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.

Relaxation 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.


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.

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 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 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).

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Table 1.

Intracellular processes limiting the rate of relaxation

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 relevant 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).

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 length-dependent 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, 1315). 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).

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Table 2.

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

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 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, 1315). 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 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 contraction-relaxation 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.

ESV, afterload, and lusitropy

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/volume on relaxation rate and extent have been shown to be consistent in animals and humans (3, 1315), 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/length-dependent 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).


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 return). When afterload increases, systolic function is preserved by increased preload and/or increased inotropy. Relaxation rate and extent may be maintained by preserved ESV and/or increased lusitropy. Preserved ESV could be explained by natural steepness of LV end-systolic pressure-ESV relationship and/or by homeometric regulation (increased inotropy thus preserving stroke volume). This latter mechanism may be combined with increased lusitropy, thus counteracting potential slowing effects of increased load. β-Adrenergic stimulation also increases lusitropy when afterload is chronically increased. On the basis of this framework, length-dependent regulatory processes predominate over load-dependent processes in the contraction-relaxation cycle of healthy myocardium.

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 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.


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.


This study was supported by grants from PHRC AOM96174, Assistance Publique-Hôpitaux de Paris.


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