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The clinical course of patients with severe “rheumatic” mitral insufficiency
Fundamentals of clinical cardiology
The clinical “rheumatic”
course of patients with mitral’ insufficiency
severe
Laurence B. Ellis, M.D.* Albert0 Ramirez, M.D. Boston, Mass.
S
urgery for mitral insufficiency has now progressed to a point where operation leading to clinical improvement can be carried out with an acceptable operative risk. However, there are still very real problems concerned with various prosthetic valves and late complications of the operation. In view of the present stage of surgery for mitral valve insufficiency, it is important to know exactly what is the clinical course of patients with this condition under medical management, so that we can better select the place for surgery in our patients. It is surprising how little attention has been paid to this recently. Most of our concepts today are based on articles written several years ago when the criteria for the clinical diagnosis of mitral insufficiency were relatively crude. Many of the published reports are concerned with patients in whom a significant degree of mitral stenosis coexisted with insufficiency. There have been, on the other hand, many articles published dealing with surgery in this condition, the use of various prosthetic and other devices as valve replacements, as well as hemodynamic and angiographic studies. Articles dealing with the selection of patients for surgery are largely based on the conven-
tional clinical wisdom of the past or on rather arbitrary and by no means infallible hemodynamic criteria, and are colored by the degree of enthusiasm or skepticism currently afflicting the authors. In particular, there is a paucity of reports dealing with what happens to patients with mitral incompetence under medical management who are already symptomatic in varying degrees when they come under observation. Many of the published follow-up studies deal with the course of rheumatic heart disease following acute rheumatic fever. Such studies, while valuable, poorly lend themselves to comparative studies of the course of the disease after surgical treatment, as has been shown in an analogous situation when attempts were made to compare the results of surgical therapy for mitral stenosis with medical management of the disease.’ Our interest in this subject was stimulated by observing a number of remarkable patients, of whom the following is an example. A young man of 23 (A. M.) with severe rheumatic mitral insufficiency was referred for medical advice as to the advisability of his marrying. A murmur had been present since the age of 9 when he had
From
the Thorndike Memorial Laboratory, Second and Fourth (Harvard) Medical Services, Boston City and the Department of Medicine. Harvard Medical School, Boston. Mass. This study was supported in part by Grants HE 10539 and HE 5244 from the National Heart Institute. Institutes of Health, United States Public Health Service. *Address: Heart Station. Boston City Hospital. 818 Harrison Ave.. Boston. Mass. 02118.
406
American
Heart
Journal
September,
1969
Vol.
78, No.
Hospital, National
3, pp. 406-418
Severe rheumatic
Fig. 1. Posteroanterior and lateral atria Irn posteriorly and to the right,
roentgenograms and apparent
of Patient A. M. shows enlargement of left and right
rheumatic fever. Since then his symptoms slowly increased so that at the time of our examination he had dyspnea on slight exertion and easy fatigue. His liver was palpable. His heart was enormous by roentgenogram (Fig. l), chiefly in the region of the left atrium, and his electrocardiogram (ECG) showed combined ventricular enlargement (Fig. 2). Because satisfactory surgical treatment was not then available he was given a dubious prognosis and not much else. Ten years later, this man was happily married with 2 children, he had less dyspnea and fatigue, and his liver was no longer palpable. Roentgenogram of his heart and ECG were unchanged. His improvement was largely due to the fortunate fact that he was enabled to budget his energy better, for he had been promoted from a bank teller to the sedentary life of a vice-president, keeping “banker’s hours.” A year later, he did deteriorate, and surgery now being available, he underwent mitral valve replacement of a grossly incompetent, nonstenotic valve. He has had marked improvement, but little or no change in heart size, since giant atria do not diminish in size without surgical excision.
mitral
insz@ciency
enormous ventricles.
enlargement
07
nf left
The observation of this and similar patients raised the question as to how frequently do symptomatic patients follow such a benign course, and how often do they deteriorate progressively. This article, therefore, will reassess the clinical profile and course of aduIt patients with severe rheumatic mitral incompetence, compared to those with mitral stenosis, and a small group of patients who had ruptured chordae or papillary muscles. Material
and methods
Group A includes 42 patients, personally seen and followed by one of us (L.B. Ellis) over a period of years, with the clinical diagnosis of pure or predominant mitral insufficiency. Classified in this group were patients who had an apical holosystolic murmur of Grade III or greater in intensity. An apical diastolic murmur might or might not be present; when present it was low-pitched and rather early, frequently following a third sound. An opening snap was absent. The etiology was assumed to be rheumatic and there was no clinical evidence of aortic or of any major complicating conditions. These patients were se-
408
Am. Heart J. Scfitember, 1969
Ellis and Ramirez
Fig. 2. ECG of Patient axis of plus 100 degrees
A. M. showing atrial (combined ventricular
flutter-fibrillation, hypertrophy).
lected from a much larger group seen in medical consultation, usually with a question of cardiac surgery in mind. Most of these patients were seen first by the author prior to 1961 at a time when there was no definitely acceptable surgery for mitral insufficiency. The diagnosis of uncomplicated severe mitral insufficiency was confirmed in 6 of these patients at subsequent cardiac surgery, in 5 more by left heart catheterization and angiography, and in 3 others by postmortem examination. Group B includes 115 consecutive patients who underwent cardiac surgery by D. E. Harken. They were found at surgery to have severe mitral insufficiency with trivial or no mitral stenosis. (The mitral valve area was estimated to be 4 cm.2 or greater in all but 6 patients in whom it was estimated to be from 2.5 to 3.9 cm.2, or the
and left ventricular
hyper trophy
with
a frc &a I
description of the surgeon was “very slight, ” “minimal,” or “no” stenosis.) The etiology was assumed to be on a rheumatic basis, and there was no evidence of any other significant valvular or cardiac lesions. Twenty-eight of these were operated by closed mitral valvuloplasty and the remaining 87 underwent open cardiac surgery with cardiopulmonary bypass. The majority of these patients had not been observed for any extended period of time by the authors prior to their referral for cardiac surgery. The purpose of selecting this group was to set up a standard of comparison between patients who have proven mitral insufficiency and the Group A patients in whom the diagnosis was based on clinical criteria. Group C includes 138 consecutive patients who underwent closed mitral valvulo-
Volume Nwnbcr
78 3
plasty and who were shown at surgery to have severe mitral stenosis without evidence of significant mitral insufficiency, other valvular disease, or cardiac disease of other nature. This group was selected for comparison with the two preceding groups. Group D includes 13 patients who were found at open heart surgery to have ruptured chordae tendineae or papillary muscles. The classification used in all the groups was that which has previously been described.? To avoid confusion with Groups A, B, C, and D of this study, what were called Groups 1, 2, etc. in the original study, are designated as Class 1, 2, etc. in this paper. Class 1 is comprised of patients who are asymptomatic on ordinary activity; Class 2 includes patients with moderate, but static, cardiac limitation of cardiac reserve, able to carry on sedentary activity; Class 3 is comprised of patients whose symptoms are clearly progressive; Class 4 is comprised of patients who are cardiac invalids, in heart failure, or only kept out of failure by a rigorous medical regimen. This classification corresponds fairly closely to the New York Heart Association classification, but takes into account a dynamic view of the patient’s clinical picture. The description of the roentgenographic findings in Group A is based on cardiac fluoroscopy personally done by the senior author. The roentgenographic findings in Groups B, C, and D are based on cardiac fuoroscopy by the hospital roentgenologist, plus review of x-ray films (posteroanterior, lateral, right, and left obliques) by the authors. The ECG’s were reviewed by the authors, using the criteria of Sokolow and Lyon.3-5 Because many of the patients were under a strict cardiac regimen, including digitalis and diuretic drugs, S-T and T segment deviations were not employed as criteria for the diagnosis of ventricular enlargement. Left ventricular hypertrophy was diagnosed if one or more of the following criteria existed: an R wave in Vs greater than 26 mm.; an R wave in Va or VS plus an S wave in Vi exceeding 3.5 mm.; the sum of Ri and Sa exceeding 24 mm.; or an R nave in aVr, greater than 11 mm. Right ventricular hypertrophy was diag-
Sez!ere rhellmatic
mitral insujiz&:nc~
409
nosed on the basis of one or more of the following: R/S in Vi greater than 1; an R wave in Vi greater than 7 mm.; qR in Vi; or a persistent RS pattern across the precordium. Combined ventricular hypertrophy was diagnosed when criteria for both left and right enlargement were present or when left ventricular enlargement existed with a frontal axis of plus 90 degrees or greater. These criteria for ventricular enlargement were admittedly arbitrary, and no claim that they are highly accurate is being made. They were merely adopted to set uniform standards of comparison. Vectorcardiograms were not done with sufficient. frequency to permit valid analysis. This study will not include a discussion of the physical findings or the clinical diagnostic criteria of mitral insufficiency, because Group A patients were obviously selected largely on the basis of predetermined criteria of physical findings, and in the other groups the nature of the study was such that many of the patients did not have detailed observations made by a single observer. Results
Groups A and B, compared to C. It is clear from a comparison of Groups A and B that the two groups were similar in every way (Table I). There \jpasa preponderance of female patients in Groups A and B, but the difference was of borderline significance when compared to those with pure mitral stenosis ((;roup C). ((;roups A and B compared to C’, p = 0.05; Group B compared to C, p = 0.25.) This is in contrast to findings reported by others,“,’ although J haveri and associate9 and Ross and associates9 had more females than males in their series. The average age of patients coming to surgery \vas the same for patients with mitral insufficiency and mitral stenosis as well as for those in Group A when first observed. In this group, however, there was a tremendous range of ages, regardless of the degree of cardiac disability when first seen. Both groups of patients with niitral insufficiency had a significantly higher incidence of a history of rheumatic fever than those with mitral stenosis (p < 0.001). A history of subacute bacterial endo-
410
Am. Hcavt I. September, 1969
Ellis and Ramirez
Table I. Groups A, B, C, and D compared Group Variables
A
Group B “Rheumatic” mitral iTLSUji&Xysurgical series
“Private series” --__
Pure
mitral surgical
C
Group D Ruptured chordae
stenosisseries
07
pafiillary
muscles
--No.
