Background The early-to-late ventricular filling ratio (E:A) is widely used to index diastolic function. While filling patterns reflect diastolic properties, they can also modulate chamber pressures due to myocardial viscoelasticity. We hypothesized that such feedback can potentially temper effects of delayed relaxation and/or volume loading on diastolic pressures.
Methods and Results Six isolated blood-perfused canine left ventricles were studied with ejection and filling controlled by an intracavitary volume servo-pump. Diastolic filling was determined by a simulated atrial pressure source that was either constant or varied to yield dual-phase filling at a specified E:A ratio. E:A ratio was randomly set to 3:1, 1:3, or 1:1, and data were recorded at each ratio at three different preloads. With principally early filling (E:A=3:1), diastolic pressure rise from viscosity increased in proportion with the relaxation time constant (r=.91, P<.0001). However, this dependence was lost as E:A ratio declined (eg, P=.63 for E:A 1:3). Furthermore, E:A=3:1 yielded 37% to 50% lower end-diastolic pressures at similar volumes (versus E:A=1:3) as initial viscous forces decayed. Offsetting early and late filling effects led to little net change in mean diastolic pressure independent of E:A ratio or preload.
Conclusions Diastolic filling pattern itself influences chamber pressures early and late in diastole due to viscoelasticity, with larger net effects on end-diastolic pressure. Since E:A ratio normally falls with delayed relaxation but rises with higher preload or reduced compliance, the present results suggest that changes in filling pattern may modulate direct effects of such factors on elevating diastolic pressure.
Diastolic ventricular chamber filling occurs in three phases: early filling, diastasis, and late filling.1 Early filling is principally determined by the transmitral pressure gradient,2 a function of chamber loading, ventricular relaxation, cardiac restoring forces or suction, and atrial and ventricular compliances.2–4 Late filling occurs as the result of atrial systole. The ratio of early-to-late ventricular filling (E:A ratio) is normally about 3:1, but this pattern often changes considerably with cardiac disease, a finding that has led to the widespread use of E:A ratio as a diastolic function index.5–7
While changes in E:A ratio are generally considered to be the consequence of diastolic abnormalities such as relaxation delay or reduced chamber compliance, varying filling pattern can itself feed back on cardiac diastolic pressures due to myocardial viscoelasticity.8–11 Both passive and active sources of viscoelasticity have been proposed. Passive factors are attributed to myocyte cytoskeletal proteins such as titin,12–14 titin-myosin interactions,12,15 microtubules,16,17 and extracellular fluid filtration and poroelasticity.18,19 Active factors include partial myocyte activation at resting calcium, and stretch-activated channels that may attenuate relaxation.20–24 The magnitude of pure viscous effects and thus the potential for diastolic pressure changes caused by varied E:A ratios in intact hearts remains unclear. Some studies have suggested increased viscosity during early filling, particularly when chamber preload is increased.8 However, Nikolic et al11 reported negligible viscosity in normal hearts when filling was allowed at low (end-systolic) volumes only after relaxation was completed. These authors speculated that chamber viscosity independent of relaxation effects might be present at higher preloads and that filling with low E:A ratios might reveal this behavior. No prior study has tested this hypothesis or compared pure effects of altered filling pattern on ventricular diastolic pressures.
Accordingly, the present study was designed to test the influence of altering the filling pattern on the course of diastolic chamber pressure development during early and late cardiac filling. To eliminate potential effects of atrial-ventricular interaction and provide direct control over the filling pattern, studies were performed with blood-perfused isolated ejecting canine ventricles, with the use of a filling circuit designed to simulate physiological or pathophysiological diastolic filling. By independently controlling chamber volume and stroke volume, pure effects of filling pattern on pressure (independent of volume) could be determined.
