Download Mechanics of Relaxation of the Human Heart

Mechanics of Relaxation of the Human Heart
Denis Chemla, Catherine Coirault, Jean-Louis Hébert, and Yves Lecarpentier
Rapid and complete relaxation is a prerequisite for cardiac output adaptation to changes in loading conditions, inotropic stimulation, and heart rate. In the healthy human heart, the rate and
extent of relaxation depend mainly on actomyosin cross bridge dissociation and on left ventricular end-systolic volume, rather than on the afterload level.
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Physiological context
Between aortic valve closure and mitral valve opening, a
major drop in LV pressure occurs while LV volume is minimal
(ESV). The rapid decrease in LV stress boosts coronary diastolic filling, especially that of the left coronary artery. Thus LV
relaxation appears to contribute to adequate coronary perfusion. After mitral valve opening, rapid myocardial lengthening
and early diastolic LV filling occur at low left atrial pressure,
such that pulmonary circulation is protected. The LV fills
under the action of the instantaneous left atrial-to-LV pressure
gradient. In the normal heart, in which left atrial pressure is
low, the rate of change and magnitude of this gradient are
influenced mainly by the rate and extent of LV pressure fall.
The ability of the LV to relax both rapidly and completely is
of paramount importance for optimal LV filling during the
early diastolic period (6, 14).
During exercise, LV stroke volume increases as a result of
both increased contractility (via sympathetic stimulation) and
increased end-diastolic LV volume/preload (via Frank-Starling mechanism). This must be paralleled by an enhanced LV
filling volume. During exercise, both the enhanced LV filling
volume and the shortened diastolic interval resulting from the
increase in heart rate contribute to the marked increase in LV
filling rate in early diastole. Given that there are only moderate changes in left atrial pressure during exercise, appropriate left atrial-to-LV pressure gradient is essentially dependent
on the ability of the LV to enhance the speed of relaxation
and create low or even negative minimum diastolic LV pressure during exercise (6, 14).
In striated muscles, there is a difference in relaxation kinetics between skeletal and cardiac muscles. In most skeletal
muscle, relaxation occurs according to an isotonic-isometric
sequence, in which muscle lengthening precedes tension fall.
Relaxation of the heart is auxotonic, i.e., it involves simultaneous changes in ventricular pressure and length/volume.
However, it can be said that the heart relaxes according to
a reverse isometric-isotonic sequence, in which isovolumic
pressure drop occurs first, followed by isotonic relaxation (i.e., myocardial lengthening).
If isotonic relaxation occurred first, as observed in skeletal
muscles, LV filling pressure would have to be of similar magnitude to systemic pressure. Therefore, under normal conditions, the specific sequence of relaxation of the heart appears
to be beneficial because it minimizes filling pressures, thus
protecting pulmonary circulation. Because the initial pressure
drop occurs at fixed LV volume, essentially no work is performed by the isometrically relaxing LV. Furthermore, given
that myocardial lengthening occurs at low pressure, the work
performed during the early filling phase is also minimized.
Overall, the specific sequence of relaxation of the heart could
be especially beneficial from a thermoenergetic point of view.
Inactivation
D. Chemla, C. Coirault, J.-L. Hébert, and Y. Lecarpentier are in the Service
de Physiologie Cardio-Respiratoire, CHU de Bicêtre, Assistance PubliqueHôpitaux de Paris, 94 275 Le Kremlin-Bicêtre, and Unité Inserm U451-LoaEnsta-Ecole Polytechnique, 91 125 Palaiseau, France.
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Inactivation is defined as the intracellular processes leading to dissociation of actomyosin cross bridges and to the
lowering of intracellular Ca2+ concentration from 10–5 M to
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elaxation is the process by which heart muscle actively
returns, after contraction, to its initial conditions of load
and length. Over the past 25 years, physiologists, clinicians,
and pharmacologists have shown increasing interest in trying
to understand the regulation of myocardial relaxation. From a
physiological point of view, rapid and complete relaxation is a
prerequisite for cardiac output adaptation to changes in loading conditions, inotropic stimulation, and heart rate. From a
clinical point of view, the relaxation phase could be impaired
earlier and more profoundly than the contraction phase in
numerous cardiac diseases. Thus clinicians have speculated
that the diagnosis of isolated relaxation abnormalities may
help with the early identification of a subgroup of patients who
will subsequently develop systolic abnormalities. Finally, therapeutic interventions aimed at improving myocardial relaxation may be useful in the management of cardiac patients.
