(Circulation. 1995;91:1575-1587.)
© 1995 American Heart Association, Inc.
Articles |
Gadolinium Attenuates the Upward Shift of the Left Ventricular Diastolic Pressure-Volume Relation During Pacing-Induced Ischemia in Dogs
From the Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco.
Correspondence to Stanton A. Glantz, PhD, Professor of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA 94143-0124.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background The mechanism of the reversible upward shift of the left ventricular diastolic pressure-volume relation during demand ischemia is controversial. To assess the possibility that cation influx through stretch-activation channels may contribute to the upward shift, we asked whether gadolinium, a blocker of the stretch-activated channels, attenuates the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia in 5 dogs.
Methods and Results To produce pacing-induced ischemia, we constricted the left anterior descending and circumflex coronary arteries to reduce their flows by approximately 30% and paced the left atrium at 150 to 180 beats per minute for 3 minutes. We measured left ventricular pressure, volume, and two segment lengths with micromanometers, a conductance catheter, and ultrasonic crystals, respectively. We recorded these variables during baseline, coronary stenosis, and pacing-induced ischemia (immediately after rapid pacing). After injecting 20 mg/kg (76 µmol/kg) gadolinium, we repeated the measurements during coronary stenosis (gadolinium experiment) and pacing-induced ischemia (pacing-induced ischemia plus gadolinium experiment). For each measurement, we recorded the variables in steady state to obtain diastolic pressure-volume and pressure–segment length loops and then during a brief (within 25 seconds) inferior vena caval occlusion to obtain the left ventricular end-diastolic pressure-volume relation. We found that left ventricular diastolic pressure-volume and pressure–segment length loops in steady-state beats shifted upward from coronary stenosis to pacing-induced ischemia. After injection of gadolinium, the upward shift from gadolinium to pacing-induced ischemia plus gadolinium was smaller than the shift from coronary stenosis to pacing-induced ischemia. Similarly, the left ventricular end-diastolic pressure-volume relation obtained during vena caval occlusion shifted upward (by 2.2±0.6 [SE] mm Hg) from coronary stenosis to pacing-induced ischemia. After injection of gadolinium, the upward shift from gadolinium to pacing-induced ischemia plus gadolinium was smaller (by -2.1±0.4 mm Hg).
Conclusions These results indicate that gadolinium, a blocker of stretch-activated channels, attenuates the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia, suggesting that the cation influx through stretch-activated channels may contribute to this upward shift.
Key Words: mechanics • ischemia • diastole • ions
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The left ventricular diastolic pressure-volume relation shifts upward after pacing that induces angina in patients1 and after rapid pacing in the presence of two-vessel coronary stenosis in dogs.2 3 4 The mechanism of this upward shift is controversial. Several studies by Grossman and his colleagues2 3 4 5 6 have suggested that an increase in diastolic sarcoplasmic calcium due to impaired calcium uptake by the sarcoplasmic reticulum contributes to this upward shift. According to these authors, high-energy demand ischemia leads to an inadequate ATP supply to the myocardium, so that diastolic sarcoplasmic calcium increases due to impaired calcium uptake by the sarcoplasmic reticulum; this increase may cause persistent interaction of myofilaments from the previous systole during diastole, which is manifest as the upward shift of the diastolic pressure-volume relation.
However, recent evidence from our laboratory suggests that the upward shift cannot result solely from persistent interaction of myofilaments from the previous systole during diastole. In experiments in dogs, our laboratory found that left ventricular filling is necessary to observe the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia.7 Using a prosthetic mitral valve that we forced closed at mid systole to prevent left ventricular filling,8 our laboratory found that the end-diastolic pressure-volume points of normally filling beats shifted upward during pacing-induced ischemia, whereas the end-diastolic points of nonfilling beats did not. Because the previous systole is the same in the nonfilling beat as in the normally filling beat, the end-diastolic pressure-volume point of the nonfilling beat also should have been shifted upward, but it was not. Thus, persistent interaction of myofilaments from the previous systole during diastole appears unlikely to be the sole mechanism of the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia.
These earlier results suggest that another factor contributing to the upward shift may be stretch of the myocardium caused by left ventricular filling. Mechanical stretch of the myocardium causes changes in electrophysiological properties and arrhythmias.9 10 11 12 13 These changes may result from cation (sodium, potassium, and calcium) influx through sarcolemmal stretch-activated channels, which open when the myocardium is stretched abruptly.14 15 The stretch-activated channels have been shown to be opened by physiological levels of tension14 and to admit a small amount of calcium,15 which may permit calcium-activated calcium release of intracellular calcium stores.16
Combining the stretch-activation theory with Grossman et al's theory, we hypothesized that left ventricular filling may cause cation influx through stretch-activated channels and thus increase diastolic sarcoplasmic calcium. The increased calcium may in turn lead to interaction of myofilaments during diastole and thus result in the upward shift of the left ventricular pressure-volume relation during pacing-induced ischemia. As a first step toward testing this hypothesis, we asked whether gadolinium, a blocker of stretch-activated ion channels,12 17 attenuates the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia in dogs.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Surgical Preparation and Instrumentation
Five mongrel dogs weighing 25.1±3.8 kg (SD) were used for analysis. The dogs were premedicated with 5 mg/kg subcutaneous morphine, anesthetized with 100 mg/kg intravenous
-chloralose,
intubated, and ventilated with a mixture of air and oxygen. Anesthesia
was supplemented with 10 mg of intravenous morphine every hour.