Six canine left ventricles were studied with the use of an isolated perfused heart preparation similar to that previously described.25 Briefly, two mongrel dogs were anesthetized with pentobarbital sodium (30 mg/kg IV) for each experiment. The femoral arteries and veins of a “support” dog were cannulated and connected to a perfusion system designed to supply oxygenated blood to the isolated heart. The support dog was premedicated with hydrocortisone (500 mg IM), diphenhydramine (50 mg IV), and indomethacin (25 mg PR). Heparin (10 000 units) was administered after the arteries and veins were cannulated and connected to the perfusion system. A second “donor” dog was ventilated, anesthetized with 35 mg/kg IV pentobarbital, and a midline sternotomy was performed. The chest was opened; the subclavian artery and right atrium were cannulated and connected to the femoral arteries and veins, respectively, of the support dog. The donor heart was removed after ligation of the azygous vein, superior and inferior vena cavae, brachiocephalic artery, descending aorta, and pulmonary hila. The left atrium was opened, and all the chordae tendinae were freed from the mitral valve leaflets. A cannula with side holes was placed through the right ventricular apex to drain coronary venous blood. A brass adapter that held the isolated heart to the ventricular volume servo-pump system was sutured to the mitral ring, and a water-filled balloon connected to the servo-pump system was placed within the left ventricular cavity and affixed to the adapter. The balloon was prestretched so that its nominal volume exceeded the upper range of the volume pump to yield negligible viscoelastic influences from the balloon itself. A catheter-tip micromanometer (PC-380, Millar Instruments) placed inside the balloon measured left ventricular cavity pressure (LVP). Pacing electrodes were sutured to the apex of the left ventricle, and the heart was paced at a rate 10 to 15 bpm above the spontaneous rate (mean, 120±10.6 minutes−1). A biploar surface ECG was measured between two electrodes sutured to the surface of the heart. The temperature of the blood perfusate was maintained ≈37°C by a heat exchanger, and the perfusion pressure was constant at 90 mm Hg. Arterial blood gases were maintained in the normal range by adjustment of support dog ventilation and administration of NaHCO3.
Servo-Controlled Left Atrial Pressure and Systemic Resistance
Fig 1A⇓ displays a schematic for the modified isolated heart servo-system controller software used in this study. The isolated beating left ventricle (LV), shown as a time-varying compliance (or elastance), was coupled to arterial and atrial loading circuits, with diodes simulating mitral and aortic valves (MV, AV). The arterial loading system was as previously described25 and consisted of a three-element Windkessel model, with proximal resistance Rc (0.1 mm Hg/mL per second), lumped arterial compliance (CA=0.8 mL/mm Hg), and peripheral resistance (RA=2.0 mm Hg/mL per second). The diastolic filling circuit was modified from previous versions of our controller software to provide time-varying as well as constant left atrial pressure sources to generate different flow profiles. Filling occurred as long as measured ventricular pressure was lower than the simulated atrial pressure. Relatively flat filling profiles were achieved by setting atrial pressure constant at 11 mm Hg. As shown in Fig 1C⇓ (thin line), this generated an inflow curve that peaked in early diastole and then declined gradually (as LVP rose).
To achieve dynamic filling, a simulated left atrial pressure was calculated that would generate early (E) and late (A) filling, each modeled by sin2(t) functions spanning 40% of the total diastolic filling period (TFP). Both phases were separated by diastasis that occupied the remaining 20% of TFP. The desired filling profile was first generated as where κ=0.4×TFP, and α and β are scaling constants. For a given ratio of total early to late net volume filling, scaling constants were calculated as and where SVcon was total net filling (stroke volume) measured from steady-state beats at a constant LA filling pressure (Fig 1B⇑). Thus for an E:A ratio of 3:1, the area under the early filling waveform reflected 75% of net SVcon, while the later waveform contained the remaining 25% (Fig 1C⇑).
Since the filling command signal to the LV volume pump was calculated from differences between measured ventricular pressure and simulated atrial pressure, FLOWin(t) was converted to a pressure command before being applied to the isolated heart. The simulated left atrial pressure (LAP) waveform that would generate FLOWin(t) was derived from where LVPm(t) was measured diastolic pressure during ventricular filling recorded from reference cardiac cycles (ie, with LAP held constant). Once LAPsim(t) was determined, this was substituted for the constant LAP in the filling circuit (Fig 1A⇑). By this method, a series of different filling patterns all could be generated at near identical stroke volume. These E:A ratios were defined by the integrated area under the filling curves (ie, net volume), not peak flow velocity, as is more commonly applied in clinical practice. However, peak flow ratios were similar to the corresponding integrated volume ratios (1:2.7 versus 1:3, 1:1.03 versus 1:1, and 2.7:1 versus 3:1, respectively).
