Comparative study between gadobenate dimeglumine and gadobutrol in rats with brain ischemia: evaluation of somatosensory evoked potentials

RATIONALE AND OBJECTIVES: The present study had two main objectives: to validate a rat model of brain ischemia in terms of somatosensory evoked potentials (SEPs) and to compare, using the validated model, the potential activity on the somatosensory function of the new, approved contrast agent gadobenate dimeglumine with that of gadobutrol, a specific contrast agent, for magnetic resonance imaging of the brain. METHODS: Rats were prepared for SEP recording at least 5 days before ischemia induction. Ischemia was induced by 30-minute right middle cerebral artery occlusion and 3-day reperfusion. The SEP responses, evoked contralaterally to the stimulated upper limb, were recorded from the primary somatosensory cortical area. Model validation, on day 3 after occlusion, was performed using iopromide, an iodinated contrast agent poorly neurotolerated in rats, intravenously injected at 7 g I/kg. The comparative study between gadobenate dimeglumine and gadobutrol was performed at an intravenously injected dose of 2 mmol/kg. Somatosensory evoked potential responses were measured as peak latencies (P2 and N2) and peak-to-peak amplitude (P2N2). The brain concentration of iopromide was measured by high-performance liquid chromatography, whereas that of the gadolinium contrast agent was measured by inductively coupled plasma-atomic emission spectrometry analysis; given the absence of metabolism for both contrast agents, the gadolinium content values can be interpreted as representing unmetabolized contrast agent. RESULTS: In the ischemic rats, the SEP responses of the lesioned hemisphere showed significant increases in P2, N2, and interpeak N2-P2 latencies and a significant reduction in peak-to-peak (P2N2) amplitude. In the validation experiments, iopromide dramatically increased the P2N2 amplitude of the SEP responses recorded from both hemispheres of ischemic rats without affecting the P2, N2, and interpeak N2-P2 latencies. The iopromide effect was coupled with high concentrations of the contrast agent in the brain. Iopromide had no effect on healthy rats. In the comparative study, gadobenate dimeglumine did not induce any alteration in SEP components of either the lesioned or unlesioned hemisphere of ischemic rats. In fact, no significant difference was found between responses obtained before and after gadobenate dimeglumine injection. Gadobutrol, administered at the same dose, on the whole showed the same behavior as gadobenate dimeglumine, although a slight but significant decrease in the P2 latency, a sign of excitatory activity, was observed 2 hours after injection. Analytic data indicated higher levels of contrast agent in the lesioned hemisphere versus the unlesioned hemisphere 2 hours after injection. CONCLUSIONS: Based on these results, three conclusions can be drawn: (1) the evaluation of SEPs in ischemic rats is a useful tool for assessing the potential neurological effects of a new contrast agent because ischemic and contrast agent effects can be clearly differentiated; (2) the experimental conditions used allow the contrast agents to penetrate into the brain, where their activity can be manifested and evaluated; and (3) the complete absence of neurological activity of gadobenate dimeglumine shows its safety profile and confirms its suitability for use in neurological diseases for which contrast-enhanced magnetic resonance imaging is indicated.     

Early MR detection of experimentally induced cerebral ischemia using magnetic susceptibility contrast agents: comparison between gadopentetate dimeglumine and iron oxide particles.

PURPOSETo evaluate early patterns of MR changes in a rat model of cerebral ischemia using the first pass of two magnetic susceptibility contrast agents.METHODSOne hours after endovascular middle cerebral artery occlusion, all animals were examined in an experimental MR unit. After bolus application of gadopentetate dimeglumine and, 10 minutes later, of iron oxide particles, the MR changes of the first pass of these contrast agents were followed using a T2*-weighted fast low-angle shot sequence. Time-density curves of both contrast agents were analyzed and compared.RESULTSAfter bolus injection of either (paramagnetic) gadopentetate dimeglumine or superparamagnetic particles, nonischemic brain parenchyma decreased markedly in signal, whereas the ischemic brain area remained relatively hyperintense (and thus became clearly delineated). Only after application of gadopentetate dimeglumine did a mild reduction in signal occur in the ischemic hemisphere, although the main artery was occluded. An explantation for this phenomenon might be residual capillary perfusion (plasma flow), which is detectable only when the smaller (paramagnetic) contrast molecules are being used.CONCLUSIONSCerebral perfusion deficits can be detected 1 hour after vascular occlusion with T2*-weighted fast low-angle shot sequences and bolus injection of paramagnetic or superparamagnetic MR contrast agents. Gadopentetate dimeglumine may be used as a marker of microcirculatory plasma flow.     

