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Mitral regurgitation in muscular subaortic stenosis
Mitral E. DOUGLAS WIGLE,
Regurgitation in Muscular Subaortic Stenosis*
M.D., ALLAN G. ADELMAN, Toronto,
M.D., PIERRE AUGER, M.D. and
YVE~ MARQUIS,
M.D.
Canada
Mitral regurgitation was assessed in 34 patients with muscular subaortic stenosis by indicator-dilution studies. All patients with obstruction to left ventricular outflow at rest had evidence of mitral regurgitation. Infusion of angiotensin resulted in amelioration or abolition of both outflow tract obstruction and mitral regurgitation in 11 of 15 patients. In 4 patients abolition by angiotensin of the outflow tract obstruction produced no change in the degree of mitral regurgitation. One of these patients was demonstrated to have an abnormality of the mitral valve. Abolition of the outflow tract obstruction by ventriculomyotomy either abolished the mitral regurgitation or reduced it to a trivial degree if there was no additional abnormality of the mitral valve. Pharmacologic intensification of the obstruction by administration of isoproterenol or amyl nitrite increased the degree of mitral regurgitation in 15 of 18 studies. These pharmacodynamic studies provided evidence that, in the majority of patients with muscular subaortic stenosis and a normal mitral valve mechanism, the degree of mitral regurgitation varied directlv with the severity of the outflow tract obstruc_ _ tion and was secondary to the obstru&ion.
ITRAL REGURGITATIONis a well recognized component of the complex hemodynamic with encountered in patients abnormality muscular subaortic stenosis.1-17 It has been found to occur in from 40 to 100 per cent of cases.sJ”-12* 16,17 The degree of regurgitation has been demonstrated to increase with increasing severity of the stenosis as in the postextrasystolic beat12*13 and during isoproterenol infusion6rLo and to decrease with decreasing severity of the stenosis during angiotensin infusion.‘” In spite of these observations, the exact relation of the mitral regurgitation to the outflow tract obstruction is incompletely understood. The present report is concerned with estimation by dyedilution technic of mitral regurgitation in patients with muscular subaortic stenosis in three during pharmacologic conditions : at rest, amelioration and intensification of the outflow tract obstruction, and after ventriculomyotomy.
M
MATERIAL AND METHODS Of 55 patients with muscular subaortic stenosis undergoing left heart catheterization in this labora-
tory, mitral regurgitation was assessed by dye-dilution technic in 34 patients. In each instance 2 ml. of indocyanine green dye was injected over several cardiac cycles through a retrograde aortic catheter proximal to the obstruction in the high pressure area of the left ventricle.‘*,‘9 Simultaneously, blood was constantly withdrawn from the left atrium by a Harvard pump through a transseptal left heart catheter; the appearance of green dye was detected by a Cambridge cuvette and a direct writing recorder.20121 In this technic no catheters traversed the mitral valve, and ventricular ectopic beats could be detected by continuous electrocardiographic monitoring. During duplicate and triplicate control determinations and during pharmacologic interventions care was taken to ensure that the intracardiac catheters remained constant in position. These dye-dilution studies were repeated at the time of a second left heart catheterization in 4 patients. Eleven patients were studied by this technic 1 to 34 months after ventriculomyotomy, and 15 patients were studied during pharmacologic amelioration or abolition of the outflow tract obstruction by the infusion of angiotensin.15.22.2a These dye-dilution studies were repeated in 10 patients during isoproterenol intensification22-26 of the outflow tract
* From the Cardiovascular Unit, Toronto General Hospital, and the Department of Medicine, University of Toronto, Toronto, Canada. This study was supported by the Ontario Heart Foundation. Manuscript received January 14, 1969, accepted March 31, 1969. Address for reprints: E. Douglas Wigle, M.D., Cardiovascular Unit, Toronto General Hospital, 101 College St., Toronto 2, Canada. THE
AMERICAN
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CARDIOLOGY
Mitral
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in Muscular
Subaortic
Stenosis
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Figure 1. The left ventricular-aortic systolicpressure gradient in 37 studies in 33 patients with muscular subaortic stenosis (ordinate) is plotted against the observed degree of mitral regurgitation (abscissa). All patients had evidence of mitral regurgitation, including one patient in whom there was no intraventricular gradient at rest. There was no statistically significant correlation between the degree of mitral regurgitation and the magnitude of the pressure gradient (p > 0.05). Each pair of open circles, squares or triangles represent the findings at the original and repeat heart catheterization of each of 4 patients who were studied on 2 occasions. amyl nitrite in-
The severity of the mitral regurgitation was qualitatively assessed in all of these studies by comparing the relation of the early appearing (regurgitant) concentration of dye to the concentration of recirculating dye in the dilution curve inscribed by the withdrawal of left atria1 blood. Using this method of grading the mitral regurgitation, four degrees of severity were arbitrarily defined. Trivial mitral regurgitation was said to be present when the concentration of early appearing dye was less than 50 per cent of the concentration of recirculating dye. In mild mitral regurgitation the concentration of early appearing dye was 51 to 100 per cent of the concentration of the recirculating dye. In moderate mitral regurgitation the concentration of early appearing dye was 101 to 200 per cent of the concentration of recirculating dye and in severe mitral regurgitation the concentration of early appearing dye was greater than 200 per cent of the concentration of recirculating dye. This qualitative and arbitrary analysis of the severity of mitral regurgitation in muscular subaortic stenosis 24, NOVEMBER
1969
Trivial
REGURGITATION
obstruction and in 8 patients during tensificatior37 of the obstruction.
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MITRAL
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Figure 2. The left ventricular systolic pressure (ordinate) in 37 studies in 33 patients with muscular subaortic stenosis is plotted against the observed degree of mitral regurgitation (abscissa). There was no statistically significant correlation between the degree of mitral regurgitation and height of left ventricular systolic pressure (p > 0.05 ). Each pair of open circles, squares or triangles represents the findings at the original and repeat heart catheterization of each of 4 patients studied on 2 occasions. was undertaken in 49 separate cardiac catheterizations (38 diagnostic and 11 postoperative). In 3 patients only one control left atria1 dye-dilution curve was available. In 29 studies, duplicate control left atria1 dye-dilution curves revealed the same degree of mitral regurgitation and in 11 studies, triplicate control dye-dilution curves failed to reveal any variation in the grading of the mitral regurgitation. In only 6 patients was there a discrepancy in the degree of mitral regurgitation reflected in duplicate or triplicate control left atria1 dye curves. In 1 instance the degree of mitral regurgitation ranged from trivial to mild and in 5 instances from mild to moderate; in 4 of these patients there was a marked spontaneous variation in the severity of the outflow tract obstruction during the procedure, which could account for the variable degree of mitral regurgitation present (see later). RESULTS
Mitral
Regurgitation
Under
Control
Conditions
in
In 37 dye-dilution studies in 33 patients with evidence of muscular subaortic stenosis at rest, mitral regurgitation
Muscular
Subaortic
Stenosis:
Wigle et al.
700
2cc
INDOCYANINS GREEN INTO LEFT VENTRICLE:&
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AORTA
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Figure 3. Spontaneous variation in severity of the outjlow tract obstruction and degree of mitral regurgitation in a patient with muscular subaortic stenosis. A, On June 8, 1965 left heart catheterization revealed a left ventricular-aortic systolic pressure difference of 85 mm.
