Download MRI assessment of LV relaxation by untwisting rate

Am J Physiol Heart Circ Physiol
281: H2002–H2009, 2001.
MRI assessment of LV relaxation by untwisting rate:
a new isovolumic phase measure of ␶
SHENG-JING DONG, PAUL S. HEES, CYNTHIA O. SIU,
JAMES L. WEISS, AND EDWARD P. SHAPIRO
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224
Received 7 December 2000; accepted in final form 18 July 2001
Dong, Sheng-Jing, Paul S. Hees, Cynthia O. Siu,
James L. Weiss, and Edward P. Shapiro. MRI assessment of LV relaxation by untwisting rate: a new isovolumic
phase measure of ␶. Am J Physiol Heart Circ Physiol 281:
H2002–H2009, 2001.—Most noninvasive measures of diastolic function are made during left ventricular (LV) filling
and are therefore subject to “pseudonormalization,” because
variation in left atrial (LA) pressure may confound the estimation of relaxation rate. Counterclockwise twist of the LV
develops during ejection, but untwisting occurs rapidly during isovolumic relaxation, before mitral opening. We hypothesized that the rate of untwisting might reflect the process of
relaxation independent of LA pressure. Recoil rate (RR), the
velocity of LV untwisting, was measured by tagged magnetic
resonance imaging and regressed against the relaxation time
constant (␶), recorded by catheterization, in 10 dogs at baseline and after dobutamine, saline, esmolol, and methoxamine
treatment. RR correlated closely (average r ⫽ ⫺0.86) with ␶
and was unaffected by elevated LA pressure. Multiple regression showed that ␶, but not LA or aortic pressure, was an
independent predictor of RR (P ⬍ 0.0001, P ⫽ 0.99, and P ⫽
0.18, respectively). The rate of recoil of torsion, determined
wholly noninvasively, provides an isovolumic phase, preloadindependent assessment of LV relaxation. Use of this novel
parameter should allow the detailed study of diastolic function in states known to affect filling rates, such as aging,
hypertension, and congestive heart failure.
diastole; hemodynamics; magnetic resonance imaging; imaging
(LV) relaxation is difficult to assess by
noninvasive means, because imaging methods cannot
directly measure cavity pressure. Echocardiographic,
Doppler, and radionuclide parameters of diastolic function are derived from rates of inflow of blood or outward
movement of the myocardium. However, the process of
relaxation occurs mostly during the diastolic isovolumic period of the cardiac cycle, before blood flow or wall
motion begins. Indexes measured later in the cycle
examine only the final stages of relaxation (33). Furthermore, these parameters are subject to “pseudonormalization,” because variation in left atrial (LA) pressure profoundly affects filling dynamics and thus
confounds attempts to indirectly estimate the relaxation rate (22, 31, 40, 41). New echocardiographic
LEFT VENTRICULAR
Address for reprint requests and other correspondence: E. P. Shapiro,
Div. of Cardiology, Johns Hopkins Univ. School of Medicine, 4940
Eastern Ave., Baltimore, MD 21224 (E-mail: [email protected]).
H2002
methods that are less sensitive to LA pressure (7, 16,
21, 39) or “adjust” for an estimated LA pressure (2, 3,
24, 37) are in clinical use, but novel noninvasive ways
of directly assessing relaxation are needed.
LV torsion is the wringing motion, or twist, of the
heart imparted by contraction of its obliquely spiralling fibers. Counterclockwise torsion develops during
ejection, but the clockwise recoil of torsion, or untwisting, is a deformation that occurs largely during isovolumic relaxation, before mitral valve opening (6, 10, 23,
29, 34, 46). This recoil is associated with the release of
restoring forces that had been accumulated during
systole and is thought to contribute to diastolic suction
(17, 29, 34, 46). The extent of torsion is correlated with
cavity pressure (14), and its recoil rate (RR) may
thereby be related to the rate of pressure fall. This
deformation can be quantified using magnetic resonance imaging (MRI) with tagging, a noninvasive
method for marking and tracking specific myocardial
sites (5, 47). In this study, we explored the relationship
between the rate of untwisting (RR) and the relaxation
time constant (␶) using various interventions to alter ␶
in intact canine hearts. The influence of LA pressure on
RR was assessed. The strength of the relationship
between ␶ and RR was compared with that between ␶
and isovolumic relaxation time (IVRT), a standard
index of relaxation that is known to be highly sensitive
to preload. We suggest that RR may provide a new
isovolumic phase measure of relaxation that is preload
independent and can be determined noninvasively.
