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Distribution of intracellular, extracellular, and intravascular contrast media for magnetic resonance imaging in hearts subjected to reperfused myocardial infarction
Distribution of Intracellular, Extracellular, and Intravascular Contrast Media for Magnetic Resonance Imaging in Hearts Subjected to Reperfused Myocardial Infarction Michael F. Wendland, PhD, Maythem Saeed, DVM, PhD, Jean-Francois Geschwind, MD, Jeffrey S. Mann, PhD, Robert C. Brasch, MD, Charles B. Higgins, MD ?
hree types of magnetic resonance (blR) imaging contrast agents with differing myocardial distribution properties were examined by !nversion-recovery gradient-recalled echoplanar imaging to determine the dependence of ct!anges in spin-lattice relaxation rate (AR1 = 1/Tlpost - 1/Tlpr e) on time elapsed since administration of the agent in rats subjected to reperfused myocardial infarction. This work was conducted to test the hypothesis that values for the ratio of AR1 in the myocardium to AR1 in the blood provide information regarding the tissue distribution of exogenously administered media that can be used to distinguish infarcted from normal myocardium and to characterize the severity of damage in the injured zone. In this evaluation, we assumed that
T
A R l m y o / A R I b l o o d = (M)my o • r l m y o / ( M ) b l o o d X rlbloo d
,
(1)
where [M] and rl are the concentration of the paramagnetic metal and the metal's apparent local longitudinal relaxivity in the indicated tissue, respectively. If the exchange of M between blood and tissue is much faster than the clearance of M from the blood, then (bl)myo/(M)blood will initially increase until reaching a "dynamic equilibrium" phase, in which the concentrations of bl in its blood and tissue distribution volumes are approximately equal. Equation 1 then becomes [1]: ARlmyo/ARlblood
= Vmy o x r l m y o / V b l o o d X rlbloo d
,
(2)
where V is the indicated tissue distribution volume for bl and gblood equals one minus.the hematocrit, or approximately 0.6. If the local relaxivities for M in the myocardium and the blood are equal, then Vmyo is given by 0.6 x ARlmyo/ARlblood. Alternatively, tile exchange of M between blood and tissue may be much slower than the clearance of M from the blood, particularly in reperfused infarcted myocardium, if perfusion is poor. In this case, tile time course for ARlmyo/ARlblood would be much different.
$402
From the Department of Radiology, University of California, San Francisco, CA. This work was supported by a grant from the Radiology Research and Education Foundation at the University of California. Address reprint requests to M. F. Wendland. PhD, Department of Radiology, Box 0628, University of California, 505 Parnassus Ave., San Francisco, CA 94143. Acad
Radio11996;3:$402-S404
9 1996, Association of University Radiologists
Vol. 3, Suppl. 2, August 1996
D I S T R I B U T I O N O F MR C O N T R A S T M E D I A IN H E A R T S
MATERIALS AND METHODS
All experimental procedures were performed in accordance with National Institutes of Health guidelines for humane handling of animals and received prior approval from the Committee of Animal Research at our institution. Twenty-four Sprague-Dawley rats (Simonsen Laboratories, Gilroy, CA) were prepared by occlusion of the anterior branch of the left main coronary artery for 60 min followed by reperfusion for 60 min before administration of contrast agents. All animals were instrumented for electrocardiographically gated acquisition (Accusync 6L, South Natick, bib,) and placed in a 2.0-T Omega chemical-shift imaging system (Bruker Instruments, Fremont, CA). A blipped echoplanar imaging sequence, preceded by a nonselective composite (90x-180y-90x) radiofrequency H pulse with subsequent gradient spoiling and a variable delay (inversion time [TI]) for relaxation evolutiofi, was used to estimate T1 by the nullpoint technique using the relationship In(2) = Tlnull/T1. A set of 10-45 images was obtained within a 2-min interval in which the TI interval varied typically between 10 and 1,000 msec to define the inversion-recovery null point for each region of interest (left ventricle chamber blood, normal myocardium, and reperfused infarcted myocardium). T1 values were determined in this manner before and at 5-min intervals after administering one of the following compounds: gadodiamide (Omniscan; Nycomed, Oslo, Norway), a low-molecular-weight agent with extracellular distribution; albumin gadopentetate dimeglumine, (prepared as described in [2]), a macromolecular compound with intravascular distribution; and manganese chloride solution (prepared by dissolving crystalline McC12 [Sigma Chemical, St. Louis, MO] in distilled water), the salt of a paramagnetic divalent cation that penetrates myocardial cells. RESULTS
Gadodiamide caused significant change in R1 in all regions of interest, with the greatest effect in reperfused infarcted myocardium, followed in decreasing order by left ventricular blood and normal myocardium. The AR1 observed for each zone decreased proportionately for all three region~'during the 30-min observation period consonant with a 25-min clearance half-time and efficient exchange of the agent between tissue and blood compartments.'i Consequently, plots of the AR1 ratio (myocardium/blood) were constant over time (Fig. 1) for both reperfused infarcted and uninfarcted myocar-
9 []
2
normal myocardium reperfused infarction
j
A
i
•
A R l m 7 ~ 1.5 ARlbl~176
1
0.5
0
ii
i
4
14 19 t i m e (rain)
ii 24
29
FIGURE 1. Change in the &R1 ratio (myocardium/blood) after administration of 0.1 mmol/kg gadodiamide to rats (n = 8) with reperfused myocardial infarction. Note that for both infarcted and uninfarcted regions, the ratio of ARf values is constant over time but is much greater for the infarcted zone.
