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(Circulation. 1995;91:2058-2070.)
© 1995 American Heart Association, Inc.
Articles |
Gradual Onset of Myocardial Ischemia Results in Reduced Myocardial Infarction
Association With Reduced Contractile Function and Metabolic Downregulation
From the Department of Medicine, Cardiology Division, University of California, San Diego, and Research Service, Veterans Administration Medical Center, San Diego, Calif.
Correspondence to Bruce R. Ito, PhD, Gensia Inc, 9360 Towne Centre Dr, San Diego, CA 92121.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background With moderate reductions in coronary blood flow, adjustments in myocardial metabolism can occur with a normalization of the imbalance between the decreased O2 delivery and tissue O2 demand. This state of "downregulated" metabolism is associated with reduced function and minimal irreversible injury and has been linked to myocardial hibernation. We hypothesized that (1) this process would occur when perfusion was reduced to severely ischemic levels, but only when flow declined at a slow rate rather than abruptly, and (2) this would result in blunted ischemia and reduced myocardial injury for a given period of low blood flow.
Methods and Results The left anterior descending coronary artery
in anesthetized open-chest pigs was cannulated and perfused with
arterial blood by an extracorporeal perfusion pump. Regional function
(percent segment shortening, %SS) was measured with sonomicrometry and
a regional coronary vein cannulated for blood gas analysis and
lactate measurements. Coronary blood flow (CBF) was reduced to 10% of
control either in a step fashion (Fast Ischemia group) or gradually in
a linear manner over 70 minutes (Ramp Ischemia group). In all animals,
CBF was held for 60 minutes at this 10% level and then followed by 2
hours of reperfusion. In the Ramp Ischemia group, the linear fall in
CBF resulted in an initial maintenance of both %SS and myocardial
oxygen consumption (M
O2)
followed by
linear decreases in both variables (r=.98 to .99) as flow
fell to the 10% level. The relation of
MO2 to function was linear
(r=.99) over the entire flow range. Although %SS,
MO2, CBF, coronary
pressure,
and hemodynamics during the 10% flow period were not different between
groups, the increases in coronary venous lactate and
PCO2 and fall in pH were blunted in the Ramp
Ischemia group compared with the Fast Ischemia group. With reperfusion,
a significant decrease in end-diastolic length was
present only in the Fast Ischemia group. Additionally, although the
region at risk was not different, infarction was markedly reduced in
the Ramp Ischemia group (6.6±1.9%) compared with the Fast Ischemia
group (31.4±6.9%).
Conclusions These data are consistent with the hypothesis that the downregulation of myocardial metabolism with gradually decreased flow to severe levels results in reduced myocardial injury for a given period of low flow. We propose that the rate at which blood flow decreases with myocardial underperfusion is a novel determinant of infarct injury. This may have clinical implication in situations in which there is a time-dependent component to the decrease in coronary blood flow in acute ischemic events, ie, thrombus formation at a site of coronary stenosis.
Key Words: myocardium • metabolism
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Abrupt occlusion of a coronary artery results in an immediate decrease in myocardial perfusion and subsequent ischemia that can be defined as an acute imbalance between oxygen delivery to the region of the myocardium supplied by that artery relative to its oxygen needs. This is associated with both functional and metabolic consequences. The former is characterized by a rapid fall in contractile motion described as a loss of systolic shortening and wall thickening. This dysfunctional state is fully reversible, provided that reperfusion is instituted before the loss of myocyte viability. Return of function can be rapid, with very short ischemic periods (<2 to 3 minutes), or can require an extended recovery period of hours to days, with longer ischemic events, ie, myocardial "stunning."1 The metabolic consequences of ischemia include a rapid fall in tissue levels of phosphocreatine (PCr), increases in inorganic phosphate (Pi), decreases in ATP, and a change from aerobic to anaerobic metabolism, with a conversion of net myocardial lactate extraction to production.2 If this period of low flow is sustained for longer than 15 to 20 minutes, there is a progressive loss of myocyte viability, ie, irreversible injury as a function of the duration of the low flow period, collateral flow, risk area, myocardial metabolic demand, and ischemic history, ie, preconditioning. With moderate and sustained decreases in flow, several recent studies have documented the normalization of metabolic indexes of ischemia, including the restoration of PCr, stabilization of ATP levels, and return to net lactate extraction.3 4 5 6 7 These changes are associated with a stable but reduced level of contractile function that has been called "acute perfusion-contraction matching."8 This state is reversible with restoration of normal flow and is associated with minimal necrosis even with 5 hours of sustained reduced flow.9 These changes have also been linked to the clinical observation of "hibernating myocardium" or "idling myocardium," coined to describe the chronic decrease in function reversed on revascularization in humans.8 10 11 12
The normalization of indexes of ischemia in the presence of reduced
oxygen delivery (supply) implies that a new steady state has been
reached and that myocardial oxygen demand has been reduced
proportionately. Although the mechanism responsible for this matching
has not been clearly defined, the process has been documented by
Pantely et al4 and Bristow et al,12 who
called it "myocardial downregulation." The conclusion from these
early studies is that the imbalance between supply and demand or the
extent of ischemia can be modulated by active reductions in the demand
term as supply falls. This implies a tight coupling of tissue
respiration and muscle function to oxygen supply and is supported by
recent studies in skeletal and cardiac muscles indicating that oxygen
availability and tissue oxygenation significantly influence tissue
respiration at submaximal
O2.13 14 15
In skeletal
muscle, reductions in oxygen delivery with hypoxia or ischemia have
been shown to result in proportional decreases in function and
O2 without significant
falls in tissue
ATP levels.13 16 This matching of mitochondrial
respiration and oxygen utilization to oxygen availability would serve
to maintain myocyte viability and ATP levels in the face of reduced
perfusion by downregulating function and oxygen demand.
It has recently been shown that there is a time-dependent component to this downregulation process. With abrupt but moderate decreases in myocardial perfusion, there is a rapid fall in PCr, with net lactate production that returns to control conditions, and a stable but reduced ATP level and flow.4 5 However, if blood flow is reduced gradually to the same level, the changes in these metabolic indexes of ischemia are blunted.17 This latter observation suggested to us that the downregulation of myocardial metabolism might also occur with gradual but continuous reductions of blood flow to very low levels normally associated with extensive myocyte loss. We hypothesized that with rapid reductions in coronary blood flow (CBF), such as that occurring with abrupt ligation of a coronary artery, this downregulation process would not have time to develop compared with the situation of a gradual flow reduction. Thus, for a given period of severe low flow, one might expect much less myocardial injury in the latter instance compared with the abrupt decrease in flow. If this is indeed the case, this would suggest that the rate of the decrease in myocardial perfusion with developing ischemia would be a determinant of the extent of infarction injury and might have important implications regarding the time frame in which reperfusion in a clinical setting might potentially salvage ischemic myocardium.
