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Circulation Research
OCTOBER
1974
VOL. 35
NO. 4
An Official •Journal of the American Heart Association
Brief Reviews
Reconsideration of the Ultrastructural Basis of Cardiac
Length-Tension Relations
By Edmund H. Sonnenblick and C. Lynn Skelton
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• A fundamental property of vertebrate striated
muscle is the dependence of developed tension and
extent of shortening on initial muscle length. In
both cardiac and skeletal muscle, the tension
developed during an isometric contraction decreases as the length of the muscle is altered in
either direction from an optimal value. The importance of this phenomenon in the intact heart was
recognized more than 50 years ago by Frank (1) and
Starling (2) and became the basis for Starling's law
of the heart, which states that ventricular stroke
volume varies directly with changes in end-diastolic ventricular volume. Stroke volume can also be
increased by interventions such as catecholamines
which enhance contractility, or it can be decreased
when ventricular performance is depressed as it is
in congestive heart failure. The constant interplay
of the Frank-Starling mechanism (changing diastolic volume) and changing contractility determines the manner in which the heart varies its
output relative to its input on a beat-to-beat basis
and thus permits widely varying demands to be
met (3).
The mechanism whereby changes in initial
length alter tension development in striated muscle
has been largely defined by studies correlating
muscle ultrastructure with function (3-5). The
fundamental structural and functional unit of
contraction in both cardiac and skeletal muscle is
the sarcomere, the basic repeating unit in the
longitudinally oriented myofibril (6). Sarcomeres
have a distinctive detailed structure that is best
perceived with the electron microscope (Fig. 1).
Each sarcomere is delineated by a pair of Z lines.
The bandlike appearance of the sarcomere results
from the disposition of two sets of filaments which
are arranged in a partially overlapping, interFrom the Cardiovascular Research Laboratory, the Department of Medicine, Peter Bent Brigham Hospital and Harvard
Medical School, Boston, Massachusetts 02115.
Circulation Research. Vol. 35, October 1974
digitating array. The thick myosin filaments are
100-120 A in diameter and 1.65^t in length, and the
thin actin filaments are 50-70 A in diameter and
1.0^ in length. In the cross-banded pattern, the
length of the darker A band is determined by the
length of the myosin filaments and is constant.
Two sets of actin filaments, which are also constant
in length, are connected end to end at the Z line,
and their opposite ends interdigitate to a varying
degree with the myosin filaments in the A band.
The width of the lighter I band corresponds to that
portion of the actin filaments which does not
extend into the adjacent A band. Therefore, the
width of the I band varies with the length of the
sarcomere. The lighter central region of the A band
between the ends of the interdigitating sets of actin
filaments constitutes the H zone. In the center of
the H zone lies the pseudo H zone, a region of even
lower density that maintains a constant width of
0.15-0.20^. This light zone flanks a thin, dark strip
known as the M line which probably represents
fixed structural cross-connections between myosin
filaments.
Present evidence indicates that shortening and
force generation in striated muscle are related
to the interaction between cross-bridges on the
myosin filaments and sites on the actin filaments
(5-7). When the fiber is at rest, troponin located
periodically along each actin filament in association with tropomyosin inhibits cross-bridge interaction (8). However, when excitation of the fiber
occurs, calcium is released from the sarcoplasmic
reticulum and interacts with troponin, thereby
removing its inhibition of the interaction of actin
and myosin. During excitation in cardiac muscle,
calcium also enters the intracellular space from the
extracellular space and possibly from sarcolemmal
storage sites (9). In association with activation of
an actomyosin adenosinetriphosphatase, the myosin cross-bridges undergo a conformational change
517
518
SONNENBLICK. SKELTON
Z LINE
THIN
FILAMENT
THICK
FILAMENT
Z LINE
Cross
I.Oju
Thin Filament
c'"""""
1.0/J
'""•""»»)
3.6
Thick Filament I.6>J
IIIIIHIIlllll
Illlllillllllll
2.5
•2/1
Pseudo
H ZONE
2.2
'<*-H ZONE"
M : BAND-*
-A 8AND-
\ Optimum
| Overlap
BANDnl
FIGURE 1
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Schematic representation of the arrangement of filaments
within a sarcomere. The sarcomere is delimited by the Z lines.
The H zone, a region of uariable width determined by the
relative position of the thin filaments in the A band, should be
distinguished from the pseudo H zone, a region of fixed width
corresponding to the portion of the thick filaments devoid of
cross-bridges. The relative positions of the thick and thin
filaments in this illustration provide for an overall sarcomere
length of approximately 2.5^.
