Download - Mitral valve prolapse and the mitral valve prolapse syndrome: A diagnostic classification and pathogenesis of symptoms

CURRICULUM IN CARDIOLOGY

Mitral valve prolapse and the mitral valve prolapse syndrome: A diagnostic classification and pathogenesis of symptoms

Harisios Boudoulas, MD, Albert J. Kolibash, Jr., MD, Peter Baker, MD, Bernard D. King, MD, and Charles F. Wooley, MD. Columbus, Ohio, and Philadelphia, Pa.

Although mitral valve prolapse (MVP) is a common valvular abnormality, a clinically relevant classification is incomplete and the pathogenesis of symptoms is not completely understood.1-4 Based on our experience with 399 symptomatic patients with MVP during the past decade, and on the experience of others, we developed a clinical classification in order to improve nosology, better identify subsets of patients with MVP, and develop greater insight into the mechanism of symptoms in patients with MVP. Symptoms or complications were primarily or directly related to progressive mitral valvular dysfunction in 86 patients who were classified under the heading of MVP-anatomic, while 313 patients whose symptoms were related to neuroendocrine or autonomic dysfunction rather than valvular dysfunction were classified under the heading of the MVP- syndrome (MVPS) (Fig. 1).

MVP: NOSOLOGY, INHERITANCE, AND CARDIAC DISORDERS OF CONNECTIVE TISSUE

Recent evidence suggests that MVP is inherited as an autosomal dominant phenotype and that a large proportion of patients with MVP have evidence, aside from MVP, of an aberration in connective tissue, that is, the systemic features and their associa- tions are the same as occur in patients with heritable disorders of connective tissue. Examples of such fea-

From the Division of Cardiology and the Department of Pathology, The Ohio State University; and the Medical Department, Smith Kline & French Laboratories, Division of Smith Kline Beckman, Philadelphia.

Supported in part by Clinical Research Center training grant RR-34 from the Central Ohio Heart Chapter, Columbus, Ohio; the Overstreet Teaching and Research Laboratory; and the Columbus Foundation, Columbus, Ohio.

Received for publication March 7, 1989; accepted May 1, 1989.

Reprint requests: H. Boudoulas, MD, Division of Cardiology, The Ohio State University, 1654 Upham Drive, Columbus, OH 43210.

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tures are deformity of the anterior chest, vertebral column, dolichostenomelia, and joint hypermobility. Further, biochemical studies in mitral valves obtained from patients with severe MVP and significant mitral regurgitation demonstrated collagen abnormalities. MVP has been documented in a number of recognized heritable connective tissue disorders such as the Marfan syndrome, the Ehlers-Danlos syndrome, the Stickler syndrome, and adult polycystic kidney disease. In recognition of this worldwide experience, committee experts recently classified familial MVP as one of the heritable connective tissue disorders.5-35 By virtue of its high frequency in the general population, MVP designates the largest group of patients with a connective tissue abnormality of the heart. Although cardiovascular involvement in patients with heritable disorders of connective tissue has been recognized, the widespread appreciation of these disorders has been limited by a lack of logical classification. The widely used New York Heart As- sociation Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels includes only the Marfan syndrome under the etiologic cardiac diagnosis. 36 While it is likely that the classification of heritable connective tissue disorders will be based upon their biochemical and genetic characteristics in the future, at present a logical approach would be to consider the cardiovascular abnormalities in both the recognized syndromes and in the isolated abnormalities within a system of classifications already in general use. An illustration of how this could be done is provided in Table I, in which the New York Heart Association etiologic categories are adapted to include connective tissue disorders.35

MVP-ANATOMIC

Eighty-six patients, 53 men and 33 women, with an age range from 26 to 82 years (mean age 67 years) with

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MVP: DYNAMIC SPECTRUM 8 NATURAL PROGRESSION

MVP-SYNDROME

MVP-ANATOMIC

I

TIME (YEARS)

Fig. 1. Left panel, The dynamic spectrum, time in years, and the progression of mitral valve prolapse (MVP) are shown. A subtle gradation (cross-hatched area) exists between the normal mitral valve and valves that produce mild MVP without mitral regurgitation (No MR). Progression from the level MVP - No MR to another level may and may not occur. Most of the patients with MVP-syndrome occupy the area above the dotted line, while patients with progressive mitral valve dysfunction occupy the area below the dotted line. Right panel, The large circle represents the total number of patients with MVP. Patients with MVP may be symptomatic or asymptomatic. Symptoms may be directly related to mitral valve dysfunction (black circle), or to autonomic dysfunction (cross-hatched circle). Certain patients with symptoms directly related to mitral valve dysfunction may present and continue to have symptoms secondary to autonomic dysfunction. (From Boudoulas H, Wooley CF. Mitral valve prolapse and the mitral valve prolapse syndrome. Mount Kisco, NY: Futura Publishing Co, Inc., 1988. Ref. 240. Reproduced with permission.)

MVP had symptoms directly related to mitral valve dysfunction.37 All patients had a mitral regurgitation murmur; 86 (93 % ) had known of a heart murmur for an average of 24 years prior to the development of symptoms. Seventy-three of the patients (85%) had a history of congestive heart failure; 48 patients (58%) had atrial fibrillation; 13 patients (15% ) had a remote history of documented, successfully treated infective endocarditis.

Cardiac catheterization was performed in 84 of these patients. Mitral regurgitation was confirmed in all and MVP was documented angiographically in 61 (73%) of the patients studied. Coexistent tricuspid regurgitation was present in 24 (29 % ) of the patients, with cineangiographic definition of tricuspid valve prolapse in 17 (20% ). Although coronary artery disease was present by angiography in eight (10 % ) of the patients, there was no history or evidence of previous myocardial infarction. Mitral valve surgery (valve replacement) was performed in 76 (88%) of these patients because of progressive severe mitral valvular regurgitation.

The relation between patient age at which a murmur was first detected, patient age at onset of cardiac symptoms, and patient age when mitral valve surgery was performed are shown in Fig. 2. Sixty-two patients (72 % ) were younger than 50 years when a murmur

Table I. New York Heart Association etiological categories: Proposed revision

Acromegaly Alcoholism, etc. Cardinoid tumor (argentaffinoma) Connective tissue disorder, Recognized syndromes:

Marfans syndrome Homocystinuria Ehlers-Danlos syndrome Combined Ehlers-Danlos/Marfan syndromes Adult polycystic kidney disease Osteogenesis imperfecta Pseudoxanthoma elasticum Menkes kinky-hair syndrome Custis laxa The mucopolysaccharidoses

Connective tissue disorder, isolated abnormalities: Isolated valvular prolapse Combined valvular prolapse Isolated aortic regurgitation Annuloaortic e&t&a Pulmonary artery aneurysm

Congenital anomaly, etc.

From Bowen J, Boudoulas H, Wooley CF. Am J Med 1987;82:481-7. Repro- duced with permission.

was first detected but most (87 % ) were older than 50 years when progressive symptoms developed and valve surgery was considered.

