Dirk L. Brutsaert 1980

NOVEMBER 1980
Circulation Research VOL. 47 NO. 5

An Official Journal of the American Heart Ansociation
BRIEF REVIEWS
Dual Control of Relaxation

Its Role in the Ventricular Function in the Mammalian
Heart
DIRK L. BRUTSAERT, PHILIPPE R. HOUSMANS, AND MARC A. GOETHALS
II y a toujours plus de chaleur dans le coeur qu' Hence the very opposite of the opinions com-
en aucun autre endroit du corps. Cette chaleur est monly received, appears to be true; inasmuch as it
capable de faire que, s'il entre quelque goutte de is generally believed that when the heart strikes
sang en ses concavite's, elle s'enfle promptement et the breast and the pulse is felt without, the heart
se dilate, ainsi que font ge'ne'ralement toutes les is dilated in its ventricles and is filled with blood;
liqueurs, lorsqu'on les laisse tomber goutte a goutte but the contrary of this is the fact, and the heart,
en quelque vaisseau qui est fort chaud. Ces gouttes when it contracts, is emptied. Whence the motion
se rare'fient et se dilatent, a cause de la chaleur which is generally regarded as the diastole of the
qu'ellesy trouvent, au moyen de quoi, faisant enfler heart, is in truth its systole. And in like manner
tout le coeur, elles poussent et ferment les cinq the intrinsic motion of the heart is not the diastole
petites portes*; et continuant a se rare'fier de plus but the systole; neither is it in the diastole that the
Downloaded from http://ahajournals.org by on July 24, 2022
en plus, elles poussent et ouvrent les six autres heart grows firm and tense, but in the systole, for
petites portes'f qui sont aux entrees des deux then only, is it moved and made vigorous.
autres vaisseaux par ou elles sortent; le coeur,
incontinent apres, se de'senfle.
(Rene Descartes, 1637 : Discours de la me'thode). (William Harvey, 1628 : De motu cordis).
" The mitral and tricuspid valve leaflets.
f The aortic and pulmonic valve leaflets.
MECHANICAL relaxation of the heart is the pro- for the controversial concept of ventricular diastolic
cess by which the heart returns to its precontracts suction, which has been debated over the years,
configuration. Yet, the exact underlying controlling mainly by physiologists (Bloom and Ferris, 1956;
mechanisms are still largely unknown. The classic Brecher, 1958; Tyberg et al., 1970a), the relevance
studies of Harvey (1628) shifted the emphasis of of the relaxation phase to ventricular function of
the cardiac cycle from the concept of a heat-con- the heart has been ignored. However, recently the
trolled dilating-collapsing heart (Descartes, 1637) relaxation phase has been analyzed in order to
to that of a contracting-relaxing muscle-pump sys- evaluate ventricular performance in the cardiac pa-
tem. Thereafter, muscle contraction rather than tient (Meijler and Brutsaert, 1978). In various heart
thermal dilation (or relaxation) of the heart was diseases, relaxation may be affected long before
considered to be the major energy source for the contraction has become inadequate; abnormalities
pulsatile movement of the blood. Observations on in relaxation could thus be early indicators of heart
the functional significance of the relaxation phase disease. Still, the exact significance of abnormalities
of the heart were considered less important. Except of ventricular relaxation in heart disease remains
unclear. This is not too surprising given the diver-
From the Department of Physiology and Medicine, University of gence of views on the underlying fundamental pro-
Antwerp, Antwerp, Belgium. cesses at the cellular level and the difficulty of
Address for reprints: Dirk L. Brutsaert, M.D., Professor of Physiology, measurement in the intact heart. The present re-
Department of Physiology and Medicine, University of Antwerp, Ant-
werp, Belgium. view will focus mainly on recent developments in
638 CIRCULATION RESEARCH VOL. 47, No. 5, NOVEMBER 1980
our understanding of relaxation. Ventricular dia- as documented by the calcium-sensitive photopro-

stolic compliance and late diastolic pressure-volume tein aequorin, increases rapidly, reaches an early
relations will receive less attention. We will first peak (Ashley and Ridgway, 1970; Blinks et al., 1978;
summarize briefly our present knowledge of relax- Taylor et al., 1975; Gordon and Ridgway, 1978;
ation at the cellular level and in particular how Allen and Blinks, 1978), and decreases thereafter so
relaxation ensues from the preceding excitation- that the level of ionized calcium is almost back to
contraction coupling (or activation). Then, at the pre-excitation levels at the time of peak force. In
multicellular level of isolated cardiac muscle, we the next step, calcium ions bind to the C-subunit of
will describe the striking sensitivity of relaxation to the regulatory protein troponin. Troponin-C and
the prevailing load and how this load-dependence, tropomyosin, both located on the thin filament,
through interactions with the dissipation of activa- generally are thought to regulate the interaction of
tion, results in a dual control mechanism of relaxa- myosin and actin. One possible mechanism is as
tion in mammalian cardiac muscle. Finally, this follows: calcium bound to troponin-C causes a series
dual control mechanism of relaxation will be con- of structural changes (step 2) which are transmitted
sidered at the level of the in situ heart; the signifi- through troponin-I to actin and through troponin-
cance and the diagnostic and pharmacological im- T to tropomyosin; the resulting movement of tro-
plications for the cardiac patient will receive our pomyosin deeper into the actin groove unblocks
special attention. neighboring actin molecules (Haselgrove, 1973;
Huxley, 1973). The now-activated thin filament
Excitation-Contraction-Relaxation then interacts with myosin molecules in the adja-
Coupling at the Cellular Level cent overlapping parts of the thick filaments
through formation of activated crossbridges (step
Figure 1 schematically illustrates the various 3). Cyclic interaction of such crossbridges between
steps involved in excitation-contraction-relaxation the interdigitating thick and thin filaments (step 4)
coupling. The first event in the activation scheme finally results in the generation of force (step 5)
is the action potential (step 1). This electrical phe- and/or shortening.
nomenon is followed by a rise in the concentration
of free intracellular calcium ions. Relaxation of ventricular cardiac muscle was re-
The concentration of free myoplasmic calcium, cently shown (Brutsaert et al., 1978c) to depend on
the interaction and interdependence of two control-
mechanisms: (1) the rate of decay of the events
activation force generation leading to contraction and (2) the load. The decay
of free myoplasmic calcium depends on the slowing
and termination of calcium entry into the myoplasm
K (decay of reaction step 1) as well as on the translo-
cation of calcium by the membranous calcium-se-
questering systems (activation of reaction step —1).
Ca + TnC 4 - AT J^ XBA A XBC J ^ F Dissipation of force, i.e., force degeneration, prob-
-2 -3 -4 -5 ably involves the reversal of reaction steps 5, 4, and
3 (detachment of actin from myosin), followed by
SR + SL the switching of actin into the "off' state, probably
coupled to a reorganization of the thin filament
step 1 (reversal of step 2). If the pumping activity of the
calcium-sequestering systems is low (—1 rate low)
for a given degree of activation, this becomes the
inactivation force degeneration rate-limiting step and dictates the time course of
FIGURE 1 Schematic diagram of activation and deac- relaxation.
tivation of force generation in cardiac muscle where Ca In summary, although there is general agreement
= calcium, TnC = troponin C, AT = activated thin that mechanical relaxation involves the dissipation
filament, XBA = attached crossbridge, XBC = cycling of force, the biochemical processes underlying re-
crossbridge, and F = force. SR+SL = calcium transport laxation already have started in early contraction
mechanisms in sarcoplasmic reticulum (SR) and sarco- and might still be operating later in contraction,
lemma (SL). The concentric circles to the left of reaction thereby affecting inactivation and, hence, mechan-
step 1 represent the activation calcium pool. An action ical relaxation. This inactivation-dependent control
potential is depicted above reaction step 1. Five reaction system modulates relaxation in a subtle interplay
steps (1-5) with their respective rate constants for for- with the load as a superimposed extrinsic control-
ward reactions (e.g., 1) and backward reaction (e.g., —1) ling factor. This load is continuously faced by the
are shown. Reaction steps 2-5 are considered as revers- force generated by the muscle at any time during
ible, whereas step 1 is not reversible. (We wish to ac- contraction and relaxation. The existence of load
knowledge the helpful advice of Dr. N. Briggs in the dependence of relaxation as a superimposed control
conceptual design of this diagram.) system will be dealt with in the next section.
RELAXATION AND VENTRICULAR FUNCTION/Brutsaert et al. 639
LOAD INACTIVATION Mechanical Aspects of Relaxation of