Therefore, the goal of the present study was to answer these
questions: (1) Does a gradual reduction in myocardial perfusion result
in a matched decrease in contractile function and myocardial oxygen
consumption (MO2)? (2) Is
this
associated with blunted indexes of myocardial ischemia during a period
of low flow compared with an abrupt decrease in flow? (3) Is the extent
of myocardial infarct injury resulting from a given period of low blood
flow reduced when flow falls gradually compared with the abrupt
situation? The experimental approach was to reduce CBF in a major
coronary artery in either a slow linear fashion or abruptly while
measuring regional function,
MO2, release of lactate,
and
the extent of infarction.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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General Preparation
The experimental preparation has been described in detail.18 Briefly, domestic farm pigs (18 to 25 kg) were premedicated with ketamine hydrochloride (2.5 mg/kg IM) and anesthetized with sodium thiamylal (15 to 25 mg/kg IV) followed by
-chloralose (100 mg/kg IV) and morphine sulfate (30 mg/h SC).
Animals were artificially ventilated at an end-expiratory pressure of 3
to 5 cm H2O. Arterial blood gas and pH levels were
monitored (Radiometer ABL-300) and maintained within the physiological
range. Animal temperature was monitored (Yellow Springs Instrument) and
maintained at 37°C with a circulating-water heating pad. Aortic blood
pressure was measured (Statham P23Db) via a catheter placed into the
aorta. Left ventricular (LV) pressure, LV end-diastolic
pressure, and LV dP/dt were obtained with a catheter-tip manometer (7F,
Millar) inserted into the left ventricle via the right carotid artery.
A pair of bipolar pacing electrodes was placed on the right atrium to
allow cardiac pacing. The heart was exposed via a combination of a sternotomy and left thoracotomy. The distal portion of the left anterior descending coronary artery (LAD) approximately 1.5 to 2.5 cm from the left main bifurcation was cannulated and perfused with arterial blood from the left carotid artery with an extracorporeal perfusion system described below. Typical time between ligation and cannulation was 15 to 20 seconds, with no animals requiring more than 30 seconds to reinstate perfusion. A small catheter was placed into the interventricular vein draining the LAD region to allow for sampling of coronary venous blood for measurement of blood gas levels and pH (ABL-300) as well as total hemoglobin and oxygen content (OSM-3 Hemoximeter, Radiometer). The OSM-3 measures lysed blood hemoglobin absorbance at six wavelengths and incorporates algorithms for automatic correction for nonhuman species, including pig. In repeated trials, we have found this instrument to yield O2 content data comparable to the LEX-O2-Con Instrument (Hospex) but with far superior reliability and reproducibility. Coronary venous blood was also obtained for measurement of total blood lactate with a semiautomatic lactate analyzer (YSI-23L, Yellow Springs Instrument) calibrated at four levels of lactate concentration.
Coronary Perfusion
The extracorporeal perfusion system has
been described in
detail18 and is constructed of short lengths of Tygon and
Silastic tubing. This system includes a low-pulsation linear output
coronary perfusion pump that can be operated in a controlled-flow or
servo-feedback constant pressure mode. One advantage of this system is
that it allows the set point to be varied in a user-controlled fashion.
In the present experiment, in the controlled-flow mode, the control
signal was either decreased in a step fashion or decreased linearly
over a defined time interval by use of a voltage divider circuit with
the resistance (thus voltage) controlled by a linear potentiometer
mounted in an infusion pump (model 975, Harvard Apparatus). The
set-point voltage could thus be decreased from a user-defined upper
level to a lower level in a linear and reproducible manner. Coronary
perfusion pressure was measured via a T-connection close to
the cannula end. The extracorporeal circuit also included a small
Windkessel (15 mL) and a transit-time flowmeter (Transonics Inc). Blood
temperature was measured at the coronary end of the perfusion circuit
with a miniature in-line probe (Yellow Springs Instrument) and was
maintained at body temperature by circulating water coils on all
exposed tubing. Anticoagulation was achieved with sodium heparin (500
U/kg IV) and maintained by hourly supplemental doses of 250 U/kg.
Regional Myocardial Function
Regional myocardial function was
measured with a sonomicrometer
(Triton Technology) and pairs of lensed sonomicrometer crystals (2 mm)
placed into the inner third of the LV wall (6 to 8 mm deep),
approximately 1.0 to 1.5 mm apart and perpendicular to the base-apex
chord. One set was placed into the externally perfused LAD region and
the second set in the normally perfused circumflex (Cx) area in the
basal lateral portion of the heart.
Myocardial Infarction Quantification
After termination of the
experiment, 150 mg of zinc cadmium
fluorescent microspheres (Duke Scientific) in 50 mL Ringer's solution
was rapidly injected into the ascending aorta, the heart was
fibrillated with a 60-Hz, 10-V square-wave signal applied directly to
the surface of the heart, and the LAD coronary perfusion was stopped.
In this fashion, myocardium perfused via the extracorporeal perfusion
circuit did not receive microspheres, in contrast to the rest of the
heart. The atria, right ventricle, and great vessels were weighed and
trimmed from the left ventricle. The LV chamber was then sliced in
approximately 10 to 12 pieces from apex to base, with the last slice
located just above the cannulation site on the LAD, and the slices were
individually weighed. Heart slices were incubated at 37°C in
triphenyltetrazolium chloride (TTC) (1%) in PBS, pH 7.0, for 30 to 45
minutes and then placed in 6% formalin overnight. The next day, heart
slices were mounted between two sheets of glass, shimmed to a constant
width of 4 mm, and visualized on both sides in available and UV light.
Three areas were traced: total slice area (TA), microsphere-absent
regions (MS-), and areas of infarction (IA) indicated by the absence
of the characteristic red TTC stain. Average values for each area were
calculated as the mean of the data from the two sides of each slice.