Arterial blood gases were analyzed periodically, and the respiratory
rate and oxygen flow were adjusted to keep pH at 7.35 to 7.45,
PO2 >100 mm Hg, and
PCO2 at 35 to 50 mm Hg. Sodium bicarbonate
was infused when necessary. The dogs were placed in the left-side-up
position, and the left thorax was opened at the sixth intercostal
space. The pericardium was opened along the left phrenic nerve, and the
heart was suspended in a pericardial cradle.
To measure high-fidelity
pressures, catheter-tipped micromanometers (5F
Millar) were inserted into the left ventricle, right ventricle, and
left atrium via the femoral artery, jugular vein, and pulmonary vein,
respectively (Fig 1
). Catheters were warmed at 37°C in
a water bath for 12 hours before use; bench tests in our laboratory
have shown that the Millar catheters drift <0.5 mm Hg/5 hours after
being stabilized in this manner.
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To measure left ventricular volume, a
7F, eight-electrode conductance
catheter (Webster Laboratories, Inc) was inserted into the left
ventricle through the left ventricular apex and connected to
electronics (Stiching Leycom, Sigma-5) that converted the conductance
signal into volume. Proper positioning of the conductance catheter was
checked from the contours of the segment volume signals and confirmed
at the postmortem examination. To avoid introducing errors due to
uncertainties in existing methods used to estimate the parallel
conductance volume and slope, , which relates conductance catheter
volume to true left ventricular volume in individual
dogs,18 we used a standard calibration function for the
conductance catheter derived from a similar preparation in our
laboratory by comparing left ventricular conductance catheter volume to
epicardial volume measured with ultrasonic
crystals19 :
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where V is the corrected left ventricular volume (in milliliters) and VCC is the uncorrected conductance catheter volume (in milliliters). Because this calibration is to volume computed with epicardial crystals, it includes the (constant) left ventricular wall volume. As a result, the reported volumes are larger than those of the left ventricular cavity alone, and the ejection fractions are smaller.
To measure coronary arterial flows and to create the coronary stenoses, the short segment of the left anterior descending artery (LAD) just distal to the bifurcation of the first diagonal branch and the proximal segment of the left circumflex artery (LCx) were carefully dissected. Transit-time ultrasonic flow probes (Perivascular Flowprobe H2SB, Transonic Systems Inc) were placed around the arteries and connected to a dual-channel, transit-time ultrasound flowmeter (model T201, Transonic Systems Inc). Specially made small metal vessel occluders7 then were placed around the arteries just distal to the flow probes.
To confirm the absence of impaired systolic segment shortening when making critical coronary stenoses and to assess the diastolic pressure–segment length relation, two pairs of miniature ultrasonic dimension crystals were implanted in areas perfused by the LAD and LCx and connected to a sonomicrometer (Triton Technology). The ultrasonic crystal pairs were aligned perpendicular to the long axis, close to the endocardium.
To control heart rate, a pair of pacing wires was attached to the left atrium and connected to a demand-type stimulator (Medtronic Pacing System Analyzer model 5309).
To obtain a wide range of left ventricular volumes and pressures so that left ventricular end-systolic and end-diastolic pressure-volume relations could be defined, an 8F Fogarty venous thrombectomy balloon catheter was inserted into the inferior vena cava from the femoral vein to provide a transient vena caval occlusion. To be acceptable for analysis, the maximum left ventricular pressure had to be reduced by at least 30 mm Hg by inflating the balloon.
Protocol
The protocol for each dog consisted of six
consecutive
experiments: baseline, coronary stenosis, pacing-induced ischemia,
before gadolinium, gadolinium, and pacing-induced ischemia plus
gadolinium. During each experiment, we obtained left ventricular
diastolic pressure-volume and pressure–segment length loops and the
end-diastolic pressure-volume relation, and we then
compared the shift of the loops and the relation from coronary stenosis
to pacing-induced ischemia (the shift produced by pacing-induced
ischemia) and the shift from gadolinium to pacing-induced ischemia plus
gadolinium (the shift produced by pacing-induced ischemia after
injection of gadolinium).
Before the first experiment, we administered propranolol (0.5 mg/kg) by slow bolus injection to prevent ventricular fibrillation during rapid pacing and to suppress the heightened sympathetic tone associated with anesthesia. In 4 dogs, we then injected 1 mg/kg UL-FS4920 to reduce the heart rate and paced the left atrium at 100 beats per minute (bpm). In the other dog (dog 443), for which UL-FS49 was not available, the baseline heart rate was 133 bpm.
After hemodynamics in each dog stabilized, we recorded data for the baseline experiment. Next, we created the coronary stenoses. To create a coronary stenosis, we adjusted the occluders to narrow each coronary artery until we observed impaired systolic shortening of the corresponding segment length; we then slightly released the occluder so that the stenosis had no detectable effect on systolic shortening. After we made stenoses in both the LAD and the LCx, we recorded data for the "coronary stenosis" experiment. Next, we paced the left atrium at 50 bpm above the baseline rate (150 bpm for the 4 dogs in which the baseline heart rate was 100 bpm and 180 bpm for dog 443) for 3 minutes to create pacing-induced ischemia and abruptly returned the pacing rate to 100 bpm (stopped pacing in dog 443). Two or three seconds later, we recorded data for the "pacing-induced ischemia" experiment.
