(Circulation. 1997;95:745-752.)
© 1997 American Heart Association, Inc.
Articles |
Relaxation–Systolic Pressure Relation
A Load-Independent Assessment of Left Ventricular Contractility
the Cardiovascular Research Unit (Department of Experimental Surgery), the Division of Cardiology (T.C.G.), and the Division of Anesthesiology (S.G.D.), University of Antwerp, Belgium; and the Laboratory of Physiology (A.F.L.-M.), Faculty of Medicine, University of Porto, Hospital de Sao Joao, Oporto, Portugal.
Correspondence to Thierry C. Gillebert, MD, Division of Cardiology, University Hospital Antwerp, Wilrijkstraat, 10, B2650 Edegem, Belgium. E-mail gillebe@uia.ua.ac.be.
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Abstract |
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 Top Abstract IntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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Abstract This contribution reviews the regulation of left ventricular pressure (LVP) fall by load and relates this regulation to left ventricular contractility. Load regulation of LVP fall has to be distinguished from neurohumoral regulation, from effects induced by arterial reflected waves and from long-term load effects on contractility. The response of LVP fall to a moderate elevation of systolic LVP is highly variable. It depends on the ratio between the actual systolic pressure and peak isovolumetric pressure, defined as "relative load". Up to a relative load of 81% to 84%, LVP fall accelerates. Above this relative load, LVP fall decelerates. Depending on the level of relative load there is a wide variety of effects ranging from moderate acceleration of LVP fall to marked deceleration of LVP fall. Acceleration of LVP fall in response to a load elevation is associated with normal cardiac function, while slowing of LVP fall is associated with impaired cardiac function. Similar but opposite effects are observed with reductions of systolic LVP. Effects of changes in systolic LVP on time constant
reveal a fair correlation with systolic elastance (Ees), peak dP/dtmax and regional fractional shortening (or ejection fraction). There is an excellent correlation with measured isovolumetric LVP, indicating that contraction-relaxation coupling is close when contractility is expressed in terms of peak isovolumetric pressure. Assessment of contractility with systolic LVP-relaxation relation is precise and load independent and can be performed with the sole use of a high-fidelity pressure gauge positioned in the left ventricular cavity.
Key Words: hemodynamics • diastole • contractility • heart failure • mechanics
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Introduction |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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Most parameters describing contractile cardiac function are influenced by load. A relative exception is the peak rate of LVP rise (dP/dtmax), which varies with preload but is independent of afterload.1 Load effects on the parameters of cardiac function have triggered research into load-independent indexes. These indexes evaluate how changes in load affect a given parameter, such as ejection rate, ejection fraction, systolic volume, or systolic wall thickness. The most popular of these indexes is the end-systolic PV relation. Even if a preload-induced curvilinearity has to be taken into account2 3 and even if it is not entirely independent of load history,4 5 6 the linear relation constructed with systolic PV data has gained wide acceptance as a load-independent index of systolic function.
Systolic PV relations describe how systolic pressure depends on systolic volume. It is possible as well to invert this concept and to investigate how systolic volume is altered by systolic load or pressure. When cardiac function is normal, systolic left ventricular volume hardly varies with systolic pressure, and the linear PV relation is steep. When cardiac function deteriorates, systolic volume increases with an elevation and decreases with a reduction of systolic pressure. The linear PV relation becomes more horizontal, and systolic left ventricular volume becomes increasingly dependent on load.
Major limitations for widespread use of the systolic PV relation are the technology for accurately measuring volume and the need to generate variably loaded heartbeats without altering heart rate, autonomic tone, contractile state, and the position of the end-systolic PV relation. PV relations are most useful for assessing consecutive hemodynamic conditions. Individual computation of slope and intercept is somewhat difficult to interpret because these variables can be affected by left ventricular size, heart rate, stroke volume, and other confounding variables. Therefore, an alternative load-independent index that could be performed more easily both in the catheterization laboratory and in the surgical theater would be clinically useful. The present report describes such a potential alternative, which is based on analysis of contraction-relaxation coupling. We will analyze the relation between the rate of LVP fall and systolic LVP and will explain what information on systolic cardiac function this relation provides.