Only 11 patients (13%) became symptomatic and

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L 11(13%)~ 1. II (13%)

=4 62(72%)

20

IO

AGE WRMUR AsEmsr AoEAfMvR- FIRST mmrEo SYMPi-cw ORm

Fig. 2. Chronologic relation among the ages when a murmur was first detected {left), and the ages when the first symptoms became manifest (middle) and the ages when mitral valve surgery (replacement) (MVR) or the most recent catheterization (CAZH) was performed. Each patient in each column is represented by a dot. Open dots in the right column indicate those patients who did not have surgery. Dashed horizontal line divides patients above and below age 50 years, and solid line indicates the mean age in each column. Most patients (62 patients, 72%) were younger than age 50 when a murmur was first detected, but most (75 patients, 87%) were older than age 50 when symptoms developed and mitral valve surgery was considered. Note also the prolonged period (24 years) between initial detection of a heart murmur and onset of symptoms (average age 35 to 59 years) but the relatively short interval (1 year) from symptom onset to mitral valve surgery. (From Kolibash AJ, et al. Am J Cardiol1986;58:762-7. Re- produced with permission.)

underwent initial valve surgery at an age younger than 50 years. The average symptom-free interval after detection of a murmur was 24 years. Once patients became symptomatic, mitral valve surgery was required (mean age of 60 years) in a relatively short period, an average of 1 year after symptom onset.

All surgical patients had large, floppy, myxomatous mitral valves (Fig. 3). Ruptured chordae tendineae were present in 39 (51% ) of these patients. Ex- tensive gross morphologic and histologic studies in 60 of the excised mitral valves showed increased surface area, increased annular diameter, elongated chordae tendineae, and collagen dissolution or disruption, as previously described 8, lo, 38 (Fig. 4).

Histologic abnormalities and abnormal mechna- ical properties have been demonstrated in chordae tendineae from floppy mitral valves in a recent

study from our laboratory.lO, XI Normal mitral valve chordae tendineae uniformly had a dense central collagenous core surrounded by a thin layer of com- pact elastic fibers with or without small deposits of acid mucopolysaccharides. Collagen alterations and moderate to severe acid mucopolysaccharide accumulation, rarely found in normal mitral valve chordae tendineae, were frequently present in floppy mitral valve chordae tendineae. The collagen alterations in floppy mitral valve chordae tendineae are illustrated in Fig. 5. The histology of floppy mitral valve chordae tendineae was not uniform, however, ranging from a normal histologic appearance to severe collagen fragmentation, attenuation, and separation with associated severe acid mycopolysaccha- ride accumulation.

Scanning electron photomicrographs demonstrated surface folds and focal loss of endothelial cells on mitral valve leaflets obtained from patients with severe MVP and significant mitral regurgitation (Fig. 6). These abnormalities may be related to thromboembolic complications and to infectious endocarditis.

Mechanical abnormalities in floppy mitral valve chordae tendineae were demonstrated. Chordae tendineae were tested in a uniaxial tension mode and load versus elongation curves were obtained for each chorda by increasing the load until the chorda frac- tured. The fracture stress in floppy mitral valve chordae tendineae was significantly lower compared with that in normal mitral valve chordae tendineae. This indicates a loss of tissue strength that may contribute to chordal elongation and rupture.lO, 38

MVP-anatomic: Major complications. Symptoms and serious complications related to mitral valve dysfunction in patients with anatomic MVP include infectious endocarditis, progressive mitral regurgitation that requires mitral valve surgery, ruptured chordae tendineae, thromboembolic phenomena, serious supraventricular or ventricular arrhythmias, atrioventricular conduction defects, congestive heart failure, and death. As a general rule, complications related to anatomic MVP increased with age.3g-4 Myxomatous or floppy mitral valves are now recognized as the most common etiologic diagnosis in patients having mitral valve surgery for pure mitral valvular regurgitation in the western world.37s 3g The association between myxomatous or floppy mitral valves and infectious endocarditis has also been recognized with increasing frequency.

There are two prospective long-term follow-up studies in adult patients with MVP, with results of which are here briefly summarized. Duren et a1.r4r recently reported the results of a long-term prospec-

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Fig. 3. A, Myxomatous mitral valve, atria1 view, from a patient with severe mitral regurgitation. The surface area of the valve is increased. Ballooning is evident in both cusps. The widths of the anterior leaflet and the posterior leaflet from the anulus to free edges are almost equal. Individual scallops of the posterior leaflet are enlarged and redundant. B, Comparison of an excised myxomatous mitral valve from a patient with severe mitral regurgitation (bottom) with a normal mitral valve from a patient who died of noncardiac cause (top), showing the increased surface area of both anterior leaflets and posterior leaflets of the myxomatous valve with enlarged and redundant posterior leaflet scallops and enlarged mitral anulus. The dis- tance between each line on the bottom scale is 1 cm.

tive follow-up study in 300 patients with MVP diag- nosed by clinical, cineangiographic, and echocardiographic criteria. All patients had auscultatory findings consistent with MVP. The ages ranged from 10 to 87 years (mean 42.2 years). The study included all patients with MVP irrespective of clinical condition at the onset. The average follow-up period was 6.2 years.

The clinical condition remained stable in 153 patients. Twenty-seven of the 153 patients developed supraventricular tachycardia that was controlled with medications; 20 patients developed signs of mi-

tral regurgitation but remained clinically asymptomatic.

Serious complications developed in 100 patients. Sudden death occured in three, ventricuiar fibrillation in two, ventricular tachycardia in 56, and infective endocarditis in 18. Twenty-eight patients underwent mitral valve operations because of progressive mitral regurgitation, while an additional eight patients with severe mitral regurgitation were considered surgical candidates. Eleven patients had cerebrovascular accidents. Although the study population may not be representative for the entire ana-

800 Houdoulas et al. October 1999


Fig. 4. A, A normal mitral valve cusp. The histologic zones are represented in a cross-section. The atrialis is a thin zone of dense collagen immediately below the inflow surface (between arrowheads). The next zone, the spongiosa (S), consists of loose connective tissue, and the remainder of the cusp, composed of dense collagen, is the fibrosa (F). (Jones silver stain; original magnification x25.) 6, Floppy mitral valve cusp. The cusp has a large expanded central zone of myxomatous connective tissue with focal thinning and disruption of the fibrosa (arrow). The dense layer seen at the top just below the inflow surface is the markedly thickened atrialis (A). Fibrous connective tissue pads are seen on the ventricular surface. (Jones silver stain; original magnification ~4.) The lower right inset is a high magnification view of the myxomatous area showing disoriented, separated collagen bundles. A Mowrys colloidal iron stain demonstrated abundant accumulation of acid mucopolysaccharides in this area. (Jones silver sbain; original magnification X100.)

tomic MVP population, the results strongly support the concept that anatomic MVP may be associated with significant morbidity and mortality.

