Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke.

Neonatal stroke occurs in one in 4,000 live births and leads to significant morbidity and mortality. Approximately two thirds of the survivors have long-term sequelae including seizures and neurological deficits. However, the pathophysiological mechanisms of recovery after neonatal stroke are not clearly understood, and preventive measures and treatments are nonexistent in the clinical setting. In this study, we investigated the effect of vascular endothelial growth factor (VEGF) treatment on histological recovery and angiogenic response to the developing brain after an ischemic insult. Ten-day-old Sprague-Dawley rats underwent right middle cerebral arterial occlusion (MCAO) for 1.5 h. Diffusion-weighted MRI during occlusion confirmed focal ischemia that was then followed by reperfusion. On group of animals received 5-bromo-2-deoxyuridine and sacrificed at postnatal day (P)18 or P25. A second group of animals was treated with VEGF (1.5 µg/kg, icv) or phosphate-buffered saline (PBS) at P18 and perfusion fixed at P25. Based on Nissl and iron staining, a single VEGF injection reduced the injury score, compared to the animals that underwent MCAO and PBS injection. Furthermore, neurodegeneration represented by neuronal nuclei staining was markedly diminished. In addition, animals treated with VEGF revealed a positive trend in endothelial proliferation and a significant increase in total vessel volume in the peri-infarct region of the caudate. The number of Iba1-positive microglial cells was significantly reduced after a single VEGF injection, and myelin basic protein expression was enhanced in the caudate after ischemia without an effect of VEGF treatment. In conclusion, delayed treatment with VEGF ameliorates injury, promotes endothelial cell proliferation, and increases total vascular volume following neonatal stroke. These results suggest that VEGF has a neuroprotective effect, in part by enhancing endogenous angiogenesis. These data contribute to a better understanding of neonatal stroke.

Reduced infarct size and accumulation of microglia in rats treated with WIN 55,212-2 after neonatal stroke.

Cannabinoids have emerged as brain protective agents under neurodegenerative conditions. Many neuroprotective actions of cannabinoids depend on the activation of specific receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R). The aim of the present study was to determine whether the CB2R and CB1R agonist WIN 55,212-2 (WIN) protects neonatal brain against focal cerebral ischemia-reperfusion and whether anti-inflammatory mechanisms play a role in protection. Seven-day-old rats were subjected to 90-min middle cerebral artery occlusion (MCAO), and injured rats were identified by diffusion-weighted MRI during the occlusion. After reperfusion, rats were subcutaneously administered 1 mg/kg of WIN or vehicle twice daily until sacrifice. MCAO led to increased mRNA expression of CB2R (but not CB1R), chemokine receptors (CCR2 and CX3CR1), and cytokines (IL-1ß and TNFα), as well as increased protein expression of chemokines MCP-1 and MIP-1α and microglial activation 24 h after MCAO. WIN administration significantly reduced microglial activation at this point and attenuated infarct volume and microglial accumulation and proliferation in the injured cortex 72 h after MCAO. Cumulatively, our results show that the cannabinoid agonist WIN protects against neonatal focal stroke in part due to inhibitory effects on microglia.

Reperfusion differentially induces caspase-3 activation in ischemic core and penumbra after stroke in immature brain.

