THE MITRAL VALVE PROLAPSE EPIDEMIC: FACT ORFICTION*

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 pastdecade than mitral valve prolapse (MVP). For many internists, neurol-ogists, obstetricians, psychiatrists, family practitioners, and dentists,MVP must seem like a modern epidemic. While the prognosis is said tobe benign in the vast majority of patients, sudden death, stroke, subacutebacterial endocarditis, and ruptured chordae tendinae are well publicizedcomplications. Should an already worried patient be told about thesepossibilities? Can a high risk subset be identified? Is MVP responsiblefor all of their symptoms? Or is it simply an incidental finding in apatient with chronic anxiety, or even a spurious finding? Finally, wherewere these people before echocardiography?

Before proceeding to answer these questions, we must first considerthe reliability of the diagnosis of MVP. There is significant day to dayvariation in the associated physical findings of a click or a mitral systolicmurmur or both. In all likelihood this changeability is related to neu-roendocrine factors (see later). Oar experience is that 15-20% of subjectswith symptoms and echographic MVP will not have a click or murmuron a given examination, assuming that an expert examination, includingdynamic auscultation, is performed (1, 2).Echocardiography has been the "gold standard" for establishing the

diagnosis ofMVP since the mid 1970s. In reality, this is a "soft" standard.In our experience, the pathognomonic findings of an enlarged thickenedmitral valve with clear cut systolic prolapse into the left atrium accom-panied by Doppler evidence of some degree of regurgitation are seen inonly about half of those diagnosed as having MVP. Technically inade-quate studies still occur in 10-15% of patients and false positive diagnoseshave been recognized as a problem for many years (3). Even with optimaltechnique, the finding of MVP is at best "borderline" in up to one third

* Department of Internal Medicine, Division of Cardiology, The Ohio State UniversityCollege of Medicine, Columbus, Ohio.

** Correspondence should be sent to: Richard P. Lewis, M.D., Ohio State UniversityHospitals, Division of Cardiology, 653 Means Hall, 1654 Upham Drive, Columbus, Ohio43210.

222

THE MITRAL VALVE PROLAPSE EPIDEMIC

of patients. It seems likely that diagnostic errors from both echocardiog-raphy and physical examination (false positive and false negative diag-noses) have contributed to the continuing debate over the incidence andsymptomatic manifestations of MVP.

It is the purpose of this report to present a new conceptual frameworkfrom which to view the MVP "epidemic" based upon a twenty-five yearexperience of MVP research at Ohio State University.

INCIDENCEBecause of diagnostic problems discussed above, considerable contro-

versy exists over the incidence of MVP. An incidence of 4-6% for theadult population seems generally accepted on the basis of epidemiologicstudies of population samples and from autopsy studies (4-6). If thisincidence is correct, MVP is nearly as common as ischemic heart diseasein the United States. The extremely long clinical course of MVP (50years on average) has made natural history studies virtually impossible.

Certain trends do emerge from the incidence studies. MVP is morecommon in women at all ages, but the long term prognosis seems betterin women. The incidence of more severe degrees of anatomic changes inthe mitral valve increases with age, although there are still only limitedclinical pathologic correlation data available, especially in individualsunder 40 years of age. In Davies's autopsy study the incidence of grosslyabnormal 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 consid-ered an incidental finding.There appear to be two distinct subsets of symptomatic patients with

MVP. Younger patients (especially females) have a constellation ofsymptoms termed "the MVP Syndrome" which seems largely unrelatedto the mitral valve. Older patients (especially males) develop complica-tions 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 mitralvalves have recognizable hereditable connective tissue disorders. Al-though some as yet ill defined dyscollagenosis may be present in MVP,the dire consequences of such disorders as Marfan's Syndrome are notseen. MVP is inherited as an autosomal dominant with incompletepenetrance.