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Effects of Load on Rate of LVP Fall |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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The first step in this approach is to provide a brief overview of load effects on LVP fall. With regard to load, LVP fall is mainly dependent on systolic load (afterload). Selective preload effects on rate of pressure fall are negligible in the intact heart.7 They are present but are of limited magnitude when evaluated in cardiac muscle.8
Steady-state Elevations of Systolic LVP
When elevations of systolic LVP are induced by volume loading, by administration of 
-agonist agents or by partial ascending aorta occlusion, the course of LVP fall slows and increases.9 10 11 12 With steady-state elevations of systolic LVP, long-term muscular and neurohumoral effects outweigh short-term alterations in load in determining the rate of pressure fall. This is illustrated in Fig 1
, adapted from Blaustein and Gaasch.13 is plotted against end-systolic LVP. The descending aorta was abruptly occluded (by use of a cross-clamp), which elevated systolic LVP for the next three beats. The cross-clamp was maintained for 3 minutes and then released. The last clamped beat and the first three beats after release had a longer for similar end-systolic LVPs. This means that after stabilization at higher pressures, the –systolic LVP relation had shifted upward. The effects of these steady-state elevations of systolic LVP are complex. The neurohumoral response to an increase in pressure is mediated by baroreceptors, which will stimulate parasympathetic tone, inhibit sympathetic tone, and result in decreased contractility. In addition to the neurohumoral effects and the influence of arterial wave reflections (see "Systolic Loading Sequence"), cardiac function will undergo complex influences induced by altered load. In the first minutes after an increase in aortic input impedance, afterload and preload will be higher, leading to various influences on myocardial function. Elevation of preload will enhance the force-generating capacity according to the Frank-Starling mechanism.14 Elevation of afterload will in itself reduce this force-generating capacity, as was shown in isolated cardiac muscle.15 In the intact heart, elevation of afterload will induce an increase in ventricular performance several heartbeats after aortic pressure is raised. This phenomenon, known as the Anrep effect, is a combination of the Frank-Starling mechanism and the garden-hose effect with increased coronary perfusion.16 The effects of steady-state changes of systolic pressure on LVP fall, therefore, might be too complex to allow inferences about regulation of myocardial relaxation by load.
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Systolic Loading Sequence
When load is varied briefly, neurohumoral effects should be negligible, because cardiac compensatory reflexes are not noticeable in the first heartbeats.13 17 The first three beats after clamping the descending aorta (Fig 1
) elevate systolic LVP and induce an increase in that is less pronounced than with steady-state elevations. This particular intervention, however, was shown by Hori et al10 to be not only an elevation of afterload but also an alteration of systolic loading sequence, with load increasing toward late ejection. Such a systolic loading sequence creates an imbalance during ejection between available cross-bridges and load. The imbalance increases stress on active cross-bridges, delays cross-bridge inactivation, and manifests as an earlier onset and slower course of LVP fall.5 10 18 19 Systolic loading sequence is a clinically important determinant of LVP fall in cardiac overload and in congestive heart failure. It includes the effects of arterial wave reflections on timing and rate of LVP fall.18 19 Determining the relative contribution of and measuring the systolic loading sequence was still difficult. A recent contribution by Kohno et al19 demonstrated that slowing of LVP fall induced by a given LVP elevation was related to the change of LVP at aortic valve closure. This change in LVP at aortic valve closure was shown to be a reasonable marker of the induced alteration of the systolic loading sequence.
