Mitral valve prolapse and the mitral valve prolapse syndrome

Mary E. Fontana, M.D., is a graduate of the Ohio State University College of Medicine, with postdoctoral training at the University of North Carolina and Ohio State University. She is currently an Associate Professor of Znternal Medicine in the Division ofcardblogv at the Ohio State University College of Medicine. Her interest and research involving mitral valve prolapse date from her early fellowship years. Her current interests are in adult congenital heart disease and valvular heart disease.

Charles F. Wooley, M.D., is a Professor of Medicine in the Division of Cardiology at the Ohio State University College of Medicine. He has a long-term interest in cardiac auscultation, phonocardiography, hemodynamics, and mitral valve disease. Along with his coauthors, he has been involved in the study of mitral valve prolapse, the poppy mitral valve, and the mitral valve prolapse syndrome for the past three decades. Curr

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Elizabeth A. Sparks is a registered nurse. She received her training from Columbus Technical Institute and Otterbein College. Ms. Sparks is the coordinator/Cardiovascular Associate of the James W. Overstreet Research and Teaching Laboratory at the Ohio State University. This is a noninvasive cardiovascular laboratory where students of medicine integrate physical diagnosis and state-of-the-art technology to develop logical diagnoses and finally present case histories to staff cardiologists. She has been a clinical cardiovascular nurse and staff nurse in the intensive care unit. Her interests include auscultation, valvular heart disease, and medical genetics in cardiovascular diseases.

Harisios Boudoulas, MD., is a Professor of Medicine and Pharmacy, Division of Cardiology, the Ohio State Vniversity, Columbus, Ohio. He earned his M.D. degree from the Medical School Aristotelian University of Thessaloniki, Greece. In addition to his MD. degree, Dr. Boudoulas also obtained a Doctorate Diploma (Thesis on Renal Physiology and Pharmacolo& from the Medical School Aristotelian University of Thessaloniki. He obtained his postgraduate training from the Medical School Aristotelian University of Thessaloniki and also from the Ohio State University College of Medicine. He was a key member of the team that per$ormed the first successfil renal transplantation in Greece in 1367. His research interest covers a wide spectrum of cardiovascular medicine, pathophysiologv, and pharmacology., and he has published over 270 papers and four books. 314

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MITRAL MITRAL

VALVE PROLAPSE VALVE PROLAPSE

AND TNE SYNDROME

OVERVIEW

Mitral valve prolapse (MVP) includes a wide spectrum of valvular abnormalities. Physical findings and laboratory correlates are directly related to the extent of the valvular abnormality. As a general rule, patients with more severe disease have more clinical and laboratory findings, and vice versa”’ (Fig 1). The search for a single diagnostic “gold standard” for MVP during the past three decades has been an example of reductionist simplicity in diagnostic medicine and is reminiscent of the decades of controversy over the use of the exercise electrocardiogram in the diagnosis of coronary artery disease. Nowhere else in clinical cardiology was good judgment in the diagnostic process replaced by diagnosis based on angles, degrees, and millimeters, as in MVP. Diagnoses based on subjective interpretation of auscultatory systolic clicks without echophonocardiographic confirmation, or nonspecific echocardiographic findings without other clinical correlates contributed to diagnostic confusion and to exaggerated incidence figures. In general, we are more comfortable when the diagnosis of MVP is based on coherence of the postural auscultatory complex with imaging studies that are consistent with a floppy mitral valve (FMV). However, because echocardiographic and cineangiographic studies have shown that MVP may occur without external auscultatory phenomena, we must make room for some diagnostic flexibility. It should be emphasized that it is of great clinical importance to avoid the overdiagnosis of MVP in normal individuals or in patients who fall in the zone between normal and MVP. It is equally important to stratify patients with MVP according to the clinical and laboratory findings. Results from studies of patients with MVP should be directly related to the subgroup of patients investigated. Differences among individual patients with MVP contribute to the spectrum of results regarding prevalence, echocardiographic tindings, symptoms, complications, etc. Similarly, management and natural history obviously differ in each subgroup of patients with MVP. The fallacy of Curr

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FIG 1. Left, relationship between the number of clinical and laboratory abnormalities and the severity of the disease (schematic presentation). Mitral valve prolapse (MVP) includes a wide spectrum of valvular abnormalities, from mild to severe. At any particular time the number of abnormal clinical (e.g., click, click plus late systolic murmur, holosystolic murmur, gallop rhythm, cardiac arrhythmias) and laboratory findings (e.g., late systolic prolapse, thrckened mitral leaflets, holosystolic prolapse, left ventricular and left atrial enlargement on echocardiogram, mitral regurgitation on Doppler) is directly related to the severity of the disease. Right, the spectrum of mitral valve abnormalities in patients with MVP (upper) is compared with the natural history (lower). MVP patients may have a wide spectrum of valvular abnormalities from mild to severe. The natural history of patients with MVP is directly related to the severity of mitral valve abnormalities. tines represent morbidity and mortality related to complications such as infective endocarditis, thromboembolic phenomena, cardiac arrhythmias, and mitral regurgitation (schematic presentation). (From Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura Publishing Company, Inc, 1988. Used with permission.)

comparing the natural history of one group of patients with MVP with that of another without further stratification is similar to that of comparing the natural history of two groups of patients with coronary artery disease without further stratification. Better clinical classification and imaging definition of the severity of mitral valve abnormality will help to better define the natural history in the different subgroups. Thus subgroups of MVP patients with a higher incidence of complications (progression to severe mitral regurgitation, chordae tendineae rupture, embolic phenomena, infectious endocarditis, sudden death) may be defined more effectively.

MITRAL

VALVE PROLAPSE

-A

CLINICIAN’S

CLASSIFICATION

Based on our experience and experience of others we proposed the following classification of patients with MVP1’ ’ (Table 1, Fig 2). MVP-anatomic includes patients with a wide spectrum of valvular 316

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TABLE 1. Cl%ssitication Mitral

of Mitral

Valve

Prolapse*

Valve Pmlanse-Anatomic

Mitral

Common mitral valve abnormality with a spectrum of structural and functional changes, mild to severe The basis for: Systolic click; mid-late systolic murmur Mild or progressive mitral valve dysfunction Pmgressive mitral tqurgitation, atrial fibrillation, congestive heart failure Infectious endocarditis Embolic phenomena Characterized by long natural history May be heritable, or associated with heritable disorders of connective tissue Conduction system involvement possibly leading to arrhythmias and conduction defects

‘From Mount

Boudoulas H, Wooky CF ledsl: Mitral Kisco, NY, fitwa Publishing Company.

Valve

Pmlanse

Svndmme

Patients with mitral valve prolapse Symptom complex: chest pain, palpitations, arrhythmias, fatigue, exercise intolerance, dyspnea, postural phenomena, syncope-pmsyncope, neumpsychiatric symptoms Neumendocrine or autonomic dysfunction. High catecholamines, catecholamine regulation abnormality, hyperresponsive to adrenergic stimulation, parasympathetic abnormality, bamreflex modulation abnormality, renin-aldostemne regulation abnormality, decreased intravascular volume, decreased ventricular diastolic volume in the upright posture, atrial natriurztic factor secretion abnormality may pmvide explanation for symptoms Mitral valve prolapse-a possible marker for autonomic dysfunction

v&e prolapse and the mitral he, 1988. Used by permission.

v&e

prolapse

syndrome.

from mild to severe. The term “floppy mitral valve” comes from surgical and pathologic studies and refers to the expansion of the mitral valve leaflet(s) area with elongated chordae, dilated mitral annuli, and characteristic structural changes in the valve leaflets. Symptoms, physical findings, and laboratory abnormalities in these patients are directly related to mitral valve dysfunction and progressive mitral regurgitation. The term MVP-syndrome refers to the occurrence of, or coexistence of, symptoms that result from various forms of neuroendocrine or autonomic dysfunction in patients with MVP, in whom the symptoms cannot be explained on the basis of valvular abnormality alone. This classification is clinically useful. It separates symptomatic patients with MVP and symptoms related to autonomic dysfunction from patients whose symptoms are related to progressive mitral valve dysfunction; it identifies a group of patients with MVP and autonomic dysfunction who require consideration of antibiotic prophylaxis for infectious endocarditis in addition to other forms of treatment; and it defines a group of symptomatic patients who need attention from physicians who are aware of newer developments concerning autonomic function and dysfunction. abnormalities,

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MVP: DYNAMIC

v

SPECTRUM

8 NATURAL

PROGRESSION

MVP-SYNDROME

TIME

(YEARS)

FIG 2. Left, the dynamic spectrum, time in years, and the progression of MVP are shown. A subtle gradation [cross-hatched area) exists between normal mitral valves and valves that produce mild MVP without regurgitation (no MR). Progression from the level MVP-no MR to another level may or may not occur. Most of the patients with MVP syndrome occupy the area above the dotted line, whereas patients with progressive mitral valve dysfunction occupy the area below the dotted line. Right, the large circle represents the total number of patients with MVP. Patients with MVP may be symptomatic or asymptomatic. Symptoms may be directly related to mitral valve dysfunction (black circle), or to autonomic dysfunction (cross-hatched circle). Certain patients with symptoms directly related to mitral valve dysfunction may present with, and continue to have symptoms secondary to, autonomic dysfunction (From Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Pro/apse Syndrome. Mount Kisco, NY: Futura Publishing Company, Inc, 1988. Used with permission.)

THE CENTRAL ROLE OF TI-IJZ FLOPPY MITRAL VALW IN MITRAL VALW PROLAPSE ANJJ MITRAL REGURGITATION A &CENTURY

ODYSSEY

When viewing Leonaro da Vinci’s detailed anatomic drawings, his sketches of the heart, and in particular, the details of left ventricular, aortic and mitral valve structure and relations (Fig 31, it is difficult to realize that controversy about fundamental mitral valve anatomy and function persists 480 years later. b P.M. SHAH:The authors differentiate between mitral valve prolapse, anatomic and mitral valve prolapse (MVP) syndrome largely on the basis of symptoms re318

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FIG 3. Sketches of the heart with details of left ventricular, aortic, and mitral valve structure and relations. (From Keele KD: Leonardo daVinci The Anatomist in Leonardo davinci Anatomical Drawings from the Royal Library, Windsor Castle. New York, The Metropolitan Museum of Art, 1983, pp 810-814. Used with permission.)

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lated to and objective evidences of neumendocrine or autonomic dysfunction. The clinical utility of this approach is not apparent, other than emphasizing the role of autonomic dysfunction in some patients and not in others with similar mitral valve pathology. It is likely that some patients classified initially as having MVP syndrome will develop progressive mitral valve dysfunction and the symptoms resulting from it. Similarly, antibiotic prophylaxis would be appropriate for Mvp, whether or not associated with neumendocrine dysfunction. I believe that the real clinical dilemma exists in the characterization of patients in the grey area, namely those with symptoms and objective criteria for autonomic dysfunction but without clear-cut auscultatory or echocardiographic features of floppy mitral valve. This is not an uncommon problem since auscultation findings may be intermittent or absent in some and the echocardiographic findings nondiagnostic in others. when the clinical and echocardiagraphic findings are discordant, this is not infrequent, the diagnostic dilemma for the clinician is the greatest.

Da Vinci’s anatomic drawings occupied him for nearly thirty years, from about 1485 to 1515.3 Details of the heart were among the work of the last years of his life. Most of the cardiac

work

was based on

dissections of ox hearts. Da Vinci’s interpretation of the operation of the heart was influenced by his earlier experiments on the flow of water.

