Mitral valve prolapse (MVP) is the most common valvular abnormality, affecting approximately 2-3% of the population in the United States. MVP usually has a benign course, but it occasionally leads to serious complications, including clinically significant mitral regurgitation (MR), infective endocarditis, sudden cardiac death, and cerebrovascular ischemic events.
Signs and Symptoms
Most patients with MVP are asymptomatic. Symptoms are related to one of the following:
Progression of MR
An associated complication (ie, stroke, endocarditis, or arrhythmia)
Autonomic dysfunction (The association between autonomic dysfunction and MVP remains unconfirmed.)
Symptoms related to progression of MR include the following:
Fatigue
Dyspnea
Exercise intolerance
Orthopnea
Paroxysmal nocturnal dyspnea (PND)
Progressive signs of chronic heart failure (CHF)
Palpitations (from associated arrhythmias)
Symptoms related to autonomic dysfunction are usually associated with genetically inherited MVP and may include the following:
Anxiety
Panic attacks
Arrhythmias
Exercise intolerance
Palpitations
Atypical chest pain
Fatigue
Orthostasis
Syncope or presyncope
Neuropsychiatric symptoms
Common general physical features associated with MVP include the following:
Asthenic body habitus
Low body weight or BMI
Straight-back syndrome
Scoliosis or kyphosis
Pectus excavatum
Hypermobility of the joints
Arm span greater than height (which may be indicative of Marfan syndrome)
The classic auscultatory finding is a mid-to-late systolic click. It may or may not be followed by a high-pitched, mid-to-late systolic murmur at the cardiac apex. These can vary with the following maneuvers:
A Valsalva maneuver or having the patient stand result in an earlier click, closer to the first heart sound, and a prolonged murmur. It may even bring out a murmur when none is heard at rest.
The supine position, especially with the legs raised, results in a click later in systole and a shortened murmur
See Clinical Presentation for more detail.
Diagnosis
Findings on echocardiography are as follows:
Classic MVP: The parasternal long-axis view shows greater than 2-mm superior displacement of the mitral leaflets into the left atrium during systole, with a leaflet thickness of at least 5 mm
Nonclassic MVP: Displacement is more than 2 mm, with a maximal leaflet thickness of less than 5 mm
Other echocardiographic findings that should be considered as criteria are leaflet thickening, redundancy, annular dilatation, and chordal elongation
See Workup for more detail.
Management
For purposes of treatment, patients with MVP can be divided into the following categories:
Asymptomatic patients with minimal disease
Patients with symptoms of autonomic dysfunction
Patients with evidence of progression to severe MR
Patients with neurologic findings
Patients with a mid-systolic click and late-systolic MR murmur
Treatment measures for asymptomatic patients with minimal disease
Reassurance of the benign prognosis
Initial echocardiography for risk stratification; if no clinically significant mitral regurgitation and thin leaflets are observed, clinical examinations and echocardiographic studies can be scheduled every 3-5 years
Encouragement to pursue a normal, unrestricted lifestyle with vigorous exercise
Treatment measures for patients with symptoms of autonomic dysfunction
Different measures that may be aimed at orthostatic intolerance
Abstinence from stimulants such as caffeine, alcohol, and cigarettes
An ambulatory 24-hour Holter monitor may be useful to detect supraventricular and/or ventricular arrhythmias
Treatment measures for patients with evidence of or progression to severe MR
Close follow-up and consideration for surgical referral weighing the reparability of the lesion and signs of ventricular dysfunction (eg, enlarged ventricular dimensions, presence of atrial fibrillation, or pulmonary hypertension).
Treadmill stress test for exercise tolerance if the physician is unsure the patient is asymptomatic
Treatment measures for patients with central neurologic findings
Atrial fibrillation should be actively sought (see Cryptogenic Stroke evaluation). If it is not found, antiplatelet therapy with clopidogrel or aspirin may be considered for risk factor modification.
