sirolimus and Ischemic-Attack--Transient

The Syntax score (SXscore) was recently developed as a comprehensive angiographic scoring system aiming to assist in patient selection and risk stratification of patients with extensive coronary artery disease undergoing contemporary revascularization. A validation of this angiographic classification scheme is lacking. We assessed its predictive value in patients who underwent percutaneous intervention (PCI) for 3-vessel disease and explored its performance in comparison with the modified lesion classification system of the American Heart Association/American College of Cardiology. The SXscore, applied to 1,292 lesions in 306 patients who underwent PCI for 3-vessel disease in the Arterial Revascularization Therapies Study Part II, was 4 to 54.5, and after a median of 370 days (range 274 to 400) predicted the rate of major adverse cardiac and cerebrovascular events (hazard ratio 1.08/U increase, 95% confidence interval 1.05 to 1.11, p <0.0001), with patients in the highest SXscore tertile having a significantly higher event rate (27.9%) than patients in the lowest tertile (8.7%, hazard ratio 3.5, 95% confidence interval 1.7 to 7.4, p = 0.001). By multivariable analyses, SXscore independently predicted outcome with an almost fourfold adjusted increase in the risk of major adverse cardiac and cerebrovascular events in patients with high versus low values based on the discrimination level provided by classification and regression tree analysis. Compared with the modified lesion classification scheme of the American Heart Association/American College of Cardiology, SXscore showed a greater discrimination ability (c-index 0.58 +/- 0.08 vs 0.67 +/- 0.08, respectively, p <0.001) and a better goodness of fit with the Hosmer-Lemeshow statistic. In conclusion, the SXscore is a promising tool to risk stratify outcome in patients with extensive coronary artery disease undergoing contemporary PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; Brain Ischemia; Coronary Angiography; Coronary Disease; Female; Fibrinolytic Agents; Follow-Up Studies; Forecasting; Humans; Ischemic Attack, Transient; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk Assessment; Sirolimus; Stents; Stroke; Survival Rate; Treatment Outcome

Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow.. Wistar and spontaneously hypertensive rats (≈14 weeks old, n=22 and n=15, respectively) were subjected to ischemia by middle cerebral artery occlusion (90 and 120 minutes, respectively) with or without treatment with rapamycin at 30-minute poststroke. Changes in middle cerebral artery and collateral perfusion territories were measured by dual-site laser Doppler. Reactivity to rapamycin was studied using isolated and pressurized leptomeningeal anastomoses. Brain injury was measured histologically or with triphenyltetrazolium chloride staining.. In Wistar rats, rapamycin increased collateral perfusion (43±17%), increased reperfusion cerebral blood flow (16±8%) and significantly reduced infarct volume (35±6 versus 63±8 mm. Rapamycin increased collateral perfusion and reperfusion cerebral blood flow in both Wistar and comorbid spontaneously hypertensive rats that appeared to be mediated by enhancing eNOS activation. These findings suggest that rapamycin may be an effective acute therapy for increasing collateral flow and as an adjunct therapy to thrombolysis or thrombectomy to improve reperfusion blood flow.

Topics: Animals; Cerebral Infarction; Cerebrovascular Circulation; Collateral Circulation; Fibrinolytic Agents; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Meninges; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Rats, Wistar; Reperfusion; Sirolimus; TOR Serine-Threonine Kinases

Galuteolin, a Chinese herbal medicine, purified from Lonicera Japonica. In this study, we aimed to investigate the neuroprotective effect of galuteolin against cerebral ischemia/reperfusion (I/R) injury. We administered galuteolin or galuteolin and rapamycin to rats which had middle cerebral artery occlusion/reperfusion (MCAO/R). A series of characterizations were carried out to monitor the outcomes of galuteolin in I/R rats regarding the infarct volumes, neurological deficits, and brain water, as well as its effect on neuroprotection and autophagy. It was found that galuteolin significantly reduced the infarct volume, brain water content, and the neurological deficits in a dose-dependent manner. Neuron damages were decreased in the hippocampal carotid artery 1 pyramidal layer by galuteolin. The expression levels of neuron-specific enolase (NSE) increased after galuteolin treatment. Galuteolin significantly decreased the expression levels of autophagy-related proteins. In addition, galuteolin decreased rapamycin-related neuron damages and activations of autophagy in I/R rats. Our data suggested that galuteolin can inhibit ischemic brain injuries through the regulation of autophagy-related indicators in I/R.

Topics: Animals; Autophagy; Body Water; Cerebral Infarction; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Glucosides; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Luteolin; Male; Molecular Structure; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sirolimus

A brief episode of transient ischemia (TI) can confer cerebral ischemic tolerance against a subsequent severer TI under standard condition. The brain under obesity's conditions is more sensitive to ischemic injury. However, the impact of a brief episode of TI under obesity's conditions has not been fully addressed yet. Thus, the objective of this study was to determine the effect of a brief TI in the hippocampus of high-fat diet (HFD)-induced obese gerbils and related mechanisms. Gerbils were maintained on HFD or normal diet (ND) for 12 weeks and subjected to 2 min TI. HFD gerbils were heavier, with higher blood glucose, serum total cholesterol, triglycerides, and leptin levels. Massive loss of pyramidal neurons occurred in the hippocampal cornu ammonis 1 (CA1) field of HFD animals at 5 days after 2 min of TI, but 2 min of TI did not elicit death of pyramidal neurons in ND gerbils. The HFD group showed significantly increased levels of oxidative stress indicators (dihydroethidium and 4-hydroxynonenal) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and microglial activation in pre- and/or post-ischemic phases compared to the ND group. Levels of mammalian target of rapamycin (mTOR) and phosphorylated-mTOR in the CA1 field of the HFD group were also significantly higher than the ND group. On the other hand, inhibition of mTOR activation by rapamycin (an allosteric mTOR inhibitor) significantly attenuated neuronal death induced by HFD, showing reduction of HFD-induced increases of oxidative stress indicators and proinflammatory cytokines, and microglia activation. Taken together, a brief episode of TI can evoke neuronal death under obesity's conditions. It might be closely associated with an abnormal increase of mTOR activation-mediated, severe oxidative stress and neuroinflammation in pre- and/or post-ischemic phases.