BACKGROUND AND PURPOSE: Different strategies for neuroprotection of neonatal stroke may be required because the developing brain responds differently to hypoxia-ischemia than the mature brain. This study was designed to determine the role of caspase-dependent injury in the pathophysiology of pure focal cerebral ischemia in the immature brain. METHODS: Postnatal day 7 rats were subjected to permanent or transient middle cerebral artery (MCA) occlusion. Diffusion-weighted MRI was used during occlusion to noninvasively map the evolving ischemic core. The time course of caspase-3 activation in ischemic brain tissue was determined with the use of an Asp-Glu-Val-Asp-aminomethylcoumarin cleavage assay. The anatomy of caspase-3 activation in the ischemic core and penumbra was mapped immunohistochemically with an anti-activated caspase-3 antibody in coronal sections that matched the imaging planes on diffusion-weighted MRI. RESULTS: A marked increase in caspase-3 activity occurred within 24 hours of reperfusion after transient MCA occlusion. In contrast, caspase-3 activity remained significantly lower within 24 hours of permanent MCA occlusion. Cells with activated caspase-3 were prominent in the penumbra beginning at 3 hours after reperfusion, while a more delayed but marked caspase-3 activation was observed in the ischemic core by 24 hours after reperfusion. CONCLUSIONS: In the neonate, caspase-3 activation is likely to contribute substantially to cell death not only in the penumbra but also in the core after ischemia with reperfusion. Furthermore, persistent perfusion deficits result in less caspase-3 activation and appear to favor caspase-independent injury.

Carbon dioxide reactivity and pressure autoregulation of brain tissue oxygen.

OBJECTIVE: To describe the normal relationships between brain tissue oxygen tension (PbrO2) and physiological parameters of systemic blood pressure and CO2 concentrations. METHODS: Licox Clark-type oxygen probes (GMS mbH, Kiel, Germany) were inserted in the frontal white matter of 12 swine maintained under general anesthesia with a 1.0 fraction of inspired oxygen (FiO2). In seven swine, alterations in end-tidal carbon dioxide (ET-CO2) concentration (range, 13-72 mm Hg) were induced via hyperventilation or instillation of CO2 into the ventilation circuit. In nine swine, mean arterial pressure (MAP) (range, 33-200 mm Hg) was altered; phenylephrine was used to induce hypertension, and a nitroprusside-esmolol combination or systemic hemorrhage was used for hypotension. Quantitative cerebral blood flow (CBF) was measured in two animals by using a thermal diffusion probe. RESULTS: Mean baseline PbrO2 was 41.9 +/- 11.3 mm Hg. PbrO2 varied linearly with changes in ET-CO2, ranging from 20 to 60 mm Hg (r2 = 0.70). The minimum PbrO2 with hypocarbia was 5.9 mm Hg, and the maximum PbrO2 with hypercarbia was 132.4 mm Hg. PbrO2 varied with MAP in a sigmoid fashion suggestive of pressure autoregulation between 60 and 150 mm Hg (r2 = 0.72). The minimum PbrO2 with hypotension was 1.4 mm Hg, and the maximum PbrO2 with hypertension was 97.2 mm Hg. In addition, CBF correlated linearly with PbrO2 during CO2 reactivity testing (r2 = 0.84). CONCLUSION: In the uninjured brain, PbrO2 exhibits CO2 reactivity and pressure autoregulation. The relationship of PbrO2 with ET-CO2 and MAP appears to be similar to those historically established for CBF with ET-CO2 and MAP. This suggests that, under normal conditions, PbrO2 is strongly influenced by factors that regulate CBF.

Evolution of brain injury after transient middle cerebral artery occlusion in neonatal rats.