Nishimura et al. g1 determined prognosis in a prospective (mean 6.2 years) follow-up study in 237 minimally symptomatic or asymptomatic patients with MVP documented by echocardiography. The average age was 44 years (range 10 to 69 years). Sud- den death occurred in six patients. In multivariable

analysis of echocardiographic factors, the presence or absence of redundant mitral valve leaflets (present in 97 patients) emerged as the only variable associated with sudden death, Ten patients sustained a cerebral embolic event; one had left ventricular aneurysm with apical thrombus, one had infective endocarditis, six were in atria1 fibrillation with left atria1 enlargement, and two were in sinus rhythm. Infective endocarditis occurred in three patients and progres-

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Fig. 5. A, Normal mitral valve chorda tendineae. The chorda has a large central core of dense collagen surrounded by a thin dark-staining elastic tissue layer. (Weigerts elastic stain; original magnification X25.) B, Floppy mitral valve chordae tendineae. These chordae show two patterns of histopathologic alterations. The chorda on the left shows myxomatous expansion of the peripheral connective tissue with loss of the distinct elastic layer. The central collagenous core is not extensively involved. The chorda on the right has severe separation and attenuation of collagen in the central core with fragmentation of the elastic layer. Mowrys colloidal iron stain demonstrated abundant acid mucopolysaccharide accumulation in the myxomatous areas of both chordae. (Weigerts elastic stain; original magnification X25.)

sive mitral regurgitation prompted valve replacement in 17 patients. The left ventricular end-diastolic diameter exceeding 60 mm was the best echocardiographic predictor of the subsequent need for mitral valve replacement.

Twenty patients had no clinical auscultatory findings of a systolic click or murmur; none of these patients had any complications during follow-up. The authors concluded that while most patients with echocardiographic evidence of MVP have a benign course, subsets of patients that can be identified by echocardiography are at high risk for the develop-

ment of progressive mitral regurgitation, sudden death, cerebral embolic events, or infective endocarditis.

These long-term follow-up studies in patients with MVP permit several conclusions: (1) Serious complications do occur in patients with anatomic MVP. (2) MVP patients constitute a nonhomogenous population (see later comments). (3) Complications are directly related to the specific subset of MVP patients included in the study. (4) Complications in patients with MVP appear to occur primarily in patients with diagnostic auscultatory findings. (5) Redundant mi-


Amencan Heart Journal

Fig. 6. A, Normal mitral valve. Scanning electron photomicrograph (original magnification x280) shows smooth valve cusp surface covered by endothelial cells. 8, Floppy mitral valve. Scanning electron photomicrograph (original magnification x400) shows an irregular surface with deep infolding. C, Floppy mitral valve. Scanning electron photomicrograph (original magnification x600) shows an area of denuded endo- thelium exposing the underlying collagen. (From Lewis RP. Cerebral embolism in mitral valve prolapse. In: Boudoulas H, Wooley CF, eds. Mitral valve prolapse and the mitral valve prolapse syndrome. Mount Kisco, NY: Futura Publishing Co, Inc, 1988. Reproduced with permission.)

tral valve leaflets and increased left ventricular size in patients with MVP are associated with a high frequency of serious complications.

MITRAL VALVE PROLAPSE SYNDROME (MVPS)

Three hundred thirteen patients with MVP, 217 women and 88 men, with a mean age of 30 years had symptoms not explained on the basis of valvular dysfunction alone. All had the auscultatory findings of MVP, i.e., a mobile, non-ejection mitral systolic click with or without a mid-to-late mitral apical systolic murmur.142 Patients had either mild or no detectable mitral regurgitation.

MVPS: Symptom complex. Presenting symptoms in the 313 patients with MVP included palpitations, chest pain, easy fatigability, exercise intolerance, dyspnea, syncope or presyncope, postural orthostatic phenomena, and neuropsychiatric symptoms (Table

II). Females presented with more symptoms than males. Patients with MVPS become symptomatic at any age, but in our experience the greatest proportion of the patients become symptomatic during the second or third decades.

MIPS-Evidence of high adrenergic activity. To better understand the pathogenesis of symptoms in these patients, 65 patients were studied extensively as a part of several research protocols.3, 143-155 We first demonstrated that the 24-hour urinary epinephrine, norepinephrine, and epinephrine plus norepinephrine were higher in 19 symptomatic patients with MVP compared with values in 29 normal control subjects.14 The frequency of premature ventricular beats (PVBs) detected by ambulatory monitoring paralleled urinary catecholamine excretion; both PVBs and urinary epinephrine plus norepinephrine decreased significantly during the night. When 24-

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hour urine epinephrine and norepinephrine were measured for 3 consecutive days, there was no day- to-day variability in these values.143

Plasma epinephrine and norepinephrine values at rest were also higher in patients with MVPS compared with control subjects. Plasma epinephrine and norepinephrine increased after exercise in MVPS patients and in control subjects; plasma levels after exercise were not different in MVPS patients compared with control subjects.144r 148 Patients whose number of PVBs with exercise increased more than 10 per minute had a greater plasma epinephrine and norepinephrine increase compared with patients in whom the frequency of PVBs remained relatively unchanged.143

Earlier studies in patients with heart disease demonstrated that increased urinary catecholamine excretion was associated with a shorter total electromechanical systole corrected for heart rate (Q&J), while isoproterenol infusion in normal subjects pro- duces an abbreviation of the QS&145~ 156-158 Patients with MVPS had a shorter Q&I compared with normal control subjects; this provided further evidence of increased adrenergic activity.143

These symptomatic patients with MVPS had normal thyroid function tests, normal plasma cortisol, normal diurnal variation of cortisol, normal 24-hour urinary 17-ketosteroids, 17-hydroxycorticosteroids and serotonin products excretion, and normal response to oral glucose, although the glucose and in- sulin levels were higher than in control subjects.

Pasternac et a1.15g demonstrated that MVPS patients had higher total plasma catecholamine levels and norepinephrine levels when compared with normal subjects, both in the supine and upright posi- tions. When plasma catecholamines were measured in the same patients 6 years later, the catecholamine levels were similar in both measurements, suggesting stability of the high adrenergic activity.160

MVPS-Catecholamine regulation abnormality. Low intravascular volume may be present in some patients with MVPS. To test the hypothesis that high catecholamine levels are not related to low intravascular volume, plasma epinephrine and norepinephrine were measured after volume expansion. Volume expansion was induced with isotonic sodium chlo- ride, 2.5 to 3 L, given intravenously over 10 hours. In normal control subjects, volume expansion produced a decrease in plasma epinephrine and norepinephrine in the supine and upright postures. In contrast, in patients with MVPS, volume expansion did not change the plasma epinephrine plus norepinephrine values. This suggests that catecholamine regulation

