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Effects of atenolol on exercise capacity in patients with mitral stenosis with sinus rhythm
VALVULAR
HEART DISEASE
Effects of Atenolol on Exercise Capacity in Patients with Mitral Stenosis with Sinus Rhythm HERMAN 0. KLEIN, MD, PINHAS SARELI, MD, COLON L. SCHAMROTH, MB, FCP (SA), YOONOOS CARIM, MB, FCP (SA), MENASHE EPSTEIN, MD, and BRIDGET MARCUS,
MBBCh
Exercise capacity is frequently impaired in patients with mitral stenosis (MS) and sinus rhythm (SR). The resulting increased heart rate, which shortens the diastolic filling period, and the increased cardiac output lead to further elevations of left atrial pressure and%subsequent pulmonary congestion. The effect of the @-receptor blocking agent atenolol, 100 mg/day, was assessed in 13 patients with MS and SR. Exercise performance was assessed using a modified multistage Bruce protocol after 2 weeks of placebo and after 2 weeks therapy with atenolol in a single-blind, crossover, placebo-controlled, randomized study. Atenolol resulted in significant
decreases in mean heart rates at rest and during exercise (p = 0.0015) and a significant increase in total exercise time (p = 0.0015). Maximal exercise capacity was also significantly improved (p = 0.0015). All patients were both objectively and subjectively improved by atenolol. Thus, P-blockade with atenolol improves exercise capacity in patients with MS and SR and may be of benefit to most such patients. The improved effort tolerance is attributed to reduction oft the exercise-associated sinus tachycardia by P-blockade, allowing a longer diastolic filling period and better left atrial decompression. (Am J Cardiol 1985;58:598-801)
Exercise capacity is frequently impaired in patients with mitral stenosis (MS). The pressure gradient across the mital valve is directly related to the diastolic blood flow through the orifice and inversely related to the orifice size and duration of the diastolic filling period.1-3 Any increase in cardiac output or decrease of the diastolic filling period, as occurs with tachycardia, produces an exponential rise in the pressure gradient.3 The result is reflected clinically by dyspnea on exertion and, in severe cases, by the precipitation of pulmonary edema. Intravenous administration of propranolol has been studied by catheterization and has a beneficial effect on hemodynamic values at rest3-8 and during supine exercise.6T7 D’Annunzio and Mobilij8 showed hemodynamic improvement at rest after oral propranolol administration for 1 month in 5 patients with MS and sinus rhythm (SR). We found only 1 study that compared exercise capacity both before and after the
chronic administration of P-blocking agents.9 We studied 13 patients who had significant MS and were in SR. These patients were evaluated in a single-blind, placebo-controlled, crossover study. The fi blocker selected for the study was the cardioselective agent atenolol. Methods Patients: Thirteen consecutive patients with isolated MS and SR were subjected to a prospective crossover, single-blind, placebo-controlled study. There were 11 female and 2 male patients, aged 15 to 35 years. All were in functional class II or III of the New York Heart Association classification. The diagnosis of MS was made clinically and confirmed by echocardiography in every patient. MS was considered significant in all 13 patients as judged by the echocardiographic finding of a mitral valve orifice area of less than 1.5 cm. All patients received oral diuretic therapy throughout the study period. All had evidence of pulmonary arterial hypertension, as judged by a palpable right ventricular impulse and a loud pulmonic component of the second heart sound. Chest roentgenographic and electrocardiographic findings were all compatible with the clinical diagnosis. Study protocol: The 13 patients were subjected to a 2phase, crossover study with each phase consisting of 2 weeks. Seven patients began with placebo and the other 6 with oral atenolol treatments, 100 mg taken in the morning. A P-blocker
From the Department of Cardiology, Baragwanath Hospital, and the University of the Witwatersrand, Johannesburg, South Africa. Manuscript received February 18, 1985; revised manuscript received April 23, 1985, accepted April 29, 1985. Address for reprints: Pinhas Sareli, MD, Department of Cardiology, Baragwanath Hospital, P.O. Bertsham 2013 Johannesburg, South Africa. 598