Cessation of smoking and oral contraceptive use
Appropriate anticoagulant treatment should be considered for patients with atrial fibrillation and a history of stroke/transient ischemic attack (TIA) according to general atrial fibrillation guidelines
Mitral valve prolapse (MVP) is the most common valvular abnormality, affecting approximately 2-3% of the population in the United States.[1, 2] It is generally defined as the systolic displacement of one or more abnormally thickened, redundant mitral leaflet(s) into the left atrium during systole.[3] It may be familial or sporadic with the majority of data favoring an autosomal dominant pattern of inheritance in a large proportion of individuals with MVP.[4, 5] It is also the most common cause of isolated mitral regurgitation (MR) requiring surgical repair.[6]
MVP usually results in a benign course. However, it occasionally leads to serious complications, including clinically significant MR, infective endocarditis, sudden cardiac death, and cerebrovascular ischemic events.
Mitral valve prolapse (MVP) is characterized primarily by myxomatous degeneration of the mitral valve leaflets. In younger populations, there is gross redundancy of both the anterior and posterior leaflets and chordal apparatus. This is the extreme form of myoxomatous degeneration, known as Barlow’s syndrome. In older populations, however, MVP is characterized by fibroelastic deficiency, sometimes with superimposed chordal rupture due to a lack of connective tissue support. These anatomic abnormalities result in malcoaptation of mitral valve leaflets during systole, resulting in regurgitation. Mitral annular dilatation may also develop over time, resulting in further progression of mitral regurgitation (MR). Acute severe MR results in congestive heart failure symptoms without left ventricular dilatation. Conversely, chronic or progressively severe MR can lead to ventricular dilatation and dysfunction, neurohormonal activation, and heart failure. Elevation in left atrial pressures can result in left atrial enlargement, atrial fibrillation, pulmonary congestion, and pulmonary hypertension.[7]
Myxomatous proliferation is the most common pathologic basis for MVP, and it can lead to myxomatous degeneration of the loose spongiosa and fragmentation of the collagen fibrils. Disruption of the endothelium may predispose patients to infectious endocarditis and thromboembolic complications. However, the vast majority of patients with MVP have only a minor derangement of the mitral valve structure that is usually clinically insignificant.
Mitral valve prolapse (MVP) usually occurs as an isolated entity. It also commonly occurs with heritable disorders of connective tissue, including Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum.[8, 9] MVP has also been described in association with a secundum atrial septal defect and hypertrophic cardiomyopathy. Also see Presentation.
Mitral valve prolapse (MVP) is thought to be inherited with increased expression of the gene in female individuals (2:1). The most common form of inheritance is autosomal dominant, but X-linked inheritance has been described.
MVP commonly occurs with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. In fact, 75% of patients with Marfan syndrome have MVP due to the increased redundancy of the mitral leaflets and apparatus that occurs as a result of myxomatous degeneration.
In the 1970s and 1980s, MVP was overdiagnosed because of the absence of rigorous echocardiographic criteria, with a reported prevalence of 5-15%. Subsequently, Levine et al reported that the 2-dimensional echocardiographic characterizations of prolapse, especially on the parasternal long-axis view, are most specific for the diagnosis of MVP. Use of these criteria prevents overdiagnosis.
Data from the community-based Framingham Heart Study demonstrated that MVP syndrome occurred in only 2.4% of the population.
Age- and sex-related demographics
MVP has been observed in individuals of all ages.
