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Gxrdiovascular
Research
ELSEVIER
Cardiovascular
Research
32 ( 1996) 25-37
Invited review
Stretch-induced modifications of myocardial performance: from
ventricular function to cellular and molecular mechanisms
Bertrand Crozatier *
Unite’ INSERM
U400, Facultc5
Received
de Midecine,
8, rue du &&al
7 December
1995;
accepted29
Sarrail,
March
94010
Creteil,
France
1996
Abstract
The purpose of this review is to give an integrative view of the effect of stetch on the myocardium from ventricular function changes
to cellular and molecular mechanisms. The general approach will be to discussthe cellular and molecular events which can explain the
findings obtained in the whole ventricle. Following the historical development, the classicalanalysis of the Starling mechanism and the
basis of the length-dependent processare rapidly reviewed. We then analyze in greater detail the recent findings on the mechanisms of
length-dependent activation changes in contractile protein affinity for calcium, changes in intracellular calcium release, action potential
changes and stretch-activated ion channels and discussthe opposite effects of stretch on ventricular contraction (mainly deactivation
shortening and viscoelasticproperties of the myocardium). Besidesthe short-term contractile responseto stretch, the longer-term effects
of myocardial stretch which lead to ventricular hypertrophy will be also rapidly reviewed.
Keywords:
Stretch;
Myocardial
function;
Pressure;
Volume
area; Protein
kinase
1. Introduction
The effect of stretch in increasing ventricular performance was recognized more than 100 years ago [l]. This
effect is usually referred to as the ‘Franck-Starling law of
the heart’. Intense investigations have been performed over
the century to quantitate, at the ventricular level, the
impact of this phenomenon and to look for the underlying
cellular mechanisms.
In the classical concepts which were accepted until the
1970s the cellular basis of the Starling law of the heart
was based upon the sliding filament theory at the sarcomere level [21. In parallel, ventricular performance was
analyzed either as ventricular function curves [3] or in the
end-systolic pressure-volume curve which was considered
to be unique and independent of preload and afterload,
defining the contractile state of the left ventricle [4]. A
number of reports indicated, however, that this relation
was not as unique as the initial studies demonstrated and
that it was modified by a number of parameters, particu-
* Tel.:
(+33-l)
49 81 35 93; fax: (+33-l)
0008-6363/96/$15.00
0
PII SOOOS-6363(96)00090-9
1996 Elsevier
B.V.
All rights
reserved
1,4,5+riphosphate;
Proto-oncogenes;
Stretch-activated
channels
larly heart rate [51, ejection impedance [6] and velocity of
ejection [7], inducing a curvilinearity which was more
apparent for changes in contractility [S]. Some years before, the sliding filament theory had been challenged and a
number of experimental results showed that cardiac activation was length-dependent [9]. It appeared, therefore, that
the classical concepts of ‘preload’, ‘afterload’ and ‘contractility’ were closely dependent on each other and could
not be dissociated when myocardial performance and particularly the effects of myocardial stretch were to be
investigated [ 101.
Besides its action on ventricular performance, other
effects of stretch have been discovered. Stretch induces
reflexes from the heart (see [ll] for review), stimulates
natriuretic peptide secretion and release from atria1 cells
[12] and produces arrythmias (see [13] for review). These
phenomena will not be reviewed here. Instead, we will
discuss the cardiac mechanical events induced by stretching the myocardium. The general approach will be to
discuss the cellular and molecular events which can ex-
~_
Time
49 81 94 26.
Science
C; Inositol
for primary
review
28 days.
B. Crozatier
26
/ Cardiovascular
plain the findings obtained in the whole ventricle. Following the historical development, we will first rapidly review
the classical analysis of the Starling mechanism and the
basis of the length-dependent process. We will then analyze in greater detail the recent findings on the mechanisms of length-dependent activation and discuss the opposite effects of stretch on ventricular contraction (mainly
deactivation shortening and viscoelastic properties of the
myocardium). Besides the short-term contractile response
to stretch, we will also rapidly review the longer-term
effects of myocardial stretch which lead to ventricular
hypertrophy.
2. Classical interpretations
heart
2.1. Ventricular
of the Starling law of the
level
Frank published in 1895 the fundamental concepts of
what would be called the Starling or the Frank-Starling
law of the heart, that is the increase in ventricular performance induced by increased filling. At the time when
Starling was working on the heart-lung preparation, it was
well known that muscles contract more forcibly when
stretched. In his famous Linacre lecture [ 141, Starling
summarized his findings as follows: “Within physiological limits, the larger the volume of the heart, the
greater are the energy of its contraction and the amount of
chemical change at each contraction.” The impact of the
‘Starling’s law of the heart’ was such that many cardiologists spent, during the first half of the century, their time
and effort to verify its validity. In the whole heart, the
Starling law of the heart has been represented by three
types of relationship curves.