We then compared the left ventricular pressure-volume loop during pacing-induced ischemia with that during coronary stenosis to confirm that the diastolic portion of the loop during pacing-induced ischemia shifted upward. In 3 dogs, a satisfactory upward shift was not observed on the first pacing-induced ischemia experiment. In these 3 dogs, after waiting at least 10 minutes for hemodynamics to stabilize, we changed the extent of coronary stenosis or the rate of rapid pacing and then repeated coronary stenosis and pacing-induced ischemia experiments. If the pressure-volume loop shifted rightward, we slightly released the occluder associated with increased segment length (LAD if the anterior segment length markedly increased, LCx if lateral length increased, and both if both lengths increased). If the pressure-volume loop did not shift either upward or rightward, we tightened both the LAD and the LCx occluders slightly. If changing the extent of coronary stenosis did not produce an upward shift, we increased the rate of rapid pacing to 160 to 180 bpm. We repeated this procedure until we observed an upward shift of the diastolic pressure-volume relation during pacing-induced ischemia. We were able to make an upward shift on the first pacing-induced ischemia run in 2 dogs and on the second, the third, and the fifth runs in each of the other dogs. (We attempted this procedure in 10 additional dogs but could not obtain a satisfactory upward shift of the diastolic pressure-volume loop; these dogs were not used in the results described in this article but were used in another article in which we analyzed the determinants of the direction and magnitude of the shift of diastolic pressure-volume relation.21 ) Once we achieved satisfactory coronary stenosis, we did not manipulate the occluders during the remaining experiments, and we used coronary stenosis and pacing-induced ischemia data with the occluders in their final position for analysis.
About 10 minutes after the pacing-induced ischemia experiment, we recorded data for the "before gadolinium" experiment to see whether the hemodynamic variables changed from coronary stenosis due to the effect of pacing-induced ischemia or over time. We then injected 20 mg/kg (76 µmol/kg) gadolinium chloride (GdCl3, Sigma), dissolved in saline at a concentration of 20 mg/mL, intravenously for 3 minutes. We determined the dose of gadolinium from previous preliminary experiments, in which 5 and 10 mg/kg gadolinium did not attenuate the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia. Five minutes after the gadolinium injection, we recorded data for the gadolinium experiment. We then paced the left atrium rapidly at the same rate as during pacing-induced ischemia, and after 3 minutes, we recorded data for the "pacing-induced ischemia plus gadolinium" experiment.
This project was approved by the Committee on Animal Research at the University of California and conforms to the guiding principles of the American Physiological Society.
Data Acquisition
During each experiment, we stopped the
ventilator at end
expiration and recorded hemodynamic data for approximately 25 seconds,
in steady state for the first 7 seconds and during vena caval occlusion
for the last 18 seconds to obtain end-systolic and
end-diastolic pressure-volume relations. Data recorded were
left ventricular pressure, right ventricular pressure, left atrial
pressure, coronary blood flows (LAD and LCx), left ventricular volume,
and left ventricular segment lengths (anterior and lateral). These data
were digitized on line with a personal computer (Macintosh II) with a
12-bit AD converter (National Instruments NB-MIO-16) using data
processing software (LABVIEW 2, National Instruments) at
a 200-Hz sampling rate. We uploaded the stored data to an MIPS
minicomputer and analyzed them using software developed in our
laboratory. Data during premature ventricular contractions and the
subsequent beats were excluded from the entire analysis. Fig 2
shows representative analog data during the
six experiments for one dog.
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Stability and Reproducibility of Left Ventricular End-Diastolic
Pressure-Volume Relation During Pacing-Induced Ischemia
To determine
how long the left ventricular
end-diastolic pressure-volume relation was stable during
pacing-induced ischemia, we conducted an experiment using 6 other dogs,
in which left ventricular pressure and volume were recorded during
pacing-induced ischemia without the vena caval occlusion. In this
experiment, both left ventricular end-diastolic pressure
and end-diastolic volume remained stable for at least 30
seconds after rapid pacing in every dog (Fig 3). This
stability allowed us to determine the left ventricular
end-diastolic pressure-volume relation with a brief vena
caval occlusion during pacing-induced ischemia.
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To examine whether the
response of the pressure-volume relation to the
same severity of pacing-induced ischemia was reproducible, we also
conducted an experiment on 4 dogs in which we repeated pacing ischemia
induced by the same coronary stenosis and rapid pacing rate. In this
experiment, the response of the end-diastolic
pressure-volume point was reproducible (Fig 4),
suggesting that the response of the end-diastolic
pressure-volume relation to the same severity of pacing-induced
ischemia is reproducible. (We recorded data only during steady-state
beats in this experiment, so we could not examine the reproducibility
of the end-diastolic pressure-volume relation.)
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Data Analysis
Variables During Steady-State Beats
Hemodynamic variables during steady-state beats were calculated
as the mean of the variables for the first 7 beats.