It is widely accepted that myocardial relaxation depends
essentially on the inactivating processes within the myocyte
and on loading conditions (1). Indeed, relaxation reflects the
imbalance between the number of strongly bound actomyosin
cross bridges and the total load imposed on the ventricle
(afterload + preload). Afterload is determined by extracardiac
and cardiac loading factors (Fig. 1), which potentially contribute to the so-called load dependence of relaxation (1).
Recent studies have demonstrated that left ventricular (LV)
end-systolic volume (ESV) also plays a key role in regulating
cardiac relaxation. The present paper briefly discusses the
influences of inactivation, load, and ESV on heart relaxation.
10–7 M. The term “lusitropy” is often used in place of inactivation. The rate of relaxation is determined mainly by active
Ca2+ pumping by the sarcoplasmic reticulum Ca2+ ATPase.
Phosphorylation of phospholamban, a membrane-bound
protein, removes its inhibitory effect on sarcoplasmic Ca2+
ATPase, thereby accelerating Ca2+ uptake and relaxation rate,
especially under isotonic conditions. The rate of relaxation is
also limited by 1) the affinity of troponin C (TnC) for Ca2+,
especially under isometric conditions; 2) Ca2+ extrusion outside the cell, mainly via Na+/Ca2+ exchange; and 3) the number and kinetics of working cross bridges (Table 1).
It is likely that the majority of working cross bridges detach
during isovolumic relaxation. The detachment of cross
bridges depends on ADP dissociation from the cross bridge
and on ATP binding. After the release of inorganic phosphate
and ADP, the actomyosin complex has a high affinity for ATP;
ATP binding to myosin decreases the affinity of myosin for
actin, thus leading to cross bridge detachment. Finally,
myosin ATPase activity determines the cross bridge cycling
rate and thus influences relaxation.
Troponin-tropomyosin interactions, cross bridge kinetics,
and amplification of activation (cooperativity) can be modified by 1) mechanical changes in sarcomere length and, to a
minor degree, in the strain put on cross bridges; 2) changes
in neurohormonal state (e.g., cAMP, angiotensin II); and 3)
cardiac endothelium-derived factors.
Influence of load on relaxation
The physiologist has no direct estimate of all the inactivation processes within myocytes. Furthermore, an integrated approach should improve our understanding of how
myocardial relaxation adapts to acute or chronic changes in
venous return and arterial impedance. Thus clinically rele-
vant insights into the regulatory processes of relaxation have
generally concerned the link between relaxation mechanics
and loading conditions.
The sensitivity of the timing of relaxation to the load
imposed before the onset of contraction (systolic load) is a
manifestation of the shortening-induced deactivation phenomenon: a twitch contracting against light or medium load
ends earlier than the fully isometric twitch (1, 2, 8, 9). Thus
the more the muscle is allowed to shorten the shorter the
overall duration of the contraction-relaxation cycle. A clinical illustration of this load dependence is that increased systolic load tends to delay relaxation (1).
Animal studies have shown that the rate of tension/pressure
fall is hardly affected by preload changes. The isovolumic
relaxation rate mainly depends on LV end-systolic pressure
(ESP) and/or ESV (5). Consistent results have been reported in
animals, with increased afterload having a slowing effect on
the rate of pressure fall (i.e., there is an increase in the time
constant tau of the monoexponential pressure fall) (1, 5, 6,
10). This load dependence of the isovolumic relaxation rate
has been shown to be modulated by the inotropic state and
the homogeneity of contraction, as well as the timing of imposition of peak systolic pressure (1, 5, 6, 8, 10). Recently, more
complex effects of load on relaxation rate (accelerating or
slowing effects) have been reported in dogs (7).
The results obtained in the human heart are at variance with
those obtained in animal studies. In humans, the rate of LV isovolumic relaxation appears to be essentially independent of
loading conditions in healthy subjects, provided that changes in
afterload are moderate. Conversely, the relaxation rate becomes
gradually more load dependent as systolic dysfunction progresses (4). The unexpected finding regarding the load independence of the isovolumic relaxation rate in healthy humans
has yet to be explained (4, 7, 11).
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FIGURE 1. Factors that determine left ventricular (LV) afterload at any time. LV afterload is determined by factors intrinsic to LV chamber (anatomical factors,
intrinsic LV load) and by factors extrinsic to LV chamber (arterial load, other factors). All these factors may potentially be involved in load dependence of relaxation. RV, right ventricle.