I I I I I I ( I I I 1
1 I I 1 I 1 I I I I
III!
2.0
1.8
1.6
which produces a directional force, and the actin
filaments are drawn inward toward the center of
the A band. By means of a repetitive making and
breaking of cross-links, force is generated and
muscle shortening occurs. Despite changes in sarcomere length, there is no perceptible change in the
length of either the actin or the myosin filaments;
this observation provides the basis for the sliding
filament theory of muscle contraction (5-7).
SKELETAL MUSCLE LENGTH-TENSION RELATIONS
According to the sliding filament theory of muscle contraction (5-7), the total force on any one
filament is the sum of the forces contributed by
each cross-bridge interaction with actin (crosslink), which in turn is proportional to the number
of cross-links formed and, therefore, to the width of
the overlap zone between actin and myosin filaments. In skeletal muscle, it has been well documented that changes in filament overlap (Fig. 2)
largely account for length dependent changes in
isometric tension development. Using tetanized
single fibers from frog muscle, Gordon et al. (10)
found that developed isometric tension remains
constant between sarcomere lengths of 2.00/* and
2.20/i (Fig. 3). Since there is a central zone
0.15-0.20^ wide in the myosin filament (the pseudo
H zone) which is devoid of cross-bridges, the
myofilament overlap and the number of force
generating sites remain optimal between sarcomere
lengths of 2.00M and 2.20M, accounting for the
constancy of developed tension. When sarcomere
length is increased progressively from 2.20/J, ten-
Double Overlap
FIGURE 2
Schematic representation of the relative positions of the thick
myosin filaments and the thin actin filaments in vertebrate
striated muscle at six selected sarcomere lengths ranging from
1.6)1 to 3.6(t. The area of overlap between actin filaments and
portions of the myosin filaments containing force-generating
cross-bridges remains constant between 2.0p and 2.2n and
decreases linearly at lengths beyond 2.2fi.
sion falls linearly to almost zero at 3.65/x where
overlap of myosin and actin filaments ceases (Fig.
3). This behavior is exactly that predicted by the
change in the number of cross-bridges on the
myosin filaments which are overlapped by actin
filaments (Fig. 2).
At shorter skeletal muscle lengths, the direct
relation between isometric tension development
and the number of myosin cross-bridges overlapped
by actin filaments no longer holds. When sarcomere length is decreased from 2.00^ to 1.65^,
there is a progressive decline in developed tension
without a change in the number of myosin crossbridges overlapped by actin filaments (Figs. 2 and
3). The explanation for this decline in active
tension is uncertain, but it may be related to a
passive resistance to force generation and shortening resulting from the meeting of actin filaments at
the center of the sarcomere and their subsequent
passage into the opposite half of the sarcomere (11,
12). In addition, if the actin filaments are able to
interact with active sites on the opposite half of the
myosin filament, an active resistance to contracCirculation Research. Vol. 35, October 1974
519
CARDIAC LENGTH-TENSION RELATIONS
I00
80
— Skeletol Muscle
60
z
o
20
UJ
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Hh—
1.2
SARCOMERE LENGTH (microns)
FIGURE 3
Relation between actively developed isometric tension and resting sarcomere length for frog skeletal
muscle fibers and cat right ventricular papillary muscles. The curve for skeletal muscle fibers is
derived from the data of Gordon et al. (10). In both tissues, peak developed tension is attained at a
sarcomere length of 2.2fi. At a sarcomere length of 2.0fi, tension development is substantially
decreased in cardiac muscle but remains maximal in skeletal muscle. At sarcomere lengths less than
2.0)1, developed force falls in both types of muscle, but it falls more precipitously in cardiac tissue. At
sarcomere lengths longer than 2.0^, cardiac muscle is resistant to further extension and its developed
force declines precipitously compared with the linear fall determined for skeletal muscle. In cardiac
muscle, this decrease in force cannot be entirely explained by sarcomere elongation and a decrease in
myofilament overlap.
tion could be produced by the generation of an
opposing force. Furthermore, it has been shown
that, when skeletal muscle fibers are shortened
below their slack length (sarcomere length
2.00-2.10^), forces are exerted during relaxation to
reextend the fibers toward their slack length (10,
13). It seems likely that such a restoring force
would oppose contraction at short muscle lengths
and thereby reduce the measured tension.
At skeletal muscle sarcomere lengths shorter
than 1.65jz, the slope of the decline in developed
tension increases markedly (Fig. 3), and tension
reaches zero at a sarcomere length of approximately 1.30^ (10). This corner in the skeletal
muscle length-tension relation occurs at a sarcomere length (1.65/i) corresponding to the point at
which myosin filaments collide with Z lines. Such a
collision should oppose force generation, and folding or crumpling of the myosin filaments with
further shortening should reduce the number of
cross-bridge sites available for tension generation.