Protective Effects of Repetitive Injections of Radiographic Contrast Media on the Subsequent Tolerance to Ischemia in the Isolated Rat Heart

Purpose: Despite detailed knowledge of the effects of X-ray contrast media on cardiac function, no studies have examined the effect of contrast media injections on the subsequent tolerance to ischemia in the heart. Methods: Isolated perfused rat hearts were exposed to repetitive injections of iohexol, iodixanol, or ioxaglate before 30 min of global ischemia and 120 min of reperfusion. These groups were compared with control (no pretreatment) and ischemic preconditioning known to reduce infarct size. Physiologic variables and infarct size were measured Results: Pretreatment with iodixanol reduced infarct size significantly compared with control and thus afforded protection against ischemia. Injections with iohexol and ioxaglate reduced infarct size, although not significantly, compared with control. Conclusion: Pretreatment of the isolated rat heart with commonly used contrast media enhances the cardiac tolerance to subsequent ischemia. The mechanism behind this protective effect could not be determined, but could involve stretching of the heart and/or generation of nitric oxide.     

Gd(ABE-DTTA)-enhanced cardiac MRI for the diagnosis of ischemic events in the heart

PURPOSE: To demonstrate that contrast-enhanced MRI (ceMRI) with the aid of Gd(ABE-DTTA) is able to detect ischemic events in the heart in a canine ischemia/reperfusion (30/40 minutes) model. MATERIALS AND METHODS: ECG-gated, T1-weighted MR image sets (four to five slices each) with three-minute time resolution were collected in transiently LAD-occluded dogs. Following the acquisition of control image sets, ischemia was started by occluding the LAD. Either Gd(ABE-DTTA) (N = 6) or Gd(DTPA) (N = 6) was injected, and imaging was continued for 30 minutes of ischemia and 40 minutes of reperfusion. The contrast agent (CA)-induced MRI signal intensity enhancement (SIE) and contrast were monitored. Microspheres measured myocardial perfusion (MP) to verify areas of ischemia and reperfusion. RESULTS: SIEs of 86% +/- 3% and 97% +/- 3% in nonischemic, and 25% +/- 5% and 29% +/- 8% in ischemic regions were found within three minutes of onset of ischemia with Gd(ABE-DTTA) and Gd(DTPA), respectively. For the rest of the 30 minutes of ischemia, with Gd(ABE-DTTA) SIE of 60% +/- 3% and 25% +/- 5% persisted in the nonischemic and ischemic regions, respectively. With Gd(DTPA), however, SIE in the nonischemic areas decreased rapidly after the first three minutes of ischemia, while SIE in the ischemic areas increased, abolishing contrast. Thus, there was a persistent contrast with Gd(ABE-DTTA) and a short-lived contrast with Gd(DTPA) during ischemia. Furthermore, with Gd(ABE-DTTA) some contrast was still visible in the early reperfusion period. CONCLUSION: Gd(ABE-DTTA) in an ischemia/reperfusion model induces a persistent MRI contrast between regions of normal and ischemic myocardium, and verifies reperfusion. Therefore, it can be used to detect myocardial ischemic events.     

