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Experimental Studies |
1 From the Medical Institute (C.W., K.H., G.E., W.R.B.) and the Physical Institute, (E.K., K.H.H., M.N., S.V., A.H.), University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany . Received February 1, 1999; revision requested March 23; final revision received July 27; accepted August 2. C.W., K.H.H., M.N., and W.R.B. supported in part by grant SFB 355 and Graduiertenkolleg "NMR" HA 1232/8-1 of the Deutsche Forschungsgemeinschaft and of the Forschungsfonds der Universitätsklinik Mannheim/Heidelberg (Projekt 42). Address reprint requests to W.R.B. (e-mail: waller@physik.uni-wuerzburg.de).
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Abstract |
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 TOP Abstract IntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXReferences |
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MATERIALS AND METHODS: Measurement of perfusion was based on the perfusion-sensitive T1 relaxation after magnetic spin labeling of water protons. RBV was determined from steady-state measurements of T1 before and after administration of an intravascular contrast agent. The colored microsphere technique was used as a reference method for perfusion measurement. RBV and perfusion maps were obtained with the rats at rest and during administration of 3 mg of adenosine phosphate per kilogram of body weight per minute.
RESULTS: At MR imaging, perfusion during resting conditions was 3.5 mL/g/min ± 0.1 (SEM), and RBV was 11.6% ± 0.6 (SEM). Adenosine phosphate significantly increased perfusion to 4.5 mL/g/min ± 0.3 (SEM) and decreased mean arterial pressure from 120 mm Hg to 65 mm Hg, which implies a reduction of coronary resistance to 40% of baseline. RBV increased consistently to 23.8% ± 0.6 (SEM).
CONCLUSION: The study results show that quantitative mapping of perfusion and RBV may be performed noninvasively by means of MR imaging in the intact animal. The presented method allows determination of vasodilative and perfusion reserve, which reflects the in vivo regulation of coronary microcirculation for a given stimulus.
Index terms: Adenosine • Blood, flow dynamics, 511.91 • Blood, volume, 511.91 • Heart, perfusion, 511.91 • Magnetic resonance (MR), perfusion study, 511.121413 • Microspheres, 511.1269 • Myocardium, blood supply, 511.91
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXReferences |
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Today, only a few methods are available for spatial measurement of both parameters in animal experiments. Myocardial blood volume may be determined by means of morphometric studies (3,4), methods in which radiolabeled red blood cells and plasma proteins are used (5–7), or contrast agent–enhanced radiography (8). Appropriate methods for measuring myocardial perfusion are microsphere (9) or protein-labeling techniques (7). However, morphometric methods are sensitive to preparation artifacts and contain no functional information, and microsphere data can be obtained only ex vivo.
Magnetic resonance (MR) techniques may provide functional and spatial information during in vivo conditions. First-pass MR imaging with a contrast agent quantitates both parameters (10). However, sequential measurements may be hampered by residual intravascular contrast agent after the first pass. Other MR imaging techniques that can be used to determine perfusion without a contrast agent require a special magnetic labeling of the perfusate (11). However, owing to the complex topography of left ventricular myocardium and coronary arteries, this method today is restricted to the isolated rat heart. A technique presented recently (12–14) quantifies alterations of perfusion in the isolated heart without a special preparation of the perfusate.
The aim of our study was therefore to adapt this technique to the intact animal and to validate it by means of the well-established microsphere technique for measurement of myocardial perfusion. The method without a contrast agent was combined with mapping of myocardial blood volume, which requires an intravascular contrast agent. This regional blood volume (RBV) technique has been validated previously by means of first-pass MR imaging (15). Perfusion and myocardial blood volume were determined during resting conditions and during injection of adenosine phosphate, which is a strong dilator of microvessels (16,17).