dial regions. The characteristic value for the AR1 ratio was approximately 1.7 for infarcted and 0.35 for normal myocardium, consistent with tissue distribution volumes for gadodiamide of 1.0 and 0.2, respectively. These values suggest that essentially all myocardial cells in the infarcted zone fail to exclude the contrast agent and may be considered nonviable. The apparent distribution volume in normal myocardium is much less than that found in the dog using radiotabeled gadopentetate diineglumine, 0.35 [3], and may imply a reduction in the local relaxivity (rlmyo) by limited water exchange between interstitial and cellular compartments. Gadopentetate dimeglumine albumin caused the greatest change in R1 in the blood and much smaller changes in the normal and reperfused infarcted zones. Thereafter, the AR1 in the blood decreased very slowly during the 60-min examination period, consistent with an extrapolated clearance half-time of approximately 2 hr. A similar slow decrease in AR1 was noted in the normal myocardium but not in the reperfused infarction, which showed an increasing AR1 over time, indicating leakage through the damaged vasculature and accumulation of gadopentetate dimeglumine albumin in the infarcted zone. The AR1 ratio of myocardium to blood was constant over time at a value of 0.1 in normal myocardium, similar to previous restllts [4], and it increased toward an apparent limit of approximately 0.6 in the reperfused infarction (Fig. 2). If it is considered that the concentrations of gadolinium in the myocardial and blood distribution volumes equilibrate w h e n the endpoint is reached, a tissue distribution volume of approximately 0.36
$403
WENDLAND
ET AL.
Vol. 3, Suppl. 2, August 1996
35
1~ normal myocardium reperfused infarction
AR 1m:/o
30 1 ARlm),o 25
0.8
ARlblood 0.6
9 []
normal myocardium infarcted myocardium
ARlbloo d 20
r1 I
0.4 10
0.2-
5
_
0
4
9 14 19 24 29 39 49 59 time (min)
FIGURE 2. Change in the ~R1 ratio after administration of 0.02 mmol/kg gadopentetate dimeglumine albumin to rats (n = 8) with reperfused infarction. Note that values for normal myocardium are constant over time and low, consistent with vascular distribution of the compound; in reperfused infarction, values increase over time, showing leakage of the agent into the damaged tissue.
would be:indicated by the AR1 ratio for the reperfused infarction. This value is substantially less than the anticipated limiting AR1 ratio value of 1.7 (i.e., the value consistentwith a tissue distribution of 1.0 in the reperfused_ infarcted region when rlmyo/rlblood is unity), suggesting that the macromolecular compound is excluded from cellular spaces. Other explanations for the low endpoint include the following: (1) a partially active lymphatic system provides an additional pathway out of the tissue for the macromolecule such that keftlux is greater than kinflux, preventing equilibration of the compound between tissue and blood distribution volumes when the dynamic "steady state" is reached and (2) the macromolecule is prevented from fully penetrating available tissue spaces because of elevated interstitial pressure. Manganese chloride produced a much greater change in R1 in all myocardial zones than in the blood, and initially, ARls in normal and reperfused infarction were equal. In blood, AR1 decreased rapidly, consistent with a clearance half-time of less than 10 min for manganese. In normal myocardium, AR1 did not change appreciably from its initial high value during 30 rain of observation. In reperfused infarcted myocardium, AR1 exhibited a substantial decrease over time, consistent with a tissue clearance half-time of approximately 20 rain. These findings indicate that manganese is rapidly (within 5,rain) taken up by viable myocardial cells and retained; {in reperfused infarcted tissue, manganese is rapidly distributed throughout the tissue but is not retained by nonviable cells and is efficiently cleared /
$404
9
4
9
14 19 time (min)
24
29
FIGURE 3. Change in the AR1 ratio after administration of 0.025 mmogkg manganese chloride to rats (n = 8) with reperfused myocardial infarction. Note that values are high, consistent with distribution of manganese into the entire tissue volume and increased relaxivity in tissue versus blood due to binding of manganese to macromolecules.