Table II. Classification of mitral valve prolapse

Mitral valve Mitral valve prolapse-anatomic prolapse syndrome

0 Common mitral valve abnormality with a spectrum of structural and functional changes, mild to severe

The basis for: l Systolic click; mid-late

systolic murmur l Mild or progressive mitral

valve dysfunction 0 Progressive mitral

regurgitation, atria1 fibrillation, congestive heart failure

l Infectious endocarditis l Embolic phenomena l Characterized by long

natural history l May be heritable, or

associated with heritable disorders of connective tissue

l Conduction system involvement possibly leading to arrhythmias and conduction defects

l Patients with mitral valve prolapse

l Symptom complex: chest pain, palpitations, arrhythmias, fatigue, exercise intolerance, dyspnea, postural phenomena, syncope-presyncope, neuropsychiatric symptoms

l Neuroendocrine or

autonomic d.ysfunction

(high catecholamines, catecholamine regulation abnormality, hyperresponse to adrenergic stimulation, parasympathetic abnormality, baroreflex modulation abnormality, renin-aldosterone regulation abnormality, decreased intravascular volume, decreased ventricular diastolic volume in the upright posture, atria1 natriuretic factor secretion abnormality) may provide explanation for symptoms

l Mitral valve prolapse-a possible marker for autonomic dysfunction

abnormality may be present in patients with ~vps.146>153

MVPS: Hyperresponse to adrenergic stimulation. The demonstration of increased adrenergic tone in MVPS patients prompted a study of adrenergic stimulation response.144 During isoproterenol infusions, none of the 12 control subjects developed symptoms, exclud- ing palpitations. Conversely, isoproterenol infusion reproduced symptoms in patients with MVPS on a dose-related basis. During isoproterenol infusion, 3 of 16 patients developed symptoms with 0.5 pg/min of isoproterenol infusion, 5 of 13 patients developed symptoms with 1.0 pglmin of isoproterenol infusion, and 9 of 11 patients developed symptoms with 2.0 pg/min of isoproterenol infusion. Reproduction of symptoms occurred with isoproterenol infusion; symptoms included chest pain in seven patients, extreme post-infusion fatigue in six patients, dyspnea



IOOO-

soo- b \, Total Diastolic Period

Heart Rate (beatslmin)

Fig. 7. Left panel, The relationship of heart rate to diastolic time is shown. Due to nonlinear relationship between heart rate and diastolic time, small changes in heart rate (particularly at slower rates) produce significant changes in diastolic time. Right panel, Recordings of the aortic (Ao) pressure and left ventricular (LV) pressure. The tension time index (TTI) and diastolic time index (DPTZ) are shown. Phasic coronary blood flow in relationship to DPTI is also shown.

in six patients, dizziness in four patients, and panic attacks in two patients. Four patients had cool hands during isoproterenol infusion.144

The increase in heart rate during isoproterenol infusion was significantly greater in patients with MVPS compared with control subjects and was dose-related, whereas baseline heart rate was not significantly different between the two groups.44

Diastolic time has a nonlinear relationship with heart rate.161 Thus small changes in heart rate will result in significant changes in diastolic time (Fig. 7). During isoproterenol infusion, diastolic time per beat and per minute decreased significantly in both groups (MVPS and control subjects). However, the decrease in diastolic time with isoproterenol infusion was significantly greater in MVPS patients compared with control subjects. 144 These changes in diastolic time may be of clinical significance under certain circum- stances, since the greater proportion of coronary blood flow occurs in diastole and subendocardial flow is almost totally diastolic.161-163 Spontaneous inappropriate sinus or ectopic tachycardia in patients with MVPS results in a significant decrease in diastolic time, which under certain conditions may produce subendocardial ischemia and chest pain.

The duration of electrical systole (QT) in normal subjects is shorter than and parallels the duration of electromechanical systole (Q&J throughout the normal range of the resting heart rate.164s 165 The QT-QSz interval represents a basic cardiac electrical mechanical relation; synchrony or parallel behavior appears to be a normal phenomenon, while asynchrony is abnormal. Changes in the QT-QS2 relationship during isoproterenol infusions were dose-related, both in

MVPS patients and in control subjects. Isoprotere- no1 infusion resulted in a QT prolongation relative to QS2 (QT > QSs) in MVPS and in control subjects, but the relative QT prolongation (QT minus QSZ interval) was significantly greater in MVPS compared with control subjects. 144 This electrical mechanical asynchrony induced by isoproterenol is of interest in view of postulated mechanisms of arrhythmic provocation. 166 Spontaneous transient appropriate or inappropriate increases of catecholamines during daily activities in patients with MVPS may produce transient prolongation of electrical systole compared with electromechanical systole.

Thus hyperresponse to adrenergic stimulation in patients with MVPS was demonstrated by reproduction of symptoms, greater heart rate increase, greater diastolic time abbreviation, and greater QT prolongation relative to electromechanical systole compared with corresponding values in control subjects.

MVPS: Beta-adrenergic receptors. These responses to adrenergic stimulation provide an insight into the mechanisms of symptoms in MVPS patients; however, the precise explanation is not well understood. According to the receptor theory, the number of active P-adrenergic receptors should be low in the presence of high catecholamines.167 Patients with a decreased number of active P-adrenergic receptors should have a diminished response to adrenergic stimulation. The hyperresponsiveness to isoprotere- no1 infusion in these studies suggests increased P-receptor function.156 If P-receptor function is increased, then either a defective autoregulatory mechanism at the catecholamine receptor level, or many transient increases of plasma catecholamines during the day,

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or both, may be responsible. The number of active ,8- adrenergic receptors has been shown to increase with isoproterenol infusion of 30 to 60 minutes duration, while longer periods of isoproterenol infusion decrease the number of /3-adrenergic receptors.168 Thus an increase in total urinary catecholamine excretion in patients with MVPS is likely to be due to multiple transient secretory catecholamine peaks during the day. Although the receptors are stimulated during these peaks, the stimulation is not long enough to decrease the number of active P-adrenergic receptors. Our observation that the urinary excretion of epinephrine and norepinephrine decreases significantly during the night supports this hypothesis143 (Fig. 8). Recently, Davies et al. 16g demonstrated supercou- pling of /3-adrenergic receptors in patients with MVP compared with control subjects, which may explain the hyperresponse to adrenergic stimulation reported from our laboratory.

MVPS: LOW intravascular volume. Patients with MVPS often present with postural phenomena such as orthostatic tachycardia and hypotension.26y 170-174 Low intravascular volume and/or an abnormality in the renin-aldosterone axis may contribute to the orthostatic changes. 147-148,153 G&&y et alal% mea-

sured plasma volume in symptomatic MVPS patients with orthostatic intolerance. Plasma volume, corrected for body size, was lower in the patients compared with the control subjects. There was also an inverse relationship between plasma volume and total peripheral resistance on standing. Those patients with the highest total peripheral resistance had the lowest plasma volume, and patients with lowest total peripheral resistance had the highest plasma volume. Low intravascular volume in patients with MVPS has also been demonstrated from several other laboratories.147* 148s 153

MVPS: Renin-aldosterone regulation abnormality. To further evaluate the renin-aldosterone axis, plasma renin activity and aldosterone were measured before and after volume depletion.147l 153 Volume depletion was produced with furosemide, 0.5 mg/kg, given intravenously. After volume depletion, plasma norepinephrine (NE) increased slightly more in five patients with MVPS in the supine and the upright position compared with results in five control subjects. Plasma renin activity increased slightly less in patients with MVPS in the supine and upright position compared with values recorded for control subjects. For each degree of volume depletion, plasma renin activity increased significantly less in patients with MVPS compared with control subjects. Plasma aldosterone was significantly less in the supine and upright posture in patients with MVPS compared

