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(Circulation. 1995;92:2327-2332.)
© 1995 American Heart Association, Inc.
Articles |
Adrenergic Control of the Force-Frequency Relation
From the Division of Cardiology, Department of Medicine, University of California, San Diego.
Correspondence to John Ross, Jr, MD, Department of Medicine, 0613B, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0613.
 |
Abstract |
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Abstract This article briefly reviews recent experimental studies which show that ß-adrenergic receptor stimulation produces an important enhancement of the force-frequency relation on myocardial contractility. The basic property of the force-frequency effect to progressively enhance myocardial contractility as heart rate increases is augmented at each level of increasing adrenergic stimulation. This newly described intrinsic mechanism for the control of cardiac inotropic state, graded ß-adrenergic amplification of the force-frequency relation, is strongly manifested during normal exercise and infusion of a ß-adrenergic agonist at rest, and it influences both systolic and diastolic ventricular function. Significant impairment of adrenergic amplification of the force-frequency relation is observed in experimental heart failure and could contribute to impaired cardiac function during stress or exercise in this setting.
Key Words: heart rate • ventricles • heart failure • exercise
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Introduction |
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In addition to the interrelated effects on cardiac performance of preload, afterload, and myocardial contractility, heart rate has long been known to play an important role by enhancing cardiac output through an increased number of beats per minute when the venous return is increased, as during exercise, and by its action on basal myocardial contractility.1 The latter effect, often called the force-frequency or strength-interval relation (the Bowditch staircase2 ), is known to influence myocardial contractility (inotropic state) in isolated cardiac muscle3 4 and in anesthetized animals.5 6 Such an effect was considered minor in conscious animals,7 although significant enhancement of contractility during rapid atrial pacing in conscious dogs was later suggested on the basis of a sustained maximum first derivative (dP/dtmax) of LV pressure at increased heart rates, despite a fall in LVEDP.8 Thus, because LV dP/dtmax is sensitive to preload,9 10 a reduction in LVEDP alone would have been expected to reduce LV dP/dtmax.8 A positive inotropic effect of increased heart rate produced by pacing also has been demonstrated in healthy human subjects.11 12 More recently, progressive enhancement of the slope of the relation between LVESV and LVESP (an estimate of maximum elastance [Emax] as defined in the isolated heart13 ) was shown as heart rate was increased progressively by atrial pacing in conscious resting dogs,14 although the volume intercept of this relation was variable and often shifted.
Because the relation between LVEDV and LV dP/dtmax was previously shown to be positive and linear and to exhibit an upward shift with increased slope in response to ß-adrenergic stimulation,10 and because LV dP/dtmax (like dF/dt in isolated cardiac muscle15 ) provides a measure of the velocity of contraction and myocardial contractility, provided that the preload is considered, we have relied primarily on dP/dtmax in assessing force-frequency effects.
The force-frequency relation has been shown to be of major importance in the regulation of myocardial contractility in vivo on the basis of recent experiments in conscious animals both during exercise and at rest, as discussed later. These studies indicated that, in addition to the primary intrinsic control of ventricular contractility by neurohormonal ß-adrenergic stimulation, preload and length-dependent activation, and the heart rate under normal conditions, amplification of the force-frequency relation during ß-adrenergic receptor stimulation during stress or severe exercise provides a fourth primary mechanism influencing contractility. Moreover, loss of such adrenergic control of the force-frequency relation may be a significant factor in heart failure.
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Cardiac Responses During Normal Exercise |
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 TopAbstractIntroduction Cardiac Responses During Normal... Effect of Heart Rate...Adrenergic Control of Force...Heart Rate and Diastolic...Normal Physiological Control Force-Frequency Relations in...References |
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The remarkable ability of the normal heart to increase its performance during exercise has been attributed chiefly to a direct effect of increased ß-adrenergic stimulation on the myocardium to increase contractility. The influence of exercise on myocardial contractility was shown to shift the ESP-ESV relation upward and to increase end-systolic elastance in conscious dogs.16 This effect, together with decreased systemic vascular resistance, increased venous return, and augmented heart rate, can produce a fourfold to sixfold increase in cardiac output. As shown in conscious dogs,17 the increased myocardial inotropic state during strenuous exercise also permits the LV to relax more rapidly, to enhance stroke volume, and to lower the ESV, thereby producing early LV diastolic pressure that is below zero. As a result, diastolic filling is markedly enhanced during strenuous exercise, despite a decrease in the diastolic filling period by >60%.17 These events have been shown to be accompanied by an increase in the early-diastolic mitral valve pressure gradient18 and to prevent a significant increase in mean left atrial pressure during exercise.17 18
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Effect of Heart Rate on Cardiac Contractility and Performance During Exercise |
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As suggested above, the primary effects of exercise on myocardial contractility have been attributed to the increased direct effect of myocardial ß-adrenergic receptors to enhance myocardial contraction, but recent studies indicate that ß-adrenergic control of the force-frequency relation is at least as important.19
To study the effects of heart rate alone during exercise, a method was needed in which the normal sequence of AV contraction and normal electric activation of the ventricles could be preserved, obviating the effects of such measures as surgical induction of complete heart block with ventricular pacing or AV sequential pacing. Therefore, we took the approach of controlling the atrial rate by electric stimulation of the atrium after slowing the spontaneous rate with the specific sinus node inhibitor zatebradine (UL-FS 49).19 This agent has been shown to act primarily on the If pacemaker channel20 and to have no direct effect on myocardial contractility.21 22 Thus, contractility changes observed when heart rate is slowed with this agent are mediated only by the force-frequency effect operating in a negative manner.
