Aortic occlusion for cerebral ischemia: From theory to practice

Ischemic stroke is a devastating disorder with limited treatment options. Arterial recanalization with thrombolysis or mechanical thrombectomy may be used to restore perfusion in only a subset of cases. Collateral therapeutic strategies such as partial aortic occlusion attempt to reverse ischemia, the principal detrimental element in stroke pathophysiology. This article considers the theoretic basis of aortic occlusion as a therapeutic strategy for cerebral ischemia, procedural details employing the NeuroFlo (CoAxia, Maple Grove, MN) device, ongoing and prior clinical studies, and potential practice implications in the future. The hemodynamic mechanisms associated with flow redistribution due to aortic occlusion and impact on the dynamic role of collateral perfusion in the ischemic brain are considered. Targeting ischemia rather than clot disruption or consideration of venous hemodynamics and flow redistribution may initiate a radical transformation in stroke care. Ultimately, demonstration of a rational mechanism that averts ischemia will be essential.     

颈内动脉狭窄或闭塞的血流代偿途径

颈内动脉狭窄或闭塞的临床表现与脑血流代偿密切相关。目前认为,脑血流代偿主要通过以下3种方式实现:侧支循环建立,新血管形成,脑血管自动调节。其中,侧支循环在代偿中起着重要作用,主要包括前交通动脉、后交通动脉、眼动脉和其他侧支循环。脑微血管重建是颈内动脉重度狭窄或闭塞时的代偿反应,可能会增高缺血性卒中患者的存活率。     

Imaging-Based Patient Selection and Endovascular Therapy of Ischemic Stroke: A Stratified Meta-Analysis

The positive results of recent trials for the treatment of acute ischemic stroke have highlighted the importance of imaging selection before endovascular therapy. We performed a stratified meta-analysis to confirm this new understanding.We searched EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov in April 2015 for randomized controlled trials evaluating the effect of endovascular treatment in patients with acute ischemic stroke. The meta-analysis was stratified by whether computed tomographic angiography (CTA) was used to select patients. Outcome data were pooled using fixed-effects models.Seven randomized controlled trials with 2217 patients were included in this study. Endovascular therapy significantly increased the rate of 90-day functional independence (a modified Rankin score of 0–2) in patients with a CTA-confirmed large-vessel occlusion (relative risk [RR] = 1.75, 95% confidence interval [CI]: 1.48–2.06, I² = 0.0%), and reduced 90-day mortality in patients with occlusion stroke with a small ischemic core (RR = 0.58, 95% CI: 0.37–0.89, I² = 0.0%). The functional benefit was significantly greater in patients with CTA-based selection than in those without (Z = 5.04, P < 0.001). The mortality benefit was significantly greater in patients with a large-vessel occlusion and a small ischemic core than in those without CTA-based selection (Z = 2.04, P = 0.041). There was no evidence of between-study heterogeneity or publication bias.This meta-analysis showed the effect of vascular imaging on identifying patients with acute ischemic stroke with a proximal vessel occlusion and a small ischemic core, who would benefit from endovascular therapy.     

Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model

Although cerebral hypoperfusion caused by cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. Recently, a novel therapeutic strategy for ischemic disease using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. Therapeutic angiogenesis might be useful for the treatment of cerebral occlusive disease. Hepatocyte growth factor (HGF) is a potent angiogenic factor, in addition to vascular endothelial growth factor (VEGF), whereas in the nervous system HGF also acts as neurotrophic factor. Therefore, we hypothesized that gene transfer of these angiogenic growth factors could induce angiogenesis, thus providing an effective therapy for cerebral hypoperfusion or stroke. In this study, we employed a highly efficient gene transfer method, the viral envelop (Hemagglutinating Virus of Japan [HVJ]-liposome) method, because we previously documented that beta-galactosidase gene could be transfected into the brain by the HVJ-liposome method. Indeed, we confirmed wide distribution of transgene expression using beta-galactosidase via injection into the subarachnoid space. Of importance, transfection of HGF or VEGF gene into the subarachnoid space 7 days before occlusion induced angiogenesis on the brain surface as assessed by alkaline phosphatase staining (P<0.01). In addition, significant improvement of cerebral blood flow (CBF) was observed by laser Doppler imaging (LDI) 7 days after occlusion (P<0.01). Unexpectedly, transfection of HGF or VEGF gene into the subarachnoid space immediately after occlusion of the bilateral carotid arteries also induced angiogenesis on the brain surface and had a significant protective effect on the impairment of CBF by carotid occlusion (P<0.01). Interestingly, coinjection of recombinant HGF with HGF gene transfer revealed a further increase in CBF (P<0.01). Here, we demonstrated successful therapeutic angiogenesis using HGF or VEGF gene transfer into the subarachnoid space to improve cerebral hypoperfusion, thus providing a new therapeutic strategy for cerebral ischemic disease.     