II ISOPROTERENOL

RESTING CELL

RESTING CELL

Fig. 8. Adrenergic stimulationand /I-adrenergic receptor sensitivity. Normal active adrenergic receptors and normal response to isoproterenol during short-term infusion (upper panel). The number of active adrenergic receptors or responsiveness increases with isoproterenol infusions of duration 30 to 60 minutes, and therefore the response to isoproterenol infusion is increased (middle panel). The number of active P-adrenergic receptors decreases during long-term isoproterenol infusion. Therefore the response to isoproterenol infusion is blunted (lower panel). (From Boudoulas H, et al. Psychopathology 1984; 17(SupplI):98- 106. Ref. 152. Reproduced with permission.)

with plasma aldosterone in control subjects after volume depletion.147T 153

MVPS-Atrial natriuretic factor. Pasternac et al.r60 studied plasma volumes and atria1 natriuretic factor in patients with MVPS. Two groups were identified: seven patients (44%) had a significant increase in atrial natriuretic factor, with a mean value of 31.9 f 9.1 pg/ml, compared with normal subjects; in the other nine patients, atrial naturetic factor was within the normal range (mean value of 11.4 + 1.4 pg/ml). Patients with the higher values of atria1 natriuretic factor tended to be older, had a higher systolic blood pressure, a faster heart rate, and a larger left atrium, although the differences were not significant. Patients with higher atria1 natriuretic factor values had significantly lower blood volume than those with normal values of atrial natriuretic factor (2999 +- 94 ml versus 3544 +- 220 ml, p < 0.01). In addition, there was an inverse relationship between atrial natriuretic factor and blood volume, and an inverse relationship between plasma volume and plasma norepinephrine.

MVPS: Parasympathetic abnormality-other auto-



Fig. 9. Left panel, Dynamic spectrum and progression of mitral valve prolapse (MVP). A subtle gradation exists (cross-hatched area) between a normal mitral valve and minimal to mild MVP. Progression from one level of valvular dysfunction to a more severe form may occur. Right panel, Factors that may produce or aggravate arrhythmias. Cardiac arrhythmias are related to both the severity of MVP and to factors that may produce or aggravate arrhythmias. QT. Electrical systole; MR, mitral regurgitation; QT > QS,, QT greater than electromechanical systole.

Natural Progression of MVP

J&gq

Autonomic Dysfunction

Long QT, QTK&S

f l+Tq Repolarlzatlon Abnormalities

E e

+, Myocardlal lschemla

2

Abnormal AV Conductlon

, Time (years)

nomic dysfunction (Table il).Coghlan et al.174-176 exam- ined heart rate response to the Valsalva maneuver and to head-up tilt in 44 patients with MVPS. MVPS patients had heart rates that were lower during the control periods before both interventions and higher with standing and during the strain phase of the Valsalva maneuver. During the recovery phase of the Valsalva maneuver, there was an inappropriate bradycardia that persisted for several minutes. The beat-to-beat variation in these patients was also excessive. The authors postulated that MVPS patients had excessive vagal tone, with a generally unstable autonomic nervous system leading to poor cardiovascular control. The diffuse nature of the abnormalities suggested the presence of a central autonomic nervous system defect. Coghlan74 defined three types of autonomic dysfunction in patients with MVPS: the hypervagal(33 % ), the hyperadrenergic (lo%), and the mixed type (54%).

Autonomic dysfunction leading to cardiovascular instability has also been reported by Gaffney et ,1.,172, 175, 177 w h o studied symptomatic women with auscultatory findings and echocardiographic docu- mentation of MVP by means of lower body negative pressure, phenylephrine infusion, facial immersion in ice, and noninvasive measures of cardiac output. Patients with MVPS and cardiac arrhythmias had significantly higher heart rates at rest, during the dive test, and with lower body negative pressure compared with corresponding values in control subjects. The less symptomatic MVPS patients had a relative bradycardia, similar to those patients re-

ported by Coghlan et al. 176 All patients exhibited marked vasoconstriction during orthostatic stress and actually increased mean blood pressures despite large decreases in cardiac output. They also found that vagal responsiveness, reflected by the slopes of the regression lines relating mean arterial pressure to R-R intervals during phenylephrine infusion, were different in patients with MVPS compared with normal control subjects. This finding is consistent with baroreflex abnormality. Baroreflex modulation abnormality in patients with MVPS has also been reported from our laboratory.15

MVP: Evidence of autonomic dysfunction in asymptomatic individuals. Seventy-eight asymptomatic U.S. Air Force air crewmen with auscultatory and/or echocardiographic evidence of MVP were evaluated by Whinnery 178 for tolerance to high positive G stress (+G). The MVP group had a normal response to gradual onset of +G stress, both while relaxed and when performing a protective straining maneuver, and a small but statistically significant decrease in tolerance to rapid onset of +G stress. During the +G stress, 15% of the MVP individuals loss conscious- ness. This incidence of syncope was greater (p < 0.01) compared with a 7% incidence of syncope in 1126 normal individuals without MVP. The incidence of motion sickness during the +G stress was also greater in MVP individuals compared with 1126 normal individuals (17 % versus 11%). High +G stress in certain individuals with MVP may also induce ventricular arrhythmias.17g

MVPS-Chest pain. Overall, chest pain is present in

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approximately 60% of patients with MVPS52g 154; it is the most common symptom in men. The cause of chest pain in patients with MVPS may be multifactorial.152T 154, 180-186 Excessive stretching of the chordae tendineae has been suggested as a possible mechanism for chest pain. Increased tension of the chordae tendineae presumably causes forceful traction on the papillary muscles and the adjacent left ventricular wall, which may produce variations in papillary muscle and subendocardial blood flow and oxygen demand with resulant papillary muscle ischemia and chest pain.la4

Platelet aggregation, hemorrhage, and fibrin deposits have been observed in the angle between the left atrium and the posterior mitral leaflet: microembolism from these deposits may involve the coronary circulation with subsequent myocardial ischemia.@

Subendocardial blood flow is totally diastolic and thus depends on the duration of diastole (Fig. 7). Ex- tremely fast heart rate, inappropriate sinus tachycardia with excessive postural changes, and physical and emotional stresses may occur in patients with MVPS. Sudden heart rate increases will produce disproportionately greater decreases in the diastolic time necessary for subendocardial flow than in systolic time because of a nonlinear relationship between heart rate and diastolic time.161-163 Presence of a hyperadrenergic state in certain patients with MVPS further increases myocardial oxygen con- sumption.143~ 144,169

Coronary artery vasoregulatory abnormalities may be present in certain patients with MVPS and may contribute to the pathogenesis of subendocardial or papillary muscle ischemia. Coronary artery spasm has been documented in a few patients with MVPS.lso Myocardial or subendocardial ischemia may be secondary to a combination of the above- mentioned factors. Indeed, studies that use rapid atrial pacing have shown myocardial lactate produc- tion with chest pain and ischemic electrocardiographic changes in patients with MVPS and normal coronary arteries.153* 154, lal, 182

