Wednesday 3 August 2016

Turning Up the Pressure on Vascular Disease

Author(s):

Kenneth MaiesePages 291-293 (3)

Abstract:


Vascular cell injury, whether it occurs in the central nervous system or in other locations throughout the body, represents a significant factor for subsequent disability and death in individuals worldwide. In fact, coronary artery disease remains the leading cause of mortality and can be caused by vessel stenosis, atherosclerosis, embolic disease, or thrombosis. Loss of blood flow to critical areas in the vascular system leads to endothelial cell dysfunction and death. Treatments to avert coronary artery disease and maintain adequate blood flow include the use of antiplatelet agents, angiotensin-converting-enzyme inhibitors, statins, -blockers as well as re-vascularization techniques that include coronary artery bypass grafting and percutaneous coronary intervention. Other new strategies include the induction of angiogenesis such with trophic factors that include vascular endothelial growth factor and fibroblast growth factor, the use of stem cell therapies, and the use of cytokines such as erythropoietin to directly protect cardiomyocytes and endothelial cells. In the nervous system, approximately 15 million individuals suffer some form of a stroke every year. In addition to cerebral blood vessel occlusion or intra-cerebral hemorrhage as causes of stroke, rupture of intracranial aneurysms with subarachnoid hemorrhage also can lead to ischemic cerebral injury. Intracranial aneurysms can result from genetic origins or be acquired through conditions such as tobacco use, excessive ethanol consumption, and hypertension. Although stroke leads to significant mortality and morbidity, stroke is no longer ranked as the third leading cause of death in the United States. Multiple factors have resulted in the reduction of stroke incidence, now classified as the fourth leading cause of death, that include reduction in tobacco consumption, heightened awareness to seek rapid treatment for stroke, improved care of hypertension, and better management of low-density lipoprotein cholesterol. Treatment with recombinant tissue plasminogen activator in patients suitable for this therapy also has led to a reduction in mortality and morbidity in stroke patients. Several new treatment strategies are under consideration for stroke that also address central nervous system inflammation to include treatment with cytokines and growth factors, progenitor stem cells, metallic ions, and small molecular regulators of hypoxia inducible factor. Improved management of metabolic disorders such as diabetes also have accounted for the reduction in the incidence of stroke. Yet, diabetes continues to remain a significant factor that leads to vascular cell injury. Diabetes mellitus may affect approximately 170-200 million individuals in the world with millions of additional individuals currently undiagnosed. Complications of diabetes and insulin resistance are associated with oxidant stress that can affect both the cerebrovascular and cardiovascular systems as well as other vessels in the body. Diabetes can lead to platelet dysfunction, acute cerebral or coronary injury, and dysfunction in the sympathetic nervous system. Elevated glucose in vascular endothelial cells can result in the increase of antioxidants that involve superoxide-dismutase, catalase, and glutathione peroxidase. This may represent a reparative response by the body to attempt to reverse the effects of oxidant stress injury in the vascular system. Infection and sepsis are additional disorders that can lead to vascular compromise in the body. Coagulation abnormalities occur in sepsis and can lead to diffuse microvascular thrombosis, depleted platelet counts, disseminated intravascular coagulation, and thrombosis in larger vessels. Infection that leads to vascular cell injury may be bacterial, viral, or parasitic in origin. For example, during infection of the parasite Plasmodium falciparum that leads to malaria, parasitized red blood cells can adhere to endothelial cells and produce impaired blood flow, mechanical occlusion, and ischemic tissue in the brain as well as in the cardiovascular system. Impaired perfusion and vessel occlusion can even occur in the vasculature of the retina. Vasoconstriction and direct endothelial cell dysfunction also have been reported that may be mediated through impaired nitric oxide bioavailability and modulation of endothelins. In this issue of Current Neurovascular Research, new work targets several novel mechanisms for the treatment of vascular disease in the body that can significantly impact blood vessel and vascular endothelial function. In the paper by Lin et al., the authors examined a mechanism for the development of sporadic aneurysms in the Chinese Han population as a result of endoglin, a gene that is involved in vascular development and angiogenesis. Endoglin, as a potential biomarker, would be of great interest to follow and potentially prevent intracranial aneurysm rupture, since most individuals have no symptoms until intracranial aneurysms become symptomatic. The investigators illustrate in the population examined that the endoglin D366H variant (rs1800956) may be clinically relevant since it has an increased association with intracranial aneurysms and may contribute to the sporadic risk in the development and progression of intracranial aneurysms. Takagi et al. consider factors that can lead to intracranial hemorrhage during excessive alcohol consumption. In a model of ethanol-induced endothelial damage, they identify metalloproteinase 9 (MMP-9) as a key mediator of cell injury and show that tight junction disruption and loss of transendothelial electrical resistance was a result of MMP-9 activation in the setting of oxidative stress. Endothelial damage during ethanol-induced damage could be blocked by cilostazol, a phosphodiesterase III inhibitor, through cellular pathways that require protein kinase A and decrease MMP-9 activity. In regards to the use of stem cells for regenerative strategies following vascular injury, Banik et al. identify an enriched population of CD45, CD34 and CD117 stem cells in human umbilical cord. The authors advocate that this cell population is a viable primitive stem cell source that may possess high regenerative properties for the development of future vascular repair strategies. The work of Martonc ikova et al. is an interesting companion to the Banik study. Martonc íkova et al. show in the rostral migratory stream in a rat model that blood vessels may form a scaffold for the migration of neuronal precursors in the brain, illustrating the vital role of the vascular system in the brain during development and potentially during repair processesfollowing injury. Carvalho et al. focus upon the pathways that contibute to vascular injury during Type 2 diabetes and examine the antioxidant defenses as future therapeutic targets that exist in brain vessels and synaptosomes in animal models of experimental diabetes. They identify several cellular pathways of oxidative imbalance and show that manganese superoxide dismutase activity and vitamin E levels increase with a concomitant decrease in aconitase and glutathione reductase activities, glutathione (GSH)/glutathione disulfide (GSSG) ratio, and GSH and malondialdehyde levels in brain vessels and synaptosomes. Interestingly, an age-dependent increase in hydrogen peroxide levels in both diabetic synaptosomes and vessels was also noted. In their meta-analysis, Panato et al. identify biomarkers markers of bacterial and aseptic meningitis, disorders that can directly lead to vascular cell dysfunction and injury. They show that tumor necrosis factor- α and interleukin-1β are accurate markers to differentiate between bacterial and aseptic meningits with significant elevation of these markers in bacterial meningitis but lower levels of these markers in aspetic meningitis. In our review articles for this issue of Current Neurovascular Research, Maiese presents Wnt1 inducible signaling pathway protein 1 (WISP1) as an emerging novel target for a number of therapeutic strategies especially those relevant for vascular and cardiovascular restoration. WISP1 is a target of the wingless pathway Wnt1 that fosters neuronal and vascular development. WISP1 promotes vascular smooth muscle proliferation that may be important for tissue repair during injury. The reparative properties of WISP1 may be driven by the ability of WISP1 to influence stem cell proliferation, migration, and differentiation. Nabavi et al. examine the antioxidant properties of resveratrol, a natural polyphenolic antioxidant, during stroke. They describe the therapeutic potential of this agent for stroke that modulates several pathways including sirtuins, superoxide dismutase 2, glutathione peroxidase, and nuclear factor-erythroid 2-related factor-2 as well as anti-inflammatory mediators. In this issue of Current Neurovascular Research, new insights into vascular disease and endothelial cell survival are brought forward for the exciting development of new clinical entities. Of course, as with any new developments, we must continue to acquire further understanding of the relevant biology critical for the initiation of new therapeutic strategies and clinical care of vascular disease to avoid unwanted outcomes such as unchecked vascular proliferation. In any event, elegant and focused studies on the problem at hand are always warranted as we “turn up the pressure on vascular disease”.