DEPENDENCE DEPENDENCE Isolated Cardiac Muscle
Load Dependence of Relaxation of
Mammalian Cardiac Muscle
The mechanical properties of the relaxation
phase of cardiac muscle are less well understood
than those of the contraction phase. In recent years,
there have been several studies on relaxation in
cardiac muscle from cat (Parmley and Sonnenblick,
1969; Strauer, 1973; Strobeck et al., 1975), dog (Ta-
miya et al., 1977), rat and guinea pig (Meerson and
Kapelko, 1975), and frog (Goto et al., 1972). Nev-
ertheless, these studies have given little insight into
how the capacity to bear a load disappears, when
cardiac muscle returns to its initial length or resting
tension.
Insight into this load-bearing capacity during
relaxation of cardiac muscle was recently obtained
by load clamp analysis (Brutsaert et al., 1978a,
1978b, 1978c). Figure 2 illustrates the most promi-
nent features of these fundamental observations. In
mammalian ventricular heart muscle, relaxation ap-
peared sensitive to the loading conditions (Fig. 2,
left). It was postulated that this 'load-dependent'
relaxation could be the mechanical expression of
FIGURE 2 Load dependence vs. inactivation depend- the relation of the number of force-generating sites
ence of cardiac muscle relaxation. The graphs of load- at any time to the load to be carried. By contrast,
dependent contractions (left) were obtained in cat pap- the time course of relaxation of single, partially
illary muscle; those of load-independent contractions
skinned, Brij-58 treated ventricular cardiac cells of

(right) in frog ventricular strips were obtained under these same species appeared insensitive to load but
identical conditions. Each panel contains length (upper) predominantly controlled by the diminishing acti-
and force (lower) traces as a function of time. In panel vation; 'inactivation-dependent' relaxation of these
A, a series of various afterloaded isotonic contractions membrane-deprived cells resembled relaxation in
is shown. In cat papillary muscle isotonic contractions intact frog myocardium (Fig. 2, right) in this re-
always are over before the isometric control beat and spect. Load-dependence of relaxation in mamma-
isometric relaxation phases at different loads are well lian cardiac muscle thus appears to require the
separated; this reduction in duration of isotonic con- presence of calcium-sequestering membranes, and
tractions is due mainly to an abbreviation of relaxation load would predominate over inactivation when the
and probably constitutes an inherent property of the sarcoplasmic calcium has been reduced to suffi-
isotonic lengthening phase during relaxation. By con- ciently low levels by the pumping action of these
trast, in frog myocardium the overall duration of all calcium-sequestering membranes. The presence of
contractions was little affected by loading conditions, an efficient calcium-sequestering system as a pre-
with the isometric relaxation phases coinciding over requisite for load dependence to become manifest
their largest portion. In panel B, load clamps of increas- is supported (1) by the conversion in frog myocar-
ing magnitude were suddenly applied near the time of dium of load-independent into load-dependent re-
peak shortening of a preloaded contraction. An isomet-
ric contraction was superimposed. In contrast to the
relative load independence of frog myocardium, in cat
papillary muscle the contractions are abruptly abbrevi- activation-dependent cardiac muscle preparations. Re-
ated by these load clamps, indicating again marked laxation is load dependent in intact mammalian cardiac
load-dependence. In panel C, a loading and an unload- muscle (left), in spontaneously beating single cardiac
ing step of the same magnitude and towards the same cells with intact S.R., in frog ventricular cardiac muscle
final load were imposed at the same time during the in high Ca2*, low Na+, or ouabain, and in skeletal
contraction. The control afterloaded isotonic contrac- muscle twitch. Relaxation is inactivation dependent in
tion and the isometric contraction are superimposed. single mammalian cardiac cells without functional S.R.,
Again, the duration of contraction and the time course in rat and cat papillary muscle twitch after caffeine
of relaxation are greatly affected by load in load-depen- and/or hypoxia, in tetanized mammalian cardiac mus-
dent cardiac muscle preparations, whereas load does cle, in intact frog ventricular cardiac muscle (right), and
not influence the onset and course of relaxation in in- in venous smooth muscle.
taxation when the function of the sarcoplasmic re- crease in dispersion of sarcomere lengths during
ticulum becomes more apparent by interventions early relaxation (Krueger and Strobeck, 1978), but
which affect the duration of activation (Lecarpen- only in late relaxation (Edman, 1980). However, if
tier et al., 1979); (2) by the demonstration of load non-uniformity should exist in some conditions, this
dependence in spontaneously beating single cardiac would contribute further to load sensitivity, since
cells having intact membranes (Lecarpentier et al., shortening fibers in some areas of the muscle during
1979); (3) by the suppression of load dependence in relaxation would add to the external load to disrupt
mammalian myocardium by caffeine and hypoxia more easily the already relaxing fibers in other
(LH Chuck, MA Goethals, WW Parmley, and DL areas.
Brutsaert, unpublished observations). In frog (Jew-
ell and Wilkie, 1960) and rat (unpublished obser- Load Dependence of Physiological
vations) skeletal muscle, where calcium-sequester- Relaxation
ing membranes are abundant, relaxation is also very Load dependence of relaxing mammalian cardiac
sensitive to load, implying the predominance of a muscle could be of particular benefit during the
load-dependent mechanism for relaxation in this early rapid-filling phase in the intact heart, allowing
type of muscle too. By contrast, load dependence for the heart to be filled quickly despite the rather
was shown to be absent from venous smooth muscle low transmural pressure gradient in the ventricles.
(Johansson and Hellstrand, 1975). However, the familiar isotonic-isometric relaxation
From these results, we previously have proposed sequence of an afterloaded contraction does not
that relaxation of cardiac muscle is governed by the directly reflect relaxation in the intact heart, where
continuous interaction and interdependence of an isovolumic pressure decline at the end-systolic vol-
inactivation-controlled and a load-controlled decay ume precedes filling (Sulman et al., 1974; Tamiya
mechanism, the relative contributions of inactiva- et al., 1977; Wiegner and Bing, 1977, 1978). Reversal
tion and load differing among various animals spe- of the familiar isotonic-isometric into an isometric-
cies and load being predominant in mammalian isotonic relaxation sequence more closely approxi-
ventricular cardiac muscle. In the crossbridge mates the relaxation sequence of the average mus-
model of muscle contraction (Huxley and Simmons, cle fiber in the ventricular wall of the intact heart.
1973), the load would put a progressively increasing Figure 3 demonstrates marked load dependence
strain on the crossbridges that were still attached. during this physiological relaxation. Minor in-
It was previously proposed (Housmans and Brut- creases in load applied at the onset of isotonic
saert, 1976) that this would cause them to rotate

backwards over their full range of movement and
to detach, causing the myofilaments to slide back LOAD DEPENDENCE OF PHYSIOLOGICAL RELAXATION
to their original positions (Fig. 1, steps —4 and —3). I 1.AFTERLOADED TWITCH
/ \ \
Detachment of crossbridges is substantiated by the 1- / \ \
(isotonic-isometric
relaxation sequence)
o / \ 3l\
abrupt fall of force during the subsequent isometric
relaxation phase of the afterloaded twitch. Load-
induced or load-revealed length dependence of re-
z
LU
—'
/
/ i
L- 2. PHYSIOLOGICAL RELAXATION
(isometric- isotonic
relaxation sequence)
3. LOAD-CLAMPED PHYSIOLOGICAL
laxation might, therefore, perhaps be a more appro- RELAXATION
priate term to describe this phenomenon. However, LU
UJ
we prefer the term load-dependence in order to o
ORC
avoid confusion with the familiar term of length-