For each slice, the masses of the region at risk (RAR) and infarct
region (IR) were calculated by the following formulas, in which a
mass-per-unit-area factor was derived for each slice (constant
thickness) and multiplied by the area of interest: RAR=slice
weight/TAxMS- and IR=slice weight/TAxIA. For heart
tissue containing
no MS- areas, tracing was not necessary, and the entire weight counted
as normal tissue. The data from all pieces were summed to yield total
LV weight, RAR weight, and IR weight. By this method, both RAR and IR
were calculated in units of mass (grams). The RAR was also expressed in
the traditional manner as percent of LV. Similarly, IR was also
expressed as percent of RAR.
Experimental Design
It was our hypothesis that the rate at
which myocardial ischemia
developed would be an important determinant of the extent of myocardial
injury to a given period of low flow. To test this, animals were
randomized to two experimental protocols.
(1) In the Fast Ischemia group (n=7), after control measurements, LAD CBF was decreased from normal flow at a coronary pressure of 90 to 100 mm Hg to 10% of that value in a step manner. CBF was held at this level for 60 minutes. At the end of this period, normal coronary perfusion was instituted in a gradual manner over 1 minute, and then coronary pressure was maintained for 2 hours at a level of 75 to 85 mm Hg.
(2) In the Ramp Ischemia group (n=7), CBF was linearly reduced over a period of 70 minutes from normal flow at a coronary pressure of 90 to 100 mm Hg to the same level as achieved in the Fast Ischemia group, that being 10% of normal flow. At the end of this 70-minute period, CBF was held for 60 minutes at this 10% value. Reperfusion was done in exactly the same fashion as in the Fast Ischemia group, also for 2 hours.
Experimental Protocol
After instrumentation, heart rate was
paced at 90 to 100 beats
per minute with the coronary perfusion pump in the
constant-coronary-pressure mode (90 to 100 mm Hg). The CBF in mL/min
at this pressure was recorded, and the perfusion pump was then switched
to a constant-flow mode at this same flow. Control measurements of
hemodynamic, arterial, and coronary venous oxygen content and lactate
were taken. CBF was then decreased to 10% of the control value either
in a rapid manner (Fast Ischemia group) or gradually over 70 minutes
(Ramp Ischemia group). In either case, CBF was held at the 10% level
for 60 minutes. At the end of this ischemic period, CBF was returned to
the control value over a period of 1 minute, and then the perfusion
pump was switched to constant pressure (75 to 85 mm Hg) for the
duration of the 2-hour reperfusion period. During this reperfusion
period, the cardiac pacing rate was increased to just above intrinsic
rate to minimize arrhythmias. Hemodynamic and blood oxygen and lactate
content were taken at 5, 10, 15, 20, 30, 45, and 60 minutes of ischemia
and 5, 10, 15, 30, 60, 90, and 120 minutes of reperfusion. In the Ramp
Ischemia group, measurements were taken every 5 minutes for the
duration of the 70-minute ramp protocol. At the end of the reperfusion
period, the RAR was determined and the heart tissue processed as
described above.
Exclusion of Animals
It is our experience that acute proximal
ligation of the LAD in
pigs is associated with high ventricular fibrillation (VF) rates,
>40%, probably because of the absence of significant collateral blood
flow. In the present experiments, CBF was reduced to 10% of its
control value, approximately 0.12 to 0.15
mL · min-1 · g-1, when
normalized for the mass of the perfused region. In pilot experiments,
we found that this greatly decreased the rate of VF. The rates of
animal attrition due to VF and other problems in the present study
are as follows. Eighteen animals were anesthetized. One animal was
immediately excluded because of pericarditis, leaving 17 that were
instrumented. Of these, 9 were randomized to the Fast Ischemia group.
Of these 9 animals, 2 developed VF (1 during the ischemic period, 1
during reperfusion) and were excluded, to yield 7 animals completing
the protocol. Eight animals of the 17 were randomized to the Ramp
Ischemia group. One developed VF during early reperfusion and was
excluded, to yield 7 animals in the data set.
Data Analysis
At each time point, mean CBF, systolic and
diastolic
aortic blood pressures, peak LV pressure, LV end-diastolic
pressure, LV dP/dt, and segment lengths were read from digitally
acquired files (CODAS, Dataq Corp). Data from two or three consecutive
cardiac cycles were averaged for each experimental time point. Regional
segment lengths, in millimeters, were determined at end diastole and
end systole. The end-diastolic length (EDL) was measured
after the a wave, at the time of the sharp upsweep in the high-gain LV
pressure signal. The end-systolic length (ESL) was defined at the point
20 ms before peak negative dP/dt. Regional myocardial function was
calculated as percent segment shortening (%SS) defined as
(EDL-ESL/EDL)x100. To allow comparison of changes in EDLs between
groups, EDLs of each animal were normalized to a control value of 10 mm
defined at the control, preischemia time point.
MO2 was calculated as CBF
times
(arterial O2 content minus coronary venous
O2 content) and expressed as mL
O2 · min-1 · 100 g wet
wt-1. LAD CBF in mL/min was normalized to perfused wet
weight of myocardium based on the mass of cardiac tissue that was
fluorescent microsphere–negative.
The SEMs given in the figures and text were derived from data sets containing one value from each pig studied in each experimental group (n-1 df). Statistical analyses of the time data were done with a two-level ANOVA (time and treatment) for both the Ramp Ischemia and Fast Ischemia experimental groups. When they were found to be different, linear contrast comparisons were made at each time point, with correction for multiple comparisons. A statistical significance level was set at P=.05. For comparison of group differences with respect to lactate, pH, PCO2, and infarct size, a one-level ANOVA was performed and is indicated in the figures.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Global Hemodynamics
In both the Fast Ischemia group and the Ramp Ischemia group, heart rates were similar, approximately 100 to 105 beats per minute at the control point, and remained stable for the duration of the ischemic period (Fig 1
). Heart rate was also stable at this level
for the duration of the 70-minute ramp period of the Ramp Ischemia
group. At the onset of reperfusion, there was an increase in heart rate
of approximately 15 to 20 beats per minute in both groups of animals,
with no significant differences between the groups. Although there was
a gradual decrease in LV systolic pressures over the course of the
experimental protocol, there were no significant differences either at
the control time point or during ischemia and reperfusion between the
Fast Ischemia and Ramp Ischemia groups (Fig 1). Similarly,
there were
no differences in the calculated heart rate–systolic blood pressure
product.