Table 1.
Intracellular processes limiting the rate of relaxation
Rate of Ca2+ dissociation from troponin C
Affinity of troponin C for Ca2+
Ca2+ uptake by the Ca2+ ATPase of the sarcoplasmic reticulum
Na+ / Ca2+ exchange
Sarcolemmal Ca2+ ATPase
Ca2+ buffers
Troponin-tropomyosin interaction with actin
Crossbridge properties
Resynthesis of ATP
Ca2+ affinity and sensitivity of myofilaments are modulated by several factors, including sarcomere length, troponin I, C protein,
myosin LC2, Ca2+, pH, inorganic phosphate, Mg2+, temperature, ionic strength, and neurohormonal and endothelium-derived
factors. Ca2+-pumping ATPase of the sarcoplasmic reticulum requires phosphorylation of membrane protein phospholamban.
Such phosphorylation is acheived either by cAMP-dependent pathway (β-adrenergic stimulation) or by Ca2+ -calmodulin
pathway. Na+ / Ca2+ exchanger is energetically linked to Na+/K+ ATPase. Energetic changes for phosphocreatine hydrolysis
have a key role in regulating intracellular ADP and ATP concentrations.
The effects of load on the relaxation rate may be intrinsically linked to the afterload level (via increased strain put on
cross bridges and cooperativity, changes in homogeneity,
coronary circulation, or neurohormonal stimulation) or afterload timing. The effects of load may also be explained by
changes in ESV, thus modifying intrinsic load and lengthdependent inactivation.
Rate and extent of relaxation: the role of ESV
The ability to reduce ESV contributes to the active restoration of LV dimension in early diastole. Reduced ESV enhances
the rate and extent of the isovolumic pressure fall (3, 13, 14)
and enhances the rate of myocardial active lengthening (15).
In both cases, this accelerating effect has been observed irrespective of the loading conditions (3, 13–15). Two mechanisms explain why the rate and extent of relaxation are so
tightly linked to ESV. First, the amount of potential energy
stored during contraction and released during relaxation is
negatively related to the end-systolic length/volume; second,
the decay of mechanical activity could be accelerated at short
end-systolic length (length-dependent inactivation) (Table 2).
Restoring forces are generated when the LV contracts
below its equilibrium volume (Veq). The magnitude of restoring forces is inversely related to ESV. This suction effect contributes to LV filling at low physiological filling pressure and
when higher filling rates are required (e.g., exercise). There is
also an elastic recoil of external forces surrounding the
myocytes, mainly the extracellular elastic components
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deformed and compressed during ventricular contraction
(transmural and three-dimensional deformations).
The (sarcomere) length dependence of activation has
been related to length-dependent changes in myofilament
overlap and interfilament lattice spacing, Ca2+ release by
the sarcoplasmic reticulum, and the affinity of TnC for Ca2+.
If these length-induced changes still operate at end systole,
hastening of relaxation would occur at small ESV. Furthermore, shortening may be associated with changes in myofilament-bound Ca2+ and with a decreased likelihood of new
actomyosin interactions.
Lusitropic reserve
A physiological approach to cardiac relaxation should
also help improve our understanding of how relaxation
adapts to changes in inotropy and heart rate. When contractility is increased, ESV decreases, helping to accelerate
relaxation. Furthermore, increased contractility increases
restoring forces for a given ESV below Veq and also increases
the peak lengthening rate at any end-systolic length (3,
13–15). Thus relaxation can be intrinsically promoted (i.e.,
independently of any effect on systolic shortening) thanks to
the amount of lusitropy in reserve. β-Adrenergic stimulation
and increased heart rate are two major ways by which
lusitropic reserve can be mobilized.
Increased cAMP leads to increased cross bridge cycling
and activates protein kinase A-induced phosphorylation of
both phospholamban and troponin I (TnI). End-systolic
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Cross bridge number, and proportion of strongly bound cross bridges
Activation dependence
Length dependence
Load dependence
Cross bridge detachment
[ADP]i and [ATP]i dependence
Activation dependence (cycling rate, myosin ATPase activity)
Elasticity
Viscous-like friction
length modulates the extent to which β-adrenergic stimulation exerts its positive lusitropic effects (12). Tachycardia
induces a positive lusitropic effect by speeding up the activation/inactivation processes. Enhanced inotropy (the positive
staircase phenomenon), increased homogeneity, and/or the
associated cAMP increases may also be involved.