LL J
dependence of activation during the contraction \^_3 -"3 jj "-
phase. After appropriate unloading during relaxa- TIME LENGTH
tion of afterloaded twitch contractions, the balance FIGURE 3 Load dependence of physiological relaxa-
between the number of prevailing crossbridges and tion. Three isotonic contractions are displayed as a
load is temporarily restored (Fig. 2, left, panel C), function of time and as force-length relations. After
so that the muscle can sustain the clamped load for reversal of the isotonic-isometric relaxation sequence
a somewhat longer time than it can during the (contraction 1) into the more physiological isometric-
control afterloaded contraction. With successive isotonic relaxation sequence (contraction 2), isotonic
unloading steps, isotonic relaxation can be post- lengthening is also sensitive to alterations in load, as
poned further (Brutsaert and Housmans, 1977, minor increases in load induce an abrupt pull-out of the
1979). muscle (contraction 3). In contraction 2, isometric relax-
If sarcomere motion during relaxation is non- ation starts at end-systolic length and proceeds to below
uniform, this must also be taken into account. Laser the preload at /„,„„• The force scale on the force-length
diffraction studies of skeletal muscle during isomet- diagram is the same as for the force-time traces. The
ric relaxation have shown that sarcomeres in some three contractions on the force-length diagram describe
segments of a skeletal muscle fiber shorten during a counter-clockwise loop with all three contractions
late relaxation, thus lengthening others (Cleworth starting from the same resting force-length point. The
and Edman, 1972; Edman and Flitney, 1977). The resting force-length curve below this point is also super-
evidence available so far does not indicate an in- imposed.
lengthening (contraction 3) abruptly abbreviate the be derived from Noble's work (1968); a sudden
twitch by reextending the muscle to the final resting aortic occlusion during the last third of ejection
length. When relaxation in the intact heart is ana- resulted in a fall of left ventricular pressure. Similar
lyzed, the auxotonic nature of the loading also results were obtained from experiments conducted
should be taken into account. in our laboratory (see below, Fig. 5). These results
In summary, at the multicellular level of isolated are analogous to the abrupt fall in force after a load-
cardiac muscle, relaxation is governed by the con- clamp imposed during relaxation of afterloaded iso-
tinuous interplay of load and the dissipating acti- tonic contractions of isolated mammalian cardiac
vation (inactivation). Whereas inactivation is re- muscle (Brutsaert et al., 1978a, 1978c). The analogy
lated to the decline of myoplasmic calcium, load with a load clamp is validated by the initial rise in
constitutes a delicate state of equilibrium with the pressure at the time of the occlusion. Noble (1968)
prevailing force generated by the muscle at any interpreted the subsequent fall in pressure as re-
time. As load exceeds this force potential in the sulting from separation of the ventricle from the
presence of a sufficiently low myoplasmic calcium, aorta, the aorta acting as the pressure source in the
the predominance of load dependence becomes ap- later phase of ejection due to the momentum of the
parent and mechanical relaxation is induced. blood. The possibility that a sudden aortic occlusion
would, instead, act as a "load-clamp" on the ventri-
Determinants of Relaxation in the Intact cle, with subsequent load-induced premature relax-
Heart ation of the muscle fibers, seems to us a more
There has been a renewed interest in the mech- plausible interpretation.
anisms of relaxation in the intact heart. Most stud- How Relevant is Load-Dependent Relaxation for
ies have focused on the maximal rate of pressure the Intact Heart?
fall, on the time constant of isovolumic pressure
fall, on the duration of isovolumic relaxation, on Load dependence of relaxation implies that the
thinning and thinning velocity of the ventricular second half of the contraction cycle of the intact
wall, and on the relation of all these measurements heart, i.e., during the later portion of ejection, be-
to ventricular compliance. Some of these measure- comes disconnected from the initial activation pro-
ments have been shown to be potentially useful in cess. Thereafter, relaxation is controlled mainly by
the clinical evaluation of relaxation disorders; but the prevailing loading conditions and less by the
these indices have as yet failed to provide sufficient underlying dissipation of activation. Reestablish-
insight into the fundamental process of relaxation ment of the optimal precontractile configuration
in the intact heart as a muscle-pump system. We then easily could be accomplished despite a low
will now describe a dual control mechanism during filling pressure, so that major filling of the pump
relaxation in the intact mammalian heart. First, we can occur early in diastole when it will be hardly
will show the presence, significance, and nature of affected by abrupt abbreviations of diastole with
load-dependent control, and how it can be modified changing heart rates. Moreover, load dependence of
through the specific distribution patterns of loading relaxation could underlie both the propulsive be-
in the ventricular wall. Second, we will analyze how havior of freshly excised unloaded hearts immersed
this load dependence can be modulated through in saline (Bloom and Ferris, 1956), as well as the
interventions which interact with the inactivation- concept of active ventricular diastolic suction
dependent control mechanism of relaxation. (Brecher, 1958; Tyberg et al., 1970a). Yet, to clarify
this point we must first consider the various loading
Loading conditions that are present in the ventricular wall.
Load-Dependent Control of Relaxation Nature of Loading in the Intact Heart during
Although previous work has demonstrated load Relaxation
independence of relaxation in servo-controlled iso- Given the fundamental importance of the pre-
tonic contractions in intact left ventricle of dogs vailing loading conditions in determining relaxation
(Covell et al., 1969), there is now experimental in the mammalian heart, we now may ask what
evidence that relaxation in the intact mammalian these loads are in the in situ heart. In the following
heart is normally load-controlled. Weber and Jan- sections, we will analyze the nature of these loads
icki (1977) showed a distinct separation of the onset at three levels, i.e., the cardiac fiber as part of the
and rate of decline of ventricular mural force during ventricular wall, the isolated whole heart, and the
relaxation in variably afterloaded beats in servo- in situ heart.
controlled dog hearts. Similarly, Tamiya et al. Internal Restoring Forces: Cardiac Fiber. Any
(1977) showed that the maximum rate of tension attempt to reduce the length of a resting muscle
fall in the in situ blood-perfused papillary muscle of fiber below its so-called slack length will generate
the dog, relaxing isometrically at the end-systolic internal restoring forces, which tend to elongate the
length, depended strongly on the tension developed muscle fiber to the slack length (Parsons and Por-
during the contraction phase. Evidence that relax- ter, 1966; Fabiato and Fabiato, 1976). This is illus-
ation in the intact heart is load dependent also can trated schematically in Figure 4. Although no quan-
titative data indicating how restoring forces vary assumption that double overlap of actin filaments
with muscle lengths below slack length are pres- in the region of the M-band elicits restoring forces,
ently available, we have assumed an exponential restoring forces could come into play over a wide
relationship in accordance with the exponential range of sarcomere lengths. This is especially true
stress-strain behavior of elastic structures in biolog- for atrial tissue, where the variability of the length
ical systems. Jewell (1977) has ascribed these inter- of thin filaments is greater (0.6 to 1.1 /an) than in
nal restoring forces to the resistance to overlapping ventricular muscle (0.9 to 1.1 jum) (Robinson and
of the thin filaments in the middle of the sarcomere Winegrad, 1979). As indicated in Figure 4, in after-
at lengths below 1.95 /un, the longitudinal compres- loaded contractions, mammalian cardiac muscle
sion of the thick filaments at sarcomere lengths less rarely shortens to less than slack length. Similarly,
than 1.65 jum, and the constraints imposed by the in the intact heart, during systole the sarcomere
sarcolemma and the surrounding connective tissue, length of midwall muscle fibers decreases by only
which will be stretched circumferentially at short about 10% (Sonnenblick et al., 1967; Vatner et al.,
lengths due to the constant volume behavior of the 1976). This would make it unlikely that the passive
cell. Jewell (1977) estimated slack length at 85% of restoring forces intrinsic to the myocardial fiber
the muscle length at which force development is contribute to relaxation in the intact heart, since
maximal (lmax) (Fig. 4). However, other studies these forces would come into play only below this
(Page, 1974; Robinson and Winegrad, 1979) indicate range of lengths. In the physiological range of
considerable variability in the lengths of thin, but lengths larger than slack length, isotonic lengthen-
not thick, filaments in cardiac muscle. Thus, on the ing of the muscle fiber during relaxation is deter-
mined mainly by the difference between the exter-
nal load and forces resulting from deformation of
FORCES parallel elastic structures at lengths greater than
slack length; these latter forces make the muscle
recoil back to the slack length. From experiments
suggesting that each crossbridge can generate neg-
ative as well as positive force, the possibility has
been raised that forces during relaxation could be
MUSCLE related to crossbridge interaction (Huxley, 1974;
LENGTH Podolsky et al., 1976). Such forces would help to
return the muscle back to the initial length, inde-
pendently of the length range over which relaxation

