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Tag: Blood Vessels

  • Optimizing antithrombotic treatment for individualized cardiovascular care

    Optimizing antithrombotic treatment for individualized cardiovascular care

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    Announcing a new article publication for Cardiovascular Innovations and Applications journal. Thrombosis, the process of blood clot formation in blood vessels, is an important protective mechanism for avoiding excessive blood spillage when an individual is exposed to trauma. The body has both a thrombosis inhibition and a thrombus removal system, which interact in a balanced manner. If these mechanisms become unbalanced, and too many clots form and block the lumen, thrombosis occurs.

    Thrombosis is currently the leading cause of death from disease in humans and is one of the most common events leading to many cardiovascular diseases. Antithrombotic drugs are an integral part of the pharmacological treatment regimens, and interventional strategies are currently recommended for thrombotic complications in patients with thrombosis. Despite major advances in these therapies, the high risk associated with thrombosis and bleeding remains, because of the complex interplay among patient comorbidities, drug combinations, multifaceted dose adjustments, and care settings.

    Detailed assessment of the effects of bleeding and thrombosis is necessary to establish optimal treatment plans for patients with thrombosis. This study retrospectively evaluated methods for assessing the risk of bleeding/ischemia in thrombosis and the individualized use of these methods.

    Source:

    Journal reference:

    Yuan, M., et al. (2024). Precision Monitoring of Antithrombotic Therapy in Cardiovascular Disease. Cardiovascular Innovations and Applications. doi.org/10.15212/cvia.2024.0013.

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  • Nanoparticle therapy offers hope for aortic aneurysm treatment

    Nanoparticle therapy offers hope for aortic aneurysm treatment

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    Aortic aneurysms are bulges in the aorta, the largest blood vessel that carries oxygen-rich blood from the heart to the rest of the body. Smoking, high blood pressure, diabetes, or injury can all increase the risk of aneurysms, which tend to occur more often in Caucasian male smokers over the age of 65. 

    The soft tissues that make up blood vessels act essentially like rubber bands, and it’s the elastic fibers within these tissues that allow them to stretch and snap back. These fibers are produced primarily before and just after birth. After that, they don’t regenerate or undergo natural repair after injury. So when they become injured or diseased, the tissue weakens and causes an aneurysm, which can grow over time. After about seven to 10 years, it typically reaches the rupture stage.”


    Professor Anand Ramamurthi, Chair of the Department of Bioengineering in Lehigh University’s P.C. Rossin College of Engineering and Applied Science

    During that period, there is no treatment. Patients are screened regularly via imaging to monitor the rate of the aneurysm’s growth. Once it’s deemed big enough to potentially rupture (an occurrence that is fatal 90 percent of the time), surgery is the only option. But it’s a risky one for elderly patients.

    Ramamurthi and his team are working on minimally invasive ways to regenerate and repair these elastic fibers using polymeric or biological nanocapsules, called nanoparticles, that are designed to release novel regenerative therapeutics. Their innovative techniques could enable treatment soon after an aneurysm is detected and potentially slow, reverse, or even stop its growth. Findings from their most recent paper, published in the Journal of Biomedical Materials Research, build on their earlier work and represent a step toward a future where surgery is no longer the best, and only, treatment option. 

    “In previous research, we’ve identified drugs and gene-silencing agents that can actually coax adult diseased vascular cells to produce new elastic fibers and inhibit the enzymes that break down existing fibers,” he says. “We’ve also been working on how to deliver these therapeutics efficiently only at the site of tissue repair.”

    The team has also developed a nanoparticle design called active-targeting that incorporates small protein fragments, or peptides, on the nanoparticle’s surface. “These peptides recognize components that are unique to the aneurysm tissue. So when the nanoparticles are injected into the bloodstream, they stick only to the aneurysm wall, where they slowly degrade and release the drug.

    For this paper, he says, the researchers “investigated how the nanoparticles actually penetrate the blood vessel wall to deliver the drug to the affected tissue.”

