THE MITRAL VALVE PROLAPSE EPIDEMIC: FACT OR FICTION*

RICHARD P. LEWIS**, and (by invitation) CHARLES F. WOOLEY, ALBERT J. KOLIBASH, and HARISIOS BOUDOULAS
COLUMBUS

Few disorders have evoked more interest and controversy over the past decade than mitral valve prolapse (MVP). For many internists, neurologists, obstetricians, psychiatrists, family practitioners, and dentists, MVP must seem like a modern epidemic. While the prognosis is said to be benign in the vast majority of patients, sudden death, stroke, subacute bacterial endocarditis, and ruptured chordae tendinae are well publicized complications. Should an already worried patient be told about these possibilities? Can a high risk subset be identified? Is MVP responsible for all of their symptoms? Or is it simply an incidental finding in a patient with chronic anxiety, or even a spurious finding? Finally, where were these people before echocardiography? Before proceeding to answer these questions, we must first consider the reliability of the diagnosis of MVP. There is significant day to day variation in the associated physical findings of a click or a mitral systolic murmur or both. In all likelihood this changeability is related to neuroendocrine factors (see later). Oar experience is that 15-20% of subjects with symptoms and echographic MVP will not have a click or murmur on a given examination, assuming that an expert examination, including dynamic auscultation, is performed (1, 2). Echocardiography has been the "gold standard" for establishing the diagnosis of MVP since the mid 1970s. In reality, this is a "soft" standard. In our experience, the pathognomonic findings of an enlarged thickened mitral valve with clear cut systolic prolapse into the left atrium accompanied by Doppler evidence of some degree of regurgitation are seen in only about half of those diagnosed as having MVP. Technically inadequate studies still occur in 10-15% of patients and false positive diagnoses have been recognized as a problem for many years (3). Even with optimal technique, the finding of MVP is at best "borderline" in up to one third

* Department of Internal Medicine, Division of Cardiology, The Ohio State University College of Medicine, Columbus, Ohio. ** Correspondence should be sent to: Richard P. Lewis, M.D., Ohio State University Hospitals, Division of Cardiology, 653 Means Hall, 1654 Upham Drive, Columbus, Ohio

43210. 222

THE MITRAL VALVE PROLAPSE EPIDEMIC

223

of patients. It seems likely that diagnostic errors from both echocardiography and physical examination (false positive and false negative diagnoses) have contributed to the continuing debate over the incidence and symptomatic manifestations of MVP. It is the purpose of this report to present a new conceptual framework from which to view the MVP "epidemic" based upon a twenty-five year experience of MVP research at Ohio State University.

INCIDENCE Because of diagnostic problems discussed above, considerable controversy exists over the incidence of MVP. An incidence of 4-6% for the adult population seems generally accepted on the basis of epidemiologic studies of population samples and from autopsy studies (4-6). If this incidence is correct, MVP is nearly as common as ischemic heart disease in the United States. The extremely long clinical course of MVP (50 years on average) has made natural history studies virtually impossible. Certain trends do emerge from the incidence studies. MVP is more common in women at all ages, but the long term prognosis seems better in women. The incidence of more severe degrees of anatomic changes in the mitral valve increases with age, although there are still only limited clinical pathologic correlation data available, especially in individuals under 40 years of age. In Davies's autopsy study the incidence of grossly abnormal valves (floppy valves) was 3.9% in males and 5.2% in females. Such valves were felt to have been a significant cause of morbidity. However, another 5% had a minimal abnormality which Davies considered an incidental finding. There appear to be two distinct subsets of symptomatic patients with MVP. Younger patients (especially females) have a constellation of symptoms termed "the MVP Syndrome" which seems largely unrelated to the mitral valve. Older patients (especially males) develop complications which are clearly related to the mitral valve. For practical purposes, therefore, there seem to be two clinical entities of MVP.
ANATOMIC MITRAL VALVE PROLAPSE ("FLOPPY" VALVES) It is a common misconception that many patients with floppy mitral valves have recognizable hereditable connective tissue disorders. Although some as yet ill defined dyscollagenosis may be present in MVP, the dire consequences of such disorders as Marfan's Syndrome are not seen. MVP is inherited as an autosomal dominant with incomplete penetrance.

