Propranolol in mitral stenosis during sinus rhythm

Clinical communications I

I

Propranolol in mitral stenosis during sinus rhythm* Steven G. Meister, M.D. Toby R. Engel, M.D. Gilson S. Feitosa, M.D. Richard H. Helfant, M.D. William S. Frankl, M,D. Philadelphia, Pa.

In mild or moderate mitral stenosis symptoms are typically those of pulmonary congestion due to left atrial and pulmonary venous hypertension. Resting cardiac output may be normal and may increase in response to peripheral demand. 1 Patients at this stage of the disease are commonly in sinus rhythm and become symptomatic chiefly in situations where heart rate, cardiac output or both are substantially increased. Beta-adrenergic blocking drugs are capable of lowering both heart rate an.d cardiac output s and might be expected to reduce the diastolic pressure gradient across a stenotic mitral valve, thereby reducing pulmonary congestion. However, the negative inotropic effect of an agent such as propranolol might tend to increase left ventricular diastolic pressure~, and thereby negate this potentially beneficial effect. Several reports documenting the existence of impaired left ventricular function in some patients with mitral stenosis 3-5 lend substance to this concern. Accordingly, this study was intended to determine whether proprano.lol administered acutely to patients with early symptomatic isolated mitral stenosis, in sinus rhythm, would result in a potentially useful net reduction in pulmonary capillary wedge pressure. The Medical College of Pennsylvania, Philadelphia, and the Presbyterian-University of Pennsylvania Medical Center, Philadelphia. Pa. Received for publication June 30, 1976. Accepted for publication Dec. 17. 1976. Reprint requests: Steven G. Meister. M.D., 3300 Henry Ave., Philadelphia, Pa. 19129. *This study was presented in part at the 24th Annual Scientific Session of The American College of Cardiology.

December, 1977, VQl. 94, No. 6, pp, 685-688

Methods

Eight patients with a clinical diagnosis of mitral stenosis who were in sinus rhythm were studied during cardiac catheterization performed to evaluate their need for cardiac surgery. All had been experiencing intermittent symptoms of pulmonary congestion. All were considered to be in the New York Heart Association (NYHA) status and prognosis class 2.2. None had clinical evidence of severe pulmonary hypertension or right heart failure. None had evidence at catheterization of aortic valve disease or more than trivial mitral regurgitation. None gave a history of angina pectoris, and the four patients who had coronary arteriography had normal coronary arteries. Biographical and baseline catheterization data are summarized in Table I. Heart rate, pulmonary arterial pressure, pulmonary wedge pressure, l e f t ventricular sYStolic and end-diastolic pressures as well as Fick or Cardio-Green dye dilution cardiac outputs were obtained immediately prior to and ten minutes following intravenous bolus injection of 2 mg. of propranolol hydrochloride. All measurements were obtained either prior to or at least twenty minutes following angiography, utilizing fluid filled catheters and Statham P 23 Db strain gauges. Recordings were made at 75 mm./second on an Electronics-for-Medicine DR-12 amplifier-recorder system. Pulmonary wedge pressures were validated by withdrawal of fully arterialized blood from the wedged catheters. Mitral diastolic pressure gradients were calculated by p!animetry of simultaneously recorded, phase corrected, equisensitive pulmonary wedge a n d left ventric-

American Heart Journal

685

Meister

et al.

Table I. Clinical and catheterization data

I Patient P.Z. D.L, J.C. M.S. E:P. F,W. E.R. A.M.

Age

Sex

M VA (cm2)

60 42 44 64 36 43 64 38

F F M M F F F F

0.8 0.5 0,9 0.7 i.6 0.8 0.9 0,9

IBaseline CI (L. / rain. L VEF /M 2) .60 -.52 .75 .68 .65 .74 -

2.8 2.1 2.4 2.4 3.1

2.2 2.8 3.2

Abbreviations: MVA = mitral valve area; LVEF = left ventricular. ejection fraction; CI = cardiac index.

ular pressure tracings. Stroke volume was derived according to the standard formula. Mitral valve areas were calculated according to the Gorlin formula, ~ using a constant of 38. 7 Statistical comparisons were made with a paired t test. Changes following propranolol were expressed as mean differences +__ standard error of the difference (SED). Results

