(Circulation. 1996;93:1556-1566.)
© 1996 American Heart Association, Inc.
Articles |
Calcium Responsiveness in Regional Myocardial Short-term Hibernation and Stunning in the In Situ Porcine Heart
Inotropic Responses to Postextrasystolic Potentiation and Intracoronary Calcium
From the Abteilung für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums Essen, Federal Republic of Germany.
Correspondence to Prof Dr Gerd Heusch, FESC, FACC, Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstraße 55, 45122 Essen, Federal Republic of Germany.
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Abstract |
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Background We tested the hypothesis that decreased calcium responsiveness is responsible for the reduction in contractile function in regional hibernating and stunned myocardium in situ.
Methods and Results In 19 anesthetized swine, the
left anterior descending coronary artery flow was reduced to
decrease anterior myocardial work index (sonomicrometry) by 
60%.
During 90 minutes of hypoperfusion, creatine phosphate recovered (as
determined by biopsy specimens and bioluminescence) and no necrosis
developed (as determined by staining with triphenyl tetrazolium
chloride). In 10 swine, changes in the intracellular calcium
concentration were induced by systematic variation of the
postextrasystolic time interval at a constant
prematurity. In 9 additional swine, a graded IC calcium infusion was
performed. Under control conditions, anterior myocardial work increased
with a fully compensated postextrasystolic time
interval from 380±93 (mean±SD) to 523±98 mm Hg·mm. IC calcium
infusion increased anterior myocardial work under control conditions
from 356±85 to a maximum of 428±93 mm Hg·mm. Although the maximal
responses were decreased during postextrasystolic
potentiation (222±68 versus 523±98 mm Hg·mm) and calcium infusion
(176±32 versus 428±93 mm Hg·mm) after 90 minutes of
ischemia, the relationships between increases in anterior
myocardial work and, respectively,
postextrasystolic time interval and IC calcium were
not different. The same was true after 30 minutes of reperfusion.
Conclusions Both regional hibernating myocardium and stunned myocardium in situ are characterized by a decrease in overall myocardial calcium responsiveness; however, there appears to be no significant myocardial desensitization to calcium.
Key Words: stunning, myocardial • calcium • ischemia • contractility
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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When a severe reduction of coronary blood flow persists for >20 minutes, myocardial necroses begin to develop and contractile function eventually is irreversibly lost.1 When myocardial ischemia is less severe, the myocardium can remain viable. Contractile function of such myocardium is reduced but recovers at the occurrence of reperfusion. This situation of chronic contractile dysfunction that is reversible on reperfusion has been termed myocardial hibernation.2 The recovery of contractile function on reperfusion, however, may require substantial time, ie, the myocardium is stunned.3 The metabolic status of hibernating myocardium improves over the first few hours as myocardial lactate production is attenuated4 5 and CP, after an initial reduction, returns toward control values.5 6 7 8 The hibernating myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status.5
The alterations in excitation-contraction coupling that ultimately underlie the reduction in contractile function in hibernating myocardium are not clear in detail. Alterations in sarcoplasmic reticulum function during short-term global ischemia have been observed.9 Alterations at the level of the myofibrils are particularly unclear, largely because of the methodological difficulties in analyzing the intracellular calcium concentration and contractile function simultaneously in a physiological setting. Isolated, buffer-perfused heart preparations that permit the measurement of intracellular free calcium by use of aequorin-fluorescence or nuclear magnetic resonance spectroscopy are characterized by low contractile performance,10 11 12 13 14 15 16 17 even at unphysiologically high extracellular calcium concentrations.11 12 13 14 On the other hand, in vivo preparations that are more physiological do not permit the measurement of intracellular calcium concentrations and rely on the ability of biophysical (eg, postextrasystolic potentiation18 ) or pharmacological maneuvers (eg, IC calcium, catecholamines5 19 ) to alter the intracellular calcium concentration or to modify the calcium sensitivity of the myofibrils (eg, calcium sensitizers).20 21 Marban,22 therefore, emphasized the importance of a synopsis based on both types of preparations: more insightful but more artificial and more indirect but more physiological models.
Whereas intracellular calcium concentration is increased consistently during no-flow ischemia,10 11 15 16 17 23 24 25 26 27 the few existing data during low-flow ischemia indicate a decreased12 28 29 30 or unchanged intracellular calcium concentration.31 Maximal developed isovolumic pressure decreases rapidly and calcium sensitivity is decreased during no-flow ischemia.25 Data during low-flow ischemia are lacking. In an isolated buffer-perfused ferret-heart model of short-term hibernation, characterized by a perfusion pressure of 60 mm Hg without concomitant metabolic evidence of ischemia, the reduction in intracellular calcium concentration was sufficient to explain the decrease in contractile function, whereas maximal calcium-activated isovolumic pressure was unaltered.12 Data from more physiological in situ preparations on excitation-contraction coupling in short-term hibernating myocardium are not available. We therefore investigated the calcium responsiveness in regional hibernating myocardium in situ.
