Directory UMM :Data Elmu:jurnal:A:Advances in Physiology Education:Vol277.Issue6.Dec1999:

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INTEGRATION OF MY OFILAMENT RESPONSE
TO CA2 1 WITH CARDIAC PUMP REGULATION
AND PUMP DY NAMICS
R. John Solaro

Depa rtm ent o f Physiology a nd Biophysics, College of Medicine,
University o f Illino is a t Chica go, Chica go, Illinois 60612-7342

I

n this paper I present some ideas related to teaching cardiac pump dynamics and
regulation to first-year medical students. I emphasize explicit presentation of the
relation between the activity of the contractile machine in the myocytes to pump

dynamics, pressure-volume relations, and cardiac output regulation, with matching
oxygen supply to tissue demands serving as a focal point. Important ideas here are 1 ) the

concept that regulation is at the cellular level of regulation; 2 ) that force and shortening
properties of the cells are ultimately dependent on the number of cross bridges reacting
with the thin filament and on the rate of cross-bridge cycling; 3 ) that the concepts of
preload, afterload, and contractility originated in studies of muscle mechanics; 4 ) that
there is a reserve of force-generating cross bridges, i.e., the myofilaments are not fully
activated by Ca2 1 in the basal state, and that force-generating cross bridges can
themselves activate the thin filament; and 5 ) that length dependence of myofilament
Ca2 1 activation is important in the cellular basis of Starling’s law of the heart. The
elaboration of these processes serves to elucidate how these mechanisms play a role in
coupling tissue oxygen demands to supply.
AM. J. PHYSIOL. 277 (ADV. PHYSIOL. EDUC. 22): S155–S163, 1999.

Key words: cardiac function; myocytes; cross bridges; calcium; pressure-volume relation

TISSUE OXYGEN DEMANDS AS A FOCAL POINT

equation, pressure gradient as a driving force, and
resistance or impedance as a determinant of flow
regulated significantly by the radius of the vessels),
compliance, and the Law of LaPlace. Hemodynamics
is reinforced in other lectures after the series of
lectures on cardiac pump dynamics and regulation
and also during lab and small group sessions.

I begin the lectures on cardiac pump regulation by
considering the heart in the context of the entire
circulation and cardiovascular tree, with a general
introduction to cardiac output and venous return and
mechanisms by which bulk flow may be regulated.
Although not detailed here, before they consider
pump function and regulation, I prefer that the
students have some understanding of hemodynamics
and an answer to the question, ‘‘What makes the
blood go around?’’ Thus, when considering what
follows, the students have an understanding of where
pressure comes from in the cardiovascular system,

general features of flow regulation (the bulk flow

By showing data on oxygen consumption and cardiac
output plotted as functions of increasing workload
during exercise on a stationary bicycle, I emphasize
the tight coupling between workload on the abscissa
and cardiac output and oxygen consumption on the
ordinates.

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I emphasize that homeostasis demands that there
must be tight coupling between the increases in tissue
demands for oxygen and the increases in cardiac
output. As an aside I mention that the homeostatic
mechanisms fall apart in syndromes such as heart
failure. This coupling requires that the mechanisms by
which cardiac output is varied must sense tissue
oxygen demands. I also indicate that inasmuch as
oxygen is a ‘‘flow-limited’’ substance in blood, with a
high extraction ratio, meeting the demands for oxygen automatically meets the demands for all other
substances in blood. I also mention that carbon
dioxide and heat are also flow limited but that we will
emphasize oxygen.
A central question guiding the lectures becomes,
‘‘How does the regulation of the cardiac pump play a
role in varying the oxygen supply to meet the variations in oxygen demands?’’ This is depicted schematically as follows with the double arrows used to infer
coupling
Exercise & Increased O2 demand

& Increased O2 supply & Increased cardiac output

The schematic not only serves to provide a point of
departure into the details of the molecular, cellular,
and integrated biology of cardiac myocytes but also
serves as the focal point of the lectures to which I
return as the information unfolds. I return to this
schematic at the end of the lecture series with a partial
answer that leads into the lectures on the vascular
system.