Total no. of patients Average age* (years) Sex Female Male Degree of disability Class 1 Class 2 Class 3 Class 4 History of: Rheumatic fever Subacute bacterial endocarditis Systemic emboli Initial symptoms Dyspnea Fatigue Dyspnea, fatigue Congestive failure Palpitation None Atria1 fibrillation Class 1 Class 2 Class 3 Class 4
Group
No.
%
42
l 1
%
115 43
/
No.
69 31
92 23
12 18 6 6
29 43 14 14
26
No.
%
138 44
29 13
I 1
119 19
0 0 63 52
62
3 3
;
15 3 11 1 3 9
36 7 26 2 7 21
%
13 44
80 20
/
57 86 14
2 11
1.5 85
54 46
0 0 87 51
62 38
0 0 2 11
1.5 8.5
81
70
63
46
1
8
8 14
7 12
4 30
3 22
1 0
8 0
49 6 52 0
43 5 4.5
51 5 6.5 0
41 4 47
1 1 3 8
8 8 23 61
-
w
611: 83 100
-
78
31
90
70
*Age when first seen by L. B. Ellis in Group A, and age at surgery in Groups B, C, and D. tone patient in normal rhythm, later deteriorated to Class 3 and developed atrial fibrillation. $Two of these patients had paroxysmal atria1 fibrillation. Two others in normal rhythm later still in Class 2 and one after deteriorating to Class 3.
carditis occurred more than twice as frequently in mitral insufkiency as in stenosis, but the difference was not statistically significant (p = 0.2). Atria1 fibrillation occurred early in the course of mitral incompetence and was almost always present when the patients were seriously disabled. Dyspnea or a combination of dyspnea and fatigue were the usual initial complaints for the groups with insufficiency and those with stenosis. Palpitation was not a common initial complaint, although it often occurred as a secondary symptom in association with other symptoms. A history of systemic embolization was
developed
50 16
atria1
fibrillation,
one while
more commonly found in patients with mitral stenosis than in those with insufficiency and the difference was significant (p = 0.02). As judged by the ECG’s (Table II), a majority of patients with mitral insufficiency had either left ventricular or combined ventricular hypertrophy, whereas patients with mitral stenosis rarely had positive evidence of left ventricular hypertrophy and frequently (47 per cent) showed right. A third of the patients with insufficiency showed no clear evidence of hypertrophy by ECG. Such a finding could mean either that no hypertrophy actually was present or that combined hypertrophy
Volume Number
78 3
Severe rheumatic
Table I I. Electrocardiographic
and x-ray
mitral insu&cienry
411
changes
Group A Class (No. patients) Variables
Electrocardiographic of ventricular
evidence hypertrophy
None Left Right Combined
6 6 0 0
+3 f4 None Left Right Combined
5 3 2 2 4 5 0 3
Roentgenographic findings Left atria1 enlargement
Ventricular
enlargement
Pulmonary artery prominence Mitral valve calcification surgery or post mortem
*In
Group
B, ECG’s
were
5 10 2 1
8 3 3 6 2 7
1 1 1 3
1 2 0 0 0 6
1 3 1 1
31 48 9 12
34 35 13 30
49 3 47 1
15 77 0 8
4 1 0 4 1 1
19 26 36 19 17 36 7 40
4 34 46 16 3 10 21 66
11 67 20 2 2 11 64 23
15 69 8 8 0 38 0 62
Not
analyzed
59
75
46
Not
analyzed
22
43
0
at
analyzed
in 112 patients,
roentgenograms
existed and the abnormal vector forces from the enlargement of the two ventricles neutralized each other. The roentgenographic findings were less clear-cut. Although “right ventricular enlargement” was diagnosed with about the same degree of frequency by this technique as by the ECG, “combined ventricular enlargement” was reported much more frequently by roentgenogram in the mitral insufficiency series and to a lesser degree in the mitral stenosis series. This discrepancy with the electrocardiographic findings can possibly be explained by the great degree of atria1 enlargement that tended to occur in the mitral insufficiency groups. It is an obvious fact, although frequently overlooked, that when the left atrium enlarges, it not only intrudes on the posterior mediastinal space, and as it becomes progressively bigger, extends to the left or right, but it also pushes the rest of the heart anteriorly and rotates it in a clockwise direction so that apparent enlargement of either or both of the ventricles may be described. Thus, in patients showing gross enlargement of the left atrium, there is
in 110.
almost invariably the roentgenographic picture of both right and left ventricular enlargement, even though such combined enlargement may not be evident in the ECG (Table III). This effect of atria1 enlargement is apparently also evident to some extent in patients with mitral stenosis.
Table I I I. Group A-Relationship between left atria1 size and ventricular enlargement as observedat cardiac jluoroscopy and by ECG Left atria1 enlargement Ventricular +1
+2 +3 14 Ventricular +1
+2 +3 +4
I
I None
/
Left
/
Right
; Comj bined
enlargement 5 1 1 0
by fluoroscopy 3 4 8 0
0 0 2 1
0 6 4 7
enlargement 3 4 5 1
by ECG 4 5 7 4
0 2 1 1
1 0 2 2
Table IV. Duration
First
Am. Heart I. Sefitember, 1969
Ellis and Ran&es
412
seen in Class 1
(Average
age, 40)
2
(Average
age, 43)
3 (Average
age, 36)
4 (Average
age, 48)
of disease in Group A patients
when Jirst seen 23 2.5 25 28 3.5 37 39 42 53 56 59 62 12 27 28 33 3.5 38 39 39 40 45 47 48 49 52 59 61 63 72 21 24 27 34 47 62 20 47 53 54 58 59
No. years Class 1 1 2 15 22 22 18 13 5 22 24 5 25 4 54
7
]
3
:
31
2
7
3 4 10 2
23
2
9 11 14 10 6 7
31 30 10 57 52 43 65 3 9
1
2
?
8 5
44
4
5 3
2
30
1
3
10 12 12 32 5 30 10 12 10 1 6 7 21 5 1 1 6 1
9 7 18
Total
in each class
?
11 8 4
Enlargement of the main pulmonary artery was noted less frequently in patients with mitral insufficiency than in patients with stenosis (Table II). Valvular calcification was significantly less common in mitral insufficiency (Table II) (p < O.OOl), although it was seen in
2
1 11 9 6 3 1 4
duration
he?y,“izzse
~~~.‘??L$
15 32 22 18 18 8 26 18 5 27 4 54
9 18 12 8 8 3 13 7 1 22 1 2
12 12 22 39 23 30 40 12 12 32 6 37 21 17 58 53 49 66
11 3 10 14 3 3 9 5 7 1 4 4 21 6 1 1 2 1
1.5 24 24 19 7 32
9 9 8 6 6 7
19 14 6 14 9 52
11 4 1 3 3 4
Outcome
Died,
pulm.
emb.
Operated Operated
Operated
Died,
cancer
Operated
Sudden Died,
death C.H.F.