In addition, as part of the protocol, the calcium responsiveness in stunned myocardium was reexamined, since changes in calcium responsiveness in stunned myocardium remain controversial. Whereas maximal calcium-activated force was reduced in buffer-perfused hearts,14 15 32 33 maximal calcium-activated segment shortening was not different from control in an in situ canine-heart preparation.19 Calcium sensitivity was reported to be decreased14 32 33 34 or unaltered.15
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Methods |
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The experimental protocols used in the present study were approved by the bioethical committee of the district of Düsseldorf, and they adhere to the guiding principles of the American Physiological Society.
Experimental Model
Nineteen Göttinger miniswine (weight, 20 to 40 kg) of
either sex were initially sedated with ketamine hydrochloride
(1 g IM) and then anesthetized with thiopental (Trapanal 500 mg
IV). Through a midline cervical incision, the trachea was intubated for
connection to a respirator (Dräger). Anesthesia was
then maintained with enflurane (1% to 1.5%) with an oxygen/nitrous
oxide mixture (40%:60%). Arterial blood gases were
monitored frequently in the initial stages of the preparation until
stable and then periodically throughout the study (Radiometer). Rectal
temperature was monitored and body temperature was kept above 37°C by
the use of a heated surgical table and drapes.
Through the cervical incision, both common carotid arteries and internal jugular veins were isolated. The arteries were cannulated with polyethylene catheters, one for the measurement of arterial pressure and the other to supply blood to the extracorporeal circuit. The jugular veins were cannulated for volume replacement with warmed 0.9% NaCl and for the return of blood to the animal from the coronary venous line (see below).
A left lateral thoracotomy was performed in the fourth intercostal space and the pericardium opened. A micromanometer (P7, Konigsberg Instruments) was placed in the LV through the apex together with a saline-filled polyethylene catheter (used to calibrate the micromanometer in situ). Ultrasonic dimension gauges were implanted in the LV myocardium to measure the thickness of the anterior and posterior (control) walls (System 6, Triton Technologies, Inc).
The proximal LAD was dissected over a distance of 1.5 cm, ligated, and cannulated, and the distal LAD was perfused from an extracorporeal circuit. Before coronary cannulation, the pigs were anticoagulated with 20 000 IU sodium heparin; additional doses of 10 000 IU were given at hourly intervals. The system included a roller pump, windkessel, and two side ports, one for the injection of radiolabeled microspheres, the other for dobutamine or calcium infusion.5 35 Coronary arterial pressure was measured from the sidearm of a polyethylene T-connector (Cole-Parmer) used as the catheter tip with an external transducer (Bell and Howell type 4-327I). The large epicardial vein parallel to the LAD was dissected and cannulated. Coronary venous blood was drained to an unpressurized reservoir and then returned to a jugular vein through use of a second roller pump. Heart rate was controlled throughout the study by left atrial pacing (Hugo Sachs Elektronik type 215/T). The completed preparation was allowed to stabilize for at least 30 minutes before control measurements were made. The flow-constant perfusion pump was adjusted so that the minimum coronary arterial pressure was not <70 mm Hg under control conditions to avoid initial hypoperfusion. Therefore, mean coronary arterial pressure exceeded LVPP.
Regional Myocardial Function
End diastole was defined as the point when LV dP/dt
started its rapid upstroke after crossing the zero line. Regional end
systole was defined as the point of maximal wall thickness within 20 ms
before peak negative LV dP/dt.36 Systolic wall
thickening was calculated as end-systolic wall thickness
minus end-diastolic wall thickness, divided by the
end-diastolic wall thickness.
Because the regional calcium and dobutamine infusion changed the contraction pattern of the stimulated area in some swine such that an augmented early systolic thickening was followed by late systolic thinning, the regional myocardial work performed by the LAD-perfused myocardium was calculated in addition to systolic wall thickening. Regional myocardial work was determined as the sum of the instantaneous LV pressure–wall thickness product over the time of the cardiac cycle, with the equation:
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where ed=end diastole, n=actual cardiac cycle, m=sampling point within cardiac cycle n at a sampling frequency of 5 ms, LVPn,m=instantaneous LV pressure within cardiac cycle n and at sampling point m, LVPn,min=minimum LV pressure within cardiac cycle n, and WTh=wall thickness. The maximal work value during systole is reported as WI.5 35
Ischemia decreased the baseline value of WI. Therefore, to analyze responses of WI to postextrasystolic potentiation or IC calcium infusion (see below) during control conditions and during ischemia and reperfusion, increases in WI were expressed as a fraction of the maximal increase during the respective intervention, as reported previously by other investigators.19 25
Regional Myocardial Blood Flow
Radiolabeled microspheres (15-µm diameter,
141Ce, 114In, 51Cr,
113Sn, 103Ru, 95Nb, or
46Sc; NEN/DuPont Co) were injected into the
coronary perfusion circuit (1 to 2x105 suspended
in 1 mL saline) to determine the regional myocardial blood flow
and its distribution throughout the LAD perfusion bed. This
procedure for the determination of blood flow has been validated
extensively.35 Blood flow to the tissue at the site of the
ultrasonic crystals is reported, and this piece of tissue was divided
into transmural thirds of approximately equal thickness.
