Left ventricular abnormality with late mitral insufficiency and abnormal electrocardiogram

OCTOBER 1970

The American Journal of CARDIOLOGY VOLUME 26 NUMBER 4

Clinical Studies

Left Ventricular Abnormality with Late Mitral Insufficiency and Abnormal Electrocardiogram

KATHRYN H . EHLERS, MD, FACC MARY ALLEN ENGLE, MD, FACC AARON R . LEVIN, MD, MRCP HERMAN GROSSMAN, MD RICHARD J . FLEMING, MD . New York, New York

From the Departments of Pediatrics and Radiology, The New York Hospital-Cornell University Medical Center, New York, N . Y . Manuscript received November 24, 1969, accepted January 5, 1970 . Address for reprints : Kathryn H . Ehlers, MD . The New York Hospital, 525 E . 68 St ., New York, N . Y . 10021 .

VOLUME 26, OCTOBER 1970

An abnormal contraction that alters the contour of the left ventricle only during systole but not in diastole and results in mild mitral insufficiency has been demonstrated in 6 girls with apical systolic click, late systolic murmur and T wave inversion . They have remained asymptomatic during a period of follow-up studies ranging from 3 to 17 years . Their young age and the absence of myocarditis, pericarditis and coronary arterial abnormality suggest that they have a congenital anomaly in a localized area of the left ventricular myocardium which results in late systolic dysfunction of the mitral apparatus . We believe that the findings in this group constitute a distinctive syndrome among the heterogeneous causes of mitral insufficiency late in systole .

Until quite recently, the late systolic murmur at the apex, which is often preceded by a click, was assumed to be innocent or extracardiac in origin .'-r With the development of more precise diagnostic techniques, left ventricular angiocardiographic studies have shown several individuals with such findings to have mild late systolic mitral valve regurgitation in association with prolapse of the leaflets into the left atriums -''^ The intracardiac phonocatheter has localized the click and the murmur to the region of the left atrium and mitral valve.`° The click has been shown to coincide with the time of maximal prolapse of the mitral valve leaflet, and the onset of the murmur has been correlated with the appearance of contrast medium in the left atrium .'' This is a report of the abnormal left ventricular contour in 6 asymptomatic white girls with a late systolic murmur at the apex preceded by a click and with abnormal T waves in the electrocardiogram . On left ventricular angiocardiography all had mild late mitral regurgitation and an abnormality of the left ventricular contour during systole . We have followed their courses from the ages of 7 to 14 years into adolescence or adulthood . The findings of this group have been so remarkably similar that we believe they constitute a distinct syndrome among the heterogeneous causes of mitral insufficiency late in systole . The history of the first such patient who came to our attention follows .

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Figure 1 . Case 1 . Phonocardiogram recorded at the apex at a paper speed of 75 mm/sec and with time lines 0 .04 second apart . In the upper panel at a frequency of 12/200 cycle/sec the mid-systolic click (C) is well seen . The lower panel is recorded at 120/500 cycle/sec and shows the mid-systolic click followed by a late systolic murmur that extends up to the second heart sound .

Illustrative Case Report

(Fig . 2) showed these findings and, in addition, the tall R waves in left precordial leads fulfilled voltage criteria

Case 1. This girl was born after an uncomplicated term pregnancy. She was seen in the Pediatric Clinic of The New York Hospital-Cornell Medical Center on several occasions between the ages of 6 months and 4 years, and no cardiac murmur was noted . She returned at age 8 years because her mother had noticed a prominence of the left side of the chest. A systolic murmur was heard and she was referred to the Cardiac Clinic, where she has continued under regular follow-up study for the past 17 years . The auscultatory findings have remained constant: a mid-sys-

for left ventricular hypertrophy . However, at age 17 years (Fig . 3) voltage criteria for left ventricular hypertrophy were no longer present, and T waves were less abnormal . In the patient's 13 records the frontal plane QRS-T angle has always been abnormally wide, greater than 60° . Unusually tall T waves in the mid-precordial leads and prominent U waves have appeared in all tracings . Chest roentgenograms in all views, obtained after barium swallow, have demonstrated normal heart size . Intravenous angiocardiography (Fig . 4) at age 16 showed that during the systolic phase of filling of the left heart chambers, the left ventricle assumed a peculiar doublechambered appearance although in diastole it had a normally smooth contour. At age 20 years the patient underwent right and left heart catheterization with visualization by contrast medium (Table I) . Pressures were normal, and the pulmonary

tolic click followed by a late systolic murmur heard maximally at the apex and radiating over the precordium as well as faintly over the left lung field posteriorly . The heart sounds have been normal (Fig . 1) . The electrocardiogram has generally shown various degrees of inversion of T waves in leads II, III, aVF, V and V,, An electrocardiogram recorded at age 12 years

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Figure 2. Case 1 . Electrocardiogram at age 12 years . Note inverted T waves in leads 11, III, aVF and V, and the U wave in leads V, to V, . The latter leads were recorded at half-standardization . Tall R waves in lead V, fulfill voltage criteria for left ventricular hypertrophy . The electrical axis is 120° .