occurred.
Thus, there is at present little evidence that
internal restoring forces contribute significantly to
relaxation in physiologically afterloaded intact
FIGURE 4 Forces either promoting or opposing heart muscle or in the intact heart. As evident from
lengthening during isotonic relaxation. The force scale Figure 4, the net force above slack length is deter-
(vertical) is given in arbitrary units. On the length scale mined mainly by the external load. In isotonic af-
(horizontal), slack length of isolated muscle is indicated terloaded contractions of isolated cardiac muscle,
as well as the physiological shortening range (dark this load is constant. By contrast, in the intact
shaded area). Under conditions of high inotropic state heart, external load on the wall muscle fibers varies
or low loading, the shortening range may extend down continuously, or in other words, relaxation is auxo-
to below slack length (light shaded area). The curve tonic. Here, external load results both from external
indicated by parallel elastic force corresponds to the restoring forces and from hemodynamic loading
length-force relation of the muscle at rest. The external factors.
load during the lengthening is maintained at a constant External Restoring Forces: Intact Heart. Since
level, as indicated by the lower horizontal broken line. an important part of relaxation of the ventricles is
(1) Below slack length, the net force at any given length accomplished with the two valve systems closed
is the external load plus the internal restoring force (see and since the heart is filled in the presence of low
text). (2) At slack length, the net force acting on the filling pressures, the heart might benefit from stored
muscle to return it to its initial muscle length is the potential energy resulting from systolic deformation
external load. (3) Beyond slack length (i.e., including the of elastic structures. Rushmer et al. (1953) provided
physiological length range of the relaxing ventricular evidence that, due to the architecture of the heart,
wall muscle fiber), the net force that helps the muscle to whose muscle layers run at different angles to the
return to its initial starting length progressively dimin- base of the heart, tension is exerted on the muscular
ishes due to the presence of parallel elastic elements, and connective tissue connections between different
e.g., at a length of approximately 0.95 Z//ma». Obviously, layers during ejection. This interfascicular tension
in addition to these forces, other modulating forces, such represents potential energy that is wasted with
as those due to friction and viscosity, must also be taken respect to ejection but that could be released during
into account. isovolumic relaxation and early diastolic filling.
Analysis of the determinants of peak rate (negative tion can result from reflections of pressure waves in
dP/dt max) and the time constant of isovolumic the vascular tree (Van den Bos et al., 1976). Changes
pressure decline indeed suggested that, besides ino- in shape of the ventricular pressure pulse resulting
tropic influences, either the configurational defor- from alterations in arterial impedance are well
mation at the end-systolic volume (Cohn et al., known (Elzinga and Westerhof, 1973), but their
1972; Papapietro et al., 1979) or the wall stress at direct mechanical effect on ventricular relaxation
peak systolic pressure (Weisfeldt et al., 1974) or at has never been examined and might be difficult to
end-ejection (Mathey et al., 1974) was the major evaluate due to neurohumoral adjustment. As will
determinant of isovolumic relaxation. The impor- be explained in a later section, drugs and neurohu-
tance of this geometrical determinant acting as a moral factors may indeed have two effects on ven-
load during relaxation in the intact heart also can tricular relaxation: (1) an influence on the onset and
be derived from the observation of negative dia- possibly the rate of isovolumic relaxation due to
stolic ventricular pressure when ventricular inflow alterations in arterial impedance, and hence load-
is prevented (Tyberg et al., 1970a). In addition to ing, on the relaxing myocardial fibers, and (2) an
these physical loading determinants of relaxation, effect on the inactivation-dependent factors that
biological factors (e.g., the history of cardiac muscle underly myocardial relaxation. In addition, they
or the way in which end-systolic volume and/or may affect ventricular relaxation through the cor-
peak wall stress are attained) may result in a su- onary circulation (see below). Although there is
perimposed control mechanism by affecting the un- some disagreement concerning the influence of peak
derlying inactivation-dependence of relaxation. systolic pressure on various determinants of isovo-
Stroke volume was indeed found to be an important lumic relaxation, from Noble's work (1968) and
determinant of relaxation (Suga and Yamakoshi, from similar experiments conducted in our labora-
1977; Weiss et al., 1976; Gibson and Brown, 1973). tory (Fig. 5) it is evident that the onset of isovolumic
This finding could be in accordance with the famil- relaxation is sensitive to experimentally induced
iar shortening deactiyation of isolated cardiac mus- increments in aortic pressure and to the timing at
cle (Brady, 1968; Edman and Nilsson, 1971; Brut- which a given increment in pressure is imposed. If
saert, 1974). In a recent study (Frederiksen et al., the pressure increment is imposed during the first
1978), isovolumic relaxation of the intact heart was third of ejection, ejection is prolonged and the onset
relatively independent of stroke volume and peak
ventricular pressure, both within the physiological
range, but dependent on heart rate and neurohu-
moral and pharmacological interventions, suggest-