Hg and moderately severe mitral regurgitation, as evidenced by the extreme elevation of the left atria1 ZJwaves and the large amount of early appearing (regurgitant) dye in the left atrium after left ventricular injection of 2 ml. of indocyanine green (arrow). The left atria1 dye curves in this patient were inscribed from right to left and the recording of the dye is indicated by a downward deflection. B, Four months after the first catheterization, the patient was readmitted for consideration of cardiac surgery but his symptoms of retrosternal chest pain and dyspnea had become much less severe. Hemodynamic study at that time (October 5,1965) revealed a systolic pressure gradient of 10 mm. Hg between the left ventricular inflow tract (L.V.I.T.) and outflow tract (L.V.O.T.). In addition, the left atria1 u waves were less than 25 mm. Hg and only a trivial degree of mitral regurgitation
was evident from the dye-dilution studies.
was demonstrated in every instance. The mitral regurgitation was graded trivial in 9 studies, mild in 11, moderate in 11 and severe in 6 (Fig. 1 and 2). The thirty-fourth patient had neither an intraventricular pressure gradient nor mitral regurgitation at rest, but a pressure gradient developed during isoproterenol infusion. There was no statistical correlation between the degree of mitral regurgitation and the left ventricularaortic systolic pressure gradient or the left ventricular systolic pressure (p > 0.05; Fig. 1 and 2). Similarly, the degree of mitral regurgitation estimated by this dye-dilution technic could not be correlated with mean left atria1 pressure, the height of the left atria1 v wave, or left ventricular end-diastolic pressure. Four patients were studied on two different occasions (Fig. 1 and 2). In 1 patient, the in-
traventricular pressure gradient and the degree of mitral regurgitation were unchanged. In 2, the degree of mitral regurgitation increased from mild in the first study to moderate in the second. The intraventricular pressure gradient was unchanged in 1 of these patients and slightly increased in the second. The fourth patient demonstrated a marked reduction in both the dye-dilution and hemodynamic evidence of mitral regurgitation in the second study, at which time the intraventricular pressure gradient was also markedly reduced (Fig. 3, A and B). Eject of Ventriculomyotomy on Mitral Regurgitation: The mitral regurgitation was assessed in 11 patients from 1 to 34 months after ventriculomyotomy. 28-30 Eight of these patients had no evidence of outflow tract obstruction postoperatively. Four of the 8 had no evidence of THE
AMERICAN
JOURNAL
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Mitral
Regurgitation
in Muscular
Subaortic
Stenosis
Xl
FEMORAL IRTER”
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GRAOIENT “a
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mm Hg
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159
165
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GREEN
INTO
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Figure 4. Effect of angiotensin infusion. Simultaneous left ventricular and femoral arterial pressure recordings (top) and left atria1 dye-dilution curves inscribed from right to left (bottom) after left ventricular injection of 2 ml. of indocyanine green dye (arrow) under control conditions (first panel) and during angiotensin infusion (second and third panels). Regurgitant dye concentration is indicated by the upward deflection of the left atria1 dye curve immediately to the left of the arrow. Angiotensin infusion initially reduced (middle panel) and finally abolished (right panel) both the outflow tract obstruction and the mitral regurgitation. Note that the reduction and abolition of the mitral regurgitation occurred whether left ventricular systolic pressure was reduced or elevated in relation to control conditions.
_-_-“v?,_
-._&-\
, - -\._ _
Figure 5. Amy1 nitrite inhalation compared to angiotemin infusion. Simultaneous left ventricular and aortic pressure recordings (top) and left atria1 dye-dilution curves (bottom) inscribed from right to left after left ventricular injection of 2 ml. of indocyanine green dye in a patient with muscular subaortic stenosis, in control conditions (first panel), after amyl nitrite inhalation (second panel), and during angiotensin infusions (third and fourth panels). The amount of dye leaking back into the left atrium is indicated by the upward deflection of the dye curve occurring immediately to the left of the arrow, which indicates the time of left ventricular injection of the dye. To the left of this regurgitant dye deflection is the recirculation concentration. The intensification of the outflow tract obstruction due to administration of amyl nitrite was accompanied by an increase in the amount of regurgitant dye appearing in the left atrium (second panel). Angiotensin infusion initially reduced (third panel) and eventually abolished (fourth panel) both the outflow tract obstruction and the mitral regurgitation.
mitral regurgitation; 2 had evidence of a trivial mitral leak; and 1 had moderate, and another severe, mitral regurgitation. In each of the latter 2 instances the mitral regurgitation was a result of torn chordae tendineae of the anterior leaflet of the mitral valve. 2g In the remaining 3 patients, surgical treatment failed to relieve the outflow tract obstruction. In 1, the intraventricular pressure gradient VOLUME
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1969
and the degree of mitral regurgitation were unchanged postoperatively, while in 2, the operation reduced, but failed to abolish, the pressure gradient or the mitral leak. Amelioration or Abolition of the Outjow Tract Obstruction and Mitral Regurgitation (Angiotensin Infusion) : In 15 patients the mitral regurgitation was restudied during amelioration or abolition of the outflow tract obstruction by the infusion of
Wigle et al.
702
ANOIOTENSIN
ISOPROTERENOL mm.Hg.
mm.Hg.
LEFT VENTRICLE BRACHIAL ARTERY
L.C.& CRADIEWT rdlg. L.V.PRESSURE mdlg.
0 124
03 I72
64 147
2~. INDOCYAWINE6REEN DYE INTO LEFT VENTRICLE(1)
Figure 6. Isoproterenolcompared to angiotensin infusion. Simultaneous left ventricular and brachial arterial pressure recordings (top) and left atria1 dye dilution curves inscribed from left to right (bottom) after left ventricular injection of 2 ml. of indocyanine green dye (arrow) under control conditions (first panel), during isoproterenol infusion (second panel) and during angiotensin infusion (third panel). Isoproterenol increased both the outflow tract obstruction and the degree of mitral regureitation while anziotensin abolished the outflow tract obstruction and greatly reduced, but failed to abolish, the-mitral regurgitation.
angiotensin (Table I, Fig. 4 to 8). In 5 patients (group I, Table I) infusion of angiotensin completely abolished both the outflow tract obstruction and the mitral regurgitation (Fig. 4 and 5). In these patients a linear relation existed between the severity of the obstruction in the outflow tract and the degree of mitral regurgitation (Fig. 4 and 5). In 2 patients (group II, Table I) angiotensin infusion abolished the outflow tract obstruction and greatly reduced, but failed to abolish, the mitral regurgitation (Fig. 6). In 4 patients (group III, Table I) the amount of angiotensin infused was sufficient to reduce but not abolish the outflow tract obstruction. In each of these patients the reduction in the intraventricular pressure gradient was accompanied by a significant reduction in the degree of mitral regurgitation.15 If the amount of angiotensin infused had been increased to the point of abolishing the outflow tract obstruction the classification of these patients could then have been altered to either group I or group II. In the 11 patients in groups I to III (Table I), angiotensin infusion reduced or abolished both the outflow tract obstruction and the mitral regurgitation whether the left ventricular systolic pressure was increased (4 cases, Fig. 4), unchanged (4 cases), or decreased (3 cases, Fig. 5 and 6).