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MATERIALS AND METHODS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXReferences |
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Experiment Preparation
We studied 35 male Wistar rats (Harlan-Winkelmann, Hannover, Germany) that weighed 250–330 g. All animals were maintained according to the European regulations for the care and use of laboratory animals. Each was anesthetized by means of intraperitoneal injection of 40–60 mg of pentobarbital sodium (Narcoren; Rhone Merieux, Laupheim, Germany) per kilogram of body weight. After oral intubation, they breathed room air by using a rodent ventilator (BAS-7025; Föhr Medical Instruments, Seebach-Oberseebach, Germany) supplemented by oxygen at a tidal volume of 3 mL and a respiratory rate of 65 cycles per minute. Anesthesia was maintained with 10–30 mg/kg/h pentobarbital sodium administered via a tail vein. The body temperature was kept constant at 37°C ± 1 by using a heated water pad. Electrodes connected to an electrocardiographic unit we built (20) were positioned on the forelegs to record cardiac frequency during the experiment and to trigger the MR images. The heart rate was typically about 350–400 beats per minute. During image acquisition, ventilation was automatically stopped to eliminate respiratory motion.
Pilot Studies
In group 1 (n = 5; weight range, 250–310 g), the persistence of albumin gadopentetate dimeglumine (produced in-house) in the intravascular space was established by means of sequential injections of a bolus of approximately 0.2 mL of contrast agent to a total of 200 µmol of gadolinium per kilogram over 60 minutes. The dynamics of the intravascular concentration of albumin gadopentetate dimeglumine and its effect on myocardium was determined every minute with the use of T1 mapping in the left ventricle and left ventricular wall. Potential penetration of contrast agent from intra- to extravascular space would have resulted in a dissociation of kinetics of intravascular and myocardial T1 after bolus administration.
In group 2 (n = 5; weight range, 250–280 g), section-selective and global T1 maps of left ventricular myocardium were determined with the rats at rest and were recorded at 10-minute intervals for 80 minutes to demonstrate the stability of these parameters.
Reference Method for Myocardial Perfusion: Colored Microsphere Technique
The microsphere technique has become the standard method for measuring myocardial perfusion in various experimental settings (9,21). Colored microspheres have been used successfully in vivo and in the isolated rat heart (22–24). This method was used to validate the in vivo MR imaging perfusion technique. Animals were prepared as described earlier. After MR imaging perfusion measurement, a femoral arterial catheter (PE-50; Portex, Kent, UK) was placed for withdrawal of microsphere reference samples. Microspheres (Dye-Trak; Triton Technology, San Diego, Calif) were dispersed by vortex mixing. The number of microspheres of one color (mean diameter, 15 mm) injected into the left atrium was about 300,000/0.3 mL. Starting 10 seconds before injection and continuing until 2 minutes after injection, arterial blood was collected with a constant withdrawal pump (pump 944; Boston Scientific, Natick, Mass) from the femoral arterial catheter at a rate of 0.25 mL/min.
After the final microsphere injection, each animal was sacrificed with the use of pentobarbital sodium, and the hearts were removed, frozen in liquid nitrogen, and cut into four transverse slices with a thickness of about 4 mm. Each slice except the aortic root was divided into the right and left ventricle. The sample processing was described elsewhere in detail (24). After the tissue probes were digested, dye was removed from the microspheres with the use of 100 mL of dimethylforamamide (Sigma, Deisenhofen, Germany). The absorption spectrum of each sample was detected with the use of a personal computer–controlled (BDF, Langenzenn, Germany) ultraviolet spectrometer (Ultrospec II; Biochrom, Cambridge, UK) with a wavelength range of 200–820 nm and a bandwidth of 2 nm. The composite spectra of the dyes were corrected for solvent and afterwards separated into the single spectrum of each dye by means of a matrix inversion program.
Contrast Agent
The macromolecular contrast agent albumin gadopentetate dimeglumine used for the present study was synthesized by labeling porcine serum albumin with the paramagnetic gadopentetate dimeglumine according to a method described by Ogan et al (25). The albumin gadopentetate dimeglumine conjugate had a mean of 36 Gd3+ ions per albumin molecule as determined after oxidative decomposition with concentrated nitric acid at inductively coupled plasma–atomic emission spectroscopy at 342,247 nm. Because of its high molecular mass (67,000 D), albumin and, hence, albumin gadopentetate dimeglumine, stayed in the intravascular space of myocardium at least for the duration of our experiments. This was also proved in these pilot studies. Animals in which RBV was determined received injection of a single bolus of 0.75 µmol/kg albumin gadopentetate dimeglumine (
0.3 mL).