Effects of amlodipine on myocardial ischemia-reperfusion injury in dogs

The effects of the dihydropyridine calcium channel blocker amlodipine on subendocardial segment shortening (%SS), regional myocardial blood flow, myocardial high-energy phosphate levels and tissue water content were compared with those of a saline-treated group of barbital-anesthetized dogs subjected to a 45-minute coronary artery occlusion followed by 60 minutes of reperfusion. Saline or amlodipine (200 micrograms/kg administered intravenously) was given 15 minutes before coronary occlusion. There were no significant differences between groups in ischemic bed size or hemodynamics although dP/dt was higher after amlodipine administration. Subepicardial collateral blood flow was higher in the amlodipine group during coronary occlusion. After occlusion, %SS in the ischemic region was markedly decreased in both series and passive systolic lengthening resulted. Despite similar decreases in %SS during occlusion, the amlodipine-treated dogs showed a marked improvement in myocardial segment function of the ischemic reperfused region throughout 60 minutes of reperfusion compared with saline-treated dogs. In addition, amlodipine prevented the rebound increase in phosphocreatine and attenuated the loss of adenine nucleotides and increase in tissue water in the ischemic reperfused area at 60 minutes of reperfusion. These results suggest that amlodipine has a favorable effect on the functional and metabolic recovery of the ischemic reperfused myocardium and may have potential as a therapeutic agent for the treatment of coronary artery disease. The mechanism of action of amlodipine in this model is unknown but may be partially related to a drug-induced increase in coronary collateral blood flow or a decrease in afterload.     

Hyperacute Management of Ischemic Strokes: JACC Focus Seminar

Acute ischemic stroke is the leading cause of disability and among the leading causes of mortality worldwide. Intravenous tissue plasminogen activator has been a cornerstone for treatment of acute ischemic stroke for more than 20 years; however, its use is limited due to a narrow therapeutic window, several contraindications, and low efficacy to recanalize the artery in large vessel occlusion. Recently, the addition of endovascular mechanical thrombectomy of large artery occlusion has revolutionized the stroke treatment for most disabling strokes. The paper reviews updates to the thrombolytic treatment as well as catheter-based treatment, and results from recent trials in the selection of patients in an extended time window using perfusion imaging.     

Systemic lupus erythematosus associated with moyamoya syndrome

Moyamoya disease is an uncommon clinical entity, characterized by bilateral occlusion of the internal carotid artery and the development of collateral arteries. An 18-year-old Saudi male with systemic lupus erythematosus (SLE) presented with mild right hemiparesis, followed by recurrent ischemic stroke. Cerebral angiography showed bilateral internal carotid artery stenosis associated with the development of collateral circulation (moyamoya vessels). There was no evidence of active SLE or other risk factors for cerebral occlusion, such as antiphospholipid antibody syndrome. Medical and surgical interventions did not influence the poor outcome of the recurrent ischemic insults.     