TABLE
I
Measurements
During Atenolol
and Placebo
Phases
Placebo Rest heart rate (beatsimin) Exercise heart rate (beats/min) Stage I Stage II Stage Ill Stage IV Stage V B;;“,“, pressure (mm Hg) Systolic Diastolic Stage I Systolic Diastolic Stage II Systolic Diastolic Stage Ill Systolic Diastolic Stage IV Systolic Diastolic Stage V Systolic Diastolic Exercise time (min) Maximal exercise capacity
(13)
88 f
12
(13)
(13) (13) (9) (3)
115 f 127 f 146f 164 f
16 17 11 10
106 f 71 f
0.0015
(13) 81 f (13) 93 f (13) 106 f (9) 119 f (4) 140 f
15 16 15 12 10
0.0015 0.0015 0.0077 0.001.5
12 10
101 f 70 f
10 7
NS NS
111 f 66f
16 10
105 f 66f
16 11
NS NS
110 f 63f
16 11
110 f 62f
15 16
NS NS
117 f 60f
19 16
101 f 57f
14 18
NS NS
107 f 53 f
15 6
99 f 7 50 f 12
29
97 f 21 42f 15 11 f2 84 f 47
who reached
effect was considered to be present if the heart rate at rest decreased by 10% or more from placebo to atenolol phases. The tablets of atenolol and placebo were identical in appearance. Serum atenolol concentration was measured in 3 patients chosen at random at the end of the Z-week atenolol phase. Exercise protocol: The 13 patients underwent exercise testing on a commercial treadmill according to a modified Bruce protocol until the point of exhaustion, dizziness or severe dyspnea was reached. The following measures of functional capacity were compared during placebo and atenolol phases: (1) heart rate and blood pressure at rest, at the end of each exercise stage and at the completion of exercise; (2) total duration of exercise; and (3) maximal exercise capacity index (expressed as work units). Maximal exercise capacity was derived from the fol-
58 f
p Value 8
9f2 45 f
(units)
Values are mean f standard deviation. Brackets indicated number of patients NS = not significant.
Atenolol
0.0015 0.0015
that stage.
lowing formula, which was calculated for each stage of exercise and then summated: [time (min) X speed (km/hr) X incline (degrees)/3 minutes]. For example, in a patient who completed stage 1 but managed only 2 minutes of stage 2: [(3 X 2.7 X I)/3 + (2 X 2.7 X 5)/3] = 11.7 work units. This index, adapted from Redfors,ro takes into account not only the total time spent exercising, but also the increasing difficulty of exercise with each successivestage. Plasma atenolol concentration: Atenolol concentrations were measured at random in 3 patients. The plasma concentration of atenolol was determined by the procedure described by Yin-Gail et a1.l’ Statistical analysis: Wilcoxon’s signed-rank test procedure was used for analysis of all variables.12 This test was modified where applicable according to the method of Bonferroni.13 A p value of -CO.01was considered significant.
HEART RATE (bpm)
FIGURE I. Mean heart rates at different stages of exercise during atenolol and placebo phases. Brackets indicate number of patients reaching a particular stage.
STAGE OF EXERCISE
600
zoor
ATENOLOL
AND
EXERCISE
IN MITRAL
STENOSIS
MEC (units) I
FIGURE atenolol
Results Values at rest: Values measured at rest are listed in Table I. Mean heart rate at rest for the 13 patients was 88 f 12 beats/min (range 57 to 100) during the placebo period, and decreased to 58 f 8 beats/min (range 51 to 75) after 2 weeks of atenolol treatment (p = 0.0015). The mean decrease in heart rate at rest was 34%. Systolic and diastolic blood pressures did not change significantly. Response to exercise: All individual and mean heart rates were significantly lower at each stage of exercise during atenolol treatment than during placebo (Fig. 1, Table I). Blood pressure values did not change significantly. The maximal exercise capacity and the total time spent on the treadmill increased significantly during the atenolol phase (Fig. 2 and 3, Table I). Plasma atenolol concentration: The plasma atenolol concentrations in the 3 patients chosen at random were 193,246 and 665 rig/ml (mean 368). Discussion The results of previous studies3-8 reflecting acute hemodynamic changes in MS with SR strongly suggested that P-blocker administration on a long-term basis could improve exercise capacity. The only study
2. Maximal and placebo
exercise phases.
