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Annu. Rev. Med. 1976.27:165-178. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/30/15. For personal use only.
MITRAL VALVE PROLAPSE!
.:.7190
E Douglas Wigle, MD. Division of Cardiology, Toronto General Hospital, and Department of Medicine, University of Toronto, Toronto, Canada M5G lL7
Harry Rakowski, MD. Cardiovascular Unit, Toronto General Hospital, and University of Toronto, Toronto, Canada M5G lL7
Narasimhan Ranganathan, MB.B.S Division of Cardiology, St. Michael's Hospital, and Department of Medicine, University of Toronto, Toronto, Canada M5G IL7
Malcolm D. Silver, MD. Department of Pathology, Toronto General Hospital, and University of Toronto, Toronto, Canada M5G IL7
INTRODUCTION AND HISTORICAL BACKGROUND Mitral valve prolapse is a condition in which one or both mitral valve leaflets prolapse or balloon back into the left atrium during left ventricular systole, and which may or may not be accompanied by mitral regurgitation. Because of the clinical findings, it has also been called the mid-systolic click-late systolic murmur syndrome,mid-systolic click syndrome,or late systolic murmur syndrome; because of the pathological and surgical findings it has also been called the floppy valve syndrome. Cutrer & Barbillon (I) in 1887 first described the "mid-systolic click" (2) as a "bruit de galop mesosystolique." In 1913 and again in 1932 Gallavardin (3, 4) attributed these clicks to pleuropericardial adhesions, thereby influencing several generations of authors to think they were extracardiac in origin and hence "inno cent" (2, 5-11). This thinking prevailed until the early I 9 60s in spite of the fact that Griffith in 189 2 (12), Hall in 1903 (13), and White in 1931 (14) attributed the click and/or late systolic murmur to mitral valve dysfunction. In 1961 Reid (IS) again postulated that the click and murmur were of mitral valve origin, the click or "chordal snap" being due to sudden tautening of previously lax chordae, and the IWork supported by the Ontario Heart Foundation.
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Annu. Rev. Med. 1976.27:165-178. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/30/15. For personal use only.
murmur, when present, to mitral regurgitation. In 1963, Barlow et al ( 16) demon strated angiographically the presence of mitral regurgitation in patients with the "click-murmur" syndrome. Subsequently a myriad ( 17- 1 1 1) of reports have con firmed and expanded these observations, and have begun to delineate an evolving syndrome that is still poorly understood in many respects. Indeed, in the past five years the literature on this subject has become as voluminous as the prolapsed leaflets themselves (see section on pathology and pathogenesis, and Figure 1). This fact has dictated that the literature review be selective.
ETIOLOGY AND ASSOCIATED CONDITIONS Mitral valve prolapse or the "click-murmur" syndrome has been described in Mar fan's syndrome ( 16-22), in Turner's syndrome ( 17, 20), in hypertrophic cardi omyopathy ( 19), in patients with a history of acute rheumatic fever (16, 19, 23-26), following mitral commissurotomy ( 19, 26), in coronary artery disease (21, 25-29), as well as in association with ruptured chordae· (30) and secundum atrial septal defect ( 17, 26, 3 1-35). However, the majority of cases are idiopathic (26), and in many instances prolapse occurs in familes ( 17, 21, 23, 26, 35-40), apparently with a Mendelian dominant inheritance (36, 39, 40). Many patients with the idiopathic or familial form of prolapse have thoracic or other skeletal abnormalities reminis cent of Marfan's syndrome (42-44). As a result, some authors have suggested that the idiopathic or familial form of the condition is a forme fruste of Marfan's syndrome (44, 45). This review focuses on the idiopathic or familial condition, but discusses other forms of prolapse where appropriate.
PATHOLOGY AND PATHOGENESIS Myxomatous degeneration of the mitral valve leaflets has been demonstrated in mitral valve prolapse of the idiopathic ( 19, 20, 35, 46-56) and familial type (41), as well as in Marfan's syndrome (22, 54, 57-59) and when prolapse has been associated with secundum atrial septal defect (47). The posterior leaflet is always involved, the anterior leaflet less frequently (47, 53). In a significant percentage of cases the tricuspid valve is involved (47, 60). Involved leaflets (or individual scallops of the posterior leaflet) are voluminous, thickened, and elongated; they present a hooded or domed appearance convex toward the left atrium (Figure 1). The chordae ten dineae are usually elongated and thickened (Figure 1), but may be thinned. A significant proportion of cases show ruptured chordae (19, 47, 49, 52, 53, 55, 56). Thrombi on the valve leaflets have been observed either in the acute angle between the prolapsed posterior leaflet and left atrial wall (unpublished observation by the authors), or over cracks in the endothelial surface (47). Jet lesions in the left atrium as well as enlargement of the atrium and left ventricle occur in cases with a signifi cant degree of mitral regurgitation (47). Microscopy of involved leaflets shows replacement of the central fibrous part by metachromatically staining loose myx omatous material, with fibroelastic thickening of the adjacent endocardium (35, 4 1, 47, 48, 5 1). These myxomatous changes also occur in the mitral annulus and chordae tendineae, with sclerosis also affecting the latter (47, 48). Although myx-
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Figure J Comparison of a sectioned middle scallop from a prolapsed posterior mitral valve leaflet (left) with that from a patient of the same age with a normal leaflet, but left ventricular hypertrophy (right). In the voluminous prolapsed leaflet (left), most of the thickening and lengthening of the leaflet has occurred in the rough zone, into which the elongated thickened chordae insert. Scale in centimeters. [Rep rinted from American Heart Journal (48, p. 539) by permission.] omatous degeneration appears to be the common pathologic basis for mitral valve prolapse, in our present state of knowledge it is perhaps best to think of this type of degeneration as a nonspecific reaction that may be familial or a forme fruste of Marfan's syndrome in some cases, but in others it may be a'result of the abnormal stresses and strains to which the mitral valve is exposed. Indeed, up to 80% of patients with mitral valve prolapse have abnormal left ventricular function (42, 61-68), causing some authors to suggest that the prolapse may be secondary to an ill-understood form of cardiomyopathy (68). The valves of patients with the "c1ick murmur" syndrome and a history of rheumatic fever, or in association with hyper trophic obstructive cardiomyopathy, have not, to our knowledge, been examined pathologically. Mitral valve prolapse can clearly result from coronary artery disease (21, 25-29), and in four such patients postmortem examination demonstrated nor mal mitral leaflets (29). In three there was a healed diaphragmatic myocardial infarct with fibrosis of the posteromedial papillary muscle, while in the fourth there was a healed anterolateral infarct with fibrosis of the anterolateral papillary muscle (29). In such instances prolapse is thought to be a form of papillary muscle dysfunc tion. However, myxomatous degeneration of the mitral valve may coexist with occlusive coronary artery disease (unpublished observation by the authors).
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ANATOMIC-ANGIOGRAPHIC CORRELATIONS Pertinent to mitral valve prolapse and to its angiographic recognition is a recent redefinition of mitral valve anatomy (Figure 2) (49, 69). Both anterior and posterior leaflets have a rough zone at their distal free edge where rough zone chordae tendineae attach. Proximal to this is a clear zone to which no chordae attach. The two leaflets are separated from one another by commissures, into which fan-shaped commissural chordae insert. In 92% of normal human mitral valves the posterior leaflet has a triscalloped structure with a large middle scallop and smaller lateral scallops, termed the posteromedial commissural scallop (next to the posteromedial commissure) and the anterolateral commissural scallop (next to the anterolateral commissure). Fan-shaped chordae tendineae insert into clefts between the scallops of the posterior leaflet. This leaflet has a greater length of insertion into the mitral annulus than does the anterior leaflet, and has basal or "third order" chordae inserting into its base (Figure 2) (49, 69). Many authors have described the angiographic appearance of posterior and an terior mitral leaflet prolapse (11, 18, 20, 23, 35, 36, 38, 48, 53, 61, 62, 70-74). Our own interpretation of the angiographic appearance of prolapse of the posterior leaflet is based on the redefined anatomy of this leaflet (Figures 2 and 3). Thus it is now possible to recognize angiographically prolapse of the individual scallops of
Figure 2 Diagrammatic representation of the normal mitral valve with typical commissural and cleft chordae tendineae attached. A-B anterolateral commissure; B-C anterior leaflet; CoD posteromedial commissure; D-A' posterior leaflet; D E posteromedial commissu ral scallop; E-F middle scallop; F-A' anterolateral commissural scallop; c cleft; pm papillary muscle; tcoc typical commissural chorda; tee typical cleft chorda. Basal or "third order" chordae insert into the basal zone (broken line) of the posterior leaflet. Rough zone chordae of both leaflets insert into the rough zones of these leaflets (cross-hatched areas). The intervening areas of the leaflets are the clear zone, to which no chordae attach. [Reprinted from Circulation (49, p. 459) by permission.] =
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Annu. Rev. Med. 1976.27:165-178. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/30/15. For personal use only.