RELATIONS AMONG THE ACTIVITY OF THE
CONTRACTILE MACHINE OF THE CELLS AND
VENTRICULAR PRESSURE AND VOLUME
Armed with a general knowledge of hemodynamics as
described above, the students are presented a traditional introduction to the pump cycle in a partial
Wiggers-type diagram that includes the electrocardiogram, left atrial pressure, left ventricular pressure and
volume, and aortic pressure. Our students have already had the series of lectures on striated and smooth
muscle physiology and cardiac electrophysiology. They
are, therefore, well prepared to begin to understand
muscle physiology when the muscle cells are wrapped
around a bolus of blood. It is important to emphasize

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that all of the myocytes in each of the cardiac
chambers participate in contraction and that recruitment of cells is not a regulatory device in the heart.
This means that the control of cardiac function occurs
at the level of cells and that each cell must be able to
vary its activity. I take the students step by step
through a beat of the heart, going back and forth
between the overt changes in pressure and circumferential shortening. To make the transition from blood
flow to cardiac myocyte properties, it is important
that the students understand the relations between
ventricular volumes and cell length as well as ventricular pressure as ultimately determined by cell and wall
tension and the Law of LaPlace. Figure 1 illustrates this
concept using a cross section of the ventricular
chambers that relates the ventricular volume changes
during a beat of the heart in the context of the
calculation of cardiac output. The point is made that
the volume changes are a reflection of changes in
circumferential shortening, and the bottom of Fig. 1

provides an expanded view of the contractile machine
as it resides in one of the cells along the circumference.
I find it useful to use the diagrams in Figs. 1 and 2 to
introduce the concepts of preload, afterload, and
contractility. I refer to the volume of blood returning
to the ventricle during diastole as the loading volume
and explain that this volume is added to existing
end-systolic volume (ESV); i.e., the heart does not
empty with each beat and there is a reserve of volume
for ejection. The end-diastolic volume (EDV) is pictured as representing a load not yet sensed (and thus a
preload) by the ventricles that serves to establish the
length of the cells and sarcomeres. The afterload is
presented with the use of another drawing showing
the ventricular chamber ejecting into the aorta. Aortic
pressure is pictured as the load against which the cells
must develop tension to shorten and therefore eject
blood. A rationale for the term ‘‘afterload’’ is that this
load is ‘‘seen’’ only after the valve opens. With the use
of Figs. 1 and 2 and the equation CO 5 (HR)(EDV 2
ESV), where CO is cardiac output and HR is heart rate,

I indicate that CO is varied not only by regulation of
the HR (usually the first thing that will come into the
minds of the students) but also by increases and
decreases in EDV and ESV. The students already know
the disadvantages of elevating EDV to increase CO
because of their knowledge of the Law of LaPlace, but

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FIG. 1.

Schematic depicting various views of the end-diastolic and end-systolic
states at the level of or ganization of the left ventricle and the sar comer e.
Dashed lines indicate cells arrayed ar ound the cir cumfer ence of the left
ventricular chamber ( top ), also shown in cr oss section ( middle ). Pr eload
is depicted as the end-diastolic volume loading the ventricle befor e active
contraction. Afterload is depicted as the pr essur e opposing ejection and
as the for ce against which the cells in the ventricular chambers must
develop wall tension and contract after activation. Car diac output (CO) is
r elated to these ventricular volumes by the r elation CO 5 HR 3 (EDV 2
ESV), wher e EDV is the volume of blood in the ventricle at end diastole,
ESV is the volume at end systole, and HR is the heart rate. At an HR of 70
beats/ min in the ex ample shown, CO would be 4.2 l/ min.

schematically changes in a ‘‘giant sarcomere’’ with
associated series elastic element. How experiments
on a linear muscle account for the origin of the terms
of afterload and preload is presented by comparing
the pressure-volume changes during a beat with
experimental simulation using the giant sarcomere. At
this point the students should have some clear understanding of the cellular and indeed the molecular basis

of the heart beat. With the concept that the number of
force-generating cross bridges determines the tension
comes the question, ‘‘What regulates the number of
force-generating cross bridges?’’ The students have
been introduced to excitation-contraction coupling
cellular mechanisms of Ca2 1 homeostasis, so they
know that Ca2 1 binding to the thin filament of the
myofilaments activates the actin-cross bridge reaction.

this needs to be reinforced. Variations in ESV are
presented as having been changed by control of the
extent of shortening of the cells, i.e., their ability to
contract (‘‘contractibility,’’ or the more commonly
used term ‘‘contractility’’) at a constant afterload.