METHODS
Terminology. In this paper, the term “LV relaxation” refers
to the time course of LV pressure decline, a process that
depends on both deactivation of actin-myosin cross-bridges
and the release of restoring forces due to chamber and myocardial deformation (45). The term “preload” refers to LA
pressure, which constitutes the preload to ventricular filling.
Animal preparation. Ten adult mongrel dogs (9 males and
1 female, weighing 24 ⫾ 3 kg) were anesthetized with intravenous pentobarbital sodium (25–35 mg/kg). After intubation, the dogs were mechanically ventilated (model 613, Harvard Apparatus). The left jugular vein was cannulated for
fluid and drug administration, and the right jugular vein was
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ASSESSMENT OF RELAXATION BY LV RECOIL
cannulated for placement of a right atrial pacing lead. Each
dog was instrumented with magnetic-compatible micromanometer-tipped catheters (Millar Instruments) to measure
LA, LV, and aortic pressures as follows. A left thoracotomy
was performed, and a small transverse incision (⬃3 cm) was
made at the ventrolateral pericardium along the base of the
heart for the placement of a LA catheter through the LA
appendage with a purse-string suture. A LV catheter was
placed through cannulation of the left internal carotid artery.
An aortic catheter was inserted through cannulation of the
left femoral artery. After surgical preparation, the animal
was allowed to stabilize for 30 min. Throughout the experiments, body temperature was maintained by a heating pad,
the chest was left open, and the electrocardiogram (lead II)
was monitored and also used as a trigger for MRI. At the end
of experiment, the animal was euthanized using intravenous
KCl. If hemodynamic instability or arrhythmias precluding
further MRI developed, the protocol was terminated without
additional interventions. All procedures were approved by
the institutional Animal Care and Use Committee.
Experimental protocol. Interventions were planned with the
main goal of recording hemodynamic and MRI data (during
steady-state conditions) over a wide range of values of ␶ and
with variations of LA and aortic pressures. The conditions
studied were as follows: 1) first baseline, 2) dobutamine infusion, 3) dobutamine infusion plus volume loading, 4) second
baseline (stopping dobutamine infusion), 5) esmolol infusion, 6)
third baseline (stopping esmolol infusion), and 7) methoxamine
infusion. Dobutamine (Eli Lilly) was diluted (250 mg in 500 ml
saline) and infused to increase systolic LV pressure by at least
15%. Volume load was performed by infusing saline at 10–12
ml/kg body wt (range, 200–300 ml) in each individual experiment. Esmolol (Ohmeda) was diluted (2,500 mg in 500 ml
saline) and infused to decrease systolic LV pressure by at least
15%. Methoxamine (Burroughs-Wellcome) was diluted (20 mg
in 500 ml saline) and infused to increase systolic LV pressure by
at least 15%. Solutions were mixed immediately before infusion.
After stabilization of each condition, hemodynamic and MRI
data were acquired.
Hemodynamic analysis. All signals were amplified (Gould
Instrument) and digitized at sampling frequencies of 250 Hz for
5 s under each condition. ␶ was calculated by measuring LV
pressure every 4 ms from the point of the minimal instantaneous rate of change of LV pressure with respect to time (dP/dt)
until its upturn and fitting the curve to the following equation:
p(t) ⫽ p0e⫺t/␶ ⫹ p⬁ (20), where p is pressure, p0 is pressure at
minimal dP/dt, t is time thereafter, p⬁ represents the pressure
asymptote. IVRT was measured from the LA, LV, and aortic
pressures as the interval from the crossover of the LV and aortic
pressures to the crossover of the LV and LA pressures.
MRI image acquisition. Myocardial tagging was used in
these experiments to measure torsion and its rate of recoil.