Regional Myocardial Metabolism
Oxygen content was measured with use of
anaerobically sampled blood drawn
simultaneously from the cannulated coronary vein
and an artery (Cavitron/LexO2-Con-k, Dr B.G. Schlag).
Oxygen consumption of the anterior myocardial wall
(M
O2) was calculated by multiplying the
arterial-coronary venous oxygen difference by
the transmural blood flow at the crystal site.
Lactate was measured in simultaneously drawn coronary venous and arterial blood samples by use of enzymatic dehydrogenation and subsequent photometry of NADH,37 and lactate consumption was calculated by multiplying the arterial-coronary venous difference by the transmural blood flow at the crystal site.
Transmural myocardial biopsy specimens (10 mg each) were taken with
a modified dental drill from the LAD perfusion bed for analysis
of ATP and CP content. Care was taken to ensure that the biopsy samples
originated from within the LAD perfusion territory (with epicardial
arteries used as landmarks) but distal to the site of the ultrasonic
dimension gauges and blood-flow measurements. Samples that required
>1 to 2 seconds for acquisition were not used for this
analysis. The analytical procedures (bioluminescence) have been
described in detail previously.5
Morphology
At the end of each study, the heart was removed and sectioned
from base to apex into five transverse slices in a plane parallel to
the atrioventricular groove. The tissue slices were
immersed in a 0.09 mol/L sodium phosphate buffer (pH 7.4) containing
1.0% triphenyl tetrazolium chloride (TTC, Sigma) and 8% dextran (mol
wt, 77 800) for 20 minutes at 37°C to verify the absence of
infarcted tissue.
Experimental Protocols
In both groups of swine, a 90-minute ischemic period was
followed by 120 minutes of reperfusion. During ischemia,
coronary inflow was decreased to reduce WI by 60%; this
degree of ischemia has been previously shown to be compatible
with the development of myocardial hibernation.5 38 39
Under control conditions and at 5 and 85 minutes of ischemia,
pairs of arterial and coronary venous blood samples
were simultaneously withdrawn. During the blood sampling,
microspheres were injected into the LAD perfusion system for
measurement of regional myocardial blood flow, and
hemodynamic and regional dimension data were
recorded. Coronary arterial pressure was
continuously monitored during the microsphere injection to
ensure that it was unaffected by the injection. Immediately after the
microsphere injection, myocardial biopsy specimens were taken.
A set of measurements was obtained within 2 to 3 minutes.
Group 1 (n=10): Postextrasystolic
Potentiation
The prematurity of the electrically induced extrasystole that
resulted in maximal postextrasystolic potentiation
of WI was determined under control conditions and then kept constant.
Extrasystoles with constant prematurity were then followed by three
different postextrasystolic time intervals: a fully
compensated interval, an interval as long as the regular
beat-to-beat interval, and an abbreviated interval (set to 65%
of the regular beat-to-beat interval). Sets of measurements,
including postextrasystolic potentiation with the
three different postextrasystolic time intervals,
were performed under control conditions and at 5 and 85 minutes of
ischemia. After 85 minutes of ischemia,
dobutamine (2.5±1 µg/min) was infused into the
coronary perfusion system. The infusion rate was set to
increase LV dP/dtmax by 30%. After 2 to 3 minutes
of the dobutamine infusion, a further set of measurements
was performed. Thereafter, the myocardium was reperfused
and a final set of measurements was obtained at 30 minutes of
reperfusion.
Group 2 (n=9): IC Calcium Infusion
Under control conditions, CaCl2 was infused into the
perfusion system with a syringe pump, starting at an infusion rate of
10 mL/h, with stepwise increases up to 240 mL/h. These calcium infusion
rates were normalized for the actual LAD inflow and finally expressed
in micrograms of added CaCl2 per milliliter of blood. The
recruitment of maximal calcium-activated work was verified
by the lack of further increases of WI despite further increased
calcium infusion rates. Since IC calcium infusion increased contractile
function, it was also expected to deteriorate the metabolic
status of the myocardium during ischemia, as
previously shown for dobutamine.39 Therefore,
to not interfere with the development of hibernating
myocardium, IC calcium infusion early during
ischemia was avoided. After 85 minutes of ischemia, the
three doses of IC calcium that resulted in an 10% increase,
half-maximal increase, and maximal increase in WI during control
conditions were repeated. The infusion rates were corrected for the
reduced coronary inflow during hypoperfusion to obtain
identical calcium doses (in micrograms of added CaCl2 per
milliliter of blood) as during control conditions. These doses are
referred to as Ca1 (56.6±20.3 µg/mL), Ca2 (164.9±42.8 µg/mL), and
Ca3 (407.5±117.9 µg/mL). With the maximal functional response to
added calcium, the last microsphere measurement was performed.
