Exercise training improves left ventricular contractile response to ,@-adrenergic agonist ROBERT J. SPINA, TAKESHI OGAWA, ANDREW R. COGGAN, JOHN 0. HOLLOSZY, AND AL1 A. EHSANI Section of Applied Physiology, and The Cardiovascular Division, Department of Medicine, and Irene Walter Johnson Institute of Rehabilitation, Washington University School of Medicine, St. Louis, Missouri 63110 crease in stroke volume at maximal exercise can be due to enhanced inotropic state, a larger end-diastolic volume (14), reduced left ventricular end-systolic wall stress ((T,,~),or any combination of these variables. Most studies whether enduranceexercisetraining can improve left ventricu- have reported no change in left ventricular contractile lar function in responseto p-adrenergic stimulation, young function after training in humans (2). However, Wyatt et healthy sedentary subjects(10 womenand 6 men) were studied before and after 12 wk of enduranceexercisetraining. Training al. (30) reported increased inotropic sensitivity to a ,8consisted of 3 days/wk of interval training (running and cy- adrenergic agonist in an isolated cardiac muscle preparacats. Thus it is possible that cling) and 3 days/wk of continuous running for 40 min. The tion from exercise-trained training resulted in an increase in maximal 0, uptake from endurance exercise training may enhance the inotropic response to catecholamines without affecting intrinsic 41.0 t 2 to 49.3 t 2 ml kg-’ mine1(P < 0.01). Left ventricular function was evaluated by two-dimensional echocardiography myocardial contractility. This could be one potential under basalconditions and during /3-adrenergicstimulation in- mechanism underlying the higher stroke volume at maxduced by isoproterenol infusion. Fractional shortening (FS) imal exercise in the trained state. Therefore the present under basalconditions wasunchangedafter training (36 t 1vs. study was designed to test the hypothesis that endurance 36 + 2%). During the highest doseof isoproterenol, FS was52 t exercise training can enhance left ventricular contractile l%before and 56 t 1%after training (P < 0.05). At comparable changesin end-systolic wall stress(ues),the increasein FS in- function in response to a /3-adrenergic agonist in young duced by isoproterenol was significantly larger afIer training healthy subjects.
SPINA, ROBERT J., TAKE~HI OGAWA, ANDREW R. COGGAN, JOHN 0. HOLLOSZY, AND ALI A. EHSANI. Exercise training improves left ventricular contractile response to ,&adrenergic agonist. J. Appl. Physiol. 72(l): 307-311, 1992.-To determine
l
l
(13 -+ 1 vs. 17t 2%, P K 0.01). Furthermore there wasa greater decreasein end-systolic dimensionat similar changesin oesin the trained state during isoproterenol infusion (-4.6 k 0.1 mm before vs. -7.0 -+ 0.1 mm after training, P < 0.01). There were no concurrent changesin end-diastolic dimensionbetweenthe trained and untrained states during isoproterenol infusion, suggestingno significant changesin preload at comparablelevels of oes.Under basalconditions, end-diastolic dimensionwas increased(46 ? 0.5 vs. 50 & 0.5 mm, P < 0.03) after training (P < O-03),with no significant change in left ventricular wall thickness-to-radius ratio after training, consistent with volume-overload hypertrophy. The results indicate that endurance exercisetraining enhancesthe left ventricular contractile responseto ,8-adrenergicstimulation without affecting basal contractility in young subjects. exercisetraining; /3-adrenergicstimulation; contractility
EXERCISE TRAINING increases maximal 0, uptake (VO, m,) in young healthy subjects by inducing adaptive increases in cardiac output and arteriovenous 0, content difference at maximal exercise (2,6,22). The augmentation in maximal cardiac output in the trained state is entirely the result of a larger stroke volume, because maximal heart rate does not increase in response to exercise training (6). Stroke volume at maximal exercise is regulated by a highly integrated mechanism that involves changes in contractility, cardiac loading conditions, or both (9,18). Therefore the training-induced in-
ENDURANCE
METHODS
Subjects. Seventeen healthy sedentary subjects, 10 women and 7 men [27 t 4 (SE) yr old], volunteered for this study. The experimental procedures were approved by the Human Studies Committee at Washington University School of Medicine, and subjects gave their written consent to participate. All subjects were asymptomatic, with no history of cardiovascular disease; they had a normal physical examination as well as resting and exercise electrocardiogram (ECG). None of the subjects had performed regular endurance exercise for at least 6 mo before participation in the study. Measurement of Vo2-. Vo2,, was determined during a continuous treadmill exercise protocol at a constant speed with the grade increasing by 2% every 2 min. Peak 0, uptake (TO,) during cycle ergometer exercise was also determined during a continuous exercise protocol in which power output was increased by 25-50 W every 2 min. VO 2 maxand peak ir0, were defined as the attainment of a plateau of VO, with increasing work rate and the respiratory exchange ratio >l.lO, 00, was measured by the standard technique of open-circuit spirometry, which incorporated a computer for calculation of Vo, every 30 s during exercise (3). Inspiratory volume was measured by a Parkinson-Cowan CD-4 dry gas meter. Fractional concentrations of expired 0, and CO, were measured from a mixing chamber by electronic 0, (Applied Electrochemis-