Tags are noninvasive markers that are imprinted on the
myocardium by selective radiofrequency saturation of planes
perpendicular to the imaging planes; they change the magnetization of the protons in the tagged plane compared with
the neighboring nontagged regions, resulting in a difference
in signal intensity. When placed at end diastole and then
imaged throughout the cardiac cycle, tags reveal the deformation and displacement of the myocardium on which they
are placed (Fig. 1). Tags may be positioned in a radial pattern
(47), which is ideal for the measurement of torsion, or in a
Fig. 1. Magnetic resonance basal and apical short-axis images of a canine heart, with radial tags at end diastole, end
ejection, and mitral valve opening. At end ejection, there has been rotation of the cardiac portion of the tags (particularly
at the apex), which are no longer continuous with the portions that pass through nonmoving structures such as the
chest wall. Arrows mark the initial positions of two tags. Note that the cavity is smaller at end ejection. By the end of
isovolumic relaxation, tags have recoiled almost completely to their starting position despite the fact that cavity size is
unchanged and filling has not yet begun. The measurement of torsion is derived from the difference in tag position
between basal and apical slices. Torsion is counterclockwise when viewed from apex to base but appears clockwise when
viewed from base to apex (as shown here). This figure illustrates the concept that recoil is largely an isovolumic event.
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ASSESSMENT OF RELAXATION BY LV RECOIL
grid pattern (5), which is commonly used for calculation of a
full strain field.
Tagged MRI was performed on a Resonex 0.38-T iron-core
resistive magnet (Sunnyvale, CA). The image acquisition
technique used in these experiments was similar to that
reported in detail in previous studies from this laboratory
and others (5, 9, 14, 34, 47). Briefly, image acquisition includes a gradient echo sequence modified to include tissue
tagging, with temporal resolution of 16 ms, time to echo of 10
ms, and time to repeat of two R-R intervals, 128 phase- and
256 frequency-encoding steps, two averages of excitation, and
field of view of 20–25 cm. After serial scout images, two
(basal and apical) short-axis images, 3.0 cm apart, with eight
radial tags perpendicular to the image planes were acquired
(14). Tagging and imaging were triggered by the R wave of
the electrocardiogram: tags were placed at end diastole, and
19–22 images were acquired thereafter. The image slice
thickness was 1.0 cm and tag thickness was 0.3 cm. Heart
rate was kept constant by pacing at the right atrium (mean
heart rate was 159 ⫾ 7 beats/min).
MRI image analysis. The digital MRI data were processed
using a special software package (Cardiology Image Processing System, Johns Hopkins University). The tag-endocardium intersection points on both basal and apical short-axis
images were identified manually and digitized (8 points/
slice).
Torsion at each tag-endocardium intersection point was
calculated as an angle between the tag line of the apical slice
and the projection of the basal tag line on the apical slice at
end systole, as previously reported (Fig. 2) (9, 14). With the
use of this method, clockwise rotation of the base and counterclockwise rotation of the apex are combined to yield a
measure of the total base-to-apex deformation. Mean torsion
was then calculated as the average of eight values for the
eight tag-endocardial intersection points. Recoil, the directional reversal of systolic counterclockwise torsion during
diastole, was expressed as the percentage of maximum systolic torsion: recoil ⫽ Tort/Tormax ⫻ 100, where Tort is torsion
at time t and Tormax is the maximum systolic torsion. [Normalization to maximum torsion was performed as the primary analysis here because ␶, the gold standard for relaxation, is based on the time required for a percentage of
pressure fall (1/eth) rather than an absolute pressure drop in
mmHg. However, analyses were repeated using the nonnormalized torsion values.] RR was defined as the slope of
the linear regression of recoil versus time, which is similar to
the method used by DeAnda et al. (13), during the first 64 ms
after peak torsion (i.e., using data from five images).
Statistical analysis. The overall effect of each intervention
(dobutamine, volume, esmolol, and methoxamine) on hemodynamic and MRI parameters was assessed by paired t-tests.
A value of P ⬍ 0.05 was considered statistically significant.
