- Email: [email protected]
Mitral valve prolapse
I’OLI JME
The
American
Journal
(37,
NIJMBER
5
NOVI:h;lHl3R
1979
of Medicine@ EDITORIAL
Mitral Valve Prolapse RICHARD
I an
B. DEVEREUX,
n the past 15 years mitral valve prolapse has become extraordinarily common finding in clinical practice [l-3]. Many symptomatic patients and an even larger number of asymptomatic persons are found to have a mid-systolic click, with or without a late systolic murmur, or an echocardiogram that is diagnostic of mitral valve prolapse. Initially, the ability to detect mitral prolapse advanced more rapidly than did knowledge of the nature and significance of this entity. This problem was compounded by uncertainty as to whether or not patients with prolapse detected by auscultation, echocardiography and cardiac angiography had, in fact, the same entity and by even more serious questions concerning the relation of clinically detected mitral prolapse to the pathologist’s “floppy” valve. Now, however, numerous studies [4-121 are narrowing the gap between our ability to diagnose mitral valve prolapse easily and our hitherto uneven understanding of its anatomic, laboratory and clinical features. The clinical impression of mitral valve prolapse’s ubiquity is supported by its prevalence in the population. Auscultatory, echocardiographic [4] and autopsy [5] studies all indicate that 5 per cent or more of the population is affected: although clinical expression is most common in young women, actual anatomic cleformity of the mitral valve is equally common in both sexes, and increases in frequency and severity with advancing age [5]. In contrast, the frequency of mitral valve prolapse has varied remarkably from one angiographic study to another, ranging from 1 to 43 per cent-reflecting methodologic diversity. A recent report by Cohen et al. [S] indicates that the angiographic diagnosis of mitral valve prolapse is much more accurate when the point of attachment of the posterior mitral leaflet to the anulus is identified on the right anterior oblique angiogram, and the diagnosis is made only when the posterior leaflet protrudes inferiorly to this fulcrum. All 21 patients with the diagnosis of mitral valve pro-
M.D.
lapse by this approach also had compatible findings by both auscultation and echocardiography. However, such 100 per cent concordance between methods of diagnosis is not the general rule. Most investigators find that roughly 10 per cent of patients with a typical mid-systolic click do not have prolapse on echocardiography and vice versa. Extensive evidence, including clinicopathologic correlation in numerous patients, indicates that most patients with mitral valve prolapse have anatomically “floppy” valves [2-3,5,7]. The essential anatomic fault is disruption of the valve’s central collagenous layer, the fibrosa, with microscopically visible fragmentation of collagen bundles and secondary but apparently nonspecific accumulation of acid mucopolysaccharides (51. Characteristically, the affected leaflets are voluminous. At autopsy, grossly visible prolapse most often involves one or more scallops of the posterior mitral leaflet, but it may also involve the anterior leaflet; the same process may allow elongation of chordae tendineac and dilatation of the mitral anulus. The tendency for anatomic mitral valve prolapse to be both more common and more severe with advancing age has been reasonably explained as reflecting slow stretching of the wcakonocl valves by repetitive hemodynamic stress with each heart beat [5]. Similar changes may also bc seen in the tricuspid valve and, rarely, in the aortic valve. The finding of abnormalities of the Irony thor;lxpcctus excavatum, scoliosis or loss of normal kyphosis of the thoracic spine--in a rnajority of patients with mitral valve prolapse has provided suggestive evidence of a more generalized disorder of conncctivt: tissue [3]. On the basis of numerous published family histories and a few small echocardiographic studies, it has been accepted that mitral prolapse is a dominantly inherited condition [8]. This pattern of inheritance would be compatible with a defect in a structural protein such as collagen. However, the fact that the thoracic bony ab-
From the Depurtment of Medicine, Division ofCardiology, The Nmv York flospitol-Cornell Meti~ctrl Center, New York, New York. Requests for reprints should be addressed to Dr. Richurtl H. Devrrcur, IIepartment of Medicine, Division of Cardiology, The New York ffrqlitul-Cord1 Metlicd Cer~t~r, 525E:ust 66th Street, New York, New York 111021.