Acute therapy and prevention of stroke in spontaneous carotid dissection

No randomized and controlled study has evaluated acute stroke therapy and antithrombotic agents for stroke prevention in patients with spontaneous cervical artery dissection (CAD). CAD was not a contraindication for including cases with acute ischemic stroke in trials evaluating systemic fibrinolysis with recombinant tissue plasminogen activator (rt-PA). Small case series have reported successful systemic and local intra-arterial thrombolysis without clinical signs of rupture of the dissected vessel. Thus, thrombolysis seems to be a therapeutic option in acute CAD causing ischemic stroke, although it remains unclear whether rt-PA increases the obstruction of the dissected vessel by enlarging the wall hematoma or diminishes the obstruction by enhancing the recanalization of the thrombus adhering to the dissection. Meta-analyses have shown no benefit of anticoagulation compared to aspirin in stroke prevention of patients with CAD. It is also unclear, whether long-term antithrombotic therapy is necessary. Many centers and ours maintain the antithrombotic therapy for 3 to 6 months. Dissections of the internal carotid artery (ICAD) have a benign long-term prognosis with low stroke rates that are not related to the persistence of severe carotid stenosis or occlusion. These results suggest that surgical or endovascular therapy of ICA stenosis or occlusion related to ICAD should only be taken into consideration in the very rare patients with stroke recurrence in spite of an optimal medical treatment. Cervical aneurysms caused by CAD have an excellent long-term outcome with a low stroke risk, and no vessel rupture has been reported. Thus, surgical or endovascular therapy should be restricted to the very rare cases developing ischemic symptoms in the vascular territory supplied by the dissected aneurysm in spite of antithrombotic therapy.     

Acute Therapy and Prevention of Stroke in Spontaneous Carotid Dissection

No randomized and controlled study has evaluated acute stroke therapy and antithrombotic agents for stroke prevention in patients with spontaneous cervical artery dissection (CAD). CAD was not a contraindication for including cases with acute ischemic stroke in trials evaluating systemic fibrinolysis with recombinant tissue plasminogen activator (rt-PA). Small case series have reported successful systemic and local intra-arterial thombolysis without clinical signs of rupture of the dissected vessel. Thus, thrombolysis seems to be a therapeutic option in acute CAD causing ischemic stroke, although it remains unclear whether rt-PA increases the obstruction of the dissected vessel by enlarging the wall hematoma or diminishes the obstruction by enhancing the recanalization of the thrombus adhering to the dissection. Meta-analyses have shown no benefit of anticoagulation compared to aspirin in stroke prevention of patients with CAD. It is also unclear, whether long-term antithrombotic therapy is necessary. Many centers and ours maintain the antithrombotic therapy for 3 to 6 months. Dissections of the internal carotid artery (ICAD) have a benign long-term prognosis with low stroke rates that are not related to the persistence of severe carotid stenosis or occlusion. These results suggest that surgical or endovascular therapy of ICA stenosis or occlusion related to ICAD should only be taken into consideration in the very rare patients with stroke recurrence in spite of an optimal medical treatment. Cervical aneurysms caused by CAD have an excellent long-term outcome with a low stroke risk, and no vessel rupture has been reported. Thus, surgical or endovascular therapy should be restricted to the very rare cases developing ischemic symptoms in the vascular territory supplied by the dissected aneurysm in spite of antithrombotic therapy.     

Advanced Neuroimaging to Guide Acute Stroke Therapy

Traditionally non-contrast CT has been considered the first choice imaging modality for acute stroke. Acute ischemic stroke patients presenting to the hospital within 3-hours from symptom onset and without any visible hemorrhages or large lesions on CT images are considered optimum reperfusion therapy candidates. However, non-contrast CT alone has been unable to identify best reperfusion therapy candidates outside this window. New advanced imaging techniques are now being used successfully for this purpose. Non-invasive CT or MR angiography images can be obtained during initial imaging evaluation for identification and characterization of vascular lesions, including occlusions, aneurysms, and malformations. Either CT-based perfusion imaging or MRI-based diffusion and perfusion imaging performed immediately upon arrival of a patient to the hospital helps estimate the extent of fixed core and penumbra in ischemic lesions. Patients having occlusive lesions with small fixed cores and large penumbra are preferred reperfusion therapy candidates.     