0161-7567/92 $2.00 Copyright 0 1992 the AmericanPhysiological Society
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Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (192.236.036.029) on August 26, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
308
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try S3-A) and CO, (Beckman LB-2) analyzers, respectively. Left ventricular systolic performance. Left ventricular function was evaluated using two-dimensional guided Mmode echocardiography with a 2.5mHz transducer (Hewlett-Packard model 77020A). Recordings were obtained using the standard views according to the guidelines recommended by the American Society of Echocardiography (21). The images were recorded at a paper speed of 50 mm/s on a strip chart recorder and also stored on a magnetic tape. The transducer was placed l-3 cm parasternally in the desired intercostal space (3rd or 4th), which allowed optimal recording of the mitral valve. The transducer was then angulated laterally and inferiorly to obtain simultaneous visualization of both sides of the interventricular septum, the posterior wall endocardium, the posterior chordae, and portions of the anterior chordae. The end-diastolic dimension (EDD) was taken as the distance between the left ventricular endocardial surface of the septum and the posterior endocardium measured at the time of the onset of the QRS complex of the simultaneously recorded ECG. The endsystolic dimension (ESD) was measured as the distance between the posterior wall endocardium and the left side of the septum at the time of maximal inward movement of the posterior wall endocardium. The reproducibility of these measurements from our laboratory has been reported previously (5,12). Fractional shortening (FS) was calculated as FS = (EDD - ESD) lOO/EDD. Left ventricular a,, was calculated as described by Grossman et al. (7) : %3 = Prl2h (1 + h/2r), where P is systolic blood pressure expressed as g/cm2, r is end-systolic radius (ESD/2), and h is posterior wall thickness at end systole. Left ventricular contractile performance was assessed by changes in 1) FS as a function of alterations in left ventricular g,, and 2) the c,-ESD relationship. Because the ejection phase indexes of left ventricular function are influenced by changes in contractility as well as cardiac loading conditions and isoproterenol can reduce afterload in addition to increasing contractility (19), the effect of exercise training on FS was examined, taking into consideration the concurrent alterations in loading conditions. To control for the confounding effect of afterload, the changes in FS were compared at similar levels of ces. This was done by selecting those subjects (n = 14) in whom the differences in ACT,,(changes in Ok, from baseline induced by isoproterenol) between the untrained and trained states were - 10 g/cm’, irrespective of the dose of isoproterenol; two time points for each subject were selected: one before and one after training. Concurrent changes in EDD were also examined at these levels to evaluate the effect of preload on FS and the a,,-ESD relationship. Study design. Left ventricular size (EDD and wall thickness) and function were evaluated at baseline and during P-adrenergic stimulation induced by infusion of isoproterenol both before and after completion of the endurance exercise training. Subjects were studied in the supine position with an intravenous catheter inserted in an antecubital vein. Baseline recordings were obtained after the subjects had rested for 20 min in a quiet dimly lit laboratory. The
AFTER
TRAINING
position of the subject on the table, transducer placement, and time of day were kept the same for the pre- and posttraining experiments. Isoproterenol was infused at 0.01, 0.02, and 0.03 pg kg-l 4min-l with a Harvard syringe pump under continuous ECG monitoring. Each stage of infusion lasted for 10 min. Two-dimensional echocardiography recordings were obtained at minutes 4-5 of each stage of infusion. Heart rate and blood pressure, measured by sphygmomanometer, were recorded simultaneously with echocardiographic recordings. One male subject developed frequent premature ventricular depolarizations during infusion of isoproterenol, necessitating termination of the experiment. Therefore his data were excluded from the analysis. Data were analyzed in a blind fashion. Endurance exercise training program. After completion of initial tests, subjects participated in a f2-wk training program consisting of running and cycling using the protocol described previously (8). Briefly, subjects exercised 6 days/wk. On 3 days/wk, they ran as fast as possible for 40 min. On the remaining 3 days, they performed six bouts of exercise of 5-min duration each on a treadmill or cycle ergometer at a power output designed to elicit 9095% of VOzmax or peak VO,, respectively. Work intervals were interspersed by 2- to 4-min recovery periods consisting of running or cycling at 40-50% of VO, rlb8xor peak VO,, respectively. VO, maxand peak VO, were determined every 3 wk to maintain a constant training stimulus, which was achieved by increasing the running pace and power output on the treadmill and cycle ergometer, respectively. Statistical analysis. The differences between the data obtained before and after training were analyzed using paired Student’s t test. Two-way analysis of variance with repeated measures was also used where appropriate. Significant interactions were isolated using the Newman-Keuls post hoc comparisons. Data are expressed as means $- SE. l
RESULTS .
