Mechanics of Relaxation of the Human Heart

8/4/2019 Mechanics of Relaxation of the Human Heart

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Relaxation is the process by which heart muscle activelyreturns, after contraction, to its initial conditions of loadand length. Over the past 25 years, physiologists, clinicians,and pharmacologists have shown increasing interest in tryingto understand the regulation of myocardial relaxation. From aphysiological point of view, rapid and complete relaxation is aprerequisite for cardiac output adaptation to changes in load-ing conditions, inotropic stimulation, and heart rate. From aclinical point of view, the relaxation phase could be impairedearlier and more profoundly than the contraction phase in

numerous cardiac diseases. Thus clinicians have speculatedthat the diagnosis of isolated relaxation abnormalities mayhelp with the early identification of a subgroup of patients whowill subsequently develop systolic abnormalities. Finally, ther-apeutic interventions aimed at improving myocardial relax-ation may be useful in the management of cardiac patients.

It is widely accepted that myocardial relaxation dependsessentially on the inactivating processes within the myocyteand on loading conditions (1). Indeed, relaxation reflects theimbalance between the number of strongly bound actomyosincross bridges and the total load imposed on the ventricle(afterload + preload). Afterload is determined by extracardiacand cardiac loading factors (Fig. 1), which potentially con-tribute 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 regulatingcardiac relaxation. The present paper briefly discusses theinfluences of inactivation, load, and ESV on heart relaxation.

Physiological context

Between aortic valve closure and mitral valve opening, amajor drop in LV pressure occurs while LV volume is minimal(ESV). The rapid decrease in LV stress boosts coronary dias-tolic filling, especially that of the left coronary artery. Thus LV

relaxation appears to contribute to adequate coronary perfu-sion. After mitral valve opening, rapid myocardial lengtheningand early diastolic LV filling occur at low left atrial pressure,such that pulmonary circulation is protected. The LV fillsunder the action of the instantaneous left atrial-to-LV pressuregradient. In the normal heart, in which left atrial pressure is

low, the rate of change and magnitude of this gradient areinfluenced mainly by the rate and extent of LV pressure fall.The ability of the LV to relax both rapidly and completely isof paramount importance for optimal LV filling during theearly diastolic period (6, 14).

During exercise, LV stroke volume increases as a result ofboth increased contractility (via sympathetic stimulation) andincreased end-diastolic LV volume/preload (via Frank-Star-ling mechanism). This must be paralleled by an enhanced LVfilling volume. During exercise, both the enhanced LV filling

volume and the shortened diastolic interval resulting from theincrease in heart rate contribute to the marked increase in LVfilling rate in early diastole. Given that there are only moder-ate changes in left atrial pressure during exercise, appropri-ate left atrial-to-LV pressure gradient is essentially dependenton the ability of the LV to enhance the speed of relaxationand create low or even negative minimum diastolic LV pres-sure during exercise (6, 14).

In striated muscles, there is a difference in relaxation kinet-ics between skeletal and cardiac muscles. In most skeletalmuscle, relaxation occurs according to an isotonic-isometricsequence, in which muscle lengthening precedes tension fall.Relaxation of the heart is auxotonic, i.e., it involves simulta-neous changes in ventricular pressure and length/volume.However, it can be said that the heart relaxes according toa reverse isometric-isotonic sequence, in which isovolumicpressure drop occurs first, followed by isotonic relax-ation (i.e., myocardial lengthening).

If isotonic relaxation occurred first, as observed in skeletalmuscles, LV filling pressure would have to be of similar mag-nitude to systemic pressure. Therefore, under normal condi-tions, the specific sequence of relaxation of the heart appearsto be beneficial because it minimizes filling pressures, thusprotecting pulmonary circulation. Because the initial pressuredrop occurs at fixed LV volume, essentially no work is per-

formed by the isometrically relaxing LV. Furthermore, giventhat myocardial lengthening occurs at low pressure, the workperformed during the early filling phase is also minimized.Overall, the specific sequence of relaxation of the heart couldbe especially beneficial from a thermoenergetic point of view.