224

RICHARD P. LEWIS

Mitral regurgitation due to ruptured chordae tendineae was first described by Williams in 1840 (7), but it was not until the modern era that rupture of the chordae tendineae as a cause for mitral regurgitation was rediscovered by Bailey and Hickam in 1944 (8). The "floppy valve syndrome" was subsequently defined by Read et al in 1965 (9). Of interest, pathologists continued to attribute the pathology of these valves to rheumatic fever until the 1970's. A quantitative study of floppy valves has been performed in our laboratory (10). A typical floppy valve is shown in Figure 1. Such valves have increased surface area (especially the posterior leaflet) and show thinning in certain areas while other areas are thickened by myxomatous deposits and fibrosis. The mitral annulus is enlarged and the chordae are variably elongated. The primary lesion appears to be collagen dissolution-not myxomatous degeneration which seems to be a secondary change. The valve surface is often rough and may show endothelial tears which can be the source of platelet or red thrombi (which can embolize) (11). Thrombi can also form at the junction of the mitral valve and left atrium. The chordae tendineae also show collagen dissolution and myxomatous deposition. The resultant diminished tensile strength is the basis

FIG. 1. Atrial views of a "floppy" mitral valve (above) from a patient with severe mitral regurgitation and a normal mitral valve (below). The floppy valve has a substantially larger surface area due mostly to increased posterior leaflet size. Ruptured chordae tendineae were present and there was annular dilatation.

THE MITRAL VALVE PROLAPSE EPIDEMIC

225

for rupture (12). Mitral annular calcification often develops after the fifth decade. Friction lesions on the posterior ventricular wall are common in advanced disease. A floppy valve per se does not necessarily produce significant regurgitation. When severe regurgitation occurs, it is usually associated with ruptured chordae tendineae, fibrous attachment of the valve to the ventricle or mitral annular dilation (5, 10, 11). Up to one third of patients have similar, though usually less extensive, changes in the tricuspid valve but the semilunar valves are usually spared. The commonest complication of floppy valves is progressive mitral regurgitation (13, 14). We estimate that this complication occurs in 510% of patients with floppy valves. Approximately one third of these patients will require mitral valve replacement or repair. Indeed, with the decline in incidence of rheumatic heart disease, severe mitral regurgitation from floppy valves is now the commonest indication for isolated mitral valve surgery (15). Bacterial endocarditis develops in a small percentage of these patients (10-15%) but endocarditis is remarkably well tolerated on floppy valves (i.e., does not necessarily require surgical intervention), and autopsy studies even suggest it may spontaneously heal (11). We recently evaluated 86 patients with progressive mitral regurgitation due to floppy valves (Figure 2) (16). Seventy-six underwent mitral valve replacement or repair. Serial studies in 28 of these patients documented progressive mitral regurgitation. Figure 2 indicates the age when a murmur was first detected (mean 34 years), the age of onset of symptoms from mitral regurgitation (mean 59), and the age at time of catheterization or surgery or both (mean 60). Most patients, therefore, had a murmur noted many years before severe mitral regurgitation developed. Once symptoms appeared there was a rapid deterioration of the clinical course. In 39 (51%) there was chordal rupture. Eleven patients had had bacterial endocarditis but in none did this result in urgent surgery. The mean duration from endocarditis to surgery was 5.6 years. Thus, while severe mitral regurgitation occasionally occurs in younger patients, in the majority of instances it develops after age 60 in patients who previously have had a long history of a murmur. Presumably progressive valvular degeneration due to the cumulative effects of mechanical stress are responsible. The literature indicates that progressive mitral regurgitation is more likely to occur in males and sixty-two percent of our series were male.
THE MITRAL VALVE PROLAPSE SYNDROME A typical patient with MVP syndrome may be described as follows. The individual, usually a young female, is often asthenic with thoracic

226

RICHARD P. LEWIS

SYMPTOM (c I YR)

75(87%)

a.I

S.
30
0

%D
*SS

20 20~
1010 0

62 (72%)

11(13%/)6

0 *

30

L
20

11(13%)

10

AGE FIRST AGE AT MVRAGE MURMUR OR CATH SYMPTOM FIRST DETECTED FIG. 2. Chronologic relationship of the age a murmur was first detected (left), the age of initial symptoms of mitral regurgitation (middle) and age at time of catheterization (CATH) or mitral valve surgery (MVR) (right). Each closed circle represents one patient. Open circles indicate those who did not have surgery. Dashed horizontal line separates patients at age 50 years. Solid line indicates mean age for each column. See text for further explanation. (From, Kolibash AJ, Jr, Kilman JW, Bush CA, et al. Mitral valve prolapse: Evidence for progression from mild to severe regurgitation. Am J Cardiol 1986; 58: 762 (lb) with permission.)