Late Ejection Load
Clamping of the ascending aorta during ejection is followed by early onset of LVP fall. This finding, initially published by Noble,20 was attributed to the momentum of the blood and to the suggestion that the ventricle is contributing little to the ejection in late systole. Clamping induces pressure elevation and slowing of LVP fall, which progressively decreases and disappears when the intervention is timed later during ejection. From 60% of ejection duration onward, an additional phenomenon manifests itself. Early onset of LVP fall is followed by brief, transient acceleration of LVP fall in its initial phase from peak LVP until dP/dtmin.20 21 22 This acceleration is due to cross-bridge back rotation with loss of force but with increased resistance to subsequent segment stretch.22 Late ejection load does not accelerate subsequent LVP fall and does not improve diastolic filling of the ventricle.22 Some reports described cross-bridge disruption, muscle yielding, and early termination of systole after similar late ejection load. However, this finding was only observed in isolated cardiac muscle with isotonic-isometric relaxation sequence23 and in isometrically contracting left ventricles subjected to abrupt volume increments.24 The clinical relevance of these findings remains unclear.
Selective Elevation of Afterload
What happens to LVP fall after a selective elevation in afterload, without long-term muscular and neurohumoral effects and without alteration of systolic loading sequence? Moderate LVP elevations (5 to 20 mm Hg), induced by abrupt beat-to-beat partial ascending aorta occlusion, do not alter systolic load sequence,18 and the pressure domain curve remains roughly horizontal throughout ejection. In the first heartbeat after such an intervention, mean remains unaltered18 or can even decrease.22 25 The finding that pressure fall can accelerate and can decrease in response to elevation of systolic LVP was unexpected initially. The finding seemed at variance with available hemodynamic literature and will be discussed later (see "Underlying Mechanism: Relative Load").
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Contraction-Relaxation Coupling |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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The second step in the approach is to analyze how changes in systolic pressure alter the rate of LVP fall and to interpret these effects as the reflection of myocardial contractility. This approach is conceptually consonant with Brutsaert and Sys's "muscle-pump" subdivision of the cardiac cycle.26 This subdivision describes myocardial relaxation, of which LVP fall is the middle part, as belonging to systole or to a single contraction-relaxation cycle of the active state. The logical next step is to look for contraction and for cardiac pump function to understand load regulation of myocardial relaxation.
Inotropy and Lusitropy
Inotropic interventions were analyzed in isometric twitches of isolated cardiac muscle.27 28 29 Various inotropic mechanisms may have disparate effects on myocardial contraction (inotropy) and relaxation (lusitropy). Similarly, Little et al30 analyzed ejecting canine hearts and found improvement in systolic function coupled with reduction in with the ß-agonist dobutamine but improvement in systolic function without noticeable change in with ouabain. Parker et al31 analyzed inotropic and lusitropic effects of dobutamine in normal and failing human left ventricles. When compared with normal ventricles, failing ventricles developed a blunted inotropic response but kept an intact lusitropic response. These various data suggest a different regulation of contraction and relaxation. The suggestion does not remain valid if subcellular and molecular mechanisms of inotropy are considered, eg, making the distinction between calcium availability and cross-bridge affinity for calcium. Both muscular and intact heart studies are relevant for understanding baseline myocardial relaxation but do not analyze contraction-relaxation coupling if they compare different inotropic states only at one load level.
Load Dependence of LVP Fall and Contractility
Blaustein and Gaasch13 described in the intact heart how the relation between and systolic LVP could be quantified by a slope, referred to as R (ms/mm Hg). R describes how much increases with systolic LVP elevation (Fig 2). The slope R is altered by ß-adrenergic tone: R increases with ß-blockade (more slowing of pressure fall) and decreases with ß-stimulation (less slowing of LVP fall). These observations were tentatively explained by intrinsic effects of catecholamines on myocardial relaxation, but the authors carefully concluded that "to characterize optimally the isovolumic relaxation velocity in intact hearts, the -load relationship must be defined, and relaxation rates should be examined relative to load and contractile state."