Table II lists individual and mean values preand post-propranolol, for selected parameters in all patients. As expected, significant reductions in both heart rate and cardiac output were observed. Heart rate fell by 1 3 . 0 beats/min. _ 2.6 S E D (p < 0.005). Cardiac output fell by 0.5 L./ min. • 0.2 (p < 0.05). Stroke volume was unchanged, suggesting t h a t the fall in cardiac output was primarily a function of the reduction in heart rate. The mitral diastolic pressure gradient was reduced significantly, and in all patients (Fig. 1). The mean reduction was 7.1 mm. Hg_+ 1.6 (p < 0,005). Although several patients had a small rise in left ventricular end-diastolic pressure after propranolol, there was no significant change for the group as a whole. The net reduction in pulmonary wedge pressure was 6,9 ram. Hg • 1.2 (p < 0.01), an average of 25 per cent: A commensurate reduction in pulmonary arterial mean pressure-9.0 mm. Hg • 1.2 (p <0.005) Was also seen. Fig. 2 shows representative simultaneous pulmonary wedge and left ventricular pressure curves before and after propranolol in one patient. A borderline significant (p > 0.004, < 0.005) and small (5.1 mm. Hg • 2.6) reduction

686

in left ventricular systolic pressure was observed after propranolol administration. The largest reduction in any individual was 16 mm. Hg. None of the subjects had symptomatic hypotension or bradycardia during the s t u d y period or in a subsequent 24 hour observation period. Discussion

The relationship between heart rate, cardiac output, and the pressure gradient across stenotic mitral valves was initially described by Gorlin and associates. 8 If the mitral valve area formula is solved for the gradient, and if the valve area, which does not vary acutely, is incorporated in a constant KA, the following expression is derived: ( G =

Cardiac output )~ KA x diastolic filling period

Thus, an increase in cardiac output or a decrease in diastolic filling period results in an exponential rise in gradient. Since diastolic filling period (as diastolic seconds per minute) is abbreviated as heart rate increases, this equation explains the clinical observation t h a t situations in which heart rate and/or cardiac output are increased commonly precipitate symptomatic intervals, particularly in patients whose mitral valve areas approach critical narrowing. When mitral stenosis patients remain in sinus r h y t h m they can be expected to derive little clinical or hemodynamic benefit from digitalis. This agent reduces heart rate only slightly in sinus r h y t h m and has no demonstrable effect on cardiac output in the absence of superimposed left ventricular failure., Diuretics have been shown to reduce pulmonary wedge pressure in patients with mitral stenosis, but apparently do so via reduction of cardiac output alone, without changing heart rate. 1~ Since beta-adrenergic blocking drugs depress both heart rate and cardiac output, they would be expected to reduce the transmitral pressure gradient and pulmonary wedge pressure in patients with mitral stenosis in sinus rhythm. This was in fact observed in all of our patients and has been noted in differing context by others. Bhatia and co-workers, 11 utilizing right heart catheterization only, studied the effects of propranolol in four patients with isolated mitral stenosis in sinus rhythm. They observed a similar reduction in pulmonary wedge pressure and

December, 1977, Vol. 94, No. 6

Propranolol in mitral stenosis 30

28 26 24

22. E 20 E w 18 ~r

~BEFORE

c~

~AFTER

PROPRANOLOL PROPRANOLOL

12 I0 8

6 4 2

MVG

PWP

LVEDP

Fig. 1. Propranolol-induced changes in pulmonary wedge pressure (PWP), pressure gradient across the mitral valve (MVG), and left ventricular end-diastolic pressure (LVEDP). Standard errors of the mean are bracketed.

T a b l e II. H e m o d y n a m i c d a t a pre- a n d p o s t - p r o p r a n o l o l

Pre-propranolol Patient I PWPI PAP LVEDP LVSP I CO I HR I SV 1. P.Z. 2. D.L. 3. J.C. 4. M.S. 5. E.P. 6. F.W. 7. E.R. 8. A.M. Mean • SEM

35 34 24 37 25 20 20 28 27.9 •

38 10 60 4 33 12 72 9 32 8 6 28 12 47 8 44.3 8.6 • 6.2 • 1.0

136 4.4 100 3.8 108 4.3 140 4.0 152 6.2 120 3.3 133 4.2 116 5.4 125.6 4.45 • 6.2 • 0.33

120 100 78 97 100 108 60 66 91.1 • 7.4

37 38 55 41 62 31 70 82 52 • 6.4

Post-propranolol PWP I PAP ]LVEDP LVSP I CO I HR 21 27 20 31 15 15 16 23 21.0 • 2.1