November 1979
The American Journal of Medicine
Volume 67
729
normalities are not uniformly present indicates that patients with mitral valve prolapse may be etiologically heterogeneous. The report by Hammer et al. [13] in this issue of the IournaJ represents the first evidence of a biochemical defect in mitral valve prolapse. Types III and AB collagen could not be detected in the solubilized collagen from the mitral valve of one patient with mitral valve prolapse, but they were normally present in the valves of five other patients with prolapse. Although these preliminary data cannot distinguish between actual absence of type III and AB collagen, or a profound al‘teration in either their solubility or electrophoretic character, they suggest that at least some instances of mitral valve prolapse represent a true collagen disease. Of no less importance, the normal collagen comppsition of other prolapsed mitral valves provides evidence that the heterogeneity of miiral valve prolapse may extknd to a molecular level as well. Only further study will determine if these results provide an important clue to the etiology of mitral valve prolapse in sign&cant numbers of patients or, alternatively, if they are the first evidence of an uncommon entity which, like several types of the Ehlers-Danlos syndrome, is due to a collagen deficiency and has mitral valve prolapse as one of its manifestations. The mountink evidence of anatomic defects in mitral valve prolapse is complemented by an increasing understanding pf associated functional abnormalities. Because normal function of the mitral valve requires delicately coordinated action of its components-the leaf&, chordae, an&s, papillary muscles and the supporting left ventricular myocardium-it is not only the absolute redundancy of leaflets which causes prolapse, but also their relative redundancy compared to the size of the left ventricle [3]. Thus, Towne et al. [9] recently show&d that progressive passive head-up tilt, a maneuver which decreases venous return and hence shrinks left ventricular size, caused a mid-systolic click to move earlier in systole in most of their i8 patients, whereas augmentation of prolapse allowed a new systolic murmur to appear in two subjects. Under most circumstances such dynamic variations in left ventricular geometry continuously modtilate the auscultatoFy and, quite likely, echocardiographic expression of the aforementioned anatomic abnormalities. Occasionally, however, marked distortion pf left ventricular size and shape ma,kes it possible for normal leaflets to prolapse. The clearest de’monstration of this has been proSided by Weyman et al. [lo]in a longitudinal study using two-dimensional echocardiography in 14 patients with ostium secundum atria1 septal defect, of whom seven’@ per cent] had unequivocal prolapse on echocardiography. Following surgical correction of the atria1 septal defect and the resultant increase in left ventricular filling, mitral prolapse disappeared or became much less marked in six, and persisted unchanged
730
November 1979 The American Journal of Medicine
in only one (7 per cent] of the entire group. The proportion with persistent prolapse among their patients is strikingly similar to that found in other, unselected, populations. It is important to point out that many patients with such laboratory evidence of mitral leaflet prolapse in the presence of atria1 septal defect or extensive left ventricular contraction abnormalities due to coronary artery disease do not have either a typical click or murmur, or other common features such as abnormalities of the bony thorax. These instances may be more accurately thought of as mimicking the mitral valve prolapse syndrome than as comprising part of its spectrum [2]. A clearer picture of the long-term course of mitral valve prolapse is emerging from a variety of sources. Groups of patients who had sufficiently alarming symptoms or physical findings to have been sent to referral centers in the years before the accurate diagndsis of niitral valve prolapse could be made, exhibit a !ow, but cumulatively significant, rate of morbidity. For example, Mills et al. [ll]reported on 53 patients followed an average of 14 years: death in two patients and significant complications, including bacterial endocarditis, progressive mitral regurgitation and ventricular fibrillation, in six others were considered to be related to the valvular abnormality, whereas the remaining 45 remained unaffected. Patients with a late systolic murmur were more likely to suffer morbid events than those wjth a mid-systolic click alone. This finding suggests that the likelihood of complications is greate: in patients with more marked valvular deformity, but it may also qean that some patients with other, more dangerous causes of late systolic mitral regurgitation have been lumped with those with mitral valve prolapse, both in this study and in clinical practice [2]. The conclusion that mitral valve prolapse is relatively benign is supported by the finding in a large, unselected autopsy series by Davies et al. [5] that nearly three quarters of the deaths attributed to “floppy” mitral valves occurred in patients over the age of 70years. Nevertheless, it is clearly appropriate to recommend antibiotic prophylaxis to prevent infective endocarditis, at least for all patients who even intermittently have a murmur of mitral regurgitation, atid to treat the malignant arrhythmias which occur in a small minority of patients and which may respond only to investigational drugs [12]. Despite the advances which have been made, many problems remain unresolved. Only the barest beginning has been made in elucidating the etiology of mitral valve prolapse and in defining its molecular abnormalities. The marked variability of clinical and laboratory findings of mitral valve prolapse between patients and from day to day in individual patients requires explanation. Much additional information concerning the clinical course and prognosis is awaited from the sever?1 ongoing prospective studies of this disorder. Only when the problems concerning the etiology, expression and
Volume 67
clinical impact of mitral valve prolapse have been resolved will it be possible to advise patients with complete accuracy as to the significance of their condition or what treatment may be required.
