Download Point of View Maladies Attributed to Myxomatous Mitral

328
Point of View
Maladies Attributed to Myxomatous
Mitral Valve
Elliot Chesler, MD, and Charles C. Gornick, MD
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"To observations which ourselves we make,
we grow more partial for the observers sake."
Alexander Pope
Moral Essays
TNhe relation among the late systolic murmur,
nonejection click, and prolapse of the mitral
valve was established by Barlow and Pocock
in 1963.1 In the past decade, 1,545 articles have
discussed various aspects of this form of mitral
regurgitation. How much this literature has added to
our knowledge and to patient care is debatable.
The pathology of the myxomatous mitral valve and
related complications have been described with elegance and precision.2 4 Myxomatous replacement of
the fibrosa weakens the involved mitral leaflet. Under the influence of left ventricular pressure, the
leaflets and chordae become stretched -a process
variously called "billowing," "ballooning," "prolapse," or "floppy" mitral valve but most often clinically referred to as mitral valve prolapse (MVP).
Clinical observations have delineated the auscultatory characteristics of the nonejection click and the
associated regurgitant murmur.5 Also, the electrocardiographic, cineangiographic, and echocardiographic
findings in the typical case have been well documented.6-8
However, the waters have become muddied by
reports associating the myxomatous mitral valve with
various conditions, including sudden death and
neuroendocrine disorders. These associations may be
purely coincidental or a bias of sample selection. In
particular, symptoms encountered among patients
with the so-called "MVP syndrome" are more likely
a result of psychogenically induced anxiety or comorbidity than neuroendocrine dysfunction. This point of
view is elaborated on.
Associated Conditions
It is established that the myxomatous valve may be
complicated by varying degrees of mitral regurgitaThe opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
From the Department of Cardiology, Veterans Administration
Medical Center, and the University of Minnesota, Minneapolis,
Minn.
Address for reprints: Elliot Chesler, MD, Cardiovascular Section (1l1C), Veterans Affairs Medical Center, One Veterans
Drive, Minneapolis, MN 55417.
tion and infective endocarditis.9 14 Also, there is a
pathological basis for less causally established complications such as stroke and coronary embolism in
the form of aggregations of platelets in the angle
between the posterior mitral leaflet and the left atrial
wall and on the leaflets themselves.15-18 There is a
definite association with other inherited connective
tissue abnormalities such as Marfan's and the EhlersDanlos syndromes, pectus excavatum, and pseudoxanthoma elasticum.19-21 Other associations are
questionable.
MVP detected by echocardiography does not necessarily imply that the valve is myxomatous. Often,
the distinction in the literature between normal,
myxomatous, "billowing," "prolapsing," "floppy, "
and "hooded" leaflets is hazy, and interpretation of
information may therefore be difficult. Also, there is
considerable interobserver and intraobserver variation in interpreting echocardiograms; this introduces
sampling bias into both patient and control populations. In atrial septal defect and hypertrophic obstructive cardiomyopathy, prolapse of normal leaflets
may occur when there is a disproportion between the
volume of the left ventricle and the size of the mitral
annulus.22 Similarly, prolapse of normal leaflets may
occur in inferior myocardial infarction and other
myocardial diseases such as myocarditis and cardiomyopathy because of failure of chordal systolic tension.23 This finding has also been reported in approximately 10% of trained athletes by Lewis et al.24
Markiewicz et a125 found a similar incidence in 100
nonathletic young women, although this series may
have been biased because the subjects were volunteers who responded to advertisement. In these
cases, the leaflets appear thin and do not have the
thickness and redundancy of the myxomatous valve.
Consequently, attempts by echocardiographers to
identify minor degrees of prolapse of normal leaflets
beyond the plane of the annulus appear to be inappropriate. In support of this view, some interchordal
hooding is present in the normal mitral valve, and
even a skilled pathologist may have to rely on histology to support a diagnosis of minor degrees of change
in excess of the normal. Identifying minor degrees of
prolapse of the mitral leaflets simply increases the
"background prevalence" and the chances of finding
a coincidental association with another condition.