    All blood vessels are lined with a protective barrier made of endothelial cells, which can become “leaky” as inflammation from tissue damage or disease breaks down the endothelium and creates gaps between the cells. These gaps allow white blood cells to move in and start the tissue repair process, and they also serve as the entry point for nanoparticles that accelerate healing.

    “We wanted to know how the shape and the aspect ratio of these nanoparticles affect their ability to cross that endothelial cell barrier,” says Ramamurthi. 

    It was a critical question to answer because not all nanoparticles are created alike, and if they can’t penetrate the barrier, they can’t repair the tissue.

    Ramamurthi and his team developed a novel cell culture model in which they simulated disease and then examined mechanisms of transport: specifically, how nanoparticles of different kinds interacted with endothelial cells and moved through them. Did they enter through gaps among the endothelial cells (a process called extravasation) or through the cells themselves (what’s known as translocation)?

    “Let’s say a nanoparticle goes through an endothelial cell. Some of it might stay within that cell and not come out the other side, which means you lose that particle, and it’s no longer useful to the healing process. The goal is transportation with minimal retention.”

    The team found that rod-shaped particles, as opposed to spherical particles, with a high aspect ratio (i.e., long and skinny versus short and stubby) were selectively taken up by diseased endothelial cells. “And they showed very little uptake into healthy endothelial cells compared with the spheres, which is good because we don’t want them interacting with healthy vessel walls,” he says.

    They also found that particles reached the tissue primarily by extravasation (or via the cell gaps). “The longer and skinnier they were, the less likely they were to remain within the endothelial cell layer, which means they’re getting through to the affected tissue for more effective therapy.”

    The team will now integrate these findings with their work on active targeting-;incorporating components on the surface of nanoparticles that recognize proteins expressed by diseased cells-;in animal models.

    The ultimate goal is to develop a nonsurgical regenerative therapy capable of slowing aneurysm growth. For example, increasing the current growth-to-rupture stage from seven years to 15 years. An even more ambitious outcome, says Ramamurthi, would be to revert that growth. 

    “Regression of aneurysm growth would be the preferred long-term outcome,” he says. “That’s a long way off, but we’re excited because these findings will help guide us on how to design our nanoparticles for more efficient delivery to the aneurysm wall. It’s an opportunity to get closer to that reality.”

    Source:

    Journal reference:

    Yau, J., et al. (2024). Assessing trans‐endothelial transport of nanoparticles for delivery to abdominal aortic aneurysms. Journal of Biomedical Materials Research Part A. doi.org/10.1002/jbm.a.37667.

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  • Researchers identify potential treatment for cardiovascular disease linked to Type 2 diabetes

    Researchers identify potential treatment for cardiovascular disease linked to Type 2 diabetes

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    New research at the Roy Blunt NextGen Precision Health building has discovered a potential treatment for an underlying cause of cardiovascular disease in people with Type 2 diabetes.

    More than 30 million Americans live with Type 2 diabetes. One common feature of diabetes is the hardening and inflexibility of blood vessels caused by damage to the endothelial cells in the vascular system. Over time, this can lead to the development and progression of cardiovascular disease, which is the number one cause of death in diabetics. Because endothelial dysfunction is causally linked to cardiovascular disease, there is a considerable need to identify new therapeutic targets to improve endothelial function in Type 2 diabetics.

    A research team from the University of Missouri has found that neuraminidase activity is elevated in the circulation of Type 2 diabetic mice and humans. In a series of mechanistic experiments in cultured endothelial cells and isolated blood vessels, they were able to link increased neuraminidase to endothelial dysfunction. 

    Because we know that Type 2 diabetics have this increased neuraminidase circulating in their blood, and that the presence of it promotes endothelial dysfunction, it is important to target it as a means of addressing the cardiovascular complications faced by those with Type 2 diabetes.”