磁共振血管成像显示颅内大血管闭塞与急性缺血性脑卒中预后的相关研究

目的对照不同大血管病变的急性缺血性脑卒中患者的主要临床结局,探讨磁共振血管造影术(MRA)对大血管病变分型指导临床治疗方案的价值。方法选择发病6h内、急诊MRI显示存在缺血半暗带的缺血性脑卒中患者47例,根据MRA是否存在颅内大血管闭塞分为无闭塞错配未溶栓组(无闭塞组,20例)和有闭塞错配未溶栓组(闭塞组,27例),常规治疗90天后,随访两组改良的Ranking量表(mRS)评分结果。结果闭塞组与无闭塞组接受常规治疗前,美国国立卫生研究院脑卒中量表评分差异有统计学意义(P=0.003);治疗90天后随访,无闭塞组疗效显著优于闭塞组(P<0.05),mRS0～1分的比例分别为75.0%和33.3%。结论MRA有助于急性缺血性脑卒中患者临床治疗方案的确立,无大血管闭塞的急性缺血性脑卒中患者可以应用常规治疗。     

A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window

The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide therapeutic window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 +/- 22% when the treatment is started 12 h before ischemia and by 63 +/- 35% when started even 4 h after the onset of ischemia. The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1beta-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E(2) production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant therapeutic window.     

Imaging of acute stroke

Acute stroke patients represent an important diagnostic and therapeutic challenge. Patients with brain damage in the ischemic, but not yet infarcted, phase have the greatest potential for recovery. Here we review the most commonly employed diagnostic tools that are currently used before stroke therapy. While computed tomography is pertinent to differentiate ischemic from hemorrhagic stroke, this technique cannot be used as an etiological screening too. The ischemic origin of symptoms can be confirmed with magnetic resonance imaging which also contributes to for therapeutic decision making, prognosis assessment and etiological screening.     

Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.     

缺血性卒中或短暂性脑缺血发作患者FLAIR序列高信号血管征可能与脑侧支循环有关：回顾性病例系列研究

目的探讨缺血性卒中或短暂性脑缺血发作（transient ischemic attack,TIA）患者液体衰减反转恢复序列（fluid—attenuated inverson recovery,FLAIR）高信号血管征（hyperintense vessel sign,HVS）的可能形成机制和影像学特征。方法回顾性从南京卒中注册系统中提取自2010年1月到2011年7月期间临床表现为大脑中动脉（middle cerebral artery,MCA）供血区缺血性卒中或TIA且数字减影血管造影（digital subtraction angiography,DSA）显示MCAM1段病变患者的基线资料,FLAIR观察HVS,DSA评估血管狭窄程度和脑侧支循环。结果共纳入101例患者,男性76例（75．2％）,平均年龄（53．94±13．47）岁;缺血性卒中90例（89．1％）,TIA11例（10．9％）;HVS阴性55例（54．5％）,HVS阳性46例（45．5％）。在MCA狭窄程度〈50％、50％～70％、70％～90％以及≥90％的患者中,HVS阳性率依次为0％（0／8）、25．0％（3／12）、17．6％（3／17）和62．5％（40／64）,差异有显著统计学意义（Z=-4．479,P〈0．001）。HVS阳性组软脑膜侧支循环显著性多于HVS阴性组（Z=-6．196,P〈0．001）。多变量logistic回归分析显示,MCA狭窄程度是影响HVS形成的独立危险因素（优势比3．943,95％可信区间2．03～7．659;P〈0．001）。结论颅内大血管严重狭窄或闭塞后形成的颅内软脑膜侧支循环是缺血性卒中或TIA患者FLAIR序列HVS形成的主要病理生理学基础。     

Schlaganfall und Vorhofflimmern

Approximately 80% of all strokes are ischemic, the remaining being hemorrhagic. The major reason for cerebral ischemia is occlusion of a cerebral artery by a cardiac thrombus in a patient with atrial fibrillation. This article focuses on the therapeutic management of patients with cerebral ischemia due to atrial fibrillation and is based on the guidelines of the German Society of Neurology and the European Stroke Organization: Patients with cerebral ischemia and atrial fibrillation require oral anticoagulation with an INR of 2.0–3.0. After a TIA (transient ischemic attack) or minor ischemic stroke, anticoagulation can be initiated within the first week after the stroke. Combination therapy of aspirin and clopidogrel is less effective than oral anticoagulation.     