skeletal abnormalities (pectus excavatum, scoliosis, or straight back). The systolic blood pressure may be low. Hypomastia is often present in females. Arm span is greater than height and hyperextendable joints are frequent but other stigmata of Marfan's Syndrome are not seen. Inappropriate tachycardia on standing is typical. The commonest symptoms are palpitations (premature beats, "pounding" heart beat, and rapid heart action), chest pain (usually chest wall type and often prolonged), exertional dyspnea, lightheadedness, and syncope. Fatigue is common but tends to be episodic and it is profound when it occurs, usually following

THE MITRAL VALVE PROLAPSE EPIDEMIC

227

periods of intense activity or stress. Excessive sensitivity to certain drugs (including caffeine, nicotine, and alcohol) is typical. The symptoms of MVP syndrome could be attributed to anxiety or hypochondriasis. However, it is our opinion that MVP syndrome patients differ significantly from classic anxiety neurosis. In the MVP syndrome, anxiety seems directed to specific symptoms rather than being diffuse and untargeted. "Why is my body reacting this way, Doctor?" is what patients want to know. When provided with an explanation for the basis of symptoms and appropriate life style modification, many learn to handle their symptoms effectively without resort to psychotherapy or psychotropic drugs. In fact, contrary to the popular image, many of these patients are extremely productive individuals (perhaps aided by catecholamines as discussed below). Table 1 lists the relative frequency of the major symptoms of the MVP syndrome in 313 patients studied at our institution (227 females and 86 males). The population was young (mean age 30) and the onset of symptoms was typically in the third or fourth decade. These MVP subjects had a significantly higher height to weight and arm span to height ratio than normal controls. This study while clearly reflecting the experience of most academic institutions, has a selection bias-only MVP patients with symptoms were studied. Therefore the true incidence of symptoms in the total population of patients with MVP may be exaggerated. Recently Devereux addressed this issue by studying all first degree relatives of symptomatic MVP patients referred to his institution (17). Undiagnosed MVP was found (echocardiography and physical exam) in one third of these relatives indicating that the incidence of MVP was 50% in these families. 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 to non MVP relatives. Of interest, the typical thoracic skeletal abnormalities, asthenic habitus, and low systolic blood pressure were equally prevalent in both MVP
TABLE 1 Symptoms in the Mitral Valve Prolapse Syndrome
Females (n = 227) 75% 63% 48% 34% 16%
Males (n = 86)

Palpitations Chest Pain Fatigue Dyspnea

Syncope/Presyncope

48% 59% 28% 16% 13%

228

RICHARD P. LEWIS

groups and significantly more common than in non MVP relatives. Thus MVP patients do appear to be a distinct population, although clinical studies of symptomatic patients overstate the incidence of symptoms of the entire MVP population. Dr. Charles Wooley from our institution has explored the historical literature to determine the evolution of thought concerning what is now termed the MVP syndrome (18). A fascinating picture emerges. Patients with this symptom complex and physical characteristics have been well described as far back as the 17th century. It was not until the midnineteenth century that the first clinical studies were performed in England and the United States (DaCosta) (19-21). Both experiences resulted from mobilization of large numbers of young men for war. A significant number of young soldiers were found to be unfit for duty because of symptoms typical of MVP syndrome (most other forms of heart disease could be identified at that time). Auscultatory findings of mid-systolic clicks and murmurs were described as well as the typical physical habitus of MVP patients. The English coined the term "Irritable Heart" while in the United States the term "DaCosta's Syndrome" eventually gained acceptance. Such was the magnitude of the problem that DaCosta was able to establish a special hospital wing at Turner's Lane Hospital in Philadelphia for the study of these patients (22). Of note, several years later DaCosta also described progressive mitral regurgitation in some of these people. In 1887 Sir William Osler described "Irritable Heart in Civil Life" which he stated was a "condition comparable to the irritable heart mentioned by DaCosta as occurring in military life" (23). Osler noted that in civil life the condition was more common in women. In keeping with the "new cardiology" then emerging which stressed disorders of function rather than morbid pathology, Osler presented the syndrome under "Functional Affectations of the Heart" in his text book. It is of interest that the term "functional" did not originally carry the pejorative meaning which it subsequently acquired in the 20th century. By the turn of the century, further work in the United States had clearly identified systolic clicks and apical mid or late systolic murmurs as being of mitral valve origin (24). However, the European school led by Potain declared these auscultatory findings to be extracardiac-a dogma which persisted until the 1960s (25). World War I led to a resurgence of interest in "Irritable Heart" as once again the symptom complex became one of the commonest causes of disability among young soldiers in Britain (26-28). So great was the government's fear of having to provide disability pensions that most of the great thinkers in internal medicine and cardiology were recruited to study the problem (Thomas Lewis, William Osler, James Mackenzie,