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Some recent studies computed the effects of systolic load on and related these effects to measured parameters of contractility. Eichhorn et al32 analyzed patients with cardiac dysfunction during nitroprusside administration. With nitroprusside, a steady-state reduction of systolic LVP was obtained and was decreased. The slope R of the –systolic LVP relation was inversely correlated with the linear slope of the end-systolic PV relation. This relation, described as hyperbolic, is illustrated in Fig 3. Similarly to what had been discussed above for LV volume, the rate of pressure fall becomes increasingly load dependent when systolic cardiac function is severely impaired. The analysis of myocardial relaxation at different systolic pressures reveals a physiological coupling between contraction and relaxation, with relaxation relatively preserved in early heart failure and markedly slowed when systolic heart function is severely impaired. Of note is the observation that in the failing heart, prolonged ß-blockade and digitalis (deslanoside) both improve systolic function evaluated with PV relations, and both accelerate pressure fall. These drugs, however, do not alter the hyperbolic relation between load dependence of pressure fall and the Ees. The uniqueness of this hyperbolic relation was confirmed over a wide range of contractility states by Asanoi et al.33 In that experimental canine study, systolic load was altered with bicaval occlusion, contractility was stimulated with the calcium sensitizer pimobendam, and cardiac dysfunction was induced with prolonged rapid pacing.
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Ishizaka et al34 recently performed caval occlusion in dogs before and after tachycardia-induced cardiomyopathy. They analyzed the relation between and systolic LVP. Their study revealed that at baseline, did not vary with caval occlusion: could slightly decrease, remain unchanged, or slightly increase. After induction of cardiomyopathy, markedly decreased with caval occlusion and therefore became load dependent. Cheng and Little35 performed a similar canine study before and after tachycardia-induced cardiomyopathy. They used phenylephrine for altering load instead of caval occlusion. Interestingly, the results were similar, with phenylephrine elevating systolic LVP but not increasing at baseline, elevating systolic LVP but increasing in the presence of cardiomyopathy.
The explanation for increased load dependence of with experimental or clinical congestive heart failure is not readily apparent. Ishizaka et al34 calculated that with cardiomyopathy, systolic load peaks later during ejection, and it was discussed above that this might reduce the rate of LVP fall. With the available data, it was not possible to differentiate between changes in load level, changes in loading sequence, or intrinsic changes in load dependence of myocardial relaxation.36 This differentiation requires a more elaborate series of animal experiments encompassing the analysis of relaxation over the entire range of load levels, up to isovolumetric levels,22 as will be discussed next.
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Underlying Mechanism: Relative Load |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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Relative Load
The third step in the approach of the present report is to demonstrate how load and contractility interact in regulating the load dependence of LVP fall.22 Load dependence in its revised definition26 is a concept derived from cardiac muscle research. It describes the extent of the temporal separation of relaxation between isometric and isotonic twitches, relaxation of isometric twitches being delayed compared with isotonic twitches. Extrapolating this concept to the in vivo situation is not feasible without knowledge of what "isotonic" and "isometric" mean in hemodynamic terms. Understanding the load dependence of LVP fall requires insight into the systolic load of the working left ventricle in relation to peak isovolumetric systolic load. Fig 4
displays two superposed heartbeats, control and isovolumetric. The isovolumetric heartbeat was experimentally obtained in dogs by occluding the ascending aorta during the diastole that separated the displayed heartbeats. In the top panel of Fig 4, isovolumetric pressure elevation is limited (32 mm Hg). In the bottom panel of Fig 4, isovolumetric pressure elevation is fair (56 mm Hg). Accordingly, contractile reserve is limited in the top panel and fair in the bottom panel. This contractile reserve can be quantified by calculating relative load. Relative load is defined as the ratio of baseline systolic LVP to isovolumetric LVP and expressed as a percentage.22 This ratio is 79% and 68%, respectively, in the top and bottom panels of Fig 4. Low relative load (<70%) is associated with normal systolic function, whereas high relative load (>80%) is indicative of overt cardiac dysfunction. The concept of relative load is useful to explain why the normal heart responds to a moderate elevation of systolic LVP with delayed onset and faster rate of LVP fall, whereas a similar intervention in the failing heart induces premature onset and slowing of LVP fall.