.
VO vo increased by 19% (from 2.7 + 0.2 to 3.20 i-yi diPlax in, P < 0.001) in response to endurance exercise training. When expressed relative to body weight, 00, maXimproved from 41.0 t 2 to 49.3 t 2 ml W-1min-’ (P < 0.001). Body weight did not change significantly (66 t 3 kg before and 65 t 3 kg after training). Effect of training on left ventricular systolic function. FS under basal conditions was virtually identical before and after endurance exercise training (36 t 1 vs, 36 t 2%; Fig. 1A). As expected, FS increased (P < 0.001) both before and after training during isoproterenol infusion. However, the increase in FS at higher doses of isoproterenol was significantly greater after than before training (P < 0.01; Fig. 1A). At the highest dose of isoproterenol (0.03 min-l), FS was 52 t 1% before and 56 + 1% after training, respectively (P < 0.05; Fig. 1A). At the lowest dose of isoproterenol(O.01 pg kg-l min-l), however, FS was not different between the untrained and trained states (Fig. 1A). Left ventricular u,, decreased significantly during isoproterenol infusion both before and after endurance exercise training (before training: l
l
kg
Pg
l
k-l
l
l
l
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (192.236.036.029) on August 26, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
LEFT
VENTRICULAR
CONTRACTILITY
AFTER
309
TRAINING
A0
0 1-J
i
12
* J
wi -20 F
\*
cc
\
1
zk
Q)
F
a
post
*
Pa.05
I
I
-8
-4
1
B
20 *
L
13
[
AESD
m
?I
(mm)
FIG. 3. A: changes in ESD-ge, relationship before and after exercise training. At a given change in q,,, decrease in ESD induced by isoproterenol was greater after than before exercise training. B: AEDD were not significantly different between untrained and trained states.
A IV EDD (mm)
60
I
Y-+
-L
-12
A
Post
p=ns
0 we
t
-40
I I t b 0.01 0.02 0.03 state ISOPROTERENOL (pg/kg/min) FIG. 1. A: left ventricular fractional shortening (LVFS) at baseline and in response to isoproterenol before (0) and after (a) exercise training. B: change in end-systolic dimension (AESD) from baseline induced by isoproterenol before (0) and after (a) exercise training.