27 50 30 60 22 22 36 35.3 • 5.5

8 6 17 11 8 5 13 9 9.6 • 1.4

120 98 107 142 142 110 123 122 120.5 • •

3.9 3.2 4.4 4.3 4.8 2.6 3.6 5.5 4.04

100 78 72 86 90 84 55 60 78.1 • 5.4

SV 39 41 61 50 53 29 66 92 53.9 • 6.9

A b b r e v i a t i o n s : C O = c a r d i a c o u t p u t ( L . / m i n . ) ; H R = h e a r t r a t e ( b e a t s / m i n . ) ; L V E D P = left v e n t r i c u l a r e n d - d i a s t o l i c p r e s s u r e ( m m . H g ) ; L V S P = left v e n t r i c u l a r systolic p r e s s u r e ( m m . H g ) ; P A P = m e a n p u l m o n a r y a r t e r y p r e s s u r e ( m m . H g ) ; P W P = p u l m o n a r y w e d g e p r e s s u r e ( m m . H g ) ; S V = s t r o k e v o l u m e (c.c,/beat); S E M = s t a n d a r d e r r o r o f t h e m e a n .

s u g g e s t e d a p o t e n t i a l t h e r a p e u t i c role for p r o p r a nolol in selected patients. C o n v e r s e l y , C u m m i n g a n d C a r r 12 also o b s e r v e d a r e d u c t i o n i n t r a n s m i t r a l g r a d i e n t , b u t concluded t h a t propranolol resulted in a n over-all reduction in cardiac performance a n d has no place i n t h e t h e r a p y of m i t r a l s t e n o s i s . T h i s assessment was a p p a r e n t l y based on the observat i o n of r e d u c e d c a r d i a c o u t p u t a n d a rise i n left v e n t r i c u l a r e n d - d i a s t o l i c pressure. H o w e v e r , t h e i r patients had a variety of associated cardiac pathologies, including m i t r a l a n d tricuspid insufficiency, a o r t i c stenosis, c o r o n a r y a r t e r y disease, a n d a t r i a l f i b r i l l a t i o n . W e did n o t o b s e r v e a s i g n i f i c a n t rise i n left v e n t r i c u l a r end-diastolic pressure, p r e s u m a b l y

American Heart Journal

b e c a u s e o u r p a t i e n t s were s e l e c t e d t o a v o i d assoc i a t e d p a t h o l o g y l i k e l y t o i m p a i r left v e n t r i c u l a r function. Since patients with early symptomatic m i t r a l s t e n o s i s suffer f r o m p u l m o n a r y c o n g e s t i o n rather than diminished tissue perfusion, small reductions in cardiac output seem acceptable in e x c h a n g e for a l o w e r e d left a t r i a l p r e s s u r e . A similar exchange occurs when diuretics are used in p a t i e n t s with m i t r a l stenosis. T h e h e m o d y n a m i c effects o b s e r v e d i n t h i s a c u t e s t u d y m i g h t i n d e e d be u s e f u l if a c h i e v a b l e on a long-term basis with oral propranolol. P r o p r a n o l o l t h e r a p y is n o t s u g g e s t e d as a s u b s t i t u t e for d e f i n i t i v e s u r g e r y . I t m i g h t h o w e v e r , p r o v e a u s e f u l c o m p o n e n t of m e d i c a l t h e r a p y i n t h o s e p a t i e n t s for w h o m s u r g e r y is p r e m a t u r e or

687

Meister et al.

study, intravenous propranolol administered to p a t i e n t s w i t h pure m i t r a l stenosis in sinus r h y t h m r e s u l t e d in significant r e d u c t i o n s in m i t r a l diastolic g r a d i e n t ( - 7 . 1 m m . H g _ 1,6 S E D ) , m e a n p u l m o n a r y wedge p r e s s u r e ( - 6 . 9 m m . H g _+ 1.2) a n d m e a n p u l m o n a r y a r t e r y p r e s s u r e s ( - 9 . 0 ram. H g _+ 1.2). T h i s was d u e to s i m u l t a n e o u s r e d u c t i o n of h e a r t r a t e ( - 1 3 . 0 b e a t s / m i n u t e ___ 2.6) a n d c a r d i a c o u t p u t ( - 0 . 5 L . / m i n u t e +_ 0.2). A s m a l l a s s o c i a t e d r e d u c t i o n of left v e n t r i c u l a r systolic p r e s s u r e ( - 5 . 1 m m . H g _+ 2.6) w a s n o t a c c o m p a nied b y a d v e r s e clinical effects. A p o t e n t i a l role for p r o p r a n o l o l in m e d i c a l m a n a g e m e n t of p u r e m i t r a l stenosis in t h e p r e s e n c e o f sinus r h y t h m is suggested.