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CBF/Pressure
Average data depicting CBF and coronary pressure
in the two
experimental groups are shown in Fig 2. There were no
statistical differences in CBF between groups. Flows at the control
time point (1.17±0.15 versus 1.16±0.08
mL · min-1 · g-1) and during
the
ischemic period (0.11±0.02 versus 0.12±0.02
mL · min-1 · g-1) were
virtually
identical in the Fast and Ramp Ischemic groups, respectively. As is
apparent from Fig 2, CBF in the Ramp group decreased in a
linear
fashion over the course of the 70-minute ramp period, in contrast to
the abrupt decrease in the Fast Ischemia group. Similar to flow,
coronary perfusion pressures at control (101.8±7.0 versus
98.3±7.0
mm Hg) and during the ischemic period (15 to 17 mm Hg) were
indistinguishable between groups. With reperfusion, there was a
substantial hyperemia, with CBF rising to similar levels (2.37±0.31
versus 2.58±0.20
mL · min-1 · g-1)
at 5 minutes of reperfusion. At the end of the 120-minute reperfusion,
there was a tendency for CBF to remain above preischemia levels in the
Fast group (1.62±0.30
mL · min-1 · g-1) compared
with the
Ramp group (1.25±0.10
mL ·min-1 · g-1) at similar
coronary pressures.
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Regional Function/EDL
Average contractile function in the
LAD-perfused and control left
Cx regions and normalized EDLs are shown in Fig 3. Under
control conditions, there were no significant differences in either
%SS (21.8±2.1% versus 26.7±1.2%) or EDL (10.54±0.64
versus
10.98±0.51 mm) in the LAD region in the Fast or Ramp groups,
respectively. In the Ramp group, as flow was ramped down, shortening
was initially relatively constant from 0 to 20 minutes and then
exhibited a gradual decrease from 20 to 70 minutes, falling to a stable
level (from -3.2% to -3.9%). This level of paradoxical systolic
lengthening during the ischemic period was not different between
groups. Similarly, the level of depressed function during the
reperfusion period was not significantly different between the Fast and
Ramp Ischemia groups. In both groups, contractile function in the Cx
area remained stable at or above control levels for the entire
experimental protocol.
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End-Diastolic Lengths
Within 5 minutes from the onset of the
ischemic period, normalized
EDL in the LAD region of the Fast Ischemia group increased
significantly, by an average of 18.1±2.2% from control
(P<.01) (Fig 3
, bottom), and remained elevated for
the
duration of the ischemic period. This occurred coincidently with an
increase in LV end-diastolic pressure from a control level
of 6.3±0.4 mm Hg to an ischemic value of 9.7 to 10.6 mm Hg. In
contrast, in the Ramp Ischemia group, the increase in EDL was gradual
and returned to control levels by the end of the ischemic period. This
result could not be accounted for by differences in
end-diastolic pressure, which actually increased to a
greater extent (from 6.9 mm Hg at control to 10.6 to 11.4 mm Hg
during ischemia) in the Ramp Ischemia group. The increase in EDL in the
Fast group was significantly greater than that observed in the Ramp
group at each time point of the ischemic period. On reperfusion, there
was a rapid fall in EDL that was significantly greater in the Fast
Ischemia group than in the Ramp Ischemia group and was sustained for
the duration of the reperfusion period. In contrast, the fall in EDL in
the Ramp Ischemia group was transient and reversed to control levels
within 30 to 45 minutes. This difference in reperfusion EDL could also
not be accounted for by differences in end-diastolic
pressure, which actually tended to be greater in the Fast Ischemia
group (12 to 15 mm Hg) than in the Ramp Ischemia group (10 to 12
mm Hg).
Oxygen Extraction
Average arterial blood oxygen contents were
approximately 11.5 to
12.0 vol% in both the Fast and Ramp Ischemia groups and did not vary
significantly over the experimental protocol (Fig 4,
top). Coronary venous blood oxygen contents at the
control time point were also similar between groups, approximately 5.6
to 5.8 vol%. With the onset of the ischemic period in the Fast
Ischemia group, myocardial oxygen extraction increased with coronary
venous oxygen content, falling to an average of 2 to 2.3 vol% within 5
minutes. In the Ramp Ischemia group, oxygen extraction increased
gradually over the ramp flow period, with coronary venous oxygen
content falling to a stable level at 55 minutes and remaining at this
level (1.7 to 1.9 vol%) for the duration of the ischemic period. This
level was not significantly different from the Fast Ischemia group
(P>.1). In both groups of animals, reperfusion resulted in
an abrupt decrease in oxygen extraction, with coronary venous oxygen
contents rising to similar levels of 9.5 to 10.5 vol% at 10 minutes of
reperfusion. Oxygen extraction remained reduced in the Fast Ischemia
group for the duration of the reperfusion period. In contrast, during
reperfusion in the Ramp Ischemia group, oxygen extraction steadily
increased toward control levels, with coronary venous O2
contents falling to 7.2±1.4 vol% by the end of the reperfusion,
significantly less than that in the Fast Ischemia group
(P<.05).
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Myocardial Oxygen Consumption
Fast Ischemia Group
At the control time point, average
MO2 of the LAD-perfused
region in these
animals was 7.4±0.5 mL
O2 · min-1 · 100
g-1 (Fig 4, bottom). With the onset of the
ischemia,
MO2 fell to 0.9 to 1.0 mL
O2 · min-1 · 100
g-1 and
remained at this level for the duration of the ischemic period. The
restoration of normal blood flow was associated with an early increase
in MO2 toward control
levels at 10
minutes, which decreased to a stable but low value of 2.0 to 2.5 mL
O2 · min-1 · 100
g-1 over
the 120-minute reperfusion period.
Ramp Ischemia Group
At the control time point, the average
MO2 in these animals
(6.9±0.6 mL
O2 · min-1 · 100
g-1) was
not different from that in the Fast Ischemia group. Similar to regional
function, MO2 remained
constant for
the first 15 to 20 minutes of the ramp period, followed by a gradual
fall in MO2 to a stable
level (1.1 to
1.3 mL O2 · min-1 · 100
g-1) for the duration of the 60-minute ischemic period.
This value was slightly but not significantly greater than in the Fast
Ischemia group. Reperfusion was associated with a transient increase in
MO2 at 10 minutes of
reperfusion that
was significantly greater than in the Fast Ischemia group
(P<.05). Also, in contrast to the Fast Ischemia group,
there was an improvement in
MO2 from
30 to 120 minutes of reperfusion. At the end of the reperfusion period,
MO2 had recovered to within
65% of
the control value, compared with 31% for the Fast Ischemia group
(P<.05).