Another factor which may further reduce tension
generation at these short muscle lengths has been
suggested by the work of Taylor and Rudel (14),
who ha%e found that electrically stimulated muscle
Circulation Research. Vol. -i5. October 197-4
fibers shortening below a sarcomere length of 1.6j/
develop a central waviness which they have attributed to inactivation of contraction. This phenomenon has not been observed in fibers shortening to a
similar degree in the presence of caffeine (15), a
drug believed to improve the effectiveness of membrane depolarization during activation. Furthermore, in skinned frog muscle fibers activated
directly by calcium, the decline in tension development at sarcomere lengths shorter than 1.7n is
significantly less than that observed in electrically
stimulated fibers (16). These findings suggest that
the deactivation observed when electrically stimulated fibers shorten to sarcomere lengths below 1.6^
results from an interruption of the inward spread of
the activating signal or perhaps from an uncoupling of the transverse tubular system and the
sarcoplasmic reticulum. The close similarity of
skeletal muscle sarcomere length-tension relations
for electrically stimulated, intact fibers and calcium-activated, skinned fibers at sarcomere
lengths of 1.7-3.6^ (10, 16) suggests that deactivation of contraction becomes an important determinant of force generation only at sarcomere lengths
shorter than 1.7fi.
520
SONNENBLICK. SKELTON
CARDIAC MUSCLE LENGTH-TENSION RELATIONS
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Attempts to define the ultrastructural basis of
the length-tension relation in cardiac muscle have
been hampered by the lack of a suitable in vitro
preparation comparable to the isolated single-fiber
preparations used in skeletal muscle studies. Most
of the information currently available concerning
cardiac sarcomere length-tension relations has
been obtained from studies using isolated papillary
muscles fixed for electron microscopic study at
various resting muscle lengths corresponding to
different points on the muscle length-tension
curve. Such studies have established a general
relation between muscle length, sarcomere length,
and developed tension similar in many respects to
that found in skeletal muscle (17-20). However,
certain critical differences between these two types
of striated muscle raise fundamental questions as
to the basis for the observed length-tension relation
in cardiac muscle.
In an attempt to resolve some of these differences, we recently reexamined the sarcomere
length-tension relation in isolated cat papillary
muscles using an improved isometric myograph
which allowed direct, continuous measurements of
length and force in muscles mounted between rigid
metal clips (21). Active and resting length-tension
curves were determined; each muscle was then
fixed in glutaraldehyde while it was resting at a
preselected length along either the ascending or the
descending portion of the length-active tension
diagram. Average sarcomere lengths at Lmax, the
muscle length at which active tension is maximal,
measured 2.18 ± 0.02M (SE) (range 2.12/1 to 2.26M).
This result is virtually identical to the values of
2.15/i to 2.25ji reported in previous studies (17, 19,
20). Sections along the entire length of muscles
fixed at Lmax showed little variation in sarcomere
length and no evidence of fiber buckling. The
ascending limb of the developed tension curve
extended from 707c to 100% of optimal length
(Lmax) (Fig. 4). However, resting tension was not
measurable until muscle lengths of 85% of Lmax
were reached. Thereafter resting tension increased
exponentially, accounting for 15% of the total
tension developed at Lmax (total tension = active
tension + resting tension). In this respect cardiac
muscle differs markedly from skeletal muscle in
which resting tension is negligible at the optimal
length for active tension development. Sarcomere
lengths in cardiac muscle were directly related to
resting muscle length at lengths greater than 85%
of Lmax. At muscle lengths between 70% and 85%
of Lmax, myofibrillar curling and buckling were
noted in association with a fairly constant sar-
100 -
RESTING
TENSION
SE Extension During
Isometric Contraction
RESTING
TENSION
MUSCLE-L/Lmox
2.2
2,0
SARCOMERE -p
LENGTH
FIGURE 4
Length-tension relations in the right ventricular papillary
muscle of the cat. A: Resting and actively developed tension
plotted as a function of resting or diastolic muscle and sarcomere length. Lmax is the resting length at which active
tension is maximal. B: Developed tension replotted as a function of the predicted end-systolic sarcomere length which would
result from stretching of the series elastic element during isometric contraction. The amount of series elastic (SE) extension is determined by the stress-strain characteristics of this
element at a given initial muscle length as previously measured
(45, 46). At the bottom of the diagram is a schematic representation of sarcomeres showing the degree of myofilament overlap at
three different sarcomere lengths. See text for a more detailed
discussion.
comere length of 1.75-1.85^. These results agree
with those previously reported by Grim et al. (20)
in rat papillary muscles and suggest the presence of
a restoring force in cardiac muscle similar to that
seen in skeletal muscle (22) which tends to reextend sarcomeres to a minimum rest length of about
85% of Lmax.