BACKGROUND AND PURPOSE: Stroke in preterm and term babies is common and results in significant morbidity. The vulnerability and pathophysiological mechanisms of neonatal cerebral ischemia-reperfusion may differ from those in the mature cerebral nervous system because of the immaturity of many receptor systems and differences in metabolism in neonatal brain. This study details the neuropathological sequelae of reperfusion-induced brain injury after transient middle cerebral artery (MCA) occlusion in the postnatal day 7 (P7) rat. METHODS: P7 rats were subjected to 3 hours of MCA occlusion followed by reperfusion or sham surgery. Diffusion-weighted MRI was performed during MCA occlusion, and maps of the apparent diffusion coefficient (ADC) were constructed. Contrast-enhanced MRI was performed in a subset of animals before and 20 minutes after reperfusion. Triphenyltetrazolium chloride (TTC) staining of the brain was performed 24 hours after reperfusion. Immunohistochemistry to identify astrocytes (glial fibrillary acidic protein), reactive microglia (ED-1), and neurons (microtubule-associated protein 2) and cresyl violet staining were done 4, 8, 24, and 72 hours after reperfusion. RESULTS: On contrast-enhanced MRI, nearly complete disruption of cerebral blood flow was evident in the vascular territory of the MCA during occlusion. Partial restoration of blood flow occurred after removal of the suture. A significant decrease of the ADC, indicative of early cytotoxic edema, occurred in anatomic regions with a disrupted blood supply. The decline in ADC was associated with TTC- and cresyl violet-determined brain injury in these regions 24 hours later. The ischemic core was rapidly infiltrated with reactive microglia and was surrounded by reactive astroglia. CONCLUSIONS: In P7 rats, transient MCA occlusion causes acute cytotoxic edema and severe unilateral brain injury. The presence of a prominent inflammatory response suggests that both the ischemic episode and the reperfusion contribute to the neuropathological outcome.

Cerebral oxygenation during hemorrhagic shock: perils of hyperventilation and the therapeutic potential of hypoventilation.

OBJECTIVES: Prophylactic hyperventilation of patients with head injuries worsens outcome, presumably by exacerbating tissue hypoxia. Oxygen tension in brain tissue (PbrO2) provides a direct measurement of cerebral metabolic substrate delivery and varies with changing end-tidal carbon dioxide tension (ETCO2) and mean arterial pressure. However, the effects of hyperventilation and hypoventilation on PbrO2 during hemorrhagic shock are not known. The aim of this study was to examine the effects of alteration in ventilation on PbrO2 in hemorrhaged swine. METHODS: Clark-type polarographic probes were inserted into the brain tissue of seven swine to measure PbrO2 directly. To examine the effects of alterations in ventilation on hemorrhage-induced hypotension, swine were hemorrhaged to 50% estimated blood volume and PbrO2 was monitored during hyperventilation (RR = 30) and hypoventilation (RR = 4). RESULTS: After the 50% hemorrhage, PbrO2 declined rapidly from 39.8 +/- 4.6 mm Hg to 11.4 +/- 2.2 mm Hg. Hyperventilation resulted in a further 56% mean decrease in PbrO2. Hypoventilation produced a 166% mean increase in PbrO2. These changes were significant (p = 0.001) for absolute and percentage differences from baseline. CONCLUSION: During hemorrhage, alterations in ventilation significantly changed PbrO2: hyperventilation increased brain-tissue hypoxia whereas hypoventilation alleviated it. This finding suggests that hyperventilation has deleterious effects on brain oxygenation in patients with hemorrhagic shock and those with head trauma. Conversely, hypoventilation with resultant hypercapnia may actually help resolve hemorrhagic shock-induced cerebral hypoxia.

Mild hypothermia decreases the incidence of transient ADC reduction detected with diffusion MRI and expression of c-fos and hsp70 mRNA during acute focal ischemia in rats.

The effects of mild hypothermia on the apparent diffusion coefficient of water (ADC) and expression of c-fos and hsp70 mRNA were examined during acute focal cerebral ischemia. Young adult rats were subjected to 60-min middle cerebral artery occlusion under either normothermia (37.5 degrees C) or hypothermia (33 degrees C). Diffusion-weighted echo-planar magnetic resonance imaging was used to monitor changes in ADC throughout the ischemic period. Perfusion MRI with dysprosium contrast was used at the end of the ischemic period to verify that the occlusion was successful. C-fos and hsp70 mRNA expression were examined with in situ hybridization at the end of the ischemic period. The results indicate that the size of the region that exhibited reduced ADC was smaller during hypothermia than during normothermia. Hypothermia also decreased the frequency of occurrence of transient ADC reductions, especially in dorsal aspects of cortex. Expression of both c-fos and hsp70 mRNA were markedly reduced by hypothermia. Transient ADC reduction and c-fos expression are associated with spreading depression, which is believed to contribute to lesion expansion during acute focal ischemia. The results suggest that part of the neuroprotective effect of hypothermia may be due to a reduced incidence of spreading depression.