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Figure 3 Line diagram of a left ventriculogram in the right anterior oblique projection. The upper continuous and barred line, extending from the posteromedial (PMC) to the anterolat eral commissure (ALC), outlines the prolapsed scallops of the posterior leaflet of the mitral valve. PMCS posteromedial commissural scallop; MS middle scallop; ALCS anterolat eral commissural scallop. For orientation, the locations of the posteromedial papillary muscle (PMPM) and anterolateral papillary muscle (ALPM) have been outlined in the left ventricle (L V) . Their tips usually point toward the respective commissures. Also included is the location of the normal mitral valve ring, shown by the lower dotted and barred lines forming a circle. The barred line represents the posterior mitral ring. Note that the anterior part of the mitral ring (dotted line) has a common attachment with the aortic root (AO). [Reprinted from Circulation (53, p. 514) by permission.] =
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the posterior leaflet of the mitral valve (Figure 3) (48. 53)". In the right anterior oblique left ventricular cineangiogram, prolapse of the middle scallop occurs cen trally overlying the left atrium. whereas prolapse of the posteromedial commissural scallop causes an inferior bulge. and prolapse of the anterolateral commissural scallop causes a superior bulge (Figure 3). Jeresaty (73) , who has based many of his observations on these anatomic findings. believes that when the superior bulge is large it represents prolapse of the anterior leaflet rather than the anterolateral commissural scallop of the posterior leaflet, a point with which we do not agree (74). In our opinion, the size of the superior bulge would be determined by the degree of prolapse of the anterolateral commissural scallop (74). Prolapse of the posterior leaflet occurs in virtually every case (18,35,36,38,53,74). Anterior leaflet prolapse is less common (35. 53). Criteria for the angiographic diagnosis of anterior leaflet prolapse have been described (74) . In the right anterior oblique left ventricular cineangiogram, prolapse of the anterior leaflet often overlaps prolapse of the middle scallop of the posterior leaflet, but the two can be distinguished by the presence of discontinuity in the angiographic outline, as well as by temporal dissociation (74) . The left anterior oblique left ventricular cineangiogram is particularly valuable in documenting anterior leaflet prolapse (74). where its appearance is distinct from the
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cauliflower-like appearance of posterior leaflet prolapse in this view (38) . Using these criteria, we found that of 55 patients with angiographically proven prolapse, 16 had anterior as well as posterior leaflet prolapse. Pathologic proof of combined leaflet prolapse was demonstrated in 5 of these patients (unpublished observations by the authors).
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THE CLINICAL SYNDROME History
Idiopathic or familial mitral valve prolapse occurs predominantly in females and at virtually any age (17, 26, 35) . These patients commonly present with palpitations, presyncope, syncope, chest pain, dyspnea, and/or fatigue (17-19 , 35, 38). The palpitations, presyncope, and syncope can usually be attributed to atrial and/or ventricular arrhythmias (17, 35) . Sudden death has been reported in a number of instances and is presumed due to ventricular arrhythmias (17, 19 ,40,41,48,68) . We have recorded seven instances of ventricular fibrillation as the cause of syncope in these patients. Spontaneous defibrillation was observed in three of four patients with recurrent syncope (Rakowski, H., Wald, R., Waxman, M. B., and Wigle, E. D., unpublished observations). The chest pain may be of several different types; (a) typical angina of effort, (b) unstable angina pectoris, (c) prolonged episodes of atypical anterior chest pain lasting for hours or days and not resembling a or b, or (d) sharp stabbing left chest pain suggestive of cardiac neurosis. Increased arterial systolic pressure can induce the atypical episodes of chest pain, suggesting an imbalance between oxygen supply and demand as the basis for this common symp tom (75) . Dyspnea, fatigue, and evidence of left and right heart failure may result from left ventricular dysfunction (68) or from hemodynamically significant mitral regurgitation (53) . More commonly the dyspnea and fatigue cannot be explained on the basis of hemodynamic abnormalities, nor does controlled exercise testing pro vide objective evidence to explain these symptoms (65) . Cerebral ischemic episodes (76) and neurologic deficits (36,76) may be due to emboli (76) arising from thrombi on the mitral leaflets (47) . A number of patients with idiopathic prolapse are asymptomatic and come to cardiological attention because of abnormal findings on physical examination. Physical Examination EXTRACARDIAC In some series (42--44, 65) , up to 70% of patients with mitral valve prolapse have thoracic skeletal abnormalities suggestive of a forme fruste of Marfan's syndrome: pectus excavatum, straight back syndrome, scoliosis, or narrow anteroposterior diameter of the chest. Many patients, however, have no such stig mata.