Another striking difference between skeletal and
cardiac muscle length-tension relations becomes
apparent when developed tension is compared in
the two tissues at sarcomere lengths between 2.00/i
and 2.20^ (Fig. 3). At these sarcomere lengths,
myofilament overlap is optimal and, because the
central 0.15-0.20^ region of the myosin filament is
devoid of cross-bridges, the number of active forcegenerating sites should be constant. As predicted
Circulation Research. Vol. 35. October 1974
CARDIAC LENGTH-TENSION RELATIONS
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by the sliding filament theory, there is a plateau of
maximal tension development between sarcomere
lengths of 2.00// and 2.20// in skeletal muscle (10,
16). However, no plateau of actively developed
tension is observed in cardiac muscle; instead,
active tension decreases rapidly at sarcomere
lengths both above and below 2.20// (Fig. 4). A 10%
reduction in sarcomere length from 2.20/1 to 2.00/1
results in a 30% decrease in developed tension (Fig.
4). At sarcomere lengths below 1.90//, developed
tension declines extremely rapidly, approaching
zero at 1.65-1.75//. At these short lengths, considerable buckling in the papillary muscles results in
wide variations in sarcomere length between adjacent sections of muscle. Thus, sarcomere lengthtension relations cannot be well defined in papillary muscles at resting lengths shorter than 80-85%
of Lmax.
Other discrepancies between cardiac and skeletal muscle are observed when length-tension relations beyond Lmax are examined. Resting cardiac
muscle is very stiff compared with skeletal muscle;
cardiac muscle resting tension rises exponentially
at lengths greater than 85% of Lmax. At Lmax,
resting tension is quite substantial and rises precipitously with further elongation of the muscle
(Fig. 4). In contrast, resting tension is negligible in
skeletal muscle until the muscle is stretched to
lengths 20% or more beyond Lmax. Once resting
tension appears, further lengthening of skeletal
muscle results in an exponential increase in resting
tension as it does in cardiac muscle. In skeletal
muscle, active tension decreases at lengths beyond
Lmax in accordance with the decreasing filament
overlap, as predicted by the sliding filament theory
(10, 16). However, a simple relation between tension development and filament overlap does not
hold for cardiac muscle at lengths beyond Lmax.
Sarcomeres in cardiac muscle resist overstretching.
An extension of papillary muscle to a length 20%
beyond Lmax results in an average sarcomere
length of only 2.35//, which is considerably less than
that expected based on a one-to-one relation between muscle and sarcomere length. The basis for
the discontinuity between sarcomere and muscle
length measurements beyond Lmax has not been
explained, but it may be related to internal fiber
rearrangements or slippage (18, 23). At papillary
muscle lengths 20% beyond Lmax, actively developed tension is decreased to 40% of that at Lmax,
while resting tension rises to an exceedingly high
level. Thus, unlike skeletal muscle, the fall in
actively developed tension in heart muscle
stretched beyond the optimal length for force
development is much greater than that expected
Circulation Research. Vol. :L5, October 1974
521
from a decrease in myofilament overlap alone and a
reduction in the number of force-generating crossbridges (Fig. 2).
Recent studies of sarcomere length-tension relations (24, 25) using live right ventricular papillary
muscles or trabeculae carneae from rats have
largely confirmed the findings obtained using tissue fixed for light or electron microscopy (17, 21,
23). When sarcomere length is measured directly
using the light microscope and laser techniques in
muscles at rest and during isometric contraction,
maximal active tension development is generally
observed at sarcomere lengths of 2.29-2.32//. These
values are almost identical to those found in
muscles fixed in glutaraldehyde after corrections
are made for the known 3-5% shrinkage that occurs
during fixation. Below Lmax, resting sarcomere
length decreases as a direct function of muscle
length down to approximately 2.00//. There is no
plateau of active tension development between
sarcomere lengths of 2.00// and 2.30//; tension
increases approximately 75% over this length
range. Isometric contractions initiated at sarcomere lengths from 2.30// to 2.00// result in considerable sarcomere shortening of approximately 10%
despite the fact that overall muscle length is
constant. This internal sarcomere shortening during isometric contraction cannot be entirely explained by stray compliances in the equipment and .
may be related to the large internal series elastic
compliance found in cardiac muscle. The possible
importance of internal sarcomere shortening during isometric contraction in determining the length
dependency of force development in heart muscle
has been pointed out previously (26-28) and will be
discussed in detail later in this review.
