “reconstruction” of the mitral valve complex with close attention to anatomic principles has been a recent important contributionY7 Rediscovery of increased mitral valve thickness with valvular and annular dimensional analysis as diagnostic criteria led echocardiographers and clinicians back to the floppy mitral valve concept and also formed a rational basis for prognostic considerations.75-77 This reconciliation, which took the better part of two decades, is still in progress. Auscultatory-phonocardiographic-imaging coherence has been a continuing source of controversy in the diagnostic process involving patients with floppy mitral valves and mitral valve prolapse. The intracardiac phonocardiographic observations noted previously have been extended and clarified by contemporary twodimensional echo-Doppler phonocardiographic correlative studies.78-m Follow-up studies (average 4.3 years) from Tokyo, Japan in 116 patients with mitral valve prolapse using external phonocardiograms, M-mode, and two-dimensional echocardiography and pulsed Doppler echocardiography placed emphasis on the systolic murmur confirmed by phonocardiography as a prognostic indicator in patients with mitral valve prolapse. During follow-up, left atria1 and left ventricular dimensions increased in patients with systolic murmurs, and a more severe degree of prolapse with a higher incidence of mitral regurgitation occurred in patients with systolic murmur than in those without the murmur.79 Akasaka et al@’ used external phonocardiographic and Doppler color echocardiography to time the onset and duration of mitral regurgita-

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tion in two groups of mitral valve prolapse patients, one group with mid-systolic clicks or late-systolic murmurs, the second group with pansystolic mitral regurgitation murmurs with late-systolic accentuation. M-mode Doppler color echocardiography was valuable in the temporal resolution of mitral regurgitation. Mitral regurgitation as defined by Doppler was frequently present throughout systole and isovolumic relaxation in these patients with varying phonocardiographic expressions of mitral valve prolapse, reminiscent of the intracardiac-externally recorded chest wall murmur inconsistencies noted by Leighton et a1.67 It is apparent that auscultatory-phonocardiographic and imaging coherence and correlations provided a multidimensional approach to the diagnosis of patients with floppy mitral valves, mitral valve prolapse, and mitral valvular regurgitation. Similarly, dissociation of auscultatoryphonocardiographic-imaging phenomena in the floppy mitral valve diagnostic process contributed to widespread diagnostic uncertainty. Barlow’s detailed “Perspectives on the Mitral Valve” in 1987,‘l and our 1988 text book; “Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome,“82 contained the views of many original investigators, including Barlow and Criley, and encapsulated the extraordinary developments during the past century. FLOPPY MITRAL VALVE DYSFUNCTION

Concept: Altered Mitral Valve Composition Is Responsible for Clinical Phenomena Floppy “myxomatous” mitral valves stretch. Floppy mitral valve stretch reflects altered mitral valve material properties resulting from replacement of the normally dense collagenous fibrosa by loose “myxomatous” connective tissue with high acid mucopolysaccharide content. The incessant effect of left ventricular systolic pressure contributes to the progressive deformation process.49,58 The characteristic gross morphological changes occur in the presence of histological evidence of myxomatous degeneration, collagen disruption and dissolution, mucopolysaccharide infiltration, and elastin fragmentation (Fig 14). The most specific, fundamental, and characteristic change appears to be collagen dissolution

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and disruption in the pars fibrosa of the valve substance and that of the chordae.” The presence of collagen dissolution and disruption, accompanied by proteoglycan accumulation provoked questions about sequence and specificity. When molecular organization of collagen in floppy valve chordae was examined with a polarized light microscopic technique, Whittaker et al observed that although proteoglycan infiltration may not be a specific marker for floppy valves, its presence was associated with evidence of collagen matrix degradations3 The investigators suggested that perhaps the initial degradation did not involve collagen per se but rather represented the removal of ground substance bound to the collagen fibre. Floppy mitral valves leak Mitral valve dysfunction associated with floppy mitral valves results from the broad pathological spectrum described previously and the unusual nature of the multiple pathogenetic mechanisms involved. Mitral valve complex dysfunction is related to failure of floppy leaflets to maintain the usual coaptation-apposition relations during early ventricular systole when the valve leaflets are exposed to an increased proportion of ventricular force directed superiorly,84 chordae are exposed to increased stretch, mitral valve “motion” time extends into ventricular systole, and prolapse of one, both, or portions of the mitral leaflets into the left atrium occurs during early and mid-left ventricular systole (Figs 15 and 16). Mild mitral valvular regurgitation occurs with failure to seal along the valvular coaptationapposition line. Stress-induced elongation of the morphologically abnormal chordae contributes to failure to seal as does disordered sphincteric function of the enlarged mitral annulus. The precise chronology of these interrelated events in this sequence is still uncertain. Mitral valvular regurgitation increases in severity with greater degrees of valvular deformation. The mitral valve may become flail with progressive valvular and excessive chordal elongation. Chordal rupture usually results in a flail mitral scallop, leaflet, or commissure. Experimental chordal rupture produces increased tension on the remaining intact chordae, and we

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Fig 13. (A) M-mode echocardiogram from a patient with a floppy mitral valve. There is a thickening of the anterior mitral leaflet and systolic prolapse of both leaflets (arrows). (B) Twodimensional echocardiogram. Apical four-chamber view of a floppy mitral valve from a patient with significant mitral regurgitation. Marked thickening of posterior mitral leaflet is present and the left atrium is dilated. (C) Spectral Doppler recording of mitral valve flow from a patient with a floppy mitral valve and severe mitral regurgitation. Holosystolic turbulent retrograde flow into the left atrium [arrows). [D) Floppy mitral valve, mitral valve prolapse, mitral regurgitation, color-flow Doppler from a 30year-old woman with severe mitral regurgitation. Yellow and blue areas (arrows) represent systolic, turbulent retrograde flowthrough the mitralvalve into the left atrium. ECG, electrocardiogram; AML, anterior mitral leaflet; PML, posterior mitral leaflet; FMV, floppy mitral velve; LA, left atrium; LV, left ventricle.

presume this occurs in the clinical setting as well. Relatively little is known about the role of altered chordal tension and abnormal stressstrain relations in the progression of valvular dysfunction; studies to date suggest they are important contributing factors. The progession of mild or moderately severe mitral regurgitation to severe mitral regurgitation is usually gradual. Although acute, cata-

strophic mitral regurgitation may accompany major chordal rupture, rupture of lesser chordae may be tolerated for prolonged intervals. Left atria1 and left ventricular architectural and performance changes occur in patients with gradually progressive mitral regurgitation. Left atria1 enlargement results from left atria1 hypertension and increased left atria1 volumes. Changes in left atria1 function are manifested by