IMPEDANCE LOADING
ing thereby that inactivation-dependence of relax-
ation is an important underlying control mechanism
in early diastole. These mechanisms will be dis-
cussed below in the section on inactivation-depen-
dent control mechanisms.
Thus, relaxation in the intact heart is regulated
by mechanisms that are determined by the physical
stress-strain characteristics of the system (load de- 1 NEUROHUMORAL CONTROL
pendence), resulting from systolic configurational 2 VAS0ACT1VE DRUGS
deformation, and these mechanisms are modulated (VC or V D )
by biological factors resulting from the history dur-
ing the contraction itself (inactivation dependence).
Again, these two types of mechanisms are manifes- DIRECT EFFECT ON
tations of the interaction of the dual control of a MYOCARDIAL RELAXATION
load-dependent and an inactivation-dependent re-
laxation.
Hemodynamic Loading: Cardiocirculatory Sys- TIME
tem. In the intact heart, hemodynamic loading fac- FIGURE 5 Impedance loading. The electrocardiogram
tors must be considered, in addition to the already (upper), aortic pressure (middle), and left ventricular
mentioned loading determinants. pressure (lower) are shown as a function of time. The
1. Before the aortic valve closes, arterial imped- pressure was increased abruptly at various times during
ance will help to induce relaxation as soon as the ejection by occlusion of a cuff around the descending
aortic pressure created for a given arterial imped- aorta. In contrast to early occlusions, occlusions in the
ance exceeds the load-bearing capacity of the mus- second half of the ejection phase abbreviated ejection
cle fibers in the ventricular wall. Variations in ar- and induced early isovolumic relaxation. All beats, dur-
terial input impedance caused by changes in the ing which a pressure increment was imposed, were sep-
characteristic impedance of segments of the vascu- arated by an equal number of control beats, so that
lar tree could result in variable loading for the virtually no neurohumoral adjustment could have oc-
relaxing ventricle. Increases in pressure in late ejec- curred.
of relaxation is delayed. If, however, the pressure of the coronary circulation might contribute to ven-
increment is imposed during the last third of ejec- tricular relaxation (Hoffman, 1978); the sudden in-
tion, relaxation begins prematurely (Goethals et al., flation of a compliant coronary vascular bed may
1980). Alternatively, if in analogy with our unload- augment intramyocardial turgor and, hence, the
ing experiments in isolated cardiac muscle (Fig. 2, lateral pressure or loading on the musclefibers(Fig.
left, panel C) (Brutsaert and Housmans, 1977,1979), 6). The further increase in wall thickness during
the intact ventricle is allowed to eject against an isovolumic relaxation could imply that augmented
appropriately decreasing afterload during relaxa- intramyocardial turgor due to coronary engorgment
tion, as much as 70% of the pressure-volume area would probably greatly outweigh thinning and reo-
can be converted into external mechanical work rientation of the relaxing muscle fibers in the wall.
(Suga, 1979). In addition, engorgment of the coronary circulation
2. After the aortic valve closes, the ventricle may also contribute to relaxation through effects
relaxes isovolumically. Some investigators have on myocardial stiffness. For a given lengthening
shown that the time course of isovolumic left ven- rate of the contractile tissue, the rate of tension fall
tricular relaxation is exponential and can be char- will be greater when the myocardium is stiffer ac-
acterized by a time constant (Karliner et al., 1977; cording to (-dT/dt) = (-dl/dt) • (dT/dl). There is,
Frederiksen et al., 1978). From these studies, the however, some disagreement on the effects of the
time constant appears relatively independent of coronary circulation on chamber stiffness: even
loading determinants operating during left ventric- when the accumulation of significant amounts of
ular ejection under steady state conditions (Fred- interstitial edema was not taken into consideration,
eriksen et al., 1978) but not with acute alterations some workers found an increase in chamber stiff-
in loading (Weiss et al., 1976). These differences ness with increasing coronary perfusion pressure
may be due to neurohumoral adjustments in the (Salisbury et al., 1960), whereas others did not (Abel
steady state experiments. During the isovolumic and Reis, 1970; Arnold et al., 1968; Templeton et
phase, loading on the muscle fibers arises from al., 1972). Templeton et al., (1972) and Gaasch et
within the ventricular wall. However, even under al. (1978) found only minor influences of coronary
physiological conditions, some of the blood con- perfusion pressure on the diastolic properties of
tained in the patent aortic valve cusps flows back
into the ventricle at the end of ventricular ejection.
This backflow, amounting to about 10% of the end- LOADING FACTORS
systolic volume (Ruttley et al., 1974), constitutes an