    Luis Martinez-Lemus, DVM, PhD, James O. Davis distinguished professor in cardiovascular research at the University of Missouri School of Medicine

    The team also found that neuraminidase inhibition using zanamivir, an oral inhalation drug used to treat the flu virus, improved endothelial function in diabetic mice. 

    “This research lays out the molecular mechanisms by which neuraminidase promotes endothelial dysfunction and these mechanisms can be exploited therapeutically,” said Jaume Padilla, PhD, an associate professor of nutrition and exercise physiology at MU. “Improving vascular function in people with Type 2 diabetes can help them live longer and better lives, which is why this research is so important.”

    “Neuraminidase inhibition improves endothelial function in diabetic mice” and “Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells” were recently published in the American Journal of Physiology-Heart and Circulatory Physiology. In addition to Martinez-Lemus and Padilla, the research team at MU includes Camila Manrique-Acevedo, MD, distinguished professor in diabetes and director of faculty research at the School of Medicine; Larissa Ferreira-Santos, PhD, Thaysa Ghiarone, PhD and Francisco Ramirez-Perez, PhD, postdoctoral fellows at NextGen Precision Health; Christopher Foote, PhD, assistant research professor of medical pharmacology and physiology; James Smith, Marc Augenreich, Neil McMillan, and Gavin Power, doctoral students in Nutrition and Exercise Physiology; Andrew Wheeler, MD, surgeon, MU Health Care Weight Management Center; Katherine Burr, senior research specialist at the School of Medicine; Annayya Aroor, MD, assistant research professor at the School of Medicine; Shawn Bender, PhD, associate professor, College of Veterinary Medicine; Mariana Morales-Quinones, PhD, senior research specialist at NextGen Precision Health; Morgan Williams and Juan Gonzalez-Vallejo, NextGen Precision Health.

    Source:

    University of Missouri-Columbia

    Journal references:

    • Foote, C. A., et al. (2023). Neuraminidase inhibition improves endothelial function in diabetic mice. American Journal of Physiology-Heart and Circulatory Physiology. doi.org/10.1152/ajpheart.00337.2023.

    • Ferreira-Santos, L., et al. (2024). Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells. American Journal of Physiology-Heart and Circulatory Physiology. doi.org/10.1152/ajpheart.00638.2023.

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  • Major discovery improves the understanding of brain fog associated with Long COVID

    Major discovery improves the understanding of brain fog associated with Long COVID

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    Today, a team of scientists from Trinity College Dublin and investigators from FutureNeuro announced a major discovery that has profound importance for our understanding of brain fog and cognitive decline seen in some patients with Long COVID.

    In the months after the emergence of the novel coronavirus SARS-CoV2 in late 2019 a patient-reported syndrome termed Long-COVID began to come to the fore as an enduring manifestation of acute infection.

    Long COVID has up to 200 reported symptoms to date, but in general patients report lingering symptoms such as fatigue, shortness of breath, problems with memory and thinking and joint/muscle pain. While the vast majority of people suffering from COVID-19 make a full recovery, any of these symptoms that linger for more than 12 weeks post infection can be considered Long COVID. 

    Long COVID has now become a major public health issue since the outbreak of the pandemic in 2020. While international incidence rates vary, it is estimated to affect up to 10% of patients infected with the SARS-CoV2 virus. Of these patients suffering from Long-COVID, just under 50% of them report some form of lingering neurological effect such as cognitive decline, fatigue and brain fog. 

    Now, the findings reported by the Trinity team in the top international journal Nature Neuroscience showed that there was disruption to the integrity of the blood vessels in the brains of patients suffering from Long COVID and brain fog. This blood vessel “leakiness” was able to objectively distinguish those patients with brain fog and cognitive decline compared to patients suffering from Long-COVID but not with brain fog. 

    The team led by scientists at the Smurfit Institute of Genetics in Trinity’s School of Genetics and Microbiology and neurologists in the School of Medicine have also uncovered a novel form of MRI scan that shows how Long-COVID can affect the human brain’s delicate network of blood vessels. 

