Monitoring dynamic alterations in calcium homeostasis by T (1)-weighted and T (1)-mapping cardiac manganese-enhanced MRI in a murine myocardial infarction model

Manganese has been used as a T(1)-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn(2+)) enter viable myocardial cells via voltage-gated Ca(2+) channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca(2+) regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca(2+) homeostasis in affected cardiac tissues are limited. This study implements a T(1)-mapping method to obtain quantitative information both dynamically and over a range of MnCl(2) infusion doses. To optimize the current Mn(2+) infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl(2) solution dose and increase in left ventricular wall relaxation rate (DeltaR(1)) was observed. Control mice also exhibited significant Mn(2+) clearance over time, with a decrease in DeltaR(1) of approximately 50% occurring in just 2.5 h. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. With the use of the measured relationship between infused Mn(2+) dose, DeltaR(1), and inductively coupled plasma mass spectrometry data analysis provided a means of estimating the absolute heart Mn concentration in vivo. We show that this technique has the sensitivity to observe or monitor potential alterations in Ca(2+) handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DeltaR(1) values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than in healthy tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future treatment or evaluation of disease progression.     

Manganese enhancement in non-CNS organs

Manganese-enhanced magnetic resonance imaging (MEMRI) is a novel imaging technique capable of monitoring calcium influx, in vivo. Manganese (Mn2+) ions, similar to calcium ions (Ca2+), are taken up by activated cells where their paramagnetic properties afford signal enhancement in T(1)-weighted MRI methodologies. In this study we have assessed Mn2+ distribution in mice using magnetization-prepared rapid gradient echo (MP-RAGE) based MRI, by measuring changes in T(1)-effective relaxation times (T(1)-eff), effective R(1)-relaxation rates (R(1)-eff) and signal intensity (SI) profiles over time. The manganese concentration in the tissue was also determined using inductively coupled plasma atomic emission spectrometry (ICP-AES). Our results show a strong positive correlation between infused dose of MnCl2 and the tissue manganese concentration. Furthermore, we demonstrate a linear relationship between R(1)-eff and tissue manganese concentration and tissue-specific Mn2+ distribution in murine tissues following dose-dependent Mn2+ administration. This data provides an optimized MnCl2 dose regimen for an MP-RAGE based sequence protocol for specific target organs and presents a potential 3D MRI technique for in vivo imaging of Ca2+ entry during Ca2+-dependent processes in a wide range of tissues.     

Myocardial infarction quantification with Manganese‐Enhanced MRI (MEMRI) in mice using a 3T clinical scanner

Manganese (Mn²⁺) was recognized early as an efficient intracellular MR contrast agent to assess cardiomyocyte viability. It had previously been used for the assessment of myocardial infarction in various animal models from pig to mouse. However, whether Manganese‐Enhanced MRI (MEMRI) is also able to assess infarction in the acute phase of a coronary occlusion reperfusion model in mice has not yet been demonstrated. This model is of particular interest as it is closer to the situation encountered in the clinical setting. This study aimed to measure infarction volume taking TTC staining as a gold standard, as well as global and regional function before and after Mn²⁺ injection using a clinical 3T scanner. The first step of this study was to perform a dose‐response curve in order to optimize the injection protocol. Infarction volume measured with MEMRI was strongly correlated to TTC staining. Ejection fraction (EF) and percent wall thickening measurements allowed evaluation of global and regional function. While EF must be measured before Mn²⁺ injection to avoid bias introduced by the reduction of contrast in cine images, percent wall thickening can be measured either before or after Mn²⁺ injection and depicts accurately infarct related contraction deficit. This study is the first step for further longitudinal studies of cardiac disease in mice on a clinical 3T scanner, a widely available platform. Copyright © 2010 John Wiley & Sons, Ltd.     