Fig. 2. Simultaneous, equisensitive left ventricular and pulmonary wedge pressures before and after propranolol in a representative patient. The left portion of each panel shows mean wedge pressure (paper speed ffi 10 mm./sec.). The right portion shows phasic tracings (50 mm./sec.)

i n a d v i s a b l e b e c a u s e o f a s s o c i a t e d illnesses. I t w o u l d seem p a r t i c u l a r l y a p p r o p r i a t e for m i t r a l stenosis p a t i e n t s w i t h reversible c o n d i t i o n s c a u s ing i n c r e a s e d h e a r t rate, c a r d i a c o u t p u t or b o t h , s u c h as fever, a n e m i a , p r e g n a n c y , a n d h y p e r t h y roidism. I t m i g h t also p r o v e u s e f u l in a r e a s of t h e w o r l d w h e r e t h e a v a i l a b i l i t y o f c a r d i a c s u r g e r y is limited. I t s a p p l i c a b i l i t y w o u l d be limited, however, to patients with isolated mitral stenosis in sinus r h y t h m w i t h well m a i n t a i n e d c a r d i a c o u t p u t a n d n o e v i d e n c e o f failure o f e i t h e r v e n t r i cle. A longer term study employing oral propranolol in a p p r o p r i a t e p a t i e n t s s e e m s justified. Summary Patients with early symptomatic mitral stenosis u s u a l l y suffer f r o m p u l m o n a r y c o n g e s t i o n o n t h e basis o f l e f t a t r i a l a n d p u l m o n a r y v e n o u s h y p e r t e n s i o n . T h e y are o f t e n in s i n u s r h y t h m , a n d c a r d i a c o u t p u t is u s u a l l y well m a i n t a i n e d . S y m p t o m s o c c u r m o s t o f t e n w h e n h e a r t rate, c a r d i a c o u t p u t , or b o t h are increased. I n this

688

REFERENCES 1. Schlant, R. C.: Altered cardiovascular function of rheumatic heart disease, chapt. 44 in The heart, arteries, and veins, 2nd ed., Hurst, J. W., and Logue, R. B., ed. New York, 1970, McGraw-Hill Book Company, Inc., 753 pp. 2. Cumming, G. R., and Carr, W.: Hemodynamic response to exercise after propranolol in normal subjects, Can. J. Physiol. Pharmacol. 44:465, 1966. 3. Harvey, R. M., Ferrer, I., Samet, P., Bader, R. A., Bader, M. E., Cournand, A., and Richards, D. W.: Mechanical and myocardial factors in rheumatic heart disease with mitral stenosis, Cirulation 11:531, 1955. 4. Heller, S. J., and Carleton, R. A.: Abnormal left ventricular contraction in patients with mitral stenosis, Circulation 42:1099, 1970. 5. Horowitz, L. D., Mullins, C. B., Payne, R. M., and Curry, G. C.: Left ventricular function in mitral stenosis, Chest 64:609, 1973. 6. Gorlin, R., and Gorlin, S. G.: Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves and circulatory shunts. I, AM. HEARTJ. 41:1, 1951. 7. Herman, M. V., Cohn, P. F., and Gorlin, R.: Resistance to blood flow by stenotic valves: Calculation of orifice area, in Cardiac catheterization and angiography, Grossman, W., ed., Philadelphia, 1974 Lea & Febiger, Publishers, p. 89. 8. Gorlin, R., Lewis, B. M., Haynes, F. W., Spiegl, R. J., and Dexter, L.: Factors regulating pulmonary capillary pressure in mitral stenosis. IV, AM HEARTJ. 41:834, 1951. 9. Werko, L.: The use of digitalis in mitral stenosis without right heart failure, Progr. Cardiovasc. DIS. 7:284, 1964. 10. Austin, S. M., Schreiner, B. F, Kramer, D. H., Shah, P. M., and Yu, P. N.: The acute hemodynamic effects of ethacrynic acid and furosemide in patients with chronic postcapillary pulmonary hypertension, Circulation 53:364, 1976. 11. Bhatia, M. L., Shrivastava, S., and Roy, S. G.: Immediate haemodynamic effects of a beta adrenergic blocking agent--propranolol--in mitral stenosis at fixed heart rates, Br. Heart J. 34:638, 1972. 12. Cumming, G. R., and Carr, W.: Hemodynamic response to exercise after beta-adrenergic blockade with propranolol in patients with mitral valve obstruction, Can. Med: Assoc. J. 95:527, 1966.

December, 1977, Vol. 94, No. 6