The relationships between ␶ and RR, and likewise between
␶ and IVRT, were initially explored by simple linear regression analysis. In each individual animal, correlations (r and
r2) were determined for both relationships. To compare the
significance of these two relationships (␶-RR vs. ␶-IVRT),
paired t-tests were applied based on the derived r2 for each
relationship; to compare the consistency of the two relationships, the test for correlated variances was applied to SD2
(38). Overall correlations of ␶ and RR, and of ␶ and IVRT,
were derived using linear regression analysis adjusting for
effects in individual dogs (20).
Finally, multiple regression analysis was performed to
determine the significance of the ␶-RR and ␶-IVRT relationships in the presence of other hemodynamic variables and to
test whether the other variables were independent determiAJP-Heart Circ Physiol • VOL
Fig. 2. Measurement of the angle of torsion from tagged images.
Tags are placed at end diastole, intersecting the base at point a and
the apex at point b. By end ejection, there has been clockwise
rotation of the basal tag to point c and counterclockwise rotation of
the apical tag to point d. Systolic torsion is the angle (␪) between the
apical tag position (point d) and the basal tag position (reflected onto
the apex as point e). Torsion therefore combines the opposite rotations of base and apex into a single deformation. Arrows show the
direction of torsion and recoil.
nants of RR and IVRT using the Generalized Estimating
Equation (GEE) method for repeated-measures data (25).
The independent, or explanatory, variables in the GEE model
included LA pressure, aortic pressure, LV systolic pressure,
␶, and peak ⫹dP/dt. The dependent variables were RR for the
␶-RR relationship and IVRT for the ␶-IVRT relationship. The
correlations among the repeated observations for individual
dogs were modeled as exchangeable correlations. A value of
P ⬍ 0.05 was considered statistically significant. These analyses were all repeated for the non-normalized RR.
RESULTS
Effects of interventions. Ten dogs were instrumented
and studied. All 10 dogs had hemodynamic and MRI
measurements at first baseline, during dobutamine
infusion, and after volume loading. Seven dogs had
additional measurements at second baseline and during esmolol infusion, and four dogs had additional
measurements made at third baseline and during methoxamine infusion.
The average effects of catecholamine stimulation,
volume infusion, ␤-blockade, and increased afterload
on the variables of interest are detailed in Table 1. Of
note, the predominant effect of dobutamine was a re-
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ASSESSMENT OF RELAXATION BY LV RECOIL
Table 1. Effects of interventions on hemodynamic and imaging parameters
First baseline
Dobutamine
Dobutamine ⫹ volume
Second baseline
Esmolol
Third baseline
Methoxamine
LA Pressure,
mmHg
Aortic Pressure,
mmHg
␶, ms
IVRT,
ms
Torsion, °
RR, %/ms
9.8 ⫾ 14
9.0 ⫾ 9.5
14.6 ⫾ 4.9‡
16.7 ⫾ 7.5
22.2 ⫾ 9.0
20.3 ⫾ 4.3
34.8 ⫾ 9.9*
81.1 ⫾ 21
93.3 ⫾ 4.5*
103.2 ⫾ 22*
93.6 ⫾ 18
77.4 ⫾ 17†
83.1 ⫾ 21
123.2 ⫾ 19‡
34.0 ⫾ 7.3
27.2 ⫾ 8.2‡
24.0 ⫾ 5.9*
35.1 ⫾ 5.8
37.9 ⫾ 7.8
37.0 ⫾ 6.7
47.3 ⫾ 4.6*
70 ⫾ 13
59 ⫾ 14‡
49 ⫾ 11‡
67 ⫾ 9.7
69 ⫾ 15
58 ⫾ 6.0
68 ⫾ 6.0
14.7 ⫾ 7.4
19.9 ⫾ 4.9
16.0 ⫾ 4.8†
13.0 ⫾ 4.2
7.1 ⫾ 4.6*
11 ⫾ 5.3
8.1 ⫾ 4.8*
0.69 ⫾ 0.33
0.81 ⫾ 0.33*
0.81 ⫾ 0.30
0.67 ⫾ 0.30
0.62 ⫾ 0.22
0.52 ⫾ 0.18
0.36 ⫾ 0.09
Values are means ⫾ SD. LA, left atrial; ␶, relaxation time constant; IVRT, isovolumic relaxation time; RR, recoil rate. The following
conditions were studied: 1) first baseline, 2) dobutamine infusion, 3) dobutamine infusion ⫹ volume loading (dobutamine ⫹ volume), 4) second
baseline (stopping dobutamine infusion), 5) esmolol infusion, 6) third baseline (stopping esmolol infusion), and 7) methoxamine infusion. For
dobutamine, esmolol, and methoxamine effects, comparisons are made with the respective baselines. For volume effect, dobutamine ⫹
volume is compared with dobutamine alone. * P ⬍ 0.05; † P ⬍ 0.01; ‡ P ⬍ 0.001.