THE MITRAL VALVE PROLAPSE EPIDEMIC

229

Clifford Albutt). A special "Heart Hospital" was established by the government under the leadership of Lewis. The English developed the terms "Soldiers Heart" and "Effort Syndrome". Lewis felt the syndrome was benign but Albutt who had been in consulting practice for many years recognized that some of these patients developed progressive mitral regurgitation. An American contingent, including Samuel A. Levine, Frank Wilson, and Paul Dudley White was invited to England to participate in the studies. The Americans termed the disorder "Neurocirculatory Asthenia", and soon an American Heart Hospital was established under Francis Peabody (29). The end of World War 1 once again led to a decline in interest in the problem, but Paul D. White and Mandel Cohen (a psychiatrist) continued to study and follow such patients in the civilian population (30). Of note, White believed these patients represented a separate entity from "cardiac or anxiety neurosis". At the outbreak of World War II, the great English cardiologist Paul Wood and Aubrey Lewis (a psychiatrist) once again studied the problem in England and concluded that "Soldiers Heart" was not a distinct clinical entity, but was rather a set of cardiovascular manifestations of a psychiatric disorder (31). However, in the United States, based upon the World War 1 experience, patients with "neurocirculatory asthenia" were excluded from military service in World War II (30). After World War II the entity was once again largely forgotten until the 1960s (32). In the 1960s, studies by Barlow and Criley clearly showed that systolic clicks and late systolic murmurs were due to prolapsing mitral valves (33, 34). Soon afterwords the echocardiographic diagnosis of MVP was described and the connection of MVP with the symptom complex which is now called MVP Syndrome was made (35). Subsequently several neuroendocrine studies of MVP syndrome patients documented abnormalities which provided a basis for many of the symptoms of the MVP syndrome (36-42). Several of these studies have been performed in our laboratory. Table 2 lists the known neuroendocrine abnormalities in symptomatic MVP syndrome. The resemblance of the
TABLE 2 Neuroendocrine Abnormalities in the Mitral Valve Prolapse Syndrome Increased adrenergic tone during waking hours. Increased sensitivity to adrenergic stimulation. Increased parasympathetic responsiveness. Reduced plasma volume and subnormal sodium intake. Impaired renin-angiotensin-aldosterone response to volume depletion. Potassium depletion. Impaired cardiac output response to exercise.

1. 2. 3. 4. 5. 6. 7.

230

RICHARD P. LEWIS

current MVP syndrome to its historical predecessors is clear. In fact they appear to be the same disorder. A central finding of recent studies of MVP syndrome is autonomic nervous system dysfunction. Loss of normal modulation is apparent. (A patient described this as having "no rheostat".) Excessive adrenergic tone is present during waking hours as well as an excessive response to adrenergic stimulation. On the other hand excessive vagal responsiveness is also seen. There is abnormal plasma volume regulation. A low plasma volume is paradoxically associated with a tendency for low sodium intake and an inappropriately blunted renin-angiotensin-aldosterone system. Hypovolemia and excessive adrenergic tone most likely are related to the hypotension, postural phenomena, and palpitations seen in MVP patients. Hypokalemia is common, perhaps related to excessive beta 2 adrenergic stimulation. Recently we have studied the exercise response in MVPS by employing radionuclide angiography to measure cardiac output and ventricular volumes. Symptomatic patients with MVPS show a subnormal increase in cardiac output as well as an excessive decrease in left ventricular volumes with upright exercise (43). Arrhythmias are extremely common in the MVP syndrome and appear to have both a metabolic and structural basis (Table 3) (44-46). For reasons unclear, there is an increased incidence of dual AV nodal pathways and anomalous atrio-ventricular bypass tracts which result in supraventricular tachycardia. AV conduction disorders are also common. It has been postulated that mechanical stimulation of the left ventricle by the redundant valve contributes to the ventricular ectopy commonly seen, but excessive adrenergic stimulation and hypokalemia also probably play a role. Excessive bradycardia, including reflex asystole, can produce syncope or even sudden death. Sudden death, while not common, does occur in MVP patients and is a recognized cause for sudden death among
TABLE 3 Arrhythmias in Mitral Valve Proplase I. Anatomic Basis Paroxysmal Atrial Tachycardia Dual A-V nodal pathways Anomalous atrio-ventricular pathways Mechanical stimulation of left atrium and ventricle by redundant valve Atrial fibrillation from dilated left atrium II. Functional Basis Excessive adrenergic tone Atrial tachyarrhythmias Ventricular tachyarrhythmias (including ventricular fibrillation) Hypokalemia-aggravates tachyarrhythmias Excessive sensitivity to nicotine, caffeine, alcohol, cardioactive drugs