223

RICHARD P. LEWIS

Mitral regurgitation due to ruptured chordae tendineae was first de-scribed by Williams in 1840 (7), but it was not until the modern era thatrupture of the chordae tendineae as a cause for mitral regurgitation wasrediscovered by Bailey and Hickam in 1944 (8). The "floppy valvesyndrome" was subsequently defined by Read et al in 1965 (9). Of interest,pathologists continued to attribute the pathology of these valves torheumatic 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 valveshave increased surface area (especially the posterior leaflet) and showthinning in certain areas while other areas are thickened by myxomatousdeposits and fibrosis. The mitral annulus is enlarged and the chordae arevariably elongated. The primary lesion appears to be collagen dissolu-tion-not myxomatous degeneration which seems to be a secondarychange. The valve surface is often rough and may show endothelial tearswhich 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 leftatrium. The chordae tendineae also show collagen dissolution and myxo-matous deposition. The resultant diminished tensile strength is the basis

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

224

THE MITRAL VALVE PROLAPSE EPIDEMIC

for rupture (12). Mitral annular calcification often develops after thefifth decade. Friction lesions on the posterior ventricular wall are com-mon in advanced disease.A floppy valve per se does not necessarily produce significant regurgi-

tation. When severe regurgitation occurs, it is usually associated withruptured chordae tendineae, fibrous attachment of the valve to theventricle or mitral annular dilation (5, 10, 11). Up to one third of patientshave similar, though usually less extensive, changes in the tricuspid valvebut 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 5-10% of patients with floppy valves. Approximately one third of thesepatients will require mitral valve replacement or repair. Indeed, with thedecline in incidence of rheumatic heart disease, severe mitral regurgita-tion from floppy valves is now the commonest indication for isolatedmitral valve surgery (15). Bacterial endocarditis develops in a smallpercentage of these patients (10-15%) but endocarditis is remarkablywell tolerated on floppy valves (i.e., does not necessarily require surgicalintervention), and autopsy studies even suggest it may spontaneouslyheal (11).We recently evaluated 86 patients with progressive mitral regurgitation

due to floppy valves (Figure 2) (16). Seventy-six underwent mitral valvereplacement or repair. Serial studies in 28 of these patients documentedprogressive mitral regurgitation. Figure 2 indicates the age when amurmur was first detected (mean 34 years), the age of onset of symptomsfrom mitral regurgitation (mean 59), and the age at time of catheteriza-tion or surgery or both (mean 60). Most patients, therefore, had a murmurnoted many years before severe mitral regurgitation developed. Oncesymptoms appeared there was a rapid deterioration of the clinical course.In 39 (51%) there was chordal rupture. Eleven patients had had bacterialendocarditis but in none did this result in urgent surgery. The meanduration 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 patientswho previously have had a long history of a murmur. Presumably pro-gressive valvular degeneration due to the cumulative effects of mechanicalstress are responsible. The literature indicates that progressive mitralregurgitation is more likely to occur in males and sixty-two percent ofour 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

225

RICHARD P. LEWIS

SYMPTOM (c I YR)

r

S

S.w0

*SS

30 0*0 11(13%/)6 L

20 62(72%)20~

1010 0

AGE MURMUR AGE FIRST AGE AT MVR-FIRST DETECTED SYMPTOM OR CATH

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 infemales. Arm span is greater than height and hyperextendable joints are

frequent but other stigmata of Marfan's Syndrome are not seen. Inap-propriate tachycardia on standing is typical. The commonest symptomsare palpitations (premature beats, "pounding" heart beat, and rapid heartaction), chest pain (usually chest wall type and often prolonged), exer-

tional dyspnea, lightheadedness, and syncope. Fatigue is common buttends to be episodic and it is profound when it occurs, usually following

75(87%)

%D

30

11(13%)20

10

226

I

I

a.I

THE MITRAL VALVE PROLAPSE EPIDEMIC

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 patientsdiffer significantly from classic anxiety neurosis. In the MVP syndrome,anxiety seems directed to specific symptoms rather than being diffuseand untargeted. "Why is my body reacting this way, Doctor?" is whatpatients want to know. When provided with an explanation for the basisof symptoms and appropriate life style modification, many learn tohandle their symptoms effectively without resort to psychotherapy orpsychotropic drugs. In fact, contrary to the popular image, many of thesepatients are extremely productive individuals (perhaps aided by cate-cholamines 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 86males). The population was young (mean age 30) and the onset ofsymptoms was typically in the third or fourth decade. These MVPsubjects had a significantly higher height to weight and arm span toheight ratio than normal controls. This study while clearly reflecting theexperience of most academic institutions, has a selection bias-onlyMVP patients with symptoms were studied. Therefore the true incidenceof symptoms in the total population of patients with MVP may beexaggerated.

