Download Prolonged Diastolic Time Fraction Protects Myocardial

Prolonged Diastolic Time Fraction Protects Myocardial
Perfusion When Coronary Blood Flow Is Reduced
Daphne Merkus, PhD; Fumihiko Kajiya, MD, PhD; Hans Vink, PhD; Isabelle Vergroesen, PhD;
Jenny Dankelman, PhD; Masami Goto, MD, PhD; Jos A.E. Spaan, PhD
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Background—Because coronary blood flow is impeded during systole, the duration of diastole is an important determinant
of myocardial perfusion. The aim of this study was to show that coronary flow modulates the duration of diastole at
constant heart rate.
Methods and Results—In anesthetized, open-chest dogs, diastolic time fraction (DTF) increased significantly when
coronary flow was reduced by lowering perfusion pressure from 100 to 70, 55, and 40 mm Hg. On average, DTF
increased from 0.4760.04 to 0.5560.03 after a pressure step from 100 to 40 mm Hg in control, from 0.4260.04 to
0.4760.04 after administration of adenosine, and from 0.4660.07 to 0.5560.06 after L-NMMA (mean6SD, 6 dogs for
control and adenosine, 4 dogs for L-NMMA, all P,0.05). Flow normalized to its value at full dilation and pressure of
90 mm Hg (375625 mL/min) increased during the period of reduced pressure at 40 mm Hg; control, from 0.005663
(2 seconds after pressure step) to 0.0960.06 (15 seconds after pressure step); with adenosine, from 0.1960.06 to
0.2260.06; and with L-NMMA, from 0.01360.007 to 0.1260.02 (all P,0.05). The increase in DTF at low pressure
may be explained by a decrease in interstitial volume at low pressure, which either decreases the preload of the myocytes
or reduces the buffer capacity for ions determining repolarization, thereby causing an earlier onset of relaxation.
Conclusions—Because the largest increase in DTF occurs at pressures below the autoregulatory range when blood flow
to the subendocardium is closely related to DTF, modulation of DTF by coronary blood flow can provide an important
regulatory mechanism to match supply and demand of the myocardium when vasodilatory reserve is exhausted.
(Circulation. 1999;100:75-81.)
Key Words: diastole n metabolism n circulation n perfusion n contractility
W
important mechanism for matching coronary supply and
demand of oxygen by simultaneously decreasing demand and
increasing supply.
ith progression of atherosclerosis, the increase of
resistance in the diseased coronary artery is compensated by reduction of tone in resistance vessels.1,2 However,
when dilatory reserve is exhausted, coronary flow will
depend strongly on the relative duration of diastole. This DTF
is determined by heart rate3,4 and by factors that modulate
systolic duration through modulation of myocyte contraction,
such as endothelin-1, angiotensin II, and nitric oxide.5– 8 In
earlier studies, it has been demonstrated that occlusion of a
major coronary artery results within seconds in shortening of
the duration of systole.9 However, because heart rate was not
controlled, this may be explained in part by an increase in
heart rate.
We hypothesized that at constant heart rate, the effect of a
decrease in perfusion pressure on coronary flow could be
compensated by an increase in diastolic time fraction (DTF).
This would be especially beneficial for subendocardial perfusion.3 An increase in diastolic duration may therefore be an
Methods
Six dogs with a body weight of '20 kg were sedated with an
injection of ketamine (10 mg/kg IM) followed by an injection of
sodium pentobarbital (25 mg/kg IV) for anesthesia. Depth of
anesthesia was monitored by checking reflexes, and additional
anesthesia was given when necessary. After tracheal intubation, dogs
were ventilated with a mixture of room air and oxygen by use of a
jet ventilator at a rate sufficient to maintain arterial oxygen and
carbon dioxide tensions in the physiological range (pH 7.35 to 7.45,
PCO2 25 to 40 mm Hg, PO2 .70 mm Hg). When necessary, sodium
bicarbonate was given to avoid acidosis. A thin polyethylene catheter
was inserted into the left jugular vein for administration of drugs. An
8F pigtail double-lumen manometer catheter (microtip catheter
transducer, model SPC-784A, Millar) was inserted, with 1 of its sites
of measurement placed in the left ventricle and the second in the
ascending aorta. A medial sternotomy and a thoracotomy between
the third and fourth ribs were performed, and the heart was
Received December 10, 1998; revision received March 25, 1999; accepted March 30, 1999.