Transient MRI-detected water apparent diffusion coefficient reduction correlates with c-fos mRNA but not hsp70 mRNA induction during focal cerebral ischemia in rats.

Cerebral ischemia induces immediate early genes such as c-fos and stress genes such as hsp70. In this study, the spatial relationships between c-fos and hsp70 mRNA expression and changes detectable with diffusion and perfusion magnetic resonance (MR) imaging were examined. The middle cerebral artery (MCA) of young adult rats was occluded for 30 or 60 min. Diffusion MR (D-MR) images were acquired continuously during the ischemic period and dysprosium-contrast perfusion (P-MR) images were acquired at the end of the ischemic period. C-fos and hsp70 mRNA expression were examined with in situ hybridization. The most significant finding of this work was that for both durations of ischemia, c-fos induction was observed in cortical and sub-cortical regions exhibiting a transient reduction in the apparent diffusion coefficient of water (ADC). Transients which occurred on a time scale of 3 min may have been caused by spreading depression. Those occurring on a 10-min time scale may have been caused by an initial reduction in blood flow with occlusion that was followed by an ischemia-induced increase in collateral blood flow. P-MR imaging showed that perfusion in c-fos positive regions was higher than in regions with persistently reduced ADC. Hsp70 induction did not correlate with transient ADC reduction. It was induced in the MCA territory in regions showing persistent ADC changes, with induction being greatest at the periphery of these regions. It was also induced in regions that exhibited both spontaneous reversal of the diffusion changes and decreased perfusion.

Neonatal reversible focal cerebral ischemia: a new model.

While numerous animal models exist for studying neonatal brain injury after cerebral ischemia-hypoxia, an adequate model for assessing reversible focal ischemia in the neonatal rat has not been reported. This paper describes in detail a new surgical procedure for creating a non-hemorrhagic, reperfused focal ischemic lesion in the neonatal, 7-day-old rat pup.

Influence of severity of myocardial injury on distribution of macromolecules: extravascular versus intravascular gadolinium-based magnetic resonance contrast agents.

OBJECTIVES: This study sought to 1) compare the distribution of extravascular (573 Da) and intravascular (92 kDa) magnetic resonance (MR) contrast agents in reperfused infarcted myocardium, and 2) investigate the effect of injury severity on these distribution patterns. BACKGROUND: Myocardial distribution of low and high molecular weight contrast agents depends on vascular permeability, diffusive/convective transport within the interstitium and accessibility of the intracellular compartment (cellular integrity). METHODS: To vary the severity of myocardial injury, 72 rats were subjected to 20, 30, 45 or 75 min (n = 18, respectively) of coronary artery occlusion. After 2 h of reflow, the animals received either 0.05 mmol/kg of gadolinium-diethylenetriaminepentaacetic acid-bismethylamide (Gd-DTPA-BMA) (n = 24), (Gd-DTPA)30-albumin (n = 24) or saline (control group, n = 24). Three minutes after injection, the hearts were excised and imaged (spin-echo imaging parameters: repetition time 300 ms, echo time 8 ms, 2-tesla system), followed by triphenyltetrazolium chloride staining for infarct detection and sizing. RESULTS: Histomorphometric and MR infarct size (expressed as percent of slice surface) correlated well: r = 0.96 for Gd-DTPA-BMA; r = 0.95 for (Gd-DTPA)30-albumin. On Gd-DTPA-BMA-enhanced images, reperfused myocardial infarctions were homogeneously enhanced. The ratio of signal intensity of infarcted/ normal myocardium increased with increasing duration of ischemia (overall p < 0.0001, analysis of variance [ANOVA]), indicating an increase in the distribution volume of Gd-DTPA-BMA in postischemic myocardium. On (Gd-DTPA)30-albumin-enhanced images, reperfused infarctions consisted of a bright border zone and a less enhanced central core. The extent of the core increased with increasing duration of ischemia (overall p value < 0.0001, ANOVA). CONCLUSIONS: At 2 h of reperfusion, the distribution of MR contrast agents in postischemic myocardium is 1) specific for extravascular and intravascular agents, and 2) modulated by the duration of ischemia.