Sarnoff and his associates [15] popularized in the early
1960s the use among physiologists and clinical cardiologists of the ventricular function curves plotted as the
work-preload relationship which was the first representation of the Starling law of the heart. They described a
family of Starling curves instead of a single one to account
for the changes in contractility. This approach was revisited recently by Glower et al. [16] by the plot of stroke
work index versus end-diastolic volume.
The second representation of Starling’s curves interrelates the measured aortic flow to the blood return as
measured by the mean caval vein pressure or the mean
right atria1 pressure. This representation is associated with
the name of Guyton [17]. A derived analysis of cardiac
function was proposed by Ross [18]-the
afterload mismatch and preload reserve. In this framework, the ventricle
maintains its normal shortening by the use of its ‘preload
reserve’ (the Starling mechanism) in the face of an increased afterload. When the limit of the Starling reserve is
reached, the ventricle uses its contractile reserve or de-
Research
32 (1996125-37
adapts, which is indicated by a decreased systolic shortening.
The third representation of the Starling law of the heart
is the end-systolic pressure-volume relationship (ESPVR)
as originally described by Frank. Monroe and his coworkers 119,201 revived in the early 1960s the use of the
end-systolic pressure diagram to analyze cardiac function
as an anolog representation in the whole heart of the
tension-length curve of isolated muscles (see below). Using excised dog heart perfused with a support dog blood,
they showed that the end-systolic pressure-volume data
points approximated to a linear relationship, the slope of
which increases with an increase in inotropic state. In the
late 1960s Suga 121-231 began his serial studies in the
canine heart in Japan and later at Johns Hopkins [24,2.5] in
isolated blood perfused hearts. These studies showed that
the ESPVR was highly linear and independent of preload
and afterload. Its slope, called E,,,. was shown to depend
only on contractility. Further studies lead to the definition
of the time-varying elastance (EC t)) of the ventricle as:
E(itl = P(t)/[(V(t)
- V,] where P(t) is the instantaneous
time, V(t) is the instantaneous volume and V,, the volume
axis intercept of E,,, This analysis of ventricular contraction as a time-varying elastance implied that end-systolic
volume was the only determinant of end-systolic pressure.
This was the basis of the ESPVR which was obtained at
the maximal value of E(t) [25].
2.2. Muscle
and cellular
level
The underlying mechanism at the muscle and cellular
level was under intense investigation at the same time.
Studies performed on isolated papillary muscles by Sonnenblick and his group [26-281 analyzed in detail the
interrelations between force, length and velocity of shortening. The force-length diagram obtained with different
preloads and for different types of contractions (isometric
or isotonic) described a unique relation, independent of
loading and shortening conditions. Further studies by Brutsaert and his colleagues [29,30] used load-clamp techniques to demonstrate a force-velocity-length
relation of
contraction defining a three-dimentional surface which was
independent of time during most part of muscle shortening
and was independent of the initial length of the muscle.
At the structural level, the key assumption was that the
sliding filament theory, brillantly presented by A.F. Huxley’s laboratory in skeletal muscles [31,32], was applicable
to the heart. The basis of the theory was that tension in the
length-tension relation of isolated muscle fibres was generated by cross-bridges which form in the region of overlap between thick and thin filaments, the amount of overlap determining the number of potential tension-producing
sites of interaction between these filaments. This had a
strong experimental basis in skeletal muscles in which
studies used X-ray diffraction. In cardiac muscles, sarcomere lengths were initially measured in vitro after formal-
B. Crozatier/
Research
Cardiovascular
3.1. End-systolic pressure-volume
of the
relation
The analysis of ventricular function based on ESPVR
remained popular for a long time among cardiologists
since there had been a long search for an index of ‘contractility’ independent of preload and afterload and this
appeared to be a good one on a sound experimental basis.
The similarity between force-velocity-length
relations obtained in isolated sevo-controlled dog hearts [38,39] and
those obtained in papillary muscles [28] appeared as striking, particularly that of the length-tension relation which
was the basis of ESPVR. A number of means of analysis
of ventricular function were derived from the time-varying
elastance model, the principal being the peak dP/dt vs.
end-diastolic volume relation [40] and the oxygen consumption vs. pressure-volume area relation [41].
It appeared, however, that ESPVR was not as linear as
had been described initially and it was not unique, being
modified by other factors such as heart rate [51 or
impedance changes [6] (which will not be reviewed here)
and also contractility-induced modifications [8], instantaneous flow velocity [42.43] or velocity of ejection [7] and
preload-induced modifications [44].
The first description of a curvilinearity of the end-systolic pressure-volume relation was published by Burkoff
0
20
50
VOLUME
Fig. 1. Lefr panel: Pressure-volume
loop obtained at the
larger than end-systolic
volume of the ejecting beat. Note
loops at a given end-diastolic
volume and different beats
connecting
the isovolumic
points. Data were obtained in
(ml)
21
25-37
et al. [8]. For a basal control state in which the relation
appeared as fairly linear, contractility was either increased
by infusion of dobutamine or BAY K 8644 or decreased
by lowering coronary perfusion pressure or nifedipine
injection. The increase in contractility induced the expected increase in E,,, without changes in V,, but produced a curvilinearity of the relation concave towards the
x-axis while both means of decrease in contractility induced a curvilinearity of the relation in the opposite direction.