Stroke volume was calculated as
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where SV is stroke volume, Ved is end-diastolic volume, and Ves is end-systolic volume. End diastole was defined as the starting point of rapid upstroke of the first derivative of left ventricular pressure (dP/dt), and end systole was defined as the point of maximum systolic elastance, computed using Kono et al's iteration method.22
Stroke work was calculated as
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where SW is stroke work, P is left ventricular pressure, and V is left ventricular volume, and the integral is from end diastole to the end diastole of the subsequent beat.
Percent systolic shortening of the segment length was calculated as
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where SS is the percent systolic shortening, EDL is the end-diastolic segment length, and ESL is the end-systolic segment length.
The time constant of left ventricular isovolumic relaxation was obtained by the linear regression of
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where
P is the left ventricular pressure, 
is the estimated
time constant of left ventricular isovolumic relaxation, t is time from
the minimum dP/dt (dP/dtmin) point, and
P0 is the estimated left ventricular pressure at the time
of the dP/dtmin.23 Left ventricular
pressure data from the time of dP/dtmin to the time
when left ventricular pressure equals left atrial pressure were
used.
To test whether changes in the time constant of isovolumic relaxation could account for the upward shift of the pressure-volume relation, we calculated total diastolic time, defined as the time from dP/dtmin to end diastole, and calculated the ratio of total diastolic time to the time constant. A value of this ratio above 3.5 indicates that the ventricle is virtually completely relaxed before end diastole, assuming an exponential pressure fall.24
The End-Systolic Pressure-Volume
Relation and
dp/dtmax–End-Diastolic Volume Relation
To assess left
ventricular contractility, we calculated two
indices, the slope of the end-systolic pressure-volume relation (ESPVR)
and the slope of dP/dtmax to
end-diastolic volume (Ved) relation. To obtain
the slope of ESPVR to end-systolic elastance (Ees), we
applied linear and curvilinear regression to the left ventricular
end-systolic points of the pressure-volume loops during vena caval
occlusion. The linear ESPVR was defined as
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where Pes is the end-systolic pressure, Ves is the end-systolic volume, and Vd is the volume-axis intercept.25 Ees and Vd were estimated using the iteration procedure described by Kono et al.22 The curvilinear ESPVR was defined by the quadratic equation26
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The coefficients a, b, and c were estimated with polynomial regression. The coefficient a represents a measure of the curvilinearity of the relation. Although it was proposed to use the slope of the curvilinear relation at Pes=0 mm Hg as an index of contractility,26 we did not have data at low enough pressures to estimate the slope at 0 mm Hg in all ESPVRs. To avoid problems with extrapolation of the curvilinear ESPVR to zero pressure, we calculated local elastance (dPes/dVes or E'es) located on the ESPVR at a common pressure within the measured range.27 As the common pressure, we used the lowest end-systolic pressure that was commonly observed in all ESPVRs in a given dog. The lowest end-systolic pressure was 77.7±11.6 mm Hg (SD) for the 5 dogs. E'es', the slope of the curvilinear ESPVR at the end-systolic pressure of Pm is
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The quadratic equation provided a significantly better fit of the ESPVR points than did linear regression (the coefficient a in the quadratic equation was significantly different from 0) in 23 of 30 ESPVRs. Because it is now accepted that the ESPVR is curvilinear,26 28 29 we used Ees obtained from the curvilinear regression in these 23 ESPVRs. In other 7 ESPVRs to which the quadratic term was not significant, we used E'es=Ees from the linear regression.
The dP/dtmax-Ved relation was defined as
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where dE/dtmax is the slope of the dP/dtmax-Ved relation, Ved is end-diastolic volume, and VdP/dt is the intercept with the volume axis.30 The dP/dtmax-Ved points during the vena caval occlusion were fit using linear regression.
Diastolic
Pressure-Volume and Pressure–Segment Length Loops
To examine the
shift of the left ventricular pressure-volume and
pressure–segment length loops, the diastolic portions (to end
diastole) of single pressure-volume and pressure–segment length loops
of steady-state beats for the six experiments were plotted and visually
compared in each dog.
The End-Diastolic Pressure-Volume
Relation
The left ventricular end-diastolic pressure-volume
relation was defined as the end-diastolic pressure-volume
points obtained during vena caval occlusion. End-diastolic
pressure-volume points for the six experiments were plotted and
visually compared in each dog. In addition, the shift of the
end-diastolic pressure-volume relation was statistically
examined as described below in "Statistical Analysis."
Statistical Analysis
To test for significant changes in the
hemodynamic variables
caused by interventions, we used a multiple linear regression
implementation of a repeated-measures ANOVA with dummy variables that
account for the interventions and differences between
dogs.31 The specific regression model was
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where y is the dependent variable of interest. The dummy variables St, Pi, Bf, and Gd were defined according to the (0,1) convention. St equaled 0 before coronary stenosis was induced (baseline) and 1 afterward. Pi equaled 0 in the absence of pacing-induced ischemia and 1 in its presence (pacing-induced ischemia and pacing-induced ischemia plus gadolinium). Bf equaled 0 before the before gadolinium experiment (baseline, coronary stenosis, and pacing-induced ischemia) and 1 during and afterward (before gadolinium, gadolinium, and pacing-induced ischemia plus gadolinium). Gd equaled 0 before gadolinium injection (baseline, coronary stenosis, pacing-induced ischemia, and before gadolinium) and 1 afterward (gadolinium and pacing-induced ischemia plus gadolinium). The product of the dummy variables PiGd, which equaled 1 only during pacing-induced ischemia plus gadolinium and 0 otherwise, represents interaction between pacing-induced ischemia and gadolinium. The n-1 dummy variables Di account for between-dog differences by allowing the n=5 dogs to have different mean responses. These dummy variables are defined according to
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The
ai represent the deviation from the
overall mean value for dog i (i=1,. . . ,n-1). The deviation of
dog
n from the overall average is
an=-
ai, i=1,. . . ,n-1.