A different interpretation of the ultrastructural
basis for the cardiac length-tension relation has
been suggested by Gay and Johnson (29). Using
direct microscopic techniques, these investigators
studied the relation between muscle length and
sarcomere length in unstimulated strands of cardiac muscle obtained from right ventricular trabeculae carneae of rabbits. They found considerable
fiber buckling and a wide dispersion of sarcomere
lengths ranging from approximately 1.7// to 2.0// at
muscle lengths at which the strand was just taut.
Considerable further extension of the strand was
required (about 40-60% of its overall length) before
the fibers became straightened and aligned with
the long axis of the strand. At this length most of
the sarcomeres measured between 2.0// and 2.2//
and closely approximated the sarcomere length
previously observed at the apex of both the skeletal
and the cardiac muscle length-tension relation.
522
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With extension beyond the point at which all fibers
appeared straightened, the length of sarcomeres
did not increase uniformly. Generally, no predictable relation was found between the overall length
of the muscle strand and the length of sarcomeres
within it. Furthermore, no strand length was identified at which the majority of the sarcomeres did
not shorten during an isometric contraction induced by electrical stimulation. These authors
attributed length-dependent increases in cardiac
tension development not to a uniform increase in
contractile sites arranged in parallel but to a wide
dispersion of sarcomere lengths: more fibers
straighten as the muscle is stretched, thereby increasing the number of sarcomeres at a resting
length of 2.0-2.4^. However, because neither resting nor active tension was measured in these
preparations, it is impossible to correlate the sarcomere length measurements with known portions
of the length-tension curve. However, the extensive
curling of the fibers in their preparation suggests
that Gay and Johnson (29) were studying sarcomeres at muscle lengths at which restoring forces
become important and there is no direct relation
between muscle and sarcomere lengths, i.e., below
85% of Lmax in resting muscle (20, 21). Furthermore, the right ventricular trabeculae carneae used
in their study may not be representative of ventricular myocardium in general because of the presence of relatively large amounts of connective
tissue and variable numbers of noncontractile Purkinje fibers. Therefore, the true significance of
these findings remains to be determined.
More recently, preliminary reports from Dr.
Johnson's laboratory (30, 31) have appeared in
which the technique of light diffraction was used to
measure sarcomere spacing in frog atrial trabeculae
at rest and during isometric contraction. Unlike the
situation with ventricular muscle sarcomeres,
which are extremely resistant to overstretching,
sarcomere lengths up to 3.5j/ could be produced in
these atrial trabeculae by an appropriate stretch.
An anatomical basis for this marked difference
between atrial and ventricular myocardium in the
capacity to resist passive stretch has not been
defined. At such long sarcomere lengths, atrial
muscles could still generate significant amounts of
active tension. During isometric contractions, internal sarcomere shortening of up to 35Tr of resting
sarcomere length was uniformly observed despite
no change in overall muscle length. Although a
complete description of the sarcomere length-active tension curve was not given, the results suggest
that actively developed tension was more closely
related to the final sarcomere length reached after
SONNENBLICK. SKELTON
internal shortening than it was to the initial resting
sarcomere length. These results again suggest the
role of an internal elastic compliance in the determination of cardiac length-active tension relations.
Ultrastructural Basis for Cardiac Muscle
Length-Tension Relations.—In skeletal muscle,
the relation between muscle length and active
tension development can be reasonably well explained at lengths greater than Lmax by the degree
of myofilament overlap which in turn determines
the number of force-generating cross-bridge attachments (10, 16). Below Lmax other factors in
addition to myofilament overlap become important
determinants of measured force; these factors include internal resistive forces (11, 12), restoring
forces (13), and deactivation induced by shortening
(14). Although the basic mechanisms determining
cardiac length-tension relations are probably similar to those acting in skeletal muscle, certain
critical observations mentioned previously raise
important questions concerning the fundamental
nature of this process in cardiac muscle. (1) Resting
cardiac muscle is relatively stiff: tension rises
exponentially as the muscle is stretched over a
sarcomere length range for which resting tension is
minimal in skeletal muscle. At lengths beyond
Lmax, resting tension rises extremely rapidly; a
disparity develops between sarcomere length and
muscle length with muscle length increasing more
than sarcomere length. (2) The decline in active
tension development at cardiac muscle lengths
beyond Lmax is much greater than that expected
from a simple decrease in myofilament overlap. (3)
There is no plateau of constant tension development in cardiac muscle between sarcomere lengths
of 2.00^ to 2.20ji where myofilament overlap is
optimal. (4) During isometric contraction, there is
substantial internal sarcomere shortening in cardiac muscle which may be attributed to a large
internal compliance effectively in series with the
contractile components of the sarcomere.