from the tissue, but more slowly than it is cleared from the blood. Consequently, the plot of AR1 ratio versus time exhibited an exponential increase for normal myocardium (due to the clearance from blood) and a much less steep rise for reperfused infarcted myocardium (Fig. 3). CONCLUSIONS
We conclude that temporal monitoring of the AR1 ratio of myocardium to blood after administration of contrast media provides information regarding the distribution properties of the exogenous agent in tile myocardium. Because the distribution of such compounds differs in normal versus reperfused infarcted myocardium, it is possible to identify the injured zone on tile basis of these differences regardless of the particular distribution properties of the administered agent. Importantly, using clinically approved compounds such as gadodiamide, it may be possible to crudely quantify the fraction of nonviable cells within the infarcted territory. REFERENCES 1. Dean PD, Niemi P, Kivisaari L, Kormano M. Comparative pharmacokinetics of gadolinium DTPA and gadolinium chloride. Invest Radiol 1988; 23[suppl 1]:$258-$260. 2. Schmiedl U, Moseley ME, Sievers R, et al. Magnetic resonance imaging of myocardial infarction using albumin-(Gd-DTPA), a macromolecular bloodvolume contrast agent in a rat model. InvestRadio11987;22:713-721. 3. Tong CY, Prato FS, Wisenberg G, et al. Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn Reson Med 1993;30:337-346. 4. Wendland MF, Saeed M, Yu KK, et al. Inversion recovery EPI of bolus transit in rat myocardium using intravascular and extravascular gadolinium-based MR contrast media: dose effects on peak signal enhancement. Magn Reson Med 1994;32:319-329.
hree types of magnetic resonance (blR) imaging contrast agents with differing myocardial distribution properties were examined by !nversion-recovery gradient-recalled echoplanar imaging to determine the dependence of ct!anges in spin-lattice relaxation rate (AR1 = 1/Tlpost - 1/Tlpr e) on time elapsed since administration of the agent in rats subjected to reperfused myocardial infarction. This work was conducted to test the hypothesis that values for the ratio of AR1 in the myocardium to AR1 in the blood provide information regarding the tissue distribution of exogenously administered media that can be used to distinguish infarcted from normal myocardium and to characterize the severity of damage in the injured zone. In this evaluation, we assumed that
T
A R l m y o / A R I b l o o d = (M)my o • r l m y o / ( M ) b l o o d X rlbloo d
,
(1)
where [M] and rl are the concentration of the paramagnetic metal and the metal's apparent local longitudinal relaxivity in the indicated tissue, respectively. If the exchange of M between blood and tissue is much faster than the clearance of M from the blood, then (bl)myo/(M)blood will initially increase until reaching a "dynamic equilibrium" phase, in which the concentrations of bl in its blood and tissue distribution volumes are approximately equal. Equation 1 then becomes [1]: ARlmyo/ARlblood
= Vmy o x r l m y o / V b l o o d X rlbloo d
,
(2)
where V is the indicated tissue distribution volume for bl and gblood equals one minus.the hematocrit, or approximately 0.6. If the local relaxivities for M in the myocardium and the blood are equal, then Vmyo is given by 0.6 x ARlmyo/ARlblood. Alternatively, tile exchange of M between blood and tissue may be much slower than the clearance of M from the blood, particularly in reperfused infarcted myocardium, if perfusion is poor. In this case, tile time course for ARlmyo/ARlblood would be much different.