    For the first time, we have been able to show that leaky blood vessels in the human brain, in tandem with a hyperactive immune system may be the key drivers of brain fog associated with Long COVID. This is critically important, as understanding the underlying cause of these conditions will allow us to develop targeted therapies for patients in the future,”


     Prof. Matthew Campbell, Professor in Genetics and Head of Genetics at Trinity, and Principal Investigator at FutureNeuro

    This project was initiated by a rapid response grant funded by Science Foundation Ireland (SFI) at the height of the pandemic in 2020 and involved recruiting patients suffering from the effects of Long-COVID as well as patients who were hospitalised in St James’ Hospital. 

    “Undertaking this complicated clinical research study at a time of national crisis and when our hospital system was under severe pressure is a testament to the skill and resource of our medical trainees and staff. The findings will now likely change the landscape of how we understand and treat post-viral neurological conditions. It also confirms that the neurological symptoms of Long Covid are measurable with real and demonstrable metabolic and vascular changes in the brain,” said Prof. Colin Doherty, Professor of Neurology and Head of the School of Medicine at Trinity, and Principal Investigator at FutureNeuro. 

    Moving beyond COVID-19 

    In recent years, it has become apparent that many neurological conditions such as Multiple sclerosis (MS) likely have a viral infection as the initiating event that triggers the pathology. However, proving that direct link has always been challenging.

    Prof. Campbell added: “Here, the team at Trinity was able to prove that every patient that developed Long-COVID had been diagnosed with SARS-CoV2 infection, because Ireland required every documented case to be diagnosed using the more accurate PCR-based methods. The concept that many other viral infections that lead to post-viral syndromes might drive blood vessel leakage in the brain is potentially game-changing and is under active investigation by the team.” 

    Dr Chris Greene, Postdoctoral research fellow and first author of the study, added: “Our findings have now set the stage for further studies examining the molecular events that lead to post-viral fatigue and brain fog. Without doubt, similar mechanisms are at play across many disparate types of viral infection and we are now tantalizingly close to understanding how and why they cause neurological dysfunction in patients.”  

    The research was supported by Science Foundation Ireland, the European Research Council and FutureNeuro, the SFI Centre for rare and chronic neurological, neurodevelopmental and neuropsychiatric conditions.

    Source:

    Journal reference:

    Greene, C., et al. (2024). Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience. doi.org/10.1038/s41593-024-01576-9.

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  • Managing migraines and menopausal symptoms to reduce cardiovascular risks in middle-aged women

    Managing migraines and menopausal symptoms to reduce cardiovascular risks in middle-aged women

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    For middle-aged women plagued by migraines, or hot flashes and night sweats, another worry may linger in the backs of their minds: whether these experiences have set them up for a heart attack, a stroke or another cardiovascular crisis.

    After all, past research suggesting such a link during and after menopause has gotten a lot of attention.

    But a pair of new studies in the journal Menopause suggest that most of them don’t need to worry as much, especially if they don’t have both migraines and long-term hot flashes and night sweats.

    Instead, they should focus on tackling the other factors that can raise their cardiovascular risk by getting more sleep, exercise and healthy foods, quitting tobacco, and minding their blood pressure, blood sugar, cholesterol and weight.

    For women who have experienced both migraines and hot flashes or night sweats over many years, one of the new studies does suggest an extra level of cardiovascular risk. That makes heart disease and stroke prevention even more important in this group, says study leader Catherine Kim, M.D., M.P.H., of the University of Michigan.

    And for women currently in their 20s and 30s who experience migraines, the new research suggests that they might be heading for a higher risk of long-term menopause-related symptoms when they get older.

    Long-term study yields important insights

    Kim and her colleagues at Michigan Medicine, U-M’s academic medical center, published the new pair of studies based on an in-depth analysis of data from a long-term study of more than 1,900 women who volunteered to have regular physical exams and blood tests, and to take yearly health surveys, when they were in their late teens to early 30s.