Inactivation

Inactivation is defined as the intracellular processes lead-ing to dissociation of actomyosin cross bridges and to thelowering of intracellular Ca2+ concentration from 105 M to

78 News Physiol. Sci. Volume 15 April 2000 0886-1714/99 5.00 2000 Int. Union Physiol. Sci./Am.Physiol. Soc.

Mechanics of Relaxation of the Human HeartDenis Chemla, Catherine Coirault, Jean-Louis Hbert, and Yves Lecarpentier

Rapid and complete relaxation is a prerequisite for cardiac output adaptation to changes in load-ing conditions, inotropic stimulation, and heart rate. In the healthy human heart, the rate andextent of relaxation depend mainly on actomyosin cross bridge dissociation and on left ven-

tricular end-systolic volume, rather than on the afterload level.

D. Chemla, C. Coirault, J.-L. Hbert, and Y. Lecarpentier are in the Servicede Physiologie Cardio-Respiratoire, CHU de Bictre, Assistance Publique-Hpitaux de Paris, 94 275 Le Kremlin-Bictre, and Unit Inserm U451-Loa-Ensta-Ecole Polytechnique, 91 125 Palaiseau, France.


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107 M. The term lusitropy is often used in place of inacti-vation. The rate of relaxation is determined mainly by activeCa2+ pumping by the sarcoplasmic reticulum Ca2+ ATPase.Phosphorylation of phospholamban, a membrane-boundprotein, removes its inhibitory effect on sarcoplasmic Ca2+

ATPase, thereby accelerating Ca2+ uptake and relaxation rate,especially under isotonic conditions. The rate of relaxation isalso limited by 1) the affinity of troponin C (TnC) for Ca2+,especially under isometric conditions; 2) Ca2+ extrusion out-side the cell, mainly via Na+/Ca2+ exchange; and 3) the num-ber and kinetics of working cross bridges (Table 1).

It is likely that the majority of working cross bridges detachduring isovolumic relaxation. The detachment of crossbridges depends on ADP dissociation from the cross bridgeand on ATP binding. After the release of inorganic phosphateand ADP, the actomyosin complex has a high affinity for ATP;ATP binding to myosin decreases the affinity of myosin foractin, thus leading to cross bridge detachment. Finally,myosin ATPase activity determines the cross bridge cyclingrate and thus influences relaxation.

Troponin-tropomyosin interactions, cross bridge kinetics,and amplification of activation (cooperativity) can be modi-fied by 1) mechanical changes in sarcomere length and, to a

minor degree, in the strain put on cross bridges; 2) changesin 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 inactiva-tion processes within myocytes. Furthermore, an inte-gra ted approach should improve our understanding of howmyocardial relaxation adapts to acute or chronic changes invenous return and arterial impedance. Thus clinically rele-

vant insights into the regulatory processes of relaxation havegenerally concerned the link between relaxation mechanicsand loading conditions.

The sensitivity of the timing of relaxation to the loadimposed before the onset of contraction (systolic load) is amanifestation of the shortening-induced deactivation phe-nomenon: a twitch contracting against light or medium loadends earlier than the fully isometric twitch (1, 2, 8, 9). Thusthe more the muscle is allowed to shorten the shorter theoverall duration of the contraction-relaxation cycle. A clini-cal illustration of this load dependence is that increased sys-tolic load tends to delay relaxation (1).

Animal studies have shown that the rate of tension/pressurefall is hardly affected by preload changes. The isovolumicrelaxation rate mainly depends on LV end-systolic pressure(ESP) and/or ESV (5). Consistent results have been reported inanimals, with increased afterload having a slowing effect onthe rate of pressure fall (i.e., there is an increase in the timeconstant tau of the monoexponential pressure fall) (1, 5, 6,10). This load dependence of the isovolumic relaxation ratehas been shown to be modulated by the inotropic state andthe homogeneity of contraction, as well as the timing of impo-sition of peak systolic pressure (1, 5, 6, 8, 10). Recently, more

complex effects of load on relaxation rate (accelerating orslowing 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 iso-volumic relaxation appears to be essentially independent ofloading conditions in healthy subjects, provided that changes inafterload are moderate. Conversely, the relaxation rate becomesgradually more load dependent as systolic dysfunction pro-gresses (4). The unexpected finding regarding the load inde-pendence of the isovolumic relaxation rate in healthy humanshas 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 relax-ation. RV, right ventricle.