Angiotensin infusion in 4 of 15 patients (group Table I) had no significant effect on the degree of mitral regurgitation although the outflow tract obstruction was completely abolished (Fig. 7 and 8). One patient in group IV was subsequently demonstrated at postmortem examination to have an unusual abnormality of the mitral valve (Fig. 8B). In this patient an abnormal muscle bundle arose from the anterolateral papillary muscle to insert at the midpoint of the ventricular surface of the anterior leaflet of the mitral valve. The pathologic anatomy was IV,
Table I. Effect of Angiotensin Infusion on Mitral Regurgitation in Muscular Subaortic Stenosis
Group
No. of Cases
I
5
II
2
III* 1”
4 4
Intraventricular Pressure Gradient Completely abolished Completely abolished Reduced Completely abolished
Mitral Regurgitation Completely abolished Greatly reduced Reduced No change
* In these patients the amount of angiotensin infused was sufficient to reduce but not abolish the outtlow tract obstruction. THE
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Regurgitation
in Muscular
CONTROL I i/‘s’ii,
Subaortic
‘703
ANGIOTENSIN
mu Hg
III,
Stenosis
I
LEFT VENTRICLE
BRACHIAL ARTERY
E.C.G. GRADIENT
mm lip
64
0
L.V. PRESSURE
mm lip
160
170
REGURGITANT FLOW (LEFT ATRIUM )
f
2 cc INDOCYANINE
GREEN
INTO L.V.
Figure 7. Failure lo abolish mitral regurgikdion with angiofensin. Simultaneous left ventricular and brachial arterial pressure recordings (top) and left atrial dyedilution curves inscribed from right to left (bottom) after left ventricular injection of 2 ml. of indocyanine green dye (arrow) in control conditions (left) and during angiotensin infusion (right). The abolition of the outflow tract obstruction by angiotensin had no effect on the degree of mitral regurgitation in this patient.
such that, in life, contraction of this anomalous muscle bundle could have pulled the anterior leaflet of the mitral valve into the outflow tract of the left ventricle. The pathologic anatomy in the other 3 patients in group IV is not known at present. Intenszjication of the Outflow Tract Obstruction and Mitral Regurgitation (Amy1 Nitrite Inhalation or Isoproterenol Infusion): Pharmacologic intensification of the outflow tract obstruction after amyl nitrite inhalation resulted in an increased degree of mitral regurgitation in 7 of 8 patients (Fig. 5). Isoproterenol-induced intensification of the outflow obstruction increased the degree of mitral regurgitation in 8 of 10 patients (Fig. 6). In 1 patient in group IV (Table I&-the only patient in this study who had mitral regurgitation at rest in the absence of an intraventricular pressure gradient-stimulation of the obstruction by isoproterenol and amyl nitrite was associated with a decrease in the degree of mitral regurgitation. One patient in group II (Table I) VOLUME
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-with a variable relation between the severity of the outflow tract obstruction and the degree of mitral regurgitation at rest-demonstrated an increased degree of mitral regurgitation after amyl nitrite, but not during isoproterenol intensification of the outflow tract obstruction. Other than these 2 patients, pharmacologic intensification of the intraventricular pressure gradient in 15 of 18 studies was associated with an increased degree of mitral regurgitation regardless of the response of the mitral regurgitation to the infusion of angiotensin (Table I). DISCUSSION
These indicator-dilution studies, performed with no catheter across the mitral valve and in the absence of ventricular premature beats, demonstrated the presence of mitral regurgitation in every patient with muscular subaortic stenosis who had an intraventricular pressure gradient at rest. In this group of studies at rest, the degree of mitral regurgitation could not be
Wigle et al. ANGIOTENSIN
CONTROL mm Hg
GRADIENT
mm Hg
L.V. PRESSURE
mm Hg
35
5
154
165 A
REGURGITANT FLOW ( LEFT ATRIUM
0A
)
4
Figure 8. Failure to abolish mitral regurgitation with angiotensin. A, simultaneous Irft vcrrtricular and aortic prcssurc recordings (top) and left atria1 dye dilution curves inscribed from right to left (bottom) aftrr left ventricular injection of 2 ml. of indocyanine green dye (arrow) under control conditions (left) and during angiotensin infusion (right). The virtual abolition of the outflow tract obstruction by angiotensin had no effect on thr dcgrre of mitral rrgurgitation in this patient with an abnormal mitral valve. B, opened left ventricle in same patient, demonstrating an anomalous muscle bundle (lower arrow) arising front thr anterolateral papillary muscle to insert on the ventricular surface of the anterior mitral leaflet at its midpoint (upper arrow). The anterior mitral leaflet has been cut and deflected to the left of the photograph to show the ventricular surface of the leaflet. The pathologic anatomy was such that, in life, contraction of this anomalous muscle could have pulled the anterior mitral leaflet into the outflow tract during systole.
correlated with the magnitude of the intraventricular pressure gradient, left ventricular systolic left atria1 hemodynamics, or left pressure, ventricular end-diastolic pressure. However, in 11 of 15 individual case studies, pharmacologic amelioration or abolition of the outflow tract obstruction by the infusion of angiotensin reduced or abolished the mitral regurgitation. Since left ventricular systolic pressure was increased, unchanged or decreased during angiotensin reduction or abolition of the outflow tract obstruction and mitral regurgitation, the change in the latter was believed related to the change in the outflow tract obstruction and not to the change in left ventricular systolic pressure. Similarly, in 15 of 18 studies, pharmacologic intensification of the outflow tract obstruction by the administration of isoproterenol or amyl nitrite increased the degree of mitral regurgitation. These pharmacodynamic studies in muscular subaortic stenosis demonstrated that the degree of mitral regurgitation in most patients
varied directly with the severity of the outflow tract obstruction. Importance of Preoperative Assessment by Angiotensin Infusion: The assessment of the effect of angiotensin infusion (or the infusion of another systemic vasoconstricting agent) on the degree of mitral regurgitation in muscular subaortic stenosis is believed of practical importance before the consideration of surgical treatment in these patients. The demonstration that the mitral regurgitation is completely (or almost completely) abolished during angiotensin abolition of the intraventricular pressure gradient suggests that the mitral leak is secondary to the outflow tract obstruction and that surgical relief of this obstruction should also completely (or almost completely) abolish the mitral regurgitation. Postoperative dye-dilution studies in 8 patients in whom surgical treatment abolished the outflow tract obstruction revealed that if the mitral valve mechanism was intact, mitral regurgitation was absent or trivial. In preoperative studies THE