    Those women, now in their 50s and 60s, have provided researchers with a priceless view of what factors shape health in the years leading up to menopause and beyond, through their continued participation in the CARDIA study.

    “The anxiety and dread that women with migraines and menopausal symptoms feel about cardiovascular risk is real – but these findings suggest that focusing on prevention, and correcting unhealthy habits and risk factors, could help most women,” said Kim, who is an associate professor of internal medicine at U-M and a primary care physician.

    “For the subgroup with both migraines and early persistent hot flashes and night sweats, and for those currently experiencing migraines in their early adulthood, these findings point to an added need to control risks, and address symptoms early,” she adds.

    Just over 30% of the middle-aged women in the study reported they had persistent hot flashes and night sweats, which together are called vasomotor symptoms or VMS because they relate to changes in the diameter of blood vessels.

    Of them, 23% had reported also having migraines. This was the only group for whom Kim and her colleagues found extra risk of stroke, heart attack or other cardiovascular events that couldn’t be explained by other risk factors that have long been known to be linked to cardiovascular problems.

    In addition to those with persistent vasomotor symptoms starting in their 40s or before, 43% of the women in the study had minimal levels of such symptoms in their 50s, and 27% experienced an increase in VMS over time into their 50s and early 60s.

    The latter two groups had no excess cardiovascular risk once their other risk factors were taken into account, whether or not they had migraines. Use of hormone-based birth control and estrogen to address medical issues did not affect this risk.

    Controlling destiny

    In the study of data from the same women in their earlier stages of life, the researchers found that the biggest factors in predicting which ones would go on to have persistent hot flashes and night sweats were having migraines, having depression, and smoking cigarettes, as well as being Black or having less than a high school education.

    These two studies, taken together, underscore that not all women have the same experiences as they grow older, and that many can control the risk factors that might raise their chances of heart disease and stroke later in life. In other words, women can do a lot to control their destiny when it comes to both menopause symptoms and cardiovascular diseases.”


    Catherine Kim, M.D., M.P.H., University of Michigan

    She notes that the American Heart Association calls these risk factors the “Essential 8” and offers guides for what women, men and even children and teens can do to address them.

    Evolving knowledge and treatment

    The long-term study that the two new findings come from was specifically designed to look at cardiovascular risks when it launched in the mid-1980s. CARDIA stands for Coronary Artery Risk Development in Young Adults.

    Back in the 80s, knowledge about the biology of blood vessels, down to the cellular and molecular level, was nowhere near where it is today. Both vasomotor symptoms in menopause and migraines have to do with blood vessel contraction and dilation.

    But decades of research has shown the microscopic impacts on blood vessels of years of smoking, poor sleep, poor eating habits and lack of activity, as well as a person’s genetic inheritance, life experiences and hormonal history.

    Newer injectable migraine medications called calcitonin gene-related peptide (CGRP) antagonists have reached the market in recent years.

    Using monoclonal antibodies, they target a key receptor on the surface of blood vessel cells to prevent migraines and cluster headaches. But they are expensive and not covered by insurance for all people with migraines.

    While the new study is based on data from years before these medications became available, Kim said she recommends them to her patients with persistent migraines, as well as working with them to understand what triggers their migraines and how to use other medications including pain relievers and antiseizure medications to prevent them.

    She also notes that the paper on future risk of persistent hot flashes and night sweats echoes the recent trend of using antidepressant medications to try to ease these menopause effects.

    Kim also says that evidence has grown about the importance of healthy sleep habits for reducing hot flashes, as well the short-term use of estradiol-based hormone therapy patches, which have not been shown to have a link to cardiovascular risk. And, she notes that research has not shown any over-the-counter supplement or herbal remedy to be effective, and that these are far less regulated than medications.