Quantification of area at risk during coronary occlusion and reperfusion by means of MR perfusion imaging.

PURPOSE: Considerable clinical interest has focused on the size of ischemic myocardium. Fast MR imaging in conjunction with MR contrast media has the potential to identify hypoperfused and infarcted myocardium. This study used MR perfusion imaging to detect and quantify reperfused ischemic myocardium during a brief coronary occlusion and reperfusion, and to characterize the spatial extent of ischemic and reperfused ischemic myocardium relative to the "true" size of the area at risk as defined in histochemical morphometry at post mortem. MATERIAL AND METHODS: The left circumflex (LCX) coronary artery in 8 dogs was occluded for 15 min followed by reperfusion in order to produce regional reversible myocardial ischemia. Perivascular Doppler probes were used to measure blood flow in the left anterior descending (LAD) and LCX coronary arteries. Fast inversion recovery-prepared gradient-recalled-echo images were acquired to delineate the ischemic area during occlusion, and the area of reversible ischemic injury at 1 and 30 min of reperfusion. The size of ischemic and reperfused ischemic myocardium were compared with the area at risk as determined by histochemical morphometry at post mortem. RESULTS: During LCX occlusion, LCX flow decreased from 16+/-1 to 0.2+/-0.1 ml/min. On contrast-enhanced images, ischemic myocardium was evident as a zone of relatively low signal intensity (SI) compared to normal myocardium. The size of the ischemic region was significantly smaller (30+/-2%) than at post mortem (36+/-3%; p<0.05). Immediately after reperfusion, LCX flow increased to 83+/-11 ml/min and the contrast medium caused greater enhancement in the reperfused ischemic region than in the normal myocardium (69+/-3 vs 42+/-3 arbitrary units; p<0.05). The increase in regional SI correlated closely with the increase in regional blood flow (r=0.73). At 1 min of reperfusion, the size of the reperfused ischemic myocardium was larger (48+/-3%, p<0.05) than the area at risk measured at post mortem. At 30 min of reperfusion, when the flow returned to baseline values (16+/-2 ml/min), contrast bolus produced no differential enhancement between the 2 myocardial territories. CONCLUSION: MR perfusion imaging has the potential to detect and quantify the size of ischemic myocardium and the region of post-occlusive hyperemia in the early reperfusion period. There is a significant direct linear relationship between the regional contrast enhancement of reperfused ischemic myocardium and the blood flow during post-occlusive hyperemia. The difference in the size of the area at risk at MR perfusion imaging and at histochemical morphometry may reflect an influence of coronary collateral circulation.

Measurement of collateral blood flow in a porcine model of aortic coarctation by velocity-encoded cine MRI.

The purpose of this study was to investigate the time course of development of collateral blood flow in an animal model of aortic coarctation. A juxtaductal aortic stenosis (model coarctation) was surgically created in five juvenile pigs. MRI was performed preoperatively, 1 to 2 days postoperatively, and 2 to 10 weeks postoperatively. Aortic blood flow was measured by velocity-encoded cine MR (VENC-MR). The percent change in aortic blood flow (delta BF) from proximal to distal descending thoracic aorta was calculated, and a multiple-comparison paired t test used to assess changes in delta BF over time. Invasive flow measurements were obtained in one animal before sacrifice using an ultrasonic probe. delta BF preoperatively was -2 +/- 8% (mean +/- SE). delta BF increased to 32 +/- 7% (mean +/- SE, P = .022) 2 days postoperatively and 55 +/- 19% (P = .032) 2 to 8 weeks postoperatively. Invasive measurements were in qualitative agreement with the VENC-MR data. VENC-MR is an accurate noninvasive method of measuring collateral blood flow in aortic coarctation. Recruitment and development of collateral flow pathways occur rapidly in an animal model.