Chesler and Gomick Myxomatous Mitral Valve Maladies
Obviously, fortuitous concurrence of a truly myxomatous valve with other cardiac abnormalities must
happen.
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MVP is identified in approximately 4% of the
population,26 and coincidental association will be
most likely when some other condition, whether
cardiac or noncardiac, occurs (e.g., migraine27 or
mitral annular calcification28). For example, it is not
surprising that MVP has been described in association with mitral annular calcification in women in
their 70s as three fourths of them have been found to
have some degree of calcification at autopsy (J.E.
Edwards, personal communication). Similarly, a
pathological study found a high incidence (18%) of
myxomatous valves among patients with ventricular
septal defect, but careful comparison with other
information in that report suggested that they were
unrelated occurrences.29
Zullo et a130 have clearly illustrated the effect of
patient selection and ascertainment bias in the case of
the purported association between MVP and hyperthyroidism. By studying the prevalence of all types of
thyroid disorders among family members with and
without MVP, they were unable to demonstrate a
statistically valid link between hyperthyroidism and
symptomatic subjects with MVP. Such noncausal associations are likely to be identified in populations
who share multiple symptoms.31 In MVP and hyperthyroidism, the outstanding common symptom is palpitation, and this leads to ascertainment bias.
Sudden Death
Sudden unexpected death resulting from dysrhythmia among young people has been reported as a
complication of MVP.32 However, adequate clinical
details, electrocardiographic recordings of the final
events, and detailed pathological findings are rare, so
it is difficult to determine how definite this association is. In 1983, one of us reviewed 39 reported cases
of sudden death attributed to myxomatous mitral
valves. Autopsies were performed in only 19, and in
many, the information was so sparse that other
pathological abnormalities could not be excluded
with certainty.15 Undoubtedly, some cases of sudden
death that had been attributed to the myxomatous
mitral valve were results of drug toxicity, electrolyte
disturbances, or other unrecognized and unrelated
cardiac pathologies such as cardiomyopathy.33 In
their long and careful follow-up of patients with
MVP, Pocock and Barlow34 encountered only one
patient who died suddenly. This young woman had
been treated for multifocal ventricular extrasystoles,
and a myxomatous mitral valve was the only finding
at autopsy; ventricular fibrillation was the presumed
cause of death. More recently, Nishimura et a135
reported six sudden deaths among 237 asymptomatic
or minimally symptomatic patients with MVP who
had been followed for a mean of 6.2 years. Similarly,
Duren et a136 performed a prospective follow-up of
300 patients (mean follow-up, 6.1 years) and encountered three cases of sudden death. Unfortunately,
329
autopsies were not available in either series. Duren
et al pointed out that their data may have been
biased because their patients had been referred to a
cardiac center for evaluation and that their results
did not necessarily reflect on the natural history in
the general population.
Of our 14 patients with sudden death, in whom we
documented that the myxomatous valve was the only
pathological finding, there was no recording of the
final dysrhythmia in five patients. Because premature
ventricular complexes had been documented at some
time, the final event was presumed to be ventricular
dysrhythmia. It was postulated that the mechanism
for the dysrhythmia could be related to mechanical
friction on the endocardium by the thickened chordae.15 Evidence for this friction is the presence of
fibrous endocardial lesions, which when confluent
and calcified may be detectable by angiography and
echocardiography.37,38 Alternatively, there is experimental evidence that traction on the papillary muscles may produce ventricular ectopy.39 This observation is supported by those rare patients with
hemodynamically mild mitral regurgitation associated with repeated syncope and ventricular tachycardia in whom valvuloplasty of voluminous leaflets
abolished the dysrhythmia40'41 (J.B. Barlow, personal
communication).
These findings in so few cases must be reconciled
with other evidence. In the Framingham Study, dysrhythmias were detected with similar frequency by
resting 12-lead, exercise, and 1-hour ambulatory
electrocardiography in subjects with and without
MVP.42 The Framingham Study was population
based and avoided the selection bias evident in other
studies from tertiary referral centers that reported
life-threatening cardiac dysrhythmias. The effect of
selection bias was clearly demonstrated by Kramer et
al,43 who compared patients with MVP with similarly
symptomatic controls: Patients with prolapsed valves
did not have an excessive prevalence of dysrhythmias.