6.
7.
8.
REFERENCES [~xlc~wIB, Pocock WA: Mitral valve prolapse,
the specific liillowing mitral leaflet syndrome, or an insignificant non-ejection systolic click. Am Heart J 97: 277, 1979. Jcr;;;~ RM: Mitral Valve Prolapse, New York, Raven Press, Dcvereux RB, Perloff JK. Rcichek N, et al.: Mitral valve prolapse. Circulation 54: 3. 1976. l)arsce JR, Mikolich JR;Nicoloff NB. et al.: Prevalence of mitral valve prolapse in presumably healthy young men. Circulation 59: 619, 1979. Davies MJ. Moore PH. Braimbridge MV: The floppy mitral valve. Study of incidence, pathology, and complications in surgical, necropsy and forensic material. Br Heart J 40: 468. 1978.
9.
10.
11. 12.
13.
Cohen MV, Shah PK, Spindola-Franc0 H: .4ngiographicechocardiographic correlation in mitral valve prolapse. Am flcort J 97: 43, 1979. Gttthrie RB. Edwards JE: Pathology of the myxomatous mitral valve. Nature, secondary changes and complications. Minn Mcd 59: 637 1976. McKusick VA: Mcntlelinn Inheritance in Men. 5th cd, Baltimore Johns Hopkins [Jnivcrsity Press. 1978. p 259. Towne WD, Pate1 R, Cruz J, Kramer N. et al.: Effects of gravitational stress on mitral valve prolapse. Br Heart J 40: 482. 1978. Schreiber T, Feigenbaum H, Weyman AE. et al.: Effects of atrial septal defect repair on left ventricular geometry and degree of mitral valve prolapse. Circulation (in press]. Mills PB, Rose J, Hollingsworth J. et al.: Long-term prognosis of mitral valve prolapse. N Engl J Med 297: 13, 1977. Wci JY. Bulkley BH , Schaeffcr AH, et al.: Mitral valve proIapsc syndrome and recurrent ventricular tachyarrhythmins. Ann Intern Mcd 89: 6. 1978. Hammer D. Leier CV. Baba N. et al.: Altered collagen composition in a prolapsing mitral valve with ruptured chordae tendineae. Am J Med 67: 863,1979.
November 1979 The American Journal of Medicine
Volume 67
731
The
American
Journal
(37,
NIJMBER
5
NOVI:h;lHl3R
1979
of Medicine@ EDITORIAL
Mitral Valve Prolapse RICHARD
I an
B. DEVEREUX,
n the past 15 years mitral valve prolapse has become extraordinarily common finding in clinical practice [l-3]. Many symptomatic patients and an even larger number of asymptomatic persons are found to have a mid-systolic click, with or without a late systolic murmur, or an echocardiogram that is diagnostic of mitral valve prolapse. Initially, the ability to detect mitral prolapse advanced more rapidly than did knowledge of the nature and significance of this entity. This problem was compounded by uncertainty as to whether or not patients with prolapse detected by auscultation, echocardiography and cardiac angiography had, in fact, the same entity and by even more serious questions concerning the relation of clinically detected mitral prolapse to the pathologist’s “floppy” valve. Now, however, numerous studies [4-121 are narrowing the gap between our ability to diagnose mitral valve prolapse easily and our hitherto uneven understanding of its anatomic, laboratory and clinical features. The clinical impression of mitral valve prolapse’s ubiquity is supported by its prevalence in the population. Auscultatory, echocardiographic [4] and autopsy [5] studies all indicate that 5 per cent or more of the population is affected: although clinical expression is most common in young women, actual anatomic cleformity of the mitral valve is equally common in both sexes, and increases in frequency and severity with advancing age [5]. In contrast, the frequency of mitral valve prolapse has varied remarkably from one angiographic study to another, ranging from 1 to 43 per cent-reflecting methodologic diversity. A recent report by Cohen et al. [S] indicates that the angiographic diagnosis of mitral valve prolapse is much more accurate when the point of attachment of the posterior mitral leaflet to the anulus is identified on the right anterior oblique angiogram, and the diagnosis is made only when the posterior leaflet protrudes inferiorly to this fulcrum. All 21 patients with the diagnosis of mitral valve pro-
M.D.