Operated Operated Died Died, C.H.F. Died Sudden death Died Died
some patients even with “pure” insufficiency. Course of the disease (Table IV). Our findings having to do with the clinical course of mitral insufficiency are based on the Group A patients. The length of time patients were stated to be in Class 1 is
Severe rheumntic mitral
based on the known duration of the asymptomatic phase of their heart disease, from the occurrence of rheumatic fever with cardiac involvement or the discovery of a murmur or other cardiac abnormality, such as enlargement. Thus, the estimated duration of the disease in many instances must have been shorter than its actual duration. Jlany patients had a remarkably long duration of known heart disease before the) showed symptoms. Fifteen of the 28 patients in whom heart disease had first been recognized in an asymptomatic phase were observed in Class 1 from 22 to 65 years. If the span of years from first knowledge of heart disease to last observation is considered, 6 patients were known to have had heart disease from 49 to 66 years. Six more had had recognized disease from 31 to 40 years, 9 from 21 to 30 years, 14 from It to 20 years, and 7 from 4 to 10 years. Of the 12 who were first observed while in Class 1, 7 were in atria1 fibrillation, 6 showed left ventricular enlargement b) ECG, ail showed some, and 4 showed marked or extreme atria1 enlargement. After an average of seven more years of observation : 6 were still symptom-free; 3 developed mild symptoms; and 3 deteriorated to Class 3, one of whom died of a pulmonary embolus, and the other 2 underwent heart surgery. Patients who were first observed ivith mild symptoms (Class 2) have also tended to do well. In 13 patients, the cardiac situation remained static for an observation period of 1 to 32 years (average 10 years), although 1 died of cancer and 1 underwent cardiac surgery. One patient died suddenly after 7 years of mild symptoms. Of the remaining 4, 2 have deteriorated to Class 3 after 10 and 12 years in Class 2; 1 underwent heart surgery after 2 years in Class 3; and 1 died after 2 years of congestive failure. Patients first seen when moderately disabled in Class 3 have also fared well. In 2 patients heart disease was first diagnosed when they were in Class 2 and Class 3, respectively. Of the 6, 5 were followed for 7 to 14 years at this stage, although 2 finally underwent heart surgery. One patient deteriorated after 6 years in Class 3 to Class 4 and died after a year of congestive failure. Thus, of these 36 patients, only 4 have
ins?ifiiicnr-:l
413
died a possible cardiac death, including one sudden death and one from a pulmonary emholus. The 6 patients first seen in congestive failure (Class 4) have not done well. In 4, heart disease lvas first diagnosed when they lvere symptomatically in Class 3, and in a fifth patient, knowledge of heart disease COincided \vith the development of congestive heart failure. Only one is alive after 4 years of failure. Five are dead, 1 after 11 years of failure; the others were in failure from 1 to 9 J’ears. Croup D. The profile of 13 patients with ruptured chordae or papillary muscles differed in many ways from the other patients with mitral insufficiency (‘I‘al)les I and II). It was ntainly a disease of males (8.5 per cm), and they I\-ere older on the average t ban the other groups (average age 57 h-ears). Four had a history of myocardial infarction 4 months to 6 years before also had surgery ; one of these patients sul~acute bacterial endocarditis. Only one had had rheumatic fever, Ijut in 3 other patients mild rheumatic mitral valvulitis uxs found at postmortem examination. In the remaining 5 the etiology was llnclear. Atria1 fibrillation leas present in ouly 3, 2 of whom had rheumatic mitral insufficiency. Tile E(‘C.; showed left ventricular enlargement in 77 per cent of the patients, and either left or combined enlargement was described in all of the patients by roentgenogram. The left atrium cl as only slightly to moderately enlarged in all except 2 patients. Valvular calcification did not occur. Sone had a history of systemic em boli. The 2 patients who were operated while in Class 3, had symptoms for 7 months and 4 years, respectively. Three patients had been in Class 3 for 6 months, 8 months, and 4 years before slipping to Class 4 for 4 to 12 months before surgery. In 8 patients, the congestive failure came on abruptly and persisted for 1; i to 12 months in 7, and for 4 years in tllct eighth patient before surgery took place. It is recognized that there is a spectrum of mitral valve disturbances, ranging from pure stenosis without insufficiency, through varying degrees of stenosis with insuffi-
414
Ellis and Ramirez
ciency, to pure insufficiency. Both of these abnormalities of mitral valve function put hemodynamic strains on the heart and the circulation, but the strains differ somewhat in their nature. In mitral stenosis, the pathologic physiology and the early symptomatology are clearly related to the block at the valve and often a marked increase in pulmonary vascular resistance. These abnormalities lead to increase in left atria1 and pulmonary vascular pressure. They also lead to a reduction in cardiac output, especially during exercise, for reasons not entirely clear at the present time. This diminished blood flow and increase in pulmonary resistance result in the sensations of fatigue and of dyspnea which may progress so as to become incapacitating. Left ventricular failure does not occur. Failure of the right ventricle is seen late, secondary to the long-standing pulmonary hypertension. In contrast, the severely symptomatic phase of mitral insufficiency is due to left ventricular failure, resulting from the overwork of the left ventricle. Reduction in cardiac output due to reduced forward blood flow, as well as to some degree of pulmonary vascular congestion from the backflow into the left atrium, may be responsible for some early symptoms of fatigue and dyspnea before myocardial failure develops. In the present study, patients were deliberately chosen who gave evidence of predominant mitral incompetence, in order to avoid the possibility that the clinical symptoms manifested by them were due to a stenotic lesion. Since the symptomatology of advanced mitral insufficiency is due to left ventricular failure, the question arises: Is the failure secondary to the strain imposed by the leaking valve or is it, at least in part, due to primary myocardial failure, with the valvular insufficiency of secondary importance? The latter is obviously true in patients with primary disease of the left ventricle and “functional” valvular insufficiency. It is not such patients that concern us, but those who have severe organic disturbances of the valve itself. The question of the importance of myocardial disease in such patients cannot at the present time be answered, and the relative importance
Am. Heart 1. September, 1969
of valve leak versus myocardial disease accurately assessed, except ex post facto by the results of surgery with replacement of the damaged mitral valve by a competent one. Even after such surgery the answer may not be forthcoming, because the circulation may not be restored to a completely normal hemodynamic state. This may be because the artificial valves themselves may not be hemodynamically perfect, or because such prolonged strain may have led to some irreversible physiologic and even morphologic cardiac changes, since most patients do not come to surgery until they have sustained a long-standing strain on their left ventricles. The question of a primary myocardial factor in rheumatic mitral insufficiency is not yet ruled out, however. Although it is virtually axiomatic to assume that mitral stenosis in adult patients is always due to a preceding rheumatic fever, such an assumption cannot be made for mitral incompetence. In spite of the fact that a greater percentage of patients with this lesion have a previous history of rheumatic fever than patients with mitral stenosis, nevertheless, there are some patients in whom clearly there is an etiologic cause other than rheumatic fever. Perhaps, the early appearance and the ease of recognition of the systolic murmur of mitral insufficiency (in contrast to the easily missed and later developing diastolic or presystolic murmur of stenosis) are responsible for a larger number of the former patients being diagnosed as having rheumatic fever in the acute stage. Patients in whom combined mitral stenosis and insufficiency has been proven to be present, as well as those who have organic mitral and aortic valvular disease, can be considered to be rheumatic, and this is the etiologic cause in persons coming to surgery because of dominant mitral insufficiency without other valve involvement in about 90 per cent of adult patients. A few adult patients have isolated congenital anomalies of the mitral valve, such as a cleft valve with or without associated cardiac defects. A syndrome of voluminous billowing of the posterior mitral leaflet, associated with a late systolic murmur and click or “honk,” has been described.iO This may be a hereditary characteristic. Subacute bac-
Severe rheumatic
terial endocarditis may cause or exacerbate insufficiency by perforating a leaflet or causing chorda rupture, but this almost always occurs in a valve already damaged by rheumatic disease. The same can be said for trauma, One of the most difficult diagnostic problems is differentiating organic mitral insufficiency from a cardiomyopathy. Indeed, some cardiomyopathies do produce organic changes in the mitral valve and, in any of them, functional insufficiency may occur as the result of left ventricular dilatation (with inadequate closure of the mitral leaflets that are held open by the relatively shortened chordae, which cause elongation of the left ventricle and displacement of the papillary muscles toward the apex) as well as by dilatation of the mitral annulus. Insufficiency can also occur in patients with left ventricular dilatation and failure of known etiology, e.g., hypertensive or ischemic heart disease. Careful clinical, hemodynamic, and angiographic assessment will usually establish whether mitral insufficiency is or is not a major factor, so that patients will not inadvertently be subjected to valvular surgery. In a series of 400 patients undergoing open heart surgery for mitral valve disease, there were only 3 in whom a diagnosis of cardiomyopathy was made at surgery or at postmortem examination.ll Coronary artery disease may lead to infarction of the papillary muscle and rupture of the muscle or attached chordae with resulting free mitral insufficiency. The clinical profiles of these patients with coronary artery disease, as well as those with ruptured rhordae from other causes, differ strikingly as a rule from the profiles seen in cases of usual rheumatic mitral incompetence, and they are often relatively easy to recognize; the malignant course these patients follow should bring them to surgery promptly. Our findings in regard to the clinical findings and course of these patients are in accord with those reported by others.12 The study which we have reported shows certain similarities in the clinical profiles of patients with severe insufficiency, assumed to be of rheumatic origin, and those with mitral stenosis. The age and sex of the patients are the same. A rheumatic history
mitral
inszificiency
41s