On the inside of his sketch of the aorta he gave instructions for making a glass model so as to observe the movements of water, and so the blood, as it passed through the aorta. His involvement with the technology of the day, coupled with his extraordinary way of presenting the operating power of a machine was projected into these anatomic images. Moving ahead to the 1830s in England, the post-Laennec auscultation era and the beginning? of cardiology as it would be recognized by today’s clinicians, the ob@vations by James Hope, who has been considered the first carditilogist, and his contemporary, CJ.B. Williams,

bring us to the dia@osis

and confirmation

of mitral

regur-

gitation. A series of studies by R&anet, Magendie, and Bouillaud on the continent, and Hope and Williams in England, clarified the sequence of the first and second heart sounds, so that clinicians could separate systole from diastole. Hope established the relationship of apical systolic thrills and murmurs

with mitral

vaIvular

regurgitation,

and described

mitral

re-

gurgitation as a distinct lesion, due either to disease of the mitral valve leaflets or dilatation of the left ventriclee4 Williams established the relation between a loud, blowing apical systolic murmur heard during life and rupture of the mitral tendons (chordae) in the same patient at autopsy. The mitral valve was characterized by “warty and fibrinous concretions.” By the end of the nineteenth century mitral regurgitation was recognized as the most common valvular lesion, the significance of api320

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cal systolic thrills and murmurs as clinical indicators of mitral regurciatefj, atkd the potential for multiple etiobgies for on had been established. However, during the first half of the twentieth century there were a variety of conceptual detours by authoritative sources, so that the existence and significance of mitral regurgitation were questioned, accompanied by a preoccupation with rheumatic fever as the cause of most valvular disorders. Heavy doses of dogma without data caused a great deal of confusion for those clinicians and investigators involved in unravelling the mitral regurgitation skein. One of the great physical diagnosis exercises of all time took place in the United States during the 1917-1918 period when, following declaration of war in April 1917, the Selective Service Act of May 1937 provided for the registration of all men 21 to 39 years old, which in turn set the stage for the eventual examination of almost 4 million men.5 Valvular heart disease as diagnosed by the physical diagnostic criteria of the time was found in 85,143 men, or 3.39% of 25 million men e xamined and neported on. Of these men, 49,330 were further classified, and among these, 29,610 or 73.4% were diagnosed as mitral regurgitation. We e&mated the frequency of mitral regurgitation among these 2.5 million young men at 2.48%, a figure that continues to be relevant today. During World War I, the frequency of apical systolic murmurs in young men in Great Britain and the United States was such that the topic was one of great debate. However, the pragmatic approach at the time, given the needs of the military for ever-increasing numbers of soldiers for the war in France, was to ignore the apical systolic murmur regardless of intensity when evaluating young men for military duty. This attitude infiltrated clinical practice for some time after the conflict. When mitral valve structure and function is looked at from this multi-century perspective, perhaps it is not so surprising that 480 years after da Vinci, 160 years after mitral regurgitation was described in clinical and clinical-pathologic terms, and 75 years after the World War I medical experiences, we are still organizing bits and pieces of the mitral regurgitation puzzle, and still searching for Leonardo’s glass model to observe the movements of the blood in the left heart. THE FLOPPY MITRAL

VALVE

Floppy mitral valve description and definition came about in a variety of ways (Fig 4). The morphologists and pathologists had the advantage of seeing and handling the floppy mitral valves, and the cardiovascular surgeons had the additional advantage of direct visualization of valve Cum

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FIG 4. Floppy mitral valve, from a patient with severe mitral regurgitation, excised at surgery. Atrial surface. The anterior mitral leaflet is at the top, and the posterior mitral leaflet occupies the lower portion of the picture. The total valve surface area is increased. The annulus is enlarged. Scallops of the posterior leaflet balloon toward the left atrial chamber. Both leaflets are thickened, the chordae are elongated, and chordal rupture may be seen at the right margin.

appearance and dynamics in the beating heart. Their disadvantage resulted from the highly selective nature of the patients who came to their attention at autopsy or surgery, and the need to work backward in order to understand the natural history and the clinical indicators for recognition. The largest hurdle to overcome was the rheumatic feverrheumatic heart disease etiologic barrier. During the time that rheumatic fever was such a scourge in the Western countries, rheumatic fever as the etiologic basis for most forms of valvular heart disease was so pervasive a concept that it is difficult to comprehend in retrospect. As a result, recognition of nonrheumatic forms of mitral regurgitation as an entity was a late development, and an appreciation of the frequency of nonrheumatic mitral regurgitation occurred even later. Morphologic Beginnings The article that pointed the way toward the floppy mitral valve as a discrete, probably nonrheumatic entity was published in the 322

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American Heart Journal in 1~44 by Orville Bailey and John Hickam.” The emphasis of the paper was on mitral chordae rupture not associated with bacterial endocarditis. Disease of the mitral valve and its chordae appeared to antedate the chordal rupture; fibrosis of the mitral valve without stenosis occurred in certain valves without indications of rheumatic fever; stumps cf chordae were composed of partially degenerated connective tissue; and the varying stages of gross and microscopic appearances of chordal pathology in one case suggested that chordae had ruptured at two periods separated by a long interval. Loud systolic murmurs, some known to be of prolonged duration; atrial fibrillation; and congestive heart failure, which varied in duration and severity, were parts of the retrospective clinical profile. Increased valve thickness .with dense, relatively acellular connective tissue thickening and basophilic areas of degeneration were noted on microscopic examination. The gross illustrations in the article are consistent with floppy mitral valve morphology, and were described in the paper as “ballooning” upward into the left atrium. The authors emphasized the long natural history of the disorder, while the lack of clear-cut evidence of rheumatic etiology in most of the valves led them to question the etiology of the chronic valvular and chordal process. Brigden and Leatham, in 1953,7 described “pure” mitral regurgitation in 30 patients, predominantly males, without a history of rheumatic fever, and emphasized the long natural history of the disorder, the susceptibility to bacterial endocarditis, and the late onset of congestive heart failure that was usually rapidly progressive. In contrast to the retrospective clinical analysis in the Bailey-Hickam paper, the authors were involved in the clinical evaluation of most of the patients, and contemporary diagnostic studies were performed as part of their clinical evaluations. Eight of the patients were known to have a murmur for more than 25 years, “the date being settled by an examination for military service in the First World War.” Nine patients came to necropsy; the mitral orifice was dilated in eight, and the mitral valves were described as “thickened and deformed.” The illustrations were those of exuberant mitral valves. “The Floppy Valve Syndrome” and Valvular Regurgitation Because of Valve Prolapse Read et al. used the term floppy valve syndrome in 1965’ to describe patients with significant valvular incompetence who had “myxomatous transformation” of the aortic and mitral valves at surgery or autopsy but did not fit all the clinical criteria for the Marfan syndrome. Valvular regurgitation “apparently resulted because of valve prolapse from either structural fatigue, ruptured chordae, loss Cut-r Probl

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of substance, interference with coaptation, or supervening endocarditis.” In addition to the descriptive terminology (i.e., “floppy valve” as a term for myxomatous changes, and “prolapse” as a term for the mechanism producing mitral or aortic valvular regurgitation), the paper called attention to the lineage of valvular involvement in connective tissue disorders and placed emphasis on cardiovascular disorders of connective tissue origin rather than on the traditional rheumatic etiology. The Clinicians The problem the clinicians faced was of a different order of magnitude, and they approached the problem from a different direction. In&ally the problem presented itself as an auscultatory dilemma. The interpretation of apical systolic sounds referred to as systolic clicks or systolic gallop sounds, and of apical mid- or late systolic murmurs that were not conducted, as contrasted to the loud, holosystolic murmurs of mitral regurgitation that were transmitted to the back, puzzled the auscultatom for l&O years? These systolic sounds and non-conducted apical systolic murmurs were long considered to be “extra-cardiac” in origin, based on minimal data and maximal dogma. As auscultation became a more objective discipline with the development of phonocardiography during the first half of the twentieth century, these auscultatory phenomena were recorded, and then in time were subjected to new types of analyses as other technologies became available. As part of the ferment in dynamic auscultatory-phonocardiographic-hemodynamic-angiographic correlative studies during the 196Os, John Barlow and his associates in South Africa performed systematic studies in patients with late systolic murmurs and systolic clicks, With vasoactive maneuvers the auscultatory and phonocardiographic responses were compatible with the behavior of a regurgitant systolic murmur of mitral incompetence, They also observed mitral regurgitation on left ventricular cineangiography in patients with murmurs confined to late systole on phonocardiography. Systolic click behavior was also compatible with an intracardiac origin, and the term non-ejection click was introduced to differentiate these sounds from aortic and pulmonic ejection clicks and soundslo Criley and associates published “Prolapse of the Mitral Valve: Clinical and Cine-anglocardiographic Findings” in 1966,l* describing a “unique” anatomic type of mitral regurgitation as recognized cineangiographically, occuning in association with a murmur in the latter part of systole, correlated with phonocardiograms, which provided a functional anatomic basis for the late onset of the murmur and the click. The authors speculated that the aneurysmal bulging of the 324

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leaflets might be the angiogmphic counterpart of the hoodlike or balloon deformity seen at necropsy in patients with ruptured chordae as described by Bailey and Hickam in 1944.6 These studies and a number of earlier, contemporary, and later studies from around the world erased incomplete or incorrect concepts that had existed for a 150 years. It is important to emphasize that the clinicians resolved these issues by utilizing and modifying the conventional physical diagnostic wisdom of the day. They incorporated the technology of the day, using external and intracardiac phonocardiography correlated with cineangiography and vasoactive hemodynamic interventions, but the result was always correlated with the clinical situation and the physical examination. In fact, the clinicians who performed the investigative studies also performed the clinical evaluations. This was lost sight of with the proliferation of technology and the separation of diagnostic procedures from the clinical examination that occurred during the next two decades. The sum total of the multiple investigations that were performed around the world during the decade of the 1960s (11 confirmed the association of this unique type of mitral regurgitation with a deformity of the mitral valve structure, which at surgery or autopsy was the myxomatous or floppy mitral valve; (2) demonstrated that the floppy mitral valve functioned in a peculiar manner by prolapsing into the left atrium during ventricular systole, and leaking during mid- or late ventricular systole; (3) established the association between the intrinsic valve abnormality, the prolapse mechanism, and the auscultatory complex, which in turn provided diagnostic clues for clinical recognition by competent clinical examiners. The Floppy Mitral Valve as a Pathologic Entity In 1958, Fernex and Fernex12 used ‘mucoid degeneration” to describe the changes in mitral valves from two older patients with mitral regur@tation, mitral valves with multiple domes, and augmentation of the valve surface, without evidence of the Marfan syndrome. This study reinforced the concept of a connective tissue etiology for floppy mitral valves, and may be viewed as a successor of a variety of papers linking the Marfan syndrome with the floppy mitral valve, and as the precursor to Read’s 1965 clinical study.’ Beginning in the mid- and late 196Os, multiple reports were published that described the morphology of the floppy mitral valve. In time, these studies overlapped and then complemented the numerous clinical studies dealing with the “systolic click-late systolic murmur syndrome,” and mild mitral valvular regurgitation. What the valve did, i.e., the mitral valve prolapsed, was linked to what the valve was made of, that is, the myxomatous, floppy mitral valve. As Pomerance noted,13 the basic pathology appeared identical to Cut-r Probl

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that described by Fernex and Fernex in 1958.l’ Pomerance described most of the floppy mitral valve morphologic changes in 1969 with emphasis on the spectrum of pathologic change-from enlargement of only the posterior cusp of the mitral valve, to involvement of both mitral cusps, and in certain cases with involvement of the tricuspid valve as well. The mitral cusps were thickened, opaque, and voluminous; chordae became attenuated and might rupture; characteristic histologic changes involving the valve fibrosa were present; the severity of the condition was variable from localized areas of ballooning in the center of the posterior cusp to gross ectasia of the entire valve. The voluminous cusps prolapsed into the left atrium during systole, resuhing in mitral regurgitation. Most of the leading cardiac pathologists participated in the expansion of knowledge that occurred during the 1960s and 197Os, as the pathologists, clinicians, and cardiovascular surgeons became aware of the frequency of the floppy mitral valve in the pathogenesis of mitral valvular disease. A major study of the floppy mitral valve at autopsy by Davies et al. in 197814 deserves particular attention. A standardized approach to mitral valve morphology, function, and clinical significance was used in a prospective study of approximately 2,000 consecutive autopsies in London hospitals to evaluate the incidence and severity of floppy mitral valves. Clinically sign&cant floppy mitral valves were found in 3.9% of the men and 5.2% of the women. Severely floppy valves were not apparent until age 40, and the incidence of severely floppy valves increased with age. Prolapse was limited to the posterior mitral leaflet in about 67% of the hearts, affected the anterior leaflet in lo%, and involved both leaflets in 23%. Minor morphologic abnormalities were not of clinical significance in this study. Concurrent interest in reconstructive surgery of floppy mitral valves by the cardiovascular surgeons dut+ng the 1960-1970 period meant that the basic morphologic changes in valves obtained at surgery and at autopsy were of great clinical significance as blueprints for the design of plastic and reconstructive repair procedures. The sum total of multiple studies that dealt with the pathology and surgical pathology of the floppy mitral valves by multiple investigators during this period included (1) the basic definition of the floppy mitral valve as a discrete anatomic-morphologic-pathologic entity with specific gross and histologic characteristics; (2) identifkation of the broad spectrum of the floppy mitral valve pathologq with varying degrees of redundancy, prolapse, and valvular dysfunction; (3) confirmation that longevity was not influenced by the mere presence of a floppy mitral valve; and of great clinical significance, (4) that certain complications occurred in a rather consistent manner in patients with floppy mitral valves, and affected survival in these patients. 328

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Complications and Clinical Implications The realization that floppy mitral valve intrinsic tissue composition held etiologic, functional, and long-term behavioral information was gradual, and the process is still evolving. Fundamental pathology demonstrated by multiple investigators included the gross characteristics (see Fig 4) of increased mitral valve surface area, with alteration of the usual 2:l ratio of anterior leaflet to posterior leaflet surface area, since atI OF portions of the posterior leaflet were enlarged; hooding OF ballooning of the voluminous leaflets; variable increases in the size of the mitral annulus, particularly marked in those patients with systemic connective tissue abnormalities; chordal abnormalities with thin, elongated chordae, frequently with major deviations of chordal branching and insertion, and with chordal rupture in certain instances; and increased mitral valve weight and valve thickness. A broad spectrum of change was a consistent observation.13’14 Histologic changes included myxomatous degeneration, collagen disruption and dissolution, mucopolysaccharide infiltration and elastin fragmentation (Fig 5). The collagen changes appeared to be