Lactate/pH/PCO2
Marked differences in the
changes in coronary venous lactate, pH,
and PCO2 were associated with the low-flow
period between the two groups of animals (Fig 5). In the
case of lactate, arterial and coronary venous levels were similar
between the two experimental groups under control conditions, with a
small but significant net transcardiac extraction of lactate (Fig
5,
top). With the acute reduction in CBF in the Fast Ischemia group,
lactate extraction reversed to production within 5 minutes to a peak
value of -3.9±0.5 mmol/L. In the Ramp Ischemia group, net lactate
extraction was present for the first 20 minutes of the ramp period,
with blood flows greater than 0.7 to 0.8
mL · min-1 · g-1. With lower
blood
flows, net lactate production rose steadily to a peak of -2.2±0.6
mmol/L at the onset of the ischemic period, which was significantly
less than that observed in the Fast Ischemia group (P<.05).
There were no significant differences in either arterial or coronary
venous lactate levels between the groups during the reperfusion
period.
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As with lactate, there were no differences in either coronary
venous
blood pH or PCO2 under control conditions
between the two groups of animals (Fig 5, middle and bottom).
With the
reduction in CBF to the same 10% level, the fall in pH and the
increase in PCO2 were significantly blunted
in the Ramp Ischemia group compared with the Fast Ischemia group
(P<.01).
Flow-Function/Flow-MO2
Relations
To investigate the relation of blood supply to contractile
function, LAD %SS (normalized to control conditions) was plotted
against myocardial blood flow for both groups of animals (Fig
6,
top). For the Ramp group, it was apparent that function
was stable above a flow of approximately 0.8
mL · min-1 · g-1 and decreased
gradually at lower flows during the ramp period. A linear regression
analysis of the data at flows of 0.8
mL · min-1 · g-1 and below
revealed
the highly linear nature of this decrease (r=.99).
Similarly, there was a clear relation of
MO2 to myocardial flow in
the Ramp
Ischemia group, with an initial flow-independent portion above a level
of 0.8 mL · min-1 · g-1,
followed by a gradual decrease with lower flows (Fig 6,
bottom). This
also was highly linear (r=.98). It should be noted that
there were no differences in
MO2, function, or flow
between
the Ramp and Fast Ischemia groups either during the control or low-flow
conditions.
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To investigate the relation of regional
MO2 to regional function,
the two
variables were plotted against each other with data from both
experimental groups. As shown in Fig 7 (top), there was
a highly linear relation of
MO2 to
function (r=.99) when data from the Ramp group were analyzed
by linear regression. Furthermore, the low-flow data point for the Fast
Ischemia group was very close to this relation. These data clearly
indicate the tight coupling of
MO2 to
function under conditions of reduced blood flow.
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To compare the
dependence of MO2 with
oxygen delivery under conditions of reduced perfusion,
MO2 was plotted against
oxygen
delivery calculated as the product of blood flow and arterial oxygen
content using blood flow data below 0.8
mL · min-1 · g-1 (Fig
7, bottom).
This relation was highly linear, with a value of r=.99. In
addition, as shown in Fig 7, bottom, the slope of this relation
was
strikingly similar to that generated from data from Hogan et
al13 obtained from contracting skeletal muscle under
conditions of varied levels of hypoxia, illustrating the influence of
oxygen delivery on tissue respiration.
Infarct Size
There were also marked differences in the degree
of infarction
between the two experimental groups. The average data for all
experiments are shown in Fig 8. The mass of TTC-negative
myocardium expressed as absolute weight or as a percent of RAR was
considerably less (6.6±1.9%) in the Ramp Ischemia group than in the
Fast Ischemia group (31.4±6.9%) (P<.01). The difference
in infarction could not be attributed to differences in perfused
myocardium. In the Fast Ischemia group, the LAD perfusion mass at risk
averaged 40.0±2.1% compared with 36.5±2.6% of the left ventricle
in
the Ramp Ischemia group. These values were not significantly different
(P>.1).
|
|
Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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There are three important findings of the present study. (1) The relation of regional function and M
O2 to CBF was
characterized by a
flow-independent region and a linear flow–dependent region. (2) A
severe reduction in myocardial perfusion produced in a gradual manner
resulted in substantially less myocardial infarction and reduction in
segment EDL compared with the condition in which CBF was reduced
rapidly. (3) This reduction in myocardial injury was associated with
blunted indicators of an imbalance between oxygen delivery and oxygen
demand (ischemia), ie, pH, lactate, and PCO2.
The results will be discussed in relation to the postulated
determinants of infarction. At present, there are five recognized determinants of irreversible myocardial injury resulting from ischemia: (1) the size of the RAR; (2) the magnitude of the myocardial blood flow reduction and collateral flow; (3) the duration of the ischemic period; (4) global metabolic state, ie, myocardial oxygen demand; and (5) ischemic history, ie, acute preconditioning. Although this is more controversial, inflammatory processes associated with reperfusion, including the activation of the complement cascade and neutrophil accumulation, have also been suggested as contributing to myocardial injury. The results from the present study will be discussed in relation to these recognized determinants of myocardial ischemic injury.
Region at Risk
It is known that the mass of the ischemic
myocardium or RAR is a
determinant of infarct size.19 20 21 In
the present
study, the RAR was measured by an anatomic method that delineated the
myocardium perfused from the cannulated LAD from the remainder of the
heart based on the distribution of fluorescent microspheres. This
method is similar to that in common use in other models, ie, rabbits,
and yields unambiguous perfusion boundaries. The RAR expressed as
either absolute mass or percent of LV weight was not different between
the Ramp and Fast Ischemia groups (Fig 8). Thus, a random
difference in
this variable cannot account for the reduction in infarct size found in
the Ramp Ischemia animals.
Myocardial Blood Flow/Collateral Flow
Residual flow or
collateral blood flow is a strong determinant of
myocardial ischemic
injury.20 21 22 23 Although
it is possible
that unequal blood flow is responsible for the difference in infarction
observed in the present study, this is unlikely. In our model,
there would be two potential sources of blood delivery to the region
supplied by the cannulated LAD: residual flow through the LAD artery
and collateral flow. We used a precision coronary perfusion pump that
made it possible to lower blood flow to the same level in both groups
of animals in a reproducible fashion. Perfusion blood flow was not
different either during control or at any time during the 10% low-flow
period (Figs 2 and 6). Although collateral flow
was not measured, it is
also unlikely that this was a confounding factor, for the following
reasons. First, it is commonly accepted, based on numerous studies,
that innate collateral blood flow in swine is very low in contrast to
dogs24 25 26 and is approximately 0.01
mL · min-1 · g-124 25
and inversely related to bed size. Bed size in absolute mass or percent
of LV in the present study was the same between groups (Fig 8).