occurs in half or more of the cases. Bacterial endocarditis was diagnosed in a somewhat greater number of patients with insufficiency, but this may be because such endocarditis may itself produce or aggravate the leak. Systemic embolization is less common in mitral insufficiency. Strikingly different is the tendency for many patients with insufficiency -to develop great enlargement of the left atrium, as well as left ventricular enlargement, and these changes, together with the onset of atria1 fibrillation, may occur at an early, or at least asymptomatic, stage of the disease. There have been numerous reports of the electrocardiographic findings in miwith or without assotral insufficiency, ciated stenosis, in which the importance of left ventricular hypertrophy as an indication of incompetence is stressed. 1311 occasional patient with pure mitral insufficiency shows right or combined ventricular hypertrophy in the ECG.gJ3 In view of these clinical dissimilarities-as well as the difference in the type of physiological strain imposed on the heart in the two conditions, is there a difference in the clinical course of the disease, i.e., do patients with mitral insufficiency deteriorate at a more rapid rate than those with stenosis? It has been shown that patients followed from the time of their acute rheumatic fever with a diagnosis of mitral insufficiency, based on the presence of an apical systolic murmur, tend to follow a benign course.14-1G Other studies have shown that patients with pure or predominant mitral insufficiency do become symptomatic and ultimately die of their disease, even though they may have a long latent period before serious symptoms develop.“*7zgJ7 The occasional catastrophic progression of heart failure in pat,ients, in which inadvertent severe rupture of the aortic leaflet of the mitral valve has been produced in the course of surger1. for mitral stenosis, is well known.‘8 The malignant course of the disease in patients with ruptured chordae or papillary muscles has already been discussed. Our study shows that patients with rheumatic mitral insufficiency, who are not totally disabled, may have a prolonged course under medical therapy. The patients with mitral insufficiency discussed in this stud>- are, of
416
Ellis and Ramirez
course, a selected group, for the most part symptomatic and with well-marked cardiac abnormalities. We are not suggesting that patients who have mitral incompetence invariably, or even frequently, develop such cardiac pathology in the asymptomatic phase of their disease. Rather, it was our intention to study the course of disease in those patients who are thus afflicted. We have not attempted to distinguish between patients who had “pure” mitral insufficiency with no stenosis whatsoever and those with slight stenosis. We have chosen patients in whom the essential hemodynamic fault was valvular incompetence, with any stenosis that might exist playing an inconsequential role. An appreciation of the nature of the clinical course of mitral insufficiency under medical management is essential if a valid judgment is to be made as to the proper place for surgery in the relief of this condition. At the present time, such cardiac surgery always means open heart surgery using cardiopulmonary bypass, and very frequently means valve replacement with a prosthetic device. Reconstructive operations of the valve itself are now carried out mainly in special situations such as a split leaflet or possibly a ruptured chorda. Homographs and other tissue replacements are still very much in the experimental stage. The early publications on surgery with valve replacement reported rather poor operative mortality figures, of the order of 20 to 25 per cent. Recently, the operative mortality rate has improved considerably, and chance for recovery now probably approaches 5 to 10 per cent in patients not severely disabled.ig Hemodynamic and clinical improvement, which often was disappointing when a large cagedball prosthesis was employed, appears to be more satisfactorily obtained with the low-profile disc or lens type valve.20 Of more concern, however, are the number of late complications which have continued to occur. Systemic embolization from valvular thrombus formation continues to be a major problem, although reports have been made that full and prolonged anticoagulation with bishydroxycoumarin or allied drugs, and even more strikingly the use of drugs which reduce platelet adhesiveness such as dipyridamole,21 as well as the
Am. Heart I. Sefitember, 1969
employment of some of the newer types of valves, may reduce this hazard. Parabasal leaks, requiring operation for the relief of the recurrent insufficiency or of the hemolytic anemia which not infrequently develops in association with such leaks, occur all too often. More recently, evidence of deformation of the Silastic ball employed in many aortic valve replacements, occurring in a discouragingly high percentage of patients, has led to an abandonment of this type of aortic valve prosthesis by many surgeons. In view of this, one should be cautious in any estimate of the permanence of the prosthetic devices now employed in the mitral area, although reports of disintegration of a mitral prosthesis are rare indeed. In summary, therefore, although surgery for mitral insufficiency often leads to dramatic improvement and may be life-saving, it must still be considered to be in the developmental stage. Long-term follow-up studies of a significantly large number of patients are not yet available and the problems attendant on late complications have not yet been surmounted. Design of prosthetic valves are being altered and hopefully improved; grafts are still experimental. It has been shown in this study that mitral insufficiency may exist in the symptomfree stage for a great many years. Many of these Class 1 patients are in atria1 fibrillation and have large and even gigantic left atria1 as well as ventricular enlargement, usually left. Physicians may become alarmed by these huge fibrillating hearts and urge surgery for their patients while they are still relatively symptom-free. Yet it has been shown that the rate of deterioration at this stage may be slow, and even when symptomatic patients in Class 2 or 3 are observed, the course of the disease may be remarkably static, or the downward progression prolonged. Sudden death is uncommon but may occur at any stage of the disease. Systemic embolization is less common than in mitral stenosis, even though the incidence of atria1 fibrillation is higher. In view of all these considerations, it would appear that there should be no urgency about carrying out surgery in patients who have not been in congestive failure or who are not virtually completely
Volume Nwmber
417
Severe rheumatic mitral insufficiency
78 3
disabled. Cardiac enlargement by itself does not constitute an indication for surgery. Surgery should not be offered to Class 1 or 2 patients, since these patients should be able to carry on a satisfactory life and postponing surgery reduces the risk of death at operation and late complications. Such delay also may buy time while a better operation is being perfected. Since the operative risk of Class 3 patients is substantially lower than that of Class 4 patients, and since it is likely that long-term surgical results will be better in the Class 3 patients, as they have been shown to be in similarly disabled patients with mitral stenosis, surgery should not be postponed until a patient deteriorates into Class 4 if possible. Hence, patients in
Class 3 should be given serious consideration for heart surgery. Since the medical prognosis of Class 4 patients is poor, patients with this degree of disability should be offered surgery without delay. Although the operative mortality rate is high and the degree and duration of improvement uncertain, such risks are less than the ominous outcome to be expected nith medical therapy alone.
left ventricular enlargement. Deterioration may be very slow, although sudden death may occur occasionally. The more malignant
course
and
the
difference
in clinical
profile of patients with ruptured papillary muscles or chordae tendineae is described in a group
of 13 such patients.
The implications of this study in connection with the cardiac surgery
selection have been
of patients discussed,
for
The authors are grateful to Dr. Dwight E. Harken for permission to utilize information on surgical patients in Groups B, C, and D, operated by him at the Peter Bent Brigham Hospital, Boston, and the Mount Auburn Hospital, Cambridge, Mass. REFERENCES 1. Ellis, L. B., and Harken, D. E.: Closed valvuloplasty for mitral stenosis. A twelve-year followup study of 1571 patients, New England J. Med. 270:643,
1964.
Harken, D. E., Ellis, L. B., Dexter, L., Farrand, R. E., and Dickson, J. F., III: The responsibility of the physician in the selection of patients with mitral stenosis for surgical treatment, Circulation 5:349, 19.52. 3. Sokolow, M., and Lyon, T. P.: The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads, 2.
AM.
HEART
J. 37:161,
1949.
Heine, W. I., Sackett, C. F., and Serber, W.: Electrocardiographic criteria of left ventricular hypertrophy, Am. J. Med. SC. 224:424, 1952. 5. Sokolow, M., and Lyon, T. P.: The ventricular complex in right ventricular hypertrophy as obtained by unipolar precordial and limb leads, 4.
Summary This study has been concerned chiefly with the clinical course of adult patients with predominant rheumatic mitral insufficiency under medical management. It is based on a series of 42 patients followed medically, and a group of 115 patients who underwent cardiac surgery. These have been compared with a group of 138 patients proven to have pure mitral stenosis at surgery. The patients were similar in age and sex. Rheumatic fever had been diagnosed in more than half the patients with insufficiency, and subacute bacterial endocarditis had occurred more frequently, but a history of systemic embolism was less frequent in insufficiency than in stenosis.
Strikingly
different
AM.
10.
was the tendency of
patients with insufficiency to develop atria1 fibrillation and enlargement of the left ventricles and left atria, the latter often very marked. It has been shown that mitral insufficiency may exist in the symptom-free stage for many years, and many of these patients may be in atria1 fibrillation and have large and even gigantic left atria, and
HEART
J. 3%:273,
1949.
Brigden, LV., and Leatham, A.: Mit.ral incompetence, Brit. Heart J. 15:.55, 1953. 7. Wood, P.: An appreciation of mitral stenosis. Part 1. Clinical features, Brit. Med. J. l:lOSl, 1954. 8. Jhaveri, S., Czoniczer, G., Reider, K. B., and Massell, B. F.: Relatively benign “pure” mitral regurgitation of rheumatic origin, Circulation 22:39, 1960. 9. Ross, J., Jr., Braunwald, E., and Morrow, A. G.: Clinical and hemcdynamic observations in pure mitral insufficiency,.Am. J. Cardioi. 2:11, 1958. 6.
11. 12.
13.
14.
Barlow. T. B.. Bosman. C. K.. Pocock. W. A.. and M&ha& P.: Late systoiic murmurs and non-ejection (“mid-late”) systolic clicks, Brit. Heart J. 30:203, 1968. Personal observation. Sanders, C. A., Austen, W. G., Iiarthorne, J. W., Dinsmore, R. E., and Scannell, J. G.: Diagnosis and surgical treatment of mitral regurgitation secondary to ruptured chordae tendineae, New England J. Med. 276:943, 1967. Bentivoglio, L., Uricchio, J. F., and Likoff, W.: The paradox of right ventricular enlargement in mitral insufficiency, Am. J. Med. 24:193, 1958. Bland, E. F., and Jones, T. D.: Rheumatic fever
418
15.
16.
17.
Ellis and Ramirez
and rheumatic heart disease. A twenty year report on 1,000 patients followed since childhood, Circulation 4:836, 1951. Wilson, M. G., and Lim, W. N.: Natural history of rheumatic heart disease in third, fourth and fifth decades of life. I. Prognosis with special reference to survivorship, Circulation 16:700, 1957. Magida, M. G., and Streifeld, F. H.: Natural history of rheumatic heart disease in third, fourth and fifth decades of life. II. Prognosis with special reference to morbidity, Circulation 16:713, 1957. Abelmann, W. H., Ellis, L. B., and Harken, D. E.: The diagnosis of mitral regurgitation. An evaluation of clinical criteria, fluoroscopy,
18.
19. 20.
21.
phonocardiogram, auricular esophagogram, and electrokymogram, Am. J. Med. 15:5, 1953. Brest, A. N., Uricchio, J. F., and Likoff, W.: Traumatic mitral insufficiency. A complication of mitral commissurotomy, J.A.M.A. 1751081, 1961. Unpublished observations. Matloff, J. M., Dalen, J. E., Dexter, L., and Harken, D. E.: Hemodynamic response to discord mitral valve replacement, Circulation 37 (Suppl. 11):94, 1968. Sullivan, J. M., Harken, D. E., and Gorlin, R.: Pharmacologic control of thromboembolic complications of cardiac valve replacement, New England J. Med. 279:576, 1968.