FIG 5. Floppy mitral valve. Histopathology. Atrial surface at the top, ventricular surface at the bottom. Histologic levels, top to bottom: A = atria@ with fibrosis; M = large zone of loose myxomatous tissue; F = valve fibrosa. disrupted by myxomatous tissue, at arrows; P = fibrous pads on ventricular endocardium. Curr

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most specific.15 Mitral valve material properties were altered by replacement of the normally dense collagenous fibrosa by the loose myxomatous connective tissue. Elongation and stretching of the valve results in a series of events when the mitral leaflets do not maintain their normal coaptation-apposition relations during ventricular systole, and prolapse of one, both, or portions of the mitral leaflets back into the left atrium occurs during early, mid- or late systole (Fig 6). With failure to seal alotig the line of valvular coaptation-apposition, mitral valvular regurgitation ‘occurs, with formation of a regmgitant jet or jets of various configurations, directions, and timing, which in turn influence the timing of the non-ejection systolic clicks and the location and audibility of the systolic murmurs transmitted to the chest wall. With greater degrees of valvular deformation and stress-induced elongation of abnormal chordae, mitral regurgitation increases in severity, the regurgitant jet configuration is exaggerated and expanded, chest wall transmission of the murmur is influenced accordingly, the hemodynamic changes of mild to moderately severe mitral regurgitation intrude, and the chest wall murmur configuration

FIG 6. Floppy mitral valve. Graphic presentation of the morphologic characteristics of normal mitral valve and floppy mitral valve associated with severe mitral regurgitation. Valve diameter (mm), valve surface area (mmZ), and chordal length (cm) are presented. 32s

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changes reflect the left ventricular-left atrial systolic pressure gradient. The cascade of events that occur related primarily to valvular dysfunction includes progressive mitral regurgitation; left atrial hypertension, enlargement and dysfunction; left atrial electrical instability manifested as atrial fibrillation; and the eventual development of left ventricular dysfunction and the syndrome of congestive heart faitWI?.

Those complications that result from combinations of abnormalities in intrinsic valve structure and hemodynamic stresses include chordal rupture with flail mitral leaflet dynamics, valve surface changes that result in surface thrombi with the potential for thromboembolic events or infectious endocarditis, and left ventricular endocardial friction or contact lesions related to excessive leaflet and chordal mobility. Clinical Dejhition As we have seen, it took a long time for the morphologists and pathologists to recognize the floppy mitral valve. When the clinicians mastered cardiac catheterization, and participated with the radiologists in the development of what became cineangiocardiography, an entire new discipline came into existence, the beginnings of what we now call cardiac imaging. Floppy mitral valve definition in the clinical arena came about when cineangiography was used to identity normal mitral valve anatomy and function, and the alterations that took place in the various disease states. Criley and his associates were leaders in this effort, and particularly adept in the new sub-discipline of explaining time-honored physical diagnostic phenomena in hemodynamic and cineangiographic terms. This was not an automatic or immediate process, since catheterization and angiographic techniques and equipment varied widely, and angiographic-anatomic correlates did not exist. A prolonged interval followed the initial studies during the late 1960s until a degree of unanimity about proper positioning of the patient, degrees of.obliquity and injection techniques for proper viewing of the mitral valve apparatus, and precise criteria for normalcy and disease existed among angiographers and clinicians. At this time, the diagnosis of mitral valve prolapse was primarily limited to patients with (1) the auscultatory-phonocardiographic complex involving documentation of a non-ejection systolic click or clicks, an apical mid- or late systolic murmur, with dynamic changes in the auscultatory-phonocardiographic complex with posture, isometrics, or pharmacologic interventions, and (2) the angiographic criteria for mitral valve prolapse associated with a floppy mitral valve. Clinicians were reassessing auscultatory concepts, while more precise catheterization-angiographic criteria were being developed. Cur-r

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19%

3243

Criteria for the diagnosis of mitral valve prolapse were developing, and the diagnosis was in its conservative phase. The advent of M-mode echocardiography was extremely beneficial in many areas of cardiologv, and precise diagnostic criteria were developed for a variety of clinical cardiovascular disorders. The early M-mode criteria for mitral valve prolapse were less than satisfactory during the 197Os, and false-positive and false-negative studies produced a period of diagnostic uncertainty. Certain criteria were established for chordal rupture, and indices of valve thickness that reflected floppy mitral valve pathology were developed. The auscultatory criteria were frequently dissociated from the diagnostic process, phonocardiography fell on difllcult times and clinical auscultation fell into disrepute, clicks were heard throughout the land without phonocardiographic conilrmation, and there were few studies that examined correlates with any other diagnostic techniques. Two-dimensional echocardiography came into its own in the 1980s. Improvements in imaging techniques, better definition of mitral valve anatomy, rediscovery of floppy mitral valve pathologic characteristics such as increased mitral valve thickness and redundancy, clinical correlative studies, and the additional dimensions provided by Doppler and color flow technology have added greatly to our understanding of the central role of the floppy mitral valve in mitral valve prolapse. Cardiovascular Disease of Connective Tissue Origin-The Central Role of the Floppy Mitral Valve and Mitral Vdve Prolapse A developing theme during the past four decades has been the recognition and classification of cardiovascular disorders of connective tissue origin.1”,17 Mitral valve prolapse associated with the floppy mitral valve, with or without aortic root or aortic valve involvement, has been a consistent and integral part of the cardiac man&stations: (1) in recognized heritable disorders of connective tissue such as the Marfan syndrome, the spectrum of the Ehlers-Danlos syndrome, adult polycystic kidney disease, and the Stickler syndrome; (2) as an isolated heritable disorder with autosomal inheritance; and (3) as part of connective tissue syndromes that are incompletely defined at present. Recognition of the floppy mitral valve-mitral valve prolapse spectrum within the continuum of heritable disorders of connective tissue has implications for clinicians. Detailed, multi-generation family history and clinical studies, a careful search for connective tissue phenotypic phenomena at the time of the clinical examination, awareness of a “think connective tissue” approach to etiology, and expansion of the cardiologist’s role into contemporary medical genetics represent the beginnings of a new era in cardiology. 330

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CLINICAL EVALUATION VALVE PROLAPSE

OF THE PATueNT

WITH

MITRAL

THE MEDICAL, HISTORY The incidence of MVP in the general population is thought to be 3% to 4% .14,18--26 The vast majority of MVP patients are asymptomatic. The incidence of symptoms is exaggerated since those with symptoms will seek medical attention. Referral centers see especially patients with signiticant symptoms, sometimes disabling, who can be difficult management problems. MVP plus symptoms is called the Mvp syndrome, which is discussed in detail in a later segment of this monograph. Symptomatic patients with MVP have a variety of complaints; chest pain and palpitations are by far the most common, with dyspnea, fatigue, anxiety, light-headedness and syncope, and focal neurologic signs occurring less often. The chest pain in mitral valve prolapse is usually atypical for angina pectoris, often being left precordial or inframammary in location, often sharp but sometimes dull pressure, lasting seconds to hours, and often not related to exertion. The pain can be cyclic with exacerbations and remissions, or on a several day, weekly, or monthly pattern. Palpitations are described as fluttering, skipping, racing, or a feeling that the heart ‘stops.’ There is often poor correlation of symptoms with dysrhythmias recorded by Holter monitoring, transtelephonic monitoring, or stress testing. Most commonly, no abnormal rhythm is seen when the patient complains of palpitations. Significant dysrhythmia that is asymptomatic is quite rare. MAT patients who seek medical attention tend to have enhanced cardiac consciousness and are sensitive to even minor disturbances in heart rate. The most common correlate that we see in MVP patients is sinus tachycardia, inappropriate for the level of activity, and especially pronounced in the upright position. Premature atrial and ventricular contractions, supraventricular tachycardias, ventricular tachycardia, ventricular fibrillation, and atrioventricular block all are seen in approximate descending order of frequencyF7 Dyspnea and fatigue occur similar to symptoms in patients with left heart failure, but clinical correlates of such are absent, such as tales, edema, or abnormal apex impulse. In patients with floppy, severely regurgitant valves, the signs of congestive ‘heart failure are generally present but not in the younger systolic click-late systolic murmur group. Anxiety is present in many MVP patients. It may be related to or associated with adrenergic stimulation, concern over symptoms, hyperthyroidism, or contributed to by physicians. Psychoneuroses and panic attacks occur as well. Curr

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331

Light-headedness may be positional, especially in the upright position. Syncope may occur with or without premonitory symptoms. Postural hypotension and dysrhythmias should be sought, but clinical correlates may not be present. The symptoms described above are frequent complaints of patients who seek medical attention. A physician should consider the association with MVP in patient evaluation. Many patients without MVP have similar complaints, therefore, making a diagnosis of MS@ based on symptoms alone inappropriate. Care should be taken not to label people with the MVP diagnosis without auscultatory or echocardiographic confirmation, or use an MVP diagnosis as an excuse not to pursue the mechanisms of the symptoms. Many cardiac neuroses can be created in this way. In 1976 Barnett called attention to the remarkable prevalence of MVP in a series of patients under 45 years of age with focal neurologic signs.“” His and other subsequent reviews have described transient ischemic attacks, amaurosis fugax, retinal artery occlusions, and occasional hemiparesis.zg-31 Documentation of these neurologic events and determining the precise source may be difficult. Possible mechanisms of neurologic events in h4VP patients include emboli from surface erosions on a myxomatous valve or at the atrialvalvular junction, endocardial friction lesions, or coexisting mitral annular calcification.3z~ 33 Abnormal platelet function has been described in some patients.34-36 In older patients, coexisting cerebral vascular disease may be responsible for the focal neurologic signs. The true incidence of emboli in MVP patients is unknown but is clearly less than 1% of the MVP population. The incidence of neurologic complaints in patients seeking medical attention may be as high as 15% at referral centers, where predominantly symptomatic patients are seen.37 Embolic events are more frequent in patients with hemodynamically significant mitral regurgitation who have enlarged left atrium and ventricle, atrial arrhythmias, and congestive heart failure.38 Obtaining a detailed family history is important. MVP illustrates autosomal dominant inheritance with variable expression.3g The apparent greater prevalence of MVP in young women compared with infants, men of all ages, and elderly women may be in part a manifestation of the variable expression, but may be influenced by changes in left ventricular geometry and valvular characteristics unrelated to genetic factors.36-43 Of the heritable diseases of connective tissue associated with MVP, the Marfan syndrome and Ehlers-Danlos syndrome, and milder forms of osteogenesis imperfecta also have autosomal dominant transmission, whereas pseudoxanthoma elasticum usually illustrates autosomal recessive inheritance.@ Table 2 lists disorders associated with MVP. 332

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TABLE 2. Conditions Associated Valve Prolapse

With

Mitral

Connective tissue dkuwdem-genetic Mitral valve prolapseisolated The Marfan syndmme Ehlers-Danlos syndrome-‘I&es I and II, lv Pseudoxanthoma elasticum Osteogenesis impetiecta Polycystic kidneys Other genetic disorders Duchenne’s muscular dystmphy Myotonic dystrophy Fragile X syndmme Mucopolysaccharidoses Acquired collagen-vascular disorders Systemic lupus erythematosis Relapsing polychondritis Rheumatic endocarditis Polyarteritis nodosa Other associated disorders Atrial septal defectsecundum Hypertmphic obstructive cardiomyopathy Wolff-Parkinson-White syndmme Papillary muscle dysfunction Ischemic heart disease Myocarditis Cardiac trauma Post mitral valve surgery Von Willebrand’s disease

PHYSICAL EXAMlNATION

Clues to the presence of mitral valve prolapse &lV’P) may be evident on initial contact with the patient. MVP patients tend to have a slender body habitus with less than expected weight for their height.45 Skeletal abnormalities have been reported in up to 67% of hNP patients.47-51 The high association with heritable diseases of connective tissue (see Table 2) that also exhibit skeletal abnormalities makes a thorough evaluation of the musculoskeletal system mandatory. GENERAL EX4MiNATlON

Height is routinely measured in general physical examinations, but arm span measurements should also be done (Fig 7); MVP patients often have an arm span greater than their height. MeasureCurr

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FIG 7. Anthropometric measurements. Height (leti panel), arm span (center panel), and pubis to floor (right panel) measurements should be made. The crown to pubis measurement is obtained by subtraction, so that the upper segmenVlower segment ratio can be calculated.