capacity
(MEC)
during
that investigated this issue with oral therapy was not completely placebo-controlled and used a noncardioselective agent.g The present placebo-controlled study demonstrated that p blockade significantly improves exercise capacity in patients with MS and intact sinus node function. The results are similar to those of Penas et a1.g The increase in exercise capacity is probably mediated by the negative chronotropic effect of pblocking drugs on sinus node function, both at rest and in response to exercise. Effort dyspnea is reduced and the risk of exercise induced pulmonary edema is diminished. Amery et all4 showed that there is a clear relation between plasma atenolol concentration and percent reduction in exercise heart rate. The therapeutic plasma atenolol concentrations determined by these investigators (100 to 500 rig/ml) are similar to those obtained in the present study. In practice, the determination of plasma atenolol concentration is not necessary for the clinical management of compliant patients, although its availability permits the exclusion of placebo-related or conditioning effects. A decrease in heart rate of at least 10% at rest after a starting dose of 100 mg/day of atenolol is usually an adequate means of monitoring the compliance and clinical response of patients.
__ tXERCISE TlME (min)
FIGURE phases.
I 4-
p=o.o015
3. Exercise
time
during
atenolol
and placebo
October
Physicians may be reluctant to use P-blocking drugs in patients with MS because of the negative inotropic effect of these drugs. l5~ The deleterious effects of this action, however, in the context of MS without severe pulmonary arterial hypertension or evidence of right heart failure, is negligible. 4y5The choice of atenolol was motivated by its easy (once a day) administration, as well as its long duration of action, cardioselectivity and hydrophilic properties. Although there is a potential and theoretical adverse effect of ,8 blockade in reducing left atria1 contractility, this effect was not evident in our patients or was negated by the advantageous effects of a slower heart rate. Although the use of atenolol in pregnant and lactating women is limited, there is no evidence of teratogenicity, nor of neonatal or infant toxicity either in our experience or that of other investigators.17-20 Outside of this study we have used atenolol in several pregnant women with MS without mishap. Beta-blocking drugs should be administered cautiously when pulmonary arterial hypertension is marked, and their use may be contraindicated in some patients with MS and right ventricular failure. The clinical application of this study is readily apparent. The long-term use of a P-blocking drug, such as atenolol will improve exercise capacity and allow the postponement of surgical intervention in many patients with significant MS.
We thank Joseph Di Nicola for technical assistance and the Photographic Unit, University of the Witwatersrand, Johannesburg, for the photographic reproductions. The tablets of atenolol and placebo were kindly supplied by Imperial Chemical Industries, Inc. Acknowledgment:
1, 1985
THE
AMERICAN
JOLIPXAL
3;
‘ZAX?8i3GY
Volume
56
1. Gorlin R, Gorlin SO. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves and circulatory shunts. I, Am Heari J 1951:41:1-29. 2. Gortin R, Lewis BM, Haynes FW, Spiegl Rd, Dexter L. Factors regulating pulmonary capillary pressure in mitral stenosis. Am Heart J 1961;41: 834-854. 3. Meister SG, Engel TR, Feitosa GS, Helfant RH, Frank1 WS. Propranolol in mitral stenosis during sinus rhythm. Am Heart J 1977;94:685-688. 4. Goyle KK, Mathur VS, Bhatia ML, Roy SB. Hemodynamic effects of beta adrenergic blockade in patients with mitral stenosis. Ind Heart J 1969;21: 364-368. 5. Bhatla ML, Shrivastava S, Roy SB. Immediate haemodynamic effect of a beta adrengeric blocking agent-propranolol-in mitral stenosis at fixed heart rates. Br Heart J 1972;34:638-644. response to 6. Bhatia ML, Goyle KK, Mathur VS, Roy SB. Hemodynamic exercise in patients wrth mitral stenosis before and after beta adrenergic blockade. Ind Heart J 1969;27:33-40. 