Cardiac contractility after transplantation of autologous mononuclear bone marrow cells in patients with myocardial infarction

Autologous bone marrow mononuclear cells were transplanted by intracoronary infusion to patients with myocardial infarction after recovery of coronary perfusion. Controls received traditional therapy alone. Echocardiography was carried out before and 3 and 6 months after cell therapy. Cell transplantation did not appreciably improved left-ventricular contractility in comparison with the control group. In none patient cell therapy provoked malignant ventricular arrhythmias. Intracoronary infusion of bone marrow mononuclear cells in patients with myocardial infarction did not improve cardiac contractility and did not aggravate the course of the disease. __________ Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 1, pp. 15–20, January, 2006     

Selective tissue accumulation of manganese and its effect on regional blood flow and haemodynamics after intravenous infusion of its chloride salt in the rat

Manganese chloride (MnCl2), with or without the addition of trace amounts of 54Mn2+, was administered as a 7-min i.v. infusion in rats. Tissue accumulation of 54Mn2+ was determined 0-15 min after the infusion, and cardiac output, regional blood flows and vascular resistances were measured 5 and 60 min after the infusion by the microsphere technique. The plasma half-life of 54Mn2+ was found to be 4.7 min. Mn2+ accumulated in several organs, the highest relative concentrations being seen in the liver, duodenum, jejunum, kidney and heart, and intermediate concentrations in the ileum, colon, stomach and spleen. There was no uptake in the lung, skeletal muscle or brain. During the infusion of 180 mumol/kg b.w. of Mn2+, the arterial blood pressure fell from a mean of 123 +/- 5 mm Hg to a minimum of 85 +/- 7 mm Hg, and thereafter returned to normal. Five minutes after termination of the infusion, there was a decrease in cardiac output and minute work but not in total peripheral resistance, a finding interpreted as a negative inotropic effect of Mn2+. At this time blood flow was decreased in the stomach, ileum, colon, spleen and skin, and increased in duodenum, jejunum and liver. The blood flows were normalized 60 min after termination of the infusion in all organs except the liver and heart. The effects are probably due to the calcium-antagonistic properties of Mn2+ and the tissue accumulation is most probably a result of intracellular accumulation through calcium channels. The relation between tissue accumulation and tissue selectivity of blood-flow alterations is unexplained.     

Effect of chemical sympathectomy on cardiac hypertrophy and hemodynamics following myocardial infarction in the rat

The effects of sympathectomy on cardiac structure and function were studied in an animal model of myocardial infarction. Ninety-six rats were double randomized to control or infarction disease state and to placebo or chemical sympathectomy (guanethidine, 30 mg/kg daily, intraperitoneal). Five weeks after anterior infarction, there was hypertrophy in placebo-treated animals in myocardial fibers remote from the infarct (9.8 +/- 1.8 microns in infarction vs 8.1 +/- 1.0 microns in control, p less than 0.05). However, myocardial hypertrophy was not present in guanethidine-treated animals (8.6 + 1.6 microns in infarction vs 8.0 + 0.6 microns in control, p = N.S.). Guanethidine treatment caused significant reductions in systolic arterial blood pressure and indices of left ventricular contractility and relaxation (p less than 0.05), but these effects were not different between infarct and control treatments (p = N.S.). Although both effects of guanethidine treatment (sympathectomy and hemodynamic) were correlated with myocardial fiber diameter by univariate analysis, only sympathectomy was significant by stepwise regression analysis (p less than 0.05). Therefore, the cardiac sympathetic nerves have important effects on the development of hypertrophy after myocardial infarction, and sympathectomy alters this process in the rat model.     

Induction of a reversible cardiac lipidosis by a dietary long-chain fatty acid (erucic acid). Relationship to lipid accumulation in border zones of myocardial infarcts.

Previous studies have demonstrated that cardiac myocytes in the border zone of acute myocardial infarction become markedly overloaded with neutral lipid during the transition from reversible to irreversible injury. To examine directly the role of these changes in neutral lipid metabolism in the development of irreversible cellular injury and associated increases in tissue Ca2+ content, the authors fed rats large amounts of a fatty acid (erucic acid) that is poorly oxidized by the heart and that subsequently accumulates as neutral lipid. Rats fed a high erucic acid (C22:1) diet in the form of 20% rapeseed oil for 3-5 days had a fourfold increase in triglyceride (49.5 +/- 3.8 SEM mg/g wet wt versus 13.6 +/- 13, n = 4) and a 60% increase in long-chain acyl CoA content (166.0 +/- 21.9 versus 91.5 +/- 9.0 nM/g wet wt, n = 4), compared with controls. However, there was no change in long-chain acyl carnitine or total phospholipid content. Histochemical studies showed accumulation of numerous lipid droplets in the myocytes, and electron microscopy revealed localization of lipid vesicles in direct contact with mitochondria, thus mimicking the lipid-laden cells in the border zone regions of acute myocardial infarcts. The acute lipidosis was reversible with either continued feeding of erucic acid for several weeks or conversion to a normal diet. It was not associated with an increased tissue Ca2+ content, nor with cell necrosis. However, continued erucic acid intake for 3 months was associated with focal myocardial degeneration and loss of myocytes. These results suggest that acute increases in neutral lipids, as found in the border zone of acute myocardial infarction, may not be the cause of progression to irreversible damage during acute myocardial injury, but that the persistent presence of similar lipid material over months may result in focal myocardial degeneration.     