We report
sd, the square root of the mean square associated
with the ai, as a measure of between-dog
variability. Using this coding, a0 is the mean value over
all dogs during the baseline experiment, and the coefficient
aSt estimates the change from baseline to coronary
stenosis, that is, the effect of coronary stenosis. aPi
estimates the change from coronary stenosis to pacing-induced ischemia,
that is, the effect of pacing-induced ischemia beyond the effect of
coronary stenosis alone. aBf estimates the change from
coronary stenosis to before gadolinium. aGd estimates the
change from before gadolinium to gadolinium, that is, the effect of the
gadolinium injection. The interaction coefficient aPiGd
estimates the additional change from gadolinium to pacing-induced
ischemia plus gadolinium beyond the effect of pacing-induced ischemia
before gadolinium injection (aPi).
To quantify the shifts of the left ventricular end-diastolic pressure-volume relation caused by the interventions in each dog, we used a polynomial to describe the end-diastolic pressure-volume relation32 with dummy variables that account for the interventions. The specific regression model was
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where P is left ventricular end-diastolic pressure and V is left ventricular end-diastolic volume. The dummy variables St, Pi, Bf, and Gd are described above. Using this coding, the coefficients, b3, b2, b1, and b0 estimate the end-diastolic pressure-volume relation curve at baseline, and the coefficients bSt, bPi, bBf, bGd, and bPiGd estimate the amounts of the vertical parallel shifts of the end-diastolic pressure-volume relation caused by the effects encoded by the dummy variables. All end-diastolic pressure-volume points obtained during vena caval occlusion in the six experiments in each dog were put into the equation, and the coefficients were computed by multiple linear regression analysis. Data from each of the 5 dogs were analyzed separately. We then tested each coefficient for the 5 dogs for a significant difference from 0 by t test.
In this study, we especially focused on the change in hemodynamic variables or the shift of the end-diastolic pressure-volume relation from coronary stenosis to pacing-induced ischemia (coefficient aPi or bPi) and the change or the shift from gadolinium to pacing-induced ischemia plus gadolinium beyond that from coronary stenosis to pacing-induced ischemia (coefficient aPiGd or bPiGd). The value of aPiGd or bPiGd does not mean the change or shift from gadolinium to pacing-induced ischemia plus gadolinium but the change or the shift from gadolinium to pacing-induced ischemia plus gadolinium beyond that from coronary stenosis to pacing-induced ischemia. A significant value of aPiGd or bPiGd indicates that the change in hemodynamic variables or the shift of the end-diastolic pressure-volume relation from gadolinium to pacing-induced ischemia plus gadolinium is significantly different from the change or the shift from coronary stenosis to pacing-induced ischemia, that is, that the effect of pacing-induced ischemia on the change or the shift is significantly different before and after gadolinium injection.
All regression coefficients are reported with their associated standard errors. Computations were done with SIGMASTAT (Jandel Scientific). We considered differences significant at P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Changes in Variables During Steady-State Beats and in End-Systolic Elastance
Left ventricular end-diastolic pressure increased from coronary stenosis to pacing-induced ischemia (aPi=9.9 mm Hg) (Table 1
). The increase in
end-diastolic pressure from gadolinium to pacing-induced
ischemia plus gadolinium was smaller by -6.8 mm Hg
(aPiGd=-6.8 mm Hg) than that from coronary stenosis to
pacing-induced ischemia. Thus, the net increase from gadolinium to
pacing-induced ischemia plus gadolinium was
aPi+aPiGd=9.9-6.8=3.1 mm Hg.
Left ventricular
end-diastolic volume and end-diastolic segment
lengths also increased from coronary stenosis to pacing-induced
ischemia. The increase in end-diastolic anterior segment
length from gadolinium to pacing-induced ischemia plus gadolinium was
smaller than the increase from coronary stenosis to pacing-induced
ischemia, but the increases in volume and lateral segment length were
not different. Thus, the left ventricular end-diastolic
pressure-volume or pressure–segment length point was moved upward and
rightward by pacing-induced ischemia before and after gadolinium
injection, but the movement was smaller after gadolinium
injection.
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Regarding left ventricular relaxation, dP/dtmin became less negative and the time constant of left ventricular isovolumic relaxation increased from coronary stenosis to pacing-induced ischemia. The changes in dP/dtmin and the time constant from gadolinium to pacing-induced ischemia plus gadolinium were not significantly different from the changes from coronary stenosis to pacing-induced ischemia. The ratio of total diastolic time to the time constant decreased from coronary stenosis to pacing-induced ischemia, and the decrease from gadolinium to pacing-induced ischemia plus gadolinium was not different from the decrease from coronary stenosis to pacing-induced ischemia. Nevertheless, the ratio was consistently above 4 throughout the experiments. Thus, although left ventricular relaxation was slowed by pacing-induced ischemia both before and after gadolinium injection, this slowed relaxation was not large enough to account for either the increase in end-diastolic pressure caused by pacing-induced ischemia before gadolinium injection or the smaller increase after gadolinium injection.