Effects of contrast media on myocardial function during acute left ventricular failure in the dog

We studied the hemodynamic side effects of intracoronary injection of contrast media during acute ischemic heart failure by using anesthetized dogs. Induction of failure was performed by microembolization of the area supplied by the left main coronary artery. Six ml of iohexol (Omnipaque) increased contractility during the normal state, while this contrast medium induced no alterations in any of the recorded hemodynamic variables during left ventricular failure. Ioxaglate (Hexabrix) was also well tolerated during the normal state, while sodium-meglumine diatrizoate (Renografin) markedly decreased systolic variables. However, in the failing heart both ioxaglate and diatrizoate resulted in greater reduction in all systolic variables than in the normal heart. We conclude that both ionic contrast media may be harmful in acute ischemic heart failure. Non-ionic iohexol appears safer in this condition.     

Comparison of Fenestra VC Contrast-enhanced computed tomography imaging with gadopentetate dimeglumine and ferucarbotran magnetic resonance imaging for the in vivo evaluation of murine liver damage after ischemia and reperfusion

OBJECTIVES: Comparison of intravenous Fenestra VC-enhanced computed tomography (CT) with gadopentetate dimeglumine and Ferucarbotran contrast-enhanced magnetic resonance imaging (MRI) for the in vivo imaging of hepatic ischemia/reperfusion injury (IRI) in a murine model. MATERIAL AND METHODS: After induction of hepatic IRI by left liver lobe (LLL) ischemia (30, 45, and 75 minutes) and reperfusion (4 hours and 24 hours), a total of 130 mice were imaged either by Fenestra VC-enhanced 3-D CT or by dynamic, T1-weighed gadopentetate dimeglumine or static, T2*-weighed Ferucarbotran 2-D MRI (4.7 T). RESULTS: Detection of liver tissue damage as a consequence of IRI was not possible by CT or MRI without the use of contrast media. (1) Mice subjected to liver IRI (45 minutes of ischemia) and injected with Fenestra VC showed a distinct liver enhancement of the viable liver tissue or a nonenhancement of the necrotic tissue. The Fenestra VC CT-unenhanced liver volume increased as a function of time of ischemia and reperfusion. The unenhanced liver volume also correlated positively with serum liver enzyme activities and damage scores from liver histology. (2) The signal intensities (SI) between normal liver tissue and livers subjected to 30 minutes of ischemia were not different on dynamic gadopentetate dimeglumine-enhanced magnetic resonance images. More severe IRI as induced by 45 or 75 minutes of ischemia was characterized by (a) early hyperenhancement of regions in the LLL with rapid increase of SI higher than that observed in the undamaged liver within the first few minutes and (b) delayed hyperenhancement in the later course after gadopentetate dimeglumine injection, respectively. (3) Ferucarbotran MRI detected signs of IRI after only 30 minutes of liver ischemia and hence detected IRI earlier than Fenestra VC or gadopentetate dimeglumine. With longer duration of ischemia, Ferucarbotran SI increased in the LLL, but viable and necrotic tissues were not clearly distinguishable. CONCLUSIONS: MicroCT with Fenestra VC enhancement and MRI using either gadopentetate dimeglumine or Ferucarbotran enhancement of the liver revealed that all techniques allow in vivo determination of hepatic IRI as a function of the duration of ischemia and reperfusion of the liver. However, Fenestra VC-enhanced CT of the murine liver is superior to gadopentetate dimeglumine and Ferucarbotran for localization, quantification, and differentiation of viable from metabolically inactive/damaged liver tissue after hepatic ischemia/reperfusion but Fenestra VC is less sensitive than Ferucarbotran to detect the early onset of subtle consequences of hepatic IRI.     

Quantitative assessment of myocardial enhancement with iodinated contrast medium in patients with ischemic heart disease by using ultrafast x-ray computed tomography.

BACKGROUND AND RATIONALE. The authors report the quantitation of myocardial enhancement using iodinated contrast medium in patients with ischemic heart disease. Twenty-eight patients with chronic ischemic heart disease and 11 controls were examined by ultrafast computed tomography (CT) using 100-msecond scans. METHODS. The authors analyzed M/L (ratio of post-contrast incremental increases in the left ventricular myocardial and luminal CT number) in early and late phases after contrast injection. RESULTS. In controls, mean values of early and late M/L were 30% and 51%, respectively. In infarcted or severely ischemic segments, early M/Ls (19%, 16%) were significantly small (P less than .001), whereas late M/Ls (90%, 63%) were higher (P less than .001, .01) than controls. Segments with infarction or severe ischemia were differentiated from mild or nonsignificant ischemia by using this parameter (sensitivity, 99%; specificity, 88%). CONCLUSIONS. M/L is useful for detection of the ischemic myocardium.     