Recently Devereux addressed this issue by studying all first degreerelatives of symptomatic MVP patients referred to his institution (17).Undiagnosed MVP was found (echocardiography and physical exam) inone third of these relatives indicating that the incidence of MVP was50% in these families. While the referral MVP patients had a higherincidence of symptoms than the undiagnosed MVP patients, palpitations,documented arrhythmias, and chest pain were significantly more com-mon 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 1Symptoms in the Mitral Valve Prolapse Syndrome

Females Males(n = 227) (n = 86)

Palpitations 75% 48%Chest Pain 63% 59%Fatigue 48% 28%Dyspnea 34% 16%Syncope/Presyncope 16% 13%

227

RICHARD P. LEWIS

groups and significantly more common than in non MVP relatives. ThusMVP patients do appear to be a distinct population, although clinicalstudies of symptomatic patients overstate the incidence of symptoms ofthe entire MVP population.

Dr. Charles Wooley from our institution has explored the historicalliterature to determine the evolution of thought concerning what is nowtermed the MVP syndrome (18). A fascinating picture emerges. Patientswith this symptom complex and physical characteristics have been welldescribed as far back as the 17th century. It was not until the mid-nineteenth century that the first clinical studies were performed inEngland and the United States (DaCosta) (19-21). Both experiencesresulted from mobilization of large numbers of young men for war. Asignificant number of young soldiers were found to be unfit for dutybecause of symptoms typical of MVP syndrome (most other forms ofheart disease could be identified at that time). Auscultatory findings ofmid-systolic clicks and murmurs were described as well as the typicalphysical habitus of MVP patients. The English coined the term "IrritableHeart" while in the United States the term "DaCosta's Syndrome"eventually gained acceptance. Such was the magnitude of the problemthat DaCosta was able to establish a special hospital wing at Turner'sLane Hospital in Philadelphia for the study of these patients (22). Ofnote, several years later DaCosta also described progressive mitral regur-gitation 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 heartmentioned by DaCosta as occurring in military life" (23). Osler notedthat in civil life the condition was more common in women. In keepingwith the "new cardiology" then emerging which stressed disorders offunction rather than morbid pathology, Osler presented the syndromeunder "Functional Affectations of the Heart" in his text book. It is ofinterest that the term "functional" did not originally carry the pejorativemeaning 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 murmursas being of mitral valve origin (24). However, the European school ledby Potain declared these auscultatory findings to be extracardiac-adogma 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 ofdisability among young soldiers in Britain (26-28). So great was thegovernment's fear of having to provide disability pensions that most ofthe great thinkers in internal medicine and cardiology were recruited tostudy the problem (Thomas Lewis, William Osler, James Mackenzie,

228

THE MITRAL VALVE PROLAPSE EPIDEMIC

Clifford Albutt). A special "Heart Hospital" was established by thegovernment under the leadership of Lewis. The English developed theterms "Soldiers Heart" and "Effort Syndrome". Lewis felt the syndromewas benign but Albutt who had been in consulting practice for manyyears recognized that some of these patients developed progressive mitralregurgitation.An American contingent, including Samuel A. Levine, Frank Wilson,

and Paul Dudley White was invited to England to participate in thestudies. The Americans termed the disorder "Neurocirculatory Asthenia",and soon an American Heart Hospital was established under FrancisPeabody (29). The end of World War 1 once again led to a decline ininterest in the problem, but Paul D. White and Mandel Cohen (apsychiatrist) continued to study and follow such patients in the civilianpopulation (30). Of note, White believed these patients represented aseparate 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 problemin England and concluded that "Soldiers Heart" was not a distinct clinicalentity, but was rather a set of cardiovascular manifestations of a psychi-atric disorder (31). However, in the United States, based upon the WorldWar 1 experience, patients with "neurocirculatory asthenia" were ex-cluded from military service in World War II (30).