Affiliation:

Laboratory of Cellular and Molecular Signaling Cancer Center, F 1220 New Jersey Health Sciences University 205 South Orange Avenue, Newark, NJ 07101, USA.


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Platelets in the Alzheimer’s Disease Brain: do they Play a Role in Cerebral Amyloid Angiopathy?

Author(s):

Kathrin M. Kniewallner, Daniela Ehrlich, Andreas Kiefer, Josef Marksteiner and Christian HumpelPages 4-14 (11)

Abstract:


Alzheimer’s disease (AD) is characterized by extracellular beta-amyloid plaques and intracellular tau tangles. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis. Platelets circulate along the vessel wall responding immediately to vascular injury. The aim of the present study was to explore the presence and migration of platelets (thrombocytes) to sites of small vascular bleedings and/or to beta-amyloid plaques in the brain. We infused fluorescently labeled red PKH26 mouse platelets into transgenic Alzheimer mice overexpressing APP with Swedish/Dutch/Iowa mutations (APP_SDI) and explored if platelets migrate into the brain. Further we studied whether platelets accumulate in the vicinity of β-amyloid plaques. Our animal data shows that infused platelets are found in the liver and partly in the lung, while in the brain platelets were visible to a minor degree. In mice, we did not observe a significant association of platelets with beta-amyloid plaques or vessels. In the brain of Alzheimer postmortem patients platelets could be detected by immunohistochemistry for CD41 and CD62P, but the majority was found in vessels with or without beta-amyloid load, and only a few single platelets migrated deeper into the brain. Our findings suggest that platelets do not migrate into the brains of Alzheimer disease but are concentrated in brain vessels.

Keywords:

Alzheimer, migration, postmortem, platelet, vessel.