MVPS: Cardiac arrhythmias-Palpitations. The cause of arrhythmias in patients with MVP is multifactorial and appears to be related to the anatomic substrate and to the modulating role of the autonomic nervous system (Fig. 9).* Progressive mitral regurgitation with left ventricular and left atria1 enlargement and papillary muscle traction may be responsible for cardiac arrhythmias. Certain patients with MVP may have abnormal atrioventricular con-

*References 55, 57, 62-65, 78, 81, 83, 92, 97-100, 107, 106, 117.127, 143, 151,166, 187.199.

duction that may predispose to supraventricular arrhythmias. Endocardial friction lesions resulting from friction between the chordae and left ventricular myocardium have been reported in patients with MVP, and it is possible that these lesions may be responsible for or contribute to the development of ventricular arrhythmias. Platelet aggregation, hemorrhage, and fibrin deposits have been observed in the angle between the left atrium and the posterior mitral leaflet, and microembolism from these deposits may involve the coronary circulation with subsequent myocardial ischemia and ventricular arrhythmias. Chesler et al.@ reported the clinical pathology in 14 instances of sudden death attributable to arrhythmias associated with MVP (only two had significant mitral regurgitation). Endocardial friction lesions were present in 11 individuals; five patients had a thrombotic lesion in the angle between the posterior leaflet and the left atria1 wall containing fibrin and platelets.

Autonomic dysfunction may initiate, precipitate, or contribute to arrhythmias in patients with MVPS.143p 15g, 17& 177 Increased adrenergic activity may intensify ventricular and supraventricular arrhythmias. Extreme vasovagal reaction may be responsible for bradyarrhythmias in patients with or without sinoatrial or atrioventricular node disease. Inappropriate postural tachycardia secondary to autonomic dysfunction may result in subendocardial ischemia and ventricular arrhythmias. Electrolyte abnormalities and/or pharmacologic agents may also be contributory factors for the pathogenesis of cardiac arrhythmias.153T 154, lg7

Endocardial friction lesions resulting from friction between the chordae tendineae and the left ventricular myocardium have been reported in patients with MVP, and it is possible that these lesions may be responsible for or contribute to the development of ventricular arrhythmias.@

Palpitations may be related to cardiac arrhythmias. Ambulatory monitoring, however, often dem- onstrates a discordance between rhythm abnormalities and symptoms. Patients may record palpitations while in sinus tachycardia and frequently fail to record symptoms where atria1 or ventricular arrhythmias are present.153, 154 The cause of palpitations in patients with MVPS while they are in sinus rhythm is not completely understood.

MVPS-Fatigue. Overall, fatigue is present in approximately 50% of the women and in 30% of the men with MVPS.53,54 Fatigue is a common and nonspecific symptom of an underlying physical or emotional disorder and can be conceptualized as one of two neurobiologic emergency systems employed by

808 Houdouias rt al. October 1989


most higher organisms for self preservation200-20: the fight-flight response mediated through the sympathetic neuroendocrine system, and the conservation- withdrawal response characterized by a general dampening of metabolic and physical activity. Ac- cording to Engel, 202 the conservation-withdrawal response is the next progression from fight-flight when fight-flight has proven ineffective in dealing with a presumed or real danger. Common precipitating factors evoking the conservation-withdrawal response include physical or emotional crisis, physical exhaus- tion, diminished sleep, and disease. The physiologic responses to conservation-withdrawal are similar to those observed during sleep. They include a diminu- tion of sympathetic nervous system activity with a resultant decrease in muscle activity, heart rate, cardiac output, and respiratory rate. Gastrointestional blood flow, adrenocorticotropic and growth hormone secretion decline. The net result is an overall slowing of biochemical activity.

Isoproterenol infusion in patients with MVPS produced fatigue that lasted for several hours following infusion. Thus fatigue is more than a state of mind, it is usually associated with physiologic alterations, and in patients with MVPS may have a basis in disturbances of autonomic function.

MVPS: Exercise intolerance-abnormal exercise stress test. Patients with MVPS with exercise intol- erance14, 174 and normal coronary arteries may have exercise-induced ischemic electrocardiographic (ECG) changes. 148 False positive exercise tests have been reported to be present in up to 40% of patients with MVPS.204-og Engel et a1207 performed a maximal treadmill exercise test in 43 patients with MVPS. Twelve of 43 patients (28% ) had greater than 0.1 mm of flat or downsloping ST segment depression during or following treadmill exercise. The precise mechanism(s) for these ischemic ECG changes is not well understood and may be related to autonomic dysfunction, hyperadrenergic state, and in some cases may represent myocardial ischemia.

Abinader and Shahar205 performed exercise ECG tests before and after P-blockade in 12 patients with MVP and normal coronary artery anatomy who had a positive exercise test. All abnormal exercise tests returned to normal after adequate P-blockade, while at the same time the resting and exercise heart rate decreased significantly compared with values before P-blockade. They concluded that the elimination of false-positive ECG responses by P-blockade should help improve the specificity of the exercise test. Abinader208 also performed exercise tests in 55 patients with MVP in another study. Twenty-two (40%) had a positive response and underwent a

repeat test after the administration of P-blocking drugs; of the 22 patients, 19 patients (86 7; ) had a normal exercise ECG after P-blockade. This effect of P-blocking drugs on the exercise ECG is not specific to MVP and similar responses may be seen in patients with coronary artery disease.

MVPS-Dyspnea. Dyspnea in MVPS patients cannot be explained on the basis of clear-cut cardiac or pulmonary abnormalities. Pulmonary function abnormalities have been described in patients with MVP/MVPS but are not severe enough to explain the dyspnea.211 Further, discrete pulmonary function abnormalities were not demonstrated in patients with MVPS and dyspnea.14l IS5 Left ventricular function and central hemodynamics are usually normal in MVPS patients with dyspnea. The respiratory awareness and symptoms in patients with the MVPS may represent alterations in centrally modulated breathing cycle control. These are areas for further investigation.

MVPS: Postural phenomena. Patients with MVPS often present with postural phenomena such as orthostatic decreases in cardiac output, orthostatic hypotension, tachycardia, arrhythmias, and symptoms related to alterations in heart rate, blood pressure, and cardiac output. 26.148.171-178 Orthostatic phenomena are multifactorial in origin. A decreased intravascular volume, an abnormal renin-aldosterone response to volume depletion, a baroreflex modulation abnormality, a hyperadrenergic state, or a parasympathetic abnormality may partially account for these phenomena. Further, inability of patients with MVPS to maintain normal left ventricular diastolic volume in the upright posture will result in a greater MVP and papillary muscle tension; these changes in left ventricular size and mitral valve apparatus are also important factors and may contribute to orthostatic changes.IJg, 171. 176, 185

MVPS-Syncope or presyncope. Syncope and presyncope are relatively common symptoms in patients with MVPS15I. ls4; the causes are multifactorial.* Arrhythmias definitely play some role in certain patients with MVPS. Syncope or presyncope, like palpitations, often correlate poorly with cardiac arrhythmias. A given arrhythmia, however, may not always produce symptoms, depending upon the set- ting in which it occurs (supine versus upright position). Further, the occurrence of syncope related to activity may depend not only on the kind of activity but also on its level of intensity. Other factors such as decreased intravascular volume, orthostatic hy-

*References 26. 44. 70. 76. 97, 105-10x. 1x. 1%2-l?& 171. 171-178. 187 .., 194 195 1 11.:!1.