Thereafter, the myocardium was reperfused and at 30 minutes
of reperfusion, the stepwise calcium infusion was repeated. Calcium
infusion rates were once more corrected for the increased
coronary inflow during reperfusion.
At the end of each study, the digital reading of the roller pump was calibrated by timed collection of arterial blood in a graduated cylinder.
Data Analysis and Statistics
Hemodynamic data were recorded on an
8-channel recorder (Gould MK 200A) and stored directly on the hard
disk of an AT-type computer. Hemodynamic and functional
parameters were digitized and recorded over a 20-second
period during each microsphere injection (33 consecutive
beats over at least two complete respiratory cycles) with CORDAT II
software (Triton Technologies, Inc).40
Hemodynamic parameters reported are heart
rate, LVEDP and LVPP, LV dP/dtmax, and mean
LAD pressure. Regional wall function parameters include
AWED, AWT, and AWI,35 and PWT. Metabolic
parameters include the myocardial contents of ATP and CP
and the consumption of oxygen and lactate (positive values indicate
myocardial uptake).
In group 1, 33 consecutive beats were averaged for
hemodynamic and regional wall function
parameters and compared with single beats with an
abbreviated, regular, or fully compensated
postextrasystolic time interval. In group 2, 33
consecutive beats were averaged for the calculation of
hemodynamic and regional wall function
parameters.
Statistical analyses were performed by use of SYSTAT software. In both groups of swine, changes in regional myocardial blood flow and metabolism over the time course of the experiment were evaluated by one-way ANOVA.
In addition, in group 1, changes in systemic hemodynamics and regional myocardial function during postextrasystolic potentiation were assessed by two-way ANOVA, accounting for the different time points throughout the experiment and the three postextrasystolic time intervals. In group 2, changes in systemic hemodynamics and regional myocardial function during increasing calcium infusion rates were assessed by two-way ANOVA, accounting for the different time points throughout the experiment and the three different calcium doses (minor, half-maximal, and maximal increase in myocardial work). When significant differences were detected, individual mean values were compared by use of post hoc tests.
Linear regression analyses between the postextrasystolic time interval (expressed on a logarithmic scale, group 1) and all doses of added calcium (expressed on a logarithmic scale,19 group 2) and the response in the work index (expressed as a fraction of the maximal response19 25 ) were performed in groups 1 and 2. Regression lines were compared by ANCOVA.
All data are reported as mean±SD, and a value of P<.05 was accepted as indicating a significant difference.
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Results |
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In both groups of swine, there was no myocardial necrosis after 90 minutes of ischemia and 2 hours of reperfusion.
Group 1: Postextrasystolic
Potentiation
Data regarding systemic hemodynamics, regional
myocardial function, blood flow, and metabolism are
summarized in Tables 1
and 2. An original
tracing from one experiment in group 1 is given in Fig 1
for a fully compensated postextrasystolic time
interval, and the effects of postextrasystolic
potentiation on AWI are displayed in Fig 2.
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P<.05 vs respective REST.
Systemic Hemodynamics
Under control conditions, postextrasystolic
potentiation at an abbreviated postextrasystolic
time interval reduced LVPP (P=NS) and LV
dP/dtmax (P<.05), whereas LVEDP
(P<.05) was increased. At a regular and fully compensated
postextrasystolic time interval, LVEDP
(P=NS), LVPP (P=NS), and LV
dP/dtmax (P<.05) were increased (Table 1
). With the reduction in coronary inflow, LVPP
(P=NS) and LV dP/dtmax
(P<.05) were decreased, with no further significant changes
when ischemia was prolonged to 85 minutes (Table 1). Infusion
of dobutamine after 85 minutes of ischemia
significantly increased LV dP/dtmax. After 30
minutes of reperfusion, LVPP and LV dP/dtmax tended
to be reduced further. The responses to
postextrasystolic potentiation at 5 and 85 minutes
of ischemia and at 30 minutes of reperfusion were comparable to
the responses under control conditions (Table 1).
Regional Myocardial Function
Under control conditions, postextrasystolic
potentiation at an abbreviated postextrasystolic
time interval increased the AWED (P<.05) but reduced AWT
and AWI (both P<.05). Also, PWT was decreased
(P<.05). At a regular and fully compensated
postextrasystolic time interval, AWED was decreased
(P=NS) and AWT, AWI (Fig 2), and PWT were increased. At 5
minutes of ischemia, AWED tended to be reduced
(P=NS), and AWT and AWI were significantly decreased to
17.3±6.9% and 133±51 mm Hg·mm, respectively, whereas PWT
remained unchanged. Again, postextrasystolic
potentiation at an abbreviated postextrasystolic
time interval increased AWED (P<.05) and reduced AWT, AWI,
and PWT (all P<.05). At a regular and fully compensated
postextrasystolic time interval, AWED was decreased
(P=NS), whereas AWT and AWI were increased. However, the
absolute values of AWT and AWI always remained below their respective
values during control conditions (P<.05, Fig 2). In
contrast, the increase in PWT during
postextrasystolic potentiation at a regular and
fully compensated postextrasystolic time interval
was comparable to that observed during control conditions. With
prolongation of ischemia to 85 minutes, neither the absolute
values of AWT, AWI (Fig 2), or PWT nor their responses to
postextrasystolic potentiation were changed. With
IC dobutamine infusion, the contraction pattern of the
anterior wall changed in that the maximal wall thickness was reached
early during systole followed by a late systolic wall thinning.