FORCE-GENERATING CROSS BRIDGES AND
THEIR CYCLE RATE AS THE ULTIMATE
DETERMINANT OF CARDIAC ACTIVITY AND
DYNAMICS, AND THE CONCEPT OF RESERVE
OF FORCE-GENERATING CROSS BRIDGES

I next introduce the students to the concept that the
ultimate determinant of the ability of cells to develop
tension (and therefore pressure in the ventricle) and
to shorten (and therefore eject blood) is the reaction
of myosin cross bridges with actin. Figure 2 shows

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FIG. 2.
Relations between ventricular states in the car diac cycle and the mechanics of isolated
muscle pr eparations. The cycle begins at left at an ESV and end-systolic sar comer e
length. In the linear muscle setup the analog of EDV is a weight, the pr eload, added
befor e activation. Addition of the pr eload establishes sar comer e length. The load the
sar comer e discovers it must lift is not ‘‘seen’’ until after activation and is the afterload,
which is supported on the platfor m. With activation, for ce-generating cr oss bridges r eact
with actin, developing tension isometrically until the tension developed matches the
afterload. At that point the sar comer e shortens with a velocity appr opriate to match the
number of r eacting cr oss bridges to the load. This sar comeric activity is r eflected in the
ventricle as an incr ease in wall tension, isovolumic pr essur e development followed by
opening of the aortic valve, and ejection of blood against the rising pr essur e in the aorta.
(One may wish to point out the differ ence between isotonic and aux otonic contraction at
this point).

I believe this must now be made clear and extended to
the case of cardiac muscle contraction/relaxation. I
find it worthwhile to present a cartoon of a region of
overlap, showing at least one structural unit of the
thin filament (7 actins:1 tropomyosin:1 troponin complex) as illustrated in Fig. 3. Figure 3 shows this
structural unit in a diastolic and systolic state (3). It
indicates that the actin-cross bridge reaction is turned
on not only by binding of Ca2 1 to troponin but also by
a cooperative ‘‘spread’’ of activation through contiguous tropomyosins (see legend to Fig. 3). The cooperative activation is clarified by stating that by cooperativity, we mean that the binding of one cross bridge

facilitates the binding of a near neighbor cross bridge.
This occurs by the cross bridge reaction itself ‘‘pushing’’ tropomyosin away from the binding sites on
actin. Figure 3 thus shows a force-generating cross
bridge that has been turned on without Ca2 1 bound to
troponin, whereas the near neighbor cross bridge is
reacting with actin with Ca2 1 bound to troponin. A
concept that is critical to the understanding of cardiac
pump regulation is that during basal, resting conditions, it is estimated that only 25% or so of the cross
bridges are engaged in force-generating interactions
with the thin filament during each beat. This means
that there is a reserve of cross bridges that can be

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FIG. 3.
Structural unit of the myofilament contractile machinery in
diastole and during systole. The cartoon shows myosin heads
pr otruding fr om the thick filament and one strand of actin
monomers with associated thin filament pr oteins, tr opomyosin
(Tm), and the tr oponin (Tn) complex . In diastole, Tm is fix ed in
its position on the thin filament by the Tn complex , which is
tether ed to Tm thr ough TnT and to actin via the COOH ter minus of
TnI, the inhibitory unit of the complex . The position of Tm is such
that myosin cr oss bridges ar e impeded fr om r eacting with actin.
The for ce-generating actin-myosin r eaction is trigger ed by Ca 2 1
binding to an NH2 -ter minal site on TnC, the Ca 2 1 r eceptor. The
Ca 2 1 binding signal is transmitted to Tm thr ough TnT, the Tm
binding unit of the Tn complex , and to TnI, which is r eleased fr om
its tether on actin by pr omotion of a tight interaction between the
COOH ter minus of TnI and the NH2 ter minus of TnC. Tm is now
fr ee to move on the filament, r emoving the steric hindrance of the
actin-cr oss bridge r eaction (cr oss bridge at left). As indicated by
the actin-cr oss bridge r eaction at r ight, str ong binding of a cr oss
bridge pr omotes the r eaction of a near neighbor cr oss bridge by
actively pushing Tm away fr om its blocking position. Movements
of one Tm ar e transmitted to a contiguous Tm by a str etch of
overlapping amino acids. Thus the cr oss bridge at r ight is shown
to r eact with actin without Ca 2 1 bound to Tn. With r emoval of
cytosolic Ca 2 1 by the sar coplasmic r eticulum, Ca 2 1 is r eleased
fr om TnC and these r eactions ar e r eversed.