A positive effect of initial muscle length on end-systolic
pressure was demonstrated by Hunter [45]. When isolated
blood-perfused canine hearts were loaded with a simulated
arterial system, ejecting end-systolic pressure exceeded
isovolumic pressure by about 10 mmHg when ejection
fraction was small (Fig. 1). This phenomenon was attributed to the length-dependent activation which had been
described some years before [46].
dehyde fixation of isolated muscles [33] or whole ventricles [34-361 at different end-diastolic lengths or pressures;
the basis of the ascending limb of the Starling relation was
defined, in the whole ventricle, by a lengthening of sarcomeres of all ventricular layers until a pressure of 12
mmHg was reached, after which recruitment and lengthening of shorter sarcomeres occurred, particularly in the
subendocardial and subepicardial layers, until a maximal
length of about 2.2 pm was reached, corresponding to the
limit of the Starling reserve [37].
3. Limitations of the classical interpretations
Starling law of the heart
32 (1996)
3.2. Length-dependent activation
It appeared in the mid 1970s that the classical interpretation of the Starling law of the heart had to be revisited at
the cellular level. Instead of the sliding filament theory, the
concept of length-dependent activation which had been
described for the first time by Parmley and Chuck [47] in
1973 was developed and Allen et al. [48] showed that the
length-tension curve varied with contractility.
Pollack’s group [49] and Julian’s group [50,51] on
papillary muscles and Fabiato on skinned fibers showed
that changes in activation rather than sarcomere length
were the major determinants of the changes in force after a
change in end-diastolic length (see Jewell, [53], for a
review of these works). Further investigations later confirmed and made more precise this interpretation [54].
The time course of length-dependent activation was
initially described by Parmley and Chuck ([47], Fig. 2).
When a muscle was stretched, developed tension did not
reach its final steady state before several minutes and this
slow increase in developed tension contributed signifi-
0
20
30
VOLUME
40
(ml)
end of a series of ejecting beats followed by an isovolumic
beat with a ventricular
volume slightly
the smaller end-ejection
pressure of the beat. Right panel: Superimposition
of different ejecting
with different isovolumic
volumes. End-systolic
pressure of ejecting beats appears above the line
isolated servocontrolled
dog hearts and are reproduced
from Ref. [45].
B. Cmzatier/
28
Cardimascular
Research
32 (1X6125-37
techniques [57]. Immediately after the stretch, when force
was already increased, the amplitude of aequorin light (a
function of intracellular free calcium concentration) was
unchanged and its duration was shortened, but its amplitude increased slowly in the following minutes when force
was increasing [571.
4. Cellular mechanisms of length-dependent
activation
Although much new information is now avalaible concerning the influence of stretch on myocardial performance, there are still controversies or uncertainties. One of
the difficulties is the gap between results obtained in
stretched cells and more intact preparations. The changes
induced by stretch are summarized in Fig. 3 which shows
the accepted modifications induced by stretch and those
which are more controversial or uncertain.
Fig. 2. First demonstration
of length-dependent
activation
in isometrically
contacting
papillary muscles. The upper panel shows the abrupt decrease
in active force after an abrupt decrease in preload (A) which is followed
by a progressive
decrease in force (B). After an abrupt increase in preload
(C), active force immediately
increases. This is followed by a progressive
increase in force (D). The lower panel shows the corresponding
tracings
as a force vs. time tracing. Reproduced
from Ref. [47].
cantly to the steepness of the steady-state length-tension
relation. Similar time-dependent changes in left ventricular
pressure have been shown after changes in diastolic volume in intact canine hearts [55,56]. The time course of
increase in force following a muscle stretch was compared
to that of the calcium transient measured by luminescent
4.1. Changes of contractile protein afJinity for calcium
There is now considerable evidence for a change in
affinity of cardiac troponin C for calcium induced by
mechanical events (see [58] and [59] for review). This was
suggested by the transient increase in aequorin light after a
quick release in length [57] and by the higher calcium
concentration during active shortening of papillary muscles
than during isometric twiches 1601. However, the interpretation of these results was complicated by the presence of
normal membranes in these intact muscles with a possible
increase in calcium entry through the sarcolemma and
increased calcium release by the sarcoplasmic reticulum.
In more recent studies, Allen and Kentish [61] performed
STRETCH
I
I
i, ’ L
,
.AGL-
I
\ Inactive PKC
Active PKC
\ _ _ _ _ _ _ _ _ Phos ,,o ,a&
Myosin
light chain
-----
Fig. 3. Schematic representation
of the effects
discussed mechanisms.