In the typical case, the heart is not enlarged and abnormalities on physical examination are restricted to auscultation at the cardiac apex, where a mid-systolic click and/or late systolic murmur are heard. The clicks may be multiple (15, 17,36,38,77) and may occur in early (17,78,79 ) ,mid (15, 17,36) or late (17,
CARDIAC
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19, 38) systole. They usually initiate the murmur but may occur in the middle or towards the end of it. Because of the variable timing of the clicks, they should not all be termed mid-systolic, but rather nonejection clicks (19), to distinguish them from the ejection variety. Although the earliest click vibrations occur shortly after the onset of prolapse (80), the loudest vibrations coincide with maximal prolapse of the leaflets (18) and have been ascribed to a tautening of the lax chordae (chordal snap) (IS) or to the leaflets themselves (18), similar to an opening snap in mitral stenosis (28). Multiple clicks may be due to asynchronous prolapse of either the leaflets or individual scallops of the posterior leaflet, or to asynchronous chordal tautening (unpublished observations by the authors). The murmur is most com monly late systolic and crescendo, or crescendo-decrescendo, up to and beyond aortic valve closure (17, 19, 24, 37, 77). In cases with more severe degrees of mitral regurgitation the murmur is usually pansystolic, sometimes with late systolic accen tuation. Intracardiac phonocardiography has shown that the click and murmur arise in the mitral area and radiate into the left atrium (18, 24, 37, 77). The murmur and click may also be recorded in the inflow tract of the left ventricle (19, 70). A late systolic murmur may have an early systolic component (24). Intraatrial sound recordings, as well as other studies, have demonstrated that precordial "honks" or "whoops" are usually due to mitral valve prolapse (19, 21, 24, 37, 81, 82). Although a systolic retraction coincident with the click of prolapse can be recorded by apex cardiography (83-86), this phenomenon is rarely appreciated on palpitation. A number of patients with angiographically documented prolapse have no abnormali ties on physical examination. Some, but not all, will manifest a click and/or murmur with various provocative maneuvers, such as standing (19, 21). This is important to realize because patients may have symptoms attributable to prolapse, but no clinical evidence of it. In such patients echocardiography and/or angiography are required for an accurate diagnosis. It is important to indicate that systolic clicking sounds have been heard in mediastinal emphysema (87) and left-sided pneumo thorax (88, 89). Systolic clicks have also been reported in aneurysms of the membra nous ventricular septum (90, 91). Whether they can also be attributed to pericardial (I1) or pleuropericardial (3, 4) adhesions is in some doubt at this time. Patients with mitral valve prolapse due to coronary artery disease tend to be older and male; they usually manifest a loud first heart sound and third and fourth heart sounds, in addition to a late systolic murmur, with or without a nonejection click (21, 25-29). Inspiration accentuates these findings (29). In the click-murmur syn drome following mitral commissurotomy, the click occurs in early systole and the apical murmur is longer (19). We have recently noted the preoperative occurrence of prolapse associated with mitral stenosis in five patients. In four the prolapse was visualized angiographically, and in two it was recognized clinically by the presence of a click in one patient, and a pansystolic murmur with late systolic accentuation in the second (unpublished observations by the authors). The occurrence of mitral valve prolapse in association with secundum atrial septal defect is well recognized (17, 26, 31-35, 47) and occurs in about 40% of cases (34). Half of these cases had clinically silent prolapse and in the remainder an apical pansystolic murmur was the commonest finding indicating prolapse (34). This combination must be distin-
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guished from primum atrial septal defect, in which left axis deviation in the elec trocardiogram is virtually diagnostic. VARIABILITY OF SIGNS Tremendous interest has centered on maneuvers that alter the timing and intensity of the click and murmur (6, 16-21, 61, 80, 92-94). Amyl nitrite inhalation causes the click to move earlier in systole and the murmur to lengthen, sometimes becoming pansystolic (16, 17, 19, 20, 80,92). Soon after inhalation, the murmur becomes fainter (16, 17), but later it becomes louder (l6). The strain period of the Valsalva maneuver also causes the click and murmur to move to early systole (16, 19, 92). Sitting or standing causes a click, murmur, or honk to appear when not present in the supine position, and causes clicks and murmurs to occur earlier in systole (19, 21, 61, 92). Murmurs also become louder (19, 21, 61, 92). Squatting reverses the changes brought about by standing (21). Right atrial pacing tends to move the clicks and murmurs to early systole (94). Infusion of pressor amines either does not change the timing of the click, or causes it to disappear while accentuating the late systolic murmur (16, 19, 93). Many of these variations have been attributed to changes in left ventricular volume in the presence of elongated chordae tendineae (16, 19-21, 80, 93). Thus when left ven tricular volume decreases,the chordae are relatively longer and permit earlier and greater prolapse to occur, accounting for the altered clinical findings. Cineangiogra phy has demonstrated a greater degree of prolapse following amyl nitrite inhalation (20) and in the 45° head-up tilt position (93). A recent suggestion is that changes in left ventricular contractility or ejection rate, rather than altered ventricular volume,account for the variability in the degree of prolapse and in the accompa nying clinical signs (94).
Laboratory Investigation ELECTROCARDIOGRAM AND VECTORCARDIOGRAM Many patients with mi tral valve prolapse have a normal electrocardiogram and vectorcardiogram, but a very significant percentage manifest definite abnormalities in the absence of coro nary artery disease ( l 7, 26, 35, 36, 38,40, 61, 65, 68, 71, 79, 92, 95-98). The most characteristic change is ST segment change,and T-wave inversion in leads II,III, AVF, V5, and V6, suggesting inferolateral ischemia (17, 36). These abnormalities are sometimes accompanied by tall, peaked T-waves in leads V2 and V3. Others have reported T-wave inversions in the anterior (precordial) leads (35, 68, 79, 97). Q-waves suggestive of both inferior (36, 48, 68, 92, 98) and anterior (68, 95, 98) myocardial infarction have been observed. The explanation of these abnormalities is not known but myocardial and/or papillary muscle ischemia has been suggested (26). Papillary muscle fibrosis has been demonstrated in one patient showing these electrocardiographic abnormalities (48). Prolonged Q-T intervals (17, 34, 65), and prominent U-waves (17, 65) have also been noted. Nearly every conceivable arr hythmia and conduction defect has been recorded in these patients, and exercise electrocardiograms have revealed ischemic ST segment depressions in a significant number (68, 79, 92, 95, 96). Left ventricular hypertrophy has been reported both in the presence of significant mitral regurgitation and in its absence (38,53, 65, 95).
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ARRHYTHMIAS Cardiac rhythm disturbances can account both for the symptoms of palpitations, presyncope, and syncope, and for the occurrence of sudden death in this syndrome. Atrial,junctional,and ventricular arrhythmias of most types have been clearly documented at rest (17, 26, 35, 65, 68, 95, 96, 99, 1(0),during exercise (26, 65, 68, 95, 96, 99, 1(0), in the post-exercise period (26, 65, 95, 96, 1(0), and by ambulatory monitoring (35, 79, 9 9 ; 1(0). Criley has suggested that the atrial arrhythmias may arise from systolic stretch of the valve leaflets and that the ven tricular arrhythmias may result from the "diastolic dumping" of the blood held under the prolapsed leaflets in systole (100). The prolonged Q-T interval may predispose to the occurrence of ventricular arrhythmias (17), but the latter may occur in the absence of Q-T prolongation (26, 95). The fact that the click often coincides with the peak of the T-wave indicates that the mechanical force of the prolapse itself might incite a ventricular arrhythmia. Serious ventricular arrhyth mias occur in the absence of resting electrocardiographic abnormalities (26). Bra dyarrhythmias, including all degrees of heart block, occur in these patients but are relatively rare (68, 1(0). ECHOCARDIOGRAPHY Two basic types of echocardiographic abnormalities have been described in patients with mitral valve prolapse (101-10 5): ( a ) mid systolic "buckling" associated with mid-systolic prolapse, and (b) pansystolic "hammocking" associated with pansystolic prolapse. Another echocardiographic abnormality, "pansystolic collapse," has been described (105). In essence, all of these findings record the prolapse of one or both mitral leaflets into the left atrium during systole. Single-beam echocardiography probably strikes the middle scallop of the posterior leaflet, as well as the anterior leaflet. Prolapse of the posteromedial and/or anterolateral scallop could therefore be missed (unpublished observations by the authors). For this and other reasons,left ventricular cineangiography remains the standard for the definitive diagnosis of mitral valve prolapse, even though the echocardiographic diagnosis of prolapse represents a tremendous advance. RADIOLOGICAL EXAMINATION Frontal and lateral chest X rays usually re veal a normal heart size and, frequently, thoracic skeletal abnormalities (42-44). Left atrial and ventricular enlargement occurs in the presence of hemodynamically significant mitral regurgitation (53, 68). Left ventricular cineangiography permits assessment of the anatomy of the leaflet prolapse (see section on anatomic-angio graphic correlations), the degree of mitral regurgitation, and left ventricular func tion. The mitral regurgitation may vary from being absent to severe and may begin at the onset of systole in pansystolic prolapse, or in mid-systole in mid-systolic prolapse. Various abnormalities of left ventricular function in systole and diastole have been described in up to 82% of patients studied (42, 61-68). The commonest abnormalities in systole are: (a) an inferior contraction ring (42,62,65),which may occur alone or be associated with increased (42) or decreased (42,65,67) contraction of the anterior wall; (b) decreased contraction or expansion of the anterior wall alone (65, 67, 68); (c) generalized hypokinesis (68); (d) hypokinesis of the in ferobasal segment (42, 66), with poor contraction (66) or expansion of the mitral
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annulus (63, 66), sometimes associated with basal displacement of the tip of the posteromedial papillary muscle (66); (e) decreased shortening of the long axis of the ventricle (42, 65, 68); or (f) cavity obliteration (42, 64). Early diastolic relaxation, particularly of the anterior wall, has been a frequent finding (42, 65, 67, 68). The ejection fraction may be normal, increased, or decreased, depending on the degree of left ventricular dysfunction and mitral regurgitation (68). The evidence of left ventricular dysfunction has caused some workers to suggest that patients with mitral prolapse may have a cardiomyopathy (68). However, left ventricular function has been normal in some patients with documented prolapse (34, 42, 65). Tricuspid valve prolapse has been observed angiographically in up to 54% of patients with mitral prolapse (42,106). Selective coronary arteriograms are normal in individuals with idiopathic or familial prolapse, but may demonstrate an unduly tortuous or "corkscrew" appearance (42, 79). Coronary arteriograms in patients with prolapse due to coronary artery disease usually demonstrate severe obstructive lesions (29). HEMODYNAMICS Intracardiac pressures and flow are usually normal in the ab sence of significant left ventricular dysfunction or mitral regurgitation. In the pres ence of either, however, left ventricular end-diastolic pressure may rise and cardiac
index may be reduced
(68).