Figure 3 . Case 1 . Electrocardiogram at 17 years shows only slight abnormalities of T waves in limb leads . U waves are seen in leads II, aVF and V, to V, . The electrical axis is 100° .

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The American Journal of CARDIOLOGY

LEFT VENTRICULAR ABNORMALITY AND LATE MITRAL INSUFFICIENCY

capillary pressure tracing did not suggest mitral regurgitation . Shunts were excluded by oxygen analyses and hydrogen and ascorbate-dilution curves . Biplane selective left ventricular angiocardiography17 and cineangiocardiography demonstrated that during systole the inferior aspect of the left ventricle bulged inward, forming a convex ridge that partially divided the cavity into posterior and anterior subchambers . During diastole the bulge vanished . Slight opacification of the left atrium indicated mild mitral insufficiency . The coronary arteries and ascending aorta were within normal limits. No pressure differences were recorded in any area of the left ventricular cavity at rest or during an infusion of isoproterenol . In the first cardiac cycle following catheter-induced ventricular premature contractions, the aortic pulse pressure increased normally and exceeded the pulse pressure in the cycle preceding the ectopic beat. The form of the aortic pulse pressure was normal, and the left ventricular tracing showed no break on the ascending limb . The patient, now aged 25, teaches school and is asymptomatic. Results in 6 Cases The family and gestational histories of the 6 girls revealed no abnormalities. No girl had a history of rheumatic fever, myocarditis, pericarditis or endocarditis . Moderately severe scoliosis was present in 2 patients, 1 of whom had the Marfan syndrome . One girl had neurofibromatosis with lymphangiomas as well as bilateral hydronephrosis secondary to congenital ureteropelvic junctional obstructions. All 6 were asymptomatic and were referred from age 7 to 14 years because of a murmur heard between the ages of 5 and 8 years . In each a soft grade 1-2/6 late systolic murmur was maximal at the apex . It frequently radiated toward the left lower sternal border and axilla . The murmur tended to be heard better when the patient was seated, and in 1 girl the murmur was definitely accentuated by sitting and by held expiration (Fig . 5) . A mid-systolic click preceded the murmur in each instance . Heart sounds were normal . The cardiac series of chest roentgenograms was normal in each girl.

All of the 38 electrocardiograms recorded in the 6 subjects exhibited some abnormality of T waves although serial tracings showed some variation in their form . The AQRS in the frontal plane ranged from +45° to +110°, and the AQRS-T angle in the frontal plane ranged from 45° to 140° . On all records except for 2 of the 4 tracings in 1 subject, the AQRS-T angle was greater than 75° . In 3 patients voltages were consistent with left ventricular hypertrophy on some tracings . U waves were present in all 6 subjects, and unusually tall T waves in midprecordial leads were observed in 3 girls. Q waves were not remarkable in any tracing, and the Q-T interval was within the normal range in all . No arrhythmia was documented or suggested by history . Cardiac catheterization and angiographic findings : All 6 girls were recognized as having a similar condition and were hospitalized for cardiac catheterization with contrast visualization at ages 12, 14, 15, 16, 20 and 24 years, respectively . Pressures in the right and left heart chambers were normal in all . No pressure differences were observed in a number of catheter positions in the left ventricle . Shunts were excluded by oxygen analyses, dye-dilution techniques and the hydrogen electrode . Left ventricular angiocardiography was accomplished in frontal, lateral and oblique views . Four patients had biplane left ventricular angiocardiograms recorded on Elema-Schonander roll film, and 4 had left ventricular cineangiocardiograms . The origin and distribution of the coronary arteries were judged normal in all . Of particular interest in all 6 was the strikingly similar and unusual appearance of the opacified left ventricular cavity (Fig . 4,6 and 7) . During ventricular systole the posteroinferior aspect of the left ventricle appeared to bulge into the cavity of the left ventricle, becoming a convex ridge that in the frontal projection gave the appearance of a double-chambered left ventricle . On cineangiography the contrast material appeared to rock back and forth between the anterior and posterior subchambers formed by this ridge .