SAC = stretch-activated
= ryanodine
receptor;
PL = phospholamban;
of stretch of a cardiomyocyte.
Solid lines represent accepted mechanisms
ion channels; PLC = phospholipase
C; IP3 = inositol trisphosphate;
PKC = protein kinase C; DAG
= diacylglycerol.
and dashed lines hypothesized
PIP, = phosphatidyl-inositol;
or
RR
B. Croxrtier/
Curdiotzscultrr
experiments similar to their earlier studies [57] but on
skinned cardiac muscles in which all membranes had been
removed and troponin C was directly accessible to calcium. They showed [61] that the change in affinity of
troponin C for calcium was more closely correlated with
the increase in tension than with the increase in length.
The problem of whether changes in load or stretch are the
determinant of the change in contractile protein affinity is
however still a subject of controversy since it is difficult to
separate these phenomena, one producing the other.
An oscillatory response of aequorin light to step length
changes in phase with the tension responses has been
recently found in papillary muscles, suggesting that changes
in aequorin light were the result and not the cause of
changes in tension, probably through an increase in affinity
for calcium of troponin C [62]. With further treatment of
ryanodine-treated muscles with 2,3-butanedione monoxime
(BDM, a selective inhibitor of cross-bridge cycling) tetanic
tension decreased markedly with an unchanged level of
aequorin light which was also unaffected by length changes
[62]. This suggested that Ca*+ affinity of cardiac troponin
C was increased with an increased tension (i.e., cross-bridge
attachment).
The molecular basis of the change in contractile protein
affinity for calcium was elegantly demonstrated by Babu et
al. [63]. The length-induced shift of the relation between
pCa and force is known to be significantly less in skeletal
muscles than in cardiac muscles [64]. By substituting the
cardiac form of troponin C with the skeletal protein, Babu
et al. [63] showed that enhancement of myocardial performance at stretched length was greatly suppressed with
skeletal troponin C as compared with cardiac troponin C.
However, these findings could not be replicated in a series
of experiments by Moss’s group [65]. Recently, McDonald
et al. [66] showed that osmotic compression of single
myocytes eliminates the reduction in Ca’+ sensitivity to
tension at short sarcomere lengths, supporting the idea that
the length dependence of Ca’+ sensitivity of tension in
cardiac muscles arises in large part from the changes in
filament lettice spacing that accompanies changes in sarcomere length.
4.2. Chunges in intracellular
calcium release
Ryanodine treatment allows the analysis of muscle behavior in the absence of functional sarcoplasmic reticulum
which is the major source of activator calcium in mammals
[67]. In their pioneering studies, Fabiato and Fabiato [52]
showed that contractions caused by calcium-induced calcium release (CICR) from the sarcoplasmic reticulum of
skinned fibers exhibited a steep dependence on length. The
decline in the strength of contraction with decreasing
stretch was markedly reduced when caffeine was added to
the preparations, leading to a sarcomere-length tension
relation similar to that obtained with maximally activated
fibers, suggesting that calcium loading of the sarcoplasmic
Reseurch
32 (19961 25-37
29
reticulum (the source of calcium during both calcium- and
caffeine-induced contractions) is not affected by initial
muscle length while CICR is.
In spite of major recent advances in our knowledge of
the molecular structure of calcium ATPase, ryanodine
receptors, and the calcium release channels, little new
information concerning the effect of stretch on sarcoplasmic reticulum function is avalaible. Fabiato [68] presented data which contradict in part his previous results
since no evidence of length dependence of sarcoplasmic
calcium release was observed with aequorin in mechanically skinned Purkinje fibers. Using rapid cooling contractures of rat ventricular muscles, Gamble et al. [69] recently
concluded from their experiments that the same percentage
of calcium is released from the sarcoplasmic reticulum
with short and long lengths and that its loading capacity
increases with shorter diastolic lengths. In the paper by
Saeki et al. [62] which showed change in sensitivity of
troponin with length, a length-dependent increase in CICR
was suggested. In ouabain-activated muscles (with normal
sarcoplasmic reticulum function), the mean level of aequorin light was lower than that present just prior to a step
release, in contrast to ryanodine-treated preparations 1621.
Although the role of inositol phosphates as second
messengers in the heart has been excluded or has been
considered as minimal [70], inositol triphosphate (IPj> has
been shown to enhance calcium release in skinned fibres
[71]. Using whole heart preparations, von Harsdorff et al.