7. Giuffrida G, Boruani G, Betoccht S, Piscione F, Guidice P, Yiceli D, Mazza F, Condorelti M. Hemodynamic response to exercise after propranolol in patients with mitral stenosis. Am J Gardiol 1979;44:1076-1082. 6. D’Annuzio E, Mobilij A. Terapia con betabloccanti nei malati affetti da stenosi mitralica. Minerva Med 1980;71:3131-3137. 9. Penas Y, Cosio F, Palacios J, Castro C, Oria J, Garcia-Pascual J. Effect0 del propranolol sobre la capacidad functional en la estenosis mitral no comolicada. Rev Lat Cardiol 1981:2:175-183. 10. Redfors A. The effect of different digoxin doses on subjective symptoms and physical working capacity in patients with atrial fibrillation, Acta Med Stand 1971;190:307-320. 11. Yln-Gall Y, Rubin P, Blaschke TF. Atenolol determination by high-performance liquid chromatography and fluorescence detection. J Chromatogr 1979;171:352-362. 12. Sl el S. Nonparametric statistics for the behavioral sciences. New York: Maraw-Hill 1956:75-83. 13. Neter J, Wasserman W. Applied Linear Statistical Models. Homewood, IL: Richard D. Irwin, Inc, 1974:730. 14. Amery A, DePlaen JF, Lijnen P, McAinsh J, Reybrouch T. Relationship between blood level of atenolol and pharmacologic effect. Clin Pharmacol Ther 1977;21:691-699. 15. Cummlng GR, Carr W. Hemodynamic response to exercise after beta adrenergic blockade with propranolol in patients with mitral valve obstruction. Can Med Assoc J 1966;95:527-531. 16. Llchtlen P, Amende I, Simon R, Engel HJ, Hundeshagen H. Left ventricular function and regional myocardial blood flow after atenolol in normals and !;I? with coronary artery disease. Postgrad Med J 1977;53:suppl 3: of atenolol in pregnancy and lactation. In: 17. Thurley KJ. Pharmacokinetics Robertson JIS, ed. Drugs. Beta Blockade in the 1980s. Facus on Atenolo!. 1983;25:suppl 2:216-217. 19. Lledholm H. Atenolol in tie treatment of hypertension of pregnancy. in: Ref. 17:206-211. 19. Rubln PC, Butters L, Low RA, Reid JL. Atenolol in the treatment of essential hypertension during pregnancy. Br J Clin Pharmacol 1982;14:277-281. 20. Rubln PC, Butters L, Low RA, Clark DL, Reid JL. Atenolol in the management of hypertension during pregnancy. In: Ref. 17:212-214.
HEART DISEASE
Effects of Atenolol on Exercise Capacity in Patients with Mitral Stenosis with Sinus Rhythm HERMAN 0. KLEIN, MD, PINHAS SARELI, MD, COLON L. SCHAMROTH, MB, FCP (SA), YOONOOS CARIM, MB, FCP (SA), MENASHE EPSTEIN, MD, and BRIDGET MARCUS,
MBBCh
Exercise capacity is frequently impaired in patients with mitral stenosis (MS) and sinus rhythm (SR). The resulting increased heart rate, which shortens the diastolic filling period, and the increased cardiac output lead to further elevations of left atrial pressure and%subsequent pulmonary congestion. The effect of the @-receptor blocking agent atenolol, 100 mg/day, was assessed in 13 patients with MS and SR. Exercise performance was assessed using a modified multistage Bruce protocol after 2 weeks of placebo and after 2 weeks therapy with atenolol in a single-blind, crossover, placebo-controlled, randomized study. Atenolol resulted in significant
decreases in mean heart rates at rest and during exercise (p = 0.0015) and a significant increase in total exercise time (p = 0.0015). Maximal exercise capacity was also significantly improved (p = 0.0015). All patients were both objectively and subjectively improved by atenolol. Thus, P-blockade with atenolol improves exercise capacity in patients with MS and SR and may be of benefit to most such patients. The improved effort tolerance is attributed to reduction oft the exercise-associated sinus tachycardia by P-blockade, allowing a longer diastolic filling period and better left atrial decompression. (Am J Cardiol 1985;58:598-801)