Figure 4 . Case 1 . Levoangiocardiogram in systole (A) and diastole (B) shows apparent double-chambered left ventricle with a constriction ring (arrows) in systole . In diastole the cavity is of normal contour .

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EHLERS ET AL .

During diastole the ridge disappeared, and the contour of the left ventricular cavity was smooth, Faint opacification of the left atrium, unrelated to premature ventricular contractions, was seen in all as a result of mild mitral insufficiency . Ballooning during mid-systole of the mitral valve leaflets, especially the posterior leaflet, was associated with faint reflux of contrast medium into the left atrium . TABLE I Right and Left Heart Catheterization Site

Pressures (mm Hg)

Right atrium Right ventricle Pulmonary artery Pulmonary artery wedge Left ventricle Aorta

2 19/4 17/6 (9) 5 123/6 123/77 (97)

a-v oxygen difference (vol %) Cardiac index (liters/min per m') Pulmonary vascular resistance (dynes sec cm-')

3.35 4.98 41

a-v = arteriovenous . Figures in parentheses = mean pressures .

Figure 5. Case 2 . Phonocardiogram taken at the apex in supine position with quiet respiration (top panel) and in upright position early in held expiration (middle panel) and later in held expiration (bottom panel). Mid-systolic click is indicated by C and systolic murmur by SM . Note increase in intensity of murmur in upright position as held expiration progresses .

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All 6 girls have remained asymptomatic during a follow-up period that has ranged from 3 to 17 years, a total of 56 patient years . Discussion This report confirms the long-held impression that patients with a mid-systolic click and late systolic murmur are frequently symptom-free and have a good prognosis. It also confirms the recently recognized relation of the murmur to mitral regurgitation . It further provides an explanation for the late mitral insufficiency and ischemic-like T waves in 6 female children followed up to adulthood: an anatomic abnormality during left ventricular systole . Humphries and McKusick , in 1962 described abnormalities of the T waves in 11 patients with a late apical systolic murmur. They termed their findings an electrocardiographic-auscultatory syndrome, possibly the result of previous pericarditis in accordance with Gallaverdin's reports3 3 9 of pleuropericardial adhesions found at autopsy in 3 patients with midsystolic clicks . Griffith" in 1892 and Hall" in 1903 suggested that the late systolic murmur denoted mitral regurgitation, and White 31 in 1931 proposed that mid-systolic sounds might sometimes arise from chordae tendineae . However, the notion of extracardiac origin of such findings prevailed until 1961 when Reid J3 proposed that both the apical mid-systolic click and late systolic murmur were of mitral valvular origin. He speculated that elongated or redundant chordae tendineae or inadequate papillary muscle contraction could result in slackening of the chordae in mid-systole . At this time a high pressure gradient across the valve could snap a slack chorda taut, producing a click ; the attached valve cusp then might be competent, producing no murmur, or incompetent, producing a murmur in late systole . Proof came in 1963 with the demonstration by Barlow et al." of mitral insufficiency on left ventricular cineangiocardiograms in 8 patients with an apical late systolic murmur . Criley et al." used an electrocardiographic timing device during left ventricular cineangiocardiography and were able to correlate and time the intracardiac phonocardiographic data in such patients. These investigators found that the systolic click coincided with the time of maximal valve prolapse, and the late onset of the systolic murmur could be attributed to the developing incompetence of the initially competent mitral valve as valve prolapse occurred . Since then, evidence from a number of investigations 9-28 has confirmed the presence of mild to moderate mitral regurgitation . Ballooning or billowing of the posterior mitral valve leaflet or of both leaflets in mid-systole has frequently been described on angiography . Though not commented on by the authors, several of these reports"' . 13,22,24 contain pictures of an abnormality of left ventricular systole such as we describe . •2

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LEFT VENTRICULAR ABNORMALITY AND LATE MITRAL INSUFFICIENCY

The pathogenesis of the apical late systolic murmur, click and abnormal electrocardiogram has not been clear, and pathologic documentation is lacking . Individuals of both sexes at various ages without any recognized underlying cardiac or other disorder have been described . Though generally asymptomatic, a few have complained of ill defined chest pain or palpitations, or both-18 's " ~'

Similar auscultatory and often electrocardiographic findings have been reported in individuals in the same and in successive generations of the same family.10 ' ' '^ '' Shell et al." reported on the results of auscultatory and electrocardiographic evaluation of 23 relatives in 2 or 3 generations of 4 families . In these families the propositus had an apical late systolic murmur preceded by a click in

Figure 6 . Case 2. Selective left ventricular angiocardiogram in systole (A and C) and diastole (B and D) in frontal (A and B) and left lateral projections (C and D) . The inward bulging of the left ventricle inferiorly is well seen during systole . There is slight mitral regurgitation . Arrows indicate constriction ring . Coronary arterial origin and distribution are normal, as in our other patients .