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The effects of load on the relaxation rate may be intrinsi-cally linked to the afterload level (via increased strain put oncross bridges and cooperativity, changes in homogeneity,coronary circulation, or neurohormonal stimulation) or after-load timing. The effects of load may also be explained bychanges in ESV, thus modifying intrinsic load and length-dependent inactivation.

Rate and extent of relaxation: the role of ESV

The ability to reduce ESV contributes to the active restora-tion of LV dimension in early diastole. Reduced ESV enhancesthe 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 irre-spective of the loading conditions (3, 1315). Two mecha-nisms explain why the rate and extent of relaxation are sotightly linked to ESV. First, the amount of potential energy

stored during contraction and released during relaxation isnegatively related to the end-systolic length/volume; second,the decay of mechanical activity could be accelerated at shortend-systolic length (length-dependent inactivation) (Table 2).

Restoring forces are generated when the LV contractsbelow its equilibrium volume (Veq). The magnitude of restor-ing forces is inversely related to ESV. This suction effect con-tributes to LV filling at low physiological filling pressure andwhen higher filling rates are required (e.g., exercise). There isalso an elastic recoil of external forces surrounding themyocytes, mainly the extracellular elastic components

deformed and compressed during ventricular contraction(transmural and three-dimensional deformations).

The (sarcomere) length dependence of activation hasbeen related to length-dependent changes in myofilamentoverlap and interfilament lattice spacing, Ca2+ release bythe 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. Further-more, shortening may be associated with changes in myofil-ament-bound Ca2+ and with a decreased likelihood of newactomyosin interactions.

Lusitropic reserve

A physiological approach to cardiac relaxation shouldalso help improve our understanding of how relaxationadapts to changes in inotropy and heart rate. When contrac-tility is increased, ESV decreases, helping to accelerate

relaxation. Furthermore, increased contractility increasesrestoring forces for a given ESV below Veq and also increasesthe peak lengthening rate at any end-systolic length (3,1315). Thus relaxation can be intrinsically promoted (i.e.,independently of any effect on systolic shortening) thanks tothe amount of lusitropy in reserve. -Adrenergic stimulationand increased heart rate are two major ways by whichlusitropic reserve can be mobilized.

Increased cAMP leads to increased cross bridge cyclingand activates protein kinase A-induced phosphorylation ofboth phospholamban and troponin I (TnI). End-systolic

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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 reticulumNa+/ Ca2+ exchangeSarcolemmal Ca2+ ATPaseCa2+ buffers

Troponin-tropomyosin interaction with actin

Crossbridge properties Cross bridge number, and proportion of strongly bound cross bridgesActivation dependenceLength dependenceLoad dependence

Cross bridge detachment[ADP]i and [ATP]i dependenceActivation dependence (cycling rate, myosin ATPase activity)Elasticity

Viscous-like friction

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-derivedfactors. Ca2+-pumping ATPase of the sarcoplasmic reticulum requires phosphorylation of membrane protein phospholamban.Such phosphorylation is acheived either by cAMP-dependent pathway (-adrenergic stimulation) or by Ca2+ -calmodulinpathway. Na+ / Ca2+ exchanger is energetically linked to Na+/K+ ATPase. Energetic changes for phosphocreatine hydrolysishave a key role in regulating intracellular ADP and ATP concentrations.


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length modulates the extent to which -adrenergic stimula-tion exerts its positive lusitropic effects (12). Tachycardiainduces a positive lusitropic effect by speeding up the activa-tion/inactivation processes. Enhanced inotropy (the positivestaircase phenomenon), increased homogeneity, and/or theassociated cAMP increases may also be involved.

It is widely acknowledged that, in addition to inactivation(lusitropy) and load, myocardial relaxation also depends on athird regulatory process: the homogeneity of the contraction-

relaxation cycle (1). Indeed, the lusitropic reserve may be mobi-lized by interventions increasing the homogeneity of the con-traction-relaxation cycle via different mechanisms that increasethe speed of conduction, the extracellular temperature, theheart rate, and the inotropic state. Finally, it has been suggestedthat internal load would be activation/inactivation dependent.

ESV, afterload, and lusitropy

We have discussed the respective influences of LV pressureand volume on myocardial relaxation. It is important to remem-ber when studying the hemodynamic correlates of relaxationrate that LVESP and ESV are not interchangeable variables. Thus

the question arises as to whether relaxation is influenced ratherby LVESP (load dependence) or by ESV (length dependence).