With significant mitral �egurgitation the left atrial
V-wave may rise significantly (53).
COMPLICATIONS A number of life-threatening complications may occur in patients with mitral valve prolapse. Those with serious ventricular arrhythmias (particularly ventricular tachycardia and fibrillation) are prone to recurrent presyncope, syncope, and sudden death. Infective endocarditis has been well documented (23,40, 45, 47,54,56,107, 108). Chordae tendineae may rupture from the myxomatous degeneration, or from infective endocarditis, producing severe mitral regurgitation, left and right heart failure, and the need for mitral valve replacement. Emboli can arise from the bland thrombi that may form on the valves of these patients.
NATURAL HISTORY AND PROGNOSIS Several reports have suggested that the clinical course of patients with mitral valve prolapse is usually benign (56,109). In one report (109), 62 patients were followed an average of 14 years. Forty-one were unchanged, ten had slight deterioration, and the remainder either developed infective endocarditis, severe mitral regurgitation, or were lost to follow-up. Patients with cardiac enlargement, abnormal electrocardi ograms, and chest pain resembling angina were excluded from this study (109). In contrast with this relatively benign course are the many reports of sudden death (17, 19,40,41,48,68),the onset of heart failure from mitral regurgitation requiring valve replacement (50,56),the occurrence of infective endocarditis (23,40,45,47,54,56, 107, 108), and reports of continued disability with nonlethal arrhythmias, chest pain, dyspnea, and fatigue. Obviously, the natural history can vary tremendously,
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and this presents a challenge in medical care today. It is important not to induce a cardiac neurosis in these patients with too much concern, while at the same time dealing appropriately with the complications known to occur, particularly life threatening ventricular arrhythmias.
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MANAGEMENT To prevent infective endocarditis, patients with mitral valve prolapse require antibi otic prophylaxis at appropriate times. The treatment of endocarditis should be according to the antibiotic sensitivities of the infective agent. The development of heart failure from significant mitral regurgitation requires appropriate antifailure therapy initially and may require subsequent mitral valve replacement. A number of reports have stressed a high incidence of valve dehiscence in patients treated surgically (45, 55, 56, 110), presumably because of myxomatous change in the annulus. The insertion of deep, interrupted sutures has been recommended to avoid this complication (56). The greatest problem in management is the control of life-threatening ventricular arrhythmias. ,8-Adrenergic blocking agents appear to be the drugs of choice, but are not universally efficacious, requiring the additional or sole use of other antiarrhythmic agents. It has been suggested that the mitral valve be replaced to control particularly persistent ventricular arrhythmias, but the long term value of this aggressive form of therapy is not known (Il l). Five years ago we replaced the mitral valve in one patient with recurrent ventricular fibrillation who also had severe mitral regurgitation. Ventricular fibrillation has not recurred, but the patient has required continued antiarrhythmic therapy (A. G. Adelman, unpub lished observation). ,8-Adrenergic blocking agents have also been of value in the management of patients with angina or atypical chest pain.
SUMMARY Mitral valve prolapse is a condition that is being recognized with increased fre quency. 1t is not known whether its incidence is increasing, or whether we are better. able to diagnose it today. In the idiopathic or familial variety, the mitral valve pathology is almost always that of myxomatous degeneration. Some authors have suggested the presence of a cardiomyopathy because of significant left ventricular dysfunction in many cases. Idiopathic prolapse occurs predominantly in females, often at a young age, and may be associated with chest pain, dyspnea, fatigue, presyncope, syncope, and/or sudden death. The clinical findings are variable and typically consist of a nonejection click and/or late systolic murmur, heard best at the cardiac apex. Diagnosis can be confirmed by echocardiography and/or ventricu lar cineangiography, the latter permitting accurate recognition of the anatomy of the prolapsed leaflets. The complications of infective endocarditis, severe mitral insufficiency, and life-threatening ventricular arrhythmias represent the major prob lems of management. It is important to distinguish the idiopathic form of mitral valve prolapse from that due to coronary artery disease and to realize that mitral valve prolapse may occur in Marfan's syndrome, Turner's syndrome, or in associa-
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tion with secundum atrial septal defect or ruptured chordae tendineae. Typical clicks and/or murmurs have also been described in patients with a history of rheumatic fever and in hypertrophic cardiomyopathy. Although much descriptive knowledge has accumulated over the past 15 years, many unanswered questions remain regarding the idiopathic type of prolapse. What is the nature and cause(s) of myxomatous degeneration? What is the relation of the valve pathology to the left ventricular dysfunction? What is the relation of both of these factors to disabling chest pain, electrocardiographic changes, and life-threatening arrhythmias? Hope fully, answers to these and other important questions regarding mitral valve pro lapse will be forthcoming. ACKNOWLEDGMENT
The authors acknowledge, with great sincerity and appreciation, the very excellent secretarial assistance of Miss Aileen Allbright. Literature Cited I. Cuffer, Barbillon. 1887. Nouvelles re cherches sur Ie bruit de galop. Arch. Med. Gen. Trop. 1:131-49, 301-20 2. Wolferth, C. C., Margolies, A. 1940. Systolic gallop rhythm. Am. Heart J. 19:129-40 3. Gallivardin, L. 1913. Pseudodedouble ment du deuxieme bruit de coeur simu lant Ie dedoublement mitral par bruit extracardique telesystolique surajoute. Lyon Med. 121:409 4. Gallivardin, L. 1932. Nouvelle observa tion avec autopsie d'un pseudodedou blement du 2e bruit de coeur simulant Ie dedoublement mitral. Prot. Med. Fr. 13:19 5. Lian, c., Deparis, M. 1933. Le c1aque ment mesosystolique pleuropericar dique. Dull Mem. Soc. Med. Hop. Paris 49:496 6; Johnston, F. D. 1938. Extra sounds oc curring in cardiac systole. Am. Heart J. 15:221·-31 7. McKusick, V. A., Kline, E. W., Webb, G. N. 1955. Spectral phonocardio graphic demonstrations of selected vari eties of cardiovascular sounds. Am. Heart J. 49:911-33 8. Leatham, A. 1958. Auscultation of the heart. Lancet 2:703-8, 757-66 9. Minhas, K., Gasul, B. M. 1959. Systolic clicks: a clinical phonocardiographic · and hemodynamic evaluation. Am. Heart J. 57:49-65 10. Bleifer, S., Kahn, M., Grishman, A., Donoso, E. 1959. Systolic triple rhythms. Am. J. Cardiol. 4:492-500
II. Humphries, J. 0., McKusick, V. A. 1962. The differentiation of organic and "innocent" systolic murmurs. Prog. Cardiovasc. Dis. 5:152-71 12. Griffith, J. P. C. 1892. Mid-systolic and late systolic mitral murmurs. Am. J. Med. Sci. 104:285-94 13. Hall, J. N. 1903. Late systolic mitral murmurs. Am. J. Med. Sci. 125:663 14. White, P. D. 1931. Heart Disease. New York: MacMillan 15. Reid, J. V. O. 1961. Mid-systolic clicks. S. Afr. Med. J. 35:353-55 16. Barlow, J. B., Pocock, W. A., Mar chand, P., Denny, M. 1963. The signifi cance of late systolic murmurs. Am. Heart J. 66:443-52 17. Hancock, E. W., Cohn, K. 1966. The syndrome associated with mid-systolic click and late systolic murmur. Am. J. Med. 41:183-96 18. Criley, J. M., Lewis, K. B., Humphries, J. 0., Ross, R. S. 1966. Prolapse of the mitral valve: clinical and cineagio graphic findings. Br. Heart J. 28: 488-96 19. Barlow, J. B., Bosman, C. K., Pocock, W. A., Marchand, P. 1968. Late systolic murmurs and non-ejection (mid-late) systolic clicks. Dr. Heart J. 30:203-18 20. Bittar, N., Sosa, J. A. 1968. The billow ing mitral valve leaflet: report on four teen patients. Circulation 38:763-70 21. Fontana, M. E., Pence, H. L., Leighton, R. F., Wooley, L. F. 1970. The varying clinical spectrum of the systolic c1ick late systolic murmur syndrome. Circu lation 41:807-16
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Annu. Rev. Med. 1976.27:165-178. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 01/30/15. For personal use only.