Also, electrophysiological studies have not contributed to defining the role of ventricular ectopy.
Among patients with MVP and high-grade ventricular ectopy, some studies have demonstrated normal
intracardiac conduction and refractoriness.44 Others
have pointed out that programmed ventricular stimulation may induce polymorphic ventricular tachycardia that could be simply a nonspecific response to
aggressive stimulation protocols.45
Episodes of sudden death among the population at
large are not usually recorded by ambulatory electrocardiography.46,47 Ventricular tachycardia and fibrillation are the usual findings and complicate ischemic
heart disease. However, occasional cases of asystolic
cardiac arrest have also been documented. Recently,
Milstein et a148 reported their findings in six survivors
of cardiac systole. None of these young patients had
detectable heart disease. A hypotensive-bradycardiac
response with syncope reproduced in the survivors by
passive orthostatic tilt was thought to be neurally
mediated via mechanoreceptors in the left ventricle.
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Cardiac asystole could explain those cases in
pathological and forensic literature in which sudden
death in young people has not been associated with
demonstrable cardiac abnormality and the conduction system was normal.49,50 It also raises the question
of whether some sudden deaths have been erroneously attributed to the myxomatous mitral valve when
the actual causes were neurally mediated hypotension cardiac asystole. This association has been documented by Leichtman et al,51 who described 11
members of a family with a high prevalence of MVP
and syncope; orthostatic tilt reproduced the symptoms coincident with hypotension and marked bradycardia. Similar findings were reported by Santos et
a152 in 12 of 86 patients with MVP, but there were no
controls in this study, so the association could be a
result of selection bias. Thus, the causal relation
between the myxomatous mitral valve and sudden
death remains unclear. What is clear is that in the
absence of severe mitral regurgitation and left ventricular dysfunction, the risk of sudden death in
young people without ventricular dysrhythmias, syncope, or presyncope is so remote that patients should
not be told of the possibility.
Mitral Valve Prolapse Syndrome
a
When diagnosis of MVP is made clinically and no
other conditions or symptoms are present, such patients have been considered to have "primary" or
idiopathic" MVP. The term "billowing mitral leaflet
syndrome" was introduced by Barlow and Pocock53
when symptoms such as fatigue, anxiety, weakness,
and palpitation were associated with MVP. Recently,
the term "mitral valve prolapse syndrome" was used
by Boudoulas et a120 to categorize symptomatic patients whom they believe had neuroendocrine or
autonomic dysfunction with a "hyperadrenergic"
state. They proposed that MVP may be a marker for
autonomic dysfunction.54
Several studies have reported autonomic dysfunction among patients with MVP prolapse. Pasternac et
a155 studied 15 symptomatic patients. They measured
plasma norepinephrine levels, heart rate, and supine
and standing systolic and diastolic blood pressures.
Total plasma catecholamine and norepinephrine levels were significantly increased in patients in both
positions, and the heart rate was lower than normal
in patients in the supine position but returned to
normal in patients in the upright position. These
investigators believed that this "hyperadrenergic"
and vagotonic state could explain many of the manifestations of the MVP syndrome. These observations
are supported by Coghlan et a156 but somewhat at
variance with those of Gaffney et al,57 who found
diminished vagal response to the diving reflex and to
phenylephrine infusion. Boudoulas et a158 found increased 24-hour urinary norepinephrine and epinephrine excretion in symptomatic patients with
MVP. Also, isoproterenol infusion produced a doserelated increase in heart rate in MVP patients that
was greater than that in controls. They thought that
MVP may be a specific marker in certain people "for
the constitutional, neuroendocrine-cardiovascular
process that is currently designated as the MVP
syndrome."59 Other studies have reported decreased
epinephrine excretion and increased vagal tone in
patients with MVP.60 We believe that these conflicting findings are a result of several factors. First,
many study populations have been small, symptomatic, and mostly female, and not all control
populations have been clearly defined. Second, MVP
has not always been excluded by echocardiography in
controls.55,5758 Third, some studies have drawn conclusions from measuring catecholamines at rest or
during passive standing.56,58 It is preferable to study
changes in circulating catecholamines during orthostatic stress and isometric exercise. We have shown
that among 11 consecutive patients with myxomatous
valves encountered in hospital practice who were
evenly matched with controls for age and sex, there
was no significant difference between plasma norepinephrine levels, heart rates, and blood pressures in
response to orthostatic tilt. Also, psychological testing for anxiety neurosis demonstrated no difference
between the two groups.61 These findings have been
amply confirmed. In a comparison of patients who
have neurocirculatory asthenia with normal controls,
Mantysaari62 reported no significant difference in
response to hyperventilation, orthostatic tilt, Valsalva maneuver, cold pressor test, or isometric handgrip. Similarly, Lenders et a163 found no differences
in neurohumoral responses to orthostatic tilt of
symptomatic and asymptomatic patients with MVP.