The clinical “rheumatic”
course of patients with mitral’ insufficiency
severe
Laurence B. Ellis, M.D.* Albert0 Ramirez, M.D. Boston, Mass.
S
urgery for mitral insufficiency has now progressed to a point where operation leading to clinical improvement can be carried out with an acceptable operative risk. However, there are still very real problems concerned with various prosthetic valves and late complications of the operation. In view of the present stage of surgery for mitral valve insufficiency, it is important to know exactly what is the clinical course of patients with this condition under medical management, so that we can better select the place for surgery in our patients. It is surprising how little attention has been paid to this recently. Most of our concepts today are based on articles written several years ago when the criteria for the clinical diagnosis of mitral insufficiency were relatively crude. Many of the published reports are concerned with patients in whom a significant degree of mitral stenosis coexisted with insufficiency. There have been, on the other hand, many articles published dealing with surgery in this condition, the use of various prosthetic and other devices as valve replacements, as well as hemodynamic and angiographic studies. Articles dealing with the selection of patients for surgery are largely based on the conven-
tional clinical wisdom of the past or on rather arbitrary and by no means infallible hemodynamic criteria, and are colored by the degree of enthusiasm or skepticism currently afflicting the authors. In particular, there is a paucity of reports dealing with what happens to patients with mitral incompetence under medical management who are already symptomatic in varying degrees when they come under observation. Many of the published follow-up studies deal with the course of rheumatic heart disease following acute rheumatic fever. Such studies, while valuable, poorly lend themselves to comparative studies of the course of the disease after surgical treatment, as has been shown in an analogous situation when attempts were made to compare the results of surgical therapy for mitral stenosis with medical management of the disease.’ Our interest in this subject was stimulated by observing a number of remarkable patients, of whom the following is an example. A young man of 23 (A. M.) with severe rheumatic mitral insufficiency was referred for medical advice as to the advisability of his marrying. A murmur had been present since the age of 9 when he had
From
the Thorndike Memorial Laboratory, Second and Fourth (Harvard) Medical Services, Boston City and the Department of Medicine. Harvard Medical School, Boston. Mass. This study was supported in part by Grants HE 10539 and HE 5244 from the National Heart Institute. Institutes of Health, United States Public Health Service. *Address: Heart Station. Boston City Hospital. 818 Harrison Ave.. Boston. Mass. 02118.
406
American
Heart
Journal
September,
1969
Vol.
78, No.
Hospital, National
3, pp. 406-418
Severe rheumatic
Fig. 1. Posteroanterior and lateral atria Irn posteriorly and to the right,
roentgenograms and apparent
of Patient A. M. shows enlargement of left and right
rheumatic fever. Since then his symptoms slowly increased so that at the time of our examination he had dyspnea on slight exertion and easy fatigue. His liver was palpable. His heart was enormous by roentgenogram (Fig. l), chiefly in the region of the left atrium, and his electrocardiogram (ECG) showed combined ventricular enlargement (Fig. 2). Because satisfactory surgical treatment was not then available he was given a dubious prognosis and not much else. Ten years later, this man was happily married with 2 children, he had less dyspnea and fatigue, and his liver was no longer palpable. Roentgenogram of his heart and ECG were unchanged. His improvement was largely due to the fortunate fact that he was enabled to budget his energy better, for he had been promoted from a bank teller to the sedentary life of a vice-president, keeping “banker’s hours.” A year later, he did deteriorate, and surgery now being available, he underwent mitral valve replacement of a grossly incompetent, nonstenotic valve. He has had marked improvement, but little or no change in heart size, since giant atria do not diminish in size without surgical excision.
mitral
insz@ciency
enormous ventricles.
enlargement
07
nf left
The observation of this and similar patients raised the question as to how frequently do symptomatic patients follow such a benign course, and how often do they deteriorate progressively. This article, therefore, will reassess the clinical profile and course of aduIt patients with severe rheumatic mitral incompetence, compared to those with mitral stenosis, and a small group of patients who had ruptured chordae or papillary muscles. Material
and methods
Group A includes 42 patients, personally seen and followed by one of us (L.B. Ellis) over a period of years, with the clinical diagnosis of pure or predominant mitral insufficiency. Classified in this group were patients who had an apical holosystolic murmur of Grade III or greater in intensity. An apical diastolic murmur might or might not be present; when present it was low-pitched and rather early, frequently following a third sound. An opening snap was absent. The etiology was assumed to be rheumatic and there was no clinical evidence of aortic or of any major complicating conditions. These patients were se-
408
Am. Heart J. Scfitember, 1969
Ellis and Ramirez
Fig. 2. ECG of Patient axis of plus 100 degrees
A. M. showing atrial (combined ventricular
flutter-fibrillation, hypertrophy).
lected from a much larger group seen in medical consultation, usually with a question of cardiac surgery in mind. Most of these patients were seen first by the author prior to 1961 at a time when there was no definitely acceptable surgery for mitral insufficiency. The diagnosis of uncomplicated severe mitral insufficiency was confirmed in 6 of these patients at subsequent cardiac surgery, in 5 more by left heart catheterization and angiography, and in 3 others by postmortem examination. Group B includes 115 consecutive patients who underwent cardiac surgery by D. E. Harken. They were found at surgery to have severe mitral insufficiency with trivial or no mitral stenosis. (The mitral valve area was estimated to be 4 cm.2 or greater in all but 6 patients in whom it was estimated to be from 2.5 to 3.9 cm.2, or the
and left ventricular
hyper trophy
with
a frc &a I
description of the surgeon was “very slight, ” “minimal,” or “no” stenosis.) The etiology was assumed to be on a rheumatic basis, and there was no evidence of any other significant valvular or cardiac lesions. Twenty-eight of these were operated by closed mitral valvuloplasty and the remaining 87 underwent open cardiac surgery with cardiopulmonary bypass. The majority of these patients had not been observed for any extended period of time by the authors prior to their referral for cardiac surgery. The purpose of selecting this group was to set up a standard of comparison between patients who have proven mitral insufficiency and the Group A patients in whom the diagnosis was based on clinical criteria. Group C includes 138 consecutive patients who underwent closed mitral valvulo-
Volume Nwnbcr
78 3
plasty and who were shown at surgery to have severe mitral stenosis without evidence of significant mitral insufficiency, other valvular disease, or cardiac disease of other nature. This group was selected for comparison with the two preceding groups. Group D includes 13 patients who were found at open heart surgery to have ruptured chordae tendineae or papillary muscles. The classification used in all the groups was that which has previously been described.? To avoid confusion with Groups A, B, C, and D of this study, what were called Groups 1, 2, etc. in the original study, are designated as Class 1, 2, etc. in this paper. Class 1 is comprised of patients who are asymptomatic on ordinary activity; Class 2 includes patients with moderate, but static, cardiac limitation of cardiac reserve, able to carry on sedentary activity; Class 3 is comprised of patients whose symptoms are clearly progressive; Class 4 is comprised of patients who are cardiac invalids, in heart failure, or only kept out of failure by a rigorous medical regimen. This classification corresponds fairly closely to the New York Heart Association classification, but takes into account a dynamic view of the patient’s clinical picture. The description of the roentgenographic findings in Group A is based on cardiac fluoroscopy personally done by the senior author. The roentgenographic findings in Groups B, C, and D are based on cardiac fuoroscopy by the hospital roentgenologist, plus review of x-ray films (posteroanterior, lateral, right, and left obliques) by the authors. The ECG’s were reviewed by the authors, using the criteria of Sokolow and Lyon.3-5 Because many of the patients were under a strict cardiac regimen, including digitalis and diuretic drugs, S-T and T segment deviations were not employed as criteria for the diagnosis of ventricular enlargement. Left ventricular hypertrophy was diagnosed if one or more of the following criteria existed: an R wave in Vs greater than 26 mm.; an R wave in Va or VS plus an S wave in Vi exceeding 3.5 mm.; the sum of Ri and Sa exceeding 24 mm.; or an R nave in aVr, greater than 11 mm. Right ventricular hypertrophy was diag-
Sez!ere rhellmatic
mitral insujiz&:nc~
409
nosed on the basis of one or more of the following: R/S in Vi greater than 1; an R wave in Vi greater than 7 mm.; qR in Vi; or a persistent RS pattern across the precordium. Combined ventricular hypertrophy was diagnosed when criteria for both left and right enlargement were present or when left ventricular enlargement existed with a frontal axis of plus 90 degrees or greater. These criteria for ventricular enlargement were admittedly arbitrary, and no claim that they are highly accurate is being made. They were merely adopted to set uniform standards of comparison. Vectorcardiograms were not done with sufficient. frequency to permit valid analysis. This study will not include a discussion of the physical findings or the clinical diagnostic criteria of mitral insufficiency, because Group A patients were obviously selected largely on the basis of predetermined criteria of physical findings, and in the other groups the nature of the study was such that many of the patients did not have detailed observations made by a single observer. Results
Groups A and B, compared to C. It is clear from a comparison of Groups A and B that the two groups were similar in every way (Table I). There \jpasa preponderance of female patients in Groups A and B, but the difference was of borderline significance when compared to those with pure mitral stenosis ((;roup C). ((;roups A and B compared to C’, p = 0.05; Group B compared to C, p = 0.25.) This is in contrast to findings reported by others,“,’ although J haveri and associate9 and Ross and associates9 had more females than males in their series. The average age of patients coming to surgery \vas the same for patients with mitral insufficiency and mitral stenosis as well as for those in Group A when first observed. In this group, however, there was a tremendous range of ages, regardless of the degree of cardiac disability when first seen. Both groups of patients with niitral insufficiency had a significantly higher incidence of a history of rheumatic fever than those with mitral stenosis (p < 0.001). A history of subacute bacterial endo-
410
Am. Hcavt I. September, 1969
Ellis and Ramirez
Table I. Groups A, B, C, and D compared Group Variables
A
Group B “Rheumatic” mitral iTLSUji&Xysurgical series
“Private series” --__
Pure
mitral surgical
C
Group D Ruptured chordae
stenosisseries
07
pafiillary
muscles
--No.