THE MITRAL VALVE PROLAPSE EPIDEMIC

231

forensic pathologists (11). Although sudden death may occur as a result of significant mitral regurgitation, primary ventricular fibrillation has been documented in the absence of significant mitral regurgitation and the prognosis is excellent after successful resuscitation (47, 48). From our experience, as well as that of others, patients with the MVP syndrome can have all degrees of echocardiographic severity of mitral valve abnormality. It is only recently that attempts have been made to stratify prolapsing mitral valves on the basis of echocardiography (49, 52). It does appear that those with thickened valves (probably truly floppy valves which constitute nearly half of the MVP population) have a higher incidence of all of the complications of MVP. SUMMARY AND CONCLUSIONS In spite of two decades of research, the precise relationship of anatomic mitral valve prolapse (floppy valve) to the neuroendocrine disorder (MVP syndrome) remains unclear. In all likelihood they are two separate genetic disorders which travel together in some fashion (Table 4). Mitral valve prolapse is a common disorder but progressive mitral regurgitation usually occurs late in life and in only a few patients. Other complications such as bacterial endocarditis, stroke, and sudden death are far less common but can occur at younger ages. The neuroendocrine syndrome in civilian life is mainly seen in young females (interestingly the peak incidence years correspond to peak female sex hormone output) but can be seen in males when subjected to unusual stress such as military service.
TABLE 4 Spectrum of Mitral Valve Prolapse (MVP) Anatomic MVP (Floppy Valve) 1. Variable annular dilitation, excessive and weakened tissue in valve and chordae tendineae, abnormal valve surface-collagen degeneration and myxomatous deposition. 2. Basis for systolic click and/or murmur. 3. Basis for progressive mitral regurgitation, SBE, cerebral emboli, arrhythmias (?). 4. May be associated with other connective tissue abnormalities. 5. Progressive mitral regurgitation primarily affects older males. 6. Autosomal dominant. Mitral Valve Prolapse Syndrome 1. Neuroendocrine cardiovascular syndrome. 2. Symptoms not due to mitral valve dysfunction. 3. MVP present on echo-but are all of these valves abnormal? 4. May be genetically separate from floppy valve but closely associated. 5. Does it eventually lead to floppy valve syndrome? 6. Primarily affects younger feriales. 7. Autosomal dominant.

232

RICHARD P. LEWIS

More recent echocardiographic studies have questioned whether all prolapsing valves are truly abnormal. It has been shown that echographic prolapse can be produced in normal subjects by reducing venous return (53) and impaired venous return may be present in some patients with the MVP syndrome. However, clicks and murmurs are apparently not heard when normal valves prolapse. It is our opinion that the presence of a click or typical murmur requires some anatomic abnormality of the mitral valve. One wonders if minimal valve abnormality (noted and dismissed by Davies) is the valve abnormality present in many young females with MVP syndrome, and that it may remain a mild abnormality throughout life. Recent psychiatric studies suggest that MVP is present in 30% of patients with Panic Disorder (54). It is not clear that this psychiatric syndrome is the same thing as the MVP syndrome. In Devereux's study, anxiety proneness was no different in the MVP cohort than in relatives without MVP. It is possible that diagnostic mixing of two similar but separate disorders has occurred, as has been the case since World War I. Perhaps the most important question is whether young patients with MVP syndrome and no echocardiographic criteria for "floppiness" will develop progressive mitral regurgitation or other complications in later life. In other words, how often is MVP syndrome in a young individual without echocardiographic evidence of a floppy valve a precourser to eventual progressive mitral regurgitation? Are there two different populations? Because of the long course of the disorder, several more years of observation (and, it is hoped, prospective longitudinal study) will be required to answer this question.
REFERENCES
1. Fontana ME, Wooley CF, Leighton RF, et al. Postural changes in left ventricular and mitral valvular dynamics in the systolic-click late systolic murmur syndrome. A postural auscultatory phenomenon. Circulation 1970; 41: 807. 2. Boudoulas H and Wooley CF. Mitral valve prolapse and the mitral valve prolapse syndrome. In: Yu PN, Goodwin JF, eds. Progress in Cardiology Philadelphia: Lea and Febiger; 1986: 275. 3. Shah PM, Update of mitral valve prolapse syndrome: when is echo prolapse a pathologic prolapse? Echocardiography 1984; 1: 87. 4. Procacci PM, Savran SV, Schreiter SL, et al. Prevalence of clinical mitral valve prolapse in 1169 young women. N Engi J Med 1976; 294: 1086. 5. Davies MJ, Moore BP, Braimbridge MV. The floppy mitral valve. Study of incidence, pathology, and complications in surgical, necropsy, and forensic material. Brit Heart J 1978; 40: 468. 6. Savage DD, Garrison RJ, Devereux RB, et al. Mitral valve prolapse in the general population. I Epidemiologic features: The Framingham study. Am Heart J 1983; 108: 571. 7. Keele KD. The application of the physics of sound to 19th century cardiology: with

THE MITRAL VALVE PROLAPSE EPIDEMIC

233

8. 9. 10. 11.