additional load on the wall muscle fibers, since, r FILLING Of 2. LAPLACE
according to the Law of Laplace, wall tension will CORONARY RESERVOIR RELATIONSHIP
be greater at each intraventricular pressure. Even
in the absence of backflow of blood, the muscle
fibers of the wall may elongate due to displacement
of the mitral and aortic valve cusps toward the
center of the ventricle as the ventriculo-atrial pres-
sure gradient decreases and the ventriculo-aortic
pressure gradient is built up, according to the stress-
strain characteristics of the valve leaflets and sup- END-EIECTION ONSET or RAPID E N D - DIASTOLE
porting structures. In addition, changes in shape of FILLING
the ventricular cavity during isovolumic relaxation FIGURE 6 Loading induced by filling of the coronary
(Rankin et al., 1976) may cause shortening of fibers reservoir and by the application of the Laplace relation-
in some areas and elongation in others. ship. During ejection, a high-pressure reservoir is gen-
After aortic valve closure, intramyocardial pres- erated in the aorta, which becomes disconnected from
sure drops suddenly, allowing blood to flow into the the left ventricular cavity after the aortic valve closes.
coronary system as a result of the prevailing gra- The coronary reservoir fills because of the decline in
dient between aortic diastolic pressure and the ventricular cavity pressure during isovolumic relaxa-
transmural ventricular pressure. As blood flows in tion. This coronary perfusion pressure may augment
from the aorta, the coronary vascular tree is en- intramural loading of the already relaxing muscle fi-
gorged with blood, which, in healthy human sub- bers, thus promoting further relaxation and muscle
jects, increases wall thickness by about 10% during lengthening. After the mitral valve opens, thus increas-
isovolumic relaxation (Traill et al., 1978). In dogs, ing the size of the left ventricular cavity, the load on the
end-diastolic wall thickness could vary up to 25% wall muscle fibers increases according to the Laplace
between the extremes of complete occlusion of the relationship. Ao = aorta, LeAtr = left atrium, IVS =
perfusing coronary artery and reactive hyperemia interventricular septum, LeVe = left ventricle, LVPW
(Gaasch and Bernard, 1977; Gaasch et al., 1978). = left ventricular posterior wall, aML = anterior mitral
Because intramyocardial pressure depends to some leaflet, pML = posterior mitral leaflet, T = wall tension,
extent on the coronary perfusion pressure (Salis- P = intraventricular pressure, r = radius, w = wall
bury et al., 1962; Gerke et al., 1975), engorgement thickness.
normal hearts, but marked effects in severely in- cavity shape and dimensions, and transmural pres-
jured, depressed hearts. Thus, there may be a me- sure. In the normal heart (as in the isolated muscle)
chanical effect of the coronary circulation on ven- non-uniformity of load distribution in the ventric-
tricular relaxation, mediated by an increase in in- ular wall would be expected to contribute further
tramyocardial pressure and possibly by an increase to the manifestation of load-dependent relaxation,
in chamber stiffness. This mechanical effect of the since shortening fibers in some areas of the wall
coronary circulation might become manifest from would help to disrupt more easily the already relax-
beat to beat, depending on the aortic diastolic pres- ing fibers in other areas. However, although non-
sure, the ventricular diastolic pressure, and ventric- uniformity may be important in modulating normal
ular volume; by contrast, the metabolic effects of relaxation, it is probably more important in im-
the coronary circulation may require some time to paired relaxation and filling of the diseased heart.
become established. These mechanical influences Here, if relaxation is non-uniform or incoordinate,
of the coronary circulation would likewise become it may be prolonged, thus delaying mitral valve
suppressed when the gradient for coronary inflow opening and reducing early diastolic filling rate in
was diminished, as, e.g., during narrowing of the the ischemic heart, in left ventricular hypertrophy,
coronary arteries, during arterial hypotension, or and in hypertrophic cardiomyopathy (Gibson et al.,
during elevation of left ventricular diastolic pres- 1979; Sandersson et al., 1977,1978; St. John Sutton
sure. et al., 1978b; Stewart et al., 1968); regional differ-
3. At the completion of isovolumic relaxation, ences in the stress-strain relation during relaxation
the mitral valve opens and the ventricle dilates may be large and may contribute to shape changes
almost explosively, mainly through the suddenly during isovolumic relaxation. In addition, impaired
increasing intracavitary radius (r) and the rapid dissipation of the underlying activation also may
decrease of the ventricular wall thickness (w), ac- contribute in delaying relaxation in these condi-
Pr tions.
cording to the Laplace relationship, T , where
2w Inactivation
T is wall tension and P is intraventricular In various disease states of the heart, ventricular
pressure (Fig. 6). Echocardiographic analysis in hu- relaxation is impaired. Given the dual control of
mans has shown that the changes in ventricular relaxation, these abnormalities may result either
transverse dimension during rapid filling are me- from a decrease in the prevailing loading conditions
diated largely by changes in wall thickness (Traill generated by the diseased ventricle in the presence
et al., 1978). This loading induced by the Laplace of an undiminished load-sensitivity, or from a di-
relationship thus represents the dominant load on minished load-sensitivity (aggravated by alterations
the wall muscle fibers during the final phase of in the dissipation of activation under a constant set
relaxation. At this stage, load-sensitivity of the re- of loading conditions), or from both. Since, in many
laxing muscle fibers is valuable because it enables disease states, relaxation abnormalities may be ob-
the fibers to elongate instantaneously, thus enabling served long before systolic performance starts to
the ventricle to fill rapidly in early diastole, despite decline, this would imply that in these early stages
the low filling pressure. loading conditions generated by the ventricle seem
Although a distinct mutual influence between relatively unimpaired but that the underlying in-
left and right ventricular hemodynamics has been activation dependence would become more impor-
described with respect to systolic pressure devel- tant. Thus, delaying the decay of activation would
opment and late diastolic pressure-volume relations diminish load dependence.
(Glantz and Parmley, 1978; Ross, 1979), the influ-
ence of the "cross-talk" between the ventricles, and Metabolic Control
a possible effect of the pericardium (Glantz and
Parmley, 1978) on relaxation or early diastole re- As outlined above, several processes that require
quires further investigation. energy (Fig. 1) determine the decay of activation
and hence contribute to relaxation of cardiac mus-
Non-uniformity of Load Distribution in the cle; this inactivation-dependent control mechanism
Ventricular Wall during Relaxation modulates the dominant load-dependent control.
Variations in mechanical uniformity of relaxation Accordingly, in addition to contributing to mechan-
may constitute another intrinsic control mechanism ical loading during relaxation, an unimpeded filling
of the visco-elastic return of the relaxing ventricular of the coronary circulation appears to be a major
wall to the initial configuration. Non-uniformity of extrinsic determinant of relaxation in the intact
relaxation may result from temporal or spatial in- heart through its metabolic effects. If cell metabo-
homogeneity due to regional and transmural differ- lism is blocked, the muscle fails to relax completely,
ences in the onset of relaxation, in filling of the then develops contracture and, eventually, rigor.
coronary reservoir, and in the distribution and de- Incoordinate Relaxation in Ischemic Heart Dis-
cay of force, as different regions of the ventricle are ease. In the ischemic heart, ventricular relaxation
subjected to different stresses and strains depend- is impaired. Evidence of impairment is that the
ing on the dynamic regional ventricular geometry, maximal rate of pressure decline is lower, the iso-
volumic relaxation is prolonged, the time constant may occur under acutely ischemic conditions, their
of isovolumic pressure decline increases and the contribution to incoordinate relaxation is unknown.
subsequent resistance to ventricular filling is higher In vitro experiments with two papillary muscles in
(McLaurin et al., 1973; Mathey et al., 1974; Watan- series (Tyberg et al., 1969) showed that stimulating
abe et al., 1975; Gibson et al., 1977, 1978; Upton et one muscle as long as 40 msec before stimulating
al., 1976; Weiss et al., 1976; Taw et al., 1976; Amende the second had only minor effects on tension devel-
et al., 1975; Rickards and Seabra-Gomes, 1978; De- opment of the muscles in series. This finding sug-
coodt et al., 1979). These abnormalities probably gests that, without changes in the mechanical per-
result from abnormalities in regional wall motion. formance of the affected segments, conduction de-
For example, localized outward wall motion during lays probably cannot explain the observed asyn-
isovolumic relaxation, termed the "segmental early chronous mechanical behavior in ischemia.
relaxation phenomenon," can be seen frequently on 2. The Role of Segmental Abnormalities in Me-
left ventricular angiograms of patients with signifi- chanical Behavior
cant coronary artery disease (Altieri et al., 1973; Effects of hypoxia
Hamby et al., 1974; Ruttley et al., 1974; Wilson et
al., 1975; Alam et al., 1979). Although this outward In isolated cardiac muscle, hypoxia depresses
motion has been ascribed to some regurgitation of systolic performance and abbreviates overall twitch
blood contained between the aortic leaflets (Ruttley duration (Tyberg et al, 1969, 1970b; Bing et al,
et al., 1974), it could also reflect an abnormal change 1971; Henderson and Brutsaert, 1973; Brodie et al,
in the shape of the left ventricular cavity during 1976). Along with these effects, isotonic relaxation
isovolumic relaxation (Upton et al., 1976), since it is prolonged, and relaxation is changed from load
is accompanied by simultaneous inward movement dependent into load independent (LH Chuck, MA
at other sites (Gibson et al., 1977). This change in Goethals, WW Parmley, and DL Brutsaert, unpub-
shape during isovolumic relaxation delays the open- lished observations). However, it has been sug-
ing of the mitral valve (Upton et al., 1976). These gested recently that the abbreviated twitch dura-
alterations in cavity shape appear to be related to tion does not result from hypoxia but from the low
reciprocal changes in the thickness of the adjacent temperatures that are commonly used in in vitro
wall (Gibson et al., 1977; Traill et al., 1978) and, studies of myocardial mechanics, because, at 37°C,
thus, to myocardial segment length (Ross and twitch duration was actually prolonged (Frist et al,
Franklin, 1976). Although a correlation between the 1978). Nevertheless, the hypoxia-induced depres-
"segmental early relaxation phenomenon" (which sion of systolic performance alone may cause in-
is most often seen in the antero-apical region) and coordinate and slowed ventricular relaxation (see
significant stenosis of the left anterior descending below). On the other hand, hypoxia may not en-
coronary artery has been suggested (Wilson et al., tirely mimic the specific conditions of ischemia
1975), many investigators agree that this early re- since, in ischemia, pH, osmolality, and ionic activity
laxation is observed in segments showing normal may be altered and substrate may be depleted, in
systolic motion patterns (Altieri et al., 1973; Ruttley addition to the presence of hypoxia.
et al., 1974; Gibson et al., 1977). Moreover, calling Effects of ischemia
the thinning of normal wall segments, which is
associated with outward endocardial motion before Relaxation disturbances which diminish ventric-
mitral valve opening, "premature" (Traill et al., ular relaxation rate were ascribed to impaired me-
1978) seems inappropriate since it occurs at a time chanical behavior of "ischemic" segments (Gross-
corresponding generally to normal ventricular re- man and McLaurin, 1976). Global ischemia of the
laxation (Alam et al., 1979). Accordingly, the in- left ventricle indeed prolongs the duration of the
coordinate (or asynchronous) ventricular relaxation isovolumic relaxation period (Palacios et al, 1978).
ought to be explained by impaired mechanical be- Similarly, wall-thinning rate in wall segments with
havior of the ischemic zones (Grossman and Mc- preserved systolic function, but supplied by criti-
Laurin, 1976). cally stenosed arteries, was lower than in control
segments (St. John Sutton et al, 1978a); during
Mechanisms of Impaired Relaxation in Is- effort-induced angina, the velocity of diastolic en-
chemic Heart Disease. Both in the acutely and docardial wall movement was lower than at rest
chronically ischemic heart, the relation between (Fogelman et al, 1972). Hence, impaired relaxation
prolonged ventricular relaxation and impaired me- in ischemic segments may play a role in regional
chanical behavior of the abnormal wall segments is wall dynamics and may be a more sensitive indica-
not clear. To clarify this relation, various problems tor of a critical perfusion than systolic abnormali-
must be dealt with. ties. Yet, given the regional nature of ischemic heart
1. The Role of Asynchronous Electrical Activa- disease, its impact on overall ventricular relaxation
tion. Asynchronous electrical activation of the nor- remains to be demonstrated. Indeed, the delayed
mal and ischemic segments due to conduction de- opening of the mitral valve, which is so character-
lays has been proposed as an explanation for asy- istic of the ischemic heart, was not observed when
nergy during contraction and relaxation (Herman there was diffuse ischemic involvement of the heart
and Gorlin, 1969). Although local conduction delays (Upton e t a l , 1976).
Effects of reoxygenation and/or reperfusion segments in the intact heart (Wiegner et al., 1978)
The versatile nature of myocardial ischemia (Ty- (Fig. 7). This pattern of motion usually has four
berg et al., 1969) also may have a significant impact phases. An early systolic stretch (phase a) results
on ventricular relaxation. Reoxygenation of previ- from the decreased rate of force development in the
ously hypoxic myocardium and reperfusion of pre- weak hypoxic segment. This early stretch is analo-
viously ischemic myocardium greatly prolonged gous to the early systolic bulge of an ischemic zone
twitch duration, mainly due to a disproportionate in the intact ventricle (Herman and Gorlin, 1969;
increase in the duration of the relaxation phase Theroux et al., 1976). As a result of this early
(Bing et al., 1971; Henderson and Brutsaert, 1973; lengthening of the weak segment, force develop-
Weisfeldt et al., 1974). ment may increase, according to the length-active
Polyphasic motion pattern of weak and tension relation, so that a transient shortening
strong segments of myocardium in series phase (phase b) may occur subsequently. Late sys-
Relaxation disturbances of the ventricle may re- tolic lenthening (phase c) then may follow, due to
sult simply from contraction of stronger and weaker the abbreviation of the twitch duration in the weak
muscle segments in series, irrespective of whether segment at a time when the strong muscle is still
the latter segments are weaker due to a relative shortening. This late systolic lengthening is analo-
paucity of muscle fibers in flbrotic areas, or to gous to the mid- to late-systolic expansion or early
ischemia (Tyberg et al., 1969; Waters et al., 1977; relaxation of ischemic zones (Theroux et al., 1974;
Wiegner et al., 1978). Experiments in which the Waters et al., 1977). This phenomenon should not
dynamic stress of a normally functioning segment, be confused with the above-mentioned "segmental
relaxing in a physiological sequence, was imposed early relaxation phenomenon" occurring in the nor-
upon a hypoxic papillary muscle disclosed a poly- mally functioning regions of the ventricle during
isovolumic relaxation. When the hypoxia lasts
phasic motion pattern in the hypoxic muscle that longer or is more severe, the systolic shortening
was analogous to the motion pattern of ischemic (phase b) may be briefer and eventually may be
completely masked by fusion of the early systolic
stretch and the late systolic lengthening, thus re-
Shortening (mm) HYPOXIA sulting in a pansystolic bulge of ischemic segments
60 in the intact ventricle (Fig. 7). When force declines
in the normally functioning stronger segments, the
0 overstretched weaker segment will recoil in accord-
ance with its passive elastic properties, resulting in