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alterations in pulmonary venous and left atria1 flow-velocity patterns, resulting in changes in the distribution of left ventricular diastolic filling. Left atria1 electrical instability accompanies the atria1 myopathy and eventually results in atria1 fibrillation which contributes to, may initiate, or reflect left atria1 pump failure. Left ventricular enlargement occurs initially as a result of left ventricular volume overload. Left ventricular dysfunction eventually trans-

lates into left ventricular pump failure and the development of congestive heart failure. Right side of the heart involvement occurs during the course of these left side of the heart changes, and pulmonary hypertension may occur with preserved left ventricular systolic function.8s Natural history studies suggest that the entire process enters an accelerated phase after a prolonged asymptomatic interval in the presence of, and most likely as the result of, left

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Fig 14. Floppy mitral valve leaflat oriented with the inflow (atrial) surface at the top and ventricular (outflow) surfaca at the bottom. The histological layen shown from top to bottom are atrialir with fibrosis (A), large zone of loose myxomatour tissue (M), fibrosa (F), which is attenuated and focally disrupted by myxomatous tissue (arrows), and fibrous pads (P) on the ventricular endocardium. Jones’s methenamine silver stain; original magnification x 16. (6) Floppy mitral valve. Graphic presantation of collagen alteration and myxomatous degeneration. Control mitral valve compared with floppy mitral valve. Severity and percentage of patients with collagen degeneration or myxomatous degeneration are shown. 0, no change; 1+, mild change; 2+, moderate change; 3+, severe change; FMV, floppy mitral valve.

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Fig 15. Floppy mitral valve. Cineangiographic illwtretion of floppy mitral valve morphology from a young man with mild regurgitation and a late systolk murmur. Right anterior oblique projection, left ventricular injection. LV, left ventricle; Ao, aorta. Systoliiframe shows unusual left ventricular configuration, with prolapse into the left atrium of all the elements of both mitral leaflets. AL, anterior leaflet; PL, posterior leaflet, l , individual scallops of posterior leaflet. (Reprinted wkh permission.“‘)

atria1 failure, atria1 fibrillation, and in certain instances ruptured mitral chordae. The precise sequence of these architecturalperformance changes in humans has not been studied extensively. Reorganization or remodeling of left heart inflow-outflow relations are apparent on review of imaging procedures in patients with significant mitral regurgitation. Morphological and dynamic analysis may be enhanced when these valves are viewed or imaged in the beating heart at surgery, or when imaging techniques are used that provide multi-

ple projections or views.% The ventricularvalvular disproportion is apparent during ventricular systole when the billowing, prolapsing valve structures become space-occupying lesions within the left atrium (Figs 15 and 16). The conformational changes in the left ventricular contraction pattern that result from the loss of the integrity of mitral valve unit, a form of left ventricular remodeling, may also be appreciated. The mitral valvular regurgitation that results is quite distinct from mitral regurgitation associated either with retracted, fibrotic mitral

Fig 16. Floppy mitral valve. Cineangiographic illustration of left heart anatomy in a 5&yearold patient with a floppy mitral vafve, long-term mftral regurgltation, and recent congestive heart failure. Left anterior oblique projection, left ventricular Injection. Arrows indicate thickened mitral valve leaflets with prolapse into the left atrium; opecffication of left atrium (LA) as result of severe mitral regurgitation. Left ventriculer (LV) contraction pattern wes normal. Opacificetlon of ascending aorta [Ao) is also noted.

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valves or left ventricular dysfunction with wall motion abnormalities that interfere with papillary muscle function and mitral leaflet apposition. Mitral regurgitation has been treated as a relatively homogeneous entity from a hemodynamic viewpoint. However, as with the morphological heterogeneity in floppy valve expression, the resultant eccentric and at times multiple regurgitation jet lesions, the left atria1 spaceoccupying mitral leaflets, abnormal chordal tension, and abnormal ventricular contraction patterns all suggest hemodynamic heterogeneity. FLOPPY MITRAL VALVES-LEFT ATRIAL DYSFUNCTION AND ATRIAL FIBRILLATION

Individual and aggregate patient histories, a variety of indicators of left ventricular function, and the evolving state of mitral valve surgery have been important factors in decisions about the timing of cardiovascular surgery in patients with floppy mitral valves and progressive mitral regurgitation. Less attention has been directed to indices of left atria1 function. The natural history studies of patients with floppy mitral valves by Kolibash et als7@ have identified the onset of atria1 fibrillation as a major cause of clinical deterioration. The prog nostic implications of atria1 fibrillation, once developed, include increased long-term mortality, increased numbers of cardiovascular events including thromboembolism, and the lower probability of conversion to sinus rhythm with time. Significant left atria1 enlargement and the development of chronic atria1 fibrillation indicate the development of left atria1 myopathy and represent late stages of left atria1 dysfunction. More sensitive indicators of left atria1 function with detection of early stages of atria1 dysfunction long before development of left atria1 failure and chronic atria1 fibrillation should be the goals of medical therapy and surgical intervention. FLOPPY MITRAL VALVE ANNULUS-MORPHOLOGY, FUNCTION, AND CALCIFICATION

The normal mitral valve annulus is a structure with “marked variation, not only from heart to heart but within the same heart.“58 A spectrum of annular involvement has been described in

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patients with floppy mitral valves.49’53’54,58-60 The mean annular circumference in patients with floppy mitral valves and severe mitral regurgitation was greater than 65% above normal valves, and approximately 30% above normal in patients with competent floppy mitral valves.89 Annular dilatation was present in 7% in Davies large necropsy series.” Mitral annular circumference is dynamic, cyclical within the cardiac cycle, increasing to a maximum at the onset of atria1 contraction, followed by annular narrowing during early and mid-systole.89 Mitral valve prolapse patients studied by Ormiston et al” with echocardiographic reconstruction techniques were separated into three groups based on annular size and degree of mitral regurgitation (Fig 17). Annular area reduction, an index of mitral annular dynamic function, decreased from values of 25% in patients with a normal annular area index and

Fig 17. Changes in mitral annular area index during the cardiac cycle in normal subjects (closed circles), mitral valve prolapse ‘(MVP) group (gp) 1 (open circles), MVP group 2 (closed triangles) and MVP group 3 (open triangles). MVP group 1, minimal mitral regurgitation (MR) and normal annular size; MVP group 2, minimal MR and dilated annulus; MVP group 3, moderate or severe MR and dilated annulus. See text for further details. (Reprinted with permission.W)