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potension, sympathetic-parasympathetic abnormality, and baroreflex modulation abnormality may also play a role.

MVPS-Neuropsychiatric symptoms. A consistent, yet controversial, finding in many clinical studies of patients with MVPS has been the incidence of anxiety, panic attacks, and other complaints that are considered to be neuropsychiatric symptoms. Fur- ther, the incidence of MVP is greater in patients with conditions considered to be related to autonomic dysfunction.* Thus MVP was present in 38% of a group of patients with panic disorders, in 40% of a group of patients with agoraphobia, in 35 % of a group of patients with mixed disorders presenting with anxiety attacks, in many patients with migraine headache, and in 20% to 25% of a group of patients with primary disorders of sleep. The relationship between MVP and anxiety disorders remains some- thing of an enigma, however, since other studies showed no association of MVP in patients with anxiety disorder, questioned the basis for the diagnosis of MVP in the earlier studies, and concluded that MVP and neurosis are independent conditions.224

The pathophysiology of panic disorder is incompletely understood. The recent demonstration of discrete abnormalities in a region of the human brain thought to be important in the expression of emotion in patients with lactate-induced panic disorder places the matter in a neurobiologic realm. Carr and Sheehan225 presented a biologic model to explain certain aspects of panic disorder in which the primary defect is neuroendocrine rather than psychiatric, located within the redox-regulating apparatus of the brain stem. They anticipate the day when panic anxiety, now conceptualized in psychiatric terms, will be seen as merely a behavioral consequence of a primary metabolic disorder of neurons within the brain stem.225

MVPS- Pathogenesis of symptoms. Whether there is an MVPS or whether a cardiac process (MVP) co- exists with states of anxiety or autonomic dysfunction is presently controversial by virtue of lack of data.226-234 Our opinion is that symptomatic patients with MVP manifest a constitutional, neuroendocrine-cardiovascular process resulting from a close, possibly genetic relationship between anatomic MVP and centrally or peripherally mediated states of autonomic dysfunction or imbalance.2t 3s 143, 236

The true incidence of symptoms in patients with MVPS is not known and may be exaggerated because most of the studies have been performed in academic

institutions and thus may reflect a selection bias. Devereux et a1.68 addressed this issue by studying all first-degree relatives of symptomatic MVP patients referred to Cornell Medical Center. Undiagnosed MVP was found (echocardiography and physical ex- amination) in one third of these relatives. While the referral MVP patients had a higher incidence of symptoms than the undiagnosed MVP patients, palpitations, documented arrhythmias, and chest pain were significantly more common when the entire MVP cohort was compared with non-MVP relatives. Bias in the analysis of data, however, constitutes a problem with this study. When patients seeking medical care because of symptoms (of any particular disease) are excluded, the incidence of symptoms in the remainder of the patient population (not seeking medical care) will not be representative for the entire population with the disease.

Savage et al.,* in their analysis of the Framingham Heart Study population using echocardiographic criteria as evidence of MVP, found that the incidence of chest pain, syncope, and atrial or ventricular arrhythmias was not different in MVP compared with the general population. There are two major problems with this particular study. First, an ex- tremely low proportion of patients with echocardiographic findings of MVP had diagnostic auscultatory findings (9% systolic click, 9% mitral systolic murmur). Second, a high proportion of the non-MVP subjects had cardiac arrhythmias (17% supraventricular tachycardia, 40 % complex of frequent PVBs). Thus both the MVP group was different (no auscultatory findings) compared with other MVP studies, and the incidence of arrhythmias in the control group was much higher than that reported in a normal population.235

The pathogenesis of symptoms in patients with the MVPS, while incompletely understood, appears to be multifactorial, related to altered autonomic function, adrenergic responsiveness, or to combinations of these factors.*

Increased adrenergic activity, catecholamine regulation abnormality, and adrenergic hyperresponsiveness observed in certain patients with MVPS suggest that some symptoms may be catecholamine-related or mediated143, N 15~-160 Altered vagal tone, adrenergic receptor activity, or baroreceptor activity may also play a role in the pathogenesis of symptoms in certain patients.r71, 172, 174-178 The observations that patients with MVPS have low intravascular volume and a sub- normal renin aldosterone increase with volume depletion may explain why certain patients with MVPS

*References 143, 144, 149, 150, 169, 174, 175. 186. 196, 197, 200-203 ,- 13-223. *References 2,143. 144. 172, 176. 177, 337.



L Parasympathetic + Volume Abnkmality \ I I I Fig. 10. Pathogenesis of mitral valve prolapse syndrome (MVPS). Schematic presentation. (From Boud- oulas H, Wooley CF, eds. Mitral valve prolapse and the mitral valve prolapse syndrome. Mt. Kisco, NY: Futura Publishing Co, Inc, 1988:479-510. Reproduced with permission.)

may be more susceptible to volume depletion in clinical settings such as acute illness, use of diuret- ics, dehydration from vigorous physical activity, and surgical or traumatic blood 10ss.l~~, 16g-172, 174-177 The cyclical volume changes that occur in men- struating females, and the protracted volume changes present in pregnant females may produce modifica- tions in the sense of well-being or in symptoms that are related to these mechanisms. It also seems reasonable to hypothesize that in certain patients with MVPS inappropriate secretions of atria1 natriuretic factors may contribute to the pathogenesis of symptoms.160l 237* 238 Central to the understanding of the role of atrial natriuretic factor in the MVPS are the relationships of the atriopeptin-neuroendocrine system with the adrenergic system, both at a central level and at a peripheral level. The possibility that the secretion of atria1 natriuretic factor may be affected or regulated by the adrenergic nervous system and vice versa cannot be excluded.23g It is also possible that atriopeptin immune-reactive neurons may play a role in modulating the autonomic nervous system.

Thus in MVPS alterations of the heart, the kidney, the adrenals, and the autonomic nervous system co- exist and interact, creating a complex neuroendocrine cardiovascular process that may account for many of the symptoms otherwise unexplained on the basis of the valvular abnormality alone (Fig. 10).

COMMENTS

Few disorders have evoked more interest and controversy during the past three decades than MVP. Improved terminology, clarification of diagnostic criteria, and better understanding of the pathogene-

sis of symptoms will be necessary if controversy is to diminish.

MVP includes a wide spectrum of valvular abnormalities. Physical and laboratory findings are directly related to the valvular abnormality. As a general rule, patients with more severe disease will have more clinical and laboratory findings, and vice versa24o (Fig. 11). The search for a single, diagnostic gold standard has been an example of reductionist simplicity in diagnostic medicine reminiscent of the decades of controversy over the use of the exercise ECG in the diagnosis of coronary artery disease. No- where else in clinical cardiology has good judgment been replaced in the diagnostic process by diagnosis by angles, degrees, and millimeters, as in MVP. Di- agnoses based on subjective interpretation of auscultatory systolic clicks without echophonocardio- graphic confirmation, or nonspecific echocardiographic findings without other clinical correlates, have contributed to diagnostic confusion and to exaggerated incidence figures. In general, we are more comfortable when the diagnosis of MVP is based on a coherent auscultatory postural complex and con- firmatory imaging studies. However, because echocardiographic and cineangiographic studies have shown that MVP may occur without external auscultatory phenomena, we must make room for some diagnostic flexibility.