ment of the upper segment-lower segment ratio yields additional diagnostic information (see Fig 71. Height is measured, then from pubis to floor for the lower segment. The upper segment is obtained by subtraction. Normal individuals have a ratio usually not less than 0.87, whereas a ratio of 0.83 or less is consistent with the Marfan syndrome?’ Abnormalities of the thoracic cage and spine such as scoliosis, narrow AP diameter, straight back, pectus excavatum, and pectus carinatum are common in MVP and other connective tissue disorders.53-61 The extremities should be checked for arachnodactyly, and dolicostenomelia (long limbs relative to trunk) characteristic of the Marfan syndrome, a joint hypermobility, common in the EhlersDanlos syndrome and in certain patients with the Mat-fan syndrome. The fingers, wrists, elbows, knees, hips, and ankles should all be evaluated. Patients with these syndromes can overlap their little finger and thumb encircling their wrist, and their thumb protrudes significantly past their little finger when folded across the palm. Evidence of degenerative arthritis in a patient with a marfanoid body habitus suggests the Stickler syndrome. Examination of the skin may reveal abnormal striae, bruising, distensibility, and “cigarette paper” scars, which suggest the diagnosis of Ehlers-Danlos syndrome. Redundant skin with a peau d’orange appearance and thickening at points of stress suggest pseudoxanthoma elasticum. The ocular examin ation can reveal important diagnostic clues for MVP and associated disorders. Blue sclerae are consistent with osteogenesis imperfecta. Severe myopia is seen in the Marfan syn334

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drome. Lens subluxation may be visible on routine ophthalmoscopic examination but often requires slit lamp examination for detection. The direction of dislocation di@erentiates the Marfan syndrome horn homocystinuria, which has the s&me skeletal fe&ures as the Marfan syndrome but is not associated with MWP. Subluxation of the lens in an upward dire&on occurs in the Marfan syndrome; the dislocation is downward in homocystinuria. Homocystinuria is also characterized by multiple venous and arterial thrombotic events. Angioid streaks seen on fundoscopic examination suggest pseudoxanthoma elasticum. Vitreoretinal degeneration is seen in Stickler syndrome. A high, arched, or cathedral palate is another common finding in MVP and associated connective tissue disorders. Crowding of the teeth may also occur. Inspection for ctious teeth and gum disease is very important in the assessment of endocarditis risk. Measurement of supine and standing blood pressures should be routinely performed. Symptoms of light-headedness, dizziness, and syncope may be associated with orthostasis in patients with MVP, who tend to have lower baseline blood pressure than normal and therefore smaller absolute falls in systolic blood pressure could result in symptoms.46~ ” Simultaneous pulse rate should be determined as well. Many symptomatic MVP patients have an inappropriate rise in heart rate with standing, often 20 or 30 beats/minute or more, whereas normal is 10 to 12 beats/minute. The blood pressure will often remain normal on standing but may drop. These findings are consistent with relative volume depletion. Possible mechanisms for the blood pressure-heart rate responses with posture are discussed in a later section. CARDIAC EXAMINATION

The cardiac examination is the key to the diagnosis of mitral valve pro1apse.l” 63,f54 The apex impulse is usually normal in size, location, and duration. Occasionally, a palpable systolic retraction at the time of an auscultatory click may be felt. A systolic thrill may be present in a patient with a systolic whoop, especially in a slender patient and in the standing position. Patients with severe mitral regurgitation, particularly with chordal rupture, may have an apical systolic thrill. On auscultation, the first and second heart sounds are normal in most. Those patients with floppy mitral valves that
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335

TABLE 3. Auscultatory

Mimics

Non-ejection

Click

of MVP Late Systolic

Pericardial knock of conshictiva perkwditis Opening snap of mitral or tricuspfd stenosis Widely split S, of BBBB Fixed split S, of atrial septal defect Mechanical prosthetic valve sounds Ebstein’s anomaly of the tricuspid valve Ejection clicks of semilunar valve stenosis Ejection clicks of aortic or pulmonary artery dilatation Atrial sounds in complete heart block Ventricular septal aneurysm Pleurupericardial adhesions Left-sided pneumothorax Mediastinal emphysemia Xiphostemal crunch Splenic flexure syndrome S, = second

heart

sound,

RBBB = right

POSTURAL AUSCULTATORY

bun&

Mwmur

Mitral and tricuspid valve prolapse Papi@aty muscle dysfunction Hype&uphic cardiomyopathy Ventricular septal defect Severe valvuiar or infundibular pulmonic stenosis Coarctation of the aorta

branch

block.

COMPLJ3.X

Postural auscultation is the key to the diagnosis of MVP (Fig 9). The characteristic changes in the click(s) and murmur that occur with postural change constitute the most speciilc physical diagnostic criteria for the diagnosis of w3 (see Fig 8 and Table 4). The systolic clicks move toward the first heart sound with upright posture, often merging with the first heart sound if marked postural tachycardia occurs. New clicks may appear. The systolic murmur becomes longer, often louder in the upright position, becoming pansystolic if an exaggerated heart rate response occurs. A murmur may be present only in the upright position. A systolic precordial honk or whooping sound may occur with the murmur; most am heard only in the sitting or standing position but could also be present on supine auscultation. The systolic honk may be loud enough that the patient can hear it or feel a vibration on the chest wall. Prompt squatting from a standing position immediately moves the systolic clicks and the systolic murmur back to a late systolic position. The murmur may totally disappear. Essentially, the supine findings are reproduced. The patient must be able to squat quickly to obtain the desired hemodynamic result, which is marked by a reflex bradycardia. Inability to squat promptly or lack of a reflex bradycardia usually prevents the diagnostic changes in auscultatory findings from occurring, and diagnostic speciticity is lost. Auscultation should be continuous from the standing position to the squatting Cur-r

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FIG 9. Postural auscultation. Careful auscultation begins with the supine (fop left panel) and left lateral decubitus (top right panel) positions. The auscultatory findings are usually best heard at the apex with the diaphragm of the stethoscope as shown here. Auscultation in the sitting (middle leti panel) and standing (middle right panel) positions is essential for making the diagnosis of MVP and in excluding the many auscultatory mimics. Auscultation during prompt squatting is done by either squatting with the patient (bottom left panel) or having the patient squat while the examiner sits in a chair (bottom right panel). Auscultation should be continued as the patient stands up and until the heart rate stabilizes. 338

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TABLE 4. Auscuhatorv

Patterns

in Mitral

Situation

Valve

Prolapse

Auscultatorv

Left lateral Sitting

position

standing Prompt

squatting

Valsalva-

strain

Valsalva-post

Isometrics-

Chanaes

Mechanism

Click(s), murmur louder Clicks earlier, murmur longer, louder Same Click,

as sitting murmur

later

Click earlier, murmur longer, 2 louder

release

Click,

handgrip

murmur

Click, murmur later

Anxiety

later

louder,

Clicks earlier, murmur longer, louder

Exercise Beta blocker

Same as anxiety Click later, murmur softer

therapy

Pregnancy

Same as beta-blocker therapy

later,

Heart closer to chest wall Decreased venous return, decreased ventricular volume Same as sitting Increased venous return, bradycardia, increased ventricular volume Decreased venous return, increased heart rate, decreased ventricular volume Increased venous return, decreased heart rate, increased ventricular volume Increased alterload bradycardia, increased ventricular volume Increased catecholamines, increased contractility, decreased ventricular volume Same as anxiety Decreased heart rate and contractility, increased ventiicular volume Increased blood volume, increased ventricular volume

position and back to the standing position until the heart rate stabilizes. The most dramatic auscultatory changes often occur after standing from the squatting position; the systolic clicks and murmur move back to early systolic positions on a beat to beat basis as the heart rate accelerates. The systolic non-ejection clicks merging with the first heart sound can be appreciated by continuous auscultation. FJrecordial honks may be very transient and only heard for a few beats immediately after standing. If a patient is unable to squat and stand prom&y, then the Valsalva maneuver can be used as an alternative. With the patient supine, he or she bears down for several seconds, long enough to increase the heart rate. During the straining phase the murmurs and clicks move earlier in systole similar to sitting or standing, but murmur intensity may not increase. On release of the straining phase, a Cur-r

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reflex later squat chair

bradycardia occurs, and the murmurs and clicks return to a position similar to the squatting position. If the patient can promptly but the examiner cannot, the examiner can sit in a and have the patient squat (Fig 9).

b P.M. SHAH: Any bedside maneuver that decreases left ventricular filling, such as upright posture or Valsa.lva strain, results in an earlier click and a longer murmur. The intensity of the systolic murmur is nearly always softer, except for rare development of a “honk.” These findings permit an easy distinction from hypertrophic cardiomyopathy with outflow obstruction in which it is common to find aumentation of the svstolic murmur.

The auscultatory findings may vary in an individual patient from examination to examination. Adrenergic state and/or intravascular volume status of the patient can vary, and drugs that affect heart rate may change the auscultatory findings. Beta-blocking agents are frequently used in these patients and can markedly attenuate or abolish the auscultatory findings. Therefore the lack of diagnostic auscultatory-postural findings for MVP in a patient receiving these agents does not eliminate the diagnosis. Repeat examination off medication should be performed. A thorough postural auscultatory examination with appropriate changes in heart rate with position change without any interfering drugs will allow the examiner to make or exclude the diagnosis of Mvp in most cases. Serial examinations are recommended to profile the auscultatory findings in individual patients. The findings are usually more marked in patients coming to an outpatient facility from their usual daily routine than in the inpatient environment. Patients with redundant floppy valves of the classic anatomic definition may have enough regurgitation to produce pansystolic murmurs even in the supine position. Clicks may not be audible since pansystolic prolapse is often present in this group. The first heart sound may be accentuated (superimposed “clicks”). The murmur may still accentuate on standing and have more late systolic accentuation with squatting, but it generally remains pansystolic with postural changes. Once the valve is disrupted, as from chordal rupture, then no typical postural changes are evident. The murmur may accentuate with squatting. The same is true for patients with pansystolic murmurs who have significant left ventricular enlargement associated with moderate or severe mitral regurgitation. A left ventricular S, gallop and/or an early diastolic rumble may also be present in these patients. The occurrence of arrhythmias may change auscultatory findings as well. Clicks and/or murmurs are earlier during WCs, later on a post-extrasystolic beat, and may vary in position and intensity from beat to beat in ®ular rhythms much as atrial flbrillatlon. Auscultation can be very confusing under such conditions. 340

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Tricuspid valve prolapse UYP) may coexist with MW. Separation of the auscultatory phenomena of MVP for TVP by physical examination may be very dit%cult. Systolic clicks and murmurs moving later immediately on deep inspiration, with leg raising, or with squatting may suggest tricuspid valve origin, since MVP clicks and murmurs require several beats to change position. The jugular venous pulse is generally not affected unless a sufficient degree of tricuspid regurgitation is present to raise right atrial systolic pressure to accentuate the C-V wave. Such patients will have pansystolic murmurs of tricuspid regurgitation, and the diagnosis of TVP as the cause of the tricuspid regurgitation requires imaging techniques. The postural changes in auscultatory findings in MVP are not totally unique to this diagnosis. The murmur of dynamic left ventricular outflow tract obstruction (i.e., hypertmphic cardiomyopathy with a pressure gradient [HCMI) behaves similarly to an MVP murmur with postural change. Clicks are generally not present. The post-extrasystolic accentuation of the murmur is often marked, whereas in MVP the click/murmur are later, although the murmur may intensity somewhat. A double or triple apex impulse and “spike and dome” carotid pulse favor HCM, but MVP and HCM coexist more often than one may expect by chance. MECHANISMS

OF POSTURAL

AUSCZJLTATORY

CHANGES

The postural auscultatory changes occurring in MVP are primarily related to changes in left ventricular vo1ume.W4-“6 Left ventricular volume is significantly less with the patient in the upright position (sitting with feet dependent or standing) compared with supine. The position of the mitral leaflets at end-diastole is determined by the distance from the mitral valve annulus to the attachment of the chordae to the papillary muscles. Reducing ventricular volume shortens the annularpapi&uy muscle distance, so that the leaflets are closer to a prolapsed position at the onset of ventricular systole. The end-systolic volume is also smaller upright compared with supine, so the leaflets then prolapse more and earlier in systole. The click occurs at the limit of systolic prolapse; multiple clicks likely mean dyssynchmny of prolapse among the leaflet scallops. Therefore earlier valvular prolapse pmduces earlier systolic clicks. Mitral regurgitation occurs earlier and may be of greater magnitude, resulting in longer and louder murmurs, or a new murmur may appear. The reduction in ventricular volume in the upright posture results from peripheral pooling due to gravity. The reflex tachycardia that occurs reduces volume still further. The more exaggerated the tachycardia and the more the left ventricular volume change, the greater are the changes in auscultatory findings, Prompt squatting Curr

