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Contraction-relaxation coupling:
determination of the onset of diastole
STEVEN B. SOLOMON,1 SRDJAN D. NIKOLIC,2
ROBERT W. M. FRATER,1 AND EDWARD L. YELLIN1
1Department of Cardiothoracic Surgery and the Department of Biophysics and Physiology,
Albert Einstein College of Medicine, Bronx, New York 10461; 2Department of Cardiovascular and
Thoracic Surgery, Research Institute of the Palo Alto Medical Foundation, Stanford University
School of Medicine, Palo Alto, California 94306
afterload; left ventricular relaxation
THERE HAS BEEN INCREASING interest in impaired left
ventricular relaxation as a precursor to early heart
failure or as a possible cause of diastolic failure (7, 22).
Investigators (1, 4, 6, 12) have pointed to left ventricular relaxation as the link between activation during
contraction and inactivation during relaxation and to
loading conditions as a major determinant of relaxation. Several studies (3, 10, 16, 24) have investigated
the role of preload and afterload on isovolumic relaxation. Specifically, the dependence of relaxation on
afterload conditions has been investigated by transiently changing afterload at various times during
systole in isolated muscle, isolated heart, and intact
heart preparation (1, 3, 5, 10, 16, 21, 24).
Muscle twitch experiments in isolated muscle showed
that an increase in afterload early in systole both
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delays the onset and slows down the rate of relaxation,
whereas an increase in afterload late in systole abbreviates contraction time and increases the rate of relaxation (5). In isolated heart studies, interventions designed to increase afterload immediately after aortic
valve opening increased the duration of systole, whereas
an increase in afterload late during ejection decreased
the duration of systole (1, 24). In an intact heart study,
afterload was changed by inflating a balloon catheter to
occlude the aorta (10). The aortic occlusion resulted in a
decrease in the rate of relaxation when the balloon was
inflated during the first one-third of the ejection and an
increase in the rate of relaxation when the balloon was
inflated during the last one-third of the ejection. Thus
all physiological studies on the effects of afterload
dependence on the duration of systole and the rate of
relaxation showed two important findings (1, 5, 10, 24).
First, an increase in afterload while the muscle or the
ventricle was actively contracting prolonged the duration of systole and slowed relaxation. Second, an increase in afterload during muscular or ventricular
relaxation shortened the duration of systole and increased the rate of relaxation.
The dependence of the duration of systole and the
rate of relaxation on loading conditions has been ascribed to changes in the recruitment of cross bridges
(6), cooperative cross-bridge activity (2, 11, 23), crossbridge cycling rate (23), and changes in cross-bridge
inactivation (17). The increase in systolic time and
slowing of the rate of relaxation with afterloads imposed during early ejection were attributed to an increase
in cross-bridge recruitment, a cooperative activity of crossbridge formation resulting in further cross-bridge formation, a decreased rate of cross-bridge attachment/
detachment cycling, and a slower inactivation of crossbridge formation due to changes in calcium handling (6,
23). The shortening of systole and increased rate of
relaxation with increased afterload has been related to
an inability of cross bridges to sustain increasing load
while the rate of detachment was greater than the rate
of attachment, resulting in cross-bridge disruption and
increasing the rate of relaxation (13, 25).
According to these mechanisms, it is obvious that
there must be a transition point during systole when
load ceases to sustain the cross bridges and starts
opposing their formation (i.e., there must be a transition point between what is conventionally called contraction and relaxation). However, it is not clear when this
0363-6135/99 $5.00 Copyright r 1999 the American Physiological Society
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Solomon, Steven B., Srdjan D. Nikolic, Robert W. M.
Frater, and Edward L. Yellin. Contraction-relaxation coupling: determination of the onset of diastole. Am. J. Physiol.