The prevalence of MVP was similar for men and women in the Framingham Heart Study.[1] However in the Olmsted County population, women were diagnosed more often than men and at a younger age.[10] Complications related to MVP, however, are reported more frequently in men.[11] In a study from Mayo clinic, women presented more commonly with anterior and bileaflet prolapse, fewer flail leaflets, and less mitral regurgitation compared with men.[12] They also undergo mitral surgery less often than men and exhibit excess long-term mortality but equivalent survival after valve surgery compared to men.[12]
Mitral valve prolapse (MVP) has a widely varying prognostic spectrum, although most patients with MVP remain asymptomatic and have a near-normal life expectancy. Approximately 5-10% have progression to severe mitral regurgitation (MR).[13, 14] Overall, young patients (age >50 years) with normal left ventricular function and no symptoms tend to have excellent survival with medical treatment, even those with severe MR.[10, 15]
Morbidity/mortality
Most patients with MVP are asymptomatic and have a benign prognosis, with survival rates similar to those of the general population. Nonetheless, high-risk patients (ie, those with moderate-to-severe MR and reduced left ventricular systolic function) have increased cardiac morbidity and mortality rates. In a community-based study of 833 individuals diagnosed with asymptomatic MVP who were followed up longitudinally in Olmsted County, Minnesota,[16] the best predictors for cardiac mortality were the presence of MR and left ventricular dysfunction at the time of diagnosis. The study also identified certain risk factors for cardiac morbidity (defined as the occurrence of heart failure, thromboembolic events, atrial fibrillation, or need for cardiac surgery), including age older 50 years, left atrial enlargement, degree of regurgitation, the presence of a flail leaflet, and the presence of trial fibrillation at the time of the baseline echocardiogram.[16]
Complications
Complications of MVP include the following:
Severe MR
Atrial fibrillation
Infective endocarditis
Sudden cardiac death and cerebrovascular ischemic events
Mitral regurgitation (MR)
This is the most common complication of MVP and the leading cause of isolated MR requiring mitral valve surgery in the United States. Severe MR is most frequently due to rupture of the chordae tendineae.
The risk of MR increases with the following factors: age older than 50 years, male sex, history of hypertension, increased body mass index (BMI), increased mitral valve thickness or redundancy, and left atrial and left ventricular dilatation.
In a Mayo clinic series, MR volume increased more than 8 mL in 51% of 74 patients with MVP over a follow-up period of 1.5 years.[17] Progression of the valvular lesions and an increase in mitral annular diameter were the two independent predictors of an increase in regurgitant volume over time.[17] MR diagnosed on the basis of the presence of a systolic murmur is associated with an increased risk of adverse events, including progressive valve dysfunction,[18, 19, 20] infective endocarditis,[18, 21] and sudden death.[22, 23]
Infective endocarditis
The main mechanism for increased risk is a turbulent flow state due to leaflet thickness or redundancy and MR. The risk of endocarditis increases 3- to 8-fold with MVP. The risk of developing infective endocarditis is higher if a systolic murmur of MR is present.[24]
The main predictors are age older than 50 years, male sex, history of hypertension, increased body mass index (BMI), left atrial and ventricular enlargement, and increased mitral valve thickness or redundancy.
In a systematic review of 287 patients undergoing surgery for native valve endocarditis at the Mayo Clinic, MVP was present in 43% of patients and it was an independent risk factor for development of endocarditis.[25]
Sudden cardiac death (SCD) and cerebrovascular ischemic events
There is a 50-60% increased risk of atrial and ventricular arrhythmias in patients with myxomatous MVP; the risk of sudden death is 0.4-2% in these patients.[26, 27, 28] The risk is increased when patients have evidence of left ventricular dilatation and dysfunction, severe MR, or increased mitral leaflet thickness or redundancy.
A clinical syndrome of bileaflet MVP syndrome has been described, characterized by myxomatous bileaflet MVP, T-wave inversion in the inferolateral electrocardiograph (ECG) leads, and complex ventricular ectopy (arising from one or both of the papillary muscles), most often observed in young women.[29] In a registry study of 650 adults younger than years with SCD, 43 patients were identified with MVP, comprising 7% of all patients with SCD.[30] Bileaflet involvement was seen in 70%. All patients had left ventricular fibrosis at the level of the papillary muscle on histology and 88% had inferobasal fibrosis. ECGs for 12 of those patients showed right bundle-branch block. Factors cited as increasing the risk for life-threatening ventricular arrhythmias include bileaflet MVP, female sex, and frequent ventricular ectopy.[29]
In the presence of QT prolongation and frequent ventricular ectopy, especially nonsustained ventricular or sustained ventricular tachycardia, an electrophysiologic study may be indicated to quantitate the risk of inducible ventricular tachycardia and/or ventricular fibrillation and sudden arrhythmic death.