Second, the similarity of coronary perfusion pressures at equivalent
blood flows during the ischemic period in the two groups of animals
(Fig 2, bottom) suggests that nutritive myocardial perfusion
from
collateral sources, if present, was small. Third, even if
collateral blood flow were present, its magnitude would have to be
quite large to result in the magnitude of the difference in infarct
size reported here. We estimate that for the 75% reduction in infarct
size for the 60-minute period of ischemia in the Ramp group, collateral
blood flow would have to be even greater than that found in dogs (0.2
to 0.3 mL · min-1 · g-1). This
is
unlikely to be present in these normal pigs in the absence of a
chronic stenosis. Thus, for the reasons given, it is unlikely that the
difference in infarction was due to differences in myocardial blood
flow.
Duration of Ischemic Period
The duration of the period of
blood flow deficit is clearly a
determinant of myocardial injury. With restoration of blood flow within
15 to 20 minutes, even in the absence of collateral flow, the extent of
infarction is minimal.27 28 29 The
development of
irreversible injury beyond this time is highly dependent on the species
investigated and the innate collateral circulation present. In
dogs, with an average transmural collateral flow of approximately 0.2
to 0.3
mL · min-1 · g-1,21 22
fully developed infarction occurs within 3 to 6
hours.29 30 In collateral-deficient species such as
pig
and rabbit, infarction develops more rapidly, reaching a plateau within
60 to 90 minutes.28 29 In the present experiments,
average myocardial blood flow during the low-flow period was
intermediate between these two extremes, approximately 0.12
mL · min-1 · g-1, and by
design was maintained for the same period of time in both experimental
groups (Fig 2). However, it should be noted that depending on
the
definition of myocardial ischemia, the period during which inadequate
flow was present could actually be interpreted as being
considerably longer in the Ramp Ischemia group. For example, if one
considers the fall in contractile function as an index of ischemia,
then it could be argued that ischemic conditions were already
present at approximately 20 minutes into the ramp period when
contractile function fell below control (Fig 3). Similarly, if
one
considers the transition of net myocardial consumption of lactate to
production as an index of ischemia, then in the Ramp Ischemia
experiments, ischemia was present for the latter half of the ramp
period (Fig 5). In any case, it is clear that a difference in
the
duration of the ischemic period is not likely to be responsible for the
reduced injury result and actually might have been expected to result
in enhanced injury in the Ramp group.
Metabolic State
Although it has been suggested that
MO2 is an important
independent
determinant of infarction injury,31 32 33
this concept is not
universally accepted. On one hand, it seems intuitive that since
ischemia is a condition defined in relation to metabolic state, a
reduction in energy needs would decrease the magnitude of the
supply/demand imbalance for a given flow reduction and thus delay
high-energy phosphate loss and the development of irreversible injury.
In support of this position, there have been numerous reports that a
reduction in myocardial metabolism by ventricular unloading reduces
infarct size after acute coronary ligation in
dogs.34 35
Furthermore, the depletion of high-energy phosphate levels occurs
considerably more slowly with total ischemia in vitro than with severe
ischemia in vivo36 and has been attributed to the reduced
metabolism of isolated tissue devoid of electrical and mechanical
activity. Yet, there is only a poor correlation of hemodynamic
determinants of MO2 with
infarction,20 and the reduction of myocardial metabolism
with ß-blockers has not been clearly shown to be
protective.37 Nonetheless, in a careful study in which the
independent effects of both
MO2 and
collateral flow were evaluated, it was shown that a low
MO2 before and within the
first few
minutes of coronary occlusion (90 minutes), but not later in the
ischemic period, resulted in less infarction compared with the
situation with a high
MO2.38 Those
data suggest
that the MO2 at the onset
of ischemia
may be of greater importance than the
MO2 during the ischemic
period. This
point may have a bearing on the interpretation of the present
study. Although MO2 and
flow during
the ischemic period were not different between the Ramp and Fast
Ischemia groups, the myocardium was never subjected to a large mismatch
between MO2 and delivery in
the Ramp
group, since MO2 fell as a
function of
flow (Fig 7, bottom). In contrast, in the Fast group, reduced
delivery
occurred rapidly when MO2
was
initially at its normally high value; thus, the mismatch was large
early in ischemia.
Several
investigators,12 39 40 41
including
ourselves,42 have advanced the concept that the myocardium
may possess and use mechanisms that enable it to downregulate its
regional energy expenditure in the presence of reduced blood supply and
that this may be beneficial in terms of myocyte viability. Although
other investigators have shown that this process may occur with
moderate reductions in
CBF,3 4 5 6 7 the
present study is
the first to suggest that this may have beneficial consequences in the
presence of severe blood flow reductions. However, a simple
downregulation of energy consumption does not appear to be a completely
satisfactory explanation for the difference in infarct size between
groups. The problem is that both the supply (CBFxarterial oxygen
content) and the demand terms
(MO2) as
well as contractile function were similar in both groups of animals
(Figs 2 through 4) during the
ischemic period. The data do suggest that
how the myocardium got to that low-flow/low-metabolism state may be
important. As discussed above, the magnitude of the imbalance between
supply and demand early in the low-flow period may be a critical
factor.
Ischemic History/Preconditioning
Evidence is accumulating
that ischemic history influences the
extent of myocardial infarction resulting from a period of low blood
flow. This phenomenon, called preconditioning, has been defined as the
reduction in infarct size occurring in response to a sustained period
of ischemia preceded by short periods of ischemia and
reperfusion.43 44 There are several similarities and
important differences between the reduction in infarct size reported in
the present study and that resulting from preconditioning. (1) The
magnitude of protective effect of gradual ischemia (75% reduction in
infarct size) is comparable to that found in preconditioning models.