Experimental Protocol
Perfusion and RBV values were measured in 25 animals in four different groups. In group 3 (n = 7; weight range, 240–320 g), perfusion data in the same animal were determined by using the MR imaging and the colored microsphere techniques.
In group 4 (n = 6; weight range, 260–320 g), perfusion and RBV values were determined with the rats at rest, and error analysis of these parameters was performed as described earlier.
In group 5 (n = 6; weight range, 260–330 g), perfusion and RBV values were measured with the rats at rest and during intravenous injection of 3 mg/kg/min adenosine phosphate (Adrekar; Sigma). Adenosine phosphate is widely used as a potent dilator of microvessels in animals (5) and humans (26). As described in previous studies (27,28), a high dose of 3 mg/kg/min adenosine phosphate was used to greatly increase myocardial perfusion owing to its vasodilating effect. Since perfusion is attained without the use of contrast agent, an experimental sequence of measurements was observed as follows: (a) perfusion in rats at rest, (b) perfusion during administration of adenosine phosphate, (c) RBV during administration of adenosine phosphate, and (d) RBV in rats at rest (Fig 1). The acquisition time for four perfusion or RBV maps was about 15 minutes. The duration of the whole perfusion or RBV measurement was therefore about 30–35 minutes.
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MR Imaging and Data Analysis
The experiments were performed with a 7-T spectrometer (Biospec; Bruker, Karlsruhe, Germany) at a 300-MHz proton resonance frequency. We made a rat-size whole-body coil with a 7-cm inner diameter that was used as a transmitter, and a circular polarized surface coil was used as a receiver (20). T1 images were determined from an inversion-recovery snapshot fast low-angle shot (FLASH) sequence (29). After application of a global or section-selective 4-msec-long, adiabatic, hyperbolic secant, inversion pulse, a series of 24 electrocardiographically triggered snapshot FLASH images were acquired. The inversion section thickness was adjusted to 12 mm for the section-selective inversion experiment. The section thickness of the imaging volume was adjusted to 3 mm. During the waiting period between two trigger signals, dummy scans were acquired. For each snapshot FLASH image (2.25/1 [repetition time msec/echo time msec]; flip angle, about 3°), 64 phase-encoding steps and 128 steps in the read direction were recorded within a cardiac cycle. Images were obtained with a 50 x 50-mm field of view and zero filled to 128 x 128 pixels (ie, spatial resolution in plane was 390 x 780 µm2).
Detection of perfusion by means of selective preparation of the imaging section requires that the magnetization of the inflowing blood is almost that of equilibrium. Since blood supply is directed from base to apex, imaging in the short-axis view was performed. The imaging section was localized 5–6 mm beneath the atrioventricular valves.
Two successive electrocardiographically triggered T1 experiments with two different delays (t1 and t2) between the electrocardiographic trigger signal and the inversion pulse, which varied between approximately 50 and 100 msec, depending on heart rate, were performed to improve the temporal resolution of the relaxation curve and therefore the accuracy of the T1 measurement (Fig 2). Spatially resolved T1 maps were calculated pixel by pixel from 2 x 24, or 48, images acquired in the two inversion-recovery snapshot FLASH experiments. The calculation was based on a fit that corrects for the effect of saturation caused by a series of radio-frequency pulses in the FLASH procedure (30,31).
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Left ventricular myocardium was confined by a manually drawn line. Within this region, the spatial mean values and SD of perfusion and RBV were determined by averaging the pixel data. Microcirculatory values from the right ventricular wall were not considered owing to partial volume effects.
Error Analysis and Statistical Methods
The random error of the quantification of perfusion and RBV was determined by that of the T1 measurement. The error was quantitated in each pixel by means of the SD of four repeated T1 measurements. The error of perfusion and RBV measurement was determined from the latter by application of the error propagation theorem to Equations (A5) and (A6) in each pixel, and the spatial mean of this error was computed for left ventricular myocardium.