Topics: Animals; Case-Control Studies; Cell Death; Diet, High-Fat; Disease Models, Animal; Gerbillinae; Hippocampus; Interleukin-1beta; Ischemic Attack, Transient; Male; Neurons; Obesity; Oxidative Stress; Phosphorylation; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Up-Regulation

A 43-year-old woman was diagnosed with moyamoya disease (MMD) and underwent right-side bypass surgery. After surgery, previous symptoms disappeared. One month later, transient right hemiparetic attacks and motor dysphasia developed. Angiography revealed progressive severe stenosis of left supraclinoid segment of internal carotid artery. Angioplasty using a drug-eluting stent (DES) was performed. For 18 months, she presented no ischemic symptom and no instent stenosis was observed in follow-up angiography. This is the first case report about effect of DES use for MMD. Considering that intimal hyperplasia is a pathophysiology of stenosis, DES may have a role in reducing progression of stenosis in selected moyamoya patients.

Topics: Adult; Angioplasty, Balloon; Carotid Stenosis; Cerebral Infarction; Drug-Eluting Stents; Everolimus; Female; Humans; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Moyamoya Disease; Paresis; Platelet Aggregation Inhibitors; Sirolimus

Former studies indicated that programmed cell death 5 (PDCD5) protein could accelerate the process of apoptosis in response to some stimuli in various kinds of cells via the intrinsic or extrinsic pathway. In this study, we aimed to demonstrate for the first time that protein level of PDCD5 are related to autophagic activity after focal ischemic brain injury in rats. One hundred and twenty-five Sprague-Dawley rats (male) were randomly divided into the following groups: Sham operated, Middle Cerebral Artery Occlusion/Reperfusion (MCAO), MCAO+Control siRNA and MCAO+PDCD5 siRNA. Outcome measurements include neurobehavioral outcomes, brain infarct volume, brain water content, BBB disruption, MRI and double fluorescence labeling. Western blot and histopathophysiological techniques were used to measure the expression of PDCD5 and some pro-autophagic proteins such as Beclin 1 and the LC3-II/LC3-I ratio. The study found that decreased PDCD5 expression via intracerebroventricular injection of PDCD5 siRNA significantly improved the neurobehavioral outcome, reduced the infarct ratio, cerebral edema and BBB disruption. These results were associated with decreased expression of Beclin 1 and the LC3-II/LC3-I ratio in the penumbra area. Rapamycin, an inducer of autophagy, partially weakened the effect of PDCD5 siRNA. In conclusion, this study suggested that PDCD5 was a key regulator of autophagy that might play an important role following MCAO injury.

Topics: Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Blood-Brain Barrier; Brain Edema; Brain Infarction; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Microtubule-Associated Proteins; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Small Interfering; Sirolimus

The use of bare metal stents to treat symptomatic intracranial stenosis may be associated with significant restenosis rates. The advent of drug-eluting stents (DESs) in the coronary circulation has resulted in a reduction of restenosis rates. We report our technical success rate and short-term restenosis rates after stenting with DESs in the intracranial and extracranial circulation.. This study was a retrospective review of the period between April 1, 2004, and April 15, 2006, of 59 patients with 62 symptomatic intracranial or extracranial atherosclerotic lesions at 2 medical centers (University of Pittsburgh and Borgess Medical Center).. The mean age of our cohort was 61+/-12 years. The location of the 62 lesions was as follows: extracranial vertebral artery 31 (50%), intracranial vertebral artery or basilar artery 18 (29%), extracranial internal carotid artery (ICA) near the petrous bone 5 (8%), and intracranial ICA 8 (13%). There were 2 (3%) periprocedural complications: 1 non-flow-limiting dissection and 1 disabling stroke. Fifty vessels were available for follow-up angiography or computed tomography angiography at a median time of 4.0+/-2 months. A total of 2 of 36 extracranial stents (7%) and 1 of 26 intracranial stents (5%) were found to have restenosis > or = 50% at follow-up.. This report demonstrates that DES delivery in the intracranial and extracranial circulation is technically feasible. A small percentage of patients developed short-term in-stent restenosis. Longer-term follow-up is required in the setting of a prospective study to determine the late restenosis rates for DESs in comparison with bare metal stents.

Topics: Anticoagulants; Aortic Dissection; Calcinosis; Carotid Artery, External; Carotid Artery, Internal; Carotid Stenosis; Catheterization; Cohort Studies; Drug Evaluation; Drug Implants; Feasibility Studies; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Organ Specificity; Paclitaxel; Recurrence; Retrospective Studies; Sirolimus; Stents; Stroke; Vertebrobasilar Insufficiency