After World War II the entity was once again largely forgotten untilthe 1960s (32). In the 1960s, studies by Barlow and Criley clearly showedthat systolic clicks and late systolic murmurs were due to prolapsingmitral valves (33, 34). Soon afterwords the echocardiographic diagnosisof MVP was described and the connection of MVP with the symptomcomplex which is now called MVP Syndrome was made (35). Subse-quently several neuroendocrine studies of MVP syndrome patients doc-umented abnormalities which provided a basis for many of the symptomsof the MVP syndrome (36-42). Several of these studies have beenperformed in our laboratory. Table 2 lists the known neuroendocrineabnormalities in symptomatic MVP syndrome. The resemblance of the

TABLE 2Neuroendocrine Abnormalities in the Mitral Valve Prolapse Syndrome

1. Increased adrenergic tone during waking hours.2. Increased sensitivity to adrenergic stimulation.3. Increased parasympathetic responsiveness.4. Reduced plasma volume and subnormal sodium intake.5. Impaired renin-angiotensin-aldosterone response to volume depletion.6. Potassium depletion.7. Impaired cardiac output response to exercise.

229

RICHARD P. LEWIS

current MVP syndrome to its historical predecessors is clear. In fact theyappear 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. (Apatient described this as having "no rheostat".) Excessive adrenergictone is present during waking hours as well as an excessive response toadrenergic stimulation. On the other hand excessive vagal responsivenessis also seen. There is abnormal plasma volume regulation. A low plasmavolume is paradoxically associated with a tendency for low sodium intakeand an inappropriately blunted renin-angiotensin-aldosterone system.Hypovolemia and excessive adrenergic tone most likely are related to thehypotension, postural phenomena, and palpitations seen in MVP pa-tients. Hypokalemia is common, perhaps related to excessive beta 2adrenergic stimulation. Recently we have studied the exercise responsein MVPS by employing radionuclide angiography to measure cardiacoutput and ventricular volumes. Symptomatic patients with MVPS showa subnormal increase in cardiac output as well as an excessive decreasein 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). Forreasons unclear, there is an increased incidence of dual AV nodal path-ways and anomalous atrio-ventricular bypass tracts which result insupraventricular tachycardia. AV conduction disorders are also common.It has been postulated that mechanical stimulation of the left ventricleby the redundant valve contributes to the ventricular ectopy commonlyseen, but excessive adrenergic stimulation and hypokalemia also probablyplay a role. Excessive bradycardia, including reflex asystole, can producesyncope or even sudden death. Sudden death, while not common, doesoccur in MVP patients and is a recognized cause for sudden death among

TABLE 3Arrhythmias in Mitral Valve Proplase

I. Anatomic BasisParoxysmal Atrial Tachycardia

Dual A-V nodal pathwaysAnomalous atrio-ventricular pathways

Mechanical stimulation of left atrium and ventricle by redundant valveAtrial fibrillation from dilated left atrium

II. Functional BasisExcessive adrenergic tone

Atrial tachyarrhythmiasVentricular tachyarrhythmias (including ventricular fibrillation)

Hypokalemia-aggravates tachyarrhythmiasExcessive sensitivity to nicotine, caffeine, alcohol, cardioactive drugs

230

THE MITRAL VALVE PROLAPSE EPIDEMIC

forensic pathologists (11). Although sudden death may occur as a resultof significant mitral regurgitation, primary ventricular fibrillation hasbeen documented in the absence of significant mitral regurgitation andthe 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 mitralvalve abnormality. It is only recently that attempts have been made tostratify prolapsing mitral valves on the basis of echocardiography (49,52). It does appear that those with thickened valves (probably trulyfloppy valves which constitute nearly half of the MVP population) havea higher incidence of all of the complications of MVP.

SUMMARY AND CONCLUSIONS

In spite of two decades of research, the precise relationship of anatomicmitral valve prolapse (floppy valve) to the neuroendocrine disorder (MVPsyndrome) remains unclear. In all likelihood they are two separate geneticdisorders which travel together in some fashion (Table 4).

Mitral valve prolapse is a common disorder but progressive mitralregurgitation usually occurs late in life and in only a few patients. Othercomplications such as bacterial endocarditis, stroke, and sudden deathare far less common but can occur at younger ages. The neuroendocrinesyndrome in civilian life is mainly seen in young females (interestinglythe peak incidence years correspond to peak female sex hormone output)but can be seen in males when subjected to unusual stress such asmilitary service.

TABLE 4Spectrum 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 deposi-tion.

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 Syndrome1. 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.