MITRAL VALVE PROLAPSE!
.:.7190
E Douglas Wigle, MD. Division of Cardiology, Toronto General Hospital, and Department of Medicine, University of Toronto, Toronto, Canada M5G lL7
Harry Rakowski, MD. Cardiovascular Unit, Toronto General Hospital, and University of Toronto, Toronto, Canada M5G lL7
Narasimhan Ranganathan, MB.B.S Division of Cardiology, St. Michael's Hospital, and Department of Medicine, University of Toronto, Toronto, Canada M5G IL7
Malcolm D. Silver, MD. Department of Pathology, Toronto General Hospital, and University of Toronto, Toronto, Canada M5G IL7
INTRODUCTION AND HISTORICAL BACKGROUND Mitral valve prolapse is a condition in which one or both mitral valve leaflets prolapse or balloon back into the left atrium during left ventricular systole, and which may or may not be accompanied by mitral regurgitation. Because of the clinical findings, it has also been called the mid-systolic click-late systolic murmur syndrome,mid-systolic click syndrome,or late systolic murmur syndrome; because of the pathological and surgical findings it has also been called the floppy valve syndrome. Cutrer & Barbillon (I) in 1887 first described the "mid-systolic click" (2) as a "bruit de galop mesosystolique." In 1913 and again in 1932 Gallavardin (3, 4) attributed these clicks to pleuropericardial adhesions, thereby influencing several generations of authors to think they were extracardiac in origin and hence "inno cent" (2, 5-11). This thinking prevailed until the early I 9 60s in spite of the fact that Griffith in 189 2 (12), Hall in 1903 (13), and White in 1931 (14) attributed the click and/or late systolic murmur to mitral valve dysfunction. In 1961 Reid (IS) again postulated that the click and murmur were of mitral valve origin, the click or "chordal snap" being due to sudden tautening of previously lax chordae, and the IWork supported by the Ontario Heart Foundation.
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murmur, when present, to mitral regurgitation. In 1963, Barlow et al ( 16) demon strated angiographically the presence of mitral regurgitation in patients with the "click-murmur" syndrome. Subsequently a myriad ( 17- 1 1 1) of reports have con firmed and expanded these observations, and have begun to delineate an evolving syndrome that is still poorly understood in many respects. Indeed, in the past five years the literature on this subject has become as voluminous as the prolapsed leaflets themselves (see section on pathology and pathogenesis, and Figure 1). This fact has dictated that the literature review be selective.
ETIOLOGY AND ASSOCIATED CONDITIONS Mitral valve prolapse or the "click-murmur" syndrome has been described in Mar fan's syndrome ( 16-22), in Turner's syndrome ( 17, 20), in hypertrophic cardi omyopathy ( 19), in patients with a history of acute rheumatic fever (16, 19, 23-26), following mitral commissurotomy ( 19, 26), in coronary artery disease (21, 25-29), as well as in association with ruptured chordae· (30) and secundum atrial septal defect ( 17, 26, 3 1-35). However, the majority of cases are idiopathic (26), and in many instances prolapse occurs in familes ( 17, 21, 23, 26, 35-40), apparently with a Mendelian dominant inheritance (36, 39, 40). Many patients with the idiopathic or familial form of prolapse have thoracic or other skeletal abnormalities reminis cent of Marfan's syndrome (42-44). As a result, some authors have suggested that the idiopathic or familial form of the condition is a forme fruste of Marfan's syndrome (44, 45). This review focuses on the idiopathic or familial condition, but discusses other forms of prolapse where appropriate.
PATHOLOGY AND PATHOGENESIS Myxomatous degeneration of the mitral valve leaflets has been demonstrated in mitral valve prolapse of the idiopathic ( 19, 20, 35, 46-56) and familial type (41), as well as in Marfan's syndrome (22, 54, 57-59) and when prolapse has been associated with secundum atrial septal defect (47). The posterior leaflet is always involved, the anterior leaflet less frequently (47, 53). In a significant percentage of cases the tricuspid valve is involved (47, 60). Involved leaflets (or individual scallops of the posterior leaflet) are voluminous, thickened, and elongated; they present a hooded or domed appearance convex toward the left atrium (Figure 1). The chordae ten dineae are usually elongated and thickened (Figure 1), but may be thinned. A significant proportion of cases show ruptured chordae (19, 47, 49, 52, 53, 55, 56). Thrombi on the valve leaflets have been observed either in the acute angle between the prolapsed posterior leaflet and left atrial wall (unpublished observation by the authors), or over cracks in the endothelial surface (47). Jet lesions in the left atrium as well as enlargement of the atrium and left ventricle occur in cases with a signifi cant degree of mitral regurgitation (47). Microscopy of involved leaflets shows replacement of the central fibrous part by metachromatically staining loose myx omatous material, with fibroelastic thickening of the adjacent endocardium (35, 4 1, 47, 48, 5 1). These myxomatous changes also occur in the mitral annulus and chordae tendineae, with sclerosis also affecting the latter (47, 48). Although myx-
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Figure J Comparison of a sectioned middle scallop from a prolapsed posterior mitral valve leaflet (left) with that from a patient of the same age with a normal leaflet, but left ventricular hypertrophy (right). In the voluminous prolapsed leaflet (left), most of the thickening and lengthening of the leaflet has occurred in the rough zone, into which the elongated thickened chordae insert. Scale in centimeters. [Rep rinted from American Heart Journal (48, p. 539) by permission.] omatous degeneration appears to be the common pathologic basis for mitral valve prolapse, in our present state of knowledge it is perhaps best to think of this type of degeneration as a nonspecific reaction that may be familial or a forme fruste of Marfan's syndrome in some cases, but in others it may be a'result of the abnormal stresses and strains to which the mitral valve is exposed. Indeed, up to 80% of patients with mitral valve prolapse have abnormal left ventricular function (42, 61-68), causing some authors to suggest that the prolapse may be secondary to an ill-understood form of cardiomyopathy (68). The valves of patients with the "c1ick murmur" syndrome and a history of rheumatic fever, or in association with hyper trophic obstructive cardiomyopathy, have not, to our knowledge, been examined pathologically. Mitral valve prolapse can clearly result from coronary artery disease (21, 25-29), and in four such patients postmortem examination demonstrated nor mal mitral leaflets (29). In three there was a healed diaphragmatic myocardial infarct with fibrosis of the posteromedial papillary muscle, while in the fourth there was a healed anterolateral infarct with fibrosis of the anterolateral papillary muscle (29). In such instances prolapse is thought to be a form of papillary muscle dysfunc tion. However, myxomatous degeneration of the mitral valve may coexist with occlusive coronary artery disease (unpublished observation by the authors).