Perfusion and RBV data in single animals were expressed as the mean plus or minus spatial SEM. Mean values and SEM in a group were determined from these spatial mean data in a single animal. For statistical comparisons, the paired Student t test was used, and a P value less than .05 was considered the probability level for statistical significance.
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RESULTS |
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Colored Microsphere Perfusion Validation: Group 3
Perfusion data obtained with the colored microsphere technique were 3.44 mL/g/min ± 0.21 (SEM) in rats at rest and 4.65 mL/g/min ± 0.82 (SEM) during injection of adenosine phosphate (P = .04). MR imaging perfusion data obtained in a rat at rest and during injection of adenosine phosphate in the same animal were 3.32 mL/g/min ± 0.19 (SEM) and 4.65 mL/g/min ± 0.61 (SEM), respectively (P = .02). Correlations of both methods are shown in Figure 4.
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Perfusion and RBV maps of a representative animal are presented in Figure 6. In a short-axis view, the heart is clearly visible adjacent to the anterior thorax of the living rat. The substantial perfusion and RBV changes during administration of adenosine phosphate are noticeable. The time courses of perfusion and RBV prior to, during, and after adenosine phosphate administration are seen in Figure 7a. Mean perfusion increased during administration of adenosine phosphate. After contrast agent administration, RBV increased because of continuous injection of adenosine phosphate and finally decreased to resting values after withdrawal of the drug.
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DISCUSSION |
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Theoretic Model
The main mechanism by which perfusion (12) and intravascular contrast agents (32,33) affect tissue relaxation is diffusion exchange from intra- to extravascular space and vice versa. This intravascular-extravascular diffusion exchange occurs almost solely in the capillaries. In our model, we neglected other coronary vessel types (eg, arteries, arterioles, and veins), which appears to be justified owing to their small volume fractions in myocardial tissue (6,34).
The algorithm by which parameters of myocardial microcirculation are determined assumed fast exchange of water protons between the extravascular space and the capillary (11,18). We recently demonstrated an upper limit of 150 msec for the mean residence time of a water proton in the intracapillary space of rat myocardium (12). Insertion of this value into the exact dependence of relaxation rate on exchange rate revealed that the fast exchange assumption is valid as long as the relaxation time of blood is more than 200–300 msec, which was the case in our experiments.
Independent Validation of Perfusion and RBV
Microsphere techniques are established for regional myocardial flow measurement in the rat (9,22). Results of previous studies (7,28) indicated that perfusion data are valid even during vasodilative conditions. Perfusion validation indicated that our MR imaging perfusion method can be considered as a potent noninvasive tool for in vivo measurement of regional myocardial blood flow. Independent validation steps for myocardial blood volume are more complex because the reference-standard technique is less well defined. Methods in which radiolabeled blood cell and plasma markers (5,6) are used were not possible in our laboratories. However, first-pass MR imaging is a well-established technique for in vivo RBV determination. Validation steps in which this technique (15) was used indicated a good accordance between both RBV imaging techniques.
Perfusion Measurement
Our model was based on the assumption that magnetization of the inflowing blood is that of equilibrium when the section-selective gradient is applied. One might argue that arterial spins within the section are also inverted and enter the capillaries and diminish the effect of perfusion. The following consideration might weaken this argument. The vessels inside the section may be classified into following fractions: (a) arteries that supply capillaries inside the section, (b) arteries that supply capillaries from outside, (c) capillaries that are supplied by arterial fraction a, (d) capillaries in which the flow runs from outside into the section, and (e) veins.
Flow in vessels of fractions b and e does not contribute to the effect of perfusion on relaxation. For the capillaries in fraction d, the model assumption is fulfilled. Capillaries in fraction c are perfused initially by blood in which the magnetization is inverted. Since the contribution of the capillary volume to the intravascular volume is more than 90%, the volume of fractions a, b, and c is less than 10%. Hence, it is reasonable to assume that fraction a is less than 5% of the intravascular volume. Since intravascular volume is less than 20% of tissue volume, the volume of arterial fraction a is smaller than 5% of 20%, or 1% of tissue volume.