12.
13.
14.

15.
16.

17. 18.

19.
20. 21. 22.
23.

24.
25.

26.
27. 28.
29.

particular reference to the part played by CJB Williams and James Hope. Clio Medica 1973; 8: 191. Bailey OT, Hickam JB. Rupture of mitral chordae tendineae. Clinical and pathologic observations on seven cases in which there was no bacterial endocarditis. Am Heart J 1944; 28: 578. Read RC, Thal AP, Wendt VE. Symptomatic valvular myxomatous transformation (the floppy valve syndrome). Circulation 1965; 32: 897. King BD, Clark MA, Baba N, et al. "Myxomatous" mitral valve: collagen dissolution as the primary defect. Circulation 1982; 66: 288. Lucas RV, Jr., Edwards JE. The Floppy Mitral Valve. Chicago: Yearbook Medical Publishers; 1982: 1. Bansal G, Baher PB, Wooley CF, et al. Floppy mitral valves: abnormal mechanical properties-basis for elongation and rupture of chordae tendinae. Am J Cardiol 1986; 7 (No. 2): 8 (abstr). Grenadier E, Alpan G, Keider S, et al. The prevalence of ruptured chordae tendineae in the mitral valve prolapse syndrome. Am Heatt J 1983; 105: 603. Wilcken DEL, Hickey AJ. The lifetime risk of mitral valve prolapse subjects developing severe mitral regurgitation. Circulation 1986; 74 (suppl II): 453 (abstr). Waller BF, Morrow AG, Maron BJ, et al. Etiology of clinically isolated, severe, chronic, pure mitral regurgitation. Analysis of 97 patients over 30 years of age having mitral valve replacement. Am Heart J 1982; 104: 276. Kolibash AJ Jr., Kilman JW, Bush CA, et al. Mitral valve prolapse: Evidence for progression from mild to severe mitral regurgitation. Am J Cardiol 1986; 58: 762. Devereux RB, Kramer-Fox R, Brown WR, et al. Relation between clinical features of the mitral valve prolapse syndrome and echocardiographically documented mitral valve prolapse. JAm Coil Cardiol 1986; 8: 763. Wooley CF. Where are the diseases of yesteryear? DaCosta's syndrome, soldiers heart, the effort syndrome, neurocirculatory asthenia-and the mitral valve prolapse syndrome. Circulation 1976; 53: 749. Williams JC. Practical Observations on Nervous and Sympathetic Palpitation of the Heart. London: Longman, Rees, Orme, Browne; 1836: 1. Wooley CF. From irritable heart to mitral valve prolapse: British army medical reports, 1860-1879. Am J Cardiol 1985; 55: 1107. DaCosta JM. On irritable heart: a clinical study of a form of functional cardiac disorder and its consequence. Am J Med Sci 1871; 61: 17. Wooley CF. Jacob Mendez DaCosta: medical teacher, clinician, and clinical investigator. Am J Cardiol 1982; 50: 1145. Wooley CF. From irritable heart to mitral valve prolapse: the Osler connection. Am J Cardiol 1984; 53: 870. Wooley CF. From irritable heart to mitral valve prolapse: systolic clicks, apical murmurs and the auscultatory connection in the 19th century. Am Heart J In press. McKusick VA. Cardiovascular Sound in Health and Disease. Baltimore: The Williams & Wilkins Co; 1958: 21. Wooley CF. From irritable heart to mitral valve prolapse: World War I, the British experience and James Mackenzie. Am J Cardiol 1986; 57: 463. Wooley CF. From irritable heart to mitral valve prolapse-World War I, the British experience and Thomas Lewis. Am J Cardiol 1986; 58: 844. Wooley CF. From irritable heart to mitral valve prolapse-World War I, the British experience and Clifford Albutt. Am J Cardiol In press. Wooley CF. From irritable heart to mitral valve prolapse: World War I-The US experience and neurocirculatory asthenia. Am J Cardiol In press.