called into use or recruited as the need arises, for
example, during exercise. It is important to note that
the rate of turnover in the cross-bridge cycle determines the rate of sliding of the filaments and, in the
case of the heart, the rate of change of volume and
pressure. The concept that cross-bridge cycle rate is a
variable should be discussed. (Mechanisms include

potential isoform switching of heavy- and light-chain
isoforms of myosin and/or protein phosphorylation
and variations in distance between the filaments, i.e.,
interfilament spacing.) This is mentioned to prepare
the students for the use of the first derivative of
pressure with respect to time (dP/dt) and flow velocity as measures of cardiac function.

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FIG. 4.
Pr essur e-volume (P-V) r elations of left ventricle at varying EDV generated
by infusion of blood or saline into the cir culation. P-V loops r epr esent data
obtained in human subjects in a r esting condition. End-systolic pr essur e
(ESP) data points ( r) r epr esent a state in which the ventricle is neither
lengthening nor shortening and developing the peak pr essur e (tension) at
that particular ventricular volume (sar comer e length). Thus points on the
volume-ESP r elation r eflect the length tension pr operties of the muscle
cells. The r elation between these points and a cir cumfer ential array of
ventricular cells and the length of the sar comer e ar e schematically shown
to illustrate that the P-V loop is rooted in a complex relation between
sarcomere length and ventricular geometry. See tex t for further discussion.

SARCOMERE LENGTH DEPENDENCE OF
MYOFILAMENT FORCE AND CA2 1 ACTIVATION,
AND THE PRESSURE-VOLUME RELATION OF
THE LEFT VENTRICLE

large vessels, thereby increasing venous return. The
task is to understand how the heart responds to
neural, chemical, and mechanical coupling.

To prepare the students for an introduction to the
pressure-volume (P-V) relation, I present the idea that
the heart generates the pressure gradient in the tubes
by displacing a volume of blood [stroke volume (SV)]
from the high-compliance veins to the low-compliance arteries. The task of the heart is to transfer this
volume faithfully and to match the volume transfer to
the tissue oxygen needs. To do this, heart muscle must
be signaled that tissue oxygen needs are changing.
Three important coupling devices may be indicated at
this point: 1 ) neural-humoral coupling through the
autonomic nervous system and release of epinephrine, 2 ) chemical coupling through the release of
vasoactive substances, and 3 ) mechanical coupling by
the physical action of muscle contraction to compress

Exercise serves as an excellent example to illustrate
these coupling devices. During exercise, CO increases
to meet the increased tissue oxygen demands. In
essence, the task of the heart is to transfer the volume
of blood received during diastole from the venous
return to the arteries. An important associated task of
the heart is make this transfer efficiently by operating
with little or no change in EDV. How the heart
accomplishes this can be presented to the students in
the context of the P-V relation and in the context of
the dynamics of the heart beat under control conditions and during exercise.
The P-V relation may be introduced, as many textbooks do, by showing the ventricular volume changes

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FIG. 6.
P-V r elation of left ventricle generated at varying EDV
as depicted in Fig. 4. ESP points ( r) ar e shown to be
associated with points on the Ca 2 1-tension r elation of
the myofilaments. The schematic illustrates that the
shape and position of the volume-ESP r elation ultimately depends on the length-tension r elation of the
myofilaments, which is itself deter mined by filament
overlap (r eflected in plateau of tension at the various
sar comer e lengths) and by the r esponse of the myofilaments to Ca 2 1. Note that at a given level of Ca 2 1,
tension falls as sar comer e length shortens as a r esult
of length Ca 2 1-dependent activation (see Fig. 4).