Quantification of coronary artery volume flow rate using fast velocity-encoded cine MR imaging.

OBJECTIVE: Breath-hold velocity-encoded cine (VENC) MR imaging has been proposed as a method for measuring coronary blood flow. However, most studies have measured velocity rather than volume flow rate in the coronary arteries. The purpose of this study was to measure volume flow rate in the coronary artery of dogs using high-speed gradients and to compare MR flow measurements with those obtained with a sonographic flowmeter. MATERIALS AND METHODS: Fast VENC MR images were obtained with a high-speed-gradient 1.5-T MR system in seven anesthetized dogs before and after administration of dipyridamole. Images were acquired on double oblique planes perpendicular to the left anterior descending arteries with a slice thickness of 5 mm, a field of view of 20 x 10 cm, a velocity window of +/- 1 m/sec, an average imaging time of 21 sec, a TR/TE of 11/5, and a temporal resolution of 44 msec. RESULTS: Coronary flow measured with VENC MR imaging correlated well with flow measured by the flowmeter (r = .95, slope = 0.97, n = 88). Interobserver variability in measuring coronary flow volume was 8%. CONCLUSION: Fast VENC MR imaging with high-speed gradients can provide accurate quantification of volume flow rate in coronary arteries.

Alterations in T1 of normal and reperfused infarcted myocardium after Gd-BOPTA versus GD-DTPA on inversion recovery EPI.

This study tested whether Gd-BOPTA/Dimeg or Gd-DTPA exerts greater relaxation enhancement for blood and reperfused infarcted myocardium. Relaxivity of Gd-BOPTA is increased by weak binding to serum albumin. Thirty-six rats were subjected to reperfused infarction before contrast (doses = 0.05, 0.1, and 0.2 mmol/kg). delta R1 was repeatedly measured over 30 min. Gd-BOPTA caused greater delta R1 for blood and myocardium than did Gd-DTPA; clearance of both agents from normal- and infarcted myocardium was similar to blood clearance; plots of delta R1 myocardium/delta R1 blood showed equilibrium phase contrast distribution. Fractional contrast agent distribution volumes were approximately 0.24 for both agents in normal myocardium, 0.98 and 1.6 for Gd-DTPA and Gd-BOPTA, respectively, in reperfused infarction. The high value for Gd-BOPTPA was ascribed to greater relaxivity in infarction versus blood. It was concluded that Gd-BOPTA/Dimeg causes a greater delta R1 than Gd-DTPA in regions which contain serum albumin.

Transient cerebral ischemia. Association of apoptosis induction with hypoperfusion.

Apoptosis is thought to be important in the pathogenesis of cerebral ischemia. The mechanism of apoptosis induction remains unclear but several studies suggest that it is preferentially triggered by mild/moderate microcirculatory disturbances. We examined in cats whether induction of apoptosis after 2.5 h of unilateral middle cerebral artery occlusion plus 10 h of reperfusion is influenced by the degree of cerebral microcirculatory disturbance. Quantitative monitoring over time of the disturbances of cerebral microcirculation in ischemic brain areas and evaluation of cytotoxic edema associated with perfusion deficits was achieved by using two noninvasive magnetic resonance imaging techniques: (a) high-speed echo planar imaging combined with a bolus of magnetic susceptibility contrast agent; and (b) diffusion-weighted imaging. Apoptosis-positive cells were counted in anatomic areas with different severity of ischemic injury characterized by magnetic resonance imaging, triphenyltetrazolium chloride, and hemotoxylin and eosin staining. The number of apoptosis-positive cells was significantly higher in anatomic areas with severe perfusion deficits during occlusion and detectable histologic changes 10 h after reperfusion. In contrast, in areas where perfusion was reduced but maintained during occlusion there were no detectable histological changes and significantly fewer apoptosis-positive cells. A similar number of cells that undergo apoptosis were shown in regions with transient or prolonged subtotal perfusion deficits. These results suggest that the apoptotic process is induced in the ischemic core and contributes significantly in the degeneration of neurons associated with transient ischemia.