231

232 RICHARD P. LEWIS

More recent echocardiographic studies have questioned whether allprolapsing valves are truly abnormal. It has been shown that echographicprolapse can be produced in normal subjects by reducing venous return(53) and impaired venous return may be present in some patients withthe MVP syndrome. However, clicks and murmurs are apparently notheard when normal valves prolapse. It is our opinion that the presenceof a click or typical murmur requires some anatomic abnormality of themitral valve. One wonders if minimal valve abnormality (noted anddismissed by Davies) is the valve abnormality present in many youngfemales with MVP syndrome, and that it may remain a mild abnormalitythroughout life.Recent psychiatric studies suggest that MVP is present in 30% of

patients with Panic Disorder (54). It is not clear that this psychiatricsyndrome is the same thing as the MVP syndrome. In Devereux's study,anxiety proneness was no different in the MVP cohort than in relativeswithout MVP. It is possible that diagnostic mixing of two similar butseparate 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" willdevelop progressive mitral regurgitation or other complications in laterlife. In other words, how often is MVP syndrome in a young individualwithout echocardiographic evidence of a floppy valve a precourser toeventual progressive mitral regurgitation? Are there two different popu-lations? Because of the long course of the disorder, several more years ofobservation (and, it is hoped, prospective longitudinal study) will berequired to answer this question.

REFERENCES

1. Fontana ME, Wooley CF, Leighton RF, et al. Postural changes in left ventricular andmitral valvular dynamics in the systolic-click late systolic murmur syndrome. A posturalauscultatory phenomenon. Circulation 1970; 41: 807.

2. Boudoulas H and Wooley CF. Mitral valve prolapse and the mitral valve prolapsesyndrome. In: Yu PN, Goodwin JF, eds. Progress in Cardiology Philadelphia: Lea andFebiger; 1986: 275.

3. Shah PM, Update of mitral valve prolapse syndrome: when is echo prolapse a pathologicprolapse? Echocardiography 1984; 1: 87.

4. Procacci PM, Savran SV, Schreiter SL, et al. Prevalence of clinical mitral valveprolapse 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 J1978; 40: 468.

6. Savage DD, Garrison RJ, Devereux RB, et al. Mitral valve prolapse in the generalpopulation. 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

particular reference to the part played by CJB Williams and James Hope. Clio Medica1973; 8: 191.

8. Bailey OT, Hickam JB. Rupture of mitral chordae tendineae. Clinical and pathologicobservations on seven cases in which there was no bacterial endocarditis. Am Heart J1944; 28: 578.

9. Read RC, Thal AP, Wendt VE. Symptomatic valvular myxomatous transformation(the floppy valve syndrome). Circulation 1965; 32: 897.

10. King BD, Clark MA, Baba N, et al. "Myxomatous" mitral valve: collagen dissolutionas the primary defect. Circulation 1982; 66: 288.

11. Lucas RV, Jr., Edwards JE. The Floppy Mitral Valve. Chicago: Yearbook MedicalPublishers; 1982: 1.

12. Bansal G, Baher PB, Wooley CF, et al. Floppy mitral valves: abnormal mechanicalproperties-basis for elongation and rupture of chordae tendinae. Am J Cardiol 1986;7 (No. 2): 8 (abstr).

13. Grenadier E, Alpan G, Keider S, et al. The prevalence of ruptured chordae tendineaein the mitral valve prolapse syndrome. Am Heatt J 1983; 105: 603.

14. Wilcken DEL, Hickey AJ. The lifetime risk of mitral valve prolapse subjects developingsevere mitral regurgitation. Circulation 1986; 74 (suppl II): 453 (abstr).

15. 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 mitralvalve replacement. Am Heart J 1982; 104: 276.

16. Kolibash AJ Jr., Kilman JW, Bush CA, et al. Mitral valve prolapse: Evidence forprogression from mild to severe mitral regurgitation. Am J Cardiol 1986; 58: 762.

17. Devereux RB, Kramer-Fox R, Brown WR, et al. Relation between clinical features ofthe mitral valve prolapse syndrome and echocardiographically documented mitral valveprolapse. JAm Coil Cardiol 1986; 8: 763.

18. Wooley CF. Where are the diseases of yesteryear? DaCosta's syndrome, soldiers heart,the effort syndrome, neurocirculatory asthenia-and the mitral valve prolapse syn-drome. Circulation 1976; 53: 749.