From the Department of Medical Physics, Cardiovascular Research Institute Amsterdam, Academic Medical Center, University of Amsterdam (D.M.,
H.V., I.V., J.A.E.S.), and the Faculty of Design, Engineering and Production, Mechanical Engineering and Marine Technology, Laboratory for
Measurement and Control, Delft University of Technology (J.D.), Netherlands; and the Department of Medical Engineering and Systems Cardiology,
Kawasaki Medical School, Kurashiki, Okayama, Japan (F.K., M.G.).
Correspondence to Prof Dr Ir J.A.E. Spaan, Department of Medical Physics, Cardiovascular Research Institute Amsterdam, Academic Medical Center,
University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail [email protected]
© 1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
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July 6, 1999
suspended in a pericardial cradle. Two pacing wires were sewn onto
the right atrial appendage. The sinus node was destroyed by injection
of 40% formaldehyde, and the heart was paced at 100 to 120 bpm.
After administration of an initial intravenous dose of heparin
followed by continuous administration, the heart was perfused by
means of a perfusion system applying a stainless steel Gregg cannula
ligated into the left main coronary artery without disruption of
flow.10 Coronary blood flow was measured with an in-line flow
probe (Transonic 4F, T206). Perfusion pressure was measured with
a thin fluid-filled catheter at the cannula tip or with a fluid-filled
24-gauge catheter in the first diagonal branch of the LAD.
All experiments were done in accordance with the guidelines on
animal experiments of our institutions.
Protocol
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Coronary arterial pressure was decreased stepwise from 100 mm Hg
to 70, 55, and 40 mm Hg, kept at that level for 20 to 30 seconds, and
then increased back to 100 mm Hg. The interventions were repeated
with a stenosis on the perfusion line and adjustment of reservoir
pressure to obtain similar average coronary pressures. This protocol
was repeated 1) after administration of adenosine (20 to 50 mg z
kg21 z min21 IC) such that reactive hyperemia resulting from 15
seconds of occlusion disappeared and 2) after 20 minutes of
administration of NG-monomethyl-L-arginine (L-NMMA) (4 mmol z
kg21 z min21) (4 dogs) blocking nitric oxide synthesis.11 Reduction of
nitric oxide synthesis was confirmed by comparing dilation to
acetylcholine (1 mg/kg) before and after administration of L-NMMA
in 3 dogs.
Figure 2. Typical example of an occlusion and subsequent hyperemia. Increase in DTF during occlusion is rapidly reversed
during subsequent hyperemia.
Determination of the Relative Duration of Diastole
Diastole was defined as the period when left ventricular (LV)
pressure was ,25% of the range between its minimal and maximal
values and DTF as the quotient of the durations of diastole and the
entire heartbeat.
Statistics
The influences of adenosine, L-NMMA, and coronary pressure on
DTF were determined by ANOVA. If significant differences were
found, a pairwise multiple comparison method (Bonferroni) and
paired t tests were used to test the differences between the
individual groups.
Results
Figure 1. Example of influence of a stepwise decrease in perfusion pressure (Pp, top) on DTF (bottom). DTF started to increase
5 beats after decrease in pressure and reached a steady state
after another 17 beats. Second and third panels show response
of flow to decrease in pressure (phasic flow and flow averaged
per beat. Note that scales of flow axes are different). Flow
decreased on decrease in pressure and then increased slightly.
Retrograde flow in first seconds is due to discharge of intramural capacitance. LV pressure (Plv), aortic pressure (Pao), and
maximal rate of change of Plv, an index for contractility, were
only slightly influenced by decrease in pressure.
Figure 1 shows a typical example of the influence of
perfusion pressure on DTF. After pressure decreased stepwise
from 100 to 35 mm Hg (top panel), flow decreased from 38
to 230 mL/min and then increased slowly to 12 mL/min
(second and third panels). Maximal LV pressure and aortic
pressure remained constant during the intervention (fourth
panel). DTF (bottom panel) increased from 0.45 to 0.57
during the period of reduced pressure. The increase in DTF
started '6 beats (3 seconds) after the decrease in pressure and
reached 50% of the maximal response after another 4 seconds. On average, these numbers were 3.460.7 and 3.360.7
seconds (mean6SD), respectively. The increase in DTF
reversed rapidly during reactive hyperemia when pressure
was restored (Figure 2).