lapse by this approach also had compatible findings by both auscultation and echocardiography. However, such 100 per cent concordance between methods of diagnosis is not the general rule. Most investigators find that roughly 10 per cent of patients with a typical mid-systolic click do not have prolapse on echocardiography and vice versa. Extensive evidence, including clinicopathologic correlation in numerous patients, indicates that most patients with mitral valve prolapse have anatomically “floppy” valves [2-3,5,7]. The essential anatomic fault is disruption of the valve’s central collagenous layer, the fibrosa, with microscopically visible fragmentation of collagen bundles and secondary but apparently nonspecific accumulation of acid mucopolysaccharides (51. Characteristically, the affected leaflets are voluminous. At autopsy, grossly visible prolapse most often involves one or more scallops of the posterior mitral leaflet, but it may also involve the anterior leaflet; the same process may allow elongation of chordae tendineac and dilatation of the mitral anulus. The tendency for anatomic mitral valve prolapse to be both more common and more severe with advancing age has been reasonably explained as reflecting slow stretching of the wcakonocl valves by repetitive hemodynamic stress with each heart beat [5]. Similar changes may also bc seen in the tricuspid valve and, rarely, in the aortic valve. The finding of abnormalities of the Irony thor;lxpcctus excavatum, scoliosis or loss of normal kyphosis of the thoracic spine--in a rnajority of patients with mitral valve prolapse has provided suggestive evidence of a more generalized disorder of conncctivt: tissue [3]. On the basis of numerous published family histories and a few small echocardiographic studies, it has been accepted that mitral prolapse is a dominantly inherited condition [8]. This pattern of inheritance would be compatible with a defect in a structural protein such as collagen. However, the fact that the thoracic bony ab-
From the Depurtment of Medicine, Division ofCardiology, The Nmv York flospitol-Cornell Meti~ctrl Center, New York, New York. Requests for reprints should be addressed to Dr. Richurtl H. Devrrcur, IIepartment of Medicine, Division of Cardiology, The New York ffrqlitul-Cord1 Metlicd Cer~t~r, 525E:ust 66th Street, New York, New York 111021.
November 1979
The American Journal of Medicine
Volume 67
729
normalities are not uniformly present indicates that patients with mitral valve prolapse may be etiologically heterogeneous. The report by Hammer et al. [13] in this issue of the IournaJ represents the first evidence of a biochemical defect in mitral valve prolapse. Types III and AB collagen could not be detected in the solubilized collagen from the mitral valve of one patient with mitral valve prolapse, but they were normally present in the valves of five other patients with prolapse. Although these preliminary data cannot distinguish between actual absence of type III and AB collagen, or a profound al‘teration in either their solubility or electrophoretic character, they suggest that at least some instances of mitral valve prolapse represent a true collagen disease. Of no less importance, the normal collagen comppsition of other prolapsed mitral valves provides evidence that the heterogeneity of miiral valve prolapse may extknd to a molecular level as well. Only further study will determine if these results provide an important clue to the etiology of mitral valve prolapse in sign&cant numbers of patients or, alternatively, if they are the first evidence of an uncommon entity which, like several types of the Ehlers-Danlos syndrome, is due to a collagen deficiency and has mitral valve prolapse as one of its manifestations. The mountink evidence of anatomic defects in mitral valve prolapse is complemented by an increasing understanding pf associated functional abnormalities. Because normal function of the mitral valve requires delicately coordinated action of its components-the leaf&, chordae, an&s, papillary muscles and the supporting left ventricular myocardium-it is not only the absolute redundancy of leaflets which causes prolapse, but also their relative redundancy compared to the size of the left ventricle [3]. Thus, Towne et al. [9] recently show&d that progressive passive head-up tilt, a maneuver which decreases venous return and hence shrinks left ventricular size, caused a mid-systolic click to move earlier in systole in most of their i8 patients, whereas augmentation of prolapse allowed a new systolic murmur to appear in two subjects. Under most circumstances such dynamic variations in left ventricular geometry continuously modtilate the auscultatoFy and, quite likely, echocardiographic expression of the aforementioned anatomic abnormalities. Occasionally, however, marked distortion pf left ventricular size and shape ma,kes it possible for normal leaflets to prolapse. The clearest de’monstration of this has been proSided by Weyman et al. [lo]in a longitudinal study using two-dimensional echocardiography in 14 patients with ostium secundum atria1 septal defect, of whom seven’@ per cent] had unequivocal prolapse on echocardiography. Following surgical correction of the atria1 septal defect and the resultant increase in left ventricular filling, mitral prolapse disappeared or became much less marked in six, and persisted unchanged