Resting Elastic Properties.—The locale of the
increased resting stiffness in cardiac muscle has
been the subject of much speculation. In skeletal
muscle, resting tension has classically been attributed to the passive elastic characteristics of the
sarcolemma and other collagenous supporting tissues (22, 32). However, the sarcolemma does not
contribute appreciably to resting tension in skeletal muscle until sarcomere lengths greater than
3.2;/, are reached (22, 33); this length is considerably greater than that at which resting tension
becomes prominent in cardiac muscle. However,
because cardiac muscle fibers are considerably
smaller than skeletal muscle fibers, they have a
Circulation Research. Vol. 35, October 1974
CARDIAC LENGTH-TENSION RELATIONS
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relatively greater proportion of sarcolemmal material. Therefore, differences in the absolute amount
or in the elastic properties of cardiac sarcolemma
may contribute to the increased passive stiffness of
this tissue. Furthermore, despite contradictory reports (34), it seems likely that cardiac muscle
contains considerably more collagenous connective
tissue than does skeletal muscle. Gay and Johnson
found seven times more collagen in the ventricle
than they found in the psoas muscle of rabbits (29).
Thus, the resting elastic properties of cardiac
muscle may be largely due to the presence of
increased amounts of extracellular collagen in a
nonaligned matrix.
Another possible source of resting tension in
cardiac muscle has been suggested by Hill (35). He
found evidence that a certain number of myosin
cross-bridges remain attached to actin filaments in
resting skeletal muscle, thus accounting for a small
portion of the resting muscle tension. Recently,
Matsubara and Millman (36) have reported that
cross-links between myosin and actin filaments
may be present in resting papillary and trabecular
muscles from several mammalian species. The
presence of cross-links in resting cardiac muscle
has also been suggested by the finding that resting
tension can be altered upward or downward at the
same overall muscle length by various positive
inotropic interventions (37, 38). However, a possible explanation for this altered diastolic compliance other than residual actomyosin cross-links has
been provided (39) by the finding that a decrease in
resting tension related to paired pulse stimulation
is not present under isotonic conditions although it
is prominent under isometric conditions. The appearance of an apparent compliance change only
under isometric conditions may be attributed to
increased stress on viscoelastic elements of the
muscle resulting in stress relaxation. Furthermore,
Feigl (40) has shown that paired pulse stimulation
is on occasion associated with aftercontractions
which are slow in onset and can be easily confused
with altered diastolic compliance. Thus, the role of
residual cross-links in the determination of resting
length-tension relations in cardiac muscle remains
unresolved and awaits further critical experimentation.
Additional structures have been proposed to
explain the increased passive stiffness of cardiac
muscle, in particular the extremely steep increase
in resting tension at lengths beyond Lmax and the
inability to lengthen ventricular muscle sarcomeres
beyond 2.45-2.50// without their disruption. On the
basis of selective extraction studies performed in
rat papillary muscles, Grimm and VVhitehorn (41)
Circulation Research. Vol. .'15, October 197-4
523
have suggested that a large part of resting tension
in cardiac muscle is borne by intracellular structures that do not involve myosin but are critically
dependent on actin. A linkage between actin filaments across the H zone—the so-called S filaments
of Hanson and Huxley (42)—has been proposed to
account for these findings. Another alternative
explanation for the stiffness of resting cardiac
muscle is a connection between myosin filaments
and the Z line. Such so-called C filaments have
been tentatively identified in dipteran and bee
flight muscle (43). Finally, it is also possible that
cardiac muscle contains ultrathin filaments separate from myosin and actin which extend the
length of the sarcomere from Z line to Z line similar
to those described in certain crustacean muscles
(43). Although the existence of these filaments in
cardiac muscle is strictly conjectural at this time,
attempts to identify such structures should provide
a fruitful area for future research.
Elastic Properties during Contraction.—Since
there is no plateau of constant tension development
in cardiac muscle between sarcomere lengths of
2.00M and 2.20/i, we are left with the apparent
dilemma that active tension is length dependent in
a range of resting sarcomere lengths for which
myofilament overlap is optimal and the number of
available sites for cross-bridge linking is constant.