duction in ␶ (from 34 to 27 ms, P ⫽ 0.0007); there was
a concomitant increase in RR (from 0.69 to 0.81 %/ms,
P ⫽ 0.02), and IVRT shortened. The predominant effect
of volume infusion was an increase in LA pressure
(from 9.0 to 14.6 mmHg, P ⫽ 0.0001); RR was unchanged, whereas IVRT shortened significantly. Esmolol reduced aortic pressure without having a significant
effect on ␶, RR, or IVRT. Methoxamine greatly increased LA and aortic pressures and caused ␶ to increase, but did not significantly change RR or IVRT.
The average time to peak torsion was at 200 ⫾ 29 ms
after the R wave, whereas end systole occurred at
227 ⫾ 30 ms after the R wave, that is, recoil began 27
ms before aortic valve closure. Our measurement of RR
spanned 64 ms and was completed before the end of
isovolumic relaxation during all interventions.
Correlation of ␶ and RR. The correlations of RR with
␶ in each individual dog for which at least five measurements were available (7 of 10 dogs) are detailed in
Table 2. For comparison purposes, the correlations of
IVRT with ␶ are also shown. The ␶-RR correlations are
high in each individual animal studied, with an average r of ⫺0.86 (ranging from ⫺0.77 to ⫺0.93) and with
similar slopes. The ␶-IVRT relationships have less consistent slopes and lower r2 values. The correlation of
RR with ␶ is significantly better (P ⫽ 0.026 based on r2)
and less variable (P ⬍ 0.001 based on SD2) than the
correlation of IVRT with ␶.
The relation between RR and ␶ is plotted in Fig. 3.
When data from all 10 dogs were pooled and adjusted
for individual dog effects using an indicator variable, r
was 0.92 and r2 was 0.85, with P ⬍ 0.0001. The relation
between ␶ and IVRT was also significant, with r ⫽ 0.81,
r2 ⫽ 0.65, and P ⬍ 0.0001.
Multiple regression of hemodynamic parameters
against RR and against IVRT. Multiple regression
using GEE was performed to assess the correlation of
individual hemodynamic parameters with RR and
IVRT, accounting for the potential confounding effect
of other variables (Table 3). ␶ was the only independent
predictor of RR (P ⬍ 0.0001); there was no independent
relation between RR and LA pressure (P ⫽ 0.817),
aortic notch pressure (P ⫽ 0.287), LV peak systolic
pressure (P ⫽ 0.604), or peak ⫹dP/dt (P ⫽ 0.060). In
contrast, IVRT was closely related to LA pressure (P ⬍
0.0001) and aortic pressure (P ⫽ 0.015) as well as to ␶
(P ⬍ 0.0001).
When the RR based on nonnormalized values of
torsion (expressed as °/ms rather than %/ms) was used
in these analyses, the results were similar with respect
to average effects of interventions and linear regressions. Multivariate regression by GEE also showed a
close independent relation between ␶ and absolute RR
(P ⫽ 0.004, coefficient ⫽ ⫺0.0273). There was a weak
but significant relation between LA pressure and absolute RR (P ⫽ 0.02, coefficient ⫽ ⫺0.0001), probably
due to the preload dependence of absolute values of
torsion (14). The nonnormalized RR at baseline was
0.084 ⫾ 0.038 (SD) °/ms.