After isolation and attachment to the servo-pump system, hearts were stabilized for at least 30 minutes under ejecting conditions with a constant atrial pressure model. E:A ratios were then randomly selected at either 3:1, 1:1, or 1:3. Steady-state pressure-volume data were recorded at each E:A ratio, and after all sequences were recorded, the protocol was repeated at a higher or lower preload volume. This was further repeated for a total of three different preloads in each heart.
End-diastolic volume was calculated as the averaged volume during isovolumic contraction. End-diastolic pressure was the pressure at the lower right-hand corner of the pressure-volume loop, which corresponded with the end of chamber filling (ie, when LVP exceeded computer-simulated LAP). The time constant of isovolumic relaxation time (τ) was calculated by regression of lnP versus time, given that extramural pressure was atmospheric.20
Mean ranges for cardiac end-diastolic volume and pressure, maximal first derivative of pressure, isovolumic relaxation rates, and the end-systolic elastance are provided in Table 1⇓. These values are typical of the isolated, blood-perfused canine ventricle25 and indicative of cardiodepression caused by complete denervation and a low level of circulating catecholamines in the support dog blood. Similar values have been reported in dogs after autonomic blockade.26
To examine effects of varying filling patterns on diastolic pressure-volume relations, pressure-volume data from the onset to end of filling were identified from a reference beat (constant simulated atrial filling pressure) and from a beat with variable rate filling. Both curves were superimposed over their overlapping volumes, the volumes normalized and interpolated to span from 0 to 100, and the area between the curves calculated by trapezoidal integration to yield mean diastolic pressure differences (ΔPdia) attributable to the altered filling pattern. Since FLOWsim(t) was symmetric over the diastolic filling period (40% for E-wave, 20% for diastasis, 40% for A-wave), pressure differences were conveniently divided into first (ΔPdia−1st half) and second half (ΔPdia−2nd half) portions. The pressure difference for the entire filling period (ΔPdia−full) was also calculated. We chose this method of analysis, analogous to that used by Nikolic et al,11 rather than nonlinear curve fitting to derive viscoelastic coefficients because such fitting approaches are often mathematically unstable, being very sensitive to the exact data provided for nonlinear fitting.
The influence of varying filling pattern (E:A ratio) and preload volume on hemodynamic parameters was tested by repeated measures two-way ANOVA. The effect of filling pattern on the relation between relaxation time constant and mean diastolic pressure differences due to varied filling pattern were tested by covariance analysis. Statistical significance is reported at P<.05. Data are presented as mean±SD. All calculations were performed with the use of commercial software (Systat).
Effects of Filling Pattern on Ventricular Diastolic Pressures
Fig 2⇓ displays examples of ventricular volume, flow (dVol/dt), pressure-volume loops, and diastolic pressure-volume relations for each of the four principal filling patterns. The top tracings show results with a constant simulated atrial filling pressure (reference state). Diastolic pressure-volume relations for this reference state are reproduced on each corresponding lower tracing for varying filling patterns (E:A ratios). With each E:A ratio, there was a small but consistent elevation in diastolic chamber pressure during periods of increased flow. As shown by these examples, however, these changes were generally small. The arrows in the right-hand panels identify the time of maximal filling rate (two arrows are shown for E:A=1:1). When E:A was 3:1, the pressure discrepancy associated with rapid filling was greatest before the time of peak filling, whereas for E:A 1:1 or 1:3, there was a closer correspondence between the time of peak filling and maximal pressure difference. These patterns were very consistent among hearts.