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the failure of pharmacologic abolition of the outflow tract obstruction to alter the degree of mitral regurgitation should suggest the possibility of an additional abnormality of the mi u-al valve such as torn chordae tendineae or anomalous muscle attachments to the valve (Fig. 8B). When surgery is undertaken in such a case the mitral valve mechanism should be explored if the surgical approach to the obstruction to outflow so permits. Comparison of Mitral Regurgitation in Muscular Subaortic Stenosis with Other Varieties: Of considerable interest was the fact that the mitral reaurgitation in muscular subaortic stenosis reacted to the administration of certain pharmacologic agents in a manner diametrically opposed to that of other varieties of mitral regurgitation. Drugs causing systemic vasodilation increase the mitral regurgitation of muscular subaortic stenosis by increasing the severity of the outflow tract obstruction. By contrast, the same agents lessen the degree of other varieties of mitral regurgitation,31~32 with the exception of that due to prolapse of a cusp due to redundant chordae tendineae.33,34 Pharmacologic agents causing systemic vasoconstriction decrease the mitral regurgitation of muscular subaortic stenosis by decreasing the outflow tract obstruction; these satne agents increase the degree of other varieties of mitral regurgitation.31*32 Left ventricular ejection time is shortened when the common varieties of mitral regurgitation are increased in severity. 35 However, increasing the severity of mitral regurgitation in muscular subaortic stenosis by intensifying the obstruction to left ventricular outflow is associated with a prolonged left ventricular ejection time, since the ejection time is linearly related to magnitude of the intraventricular pressure gradient.36 Cause of the Mitral Regurgitation: Left ventricular cineangiography in this same group of patients with muscular subaortic stenosis revealed mitral regurgitation arising principally from the area of the left ventricle proximal to the obstruction in 26 of 28 studies.37 In 25 of these cineangiograms, the mitral regurgitation occurred in late systole after aortic ejection and after the development of the outflow tract obstruction. The late systolic timing of the mitral regurgitation in cineangiograms, as well as the fact that pharmacologic abolition of the obstruction to outflow results in abolition of the mitral regurgitation in the majority of patients, strongly suggests the secondary nature of the mitral regurgitation in most patients with muscular subaortic stenosis. Surgical VOLUME 24, NOVEMBER 1969
Subaortic
Stenosis
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abolition of the obstruction by ventric.ulolrI).otomy or muscle resection (without touching the mitral valve mechanism) also abolishes the mitral regurgitation in the majority of patients.g~zg~3”.38This fact supports the concept that the mitral regurgitation is usually secondary to the obstruction and suggests that the left ventricular muscular abnormality, and not the anterior mitral leaflet, is of primary importance in causing the obstruction. ACKNOWLEDGMENT We express our gratitude to Misses Jean McMeekan, B.SC., Neives Gonzalez and Rose Marie Cseplo, and to Mrs. Pamela Casson and ,4nn Oprysko for excellent technical assistance, to Miss Dorothy Goodwin and Mrs. Pauline Moroney for secretarial assistance, to Mr. Frederick Lammerich of the Department of Art as Applied to Medicine, University of Toronto, and to the Department of Medical Photography, Toronto General Hospital (Mr. Robert Paget, director). Dr. Malcolm Silver, Department of Pathology, University of Toronto, kindly supplied the pathologic specimen in Figure 8B. Dr. Harold Aldridge carried out the study depicted in Figure 3h. REFERENCES 1. BRAUNWALD,E., MORROW, A. G., CORNELL, W. P., AYGEN, M. M. and HILBISH, T. F. Idiopathic hypertrophic Subaortic stenosis. Am. J. Med., 29: 924, 1960. 2. WIGLE, E. D., HEIMBECKER, R. 0. and GUNTON, R. W. Idiopathic ventricular septal hypertrophy causing muscular subaortic stenosis. Circulation, 26~325, 1962. 3. STAMPBACH,V. 0. and SENN, A. Die idiopathische hypertrophische Subaortenstenose. Schweiz med. Wchnxhr., 92:125, 1962. 4. HANSEN, P. F., DAVIDSON,H. G. and FABRICIUS, J. Subvalwlar aortic stenosis of muscular type. Acta med. scandinav., 171:743, 1962. 5. NORDENSTROM,B. and OVENFORS, C. 0. Low subvalvular aortic and pulmonic stenosis with hypertrophy and abnormal arrangement of the muscle bundles of the myocardium. Acto radial., 57 :321, 1962. 6. WHALEN, R. E., COHEN, A. I., SUMNER, R. G. and MCINTOSH, H. D. Demonstration of the dynamic nature of idiopathic hypertrophic subaortic stenosis. Am. J. Cardiol., 11:8, 1963. 7. BURCHELL, H. B. Hypertrophic obstructive type of cardiomyopathy: Clinical syndrome. In: Cardiomyopathies, Ciba Symposium, p. 29. Edited by WOLSTENHOLME.G. E. W. and O’CONNOR. M. London, 1964. J. & A. Churchill. 8. COHEN, J., EFFAT, H., GOODWIN, J. F., OAKLEY, C. M. and STEINER, R. E. Hypertrophic obstructive cardiomyopathy. Brit. Heart J., 26 :16, 1964. 9. BENTALL, H. H., CLELAND, W. P., OAKLEY, C. M., SHAH, P. M., STEINER, R. E. and GOODWIN,.I. F. Surgical treatment and postoperative hemodynamic studies in hypertrophic obstructive cardiomyopathy. Brit. Heart J., 27:585, 1965. 10. CRILEY, J. M., LEWIS, K. B., WHITE, R. I., JR., and
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Ross, R. S. Pressure gradients without obstruction: New concept of “hypertrophic subaortic stenosis.” Circulation, 32:881, 1965. DINSMORE,R. E., SANDERS,C. A. and HARTHORNE, J. W. Mitral regurgitation in idiopathic hypertrouhic subaortic stenosis. New E&and J. Med., 27<:1225, 1966. Ross, J., JR., BRAUNWALD,E., GAULT, J. H., MASON, D. T. and MORROW. A. G. The mechanism of the intraventricular pressure gradient in idiopathic hypertrophic subaortic stenosis. Circulation, 34:558, 1966. RACKLEY, C. E., WHALEN, R. E. and MCINTOSH, H. D. Ventricular volume studies in a patient with hypertrophic subaortic stenosis. Circulation, 34~579, 1966. GOODWIN,J. F. Disorders of the outflow tract of the left ventricle. Brit. M. J., 2:461, 1967. WIGLE, E. D., MARQUIS, Y. and AUGER, P. Pharmacodynamics of mitral insufficiency in muscular subaortic stenosis. Canad. M. A. J., 97:299, 1967. SIMON, A. L., Ross, J., JR. and GAULT, J. H. Angiographic anatomy of the left ventricle and mitral valve in idiopathic hypertrophic subaortic stenosis. Circulation, 36 ~852, 1967. WIGLE, E. D., ADELMAN, A. G., MARQUIS, Y. and AUGER, P. Mitral regurgitation in muscular subaortic stenosis. Clin. Res., 16:253, 1968. WIGLE, E. D., AUGER, P. and MARQUIS, Y. Muscular subaortic stenosis: The initial left ventricular inflow tract pressure as evidence of outflow tract obstruction. Canad. M. A. J., 951793, 1966. WIGLE, E. D., MARQUIS, Y. and AUGER, P. Muscular subaortic stenosis: Initial left ventricular inflow tract pressure in the assessment of intraventricular pressure differences in man. Circulation, 35 : 1100, 1967. GORELICK, M. M., LENKEI, S. C. M., HEIMBECKER, R. 0. and GUNTON, R. W. Estimation of mitral regurgitation by injection of dye into the left ventricle with simultaneous left atria1 sampling. Am. J. Cardiol., 10:62, 1962. PECKHAM,G. B., CHRYSOHOU,A., ALDRIDGE, H. E. and WIGLE, E. D. Combined percutaneous retrograde aortic and transseptal left heart catheterization. Brit. Heart J., 26~460, 1964. WIGLE, E. D., DAVID, P. R., LABROSSE, C. J. and Muscular subaortic stenosis: MCMEEKAN, J. Interrelation of wall tension, outflow tract “distending pressure” and orifice radius. Am. J. Cardial., 15:761, 1965. Cardiovascular drugs in muscular WIGLE, E. D. subaortic stenosis. Fed. Prod., 24:1279, 1965. BRAUNWALD, E. and EBERT, P. A. Hemodynamic alterations in idiopathic hypertrophic subaortic
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37.