Manganese-enhanced magnetic resonance imaging (MEMRI)

Manganese ion (Mn2+) is an essential metal that participates as a cofactor in a number of critical biological functions, such as electron transport, detoxification of free radicals and synthesis of neurotransmitters. Mn2+ can enter excitable cells using some of the same transport systems as Ca2+ and it can bind to a number of intracellular sites because it has high affinity for Ca2+ and Mg2+ binding sites on proteins and nucleic acids. Paramagnetic forms of manganese ions are potent MRI relaxation agents. Indeed, Mn2+ was the first contrast agent proposed for use in MRI. Recently, there has been renewed interest in combining the strong MRI relaxation effects of Mn2+ with its unique biology, in order to further expand the already broad assortment of useful information that can be measured by MRI. Such an approach has been continuously developed in the past several years to provide unique tissue contrast, to assess tissue viability, to act as a surrogate marker of calcium influx into cells and to trace neuronal connections. This special issue of NMR in Biomedicine on manganese-enhanced MRI (MEMRI) is aimed at providing the readers of this journal with an extensive review of some of the most prominent applications of MEMRI in biological systems. Written by several of the leaders in the field, the reviews and original research articles featured in this special issue are likely to offer an exciting and inspiring view of the broad range of applications of MEMRI.     

The entry of manganese ions into the brain is accelerated by the activation of N-methyl-D-aspartate receptors

Manganese-enhanced magnetic resonance imaging (MEMRI) is receiving increased interest as a valuable tool for monitoring the physiological functions in the animal brain based on the ability of manganese ions to mimic calcium ions entering to excitable cells. Here the possibility that in vivo MEMRI can detect the entry of manganese ions (Mn2+) in the brain of rats behaving without intended stimulation is tested. This hypothesis was a result of the unexpected observation that Mn2+-dependent signal enhancement was dramatically suppressed in ketamine-anesthetized rats compared with other anesthetics, such as urethane, pentobarbital and isoflurane. The effects of noncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonists, ketamine and MK-801, on MEMRI for MnCl2 injected rats were examined. Treatment with MK-801 suppressed the signal enhancement more effectively than with ketamine. NMDAR agonists, glutamate (100 mg/kg) and N-methyl-d-aspartate (NMDA) (35 mg/kg), enhanced the signal intensities on MEMRI, and this signal enhancement was completely antagonized by MK-801. The systemic administration of the competitive NMDAR antagonist, D-2-amino-5-phosphono-pentanoate (D-AP5), which does not cross the blood-brain barrier (BBB), showed no effects on the signal enhancement induced by NMDA and glutamate. A selective AMPA receptor (AMPAR) antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), did not block the signal enhancement. These data indicated that the Mn2+-dependent signal enhancement took place as a result of the activation of glutamatergic neurons through NMDAR, but not through AMPAR in the brain.     

心肌梗死模型家猪存活心肌的磁共振延迟成像评价

背景：心脏磁共振延迟成像被认为是极有前景的无创性判断心肌存活状态的影像检查手段。目前常用的对比剂Gd-DTPA存在过高或过低评价存活心肌和不可逆性梗死心肌,而坏死亲和性对比剂ECIII-600可以准确地反映坏死心肌的面积。 目的：对比冠脉内注射坏死亲和性对比剂在猪再灌注急性心肌梗死存活心肌诊断中的应用价值。 方法：三四个月龄普通家猪12头,建立急性再灌注心肌梗死动物模型,分别冠脉内注射0.1 mmol/kg Gd-DTPA或         0.005 mmol/kg ECIII-600。胸导R波触发心电门控,T1加权FAST序列,短轴面延迟强化扫描成像。扫描结束后沿短轴面将心脏切成6 mm断面行氯化三苯基四氮唑染色和光镜检查。比较相应层面的MRI延迟强化区和氯化三苯基四氮唑染色所示梗死区的关系。 结果与结论：注射Gd-DTPA的延迟成像10 min时强化区面积与氯化三苯基四氮唑染色相比过高估计梗死心肌面积约21%,30 min时强化区面积与氯化三苯基四氮唑染色结果一致,之后则过低估计坏死心肌的面积;注射ECIII-600的延迟磁共振成像在坏死区显示强烈而持续的对比增强,强化区面积与氯化三苯基四氮唑染色所示心肌梗死面积一致。说明ECIII-600增强磁共振延迟成像可以准确反映急性心肌梗死面积。Gd-DTPA评价心肌梗死面积不稳定,观察时间窗短,心脏磁共振成像应在对比剂注射后1 h以内完成。     