Although it is likely that both ESV and systolic load play apart in regulating the rate and extent of isovolumic relaxation,we suggest that ESV has a prominent role. Our proposition isbased on the following considerations: 1) the intrinsic proper-ties of the myofilaments and the systolic storage of potentialenergy are highly dependent on myocardial length and only toa minor degree on load; 2) the effects of end-systolic length/vol-

ume on relaxation rate and extent have been shown to be con-sistent in animals and humans (3, 1315), whereas the effects ofload are almost negligible in healthy humans (4) and still needto be clarified in animal studies (1, 5, 7, 8); 3) load dependenceof relaxation can be considered a manifestation of the deacti-vating effects induced by shortening (1); and 4) pressure fall andonset of lengthening both occur at end-systolic length.

A simplified framework of afterload-independent/length-dependent behavior may help improve our understanding of

the regulation of the contraction-relaxation cycle in thehealthy human heart (Fig. 2). Contraction and relaxation per-formances may be determined by LV volume at the onset ofeach phase and by inotropy/lusitropy, thus explaining theafterload independence of the contraction-relaxation cycle.This approach would integrate the regulatory role of myocar-dial length, the contractile properties of the myocyte, and theelastic properties of the LV chamber (intrinsic load).

Integrated function

Modulation of cardiac function is mediated mainlythrough changes in preload (Frank-Starling mechanism), neu-

rohormonal stimulation, and heart rate, such that cardiacoutput can meet organ demand. Integrated function involvescoordinated changes in contraction and relaxation, andfurther studies are needed to describe the different aspectsof contraction-relaxation coupling (biochemical, genetic,mechanical, thermoenergetic, and electrical aspects).

Right ventricular (RV) filling is facilitated by elastic recoilof the LV and by elastic recoil of the RV myocardium, leadingto a piston-like motion of the tricuspid annulus. Elastic recoil

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Table 2. Main factors related to left ventricular end-systolic volume and factors that modulate rate and extent of relaxation

Stored potential energy (intrinsic load) Elasting recoilVentricular restoring forces (ESV < Veq)Internal restoring forces (when present)Twisting/untwisting

Extrinsic load LVESPStretching of great vessels and connective tissueCoronary compressionRight ventricular load

Sarcomere length at end systole Myofilament overlapLattice spacing

Instantaneous length and sliding velocity of the myofilamentsTroponin-tropomyosin interactionsAmplification 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 whentransmural pressure is 0 in fully relaxed state. At cellular level, internal restoring forces, when present, involve resistance tobending 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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could be especially important for pump function, given theextremely low RV filling pressure.

Investigation of the interplay between relaxation andmyocardial compliance did not fall within the scope of thepresent paper. Relaxation could be impaired earlier and moreprofoundly than contraction in numerous cardiac diseases (6,10). Slowed and incomplete relaxation has a negative effecton the filling function of the heart, especially in cases inwhich chamber compliance is decreased, diastolic durationis shortened, or the limit of preload reserve is reached.

Conclusions

For a given heart rate, systolic function of the healthyhuman heart depends on end-diastolic volume (preload) andon activation (inotropy). It has long been accepted thatmyocardial relaxation depends essentially on afterload andinactivation (lusitropy). Recent studies support an alternativeframework, in which relaxation depends mainly on ESV andinactivation. This approach could explain the load indepen-dence of the relaxation rate in the healthy human heart. Thisframework may help improve our understanding of the patho-physiological aspects of human heart relaxation.

This study was supported by grants from PHRC AOM96174, AssistancePublique-Hpitaux 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 givenheart rate, rate and extent of relaxation depend mainly on end-systolic volume (ESV) and inactivation (lusitropy). End-diastolic volume (EDV) and ESV are relatedthrough 1) regulatory processes whereby a constant stroke volume (SV) is maintained (ESV = EDV SV) and 2) influence of venous return (EDV = ESV + venousreturn). When afterload increases, systolic function is preserved by increased preload and/or increased inotropy. Relaxation rate and extent may be maintainedby preserved ESV and/or increased lusitropy. Preserved ESV could be explained by natural steepness of LV end-systolic pressure-ESV relationship and/or byhomeometric regulation (increased inotropy thus preserving stroke volume). This latter mechanism may be combined with increased lusitropy, thus counteract-ing potential slowing effects of increased load. -Adrenergic stimulation also increases lusitropy when afterload is chronically increased. On the basis of thisframework, length-dependent regulatory processes predominate over load-dependent processes in the contraction-relaxation cycle of healthy myocardium.