Table 2. Linear regression of ␶ against RR and IVRT in individual experiments
␶ Versus RR
Dog 1
Dog 2
Dog 3
Dog 4
Dog 5
Dog 6
Dog 7
mean
SD
␶ Versus IVRT
slope
SEE
r
r2
⫺38.8
⫺54.1
⫺41.4
⫺20.0
⫺41.1
⫺42.3
⫺48.3
⫺40.9
10.6
15.1
14.4
12.7
5.5
15.1
9.4
8.5
11.5
3.77
⫺0.83
⫺0.91
⫺0.82
⫺0.85
⫺0.77
⫺0.93
⫺0.93
⫺0.86
0.06
0.69
0.82
0.68
0.72
0.60
0.87
0.86
0.75
0.10
slope
SEE
r
r2
⫺0.20
0.43
0.36
0.88
0.70
0.49
0.48
0.45
0.34
0.32
0.14
0.21
0.39
0.37
0.61
0.23
0.32
0.16
⫺0.35
0.87
0.60
0.71
0.65
0.98
0.67
0.59
0.44
0.12
0.76
0.36
0.50
0.42
0.96
0.45
0.51
0.27
IVRT and ␶ were measured in milliseconds and RR was measured in percentages per millisecond. SEE, standard error of the estimate.
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ASSESSMENT OF RELAXATION BY LV RECOIL
Fig. 3. Correlation of the relaxation time constant (␶) with recoil rate
in 10 dogs. Symbols are different for each of the 10 dogs. Each
individual point represents one intervention.
DISCUSSION
LV relaxation begins when myofiber tension starts to
decline during late ejection (8), proceeds rapidly as
pressure falls during isovolumic relaxation, and continues through the period of early filling. Relaxation is
best quantified by measuring the rate of LV pressure
decay, which can be expressed as a time constant (␶),
based either on a monexponential model with a zero
(44) or nonzero asymptote (30) or on a “logistic” model
(27). The greatest portion of the pressure decline occurs
during isovolumic relaxation. The process of LV filling,
which begins at the time of mitral valve opening, profoundly alters the rate of LV pressure decline; pressure
changes that occur after mitral valve opening do not
reliably reflect the process of relaxation itself (15, 30).
Noninvasive methods can detect the extent and velocity of motion of the myocardium or blood. However,
standard measurements provide little information
about the isovolumic period (other than its duration),
during which most of the relaxation process occurs
(19), because deformations that are routinely studied
(e.g., myocardial lengthening or thinning, cavity volume increase, and blood inflow) are dependent on
changes in LV volume. These deformations do not
begin until after the mitral valve opens, when most of
the relaxation process has already been completed.
Like invasive measurement of pressure, these noninvasive parameters tend to be strongly influenced by
factors other than relaxation that contribute to the
early diastolic atrioventricular pressure gradient [i.e.,
LA pressure, passive myocardial stiffness (4), and viscoelasticity (15)].
Torsion mechanics. Torsion and its diastolic recoil
display a unique behavior that is, in part, volume
independent and therefore can be observed during the
isovolumic periods. With the use of implanted markers
(6, 29, 46), MRI tagging (34), and guidewire rotation
during angioplasty (23), it has been clearly shown that
during isovolumic relaxation, when cavity volume is
fixed, there is a rapid recoil of ⬃40% of the torsion that
had accumulated during systole. In addition, volume
independence has been shown in a completely isovolumic beating heart preparation, in which there is conAJP-Heart Circ Physiol • VOL
siderable torsion and recoil, despite the absence of
thickening or circumferential or longitudinal shortening (26).
Therefore, in contradistinction to other noninvasive
indexes of diastolic function, recoil of torsion is largely
an isovolumic event, as is the gold standard for relaxation, ␶. Recently, Dong et al. (14) found that during
conditions of fixed cavity volume in an isolated perfused heart model, the extent of torsion depended on
cavity pressure. We therefore hypothesized that the
rate of recoil might reflect the rate of pressure fall
during isovolumic relaxation and that its measurement might provide a more physiological and direct
noninvasive method for quantification of relaxation
than has heretofore been available.