During dobutamine infusion, AWI was increased
(P<.05), whereas AWT and PWT remained unchanged. With
reperfusion, AWT and AWI remained depressed.
Postextrasystolic potentiation again induced
similar responses such as seen during 5 and 85 minutes of
ischemia (Fig 2).
Coronary Arterial Pressure, Regional Myocardial
Blood Flow, and Metabolism
With the reduction in coronary inflow, coronary
arterial pressure was significantly reduced to 51±7 mm Hg.
Regional myocardial blood flow was reduced, particularly in the
subendocardium (Table 2). Myocardial CP and ATP content as well as
MO2 were decreased, and myocardial
lactate consumption under control conditions was reversed to net
lactate production. When ischemia was prolonged to 85
minutes, coronary arterial pressure, regional
myocardial blood flow, MO2, and
the myocardial ATP content remained unchanged, whereas the myocardial
CP content recovered toward its control value, and lactate
production was attenuated. With infusion of
dobutamine at unchanged coronary
arterial pressure, regional myocardial blood flow, and
MO2, myocardial CP content again
decreased and myocardial lactate production again increased,
whereas myocardial ATP content decreased further.
Group 2: IC Calcium Infusion
Data regarding systemic hemodynamics, regional
myocardial function, blood flow, and metabolism are
summarized in Tables 3 and 4. The effects
of IC calcium infusion on AWI are displayed in Fig 3.
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Systemic Hemodynamics
With increasing IC calcium doses (Ca1, Ca2, and Ca3), LVPP tended
to be elevated and LV dP/dtmax was increased in a
stepwise fashion (P<.05 at Ca3) (Table 3). After 85 minutes
of ischemia and at 30 minutes of reperfusion, baseline values
of LVPP (P=NS) and LV dP/dtmax
(P<.05) were reduced. Increasing IC calcium doses, however,
induced hemodynamic responses comparable to those under
control conditions.
Regional Myocardial Function
Under control conditions with increasing IC calcium doses, AWED
remained stable, whereas AWT (P=NS) and AWI
(P<.05, Fig 3) were increased at the highest IC calcium
dosage. At 85 minutes of ischemia, baseline AWT and AWI were
significantly reduced to 18.3±8.2% and 132±38 mm Hg·mm,
respectively. There was no further change at 30 minutes of reperfusion.
Again, during both ischemia and reperfusion at the highest IC
calcium dose, AWI was increased (P<.05 at Ca3, Fig 3).
However, at any given calcium dose, AWI was reduced during
ischemia and reperfusion compared with control conditions.
Systolic thickening of the posterior myocardium
remained unchanged during the entire protocol.
Coronary Arterial Pressure, Regional Myocardial
Blood Flow, and Metabolism
Coronary arterial pressure, regional
myocardial blood flow, and metabolism under control
conditions and at 5 and 85 minutes of ischemia were comparable
to those observed in group 1. With the IC calcium infusion at unchanged
coronary arterial pressure, regional myocardial
blood flow, and MO2, myocardial
CP content was again decreased and myocardial lactate
production was again increased, whereas myocardial ATP content
was decreased further.
AWI–Postextrasystolic Time Interval and
AWI-Added Calcium Relationships
The relationships between increases in AWI (expressed as a
fraction of the maximal increase in AWI) and the
postextrasystolic time interval were not different
under control conditions, at 5 and 85 minutes of ischemia, and
at 30 minutes of reperfusion (Fig 4). Also, the
relationships between AWI and added calcium were superimposable under
control conditions, at 85 minutes of ischemia (Fig 5A), and at 30 minutes of reperfusion (Fig 5B).
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Discussion |
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The major finding of the present study is that both regional short-term hibernating myocardium and stunned myocardium are characterized by a decrease in maximal calcium-activated work without apparent alterations in calcium sensitivity in the in situ porcine heart.