m
t
8 a
*pa05
1
Pre
* p
SPINA, ROBERT J., TAKE~HI OGAWA, ANDREW R. COGGAN, JOHN 0. HOLLOSZY, AND ALI A. EHSANI. Exercise training improves left ventricular contractile response to ,&adrenergic agonist. J. Appl. Physiol. 72(l): 307-311, 1992.-To determine
l
l
(13 -+ 1 vs. 17t 2%, P K 0.01). Furthermore there wasa greater decreasein end-systolic dimensionat similar changesin oesin the trained state during isoproterenol infusion (-4.6 k 0.1 mm before vs. -7.0 -+ 0.1 mm after training, P < 0.01). There were no concurrent changesin end-diastolic dimensionbetweenthe trained and untrained states during isoproterenol infusion, suggestingno significant changesin preload at comparablelevels of oes.Under basalconditions, end-diastolic dimensionwas increased(46 ? 0.5 vs. 50 & 0.5 mm, P < 0.03) after training (P < O-03),with no significant change in left ventricular wall thickness-to-radius ratio after training, consistent with volume-overload hypertrophy. The results indicate that endurance exercisetraining enhancesthe left ventricular contractile responseto ,8-adrenergicstimulation without affecting basal contractility in young subjects. exercisetraining; /3-adrenergicstimulation; contractility
EXERCISE TRAINING increases maximal 0, uptake (VO, m,) in young healthy subjects by inducing adaptive increases in cardiac output and arteriovenous 0, content difference at maximal exercise (2,6,22). The augmentation in maximal cardiac output in the trained state is entirely the result of a larger stroke volume, because maximal heart rate does not increase in response to exercise training (6). Stroke volume at maximal exercise is regulated by a highly integrated mechanism that involves changes in contractility, cardiac loading conditions, or both (9,18). Therefore the training-induced in-
ENDURANCE
METHODS
Subjects. Seventeen healthy sedentary subjects, 10 women and 7 men [27 t 4 (SE) yr old], volunteered for this study. The experimental procedures were approved by the Human Studies Committee at Washington University School of Medicine, and subjects gave their written consent to participate. All subjects were asymptomatic, with no history of cardiovascular disease; they had a normal physical examination as well as resting and exercise electrocardiogram (ECG). None of the subjects had performed regular endurance exercise for at least 6 mo before participation in the study. Measurement of Vo2-. Vo2,, was determined during a continuous treadmill exercise protocol at a constant speed with the grade increasing by 2% every 2 min. Peak 0, uptake (TO,) during cycle ergometer exercise was also determined during a continuous exercise protocol in which power output was increased by 25-50 W every 2 min. VO 2 maxand peak ir0, were defined as the attainment of a plateau of VO, with increasing work rate and the respiratory exchange ratio >l.lO, 00, was measured by the standard technique of open-circuit spirometry, which incorporated a computer for calculation of Vo, every 30 s during exercise (3). Inspiratory volume was measured by a Parkinson-Cowan CD-4 dry gas meter. Fractional concentrations of expired 0, and CO, were measured from a mixing chamber by electronic 0, (Applied Electrochemis-
0161-7567/92 $2.00 Copyright 0 1992 the AmericanPhysiological Society
307
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (192.236.036.029) on August 26, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
308
LEFT
VENTRICULAR
CONTRACTILITY
try S3-A) and CO, (Beckman LB-2) analyzers, respectively. Left ventricular systolic performance. Left ventricular function was evaluated using two-dimensional guided Mmode echocardiography with a 2.5mHz transducer (Hewlett-Packard model 77020A). Recordings were obtained using the standard views according to the guidelines recommended by the American Society of Echocardiography (21). The images were recorded at a paper speed of 50 mm/s on a strip chart recorder and also stored on a magnetic tape. The transducer was placed l-3 cm parasternally in the desired intercostal space (3rd or 4th), which allowed optimal recording of the mitral valve. The transducer was then angulated laterally and inferiorly to obtain simultaneous visualization of both sides of the interventricular septum, the posterior wall endocardium, the posterior chordae, and portions of the anterior chordae. The end-diastolic dimension (EDD) was taken as the distance between the left ventricular endocardial surface of the septum and the posterior endocardium measured at the time of the onset of the QRS complex of the simultaneously recorded ECG. The endsystolic dimension (ESD) was measured as the distance between the posterior wall endocardium and the left side of the septum at the time of maximal inward movement of the posterior wall endocardium. The reproducibility of these measurements from our laboratory has been reported previously (5,12). Fractional shortening (FS) was calculated as FS = (EDD - ESD) lOO/EDD. Left ventricular a,, was calculated as described by Grossman et al. (7) : %3 = Prl2h (1 + h/2r), where P is systolic blood pressure expressed as g/cm2, r is end-systolic radius (ESD/2), and h is posterior wall thickness at end systole. Left ventricular contractile performance was assessed by changes in 1) FS as a function of alterations in left ventricular g,, and 2) the c,-ESD relationship. Because the ejection phase indexes of left ventricular function are influenced