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ANATOMIC-ANGIOGRAPHIC CORRELATIONS Pertinent to mitral valve prolapse and to its angiographic recognition is a recent redefinition of mitral valve anatomy (Figure 2) (49, 69). Both anterior and posterior leaflets have a rough zone at their distal free edge where rough zone chordae tendineae attach. Proximal to this is a clear zone to which no chordae attach. The two leaflets are separated from one another by commissures, into which fan-shaped commissural chordae insert. In 92% of normal human mitral valves the posterior leaflet has a triscalloped structure with a large middle scallop and smaller lateral scallops, termed the posteromedial commissural scallop (next to the posteromedial commissure) and the anterolateral commissural scallop (next to the anterolateral commissure). Fan-shaped chordae tendineae insert into clefts between the scallops of the posterior leaflet. This leaflet has a greater length of insertion into the mitral annulus than does the anterior leaflet, and has basal or "third order" chordae inserting into its base (Figure 2) (49, 69). Many authors have described the angiographic appearance of posterior and an terior mitral leaflet prolapse (11, 18, 20, 23, 35, 36, 38, 48, 53, 61, 62, 70-74). Our own interpretation of the angiographic appearance of prolapse of the posterior leaflet is based on the redefined anatomy of this leaflet (Figures 2 and 3). Thus it is now possible to recognize angiographically prolapse of the individual scallops of
Figure 2 Diagrammatic representation of the normal mitral valve with typical commissural and cleft chordae tendineae attached. A-B anterolateral commissure; B-C anterior leaflet; CoD posteromedial commissure; D-A' posterior leaflet; D E posteromedial commissu ral scallop; E-F middle scallop; F-A' anterolateral commissural scallop; c cleft; pm papillary muscle; tcoc typical commissural chorda; tee typical cleft chorda. Basal or "third order" chordae insert into the basal zone (broken line) of the posterior leaflet. Rough zone chordae of both leaflets insert into the rough zones of these leaflets (cross-hatched areas). The intervening areas of the leaflets are the clear zone, to which no chordae attach. [Reprinted from Circulation (49, p. 459) by permission.] =
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Figure 3 Line diagram of a left ventriculogram in the right anterior oblique projection. The upper continuous and barred line, extending from the posteromedial (PMC) to the anterolat eral commissure (ALC), outlines the prolapsed scallops of the posterior leaflet of the mitral valve. PMCS posteromedial commissural scallop; MS middle scallop; ALCS anterolat eral commissural scallop. For orientation, the locations of the posteromedial papillary muscle (PMPM) and anterolateral papillary muscle (ALPM) have been outlined in the left ventricle (L V) . Their tips usually point toward the respective commissures. Also included is the location of the normal mitral valve ring, shown by the lower dotted and barred lines forming a circle. The barred line represents the posterior mitral ring. Note that the anterior part of the mitral ring (dotted line) has a common attachment with the aortic root (AO). [Reprinted from Circulation (53, p. 514) by permission.] =
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the posterior leaflet of the mitral valve (Figure 3) (48. 53)". In the right anterior oblique left ventricular cineangiogram, prolapse of the middle scallop occurs cen trally overlying the left atrium. whereas prolapse of the posteromedial commissural scallop causes an inferior bulge. and prolapse of the anterolateral commissural scallop causes a superior bulge (Figure 3). Jeresaty (73) , who has based many of his observations on these anatomic findings. believes that when the superior bulge is large it represents prolapse of the anterior leaflet rather than the anterolateral commissural scallop of the posterior leaflet, a point with which we do not agree (74). In our opinion, the size of the superior bulge would be determined by the degree of prolapse of the anterolateral commissural scallop (74). Prolapse of the posterior leaflet occurs in virtually every case (18,35,36,38,53,74). Anterior leaflet prolapse is less common (35. 53). Criteria for the angiographic diagnosis of anterior leaflet prolapse have been described (74) . In the right anterior oblique left ventricular cineangiogram, prolapse of the anterior leaflet often overlaps prolapse of the middle scallop of the posterior leaflet, but the two can be distinguished by the presence of discontinuity in the angiographic outline, as well as by temporal dissociation (74) . The left anterior oblique left ventricular cineangiogram is particularly valuable in documenting anterior leaflet prolapse (74). where its appearance is distinct from the
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cauliflower-like appearance of posterior leaflet prolapse in this view (38) . Using these criteria, we found that of 55 patients with angiographically proven prolapse, 16 had anterior as well as posterior leaflet prolapse. Pathologic proof of combined leaflet prolapse was demonstrated in 5 of these patients (unpublished observations by the authors).
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THE CLINICAL SYNDROME History
Idiopathic or familial mitral valve prolapse occurs predominantly in females and at virtually any age (17, 26, 35) . These patients commonly present with palpitations, presyncope, syncope, chest pain, dyspnea, and/or fatigue (17-19 , 35, 38). The palpitations, presyncope, and syncope can usually be attributed to atrial and/or ventricular arrhythmias (17, 35) . Sudden death has been reported in a number of instances and is presumed due to ventricular arrhythmias (17, 19 ,40,41,48,68) . We have recorded seven instances of ventricular fibrillation as the cause of syncope in these patients. Spontaneous defibrillation was observed in three of four patients with recurrent syncope (Rakowski, H., Wald, R., Waxman, M. B., and Wigle, E. D., unpublished observations). The chest pain may be of several different types; (a) typical angina of effort, (b) unstable angina pectoris, (c) prolonged episodes of atypical anterior chest pain lasting for hours or days and not resembling a or b, or (d) sharp stabbing left chest pain suggestive of cardiac neurosis. Increased arterial systolic pressure can induce the atypical episodes of chest pain, suggesting an imbalance between oxygen supply and demand as the basis for this common symp tom (75) . Dyspnea, fatigue, and evidence of left and right heart failure may result from left ventricular dysfunction (68) or from hemodynamically significant mitral regurgitation (53) . More commonly the dyspnea and fatigue cannot be explained on the basis of hemodynamic abnormalities, nor does controlled exercise testing pro vide objective evidence to explain these symptoms (65) . Cerebral ischemic episodes (76) and neurologic deficits (36,76) may be due to emboli (76) arising from thrombi on the mitral leaflets (47) . A number of patients with idiopathic prolapse are asymptomatic and come to cardiological attention because of abnormal findings on physical examination. Physical Examination EXTRACARDIAC In some series (42--44, 65) , up to 70% of patients with mitral valve prolapse have thoracic skeletal abnormalities suggestive of a forme fruste of Marfan's syndrome: pectus excavatum, straight back syndrome, scoliosis, or narrow anteroposterior diameter of the chest. Many patients, however, have no such stig mata.
