Experimental evidence of ischemic thresholds and functional recovery.

Heiss, Wolf‐Dieter

doi:10.1161/01.str.23.11.1668

Cited by 132 publications

(50 citation statements)

References 42 publications

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“…By applying devices for reversible blockade of the vessel, the time windows for induction of neuronal necrosis or gross infarction and the relationship between dura tion and severity of ischemia could also be established [reviewed by Heiss (1992)]. Recently, state-of-the-art PET technology enabled perfusional and metabolic changes leading to infarction in permanent MCAO to be followed (Heiss et aI., 1994).…”

Section: Discussion Experimental Modelmentioning

confidence: 99%

Repeat Positron Emission Tomographic Studies in Transient Middle Cerebral Artery Occlusion in Cats: Residual Perfusion and Efficacy of Postischemic Reperfusion

Heiss

Graf

Löttgen

et al. 1997

J Cereb Blood Flow Metab

124

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Summary:The wider clinical acceptance of thrombolytic therapy for ischemic stroke has focused more attention on experimental models of reversible focal ischemia. Such models enable the study of the effect of ischemia of various durations and of reperfusion on the development of infarc tions. We used high-resolution positron emission tomo graphy (PET) to assess cerebral blood flow (CBF), cere bral metatfolic rate of oxygen (CMR02), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) before, during, and up to 24 h after middle cere bral artery occlusion (MCAO) in cats. After determination of resting values, the MCA was occluded by a transorbital device. The MCA was reopened after 30 min in five, after 60 min in 11, and after 120 min in two cats. Whereas all cats survived 30-min MCAO, six died after 60-min and one after 120-min MCAO during 6-20 h of reperfusion. In those cats surviving the first day, infarct size was determined on serial histologic sections. The arterial occlusion immedi ately reduced CBF in the MCA territory to <40% of con trol, while CMROz was less affected, causing an increase in OEF. Whereas in the cats surviving 24 h of reperfusion after 60-and 120-min MCAO, OEF remained elevated throughout the ischemic episode, the initial OEF increase had already disappeared during the later period of ischemia in those cats that died during the reperfusion period. After and CMRglc, large infarcts developed, and intracranial pres sure increased fatally. In those surviving the day after MCAO, increased OEF persisted over the ischemic epi sode, postischemic hyperperfusion was less severe and shorter, and the perfusional and metabolic defects as well as the final infarcts were smaller. These results stress the importance of the severity of ischemia for the further course after reperfusion and help to explain the diverging outcome after thrombolysis, where a relation between the residual flow and the effectiveness of reperfusion was also observed.

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Section: Discussion Experimental Modelmentioning

confidence: 99%

Repeat Positron Emission Tomographic Studies in Transient Middle Cerebral Artery Occlusion in Cats: Residual Perfusion and Efficacy of Postischemic Reperfusion

Heiss

Graf

Löttgen

et al. 1997

J Cereb Blood Flow Metab

124

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“…In some instances, critical, but primarily not detrimental, flow disturbances may trigger a dynamic process eventually leading to delayed neuronal death resulting from selective vulnerability [15] . Many interrelated biochemical mechanisms are involved in or contribute to ischemic cell damage, and therefore various markers can be used as indicators of ischemic thresholds and of reversible or irreversible functional deficits [reviews in 16,17 ]. In accordance with the critical role that the supply of energy-rich substrates plays in brain function, cerebral ATP content and cerebral metabolic rate of glucose exhibit a threshold dependency similar to the electrophysiological variables.…”

Section: Flow Thresholds For Preservation Of Function and Morphologicmentioning

confidence: 99%

The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke

2011

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The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed ‘penumbra’, and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and duration of critically reduced blood flow was established – proving that the lower the flow, the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterized by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarizations, the peri-infarct spreading depression-like depolarizations, inducing activation of ion pumps and liberation of excitatory transmitters, have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood supply. The translation of experimental concept into the basis for efficient treatment of stroke requires non-invasive methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue that can benefit from therapeutic interventions. Positron emission tomography (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. From these variables, clear definitions of irreversible tissue damage and critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool, perfusion/diffusion-weighted (PW/DW) MRI is used, and the ‘mismatch’ between the PW and the DW abnormalities serve as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET have pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusion thresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking, its use as a surrogate marker of outcome is limited.

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“…The ischemic threshold of the mammalian brain has been reported by many authors, including the threshold of ischemia for the induction of functional and metabolic changes in the brain [1, 2]. Another concept of the ischemic threshold focuses on the level and period of local cerebral blood flow (lCBF) reduction resulting in cerebral infarction.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Blood Flow, Glucose Metabolism and TUNEL-Positive Cells in the Development of Ischemia

Terada

Inao²,

Mizutani³

et al. 2001

Cerebrovasc Dis

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Few in vivo studies were available about the relation between cerebral blood flow, glucose metabolism and the appearance of apoptotic cells in the development of cerebral infarct. To investigate this, we measured local cerebral blood flow (lCBF), local cerebral metabolic rate in glucose (lCMRglc), and histopathology in transient focal cerebral ischemia in the rat. A unilateral middle cerebral artery occlusion (MCAO) was induced for 2 h in Wistar-ST rats (n = 42). A histopathological study with hematoxylin-eosin staining and the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method was performed. lCBF was measured by means of the ¹⁴C-iodoantipyrine autoradiography technique during MCAO (n = 6), and 1, 22 and 70 h after reperfusion. lCMRglc was also measured by autoradiography with ¹⁴C-2-deoxyglucose in the animals 22 h after reperfusion. These parameters were assessed in each region of interest: the ischemic core, boundary zones (BZ-I and BZ-II) and remote area. The boundary zones were defined as the area based on TUNEL positivity (more than 5/field) at 22 h after reperfusion (BZ-I) and at 70 h after reperfusion (BZ-II). In the BZ-I, lCBF was decreased to 18% of the control during MCAO, and lCBF and lCMRglc showed 44 and 62% of the control, respectively, 22 h after reperfusion. In this area, TUNEL-positive cells increased at 22 h, then markedly decreased 70 h after reperfusion. In the BZ-II, lCBF decreased to 39% of the control during MCAO, then returned to about 90% of the control 22 h after reperfusion. lCMRglc was maintained near its normal range (82% of the control) 22 h after reperfusion. Histopathology of BZ-II was normal 22 h after reperfusion. The TUNEL positivity of neurons in our study was assumed to be a marker of apoptotic cells. Our data suggested that the apoptotic process plays an important role in the maturation of a cerebral infarct. Both lCBF and lCMRglc were maintained with only a mild reduction in the predisposing phase of apoptosis, suggesting that sufficient blood supply and glucose metabolism are required to promote the process of apoptosis.

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Experimental evidence of ischemic thresholds and functional recovery.

Cited by 132 publications

References 42 publications

Repeat Positron Emission Tomographic Studies in Transient Middle Cerebral Artery Occlusion in Cats: Residual Perfusion and Efficacy of Postischemic Reperfusion

Repeat Positron Emission Tomographic Studies in Transient Middle Cerebral Artery Occlusion in Cats: Residual Perfusion and Efficacy of Postischemic Reperfusion

The Ischemic Penumbra: Correlates in Imaging and Implications for Treatment of Ischemic Stroke

Cerebral Blood Flow, Glucose Metabolism and TUNEL-Positive Cells in the Development of Ischemia

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