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Chemical synaptic transmission involves the release of atransmitter into the synaptic cleft and the subsequent acti-vation of postsynaptic receptors. The most extensively charac-terized synapse is the neuromuscular junction, formed betweenmotor axons and skeletal muscle fibers. The transmitter acetyl-choline (ACh) is released from synaptic vesicles in multimolec-ular packets, or quanta, and activates nicotinic ACh receptors(AChRs) in the postsynaptic membrane. This generates postsy-naptic conductance changes of fast time course and largeamplitude, which induce reliable activation of the muscle fiber.

In the mammalian central nervous system (CNS), glutamate isthe main excitatory transmitter. The principles of synaptic com-munication at glutamatergic synapses, however, appear to bemore complex than at the neuromuscular junction. First, gluta-matergic synapses differ in morphological properties, such asnumber of release sites and presence of dendritic spines. Sec-ond, synapses in different circuitries differ substantially in impactand time course of synaptic signaling. Finally, glutamate acti-vates several different types of ionotropic and metabotropicreceptors: -amino-3-hydroxy-5-methyl-4-isoxazolepropionate

receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs),kainate receptors (KARs), and metabotropic glutamate receptorscoupled to either inositol 1,4,5-trisphosphate (IP3; class 1mGluRs) or cAMP-signaling cascades (class 2 and 3 mGluRs)(10). On the basis of extensive work in the last ten years, we arebeginning to understand how cellular and molecular factorsshape functional differences between glutamatergic synapses.

The time course of the excitatory postsynaptic currents

The patch-clamp technique in brain slices developed byBert Sakmann and co-workers allows us to record from neu-rons in the CNS with high resolution in an intact synapticenvironment. Analysis of several synapses revealed that fastglutamate-mediated signaling is predominantly mediated byAMPARs (5, 9, 15). However, the time course of signaling dif-

fers substantially between synapses. This is illustrated in Fig. 1,which shows AMPAR-mediated evoked excitatory postsynap-tic currents (EPSCs) at three well-characterized synapses: themossy fiber-CA3 pyramidal cell synapse in the hippocampus(9), the granule cell-basket cell synapse in the dentategyrus (5), and the calyx synapse on neurons in the medialnucleus of the trapezoid body (MNTB) in the brain stem (1).Throughout the CNS, slow AMPAR-mediated evoked EPSCsare generated at excitatory synapses on hippocampal andneocortical principal neurons (decay time constant ~5 ms at22C). In contrast, fast AMPAR-mediated evoked EPSCs aregenerated at glutamatergic synapses on hippocampal andneocortical inhibitory interneurons and on neurons in theauditory pathway (decay time constant ~12 ms).

Synchrony vs. asynchrony of quantal release

Which factors determine the time course of the AMPAR-mediated postsynaptic conductance change? First, asynchronyof 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

830886-1714/99 5.00 2000 Int. Union Physiol. Sci./Am.Physiol. Soc. News Physiol. Sci. Volume 15 April 2000

The Time Course of Signaling at CentralGlutamatergic SynapsesPeter 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 synap-tic structure and a cell-specific molecular switch in the AMPA receptor subunit expres-sion are involved in the regulation of the synaptic signaling time course.

P. Jonas is in the Physiologisches Institut der Universitt Freiburg, D-79104Freiburg, Germany.

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12. Suard, I., N. Pry-Man, C. Coirault, J. C. Pourny, Y. Lecarpentier, and D.Chemla. Relaxant effects of isoproterenol in isolated cardiac muscle:influence of loading patterns. Am. J. Physiol. Heart Circ. Physiol. 267:H1814H1823, 1994.

13. Udelson, J. E., S. L. Bacharach, R. O. Cannon III, and R. O. Bonow. Mini-mum left ventricular pressure during -adrenergic stimulation in humansubjects. Evidence for elastic recoil and diastolic suction in the normalheart. Circulation 82: 11741182, 1990.

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Mechanics of Relaxation of the Human Heart