Affiliation:

Deparment of Psychiatry and Psychotherapy, Anichstr. 35, A-6020 Innsbruck, Austria.


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    Low Baseline Urine Creatinine Excretion Rate Predicts Poor Outcomes among Critically Ill Acute Stroke Patients

    Author(s):

    Chia-Yu Hsu, Yi-Ling Wu, Chun-Yu Cheng, Jiann-Der Lee, Ying-Chih Huang, Ming-Hsueh Lee, Chih-Ying Wu, Huan-Lin Hsu, Ya-Hui Lin, Yen-Chu Huang, Hsin-Ta Yang, Jen-Tsung Yang, Meng Lee and Bruce OvbiagelePages 47-52 (6)

    Abstract:


    Urinary creatinine excretion rate (CER) is an established marker of muscle mass. Low CER has been linked to poor coronary artery disease outcomes, but a link between CER and acute stroke prognosis has not been previously explored. We prospectively collected data from patients with acute stroke (ischemic or hemorrhagic) within 24 hours from symptom onset in a Neurological and Neurosurgery Intensive Care Unit in Taiwan. Baseline CER (mg/d) was calculated by urine creatinine concentration in morning spot urine multiplies 24-hour urine volume on the second day of admission. Patients were divided into 3 tertiles with highest, middle, and lowest CER. Primary endpoint was poor outcome defined as modified Rankin Scale 3-6 at 6 months. Among 156 critically ill acute stroke patients meeting study entry criteria, average age was 67.9 years, and 83 (53.2%) patients had ischemic stroke. Patients with lowest CER (vs. highest CER) had a high risk of poor outcome at 6-month after adjustment (odds ratio 4.96, 95% confidence interval 1.22 to 20.15, p value = 0.025). In conclusion, low baseline CER, a marker of muscle mass, was independently associated with poor 6-month outcome among critically ill acute stroke patients. We speculate that preservation of muscle mass through exercise or protein-energy supplement might be helpful for improving prognosis in severe stroke patients.

    Keywords:

    Urine creatinine excretion rate, stroke, critically ill, outcome.

    Affiliation:

    Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.


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    MicroRNAs and Stem Cells to the Rescue

    Author(s):

    Kenneth MaiesePages 211-213 (3)

    Affiliation:

    Laboratory of Cellular and Molecular Signaling Cancer Center, F 1220 New Jersey Health Sciences University 205 South Orange Avenue, Newark, NJ 07101, USA.


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    Perfusion-diffusion Mismatch Predicts Early Neurological Deterioration in Anterior Circulation Infarction without Thrombolysis

    Author(s):

    Chia-Yu Hsu, Chun-Yu Cheng, Yuan-Hsiung Tsai, Jiann-Der Lee, Jen-Tsung Yang, Hsu-Huei Weng, Leng-Chieh Lin, Ying-Chih Huang, Meng Lee, Ming-Hsueh Lee, Chih-Ying Wu, Ya-Hui Lin, Huan-Lin Hsu, Hsin-Ta Yang, Yi-Ting Pan and Yen-Chu HuangPages 277-282 (6)

    Abstract:


    Perfusion-diffusion mismatch in magnetic resonance imaging (MRI) represents the non-core hypoperfused area in acute ischemic stroke. The mismatch has been used to predict clinical response after thrombolysis in acute ischemic stroke, but its role for predicting early neurological deterioration (END) in acute ischemic stroke without thrombolysis has not been clarified yet. In this study, we prospectively recruited 54 patients with acute non-lacunar ischemic stroke in anterior circulation without thrombolysis. All patients received the first perfusion MRI within 24 hours from stroke onset. Target mismatch profile was defined as a perfusion-diffusion mismatch ratio ≥ 1.2. END was defined as an increase of ≥ 4 points in the National Institute of Health Stroke Scale (NIHSS) score within 72 hours. There were 13 (24.1%) patients developing END, which was associated with larger infarct growth (p = 0.002), worse modified Rankin Scale (p = 0.001) and higher mortality rate at 3 months (p = 0.025). Target mismatch profiles measured by Tmax ≥ 4, 5 and 6 seconds were independent predictors for END after correcting initial NIHSS score. Among the 3 Tmax thresholds, target mismatch measured by Tmax ≥ 6 seconds had the highest odd’s ratio in predicting END (p < 0.01, odd’s ratio = 17), with an 80% sensitivity and a 79.5% specificity. In conclusion, perfusion-diffusion mismatch could identify the patients at high risk of early clinical worsening in acute ischemic stroke without thrombolysis.

    Keywords:

    Early neurological deterioration, acute ischemic stroke, perfusion-diffusion mismatch.

    Affiliation:

    Department of Neurology, Chang Gung Memorial Hospital, 6 West Chia-Pu Road, Putz City, Chiayi County, Taiwan.


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