In this study, RR was indeed found to correlate
closely and reproducibly with ␶. This finding is consistent with prior studies of torsion during diastole in
humans. Moon et al. (29) altered load and contractility
in transplant recipients with radiopaque markers and
reported a close relationship of early diastolic untwist
with both peak ⫺dP/dt and LV end-systolic volume,
both of which are closely related to ␶. Yun et al. (46)
noted that early diastolic rapid recoil was markedly
diminished during cardiac transplant rejection, which
would be expected to slow relaxation: the time to 50%
of peak twist was prolonged by 40%. This phenomenon
was a sensitive predictor of rejection. Knudtson et al.
(23) found that, whereas recoil of the apex was 37%
complete by the end of isovolumic relaxation in nonischemic human hearts, recoil during isovolumic relaxation was essentially absent during acute ischemia
induced by angioplasty balloon inflation, a condition
known to prolong ␶. Studies in dogs have been less
consistent. Rademakers et al. (34) reported that inotropic stimulation caused an increase in the extent of
recoil during isovolumic relaxation, whereas Gibbons
Kroeker et al. (18) reported a decrease, but ␶ was not
measured in those studies.
Mechanistic significance of recoil. In addition to providing a means to measure the rate of LV pressure fall,
the untwisting deformation may itself contribute to the
pressure decay. Relaxation is dependent on the rate of
deactivation of cross-bridges within the sarcomere but
is also associated with the release of restoring forces
Table 3. Results of multiple regression using the GEE
method, showing the relation of independent variables
with RR and with IVRT, controlling for the influence
of the other variables
RR
IVRT
Independent Variables
P
Coef
␶
LA pressure
Aortic notch pressure
LV systolic pressure
Peak ⫹dP/dt
⬍0.0001
0.817
0.287
0.604
0.060
⫺0.0309
⫺0.0007
0.0017
0.0013
⫺0.0001
P
Coef
⬍0.0001
1.228
⬍0.0001 ⫺0.898
0.015
0.278
0.012 ⫺0.221
0.510
0.0004
RR and IVRT are dependent variables. GEE, Generalized Estimating Equation; Coef, coefficient; LV, left ventricular; dP/dt, instantaneous rate of change of LV pressure with respect to time.
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ASSESSMENT OF RELAXATION BY LV RECOIL
from the ventricular wall. These forces are stored when
systolic contraction of the cavity to volumes below an
“equilibrium volume” results in the stretch or compression of cellular and extracellular proteins such as titin
(11) and collagen (29, 34, 46). The development of
counterclockwise torsion during systole leads to transmural equilibration of fiber shortening (4) and allows a
greater deformation of elements within the wall for any
given ventricular volume (14). This is particularly true
in the endocardium, where the counterclockwise
torque is in the direction opposite to the alignment of
fibers, and considerable deformation of the connective
tissue matrix must occur (35, 43). This may permit
more energy to be stored within the wall. The release of
this repository of force during isovolumic relaxation
creates ventricular suction, returning the stored energy to the circulation (45).
Preload independence. As expected, IVRT shortened
significantly with volume loading and proved highly
dependent on LA pressure in the multivariate analysis.
In contrast, RR was unchanged with fluid loading
(which increased LA pressure from 9 to 14.6 mmHg),
and, in the multivariate analysis, there was no contribution of LA pressure toward RR. This demonstration
of preload independence suggests that RR may not be
subject to “pseudonormalization” in situations where
LA pressure rises or to overestimation of diastolic
abnormalities in situations where LA pressure is low,
for example, during dehydration. The influence of other
factors not directly related to relaxation, such as mitral
inertance and atrial contractility, on RR could not be
assessed by this study but is likely to be less for this
isovolumic phase index than for indexes of diastolic
function measured during filling.
Two new Doppler measurements have also been
shown to reflect relaxation with only minimal preload
dependence. Color M-mode Doppler detects the velocity
of propagation of the filling wave between the mitral
valve and LV apex during early filling (7, 39). This
velocity is dependent on the presence of intraventricular gradients, which appear to be more closely related
to the ventricular relaxation process than to the atrial
driving force. Tissue Doppler echocardiography (16, 21)
detects myocardial long-axis lengthening velocity during early (E wave) and late (A wave) diastole. The
preload independence of this method could relate to a
preferential effect of ventricular relaxation on base-toapex dimension changes, whereas atrial driving force
might affect lengthening in the circumferential direction. However, both of these new echocardiographic
methods depend on measurements made after most of
the relaxation process has already been completed,
which reduces their sensitivity. More importantly,
they are recorded after filling begins so some influence
of load is therefore to be expected (1, 32, 42). A third
type of Doppler method has been described, which can
be measured during isovolumic relaxation; the rate of
decay of a mitral regurgitation jet (12) or rate of acceleration of an aortic regurgitation jet (36) is interrogated. However, this measure requires the presence of
a regurgitant jet that is large enough to produce a
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H2007
continuous signal, and this method is not load independent, because mitral regurgitation is determined by
atrial as well as ventricular pressure and aortic regurgitation is closely related to aortic diastolic pressure.