Exercise capacity is frequently impaired in patients with mitral stenosis (MS). The pressure gradient across the mital valve is directly related to the diastolic blood flow through the orifice and inversely related to the orifice size and duration of the diastolic filling period.1-3 Any increase in cardiac output or decrease of the diastolic filling period, as occurs with tachycardia, produces an exponential rise in the pressure gradient.3 The result is reflected clinically by dyspnea on exertion and, in severe cases, by the precipitation of pulmonary edema. Intravenous administration of propranolol has been studied by catheterization and has a beneficial effect on hemodynamic values at rest3-8 and during supine exercise.6T7 D’Annunzio and Mobilij8 showed hemodynamic improvement at rest after oral propranolol administration for 1 month in 5 patients with MS and sinus rhythm (SR). We found only 1 study that compared exercise capacity both before and after the
chronic administration of P-blocking agents.9 We studied 13 patients who had significant MS and were in SR. These patients were evaluated in a single-blind, placebo-controlled, crossover study. The fi blocker selected for the study was the cardioselective agent atenolol. Methods Patients: Thirteen consecutive patients with isolated MS and SR were subjected to a prospective crossover, single-blind, placebo-controlled study. There were 11 female and 2 male patients, aged 15 to 35 years. All were in functional class II or III of the New York Heart Association classification. The diagnosis of MS was made clinically and confirmed by echocardiography in every patient. MS was considered significant in all 13 patients as judged by the echocardiographic finding of a mitral valve orifice area of less than 1.5 cm. All patients received oral diuretic therapy throughout the study period. All had evidence of pulmonary arterial hypertension, as judged by a palpable right ventricular impulse and a loud pulmonic component of the second heart sound. Chest roentgenographic and electrocardiographic findings were all compatible with the clinical diagnosis. Study protocol: The 13 patients were subjected to a 2phase, crossover study with each phase consisting of 2 weeks. Seven patients began with placebo and the other 6 with oral atenolol treatments, 100 mg taken in the morning. A P-blocker
From the Department of Cardiology, Baragwanath Hospital, and the University of the Witwatersrand, Johannesburg, South Africa. Manuscript received February 18, 1985; revised manuscript received April 23, 1985, accepted April 29, 1985. Address for reprints: Pinhas Sareli, MD, Department of Cardiology, Baragwanath Hospital, P.O. Bertsham 2013 Johannesburg, South Africa. 598
TABLE
I
Measurements
During Atenolol
and Placebo
Phases
Placebo Rest heart rate (beatsimin) Exercise heart rate (beats/min) Stage I Stage II Stage Ill Stage IV Stage V B;;“,“, pressure (mm Hg) Systolic Diastolic Stage I Systolic Diastolic Stage II Systolic Diastolic Stage Ill Systolic Diastolic Stage IV Systolic Diastolic Stage V Systolic Diastolic Exercise time (min) Maximal exercise capacity
(13)
88 f
12
(13)
(13) (13) (9) (3)
115 f 127 f 146f 164 f
16 17 11 10
106 f 71 f
0.0015
(13) 81 f (13) 93 f (13) 106 f (9) 119 f (4) 140 f
15 16 15 12 10
0.0015 0.0015 0.0077 0.001.5
12 10
101 f 70 f
10 7
NS NS
111 f 66f
16 10
105 f 66f
16 11
NS NS
110 f 63f
16 11
110 f 62f
15 16
NS NS
117 f 60f
19 16
101 f 57f
14 18
NS NS
107 f 53 f
15 6
99 f 7 50 f 12
29
97 f 21 42f 15 11 f2 84 f 47
who reached
effect was considered to be present if the heart rate at rest decreased by 10% or more from placebo to atenolol phases. The tablets of atenolol and placebo were identical in appearance. Serum atenolol concentration was measured in 3 patients chosen at random at the end of the Z-week atenolol phase. Exercise protocol: The 13 patients underwent exercise testing on a commercial treadmill according to a modified Bruce protocol until the point of exhaustion, dizziness or severe dyspnea was reached. The following measures of functional capacity were compared during placebo and atenolol phases: (1) heart rate and blood pressure at rest, at the end of each exercise stage and at the completion of exercise; (2) total duration of exercise; and (3) maximal exercise capacity index (expressed as work units). Maximal exercise capacity was derived from the fol-
58 f
p Value 8
9f2 45 f
(units)
Values are mean f standard deviation. Brackets indicated number of patients NS = not significant.