Total no. of patients Average age* (years) Sex Female Male Degree of disability Class 1 Class 2 Class 3 Class 4 History of: Rheumatic fever Subacute bacterial endocarditis Systemic emboli Initial symptoms Dyspnea Fatigue Dyspnea, fatigue Congestive failure Palpitation None Atria1 fibrillation Class 1 Class 2 Class 3 Class 4
Group
No.
%
42
l 1
%
115 43
/
No.
69 31
92 23
12 18 6 6
29 43 14 14
26
No.
%
138 44
29 13
I 1
119 19
0 0 63 52
62
3 3
;
15 3 11 1 3 9
36 7 26 2 7 21
%
13 44
80 20
/
57 86 14
2 11
1.5 85
54 46
0 0 87 51
62 38
0 0 2 11
1.5 8.5
81
70
63
46
1
8
8 14
7 12
4 30
3 22
1 0
8 0
49 6 52 0
43 5 4.5
51 5 6.5 0
41 4 47
1 1 3 8
8 8 23 61
-
w
611: 83 100
-
78
31
90
70
*Age when first seen by L. B. Ellis in Group A, and age at surgery in Groups B, C, and D. tone patient in normal rhythm, later deteriorated to Class 3 and developed atrial fibrillation. $Two of these patients had paroxysmal atria1 fibrillation. Two others in normal rhythm later still in Class 2 and one after deteriorating to Class 3.
carditis occurred more than twice as frequently in mitral insufkiency as in stenosis, but the difference was not statistically significant (p = 0.2). Atria1 fibrillation occurred early in the course of mitral incompetence and was almost always present when the patients were seriously disabled. Dyspnea or a combination of dyspnea and fatigue were the usual initial complaints for the groups with insufficiency and those with stenosis. Palpitation was not a common initial complaint, although it often occurred as a secondary symptom in association with other symptoms. A history of systemic embolization was
developed
50 16
atria1
fibrillation,
one while
more commonly found in patients with mitral stenosis than in those with insufficiency and the difference was significant (p = 0.02). As judged by the ECG’s (Table II), a majority of patients with mitral insufficiency had either left ventricular or combined ventricular hypertrophy, whereas patients with mitral stenosis rarely had positive evidence of left ventricular hypertrophy and frequently (47 per cent) showed right. A third of the patients with insufficiency showed no clear evidence of hypertrophy by ECG. Such a finding could mean either that no hypertrophy actually was present or that combined hypertrophy
Volume Number
78 3
Severe rheumatic
Table I I. Electrocardiographic
and x-ray
mitral insu&cienry
411
changes
Group A Class (No. patients) Variables
Electrocardiographic of ventricular
evidence hypertrophy
None Left Right Combined
6 6 0 0
+3 f4 None Left Right Combined
5 3 2 2 4 5 0 3
Roentgenographic findings Left atria1 enlargement
Ventricular
enlargement
Pulmonary artery prominence Mitral valve calcification surgery or post mortem
*In
Group
B, ECG’s
were
5 10 2 1
8 3 3 6 2 7
1 1 1 3
1 2 0 0 0 6
1 3 1 1
31 48 9 12
34 35 13 30
49 3 47 1
15 77 0 8
4 1 0 4 1 1
19 26 36 19 17 36 7 40
4 34 46 16 3 10 21 66
11 67 20 2 2 11 64 23
15 69 8 8 0 38 0 62
Not
analyzed
59
75
46
Not
analyzed
22
43
0
at
analyzed
in 112 patients,
roentgenograms
existed and the abnormal vector forces from the enlargement of the two ventricles neutralized each other. The roentgenographic findings were less clear-cut. Although “right ventricular enlargement” was diagnosed with about the same degree of frequency by this technique as by the ECG, “combined ventricular enlargement” was reported much more frequently by roentgenogram in the mitral insufficiency series and to a lesser degree in the mitral stenosis series. This discrepancy with the electrocardiographic findings can possibly be explained by the great degree of atria1 enlargement that tended to occur in the mitral insufficiency groups. It is an obvious fact, although frequently overlooked, that when the left atrium enlarges, it not only intrudes on the posterior mediastinal space, and as it becomes progressively bigger, extends to the left or right, but it also pushes the rest of the heart anteriorly and rotates it in a clockwise direction so that apparent enlargement of either or both of the ventricles may be described. Thus, in patients showing gross enlargement of the left atrium, there is
in 110.
almost invariably the roentgenographic picture of both right and left ventricular enlargement, even though such combined enlargement may not be evident in the ECG (Table III). This effect of atria1 enlargement is apparently also evident to some extent in patients with mitral stenosis.
Table I I I. Group A-Relationship between left atria1 size and ventricular enlargement as observedat cardiac jluoroscopy and by ECG Left atria1 enlargement Ventricular +1
+2 +3 14 Ventricular +1
+2 +3 +4
I
I None
/
Left
/
Right
; Comj bined
enlargement 5 1 1 0
by fluoroscopy 3 4 8 0
0 0 2 1
0 6 4 7
enlargement 3 4 5 1
by ECG 4 5 7 4
0 2 1 1
1 0 2 2
Table IV. Duration
First
Am. Heart I. Sefitember, 1969
Ellis and Ran&es
412
seen in Class 1
(Average
age, 40)
2
(Average
age, 43)
3 (Average
age, 36)
4 (Average
age, 48)
of disease in Group A patients
when Jirst seen 23 2.5 25 28 3.5 37 39 42 53 56 59 62 12 27 28 33 3.5 38 39 39 40 45 47 48 49 52 59 61 63 72 21 24 27 34 47 62 20 47 53 54 58 59
No. years Class 1 1 2 15 22 22 18 13 5 22 24 5 25 4 54
7
]
3
:
31
2
7
3 4 10 2
23
2
9 11 14 10 6 7
31 30 10 57 52 43 65 3 9
1
2
?
8 5
44
4
5 3
2
30
1
3
10 12 12 32 5 30 10 12 10 1 6 7 21 5 1 1 6 1
9 7 18
Total
in each class
?
11 8 4
Enlargement of the main pulmonary artery was noted less frequently in patients with mitral insufficiency than in patients with stenosis (Table II). Valvular calcification was significantly less common in mitral insufficiency (Table II) (p < O.OOl), although it was seen in
2
1 11 9 6 3 1 4
duration
he?y,“izzse
~~~.‘??L$
15 32 22 18 18 8 26 18 5 27 4 54
9 18 12 8 8 3 13 7 1 22 1 2
12 12 22 39 23 30 40 12 12 32 6 37 21 17 58 53 49 66
11 3 10 14 3 3 9 5 7 1 4 4 21 6 1 1 2 1
1.5 24 24 19 7 32
9 9 8 6 6 7
19 14 6 14 9 52
11 4 1 3 3 4
Outcome
Died,
pulm.
emb.
Operated Operated
Operated
Died,
cancer
Operated
Sudden Died,
death C.H.F.