19. Williams JC. Practical Observations on Nervous and Sympathetic Palpitation of theHeart. London: Longman, Rees, Orme, Browne; 1836: 1.

20. Wooley CF. From irritable heart to mitral valve prolapse: British army medical reports,1860-1879. Am J Cardiol 1985; 55: 1107.

21. DaCosta JM. On irritable heart: a clinical study of a form of functional cardiac disorderand its consequence. Am J Med Sci 1871; 61: 17.

22. Wooley CF. Jacob Mendez DaCosta: medical teacher, clinician, and clinical investiga-tor. Am J Cardiol 1982; 50: 1145.

23. Wooley CF. From irritable heart to mitral valve prolapse: the Osler connection. Am JCardiol 1984; 53: 870.

24. Wooley CF. From irritable heart to mitral valve prolapse: systolic clicks, apical murmursand the auscultatory connection in the 19th century. Am Heart J In press.

25. McKusick VA. Cardiovascular Sound in Health and Disease. Baltimore: The Williams& Wilkins Co; 1958: 21.

26. Wooley CF. From irritable heart to mitral valve prolapse: World War I, the Britishexperience and James Mackenzie. Am J Cardiol 1986; 57: 463.

27. Wooley CF. From irritable heart to mitral valve prolapse-World War I, the Britishexperience and Thomas Lewis. Am J Cardiol 1986; 58: 844.

28. Wooley CF. From irritable heart to mitral valve prolapse-World War I, the Britishexperience and Clifford Albutt. Am J Cardiol In press.

29. Wooley CF. From irritable heart to mitral valve prolapse: World War I-The USexperience 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 Saun-ders; 1967: 300.

31. Wood PH. Cardiovascular disturbances associated with psychiatric states. In: WoodPH. 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 andcineangiographic findings. Brit Heart J 1966; 28: 488.

35. Kerber RE, Isaeff DM, Hancock EW. Echocardiographic patterns in patients with thesyndrome 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 withmitral valve prolapse. Circulation 1979; 67: 236.

37. Coughlan HC, Phares P, Cowley M, et al. Dysautonomia in mitral valve prolapse. AmJ Med 1979; 67: 236.

38. Boudoulas H, Reynolds JC, Mazzaferri EM, et al. Metabolic studies in mitral valveprolapse syndrome: a neuroendocrine-cardiovascular process. Circulation 1980; 61: 1200.

39. Pasternac A, Tubau JF, Puddic PE, et al. Increased plasma catecholamine levels inpatients with symptomatic mitral valve prolapse. Am J Med 1982; 73: 783.

40. Gaffney FA, Bruce BC, Lane LL, et al. Abnormal cardiovascular regulation in themitral valve prolapse syndrome. Am J Cardiol 1983; 52: 316.

41. Boudoulas H, Reynolds JC, Mazzaferri E, et al. Mitral valve prolapse syndrome: theeffect 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 responsereflects a volume disorder. JAm Coil Cardiol 1985; 5 (Part 2): 504 (abstr).

44. Winkle RA, Lopes MG, Fitzgerald JM, et al. Arrhythmias in patients with mitral valveprolapse. Circulation 1975; 52: 73.

45. Pocock WA, Bosman CK, Chessler E, et al. Sudden death in primary mitral valveprolapse. Am Heart J 1984; 107: 378.

46. Schaal SF. Mitral valve prolapse-cardiac arrhythmias and electrophysiologic corre-lates. In: Wooley CF and Boudoulas H, eds. Mitral Valve Prolapse and the Mitral ValveProlapse Syndrome. Mount Kisco, NY: Futura; in press.

47. Fellows CL, Poole JE, Bardy GH, et al. Malignant ventricular arrhythmias in mitralvalve prolapse. Circulation 1985; 72 (Suppl II): 42 (abstr).

48. Boudoulas H, Schaal SF, Stang JM, et al. Mitral valve prolapse-sudden death withlong term survival. JAm Coll Cardiol 1986; 7 (Part 2): 29 (abstr).

49. Chandraratna PAN, Nimalasuriya A, Kawaniski D, et al. Identification of the increasedfrequency of cardiovascular abnormalities associated with mitral valve prolapse by twodimensional echocardiography. Am J Cardiol 1984; 54: 1283.