It should be emphasized that it is of great clinical importance to avoid the overdiagnosis of MVP in normal individuals or in patients who fall in the gray zone between normal and MVP. It is equally important to stratify patients with MVP according to the clinical and laboratory findings. Results from studies of patients with MVP should be directly related to

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Number 4 Mitral valve prolapse 8 11

Spectrum of mitral valve dysfunction In patients with MVP. (Schematic presentation 01 patients dlstrlbution)

Clinical and Laboratory

Abnormalltles

Severity of Disease Age - Time

Morbidity and/or

Mortality

Natural hlstory of MVP in relation to mitral valve dysfunction (Schematic presentation)

Fig. 11. Left panel, Relationship between the number of clinical and laboratory abnormalities and the severity of the disease (schematic presentation). Mitral valve prolapse (MU) includes a wide spectrum of valvular abnormalities from mild to severe;iand at any particular time the number of abnormal clinical (e.g., click, click plus late systolic murmur, holosystolic murmur, gallop rhythm, cardiac arrhythmias, etc.) and laboratory findings (e.g., late systolic prolapse, thickened mitral leaflets, holosystolic prolapse, left ventricular and left atria1 enlargement on echocardiogram, mitral regurgitation on Doppler) is directly related to the severity of the disease. Right panel, The spectrum of mitral valve abnormalities in patients with MVP (upper) is compared with the natural history (lower). MVP patients may have a wide spectrum of valvular abnormalities from mild to severe. The natural history of patients with MVP is directly related to the severity of mitral valve abnormalities. Lines represent morbidity and mortality related to complications such as infective endocarditis, thromboembolic phenomena, cardiac arrhythmias, mitral regurgitation, etc. (schematic presentation). (From Boudoulas H, Wooley CF. Mitral valve prolapse and the mitral valve prolapse syndrome. Mount Kisco, NY: Futura Publishing Co, Inc, 1988. Ref. 240. Reproduced with permission.)

the subgroup of patients investigated. Differences among individual patients with MVP contribute to the spectrum of results regarding prevalence, echocardiographic findings, symptoms, complications, etc. Similarly, management and natural history obvi- ously differ in each subgroup of patients with MVP. The fallacy of comparing the natural history of one group of patients with MVP with that of another without further stratification is similar to that of comparing the natural history of two groups of patients with coronary artery disease without further stratification. Better clinical classification and imaging definition of the severity of mitral valve abnormality will help to better define the natural history in the different subgroups. Thus subgroups of MVP patients with a higher incidence of complications (progression to severe mitral regurgitation, chordae tendineae rupture, embolic phenomena, infectious endocarditis, sudden death) could be defined more effectively.

MVP-ANATOMIC AND THE MVP-SYNDROME

Based on these experiences, we proposed the following classification of patients with MVP (Table II, Fig. 12). MVP-anatomic includes patients with a wide spectrum of valvular abnormalities, from mild to severe (Fig. 1). The term floppy mitral valve comes from surgical and pathological studies and re-

fers to the expansion of the mitral valve leaflet(s) area with elongated chordae, dilated mitral anuli, and characteristic structural changes in the valve leaflets. Symptoms, physical findings, and laboratory abnormalities in these patients are directly related to mitral valve dysfunction and progressive mitral regurgitation.

The term MVP-syndrome refers to the occurrence of or coexistence of symptoms that result from various forms of neuroendocrine or autonomic dysfunction in patients with MVP, in whom the symptoms cannot be explained on the basis of valvular abnormality alone. It should be emphasized that this portion of our classification is necessarily tentative, and is subject to continuous modification and adap- tation.

This classification is clinically useful; it stratifies symptomatic patients with MVP and with symptoms related to autonomic dysfunction from patients whose symptoms are related to progressive mitral valve dysfunction; it identifies a group of patients with MVP and autonomic dysfunction who require con- sideration for antibiotic prophylaxis for infectious endocarditis in addition to other forms of treatment; and it defines a group of symptomatic patients who need attention from physicians who are aware of newer developments of autonomic function and dysfunction.

812 Houdoulcfs et al.

MITRAL VALVE PROLAPSE

AND

. .I

THE MITRAL VALVE

PROLAPSE SYNDROME

Fig. 12. Mitral valve prolapse (MVP) occurs when one or both mitral leaflets prolapse back into the left atrium during left ventricular systole. MVP can be detected by imaging techniques (echocardiogram, ventriculogram, magnetic resonance imaging, etc.). Auscultatory findings of MVP include mobile systolic click with or without mid to late systolic murmur; postural changes produce significant changes of the auscultatory findings. In MVP-syndrome, symptoms cannot be explained on the basis of valvular abnormalities alone, and result from various forms of neuroendocrine or autonomic dysfunction present in certain patients with MVP. (From Boudoulas H, Wooley CF, eds. Mitral valve prolapse and the mitral valve prolapse syndrome. Mt. Kisco, NY: Futura Publishing Co, Inc, 1988. Reproduced with permission.)

SUMMARY

A clinical classification for patients with MVP is not well defined and the pathogenesis of symptoms in symptomatic patients with MVP remains poorly understood. To this end, 399 patients from our MVP (auscultation/echocardiographic-angiographic) population were analyzed. Symptoms were primarily or directly related to progressive valvular dysfunction in 86 patients (mean age 67). Following a long clinical course, 76 of these patients eventually had mitral valve surgery with pathologic confirmation of floppy, myxomatous mitral valves in all.

Three hundred thirteen patients (mean age 30) with MVP and normal left ventricular function had symptoms (chest pain, palpitations, fatigue, exercise intolerance, dyspnea, syncope or presyncope, postural phenomena, neuropsychiatric symptoms) that

October 1989


could not be explained on the basis of valvular dysfunction alone. Studies in subsets of 65 of these patients showed: (1) increased urine catecholamine excretion and hypersensitivity to isoproterenol infusion; (2) abnormal plasma catecholamine response after volume expansion; (3) abnormal renin and aldosterone response after volume depletion; or (4) decreased exercise tolerance associated with decreased left ventricular volumes with upright exercise.

Thus two groups of symptomatic patients with MVP were defined: (1) patients with MVP in whom symptoms were directly related to mitral valve dysfunction and complications (at present we refer to this group as MVP-anatomic) and (2) patients with MVP in whom symptoms were related primarily to neuroendocrine-autonomic dysfunction (at present we refer to this group as MVP-syndrome). This classification is clinically useful in the stratification of MVP patients in general and to separate MVP patients with symptoms related to or associated with autonomic dysfunction from patients whose symptoms are related primarily to progressive mitral valve dysfunction.

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