In the typical case, the heart is not enlarged and abnormalities on physical examination are restricted to auscultation at the cardiac apex, where a mid-systolic click and/or late systolic murmur are heard. The clicks may be multiple (15, 17,36,38,77) and may occur in early (17,78,79 ) ,mid (15, 17,36) or late (17,
CARDIAC
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19, 38) systole. They usually initiate the murmur but may occur in the middle or towards the end of it. Because of the variable timing of the clicks, they should not all be termed mid-systolic, but rather nonejection clicks (19), to distinguish them from the ejection variety. Although the earliest click vibrations occur shortly after the onset of prolapse (80), the loudest vibrations coincide with maximal prolapse of the leaflets (18) and have been ascribed to a tautening of the lax chordae (chordal snap) (IS) or to the leaflets themselves (18), similar to an opening snap in mitral stenosis (28). Multiple clicks may be due to asynchronous prolapse of either the leaflets or individual scallops of the posterior leaflet, or to asynchronous chordal tautening (unpublished observations by the authors). The murmur is most com monly late systolic and crescendo, or crescendo-decrescendo, up to and beyond aortic valve closure (17, 19, 24, 37, 77). In cases with more severe degrees of mitral regurgitation the murmur is usually pansystolic, sometimes with late systolic accen tuation. Intracardiac phonocardiography has shown that the click and murmur arise in the mitral area and radiate into the left atrium (18, 24, 37, 77). The murmur and click may also be recorded in the inflow tract of the left ventricle (19, 70). A late systolic murmur may have an early systolic component (24). Intraatrial sound recordings, as well as other studies, have demonstrated that precordial "honks" or "whoops" are usually due to mitral valve prolapse (19, 21, 24, 37, 81, 82). Although a systolic retraction coincident with the click of prolapse can be recorded by apex cardiography (83-86), this phenomenon is rarely appreciated on palpitation. A number of patients with angiographically documented prolapse have no abnormali ties on physical examination. Some, but not all, will manifest a click and/or murmur with various provocative maneuvers, such as standing (19, 21). This is important to realize because patients may have symptoms attributable to prolapse, but no clinical evidence of it. In such patients echocardiography and/or angiography are required for an accurate diagnosis. It is important to indicate that systolic clicking sounds have been heard in mediastinal emphysema (87) and left-sided pneumo thorax (88, 89). Systolic clicks have also been reported in aneurysms of the membra nous ventricular septum (90, 91). Whether they can also be attributed to pericardial (I1) or pleuropericardial (3, 4) adhesions is in some doubt at this time. Patients with mitral valve prolapse due to coronary artery disease tend to be older and male; they usually manifest a loud first heart sound and third and fourth heart sounds, in addition to a late systolic murmur, with or without a nonejection click (21, 25-29). Inspiration accentuates these findings (29). In the click-murmur syn drome following mitral commissurotomy, the click occurs in early systole and the apical murmur is longer (19). We have recently noted the preoperative occurrence of prolapse associated with mitral stenosis in five patients. In four the prolapse was visualized angiographically, and in two it was recognized clinically by the presence of a click in one patient, and a pansystolic murmur with late systolic accentuation in the second (unpublished observations by the authors). The occurrence of mitral valve prolapse in association with secundum atrial septal defect is well recognized (17, 26, 31-35, 47) and occurs in about 40% of cases (34). Half of these cases had clinically silent prolapse and in the remainder an apical pansystolic murmur was the commonest finding indicating prolapse (34). This combination must be distin-
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guished from primum atrial septal defect, in which left axis deviation in the elec trocardiogram is virtually diagnostic. VARIABILITY OF SIGNS Tremendous interest has centered on maneuvers that alter the timing and intensity of the click and murmur (6, 16-21, 61, 80, 92-94). Amyl nitrite inhalation causes the click to move earlier in systole and the murmur to lengthen, sometimes becoming pansystolic (16, 17, 19, 20, 80,92). Soon after inhalation, the murmur becomes fainter (16, 17), but later it becomes louder (l6). The strain period of the Valsalva maneuver also causes the click and murmur to move to early systole (16, 19, 92). Sitting or standing causes a click, murmur, or honk to appear when not present in the supine position, and causes clicks and murmurs to occur earlier in systole (19, 21, 61, 92). Murmurs also become louder (19, 21, 61, 92). Squatting reverses the changes brought about by standing (21). Right atrial pacing tends to move the clicks and murmurs to early systole (94). Infusion of pressor amines either does not change the timing of the click, or causes it to disappear while accentuating the late systolic murmur (16, 19, 93). Many of these variations have been attributed to changes in left ventricular volume in the presence of elongated chordae tendineae (16, 19-21, 80, 93). Thus when left ven tricular volume decreases,the chordae are relatively longer and permit earlier and greater prolapse to occur, accounting for the altered clinical findings. Cineangiogra phy has demonstrated a greater degree of prolapse following amyl nitrite inhalation (20) and in the 45° head-up tilt position (93). A recent suggestion is that changes in left ventricular contractility or ejection rate, rather than altered ventricular volume,account for the variability in the degree of prolapse and in the accompa nying clinical signs (94).
Laboratory Investigation ELECTROCARDIOGRAM AND VECTORCARDIOGRAM Many patients with mi tral valve prolapse have a normal electrocardiogram and vectorcardiogram, but a very significant percentage manifest definite abnormalities in the absence of coro nary artery disease ( l 7, 26, 35, 36, 38,40, 61, 65, 68, 71, 79, 92, 95-98). The most characteristic change is ST segment change,and T-wave inversion in leads II,III, AVF, V5, and V6, suggesting inferolateral ischemia (17, 36). These abnormalities are sometimes accompanied by tall, peaked T-waves in leads V2 and V3. Others have reported T-wave inversions in the anterior (precordial) leads (35, 68, 79, 97). Q-waves suggestive of both inferior (36, 48, 68, 92, 98) and anterior (68, 95, 98) myocardial infarction have been observed. The explanation of these abnormalities is not known but myocardial and/or papillary muscle ischemia has been suggested (26). Papillary muscle fibrosis has been demonstrated in one patient showing these electrocardiographic abnormalities (48). Prolonged Q-T intervals (17, 34, 65), and prominent U-waves (17, 65) have also been noted. Nearly every conceivable arr hythmia and conduction defect has been recorded in these patients, and exercise electrocardiograms have revealed ischemic ST segment depressions in a significant number (68, 79, 92, 95, 96). Left ventricular hypertrophy has been reported both in the presence of significant mitral regurgitation and in its absence (38,53, 65, 95).
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ARRHYTHMIAS Cardiac rhythm disturbances can account both for the symptoms of palpitations, presyncope, and syncope, and for the occurrence of sudden death in this syndrome. Atrial,junctional,and ventricular arrhythmias of most types have been clearly documented at rest (17, 26, 35, 65, 68, 95, 96, 99, 1(0),during exercise (26, 65, 68, 95, 96, 99, 1(0), in the post-exercise period (26, 65, 95, 96, 1(0), and by ambulatory monitoring (35, 79, 9 9 ; 1(0). Criley has suggested that the atrial arrhythmias may arise from systolic stretch of the valve leaflets and that the ven tricular arrhythmias may result from the "diastolic dumping" of the blood held under the prolapsed leaflets in systole (100). The prolonged Q-T interval may predispose to the occurrence of ventricular arrhythmias (17), but the latter may occur in the absence of Q-T prolongation (26, 95). The fact that the click often coincides with the peak of the T-wave indicates that the mechanical force of the prolapse itself might incite a ventricular arrhythmia. Serious ventricular arrhyth mias occur in the absence of resting electrocardiographic abnormalities (26). Bra dyarrhythmias, including all degrees of heart block, occur in these patients but are relatively rare (68, 1(0). ECHOCARDIOGRAPHY Two basic types of echocardiographic abnormalities have been described in patients with mitral valve prolapse (101-10 5): ( a ) mid systolic "buckling" associated with mid-systolic prolapse, and (b) pansystolic "hammocking" associated with pansystolic prolapse. Another echocardiographic abnormality, "pansystolic collapse," has been described (105). In essence, all of these findings record the prolapse of one or both mitral leaflets into the left atrium during systole. Single-beam echocardiography probably strikes the middle scallop of the posterior leaflet, as well as the anterior leaflet. Prolapse of the posteromedial and/or anterolateral scallop could therefore be missed (unpublished observations by the authors). For this and other reasons,left ventricular cineangiography remains the standard for the definitive diagnosis of mitral valve prolapse, even though the echocardiographic diagnosis of prolapse represents a tremendous advance. RADIOLOGICAL EXAMINATION Frontal and lateral chest X rays usually re veal a normal heart size and, frequently, thoracic skeletal abnormalities (42-44). Left atrial and ventricular enlargement occurs in the presence of hemodynamically significant mitral regurgitation (53, 68). Left ventricular cineangiography permits assessment of the anatomy of the leaflet prolapse (see section on anatomic-angio graphic correlations), the degree of mitral regurgitation, and left ventricular func tion. The mitral regurgitation may vary from being absent to severe and may begin at the onset of systole in pansystolic prolapse, or in mid-systole in mid-systolic prolapse. Various abnormalities of left ventricular function in systole and diastole have been described in up to 82% of patients studied (42, 61-68). The commonest abnormalities in systole are: (a) an inferior contraction ring (42,62,65),which may occur alone or be associated with increased (42) or decreased (42,65,67) contraction of the anterior wall; (b) decreased contraction or expansion of the anterior wall alone (65, 67, 68); (c) generalized hypokinesis (68); (d) hypokinesis of the in ferobasal segment (42, 66), with poor contraction (66) or expansion of the mitral
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annulus (63, 66), sometimes associated with basal displacement of the tip of the posteromedial papillary muscle (66); (e) decreased shortening of the long axis of the ventricle (42, 65, 68); or (f) cavity obliteration (42, 64). Early diastolic relaxation, particularly of the anterior wall, has been a frequent finding (42, 65, 67, 68). The ejection fraction may be normal, increased, or decreased, depending on the degree of left ventricular dysfunction and mitral regurgitation (68). The evidence of left ventricular dysfunction has caused some workers to suggest that patients with mitral prolapse may have a cardiomyopathy (68). However, left ventricular function has been normal in some patients with documented prolapse (34, 42, 65). Tricuspid valve prolapse has been observed angiographically in up to 54% of patients with mitral prolapse (42,106). Selective coronary arteriograms are normal in individuals with idiopathic or familial prolapse, but may demonstrate an unduly tortuous or "corkscrew" appearance (42, 79). Coronary arteriograms in patients with prolapse due to coronary artery disease usually demonstrate severe obstructive lesions (29). HEMODYNAMICS Intracardiac pressures and flow are usually normal in the ab sence of significant left ventricular dysfunction or mitral regurgitation. In the pres ence of either, however, left ventricular end-diastolic pressure may rise and cardiac
index may be reduced
(68).