(2) The reduced lactate formation and fall in pH during the sustained
ischemic period observed in the present study (Fig 5) are
similar
to those described in preconditioned
animals.45 46 47 (3)
Both phenomena indicate a reduced imbalance between myocardial supply
versus demand (ischemia) during the sustained low-flow period. These
similarities support the possibility that what we report here may be
"preconditioning without reperfusion." However, since the
protective effect in the present study occurred in the absence of
prior reperfusion, with blood flow always decreasing during the ramp
period, the present phenomenon does not fall under the strict
definition of preconditioning. Also, we can state that the processes
known to be stimulated during reperfusion, including leukocyte
accumulation, oxygen-derived free radical release, hyperemic
flow/enhanced release of endothelium-derived relaxing
factor, PCr overshoot, and transient calcium entry, which have been
suggested to influence myocyte viability, are not likely to have
contributed to the present result. It should be noted that some
literature indicates that reperfusion is required48 and
that the enhanced oxygen free radical release occurring with
occlusion/reperfusion events participates in
preconditioning.49 Nonetheless, it is attractive to
speculate that the mechanism responsible for the reduction of injury
with preconditioning is in fact identical to the one that is involved
here, with a gradual reduction in CBF. Further investigation will be
needed to test this possibility.
The conclusion from the foregoing discussion is that the mechanism responsible for the protective effect observed in the present study cannot be strictly accounted for by alterations in those variables recognized by most investigators to influence the extent of myocardial infarction. At present, it is not clear whether mechanisms of inflammation occurring during reperfusion, including activation of the complement cascade and leukocyte sequestration, which have been reported by some to influence infarct size, are involved in the phenomenon we describe. However, the large magnitude of the protective effect observed here would argue that these are unlikely to be major contributors, as has been shown to be the case with preconditioning.
Perfusion-Contraction Matching
One result of the present
study was that myocardial blood flow
was a strong determinant of regional contractile function. In the Ramp
Ischemia group, a proportional decrease in blood flow below 0.8
mL · min-1 · g-1 resulted in a
linear
decrease in LAD segment shortening (Fig 6). This result is
consistent
with published data. Gallagher and coworkers50 observed a
nearly linear relation between reductions in LV subendocardial or
transmural blood flow and regional systolic thickening in dogs. In
contrast, an exponential relation between subendocardial blood flow and
subendocardial segment function was described by Vatner51
in conscious dogs. It should be noted that below the knee, the relation
was quite linear in this latter study. Also, as in the present
study, Vatner found a narrow flow-independent region at basal flow. It
should be noted that the presence of this flow-independent portion may
simply be due to a small degree of coronary vasodilation and relative
overperfusion in our two studies. Regardless, the nearly linear
decrease in contractile function with reduced myocardial perfusion has
been called "perfusion-contraction matching"8 and
has been suggested to be involved in myocardial hibernation. Our data
are consistent with this interpretation.
Perfusion-Metabolism Matching
At any given work level, ATP
turnover occurs at a rate necessary
to conduct the work required. Since it is known that myocyte ATP
content remains nearly constant over a wide range of work
intensities,52 the rate of ATP hydrolysis must be tightly
coupled to the metabolic processes that rephosphorylate ADP. This tight
coupling of ATP turnover to production is exemplified by the strong
correlation between contractile work intensity (ATPase activity) and
tissue respiration as measured by oxygen uptake
(O2) under conditions of
unrestricted
blood flow. Under conditions of restricted oxygen supply occurring with
reduced myocardial perfusion, a tight relation of contractile function
and MO2 continues to exist.
This is
shown in Fig 7, top, in the present study. The nature of this
relation is unclear. Since the oxygen extraction ratio is normally high
in the heart, a severe reduction of oxygen supply must be accompanied
by a fall in MO2, once the
upper limit
of oxygen extraction is reached. Here, in the Ramp group, this limit is
approximately 80% to 85% extraction and occurred at a blood flow of
approximately 0.3
mL · min-1 · g-1 at
55 to 60 minutes of the ramp period (Figs 2 and
4). This maximal value
of extraction is remarkably similar to that described for hypoxic
skeletal muscle.13 As discussed above, the fall in
contractile function with reduced perfusion has been shown in this and
other studies. Importantly, however, both
MO2 and contractile
function began to
fall at a blood flow of approximately 0.8
mL · min-1 · g-1 at 20 minutes
of the
ramp period. This is well before the maximal extraction limit was
reached at a level of 0.3
mL · min-1 · g-1. The
explanation for
the tight linear relation between
MO2
and function below the plateau level with reduced flow is of
interest.
Since contractile function (tension development) is an
important
determinant of MO2, it is
possible that the decrease in
MO2 is
secondary to the fall in function. However, this cannot fully account
for the magnitude of the decrease in
MO2 with reduced function.
It has been
shown that the slope of the relation between segment shortening and
MO2 when function is
decreased to
dys- kinesis with intracoronary lidocaine is reasonably linear but,
surprisingly, very shallow, with an
MO2 at akinesis of
approximately 67%
of control.53 This is in contrast to the relation we
describe, which is considerably steeper, with an
MO2 of approximately 2
mL · min-1 · 100 g-1 at
akinesis (Fig 7). This level is close to that described for the
basal metabolic state
of nonworking muscle (2 to 2.5 mL · min-1 · 100
g-1). Together, these data indicate that the reduction in
function is only one component responsible for the decrease in
MO2 at lower flows. The
nature of this
other component is not clear but may relate to the question of what
limits myocardial oxidative phosphorylation in the presence of reduced
oxygen delivery. As recently reviewed by Balaban,54
possible candidates include (1) concentrations of ATP, ADP, and
Pi; (2) the phosphorylation potential described by
[ATP][ADP][Pi]; (3) the mitochondrial
and cytoplasmic
redox potential described by
[NADH][H+]/[NAD]; (4)
PCr; and (5) molecular oxygen. Although the present study does not
clearly distinguish between these possibilities, the relation of
MO2 to oxygen delivery is
similar to
that described for an in vivo skeletal muscle preparation (Fig
7,
bottom). It was observed in that model that O2 delivery
modulated tissue respiration similarly whether achieved by hypoxia or
by ischemia in the absence of marked decreases in tissue ATP
levels.13 16 In addition, our finding has remarkable
similarities to a study by Marshall55 showing that a tight
linear relation existed between
MO2
and flow and also between
MO2 and
developed pressure in the isolated perfused rabbit heart. The linear
relation between MO2 and
oxygen
delivery or blood flow described in both skeletal and cardiac muscle
under conditions of reduced delivery can be called
"perfusion-metabolism matching" as a counterpart to the
phenomenon of "perfusion-contraction matching."