Figure 3 shows LV pressure in control and after administration of adenosine and L-NMMA in more detail. The traces
immediately after a pressure step from 100 to 40 mm Hg
(solid line) and 15 seconds later (dashed line) are superimposed, with the rise in LV pressure used as reference. The
early phase of contraction and the rate of relaxation were
comparable in both situations. However, relaxation started
earlier, 15 seconds after the decrease in coronary pressure,
resulting in prolonged duration of diastole in all conditions.
Figure 4 depicts different interventions for 1 dog. Steadystate DTF is plotted as a function of pressure and as a function
Merkus et al
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Figure 3. LV pressure (Plv) immediately after a pressure step
from 100 to 40 mm Hg (solid line) and after 15 seconds of stabilization (dashed line) in control, after administration of adenosine, and after L-NMMA. Duration of systole is shorter 15 seconds after pressure step than immediately after pressure step in
all conditions.
of flow. DTF increased with decreasing coronary pressure
with or without stenosis. With adenosine, DTF is lower at all
pressures, and the onset of the increase in DTF on a decrease
in pressure was delayed (4.860.7 seconds after adenosine
compared with 3.460.7 seconds in controls). The relation
between pressure and DTF in the presence of L-NMMA was
not different from that in controls. The reduction of DTF by
adenosine is consistent with the DTF-flow relationships in the
presence of tone (Figure 4, right).
Figure 5 depicts the average steady-state DTF for the
different interventions as a function of flow normalized with
respect to flow at full vasodilation and pressure of 90 mm Hg
Figure 4. Overall results from a typical experiment. Left,
Increase in DTF with decreasing pressure (Pp). Relation
between pressure and DTF is similar in absence (solid symbols)
and presence (open symbols) of a stenosis on perfusion line.
Administration of adenosine (E, dashed line) decreases DTF at
all pressures compared with control (‚) and L-NMMA (ƒ) (fitted
with solid line). Right, Relation between flow and DTF obtained
in control, with L-NMMA, and with adenosine in absence and
presence of a stenosis on perfusion line. This relation is steepest at low flows and flattens at high flows (solid line indicates fit
of relation).
Longer Diastolic Time Fraction at Low Flow
77
Figure 5. Overall relation between flow and DTF. Flow is normalized to flow measured at a pressure of 100 mm Hg at full
vasodilation with adenosine to compensate for variations in perfusion area. Mean flow at 100 mm Hg was 375625 mL/min.
Data are given as mean6SEM. Note that at lowest flow
obtained with adenosine, DTF was similar to that at similar flows
in control and after administration of L-NMMA. Symbols as in
Figure 4.
(average for 6 dogs in control and with adenosine, 4 dogs
with L-NMMA). DTF increased with decreasing flow in a
nonlinear way. At normalized flows .0.375 (150 mL/min),
DTF was not influenced by changes in flow, whereas DTF is
strongly related to flow below this threshold. Furthermore,
the low-flow data obtained with adenosine fit within the
relation obtained in controls and after administration
L-NMMA.
Both DTF and flow increased with time after an initial
period of '3 seconds, excluding capacitive effects. On
average, DTF increased from 0.4760.04 to 0.5560.03 after a
pressure step from 100 to 40 mm Hg in control, from
0.4260.04 to 0.4760.04 with adenosine, and from
0.4660.07 to 0.5560.06 with L-NMMA (all mean6SD, 6
dogs on control and adenosine, 4 dogs for L-NMMA, all
P,0.05). Normalized flow also increased during the period
of reduced pressure at 40 mm Hg: from 0.00560.063 (3
seconds after pressure step) to 0.0960.06 (15 seconds after
pressure step) in controls, from 0.1960.06 to 0.2260.06 with
adenosine, and from 0.01360.007 to 0.1260.02 with
L-NMMA (all P,0.05). With adenosine, the increase in flow
must be due to the increase in DTF. In control and after
L-NMMA, vasodilation contributes to the increase in flow as
well.