Atenolol
0.0015 0.0015
that stage.
lowing formula, which was calculated for each stage of exercise and then summated: [time (min) X speed (km/hr) X incline (degrees)/3 minutes]. For example, in a patient who completed stage 1 but managed only 2 minutes of stage 2: [(3 X 2.7 X I)/3 + (2 X 2.7 X 5)/3] = 11.7 work units. This index, adapted from Redfors,ro takes into account not only the total time spent exercising, but also the increasing difficulty of exercise with each successivestage. Plasma atenolol concentration: Atenolol concentrations were measured at random in 3 patients. The plasma concentration of atenolol was determined by the procedure described by Yin-Gail et a1.l’ Statistical analysis: Wilcoxon’s signed-rank test procedure was used for analysis of all variables.12 This test was modified where applicable according to the method of Bonferroni.13 A p value of -CO.01was considered significant.
HEART RATE (bpm)
FIGURE I. Mean heart rates at different stages of exercise during atenolol and placebo phases. Brackets indicate number of patients reaching a particular stage.
STAGE OF EXERCISE
600
zoor
ATENOLOL
AND
EXERCISE
IN MITRAL
STENOSIS
MEC (units) I
FIGURE atenolol
Results Values at rest: Values measured at rest are listed in Table I. Mean heart rate at rest for the 13 patients was 88 f 12 beats/min (range 57 to 100) during the placebo period, and decreased to 58 f 8 beats/min (range 51 to 75) after 2 weeks of atenolol treatment (p = 0.0015). The mean decrease in heart rate at rest was 34%. Systolic and diastolic blood pressures did not change significantly. Response to exercise: All individual and mean heart rates were significantly lower at each stage of exercise during atenolol treatment than during placebo (Fig. 1, Table I). Blood pressure values did not change significantly. The maximal exercise capacity and the total time spent on the treadmill increased significantly during the atenolol phase (Fig. 2 and 3, Table I). Plasma atenolol concentration: The plasma atenolol concentrations in the 3 patients chosen at random were 193,246 and 665 rig/ml (mean 368). Discussion The results of previous studies3-8 reflecting acute hemodynamic changes in MS with SR strongly suggested that P-blocker administration on a long-term basis could improve exercise capacity. The only study
2. Maximal and placebo
exercise phases.
capacity
(MEC)
during
that investigated this issue with oral therapy was not completely placebo-controlled and used a noncardioselective agent.g The present placebo-controlled study demonstrated that p blockade significantly improves exercise capacity in patients with MS and intact sinus node function. The results are similar to those of Penas et a1.g The increase in exercise capacity is probably mediated by the negative chronotropic effect of pblocking drugs on sinus node function, both at rest and in response to exercise. Effort dyspnea is reduced and the risk of exercise induced pulmonary edema is diminished. Amery et all4 showed that there is a clear relation between plasma atenolol concentration and percent reduction in exercise heart rate. The therapeutic plasma atenolol concentrations determined by these investigators (100 to 500 rig/ml) are similar to those obtained in the present study. In practice, the determination of plasma atenolol concentration is not necessary for the clinical management of compliant patients, although its availability permits the exclusion of placebo-related or conditioning effects. A decrease in heart rate of at least 10% at rest after a starting dose of 100 mg/day of atenolol is usually an adequate means of monitoring the compliance and clinical response of patients.
__ tXERCISE TlME (min)
FIGURE phases.
I 4-
p=o.o015
3. Exercise
time
during
atenolol
and placebo
October
Physicians may be reluctant to use P-blocking drugs in patients with MS because of the negative inotropic effect of these drugs. l5~ The deleterious effects of this action, however, in the context of MS without severe pulmonary arterial hypertension or evidence of right heart failure, is negligible. 4y5The choice of atenolol was motivated by its easy (once a day) administration, as well as its long duration of action, cardioselectivity and hydrophilic properties. Although there is a potential and theoretical adverse effect of ,8 blockade in reducing left atria1 contractility, this effect was not evident in our patients or was negated by the advantageous effects of a slower heart rate. Although the use of atenolol in pregnant and lactating women is limited, there is no evidence of teratogenicity, nor of neonatal or infant toxicity either in our experience or that of other investigators.17-20 Outside of this study we have used atenolol in several pregnant women with MS without mishap. Beta-blocking drugs should be administered cautiously when pulmonary arterial hypertension is marked, and their use may be contraindicated in some patients with MS and right ventricular failure. The clinical application of this study is readily apparent. The long-term use of a P-blocking drug, such as atenolol will improve exercise capacity and allow the postponement of surgical intervention in many patients with significant MS.