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27% in patients with a moderate annular area index (both groups with minimal to no mitral regurgitation) to 16% in patients with the largest increase in annular area index and significant mitral regurgitation. This last group had a mean maximal diastolic circumference 53% greater than normal, and a mean minimal systolic circumference 63% greater than normal. Defective systolic contraction of the floppy valve mitral annulus aggravated the effect of intrinsic annular dilatation. Mitral annular calcification occurs in patients with floppy mitral valves (Fig 18). Mitral annular calcific deposits are actually located between the undersurface of the posterior mitral leaflet and the left ventricular wall endocardium in

Fig 18. (A) Floppy mitral valve caiciffc deposits. Calcifications involve the base of this posterior leaflet, forming irregular nodules on the ventricular aspect (arrows). (8) Floppy mitral valve calcific deposits. This tissue section shows the irregular caiciffcations that involve the leaflet tissue (on the right); the loose myxomatous connective tissue is noted on the left. Hematoxyiin and eosin; original magnification x 107.

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apposition to the posterior mitral leaflet.Ws91 Although the annular circumference was not usually dilated in older individuals with mitral annular calcification, the annulus in younger patients with mitral valve prolapse and mitral annular calcification may be dilated, in particular those individuals with the Marfan syndrome. Mitral annular calcification is probably related to abnormal mitral valve stresses, particularly increased forces or tension transmitted to the mitral annulus. Mitral annular calcification interferes with active function of the mitral annulus. The potential for systemic embolization, the association of cardiac conduction disturbances, the additional difficulties that mitral annular

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calcification pose for surgical repair of the floppy mitral valve are all important clinical factors involved in the recognition of the floppy mitral valve-mitral annular calcification association. FLOPPY MITRAL VALVE CHORDAEORGANIZATION, FUNCTION, STRETCH, AND RUPTURE

Normal chordae tendineae have two distinct connective tissue layers. The fibrous layer is a large central core composed of dense collagen bundles, surrounded by the elastic layer, a thin layer of compact elastic fibers.33 There is no loose connective tissue zone comparable to the valve spongiosa (Fig. 19).

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Pathological studies of floppy mitral valves focused primarily on valve cusps with less attention directed to chordae tendineae. BakeF performed a systematic histopathological study of 128 nonruptured chordae from eight floppy mitral valves surgically replaced for severe mitral regurgitation; these were compared with 152 control chordae from 10 normal mitral valves and 8 mitral valves from patients with severe ischemic mitral regurgitation. Floppy mitral valve chordae were significantly longer than both comparison groups. Thirty-eight percent of floppy valve chordae had histopathological evidence of collagen alteration, 39% had moderate to severe mucopolysac-

Fig. lg. (A) Normal chorda tendinea. A large, central dense, collagenous core is surrounded by a peripheral thin layer of darkstaining elastic fibers. Weigert’s elastic; original magnification x 144. (B) Floppy mitral valve chorda tendinea. The central core has severe separation and loss of collagen whereas the peripheral elastic layer is preserved. Abundant acid mucopolysaccharides were demonstrated in the loose central core by Mowry’s colloidal iron stain. These histopathological changes are nonuniform and normal histological architecture is preserved in some floppy mitral valve chordae. Weigert’s elastic; original magnification x 107.

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charide accumulation, versus values of 2% and 3% involvement in control groups (Fig 20). Nonuniformity of the histopathological alterations, ranging from normal histology to patchy distribution or involvement of entire chordal length, was observed in the floppy mitral valve chordae. The nonuniformity of the histopathological alterations may explain conflicting statements in the literature about incidence of chordal involvement or rupture of “normal” chordae. Chordal attenuation and fibrotic thickening have also been described. Chordal rupture is usually to the valve area with dome-like deformity and most frequently involves the posterior mitral leaflet, particularly the posterior middle scallop. Less frequently, the anterior leaflet or both leaflets may be involved. Excessive mitral leaflet and chordal mobility may produce endocardial friction lesions on the posterior wall of the left ventricle or contact lesions (diffuse patches of endocardial fibrosis) on the interventricular septum. The clinical significance of these friction or contact lesions has not been well defined. The stress required to fracture a floppy mitral valve chordae was significantly but nonuniformly reduced compared with normal chordae; these results are consistent with the nonuniform nature of the histopathological alterations. Becker and DeWit9* studied mitral valve apparatus variability in a meticulous, postmortem

Fig 20. Floppy mitral valve chorda tendinea. Graphic presentation of histopathological characteristics. Severity and percentage of patients with collagen alteration and acid mucopolysaccharide accumulation are presented. 0, no change; I+, mild change; 2+, moderate change, 3+, severe change; FMV, floppy mitral valve.

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study and raised the question, are some floppy valves actually the end result of primary deficient chordal support? Deficient chordae were detected in 36 of 40 mitral valves showing a leaflet deformity, the area of leaflet deformity corresponded with the site of deficient chordae. The investigators concluded there was a “spectrum of normality” with respect to the anatomy of the mitral valve chordal apparatus, presented an anatomical basis for disharmonious mitral valve movements, and forwarded the proposition that such variations might play a role in the pathogenesis of mitral valve prolapse by rendering unsupported parts of the leaflets vulnerable to high ventricular pressures. Floppy mitral valve chordal anatomy, histopathology, tissue content, and stress-strain relations associated with altered hemodynamic stresses on the expanded valve cusps contribute to the predisposition of floppy mitral valve chordae to progressive elongation, thinning, or rupture, fibrotic thickening, and production of endocardial friction or contact lesions. FLOPPY MITRAL VALVE SURFACE PHENOMENA-VALVULAR ENDOTHELIAL CELL PROPERTIES

Vascular endothelial surface activities have been studied extensively. Whether normal valvular endothelial cell properties are similar is unclear, and abnormal valve endothelial cells have not been studied in detail. A variety of