Critique of Methods
Strengths and Limitations of the Experimental
Preparation
The present model of regional myocardial hibernation with its
strengths and limitations has been discussed in detail
previously.5 38 39 The degree of flow reduction, the
decrease in regional myocardial oxygen consumption, and the contractile
dysfunction of the present study were comparable to former studies
(Tables 1 and 3).5 38
In the in situ heart preparation, neither intracellular calcium concentrations nor maximal calcium-activated force can be measured; however, both can be determined in isolated myocytes, papillary muscles, or buffer-perfused heart preparations. Given the advantage of direct access to the measurement of intracellular calcium concentrations, myofilament calcium sensitivity, and maximal calcium-activated force after pharmacological elimination of the sarcoplasmic reticulum and tetanization, such preparations, however, suffer from unphysiological external conditions, ie, lack of blood perfusion, lack of autoregulation,12 lack of physiological contraction mode (isovolumic rather than ejecting), and decreased strength of contraction,10 12 13 14 15 16 17 28 even despite elevated extracellular calcium concentrations.11 12 13 14 In blood-perfused hearts with an intact autoregulation and a physiological contraction mode, responses of contractile function to IC calcium or to manipulation of the intracellular calcium concentration with varying coupling intervals during postextrasystolic potentiation must serve as surrogates for intracellular calcium concentration, myofilament calcium sensitivity, and maximal calcium-activated force. Supporting our approach, postextrasystolic potentiation or increasing concentrations of extracellular calcium have been directly demonstrated in buffer-perfused hearts to enhance the intracellular calcium concentration and to result in proportionate increases in contractile function.25 41 However, we cannot exclude that IC calcium infusion and postextrasystolic potentiation recruit different amounts of activator calcium under control conditions, in hibernating myocardium, and in stunned myocardium. In the present study, therefore, only overall myocardial calcium responsiveness can be studied under defined pathophysiological conditions such as regional myocardial ischemia and reperfusion.
Regional Myocardial Function
Depending on the duration of the
postextrasystolic time interval, preload and
afterload of the postextrasystolic beat were
altered. Thus, apart from alterations in excitation-contraction
coupling and inotropy, changes in loading conditions, in particular
preload recruitment, probably contributed to the increased regional
myocardial function during postextrasystolic
potentiation. Therefore, the increases in regional myocardial function
during postextrasystolic beats were substantially
more pronounced than those during the highest calcium infusion rate and
during dobutamine infusion, because calcium and
dobutamine infusion did not increase preload, as reflected
by the unchanged AWED and LVEDP (Table 3). Afterload tended to be
increased during postextrasystolic potentiation at
a regular and fully compensated postextrasystolic
time interval and during calcium and dobutamine infusion,
as reflected by the slightly increased LVPP (Tables 1 and 3). However,
the recruitment of preload during postextrasystolic
potentiation and the increase in afterload during
postextrasystolic potentiation and IC calcium
infusion were comparable in intact, ischemic, and reperfused
myocardium (Tables 1 and 3), thus permitting an
intraindividual comparison of regional myocardial inotropic responses
during the experimental protocol.
To better evaluate the influence of prolonged ischemia and stunning on the inotropic responses to postextrasystolic potentiation and IC calcium infusion, the apparent calcium sensitivity of normoperfused, hibernating, and stunned myocardium was assessed by plotting the response in regional myocardial work expressed as a fraction of the maximal response during each intervention against the postextrasystolic time interval or the added IC calcium dose.19 The calcium dose was calculated in micrograms per milliliter of blood to account for changes in blood flow during ischemia and reperfusion. The curves under control conditions, ischemia, and reperfusion were virtually superimposable, although during ischemia and reperfusion, there was a tendency for a small rightward shift, ie, the negative log(added calcium) for the half-maximal increase in fractional work was decreased by 2.8% (hibernation) and 0.8% (stunning), respectively.
Hibernating Myocardium
Contractile dysfunction during moderate ischemia
represents more than a reflection of the severity of
ischemia and impending infarction. The energy-sparing
effect from the loss of regional contractile function serves as an
important mechanism through which the myocardium adjusts to
an ischemic period.42 43 Severe ischemia
with total coronary occlusion causes cell death within 20
minutes in the inner wall, with progressive necrosis across the wall
over time, the so-called wave front of infarction.1
More moderate ischemia, such as in the present study, is
characterized by a less intense decrease in regional contractile
function (persistent systolic work). Such moderate
ischemia can be maintained for prolonged periods without
development of irreversible damage.5 38 44 45 46 47
Whereas during such moderate ischemia, myocardial creatine
phosphate content initially decreases during the first few
minutes of ischemia but then returns to near-control
values, the ATP content remains constant at a slightly reduced level
despite ongoing hypoperfusion.5 6 7 38 Finally, the
ischemia-induced net lactate production becomes
attenuated.4 5 38 Although basal contractile function is
depressed, the hypoperfused myocardium retains its
responsiveness to an inotropic challenge, supporting the notion that
the reduction in contractile function is not secondary or not entirely
secondary to an energetic deficit. When, after 85 minutes of
ischemia, dobutamine is infused selectively into
the ischemic region, contractile function increases, although
regional blood flow remains unchanged or slightly decreases
further5 38 (Table 2). In the present study, regional
myocardial function in the hibernating myocardium also
increased during IC calcium infusion (Table 3). The extent of
functional improvement during IC dobutamine and calcium
infusion was comparable and was associated with worsening of
metabolic parameters by both interventions, as
myocardial CP content again decreased and lactate production
increased (Tables 2 and 4).