by changes in contractility as well as cardiac loading conditions and isoproterenol can reduce afterload in addition to increasing contractility (19), the effect of exercise training on FS was examined, taking into consideration the concurrent alterations in loading conditions. To control for the confounding effect of afterload, the changes in FS were compared at similar levels of ces. This was done by selecting those subjects (n = 14) in whom the differences in ACT,,(changes in Ok, from baseline induced by isoproterenol) between the untrained and trained states were - 10 g/cm’, irrespective of the dose of isoproterenol; two time points for each subject were selected: one before and one after training. Concurrent changes in EDD were also examined at these levels to evaluate the effect of preload on FS and the a,,-ESD relationship. Study design. Left ventricular size (EDD and wall thickness) and function were evaluated at baseline and during P-adrenergic stimulation induced by infusion of isoproterenol both before and after completion of the endurance exercise training. Subjects were studied in the supine position with an intravenous catheter inserted in an antecubital vein. Baseline recordings were obtained after the subjects had rested for 20 min in a quiet dimly lit laboratory. The
AFTER
TRAINING
position of the subject on the table, transducer placement, and time of day were kept the same for the pre- and posttraining experiments. Isoproterenol was infused at 0.01, 0.02, and 0.03 pg kg-l 4min-l with a Harvard syringe pump under continuous ECG monitoring. Each stage of infusion lasted for 10 min. Two-dimensional echocardiography recordings were obtained at minutes 4-5 of each stage of infusion. Heart rate and blood pressure, measured by sphygmomanometer, were recorded simultaneously with echocardiographic recordings. One male subject developed frequent premature ventricular depolarizations during infusion of isoproterenol, necessitating termination of the experiment. Therefore his data were excluded from the analysis. Data were analyzed in a blind fashion. Endurance exercise training program. After completion of initial tests, subjects participated in a f2-wk training program consisting of running and cycling using the protocol described previously (8). Briefly, subjects exercised 6 days/wk. On 3 days/wk, they ran as fast as possible for 40 min. On the remaining 3 days, they performed six bouts of exercise of 5-min duration each on a treadmill or cycle ergometer at a power output designed to elicit 9095% of VOzmax or peak VO,, respectively. Work intervals were interspersed by 2- to 4-min recovery periods consisting of running or cycling at 40-50% of VO, rlb8xor peak VO,, respectively. VO, maxand peak VO, were determined every 3 wk to maintain a constant training stimulus, which was achieved by increasing the running pace and power output on the treadmill and cycle ergometer, respectively. Statistical analysis. The differences between the data obtained before and after training were analyzed using paired Student’s t test. Two-way analysis of variance with repeated measures was also used where appropriate. Significant interactions were isolated using the Newman-Keuls post hoc comparisons. Data are expressed as means $- SE. l
RESULTS .
.
VO vo increased by 19% (from 2.7 + 0.2 to 3.20 i-yi diPlax in, P < 0.001) in response to endurance exercise training. When expressed relative to body weight, 00, maXimproved from 41.0 t 2 to 49.3 t 2 ml W-1min-’ (P < 0.001). Body weight did not change significantly (66 t 3 kg before and 65 t 3 kg after training). Effect of training on left ventricular systolic function. FS under basal conditions was virtually identical before and after endurance exercise training (36 t 1 vs, 36 t 2%; Fig. 1A). As expected, FS increased (P < 0.001) both before and after training during isoproterenol infusion. However, the increase in FS at higher doses of isoproterenol was significantly greater after than before training (P < 0.01; Fig. 1A). At the highest dose of isoproterenol (0.03 min-l), FS was 52 t 1% before and 56 + 1% after training, respectively (P < 0.05; Fig. 1A). At the lowest dose of isoproterenol(O.01 pg kg-l min-l), however, FS was not different between the untrained and trained states (Fig. 1A). Left ventricular u,, decreased significantly during isoproterenol infusion both before and after endurance exercise training (before training: l
l
kg
Pg
l
k-l
l
l
l
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (192.236.036.029) on August 26, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
LEFT
VENTRICULAR
CONTRACTILITY
AFTER
309
TRAINING
A0
0 1-J
i
12
* J
wi -20 F
\*
cc
\
1
zk
Q)
F
a
post
*
Pa.05
I
I
-8
-4
1
B
20 *
L
13
[
AESD
m
?I
(mm)
FIG. 3. A: changes in ESD-ge, relationship before and after exercise training. At a given change in q,,, decrease in ESD induced by isoproterenol was greater after than before exercise training. B: AEDD were not significantly different between untrained and trained states.
A IV EDD (mm)
60
I
Y-+
-L
-12
A
Post
p=ns
0 we
t
-40
I I t b 0.01 0.02 0.03 state ISOPROTERENOL (pg/kg/min) FIG. 1. A: left ventricular fractional shortening (LVFS) at baseline and in response to isoproterenol before (0) and after (a) exercise training. B: change in end-systolic dimension (AESD) from baseline induced by isoproterenol before (0) and after (a) exercise training.
m
t
8 a
*pa05
1
Pre
* p