A survey of contrast media used in coronary angiography

In recent years, various contrast media have been developed for use in coronary angiography. These contrast media may be divided into ionic contrast media of high osmolality, those of low osmolality, and nonionic contrast materials. We conducted our own clinical studies with 40 patients. In random succession a standard contrast medium (ionic, of high osmolality) and a new-generation contrast medium (either nonionic or ionic with low osmolality) were injected into the right and left coronary arteries. After each injection we measured the systolic and diastolic blood pressure using a liquid-filled coronary catherter. In addition, the change in the length of the cardiac cycle was registered in terms of the R-R interval (in ms) and at the same time, leads I, II, and III of the ECG were recorded. We studied the influence of the various contrast media on the activity of ATPase in in vitro experiments, using Lasser and Lang's [30]. When ionic contrast media of low osmolality and nonionic contrast media were utilized the heart rate showed no change. Disturbances of rhythm such as ventricular tachycardia or fibrillation were not observed. All of the contrast media used produced the same ECG changes. These changes can be ascribed to the inhibition of ATPase. The arterial blood pressure was lowered significantly only by ionic contrast media of high osmolality only.     

心肌梗塞X线心脏形态改变的探讨

本文结合心电图对７２例心肌梗塞Ｘ线胸片进行观察，探讨心肌梗塞心脏Ｘ线表现及其相关因素，结果如下：１、心脏增大率５４．２％，左心室增大为主，７６．９％呈主动脉型增大。左心房增大与左心衰和乳头肌功能异常有关。右心室增大多为继发性。２、心肌缺血是心肌梗塞心脏增大的主要原因，缺血组心脏增大率及左心横径均数都高于无缺血组（Ｐ均＜０．００５）。前壁大面积梗塞也是导致心脏增大的原因之一。高血压并非影响心肌梗塞心脏增大的主要原因。３、２６．４％病例显示肺循环异常，上肺静脉扩张是常见表现。肺循环异常的发生率随心脏增大程度而升高（Ｐ＜０．００５）。     

移植成血管基因修饰MSCs改善心肌梗死大鼠左室血流动力学参数的研究

目的探讨大鼠心肌梗死模型缺血心肌局部移植血管内皮生长因子（vascular endothelial growth factor,VEGF）修饰的骨髓间充质干细胞（mesenchymal stem cells,MSCs）对左室血流动力学参数的影响。方法 Percoll液密度梯度离心法分离、贴壁培养Wistar近交系大鼠MSCs,真核表达载体pcDNA3.1（-）/hVEGF165转染MSCs。30只Wistar近交系大鼠随机均分为转染组（MSCs/VEGF组）、对照组（MSCs组）、无血清培养基组（DMEM组）。结扎前降支建立急性心肌梗死模型后在梗死区边缘区行5×106（40μl）细胞移植,DMEM组行等量培养基注射。移植前细胞行CM-DiI标记。移植1个月后行心脏B超测量EF值,经右侧颈内动脉左室内置管测量如下血流动力学参数：心率（heart rate,HR）、左室收缩末压（left ventricularend-systolic pressure,LVESP）、左室舒张末压（left ventricular end-diastolic pressure,LVEDP）、最大左室内压上升速率（＋dp/dtmax）、最大左室内压下降速率（-dp/dtmax）。大体标本组织行HE、Masson染色。结果培养的MSCs呈典型贴壁生长成纤维细胞样外观,CM-DiI能近100%标记MSCs。移植后1个月MSCs/VEGF组较其余两组LVEF、LVESP、LVEDP、＋dp/dtmax、-dp/dtmax值有显著性差异（P〈0.05）,大体标本HE、Masson染色染色病理变化亦明显优于其余两组。结论大鼠心肌梗死模型梗死心肌局部移植VEGF基因转染MSCs能显著改善左室血流动力学参数,进而改善心脏功能。     