It is widely acknowledged that, in addition to inactivation
(lusitropy) and load, myocardial relaxation also depends on a
third regulatory process: the homogeneity of the contractionrelaxation cycle (1). Indeed, the lusitropic reserve may be mobilized by interventions increasing the homogeneity of the contraction-relaxation cycle via different mechanisms that increase
the speed of conduction, the extracellular temperature, the
heart rate, and the inotropic state. Finally, it has been suggested
that internal load would be activation/inactivation dependent.
We have discussed the respective influences of LV pressure
and volume on myocardial relaxation. It is important to remember when studying the hemodynamic correlates of relaxation
rate that LVESP and ESV are not interchangeable variables. Thus
the question arises as to whether relaxation is influenced rather
by LVESP (load dependence) or by ESV (length dependence).
Although it is likely that both ESV and systolic load play a
part in regulating the rate and extent of isovolumic relaxation,
we suggest that ESV has a prominent role. Our proposition is
based on the following considerations: 1) the intrinsic properties of the myofilaments and the systolic storage of potential
energy are highly dependent on myocardial length and only to
a minor degree on load; 2) the effects of end-systolic length/vol-
Table 2.
Integrated function
Modulation of cardiac function is mediated mainly
through changes in preload (Frank-Starling mechanism), neurohormonal stimulation, and heart rate, such that cardiac
output can meet organ demand. Integrated function involves
coordinated changes in contraction and relaxation, and
further studies are needed to describe the different aspects
of contraction-relaxation coupling (biochemical, genetic,
mechanical, thermoenergetic, and electrical aspects).
Right ventricular (RV) filling is facilitated by elastic recoil
of the LV and by elastic recoil of the RV myocardium, leading
to a piston-like motion of the tricuspid annulus. Elastic recoil
Main factors related to left ventricular end-systolic volume and factors that modulate rate and extent of relaxation
Stored potential energy (intrinsic load)
Elasting recoil
Ventricular restoring forces (ESV < Veq)
Internal restoring forces (when present)
Twisting/untwisting
Extrinsic load
LVESP
Stretching of great vessels and connective tissue
Coronary compression
Right ventricular load
Sarcomere length at end systole
Myofilament overlap
Lattice spacing
Instantaneous length and sliding velocity of the myofilaments
Troponin-tropomyosin interactions
Amplification of activation (cooperativity)
Affinity of troponin C for Ca2+
Modulation of sarcoplasmic reticulum function
Ventricular restoring forces are generated when LV contracts below its equilibrium volume (Veq), with Veq = volume when
transmural pressure is 0 in fully relaxed state. At cellular level, internal restoring forces, when present, involve resistance to
bending and double overlapping of thin filaments at sarcomere length below slack length. LV end-systolic pressure (LVESP)
is a linear function of end-systolic volume (ESV), slope of which is thought to reflect cardiac inotropic state.
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ESV, afterload, and lusitropy
ume on relaxation rate and extent have been shown to be consistent in animals and humans (3, 13–15), whereas the effects of
load are almost negligible in healthy humans (4) and still need
to be clarified in animal studies (1, 5, 7, 8); 3) load dependence
of relaxation can be considered a manifestation of the deactivating effects induced by shortening (1); and 4) pressure fall and
onset of lengthening both occur at end-systolic length.
A simplified framework of afterload-independent/lengthdependent behavior may help improve our understanding of
the regulation of the contraction-relaxation cycle in the
healthy human heart (Fig. 2). Contraction and relaxation performances may be determined by LV volume at the onset of
each phase and by inotropy/lusitropy, thus explaining the
afterload independence of the contraction-relaxation cycle.
This approach would integrate the regulatory role of myocardial length, the contractile properties of the myocyte, and the
elastic properties of the LV chamber (intrinsic load).
could be especially important for pump function, given the
extremely low RV filling pressure.
Investigation of the interplay between relaxation and
myocardial compliance did not fall within the scope of the
present paper. Relaxation could be impaired earlier and more
profoundly than contraction in numerous cardiac diseases (6,
10). Slowed and incomplete relaxation has a negative effect
on the filling function of the heart, especially in cases in
which chamber compliance is decreased, diastolic duration
is shortened, or the limit of preload reserve is reached.