38.
stenosis induced by sympathomimetic drugs. Am. J. Cardiol., 10:489, 1962. GOODWIN, J. F., SHAH, P. M., OAKLEY, C. M., COHEN, J., YIPINTSOI, T. and POCOCK, W. Th? clinical pharmacology of hypertrophic obstructive cardiomyopathy. In Ref. 7, p. 189. KRASNOW, N., ROLETT, E., HOOD, W. B., YURCHAK, P. M. and GORLIN, R. Reversible obstruction of the ventricular outflow tract. Am. J. Cardiol., 11 :l. 1963. WIGLE, E. D., LENKEI, S. C. M., CHRYSOHOU, A. and WILSON, D. R. Muscular subaortic stenosis: The effect of peripheral vasodilation. Canad. M. A. J., 89:896, 1963. WIGLE, E. D., CHRYSOHOU,A. and BICELOW, W. G. Results of ventriculomyotomy in muscular subaortic stenosis. Am. J. Cardiol., 11 ~572, 1963. BIGELOW, W. G., TRIMBLE, A. S., AUGER, P., MARQUIS, Y. and WIGLE, E. D. The ventriculomyotomy operation for muscular subaortic stenosis. J. Thor&c & Cardiovas. Surg., 52~514, 1960. WIGLE, E. D., TRIMBLE, A. S., ADELMAN,A. G. and BIGELOW, W. G. Surgery in muscular subaortic stenosis. Progr. Cardiovas. Dis., 11:83, 1968. BRAUNWALD,E., WELCH, G. H. and MORROW, A. G. The effect of acutely increased systemic resistance on the left atria1 pressure pulse: A method for the clinical detection of mitral insufficiency. J. Clin. Invest., 37~35, 1958. JOSE, A. D., TAYLOR, R. R. and BERNSTEIN,L. The influence of arterial pressure on mitral incompetence in man. J. Clin. Invest., 43 :2094, 1964. BARLOW, J. B., POCOCK,W. A., MARCHAND, M. D. and DENNY, M. The significance of late systolic murmurs. Am. Heart J., 66:443, 1963. BITTAR, N. and SOSA, J. A. The billowing mitral valve leaflet. Report on fourteen patients. Circulation, 38 :763, 1968. MOSKOWITZ, R. L. and WECHSLER,B. M. Left ventricular ejection time in aortic and mitral valve disease. Am. J. Cardiol., 15 :809, 1965. WIGLE, E. D., AUGER, P. and MARQUIS, Y. Muscular subaortic stenosis: The direct relation between the intraventricular pressure difference and left ventricular ejection time. Circulation, 36:36, 1967. ADELMAN, A. G., MARQUIS, Y., AUGER, P. and WIGLE, E. D. Left ventricular cineangiographic observations in muscular subaortic stenosis. Am. J. Cardiol., 24~689, 1969. MORROW, A. G., FOGARTY, T. J., HANNAH, H., III and BRAUNWALD, E. Operative treatment in idiopathic hypertrophic subaortic stenosis: Techniques and the results of preoperative and postoperative clinical and hemodynamic assessments. Circulation, 37:589, 1968.
THE AMERICANJOURNAL OF CARDIOLOGY
Regurgitation in Muscular Subaortic Stenosis*
M.D., ALLAN G. ADELMAN, Toronto,
M.D., PIERRE AUGER, M.D. and
YVE~ MARQUIS,
M.D.
Canada
Mitral regurgitation was assessed in 34 patients with muscular subaortic stenosis by indicator-dilution studies. All patients with obstruction to left ventricular outflow at rest had evidence of mitral regurgitation. Infusion of angiotensin resulted in amelioration or abolition of both outflow tract obstruction and mitral regurgitation in 11 of 15 patients. In 4 patients abolition by angiotensin of the outflow tract obstruction produced no change in the degree of mitral regurgitation. One of these patients was demonstrated to have an abnormality of the mitral valve. Abolition of the outflow tract obstruction by ventriculomyotomy either abolished the mitral regurgitation or reduced it to a trivial degree if there was no additional abnormality of the mitral valve. Pharmacologic intensification of the obstruction by administration of isoproterenol or amyl nitrite increased the degree of mitral regurgitation in 15 of 18 studies. These pharmacodynamic studies provided evidence that, in the majority of patients with muscular subaortic stenosis and a normal mitral valve mechanism, the degree of mitral regurgitation varied directlv with the severity of the outflow tract obstruc_ _ tion and was secondary to the obstru&ion.
ITRAL REGURGITATIONis a well recognized component of the complex hemodynamic with encountered in patients abnormality muscular subaortic stenosis.1-17 It has been found to occur in from 40 to 100 per cent of cases.sJ”-12* 16,17 The degree of regurgitation has been demonstrated to increase with increasing severity of the stenosis as in the postextrasystolic beat12*13 and during isoproterenol infusion6rLo and to decrease with decreasing severity of the stenosis during angiotensin infusion.‘” In spite of these observations, the exact relation of the mitral regurgitation to the outflow tract obstruction is incompletely understood. The present report is concerned with estimation by dyedilution technic of mitral regurgitation in patients with muscular subaortic stenosis in three during pharmacologic conditions : at rest, amelioration and intensification of the outflow tract obstruction, and after ventriculomyotomy.
M
MATERIAL AND METHODS Of 55 patients with muscular subaortic stenosis undergoing left heart catheterization in this labora-
tory, mitral regurgitation was assessed by dye-dilution technic in 34 patients. In each instance 2 ml. of indocyanine green dye was injected over several cardiac cycles through a retrograde aortic catheter proximal to the obstruction in the high pressure area of the left ventricle.‘*,‘9 Simultaneously, blood was constantly withdrawn from the left atrium by a Harvard pump through a transseptal left heart catheter; the appearance of green dye was detected by a Cambridge cuvette and a direct writing recorder.20121 In this technic no catheters traversed the mitral valve, and ventricular ectopic beats could be detected by continuous electrocardiographic monitoring. During duplicate and triplicate control determinations and during pharmacologic interventions care was taken to ensure that the intracardiac catheters remained constant in position. These dye-dilution studies were repeated at the time of a second left heart catheterization in 4 patients. Eleven patients were studied by this technic 1 to 34 months after ventriculomyotomy, and 15 patients were studied during pharmacologic amelioration or abolition of the outflow tract obstruction by the infusion of angiotensin.15.22.2a These dye-dilution studies were repeated in 10 patients during isoproterenol intensification22-26 of the outflow tract
* From the Cardiovascular Unit, Toronto General Hospital, and the Department of Medicine, University of Toronto, Toronto, Canada. This study was supported by the Ontario Heart Foundation. Manuscript received January 14, 1969, accepted March 31, 1969. Address for reprints: E. Douglas Wigle, M.D., Cardiovascular Unit, Toronto General Hospital, 101 College St., Toronto 2, Canada. THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Mitral
Regurgitation
in Muscular
Subaortic
Stenosis
609
260
180
.
. 240
. .
100
80
.
. . . .
*A
a
-
. .
.
-
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.
V V* .
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.*
140
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-0 .
0
.
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120
.
Mild’
Trivial
(111
(91
MITRAL
Moderate ’
(11)
Severe
(61
Figure 1. The left ventricular-aortic systolicpressure gradient in 37 studies in 33 patients with muscular subaortic stenosis (ordinate) is plotted against the observed degree of mitral regurgitation (abscissa). All patients had evidence of mitral regurgitation, including one patient in whom there was no intraventricular gradient at rest. There was no statistically significant correlation between the degree of mitral regurgitation and the magnitude of the pressure gradient (p > 0.05). Each pair of open circles, squares or triangles represent the findings at the original and repeat heart catheterization of each of 4 patients who were studied on 2 occasions. amyl nitrite in-
The severity of the mitral regurgitation was qualitatively assessed in all of these studies by comparing the relation of the early appearing (regurgitant) concentration of dye to the concentration of recirculating dye in the dilution curve inscribed by the withdrawal of left atria1 blood. Using this method of grading the mitral regurgitation, four degrees of severity were arbitrarily defined. Trivial mitral regurgitation was said to be present when the concentration of early appearing dye was less than 50 per cent of the concentration of recirculating dye. In mild mitral regurgitation the concentration of early appearing dye was 51 to 100 per cent of the concentration of the recirculating dye. In moderate mitral regurgitation the concentration of early appearing dye was 101 to 200 per cent of the concentration of recirculating dye and in severe mitral regurgitation the concentration of early appearing dye was greater than 200 per cent of the concentration of recirculating dye. This qualitative and arbitrary analysis of the severity of mitral regurgitation in muscular subaortic stenosis 24, NOVEMBER
1969
Trivial
REGURGITATION
obstruction and in 8 patients during tensificatior37 of the obstruction.