$402
From the Department of Radiology, University of California, San Francisco, CA. This work was supported by a grant from the Radiology Research and Education Foundation at the University of California. Address reprint requests to M. F. Wendland. PhD, Department of Radiology, Box 0628, University of California, 505 Parnassus Ave., San Francisco, CA 94143. Acad
Radio11996;3:$402-S404
9 1996, Association of University Radiologists
Vol. 3, Suppl. 2, August 1996
D I S T R I B U T I O N O F MR C O N T R A S T M E D I A IN H E A R T S
MATERIALS AND METHODS
All experimental procedures were performed in accordance with National Institutes of Health guidelines for humane handling of animals and received prior approval from the Committee of Animal Research at our institution. Twenty-four Sprague-Dawley rats (Simonsen Laboratories, Gilroy, CA) were prepared by occlusion of the anterior branch of the left main coronary artery for 60 min followed by reperfusion for 60 min before administration of contrast agents. All animals were instrumented for electrocardiographically gated acquisition (Accusync 6L, South Natick, bib,) and placed in a 2.0-T Omega chemical-shift imaging system (Bruker Instruments, Fremont, CA). A blipped echoplanar imaging sequence, preceded by a nonselective composite (90x-180y-90x) radiofrequency H pulse with subsequent gradient spoiling and a variable delay (inversion time [TI]) for relaxation evolutiofi, was used to estimate T1 by the nullpoint technique using the relationship In(2) = Tlnull/T1. A set of 10-45 images was obtained within a 2-min interval in which the TI interval varied typically between 10 and 1,000 msec to define the inversion-recovery null point for each region of interest (left ventricle chamber blood, normal myocardium, and reperfused infarcted myocardium). T1 values were determined in this manner before and at 5-min intervals after administering one of the following compounds: gadodiamide (Omniscan; Nycomed, Oslo, Norway), a low-molecular-weight agent with extracellular distribution; albumin gadopentetate dimeglumine, (prepared as described in [2]), a macromolecular compound with intravascular distribution; and manganese chloride solution (prepared by dissolving crystalline McC12 [Sigma Chemical, St. Louis, MO] in distilled water), the salt of a paramagnetic divalent cation that penetrates myocardial cells. RESULTS
Gadodiamide caused significant change in R1 in all regions of interest, with the greatest effect in reperfused infarcted myocardium, followed in decreasing order by left ventricular blood and normal myocardium. The AR1 observed for each zone decreased proportionately for all three region~'during the 30-min observation period consonant with a 25-min clearance half-time and efficient exchange of the agent between tissue and blood compartments.'i Consequently, plots of the AR1 ratio (myocardium/blood) were constant over time (Fig. 1) for both reperfused infarcted and uninfarcted myocar-
9 []
2
normal myocardium reperfused infarction
j
A
i
•
A R l m 7 ~ 1.5 ARlbl~176
1
0.5
0
ii
i
4
14 19 t i m e (rain)
ii 24
29
FIGURE 1. Change in the &R1 ratio (myocardium/blood) after administration of 0.1 mmol/kg gadodiamide to rats (n = 8) with reperfused myocardial infarction. Note that for both infarcted and uninfarcted regions, the ratio of ARf values is constant over time but is much greater for the infarcted zone.
dial regions. The characteristic value for the AR1 ratio was approximately 1.7 for infarcted and 0.35 for normal myocardium, consistent with tissue distribution volumes for gadodiamide of 1.0 and 0.2, respectively. These values suggest that essentially all myocardial cells in the infarcted zone fail to exclude the contrast agent and may be considered nonviable. The apparent distribution volume in normal myocardium is much less than that found in the dog using radiotabeled gadopentetate diineglumine, 0.35 [3], and may imply a reduction in the local relaxivity (rlmyo) by limited water exchange between interstitial and cellular compartments. Gadopentetate dimeglumine albumin caused the greatest change in R1 in the blood and much smaller changes in the normal and reperfused infarcted zones. Thereafter, the AR1 in the blood decreased very slowly during the 60-min examination period, consistent with an extrapolated clearance half-time of approximately 2 hr. A similar slow decrease in AR1 was noted in the normal myocardium but not in the reperfused infarction, which showed an increasing AR1 over time, indicating leakage through the damaged vasculature and accumulation of gadopentetate dimeglumine albumin in the infarcted zone. The AR1 ratio of myocardium to blood was constant over time at a value of 0.1 in normal myocardium, similar to previous restllts [4], and it increased toward an apparent limit of approximately 0.6 in the reperfused infarction (Fig. 2). If it is considered that the concentrations of gadolinium in the myocardial and blood distribution volumes equilibrate w h e n the endpoint is reached, a tissue distribution volume of approximately 0.36
$403
WENDLAND
ET AL.