730
November 1979 The American Journal of Medicine
in only one (7 per cent] of the entire group. The proportion with persistent prolapse among their patients is strikingly similar to that found in other, unselected, populations. It is important to point out that many patients with such laboratory evidence of mitral leaflet prolapse in the presence of atria1 septal defect or extensive left ventricular contraction abnormalities due to coronary artery disease do not have either a typical click or murmur, or other common features such as abnormalities of the bony thorax. These instances may be more accurately thought of as mimicking the mitral valve prolapse syndrome than as comprising part of its spectrum [2]. A clearer picture of the long-term course of mitral valve prolapse is emerging from a variety of sources. Groups of patients who had sufficiently alarming symptoms or physical findings to have been sent to referral centers in the years before the accurate diagndsis of niitral valve prolapse could be made, exhibit a !ow, but cumulatively significant, rate of morbidity. For example, Mills et al. [ll]reported on 53 patients followed an average of 14 years: death in two patients and significant complications, including bacterial endocarditis, progressive mitral regurgitation and ventricular fibrillation, in six others were considered to be related to the valvular abnormality, whereas the remaining 45 remained unaffected. Patients with a late systolic murmur were more likely to suffer morbid events than those wjth a mid-systolic click alone. This finding suggests that the likelihood of complications is greate: in patients with more marked valvular deformity, but it may also qean that some patients with other, more dangerous causes of late systolic mitral regurgitation have been lumped with those with mitral valve prolapse, both in this study and in clinical practice [2]. The conclusion that mitral valve prolapse is relatively benign is supported by the finding in a large, unselected autopsy series by Davies et al. [5] that nearly three quarters of the deaths attributed to “floppy” mitral valves occurred in patients over the age of 70years. Nevertheless, it is clearly appropriate to recommend antibiotic prophylaxis to prevent infective endocarditis, at least for all patients who even intermittently have a murmur of mitral regurgitation, atid to treat the malignant arrhythmias which occur in a small minority of patients and which may respond only to investigational drugs [12]. Despite the advances which have been made, many problems remain unresolved. Only the barest beginning has been made in elucidating the etiology of mitral valve prolapse and in defining its molecular abnormalities. The marked variability of clinical and laboratory findings of mitral valve prolapse between patients and from day to day in individual patients requires explanation. Much additional information concerning the clinical course and prognosis is awaited from the sever?1 ongoing prospective studies of this disorder. Only when the problems concerning the etiology, expression and
Volume 67
clinical impact of mitral valve prolapse have been resolved will it be possible to advise patients with complete accuracy as to the significance of their condition or what treatment may be required.
6.
7.
8.
REFERENCES [~xlc~wIB, Pocock WA: Mitral valve prolapse,
the specific liillowing mitral leaflet syndrome, or an insignificant non-ejection systolic click. Am Heart J 97: 277, 1979. Jcr;;;~ RM: Mitral Valve Prolapse, New York, Raven Press, Dcvereux RB, Perloff JK. Rcichek N, et al.: Mitral valve prolapse. Circulation 54: 3. 1976. l)arsce JR, Mikolich JR;Nicoloff NB. et al.: Prevalence of mitral valve prolapse in presumably healthy young men. Circulation 59: 619, 1979. Davies MJ. Moore PH. Braimbridge MV: The floppy mitral valve. Study of incidence, pathology, and complications in surgical, necropsy and forensic material. Br Heart J 40: 468. 1978.
9.
10.
11. 12.
13.
Cohen MV, Shah PK, Spindola-Franc0 H: .4ngiographicechocardiographic correlation in mitral valve prolapse. Am flcort J 97: 43, 1979. Gttthrie RB. Edwards JE: Pathology of the myxomatous mitral valve. Nature, secondary changes and complications. Minn Mcd 59: 637 1976. McKusick VA: Mcntlelinn Inheritance in Men. 5th cd, Baltimore Johns Hopkins [Jnivcrsity Press. 1978. p 259. Towne WD, Pate1 R, Cruz J, Kramer N. et al.: Effects of gravitational stress on mitral valve prolapse. Br Heart J 40: 482. 1978. Schreiber T, Feigenbaum H, Weyman AE. et al.: Effects of atrial septal defect repair on left ventricular geometry and degree of mitral valve prolapse. Circulation (in press]. Mills PB, Rose J, Hollingsworth J. et al.: Long-term prognosis of mitral valve prolapse. N Engl J Med 297: 13, 1977. Wci JY. Bulkley BH , Schaeffcr AH, et al.: Mitral valve proIapsc syndrome and recurrent ventricular tachyarrhythmins. Ann Intern Mcd 89: 6. 1978. Hammer D. Leier CV. Baba N. et al.: Altered collagen composition in a prolapsing mitral valve with ruptured chordae tendineae. Am J Med 67: 863,1979.
November 1979 The American Journal of Medicine
Volume 67
731