Figure 7 . Case 3 . Selective left ventricular angiocardiogram in frontal projection during systole (A) and diastole (B). The ring-like constriction (arrows) in systole partitions the left ventricle but disappears in diastole . Compare with Figures 4 and 6 .

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association with T wave abnormalities. A late systolic murmur preceded by a click was noted in 4 relatives, a pansystolic murmur in 9, and abnormalities of the T waves in 9. Our patients with the syndrome were children when the condition was recognized. Other investigators have included children and adolescents in their series or have noted in reporting on older individuals that a murmur was first heard in infancy or childhood."- ' ' - - =" In 1968 Schwartz et al .25 in a study of 16 children (13 of them female) attributed the findings to papillary muscle dysfunction due to nonrheumatic myocarditis . Also in 1968, Sreenivasan et al.2° reported on a series of 9 such girls, aged 14 months to 12 years, and ascribed the condition to posterior papillary muscle dysfunction acquired on some as yet unknown congenital basis . Pathogenesis of mitral valve dysfunction : Mitral regurgitation can result when any one of the components of the mitral valve apparatus is anatomically or functionally„jnadequate a° - " The mitral valve apparatus consists of the 2 valve leaflets, the valve ring or annulus and the 2 papillary muscles with their chordae tendineae . The mechanism of closure of the valve depends upon the complex integration with proper time relations of the structures of the valve apparatus and the atrial and ventricular musculature . Following atrial systole the valve cusps come together and meet along the edges . As the pressure in the left ventricle rises, contraction of the deep sinospiral and bulbospiral muscles and of the papillary muscles reduces the mitral ring in size and forcefully pulls on the chordae tendineae until the leaflets come into almost complete apposition over their atrial aspect with tenting of these leaflets into the left atrium . Ordinarily when the mitral valve is abnormal and incompetent, mitral regurgitation begins with isometric ventricular contraction and continues up to or a little beyond the closure of the aortic valve, thus giving rise to a holosystolic murmur. If mitral regurgitation takes place only in the latter part of systole or is maximal in late systole, some form of papillarychordal dysfunction seems a likely explanation since these structures play a major role in maintaining closure of the valve during systolic ejection . Barlow et a] .23 proposed that a non-ejection click may occur whenever there is an uneven distribution of tension in the chordal mechanism, as when one or more chordae are lengthened or are relatively longer than the others . They suggested that the late systolic murmur and late mitral insufficiency occur when the chordae are anatomically or functionally lengthened or ruptured so that the mitral valve leaflets, particularly the posterior one, can billow abnormally. The billowing is accompanied by an increase in the surface of the leaflet, which may progressively stretch and become more voluminous. Thus, it may take

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several years for the auscultatory features to develop . This may explain why a condition that may be congenital is usually not recognized in infancy . Once detected, there is nothing to suggest worsening of the condition in previous reports or in our long-term follow-up study of these girls . Pathogenesis of left ventricular dysfunction : The presence in these 6 cases, and in illustrations in other reports, of a peculiar convex deformity along the inferior aspect of the left ventricular cavity has led us to postulate that this bulge may represent a localized area of dysfunction of the ventricular myocardium . As this area contracts in mid-systole, it throws the adjacent posterior papillary muscle and its chordae tendineae into a slack position . This allows the posterior mitral valve leaflet to billow and leak . The cause of this curious area of abnormal contraction is not clear; possibilities include a developmental abnormality, an acquired disorder such as a degenerative process or an abiotrophy of the left ventricular musculature in this area. Another postulation is that there may be a localized area of abnormal excitation and contraction of the musculature . Leon et al. 'T proposed the possibility of pericardial inflammation and thickening causing alterations in the contraction characteristics of papillary muscles . The unusual contour may represent an unusual form of asymmetric hypertrophy with resulting inequality of chordal length causing the mitral regurgitation . Support for the theory that left ventricular and papillary muscle hypertrophy can result in uneven chordal tension leading to late systolic mitral insufficiency comes from the postmortem examination of a 54 year old man described by Leon et al.,, This man had aortic stenosis and aortic insufficiency due to rheumatic heart disease and in addition had a late systolic murmur at the apex . At necropsy after aortic valve surgery, the mitral valve was found to be normally thin, and the chordae tendineae were normal. The anterior mitral valve leaflet was much larger than the posterior leaflet . The left ventricle and papillary muscles were dilated and hypertrophied in such a way that the posterior leaflet of the valve was held deeper in the left ventricular cavity, thus allowing the anterior leaflet to slip by and permit late mitral valve regurgitation . Kesteloot and Van Houte" commented on the peculiar form of the apex beat with a peaked systolic retraction in 5 patients who had a late systolic murmur preceded by a click . They believed that the depth of the retraction related directly to the loudness of the click . Perhaps the recording on the apex cardiogram related to the unusual area of contraction we have visualized . The particular vulnerability of the papillary muscles to ischemic changes as a result of coronary arterial disease and as a site of the most severe involve-