late shortening (phase d). If this late shortening of
ischemic weak segments, sometimes mistakenly
called late contraction, occurred simultaneously
0 min with lengthening of normal strong segments, it
might profoundly affect isovolumic relaxation and
early diastolic filling of the ventricle.
Force (grams - weight) Loading effects of the coronary circulation
The loading effects due to intramyocardial forces
3r induced by the sudden engorgement of the coronary
circulation may be diminished in ischemic heart
disease. First, rapid engorgement may be impeded
\ in obstructive coronary artery disease. Second, as
L a consequence of ischemia, the end-diastolic pres-
0
sure in the ventricle may rise and therefore diminish
200 400 the aorto-ventricular pressure gradient and, hence,
Time (ms) the major driving force for the sudden coronary
FIGURE 7 Polyphasic motion pattern in hypoxic mus- engorgement, during the isovolumic relaxation
cle subjected to the stress developed by a strong segment phase.
in series. Force developed by the muscle during a phys-
iologically sequenced contraction-relaxation cycle was Neurohumoral Control; Pharmacological Agents
stored in a computer and the muscle was then subjected Various interventions such as neurohumoral con-
to the stress pattern during hypoxia. Length and force trol and pharmacological agents may, though in a
are displayed as a function of time at 0 minutes (control very complex way, modulate relaxation. These in-
contraction), and after 15 and 60 minutes of hypoxia. terventions may modulate relaxation by altering
The 15-minute trace shows an initial stretch (phase a), the loading conditions (load-dependent effects),
followed by a transient shortening phase (phase b), a e.g., the potential energy stored during systolic de-
subsequent late lengthening (phase c), and a final late formation, the arterial impedance loading, or the
shortening (phase d). (Modified from Wiegner et al., dynamics of coronary filling, or by altering the
1978; with permission from the authors.) various processes which underlie inactivation-de-
pendence of relaxation (inactivation-dependent ef- tion under similar experimental conditions (Vatner
fects), e.g., by a direct effect on the myocardium or et al., 1977). The alterations in the severely ischemic
indirectly through metabolic effects of the coronary segments probably resulted from changes in con-
circulation (Fig. 6). Variations in the decay of acti- tractile performance of the normal segments, in
vation may modulate load dependence of the mus- analogy with the in vitro series combination of weak
cle indirectly either by permitting load dependence and strong myocardium (Wiegner et al., 1978). This
to manifest itself more clearly when activation de- leads us to the intriguing paradox, that catechol-
cay is accelerated or by masking it when the decay amines may well decrease relaxation rate of the
of activation is retarded. entire ventricle by enhancing the degree of asy-
Adrenergic Agonists (Catecholamines) and An- nergy, although they have a positive relaxing effect
tagonists (y8-Blocking Agents). The relaxing effects on isolated cardiac muscle. However, paradoxical
of catecholamines have been demonstrated during motion was reversed in a few cases after adrenaline
both isometric and isotonic relaxation of cardiac administration (Herman and Gorlin, 1969).
muscle (Parmley and Sonnenblick, 1969; Morad and Calcium. The effects of calcium on relaxation in
Rolett, 1972; Strauer, 1973; Tamiya et al., 1977; isolated heart muscle appear somewhat conflicting.
Morad et al., 1978). In addition to an effect on the Parmley and Sonnenblick (1969) reported an in-
decay of activation (Morad and Rolett, 1972; Morad crease in the time to half-relaxation of isometric
et al., 1978), catecholamines may enhance isotonic twitch contractions but no effect on the time con-
relaxation by their effect on the extent of shorten- stant of exponential force decline in isotonic after-
ing, which results in unloading of the parallel elastic loaded contractions. These findings are consistent
elements (Fig. 4). With extreme shortening, internal with the absence of an effect of calcium on inacti-
restoring forces may come into play. Similarly, iso- vation-dependence of relaxation, since the increase
proterenol enhances isotonic lengthening of the in time to half-relaxation can easily be explained by
apex-to-base dimension and isometric relaxation in the increase in developed tension. Strauer (1973)
wall segments of isolated rat hearts (Grassi de reported an increase in isotonic relaxation velocity
Gende et al., 1977). The influence of catecholamines at each load in high calcium, but the extent of
on ventricular relaxation is complex. In one study, enhanced shortening, which in itself may increase
adrenaline decreased the impedance to right ven- isotonic relaxation velocity (Fig. 4), was not taken
tricular filling (Buckley et al., 1955). In other stud- into account. Strobeck et al. (1975), who did take
ies, isoproterenol shortened and propranolol into account the extent of shortening, reported an
lengthened the time constant of isovolumic pressure increase in relaxation velocity in high calcium.
decline (Karliner et al., 1977; Frederiksen et al., However, they compared loads during relaxation
1978), with variable effects on the maximal rate of that were the same, relative to maximum isometric
isovolumic pressure decline, depending on whether force at each calcium concentration; this implies
or not the end-systolic volume was controlled (Cohn that they compared higher absolute loads in high
et al., 1972). Accordingly, catecholamines may af- calcium with lower absolute loads in low calcium.
fect ventricular relaxation, not only by an effect on However, since muscle feels absolute load and not
the decay of activation, but also by effects on the relative load, the effect on relaxation velocity might
loading conditions during relaxation; these effects have disappeared if they had compared similar ab-
do not necessarily act in the same direction (Cohn solute loads during lengthening. During physiolog-
et al., 1972). The effect of catecholamines on loading ical relaxation, i.e., after reversal of the isotonic -
may be dual: (1) due to their positive inotropic isometric into an isometric-isotonic relaxation se-
effect, enhancing shortening and force develop- quence, the effect of calcium, if any, was to diminish
ment, they can evoke internal or external restoring isotonic relaxation velocity for each extent of
forces; (2) the peripheral actions may either in- shortening, when the same absolute load was im-
crease or decrease hemodynamic loading factors, posed on the muscle during lengthening (MA Goe-
depending on whether the effects on a- or /?-adre- thals, PR Housmans, and DL Brutsaert, unpub-
nergic receptors predominate. In the diseased heart, lished observations). An increase in relaxation ve-
which is often asynergic, differential effects of cat- locity in high calcium was observed only when the
echolamines on normal and pathological wall seg- extent of shortening was increased beyond the
ments must be taken into account. Although no shortening capacity in the control solution, due to
particular attention was paid to the resulting effect the positive inotropic action of calcium. Accord-
on overall ventricular relaxation rate, on the dura- ingly, it can be postulated that calcium, unlike the
tion of isovolumic relaxation, or on alterations in catecholamines, does not have an effect on inacti-
the filling pattern, isoproterenol was shown to im- vation dependence of relaxation in isolated heart
prove selectively the function of normal and mod- muscle; relaxation may, instead, be influenced sec-
erately ischemic zones after experimental coronary ondary to load-dependent changes. In support of
occlusion. In severely ischemic zones, function de- this hypothesis, in isolated rat hearts calcium pro-
teriorated with an increased paradoxical motion duced symmetrical changes in the velocity of con-
and postsystolic shortening (Vatner et al., 1976). traction and relaxation (Grassi de Gende et al.,
The reverse was true after propranolol administra- 1977), in contrast to isoproterenol, which increased
the velocity of relaxation more than the velocity of pressed myocardial function in control and in is-
contraction. In isolated dog hearts the ratio of peak chemic segments to the same extent (Theroux et
positive to peak negative dP/dt was not altered by al., 1976). These differences may again be related
calcium (Cohn et al., 1972), but the time constant to differences in experimental protocol as well as to
of isovolumic pressure decline decreased signifi- the nature of the pharmacologic agents under study.
cantly after infusion of solutions containing high Digitalis. Information on the effect of digitalis
calcium into normal conscious dogs, although less on myocardial relaxation is scarce. The maximal
than with isoproterenol (Karliner et al., 1977). rate of isometric tension decline was increased by
Vasodilators. Of current clinical interest are the digoxin in cat papillary muscle (Taubert et al.,
effects of vasodilating drugs. The direct cardiac 1976). Karliner et al. (1977) showed a decrease in
effects of these widely used drugs during relaxation the time constant of isovolumic relaxation in the
are largely unknown. Nitroprusside, but not nitro- normal conscious dog after acetylstrophanthidin.
glycerin, has been shown to diminish substantially Moreover, one has to take into account the effect
the contraction prolongation, which is seen in iso- of digitalis on the contraction phase, which, to-
lated cat papillary muscle during recovery from gether with its peripheral circulatory effects, may
hypoxia (Brodie et al., 1976). Nitroprusside there- alter the loading conditions irrespective of its pos-
fore was believed to prevent incomplete relaxation, sible effects on inactivation.
an effect that would explain the downward shift of Thyroid Hormone. In experimental hyperthy-
the diastolic pressure-volume relation after nitro- roidism, relaxation rate is increased at the muscular
prusside (Brodie et al., 1977). However, similar as well as at the ventricular level (Strauer and
shifts have been observed after nitroglycerin. These Schulze, 1976; Limas, 1978). This could be due to
shifts were not accompanied by alterations in the an increased Ca2+ accumulation rate in sarco-
time constant of isovolumic pressure decline (Lud- plasmic reticulum in the hyperthyroid heart (Suko,
brook et al., 1977), indicating that factors other 1971), thus allowing load dependence to become
than myocardial relaxation were involved in these more manifest. In experimental hypothyroidism,
shifts (Glantz and Parmley, 1978). ventricular relaxation rate is slowed (Strauer and
Antiarrhythmic Agents. Little information is Schulze, 1976). The resulting prolongation of the
available on the effects of commonly used antiar- isovolumic relaxation period has been proposed as
rhythmic drugs on relaxation, especially in the asy- a clinical measure of thyroid hormone end-organ
nergic ventricles of patients with ischemic heart function (Manns et al., 1976).
disease. In addition, their influence on global and

