Magnetic resonance imaging demonstration of pharmacologic-induced myocardial vasodilatation using a macromolecular gadolinium contrast agent.

RATIONALE AND OBJECTIVES: Adenosine is a potent vasodilator used clinically in nuclear scintigraphy to assess coronary artery reserves. The potential to identify this vasodilating effect of adenosine using magnetic resonance imaging (MRI), which is superior in spatial resolution to nuclear scintigraphy, combined with a blood-pool MRI contrast agent, was investigated in normal rats. METHODS: Groups of Sprague-Dawley rats received successive infusions of either adenosine (3 mg/kg/minute; n = 7) or dipyridamole (negative control; up to 1.0 mg/kg/minute; n = 9), both before and after contrast enhancement, with a macromolecular blood-pool MRI contrast agent, albumin-gadolinium-DTPA35 (Gd-DTPA35) (4.0 mumol Gd per kilogram). Electrocardiographically (ECG) gated MRIs (2.0 Tesla), acquired serially before and after contrast enhancement, and with and without either adenosine or dipyridamole infusions, to monitor potential pharmacologic responses. RESULTS: During repeated infusions of adenosine, the postcontrast myocardial enhancement, reflecting blood volume, increased significantly (P < .05), up to 150%, compared with pre-adenosine enhancement. Infusions of dipyridamole, pharmacologically inactive in rats, produced no change in myocardial enhancement. CONCLUSIONS: The increased myocardial signal intensity observed during adenosine infusions after enhancement of the blood pool can be attributed to increased blood volume accompanying coronary vasodilatation. The method, which does not require a continuous infusion of contrast agent, has potential for the clinical evaluations of coronary artery reserves.

Contrast-enhanced magnetic resonance imaging of tumor-bearing mice treated with human recombinant tumor necrosis factor alpha.

Pharmacological effects of recombinant human tumor necrosis factor alpha (TNF) were studied in a mouse fibrosarcoma model using magnetic resonance imaging enhanced with a macromolecular contrast agent, albumin(gadolinium-diethylenetriamine pentaacetic acid)35. TNF was administered i.v. in a dose of 150 micrograms/kg, 60 to 80 min prior to imaging. Contrast-enhanced and nonenhanced magnetic resonance images of TNF-treated (n = 10) and untreated (n = 8) Meth A fibrosarcomas were obtained at 2.0 Tesla using T1-weighted spin-echo pulse sequences. Serial images spanning an interval of 60 to 120 min after TNF administration showed that the TNF-treated tumors enhanced significantly more overall than did untreated tumors (43% versus 31%). The most marked differential tumor enhancement was observed in the tumor rim (59% versus 40%). Nontumorous tissue, including muscle and brain, revealed no significant enhancement differences between TNF-treated animals and controls. The observed tumor enhancement corresponded strongly with Evans blue staining; the TNF-treated tumors stained deep blue, while untreated tumors and normal tissues observed did not stain. The different enhancement and Evans blue staining patterns between TNF-treated tumors and untreated tumors are attributed to TNF-induced changes in tumor capillary integrity. The data indicate that TNF effects on tumors include an increased capillary permeability for macromolecules at early times after administration. The ability to detect changes in capillary permeability in vivo using contrast-enhanced magnetic resonance imaging may prove to be clinically useful to monitor tumor response to TNF.

Assessment of myocardial salvage after ischemia and reperfusion using magnetic resonance imaging and spectroscopy.