In view of perfusion in rat myocardium in the range of 3 mL/g/min, or 0.05 mL/cm3/sec, or 5% per second, the blood of fraction a is exchanged in less than 1% per 5% per second, or 200 msec. Since we determined relaxation time within an observation period of 24 images per study per cardiac cycle and a cardiac cycle length of 4.8 seconds or more, this initial effect of inverted spins of fraction a was negligible. Furthermore, we obviously overestimated the volume of vessel fraction a; the contribution of spins in this volume is even smaller.
Determination of RBV
Our data for the relative intracapillary blood volume, or RBV, were in the range of 12%. Other groups reported values of about 7.5% (6,35) for the small vessel blood volume. The following factors might be responsible for this discrepancy: (a) the distribution of the contrast agent, (b) model assumptions for measurement of RBV, and (c) methodologic aspects concerning labeling of the blood by the contrast agent.
1. One might argue that penetration of the contrast agent from intracapillary to extravascular space might increase the distribution space in myocardium. However, this can be excluded by the fact that the relaxation time of tissue in our experiments was constant during a period of at least 50 minutes after contrast agent administration owing to albumin, which is an established marker for the intravascular space (27,36).
2. We assumed the fast-exchange approximation of intracapillary and extravascular spins to derive Equation (A6), which reveals the RBV. Without fast exchange, the accelerating effect of contrast agent on relaxation of extravascular tissue would be smaller (33). This implies that the application of Equation (A6) in the case of slow-to-intermediate exchange would result in an underestimation of the real RBV, the opposite of which was observed.
3. For the computation of RBV according to Equation (A6), we determined the increase in relaxation rate in the intracapillary blood from blood of the left ventricle. The contrast agent we used is a marker of the plasma volume (ie, its concentration in blood depends on the hematocrit). The concentration of contrast agent in the capillaries is Cc = CLV (1 - Hctc)/(1 - HctLV), where CLV is the concentration in the blood of the left ventricle and Hctc and HctLV are the hematocrit of the capillary and left ventricular blood, respectively. Since hematocrit of the capillary blood is 63%–75% of that of blood in large vessels (5,35,37), and hematocrit in large vessels of rats is about 48% (35), one obtains a 1.23–1.34 times higher concentration of the contrast agent in the capillary blood when compared with that in blood in larger vessels. Therefore, the increase in relaxation rate in the capillary blood is 1.23–1.34 times higher than that in the ventricular blood. Equation (A6) demonstrates that this results in 19%–25% smaller RBV values (9%–10%) as compared with data obtained from relaxation rates of ventricular blood (12%). These hematocrit-corrected data are close to values in the literature (5,6). In summary, the real RBV (RBVreal) and the RBV we determined are related by
Determination of Perfusion and RBV in Rats at Rest and during Stress
Adenosine phosphate is known as a potent vasodilative drug in the coronary system. The dose of adenosine phosphate we used resulted in an increase in RBV of more than 100% in our experiments. In contrast to our data and those of Duran et al (38), the data of Crystal et al (5) showed no substantial change in blood volume of vessels with diameters less than or equal to 100 µm during injection of adenosine phosphate. Results of Kanatsuka et al (28), however, indicate that adenosine phosphate caused dilation of microvessels smaller than 150 µm, which supports our findings.
Different groups (5,28) reported that adenosine phosphate increases myocardial perfusion fivefold to sevenfold of control values. Coronary perfusion pressure and heart rate were held constant in these experiments. In our study, however, we observed only a moderate increase in coronary perfusion. This has to be considered in context with the effect of adenosine phosphate on mean aortic pressure and heart rate, which were determined in group 6. Determination of the coronary resistance from the mean aortic pressure data in group 6 divided by perfusion data in group 5 reveals an adenosine phosphate–induced reduction of coronary resistance to 38%–44% of baseline.