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abruptly increases venous return, thereby increasing ventricular volume to levels similar to supine. The position of the click and murmur are therefore similar to supine. The systolic click and murmur may be accentuated, since squatting is associated with an increase in peripheral resistance, which creates more tension on the mitral apparatus and more preferential flow into the left atrium rather than to the peripheral circulation. Similar left ventricular volume changes occur with the Valsalva maneuver. During the &mining phase, high intrathoracic pressures reduce venous return and hence ventricular volume. Prolonged straining also reduces systemic blood pressure, which favors aortic flow rather than regurgitation into the left atrium. Therefore the timing of the systolic murmur changes due to the small left ventricular volume, but the intensity may not change, as the amount of mitral regurgitation may not increase enough to intensify the murmur, despite the presence of greater mitral valve prolapse. Release of a Valsalva maneuver combined with a deep inspiration sharply increases venous return as intrathoracic pressure becomes very negative. The sudden increase in venous return increases ventricular volume, and the clicks and murmur move to a later systolic position as with prompt squatting. Other techniques and maneuvers that manipulate ventricular volume can be used to aid in diagnosis, such as elevating the legs, isometric handgrip, tourniquets on the extremities, lower body negative pressure, or amyl nitrite inhalation.66-‘is None is as practical or helpful as a methodical postural auscultatory examination. Other situations that enhance inotropy and therefore enhance ventricular emptying (i.e., raise ejection fraction with resultant still smaller end-systolic volume) cause the clicks to move earlier and the murmur to be longer and/or louder. Naturally occurring catecholamine increases related to physical exercise or anxiety, or externally given as an isoproterenol infusion also cause similar effects. It follows then that slowing the heart rate or administering negative inotropic agents would increase ventricular volume and therefore minimize the auscultatory findings. Beta-blocking drugs have both effects, and may make clicks softer and later, and/or cause murmurs to diminish or disappear, thus masking the clinical diagnosis. Another physiologic volume load that diminishes the auscultatory findings is pregnancy. When the peak increase in blood volume occurs throughout the last trimester, the auscultatory findings tend to be less evident, but return once the volume load diminishes after delivery. The auscultatoiy findings of MVP may also be masked during pregnancy by the common systolic ejection murmur related to increased volume and cardiac output, and the mammary souffle from increased blood flow through the breast vessels. 342

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DIAGNOSTIC

EVALUATION

The vast majority of h4VP patients have norElectrocardbgram.mal electrocardiograms. ST-T changes especially in the inferior leads (including ST elevation, T wave inversion) and long QT interval have been described but are certainly not spe&c for AWP?” 63,7o-73 The explanation for the changes seen in some patients is not clear. Ischemia, traction on papillary muscles, and autonomic dysfunction have all been proposed. Int@%&@gly, the ST-T changes often improve with exercise or the administration of beta blockers. The presence of ST-T changes in the inferior leads in a young woman with chest pain and palpitat&ms would lead to consider&ion of MVP as a possible diagnosis, but the diagnosis of MVP should not be made on symptoms and ECG findings alone! The over-f% age-g&p& or the younger patients with connective tissue disorders such as the h4arfan syndrome or Ehlers-Danlos syndrome, with floppy myxomatous valves resulting in chronic, progressive, moderate, or severe regurgitation may have left atrial and lefi ventricular enlargmnt, and atrial arrhythmias from progressive mitral valve dysfunction. Chest X-ray.- Posteroanterior and left lateral chest x-ray films usually show normal heart and lung tidings. The skeletal abnormalities described earlier can be seen. Patients with mitral regurgitation may have left atrial and left ve&ricular enlargement. Varying degrees of pulmonary venous congestion can be seen once heart failure ensues. Acute chordal rupture with sudden increase in severity of mitral regurgitation can result in pulmonary edema with normal or nearly normal cardiac silhouette. Calcification of the mitral annulus may be seen in some patients, particularly adults with the Marfan Echocardiography.vasive test to deike

syndrome.

Echocardiography mitral

is the most useful nonin-

valve prolapse.

Current

echocardio-

graphic criteria for MVP are listed in Table 5.‘4-77 The echo will identify the MVP patient with the enlarged, floppy, myxomatous valve, in whom there is no question about the diagnosis, since auscultatory findings are nearly always 10). Truly “silent” echocardiographic fined by Mark~+‘~ is uncommon.

present

in these patients

(Fig

MVP of the “classic” form de-

b

P.M. SHAH:There is, at present, no consensus on the two dimensional echocardiographic criteria for mitral valve prolapse. Since echocardiography is a tomographic cross-sectional technique, no single view should be considered diagnostic notwithstanding a recent report by one group of investigators. Parasternal long axis view permits visualization of medial aspect of the anterior mitral leaflet and middle scallop of the posterior leaflet. Should the findings of

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TABLE 5. Echocardiographic

Definition

of MVP

M-mode 2 mm or greater posterior displacement of one or both leaflets Holosystolic posterior ‘hammocking” 2 3 mm Z-Dimensional 1. Systolic displacement of one or both IeafIets, and, most specifically, the closure line to left atrial side of annular plane in the parastemal long axis view 2. Leaflet thickness 2 5 mm* 3. Leaflet redundancy Enlarged mitral annulus Elongated chordae Doppler Presence or absence of mitral regurgitation Quantitation of mitral regurgitation Timing and direction of mitral regurgitant jet 1, 2, and 3 constitote “classic” Marks” which correlates with

valve described ‘Leaflet

thickness

MVP described by the floppy mitral

in this publication. difficult

to determine

accurately.

prolapse be focal and localized to the lateral scallop of the posterior leaflet, they would be best visualized by the apical four chamber view. This view should therefore not be ignored. All available echocardiographic views should be utilized with a provision that anterior leaflet sagging alone in the four chamber view is not an evidence of prolapse. However, a displacement of the posterior leaflet or the coaptation point in any view, including the apical views, should suggest a diagnosis of prolapse. The echo criteria for floppy mitral valve should include structural changes, such as leaflet thickening, redundancy, annular dilation, and chordal elongation. It should also be emphasized that the pathologic process may involve more than one valve and that in nearly 50 percent of patients, the tricuspid valve shows evidence of prolapse. The diagnostic accuracy of echocardiography may be improved by using a constellation of findings, which include structural as well as functional changes.

Patients with echo criteria for MW without evidence of thickened redundant leaflets require thoughtful analysis. If such patients have typical auscultatory findings of MVP, then the echo confirms the clinical diagnosis. A patient with typical auscultatory findings with a negative echo probably has MVIJ but is at one end of the anatomic spectrum not detectable routinely by echocardiography. One reason for the discrepancy could be that echocardiography is routinely done in the supine and left lateral positions, when ventricular vol-

344

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FIG 10. Two-dimensional rior and posterior center of frame).

echocardiogram, leaflets beyond The left ventricle

parasternal long axis view. The prolapse of both antethe annular plane, resembling a “3.” is clearly seen (low is to the left, left atrium to the right, and aorta above.

ume is maximal; the auscultatory findings of MVP are more evident in the upright positions. Using echocardiography as a screening test for MVP in patients with or without symptoms who have serial negative carefully done postural auscultatory exams is not useful. The likelihood of finding a floppy valve in such patients is extremely low. The issue is whether patients with symptoms, negative physical examinations, and mild MVP on echo should be “labeled” as having MVP and their symptoms ascribed to h4VP. We favor not labeling these patients and creating undue anxiety. As with most clinical diagnoses the echocardfogram is a confirmatory test for the diagnosis of MVP, is helpful in defining the natural history, the need for antibiotic prophylaxis, and defining associated lesions such as hypertrophic cardiomyopathy, or secundum atrial septal defect. Doppler echocardiography is useful for the detection and quantitation of mitral regurgitation as well?‘-” Serial echocardiograms are helpful in following patients with murmurs, eepecially pansystolic murmurs where quantitation of mitral regurgitaCWT Probl

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346

tion by examination& more difficult. Patients with late systolic murmurs usually have no mom than 1 or 2+ regurgitation by echo-Doppler. Two-dimensional and transesophageal echocardiography can define potential embolic sources in patients with focal neurologic signs and symptoms. Halter iUonitoring.Twenty-fbur hour Holter monitoring should be done in MVP patients with symp%oms cif palpitations, light-headedness, and syncope, The number of MVP patients with severe lifethreatening dysrhythmias is very small?’ Palpitations are often sinus tachycardia, simple premature beats &rial or ventricular), and indeed often there is no correlation between symptoms and presence of dysrhythmias. The subset of patients with AV block atrial fibrillation or flutter, supraventticular tachycardia, or sustained ventricular tachycardia . A@&l arrhythmias are much can be identified by Holter moni more common in those patients with modterate or severe mitral regurgitation. Transtelephonic mon&or+ng is particularly useful for sporadic symptoms not documented by 24hour recordings. Exercise Testing.- Treadmill exercise testing with ECG monitoring is useful in patients less than 40 years of age with palpitations. Induction of arrhythmias by stress can occur in patients with MVP. Patients over 40 with chest pain suggestive of angina should have a stress thallium examination. A normal study with adequate stress essentially excludes significant coronary disease.78 Stress nuclear angiographic studies (MUGA) may be useful in patients with unexplained persistent dyspnea or fatigue to look for associated myocardial dysfunction. In patients with hemodynamically significant mitral regurgitation, the exercise ejection fraction is useful in determining the timing of mitral valve surgery. Once left ventricular dysfunction occurs, surgical intervention should be considered, now more often consisting of mitral valve repair rather than replacement.7g-8* Cardiac Catheterization.-The diagnosis of MVP can be made by auscultation with echocardiographic definition of the anatomy and degree of regurgitation. Cardiac catheterization studies are needed in those patients with protracted symptoms unresponsive to simple therapeutic measures, where hemodynamic measurements may be of benefit, and to evaluate associated conditions (e.g., atrial septal defect, coronary artery disease, pulmonary artery hypertension, left ventricular diastolic and/or systolic dysfunction). Cineangiography and coronary arteriography are important before decisions regarding intervention in patients with symptomatic significant mitral regurgitation. Electrophysiologic Testing.- The indications for electrophysiologic testing of patients with MVP are similar to those in general clin346

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1991

ical practice (i.e., recurrent unexplained syncope, sudden death survivors, symptomatic complex ventricular ectopy, and presence of the Wolff-Parkinson-White syndrome). Upright tilt studies monitoring blood pressure and rhythm may be valuable in patients with lightheadedness or syncope and in diagnosing autonomic dysfunction. MITRAL VALVE PR43LfWW SYNDRUME: TRE CROF AUTONOMIC DYSFUNCTION IN TRE PATROGENESIS OF SYMPTOMS

ROLE

The term MVP-syndrome refers to the coexistence of symptoms that result from various forms of neuroendocrine or autonomic dysfunction in patients with MVP, in whom the symptoms cannot be explained on the basis of valvular abnormalities alone.” ’ Symptoms in patients with MVP include palpitations, chest pain, easy fatiguability, exercise intolerance, dyspnea, syncope or presyncope, orthostatic phenomena, and neuropsychiatric symptoms. Whether there is a MVPS or whether a cardiac process (MVP) coexists with autonomic dysfunction and neuropsychiatric phenomena is controversial by virtue of lack of data. Our current opinion is that symptomatic patients with MVP manifest a constitutional, neuroendocrine-cardiovascular process resulting from a close relationship between anatomic MVP and centrally or peripherally mediated states of autonomic dysfunction or imbalance.l’ ’ The true incidence of symptoms in patients with MVPS is not known and may be exaggerated because most of the studies have been performed in academic institutions and thus may reflect a selection bias. Devereux et al.” addressed this issue by studying all first-degree relatives of symptomatic MVP patients referred to Cornell Medical Center. Undiagnosed MVP was found (echocardiography and physical examination) in one third of these relatives. AL though the referral MVP patients had a higher incidence of symptoms than the undiagnosed MVP patients, palpitations, documented arrhythmias, and chest pain were signticantly more common when the entire MVP cohort was compared with non-MVP, relatives. Bias in the analysis of data, however, constitutes a problem with this study. When patients seeking medical care because of symptoms (of any particular disease) are excluded, the incidence of symptoms in the remainder of the patient population mot seeking medical care) will not be representative for the entire population with the disease. Savage et aLa in their analysis of the Framingham Heart Study population, used echocardiographic criteria as evidence of MVP. They found that the incidence of chest pain, syncope, and atrial or ventricular arrhythmias was not different in individuals with MVP compared with the general population. There are two major problems with this particular study. First, an extremely low proporCurr

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347

tion of patients with echocardiographic findings had auscultatory phenomena; 9% had a systolic click, 9% had a mitral systolic murmur. Phonocardiography was not performed, and the quality control of auscultation was not defined. Second, a high proportion of the non-MM3 subjects had cardiac arrhythmias (17% supraventricular tachycardia, 40% complex or frequent PVBs). Thus the MVP group was different (no auscultatory findings) compared with other MVP studies, and the incidence of arrhythmias in the control group was much higher than that reported in a “normal” population. p P.M. SHW: An additional problem with the Framingham on m-mode echo for diagnosis imprecise and often inaccurate. interpreted with caution.

study was reliance

of mitral valve prolapse. It is clear that this is Any conclusions based on this study should be

The pathogenesis of symptoms in patients with the IvlVPS, although incompletely understood, appears to be multifactorial, related to altered autonomic function, adrenergic responsiveness, or to combinations of these factors. Neuroendocrine abnormalities and autonomic dysfunction reported in patients with MVP are presented briefly.