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molecules interact to form the extracellular matrix and then adhere to the matrix. The resultant nonthrombogenicity of the vascular endothelial cell surface represents the normal state in health, whereas thrombogenicity occurs when these complex processes at the endotheha1 cell surface are disturbed. Composition of the vascular endothelial cell and the extracellular matrix involves several types of collagen, von Willebrand factor, fibronectin, thrombospondin, vitronectin, laminin, elastin, and proteoglycans. Fibrinolytic constituents on the endothelial cell surface involve the known coagulant factors and pathways, a family of adhesive proteins such as vitronectin and thrombospondin that interact with endotheha1 cell surface adhesive receptors, in addition to platelet adhesive interactions and receptors. Laminar or disturbed blood flow and shear rates appear to be additional important modifiers. The interactions, signals, and genetics that modulate assembly and otherwise regulate stimulate, and inhibit these processes are currently subjects of intense investigation using a variety of in vitro and in vivo vascular endothelial cell systems. To date, little has been done to identify the characteristics of floppy mitral valve endothelial cell systems. Floppy mitral valve surface phenomena and reactions most likely result from the interactions between specialized endothelial cell composition further modified by chronic mechanical forces acting on the valve structure in a disturbed hemodynamic environment. Normal mitral valves have tightly packed, organized collagen fibers with a linear orientation and a relatively smooth, continuous endothelial surface (Fig 21 A, C, and E). Floppy mitral valve surfaces display folding and surface irregularities as a result of the underlying collagen disruption, dissolution, and separation, the elastin fragmentation, and the mucopolysaccharide deposition in the floppy mitral valve substrate; the net result is an internal “Swiss cheese” effect (Fig 22 B, D, and F). Pomerance49 suggested that the endocardial surface changes were secondary to these underlying fibrosal disruptions and that with cusp stretching the endothelial layer was subjected to abrupt changes in tension with resultant loss in endothelial continuity, rupture of subendothelial connective tissue fibers, and fibrin deposition.

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FLOPPY MITRAL VALVE SURFACE PHENOMENA-ADHERENCE, THROMBI, AND INFECTIOUS ENDOCARDITIS

Alterations in surface endothelial cell morphology, chemistry, or integrity factors have been postulated to precede platelet adherence to fibrin and the development of nonbacterial thrombotic endocardial (NBTE) lesions with embolic and infectious potential (Fig 22 A and B). Binding of circulating microorganisms from bacteremia to the NBTE lesions has been presumed to be a pathogenetic mechanism for certain forms of infective endocarditis, and such model systems have been developed and studied in animals. Endothehal cell surface or bacterial binding characteristics influence adhesion to surface receptor protein complexes. Campbell and Johnson93 showed that binding of Staphylococcus aureus to cultured porcine cells was a specific receptor-mediated event, identified S aureus-binding proteins on isolated porcine cardiac valve endothelial cells, mediated by using different receptors for endothelial and subendothelial cells. The process appears to involve molecules of the extracellular matrix, such as fibronectin and laminin; however, as noted previously, multiple molecular, genetic, biochemical, and immunologic steps are involved. The specificity of the host-parasite interactions in the pathogenesis of infectious endocarditis is a topic of active investigation. An interaction hypothesized to explain adherence of streptococci to epithelial cells involves lipoteichoic acid (LTA), which is present on grampositive bacterial surfaces and is constantly released during growth of streptococci. During transit, some of these LTA molecules are bound via ionic interactions between the negatively charged polyglycerol phosphate of LTA and the positive charges of an LTA-binding protein. The lipid moiety of LTA can bind to hydrophobic pockets located in the NH,-terminal region of fibronectin on host-cell surfaces.” Other modes of bacterial attachment are related to the saccharide-lectin interactions. Saccharide groups on either the bacterial or eukaryotic cell are specifically bound by proteins on the alternative surface. The proteins that bind saccharide groups, lectins, are quite specific for defined saccharide residues. The

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Fig 21. (A) This normal mitral valve leaflet inflow surface is smooth with a gently rolling appearance. Scanning electron micrograph; original magnification x130. (B) The floppy mitral valve leaflet inflow surface is characterized by irregular folding forming narrow indentations. Scanning electron micrograph; original magnification x280. (C) A normal mitral valve was snap frozen in liquid nitrogen and the cusps were cracked. A leaflet fragment with the cracked surface oriented perpendicular to the inflow surface was digested with hyaluronidase. Collagen fibers are observed to be tightly packed and arranged in parallel. Scanning electron micrograph; original magnification x2,300. (D) Using the same preparation described in C, the floppy mitral valve demonstrates loosely arranged collagen fibers with disruption of the parallel orientation. Scanning electron micrograph; original magnification x2.500. (E) The tightly packed, parallel, normal mitral valve collagen corresponds with the cracked valve leaflet surface in C. Transmission electron micrograph; original magnification x 12,000. (F) Separated disorganized collagen fibers characterize myxomatous areas of the floppy mitral valve; this appearance corresponds with the cracked floppy valve leaflet surface in D. Transmission electron micrograph; original magnification x 12,000.

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tropism that certain organisms, eg, Streptococcus sungz& have for specific tissues such as heart valves, the variations that occur among different human populations, and the associations with certain defective human tissues might be explained on this basis. Sialic acid expression is another important factor.% Sialic acids on glycoproteins act as a barrier, preventing binding by virtue of charge to eukaryotic cells. Individuals who are unable to sialyate surface glycoproteins, because of specific enzyme deficiencies or an inability to

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synthesize appropriate basal saccharide structure for sialic acid composition, may be at greater risk for infectious endocarditis. Eukaryotic cells have families of glycoproteins on their surfaces; the best described are human blood group antigens. Modifications of terminal saccharide groups of these glycoproteins could affect the ability of microbes to adhere. The extent to which floppy mitral valve surface molecular characteristics differ from normal mitral valves has not been analyzed critically. Thrombus formation with thromboembolic

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complications and infectious endocarditis are recognized complications of floppy mitral valves and are related in part to the hemodynamics of turbulence contributing further to valve surface irregularities. The unusual susceptibility of patients with floppy mitral valves to these complications is probably related to alterations in the extracellular matrix molecules and valve surface receptors mentioned previously but as yet unstudied in floppy mitral valves. Patients with floppy mitral valves are at increased risk for infectious endocarditis. Simply stated, patients with floppy mitral valves should receive infectious endocarditis prophylaxis.% This subject has been reviewed in depth by Koletar and Para. Recommendations for infectious endocarditis prophylaxis appropriate for the presumed bacteremia have been developed. However, at present, infectious endocarditis prophylaxis is an inexact and nonselective science and will undergo modification and refinement as pathogenesis is more clearly delineated.% THE NATURAL HISTORY OF PATIENTS FLOPPY MITRAL VALVES