Some indices of left ventricular systolic
function were reduced by
pacing-induced ischemia, but the reductions were similar before and
after gadolinium injection. These indices were
dP/dtmax, stroke work, and systolic
shortening of segment lengths (Table 1
). Left ventricular
end-systolic
pressure, maximum left ventricular pressure, and stroke volume did not
change during the experiments, nor did the indices of left ventricular
contractility, end-systolic elastance (Ees) and the slope
of the dP/dtmax–Ved
relation (dE/dtmax).
Right ventricular end-diastolic and
maximum pressures did
not change significantly during the experiments (Table 1 and
Fig 2).
No variables changed significantly from coronary stenosis to before gadolinium, indicating that there was no deterioration of hemodynamics caused by the first episode of pacing-induced ischemia or over time.
Left Ventricular Diastolic Pressure-Volume and
Pressure–Segment Length Loops in Steady-State Beats
The
diastolic pressure-volume loop did not shift from baseline to
pacing-induced ischemia in 3 of the 5 dogs but shifted rightward in 2
dogs (dogs 443 and 445) (Fig 5). The diastolic
pressure-volume loop shifted upward from coronary stenosis to
pacing-induced ischemia in 4 dogs and upward and rightward in one dog
(dog 445). After gadolinium injection, the shift of the loop from
gadolinium to pacing-induced ischemia was less upward in every dog.
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The
left ventricular diastolic pressure–segment length loop during
pacing-induced ischemia shifted upward in 2 dogs (dogs 443 and 445) in
at least one of the pressure–segment length loops and shifted upward
and rightward in the 3 other dogs (Fig 6). After the
gadolinium injection, the upward shift of the loop from gadolinium to
pacing-induced ischemia plus gadolinium was smaller in every dog (Table
2).
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Left Ventricular End-Diastolic Pressure-Volume Relation During Vena
Caval Occlusion
The left ventricular end-diastolic pressure-volume
relation obtained during vena caval occlusion shifted upward from
coronary stenosis to pacing-induced ischemia in every dog (Fig
7). After gadolinium injection, the relation shifted
less upward or shifted downward from gadolinium to pacing-induced
ischemia plus gadolinium.
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The quantitative analysis of the end-diastolic pressure-volume relation showed that pacing-induced ischemia had almost no net effect on the end-diastolic pressure-volume relation after gadolinium injection. Specifically, the end-diastolic pressure-volume relation shifted significantly upward from coronary stenosis to pacing-induced ischemia in every dog. (The average value for the 5 dogs of bPi was 2.2±0.6 mm Hg). Gadolinium injection itself (without pacing-induced ischemia) made the relation shift downward (by an average bGd=-2.1±0.6 mm Hg). The shift of the relation from gadolinium to pacing-induced ischemia plus gadolinium was significantly smaller than the shift from coronary stenosis to pacing-induced ischemia in every dog (by an average bPiGd=-2.1±0.4 mm Hg). Thus, the net shift of the end-diastolic pressure-volume relation caused by pacing-induced ischemia in the presence of gadolinium was bPi+bPiGd=2.2-2.1=0.1 mm Hg.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study in dogs shows that gadolinium, a blocker of stretch-activated ion channels, attenuates the upward shift of the left ventricular diastolic pressure-volume relation during pacing-induced ischemia. In our experiments, the left ventricular end-diastolic pressure-volume relation shifted upward by 2.2 mm Hg from coronary stenosis to pacing-induced ischemia, but after injection of 20 mg/kg gadolinium, the shift from gadolinium to pacing-induced ischemia plus gadolinium was smaller by -2.1 mm Hg, yielding a net effect of pacing-induced ischemia of only 0.1 mm Hg. Similar results were obtained from qualitative inspection of the diastolic portion of the pressure-volume and pressure-segment length loops. Thus, gadolinium appeared, at least partially, to block the effect of pacing-induced ischemia on the diastolic pressure-volume relation. These results suggest that stretch-activated ion channels may contribute to the upward shift of the left ventricular diastolic pressure-volume relation. Although we do not have direct evidence, this study combined with a previous study from our laboratory7 which showed that left ventricular filling is necessary to observe an upward shift during pacing-induced ischemia, leads us to speculate that left ventricular filling may cause stretch-activated cation influx into the ischemic myocardium, which may increase diastolic sarcoplasmic calcium and induce interaction of myofilaments during diastole, resulting in an upward shift of the diastolic pressure-volume relation.
One might think that our hypothesis is contradicted by previous studies that investigated the diastolic chamber distensibility of isolated left ventricles.5 33 34 35 These studies showed a decrease in diastolic chamber distensibility (which is analogous to the upward shift of the pressure-volume relation) during ischemia in isovolumically beating rabbit or ferret hearts, in which the stretch of the myocardium is negligible. However, there appears to be some difference in the mechanism of decreased distensibility of the left ventricle (or the upward shift of the diastolic pressure-volume relation) between isolated rabbit or ferret hearts and in situ dog or human heart. In previous studies that used the in situ dog or human heart, the time constant of left ventricular relaxation during ischemia was from 40 to 70 milliseconds, which is not slow enough to affect end-diastolic pressure.2 3 36 37 38 39 In contrast, the time constant of left ventricular relaxation in the rabbit heart increased from 30 to 50 milliseconds (during baseline) to 150 to 225 milliseconds (during ischemia), which is large enough to affect the end-diastolic pressure at the heart rate of 2 to 4 Hz,33 34 because the diastolic interval is short compared with the time constant of isovolumic relaxation. Thus, the role of slowed left ventricular relaxation on the end-diastolic pressure-volume relation during ischemia in rabbit or ferret heart appears to be much more important than in dog or human heart. The changes in relaxation that we observed during ischemia were not large enough to explain our findings.