.
0 .
r
VOLUME
-?
.*
. -
.
0.
160
c+
0.
.Cl
3 ‘8.
a
a
0.
.
0
: .
.
180
A
. 20
0
.
60
40
0
Moderate
Mild
MITRAL
Severe
(11)
01)
(9)
(6)
REGURGITATION
Figure 2. The left ventricular systolic pressure (ordinate) in 37 studies in 33 patients with muscular subaortic stenosis is plotted against the observed degree of mitral regurgitation (abscissa). There was no statistically significant correlation between the degree of mitral regurgitation and height of left ventricular systolic pressure (p > 0.05 ). Each pair of open circles, squares or triangles represents the findings at the original and repeat heart catheterization of each of 4 patients studied on 2 occasions. was undertaken in 49 separate cardiac catheterizations (38 diagnostic and 11 postoperative). In 3 patients only one control left atria1 dye-dilution curve was available. In 29 studies, duplicate control left atria1 dye-dilution curves revealed the same degree of mitral regurgitation and in 11 studies, triplicate control dye-dilution curves failed to reveal any variation in the grading of the mitral regurgitation. In only 6 patients was there a discrepancy in the degree of mitral regurgitation reflected in duplicate or triplicate control left atria1 dye curves. In 1 instance the degree of mitral regurgitation ranged from trivial to mild and in 5 instances from mild to moderate; in 4 of these patients there was a marked spontaneous variation in the severity of the outflow tract obstruction during the procedure, which could account for the variable degree of mitral regurgitation present (see later). RESULTS
Mitral
Regurgitation
Under
Control
Conditions
in
In 37 dye-dilution studies in 33 patients with evidence of muscular subaortic stenosis at rest, mitral regurgitation
Muscular
Subaortic
Stenosis:
Wigle et al.
700
2cc
INDOCYANINS GREEN INTO LEFT VENTRICLE:&
)
AORTA
E.C.G.
IGO-
‘0-s;
Zss. INDOCYANINE GREEN ,NTO LEFT MNTRICLE I 4 I
1.
’
.w : (LEFT J
ATGIWI :
..:i_
.-.. .‘._’
Figure 3. Spontaneous variation in severity of the outjlow tract obstruction and degree of mitral regurgitation in a patient with muscular subaortic stenosis. A, On June 8, 1965 left heart catheterization revealed a left ventricular-aortic systolic pressure difference of 85 mm.
Hg and moderately severe mitral regurgitation, as evidenced by the extreme elevation of the left atria1 ZJwaves and the large amount of early appearing (regurgitant) dye in the left atrium after left ventricular injection of 2 ml. of indocyanine green (arrow). The left atria1 dye curves in this patient were inscribed from right to left and the recording of the dye is indicated by a downward deflection. B, Four months after the first catheterization, the patient was readmitted for consideration of cardiac surgery but his symptoms of retrosternal chest pain and dyspnea had become much less severe. Hemodynamic study at that time (October 5,1965) revealed a systolic pressure gradient of 10 mm. Hg between the left ventricular inflow tract (L.V.I.T.) and outflow tract (L.V.O.T.). In addition, the left atria1 u waves were less than 25 mm. Hg and only a trivial degree of mitral regurgitation
was evident from the dye-dilution studies.
was demonstrated in every instance. The mitral regurgitation was graded trivial in 9 studies, mild in 11, moderate in 11 and severe in 6 (Fig. 1 and 2). The thirty-fourth patient had neither an intraventricular pressure gradient nor mitral regurgitation at rest, but a pressure gradient developed during isoproterenol infusion. There was no statistical correlation between the degree of mitral regurgitation and the left ventricularaortic systolic pressure gradient or the left ventricular systolic pressure (p > 0.05; Fig. 1 and 2). Similarly, the degree of mitral regurgitation estimated by this dye-dilution technic could not be correlated with mean left atria1 pressure, the height of the left atria1 v wave, or left ventricular end-diastolic pressure. Four patients were studied on two different occasions (Fig. 1 and 2). In 1 patient, the in-
traventricular pressure gradient and the degree of mitral regurgitation were unchanged. In 2, the degree of mitral regurgitation increased from mild in the first study to moderate in the second. The intraventricular pressure gradient was unchanged in 1 of these patients and slightly increased in the second. The fourth patient demonstrated a marked reduction in both the dye-dilution and hemodynamic evidence of mitral regurgitation in the second study, at which time the intraventricular pressure gradient was also markedly reduced (Fig. 3, A and B). Eject of Ventriculomyotomy on Mitral Regurgitation: The mitral regurgitation was assessed in 11 patients from 1 to 34 months after ventriculomyotomy. 28-30 Eight of these patients had no evidence of outflow tract obstruction postoperatively. Four of the 8 had no evidence of THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Mitral
Regurgitation
in Muscular
Subaortic
Stenosis
Xl
FEMORAL IRTER”
hd---h---M-
GRAOIENT “a
29
L.” PRESSURE
162
an
mm Hg
14
0
159
165
t
? cc INDOCYANINE
GREEN
INTO
L.“.
Figure 4. Effect of angiotensin infusion. Simultaneous left ventricular and femoral arterial pressure recordings (top) and left atria1 dye-dilution curves inscribed from right to left (bottom) after left ventricular injection of 2 ml. of indocyanine green dye (arrow) under control conditions (first panel) and during angiotensin infusion (second and third panels). Regurgitant dye concentration is indicated by the upward deflection of the left atria1 dye curve immediately to the left of the arrow. Angiotensin infusion initially reduced (middle panel) and finally abolished (right panel) both the outflow tract obstruction and the mitral regurgitation. Note that the reduction and abolition of the mitral regurgitation occurred whether left ventricular systolic pressure was reduced or elevated in relation to control conditions.
_-_-“v?,_
-._&-\
, - -\._ _
Figure 5. Amy1 nitrite inhalation compared to angiotemin infusion. Simultaneous left ventricular and aortic pressure recordings (top) and left atria1 dye-dilution curves (bottom) inscribed from right to left after left ventricular injection of 2 ml. of indocyanine green dye in a patient with muscular subaortic stenosis, in control conditions (first panel), after amyl nitrite inhalation (second panel), and during angiotensin infusions (third and fourth panels). The amount of dye leaking back into the left atrium is indicated by the upward deflection of the dye curve occurring immediately to the left of the arrow, which indicates the time of left ventricular injection of the dye. To the left of this regurgitant dye deflection is the recirculation concentration. The intensification of the outflow tract obstruction due to administration of amyl nitrite was accompanied by an increase in the amount of regurgitant dye appearing in the left atrium (second panel). Angiotensin infusion initially reduced (third panel) and eventually abolished (fourth panel) both the outflow tract obstruction and the mitral regurgitation.
mitral regurgitation; 2 had evidence of a trivial mitral leak; and 1 had moderate, and another severe, mitral regurgitation. In each of the latter 2 instances the mitral regurgitation was a result of torn chordae tendineae of the anterior leaflet of the mitral valve. 2g In the remaining 3 patients, surgical treatment failed to relieve the outflow tract obstruction. In 1, the intraventricular pressure gradient VOLUME
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1969
and the degree of mitral regurgitation were unchanged postoperatively, while in 2, the operation reduced, but failed to abolish, the pressure gradient or the mitral leak. Amelioration or Abolition of the Outjow Tract Obstruction and Mitral Regurgitation (Angiotensin Infusion) : In 15 patients the mitral regurgitation was restudied during amelioration or abolition of the outflow tract obstruction by the infusion of
Wigle et al.