[72]. described an increase in inositol 1,4,5-trisphosphate
after 1 min of atria1 distension which was much larger
after 10 and 20 min of stretch. We recently showed [73] a
more rapid production of IP, in neonatal rat cardiomyocytes in culture with a peak increase as early as 10 s after
stretch which progressively decreased and returned to control over a 2 min period. Similarly. in another study,
Komuro et al. [74] did not detect any increase in IP,
production in cardiac myocytes in culture subjected to
stretch of a duration of l-5 min. However, similar to our
study, inositol monophosphate, a metabolite of IP,, was
increased, suggesting previous stimulation of IP, production. In addition, in our study [73], inositol tetrakisphosphate, which activates calcium-dependent potassium channels in synergism with IP, [75]. prolongs the duration of
inositol-trisphosphate- mediated calcium transient [75] and
may control the transfer of calcium between cellular pools
[76], increased progressively during a 2 min period of
stretch [73]. This slow increase resembles the progressive
increase in force induced by stretch following an abrupt
increase. The role of inositol tetrakisphosphate may therefore probably be as a potential mechanism of this increase,
but it is still hypothetical and other mechanisms probably
play a role. For example, Kentish et al. [77] showed a
reversal by isoprenaline of the slow response to a length
change, suggesting a role of CAMP in this response.
Another potential and likely mediator is an increase in
protein kinase C (PKC) activity since both inositol phos-
30
B. Crozafier/
CardioLlascular
phate production and PKC activity are increased by phospholipase C activation [78].
4.3. Protein kinase C
Changes in PKC might have some role in the secondary
slow increase in force induced by stretch. Its time sequence closely resembles that of PKC activation induced
by o-adrenergic stimulation [78]. Although its role in the
increase in force induced by a-adrenergic stimulation has
been excluded in one study [79], PKC may modify Ca”
transcient and cardiac contractility through phosphorylations of contractile proteins [80] and phospholamban of
sarcopasmic reticulum [81], through an increase in myosin
light-chain kinase effects on force development and ATPase activity in skinned cardiac cells [82]. Most of these
effects are however discussed and results are conflicting
depending in part on the type of preparation used. The role
of PKC in the induction of cardiac genes induced by
stretch has been intensively studied (see below, longer-term
effects of stretch), but an early stretch-induced translocation of this enzyme from the cytosolic to the particulate
fraction has not been shown yet in the heart.
Recent results of studies looking for the mechanisms of
preconditioning to ischemia are consistent with involvement of PKC in stretch. Brief episodes of myocardial
ischemia trigger an adaptative response that protects the
heart against injury from a subsequent prolonged period of
ischemia and reperfusion. This phenomenon, called ‘preconditioning’ [83], has been attributed to different mechanisms, particularly ATP-dependent potassium channels
1841, adenosine 1851 and cx-adrenergic stimulation [86].
Myocardial stretch was also recently shown to mimic the
effect of brief episodes of ischemia [87] and two recent
studies clearly demonstrated the mediation of PKC in the
preconditioning mechanism [88,89]. It can be supposed
that PKC activation is the common link between different
means of producing preconditioning. However, its activation by stretch needs further investigation.
4.4. Action potential changes
The force of contraction may be modulated during
stretch by a change in action potential. The effect of
stretch on action potential configuration leads to variable
results [13]. It has generally been considered difficult to
separate genuine current changes from artifactual ones
which might be due to damage of the cell membrane by
mechanical factors. In a recent study which measured on
the same isolated cell the effects of stretch on membrane
potential and intracellular calcium transient, White et al.
[90] found, as in previous studies in multicellular preparations [ 131, qualitatively and quantitatively variable membrane potential and action potential configurations depending upon sarcomere length changes. In the first beat fol-
Research
32 (1996)
25-37
lowing the stretch which increased sarcomere length from
1.84 to 2.70 p,m, the only parameter which changed was
action potential duration which decreased significantly.
When all stretches were analyzed, this feature persisted
and there was a tendency, although not statistically significant, towards a decrease in membrane potential and action
potential amplitude. These changes may be due to modifications of the slow inward calcium current or the inward
rectifier inward current and may be associated with changes
in the sodium-calcium exchanger, but no conclusive evidence is available yet. In contrast, stretch activates ionic
channels which are much better known.
4.5. Stretch-actiuated ion channels
The existence of stretch-activated ion channels was
initially described in embryonic chick skeletal muscles by
Guharay and Sachs in 1984 [91] and later in a variety of
other tissues including cardiac neonatal rat myocytes, adult
cardiomyocytes [92] and embryonic chick hearts [93,94].
They are non-elective channels for cations (Ca”, Na+,
Kf) but with some ionic selectivity which varies somewhat from one preparation to another. They are blocked by
gadolinium and calcium ions [95] via a binding reaction to
a site in the cation permeation pathway, a reduction in
single-channel current and a reduction in the rate of opening. Gadolinium, however, is not completely selective for
stretch-activated ion channels since it is also able to block
voltage-dependent calcium channels in pituitary cells [96].