The relations between DTF and flow for the different
conditions in 1 representative experiment are depicted in
Figure 6 (see Table 1 for average data). The course of events
is as follows: Flow decreases (measured after the first 3
seconds) after a drop in coronary pressure, as indicated by the
vertical dashed lines in Figure 6. The data points and
regression lines give the simultaneous increase of DTF and
flow during the 15-second equilibration time. These relations
are steeper in control than after adenosine, because of
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Circulation
July 6, 1999
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Figure 6. Relation between DTF and flow over time in control
(triangles) and after administration of adenosine (circles) after
pressure steps from 100 mm Hg to different pressures in 1 representative experiment (black indicates 35 mm Hg; gray, 53 to
58 mm Hg; white, 70 mm Hg). Increase in flow due to increase
in DTF and due to vasodilation equals deviation from horizontal
dotted lines. Increase in DTF is limited by increase in flow. Difference in slope between control and adenosine is due to vasodilation. Eventually, DTF and flow reach a new steady state,
represented by continuous curve in this figure (comparable to fit
in Figure 4, right).
autoregulation in the former condition. With a pressure step
to 70 mm Hg, there is almost no increase in DTF; hence, the
increase in flow must be due to vasodilation. At 35 mm Hg,
however, the slope of the relation between DTF and flow in
control is only slightly steeper than that with adenosine,
indicating a relatively small contribution of vasodilation to
the increase in flow at low pressure.
Eventually, the flow and DTF reach a new steady state,
represented by the continuous curve in Figure 6, which is the
best fit for this condition in this experiment (compare with
steady-state relation between DTF and flow in Figure 4,
right). Hence, because of the hyperbolic relation between
DTF and flow, there is little change in DTF in the high flow
range of Figures 4 (right) and 5. This interpretation is also
consistent with the rather constant DTF at pressures
.70 mm Hg in the presence of tone, as shown in Figure 4,
left, because flow is rather independent of pressure in that
pressure range.
Discussion
In this study, we elaborated on earlier observations that the
duration of systole may shorten under ischemic conditions.9,12
We clearly demonstrate that such shortening occurs even
when heart rate is controlled. We reported our results as DTF
because this parameter is closely related to subendocardial
perfusion.3,4 We found that DTF is unaffected by changes in
coronary flow above '150 mL/min, which is somewhat
higher than the physiological control flow in our experiments
with autoregulation intact. The increase in DTF was related to
the reduction in flow below this threshold, ie, flows within or
below the autoregulatory range. We further demonstrated that
this flow-related phenomenon is not based on production of
NO. Because increases in DTF occur mainly when vasodilatory reserve is exhausted, DTF-related increases in myocardial perfusion may benefit myocardial oxygen supply when
perfusion is compromised.
Discussion of Methods
We defined diastole as the period when LV pressure was
,25% of the range between its minimal and maximal values.
Estimating DTF as the period between minimal and maximal
LV dP/dt or as the period between minimal LV dP/dt and
opening of the aortic valve for 1 pressure step in each
dog3,4,9,12 resulted in values of DTF that were 0.1160.02 and
0.1060.03 higher than our initial estimate (both P,0.05).
However, the changes in DTF on a change in pressure were
similar (P50.85 and P50.40).
In earlier studies reporting on shortening of systole, a
coronary branch was occluded.9,12 These experiments demonstrate a reduced ventricular relaxation rate, which can be
explained by an inhomogeneous onset of relaxation. Minimal
LV dP/dt, as an index of relaxation rate, did not change
during our interventions with total perfusion.
The same increase in DTF was found at different rates of
pressure decrease (from stepwise to slow ramps of 3 mm Hg/s).
The increase in DTF on a decrease in flow is not species
dependent, because we found the same in goats.
Possible Mechanisms of Increasing DTF
Ischemia may occur at low perfusion pressure. Fifteen beats
after the onset of underperfusion, phosphocreatine and ATP
contents decrease in the subendocardium, without a change in
lactate content.13 This may open the ATP-dependent K1
channels, which can result in an earlier onset of relaxation.