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LEFT VENTRICULAR ABNORMALITY AND LATE MITRAL INSUFFICIENCY

ment in viral myocarditis has been stressed by Burch and DePasquale 3 1 Bashour 37 pointed out that the posterior papillary muscle is especially apt to be involved by ischemic changes because of its remoteness from the source of blood supply and because it receives blood from both the right coronary and left circumflex coronary arteries so that compromise of either vessel could affect it . Infarction of the posterior papillary muscle can result in mitral regurgitation and occurs in association with either a posterior (inferior) or posterolateral myocardial infarction . Less frequently, involvement of the anterior papillary muscle in an anterior or anterolateral infarction produces mitral regurgitation . The posterior papillary muscle has been the more severely involved in instances where mitral insufficiency has been documented in association with ischemic necrosis of the papillary muscles in such conditions as severe aortic valvular stenosis 39 and anomalous origin of the left coronary artery from the pulmonary artery .J0 . 11 Electrocardiographic changes : The origin of the T wave inversion and the variability of these waves is obscure . This pattern of T wave inversion (in leads II, III, aVF and V 6 ) is similar to that seen in conditions such as posteroinferior myocardial ischemia, hyperventilation and the Marfan syndrome .4 2 Myocardial ischemia due to arteriosclerotic coronary arterial disease seems unlikely in our young subjects who on angiocardiograms had normal origin, course and caliber of major coronary arteries . Barlow et al .2 3 postulated that there may be regional alterations in coronary blood flow and suggested that either the ballooning posterior mitral valve leaflet or the mitral valve annulus might distort the blood flow in the circumflex coronary artery as it runs in the atrioventricular groove. An abnormally contracting area of left ventricular myocardium might conceivably compromise coronary circulation in that localized area . The unusual prominence of the U waves seen in our patients has been noted by others .19 "2 Furbetta et al ."' attributed the U wave to pathologic changes in papillary muscles and related structures with resulting delayed repolarization .

Relation to Marfan's syndrome : We and other authors" , 9 1 . 15 2 4 3 have described individuals with 6 4 Marfan's syndrome and similar auscultatory and electrocardiographic findings . Mitral regurgitation in Marfan's syndrome is due to abnormalities of the chordae tendineae with resulting elongation and redundancy as well as to a fibromyxomatous change in the valve and annulus with marked redundancy of mitral leaflets .,-, 46 The papillary muscles and myocardium are generally normal . Bowers" in 1961 reported on 5 patients with Marfan's syndrome and mitral valve insufficiency . All had T wave abnormalities in leads II, III, aVF and V 2 and V,; . At postmortem examination there were severe mitral valvular and chordal abnormalities in each instance . The relation of the electrocardiographic findings to these pathologic findings was not clarified. A similar fibromyxomatous process in the mitral and aortic valves and chordae tendineae has been observed in patients without stigmata of the Marfan syndrome . 24 9 7 The term "floppy valve syndrome" has been used in these cases, and it has been proposed that this type of cardiac abnormality may represent a forme fruste of Marfan syndrome . Although the origin remains obscure, a few statements seem warranted . Because the murmur has in many instances been detected in early childhood and because it occurs most frequently in female subjects and sometimes is present in several members of the same family, the condition is probably congenital and may be genetically determined . On the basis of our experience, the hemodynamic disturbance is slight, and the prognosis during childhood and adolescence appears good . Since bacterial endocarditis has been reported, prophylaxis at times of predictable risk is therefore indicated .'" ''' "'

Acknowledgment Angiocardiographic aspects of our 6 cases have been reported separately from this center in Radiology 91 :898, 1968 .'" Figures 2, 6 and 7 have been reproduced by permission from the publishers of Radiology.

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