Operated Operated Died Died, C.H.F. Died Sudden death Died Died
some patients even with “pure” insufficiency. Course of the disease (Table IV). Our findings having to do with the clinical course of mitral insufficiency are based on the Group A patients. The length of time patients were stated to be in Class 1 is
Severe rheumntic mitral
based on the known duration of the asymptomatic phase of their heart disease, from the occurrence of rheumatic fever with cardiac involvement or the discovery of a murmur or other cardiac abnormality, such as enlargement. Thus, the estimated duration of the disease in many instances must have been shorter than its actual duration. Jlany patients had a remarkably long duration of known heart disease before the) showed symptoms. Fifteen of the 28 patients in whom heart disease had first been recognized in an asymptomatic phase were observed in Class 1 from 22 to 65 years. If the span of years from first knowledge of heart disease to last observation is considered, 6 patients were known to have had heart disease from 49 to 66 years. Six more had had recognized disease from 31 to 40 years, 9 from 21 to 30 years, 14 from It to 20 years, and 7 from 4 to 10 years. Of the 12 who were first observed while in Class 1, 7 were in atria1 fibrillation, 6 showed left ventricular enlargement b) ECG, ail showed some, and 4 showed marked or extreme atria1 enlargement. After an average of seven more years of observation : 6 were still symptom-free; 3 developed mild symptoms; and 3 deteriorated to Class 3, one of whom died of a pulmonary embolus, and the other 2 underwent heart surgery. Patients who were first observed ivith mild symptoms (Class 2) have also tended to do well. In 13 patients, the cardiac situation remained static for an observation period of 1 to 32 years (average 10 years), although 1 died of cancer and 1 underwent cardiac surgery. One patient died suddenly after 7 years of mild symptoms. Of the remaining 4, 2 have deteriorated to Class 3 after 10 and 12 years in Class 2; 1 underwent heart surgery after 2 years in Class 3; and 1 died after 2 years of congestive failure. Patients first seen when moderately disabled in Class 3 have also fared well. In 2 patients heart disease was first diagnosed when they were in Class 2 and Class 3, respectively. Of the 6, 5 were followed for 7 to 14 years at this stage, although 2 finally underwent heart surgery. One patient deteriorated after 6 years in Class 3 to Class 4 and died after a year of congestive failure. Thus, of these 36 patients, only 4 have
ins?ifiiicnr-:l
413
died a possible cardiac death, including one sudden death and one from a pulmonary emholus. The 6 patients first seen in congestive failure (Class 4) have not done well. In 4, heart disease lvas first diagnosed when they lvere symptomatically in Class 3, and in a fifth patient, knowledge of heart disease COincided \vith the development of congestive heart failure. Only one is alive after 4 years of failure. Five are dead, 1 after 11 years of failure; the others were in failure from 1 to 9 J’ears. Croup D. The profile of 13 patients with ruptured chordae or papillary muscles differed in many ways from the other patients with mitral insufficiency (‘I‘al)les I and II). It was ntainly a disease of males (8.5 per cm), and they I\-ere older on the average t ban the other groups (average age 57 h-ears). Four had a history of myocardial infarction 4 months to 6 years before also had surgery ; one of these patients sul~acute bacterial endocarditis. Only one had had rheumatic fever, Ijut in 3 other patients mild rheumatic mitral valvulitis uxs found at postmortem examination. In the remaining 5 the etiology was llnclear. Atria1 fibrillation leas present in ouly 3, 2 of whom had rheumatic mitral insufficiency. Tile E(‘C.; showed left ventricular enlargement in 77 per cent of the patients, and either left or combined enlargement was described in all of the patients by roentgenogram. The left atrium cl as only slightly to moderately enlarged in all except 2 patients. Valvular calcification did not occur. Sone had a history of systemic em boli. The 2 patients who were operated while in Class 3, had symptoms for 7 months and 4 years, respectively. Three patients had been in Class 3 for 6 months, 8 months, and 4 years before slipping to Class 4 for 4 to 12 months before surgery. In 8 patients, the congestive failure came on abruptly and persisted for 1; i to 12 months in 7, and for 4 years in tllct eighth patient before surgery took place. It is recognized that there is a spectrum of mitral valve disturbances, ranging from pure stenosis without insufficiency, through varying degrees of stenosis with insuffi-
414
Ellis and Ramirez
ciency, to pure insufficiency. Both of these abnormalities of mitral valve function put hemodynamic strains on the heart and the circulation, but the strains differ somewhat in their nature. In mitral stenosis, the pathologic physiology and the early symptomatology are clearly related to the block at the valve and often a marked increase in pulmonary vascular resistance. These abnormalities lead to increase in left atria1 and pulmonary vascular pressure. They also lead to a reduction in cardiac output, especially during exercise, for reasons not entirely clear at the present time. This diminished blood flow and increase in pulmonary resistance result in the sensations of fatigue and of dyspnea which may progress so as to become incapacitating. Left ventricular failure does not occur. Failure of the right ventricle is seen late, secondary to the long-standing pulmonary hypertension. In contrast, the severely symptomatic phase of mitral insufficiency is due to left ventricular failure, resulting from the overwork of the left ventricle. Reduction in cardiac output due to reduced forward blood flow, as well as to some degree of pulmonary vascular congestion from the backflow into the left atrium, may be responsible for some early symptoms of fatigue and dyspnea before myocardial failure develops. In the present study, patients were deliberately chosen who gave evidence of predominant mitral incompetence, in order to avoid the possibility that the clinical symptoms manifested by them were due to a stenotic lesion. Since the symptomatology of advanced mitral insufficiency is due to left ventricular failure, the question arises: Is the failure secondary to the strain imposed by the leaking valve or is it, at least in part, due to primary myocardial failure, with the valvular insufficiency of secondary importance? The latter is obviously true in patients with primary disease of the left ventricle and “functional” valvular insufficiency. It is not such patients that concern us, but those who have severe organic disturbances of the valve itself. The question of the importance of myocardial disease in such patients cannot at the present time be answered, and the relative importance
Am. Heart 1. September, 1969
of valve leak versus myocardial disease accurately assessed, except ex post facto by the results of surgery with replacement of the damaged mitral valve by a competent one. Even after such surgery the answer may not be forthcoming, because the circulation may not be restored to a completely normal hemodynamic state. This may be because the artificial valves themselves may not be hemodynamically perfect, or because such prolonged strain may have led to some irreversible physiologic and even morphologic cardiac changes, since most patients do not come to surgery until they have sustained a long-standing strain on their left ventricles. The question of a primary myocardial factor in rheumatic mitral insufficiency is not yet ruled out, however. Although it is virtually axiomatic to assume that mitral stenosis in adult patients is always due to a preceding rheumatic fever, such an assumption cannot be made for mitral incompetence. In spite of the fact that a greater percentage of patients with this lesion have a previous history of rheumatic fever than patients with mitral stenosis, nevertheless, there are some patients in whom clearly there is an etiologic cause other than rheumatic fever. Perhaps, the early appearance and the ease of recognition of the systolic murmur of mitral insufficiency (in contrast to the easily missed and later developing diastolic or presystolic murmur of stenosis) are responsible for a larger number of the former patients being diagnosed as having rheumatic fever in the acute stage. Patients in whom combined mitral stenosis and insufficiency has been proven to be present, as well as those who have organic mitral and aortic valvular disease, can be considered to be rheumatic, and this is the etiologic cause in persons coming to surgery because of dominant mitral insufficiency without other valve involvement in about 90 per cent of adult patients. A few adult patients have isolated congenital anomalies of the mitral valve, such as a cleft valve with or without associated cardiac defects. A syndrome of voluminous billowing of the posterior mitral leaflet, associated with a late systolic murmur and click or “honk,” has been described.iO This may be a hereditary characteristic. Subacute bac-
Severe rheumatic
terial endocarditis may cause or exacerbate insufficiency by perforating a leaflet or causing chorda rupture, but this almost always occurs in a valve already damaged by rheumatic disease. The same can be said for trauma, One of the most difficult diagnostic problems is differentiating organic mitral insufficiency from a cardiomyopathy. Indeed, some cardiomyopathies do produce organic changes in the mitral valve and, in any of them, functional insufficiency may occur as the result of left ventricular dilatation (with inadequate closure of the mitral leaflets that are held open by the relatively shortened chordae, which cause elongation of the left ventricle and displacement of the papillary muscles toward the apex) as well as by dilatation of the mitral annulus. Insufficiency can also occur in patients with left ventricular dilatation and failure of known etiology, e.g., hypertensive or ischemic heart disease. Careful clinical, hemodynamic, and angiographic assessment will usually establish whether mitral insufficiency is or is not a major factor, so that patients will not inadvertently be subjected to valvular surgery. In a series of 400 patients undergoing open heart surgery for mitral valve disease, there were only 3 in whom a diagnosis of cardiomyopathy was made at surgery or at postmortem examination.ll Coronary artery disease may lead to infarction of the papillary muscle and rupture of the muscle or attached chordae with resulting free mitral insufficiency. The clinical profiles of these patients with coronary artery disease, as well as those with ruptured rhordae from other causes, differ strikingly as a rule from the profiles seen in cases of usual rheumatic mitral incompetence, and they are often relatively easy to recognize; the malignant course these patients follow should bring them to surgery promptly. Our findings in regard to the clinical findings and course of these patients are in accord with those reported by others.12 The study which we have reported shows certain similarities in the clinical profiles of patients with severe insufficiency, assumed to be of rheumatic origin, and those with mitral stenosis. The age and sex of the patients are the same. A rheumatic history
mitral
inszificiency
41s