There is only a weak relationship between MVP and stroke. In a study of 777 patients with MVP who were followed for a mean period of 5.5 years, ischemic neurologic events occurred in 4% (n = 30).[31] The risk was significantly increased compared to the expected rate in the community. However, the risk was nondetectable in patients with MVP without leaflet thickening but high after either atrial fibrillation or cardiac surgery.[31] Other studies on MVP have found no relationship between MVP and cerebral events.[1] Gilon et al described the lack of an association between MVP and stroke in young 213 patients.[32]
The potential mechanisms for stroke in patients with MVP is related to the prevalence of other risk factors, primarily atrial fibrillation, which may be paroxysmal or asymptomatic. Other hypothesized mechanisms include the formation of platelet fibrin thrombi on the denuded, damaged myxomatous valves resulting in embolization. Data suggest that the prevalence of this mechanism is based on the degree of MR. Abnormal platelet function has also been reported in some studies.[33]
The major risk factors for cerebrovascular events include age older than 50 years, thickened mitral valve leaflets, atrial fibrillation, and a need for mitral valve surgery.
Patients with mitral valve prolapse (MVP) should receive education regarding their prognosis along with the signs and symptoms of disease progression.
Of emphasis, most patients with MVP have a benign course, but the risk of ruptured chordae tendinae and/or clinically significant mitral regurgitation, infective endocarditis, embolic transient ischemic attack (TIA) or stroke, and rare sudden death must also be discussed.
For patient education resources, see Heart Health Center as well as Mitral Valve Prolapse.
Mitral valve prolapse (MVP) can be categorized into primary or nonsyndromic MVP and secondary or syndromic MVP.
Primary/nonsyndromic MVP
In the community-based Framingham Heart Study, the prevalence of MVP was 2.4%.[1] A similar prevalence was described in a population-based sample of American Indians[2] as well as in a sample of Canadians of South Asian, European, and Chinese descent (SHARE study).[34] Tricuspid valve prolapse has been observed in up to 40-50% of patients with primary or nonsyndromic MVP.[35]
Secondary/syndromic MVP
MVP also occurs in the presence of connective tissue disorders, such as the following[8, 9] :
Mitral valve prolapse (MVP) is often diagnosed from the physical examination, when the classic auscultatory finding of a mid-to-late systolic click and/or murmur is appreciated. Alternatively, it may be incidentally diagnosed during routine echocardiography or discovered when complications of MVP manifest.
Most patients are asymptomatic. Those with symptomatic MVP typically present with symptoms related to (1) progression of mitral regurgitation (MR), (2) an associated complication (ie, stroke, endocarditis, or arrhythmia), or (3) autonomic dysfunction (this association remains unconfirmed; see below).
Progression of MR
Symptoms related to progression of MR include the following:
Fatigue
Dyspnea
Exercise intolerance
Orthopnea
Paroxysmal nocturnal dyspnea (PND)
Progressive signs of congestive heart failure (CHF)
Palpitations (from associated arrhythmias)
Autonomic dysfunction
Autonomic dysfunction has been reported as the mechanism underlying symptoms in patients with MVP. The spectrum of symptoms resulting from autonomic dysfunction was previously termed as MVP syndrome.[1, 36] However, the association between MVP and autonomic dysfunction remains unconfirmed.[37]
Symptoms related to autonomic dysfunction are usually associated with genetically inherited MVP and may include the following:
Anxiety
Panic attacks
Arrhythmias
Exercise intolerance
Palpitations
Atypical chest pain
Fatigue
Orthostasis
Syncope or presyncope
Neuropsychiatric symptoms
The electrocardiogram (ECG) is usually normal, but it can show nonspecific ST-segment and T-wave abnormalities, especially in leads II, III, aVF.
As noted earlier, MVP is also commonly seen in patients with heritable connective tissue disorders.
Clinical characteristics are typically benign in young women, whereas men older than 50 years tend to have serious consequences of mitral regurgitation (MR).
Common general physical features associated with mitral valve prolapse (MVP) include the following:
Asthenic body habitus
Low body weight or body mass index (BMI)
Straight-back syndrome
Scoliosis or kyphosis
Pectus excavatum
Hypermobility of the joints
Arm span greater than height (which may be indicative of Marfan syndrome)
Physical findings
The classic auscultatory finding is a mid-to-late systolic click, which is present due to the leaflets prolapsing into the left atrium, thereby resulting in tensing of the mitral valve apparatus. The click may or may not be followed by a high-pitched, mid-to-late systolic murmur at the cardiac apex.