234

RICHARD P. LEWIS

30. White PD, Donovan H. Hearts: Their Long Term Followup. Philadelphia: W B Saunders; 1967: 300. 31. Wood PH. Cardiovascular disturbances associated with psychiatric states. In: Wood PH. Diseases of the Heart and Circulation. Philadelphia: Lippincott; 1956: 937. 32. White PD. Neurocirculatory asthenia-still a common and important clinical condition. NEngl J Med 1964; 271: 1362. 33. Barlow JB, Pocock WA, Marchand P, et al. The significance of late systolic murmurs. Am Heart J 1963; 66: 443. 34. Criley JM, Lewis KB, Humphries JO, et al. Prolapse of the mitral valve-clinical and cineangiographic findings. Brit Heart J 1966; 28: 488. 35. Kerber RE, Isaeff DM, Hancock EW. Echocardiographic patterns in patients with the syndrome of systolic click and late systolic murmurs. N Engi J Med 1971; 284: 691. 36. Gaffney FA, Karlsson ES, Campbell W, et al. Autonomic dysfunction in women with mitral valve prolapse. Circulation 1979; 67: 236. 37. Coughlan HC, Phares P, Cowley M, et al. Dysautonomia in mitral valve prolapse. Am J Med 1979; 67: 236. 38. Boudoulas H, Reynolds JC, Mazzaferri EM, et al. Metabolic studies in mitral valve prolapse syndrome: a neuroendocrine-cardiovascular process. Circulation 1980; 61: 1200. 39. Pasternac A, Tubau JF, Puddic PE, et al. Increased plasma catecholamine levels in patients with symptomatic mitral valve prolapse. Am J Med 1982; 73: 783. 40. Gaffney FA, Bruce BC, Lane LL, et al. Abnormal cardiovascular regulation in the mitral valve prolapse syndrome. Am J Cardiol 1983; 52: 316. 41. Boudoulas H, Reynolds JC, Mazzaferri E, et al. Mitral valve prolapse syndrome: the effect of adrenergic stimulation. JAm Coll Cardiol 1983; 2: 638. 42. Rogers J, Boudoulas H, Wooley CF. Renin-aldosterone response to volume depletion. Circulation 1984; 70 (suppl II): 36 (abstr). 43. Bashore RM, Grines CL, Utlak D. Mitral valve prolapse: postural exercise response reflects a volume disorder. J Am Coil Cardiol 1985; 5 (Part 2): 504 (abstr). 44. Winkle RA, Lopes MG, Fitzgerald JM, et al. Arrhythmias in patients with mitral valve prolapse. Circulation 1975; 52: 73. 45. Pocock WA, Bosman CK, Chessler E, et al. Sudden death in primary mitral valve prolapse. Am Heart J 1984; 107: 378. 46. Schaal SF. Mitral valve prolapse-cardiac arrhythmias and electrophysiologic correlates. In: Wooley CF and Boudoulas H, eds. Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura; in press. 47. Fellows CL, Poole JE, Bardy GH, et al. Malignant ventricular arrhythmias in mitral valve prolapse. Circulation 1985; 72 (Suppl II): 42 (abstr). 48. Boudoulas H, Schaal SF, Stang JM, et al. Mitral valve prolapse-sudden death with long term survival. J Am Coll Cardiol 1986; 7 (Part 2): 29 (abstr). 49. Chandraratna PAN, Nimalasuriya A, Kawaniski D, et al. Identification of the increased frequency of cardiovascular abnormalities associated with mitral valve prolapse by two dimensional echocardiography. Am J Cardiol 1984; 54: 1283. 50. Nishimura RA, McGoon MD, Shub C, et al. Echocardiographically documented mitralvalve prolapse. Long term followup of 237 patients. NEngI J Med 1985; 313: 1305. 51. Devereux RB, Hawkins I, Kramer-Fox R, et al. Complications of mitral valve prolapse. Disproportionate occurrence in men and older patients. Am J Med 1986; 81: 751. 52. Pini R, Greppi B, Devereux RB, et al. Phenotypic heterogeneity in mitral valve prolapse; relation of mitral valve abnormalities to body weight and blood pressure. (abstr) J Am Coll Cardiol 1986; 7 (No. 2): 7. 53. Beattie JM, Blomquist CG, Gaffney FA, et al. Mitral valve prolapse in normal subjects during orthostatic stress. J Am Coll Cardiol 1985; 5 (No. 2): 404.

THE MITRAL VALVE PROLAPSE EPIDEMIC

235

54. Crowe RR. Mitral valve prolapse syndrome-the brain-heart connection: anxiety, panic, and personality. In: Wooley CF, Boudoulas H, eds. Mitral Valve Prolapse and the Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura; in press.