With significant mitral �egurgitation the left atrial
V-wave may rise significantly (53).
COMPLICATIONS A number of life-threatening complications may occur in patients with mitral valve prolapse. Those with serious ventricular arrhythmias (particularly ventricular tachycardia and fibrillation) are prone to recurrent presyncope, syncope, and sudden death. Infective endocarditis has been well documented (23,40, 45, 47,54,56,107, 108). Chordae tendineae may rupture from the myxomatous degeneration, or from infective endocarditis, producing severe mitral regurgitation, left and right heart failure, and the need for mitral valve replacement. Emboli can arise from the bland thrombi that may form on the valves of these patients.
NATURAL HISTORY AND PROGNOSIS Several reports have suggested that the clinical course of patients with mitral valve prolapse is usually benign (56,109). In one report (109), 62 patients were followed an average of 14 years. Forty-one were unchanged, ten had slight deterioration, and the remainder either developed infective endocarditis, severe mitral regurgitation, or were lost to follow-up. Patients with cardiac enlargement, abnormal electrocardi ograms, and chest pain resembling angina were excluded from this study (109). In contrast with this relatively benign course are the many reports of sudden death (17, 19,40,41,48,68),the onset of heart failure from mitral regurgitation requiring valve replacement (50,56),the occurrence of infective endocarditis (23,40,45,47,54,56, 107, 108), and reports of continued disability with nonlethal arrhythmias, chest pain, dyspnea, and fatigue. Obviously, the natural history can vary tremendously,
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and this presents a challenge in medical care today. It is important not to induce a cardiac neurosis in these patients with too much concern, while at the same time dealing appropriately with the complications known to occur, particularly life threatening ventricular arrhythmias.
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MANAGEMENT To prevent infective endocarditis, patients with mitral valve prolapse require antibi otic prophylaxis at appropriate times. The treatment of endocarditis should be according to the antibiotic sensitivities of the infective agent. The development of heart failure from significant mitral regurgitation requires appropriate antifailure therapy initially and may require subsequent mitral valve replacement. A number of reports have stressed a high incidence of valve dehiscence in patients treated surgically (45, 55, 56, 110), presumably because of myxomatous change in the annulus. The insertion of deep, interrupted sutures has been recommended to avoid this complication (56). The greatest problem in management is the control of life-threatening ventricular arrhythmias. ,8-Adrenergic blocking agents appear to be the drugs of choice, but are not universally efficacious, requiring the additional or sole use of other antiarrhythmic agents. It has been suggested that the mitral valve be replaced to control particularly persistent ventricular arrhythmias, but the long term value of this aggressive form of therapy is not known (Il l). Five years ago we replaced the mitral valve in one patient with recurrent ventricular fibrillation who also had severe mitral regurgitation. Ventricular fibrillation has not recurred, but the patient has required continued antiarrhythmic therapy (A. G. Adelman, unpub lished observation). ,8-Adrenergic blocking agents have also been of value in the management of patients with angina or atypical chest pain.
SUMMARY Mitral valve prolapse is a condition that is being recognized with increased fre quency. 1t is not known whether its incidence is increasing, or whether we are better. able to diagnose it today. In the idiopathic or familial variety, the mitral valve pathology is almost always that of myxomatous degeneration. Some authors have suggested the presence of a cardiomyopathy because of significant left ventricular dysfunction in many cases. Idiopathic prolapse occurs predominantly in females, often at a young age, and may be associated with chest pain, dyspnea, fatigue, presyncope, syncope, and/or sudden death. The clinical findings are variable and typically consist of a nonejection click and/or late systolic murmur, heard best at the cardiac apex. Diagnosis can be confirmed by echocardiography and/or ventricu lar cineangiography, the latter permitting accurate recognition of the anatomy of the prolapsed leaflets. The complications of infective endocarditis, severe mitral insufficiency, and life-threatening ventricular arrhythmias represent the major prob lems of management. It is important to distinguish the idiopathic form of mitral valve prolapse from that due to coronary artery disease and to realize that mitral valve prolapse may occur in Marfan's syndrome, Turner's syndrome, or in associa-
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tion with secundum atrial septal defect or ruptured chordae tendineae. Typical clicks and/or murmurs have also been described in patients with a history of rheumatic fever and in hypertrophic cardiomyopathy. Although much descriptive knowledge has accumulated over the past 15 years, many unanswered questions remain regarding the idiopathic type of prolapse. What is the nature and cause(s) of myxomatous degeneration? What is the relation of the valve pathology to the left ventricular dysfunction? What is the relation of both of these factors to disabling chest pain, electrocardiographic changes, and life-threatening arrhythmias? Hope fully, answers to these and other important questions regarding mitral valve pro lapse will be forthcoming. ACKNOWLEDGMENT
The authors acknowledge, with great sincerity and appreciation, the very excellent secretarial assistance of Miss Aileen Allbright. Literature Cited I. Cuffer, Barbillon. 1887. Nouvelles re cherches sur Ie bruit de galop. Arch. Med. Gen. Trop. 1:131-49, 301-20 2. Wolferth, C. C., Margolies, A. 1940. Systolic gallop rhythm. Am. Heart J. 19:129-40 3. Gallivardin, L. 1913. Pseudodedouble ment du deuxieme bruit de coeur simu lant Ie dedoublement mitral par bruit extracardique telesystolique surajoute. Lyon Med. 121:409 4. Gallivardin, L. 1932. Nouvelle observa tion avec autopsie d'un pseudodedou blement du 2e bruit de coeur simulant Ie dedoublement mitral. Prot. Med. Fr. 13:19 5. Lian, c., Deparis, M. 1933. Le c1aque ment mesosystolique pleuropericar dique. Dull Mem. Soc. Med. Hop. Paris 49:496 6; Johnston, F. D. 1938. Extra sounds oc curring in cardiac systole. Am. Heart J. 15:221·-31 7. McKusick, V. A., Kline, E. W., Webb, G. N. 1955. Spectral phonocardio graphic demonstrations of selected vari eties of cardiovascular sounds. Am. Heart J. 49:911-33 8. Leatham, A. 1958. Auscultation of the heart. Lancet 2:703-8, 757-66 9. Minhas, K., Gasul, B. M. 1959. Systolic clicks: a clinical phonocardiographic · and hemodynamic evaluation. Am. Heart J. 57:49-65 10. Bleifer, S., Kahn, M., Grishman, A., Donoso, E. 1959. Systolic triple rhythms. Am. J. Cardiol. 4:492-500
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