277 (Heart Circ. Physiol. 46): H23–H27, 1999.—Left ventricular relaxation is dependent on afterload conditions during
systole. An abrupt increase in afterload while the ventricle is
actively contracting prolongs the duration of systole. An
increase in afterload during ventricular relaxation shortens
the duration of systole. Therefore, we hypothesized that the
point during systole when an abrupt increase in afterload had
no effect on the duration of systole represented the onset of
ventricular relaxation. To determine when this point occurs,
we performed aortic occlusions progressively throughout the
duration of systole in six dogs. We determined the change in
systolic time (tsys ) after an intervention normalized to tsys of a
control beat (tsys,i/tsys,c ) as a function of systolic occlusion time
as a percentage of total systolic time (tocc/tsys,c ), where tsys is
the duration from time of left ventricular end-diastolic pressure to the time of minimum first derivative of left ventricular
pressure. Our results show the onset of left ventricular relaxation
during normal ejection occurs at 34 ⫾ 3% of systolic time and
⬃16% after the onset of ejection. Thus the beginning of relaxation occurs soon after the beginning of ejection, suggesting
that relaxation is modulated by variable loading conditions
during ejection, significantly before what has been conventionally been assumed to be the beginning of ventricular relaxation.
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DETERMINATION OF ONSET OF DIASTOLE
METHODS
Surgical preparation. Six mongrel dogs (wt 21–28 kg) were
anesthetized with fentanyl citrate (10 µg/kg iv), intubated,
and mechanically ventilated with 100% oxygen. Anesthesia
was maintained by administration of fentanyl citrate (30 µg)
and pancuronium bromide (4 mg) every 20 min or as needed.
The dogs were placed in the supine position, and a medial
sternotomy was performed. The pericardium was opened
wide to create a pericardial cradle. Arterial blood gases and
pH were monitored and maintained in the normal range by
ventilator adjustment, administration of sodium bicarbonate,
or both.
Instrumentation. To measure left atrial and left ventricular
pressures, two 5-Fr micromanometers (Millar Instruments)
were inserted, one into the left atrium via a small branch of a
left pulmonary vein and the other into the left ventricle via
the apex (Fig. 1). Before the experiment, the micromanometers were warmed to 37°C overnight to achieve a steady
state. The micromanometers were zeroed, and they were
calibrated against a mercury manometer before being inserted into the dog. An ultrasonic flow transducer (Transonic
System) was placed around the ascending aorta to measure
aortic flow. An electromagnetic flow probe was placed on the
mitral orifice according to a previously published procedure (15).
Pressures and flows were recorded at high gain on an oscillographic recorder (VR-12, Electronics for Medicine) at a speed of
100 mm/s. The data were also recorded on CODAS (DATAQ
Instruments), a computer-based real-time data acquisition system at 200 samples·s⫺1 · channel⫺1, which is the standard rate
of data acquisition of physiological waveforms in dogs.
Aortic occluder. An occluder was placed around the aorta to
abruptly increase the afterload of the ventricular chamber.
The aortic occluder is a free-moving right-angle clamp, carefully placed around the aorta to avoid constriction (Fig. 1).
The edges of the clamp are covered with soft plastic to
minimize trauma to the aorta on occlusion. One side of the
clamp is fixed in place, whereas the other is attached to a
Fig. 1. Cross section of the left heart instrumented with the aortic
clamp, left atrial pressure (LAP) and left ventricular pressure (LVP)
micromanometers, and mitral flow (MF) transducer.
control cable welded to the core of the solenoids. The solenoids
are adjusted to ensure that the stroke will occlude the aorta
and are positioned on an adjustable platform near the openchest area.
Protocol. The aorta was occluded progressively throughout
the duration of systole. These aortic occlusions were performed before ejection, resulting in an isovolumic contraction,
and subsequent occlusions were performed progressively
throughout the duration of systole.
Before each occlusion, a hemodynamic steady state was
achieved and the respirator was turned off to avoid respiratory variations in the hemodynamic measurements and to
control artifacts that might interfere with the signal. We
recorded hemodynamic measurements for several control
beats, and an aortic occlusion was performed. The aortic
occlusion was triggered on the R-wave from a lead II electrocardiogram. After the aortic occlusion, ⬃20 beats were allowed for the hemodynamic and flow signals to return to
steady state before another occlusion was performed.