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Increase in Afterload During Contraction
Let us consider isolated cardiac muscle studies that analyzed the effects of multiple physiological afterload steps on the timing and rate of isometric force decline. When afterload is higher, the number of interacting cross-bridges increases (cooperative activity),37 which keeps a balance between the number of cross-bridges and the load to be carried. The twitch with elevated afterload will have a delayed onset8 and an increased rate of force decline.8 26 28 29 38 As indicated above, healthy left ventricles of anesthetized dogs develop an identical response to a moderate beat-to-beat elevation of systolic LVP. The heartbeat with elevated pressure will have a delayed onset22 and an increased rate of pressure fall.22 25 Accordingly, a reduction of systolic LVP will induce premature onset and a slower rate of LVP fall.
From Contraction to Early Relaxation
The regulation described in the previous section remains valid as long as load varies early within the contraction period, when the ongoing calcium transient allows modulation of the number of interacting cross-bridges. In cardiac muscle, this type of regulation is altered from the moment in the cardiac cycle when 81% to 84% of the peak isometric force has developed. When cardiac muscle is heavily afterloaded and when 81% to 84% of the peak isometric load is exceeded, onset of force decline will be premature, and the rate of force decline will be slowed.28 29 38 The heavily afterloaded left ventricle similarly develops an early onset and a slower rate of pressure fall.20 22 We recently indicated39 that the timing at which 81% to 84% of peak isovolumetric pressure is reached (in heavily afterloaded heartbeats) or the equivalent timing early during ejection (in normally afterloaded heartbeats) should be considered as the precise time of the transition between myocardial contraction and relaxation, both in isolated cat papillary muscle and in the intact ejecting canine heart. From this time onward, a load elevation induces slowing instead of acceleration of myocardial relaxation. This suggestion is in accordance with previous cardiac muscle findings5 and with the subsequent description of this transition in cardiac muscle.26 On the basis of experimental intact heart data,22 39 we observed that this transition occurred during the first 20% of ejection of a normally afterloaded heartbeat in the healthy ventricle of anesthetized dogs. Transition from contraction to relaxation is indicated as a vertical line in both panels of Fig 4. At this transition, the myocardium abruptly shifts to early muscular relaxation, a phase in the cardiac cycle during which the number of interacting cross-bridges can increase no more. Additional elevations in load will result in increased stress on individual cross-bridges, less cross-bridge cycling, and positioning of the attached myosin head closer to the isometric position.40 The mechanism underlying premature onset and slowed rate of pressure fall in heavily afterloaded and isovolumetric heartbeats relates to an imbalance between active cross-bridges and load. This mechanism is identical to the mechanism underlying the response of LVP fall to altered systolic loading sequence.5 18 22
Both Muscle and Heart
Fig 5 illustrates elevations of systolic load in intact left ventricle (top) and isolated cardiac muscle (bottom). The top panel illustrates a normal heartbeat in a healthy left ventricle as tracing 1. From tracing 1 to tracing 2, LVP fall is delayed and accelerated. When load is further elevated, as in tracings 3 (heavily afterloaded) and 4 (isovolumetric), LVP fall is premature and markedly slowed. Heartbeat 3, heavily afterloaded, has a relative load similar to the failing heart, in which isovolumetric load is reduced. If we consider heartbeat 3 and induce a reduction of systolic load, we will observe a longer time to onset and a faster rate of pressure fall, whereas even a small elevation of load will result in earlier onset and markedly slowed LVP fall. The bottom panel of Fig 5 shows corresponding muscle twitches in cat papillary muscle. The findings are similar qualitatively but also quantitatively. The right axis displays relative load. In both panels, the transition from delayed to premature and from accelerative to decelerative (isovolumetric) relaxation is situated at 81% to 84% of peak. The timing at which this load level is reached corresponds to the transition from myocardial contraction to relaxation.