However, glibenclamide (220 mL, 1 mg/mL) administered in
similar experiments performed in goats did not influence the
TABLE 1. Slopes of the Relations Between DTF and Flow Normalized to Flow at
90 mm Hg at Full Vasodilation
Condition
Average Flow
per Beat
Maximal Flow
per Beat
Minimal Flow
per Beat
Control Pp, 3863 mm Hg
0.960.19
1.060.37*
Control Pp, 5563 mm Hg
2.0260.24
2.8760.41*
0.3960.2
Adenosine Pp, 4263 mm Hg
0.2660.05†‡
0.0860.11*†‡
0.1860.08†‡
0.260.08*
L-NMMA Pp, 3962 mm Hg
0.960.17
1.3360.32*
0.4160.17*
L-NMMA Pp, 5762 mm Hg
1.8760.38
2.5860.42*
1.3660.48*
Pp indicates perfusion pressure. Values are mean6SEM per % increase in DTF.
*Significantly different from slope average flow.
†Significantly different from control.
‡Significantly different from L-NMMA.
Merkus et al
Longer Diastolic Time Fraction at Low Flow
79
lular concentration of ions involved in repolarization.26 Interstitial volume variations are to be expected with changes in
flow, both in control and with adenosine, by variation of
capillary pressure27 but also with saline infusion by decreasing plasma oncotic pressure. Also, the time course of DTF
variation, being slower than intravascular volume variations,28 is consistent with this hypothesis.29
Interpretation of Findings
Figure 7. Typical example of a bolus saline infusion of 10 mL,
administered to separate effects of flow (interstitial volume) and
hypoxia on DTF. Because DTF decreased during injection of
saline, flow, not hypoxia, is most important parameter in determination of DTF.
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change in DTF during total coronary occlusion (data not
shown), making a role of the ATP-dependent K1 channels
unlikely.
Some other observations make it unlikely that DTF increased as a result of a possible shortage of oxygen: at a
perfusion pressure of 100 mm Hg, DTF decreased when flow
was increased by adenosine, implying that DTF can also vary
in a nonischemic heart. Moreover, injections of anoxic saline
in similar experiments always resulted in a decrease in DTF
(14 injections in 5 dogs, typical example in Figure 7) while
decreasing the oxygen content of blood. Furthermore, DTF
increases only in the first 15 seconds after the pressure
reduction and is stable thereafter, whereas a possible degree
of ischemia will develop further in time, depending on the
amount of flow reduction.
Table 2 lists a series of substances produced by endothelial
cells that may influence myocyte function.5–7,14 –23 From this
list, only the production of nitric oxide can change fast
enough to explain the increase in DTF. However, in the
experiments in which nitric oxide synthase was blocked by
administration of L-NMMA, the changes in DTF were similar
to those in control at all pressures. Hence, no known paracrine
pathway can be responsible for the increase in DTF at
decreased pressure.
DTF changes induced by underperfusion are compatible
with a dominant role of interstitial volume that may alter the
contraction duration of the myocytes either through influencing the sarcomere length24,25 or through changes in extracel-
In a heart with normal coronary regulation, local flow is
adapted to match the metabolic needs of the myocardium by
vasodilation. However, with a severe stenosis in the coronary
arteries, the possibility for further dilation of the resistance
vessels by physiological stimuli is exhausted, although further pharmacological dilatation is possible.30 –33 In these
circumstances, coronary flow is determined by mechanical
forces, such as compression of intramyocardial vessels by the
surrounding myocardium during contraction. An increase in
DTF will be beneficial to myocardial perfusion because the
time that intramyocardial vessels are compressed decreases.
Hence, lengthening of DTF may be important at some stage
of transition from normal to ischemia, resulting in delayed
occurrence of ischemia. This stage may be of either short or
long duration, depending on the rate of development of the
disease.
With a coronary stenosis, the difference between diastolic
and systolic flow becomes less, but coronary pressure becomes more pulsatile.10 Therefore, the relative contribution of
systolic flow to total flow may increase,1,34 especially if the
stenosis is compliant.35 Hence, there are 3 factors that might
have contributed to the increase in total flow at low pressure:
the increase in DTF, vasodilation, and an increased contribution of systolic flow.