心腔内超声评价心脏结构和左室收缩功能的实验研究

目的:研究心腔内超声探查心脏结构和评价左室收缩功能的方法。方法:AcuNav心腔内超声导管置于健康犬右房、右室,二维图像显示左右心腔、心瓣膜、肺静脉、冠状动脉、主动脉、肺动脉等结构,彩色及频谱多普勒记录血流状况。开胸制作犬急性心肌缺血再灌注模型,观察室壁运动和左室射血分数改变。结果:所有目标结构及血流均获得清晰显示,未发生导管相关的严重并发症。心腔内超声示心肌缺血再灌注过程中前壁厚度、增厚率、左室射血分数动态改变。结论:心腔内超声可安全、清晰地显示心脏结构和血流状态,并评价左室收缩功能。     

Neurotolerability of contrast agents in rats with brain ischemia induced by transient middle cerebral artery occlusion: EEG evaluation

RATIONALE AND OBJECTIVES: Because contrast agent (CA) formulations are injected intravenously to patients who may have a disrupted blood-brain barrier, their neurotolerability should be tested by using appropriate animal models. In the present study, a model of rat brain ischemia evaluated in terms of the electroencephalogram (EEG) was validated and then used to compare the neurotolerability of gadobenate dimeglumine to that of gadodiamide, a well-documented CA for brain MRI. METHODS: Rats were prepared for EEG recording about 15 days before ischemia induction. Ischemia was induced in the right hemisphere by 2-hour middle cerebral artery (MCA) occlusion and 3-day reperfusion. Model validation in terms of EEG, on day 3 after MCA occlusion, was performed by using iopromide, a poorly neurotolerated iodinated CA in rats, intravenously injected at 7 g iodine/kg. The EEG recording was analyzed for pathological tracings and for changes in spectral content in terms of the frequency index (FI) at 1, 2, and 3 hours after test compound injection. The comparative study between gadobenate dimeglumine and gadodiamide was performed at 2.0 mmol/kg. D-Mannitol was used as a control compound. The presence of CA in the rat brain was verified by measuring the total gadolinium content by using inductively coupled plasma-atomic emission spectrometry analysis. Given the absence of metabolism for both CAs, the values of gadolinium content can be interpreted as representing unmetabolized CA. RESULTS: On days 1, 2, and 3 after transient MCA occlusion, the lesioned hemisphere of rats presented a decreased FI value with respect to the basal value. The unlesioned hemisphere, after a slight, nonsignificant decrease in the FI value on the first 2 days, presented a normal FI value on day 3. Thus, ischemic rats on day 3 after transient MCA occlusion were chosen for these neurotolerability studies. Iopromide injected intravenously into ischemic rats at a dose 10 times higher than the maximum clinical dose caused bilateral spikes on the EEG and increases in FI values for the unlesioned hemisphere without affecting the lesioned hemisphere. Gadobenate dimeglumine, like gadodiamide when injected into ischemic rats, did not cause spikes or further changes in the FI value of the lesioned hemisphere and did not modify the normal FI value of the unlesioned hemisphere. Furthermore, no significant differences between gadobenate dimeglumine, gadodiamide, and D-mannitol were found when postinjection FI values were compared. Finally, higher levels of gadolinium were found in the lesioned hemisphere with respect to the unlesioned hemisphere after both gadobenate dimeglumine and gadodiamide administration. CONCLUSIONS: We can therefore conclude that (1) on the EEG, ischemia induced by transient MCA occlusion is an appropriate model for evaluating CA neurotolerability because ischemic and CA effects can be clearly differentiated; (2) the higher level of CA in the lesioned hemisphere compared with the unlesioned one (two to three times), even 3 hours after injection, demonstrates that the CA effectively penetrated the brain; if it were neurotoxic, any negative effects would have been detected; and (3) gadobenate dimeglumine, like gadodiamide, injected intravenously at a dose 20 times higher than the intended clinical dose for brain MRI is well tolerated and, also like gadodiamide, is suitable for use in neurological diseases for which contrast-enhanced MRI is indicated.     