Fig 3⇓ displays examples of mean pressure difference plots subtracting the pressure-volume diastolic curve from the reference state (constant LAP) from those at varied E:A filling ratio. Deviations from the ΔPdia=0 line reflected flow velocity–dependent viscous effects. Similar increases in pressure were observed whether filling was principally early (3:1) or late (1:3) (bottom and top graphs, respectively). This was further confirmed by the symmetric pattern observed when filling was equally distributed in both periods (1:1, middle panel). These findings are intriguing because there was a considerable difference in the timing of both filling periods relative to chamber relaxation.
Table 2⇓ provides summary data for these mean pressure changes and their net effect on chamber end-diastolic pressure and volume. End-diastolic volume and net stroke volume were unchanged despite altered filling pattern. As indicated by the previous examples, the net effect of varying filling pattern on diastolic chamber pressures was generally small, with a net rise over the full diastolic filing period of <1 mm Hg. Similar pressure changes were observed during dominant filling regardless of its timing early or late in diastole. For E:A of 3:1, the initial pressure discrepancy (ΔPdia 1st half) was ≈1.6 mm Hg, whereas the change for ΔPdia 2nd half with an E:A=1:3 was ≈0.97, (P=NS). The similarity of apparent viscous effects early versus late in diastole was also confirmed by the 1:1 filling data at all preloads tested. There was no significant influence of preload volume on any of the pressure effects from filling either for the full diastolic period or initial and latter halves. Pressure differences recorded at the time of peak filling are also provided in Table 2⇓ and were similarly small and not influenced by preload or E:A ratio.
Unlike total mean diastolic pressure changes, filling pattern had greater net effects on EDP. At each level of preload, filling primarily in early diastole (E:A=3:1) yielded a significantly lower EDP than when filling occurred principally late (P<.001). At higher preloads, this disparity was 6.2 mm Hg, reflecting a 60% increase in EDP at similar EDV due to the shift in filling pattern from E:A=3:1 to 1:3. E:A of 1:1 lay between these extremes.
Part of the EDP difference, particularly with E:A=1:3, stemmed from a slightly extended filling period, since LVP had to increase more before it exceeded the simulated LAP A-wave so as to terminate servo-pump filling of the heart. Although mean EDV was statistically unchanged by E:A ratio (Table 2⇑), we further ruled out effects of even small volume differences by comparing late diastolic pressure at the same EDV. EDP from the beat with the lower EDV was contrasted to the diastolic pressure of the corresponding beat at the identical EDV. This analysis confirmed a significant effect of E:A ratio (P=.0003) on the late pressure discrepancy at low and high preloads. An E:A ratio of 3:1 yielded late diastolic pressures below the reference, whereas an E:A ratio of 1:3 yielded pressures above the reference (P<.05).
Relation of Early Filling–Dependent ΔP and Relaxation
With a physiological E:A ratio of 3:1, the majority of filling occurred closer to the onset of chamber relaxation. Intrinsic relaxation delay and myocardial stretch from rapid filling that can also prolong relaxation20,27 would therefore be expected to increase apparent viscosity, yielding higher pressures with this filling pattern. Fig 4A⇓ confirms this prediction but also demonstrates that this pressure rise critically depends on the extent of early filling itself. Mean ΔP calculated during the first half of chamber filling was plot versus isovolumic relaxation time constant. Variation in relaxation delay was not directly manipulated in each heart, but the range of values were obtained from among the various ventricles, with some changes occurring during the course of a given study. Importantly, the relaxation time constant was unaltered by subsequent changes in filling pattern because it was calculated purely from isovolumetric data.
When E:A was 3:1, there was a significant direct correlation between the ΔP due to rapid filling and relaxation time (P<.0001, r=.91). However, as the E:A ratio declined with less early filling, the regression relation flattened (P<.0001 by ANCOVA), becoming insignificant at an E:A of 1:3. These results are reasonable and indicate that even if relaxation is quite slow, if the E:A ratio is also reduced even to 1:1, the influence of filling on early diastolic pressures becomes minimal.