Quantification of the extent of area at risk with fast contrast-enhanced magnetic resonance imaging in experimental coronary artery stenosis.

Fast magnetic resonance (MR) imaging techniques have the capability of demonstrating regions of ischemia caused by stenosis. The size of the potentially ischemic area determines the importance of the stenosis. The purpose of this study was to determine the relative values of relaxivity-enhancing and magnetic-susceptibility MR contrast media in detecting and sizing the area at risk in dogs. Eight dogs were subjected to critical left circumflex coronary artery (LCX) stenosis. Sixty sequential inversion-recovery- and driven-equilibrium-prepared fast gradient recalled echo images were acquired during bolus administration of 0.03 mmol/kg gadodiamide or 0.4 mmol/kg sprodiamide in basal and vasodilated (dipyridamole-stress) states. The size of the area at risk was measured and compared with that measured post mortem. In the basal state, gadodiamide and sprodiamide equivalently altered the signal intensities of nonischemic myocardium and the territory of stenosed coronary artery. Dipyridamole produced a significant increase in left anterior descending coronary artery flow with a decrease in LCX flow. The hypoperfused region was observed as a low-and high-signal intensity region after administration of gadodiamide and sprodiamide, respectively. The size of the hypoperfused region was slightly smaller with gadodiamide (37.4% +/- 2.8%) and sprodiamide (34.0% +/- 2.2%) than the true area at risk measured post mortem (41.8% +/- 2.2%; p < 0.05). Dipyridamole perfusion MR imaging with relaxivity or susceptibility contrast media is a noninvasive method to identify and quantify the area at risk in the territory of a stenotic coronary artery. Changes in myocardial signal intensity on fast gradient recalled echo images reflect the augmentation of flow and volume induced with dipyridamole and are consistent with the "steal phenomenon."

Acute hemodynamic effects of recently developed monomer and dimer magnetic resonance imaging contrast media: a comparative study.

RATIONALE AND OBJECTIVES: We evaluated and compared the acute cardiovascular effects of equiosmolar doses of recently developed nonionic monomer and macrocyclic dimer magnetic resonance (MR) imaging contrast media with the clinically available ionic and nonionic MR contrast media. METHODS: Normotensive adult Sprague-Dawley rats were divided into six groups of seven rats per group. Group 1 received the nonionic monomer Gd-CMPA-BMPA (500 mmol/l solution); group 2 received the nonionic dimer Gd(2)2(O)DO3A (500 mmol/l solution); group 3 also received Gd(2)2(O)DO3A but at a higher concentration (1,000 mmol/l solution); group 4 received gadopentetate dimeglumine (500 mmol/l solution); and group 5 received gadodiamide (500 mmol/l solution). Each rat received a rapid (1-2 sec) bolus intravenous injection of 0.1, 0.25, and 0.5 mmol/kg of each contrast agent. Group 6 was used to test the peak effects of quiosmolar glucose solutions (500, 1,000, and 2,000 mOsm/kg water). Data were acquired at baseline, 20 sec (peak effect) after injection, and 1, 3, 5, and 10 min after injection. Peripheral (systolic, diastolic, and mean) pressure, central venous pressure, left ventricular (LV) pressure (peak systolic and end diastolic) pressure, first derivative of left ventricular pressure (+/-dP/dt), rate pressure product, and heart rate were measured. RESULTS: Bolus administration (0.1, 0.25, and 0.5 mmol/kg) of Gd-CMPA-BMPA and gadodiamide (500 mmol/l) had no significant effects on the monitored cardiovascular parameters. Bolus injection of 0.25 and 0.5 mmol/kg Gd(2)2(O)DO3A (500 and 1,000 mmol/l) and gadopentetate dimeglumine (500 mmol/l) caused transient cardiovascular depression, including decreased peripheral blood pressure, LV systolic pressure, peak positive and negative dP/dt, and rate pressure product, but an increased LV end diastolic pressure. These cardiovascular effects were slightly less profound than those produced by gadopentetate dimeglumine. CONCLUSION: Gd-CMPA-BMPA and gadodiamide have no adverse cardiovascular effects. Gd(2)2(O)DO3A and gadopentetate dimeglumine cause vasodilation and reduced cardiac performance. Therefore, presuming similar effects, if Gd(2)2(O)DO3A and gadopentetate dimeglumine are to be used at high doses for the MR quantification of blood volume or as a bolus for perfusion study, appropriate consideration should be given to possible adverse physiologic changes.