Furthermore, the decline in active tension at muscle lengths beyond Lmax is much greater than that
expected from a simple decrease in myofilament
overlap. From these considerations it is clear that
cardiac length-active tension relations cannot be
entirely explained by ultrastructural findings in
accordance with the sliding-filament theory for
muscle contraction. How then do muscle length
changes modulate active tension development in
cardiac muscle as required by Starling's law of the
heart? The answer may relate in part to the
properties of the series elastic element in heart
muscle (26-28).
According to the classic concepts of Hill (44),
active muscle can be represented by three functionally discrete elements: (1) an active contractile
element which generates force and shortening, (2) a
passive series elastic element which transmits the
force generated by the contractile element to the
exterior, and (3) a passive parallel elastic element
which supports resting tension. The exact structural arrangement of these elements has been the
subject of much speculation. Xo single configuration has been uniformly successful in accounting
for the mechanical properties of cardiac muscle.
The most commonly used models differ only in the
relation of the parallel elastic element to the other
524
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elements. In the Maxwell configuration, the parallel elastic element is in parallel with both the
contractile element and the series elastic element.
The Voigt model is similar except that the parallel
elastic element is in parallel with only the contractile element. In both models, the activated contractile element shortens and stretches the series elastic element during isometric contraction, and force
develops in accordance with the stress-strain properties of the series elastic element.
The compliance of the series elastic element is
substantially greater in cardiac muscle (5-8%) (45,
46) than it is in skeletal muscle (1-2%) (47). The
stiffness of the series elastic element in skeletal
muscle permits little change in sarcomere length
during isometric contraction. However, the 5-8%
extension of the series elastic element of heart
muscle during an isometric contraction allows
significant internal translation of myofilaments
within the sarcomere despite a constant overall
muscle length. Figure 4 illustrates the effect that
this internal sarcomere shortening has on the
measured length-active tension relation of cardiac
muscle. In Figure 4A, resting and actively developed tension are plotted versus resting or diastolic
sarcomere length; in Figure 4B, developed tension
is replotted as a function of the predicted systolic
sarcomere lengths which would result from stretching the series elastic element during isometric
contraction. The dots on the resting tension curve
show the resting sarcomere lengths for three muscle
lengths. The dots on the active tension curve define
the sarcomere length reached during the course of
isometric contraction, as predicted by the stressstrain characteristics of the series elastic element.
For example, a muscle with a resting sarcomere
length of 2.10^ would shorten internally during
isometric contraction to a sarcomere length of
approximately 1.95^ based on a series elastic
extension of 8%. In this instance, despite initiation
of contraction at a sarcomere length at which
developed tension should be maximal, the actual
tension developed is 30% below maximal (Fig. 4).
Thus, although resting sarcomere lengths in cardiac muscle may correspond to the plateau region
of optimal myofilament overlap, no plateau of
tension development is seen because the substantial shortening of sarcomeres which occurs during
isometric contraction places the sarcomeres at
shorter lengths that correspond to the ascending
portion of the length-active tension curve. At
systolic sarcomere lengths below 2.00/z, developed
tension may be reduced by factors similar to those
acting in skeletal muscle such as internal loads (11,
SONNENBLICK. SKELTON
12), restoring forces (10, 13), and length-dependent
inactivation of contraction (14, 15).
Considering the internal sarcomere shortening
that occurs during contraction in cardiac muscle, it
would be expected that a plateau region of maximal tension development would be present if
contractions were initiated at appropriate sarcomere lengths beyond 2.20/i. However, this phenomenon has not proved to be the case. Papillary
muscles stretched to lengths 5-10% beyond Lmax
show a rapid decline in actively developed tension,
accompanied by a steep rise in resting tension (Fig.
4). The reason for this rapid decline in active
tension is not known, but it may be related to the
properties of the stiff parallel elastic element of
cardiac muscle. If the parallel elastic element is
arranged in parallel with the contractile element
but not the series elastic element as in the Voigt
configuration, contractile element or sarcomere
shortening during isometric contraction at the
expense of the compliant series elastic element
should also result in shortening of the parallel
elastic element. This shortening would partially
discharge the tension supported by the parallel
elastic element and transfer some of its load to the
contractile element. Under these circumstances,
only a portion of the actual tension generated by
the contractile element would be expressed in the
muscle as actively developed tension and the
remainder would support resting tension. Thus, at
cardiac muscle lengths beyond Lmax at which
resting tension rises to exceedingly high levels, it
seems possible that a significant portion of the
tension generated by the contractile element may
be diverted into supporting the resting tension
discharged by the parallel elastic element as a
result of internal shortening. Such an effect could
contribute to the observed rapid decline in actively
developed tension at cardiac muscle lengths
beyond Lmax. However, this explanation does not
apply if the true structural model of cardiac muscle
more closely resembles the Maxwell model rather
than the Voigt model. In the Maxwell model, no
transfer of resting tension from the parallel elastic
element to the contractile element would occur
during isometric contraction because, in this instance, internal sarcomere shortening would have
no effect on the length of the parallel elastic
element.