Kaul and Jayaweera (34) and Wu et al (39) proposed a relation between the coronary resistance and the myocardial intracapillary RBV. Wu et al assumed that dilation of a resistance vessel increases the cross sections of subsequent microvessels that contribute to the RBV (ie, according to the Hagen-Poiseuille law, the authors assume that coronary resistance is approximately RBV-2). Kaul and Jayaweera proposed that dilation of coronary resistance vessels results in recruitment of a number of capillaries (ie, coronary resistance is approximately RBV-1). Comparison of coronary resistance (CR) and RBV during resting conditions (CRr, RBVr) and vasodilation (CRd, RBVd) reveals CRr/CRd = (RBVd/RBVr)n with n equal to 1 for the model of Kaul and Jayaweera or n equal to 2 following the assumptions of Wu et al. Insertion of our data reveals an exponent of n of approximately 1.14–1.37 (ie, in-between both cases but closer to the value one would expect according to the model of Kaul and Jayaweera). This would imply that capillary recruitment contributes to the effect of adenosine phosphate on RBV.
Practical applications: This study demonstrates a technique for the in vivo assessment of myocardial perfusion and RBV in the intact heart. The major advantage is its noninvasiveness, since perfusion measurement is independent from contrast agent, and RBV is determined from steady-state measurements obtained prior to and after administration of the contrast agent. Therefore, the technique is particularly attractive for the mapping of myocardial microcirculation in the human heart (40). One perfusion map may be obtained in less than 8 minutes with an imaging section thickness of about 1 cm. However, further improvements in MR imaging hardware are necessary, and methods have to be developed to minimize motion artifacts due to respiration and cardiac motion. Our technique to measure RBV requires a pure intravascular contrast agent, which is currently not available for use in humans. In recent years, there has been a promising approach for a future T1-sensitive contrast agent (41). Some of these contrast agents currently are undergoing phase 3 of clinical trials (42).
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APPENDIX |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXReferences |
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is the integration parameter in the convolution integral, d is the differential of , and R is the relaxation rate–exchange rate matrix.
We could demonstrate (12) that the fast-exchange approximation derived from Equation (1) is valid as long as T1blood is greater than or equal to 200 msec. In this case, one derives (12,32) for the rate attained after section-selective inversion 1/T1sel and global inversion 1/T1glob:
is the blood-tissue partition coefficient of water, which is assumed to be 0.95 mL/g for normal blood-perfused myocardial tissue (43). Perfusion can be determined from a section-selective and a global T1 experiment according to Equations (A3) and (A4):
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Acknowledgments |
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Footnotes |
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Author contributions: Guarantors of integrity of entire study, C.W., E.K., K.H.H., W.R.B., G.E.; study concepts, C.W., W.R.B., K.H.H.; study design, C.W., E.K., K.H.H., W.R.B.; definition of intellectual content, W.R.B., C.W., E.K., K.H.H., A.H.; literature research, C.W., K.H.H., W.R.B.; experimental studies, C.W., E.K., K.H.H., K.H., M.N., S.V.; data acquisition, C.W., E.K., K.H.H., M.N., S.V.; data analysis, C.W., E.K., M.N.; statistical analysis, C.W., E.K., W.R.B.; manuscript preparation, C.W.; manuscript editing, C.W., W.R.B., G.E.; manuscript review, W.R.B., G.E., A.H., K.H.H., E.K.
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References |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXReferences |
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an K. Quantitative morphology of capillaries of the heart. Methods Achievement Exp Pathol 1971; 5:272-286.
an K. Vascular capacity and hematocrit in experimental cardiomegaly due to aortic constriction in rats. Can J Physiol Pharmacol 1971; 49:819-823.[Medline]
an K, Wachtlova M, Poupa O. An attempt to determine indirectly the vascularity of the heart muscle by measuring the tissue concentration of haemoglobin in normal and anaemic rats. Physiol Bohemoslov 1969; 18:1-5.
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t1 and 
) of a representative animal in group 1. Contrast agent was injected as a bolus in doses of 0.2 mL each (
). T1 is dependent on the amount of contrast agent administered. Notice that the T1 of the left ventricular blood and the T1 of myocardial tissue are constant over time between bolus injections. t = time (in minutes).
) and during injection of 3 mg/kg/min adenosine phosphate (•).
) are shown as the mean plus or minus SEM in the six animals in group 6. During administration of adenosine phosphate, mean aortic pressure and heart rate decrease significantly and return to resting values after withdrawal of the drug.