The midsystolic click can vary in intensity and timing, primarily depending on the left ventricular volume.
End-diastolic volume can be reduced by having the patient perform a Valsalva maneuver or by having the patient stand. These maneuvers result in an earlier click, closer to the first heart sound, and a prolonged murmur. They may even bring out a murmur when none is heard at rest. In the supine position, especially with the legs raised for increased venous return, left ventricular diastolic volume is increased, resulting in a click later in systole and a shortened murmur.
TTE is the most important study for diagnosing mitral valve prolapse (MVP).
Perloff et al set the stage for accurately diagnosing MVP by expanding the diagnostic standards to include clinical and echocardiographic criteria.[39, 40]
In a Framingham Heart Study, Freed et al historically described echocardiographic criteria for MVP as classic versus nonclassic (see below).[1]
Use of the parasternal long-axis view reduces the overdiagnosis of MVP.[41]
Echocardiographc findings/diagnostic criteria are as follows:
Classic MVP: The parasternal long-axis view shows more than 2-mm superior displacement of the mitral leaflets into the left atrium during systole, with a leaflet thickness of at least 5 mm.
Nonclassic MVP: Displacement is more than 2 mm, with a maximal leaflet thickness below 5 mm.
Other: Other echocardiographic findings that should be considered as criteria are leaflet thickening, redundancy, annular dilatation, and chordal elongation.
2D and 3D Transesophageal echocardiography (TEE)
2D-TEE takes into account several planes of imaging and is thus considered more effective in identifying prolapsing mitral valve segments.[42] 3D TEE, however, can simulate the surgeon’s view of the mitral valve and has become an essential tool in the intraoperative setting.[43]
Cardiac magnetic resonance imaging (cMRI)
CMRI represents a novel noninvasive imaging method that can identify MVP with a sensitivity and specificity of 100%, using 2D TTE as the gold standard.[44] CMRI can also serve as an important tool for follow-up of patients with MVP-related moderate to severe MR for quantitative assessment of ventricular volumes and function.[45] It can also provide insight into the biology of MV; CMRI has shown gadolinium enhancement in both the MV and papillary muscle tips in patients with MVP but not in normal subjects.[44] It is postulated that the papillary muscle is altered in MVP by repetitive traction exerted by the prolapsing leaflets.[46] CMRI-determinants of MVP-related MR include anterior leaflet length, posterior leaflet displacement, and the presence of flail leaflets.[45]
A 2015 study used CMRI for identifying the structural hallmarks of patients with MVP who had complex ventricular arrhythmias. Briefly, all patients had CMRI findings of left ventricular fibrosis at the level of papillary muscles and in the inferobasal regions. These findings correlated with autopsy findings of sudden cardiac deth (SCD} in patients with MVP.
Contrast ventriculography can also help in defining mitral valve prolapse (MVP) with or without mitral regurgitation (MR). However, with the advent of echocardiography, this study is rarely necessary.
Chest radiography
Radiographs may demonstrate the progression from asymptomatic to chronic, severe MR, with the development of cardiomegaly secondary to left atrial and left ventricular dilatation and evidence of heart failure.
Aymptomatic patients with minimal mitral valve disease should be reassured of their benign prognosis.
They should undergo initial echocardiography for risk stratification. If no clinically significant mitral regurgitation (MR) and thin leaflets are observed, clinical examinations and echocardiographic studies can be scheduled every 3-5 years.
Encourage these patients to pursue a normal, unrestricted lifestyle, including vigorous exercise.
Different measures may be aimed at orthastatic intolerance. A trial of beta-blockers for symptomatic relief can be recommended in patients with palpitations.or other symptoms of an enhanced adrenergic drive. Abstinence from stimulants such as caffeine, alcohol, and cigarettes is also recommended. An ambulatory 24-hour Holter monitor may be useful to detect supraventricular and/or ventricular arrhythmias.