Experiments were performed in conscious, instrumented dogs trained to
run on a treadmill in which high-fidelity LV pressure and LV
dP/dtmax were measured, together with LV chamber
dimensions and calculated ventricular volumes, by use of
implanted ultrasonic crystals. During strenuous exercise at a heart
rate of 240 bpm, UL-FS 49 was given to slow the exercise heart rate to
<150 bpm while the same level of exercise was continued, which
resulted in a reduction in LV dP/dtmax and an
increase in stroke volume. Heart rate was then immediately returned to
240 bpm by atrial pacing, and all measurements became identical to
those immediately before drug administration, indicating a lack of any
direct effect of UL-FS 49 on myocardial contractility.
With a pacemaker, it was then possible to lower the atrial rate
stepwise for brief periods sufficient to achieve a steady state. Heart
rate was reduced from 240 to 210, 180, and 150 bpm; it was returned to
240 bpm between each step while exercise at a constant level was
continued. A pronounced negative inotropic effect of slowing the heart
rate during exercise was evident, as reflected in a progressive fall in
LV dP/dtmax (Fig 1A
). This occurred
despite a progressive increase of LVEDP and LVEDV (Fig
1B),19 which alone would be expected to increase
LV
dP/dtmax.9 10 The ESP-ESV relation was
previously shown to be shifted upward and steepened during normal
exercise,16 and slowing the heart rate during exercise
caused the ESP-ESV points to be shifted downward, reflecting an altered
position of the ESP-ESV relation and indicating reduced myocardial
contractility (Fig 1C).19 These changes,
caused by the force-frequency effect, appeared to account for more
than one half of the positive inotropic effect of exercise, since
ß-adrenergic neurohumoral stimulation to the heart was not likely
to have changed during the brief periods of cardiac slowing during
steady state exercise.
|
|
Adrenergic Control of Force-Frequency Effects on LV dP/dtmax |
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The possibility that enhanced ß-adrenergic receptor stimulation caused the augmented positive inotropic effect of increased heart rate during exercise (studied in the above-described experiments by slowing the heart rate to produce a negative inotropic effect) was examined in conscious dogs through the study of force-frequency effects during graded infusions of the ß-adrenergic receptor agonist dobutamine under resting conditions.23 During infusions of low, medium, and high doses of dobutamine, heart rate was varied from 100 to 210 bpm by atrial pacing. A marked dose-dependent effect of dobutamine infusion to enhance the small effect of increasing heart rate on LV dP/dtmax under basal conditions was observed (Fig 2A
). During the
dobutamine infusions, despite the expected progressive fall
in LVEDP as heart rate was increased by pacing at rest, LV
dP/dtmax progressively increased as heart rate was
augmented; the increase was greater at high doses than at low doses of
dobutamine, and the range of LV filling pressures was
similar to that under resting conditions (Fig 2B). The time
constant of
LV relaxation (
) was decreased under basal conditions by an increase
in cardiac frequency, and this frequency effect on was further
magnified by ß-adrenergic stimulation in a dose-dependent
manner.23
|
The importance of a direct myocardial effect of ß-adrenergic receptor stimulation acting together with amplification of the force-frequency relation during exercise is illustrated by experiments with less severe exercise in conscious dogs before and after ß-adrenergic blockade. The resting LV dP/dtmax was reduced, and the early increase of LV dP/dtmax in response to exercise (before the development of regional ischemia in this animal model) was completely prevented by prior ß-adrenergic blockade,24 despite a modest increase in heart rate with exercise. These responses suggest that both direct myocardial ß-adrenergic stimulation and amplification by ß-adrenergic stimulation of the force-frequency effect on myocardial contraction were prevented by ß-blockade.