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Concept: Both Patient and Doctor Must Live a Long Time Clifford Allbutt’ realized that in order to understand the natural history of mitral regurgitation, longevity on the part of the patient and

the physician was necessary. Allbutt was engaged in a consulting practice for 28 years in Leeds, England from 1861 to 1889. Many years later, in 1917, in a disagreement with Lewis and Mackenzie about prognosis and significance of apical systolic murmurs during the World War I British Heart Hospital experience (mentioned previously), Allbutt recalled vividly “the subsequent lives of many a patient in whom a mitral regurgitant murmur was for years the precursor of subsequent cardiac incapacity and ultimate failure. . .” Natural history studies were confounded for a century by delays in the definition of the floppy mitral valve, the recognition of nonrheumatic causes of mitral regurgitation, and the comprehension of cardiovascular disorders of connective tissue origin. Natural history information about certain patients with floppy mitral valves initially came from the pathologists. Progression of mitral regurgitation in certain patients with floppy mitral valves producing mitral valve prolapse occurs in a reasonably predictable fashion. Kolibash presented natural history data from 86 patients with documented mitral valve prolapse who developed progressive mitral regurgitation. A chronology plot incorporated patient age when a cardiac murmur was first noted, the age of onset of initial cardiac symptoms, and the age when progressive symptoms prompted refer-

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Number at ceees

a

4

0 43

I < 20

20 - 29

30 - 39 Age

40 - 49 (Y-W

ral for cardiac catheterization or consideration for cardiovascular surgery (Fig 23). The average age at murmur detection was 34 years with a wide range. This was followed by a long asymptomatic interval that averaged 24 years before the onset of symptoms at an average age of 59 years. The interval between the onset of significant symptoms and referral for cardiovascular diagnostic studies or cardiovascular surgery was brief. Clinical recognition of floppy mitral valve

50 - 59

>60

Fig 22. (A) Infective endocarditis in floppy mitral valve. The vegetation (between arrows) in this surgically excised anterior leaflet is associated with evidence of cusp destruction. The leaflet is thickened and hooded. Scale is in centimeters. (B) Age and sex distribution of reported patients with floppy mitral valves and infectious endocarditis. (Reprinted with permission.W)

disease in the elderly was presented by Kolibash et al in a study of 62 patients 60 years or older.88 Twenty patients presented with chest pain without significant coronary artery disease, 16 with significant cardiac arrhythmias including cardisc arrest requiring resuscitation, and 26 with progressive mitral regurgitation leading to congestive heart failure. The floppy mitral valve and its complications must be considered in the differential diagnosis of symptomatic cardiovascular disease in the older patient.

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Fig 23. Natural history of patients wtth floppy mitral valves. Number of patients is plotted against age at which a murmur was first noted (front panels in white) and age at which symptoms were first noted (rear panels in black). See text for further details. (Reprinted with permission.g)

Duren’s prospective studyW from The Netherlands, with a 6.1 year average follow-up, dealt with a specific subset of adult patients with mitral valve prolapse. One hundred and fiftythree patients demonstrated a stable clinical condition, 27 experienced supraventricular tachycardia which was controlled medically, and 20 patients developed signs of mitral regurgitation. Serious complications occurred in 100 patients-sudden death in 3, ventricular tachycardia managed effectively with medications in 56, infective endocarditis in 18 with 4 deaths, valve replacements in 6 and 8 left with severe mitral regurgitation, mitral valve surgery in 28, and cerebral vascular accidents in 11. Although criticized for lack of controls, selection bias, and symptoms that may not be disease specific, the study is consistent with clinical experiences in certain subsets of patients with floppy mitral valves. Nishimura et a175determined prognosis in a prospective (mean 6.2 years) follow-up study in 237 minimally symptomatic or asymptomatic patients with mitral valve prolapse documented by echocardiography. The average age was 44 years (range 10 to 69 years). Sudden death occurred in six patients. A multivariable analysis of echocardiographic factors showed that the presence or absence of redundant mitral valve leaflets (present in 97 patients) was the only variable associated with sudden death. Ten patients sustained a cerebral embolic event; one had a left ventricular aneurysm with apical thrombus, one had infective endocarditis, six were in atria1 fibrillation with left atria1 enlargement, and two were in sinus rhythm. Infective

endocarditis occurred in three patients. Progressive mitral regurgitation prompted valve replacement in 17 patients. Left ventricular enddiastolic diameter exceeding 60 mm was the best echocardiographic predictor of the subsequent need for mitral valve surgery. Twenty patients had no clinical auscultatory findings of a systolic click or murmur; none of these patients had any complications during follow-up. The investigators concluded that although most patients with echocardiographic evidence of mitral valve prolapse have a benign course, subsets of patients can be identified by echocardiography that are at high risk for the development of progressive mitral regurgitation, sudden death, cerebral embolic events, or infective endocarditis. Marks et al” confirmed these observations in a retrospective study. Clinical and two-dimensional echocardiographic data from 456 patients with mitral valve prolapse were analyzed. Two groups of patients were compared: those with thickening of the mitral valve leaflet and redundancy and those without leaflet thickening. Complications, or a history of complications, ie, infective endocarditis, mitral regurgitation, and the need for mitral valve surgery, were more prevalent in those with leaflet thickening and redundancy compared with those without leaflet thickening. However, the incidence of stroke was similar in the two groups. The natural history studies provide several clinically important conclusions. Patients with floppy mitral valves have a prolonged natural history and for the most part complications are age related (Fig 24A). Rather than a single

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Fig. 24. Floppy mitral valve, natural history. Symptoms are plotted against patient age in years. Increased symptoms occur after age 50 and are related to progressive mitral regurgitation (MR), atrial fibrillation (Atrial fib), left atrial (LA), and left ventricular (LV) dysfunction, congestive heart failure (CHF), and infectious endocarditis. Thromboembolic complications have been reported at a wide range of ages. (B) Floppy mitral valve (FYV), natural history considerations. (Top) The spectrum of mitral valve abnormalities in patients with MVP is compared with the natural history. (Left lower) Relationship between the number of clinical and laboratory abnormalities and the severity of the disease (schematic presentation). FMV includes a wide spectrum of valvuler abnormalities from mild to severe and at any particular time the number of abnormal clinical (eg, click, click plus late systolic murmur, holosystolic murmur, gallop rhythm, cardiac arrhythmias, etc) and laboratory findings (ag. late systolic prolapse, thickened mitral leaflets, holosystolic prolapse, left ventricular and left atrial enlargement on echocardiogram, and mitral regurgitation on Doppler) is directly related to the severity of the disease. (Right lower) FMV patients may have a wide spectrum of valvular abnormalities from mild to severe. The natural history of patients with FMV is directly related to the severity of mitral valve abnormalities. Lines represent morbidity and mortafii related to complication such as infective endocarditis, thromboembolic phenomena, cardiac arrhythmias, mitral regurgitation, etc (schematic presentation). (Reprinted with permission.P)

natural history curve, patients with floppy mitral valves experience a series of natural history curves that reflect the pathological and pathophysiological spectrum (Fig 24B). Natural history curves that differ from the general population occur in patients with floppy mitral valves with complications such as infectious endocarditis, embolic events, ruptured chordae, progressive mitral regurgitation, left atria1 and left ventricular dysfunction and failure (Fig 24B). FLOPPY MITRAL VALVES AND CARDIAC ARRHYTHMIAS