Overall myocardial responsiveness to extracellular calcium
comprises three aspects: the intracellular free calcium concentration
during each cardiac cycle, ie, the calcium transient; the calcium
sensitivity of the myofilaments; and the maximal
calcium-activated force.32 Studies that used
isolated buffer-perfused hearts with low-flow ischemia
reported unchanged12 28 31 or
decreased12 29 30 end-diastolic and
unchanged31 or decreased12 28 29 30 peak
systolic intracellular calcium concentrations, ie, the calcium
transient during low-flow ischemia was either
unchanged31 or slightly decreased.12 28 29 30 If
we assume an unchanged calcium transient, the unchanged relationships
between AWI and postextrasystolic time interval
(Fig 4) or added calcium (Fig 5A) indicate a largely unchanged calcium
sensitivity in hibernating myocardium. If we assume a
decreased calcium transient, which has actually been
reported,12 these unchanged relationships even indicate an
increase in calcium sensitivity in hibernating myocardium.
The decrease in contractile function in hibernating
myocardium is therefore most likely explained by a decrease
in the maximal calcium-activated work (Figs 2 and 3).
Stunned Myocardium
In most isolated buffer-perfused heart preparations after 10
to 20 minutes of ischemia and 10 to 20 minutes of reperfusion,
both end-diastolic and peak systolic
intracellular calcium concentrations have returned to control
values,10 11 15 27 32 and in only one
study,14 peak systolic concentration has remained
slightly increased. Consequently, the calcium transient has returned to
the normal range10 11 15 27 32 or is slightly
increased.14 The maximal calcium-activated
force is decreased,14 15 32 and calcium sensitivity
remains either unchanged15 or is decreased.14
Also, in skinned myocytes obtained from in situ stunned porcine hearts
or in rat ventricular trabeculae, myofilament
calcium sensitivity is decreased.33 34 In contrast, with
in situ canine and porcine preparations, no changes in the regional
inotropic response to epinephrine48 and
postextrasystolic potentiation18 48
were found during reperfusion after 15 minutes of ischemia. In
particular, IC calcium infusion into a stunned region resulted in an
increase in segment shortening that was not different from the value
during calcium infusion under control conditions, suggesting an
unchanged maximal calcium-activated segment
shortening.19
In the present study, baseline contractile function was decreased
in reperfused myocardium, whereas the contractile response
to postextrasystolic potentiation (expressed as a
fraction of the maximal increase, Fig 4) and to IC calcium infusion
(Fig 5B) was unchanged. Because the calcium transient in stunned
myocardium (as mentioned above) has returned toward control
values, the unchanged relationships between AWI (expressed as a
fraction of the maximal increase) and
postextrasystolic time interval (Fig 4) or added
calcium (Fig 5B) indicate a largely unchanged calcium sensitivity in
stunned myocardium. The decrease in contractile function in
stunned myocardium, as in hibernating
myocardium, is therefore most likely explained by a
decrease in the maximal calcium-activated work (Figs 2 and 3).
Studies from buffer-perfused hearts,14 ventricular trabeculae,33 and skinned fibers34 reported slight but significant decreases in calcium sensitivity in stunned myocardium, ie, -log(Ca2+)i for the half-maximal tension was decreased by 2% to 3%. In the present study, calcium sensitivity also tended to be decreased (-log[added calcium] for the half-maximal increase in fractional work was decreased by 0.8%), but this effect did not reach statistical significance. Therefore, slight decreases in calcium sensitivity in stunned myocardium might not have been detected in the present study in situ. In particular, calcium sensitivity may have decreased if the calcium transient during reperfusion was slightly increased, as reported in only one study.14 Indeed, in a recent study in anesthetized swine, the purported calcium sensitizer EMD 60263 predominantly enhanced regional contractile function of the stunned region.21 Although the study protocol was different with respect to both the duration and severity of ischemia and might thus account for the different findings, the severity of contractile dysfunction was comparable between this and the present study. In particular, however, the calcium sensitizer properties and lack of other inotropic properties of EMD 60263 were not substantiated and were based solely on an unpublished communication by the manufacturer. In contrast, in the present study, we have established dose-response curves of IC calcium and contractile function and found the fractional increase in regional myocardial work during IC calcium infusion in stunned myocardium identical to that under control conditions and at 85 minutes of ischemia. Nevertheless, even if small changes in the calcium sensitivity occurred and were not detected in the present study, these changes are of minor importance compared with the substantial alterations in the maximal calcium-activated work observed in the stunned myocardium in vivo.