急性缺血性卒中的液体衰减反转恢复序列血管高信号

液体衰减反转恢复序列血管高信号(fluid-attenuated inversion recovery vascular hyperintensity, FVH)是因脑大动脉严重狭窄或闭塞致急性缺血性卒中的一种常见磁共振影像学表现.文章对FVH在急性缺血性卒中患者中的应用及相关研究进行了综述.     

烟雾病患者临床与脑血管造影特点分析

目的 分析烟雾病(MMD)患者的临床和脑血管造影(DSA)特点.方法 将45例烟雾病患者分少年组(14例,年龄≤15岁)和成年组(31例,年龄>15岁),并对两组患者的临床和脑血管造影特点进行分析.结果 45例患者中双侧颈内动脉均有不同程度的狭窄闭塞,伴有双侧大脑前动脉、中动脉狭窄并不伞闭塞或者闭塞的23例,单侧大脑前...     

Thrombolytic therapy in cerebrovascular disorders.

The knowledge obtained from the ongoing investigational trials of tPA for acute ischemic stroke will not only help establish the appropriate dose range and complication rates but will also further develop the clearly mandatory rapid, aggressive team approach needed to truly treat acute ischemic strokes successfully. Experimental cerebral ischemia data have pointed to the need to treat acute clinical stroke within only a few hours or less to effectively reduce stroke morbidity and mortality. Specifically, with reversible MCA occlusion models of focal cerebral ischemia (dogs and cats), the animals uniformly survive without neurological deficit if the occlusion is for less than 2 to 3 hours. Similarly in primates, MCA occlusion for 3 hours or less will lead to clinical improvement and a decrease in infarct size, with complete recovery generally associated with less than 2 hours of MCA occlusion. Therefore, it appears unlikely that ischemic brain can be salvaged if vascular occlusion persists longer than 4 to 6 hours (similar to the pathophysiology of myocardial ischemia). Further, at least one third of ischemic stroke patients reperfuse spontaneously (and obviously too late) within 48 hours of stroke onset. Several factors believed to be related to successful outcome after thrombolytic therapy are summarized in Table 16. A schematic approach to determining the response to thrombolytic agents in acute ischemic stroke is outlined in Table 17. Zivin succinctly reviews thrombolysis for stroke, both experimental and clinical, and summarizes some of the difficulties of the early clinical stroke trials with thrombolytic agents and speculates about future prospects. He believes tPA may prove valuable in the treatment of some forms of thromboembolic stroke. Its usefulness may depend in part on how quickly the drug can be initiated and the risk of side effects; factors that will require further study. The currently used doses of tPA may be too low to lyse large cerebral arterial clots and, therefore, if current trials do not show a positive treatment response, further trials with higher doses may be indicated. The implications of a potentially effective treatment for truly acute stroke are enormous: stroke will need to be considered by all (lay public through to caregivers) as a true medical emergency, analogous to MI and trauma.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of collateral circulation on electrophysiological properties during the acute phase of canine myocardial infarction

To investigate the effect of collateral circulation on the electrophysiological properties of the acutely ischemic myocardium, acute myocardial infarction was produced in the canine heart by coronary artery occlusion alone, and by coronary artery occlusion plus embolization with vinyl latex. Multiple bipolar electrodes for stimulation or for recording electrograms were placed on the subepicardial layer and the subendocardial layer to examine the time course of changes in excitability threshold, effective refractory period, and conduction time. Soon after coronary occlusion plus embolization, electrophysiological properties of the ischemic subepicardium became severely and almost uniformly damaged and showed no recognizable recovery of electrical activities, whereas transient deterioration and subsequent recovery of the electrophysiological properties were observed after coronary occlusion alone. On the other hand, the subendocardium was much less affected electrophysiologically by either coronary occlusion alone or coronary occlusion plus embolization. These results indicate that collateral circulation plays an important role in the recovery from electrophysiological abnormalities in the ischemic subepicardium caused by acute myocardial ischemia, but has little effect on the electrophysiological properties of the ischemic subendocardium.