Recently, Taylor et a164 studied normal controls,
asymptomatic patients with MVP, and patients with
MVP who had symptoms suggestive of autonomic
dysfunction. The autonomic responses to ice water
immersion and the administration of isoproterenol,
phenylephrine, and tyramine were the same in patients with similar symptoms and did not distinguish
between those who did and those who did not have
MVP. These authors reported that the autonomic
responses to physiological maneuvers and agonist
drugs in controls and in patients with MVP are
heterogeneous and may be partially responsible for
the divergent findings reported in the literature; bias
in patient selection and small sample size could favor
one abnormality over the other.
The symptoms associated with MVP are indistinguishable from those occurring in Da Costas syndrome and neurocirculatory asthenia and were
thought by Wood65 to be the result of a psychiatric
disorder (anxiety state). In modern terminology, they
are classified as "panic disorder with somatization"66
and occur in 2-5% of the general population,67
6-10% of patients attending primary care clinics,68
and 10-14% of patients in cardiologic practice.65 The
problem of how to reconcile the occurrence of similar
auscultatory, echocardiographic, and electrocardiographic features in patients with and without symptoms was clearly recognized by Barlow and Pocock.7
They emphasized that patients with marked prolapse
Chesler and Gomick Myxomatous Mitral Valve Maladies
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are not necessarily symptomatic, yet those with mild
prolapse may have numerous symptoms. The obvious
question is what is the mystique peculiar to the
myxomatous mitral valve compared with other causes
of mitral regurgitation that predisposes to these
symptoms and associated autonomic dysfunction?
There probably is none.
The contention of Leatham and Brigden69 that
"isolated disease of the mitral valve causing mild or
moderate reflux seldom causes symptoms other than
those of iatrogenic anxiety" is buttressed by considerable evidence. Psychiatric studies have shown that
scores for symptoms of anxiety and neurosis in patients with MVP were not different from those in
patients with other cardiac diseases.70-72 In their
extensive review, Margraf et a173 concluded that
there was no functional relation between MVP and
panic disorders and that comorbidity in highly symptomatic individuals was the likely explanation. Thus,
the weight of evidence does not support the notion
that myxomatous change in the mitral valve has any
causal relation with psychiatric disorder. We do not
doubt that there are some patients who may be
"hyperadrenergic," but we feel that this could be a
result of superimposed anxiety in a select group of
individuals subjected to a host of maneuvers, tests,
and studies in attempts to elucidate and make observations on additional facets of a "new disease."
We conclude that when all of the maladies attributed to the myxomatous mitral valve have been
considered, only mitral regurgitation of varying degrees of severity, rupture of the chordae, infective
endocarditis, and stroke will be importantly associated. Only in a minute subset of patients with complex ventricular ectopy and syncope or presyncope is
there a risk for sudden death.
Acknowledgments
The authors are grateful to Howard B. Burchell,
MD, and Professor John B. Barlow for their critical
reviews of the manuscript.
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Circulation. 1991;83:328-332
doi: 10.1161/01.CIR.83.1.328
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