Do contrast media (iomeprol, gadopentetate dimeglumine) deteriorate ischemia/reperfusion injury of the liver?

Background: Hepatic microcirculation is a main determinant of reperfusion injury and graft quality in liver transplantation. One of the important diagnostic procedures to recognize reperfusion failure is contrast-enhanced computed tomography or magnetic resonance imaging.

Purpose: To examine the additional effect of contrast media (iomeprol and gadopentetate dimeglumine) on hepatic microcirculation and hepatic cellular damage in the phase of early ischemia/reperfusion injury of the rat liver.

Material and Methods: The partial warm ischemia-reperfusion injury model of rat liver was used. Microcirculation and leukocyte-endothelium interaction were measured by intravital microscopy. Hepatic cellular damage was indicated by liver enzyme activity in the sera. The evaluation parameters were measured at baseline and at 30, 60, and 90 min after reperfusion. The contrast media (iomeprol group, n = 6; gadopentetate dimeglumine group, n = 6) or Ringer's solution (control group, n = 8) were applied after 30 min of reperfusion.

Results: No additional injury to the ischemia/reperfusion injury of the liver after intravenous application of radiographic contrast media was found. Some protective effect was even recorded after application of iodinated contrast media.

Conclusion: The use of contrast media during diagnostic procedure of the liver seems to be relatively safe, even in the stage of early reperfusion after liver transplantation.     

Evaluation of an experimental low-attenuation gastrointestinal contrast agent for CT imaging of intestinal ischemia in an animal model

RATIONALE AND OBJECTIVES: The authors evaluated the use of MRX-320, a low-attenuation, expansile oral contrast agent, for the demonstration of intestinal ischemia in an animal model. MATERIALS AND METHODS: Nine dogs were given either MRX-320, water, or diatrizoate as an oral contrast agent through a jejunostomy tube. Two dogs received no oral contrast agent. Helical computed tomography (CT) was performed before the intravenous injection of 2.5 mL/kg iohexol at 4 mL/sec, during the arterial phase, and during the portal venous phase. Mesenteric ischemia was surgically induced, and the imaging protocol was repeated. Three readers rated the randomly assigned images for quality and demonstration of ischemia. Attenuation values for the intestinal lumen and wall were recorded. RESULTS: Examinations performed with MRX-320 provided the best discrimination between ischemic and nonischemic conditions (P < .05), followed by examinations with no oral contrast medium, examinations with water, and examinations with diatrizoate. Images obtained with MRX-320 also scored significantly higher on measures of image quality than those obtained with water or no oral contrast medium (P < .05). On images obtained with MRX-320, the bowel lumen measured -836.5 HU (P < .05 compared with other techniques). Water provided the least uniformity of distention, and diatrizoate provided the least mucosal detail. CONCLUSION: The use of MRX-320 as an oral contrast agent with an intravenous bolus of iohexol at CT increased reader confidence for the diagnosis of intestinal ischemia and improved subjective measures of image quality.     

Left ventricular systolic and diastolic function during coronary arteriography before and after acute left ventricular failure in dogs. A comparison between iodixanol, iohexol and ioxaglate

The hemodynamic side effects of intracoronary injection of low osmolality contrast media were studied in anesthetised dogs, both with and without left ventricular (LV) failure. LV failure was induced by microembolization of the area supplied by the left main coronary artery. LV pressure and volume, aortic pressure, and cardiac output were recorded. 6 ml iodixanol 320 mg I/ml containing 20 mmol Na+/l, a new non-ionic dimer, was compared to iohexol and ioxaglate. Iodixanol induced small systolic alterations both before and after LV failure. Iohexol increased LV inotropy while ioxaglate depressed myocardial function. Before failure iodixanol and ioxaglate impaired isovolumic relaxation, but early diastolic filling was not reduced. After failure the relaxation process was not affected, but ioxaglate reduced early diastolic filling. Ioxaglate also increased LV end-diastolic pressure and volume more than the non-ionic contrast media. In conclusion, iodixanol induced only small changes in systolic and diastolic function. Iodixanol should therefore be hemodynamically well tolerated during coronary arteriography, and also in acute ischemic heart failure.     