MVPS:

50-

TWENTY-FOUR EXCRETION

HOURS

URINARY

E

EPINEPHRINE

IE)

8 NGREPINEFHRINE

NE

(NE)

m

CONTROL (n-22

Ea

MVPS f n491

EtNE T

40.

30. PO4 CREATININE 20.

n p .z 0.001

PI

0.001

p’o.001

FIG 11. Twenty-four-hour urinary epinephrine (f) and norepinephrine (NE) excretion. Patients with MVPS had higher levels than normal controls. (From Boudoulas H, Reynolds JC, Mazzaferri E, et al: Metabolic studies in mitral valve prolapse syndrome. Circulation 1980; 61:1200-1205. Used with permission.) 348

Cum

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1991

M-W’S: INCREASED ADRENERGIC

ACTIVITY

Twenty-four hour urinary epinephrine (El, norepinephrine (NE) and E plus NE were higher in symptomatic patients with MVP compared with values in normal control subjects Wig 11).84 The frequency of premature ventricular beats PVBs) detected by ambulatory monitoring paralleled urinary catecholamine excretion; both PVBs and urinary epinephrine plus norepinephrine decreased significantly during the night (Fig 121.~

MVPS : DIURNAL RHYTHM OF URINARY EPINEPHRINE NOREPINEF’HRINE (NE) EXCRETION (n*l4)

e

1 l

I2 6AM NOON

126 NOON PM

6

(E) PLUS

12 MIDNIGHT 6 PM

I2 MIDNIGHT

EtNE&O/ p CRE ATININE 4

2

0 NS MVPS:

PvBS/HOUR

p <0.001

(11.14)

600 PVBS /HR 400

-p c 0.001

FIG 12. Urinary epinephrine (Ej and norepinephrine (NE) excretion (upper panel) and number of premature ventricular beats (PVBs) per hour (lower panel). The frequency of PVBs and the urinary catecholamine excretion were, parallel. At night both the number of PVBs and the E + NE excretion decreased. MVPS 7 mitral valve prolapse syndrome. (From Boudoulas t$ Reynolds JC, Mazzaferri E, et al: Metibolic studies in mitral valve prolapse syndrome: Circ&don 1980: 61 :I 200- 1205. Used with permission,) Curr

Probl

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May

lSS1

343

Plasma E and NE values at rest were also high in patients with MVPS compared with control subjects. Plasma E and NE increased after exercise in MYPS patients and in control subjects; plasma levels after exercise were not different in h4VPS patients compared with control subjects. Pasternac et al.” demonstrated that MVPS patients had higher total plasma catecholamine levels and NE levels when compared with normal subjects, both in the supine and upright positions. When plasma catecholamines were measured in the same patients 6 years later, the catecholamine levels were similar in both measurements, suggesting stability of the high adrenergic activity in the h4VPS patients. MU’S:

HYPEZU3ESPONSE

TO AZlR!?NERGZC

STIMULATION

The demonstration of increased adrenergic tone in MVPS patients prompted a study of adrenergic stimulation response. During isoproterenol infusions, none of the 12 control subjects developed symptoms, excluding palpitations. Conversely, in patients with MVPS isoproterenol infusion reproduced symptoms on a dose-related basis.86 During isoproterenol infusion, 3 of 16 patients developed symptoms with 0.5 ~g/min of isopmterenol infusion, 5 of 13 patients developed symptoms with 1.0 p#min of isoproterenol infusion, and 9 of 11 patients developed symptoms with 2.0 PgImin of isoproterenol infusion. Reproduction of symptoms that occurred with isoprotereno1 infusion included chest pain in seven patients, extreme post-infusion fatigue in six patients, dyspnea in six patients, dizziness in four patients, and panic attacks in two patients. Four patients had cool hands during isoproterenol infusion. The increase in heart rate durin& isoproterenol infusion was signifkantly greater in patients with hWPS compared with control subjects and was dose-related, whereas baseline heart rate was not significantly different between the two groups. Diastolic time has a nonlinear relationship with heart rate. Thus small changes in heart rate will restllt in significant changes in diastolic time (Fig 131.8' During isoproterenol infusion, diastolic time per beat and per minute decreased significantly in both groups MVPS and control subjects). However, the decrease in diastolic time with isoproterenol infusion was significantly greater in MVPS patients compared with control subjects (Fig 14).% These changes in diastolic time may be of clinical significance under certain circumstances, since the greater proportion of coronary blood flow occurs in diastole and subendocardial flow is almost totally diastolic. Spontaneous inappropriate sinus or ectopic tachycardia in patients with lWVPS re360

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1991

FIG 13. Relationship between heart rate, systolic time (Q.&J, diastolic time, cardiac cycle (RR) and percent diastole. (From Boudoulas H, Rittgers SE, Lewis RP, et al: Changes in diastolic time with various pharmacologic agents: implications for myocardial perfusion. Circulation 1979; 60:164169. Used with permission.)

sults in a significant decrease in diastolic time, which under certain conditions may produce subendocardial ischemia and chest pain (Fig Ed.2 Thus hyperresponse to adrenergic stimulation in patients with MWS was demonstrated by dose-related reproduction of symptoms, greater heart rate increase, and greater diastolic time abbreviation, compared with corresponding values in control subjects. MVPS: BETA-ADBENERGZC RECEJ’TOB ABNOllMALJ7-Y

These responses to adrenergic stimulation provide an insight into the mechanisms of symptoms in MVPS patients; however, the precise explanation is not well understood. Recently, Davies et aI.demonstrated super-coupling of beta-adrenergic receptors in patients with MVP compared with control subjects, which may explain Curr

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1991

361

DIASTOLIC TIME BEFORE AND DURING ISOPROTERENOL INFUSIONS 500-I

CONTROL (n= 12)

N.S.

DIASTOLIC TIME

BEFORE O.Spg/min

I pg/min

2 pg/min

FIG 14. Effect of isoproterenol infusions on diastolic time per beat (upper panel) and per minute (lower panel). The decrease in diastolic time with each isoproterenol infusion was significantly greater in patients with MVPS than in normal controls. (From Boudoulas H, Reynolds JC, Mazzaferri E, et al: Mitral valve prolapse syndrome: the effect of adrenergic stimulation J Am Co/l Cardiol 1983; 2:636-644. Used with permission.)

the hyperresponse to adrenergic stimulation reported from our laboratory. Thus high adrenergic activity in patients with h4VPS is related to a combination of high catecholamine levels and exaggerated response to adrenergic stimulation. MVPS: LOW INTRAVXXXJLAR

VOLUME

Patients with MVPS often have postural phenomena such as orthostatic tachycardia and hypotension. Low intravascular volume and/or an abnormality in the renin-aldosterone axis may contribute to the orthostatic changes. 362

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1991

Pressure (mm&!)

800

‘.?otal Diastolic Period Time

600 I

“. 75

Coronary Blood Flow (cdmin)

Heart Rate (beatdmin) FIG 15. the relationship of heart rate to diastolic time is shown Due to nonlinear relationship between heart rate and diastolic time, small changes in heart rate (particularly at slower rates) produce significant changes in diastolic time. Right, recordings of the aortic (Ao) pressure and left ventricular (LV) pressure. The tension time index (TTI) and diastolic time index (D/J7/j are shown. Phasic coronary blood flow in relationship to DPTI is also shown. (From Boudoulas H, Kolibash AJ, Baker P, et al: Mitral valve prolapse and the mitral valve prolapse syndrome: a diagnostic classification and pathogenesis of symptoms. Am Heart J 1989; 118:796-818. Used with permission.) Left,

Gaffney et a18’ measured plasma volume in symptomatic MVPS patients with orthostatic intolerance. Plasma volume, corrected for body size, was lower in the patients compared with the control subjects. There was also an inverse relationship between plasma volume and total peripheral resistance on standing. Those patients with the highest total peripheral resistance had the lowest plasma volume, and patients with lowest total peripheral resistance had the highest plasma volume. Other studies from this and other laboratories in MVPS patients have shown decreased intravascular volume. In addition, patients with MVPS consistently exhibited a smaller left ventricular end-diastolic volume and cardiac output with exercise in the upright position when compared with the supine, and this difference was maintained throughout the exercise period (Figs 16 and 17).” This may be related to a decrease in venous return during upright exercise in patients with MVPS. There was no difference in the ejection fraction in the upright when compared with the supine position both in MVPS patients and in controls at rest and during exercise. Cur-r Probl

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363

Left ventricular end-diastolic volume index (LVEDVI) in the supine and uprig)Jposture,at rest and bring exercise MVPS (wi6)

Control (n=8)

60 I+ 5 m e 3 40 -

x

/ /

,x-

-

-x

2’

x”

X’

supine m-4 upright x--x

20

OL

Rest

300 Kpm/min

Psak

I Rest

a 300 Kpm/min

I PO&

FIG 16. In normal subjects at rest, the left ventricular end-diastolic volume index (LVEDVI) in the upright posture was less, compared to the supine position, but a peak exercise LVEDVI was similar in the supine and upright positions; in contrast, in patients with MVPS, LVEDVI in the upright posture remained significantly less compared with the supine position throughout the exercise. (From Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura Publishing Company, Inc., 1988. Used with permission.)

MVPS: ATRL4.L NATRIURETZC

FACTOR

Pasternac et al.85 studied plasma volumes and atrial natriuretic factor in patients with MVPS. Two groups were identified: seven patients (44%) had a significant increase in atrial natriuretic factor, with a mean value of 31.9 + 9.1 pg/mL, compared with normal subjects; in the other nine patients, atrial natriuretic factor was within the normal range (mean value of 11.4 + 1.4 pg/mW. Patients with the higher values of atrial natriuretic factor tended to be older, had a higher systolic blood pressure, a faster heart rate, and a larger left atrium, although the differences were not significant. Patients with higher atrial natriuretic factor values had significantly lower blood volume than those with normal values of atrial natriuretic factor (2999 k 94 mL versus 3544 + 220 mL, p < 0.01). In addition, there was an inverse relationship between atrial natriuretic factor and 354

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1991

Co&x tndex in the supine ond upright posturr,ot rest ond during exercise

L

1

1

Rest

300 Kpmhin

I

1

1

I

bok

Rest

300 Kpm/min

Psok

FIG 17. Cardiac index in patients with MVPS was less in the upright posture compared with the supine position; in normal subjects cardiac index was similar in the supine and upright positions. (From Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura Publishing Company, Inc, 1988. Used with permission.)

blood volume, and an inverse relationship and plasma norepinephrine.

MVPS: PAJ?ASYMPATHETIC AUTONOMIC DYSFUNCTION

ABNORh4ALITY-

between

plasma volume

OTHER

Coghlan et aLsl examined heart rate response to’the Valsalva maneuver and to head-up tilt in 44 patients with hWPS. MVPS patients had heart rates that were lower during the control periods before both interventions and higher with standing and during the strain phase of the Valsalva maneuver. During the recovery phase of the Valsalva maneuver, there was an inappropriate bradycardia that perCurr

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1991

366

sisted for several minutes. The beat-to-beat variation in these patients was also excessive. Coghlan defined three types of autonomic dysfunction in patients with MVPS: the hypervagal(33%), the hyperadrenergic (lo%), and the mixed type (54% 1. The authors postulated that MVPS patients had excessive vagal tone, with a generally unstable autonomic nervous system leading to poor cardiovascular control. The diffuse nature of the abnormalities suggested the presence of a central autonomic nervous system defect. Autonomic dysfunction leading to cardiovascular instability has also been reported by Gaffney et al?’ who studied symptomatic women with auscultatory findings and echocardiographic documentation of MVP by means of lower body negative pressure, phenylephrine infusion, facial immersion in ice, and noninvasive measures of cardiac output. Patients with MVPS and cardiac arrhythmias had significantly higher heart rates at rest, during the immersion test, and with lower body negative pressure compared with corresponding values in control subjects. The less symptomatic h4VPS patients had a relative bradycardia, similar to those patients reported by Coghlan et alY3 AR patients exhibited marked vasoconstriction during orthostatic stress and actually increased mean blood pressures despite large decreases in cardiac output. Vagal responsiveness, reflected by the slope of the regression lines relating mean arterial pressure and R-R intervals during phenylephrine infusion, was different in patients with MVPS compared with normal control subjects. These findings were consistent with a baroreflex abnormality. Baroreflex modulation abnormality in patients with MVPS has also been reported from our laboratory.