Another finding in this study that may support our stretch-activation
hypothesis is that the slope of the end-diastolic
pressure-volume relation was steeper during pacing-induced ischemia
than during coronary stenosis, that is, the increase in
end-diastolic pressure from coronary stenosis to
pacing-induced ischemia at the same end-diastolic volume
was greater at a larger end-diastolic volume than at a
smaller volume (Fig 7). This finding is consistent with those
in
previous animal40 and human38 studies that
investigated the end-diastolic pressure-volume relation
during brief coronary occlusion. Although previous authors suggested
that this finding may be evidence that the upward shift of the
diastolic pressure-volume relation is caused by ventricular interaction
or pericardial constraint because the upward shift was eliminated by
right ventricular unloading,38 40 their suggestion is
unlikely to explain our results for two reasons. First, we used
open-pericardium hearts, in which right ventricular interaction would
be minimized.41 Second, neither right ventricular
end-diastolic pressure nor right ventricular maximum
pressure changed throughout the experiments. In contrast, our findings
can be explained by the stretch-activation hypothesis. Because left
ventricular filling—the stretch of the myocardium—would be larger
at
a larger ventricular volume than at a smaller volume, the activation of
the myocardium—the increase in end-diastolic
pressure—would be greater.
There are some potential problems that merit discussion when
interpreting our results. The first potential problem is that the
severity of ischemia may have not been the same in the two
pacing-induced ischemia studies (before and after the gadolinium
injection). The left ventricular diastolic pressure-volume relation is
very sensitive to the severity of ischemia, so if the severity of
pacing-induced ischemia was different before and after gadolinium
injection, the upward shift could have been different independent of
the effect of gadolinium. However, in our experiments, coronary flows
(LAD and LCx), which were reduced by approximately 30% by stenosis,
did not change afterward (Table 1). We also recorded coronary
flows
during the rapid pacing before and after gadolinium injection (not
shown in Table 1), and they were not significantly different
from each
other (13±3 [SEM] versus 15±3 mL/min in LAD,
22±3 versus 21±2
mL/min in LCx). Thus, coronary flows during coronary stenosis, rapid
pacing, and pacing-induced ischemia before gadolinium injection were
similar to those after gadolinium injection. In addition, the duration
and the rate of rapid pacing were exactly the same before and after the
gadolinium injection. Therefore, this potential problem does not
explain the results of our study.
The second potential problem is that the upward shift of the diastolic pressure-volume relation might have been attenuated by an ischemic preconditioning effect. Ischemic preconditioning, defined as one or more brief episodes of ischemia (usually induced by coronary occlusion or aortic cross-clamping), has been known to increase myocardial tolerance to subsequent sustained ischemia.42 43 Because the pacing-induced ischemia plus gadolinium experiment was always done after the pacing-induced ischemia experiment in our protocol, it could be that the attenuation of the upward shift of the diastolic pressure-volume relation was due to the preconditioning effect and not to the gadolinium. However, whereas transient ischemia has the effect of reducing myocardial infarct size and preserving ventricular systolic function after a subsequent prolonged ischemic episode, it has not been shown whether a transient pacing-induced ischemia has the preconditioning effect of altering the diastolic pressure-volume relation during the second pacing-induced ischemia. Our control study, which showed that the response of the end-diastolic pressure-volume points to repeated pacing-induced ischemia was reproducible, suggests that there was no preconditioning effect in our pacing-induced ischemia protocol. Furthermore, in previous studies that investigated the effect of slow calcium channel blockers using a protocol similar to ours, the second episode of pacing-induced ischemia in the presence of the blockers did not attenuate the upward shift of the diastolic pressure-volume relation.4 44 Thus, the preconditioning effect also appears unlikely to explain our results.
The third potential problem is that gadolinium may have attenuated the upward shift of the diastolic pressure-volume relation by mechanisms other than blocking stretch-activated ion channels because gadolinium also blocks slow calcium channels.45 46 However, the direct effect of gadolinium on slow calcium channels is not likely to explain the attenuation of the upward shift of the diastolic pressure-volume relation during pacing-induced ischemia because slow calcium channel blockers such as verapamil4 or nifedipine44 did not attenuate the upward shift. There is also the possibility that gadolinium impaired left ventricular systolic function,47 probably through blocking slow calcium channels, and thereby attenuated the upward shift of the diastolic pressure-volume relation. It has been shown that if left ventricular systolic function is severely impaired by coronary occlusion or severe pacing-induced ischemia, the diastolic pressure-volume or pressure-segment length relation does not shift upward but shifts rightward or downward.36 48 We also have shown in the analysis of these dogs and in other dogs in which we did not observe an upward shift during pacing-induced ischemia that left ventricular contractility, assessed by Ees or dE/dtmax, during pacing-induced ischemia determines the shift of the end-diastolic pressure-volume relation21 ; the more left ventricular contractility decreases, the more the end-diastolic pressure-volume relation shifts rightward and downward. However, in the present study, most systolic function indices during pacing-induced ischemia, including Ees and dE/dtmax, were similar before and after the gadolinium injection. Thus, impaired systolic function also appears unlikely to explain the attenuation of the upward shift of the diastolic pressure-volume relation after gadolinium injection. Nevertheless, because gadolinium (without pacing-induced ischemia) increased end-diastolic and end-systolic volumes and shifted the end-diastolic pressure-volume relation downward, the possibility that some mechanism other than block of stretch-activated channels attenuated the upward shift of the diastolic pressure-volume relation may not be excluded.