DISCUSSION Barondess (N.Y.): You have defined a structural disorder and some of its apparent complications, but there's an array of symptoms that don't make a whole lot of sense. I refer to that as the illness in contrast to the anatomical disease. What evidence is available that that array of symptoms occurs more commonly in this population of patients than in sets of controls matched for age and sex? Lewis: There have been a few studies along that line Jerry. One just came out very recently from Cornell. They looked at subjects with mitral prolapse and then first degree relatives, and found that most first degree relatives had mitral prolapse. The relatives had a similar incidence of symptoms but weren't going to the physician for them. They also looked at the wives or the spouse that did not have the syndrome and found a much lower incidence of symptoms. I think if they'd done their analysis differently they would have found that the people with prolapse and their relatives had much higher incidence of these symptoms than those who didn't have prolapse, but that isn't the way they analyzed it. Even then they found that palpitations and a few other symptoms were more common in the people with prolapse. Patients with mitral valve prolapse syndrome got tossed into the anxiety camp by Paul Wood, and others in this country. If you really think about it and look at these people, they do not have "free-floating" anxiety. They're specifically anxious about their symptoms, which are very real. They're not worried about other things. In that sense I think they're different from the chronic anxiety patient. Schrier (Denver): Dr. Lewis, is it possible that in neurocirculatory asthenia left atrial pressure rises. Atrialnaturetic factor (ANF) is released and the resultant naturesis causes volume depletion. The response to volume depletion may then also be impaired by ANF plasma which is known to block the sympathetic and renin-angiotensis-aldosterone system. Thus, has plasma ANF been measured in neurocirculatory asthenia? Lewis: We're doing that right now. Glaser (Menlo Park): Dick, I enjoyed that. I would like to add an historical note. When I was a fourth year student in 1943, the very first patient I had in my medical clerkship at the Massachusetts General Hospital was a young man admitted with the diagnosis of neurocirculatory asthenia. My attending was Dr. Paul Dudley White. I can remember I had obtained a history that took me about an hour and a half to present. Dr. White listened very patiently and then, after his examination and our discussion, concluded that this man did indeed have neurocirculatory asthenia. I had not heard any murmurs, but neither did Dr. White. It would be interesting to go back and try to find out what happened to the fellow, he certainy had all the symptoms and all the characteristics that you have described. Horwitz (Philadelphia): I'd like to say something about this. I saw quite a large number of these patients during WWII. Your evidence makes me think that we're probably dealing with two different conditions. One is neurocirculatory asthenia, which I'm pretty sure is a real entity of its own. If you want to run it back far enough, you can interpolate it into Caesar's commentaries, where it is described in a vague sort of way and certainly the French literature at the time of the Napoleonic Wars describes it even better. It's probably been around for a long time. But I can't believe for an instant that all cases are due to mitral valve prolapse, or to mitral valve syndrome. One of the main reasons I believe that this is true is the day that these people are discharged from the Service, their symptoms almost invariably disappear. I followed quite a large number of them. Also, there are others that, if you push them too hard, sudden death may occur. I think that we must try not to stuff

236

RICHARD P. LEWIS

these all into one waste basket-I think we have at least two separate conditions to think about. Thank you. Chretien (Montreal): I have two quick questions. How many of these patients who have prolapses don't have murmurs? And second, what is the change in their blood pressure when they develop the syndrome? Lewis: They tend, as a group, to have low blood pressure. The question of how many of them have an abnormal echo with no physical findings: 10-15% at any one time. But the physical findings can be variable-present one day and maybe, not necessarily, the next. Weissler (Denver): Just a comment. I think that the hypovolemia may truly be the connecting link. If we could discover the cause of it we could probably put the syndrome together. Could ANF be a factor in the hypovolemia? The findings that you've shown so well in the literature, of a marked decrease in ventricular volume, sinus tachycardia, and arterial hypotension on assumption of the upright posture, together with the evidence of neuroendocrine overactivity all fit with a low total blood volume. So does the prolapse. With the drop in ventricular volume the mitral valve pouches into the left atrium as we see it on echocardiology. One wonders whether we ought to continue to search, in neurocirculatory aesthemia and the mitral valve prolapse syndromes, for the missing link-the factor which chronically reduces the blood volume. Lewis: It's been postulated also that recurrent mitral regurgitation could raise atrial pressure and lead to ANF secretion and it really does seem like it's the missing link. We're evaluating that right now. Schrier (Denver): And the one point that I didn't mention. You mention that the renal angiotensin aldosterone system isn't stimulated with volume depletion. ANF interferes with renin and aldosterone secretion.