MVP: EVIDENCE OF AUTONOMIC ASMMPTOMATIC INDIVIDUALS

DYSFUNCTION

IN

Seventy-eight asymptomatic U.S. Air Force air crewmen with auscultatory and echocardiographic evidence of MVP were evaluated by Whinnery for tolerance to high positive G stress (+ G)y4 The hJVP group had a normal response to gradual onset of SG stress, both while relaxed and when performing a protective straining maneuver and a small but statistically significant decrease in tolerance to rapid onset of +G stress. During the +G stress, 15% of the MVP individuals lost consciousness. This incidence of syncope was greater (p < 0.01) compared with a 7% incidence of syncope in 1,126 normal individuals without MVP. The incidence of motion sickness during the +G stress was also greater in MVP individuals compared with 1,126 normal individ366

Curr

J’robl

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1991

uals (17% versus 11%). High +G stress in certain MVP may also induce ventricular arrhythmias. MVPS:

AUTONOMZC

DYSFUNCTION

RELATED

individuals

with

TO SKkfP’ZUMS

Increased adrene@c activity, catecholamine regulation abnormality, and adrenetgic hyperresponsiveness observed in certain patients with MWS suggest that some symptoms may be catecholamine-related or mediated. Altered vagal tone, adrenergic receptor activity, or baroreceptor activity may also play a role in the pathogenesis of symptoms in certain patients. The observations that patients with MVPS have low intravascular volume and a subnormal renin-aldosterone increase with volume depletion may explain why certain patients with hNF% may be more susceptible to volume depletion in clinical settings such as acute illness, use of diuretics, dehydration from vigorous physical activity, and surgical OGtraumatic blood loss. The cyclical volume changes that occur in menstruating females and the protracted volume changes present in pregnant females may produce modifications in the sense of well-being or in symptoms that are related to these mechanisms. It also seems reasonable to hypothesize that in certain patients with MAPS inappropriate secretion of atrial natriuretic factor may contribute to the pathogenesis of symptoms. Central to the understanding of the role of atrial natriuretic factor in the MVPS are the relationships of the atriopeptinneuroendocrine system with the adrenergic system, both at a central level and at a peripheral level. The possibility that the secretion of atrial natriuretic factor may be affected or regulated by the adrenergic nervous system and vice versa cannot be excluded. It is also possible that atriopeptin immune-reactive neurons may play a role in modulating the autonomic nervous system.” ’ Thus, in MVPS alterations of the heart, the kidney, the adrenals, and the autonomic nervous system coexist and interact, creating a complex Yneuroendocrine cardiovascular process” that may account for many of the symptoms otherwise unexplained on the basis of the valvular abnormality alone (Fig 18).

MVPS:

THE

PATHOGENESZS

OF MOST

COMMON

SYMPTOMS

Chest Pain .-Chest pain is the most common symptom in men. The cause of chest pain in patients with MVPS may be multifactorial. Excessive stretching of the chordae tendineae has been suggested as a possible mechanism for chest pain. Increased tension of the chordae tendineae presumably causes forceful traction on the papillary muscles and the adjacent left ventricular wall, which may produce variations in papillary muscle and subendocardial blood flow and Cur-r Prabl

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367

Pathogenesis

of MVPS: Hypotheses

\yLfz.Ik;y SympatheticParasympathetic

t-

Vdume

FIG 18. Pathogenesis of mitral valve prolapse syndrome (LIVES). Schematic presentation. (From Boudoulas H, Wooley CF (eds): Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura Publishing Company, Inc, 1988. Used with permission.)

oxygen demand with resultant papillary muscle ischemia and chest pain. Subendocardial blood flow is totally diastolic and thus depends on the duration of diastole (see Fig 15).2 Sudden heart rate increases will produce disproportionately greater decreases in diastolic time necessary for subendocardial blood flow than in systolic time because of the nonlinear relationship between heart rate and diastolic time. Extremely fast heart rates related to inappropriate sinus tachycardia with postural changes, and physical and emotional stresses may occur in patients with MVPS. The presence of a hyperadrenergic state in certain patients with MVFS further increases myocardial oxygen demand. Coronary artery vasoregulatory abnormalities may be present in certain patients with MWS and may contribute to the pathogenesis of subendocardial or papillary muscle ischemia. Coronary artery spasm has been documented in a few patients with MVPS. Myocardial or subendocardial ischemia may be secondary to a combination of these factors. Indeed, studies that use rapid atrial pacing have shown myocardial lactate production with chest pain and ischemic electrocardiographic changes in some patients with MVPS and normal coronary arteries. 35s

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1991

Platelet aggregation, hemorrhage, and fibrin deposits have been observed in the angle between the left atrium and the posterior mitral leaflet; microembolism from these deposits may involve the coronary circulation with subsequent myocardial ischemia.l’ ’ Cardiac Arrhythmias --PaZjdstions.-The cause of arrhythmias in patients with MVP is multifactorial and appears to be related to the anatomic substrate and to the modulating role of the autonomic nervous system. Progressive mitral regurgitation with left ventricular and left atrial enlargement and papillary muscle traction may be responsible for cardiac arrhythmias. Certain patients with MVP may have abnormal atrioventricular conduction that may predispose to supraventricular arrhythmiasg5~ s6 Endocardial friction lesions resulting from friction between the chordae and left ventricular myocardium have been reported in patients with MVP, and it is possible that these lesions may be responsible for or contribute to the development of ventricular arrhythmias. Microemboli from the left atrium or valve may involve the coronary circulation with subsequent myocardial ischemia and ventricular arrhythmias. Chesler et aL3’ reported the clinical pathology in 14 instances of sudden death attributable to arrhythmias associated with MVP (only two had significant mitral regurgitation). Endocardial friction lesions were present in 11 individuals; five patients had a thrombotic lesion in the angle between the posterior leaflet and the left atrial wall containing fibrin and platelets. Autonomic dysfunction may initiate, precipitate, or contribute to arrhythmias in patients with hWPS. Electrolyte abnormalities and/or pharmacologic agents may also be contributory factors for the pathogenesis of cardiac arrhythmias. Fatigue.-Fatigue is common in patients with MVPS. Fatigue is a common and nonspectic symptom of an underlying physical or emotional disorder and can be conceptualized as one of two neurobiologic emergency systems employed by most higher organisms for self preservation: the tight-flight response mediated through the sympathetic neuroendocrine system, and the conservation-withdrawal response characterized by a general dampening of metabolic and physical activity. Isoproterenol infusion in patients with MVPS produced fatigue that lasted for several hours following infusion.‘” Thus fatigue is more than a state of mind; it is usually associated vvith physiologic alterations. Patients with MVPS may have fatigue on the basis of disturbances of autonomic function, however, this is an area that requires further investigation. EKercise Intolerance-Abnormal EKewise Stress Test.- Patients with MWS with exercise intolerance and normal coronary arteries Cur-r Probl

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1991

359

may have exercise-induced ischemic electrocardiographic (ECG) changes. “False-positive” exercise tests have been reported to be present in up to 50% of patients with MVPS. Engel et alT7 performed a maximal treadmill exercise test in 43 patients with MVPS. Twelve of 43 patients (28% 1 had greater than 0.1 mm of flat or downsloping ST segment depression during or following treadmill exercise. The precise mechanism(s) for these ischemic ECG changes is not well understood and may be related to autonomic dysfunction, hyperadrenergic state, and in some cases may represent myocardial ischemia. Abinader and Shaha? performed exercise ECG tests before and after beta blockade in 12 patients with MVP and normal coronary artery anatomy who had a positive exercise test. All abnormal exercise tests returned to normal after adequate beta blockade, while the resting and exercise heart rate decreased significantly compared with values before beta blockade. They concluded that the elimination of “false-positive” ECG responses by beta blockade should help improve the specificity of the exercise test. Abinader also performed exercise tests in 55 patients with Mvp in another study.ss Twenty-two (40%) had a positive response and underwent a repeat test after the administration of beta-blocking drugs; of the 22 patients, 19 patients (86%) had normal exercise ECG after beta blockade. This effect of beta blocking drugs on the exercise ECG is not specific to MVP and similar responses may be seen in patients with coronary artery disease.

Dyspnea.Dyspnea in MVPS patients can not be explained on the basis of clear-cut cardiac or pulmonary abnormalities. Pulmonary function abnormalities have been described in patients with MVP/ MVPS but are not severe enough to explain the dyspnea. Further, discrete pulmonary function abnormalities were not demonstrated in patients with MVP!S and dyspnea. Left ventricular function and central hemodynamics are usually normal in MVPS patients with dyspnea?, ’ The respiratory awareness, breathlessness, and respiratory symptoms in patients with the MVPS may represent alterations in centrally modulated breathing cycle control. Postural Phenomena .-Patients with MVPS often have postural phenomena such as orthostatic decreases in cardiac output, orthostatic hypotension, tachycardia, arrhythmias, and symptoms related to alterations in heart rate, blood pressure, and cardiac output. Orthostatic phenomena are multifactorial in origin. A decreased intravascular volume, an abnormal rerun-aldosterone response to volume depletion, a baroreflex modulation abnormality, a hyperadrenergic state, or a parasympathetic abnormality may partially account for these phenomena.’ Furthermore, inability of patients with MVPS to maintain normal left ventricular diastolic volume in the upright posture will result in a greater MVP and papillary muscle tension; these 360

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1991

changes in left ventricular size and mitral valve apparatus are also important factors and may contribute to orthostatic changes.

Syncope or Presyncope.-The causes of syncope and presyncope in patients with MVPS are multifactorial2 Arrhythmias definitely play some role in certain patients. However, syncope or presyncope, like palpitations, often correlate poorly with cardiac arrhythmias. A given arrhythmia, however, may not always produce symptoms, depending upon the setting in which it occurs (supine versus upright position). Further, the occurrence of syncope related to activity may depend not only on the kind of activity but also on its level of intensity. Other factors such as decreased intravascular volume, orthostatic hypotension, sympathetic-parasympathetic abnormality, and baroreflex modulation abnormality may also play a role.lwJ lo1 Neuropsychiatric Symptoms.- A consistent yet controversial finding in many clinical studies of patients with MVPS has been the incidence of anxiety, panic attacks, and other complaints that are considered to be neuropsychiatric symptoms. Furthermore, the incidence of MVP is greater in patients with conditions considered to be related to autonomic dysfunction.271oz Thus MVP was present in 38% of a group of patients with panic disorders, in 40% of a group of patients with agoraphobia, in 35% of a group of patients with mixed disorders presenting with anxiety attacks, in many patients with migraine headache, and in 20% to 25% of a group of patients with primary disorders of sleep.’ The relationship between MVP and anxiety disorders remains something of an enigma, however, since other studies showed no association of MVP in patients with anxiety disorder, questioned the basis for the diagnosis of MVP in the earlier studies, and concluded that MVP and neurosis are independent conditions. This is an area that requires additional collaborative studies. The pathophysiology of panic disorder is incompletely understood. The recent demonstration of discrete abnormalities in a region of the human brain thought to be important in the expression of emotion in patients with lactate-induced panic disorder places the matter in a neurobiologic realm. Carr and Sheehanlo presented a biologic model to explain certain aspects of panic disorder in which the primary defect is neuroendocrine rather than psychiatric, located within the redox-regulating apparatus of the brain stem. MITRAL

VALVE PROLAPSE:

NATURAL

HISTORY

The gradual progression of mitral regurgitation in patients with MW allows gradual enlargement of the left atrium and the left ventricle, Left atrlal dilatation results in left atrial dysfunction and atrial Cut-r

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381

fibrillation that contributes to, may initiate, or reflect left atrial (LA1 pump failum. Left ventricular enlargement also occurs gradually in patients with MVP and significant mitral regurgitation, and eventually results in left ventricular dysfunction, left ventricular pump failure, and the development of congestive heart failure. Pulmonary hypertension may occur with right heart involvement during the course of these left heart changes. Natural history studies suggest that after a prolonged asymptomatic interval the entire process enters an accelerated phase in the presence of-and most likely as the result of-left atrial and left ventricular failure, atrial fibrillation, and in certain instances ruptured mitral chordae. Symptoms and serious complications related to mitral valve dysfunction in patients with MYP include infectious endocarditis, thromboembolic phenomena, supraventricular or ventricular arrhythmias, atrioventricular conduction defects, sudden death, progressive mitral regurgitation that requires medical therapy or mitral valve surgery, ruptured chordae tendineae, and congestive heart failLll-t?.