occurs in half or more of the cases. Bacterial endocarditis was diagnosed in a somewhat greater number of patients with insufficiency, but this may be because such endocarditis may itself produce or aggravate the leak. Systemic embolization is less common in mitral insufficiency. Strikingly different is the tendency for many patients with insufficiency -to develop great enlargement of the left atrium, as well as left ventricular enlargement, and these changes, together with the onset of atria1 fibrillation, may occur at an early, or at least asymptomatic, stage of the disease. There have been numerous reports of the electrocardiographic findings in miwith or without assotral insufficiency, ciated stenosis, in which the importance of left ventricular hypertrophy as an indication of incompetence is stressed. 1311 occasional patient with pure mitral insufficiency shows right or combined ventricular hypertrophy in the ECG.gJ3 In view of these clinical dissimilarities-as well as the difference in the type of physiological strain imposed on the heart in the two conditions, is there a difference in the clinical course of the disease, i.e., do patients with mitral insufficiency deteriorate at a more rapid rate than those with stenosis? It has been shown that patients followed from the time of their acute rheumatic fever with a diagnosis of mitral insufficiency, based on the presence of an apical systolic murmur, tend to follow a benign course.14-1G Other studies have shown that patients with pure or predominant mitral insufficiency do become symptomatic and ultimately die of their disease, even though they may have a long latent period before serious symptoms develop.“*7zgJ7 The occasional catastrophic progression of heart failure in pat,ients, in which inadvertent severe rupture of the aortic leaflet of the mitral valve has been produced in the course of surger1. for mitral stenosis, is well known.‘8 The malignant course of the disease in patients with ruptured chordae or papillary muscles has already been discussed. Our study shows that patients with rheumatic mitral insufficiency, who are not totally disabled, may have a prolonged course under medical therapy. The patients with mitral insufficiency discussed in this stud>- are, of
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course, a selected group, for the most part symptomatic and with well-marked cardiac abnormalities. We are not suggesting that patients who have mitral incompetence invariably, or even frequently, develop such cardiac pathology in the asymptomatic phase of their disease. Rather, it was our intention to study the course of disease in those patients who are thus afflicted. We have not attempted to distinguish between patients who had “pure” mitral insufficiency with no stenosis whatsoever and those with slight stenosis. We have chosen patients in whom the essential hemodynamic fault was valvular incompetence, with any stenosis that might exist playing an inconsequential role. An appreciation of the nature of the clinical course of mitral insufficiency under medical management is essential if a valid judgment is to be made as to the proper place for surgery in the relief of this condition. At the present time, such cardiac surgery always means open heart surgery using cardiopulmonary bypass, and very frequently means valve replacement with a prosthetic device. Reconstructive operations of the valve itself are now carried out mainly in special situations such as a split leaflet or possibly a ruptured chorda. Homographs and other tissue replacements are still very much in the experimental stage. The early publications on surgery with valve replacement reported rather poor operative mortality figures, of the order of 20 to 25 per cent. Recently, the operative mortality rate has improved considerably, and chance for recovery now probably approaches 5 to 10 per cent in patients not severely disabled.ig Hemodynamic and clinical improvement, which often was disappointing when a large cagedball prosthesis was employed, appears to be more satisfactorily obtained with the low-profile disc or lens type valve.20 Of more concern, however, are the number of late complications which have continued to occur. Systemic embolization from valvular thrombus formation continues to be a major problem, although reports have been made that full and prolonged anticoagulation with bishydroxycoumarin or allied drugs, and even more strikingly the use of drugs which reduce platelet adhesiveness such as dipyridamole,21 as well as the
Am. Heart I. Sefitember, 1969
employment of some of the newer types of valves, may reduce this hazard. Parabasal leaks, requiring operation for the relief of the recurrent insufficiency or of the hemolytic anemia which not infrequently develops in association with such leaks, occur all too often. More recently, evidence of deformation of the Silastic ball employed in many aortic valve replacements, occurring in a discouragingly high percentage of patients, has led to an abandonment of this type of aortic valve prosthesis by many surgeons. In view of this, one should be cautious in any estimate of the permanence of the prosthetic devices now employed in the mitral area, although reports of disintegration of a mitral prosthesis are rare indeed. In summary, therefore, although surgery for mitral insufficiency often leads to dramatic improvement and may be life-saving, it must still be considered to be in the developmental stage. Long-term follow-up studies of a significantly large number of patients are not yet available and the problems attendant on late complications have not yet been surmounted. Design of prosthetic valves are being altered and hopefully improved; grafts are still experimental. It has been shown in this study that mitral insufficiency may exist in the symptomfree stage for a great many years. Many of these Class 1 patients are in atria1 fibrillation and have large and even gigantic left atria1 as well as ventricular enlargement, usually left. Physicians may become alarmed by these huge fibrillating hearts and urge surgery for their patients while they are still relatively symptom-free. Yet it has been shown that the rate of deterioration at this stage may be slow, and even when symptomatic patients in Class 2 or 3 are observed, the course of the disease may be remarkably static, or the downward progression prolonged. Sudden death is uncommon but may occur at any stage of the disease. Systemic embolization is less common than in mitral stenosis, even though the incidence of atria1 fibrillation is higher. In view of all these considerations, it would appear that there should be no urgency about carrying out surgery in patients who have not been in congestive failure or who are not virtually completely
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Severe rheumatic mitral insufficiency
78 3
disabled. Cardiac enlargement by itself does not constitute an indication for surgery. Surgery should not be offered to Class 1 or 2 patients, since these patients should be able to carry on a satisfactory life and postponing surgery reduces the risk of death at operation and late complications. Such delay also may buy time while a better operation is being perfected. Since the operative risk of Class 3 patients is substantially lower than that of Class 4 patients, and since it is likely that long-term surgical results will be better in the Class 3 patients, as they have been shown to be in similarly disabled patients with mitral stenosis, surgery should not be postponed until a patient deteriorates into Class 4 if possible. Hence, patients in
Class 3 should be given serious consideration for heart surgery. Since the medical prognosis of Class 4 patients is poor, patients with this degree of disability should be offered surgery without delay. Although the operative mortality rate is high and the degree and duration of improvement uncertain, such risks are less than the ominous outcome to be expected nith medical therapy alone.
left ventricular enlargement. Deterioration may be very slow, although sudden death may occur occasionally. The more malignant
course
and
the
difference
in clinical
profile of patients with ruptured papillary muscles or chordae tendineae is described in a group
of 13 such patients.
The implications of this study in connection with the cardiac surgery
selection have been
of patients discussed,
for
The authors are grateful to Dr. Dwight E. Harken for permission to utilize information on surgical patients in Groups B, C, and D, operated by him at the Peter Bent Brigham Hospital, Boston, and the Mount Auburn Hospital, Cambridge, Mass. REFERENCES 1. Ellis, L. B., and Harken, D. E.: Closed valvuloplasty for mitral stenosis. A twelve-year followup study of 1571 patients, New England J. Med. 270:643,
1964.
Harken, D. E., Ellis, L. B., Dexter, L., Farrand, R. E., and Dickson, J. F., III: The responsibility of the physician in the selection of patients with mitral stenosis for surgical treatment, Circulation 5:349, 19.52. 3. Sokolow, M., and Lyon, T. P.: The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads, 2.
AM.
HEART
J. 37:161,
1949.
Heine, W. I., Sackett, C. F., and Serber, W.: Electrocardiographic criteria of left ventricular hypertrophy, Am. J. Med. SC. 224:424, 1952. 5. Sokolow, M., and Lyon, T. P.: The ventricular complex in right ventricular hypertrophy as obtained by unipolar precordial and limb leads, 4.
Summary This study has been concerned chiefly with the clinical course of adult patients with predominant rheumatic mitral insufficiency under medical management. It is based on a series of 42 patients followed medically, and a group of 115 patients who underwent cardiac surgery. These have been compared with a group of 138 patients proven to have pure mitral stenosis at surgery. The patients were similar in age and sex. Rheumatic fever had been diagnosed in more than half the patients with insufficiency, and subacute bacterial endocarditis had occurred more frequently, but a history of systemic embolism was less frequent in insufficiency than in stenosis.
Strikingly
different
AM.
10.
was the tendency of
patients with insufficiency to develop atria1 fibrillation and enlargement of the left ventricles and left atria, the latter often very marked. It has been shown that mitral insufficiency may exist in the symptom-free stage for many years, and many of these patients may be in atria1 fibrillation and have large and even gigantic left atria, and
HEART
J. 3%:273,
1949.
Brigden, LV., and Leatham, A.: Mit.ral incompetence, Brit. Heart J. 15:.55, 1953. 7. Wood, P.: An appreciation of mitral stenosis. Part 1. Clinical features, Brit. Med. J. l:lOSl, 1954. 8. Jhaveri, S., Czoniczer, G., Reider, K. B., and Massell, B. F.: Relatively benign “pure” mitral regurgitation of rheumatic origin, Circulation 22:39, 1960. 9. Ross, J., Jr., Braunwald, E., and Morrow, A. G.: Clinical and hemcdynamic observations in pure mitral insufficiency,.Am. J. Cardioi. 2:11, 1958. 6.
11. 12.
13.
14.
Barlow. T. B.. Bosman. C. K.. Pocock. W. A.. and M&ha& P.: Late systoiic murmurs and non-ejection (“mid-late”) systolic clicks, Brit. Heart J. 30:203, 1968. Personal observation. Sanders, C. A., Austen, W. G., Iiarthorne, J. W., Dinsmore, R. E., and Scannell, J. G.: Diagnosis and surgical treatment of mitral regurgitation secondary to ruptured chordae tendineae, New England J. Med. 276:943, 1967. Bentivoglio, L., Uricchio, J. F., and Likoff, W.: The paradox of right ventricular enlargement in mitral insufficiency, Am. J. Med. 24:193, 1958. Bland, E. F., and Jones, T. D.: Rheumatic fever
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15.
16.
17.
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and rheumatic heart disease. A twenty year report on 1,000 patients followed since childhood, Circulation 4:836, 1951. Wilson, M. G., and Lim, W. N.: Natural history of rheumatic heart disease in third, fourth and fifth decades of life. I. Prognosis with special reference to survivorship, Circulation 16:700, 1957. Magida, M. G., and Streifeld, F. H.: Natural history of rheumatic heart disease in third, fourth and fifth decades of life. II. Prognosis with special reference to morbidity, Circulation 16:713, 1957. Abelmann, W. H., Ellis, L. B., and Harken, D. E.: The diagnosis of mitral regurgitation. An evaluation of clinical criteria, fluoroscopy,
18.
19. 20.
21.
phonocardiogram, auricular esophagogram, and electrokymogram, Am. J. Med. 15:5, 1953. Brest, A. N., Uricchio, J. F., and Likoff, W.: Traumatic mitral insufficiency. A complication of mitral commissurotomy, J.A.M.A. 1751081, 1961. Unpublished observations. Matloff, J. M., Dalen, J. E., Dexter, L., and Harken, D. E.: Hemodynamic response to discord mitral valve replacement, Circulation 37 (Suppl. 11):94, 1968. Sullivan, J. M., Harken, D. E., and Gorlin, R.: Pharmacologic control of thromboembolic complications of cardiac valve replacement, New England J. Med. 279:576, 1968.