The fourth potential problem is that we only have data for 5 dogs and the response to gadolinium varied from dog to dog. This small sample size (and the associated low statistical power) would be a problem if we were drawing a negative conclusion about the effect of gadolinium on the shift of the diastolic pressure-volume relation during pacing-induced ischemia. We were, however, able to formulate the statistical analysis in a way that the effects of gadolinium during pacing-induced ischemia were statistically significant despite the small sample size. Thus, the issue of power is moot. Moreover, the statistical analysis explicitly allows for variability in response between animals.
The fifth problem is that using our model of pacing-induced ischemia, which is very similar to those used in previous studies,2 3 4 36 48 the upward shift of the end-diastolic pressure-volume relation had a small magnitude (2.2 mm Hg on average) and was difficult to get (obtainable in only 5 dogs out of 15). The first reason for the small magnitude of the upward shift reported in our study may be our method of analysis, which assumed that the shift of the pressure-volume relation is vertically parallel in each dog. Although this analysis can estimate the overall shifts of the end-diastolic pressure-volume relation between six experiments, the parallel shift assumption underestimates the magnitude of the shift. The slope of the end-diastolic pressure-volume relation looks steeper during pacing-induced ischemia than during coronary stenosis as described above. To avoid this problem, we conducted an additional analysis. We fitted end-diastolic pressure-volume points during four conditions (coronary stenosis, pacing-induced ischemia, gadolinium, and pacing-induced ischemia plus gadolinium) separately to an exponential equation that is generally used to characterize the end-diastolic pressure-volume relation:
 |
where Ped is left ventricular
end-diastolic pressure and Ved is left
ventricular end-diastolic volume.49 This curve
fitting was more accurate than a simple parallel shift (Fig 7).
As an
index of the magnitude of the upward shift before gadolinium injection,
we calculated end-diastolic pressure during pacing-induced
ischemia minus the pressure during coronary stenosis at the largest
end-diastolic volume common to both conditions (the largest
overlapping volume). Likewise, as an index of the upward shift after
gadolinium injection, we calculated end-diastolic pressure
during pacing-induced ischemia plus gadolinium minus the pressure
during gadolinium at the largest end-diastolic volume
common to both conditions. The upward shift index from this
analysis was significantly higher before than after gadolinium
injection (Table 3). Thus, the result is consistent with
that from the analysis using parallel shift assumption.
|
The second reason for the small magnitude of the upward shift may be that we assessed the shift of the end-diastolic pressure-volume relation but not the pressure-volume loop. Most previous investigators studied only the pressure-volume or pressure-segment length loops in steady-state beats.2 3 4 36 48 The shift value of the end-diastolic pressure-volume relation is smaller than appears from inspecting the diastolic pressure-volume loops because pressure-volume or pressure-length loop can be affected by an ischemia-induced decrease in the rate of left ventricular relaxation, which result in elevated early diastolic pressure.50 Therefore, the slope of the end-diastolic pressure-volume relation is steeper than the slope of the diastolic pressure-volume loop during ischemia,51 and a small increase in end-diastolic volume greatly increases end-diastolic pressure.
The third reason for the small magnitude of the upward shift may be that it is difficult to control the severity of ischemia (for example, adjusting the coronary stenosis) in the in situ heart. The difficulty of getting an upward shift of the diastolic pressure-volume relation during ischemia was also reported in a recent study,48 and the magnitude of the shift appears similar to those in previous studies.3 4 36 Despite the small magnitude of the upward shift and the difficulty in producing the upward shift of the end-diastolic pressure-volume relation, the finding that the upward shift, though small, was attenuated by gadolinium is an important observation that may help us understand the mechanism of the upward shift during ischemia in the in situ heart.
Summary
We have shown that gadolinium attenuates the upward
shift of the
left ventricular diastolic pressure-volume relation during
pacing-induced ischemia. This result suggests that the cation influx
through stretch-activated ion channels may contribute to the upward
shift of the diastolic pressure-volume relation during pacing-induced
ischemia.
|
Acknowledgments |
|---|
This work was supported by National Institutes of Health Grant HL-25869. We thank James Stoughton for technical assistance, Steve Sizemore, Franklin Cook, and Vic Hargrave for help with the computers, and Mimi Zeiger for helpful comments on drafts of the manuscript.
|
Footnotes |
|---|
This work was presented in abstract form at the American Heart Association, 66th Scientific Sessions, November 1993, Atlanta, Ga.
Received September 19, 1994; accepted October 11, 1994.
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References |
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