    Additional authors:

    Kim and Deborah Levine, M.D., M.P.H., senior author of the paper on cardiovascular risk, are both on the faculty in the Division of General Medicine, and members of the U-M Institute for Healthcare Policy and Innovation. Levine heads the Cognitive Health Services Research Program or COG-HSR. Other authors on this paper are Pamela J. Schreiner, Ph.D., of the University of Minnesota, Zhe Yin, M.S., formerly of IHPI, Rachael Whitney, Ph.D., lead statistician at COG-HSR; Stephen Sidney, MD, MPH, of Kaiser Permanente Northern California and Imo Ebong, M.D. of the University of California, Davis.

    Schreiner is the senior author of the paper on later persistent VMS risk in younger women. Other authors on that paper are U-M’s Abbi Lane, Ph.D.; Zhe Yin, M.S.; Hui Jiang, Ph.D. and Richard Auchus, M.D., Ph.D.; as well as Thanh-Huyen Vu M.D., Ph.D. of Northwestern University and Cora Lewis, M.D. of the University of Alabama.

    The study was funded by the National Heart, Lung and Blood Institute (HL169167), which also sponsors the CARDIA study.

    Source:

    Michigan Medicine – University of Michigan

    Journal reference:

    Kim, C., et al. (2024) Migraines, vasomotor symptoms, and cardiovascular disease in the Coronary Artery Risk Development in Young Adults study. Menopause. doi.org/10.1097/GME.0000000000002311.

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  • Blocking artery plus surgery offers hope for reducing reoperations in brain hematoma patients

    Blocking artery plus surgery offers hope for reducing reoperations in brain hematoma patients

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    Injection of a substance to block an artery feeding the dura (protective sack around the brain) along with surgery to remove pooled blood reduced the risk that patients will require repeat surgery compared to surgical drainage alone, according to preliminary late-breaking science presented today at the American Stroke Association’s International Stroke Conference 2024. The meeting, held in person in Phoenix Feb. 7 – 9, 2024, is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

    A subdural hematoma occurs when there is a tear in one of the thin blood vessels that stretch between the surface of the brain and the overlying membranes that protect the brain. A subdural hematoma can occur because of physical trauma such as a car accident, however, it may also develop slowly in the days or weeks after the injury. This study explored treatment for subacute or chronic subdural hematoma. Subacute subdural hematoma occurs following less severe trauma, such as a concussion – with symptoms such as weakness, numbness, tingling, seizure, headache, confusion or dizziness that develops over hours or days after the event. Chronic subdural hematoma can result from slow bleeding after minimal trauma that the patient may not even remember – symptoms may be subtle and/or may take weeks to be noticeable enough to seek treatment.

    Chronic subdural hematoma is one of the most common neurosurgical conditions and is likely to increase in the future since we have a sizeable aging population, with many taking blood thinners to manage various medical conditions. These hematomas often form in the elderly because as we age, the brain shrinks and pulls away from the inside of the skull, stretching the veins that form a bridge between the dura and the brain, which makes them more likely to tear after a small trauma and leak blood into the protective space between the brain and skull, the dura.”


    Jason Davies, M.D., Ph.D., study co-author, associate professor in the departments of neurosurgery and biomedical informatics at the State University of New York, Buffalo

    Treatment for subacute or chronic subdural hematoma may involve a surgical procedure to drain pooled blood from the area or closely monitoring symptoms to determine if and when intervention may be necessary. The challenge is that even with surgery, repeat surgery may be needed in up to 20% of cases of subdural hematomas.

    The EMBOLISE clinical trial tested whether a subacute or chronic subdural hematoma is less likely to require additional surgery if, in addition to surgical drainage, a substance is injected to block, or embolize, one of the arteries supplying blood to the dura. The OnyxTM liquid embolic system, tested in this trial, is already used prior to surgery to reduce bleeding in people having an operation to correct an abnormal connection between arteries and veins in the brain.

    Between December 2020 and August 2023, researchers enrolled 400 adults (average age of 72; 27% women) at 39 centers (including both community and academic hospitals). All were about to undergo surgery for subacute or chronic subdural hematoma and were considered able to care for themselves and likely to survive at least one year. Patients were randomly assigned to receive either surgery alone or surgery plus embolization using the liquid embolic system to help reduce the progression or recurrence of subdural hematoma.