Myocardial apoptosis associated with the expression of proinflammatory cytokines during the course of myocardial infarction.

To clarify the role of myocardial apoptosis associated with the expression of proinflammatory cytokines in human myocardial infarction (MI), we have analyzed the expression of apoptosis positive for single-stranded DNA (ss-DNA) antibody, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-8 in 147 samples of infarcted myocardial tissue from 65 patients. ss-DNA-positive apoptotic nuclei were found mainly in cardiomyocytes in the border zones and granulation tissue cells in the infarct foci. The ss-DNA index (SI) of cardiomyocytes (average 0.13%) peaked at stage II (established myocardial necrosis), the value being significantly higher than at stages III (macrophage infiltration), IV (granulation formation), and V (scar formation) (P<0.05), whereas the SI of granulation tissue (average 0.08%) at stages III, IV, and V showed no significant differences between the three stages. These results suggest that cardiomyocyte apoptosis in the border zone is responsible for cellular loss in the acute stage of MI, whereas granulation tissue apoptosis may not be involved in the process of ventricular remodeling. TNF-alpha was expressed in cardiomyocytes in the border zones of infarct foci, but no significant positive correlation was found between SI and TNF-alpha index in cardiomyocytes (r=0.08, P = 0.37), suggesting that TNF-alpha does not serve as a direct trigger of cardiomyocyte apoptosis in vivo. The number of IL-8-positive cells peaked at stage II, and IL-8-myeloperoxidase-double-positive neutrophils were frequently detected, indicating that infiltrating neutrophils are the predominant source of IL-8 in the infarcted myocardium. These results suggest that, in human MI, TNF-alpha produced by cardiomyocytes does not play a critical role in their apoptosis, and that IL-8 produced by neutrophils is responsible for the subsequent accumulation and activation of neutrophils, thus increasing the degree of myocardial damage.     

In vivo, trans-synaptic tract-tracing utilizing manganese-enhanced magnetic resonance imaging (MEMRI)

It is well established that manganese ion (Mn2+) can access neurons through voltage-gated calcium (Ca2+) channels. Based upon this fundamental principle, Mn2+ has long been used in biomedical research as an indicator of Ca2+ influx in conjunction with fluorescent microscopy. Additionally, after entry into neurons, Mn2+ is transported down axons via microtubule based fast axonal transport. Furthermore, Mn2+ is paramagnetic, resulting in a shortening of the spin-lattice relaxation time-constant, T1, which yields positive contrast enhancement in T1-weighted MRI images, specific to tissues where the ion has accumulated. Manganese-enhanced MRI (MEMRI) utilizes a combination of these properties of Mn2+ to trace neuronal pathways in an MRI-detectable manner. The focus of this review will detail some of the current MEMRI tract-tracing methodologies in mice and non-human primates as well as biological applications of MEMRI tract-tracing.     

Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy

We performed continuous electrocardiographic ST-segment monitoring and serial coronary arteriography in 45 consecutive patients presenting in the early stages of acute myocardial infarction. During cardiac catheterization, 28 episodes of arteriographically confirmed coronary reopening and subsequent reocclusion were observed in 16 patients before (3 episodes) and during (25 episodes) continuous intracoronary infusion of streptokinase. In addition, ST-segment monitoring demonstrated 12 episodes of spontaneous transient return of the ST segment to the base line in eight patients between the time of admission and the performance of coronary arteriography. During arteriographically documented reocclusion, intracoronary isosorbide dinitrate (2 mg) reestablished the patency of the coronary artery within one to two minutes in 14 of 28 episodes that occurred in 11 of 16 patients. After streptokinase infusion, intracoronary administration of isosorbide dinitrate was followed by dilatation of the infarct-related stenosis from a mean value (+/- SD) of 1.12 +/- 0.3 mm (58.1 +/- 12.1 percent) to 1.33 +/- 0.4 mm (51.6 +/- 12.9 percent; P = 0.004). Spontaneous intermittent coronary recanalization and reocclusion resulting from a variable combination of thrombosis and vasoconstriction are frequent during the early phase of acute myocardial infarction. We propose that the combination of intracoronary streptokinase and isosorbide dinitrate may increase the rate of stable coronary recanalization.     