The existence of a real stretch-activated ion channel
activity has been discussed and attributed to a patch-clamp
artifact [97], but a number of arguments confirms the
reality of this channel activity, particularly the experiments
of Sigurdson et al. [93] who showed in cultured chick
hearts that stretch produced a calcium influx which was
blocked by gadolinium or by removing calcium. Furthermore, cultures grown in the absence of embryo extracts
which lack stretch-activated ion channels had no mechanically induced fluxes. The efficiency of gadolinium in
reducing length-dependent increase in force has been recently confirmed in papillary muscles [98]. Streptomycin
has been recently shown also to reverse the large stretchinduced increase in intracellular calcium in isolated
guinea-pig ventricular myocytes [99]. The changes in intracellular calcium concentration induced by these fluxes
were considered to be too small to induce CICR; other
mechanisms have been proposed to explain the role of
stretch-activated ion channels in length-dependent activation including improved load-sharing among fibers via
their effect on cell calcium [93]. Another possibility is a
coupling of these channels with phospholipase C. In our
studies on inositol phosphate accumulation in stretched
neonatal rat hearts, we found a suppression of this effect
by pertussis toxin, suggesting a coupling of stretch receptors with phospholipase C via a pertussis-toxin-sensitive
G-protein [73].
B. Crozatier/
20
40
30
VOlUrnl?
Cardiovascular
50
(ml)
Fig. 4. Three pairs of pressure-volume
trajectories
with the same end-diastolic volume but with different ejection fractions.
End-systolic
points of
beats with small ejection fractions
are above the isovolumic
dashed line
but not that of the beat with a large ejection fraction. Data were obtained
in isolated servocontrolled
dog hearts and are reproduced
from Ref. [45].
Besides cationic channels, stretch-activated anion channels have been described recently in rabbit cardiac myocytes [lo01 with a chloride current showing a modulatory
mechanism different from that of other cardiac chloride
currents.
5. Opposite effects of initial muscle length on ventricular function
Hunter [45] showed that instead of being determined by
end-systolic volume only, end-systolic pressure was the
result of the action of factors acting in opposite directions:
when initial muscle length is increased, this produces an
increase in end-systolic pressure due to length-dependent
activation and also a decrease in end-systolic pressure due
to shortening deactivation. This is shown in Fig. 4. In
addition to shortening deactivation, other mechanisms,
principally viscoelastic properties of the myocardium, may
lead to a decrease in shortening when muscle length has
been increased. These mechanisms will be examined successively.
5.1. Shortening deactivation
The absence of a unique ESPVR had been pointed out
in the early studies of Suga et al. [7] in which the effect of
muscle shortening during ejection was shown to produce a
decrease in end-systolic pressure below the end-systolic
line. This had been attributed to a deactivation or an
uncoupling effect of muscle shortening. At the muscle and
cellular level, besides passive elasticity, restoring forces
and a creep phenomenon which will be analyzed below, a
decrease in shortening velocity with time during contraction may be due to slowly detaching cross-bridges, which
results in reduced cross-bridge recycling as the myofila-
Research
32 (1996125-37
31
ment shortens and thus in a reduced number of crossbridges throughout systole [ 1011.
We recently showed that, in ex-vivo ejecting rabbit
hearts [ 1021, besides velocity of ejection, the timing during
which ejection takes place during systole plays an important role in shortening deactivation, with an accentuated
end-systolic pressure loss when ejection takes place in the
late systolic phase. Since both the velocity and the amount
of shortening are increased when end-diastolic length is
increased, a larger shortening during end-systole may decrease end-systolic pressure. An effect of the timing of
ejection on ESPVR is in agreement with other studies
[42,43,103,104]. Hunter et al. [42,43] using flow-pulse
techniques showed that deactivation was larger in end-systole with a larger resistance component when flow was
applied late during systole. Similar results have been shown
by Shroff et al. [104]. The effects of an altered timing of
ejection on ESP could also be mediated through changes in
the systolic left ventricular pressure waveform, since pressure was increasing during a large part of systole and
reached its peak close to the middle of systole when
ejection occurred late during systole. This mid-systolic
zone may represent the transition zone proposed by Brutsaert et al. [105], in which contraction load is converted
into relaxation load. The depressed ESP observed when
ejections occurred late during systole could be explained
by the predominance of factors related to relaxation load,
thus inducing a premature relaxation. The effect of the
timing of ejection on relaxation was also demonstrated by
Hori et al. [ 106,107] who showed in isolated canine heart
and in intact canine heart that the ejection timing, rather
than peak left ventricular pressure, may primarily regulate
ventricular relaxation rate. Similar results were found by
Gillebert and Lew [log].
5.2. Myocardial uiscoelastic properties
Another preload-induced modification of the ESPVR
was demonstrated by our laboratory [44]. In conditions in
which end-diastolic pressure was markedly increased, ESPVR showed a marked preload-induced curvilinearity
which was much larger than that obtained with normal
filling pressures. These results were similar to those previously published by our laboratory where an end-systolic
pressure-dimension shift was shown during the closure of
a fistula between the left carotid artery and the left atria1
appendage [109]. This behavior may due to some viscous
resistance against deformation among myocardial fibers
and layers as it had been suggested by LeWinter et al.