    The primary outcome was how frequently there was reaccumulation of blood (a recurrence) that required surgical drainage within 90 days.

    The analysis found:

    • Subsequent subdural hematoma within 90 days and need for surgical drainage occurred in 4.1% of patients who had surgery plus embolization and 11.3% of those who had surgery alone.

    • At 90 days after surgery, increasing disability and neurological dysfunction was found to be comparable (statistically the same) in both groups, with 11.9% of patients who had surgery plus embolization and 9.8% of patients who had surgery alone.

    • Serious adverse events attributed to embolization occurred in 2% of patients who received it.

    “The EMBOLISE trial showed that there was a nearly 3-fold reduction in re-operation for patients that were treated with surgery plus embolization,” Davies said. “Fewer trips to the operating room mean less potential for pain, complications, recovery and expense for the patient. Furthermore, we see that the complications related to the embolization procedure were low and that there was no increase in neurological problems.” 

    Study details and background:

    • The EMBOLISE (Embolization of the Middle Meningeal Artery With OnyxTM Liquid Embolic System in the Treatment of Subacute and Chronic Subdural Hematoma) study was conducted at multiple hospitals and health centers in the United States.

    • The liquid embolic system treatment starts as an injectable soft solid, flows as a liquid when force is applied, and then returns to a soft solid state to stop the leaking blood vessel.

    • Other arms of the EMBOLISE study, which included patients not undergoing surgery and randomized to either receive the liquid embolic system or not, are ongoing and not being presented at ISC 2024.

    • Additional measures to gauge success of the liquid embolic system treatment included the number of hospital readmissions; change in hematoma (pooling of blood) volume or thickness; and change in midline shift (when a hematoma pushes brain tissue out of alignment), all assessed at 90 days after treatment.

    • Safety endpoints included the incidence of neurological death or serious adverse events occurring within 30, 90 and 180 days after treatment.

    The main limitation was a relatively high loss to follow up. “One of the challenges of conducting this trial was dealing with a frail elderly population, especially in the middle of the pandemic. Tracking patients down for follow up is always a challenge, and these were compounded by the various COVID-era restrictions that many of our sites faced,” Davies said.

    Source:

    American Heart Association

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  • New treatment targeting aging cells could offer lasting relief for diabetic macular edema

    New treatment targeting aging cells could offer lasting relief for diabetic macular edema

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    A recent study published in the journal Nature Medicine showed that targeting senescent cells in the retina can be a lasting disease-modifying treatment for diabetic macular edema (DME).

    The retina is vascularized to support the higher energetic demand for vision. As such, the neural retina and associated blood vessels are susceptible to metabolic perturbations, like in diabetic retinopathy (DR). Blood-retina barrier breakdown at various stages of DR leads to DME, wherein extravasation of plasma and proteins into intra- and sub-retinal spaces causes swelling and vision loss.

    Current standard care for DME involves anti-vascular endothelial growth factor (VEGF) agents, which reduce macular edema and improve visual acuity. However, therapeutic response remains sub-optimal in most patients, with its effectiveness waning over time. Besides, while corticosteroids can effectively reduce edema, they can increase intraocular pressure. Exploring alternative safer, long-lasting, disease-modifying DME treatments can benefit patients.

    Study: Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Image Credit: Anukool Manoton / ShutterstockStudy: Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Image Credit: Anukool Manoton / Shutterstock

    The study and findings

    In the present study, researchers investigated how senescent cells contribute to DME. First, they estimated the levels of prototypical senescence-associated secretory phenotype (SASP) factors in DME patients’ vitreous. This revealed increases in interleukin (IL)-6, IL-8, and plasminogen activator inhibitor 1 (PAI1) levels in DME patients relative to controls with non-vascular pathology.