702
ANOIOTENSIN
ISOPROTERENOL mm.Hg.
mm.Hg.
LEFT VENTRICLE BRACHIAL ARTERY
L.C.& CRADIEWT rdlg. L.V.PRESSURE mdlg.
0 124
03 I72
64 147
2~. INDOCYAWINE6REEN DYE INTO LEFT VENTRICLE(1)
Figure 6. Isoproterenolcompared to angiotensin infusion. Simultaneous left ventricular and brachial arterial pressure recordings (top) and left atria1 dye dilution curves inscribed from left to right (bottom) after left ventricular injection of 2 ml. of indocyanine green dye (arrow) under control conditions (first panel), during isoproterenol infusion (second panel) and during angiotensin infusion (third panel). Isoproterenol increased both the outflow tract obstruction and the degree of mitral regureitation while anziotensin abolished the outflow tract obstruction and greatly reduced, but failed to abolish, the-mitral regurgitation.
angiotensin (Table I, Fig. 4 to 8). In 5 patients (group I, Table I) infusion of angiotensin completely abolished both the outflow tract obstruction and the mitral regurgitation (Fig. 4 and 5). In these patients a linear relation existed between the severity of the obstruction in the outflow tract and the degree of mitral regurgitation (Fig. 4 and 5). In 2 patients (group II, Table I) angiotensin infusion abolished the outflow tract obstruction and greatly reduced, but failed to abolish, the mitral regurgitation (Fig. 6). In 4 patients (group III, Table I) the amount of angiotensin infused was sufficient to reduce but not abolish the outflow tract obstruction. In each of these patients the reduction in the intraventricular pressure gradient was accompanied by a significant reduction in the degree of mitral regurgitation.15 If the amount of angiotensin infused had been increased to the point of abolishing the outflow tract obstruction the classification of these patients could then have been altered to either group I or group II. In the 11 patients in groups I to III (Table I), angiotensin infusion reduced or abolished both the outflow tract obstruction and the mitral regurgitation whether the left ventricular systolic pressure was increased (4 cases, Fig. 4), unchanged (4 cases), or decreased (3 cases, Fig. 5 and 6).
Angiotensin infusion in 4 of 15 patients (group Table I) had no significant effect on the degree of mitral regurgitation although the outflow tract obstruction was completely abolished (Fig. 7 and 8). One patient in group IV was subsequently demonstrated at postmortem examination to have an unusual abnormality of the mitral valve (Fig. 8B). In this patient an abnormal muscle bundle arose from the anterolateral papillary muscle to insert at the midpoint of the ventricular surface of the anterior leaflet of the mitral valve. The pathologic anatomy was IV,
Table I. Effect of Angiotensin Infusion on Mitral Regurgitation in Muscular Subaortic Stenosis
Group
No. of Cases
I
5
II
2
III* 1”
4 4
Intraventricular Pressure Gradient Completely abolished Completely abolished Reduced Completely abolished
Mitral Regurgitation Completely abolished Greatly reduced Reduced No change
* In these patients the amount of angiotensin infused was sufficient to reduce but not abolish the outtlow tract obstruction. THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Mitral
Regurgitation
in Muscular
CONTROL I i/‘s’ii,
Subaortic
‘703
ANGIOTENSIN
mu Hg
III,
Stenosis
I
LEFT VENTRICLE
BRACHIAL ARTERY
E.C.G. GRADIENT
mm lip
64
0
L.V. PRESSURE
mm lip
160
170
REGURGITANT FLOW (LEFT ATRIUM )
f
2 cc INDOCYANINE
GREEN
INTO L.V.
Figure 7. Failure lo abolish mitral regurgikdion with angiofensin. Simultaneous left ventricular and brachial arterial pressure recordings (top) and left atrial dyedilution curves inscribed from right to left (bottom) after left ventricular injection of 2 ml. of indocyanine green dye (arrow) in control conditions (left) and during angiotensin infusion (right). The abolition of the outflow tract obstruction by angiotensin had no effect on the degree of mitral regurgitation in this patient.
such that, in life, contraction of this anomalous muscle bundle could have pulled the anterior leaflet of the mitral valve into the outflow tract of the left ventricle. The pathologic anatomy in the other 3 patients in group IV is not known at present. Intenszjication of the Outflow Tract Obstruction and Mitral Regurgitation (Amy1 Nitrite Inhalation or Isoproterenol Infusion): Pharmacologic intensification of the outflow tract obstruction after amyl nitrite inhalation resulted in an increased degree of mitral regurgitation in 7 of 8 patients (Fig. 5). Isoproterenol-induced intensification of the outflow obstruction increased the degree of mitral regurgitation in 8 of 10 patients (Fig. 6). In 1 patient in group IV (Table I&-the only patient in this study who had mitral regurgitation at rest in the absence of an intraventricular pressure gradient-stimulation of the obstruction by isoproterenol and amyl nitrite was associated with a decrease in the degree of mitral regurgitation. One patient in group II (Table I) VOLUME
24,
NOVEMBER
1969
-with a variable relation between the severity of the outflow tract obstruction and the degree of mitral regurgitation at rest-demonstrated an increased degree of mitral regurgitation after amyl nitrite, but not during isoproterenol intensification of the outflow tract obstruction. Other than these 2 patients, pharmacologic intensification of the intraventricular pressure gradient in 15 of 18 studies was associated with an increased degree of mitral regurgitation regardless of the response of the mitral regurgitation to the infusion of angiotensin (Table I). DISCUSSION
These indicator-dilution studies, performed with no catheter across the mitral valve and in the absence of ventricular premature beats, demonstrated the presence of mitral regurgitation in every patient with muscular subaortic stenosis who had an intraventricular pressure gradient at rest. In this group of studies at rest, the degree of mitral regurgitation could not be
Wigle et al. ANGIOTENSIN
CONTROL mm Hg
GRADIENT
mm Hg
L.V. PRESSURE
mm Hg
35
5
154
165 A
REGURGITANT FLOW ( LEFT ATRIUM
0A
)
4
Figure 8. Failure to abolish mitral regurgitation with angiotensin. A, simultaneous Irft vcrrtricular and aortic prcssurc recordings (top) and left atria1 dye dilution curves inscribed from right to left (bottom) aftrr left ventricular injection of 2 ml. of indocyanine green dye (arrow) under control conditions (left) and during angiotensin infusion (right). The virtual abolition of the outflow tract obstruction by angiotensin had no effect on thr dcgrre of mitral rrgurgitation in this patient with an abnormal mitral valve. B, opened left ventricle in same patient, demonstrating an anomalous muscle bundle (lower arrow) arising front thr anterolateral papillary muscle to insert on the ventricular surface of the anterior mitral leaflet at its midpoint (upper arrow). The anterior mitral leaflet has been cut and deflected to the left of the photograph to show the ventricular surface of the leaflet. The pathologic anatomy was such that, in life, contraction of this anomalous muscle could have pulled the anterior mitral leaflet into the outflow tract during systole.