Cardiac arrhythmias may modify the natural history of certain patients with floppy mitral valves. A broad spectrum of cardiac arrhythmias occurs in patients with floppy mitral valves.

Schaal’” reviewed the various pathogenetic mechanisms that have been postulated or identified. Postulates that relate floppy mitral valve mechanics and dysfunction directIy to arrhythmias include the potential for cardiac rhythmic activity arising from anterior mitral leaflet atria1 muscle pacemaker tissue enhanced by leaflet stretch or neurohumoral activity; mechanisms involving floppy mitral valve chordal-papillary muscle stretch, tension or fibrosis; and left ventricular friction lesions, asynergy or ischemia resulting from floppy mitral valve dysfunction, stretch, and tension (Fig 25). Identified, coexisting, anatomic electrophysiological abnormalities that have been demonstrated in parents with floppy mitral valves

FLOPPY

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MVP,

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II

427

FMV-NoMR Abnormal

Fig 25. Floppy mitral valve (FMV) and the occurrence of cardiac arrhythmias. Dynamic spectrum and natural progression of patients with floppy mitral valves (FMV) plotted against time in years (panel on left) and interactions with proven or postulated mechanisms for cardiac arrhythmias (panel on right). See text for discussion. MR. mitral regurgitation; AV, atrioventricular.

FMV - MM

I

MR

\ I FMV-ModemteYR

Autonomic FW I

AV Conduction Influences

DynamkWDysfunctlon

Chordal/Paplllery Myocardlal AtriakVentrlcular

Tenalon lschamla Myopathy

include dual atrioventricular node pathways and accessory atrioventricular pathways. Autonomic influences, cardiac sympatheticparasympathetic tone alterations or abnormalities, endogenous catecholamine responsiveness, and hemodynamic interactions may be initiating or contributory factors. Progressive mitral valvular regurgitation in patients with floppy mitral valves results in left atria1 and left ventricular dysfunction, myopathic changes, and enlargement with the development of atria1 fibrillation and ventricular arrhythmias of endomyocardial origin (Fig 25). FLOPPY MITRAL VALVE-SURGICAL CONSIDERATIONS

Mitral valve repair with mitral annular plication, annuloplasty ring insertion, and repair of chordae tendineae was originally described in 1960.“’ General acceptance of repair procedures occurred gradually during the next three decades, stimulated in particular by the morphologically based techniques developed by Carpentier and coinvestigators.59 The estimated lifetime risk for mitral valve surgery has been calculated by Wilcken and Hickey in an Australian population.lM Comparisons with two US surgical experiences87+1o3are presented in Fig 26. Greater attention to the subtleties of the floppy mitral valve annulus-leaflet-chordaepapillary muscle morphology and relations, coupled with increased concern about preservation of the subvalvular apparatus in order to maintain or improve left ventricular function, have been integral parts of the evolution of surgical procedures for floppy mitral valve reconstruction and repair.‘”

Fig 26. Floppy mitral valve, surgical considerations. (A) Plots percant of patients wfth floppy mitral valves against patient age at the time of cardiovascular surgery in years at two institutions, Mayo Clinic, Rochester, MN,lm and the Ohio State University, Columbus, OH. M, male; F, female. (Reprinted with permission.P; Data from references 66 and 103.) (B) 5stimated Iffatime risk of mitral valve surgery adapted from the study of Wilcken and Hickey.” (Reprinted with permission.P) (C) Plot of Davies data,” incidence of floppy mitral valves of clinical significance at routine necropsy. (Reprinted with permissionP)

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Individually tailored procedures based on careful analysis of floppy mitral valve morphology, identification of the specific mechanisms of valvular dysfunction, and increased surgical ingenuity supplemented by the use of preoperative and intraoperative imaging with a variety of echo-Doppler techniques’” has changed the surgical approach to floppy mitral valves and will have a considerable impact on the timing of surgery for patients with floppy mitral valves and progressive mitral valvular regurgitation or dysfunction. CARDIOVASCULAR DISORDERS OF CONNECTIVE TISSUE ORIGIN

Concept: Phenotypes, Collagen, Connective TissueMatrix, and Genes Changing nosology in the “new cardiology. ”

The gradual, growing awareness that patients with floppy, myxomatous mitral valves had cardiovascular defects of connective tissue origin is a concept that arose in the early 20th century, but was generally overlooked for the next 50 years. Developing themes that run through the expanding floppy mitral valve-mitral valve prolapse literature of the mid-to-late 20th century included the association of the floppy mitral valve with mitral valve prolapse with recognized heritable connective tissue syndromes and the links between floppy mitral valves and less well-defined generalized systemic disorders. That connective tissue disorders were etiologic factors in the production of symptomatic cardiovascular diseases may be traced to Salle with mitral value involvement in a Marfan syndrome patient in 1905,19 Erdheim with cystic medial necrosis with spontaneous rupture of the aorta in 1929,‘06 and the description of aortic dissection in the Marfan syndrome in 1943.“’ True clinical comprehension and nosology began with McKusick at mid-century.24 Widespread clinical awareness is still in the developing stages. Recognition of floppy mitral valves as heritable disorders producing significant mitral valve prolapse and progressive mitral valvular dysfunction with or without aortic valve or root involvement accompanied increased recognition of the Marfan syndrome, the Ehlers-Danlos syndrome spectrum,‘08 and the adult polycystic kidney disease spectrum.lW Floppy mitral valves have emerged as a common cardiovascular denomina-