The effect of DTF on flow is clear when vasomotor tone is
abolished and is larger at lower flow and pressure levels. The
contribution of vasodilation to the increase in flow can be
estimated as the difference between the slopes of the DTFflow relations in control and with adenosine, as discussed
above in relation to Figure 6. This figure also demonstrates
that in the presence of autoregulation, the effect of DTF
becomes more important at lower perfusion pressure.
Because vasomotor tone changes are dominant, when
present, the effect of DTF on the contribution of systolic flow
to total flow can be studied only in the presence of adenosine.
At constant pressure, the influence of DTF on minimal
(systolic) and maximal (diastolic) flow was similar (Table 1).
TABLE 2. Time Course of Changes in Cardioactive Substances Released by
Endothelial Cells
Factor
Time Course of Production/Degradation
Study
Endothelin-1
Onset, 4 min; maximal effect, 20 min;
degradation half-time, 7 min
Mebazaa et al5
Levin21
Angiotensin II
ACE inhibition effect maximal, 8–12
min
Anning et al16
Nitric oxide
Within heart beat
Pinsky et al22
Atrial natriuretic peptide
Maximal release, 12–14 min
Chen et al23
Myofilament-desensitizing agent
Onset, 2 min; maximal effect, 15 min
Ramaciotti et al18
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July 6, 1999
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An increase in diastolic time, at the expense of systolic time,
reduces the time for squeezing blood out of the vessels and
increases the time for volume recovery, thereby keeping the
intramural vessels at a lower resistance. This may affect both
systolic and diastolic flow.
When discussing phasic coronary flow, one has to be aware
of capacitive effects. The perfusion system did not add any
significant compliance, because the in-line flow probe was
connected closely to a steel cannula. Coronary arterial flow is
phasic, and systolic flow can be retrograde because of the
intramyocardial pump action on the intramural compliance.10
However, the relations between DTF and systolic and diastolic flow were measured at constant coronary pressure,
minimizing these epicardial capacitive effects that could have
changed the phasic flow patterns. Obviously, the phasic flow
patterns measured at the level of the larger arteries is different
from those of the smaller vessels and veins and may be
different at the subendocardium and subepicardium. However, such differences seem not to influence the DTF–arterial
flow relationship.
In the presence of a rigid stenosis, as in our case, the
difference between systolic and diastolic flow is minimized.
Therefore, the effects of DTF on systolic and diastolic flow
are similar. It should be noted, however, that when coronary
resistance changes with either DTF or vasodilation in the
presence of a stenosis, this affects not only flow but also the
pressure drop over the stenosis. This is the reason that
DTF-flow slopes are not provided in Table 1 for the stenosis
case.
Because flow and DTF are changing continuously after a
pressure step, the microsphere technique is not suitable for
measuring subendocardial flow. However, a 1% DTF increase by lowering heart rate increases subendocardial flow
by 2.6% to 6.0% but has no effect on subepicardial flow.3,4
These findings tally well with the increase of 2.6% total flow
with 1% increase in DTF in our experiments.
Shortening of the duration of contraction may also contribute to the decreased oxygen consumption found on a decrease
in coronary arterial pressure.36 Hence, the effect of increased
DTF may affect the oxygen supply-demand ratio both by
increasing supply and decreasing demand.
Conclusions
At a constant heart rate, a decrease in coronary perfusion
results in an increase in DTF, which cannot be explained by
release of a known cardioactive factor in response to hypoxia.
The hypothesis that DTF changes in relation to changes in
interstitial volume is worth pursuing. However, further studies are necessary to definitively determine the relative importance of ischemia versus change in interstitial volume. Because DTF is an important determinant of subendocardial
flow, it may provide a potential protective mechanism against
endocardial ischemia when coronary perfusion is impaired.
Acknowledgments
Financial support from the Netherlands Heart Foundation (grant
92.128) and the Netherlands Organization for Scientific Research
(NWO, travel grant R90-160) is gratefully acknowledged.
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Prolonged Diastolic Time Fraction Protects Myocardial Perfusion When Coronary Blood
Flow Is Reduced
Daphne Merkus, Fumihiko Kajiya, Hans Vink, Isabelle Vergroesen, Jenny Dankelman, Masami
Goto and Jos A. E. Spaan
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Circulation. 1999;100:75-81
doi: 10.1161/01.CIR.100.1.75
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