Potential Mechanisms Underlying the Depression of Maximal
Calcium-Activated Force During Ischemia and
Reperfusion
Potential candidate mediators for the decrease in developed force
are an accumulation of inorganic phosphate49 50 and a
calcium overload.51 52 However, data on inorganic
phosphate in hibernating myocardium are lacking, and
inorganic phosphate returns to control levels within 20 minutes of
reperfusion in stunned myocardium.53 Likewise,
the available data indicate no increase in intracellular calcium
concentration in hibernating
myocardium12 28 29 30 31 and after severe
ischemia, a return to normal within 10 to 20 minutes of
reperfusion.10 11 15 27 32 Nevertheless, short bouts of
increased inorganic phosphate or calcium may induce long-lasting
changes in contractile function, a notion supported by the effective
attenuation of stunning only by pretreatment with calcium
antagonists before ischemia.52
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Selected Abbreviations and Acronyms |
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Acknowledgments |
|---|
This study was supported by grants from the German Research Foundation (No. He 1302/8-1 and 8-2). We thank Claus Martin, PhD, for the chemical analyses and Petra Gres, Ursula Prägler, and Anita van de Sand for their technical support.
Received September 6, 1995; revision received October 26, 1995; accepted November 5, 1995.
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References |
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 W. Wijns, S. F. Vatner, and P. G. Camici Hibernating Myocardium N. Engl. J. Med., July 16, 1998; 339(3): 173 - 181. [Full Text] [PDF]
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P. D Verdouw, M. A van den Doel, S. de Zeeuw, and D. J Duncker Animal models in the study of myocardial ischaemia and ischaemic syndromes Cardiovasc Res, July 1, 1998; 39(1): 121 - 135. [Full Text] [PDF]
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R. K. Kudej, B. Ghaleh, N. Sato, Y.-T. Shen, S. P. Bishop, and S. F. Vatner Ineffective Perfusion-Contraction Matching in Conscious, Chronically Instrumented Pigs With an Extended Period of Coronary Stenosis Circ. Res., June 15, 1998; 82(11): 1199 - 1205. [Abstract] [Full Text] [PDF]
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D. J Duncker, R. Schulz, R. Ferrari, D. Garcia-Dorado, C. Guarnieri, G. Heusch, and P. D Verdouw "Myocardial stunning": remaining questions Cardiovasc Res, June 1, 1998; 38(3): 549 - 558. [Full Text] [PDF]
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H. M. Hoffmeister, M. Strobele, M. E Beyer, S. Kazmaier, M. Fischer, A. Bassler, and L. Seipel Inotropic response of stunned hypertrophied myocardium: responsiveness of hypertrophied and normal postischemic isolated rat hearts to calcium and dopamine stimulation Cardiovasc Res, April 1, 1998; 38(1): 149 - 157. [Abstract] [Full Text] [PDF]
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R. Schulz, C. Kappeler, H. Coenen, A. Bockisch, and G. Heusch Positron Emission Tomography Analysis of [1-11C]Acetate Kinetics in Short-term Hibernating Myocardium Circulation, March 17, 1998; 97(10): 1009 - 1016. [Abstract] [Full Text] [PDF]
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H. Luss, P. Bokniek, G. Heusch, F. U. Muller, J. Neumann, W. Schmitz, and R. Schulz Expression of calcium regulatory proteins in short-term hibernation and stunning in the in situ porcine heart Cardiovasc Res, March 1, 1998; 37(3): 606 - 617. [Abstract] [Full Text] [PDF]
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G. Heusch, R. Ferrari, D. J Hearse, T. J.C Ruigrok, and R. Schulz 'Myocardial hibernation'--questions and controversies Cardiovasc Res, December 1, 1997; 36(3): 301 - 309. [Full Text] [PDF]
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S. H. Rahimtoola Hibernating Myocardium Has Reduced Blood Flow at Rest That Increases With Low-Dose Dobutamine Circulation, December 15, 1996; 94(12): 3055 - 3061. [Full Text]
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C. Vahlhaus, R. Schulz, H. Post, R. Onallah, and G. Heusch No Prevention of Ischemic Preconditioning by the Protein Kinase C Inhibitor Staurosporine in Swine Circ. Res., September 1, 1996; 79(3): 407 - 414. [Abstract] [Full Text]
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S.-J. Kim, R. K. Kudej, A. Yatani, Y.-K. Kim, G. Takagi, R. Honda, D. A. Colantonio, J. E. Van Eyk, D. E. Vatner, R. L. Rasmusson, et al. A Novel Mechanism for Myocardial Stunning Involving Impaired Ca2+ Handling Circ. Res., October 26, 2001; 89(9): 831 - 837. [Abstract] [Full Text] [PDF]
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D. K. Kalra, X. Zhu, M. K. Ramchandani, G. Lawrie, M. J. Reardon, D. Lee-Jackson, W. L. Winters, N. Sivasubramanian, D. L. Mann, and W. A. Zoghbi Increased Myocardial Gene Expression of Tumor Necrosis Factor-{alpha} and Nitric Oxide Synthase-2: A Potential Mechanism for Depressed Myocardial Function in Hibernating Myocardium in Humans Circulation, April 2, 2002; 105(13): 1537 - 1540. [Abstract] [Full Text] [PDF]
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