Data analysis. The oscillographic records were digitized
(Science Accessories) by manually tracing the pressure curve
and calculating the change in slope to determine the rate of
relaxation from the time constant of left ventricular pressure
decline. The CODAS system could not be used for this
purpose because each waveform was recorded on a separate
channel. The CODAS data were calibrated and analyzed
using Asystant (Asyst Software Technologies) to measure the
pressure and the timing of events. Systolic time was determined by taking the first derivative of left ventricular pressure (dP/dt) and measuring the interval from the onset of
mechanical contraction to the minimum of dP/dt (dP/dtmin).
Linear regression analysis using the least squares method
was applied to the occlusion data. The data were evaluated
using two statistical packages, Primer of Biostatistics (Stan-
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transition point occurs during the cardiac cycle and
when left ventricular relaxation actually begins. If the
beginning of relaxation is close to the beginning of
isovolumic relaxation, the loading condition of the left
ventricle, which is not changing dimensions, may be a
major determinant of the relaxation. If the relaxation
starts earlier during ventricular ejection, the loading
conditions of the rapidly contracting ventricle may
become the prevailing determinant of relaxation. These
two situations are dramatically different in terms of the
mechanisms that govern their contraction-relaxation
sequences and cross-bridge dynamics, and these differences may be significant in our understanding of the
physiological and pathophysiological determinants of
left ventricular function.
Therefore, the present study was designed to test the
working hypothesis that the point during systole when
an abrupt increase in afterload has no effect on the
duration of systole represents the onset of relaxation in
the intact left ventricle. To determine this point when
the left ventricle begins to relax, we changed the
afterload in six open-chest dogs by progressively occluding the aorta throughout systole. Surprisingly, the data
show that the onset of left ventricular relaxation during normal ejection occurs very early in systole, after
only ⬃16% of ejection is completed.
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DETERMINATION OF ONSET OF DIASTOLE
ton Glantz, McGraw-Hill) and Statpak (Northwest Analytical). Statistical significance was determined by a paired
t-test. Differences were considered significant when P ⬍ 0.05.
Data are means ⫾ SD. The results of the digitized data were
then plotted using SigmaPlot (Jandel Scientific).
RESULTS
DISCUSSION
The effect of afterload on the rate of relaxation and
other various determinants of filling has been investigated extensively (3, 8, 9, 10, 20, 21). Isolated muscle
experiments showed that the onset of relaxation occurred earlier with smaller loads when shortening was
the greatest (3, 21). In an intact heart, abruptly increasing afterload during early systole resulted in a delay in
the onset of relaxation and a decreased rate of relaxation (8, 10). Increasing afterload late in systole resulted in an increase in the rate of relaxation (8, 10, 20).
All of these results are consistent with the findings in
this study and can be understood within the context of
the cross-bridge theory of muscle contraction (14).
An early increase in systolic load increases the
myocardial sensitivity to free calcium, thereby increasing the recruitment of cross bridges and increasing the
duration of systole, in part, by slowing the rate of
relaxation. A late increase in systolic load does not
increase myocardial sensitivity to calcium, resulting in
a decrease in cross-bridge formation. The cross bridges
cannot maintain the increased load, resulting in an
increase in the rate of relaxation and a subsequent
decrease in the duration of systole.
The data plotted in Fig. 3 show the effect of varied
systolic interventions on the duration of systole. The
data points, which intersect the isosystolic time line,
neither increase nor decrease the duration of systole.