Fig 4B⇑ shows data for ΔPdia−2nd half versus tau for each of the three filling patterns. As expected, the dependence on relaxation (slope) was much less regardless of filling pattern, although it reached statistical significance in all cases (P=.007, .004, and .0009 for E:A of 3:1, 1:1, and 1:3, respectively). Consistent with the analysis for EDP, there was a greater disparity in the mean value of ΔPdia−2nd half, indicated by the regression offset. Data at an 3:1 ratio was lower than the reference state, whereas that at 1:1 equaled the reference and at 1:3 was above reference (P<.0001).
This study reveals three novel observations regarding the interaction between diastolic filling patterns and apparent chamber viscoelasticity. First, the mean magnitude of pressure rise associated with a filling wave is similar whether filling occurs early or late in diastole. Second, there is little influence of chamber preload on viscoelastic effects manifest by varying filling patterns. Last, altering the filling pattern from 3:1 to 1:3 can increase late and end-diastolic pressures considerably despite similar preload volumes. While generated in a highly controlled model with some features that clearly differ from the in vivo heart, these data are still probably relevant to the more intact physiological setting. Thus when underlying diastolic abnormalities induce changes in E:A filling pattern, these patterns can feed back on diastolic pressures through apparent viscoelasticity, further modifying the E:A ratio, and so forth in a closed-loop cycle.
Early Versus Late Filling and Apparent Viscosity
The finding that the pressure rise during the dominant filling phase was independent of when (ie, early or late) in diastole it occurred comes as somewhat of a surprise. While Rankin et al9 first clearly demonstrated viscoelastic behavior in the intact heart and found that a single viscous term explained pressure deviation both early and late in diastole, others found that rapid filling during early diastole near the onset of relaxation induced more pronounced changes.8 Subsequent studies demonstrated that filling superimposed on ongoing relaxation could itself delay the relaxation process,20,27 which was thought to be caused by stimulation of rapid stretch-activated calcium channels.22–24 Furthermore, Nikolic et al11 measured effects of variable filling rates on the fully relaxed heart with volume initially clamped at end systole and found negligible viscosity, further supporting the importance of relaxation effects. These authors speculated that greater viscous effects might be observed if filling was initiated at higher chamber volumes, as during atrial systole. In the present study, an E:A of 1:3 meant that most of filling started only 25% above end-systolic volume, so the discrepancy between our result and that of Nikolic et al11 is not easily explained on the basis of chamber volumes. It is possible that relaxation was still incomplete in our study, although estimated percent relaxation at the time of late rapid filling (on the basis of a monoexponential decay model) was 98.3±3%. Rather, the magnitude of volume filling in the present study, which was designed to achieve the same net EDV, was greater, probably helping to reveal even small viscous influences. In the Nikolic study, net filling volume for beats with varying initial filling velocity were matched at a lower level (about 35% of EDV).11 Our finding of similar viscous effects early and late in diastole suggests that structural elements such as titin, which are stretched during chamber filling, may modulate muscle viscosity. Preliminary data examining interactions between titin and myosin support such a hypothesis.12,15
Influence of Preload Volume
We did not observe any significant difference in the pattern or magnitude of viscoelastic responses with varied filling pattern as preload was changed. This is unlikely because of limited loading ranges, since EDP varied from 4.5 to 12 mm Hg, with EDV increasing by 50%. Furthermore, there was relatively little overlap in volumes at each preload level, and no preload-dependent changes in isovolumic relaxation time. This implies that the cellular and extracellular structures responsible for imparting viscous behavior to the myocardium are not greatly enhanced by changing muscle length in an otherwise healthy blood-perfused heart. This result, particularly for ΔPdif(1st-half) differs from earlier data8 in which early filling viscous effects rose as preload volume increased in intact dogs. However, the intact right-left ventricular and pericardial interaction may also have influenced these pressures.