correlated with the magnitude of the intraventricular pressure gradient, left ventricular systolic left atria1 hemodynamics, or left pressure, ventricular end-diastolic pressure. However, in 11 of 15 individual case studies, pharmacologic amelioration or abolition of the outflow tract obstruction by the infusion of angiotensin reduced or abolished the mitral regurgitation. Since left ventricular systolic pressure was increased, unchanged or decreased during angiotensin reduction or abolition of the outflow tract obstruction and mitral regurgitation, the change in the latter was believed related to the change in the outflow tract obstruction and not to the change in left ventricular systolic pressure. Similarly, in 15 of 18 studies, pharmacologic intensification of the outflow tract obstruction by the administration of isoproterenol or amyl nitrite increased the degree of mitral regurgitation. These pharmacodynamic studies in muscular subaortic stenosis demonstrated that the degree of mitral regurgitation in most patients
varied directly with the severity of the outflow tract obstruction. Importance of Preoperative Assessment by Angiotensin Infusion: The assessment of the effect of angiotensin infusion (or the infusion of another systemic vasoconstricting agent) on the degree of mitral regurgitation in muscular subaortic stenosis is believed of practical importance before the consideration of surgical treatment in these patients. The demonstration that the mitral regurgitation is completely (or almost completely) abolished during angiotensin abolition of the intraventricular pressure gradient suggests that the mitral leak is secondary to the outflow tract obstruction and that surgical relief of this obstruction should also completely (or almost completely) abolish the mitral regurgitation. Postoperative dye-dilution studies in 8 patients in whom surgical treatment abolished the outflow tract obstruction revealed that if the mitral valve mechanism was intact, mitral regurgitation was absent or trivial. In preoperative studies THE
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Mitral
Regurgitation
in Muscular
the failure of pharmacologic abolition of the outflow tract obstruction to alter the degree of mitral regurgitation should suggest the possibility of an additional abnormality of the mi u-al valve such as torn chordae tendineae or anomalous muscle attachments to the valve (Fig. 8B). When surgery is undertaken in such a case the mitral valve mechanism should be explored if the surgical approach to the obstruction to outflow so permits. Comparison of Mitral Regurgitation in Muscular Subaortic Stenosis with Other Varieties: Of considerable interest was the fact that the mitral reaurgitation in muscular subaortic stenosis reacted to the administration of certain pharmacologic agents in a manner diametrically opposed to that of other varieties of mitral regurgitation. Drugs causing systemic vasodilation increase the mitral regurgitation of muscular subaortic stenosis by increasing the severity of the outflow tract obstruction. By contrast, the same agents lessen the degree of other varieties of mitral regurgitation,31~32 with the exception of that due to prolapse of a cusp due to redundant chordae tendineae.33,34 Pharmacologic agents causing systemic vasoconstriction decrease the mitral regurgitation of muscular subaortic stenosis by decreasing the outflow tract obstruction; these satne agents increase the degree of other varieties of mitral regurgitation.31*32 Left ventricular ejection time is shortened when the common varieties of mitral regurgitation are increased in severity. 35 However, increasing the severity of mitral regurgitation in muscular subaortic stenosis by intensifying the obstruction to left ventricular outflow is associated with a prolonged left ventricular ejection time, since the ejection time is linearly related to magnitude of the intraventricular pressure gradient.36 Cause of the Mitral Regurgitation: Left ventricular cineangiography in this same group of patients with muscular subaortic stenosis revealed mitral regurgitation arising principally from the area of the left ventricle proximal to the obstruction in 26 of 28 studies.37 In 25 of these cineangiograms, the mitral regurgitation occurred in late systole after aortic ejection and after the development of the outflow tract obstruction. The late systolic timing of the mitral regurgitation in cineangiograms, as well as the fact that pharmacologic abolition of the obstruction to outflow results in abolition of the mitral regurgitation in the majority of patients, strongly suggests the secondary nature of the mitral regurgitation in most patients with muscular subaortic stenosis. Surgical VOLUME 24, NOVEMBER 1969
Subaortic
Stenosis
705
abolition of the obstruction by ventric.ulolrI).otomy or muscle resection (without touching the mitral valve mechanism) also abolishes the mitral regurgitation in the majority of patients.g~zg~3”.38This fact supports the concept that the mitral regurgitation is usually secondary to the obstruction and suggests that the left ventricular muscular abnormality, and not the anterior mitral leaflet, is of primary importance in causing the obstruction. ACKNOWLEDGMENT We express our gratitude to Misses Jean McMeekan, B.SC., Neives Gonzalez and Rose Marie Cseplo, and to Mrs. Pamela Casson and ,4nn Oprysko for excellent technical assistance, to Miss Dorothy Goodwin and Mrs. Pauline Moroney for secretarial assistance, to Mr. Frederick Lammerich of the Department of Art as Applied to Medicine, University of Toronto, and to the Department of Medical Photography, Toronto General Hospital (Mr. Robert Paget, director). Dr. Malcolm Silver, Department of Pathology, University of Toronto, kindly supplied the pathologic specimen in Figure 8B. Dr. Harold Aldridge carried out the study depicted in Figure 3h. REFERENCES 1. BRAUNWALD,E., MORROW, A. G., CORNELL, W. P., AYGEN, M. M. and HILBISH, T. F. Idiopathic hypertrophic Subaortic stenosis. Am. J. Med., 29: 924, 1960. 2. WIGLE, E. D., HEIMBECKER, R. 0. and GUNTON, R. W. Idiopathic ventricular septal hypertrophy causing muscular subaortic stenosis. Circulation, 26~325, 1962. 3. STAMPBACH,V. 0. and SENN, A. Die idiopathische hypertrophische Subaortenstenose. Schweiz med. Wchnxhr., 92:125, 1962. 4. HANSEN, P. F., DAVIDSON,H. G. and FABRICIUS, J. Subvalwlar aortic stenosis of muscular type. Acta med. scandinav., 171:743, 1962. 5. NORDENSTROM,B. and OVENFORS, C. 0. Low subvalvular aortic and pulmonic stenosis with hypertrophy and abnormal arrangement of the muscle bundles of the myocardium. Acto radial., 57 :321, 1962. 6. WHALEN, R. E., COHEN, A. I., SUMNER, R. G. and MCINTOSH, H. D. Demonstration of the dynamic nature of idiopathic hypertrophic subaortic stenosis. Am. J. Cardiol., 11:8, 1963. 7. BURCHELL, H. B. Hypertrophic obstructive type of cardiomyopathy: Clinical syndrome. In: Cardiomyopathies, Ciba Symposium, p. 29. Edited by WOLSTENHOLME.G. E. W. and O’CONNOR. M. London, 1964. J. & A. Churchill. 8. COHEN, J., EFFAT, H., GOODWIN, J. F., OAKLEY, C. M. and STEINER, R. E. Hypertrophic obstructive cardiomyopathy. Brit. Heart J., 26 :16, 1964. 9. BENTALL, H. H., CLELAND, W. P., OAKLEY, C. M., SHAH, P. M., STEINER, R. E. and GOODWIN,.I. F. Surgical treatment and postoperative hemodynamic studies in hypertrophic obstructive cardiomyopathy. Brit. Heart J., 27:585, 1965. 10. CRILEY, J. M., LEWIS, K. B., WHITE, R. I., JR., and
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11.
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16.
17.
18.
19.
20.
21.
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