|
Heart Rate and Diastolic Filling During Exercise |
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The effects of normal exercise to increase the relaxation rate of the LV and to shift the early portion of the EDP-EDV relation downward (below zero) with strenuous exercise17 18 were found to be markedly impaired by a decrease in heart rate.25 During exercise, the influence of heart rate on diastolic function was assessed in conscious dogs in which isolated slowing of the heart rate to 160 bpm during exercise was produced by zatebradine and compared with effects at the spontaneous exercising heart rate of 210 bpm at the same exercise level before drug administration. Not only was the time constant of LV relaxation (
) prolonged at the slowed heart
rate, but an upward shift of the early portion of the LV
diastolic pressure-volume relation occurred (Fig 3); at the
same exercise level, the mean left atrial and
LVEDPs were higher, and the mean filling rate in the first half of
diastole was lower.25 Thus, an important part
of the striking improvement in LV diastolic function during
normal exercise relates to the positive inotropic and lusitropic
effects of amplification of the force-frequency response by
ß-adrenergic stimulation. From studies of exercise in dogs with
and without ß-adrenergic blockade, Cheng et al26
also concluded that both heart rate and sympathetic stimulation are
involved in the reduction of early LV diastolic filling
pressure and improved filling during normal exercise.
|
;
heart rate [HR], 160 bpm) and after pacing back to the predrug
exercise heart rate (
; heart rate, 210 bpm). The four points used
to calculate the curve are at mitral valve opening, minimum LV
pressure, end diastole, and the midpoint between minimal LV
pressure and end diastole. Relaxation was delayed and the
early portion of the curve was shifted upward at the slowed heart rate,
whereas the late portions appeared identical. Reproduced with
permission of the American Heart Association and the authors of
Reference 25. |
Normal Physiological Control |
|---|
These important effects on myocardial contractility and diastolic function of amplification of the force-frequency relation during exercise or ß-adrenergic agonist infusion allow an expanded view of the intrinsic factors responsible for normal physiological control of myocardial contractility. Thus, in addition to the effects of direct neurohumoral stimulation to augment contractility through myocardial ß-adrenergic receptors, length-dependent activation effects on the Ca2+ sensitivity of the myofilaments, and the force-frequency relation at rest, pronounced regulation of the force-frequency effect by altered neurohumoral ß-adrenergic stimulation can be added as a fourth important control mechanism (Fig 4
).
|
The mechanisms involved in the force-frequency effects on contractility when heart rate is increased under basal conditions are related primarily to increased Ca2+ availability to the myofilaments. This occurs as a result of enhanced transsarcolemmal Ca2+ influx caused by an increased number of action potentials, corresponding increases in the filling of the SR and augmentation of subsequent Ca2+ transients,27 and the reduced time available for diastolic Ca2+ efflux through the Na+-Ca2+ exchanger.28 A lag in the Na+,K+-ATPase pump leading to a decreased Na+ gradient also appears to contribute.28 Amplification of the force-frequency effect by exercise or ß-adrenergic receptor agonist infusion probably includes a further increase in [Ca2+]i availability owing to phosphorylation of L-type Ca2+ channels by cAMP-dependent protein kinase A, which leads to increased Ca2+ entry,29 and to phosphorylation of phospholamban which causes enhanced SR Ca2+ reuptake, loading, and release.30 The effect on phospholamban also enhances the myocardial relaxation rate. ß-Adrenergic stimulation also causes cAMP-dependent phosphorylation of troponin I with a decrease in myofilament Ca2+ sensitivity. The associated off-loading of Ca2+ from troponin I could contribute further to enhanced myocardial relaxation rate with ß-adrenergic stimulation.31
|
Force-Frequency Relations in Heart Failure |
|---|
Recent experimental studies indicated that ß-adrenergic amplification of the force-frequency effect on myocardial contractility is impaired in cardiac failure.32 Heart failure was produced in pigs by rapid ventricular pacing for several weeks, which lowered the echocardiographic fractional shortening from 39% to 17% and markedly reduced LV dP/dtmax compared with values before rapid pacing. The effects of dobutamine infusion on the force-frequency response, assessed by the relation between LV dP/dtmax and heart rate (atrial pacing over the range of 100 to 225 bpm), were examined before and after heart failure. The increase in LV dP/dtmax at increasing heart rates during ß-adrenergic stimulation observed in control studies before heart failure (Fig 5
, left) was lost in
the failing heart (Fig 5, right).32 Thus, in
addition to
the known reduction of the direct myocardial inotropic response to
ß-adrenergic stimulation in heart failure,33 another
significant effect of impaired ß-adrenergic function occurred:
loss of adrenergic control of the force-frequency relation. This
effect could impair both systolic and diastolic
ventricular responses to exercise in heart failure. In this
connection, Cheng et al,34 in a study of exercise in
dogs with pacing-induced heart failure, showed that exercise caused
delayed relaxation, an increase in early diastolic LV
pressure, and higher left atrial pressure, effects that could relate in
part to impaired adrenergic enhancement of the force-frequency
effect.