To test the hypothesis that contrast-enhanced magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) can differentiate reversible from irreversible myocardial injury, these modalities were used to study ischemia and reperfusion in a rat model. The presence of ischemia and reperfusion were confirmed with radiolabeled microspheres (n = 6). Groups of animals were subjected to either 16 (n = 17), 30 (n = 14), 60 (n = 11), or 90 (n = 14) minutes of left coronary artery (LCA) occlusion and 60 minutes reperfusion. After albumin-gadolinium (Gd)-DTPA injection, contrast-enhanced, T1-weighted, spin-echo proton images were acquired at baseline and every 16 minutes during LCA occlusion and reperfusion. In separate experiments, 31phosphorus (31P) spectra were acquired at similar time points during ischemia and reperfusion. After 16 minutes occlusion, normally perfused myocardium enhanced significantly compared with ischemic myocardium on MRI (104 +/- 7.9% vs. 61 +/- 11.0%, p less than 0.05, n = 5, mean +/- SEM, % of baseline value). MRS showed reduced phosphocreatine (PCr) and adenosine triphosphate (ATP) (58.8 +/- 2.4%, p less than or equal to 0.01; 81.4 +/- 2.4, p less than or equal to 0.01, n = 12). After 16 or 30 minutes ischemia, reflow resulted in uniform MRI signal intensity of the ischemic zone compared with normal myocardium (93.5 +/- 11.3 vs. 80.9 +/- 7.0, p = NS, n = 11, % of baseline value at 30 minutes reperfusion) and PCr recovery on MRS (94.3 +/- 4.0%, p = NS, n = 20, % baseline value at 30 minutes reflow). After 60 and 90 minutes ischemia, reflow resulted in marked enhancement of reperfused compared with normal myocardium on MRI (254.0 +/- 30.0 vs. 78.3 +/- 9.2, p less than or equal to 0.01, n = 10) and no recovery of PCr on MRS (64.1 +/- 3.0, p = NS, n = 14). Triphenyltetrazolium chloride (TTC) staining revealed transmural myocardial infarction (MI) in all hearts subjected to 60 or 90 minutes ischemia and reflow, and small nontransmural MIs in only 2/11 hearts subjected to 16 or 30 minutes ischemia and reperfusion. Thus, 1) MRI with albumin-Gd-DTPA is useful for identifying myocardial ischemia by enhancing the contrast between normally perfused and ischemic myocardia; 2) MRI with albumin-Gd-DTPA is useful for identifying reperfusion after myocardial ischemia; and 3) after reperfusion, reversible can be distinguished from irreversible myocardial injury by characteristic findings on MRI and MRS.

Ascorbate-induced cancellation of nitroxide contrast media enhancement of MR images.

Ascorbate (Vitamin C), a naturally occurring reducing substance, was tested as an in vivo chemical agent to cancel magnetic resonance imaging (MRI) tissue contrast enhancement induced by a nitroxide spin label contrast agent. Paramagnetic nitroxide compounds can be reduced in vitro by ascorbate to nonparamagnetic hydroxylamine derivatives. A nitroxide agent, TES, was injected intravenously, 2 mmol/kg, in 11 anesthetized rats. Renal cortical and hepatic intensities were monitored by serial T1-weighted images (TR/TE 310/15) acquired precontrast and postcontrast. Fourteen minutes after TES administration, ascorbate (1 mmol/kg) was injected in 6 rats, and saline in 5 control rats. At twenty-nine minutes postcontrast, a second TES-injection was given to all rats. The initial TES-injection resulted in a marked enhancement of kidney cortex and liver. Ascorbate administration immediately cancelled this enhancement. Contrast enhancement could be successfully reinduced by a repeat administration of TES. Results indicate that in vivo administration of reducing agents can be used to immediately cancel enhancement induced by nitroxide contrast media, thus nonenhanced images could be obtained after enhanced images without lengthy delays for contrast media elimination.

Contrast-enhanced MRI of tumors. Comparison of Gd-DTPA and a macromolecular agent.

The study aim was to define potential differences and advantages in magnetic resonance (MR) patterns of tumoral contrast enhancement using either a small molecular, extracellular fluid contrast enhancer [Gd-DTPA] or a macromolecular agent [albumin-(Gd-DTPA)20], designed for primary intravascular biodistribution. MR images of 25 mice with implanted fibrosarcomas were obtained before and repeatedly for up to 120 minutes after injection of either Gd-DTPA [0.2 mmol/kg, n = 11] or albumin-(Gd-DTPA) [0.0029 mmol/kg, n = 14]. Histologically, this hypovascular tumor contained zones of viable tissue and non-viable, necrotic tissue. Using either type of contrast media, the viable portions enhanced strongly, up to 152% and the necrotic portions enhanced poorly, less than 31%. However, the time-course of enhancement differed between contrast agents. Gd-DTPA tended to provide maximal enhancement soon after administration with no significant changes over two hours. Enhancement from albumin-(Gd-DTPA) was weak initially, corresponding to tumor hypovascularity, but over two hours the signal of the viable tumor zones progressively increased in intensity. This gradual tumoral accumulation of the macromolecular agent within the tumor was considered to reflect abnormal capillary permeability, associated with neovascularity. Thus, the increasing intensity within the neoplastic tissues over time, reflecting abnormal capillary permeability for macromolecules, may serve as a useful, albeit indirect, marker of neoplasia.

Vascular mapping using albumin-(Gd-DTPA), an intravascular MR contrast agent, and projection MR imaging.

An intravascular magnetic resonance (MR) contrast agent is valuable for vascular mapping of tissues when used in combination with projection spin-echo MR imaging. The primary advantage of using projection imaging lies in its global depiction of anatomy. Also, relatively short echo time values can be readily achieved, reducing flow dephasing signal losses from blood and increasing overall signal-to-noise. These advantages, coupled with the reduction of blood pool T1 values due to the presence of the intravascular contrast agent, allow for detailed spatial mapping of slow-flow vascular structures using MR.