Patients with evidence of progression to severe mitral regurgitation
Asymptomatic patients with moderate-to-severe MR and left ventricular enlargement, especially those with atrial fibrillation and/or pulmonary hypertension, should undergo surgery before left ventricular function deteriorates. Echocardiographic criteria for severe MR include a vena contracta width more than 0.7 cm, a large central MR jet (area >40% of the left atrium), pulmonary vein reversal, an effective regurgitant orifice more than 40 mm2, a regurgitant fraction over 50%, and a regurgitant volume over 60 mL.[47]
According to the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of patients with valvular heart disease, mitral valve surgery is indicated for asymptomatic patients with chronic severe primary MR and a left ventricular ejection fraction (LVEF) of 30-60% and/or a left ventricular end-systolic dimension (LVESD) of 40 mm or more (class 1; level of evidence: B).[48] Timing of surgery should also take into account the anatomy of the valve lesion, the likelihood of a successful repair, and the local surgical experience.
If it is unclear whether or not the patient is asymptomatic, a treadmill stress test for exercise tolerance can be performed. That is, have the patient demonstrate that he or she can walk vigorously without symptoms.
Patients with MVP and neurologic findings
Antithrombotic therapy is not recommended in patients without a history of systemic embolism, ischemic stroke, or atrial fibrillation. However, a thorough evaluation for atrial fibrillation should be undertaken with consideration for longer term (eg, 30 day) monitoring.[49, 50] For secondary prevention, in the absence of demonstrable atrial fibrillation, antiplatelet therapy with aspirin at a dosage of 75-325 mg/day or clopidogrel 75 mg/day may be considered.
Recommend cessation of smoking and oral contraceptive use to prevent a hypercoagulable state.
Embolic events in patients with MVP and mild MR that are presumed to be secondary to paroxysmal atrial fibrillation should be treated according to general guidelines for atrial fibrillation.
Infective endocarditis prophylaxis (IE):
Endocarditis prophylaxis is no longer recommended by the current ACC/AHA guidelines for patients with MVP, except in high-risk patients and those at risk of complications from endocarditis.[47, 48, 51]
Follow-up
Depending on its severity, patients with MVP may be monitored regularly with a careful history, physical examination, and echocardiography when indicated.
If symptoms or physical findings change during outpatient care, echocardiography or other studies (ie, Holter monitor, radiography) may be indicated
In a study of 443 patients who underwent mitral valve repair formitral valve prolapse (MVP), investigators found that preoperative atrial fibrillation was a predictor of long-term mortality and postoperative left ventricular dysfunction. The investigators suggested that performing mitral valve repair surgery before the onset of atrial fibrillation may improve postoperative outcomes.[52]
In a retrospective study of 1218 patients who underwent mitral valve repair for isolated degenerative mitral regurgitation (MR), postoperative MR recurrence was associated with adverse left ventricular remodeling and late death. The investigators found a marked decrease in the incidence of MR recurrence following the first year after intervention. They recommended that patients with complex mitral valve prolapse be informed of the risk of recurrent MR during the first year after degenerative mitral valve repair.[53]
See the surgical management discussion in the Medscape article Mitral Regurgitation.
Qurat-ul-ain Jelani, MD, Fellow, Department of Medicine, Division of Cardiology, Bridgeport Hospital, Yale New Haven Health System
Disclosure: Nothing to disclose.
Coauthor(s)
Adam E Schussheim, MD, Cardiac Specialists, PC
Disclosure: Nothing to disclose.
Bhavik V Thakkar, MD, Medical Director, Internal Medicine Hospitalist, AppleCare Medical Group
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Richard A Lange, MD, MBA, President, Texas Tech University Health Sciences Center, Dean, Paul L Foster School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Justin D Pearlman, MD, ME, PhD, FACC, MA, Chief, Division of Cardiology, Director of Cardiology Consultative Service, Director of Cardiology Clinic Service, Director of Cardiology Non-Invasive Laboratory, Chair of Institutional Review Board, University of California, Los Angeles, David Geffen School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Alan D Forker, MD Professor of Medicine, University of Missouri at Kansas City School of Medicine; Director, Outpatient Lipid Diabetes Research, MidAmerica Heart Institute of St Luke's Hospital
Nidorf SM, Weyman AE, Hennessey R. The relationship between mitral valve morphology and prognosis in patients with mitral valve prolapse: a prospective echocardiographic study of 568 patients [abstr]. J Am Soc Echocardiogr. 1993. 6:S8.