左心室心肌局部缺血的生物力学模型及计算机仿真研究

目的 研究心肌局部缺血的生物力学机制,探讨局部缺血时心室不同部位心肌纤维收缩功能变化。方法 以左室外部形状、心肌纤维的空间分布方向、电信号传播和心肌力学为基础,建立了左室心肌局部缺血的时变数学模型。然后将该模型嵌入我们已有的多元循环系统模型,分别仿真研究了内、外心室壁缺血时左室收缩力变化。结果 缺血区域心肌收缩力降低,非缺血区域收缩力显著增加;与心室壁外层心肌缺血相比,内层心肌缺血时对左室收缩功能影响更大。结论 心肌局部缺血时正常心肌区域具有代偿作用,以维持心脏的正常功能;本工作建立了左室心肌局部缺血与心血管系统功能关系的模拟实验方法。     

Simultaneous measurement of blood and myocardial velocity in the rat heart by phase contrast MRI using sparse q-space sampling

PURPOSE: To measure cardiac blood flow patterns and ventricular wall velocities through the cardiac cycle in anesthetized Wistar Kyoto (WKY) rats. MATERIALS AND METHODS: A gradient-echo cine pulse sequence incorporating pulsed field gradients (PFGs) provided phase contrast (PC) motion encoding. We achieved a range of velocity sensitivity that was sufficient to measure simultaneously the large flow velocities within the cardiac chambers and aortic outflow tract (up to 70 cm s(-1) during systole), and the comparatively small velocities of the cardiac wall (0-3 cm s(-1)). A scheme of sparsely sampling q-space combined with a probability-based method of velocity calculation permitted such measurements along three orthogonal axes, and yielded velocity vector maps in all four chambers of the heart and the aorta, in both longitudinal and transverse sections, for up to 12 time-points in the cardiac cycle. RESULTS: Left ventricular systole was associated with a symmetrical laminar flow pattern along the cardiac axis, with no appearance of turbulence. In contrast, blood showed a swirling motion within the right ventricle (RV) in the region of the pulmonary outflow tract. During left ventricular diastole a plume of blood entered the left ventricle (LV) from the left atrium. The ventricular flow patterns could also be correlated with measurements of left ventricular wall motion. The greatest velocities of the ventricular walls occurred in the transverse cardiac plane and were maximal during diastolic refilling. The cardiac wall motion in the longitudinal axis demonstrated a caudal-apical movement that may also contribute to diastolic refilling. CONCLUSION: The successful measurements of blood and myocardial velocity during normal myocardial function may be extended to quantify pathological cardiac changes in animal models of human cardiac disease.     

Mapping ischemic risk region and necrosis in the isolated heart using EPR imaging.

Reperfusion of ischemic tissue is a common event in the treatment of heart attack and stroke. To study disease pathogenesis, methods are required to measure tissue perfusion and area at risk, as well as localized regions of injury. While histology can provide this information, its destructive nature precludes assessment of time course. Thus, there is a critical need for a noninvasive technique to obtain this information. To map myocardial redox state as a possible index of cellular ischemia and viability, electron paramagnetic resonance (EPR) imaging experiments were performed on isolated rat hearts before and after the onset of regional ischemia using nitroxide spin labels. With coronary artery occlusion, the EPR images clearly showed the risk region as a void of lower intensity that reversed upon reperfusion. The extent of risk region in the heart was similar in EPR imaging and histological measurements. The unique information obtained regarding the time course of changes in redox metabolism of the risk region and normal myocardium can provide important insights regarding the mechanisms of myocardial injury during and following ischemia.     