[llO] as an explanation for a time-dependent shift of the
end-diastolic filling relation after methoxamine injection.
At the muscle level, the major factors which cause the
slowing of shortening velocity with time include, besides
shortening deactivation, a passive elasticity that increases
with increasing sarcomere length which is unloaded onto
the active elements with shortening, thereby reducing ve-
B. Cro:atier/
Cardiovascular
Resmrch
32 (19%)
25-37
intact conscious dog in contrast with open-chest animals.
These results were confirmed by Boettcher et al. [I 191.
Although these data tend to lead to the conclusion that the
left ventricle operates under normal conditions close to the
apex of the Starling limit, this has been found only in dogs
in the supine position; probably, the heart becomes smaller
in the upright position, allowing further dilatation when
needed and thus Starling mechanism utilization, particularly during exercise.
‘:I
6. Longer-term
lb
LEFT VENTRICULARENO-DIASTOLICVOLUMElmll
i0
Fig. 5. End-diastolic
pressure-volume
relations obtained in instrumented
conscious dogs before and after volume loading (VL) with saline solution
and during aortic constriction
(AC) or caval occlusion
(CO). Note that in
the normal conscious
state in these reclining
dogs, the end-diastolic
pressure-volume
point indicated by an X with an arrow was close to the
vertical part of the relationship,
suggesting
that the Starling mechanism
is
fully utilized in the conscious
reclining
position. Reproduced
from Ref.
[441.
locity with time [I 111, and restoring forces (i.e., passive
elements) that tend to resist cell shortening, thus increasing
the load on the active elements with shortening [ 1 11,112].
Despite a great deal of effort, it has been difficult to
measure the relation between shortening velocity and developed force in single cardiomyocytes. However, Kent et
al. [I 131 could report viscosity-velocity relations in single
cells and, recently [I 141, the contribution of a high passive
force to increase shortening velocity under conditions of
low active force generation was shown in single cardiomyocytes permeabilized with o-hemolysin when passive force
in the cell was a greater proportion of the total force and
there were fewer bound cross-bridges, ter Keurs and de
Tombe [I 151 showed recently that, in right ventricular rat
trabeculae in which force and sarcomere lengths were
measured, viscous force increased in proportion to stretch
velocity and that the force response to stretch showed a
response compatible with an arrangement of a viscous
element in series with an elastic element.
Another factor which can explain a rightward shift of
ESPVR when end-diastolic pressure is high is a creeping
deformation of the myocardium. A slippage of myofibrils
has been shown to be the creeping mechanism in chronic
volume overload [I 16,l 171, but it is also possible that this
phenomenon appears in acute volume overload when enddiastolic pressure is markedly elevated, as it was in our
study in conscious dogs [44] in which we showed (Fig. 5)
that the left ventricle operates close to the apex of the
Starling curve in the conscious state. More than 30 years
ago, Rushmer et al. [11X] already observed that the end-diastolic ventricular size is nearly maximal at rest in the
effects of myocardial
stretch
When myocardial stretch persists for several hours, a
number of phenomena appear. The principal one is stimulation of genes which will lead to ventricular hypertrophy.
This review will not detail ventricular function changes
when hypertrophy has already developed, but will be
limited to the early (hours to days) response to stretch.
Some years ago, we showed increased ventricular function in conscious dogs 24 h after the production of an
aortic insufficiency [ 1201. This increased function was
obtained for loading conditions which were matched with
those measured in the control state and persisted under
beta-blockade treatment. The same type of response vas
observed in the early response to chronic pressure overload
[ 12 11, suggesting that a sustained increase in both preload
and afterload has long-term effect on ventricular function
before hypertrophy has already developed. One of the
possible mechanisms leading to an increasesd contractile
state has been shown to be an improved restitution phenomenon [I 221. A number of modifications of sarcoplasmic reticulum function may be the causal mechanism,
but, to date, these changes have not been demonstrated. In
contrast, the induction of a number of genes has been
demonstrated in response to stretch and are currently under
intense investigation worldwide.
Contractile protein mRNAs have been shown to be
modified as early as 24 h after overload with an increased
amount of B-isomyosin heavy-chain mRNA [123] and a
transient increase in a-actin mRNA expression after 2-4
days [ 1241. Heat shock protein HSP70 has been shown to
have an increased expression in isolated rat cardiomyocytes 2-4 days after the onset of either a volume or a
pressure overload [ 1251 and the expression of its gene was
found to be increased as early as 30 min after a single
stretch of isolated perfused rat hearts [126].