50. Nishimura RA, McGoon MD, Shub C, et al. Echocardiographically documented mitral-valve 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) JAmColl Cardiol 1986; 7 (No. 2): 7.

53. Beattie JM, Blomquist CG, Gaffney FA, et al. Mitral valve prolapse in normal subjectsduring orthostatic stress. JAm 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 andthe Mitral Valve Prolapse Syndrome. Mount Kisco, NY: Futura; in press.

DISCUSSIONBarondess (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. Irefer to that as the illness in contrast to the anatomical disease. What evidence is availablethat that array of symptoms occurs more commonly in this population of patients than insets of controls matched for age and sex?

Lewis: There have been a few studies along that line Jerry. One just came out veryrecently from Cornell. They looked at subjects with mitral prolapse and then first degreerelatives, and found that most first degree relatives had mitral prolapse. The relatives hada similar incidence of symptoms but weren't going to the physician for them. They alsolooked at the wives or the spouse that did not have the syndrome and found a much lowerincidence of symptoms. I think if they'd done their analysis differently they would havefound that the people with prolapse and their relatives had much higher incidence of thesesymptoms 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 inthe people with prolapse.

Patients with mitral valve prolapse syndrome got tossed into the anxiety camp by PaulWood, and others in this country. If you really think about it and look at these people, theydo 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'redifferent from the chronic anxiety patient.

Schrier (Denver): Dr. Lewis, is it possible that in neurocirculatory asthenia left atrialpressure rises. Atrialnaturetic factor (ANF) is released and the resultant naturesis causesvolume depletion. The response to volume depletion may then also be impaired by ANFplasma 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 atthe Massachusetts General Hospital was a young man admitted with the diagnosis ofneurocirculatory asthenia. My attending was Dr. Paul Dudley White. I can remember I hadobtained a history that took me about an hour and a half to present. Dr. White listenedvery patiently and then, after his examination and our discussion, concluded that this mandid indeed have neurocirculatory asthenia. I had not heard any murmurs, but neither didDr. White. It would be interesting to go back and try to find out what happened to thefellow, 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 numberof these patients during WWII. Your evidence makes me think that we're probably dealingwith two different conditions. One is neurocirculatory asthenia, which I'm pretty sure is areal entity of its own. If you want to run it back far enough, you can interpolate it intoCaesar's commentaries, where it is described in a vague sort ofway and certainly the Frenchliterature at the time of the Napoleonic Wars describes it even better. It's probably beenaround for a long time. But I can't believe for an instant that all cases are due to mitralvalve prolapse, or to mitral valve syndrome. One of the main reasons I believe that this istrue is the day that these people are discharged from the Service, their symptoms almostinvariably 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

RICHARD P. LEWIS

these all into one waste basket-I think we have at least two separate conditions to thinkabout. Thank you.

Chretien (Montreal): I have two quick questions. How many of these patients who haveprolapses don't have murmurs? And second, what is the change in their blood pressurewhen they develop the syndrome?

Lewis: They tend, as a group, to have low blood pressure. The question of how manyof them have an abnormal echo with no physical findings: 10-15% at any one time. Butthe physical findings can be variable-present one day and maybe, not necessarily, thenext.

Weissler (Denver): Just a comment. I think that the hypovolemia may truly be theconnecting link. If we could discover the cause of it we could probably put the syndrometogether. Could ANF be a factor in the hypovolemia? The findings that you've shown sowell in the literature, of a marked decrease in ventricular volume, sinus tachycardia, andarterial hypotension on assumption of the upright posture, together with the evidence ofneuroendocrine 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 seeit on echocardiology. One wonders whether we ought to continue to search, in neurocircu-latory aesthemia and the mitral valve prolapse syndromes, for the missing link-the factorwhich chronically reduces the blood volume.

Lewis: It's been postulated also that recurrent mitral regurgitation could raise atrialpressure and lead to ANF secretion and it really does seem like it's the missing link. We'reevaluating that right now.

Schrier (Denver): And the one point that I didn't mention. You mention that the renalangiotensin aldosterone system isn't stimulated with volume depletion. ANF interfereswith renin and aldosterone secretion.

236