segmental relaxation may be very difficult to eval- In conclusion, early detection of impaired relax-
uate (Engler et al., 1979) in view of their complex ation has been emphasized recently for the evalua-
pharmacodynamic actions on the myocardium, as tion of both global or regional ventricular function
well as on the peripheral vasculature and the neu- in patients with cardiac disease. Although there is
rohumoral adjustments that they provoke. Antiar- general agreement that performance of the heart
rhythmic agents may influence relaxation both by during the contraction phase is regulated through
a direct effect on the time course of inactivation two, though not entirely independent mechanisms,
(inactivation dependence) or by altering the loading i.e., changes in loading (volume and pressure) and
conditions (load dependence). Moreover, the use of changes in contractility, it has now been shown that
anesthetic agents in experimental animals (Vatner a dual control mechanism also operates during the
and Braunwald, 1975) may greatly alter the re- relaxation phase. Relaxation of the heart, both as a
sponse of various parameters to drug administra- muscle and a muscle-pump system, is governed by
tion, thus making extrapolation to the clinical situ- the continuous interplay of the sensitivity of the
ation difficult or impossible. In the conscious dog contractile system to the prevailing loading (load
with autonomous blockade, but without control of dependence) and the decaying activation (inacti-
hemodynamic loading factors, Engler et al. (1979) vation dependence). For a given set of loading con-
demonstrated a prolongation of the time constant ditions, relaxation can be modulated by subtle al-
of isovolumic left ventricular relaxation after quin- terations of the load sensitivity due to changes in
idine administration. the underlying dissipation of activation. Alterna-
tively, for a given load sensitivity, relaxation will be
Just as antiarrhythmic agents selectively depress influenced by alterations of the prevailing loads.
conduction and excitability in ischemic tissue (Hon- Relaxation abnormalities could therefore result
deghem and Cotner, 1978), they may selectively from alterations in the prevailing loading conditions
depress mechanical performance in ischemic wall in the presence of an unchanged load dependence,
segments. That antiarrhythmic agents can selec- or from alterations in the decay of activation under
tively depress mechanical performance in ischemic a constant set of loading conditions, or from both.
wall segments as compared to normal wall segments Because of the continuous interplay of the complex
was demonstrated for verapamil (Smith et al., loading of the intact heart during relaxation (con-
1976). This effect may slow relaxation by enhancing figurational deformation at peak systole, imped-
the degree of asynergy. Lidocaine, however, de- ance, Laplace relationship, filling of the coronary
reservoir, etc.) with the metabolic and neurohu- sients of mammalian cardiac muscle. In Crossbridge Mecha-
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NOVEMBER 1980

Circulation Research VOL. 47 NO. 5

Dual Control of Relaxation

DIRK L. BRUTSAERT, PHILIPPE R. HOUSMANS, AND MARC A. GOETHALS

our understanding of relaxation. Ventricular dia- as documented by the calcium-sensitive photopro-

LOAD INACTIVATION Mechanical Aspects of Relaxation of

skinned, Brij-58 treated ventricular cardiac cells of

saert, 1976) that this would cause them to rotate

avoid confusion with the familiar term of length-

pendently of the length range over which relaxation

moral and pharmacological interventions, suggest-

systolic volume (Ruttley et al., 1974), constitutes an

ance with its passive elastic properties, resulting in

disease. In addition, their influence on global and

Hoffman JIE (1978) Determinants and prediction of transmural

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