In in-vivo preparations, it is difficult to distinguish
which, between stretch and systolic stress or beating, is the
trigger of gene induction. For this purpose, a model of
stretch of neonatal cardiomyocytes has been developed and
is presently widely used. The first direct evidence that
muscle cells are able to ‘sense’ the external load in the
absence of neuronal or hormonal factors came from a
study of Vanderburgh and Kaufman [ 1271 who demonstrated that the rate of protein synthesis of cultured chick
B. Crozatier/
Cardiovascular
skeletal muscle cells grown on an elastic substrate increased significantly in response to static stretch. A similar
phenomenon was observed in adult cardiocytes plated on a
silicone sheet [128]. It has been shown more recently that
stretch of neonatal cardiocytes in culture causes an induction of c-fos proto-oncogene expression and skeletal oactin [74,129], a phenotype also observed in the myocardium in response to pressure overload in vivo 11301.
The induction of immediate early genes such as C-$X,
c-j,,, c-myc and Egr-1 which appear as early as 1 h after
cellular stretch is followed by that of ‘fetal’ genes such as
skeletal a-actin, atria1 natriuretic peptide and B-myosin
heavy chain [ 13 11. DNA transfection experiments showed
the localization within the promoter of the c-fos gene of a
‘stretch-response’ element [13 11.
The mechanism by which stretch induces the expression
of proto-oncogenes does not appear to involve microtubules and microfilaments [132], although they are redistributed within the first week following an aortic stenosis
[ 1331 and were shown to be involved in the transition
between the compensatory phase of hypertrophy and cardiac failure [134]. Results concerning the role of cellular
beating and systolic wall stress in signal transduction of
proto-oncogene expression during stretch lead to conflicting results. Distension of isolated left ventricles per se
was shown to have no significant effect on proto-oncogene
induction when hearts were perfused with 2,3-butanedione
monoxime which prevents systolic cross-bridge cycling
and force generation, suggesting the role of active generation of left ventricular systolic force independent of passive diastolic force [135]. Similarly, it was shown in
cultured nonatal rat heart cells that contractile arrest prevented the accumulation of B-myosin heavy chain [136],
but Sadoshima et al. [132], using the same model, showed
that arresting contractile activity of myocytes by high K’,
tetrodotoxin or Ba+ did not affect stretch-induced immediate early gene expression.
The transduction pathways utilized by stretch to induce
gene expression were shown to involve PKC since the
accumulation of C--OSmRNA by stretching was blocked
by PKC inhibitors at the transcriptional level [74]. A
number of other kinases and pathways are also activated
by stretch, particularly mitogen-activated protein (MAP)
kinase [137,138] and MAP-kinase cascade [139] along with
tyrosine kinases, p2 l’““, phospholipase C, phospholipase D
and probably phospholipase A2 and ~450 pathways [138].
The signals generated by these second messengers converge into activation of the p67SRF-p62TCF complex via a
serum response element, causing the induction of C--OS.
This suggested that the stretch response might involve an
autocrine or paracrine mechanism because stretch-conditioned medium, when transfered to non-stretched myocytes, mimicked the effect of stretch [138]. An autocrine
mechanism was demonstrated by the evidence of angiotensin II release from cardiomyocytes after myocardial
stretch [140]. The role of the renin-angiotensin system in
Research
32 (1996)
25-37
33
the development of hypertrophy was recently confirmed by
the regression of hypertrophy of spontaneous hypertensive
rats treated by the non-peptide angiotensin II receptor
antagonist, TCV- 116 [141]. Other growth factors are probably also involved in stretch-induced gene induction; TGFB1 was recently shown to potentiate c-fos mRNA expression and amino acid incorporation by modifications of the
(Y,-adrenergic and stretch-activated PKC pathway [ 1421.
In spite of the number of studies which showed an
effect of the PKC pathway on proto-oncogene expression
after a stretch, it should be noted that most of these studies
have been performed on isolated neonatal myocytes and
may not be applicable to the whole heart. As an example
of this, recent preliminary studies by Lorell’s group [143]
showed that, in isolated perfused adult rat hearts, angiotensin AT1 receptor blockade by Losartan could not
block load-induced proto-oncogene expression in contrast
with immature isolated myocytes. Studies on whole hearts
are thus necessary to confirm findings obtained in isolated
cells.
7. Conclusions
The purpose of this review was to give an integrative
view of the effect of stretch on myocardial function from
ventricular function changes to cellular and molecular
mechanisms. It appears that stretch produces a large number of excitation-contraction
coupling modifications. In
spite of the number of papers dealing with the effect of
stretch on myocardial function, a number of uncertainties
remain as shown in Fig. 2.
As previously pointed out [lo], preload and contractility
can no longer be considered as independent determinants
of ventricular performance. The analysis of ventricular
performance by the end-systolic pressure-volume relation
which has been popular does not therefore appear any
more as a measure of ventricular ‘contractility’ since it is
the result of a large number of uncontrolled, partly opposite, factors. Instead of trying to measure ‘contractility’,
integrative physiology should remain in its unique fieldthe integration at the ventricular level of all factors which
are modified by an intervention. Isolated hearts or conscious animal models will be essential to evaluate the net
effect of myocardial function on cellular or subcellular
changes such as PKC activity or gene expression after an
abrupt load modification.
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