FIG. 5.
Steady-state r elation between Ca 2 1 concentration and
tension generation of myofilaments at long and short
sar comer e lengths (SL). Data wer e generated fr om
ex periments on membrane-fr ee myofilaments of ventricular muscle cells, mounted in a for ce-measuring
setup, and immersed in various solutions mimicking
intracellular conditions. As Ca 2 1 concentration was
incr ementally incr eased, Ca 2 1 bound to TnC, pr omoting tension generation by for ce-generating cr oss
bridges. Even though ther e is a single binding site on
TnC, the r elation is steep, as ex pected fr om cooperative activation of cr oss bridges as indicated in Fig. 3.
When TnC became saturated with Ca 2 1, tension generation came to a plateau. Plateau tension is r educed as
sar comer e length is r educed accor ding to the lengthtension r elation. The Ca 2 1-tension r elation is mor e
sensitive to Ca 2 1 at r elatively long sar comer e lengths
and less sensitive to Ca 2 1 at r elatively short sar comer e
lengths. As indicated by drawings at the long sar comer e length, the distance between the thick and thin
filaments (inter filament spacing) is r elatively short,
wher eas at the shorter sar comer e lengths, inter filament spacing is r elatively long. Curr ent theories indicate that decr eases in inter filament spacing, such as
that occurring with longer sar comer e lengths, eases
cr oss-bridge r eaction with the thin filament and thus
eases cooperative activation. Thus at a given Ca 2 1
concentration, mor e tension is generated as inter filament spacing is r educed. See tex t for further discussion.

mentioned that if pressure is permitted to develop
with no shortening or ejection, then isovolumic pressure points fall on the same line as those connecting
ESP points as a function of ESV. These points thus
provide a close approximation of the maximum pressure (wall and cell tension) that could be developed at
that particular volume (cell length). This then provides a functional correlate to the number of cross
bridges reacting at constant length and load, which, in
turn, is a correlate of contractility, i.e., the extent of
the cell’s ability to generate tension and shorten
against a constant load and constant initial length. The
slope and position of the ESP-V relation is thus an
important determinant of SV. What determines the
slope and position? To develop an answer to this
question, I use the steady-state relation between Ca2 1
and tension generated by the myofilament contractile
machine in a single cell in an experimental situation in
which the experimenter has control over the Ca2 1
supplied to the myofilaments. As illustrated in Fig. 5,
the Ca2 1-tension relation is not fixed but varies with

with pictures at various points in the loop (4). Figure 4
shows a series of P-V loops generated as described in
the legend. End-systolic pressure (ESP) points are
emphasized as points at which the muscle cells are
neither lengthening or shortening. It should also be

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FIG. 8.
Dynamics of LV volume changes at a r esting HR of 60
beats/ min and an HR of 120 beats/ min during ex ercise. Data illustrate changes in LV dynamics that occur
with ex er cise. At r est, the duration of systole is 0.37 s
and that of diastole is 0.63 s. During ex er cise, the
duration of systole is 0.26 s and that of diastole is 0.14
s. The abbr eviation of systole and diastole ar e a key
featur e of the ability of the heart to fill with blood and
eject blood at fast heart rates.

FIG. 7.
Incr eased contractility as r eflected in the Ca 2 1-for ce
r elation of the myofilaments and in the P-V loops.
Steady-state P-V loops ar e shown for one beat at r est
and for one beat during ex er cise. Top : the shift in the
P-V r elation occurs by an incr ease in amounts of Ca 2 1
r eleased to the myofilaments. Small changes in the
amounts of Ca 2 1 r eleased ar e amplified in the ESP-V
r elation because of the steep r elation between Ca 2 1
and myofilament for ce. Bottom : during ex er cise with
an incr ease in HR fr om 60 to 120 beats/ min and an
incr ease in venous r etur n, CO has incr eased substantially fr om about 4.5 to 12.0 l/ min with little change in
EDV. This occurs because of the incr ease in contractility. Refer to Fig. 8 for dynamics (see tex t for further
description).