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tor in recognized heritable disorders of connective tissue”’ and in association with systemic connective tissue disorders that are as yet incompletely deflned.‘l’ Relatively little is known about the etiology and chronology of the fundamental tissue changes in the floppy mitral valve; recent studies incorporating biochemistry and genetics have extended knowledge with the potential for further advancement. Connective tissue studies and genetic research’12m115 have been stimulated by recognition that mitral valve prolapse associated with floppy mitral valve is common in heritable disorders in which collagen or connective tissue matrix defects occur, the histological evidence in the floppy mitral valve of an abnormal collagen matrix, and the autosomal dominant mode of inheritance with incomplete penetrance and variable expression suggesting a structural protein defect (rather than enzymatic abnormalities, which are usually recessive traits). Subtypes of floppy mitral valve expression may reflect genetic heterogeneity.l” In a study from St George’s Hospital, London, England, total amounts of collagen, proteoglycan, and elastin were increased approximately threefold in floppy mitral valves.58 There was a 59% increase in the mean value of the proteoglycan content, a large increase in the ease of extractability of proteoglycans from 26.7% to 57.2% of the total, and a 62% increase in the mean value of the elastin content in the anterior leaflets. Normal human mitral valves contained a mean value of 29.3% and 26.6% type III/III + I collagen ratio for leaflets and chordae respectively, whereas the ratio observed in floppy valves was dependent on the extent of secondary fibrosis. The percentage of type III collagen was increased in valves with considerable fibrosis. In patients with negligible fibrosis, the percentage of type III collagen decreased. Whether diminished synthesis or increased lysis starts the process is unclear. All the multiple steps in collagen organization could be involved. A lytic theory has been proposed, although degradation by collagenase seems improbable because of the high levels of tissue inhibitor of collagenases in floppy valves.58 Cole et a1113noted that normal mitral valves contained type I (74%), type III (24%), and type V (2%) collagen, whereas floppy valves had

FLOPPY

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VALVE,

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Diagnostic Tick-Tack-Toe

00 %0 Fig 27. Floppy mitral valve, mitral valve prolapse, mitral regurgitation. Emphasis is placed on a multidimensional approach to diagnosis and the wisdom of auscultatoryphonocardiographic imaging and clinical coherence.

and

greater amounts of type III collagen with smaller increases in type I and V. Abnormally high rates of floppy valve collagen synthesis were described by Henney et a1.114Cole considered the increased floppy valve production of collagen, in particular type III, glycosaminoglycan, and the cellular proliferation as part of a repair process in floppy mitral valves.“3 Collagen types I, III, and V predominate the mitral valve; type III is the product of a single gene (COL 3 Al) located on chromosome 2; type I is encoded by two genes (COL 1 Al chromosome 17; COL 1 A2 on chromosome 7) for type I; type V is thought to be encoded by these genes, only one of which has been cloned (COL 5 A2 on chromosome 2).“’ Henney et allI showed lack of linkage of the familial mitral valve prolapse trait to genes for collagen types I, III, and V in two large families, whereas Wordsworth”’ found that the primary gene locus for

Fig 28. Floppy mitral valve mosaic. Emphasis on contributions of various disciplines to date. See text for further details.

mitral valve prolapse was not linked to either of the two collagen I LOCI, nor probably to the collagen III locus. These studies may be interpreted in several ways. Henney concluded that other candidate genes await study-type V collagen genes or genes encoding other components of the connective tissue matrix (elastin, proteoglycans). Alternatively, if mitral valve prolapse is polygenic, this would explain why individual responsible genes cannot be identified because they do not cause major changes in phenotype. Obviously, there is much more to be done, and this chapter of the floppy mitral valve story continues as the subject of active investigation. THE FLOPPY, MYXOMATOUS MITRAL VALVE: A TWO-CENTURY ODYSSEY PRODUCED AN INCOMPLETE MOSAIC

Concept: “We Had the Experience but Missed the Meaning.llb” The floppy mitral valve occupies the central position, the high ground, in the mitral valve prolapse story (Fig 27). Floppy mitral valve morphology, biochemistry, and genetics coupled with the dynamic pathophysiology of mitral valve prolapse are powerful extensions of our knowledge of mitral valvular regurgitation and of valvular heart disease of connective tissue origin. Clinicians learn in various ways. The construction of multidisciplinary mosaics represents one

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way. Decades of laborious, painstaking, intellectual investigative activity are intermingled with frenetic bursts of activity and prolonged inactivity. The floppy mitral valve odyssey reflects patterns of learning similar to those clinicians experienced with the recognition of coronary artery disease, the links between rheumatic fever and resultant valvular heart disease, and the classification of myocardial diseases. Definition of the floppy mitral valve and its place in the hierarchy of valvular heart disease and disorders of connective tissue origin has taken two centuries, a learning process that certainly will extend into a third century. During the past two centuries, cardiovascular morphologists, pathologists, auscultors, clinicians, hemodynamicists, surgeons, and imagers “had the experience but missed the meaning” for prolonged time intervals. The development of clinically coherent patterns took time, multidisciplinary observations, and experiences, and the development of basic concepts burnished by considerable controversy. A floppy mitral valve mosaic now exists (Fig 28). The floppy mitral valve mosaic outlines may be indistinct, with missing sections; however,

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there is enough information, definition, and experience to form the basis for a rational third century approach to the meaning. “ . . . to recover what has been lost and found and lost again and again.“l17 ACKNOWLEDGEMENT Donald V. Unvergerth, MD, Carl V. Leier, MD, and Richard P. Lewis, MD from the Division of Cardiology, The Ohio State University, provided continued stimuli and support for this work. Nobuitisa Baba, MD, PhD, Department of Pathology, The Ohio State University, was a primary contributor to our thinking and analysis. Robert Anderson, MD, Professor of Cardiac Morphology, The Cardio-Thoracic Institute, Brompton Hospital, London, England; Anton Becker, MD, Professor of Pathology, University of Amsterdam, Netherlands; Michael Davies, MD, British Heart Foundation, Professor of Pathology, St George’s Hospital Medical School, London, England; Jesse E. Edwards, MD, Registry of Cardiovascular Diseases, United Hospital, St Paul, MN, and Alfred Angrist, MD, Professor of Pathology, Albert Einstein College of Medicine, NY, influenced our thoughts in so many ways that it is impossible to identify specific influences. Michael A. Apicella, MD, Professor of Medicine, University of Buffalo, provided the infectious endocarditis concepts. We gratefully acknowledge Sharon Olson RDMS, clinical associate and collaborator; Dennis Mathias, graphics design; and Dawn Serafini, manuscript preparation.