诱导多能干细胞移植后对急性心肌梗死小鼠心律的影响

背景：诱导多能干细胞被认为是治疗缺血性心肌病最具前景的一种方法,但其移植的安全性、有效性仍需进一步研究。 目的：探讨诱导多能干细胞移植后对急性心肌梗死小鼠心脏节律产生的影响。 方法：建立ICR小鼠心肌梗死模型并将其随机分为急性心肌梗死组,急性心肌梗死+生理盐水组,急性心肌梗死+诱导多能干细胞组,急性心肌梗死+成纤维细胞组,同时设立正常对照组。各组分别于移植诱导多能干细胞5 min、1周、2周、3周后,应用BL-420生物机能系统检测各组小鼠体表心电图肢体Ⅱ导联心律的变化。免疫组化染色法检测各组小鼠心肌缝隙连接蛋白43的表达,并应用Image Proplus软件进行半定量分析。 结果与结论：与急性心肌梗死组和急性心肌梗死+成纤维细胞组比较,移植2,3周时急性心肌梗死+诱导多能干细胞组小鼠体表心电图Ⅱ导联室性早搏发生率明显减少,梗死心肌缝隙连接蛋白43表达明显增加(P < 0.05),前两组相比差异无显著性意义。结果说明诱导多能干细胞移植2周后可明显减少梗死后小鼠室性早搏发生率,进而改善心肌组织的电活动并增强其电位稳定性,可使小鼠梗死心肌缝隙连接蛋白43的表达增加,而成纤维细胞移植的小鼠中则未出现此现象。     

Spatially and temporally different expression of osteonectin and osteopontin in the infarct zone of experimentally induced myocardial infarction in rats.

Osteonectin and osteopontin, two secreted matricellular proteins, have a variety of functions that are exerted through interaction with matrix components. These proteins appear in response to tissue injury. To test our hypothesis that osteopontin and osteonectin are expressed with spatially and temporally different patterns in myocardial infarct tissue, we investigated osteonectin and osteopontin expression in experimentally induced myocardial infarction in rats, in comparison with Type I collagen expression. Northern blotting demonstrated that osteonectin mRNA did not markedly increase on Day 2 after the infarction, but it increased on Days 7 and 14 by 1.7+/-0.12- and 1.8+/-0.01-fold compared to that in preligation hearts. In contrast, osteopontin mRNA was increased on Day 1 (41.9+/-11.3-fold increase) and on Day 2 (58.3+/-7.6-fold increase), and then it declined on Days 7 and 14 (24.8+/-9.0- and 13.5+/-4.7-fold increase, respectively). In situ hybridization revealed that osteonectin mRNA signals were observed in fibroblasts, myofibroblasts and macrophages around infarct necrotic tissue on Days 7 and 14. Osteopontin mRNA signals were observed in macrophages in the infarct marginal zone on Day 2. Immunopositive staining for both osteonectin and osteopontin showed the same pattern as that obtained by in situ hybridization. The time course of osteonectin mRNA was almost parallel with that of Type I collagen mRNA, while that of osteopontin was not. These results demonstrated spatially and temporally different expression patterns of osteonectin and osteopontin in myocardial infarction and suggest that osteonectin appears to be involved in the pathological course in the late phase after infarction concomitantly with Type I collagen, while osteopontin may play a role in the early phase.     