Vol. 3, Suppl. 2, August 1996
35
1~ normal myocardium reperfused infarction
AR 1m:/o
30 1 ARlm),o 25
0.8
ARlblood 0.6
9 []
normal myocardium infarcted myocardium
ARlbloo d 20
r1 I
0.4 10
0.2-
5
_
0
4
9 14 19 24 29 39 49 59 time (min)
FIGURE 2. Change in the ~R1 ratio after administration of 0.02 mmol/kg gadopentetate dimeglumine albumin to rats (n = 8) with reperfused infarction. Note that values for normal myocardium are constant over time and low, consistent with vascular distribution of the compound; in reperfused infarction, values increase over time, showing leakage of the agent into the damaged tissue.
would be:indicated by the AR1 ratio for the reperfused infarction. This value is substantially less than the anticipated limiting AR1 ratio value of 1.7 (i.e., the value consistentwith a tissue distribution of 1.0 in the reperfused_ infarcted region when rlmyo/rlblood is unity), suggesting that the macromolecular compound is excluded from cellular spaces. Other explanations for the low endpoint include the following: (1) a partially active lymphatic system provides an additional pathway out of the tissue for the macromolecule such that keftlux is greater than kinflux, preventing equilibration of the compound between tissue and blood distribution volumes when the dynamic "steady state" is reached and (2) the macromolecule is prevented from fully penetrating available tissue spaces because of elevated interstitial pressure. Manganese chloride produced a much greater change in R1 in all myocardial zones than in the blood, and initially, ARls in normal and reperfused infarction were equal. In blood, AR1 decreased rapidly, consistent with a clearance half-time of less than 10 min for manganese. In normal myocardium, AR1 did not change appreciably from its initial high value during 30 rain of observation. In reperfused infarcted myocardium, AR1 exhibited a substantial decrease over time, consistent with a tissue clearance half-time of approximately 20 rain. These findings indicate that manganese is rapidly (within 5,rain) taken up by viable myocardial cells and retained; {in reperfused infarcted tissue, manganese is rapidly distributed throughout the tissue but is not retained by nonviable cells and is efficiently cleared /
$404
9
4
9
14 19 time (min)
24
29
FIGURE 3. Change in the AR1 ratio after administration of 0.025 mmogkg manganese chloride to rats (n = 8) with reperfused myocardial infarction. Note that values are high, consistent with distribution of manganese into the entire tissue volume and increased relaxivity in tissue versus blood due to binding of manganese to macromolecules.
from the tissue, but more slowly than it is cleared from the blood. Consequently, the plot of AR1 ratio versus time exhibited an exponential increase for normal myocardium (due to the clearance from blood) and a much less steep rise for reperfused infarcted myocardium (Fig. 3). CONCLUSIONS
We conclude that temporal monitoring of the AR1 ratio of myocardium to blood after administration of contrast media provides information regarding the distribution properties of the exogenous agent in tile myocardium. Because the distribution of such compounds differs in normal versus reperfused infarcted myocardium, it is possible to identify the injured zone on tile basis of these differences regardless of the particular distribution properties of the administered agent. Importantly, using clinically approved compounds such as gadodiamide, it may be possible to crudely quantify the fraction of nonviable cells within the infarcted territory. REFERENCES 1. Dean PD, Niemi P, Kivisaari L, Kormano M. Comparative pharmacokinetics of gadolinium DTPA and gadolinium chloride. Invest Radiol 1988; 23[suppl 1]:$258-$260. 2. Schmiedl U, Moseley ME, Sievers R, et al. Magnetic resonance imaging of myocardial infarction using albumin-(Gd-DTPA), a macromolecular bloodvolume contrast agent in a rat model. InvestRadio11987;22:713-721. 3. Tong CY, Prato FS, Wisenberg G, et al. Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn Reson Med 1993;30:337-346. 4. Wendland MF, Saeed M, Yu KK, et al. Inversion recovery EPI of bolus transit in rat myocardium using intravascular and extravascular gadolinium-based MR contrast media: dose effects on peak signal enhancement. Magn Reson Med 1994;32:319-329.