|
Isometrically contracting cardiac muscle taken from failing human
hearts at the time of cardiac transplantation often shows a descending
limb of the relation between increasing contraction frequency and peak
tension.35 Although we failed to find evidence for such a
descending limb in the intact pig based on measurements of contraction
velocity (LV dP/dtmax, Fig 5
),32
a descending limb has been observed in the normal rabbit heart at high
physiological frequencies (>400 bpm) and after
pacing-induced heart failure at lower frequencies (Fig
6).36 Such a descending limb could
contribute further to dysfunction of the failing heart during stress or
exercise. An important reduction of the force-frequency
amplification by dobutamine infusion also was observed in
the failing rabbit heart in this preliminary report, and the descending
limb at high cardiac frequencies in that species could be largely
prevented by dobutamine infusion (Fig 6).36
|
Mechanisms of impaired myocardial Ca2+ handling in
heart failure that may be important in abnormal force-frequency
responses are the subject of ongoing study.37
Abnormalities described in myocardium from patients with
end-stage heart failure include impaired
[Ca2+]i transients, indicating reduced
Ca2+ release from the SR and delayed
reuptake,38 a reduction in the number of sarcolemmal
calcium channels,39 and abnormal mRNA levels of
Ca2+ transport proteins, including the
Ca2+ release channel.40 There have been
reports of decreased SR Ca2+ ATPase mRNA
levels,41 although recent evidence suggests that SR
Ca2+ ATPase protein levels are normal in cardiac
muscle from failing human hearts.42 It is possible that
the descending limb of function of the force-frequency relation in
the rabbit, which was more pronounced in heart failure, is related to
impaired function of SR Ca2+ ATPase43
or to delayed mechanical restitution as a consequence of slow recovery
of the Ca2+ release channel.28 With
regard to the latter possibility, it has been shown that mechanical
restitution is slowed in failing rabbit and dog
hearts,44 45 and it is of interest that studies in
normal
isolated papillary muscles show enhancement of mechanical restitution
by ß-adrenergic stimulation46 ; these observations
may relate to the observed correction of the descending limb by
dobutamine infusion (Fig 6).
A number of steps in the ß-adrenergic stimulation pathway are abnormal in heart failure, including a reduced number of ß-adrenergic receptors and defects in G proteins,38 47 48 which may underlie the observed impairment of ß-adrenergic amplification of the force-frequency effect in heart failure. Better understanding of such mechanisms should lead to improved therapy for the multiple effects of reduced ß-adrenergic stimulation on the failing heart.
In summary, the basic manifestation of the myocardial
force-frequency relation to increase contractility
progressively with higher heart rates has been shown to be subject to
marked enhancement by ß-adrenergic stimulation during normal
exercise or during administration of a ß-adrenergic agonist. In
the clinical setting, reduction of this amplification effect probably
is important in the reduced cardiac response to exercise after
ß-adrenergic blockade and in heart failure when
ß-adrenergic mechanisms are impaired. Also, loss of amplification
of the force-frequency effect during exercise as a consequence of
chronotropic incompetence or heart block undoubtedly contributes to
impaired cardiac responses in these conditions, despite maintained
sympathetic stimulation. Correction of impaired heart rate responses by
rate-responsive pacemakers may help to explain their beneficial
effect on exercise performance. Thus, the fourth major
intrinsic factor regulating myocardial contractility
(Fig 4) appears to be highly important under normal conditions
and may
be of functional significance in a variety of disease states.
|
Selected Abbreviations and Acronyms |
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|
Received February 6, 1995; revision received April 26, 1995; accepted May 10, 1995.
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A. Ferro, C. Duilio, M. Santomauro, and A. Cuocolo Walk test at increased levels of heart rate in patients with dual-chamber pacemaker and with normal or depressed left ventricular function Eur. Heart J., December 1, 2003; 24(23): 2123 - 2132. [Abstract] [Full Text] [PDF]
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J. Layland and J. C Kentish Effects of {alpha}1- or {beta}-adrenoceptor stimulation on work-loop and isometric contractions of isolated rat cardiac trabeculae J. Physiol., April 1, 2000; 524(1): 205 - 219. [Abstract] [Full Text] [PDF]
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W. F. Bluhm, E. G. Kranias, W. H. Dillmann, and M. Meyer Phospholamban: a major determinant of the cardiac force-frequency relationship Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H249 - H255. [Abstract] [Full Text] [PDF]
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G. Hasenfuss, W. Schillinger, S. E. Lehnart, M. Preuss, B. Pieske, L. S. Maier, J. Prestle, K. Minami, and H. Just Relationship Between Na+-Ca2+–Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium Circulation, February 9, 1999; 99(5): 641 - 648. [Abstract] [Full Text] [PDF]
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