sarcomere length. The mechanism for the shift in the
Ca2 1-tension relation is a change in interfilament
spacing, illustrated in Fig. 5 and discussed in the
legend. Ca2 1 concentration along the abscissa is meant
to reflect peak systolic free Ca2 1 concentration occurring during the beat. The connection of the steadystate Ca2 1-force relation and the ESP-V relation is
illustrated in Fig. 6. This illustration serves two purposes. It shows that hearts at rest operate at a
submaximal level of Ca2 1 activation and that the level
of Ca2 1 activation falls as sarcomeres become shorter.
Figure 7 illustrates how the ESP-V relation shifts with
an increase in Ca2 1 release to the myofilaments, as
reflected in an increase in peak systolic Ca2 1 concentration.

The P-V and ESP-V relations do not include dynamics.
It is important to indicate to the students the importance of changes in dynamics of the duration of systole
and diastole that occur with the increased HR associated with exercise. This is illustrated in Fig. 8. The
data in Fig. 8 show dynamics of left ventricular volume
over a series of beats at HR of 60 and 120 beats/min.
The data show that both the duration and systole and
diastole are reduced at the faster HR. The critical
importance of this in ensuring ventricular filling, i.e.,
accommodation of the venous return, should be
emphasized. The mental gymnastics of translating the
P-V relation to Starling curves (EDV-SV or EDV-CO
relation) may then be presented.

CONTROL OF CO IN EXERCISE: MECHANISM
OF REGULATION OF CONTRACTILITY,
PRELOAD, AND AFTERLOAD
The mechanism for the changes in levels of Ca2 1
activation and dynamics of the beat can be presented
in terms of a cellular model that is commonly presented in textbooks. Coupling of tissue oxygen needs
to pump function and dynamics via neural and humoral coupling mechanism involves the adrenergic
nervous system and circulating levels of epinephrine.

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The cellular mechanism is presented in terms of
common cellular models that include protein kinase
A-dependent phosphorylation of surface Ca2 1 channels and sarcoplasmic Ca2 1-release channels (ryanodine receptor) as well as phospholamban and troponin (1, 2).
A bout of exercise again serves as a convenient way to
integrate mechanisms at the molecular, cellular, and
organ level. I go through a calculation of CO in the
resting condition and then indicate what happens in
anticipation of a bout of exercise and during a
sustained period of moderate exercise. I compute the
CO as the exercise unfolds and show graphically how
the CO increases substantially with no or little change
in EDV, because of the increased contractility. Increases in venous return are presented as occurring
because of the ‘‘muscle pump’’ and effects of adrenergic stimulation on the vascular wall tension. The point
is made that the heart is exquisitely tuned to the
increases in HR and venous return to ensure a faithful
transfer of the loading volume with maintenance of
efficiency by optimal operation with little change in

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EDV. The points made in this example may be
revisited by considering what happens when a patient
in heart failure attempts the same bout of exercise.
Here, the chronic decrease in contractility as a result
of reduced release of Ca2 1 to the myofilaments as well
as blunting of adrenergic stimulation illustrates why
EDV increases and threatens homeostasis.
Address for reprint requests and other correspondence: R. John
Solaro, Dept. of Physiology and Biophysics (M/C 901), College of
Medicine, Univ. of Illinois at Chicago, 835 S. Wolcott Ave., Chicago,
IL 60612-7342 (E-mail: solarorj@uic.edu).

Refer ences
1. Bers, D. Excita tion-Contra ction Coupling a nd Ca rdia c Contra ctile Fo rce . New York: Kluwer Academic, 1991.
2. Solar o, R. J. Modulation of activation of cardiac myofilaments
by beta-adrenergic agonists. In: The Modula tion of Ca rdia c
Ca lcium Sensitivity, edited by D. A. P. Allen and J. L. Lee.
Oxford, UK: Oxford Univ. Press, 1993, p. 160–177.
3. Solar o, R. J., and H. M. Rarick. Troponin and tropomyosin:
proteins that switch on and tune in the activity of cardiac
myofilaments. Circ. Res. 83: 471–480, 1998.
4. Suga, H. Cardiac performance as viewed through the pressurevolume window. Circula tio n 88, Suppl. 4: I-C, 1993.

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