Recent data suggest that perfusion-metabolism matching may be important for the limitation of ischemic injury under conditions of reduced CBF. In the case of moderate, sustained reductions of blood flow, it is now apparent that the myocardium makes a metabolic adjustment characterized by a restoration of PCr levels, normalization of lactate production, reduced but stable ATP levels, and depressed but stable contractile dysfunction.4 5 6 7 It has also been shown that this state can be maintained with depressed but stable ATP and contractile function without evidence of infarction for 5 hours3 9 up to 2 weeks.56 This phenomenon has been suggested to be a condition of downregulated metabolism and ATP consumption to match the reduction in perfusion.12 A recent study by Arai17 demonstrated the time dependence of this process and showed that slow reductions in myocardial perfusion to moderate levels result in blunted indexes of ischemia, including lactate release and fall in ATP and PCr levels, compared with an abrupt decrease. Our results demonstrating a reduction in lactate formation and fall in coronary venous pH and a reduced rise in coronary venous PCO2 in the Ramp Ischemia group appear to be consistent with the findings of Arai. However, it remains possible that the reduced lactate formation observed here may be due to a depletion of tissue glycogen occurring during the slow reduction in blood flow compared with the Fast Ischemia group. Additional experiments will be necessary to evaluate this possibility.
Downing and Chen57
recently reported that severe global
ischemia for 2 hours in isolated perfused neonatal pig hearts was
associated with increased O2 extraction, reduced
MO2 and cardiac function,
and normal
PCr and glycogen levels, with relatively well-preserved ATP levels.
They concluded that when myocardial O2 supply is limited,
myocardial function diminishes and serves to preserve critical energy
stores and prevent irreversible injury. Our results in vivo are similar
in many respects. However, direct comparison of the results from our in
vivo study with those obtained in isolated neonatal hearts with global
ischemia is problematic. First, it has been shown that high-energy
phosphate depletion is reduced with global ischemia in vitro compared
with regional ischemia in vivo36 and attributed to the
electrical quiescence and reduced mechanical function found with global
ischemia. It is likely that the dramatically reduced heart rates
(decrease from 180 to between 30 and 60 beats per minute) observed by
Downing and Chen during global ischemia may have influenced the result.
It is also possible that ischemia occurring in that preparation with
relatively lengthy time from excision to perfusion (up to 10 minutes)
may have introduced some degree of myocardial preconditioning. In
contrast, in our model, both heart rates and ventricular loads were
constant between the experimental groups. Thus, these strong
determinants of myocardial oxygen demand are not likely to have played
a role. Nonetheless, the data from both of these studies yield the same
conclusion: that with limited oxygen supply, myocardial contractile
function and oxygen consumption fall proportionately and are associated
with reduced myocyte injury.
Limitations
TTC/Infarct Size
Quantification of
the mass of infarction in the present study
was done with the histochemical method of tissue incubation with TTC.
It has been reported that in some instances, the ability of TTC to
discriminate between viable and dead tissue may be influenced by some
pharmacological agents58 and is dependent on reperfusion
time. Thus, the possibility exists that the reduced infarct size
present in the Ramp Ischemia group was simply an artifact of the
technique and if recovery and longer perfusion times were used in
combination with histological assessment, this difference would not be
present. Unfortunately, this cannot be easily done in this model.
However, most studies find that a TTC or para-nitroblue
tetrazolium estimate of infarct size after 1 to 2 hours of reperfusion
is accurate in representing the ultimate infarct size as
determined days later by histology.59
Regional
Function
The reduction in infarct size in the Ramp Ischemia group
occurred
in the absence of an improvement in systolic segment shortening during
the 120-minute reperfusion period compared with the Fast Ischemia group
(Fig 3). We interpret this as being due to myocardial stunning
and
speculate that function would recover substantially in the Ramp group
over the course of several days to weeks. We would not expect this to
occur in the Fast Ischemia group, in which significant infarction is
present. This speculation is based on experimental data from
preconditioning models in which infarct size is reduced but severe
stunning remains.60 In addition, reports from both
clinical61 and laboratory studies9 indicate
that several days to weeks is required for a gradual return of wall
function after reperfusion of hibernating myocardium.
Clinical Relevance
The experimental model of myocardial
infarction currently used
usually involves acute ligation of a coronary artery within seconds,
from a level of normal coronary artery flows and perfusion pressures to
zero flow (excluding collaterals). It should be considered that this
may only mimic a clinical situation in the individual with unstable
angina, in whom a major coronary artery would be rapidly occluded from
a basal metabolic and flow state. However, comprehensive data exist
that thrombus formation and occlusion of a coronary artery at a site of
plaque rupture and the progression of coronary stenosis to occlusion
may occur over several minutes.62 In this situation,
coronary occlusion is the end result of plaque rupture, formation of an
intraplaque thrombus, extension to an intraluminal or mural thrombus,
and complete or subtotal vessel occlusion. Thus, one might expect that,
as the thrombus develops and occupies more of the cross-sectional
diameter of the vessel, CBF would fall, not over seconds, but at some
rate dependent on the geometry of the thrombus within the vessel and
its rate of growth. The data from the present study indicate that
the rate at which CBF falls is a determinant of the extent of
infarction for a period of severe low flow. Thus, our results may have
some implications regarding the rate of infarction development in
humans with acute coronary occlusion. It should be noted that 70
minutes was arbitrarily chosen for the ramp period. It remains to be
determined whether significant reduction in infarction would also occur
with faster ramps. It seems possible that a delay of infarct
development due to the phenomenon we describe here, as well as
preconditioning, may increase the window of time available for
myocardial salvage with reperfusion in humans. Extrapolating from the
present study, an individual in whom the reduction in CBF to low
levels occurred over a period of an hour would be expected to benefit
from reperfusion at late times compared with the individual in whom
sudden occlusion of a coronary artery occurred.
In summary, the present
study demonstrates that the extent of
myocardial infarction is dramatically less for a given period of
reduced flow when blood flow falls gradually. The slow reduction in
blood flow is associated with a concomitant fall in regional
contractile function and
MO2 and reduced
lactate release. These data suggest that the rate at which myocardial
ischemia develops may be an important determinant of the extent of
myocardial infarction resulting from a period of low blood flow.
Although the data are consistent with models of hibernation and
preconditioning, the mechanism responsible for this effect warrants
further investigation.
|
Acknowledgments |
|---|
This work was supported by funds provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco-Related Disease Research Program of the University of California, grant RT400, to Dr Ito. The author would like to acknowledge Barry Peters, David Stein, Maureen Lee, and Paul Tang for their expert technical assistance in the completion of these studies.
Received August 2, 1994; revision received November 9, 1994; accepted November 13, 1994.
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