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Relative Load and Diastolic Dysfunction
Relative load might prove to be a useful concept in understanding and treating diastolic dysfunction induced or facilitated by excessive load. This issue was demonstrated in the failing heart with PV loops33 34 and is reproduced in Fig 6 (taken from Reference 34). Diastolic PV relations are displayed. Bicaval occlusion induces a decrease in pressure and volume. In the normal heart, this decrease represents a shift along the normal diastolic PV relation. In the failing heart (pacing-cardiomyopathy), a downward shift of diastolic PV relation is observed, indicating that diastolic dysfunction is present at baseline but can be reversed with caval occlusion. Both slower pressure fall and impaired diastolic filling might be attributed at least in part to impaired contractility and excessive systolic load rather than to primary alterations of diastolic function in this experimental model of heart failure. These various recent findings lead to an updated analysis of the framework developed by Ross41 on afterload mismatch and preload reserve. We can add "afterload reserve" to this framework. Afterload reserve relates to the capacity of the ventricle to respond to afterload elevation with a limited increase in systolic volume and no slowing of LVP fall. The volume shift will not result in increased filling pressures because it remains on the horizontal part of the diastolic PV relation. Larger afterload elevations in healthy ventricles, or even small afterload elevations in failing ventricles, will induce markedly slowed myocardial relaxation but will also shift ventricular volumes toward the limits of preload reserve, toward the steep portion of the diastolic PV relation. Elevated filling pressures will be the consequence of limited preload reserve but will also be facilitated by impaired myocardial relaxation due to limited afterload reserve.
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Isometric Muscle Twitch: Model for Heart Failure |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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A slow rate of force decline is typically observed in isometric cardiac muscle twitch. We can look at such a twitch similarly to the way we look at the failing heart. It is a twitch with load being developed throughout contraction and still being developed during early relaxation, resulting in early onset and a markedly slowed rate of force decline. Cardiac muscle research still relies on isometric twitches for deriving information commonly accepted to be clinically relevant. Wouldn't it be more appropriate to look at the isometric muscle twitch as an experimental model of cardiac failure? The muscle twitch most relevant for clinical physiology would be the twitch with 81% to 84% of peak afterload, with a maximal recruitment of cross-bridges and a maximal recruitment of time for achieving external work, without excessive slowing of relaxation. Load dependence should be evaluated as the potential to maximally delay the onset of a rapid isometric force decline rather than the potential to maximally slow this force decline, which lacks physiological relevance. This point of view parallels the observations in isolated canine hearts published by Burkhoff et al,42 revealing limitations of the extrapolations from the analysis of isovolumetric heartbeats. When ejecting beats are compared with isovolumetric heartbeats, a marked ejection-mediated enhancement and prolongation of ventricular pressure–generating capacity during the ejection phase of the cardiac cycle is observed, with concomitant acceleration of pressure fall. Prolongation of ejection and acceleration of pressure fall have already been discussed. The additional feature is that in ejecting beats, the instantaneous pressure-generating capacity is greater than that predicted from isovolumetric beats, starting at a point early after the onset of ejection.
Relaxation–Systolic Pressure Relation
The biphasic accelerative-decelerative effect of elevating load on timing and on rate of myocardial relaxation is a continuous process, with no breaking point or inflection at the transition from contraction to relaxation.22 This process was quantified for beat-to-beat LVP elevations with a magnitude of 12 mm Hg (range, 10 to 14 mm Hg) in dogs and is illustrated in Fig 7, adapted from Reference 22. The top panel shows LVP domain curves in two consecutive heartbeats before (control) and after a beat-to-beat elevation of systolic LVP induced by partial ascending aorta occlusion (test). The bottom panels display in the vertical axis the ratio of test to control. In the bottom left panel, test/control is plotted against the peak isovolumetric LVP elevation (LVPisom.-LVPcontrol), where LVPisom. indicates systolic LVP of an isovolumetric beat and LVPcontrol indicates systolic LVP of a control beat. The relation allows computation of LVPisom., which is an afterload-independent measurement of cardiac pump function, at a given level of preload. According to the Frank-Starling mechanism, peak LVPisom. obviously will remain preload dependent. In the bottom right panel of Fig 7, test/control is plotted against the relative load of the test heartbeat (LVPtest/LVPisom., %). This approach will be less dependent on the actual value of systolic LVPcontrol and on preload and provides a better insight into potential changes in contraction-relaxation coupling and load dependence. A percentage of test/control <1 indicates acceleration of LVP fall and is associated with important isovolumetric LVP elevation and a low relative load and hence a good contractile state. A percentage of test/control >1 is associated with limited isovolumetric LVP elevation, higher relative load, and impaired contractile state. The dashed horizontal line, corresponding to an unchanged and a ratio of test/control of 1, is crossed in the bottom right panel of Fig 7 at a systolic pressure corresponding to 82% relative load. Below 82% relative load, decreases, and above 82% relative load, increases. The very close linear relations displayed in Fig 7 suggest that contraction-relaxation coupling should be optimally analyzed in terms of peak isometric force rather than contraction velocity,22 ejection fraction,22 32 or even Ees.32 33 Computations of peak isometric pressure or relative load take into account both load and contractile state and are load-independent indexes of cardiac function such as the end-systolic PV relation. The following formulas, derived from published data,22 allow computation of peak isovolumetric pressure and of relative load.