Conclusions
For a given heart rate, systolic function of the healthy
human heart depends on end-diastolic volume (preload) and
on activation (inotropy). It has long been accepted that
myocardial relaxation depends essentially on afterload and
inactivation (lusitropy). Recent studies support an alternative
framework, in which relaxation depends mainly on ESV and
inactivation. This approach could explain the load independence of the relaxation rate in the healthy human heart. This
framework may help improve our understanding of the pathophysiological aspects of human heart relaxation.
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This study was supported by grants from PHRC AOM96174, Assistance
Publique-Hôpitaux de Paris.
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FIGURE 2. A simplified, afterload-independent/length-dependent framework for regulation of contraction-relaxation cycle in healthy human heart. For a given
heart rate, rate and extent of relaxation depend mainly on end-systolic volume (ESV) and inactivation (lusitropy). End-diastolic volume (EDV) and ESV are related
through 1) regulatory processes whereby a constant stroke volume (SV) is maintained (ESV = EDV – SV) and 2) influence of venous return (EDV = ESV + venous
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Peter Jonas
Glutamate is the main excitatory transmitter in the mammalian CNS, mediating fast synaptic
transmission primarily by activation of AMPA-type glutamate receptor channels. Both synaptic structure and a cell-specific molecular switch in the AMPA receptor subunit expression are involved in the regulation of the synaptic signaling time course.
C
hemical synaptic transmission involves the release of a
transmitter into the synaptic cleft and the subsequent activation of postsynaptic receptors. The most extensively characterized synapse is the neuromuscular junction, formed between
motor axons and skeletal muscle fibers. The transmitter acetylcholine (ACh) is released from synaptic vesicles in multimolecular packets, or quanta, and activates nicotinic ACh receptors
(AChRs) in the postsynaptic membrane. This generates postsynaptic conductance changes of fast time course and large
amplitude, which induce reliable activation of the muscle fiber.
In the mammalian central nervous system (CNS), glutamate is
the main excitatory transmitter. The principles of synaptic communication at glutamatergic synapses, however, appear to be
more complex than at the neuromuscular junction. First, glutamatergic synapses differ in morphological properties, such as
number of release sites and presence of dendritic spines. Second, synapses in different circuitries differ substantially in impact
and time course of synaptic signaling. Finally, glutamate activates several different types of ionotropic and metabotropic
receptors: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate
receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs),
kainate receptors (KARs), and metabotropic glutamate receptors
coupled to either inositol 1,4,5-trisphosphate (IP3; class 1
mGluRs) or cAMP-signaling cascades (class 2 and 3 mGluRs)
(10). On the basis of extensive work in the last ten years, we are
beginning to understand how cellular and molecular factors
shape functional differences between glutamatergic synapses.
P. Jonas is in the Physiologisches Institut der Universität Freiburg, D-79104
Freiburg, Germany.
0886-1714/99 5.00 © 2000 Int. Union Physiol. Sci./Am.Physiol. Soc.
The time course of the excitatory postsynaptic currents
The patch-clamp technique in brain slices developed by
Bert Sakmann and co-workers allows us to record from neurons in the CNS with high resolution in an intact synaptic
environment. Analysis of several synapses revealed that fast
glutamate-mediated signaling is predominantly mediated by
AMPARs (5, 9, 15). However, the time course of signaling differs substantially between synapses. This is illustrated in Fig. 1,
which shows AMPAR-mediated evoked excitatory postsynaptic currents (EPSCs) at three well-characterized synapses: the
mossy fiber-CA3 pyramidal cell synapse in the hippocampus
(9), the granule cell-basket cell synapse in the dentate
gyrus (5), and the calyx synapse on neurons in the medial
nucleus of the trapezoid body (MNTB) in the brain stem (1).
Throughout the CNS, slow AMPAR-mediated evoked EPSCs
are generated at excitatory synapses on hippocampal and
neocortical principal neurons (decay time constant ~5 ms at
22°C). In contrast, fast AMPAR-mediated evoked EPSCs are
generated at glutamatergic synapses on hippocampal and
neocortical inhibitory interneurons and on neurons in the
auditory pathway (decay time constant ~1–2 ms).
Synchrony vs. asynchrony of quantal release
Which factors determine the time course of the AMPARmediated postsynaptic conductance change? First, asynchrony
of quantal release needs to be considered (Fig. 2A; Refs. 3, 5,
and 8). Evoked release of transmitter involves several steps:
invasion of the action potential into the presynaptic terminal,
activation of voltage-gated Ca2+ channels, Ca2+ entry into the
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The Time Course of Signaling at Central
Glutamatergic Synapses