An additional factor that may contribute to the
rapid decline in actively developed tension at
muscle lengths beyond Lmax is a change in membrane electrical properties induced by stretch
which possibly interferes with the process of excitaCircuktion Research. Vol. .35, October 1974
525
CARDIAC LENGTH-TENSION RELATIONS
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tion-contraction coupling. Furthermore, at papillary muscle lengths 20f7 beyond Lmax, actual
structural damage is manifested by occasional
disruption of sarcomeres and Z line obliteration
(23). Such structural changes undoubtedly contribute to the marked decline in active tension at
longer lengths, but the paucity of such changes
makes it unlikely that they constitute the primary
reason for the observed functional deterioration.
Conceptually, the contribution of a passive series
elastic element to the sarcomere length-active
tension relation in cardiac muscle is complicated
by the lack of knowledge concerning the precise
structural identity of such compliant elements.
The highly branched histological structure of this
tissue suggests one possible source (48). This
branching appears to result from the ability of a
single cardiac Z line to serve as a center for
attachment of two groups of thin actin filaments.
The longitudinal axes of the individual branch
chains of sarcomeres are necessarily at an angle
with respect to the long axis of the muscle as a
whole. Stress applied to the muscle, whether generated internally or externally, would result in a
change in the mean fiber branching angle which
would tend to lengthen the muscle. Since muscle
length is constant during isometric contraction,
internal sarcomere shortening would result. Such
changes in the angle of fiber branching with stress
could account for a significant portion of the
increased series elastic compliance seen in cardiac
muscle.
- Other possible sites for the series elastic compliance include the Z lines, intercalated discs, and
cross-bridge links between actin and myosin. Indeed, Huxley and Simmons (49) have suggested
that the series elastic properties of skeletal muscle
can be largely attributed to the force-generating
cross-bridges. Noble and Else (50) and Pollack et
al. (51) have recently reported that the compliance
of the series elastic element in cardiac muscle
varies with time after activation, suggesting that
cross-bridge elasticity may be important to the
series elastic compliance measured by quickrelease techniques. Their inability to define a
unique series elastic compliance with the properties of a passive nonlinear spring suggests that the
traditional Hill model for cardiac muscle may not
be useful for quantitative characterization of contractile element properties. These findings disagree
with earlier reports (45, 46) as well as with more
recent studies from our laboratory (52, 53) in which
the series elastic compliance of cardiac muscle
varied in a linear fashion with force and was
Circulation Research. Vol. .35. October 1974
independent of time. The reasons for the differences between these studies probably relates to
differences in experimental technique and to the
extrapolation procedure used to obtain data in the
studies by Noble and Else (50) and Pollack et al.
(51). Such extrapolations were avoided in our
laboratory (52, 53) by directly measuring muscle
force and length continuously throughout the release interval. Because of the exponential shape of
the stress-strain relation for cardiac muscle series
elasticity derived from real-time measurements, it
was not possible to exclude appreciable series
elastic compliance residing in attached myofilament cross-bridges. However, in assessing these
data concerning cardiac series elastic properties, it
should be remembered that activated cardiac muscle has an approximately three- to fourfold greater
series elastic compliance than does skeletal muscle
(45-47). Since the motion of a force-generating
cross-bridge is thought to be approximately 80-100
A or less than 1% of overall muscle length, it does
not seem possible that all or even a majority of the
measured series elastic compliance in cardiac muscle can reside in the cross-bridge links. Thus, we
believe that the traditional Hill model for cardiac
muscle should not be abandoned at the present
time.
Although speculations concerning the source of
the increased series elastic compliance in cardiac
muscle are very interesting, this problem needs to
be resolved by direct experimental methods. Refinements of the techniques currently being used
to measure sarcomere lengths in living cardiac
muscle (24, 25) may allow active tension development to be measured while the central sarcomeres
are maintained at a desired length with controlled
stretch. This approach should help to further define the true nature of the series elastic compliance
in cardiac muscle as well as its influence on cardiac
length-tension relations.
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Circulation Research, Vol. 35. October 197-4
Reconsideration of the Ultrastructural Basis of Cardiac Length-Tension Relations
EDMUND H. SONNENBLICK and C. LYNN SKELTON
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Circ Res. 1974;35:517-526
doi: 10.1161/01.RES.35.4.517
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