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Relative load of the test beat:
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The similarity between the behavior of muscle and heart, the observation that increased load and systolic volume may result until 82% relative load in faster myocardial relaxation, and the continuous evolution from acceleration to deceleration of LVP fall indicate that cross-bridge mechanisms rather than configurational restoring forces mainly determine regulation of LVP fall by afterload. The experimental relation between elevations of systolic LVP and changes in is close, unique, and reproducible.22 39 Inotropic interventions such as intravenous administration of CaCl222 and propranolol22 did not affect the curve but resulted in a shift along the same curve. Surprisingly, regional LV stunning also induced a shift along an unaltered curve, which convincingly demonstrates that stunning does not alter contraction-relaxation coupling.39 The uniqueness of contraction-relaxation coupling evaluated in this way is similar to the uniqueness of the hyperbolic relation between changes in and Ees, discussed above and illustrated in Fig 3. It remains to be evaluated how hypertrophy due to overload or secondary to loss of myocardium, in which relaxation abnormalities are present even in the absence of excessive load, will alter this contraction-relaxation coupling.
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Conclusions and Limitations |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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Experimental or clinical data on systolic LVP and rate of LVP fall may be obtained with administration of sodium nitroprusside,32 caval occlusion,33 34 phenylephrine infusion,35 partial aortic occlusion,22 39 and passive elevation of the legs.43 Each of these techniques, based on both acute and steady-state load alterations, might provide valuable information on contractile function, on the basis of contraction-relaxation coupling and relative load. The clinically relevant information may be obtained with only a high-fidelity pressure catheter in the left ventricle and does not require dimensional left ventricular measurements. The goal of the present report, however, was not to suggest direct clinical application but to foster clinical research into applying the presented concepts to cardiac patients.
Contraction-relaxation coupling could be dependent on intracellular calcium metabolism and hence species specific. The coupling is dependent on long-term load history and presumably differs if LVP elevations are compared with LVP reductions. So far, quantitative data have been published on the hyperbolic relation between changes in induced by reduction in systolic LVP and Ees in cardiac patients32 (Fig 3) and on the linear relation between test/control and relative load22 39 in anesthetized dogs in which load was increased with a single-beat intervention (Fig 7). The latter method has the advantage of revealing a closer contraction-relaxation coupling and will better discriminate between patients with moderately impaired cardiac function, which will project at the level of the inflection of the hyperbolic relation of Fig 3. Extrapolating the results of this single-beat intervention to caval occlusion, leg elevation, or steady-state load changes can provide information that might be as accurate, but preload-induced curvilinearity, right ventricular (un)loading artifact, and "long-term" load effects still will have to be considered. Standards should be developed for each of these techniques, and the limitations and drawbacks of each should be analyzed.
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Selected Abbreviations and Acronyms |
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References |
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TopAbstractIntroductionEffects of Load on...Contraction-Relaxation CouplingUnderlying Mechanism: Relative...Isometric Muscle Twitch: Model...Conclusions and LimitationsReferences |
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