The current study utilized only MRI and hemodynamic
variables and could not compare the utility of RR with
these new echocardiographic parameters. However, we
were able to compare RR with IVRT, an older index of
relaxation that can be measured by echocardiography
(28). IVRT was significantly affected by volume loading, and its correlation with ␶ was less consistent and
more variable than that of RR, probably due to its
greater dependence on LA pressure.
Limitations. Several limitations exist in the interpretation of these data. First, as noted above, our study
did not allow comparison of the relative value of this
new index of relaxation with newer echocardiographic
techniques. We also did not assess the effects of regional wall motion abnormalities. Such studies will be
important in defining the role that this method will
ultimately play. Second, correlation of RR with ␶ was
high (⫺0.86 for individual experiments, ⫺0.92 for
pooled data), but the corresponding r2 values (0.75 and
0.84, respectively) indicate that there are components
of the variation of RR that are not entirely explained by
␶. Note that the SD of RR is higher than that of ␶.
Errors in defining the endocardial-tag intersections
(which was done by hand), limitations in image resolution due to pixel size (which averaged 1.5 mm), and
image times of several minutes in the absence of respiratory gating may have contributed to this variation.
Automatic tag-tracking algorithms and improved
speed and pixel resolution in newer magnetic resonance systems will reduce these problems in the future. Third, the heart rates in the dogs studied were
high due to anesthesia and the need for atrial pacing at
a constant rate (to assure accurate gating); this prevented us from studying the rate dependence of RR. It
also raises the question of whether our results are
generalizable to slower rates. We suspect that rate is
not an important confounder here because studies of
human transplant recipients (28, 45) at physiological
rates yielded results consistent with ours. Fourth, RR
was determined using a linear regression of recoil
versus time, whereas pressure is known to decline in
an exponential fashion starting at peak ⫺dP/dt (44).
We tested an exponential model as well and found
similar correlations, but chose the more simple linear
model because our temporal resolution was not adequate to define an appropriate starting point (i.e, peak
⫺dP/dt) for an exponential relationship. Higher temporal resolution is now available using the latest magnetic resonance scanners, and future studies might
attempt various exponential fits. The pioneering works
in this field by Yun et al. (46) and Moon et al. (29) also
used linear models. Finally, we used tagged MRI for
these experiments. The availability of this technique is
currently limited, and specialized software is required
for analysis. However, cardiac magnetic resonance is
recognized as an excellent research tool and is growing
in popularity and accessibility for clinical care. Fur-
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ASSESSMENT OF RELAXATION BY LV RECOIL
thermore, there may be potential for visualizing LV
apical rotation and recoil using tissue Doppler echocardiography, a widely available technology.
In summary, the rate of recoil of LV torsion, which
can be determined wholly noninvasively, provides an
isovolumic phase, preload-independent assessment of
LV relaxation. Use of this novel parameter should
allow the detailed study of diastolic function in states
known to affect filling rates, such as aging, hypertension, and congestive heart failure, and may provide an
estimate of the function of the relaxation process in
individual patients, allowing serial measurements to
follow therapeutic interventions.
We are grateful to Dr. Edward G. Lakatta for thoughtful critiques
of these concepts and to Stephanie Bosley for superb technical
operation of the MRI scanner and processing of the image data.
This study was supported by National Heart, Lung, and Blood
Institute Grant RO1 HL-46223 (to E. P. Shapiro).
This paper was presented in part at the 70th Annual Scientific
Sessions of the American Heart Association, Orlando, Florida, November 1997.
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