These data support our hypothesis that there is a point
in the intact heart when increases in afterload do not
affect the duration of systole. We speculate that this
intersection suggests a point when the sarcomere crossbridge cycling (the attachment and detachment of cross
bridges) is in equilibrium just before the onset of
relaxation. It is surprising that the onset of relaxation
occurs this soon after the onset of ejection (34% of
systolic time, after ⬃16% of ejection). These results also
Table 1. Summary of the hemodynamic effects of isovolumic, early systolic, and late systolic occlusions
Late Systolic Occlusion
tcyc , ms
tocc , ms
tco , ms
LVPco , mmHg
SV, ml
␶, ms
tDF , ms
Early Systolic Occlusion
Isovolumic Occlusion
Baseline
Intervention
Baseline
Intervention
Baseline
Intervention
458 ⫾ 18
454 ⫾ 120
166 ⫾ 21
268 ⫾ 23
12.1 ⫾ 6.4
19.2 ⫾ 6.0‡
51.1 ⫾ 14.5*
182 ⫾ 53
470 ⫾ 117
479 ⫾ 118
65 ⫾ 20
298 ⫾ 31*
14.2 ⫾ 5.0*
9.8 ⫾ 2.5*
60.7 ⫾ 18.9†
178 ⫾ 50
480 ⫾ 134
477 ⫾ 136
271 ⫾ 35
11.7 ⫾ 5.4
23.7 ⫾ 5.4
57.9 ⫾ 19.3
201 ⫾ 45
304 ⫾ 43‡
14.6 ⫾ 6.1‡
No ejection
72.3 ⫾ 29.6†
166 ⫾ 53*
271 ⫾ 26
12.4 ⫾ 5.6
25.5 ⫾ 6.4
61.5 ⫾ 15.8
191 ⫾ 61
285 ⫾ 19
9.4 ⫾ 4.5
21.7 ⫾ 6.3
54.4 ⫾ 12.2
196 ⫾ 34
Values are means ⫾ SE. tcyc , Cycle length; tocc , time of aortic occlusion; tco , time of atrioventricular crossover; LVPco , left ventricular pressure
at atrioventricular crossover; SV, stroke volume; ␶, rate of isovolumic pressure decay; tDF , diastolic filling time; * P ⬍ 0.05, † P ⬍ 0.002, ‡ P ⬍
0.0001 vs. baseline value.
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To determine the effect of abrupt increases in afterload
throughout the duration of systole, the data were divided
into three groups: late systolic occlusion, early systolic
occlusion, and isovolumic contraction (Table 1). Late systolic occlusion was an intervention that caused the time to
dP/dtmin to decrease compared with a control systole;
early systolic occlusion increased time to dP/dt compared with a control systole. An isovolumic contraction
was defined as an occlusion performed before systolic
contraction.
Figure 2 illustrates the effect of a late aortic occlusion, an early aortic occlusion, and an isovolumic
occlusion on left ventricular pressure and the rate of
change of left ventricular pressure with respect to time
(dP/dt) compared with a control beat. The duration of
systole (systolic time) was defined as the interval from
the onset of mechanical contraction to the minimum of
dP/dt (systolic time of a control beat, tsys,c ). In normal
control beats, the beginning of ejection was calculated
to occur at 23.4 ⫾ 2.5% of systolic time and the end of
ejection occurred at 90.8 ⫾ 3.3% of systolic time. During
a late aortic occlusion, peak left ventricular pressure is
unchanged but relaxation is accelerated (51.1 ⫾ 14.5
vs. 61.5 ⫾ 15.8 ms, P ⬍ 0.05) and systolic time is
decreased. During an early aortic occlusion, peak left
ventricular pressure increases, relaxation is slowed
(60.7 ⫾ 18.9 vs. 54.4 ⫾ 12.2 ms, P ⬍ 0.002), and systolic
time is slightly increased. During an isovolumic occlusion, the peak left ventricular pressure increases
(greater than that seen during early aortic occlusion),
relaxation is slowed (72.3 ⫾ 29.6 vs. 57.9 ⫾ 19.3 ms,
P ⬍ 0.002), and systolic time is significantly increased.