MR imaging characterization of postischemic myocardial dysfunction ("stunned myocardium"): relationship between functional and perfusion abnormalities.

Stunned myocardium has been detected in patients treated successfully with thrombolytic agents. The hypothesis of this study was that fast gradient echo (GRE) imaging could be used to characterize the regional functional and perfusion abnormalities that are indicative of myocardial stunning. This study was designed to monitor and correlate the extent of wall thickness and perfusion abnormalities as determined by fast (segmented k space) cine and contrast enhanced GRE imaging, respectively. Dogs were subjected to left circumflex (LCX) coronary artery occlusion (15 min) followed by 30-minute reperfusion (n = 8). Perivascular flow probes were used to continuously measure flow in left anterior descending (LAD) and LCX coronary arteries. Short-axis inversion recovery prepared fast GRE and cine images were acquired at baseline, at occlusion, and at 1, 10, and 30 minutes of reflow. Regional signal intensity and percent systolic wall thickening were determined at 26 equally spaced circumferential positions to compare the extent of functional and perfusion abnormalities. During occlusion and reperfusion, the ischemic region was demonstrated on contrast-enhanced images as a hypointense and hyperintense region, respectively. During occlusion, the extent of the perfusion defect (32% +/- 2% of the circumference of the equatorial slice) correlated closely (r = .74) with the extent of contractile dysfunction (35% +/- 2%). After reperfusion, there was transient recovery in the percent wall thickening (26% +/- 4% vs 36% +/- 4% normal), coinciding with the reactive hyperemic response, but this was followed by a significant decline in wall thickening at 10 minutes (19% +/- 4%) and 30 minutes (12% +/- 2%). Fast MR imaging may be useful to monitor postischemic myocardial abnormalities after thrombolytic therapy and the response to pharmacologic interventions.

Evaluation of the effects of intravascular MR contrast media (gadolinium dendrimer) on 3D time of flight magnetic resonance angiography of the body.

The aims of this preliminary study were to establish the efficacy and minimum effective dose of TG(5)(FdDO3A)(52) gadolinium dendrimer for contrast-enhanced, three-dimensional (3D) time of flight (TOF) magnetic resonance angiography (MRA) of the body. In a dose ranging study in eight rabbits (Group A), each of two animals received 0.03; 0.02; 0.01; or 0.005 mmol/kg of the agent for 3D-TOF MRA of the pelvic circulation in the axial and coronal planes. An additional nine animals (Group B) received a dose of 0.02 mmol/kg for 3D-TOF MRA of the mediastinum, abdomen or of the lower limbs. Quantitative and qualitative analyses of the images from Group A demonstrated a dose-related reduction in saturation effects and improved visualization of vascular structures, with maximal augmentation of the contrast-to-noise ratio (CNR) at 0.03 mmol/kg. The dose of 0.02 mmol/kg was found to be the minimal effective dose at the three vascular regions.