Diastolic filling during atrial contraction in vivo often appears with a sudden considerable rise and subsequent fall in the LV pressure-volume curve. This is most pronounced in hearts with very elevated diastolic pressures, where the amount of filling attributable to atrial systole is correspondingly small.28 While generally ascribed to viscosity, the present data suggest otherwise, because in the absence of atrial contraction, even an E:A ratio of 1:3 produced only small pressure changes in late diastole. The intact atrium is linked to the ventricle by connective tissue attached to the annulus and valve apparatus, and time-varying atrial stiffening during contraction29,30 may transmit to the LV, making it appear more and then less stiff. Since this occurs simultaneously with atrial filling, it gives the appearance of a viscous property,31 even though the mechanism is different.
Offsetting Effects From E:A Filling Pattern on Diastolic Pressure
In intact hearts, changes in relaxation delay typically lower E:A ratio, whereas increases in chamber preload volume, or reduction in chamber compliance raise the ratio. Ohno et al28 examined E:A ratio in evolving heart failure, using the canine model of tachycardia pacing, and found that early in failure development, E:A ratio fell in consort with prolonged relaxation, whereas late in failure, and despite greater prolongation of relaxation, high LAPs caused by low compliance increased E:A. The present data suggest that these changes in filling pattern can themselves influence the cardiac diastolic pressures through viscoelasticity in a closed-loop manner, and it is intriguing to consider how this might effect the net effects. If relaxation is slower, then the falling E:A ratio would reduce viscous effects from early rapid filling superimposed on delayed relaxation (ie, Fig 4A⇑). The result would be a lower rise in early diastolic pressure than if filling patterns were maintained at 3:1. Conversely, when chamber preload rises or compliance declines, the higher E:A ratio would tend to reduce the consequent EDPs that would otherwise be anticipated (ie, Table 2⇑). Considered in this closed-loop context, filling patterns may contribute to as well as reflect underlying changes in diastolic pressure-volume behavior.
Several experimental limitations should be considered. The studies were performed in normal canine ventricles, and while the isolated heart preparation yields a lower contractility and stiffer chamber as compared with intact animals, viscous effects may be even greater in myopathic hearts.16,17 Second, relaxation delay was not directly manipulated, but the range of delays was obtained by spontaneous variations between hearts and within a heart during the study. However, the principal finding of an influence of E:A ratio on the ΔPdia−tau dependence was true when adjusted for individual hearts as well.
Although the isolated heart method facilitated precise control over filling dynamics, features of this preparation are quite different from the intact heart and may have influenced the results. These aspects include disruption of the mitral annulus with attachment of a rigid ring and electrical stimulation by the cardiac apex, potentially increasing spacial and temporal LV contraction asynchrony. This can delay chamber relaxation,32 potentially increasing apparent viscosity, particularly during early filling.
Another limitation is that the baseline or reference state was associated with a gradual decline in filling rate (caused by the rising LV diastolic pressure) rather than being held constant. Thus even this condition included some filling rate dependence and thus potential viscous effects. However, flow changes were gradual, and the identical baseline condition was used for all E:A ratio assessments in a given heart. Thus comparisons between different filling pattern data should have been little influenced by this error.
It should again be noted that the E:A ratio based on integrated flow used in the present study differs from the clinical value often based on the ratio of peak flow velocities. When E:A declines in clinical settings, A-wave duration often shortens, reducing integrated volumes. Thus our results with an E:A ratio of 1:3 may represent a more extreme instance of altered filling pattern. However, the major findings were also observed comparing E:A ratios of 3:1 to 1:1, which would certainly reflect ranges observed clinically.
Alterations in early-to-late diastolic filling pattern can modulate diastolic pressures through viscoelastic influences, which are similar at both time periods and relatively independent of cardiac preload. The nature of this interaction suggests that primary abnormalities that induce changes in cardiac filling pattern may have their influence on chamber pressure modified as a consequence of their effect on changing the pattern of cardiac filling during diastole.
This study was supported by National Health Service Grant HL-47511 (Dr Kass), and a fellowship grant from Johns Hopkins University (Dr Fraites). The authors gratefully acknowledge the superb technical assistance of Richard Tunin in performing these studies and thank Robert Paz for assisting in the data processing.
- Received May 5, 1997.
- Revision received August 22, 1997.
- Accepted September 7, 1997.
- Copyright © 1997 by American Heart Association
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