The systolic time of an intervention (time of left
ventricular end-diastolic pressure to time of dP/dPmin )
was normalized to a control beat (tsys,i/tsys,c ) to eliminate
the differences caused by heart rate. The normalized
systolic time was plotted against the occlusion time
expressed as a percentage of the systolic time of a
control beat (tocc/tsys,c ) (Fig. 3). The scatterplot shows the
results obtained from varied systolic aortic occlusions
followed by normal mitral filling. The intersection of
the regression line and the isosystolic time line (horizontal line) represents the instant during systole when an
intervention does not affect the duration of systole. The
plot shows that the onset of left ventricular relaxation
during a normal beat occurs after the first one-third of
systolic time (34 ⫾ 3%) measured from the onset of
mechanical contraction (Fig. 3).
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DETERMINATION OF ONSET OF DIASTOLE
Fig. 3. Onset of relaxation as a percentage of systolic time. Plot
shows the systolic time of an intervention normalized to a control
beat (tsys,i/tsys,c ) vs. systolic occlusion time as a percentage of total
systolic time (tocc/tsys,c ).
show that a significant portion of relaxation is influenced by variable systolic loading and length before the
isovolumic relaxation phase. If true, these results are
not consistent with the physiologically loaded isolated
muscle model of left ventricular relaxation, which assumes
isometric relaxation (3). This study agrees with the findings of Gillebert and co-workers (9, 18) that during
abrupt aortic occlusions using balloon inflation in dogs,
the transition from contraction to relaxation occurs
when 81 to 84% of peak isovolumic pressure is reached.
When this value for the transition from contraction to
relaxation is converted into the equivalent timing of a
normal beat, the results are similar to those found in
this study. Our results are also consistent with previous
work (19) that suggested inertial forces due to left
ventricular outflow were responsible for the continuing
increase in aortic pressure even after the onset on
relaxation. The pressure gradient from left ventricle to
the aorta remains positive even after the onset of
relaxation during acceleration and becomes negative
shortly after deceleration begins. Therefore, it is the
aortic outflow-left ventricular pressure gradient that determines acceleration with the fall of left ventricular pressure
being the primary determinant of the rate of deceleration.
Aside from the obvious (and inevitable) drawbacks of
an open-chest animal model, the study is limited by the
application of the aortic occluder. The aortic occluder
closes the aortic orifice in 12 ms. This abrupt occlusion
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Fig. 2. Control beat (A) compared with the
effect of a late aortic occlusion (B), an early
aortic occlusion (C), and an isovolumic
occlusion (D) on LVP and systolic time
(tsys ). The duration of systole (systolic time
of a control beat, tsys,c ) was defined as the
interval from the onset of mechanical contraction to minimum first derivative of
LVP (dP/dt). tsys,i, Systolic time of an intervention; tocc, time of occlusion; AoF, aortic
flow.
DETERMINATION OF ONSET OF DIASTOLE
S. D. Nikolic is an Established Investigator of the American Heart
Association.
This work was supported in part by National Heart, Lung, and
Blood Institute Grant HL-49614.
Address for reprint requests and other correspondence: S. Solomon, NIH, Critical Care Medicine Dept., 10 Center Dr., Rm. 7D43,
Bethesda, MD 20892 (E-mail: [email protected]).
Received 9 September 1998; accepted in final form 19 February 1999.
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of the aortic valve may change the dynamics of the
valve or the ventricle. This effect was minimized by
placing the aortic occluder a sufficient distance from
the aortic valve to avoid interfering with valve function
and the ventricle. Another limitation was the electromagnetic flow transducer on the mitral valve. This
mitral transducer fixes the mitral annulus. We did not
consider this to be a significant limitation because the
possible influence of the mitral transducer had a constant effect throughout the study.
In summary, our study shows that the onset of
relaxation occurs soon after the beginning of ejection
(after ⬃16% of ejection). This result shows that relaxation is modulated by variable loading conditions during ejection significantly before what has been conventionally assumed to be the beginning of ventricular
relaxation.
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