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22. Traisman HS, Johnson FR: Arachnodactyly associated with aneurysm of the aorta. Am J Dis Child 87~156-166, 1954 23. Miller R, Pearson RJ: Mitral insufficiency simulating aortic stenosis. Report of an unusual manifestation of Marfan’s syndrome. N Engl J Med 260:1210-1213,1959 24. McKusick VA: Heritable Disorders of Connective Tissue (ed 2). St Louis, MO, Mosby, 1960, pp 42-134 2.5. Shankar KR, Hultgren MK, Lauer RM, et al: Lethal tricuspid and mitral regurgitation in Marfan’s syndrome. Am J Cardiol20:122-1281967 26. Frothingham C, Hass GM: Rupture of normal chordae tendineae of the mitral valve. Am Heart J 9:492-499, 1934 27. Scott-Jupp W, Barnett NL, Gallagher PJ, et al: Ultrastructural changes in spontaneous rupture of mitral chordae tendineae. J Path01 133:185-201, 1981 28. Caulfield JB, Page DL, Kastor JA, et al: Connective tissue abnormalities in spontaneous rupture of chordae tendineae. Arch Path01 91:537-541, 1971 29. Marchand P, Barlow JB, DuPlessis LA, et al: Mitral regurgitation with rupture of normal chordae tendineae. Br Heart J 28:746-758,1966 30. Singh R, Schrank JP, Nolan SP, et al: Spontaneous rupture of mitral chordae tendineae. J Am Med Assoc 219:189-193.1972 31. Hickey AJ, Wilcken DEL, Wright JS, et al: Primary (spontaneous) chordal rupture: Relation of myxomatous valve disease and mitral valve prolapse. J Am Co11 Cardiol 5:1341-13461985 32. Jeresaty RM, Edwards JE, Chawla SK: Mitral valve prolapse and ruptured chordae tendineae. Am J Cardiol 55:138-142,1985 33. Baker PB, Bansal GJ, Boudoulas H, et al: Floppy mitral valve chordae tendineae: Histopathologic alterations. Hum Path01 19:507-512, 1988 34. Read RC, Thal AP, Wendt VE: Symptomatic valvular myxomatous transformation (the floppy valve syndrome). A possible forme fruste of the Marfan syndrome. Circulation 32:897-910,1965 35. Bittar N, Sosa JA: The billowing mitral valve leaflet. Report on 14 patients. Circulation 38:763-770,1968 36. Aslam PA, Eastridge CE, Bernhardt H, et al: Myxomatous degeneration of cardiac valves. Chest 57:535-539,197O 37. McCarthy LJ, Wolf PL: Mucoid degeneration of heart valves: “Blue valve syndrome.” Am J Clin Path01 54:852-856, 1970 38. Sherman

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RH, Schuster B, Knoebel SB, et al: Myxomatous degeneration of the mitral valve. Am J Cardiol28:449455,197l 41. Edwards

JE: Mitral insufficiency resulting from “overshooting” of leaflets. Circulation 43:606-612,197l 42. Cooley DA, Gerami S, Hallman GL, et al: Mitral insufficiency due to myxomatous transformation: “Floppy valve syndrome.” J Cardiovasc Surg 13:346-349,1972 43. Ranganathan N, Silver MD, Robinson TI, et al:

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Roberts WC: Congenital cardiovascular abnormalities usually “silent” until adulthood: Morphologic features of the floppy mitral valve, valvular aortic stenosis, discrete subvalvular aortic stenosis, hypertrophic cardiomyopathy, sinus of valsalva aneurysm, and the Marfan syndrome. Cardiovasc Clin 10:407-445,1979 46. Olsen EGJ, Al-Rufaie HK: The floppy mitral valve. Study on pathogenesis. Br Heart J 44:674-683,198O 47. Rippe J, Fishbein MC, Carabello B, et al: Primary myxomatous degeneration of cardiacvalves. Clinical, pathological, hemodynamic and echocardiographic profile. Br Heart J 44:621-629,198O 48. Pomerance A: Ageing changes in human heart valves. Br Heart J 29:222-231,1967 49. Pomerance A: Ballooning deformity (mucoid degeneration) of atrioventricular valves. Br Heart J 31:343-351, 1969 50. Kern WH, Tucker BL: Myxoid changes in cardiac valves: Pathologic, clinical and ultrastructural studies. Am Heart J 84:294-301,1972 51. Guthrie RB, Edwards JE: Pathology of the myxomatous mitral valve. Nature, secondary changes and complications. Minn Med 59:637-647, 1976 52. King BD, Clark MA, Baba N, et al: “Myxomatous” mitral valves: Collagen dissolution as the primary defect. Circulation 66:288-296, 1982 53. Davies MJ, Moore BP, Braimbridge MV The floppy mitral valve. Study of incidence, pathology, and complications in surgical, necropsy and forensic material. Br Heart J 40:468-481,1978 54. Lucas RV, Edwards JE: The floppy mitral valve. Curr Probl Cardiol7:1-48,1982 55. Becker AE, DeWit APM: Mitral valve apparatus. A spectrum of normality relevant to mitral valve prolapse. Br Heart J 42:680-689,1979 56. Van der Bel-Kahn J, Duren DR, Becker AE: Isolated mitral valve prolapse: Chordal architecture as an anatomic basis in older patients. J Am Co11Cardiol5:1335-1340, 1985 57. Hutchins GM, Moore GW, Skoog DJ: The association of floppy mitral valve with disjunction of the mitral annulus fibrosis. N Engl J Med 314:535-540,1986 58. Angelini A, Becker AE, Anderson RH, et al: Mitral valve morphology: Normal and mitral valve prolapse, in Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY, Futura, 1988, pp 13-53 59. Carpentier A, Guerinon J, Deloche A, et al: Pathology of the mitral valve, in Kalmanson D (ed): The Mitral Valve: A Pluridisciplinary Approach. Acton, MA, Mass Publishing Sciences Group, 1976, pp 65-77 60. McKay R, Yacoub MH: Clinical and pathological finding in patients with “floppy” valves treated surgically. Circulation 47:63-73,1973 (suppl3) 61. Barlow JB, Pocock WA: Mitral leaflet billowing and prolapse, in Barlow JB (ed): Perspective on the Mitral Valve. Philadelphia, PA, Davis, 1987, pp 45-111

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FLOPPY

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REGURGITATION

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