We thank Joseph Di Nicola for technical assistance and the Photographic Unit, University of the Witwatersrand, Johannesburg, for the photographic reproductions. The tablets of atenolol and placebo were kindly supplied by Imperial Chemical Industries, Inc. Acknowledgment:
1, 1985
THE
AMERICAN
JOLIPXAL
3;
‘ZAX?8i3GY
Volume
56
1. Gorlin R, Gorlin SO. Hydraulic formula for calculation of the area of the stenotic mitral valve, other cardiac valves and circulatory shunts. I, Am Heari J 1951:41:1-29. 2. Gortin R, Lewis BM, Haynes FW, Spiegl Rd, Dexter L. Factors regulating pulmonary capillary pressure in mitral stenosis. Am Heart J 1961;41: 834-854. 3. Meister SG, Engel TR, Feitosa GS, Helfant RH, Frank1 WS. Propranolol in mitral stenosis during sinus rhythm. Am Heart J 1977;94:685-688. 4. Goyle KK, Mathur VS, Bhatia ML, Roy SB. Hemodynamic effects of beta adrenergic blockade in patients with mitral stenosis. Ind Heart J 1969;21: 364-368. 5. Bhatla ML, Shrivastava S, Roy SB. Immediate haemodynamic effect of a beta adrengeric blocking agent-propranolol-in mitral stenosis at fixed heart rates. Br Heart J 1972;34:638-644. response to 6. Bhatia ML, Goyle KK, Mathur VS, Roy SB. Hemodynamic exercise in patients wrth mitral stenosis before and after beta adrenergic blockade. Ind Heart J 1969;27:33-40. 7. Giuffrida G, Boruani G, Betoccht S, Piscione F, Guidice P, Yiceli D, Mazza F, Condorelti M. Hemodynamic response to exercise after propranolol in patients with mitral stenosis. Am J Gardiol 1979;44:1076-1082. 6. D’Annuzio E, Mobilij A. Terapia con betabloccanti nei malati affetti da stenosi mitralica. Minerva Med 1980;71:3131-3137. 9. Penas Y, Cosio F, Palacios J, Castro C, Oria J, Garcia-Pascual J. Effect0 del propranolol sobre la capacidad functional en la estenosis mitral no comolicada. Rev Lat Cardiol 1981:2:175-183. 10. Redfors A. The effect of different digoxin doses on subjective symptoms and physical working capacity in patients with atrial fibrillation, Acta Med Stand 1971;190:307-320. 11. Yln-Gall Y, Rubin P, Blaschke TF. Atenolol determination by high-performance liquid chromatography and fluorescence detection. J Chromatogr 1979;171:352-362. 12. Sl el S. Nonparametric statistics for the behavioral sciences. New York: Maraw-Hill 1956:75-83. 13. Neter J, Wasserman W. Applied Linear Statistical Models. Homewood, IL: Richard D. Irwin, Inc, 1974:730. 14. Amery A, DePlaen JF, Lijnen P, McAinsh J, Reybrouch T. Relationship between blood level of atenolol and pharmacologic effect. Clin Pharmacol Ther 1977;21:691-699. 15. Cummlng GR, Carr W. Hemodynamic response to exercise after beta adrenergic blockade with propranolol in patients with mitral valve obstruction. Can Med Assoc J 1966;95:527-531. 16. Llchtlen P, Amende I, Simon R, Engel HJ, Hundeshagen H. Left ventricular function and regional myocardial blood flow after atenolol in normals and !;I? with coronary artery disease. Postgrad Med J 1977;53:suppl 3: of atenolol in pregnancy and lactation. In: 17. Thurley KJ. Pharmacokinetics Robertson JIS, ed. Drugs. Beta Blockade in the 1980s. Facus on Atenolo!. 1983;25:suppl 2:216-217. 19. Lledholm H. Atenolol in tie treatment of hypertension of pregnancy. in: Ref. 17:206-211. 19. Rubln PC, Butters L, Low RA, Reid JL. Atenolol in the treatment of essential hypertension during pregnancy. Br J Clin Pharmacol 1982;14:277-281. 20. Rubln PC, Butters L, Low RA, Clark DL, Reid JL. Atenolol in the management of hypertension during pregnancy. In: Ref. 17:212-214.