Contrast-enhanced MRI of murine myocardial infarction - part I

The use of contrast agents has added considerable value to the existing cardiac MRI toolbox that can be used to study murine myocardial infarction, as it enables detailed in vivo visualization of the molecular and cellular processes that occur in the infarcted and remote tissue. A variety of non-targeted and targeted contrast agents to study myocardial infarction are available and under development. Manganese, which acts as a calcium analogue, can be used to assess cell viability. Traditionally, low-molecular-weight Gd-containing contrast agents are employed to measure infarct size in a late gadolinium enhancement experiment. Gd-based blood-pool agents are used to study the vascular status of the myocardium. The use of targeted contrast agents facilitates more detailed imaging of pathophysiological processes in the acute and chronic infarct. Cell death was visualized by contrast agents functionalized with annexin A5 that binds specifically to phosphatidylserine accessible on dying cells and with an agent that binds to the exposed DNA of dead cells. Inflammation in the myocardium was depicted by contrast agents that target cell adhesion molecules expressed on activated endothelium, by contrast agents that are phagocytosed by inflammatory cells, and by using a probe that targets enzymes excreted by inflammatory cells. Cardiac remodeling processes were visualized with a contrast agent that binds to angiogenic vasculature and with an MR probe that specifically binds to collagen in the fibrotic myocardium. These recent advances in murine contrast-enhanced cardiac MRI have made a substantial contribution to the visualization of the pathophysiology of myocardial infarction, cardiac remodeling processes and the progression to heart failure, which helps to design new treatments. This review discusses the advances and challenges in the development and application of MRI contrast agents to study murine myocardial infarction.     

Cardiac adrenergic innervation within the first 3 months after acute myocardial infarction.

It is widely accepted that myocardial infarction results in adrenergic denervation of the infarcted and peri-infarcted myocardium. On the contrary, the concept of re-innervation of adrenergic nerve fibres is less well established. Although there is evidence of partial re-innervation occuring several months after myocardial infarction, the extent and time scale of re-innervation are only poorly known. In this study we investigated changes in cardiac adrenergic innervation and myocardial perfusion during the early convalescence period (the first 3 months) after an acute myocardial infarction. Single-photon emission computed tomographic imaging was conducted in 15 men 1 week and 3 months after an acute myocardial infarction with I123-metaiodobentzylguanidine (MIBG) and Tc99m-sestamibi (MIBI) to determine the extent of adrenergic denervation and impaired perfusion, respectively. A MIBG and MIBI defect was determined as regional uptake 相似文献   

Elevated sympathetic response of epicardium proximal to healed myocardial infarction

Sympathetic nerve interaction with cardiac electrophysiology was evaluated in healed myocardial infarction by monitoring the effects of sympathetic nerve stimulation on local epicardial refractoriness in cats. Single-stage distal coronary artery ligation was used to induce myocardial infarction. Regions overlying and surrounding infarcts 3 mo after healing and comparable regions in sham-operated and normal unoperated hearts were studied. Local ventricular muscle refractory periods were measured by the extrastimulus technique from 1) the epicardium overlying the infarct, 2) the area bordering the infarct, and 3) a normal area proximal to the infarct on the anterior free wall of the left ventricle. Bilateral stimulation of the ansa subclavia induced significant and disparate refractory period shortening (P less than or equal to 0.01) in hearts with healed myocardial infarction. Shortening was greatest in the normal area [-26 +/- 8 (+/-SD) ms], less in the border area (-15 +/- 6), and least in the infarct area (-7 +/- 2). In contrast, refractory periods measured in noninfarcted hearts shortened significantly (P less than or equal to 0.01) but uniformly and to a lesser extent during sympathetic stimulation. We conclude 1) the effects of sympathetic nerve stimulation are more pronounced in the areas proximal to healed infarction than in similar areas of noninfarcted hearts and 2) a marked disparity in sympathetic responsiveness occurs in hearts with healed myocardial infarction.     

Manganese-enhanced magnetic resonance imaging (MEMRI) without compromise of the blood-brain barrier detects hypothalamic neuronal activity in vivo

There is growing interest in the use of manganese-enhanced MRI (MEMRI) to detect neuronal activity and architecture in animal models. The MEMRI neuronal activity studies have been generally performed either by stereotactic brain injection or by systemic administration of Mn(2+) in conjunction with the disruption of the blood-brain barrier (BBB). These approaches, however, have limited the use of MEMRI because of the procedure-related morbidity/mortality or because brain activity measured by these methods can diverge from genuine physiological responses. In this study, the hypothesis that MEMRI, performed with systemic administration of Mn(2+) without compromising the BBB integrity, is able to detect hypothalamic function associated with feeding was tested. This procedure was tested on a simple physiological condition, fasting, and with this method temporal and regional differences in Mn(2+) enhancement could be detected. It is concluded that MEMRI can be used to study hypothalamic function in the murine brain without compromising the BBB. It was also shown that region-specific Mn(2+) enhancement in the mouse brain can be modulated by fasting. More importantly, this non-invasive in vivo imaging technique is able to demonstrate differences in brain activities, previously possible only by in vitro studies.