Cardiac MRI in ischemic heart disease with severe coronary artery stenosis

RATIONALE AND OBJECTIVES: The aim was to evaluate the left ventricular wall motion abnormalities, perfusion and late contrast enhancement patterns on magnetic resonance imaging (MRI) in patients with 70% or higher degree stenosis or occlusion of coronary arteries on coronary angiography. MATERIALS AND METHODS: Twenty-four patients (5 women, 19 men, age range 38-78, mean age 59.1) who had 70% or higher degree stenosis or occlusion of coronary arteries on coronary angiography who had been referred for cardiac MRI were included. On coronary angiography, 20 vessels were totally occluded [left anterior descending artery (LAD) 12; left circumflex coronary artery (LCx) 2; right coronary artery 6] and 20 vessels were severely stenotic (70-99%). In 5 patients' three vessels, in 6 patients' two vessels, and in 13 patients' a single vessel was involved. Wall motion, perfusion abnormalities, and late contrast enhancement consistent with nonviable myocardium were analyzed at apical, at midventricular, and basal levels on short-axis images of cardiac MRI in concordance with the segmental irrigation areas of the coronary arteries. RESULTS: Impaired perfusion was observed on the corresponding irrigation segments of 39 vessels of 40 coronary artery branches. Wall motion abnormalities were present on corresponding irrigation areas of 30 severely stenotic vessels. Combined evaluation of wall motion and perfusion, segments with the decreased left ventricular contraction, and perfusion matched with the corresponding irrigation areas of all of the 40 stenotic or occluded vessels. CONCLUSION: A correlation was found between the combined assessments of myocardial perfusion, wall motion, and viability on late contrast enhancement on cardiac MRI with the clinical and angiography findings. Thus this combined MRI protocol can be used for the evaluation of ischemic heart disease.     

Imaging acute cardiac cell death: temporal and spatial distribution of 99mTc-labeled C2A in the area at risk after myocardial ischemia and reperfusion.

The exposure of anionic phospholipids is a near-universal molecular signature for cell death. Based on our prior finding that the (99m)Tc-labeled C2A domain of synaptotagmin I accumulates intensely in the area at risk, this study quantitatively characterized the temporal and spatial distribution of the radiotracer in a rat model of myocardial ischemia and reperfusion. METHODS: Myocardial ischemia and reperfusion were induced by occlusion of the left anterior descending coronary artery in rats. The temporal uptake of the labeled fusion protein of C2A and glutathione-s-transferase (C2A-GST) in the area at risk was investigated by intravenously injecting the radiotracer at 0, 1, 3, 6, and 24 h after reperfusion, and the radioactivity uptake was quantified by gamma-counting of infarcted and ischemic noninfarcted cardiac tissues. Alternatively, the radiotracer was injected at 2 h after reperfusion, and the uptake was measured at 1, 3, 6, and 24 h after injection. In vivo planar imaging was performed on a gamma-camera using a parallel-hole collimator. The distribution of radioactivity was qualitatively examined by autoradiography. The relationship between the uptake of the radiotracer in the area at risk and the ischemic duration was examined by gamma-counting. RESULTS: Temporally, the radioactivity uptake in the area at risk maximized when the radiotracer was injected before 3 h after reperfusion. Injections at 6 and 24 h after reperfusion resulted in a 30% and 50% reduction in uptake, respectively. However, when the injection was done early (2 h after reperfusion), the tracer was retained in the area at risk with little washout for at least 24 h. Spatially prominent hot-spot uptake was seen in all cases of planar imaging. In autoradiography, the distribution of radioactivity predominantly coregistered with the infarcted regions. This distribution profile was confirmed by direct gamma-counting. In addition, the absolute radiotracer uptake in the infarcted and ischemic noninfarcted tissues, in terms of percentage injected dose per gram, was independent of the ischemic duration. CONCLUSION: (99m)Tc-C2A-GST has an uptake profile in the area at risk that is appropriate for imaging cardiac cell death in the acute phase.