Several long-term prognostic studies suggest that complications occur mostly in patients with auscultatory findings, especially in patients with mitral systolic murmur, in patients with thickened redundant mitral valve leaflets and in patients with increased left ventricular or left atrial size.lo4’ lo5 Infectious endocarditis increases with age in males but not in females. Thromboembolic complications, however, may occur at younger ages in both men and women. Kolibash et al?06 reported the natural history in 86 patients with MVP who had severe mitral regurgitation. Eighty patients had a preexisting heart murmur first detected at an average age of 34 (Fig 19). Patients remained asymptomatic for an average of 25 years before clinical symptoms first appeared. After significant symptoms developed, mitral valve surgery was necessary in most of the patients within 1 year. This rapid deterioration could generally be attributed to the onset of atrial fibrillation, chordae tendineae rupture, or both. Twenty-eight patients had serial evaluations; these serial studies demonstrated progressive mitral regurgitation, cardiomegaly, and left atrial enlargement. From this study it was apparent that a subset of patients with MVP with floppy mitral valve developed progressive, severe mitral regurgitation after long asymptomatic intervals. Duren et alTo7 reported the results of a long-term prospective follow-up study in 300 patients with MVP diagnosed by clinical, cineangiographic, and echocardiographic criteria. All patients had auscultatory findings consistent with MVP. The ages ranged from 10 to 87 years (mean 42.2 years). The study included all patients with MVP irrespective of clinical condition at the onset, with an average follow-up period of 6.1 years. The clinical condition remained stable in 362

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RELATIONSHIP

34

FIRST

SETWEEN

DETECTION

OF MURMUR

8 ONSET

OF SYMPTOMS

SYMPTOM

30 r 3

26

522 b

16

p

14

;

IO 6 2 o-9

IO-19

20-29

30-39

40-49

SO-59

60-69

TO-79

>a0

AGE

FIG 19. The decades of life when a heart murmur was first detected (clear bars) and when symptoms first developed (cross-hatched bars) are shown. Note that 62 patients (75%) were below 50 years of age when first informed of having a murmur, and 75 patients (87%) were over 50 when first becoming symptomatic. (From Kolibash AJ, Kilman JW, Bush CA, et al: Evidence for progression from mild to severe mitral regurgitation in mitral valve prolapse Am J Cardiol 1986; 58:762-767. Used with permission.)

1.53 patients. Twenty-seven of the 153 patients developed supraventricular tachycardia that was controlled with medications; 20 patients developed signs of mitral regurgitation but remained clinically asymptomatic. Serious complications developed in 100 patients. Sudden death occurred in 3, ventricular fibrillation in 2, ventricular tachycardia in 56, and infectious endocarditis in 18. ‘ILYenty-eight patients had mitral valve surgery because of progressive mitral regurgitation; an additional 8 patients with severe mitral regurgitation were considered surgical candidates. Eleven patients had cerebrovascular accidents. Although the study population may not be representative for the entire MVP population, the results strongly support the concept that MVP may be associated with significant morbidity and mortality. Nishimura et allo determined prognosis in a prospective (mean 6.2 years) follow-up study in 237 minimally symptomatic or asymptomatic patients with MVP documented by echocardiography. The average age was 44 years (range 10 to 69 years). Sudden death occurred in six patients. In multivariable analysis of echocardiographic factors, the presence or absence of redundant mitral valve leaflets (present in 97 patients) emerged as the only variable associated with Cum

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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 atrial fibrillation with left atrial enlargement, and two were in sinus rhythm. Infectious endocarditis occurred in three patients. Progressive mitral regurgitation prompted valve replacement in 17 patients. The LV end-diastolic diameter exceeding 60 mm was the best echocardiographic predictor of the subsequent need for mitral valve replacement. Twenty patients had no clinical auscultatory findings of a systolic click or murmur; none of these patients had any complications during follow-up. The authors concluded that although most patients with echocardiographic evidence of MVP have a benign course, subsets of patients can be identitled 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.74 confirmed Nishimura’s data in a retrospective study. Clinical and two-dimensional echocardiographic data from 456 patients with MVP 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 (i.e., infective endocarditis, mitral regurgitation, and the need for mitral valve replacement1 were more prevalent in those with leaflet thickening and redundancy compared with those without leaflet thickening. The incidence of stroke, however, was similar in the two groups. You-Bing,“’ in a follow-up study (average 4.3 years) from Tokyo, Japan, using external phonocardiograms, M-mode and two-dimensional echocardiography and pulsed Doppler echocardiography, in 116 patients with mitral valve prolapse placed emphasis on the systolic murmur confirmed by phonocardiography as a prognostic indicator in patients with MVP. During follow-up, left atrial 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. These long-term follow-up studies in patients with MVP associated with a floppy, myxomatous mitral valve permit several conclusions: (11 serious complications do occur in patients with MVP; (2) complications in patients with MVP appear to occur primarily in patients with diagnostic auscultatory findings; (3) redundant mitral valve leaflets and increased left ventricular size in patients with MVP are associated with a high frequency of serious complications; and (4) men and those over 50 years of age are at increased risk of complications including severe mitral regurgitation requiring surgery. Factors that may accelerate the natural history in patients with MVP-floppy mitral valves include infectious endocarditis, chordae 364

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1991

tendineae rupture, left atrial enlargement and dysfunction, the development of atrial fibrillation, left ventricular enlargement and dysfunction, and the development of cardiac arrhythmias. IDENTIFICATION

OF THE HIGH RISK PATIENT

Taking into consideration the results from published studies and our experience, clinical and laboratory descriptors that characterize the high-risk patient are as follows. Among MW tiatients with floppy

MVP - Anatomic: The High Risk Patient

m Male EZl Female

FIG 20. Patients with mitral valve prolapse (MVP) with diagnostic auscultatory findings, especially wrth mitral systolic murmur, thickening of the mitral valve leaflets and left ventricular (LVJ or left atrial (LA) enlargement are at higher risk of developing complications. When two or more of the above abnormalities exist the possrbilities of complications are increased. By contrast the absence of all three of these features can be used to identify patients with MVP of exceedingly low risk. As a general rule, complications related to VP increase with age; complications in males are more common compared with females. (From Boudoulas H, Kolibash AJ, Wooley CF: Mitral valve prolapse and the mitral valve prolapse syndrome. Primary Cardiol, In press. Used with permission.) Cum

Probl

Cardiol,

May

1991

36.5

mitral valves, men and those over 50 years of age are at increased risk of complications. A mitral systolic murmur has also been shown to be an independent risk predictor for complications. Patients with h4~P and thick redundant mitral valve leaflets (i.e., floppy mitral valve) are at higher risk of developing complications. Left ventricular enlargement in patients with MVP is a good predictor of the subsequent need for mitral valve surgery. When two or more of the preceding abnormalities coexist, the possibilities of complications are increased. By contrast, the absence of all of these features can be used to identify patients with MVP at exceedingly low risk (Fig 20).l04'105

In patients in whom h4VP is a part of a recognized heritable disorder of connective tissue, it is associated with other cardiovascular abnormalities, and the natural history may be related to coexistence of other abnormalities than to MVP per se. Patients with MVP have a prolonged natural history. For the most part, complications increase with age. Rather than a single natural history curve, patients with MVP experience a series of natural history curves that reflect the pathologic and pathophysiologic spectrum (see Fig l).*

MITRAL

VALVE PROLAPSE:

CLINICAL

MANAGEMENT

The majority of MVP patients are asymptomatic and lack the highrisk profile described earlier in the monograph. Those patients with mild symptoms and findings of milder forms of prolapse, as well as those free of symptoms, should be reassured of a benign prognosis. A normal life-style and regular exercise are encouraged. MVP is the leading predisposing diagnosis in most series of patients reported with endocarditis.llo’ ‘*’ The absolute incidence is clearly extremely low for the MVP population as a whole. There has been much discussion in the literature about endocarditis risk in Mvp.llZ-119 There is uniform agreement that those patients with murmurs and/or thickened, redundant valves by echocardiography or cineangiography (i.e., floppy mitral valves) should receive antibiotic prophylaxis.‘15, ‘1’S ‘*’ Some authors state that patients with isolated click(s) with no murmur do not need prophylaxis. The dynamic nature of MVP, with variable findings from examination to examination, makes it difficult to make judgments on omitting prophylaxis. With the increasing routine use of color-flow echo-Doppler studies, mitral regurgitation may be seen in patients in whom no murmur is heard.75 At present there are no data regarding need for prophylaxis in this group. Endocarditis can lead to destruction of even a mildly affected valve, so prophylaxis is warranted in nearly all cases. A patient with an isolated click on serial examinations with a 366

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1991

normal or only mildly abnormal echocardiogram may not need prophylaxis. Concern regarding anaphylaxis to penicillin has led some to recommend erythromycin for prophylaxis in the “low risk” clearly needs continued grouPs.lzo, 121 The issue of ptiphylaxis study. b PM. SHAH: I concur with the author’s opinion that all patients with identified floppy mitral valve (classic auscultatoly and echocardiographic criteria) should receive antibiotic prophylaxis irrespective of presence or absence of a murmur or mitral regurgitation. Cdor Doppler examination may reveal distinct jet of mild or even moderate severity regurgitation in the absence of discernable cardiac murmur. Hence, an insistence on the presence of a murmur would seem inamx-tmriate.

Patients with MVPS wjth palpitations associated with excessive tachycardia or milder tachyarrhythmias, with chest pain, anxiety, or fatigue often respond to beta blockade?” 12’ However, eliminating cyclic AMP and catecholamine stimulators such as caffeine, alcohol, cigarettes, and drugs containing catecholamine derivatives; and avoiding

diuretics

and

dehydration

may be sufficient

to control

symptoms and should be tried before drug therapy. Exaggerated sinus tachycardia with cardiac awareness may respond to minimal doses of beta-blocking agents; larger doses may be required in those with the other listed symptoms, especially if multiple symptoms are present.

If one beta blocker

does not control

symptoms

without

side

effects, others can be tried. Calcium channel blockers and clonidine have been helpful in some patients?23 Drug therapy should not be used unless efforts at reassurance and encouraging exercise fail. Orthostatic symptoms are best treated with volume expansion, preferably by liberal fluid and salt intake, although salt retaining steroids (Florinef) may be needed in severe cases. Wearing support stockings may be of benefit as well. In sudden death survivors and those patients with symptomatic complex dysrhythmias, specific antiarrhythmic therapy should be guided by monitoring techniques, up to and including electrophysiologic testing. A documented focal neurulogic event in a patient with Mvp warrants aspirin therapy, generally one tablet daily, even if the source cannot be specifically identified. The incidence of embolic events is so low in the absence of cardiac enlargement, atrial fibrillation, severe mitral regurgitation, with congestive heart failure, that prophylactic aspirin treatment is not indicated. Patients &th recurrent embolic events and those with

severe regurgitation,

atrial arrhythmias,

and congestive heart failure require long-term anticoagulation with warfarin. Patients experiencing focal neurologic symptoms should avoid cigarettes and oral contraceptives. Restriction from participation in competitive sports is required if moderate Curr

Probl

left ventricle Cardiol,

May

1991

(LV) enlargement,

LV dysfunction,

uncon367

trolled tachyarrhythmias (supraventricular or ventricular tachycardias), long QT interval, unexplained syncope, prior sudden death, or aortic root enlargement is present individually or in combination.lz4 An enlarged aortic root is likely to be present in those patients with an associated heritable disease of connective tissue, especially the Marfan syndrome, and constitutes a more potent risk factor for morbidity and mortality than presence of MVP in those patients.17, 53 The pattern of inheritance should be explained to the patient and is particularly important in those with associated diseases who are at greater risk for complications. Screening relatives can uncover high-risk individuals and potentially prevent some complications. There is no contraindication to pregnancy based on the diagnosis of MVP alone.“’ Indeed, the increased blood volume of pregnancy may ameliorate symptoms. A large aortic root in patients with connective tissue disorders or desire not to transmit a disorder to offspring are reasons for avoiding pmgnancy.*2” Patients with severe mitral regurgitation with symptoms and/or exercise induced left ventricular dysfunction require catheterization studies and evaluation for mitral valve surgery. The floppy mitral valve can often be repaired rather than replaced with a low operative mortality and excellent short-term durability.7s-81 Follow-up studies also suggest lower thromboembolic and endocarditis risk than with prosthetic valves. Valve surgery is not recommended for control of arrhythmias per se. Asymptomatic patients with MVP without floppy valves can be followed on a clinical basis every 2 to 3 years, with echocardiography every 5 years to help profile the natural history of MVP. Patients with the floppy mitral valve with regurgitation should be evaluated yearly even if no symptoms are present. Patients with moderate or severe regurgitation and those patients with symptoms associated with a click and/or late systolic murmur should be seen as often as needed, according to physician discretion, for control of symptoms and monitoring for complications. Once an entire generation of MVP patients representing the entire anatomic spectrum of the floppy mitral valve is carefully followed and documented from birth to death, we may be able to be much more specific in determining risk factors for progression and in managing patients with MVP and MVPS. b P.M. SHAH:This succinct review of the diffkult and confusing subject matter with varied and often opposing opinions in the literature is based on vast experience and a scholarly study of the subject by these authors under the leadership of Dr. Charles Wooley. The readers will find this to be a lucid presentation of the subject. Clearly, last word has yet to be written on several aspects of this complex clinical entity, and further research on pathophysiology and natural history will no doubt be forthcoming.

368

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1991

ACKNOWLEDGEMENT

Supported by the Overstreet Cardiovascular Teaching and Research Laboratory, Division of Cardi~iogy, The Ohio State University College of Medicine and The Columbus Foundation, Columbus, OH. BIBLIOGRAPHY 1. Boudoulas

H, Wooley

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