    Further, the expression of p16INK4A, a cell cycle regulator associated with senescence, in postmortem retinal sagittal sections of DME patients compared to age- and sex-matched non-diabetic control retinas. Increased p16INK4A expression was observed in the inner retina, choroidal layers, and Bruch’s membrane in retinas with DME. p16INK4A expression was confined to regions of suspected disease activity.

    Next, the researchers examined bulk RNA sequencing (RNA-seq) datasets of retinas from mice and rats with streptozotocin (STZ)-induced diabetes. Genes for cellular senescence and the SASP were positively correlated in STZ-treated animals compared to controls. For increased resolution, they assessed single-cell RNA-seq (scRNA-seq) datasets from mice with STZ-induced diabetes.

    Cone photoreceptors, endothelial cells (ECs), and Muller glia were the most transcriptionally perturbed populations compared to non-diabetic controls. Sub-clustering of ECs disclosed three distinct sub-clusters (EC1 – EC3). EC2 was predominant in diabetic retinas and was enriched for genes linked to vascular complications in diabetes and those involved in regulating cellular senescence in ECs and other cell types.

    Further experiments suggested that senescent ECs in the retina impaired barrier function. Next, whether hyperglycemia could trigger senescent phenotypes in DME was evaluated. Human retinal microvascular ECs (HRMECs) were exposed to a medium with high D-glucose (HG) or isosmotic control enantiomer (CTR). After five weeks of HG exposure, global cellular proliferation decreased by 25%, and cells with senescence-associated markers increased three-fold compared to CTR.

    Anti-apoptotic proteins such as B-cell lymphoma 2 (BCL2) and BCL-xL were induced in HG-treated HRMECs. Further, the researchers tested whether targeting BCL-xL could improve barrier function in diabetic retinas. A small-molecule inhibitor, UBX1967, was administered intravitreally to diabetic mice eight and nine weeks after STZ treatment. This significantly reduced protein levels of BCL-xL and PAI1 at 10 weeks of diabetes.

    Retinal BCL2 levels were unaltered, while transcript levels of inflammatory SASP factors were significantly reduced. Notably, UBX1967 treatment reduced retinal vascular permeability by 40% to 50%. In addition, whole-field scotopic electroretinography showed that UBX1967 treatment improved retinal function. The researchers developed UBX1325, a phosphate pro-drug with senolytic properties, as a therapeutic candidate.

    BCL-xL target engagement was confirmed for UBX0601 (active molecule of UBX1325) in senescent HRMECs. The researchers noted that apoptosis initiation through BCL-xL inhibition required senescent cells to be present. Apoptosis with BCL-xL inhibition did not occur in healthy retina. UBX1325 also decreased retinal vascular permeability (40% – 50%) in the STZ model compared to vehicle-treated controls.

    Next, the team performed a phase 1 safety and tolerability trial of UBX1325 in patients with advanced DME or neovascular age-related macular degeneration for whom anti-VEGF therapy was no longer beneficial. Intravitreal UBX1325 injection was well tolerated with no reports of inflammation. However, a few treatment-emergent adverse events (TEAEs) were observed that were deemed unrelated to UBX1325.

    TEAEs were more likely observed in patients receiving higher doses, which were considered due to their underlying disease. Initial safety assessment suggested that UBX1325 could be advanced into later-stage clinical studies. Plasma levels of UBX1325 and UBX0601 were below the lower quantification limit. Among DME patients, a single injection improved visual acuity. Higher UBX1325 doses reduced central subfield thickness.

    Conclusions

    Together, the findings illustrate that therapeutic clearance of senescent cells could result in long-term improvements in visual function in DME patients. Intravitreal administration of BCL-xL inhibitor eliminated senescent ECs, resulting in lower local inflammation and improved barrier function, ultimately augmenting visual function. Efficacy data suggested that vision improvements persist for at least six months.

    Journal reference:

    • Crespo-Garcia S, Fournier F, Diaz-Marin R, et al. Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results. Nat Med, 2024, DOI: 10.1038/s41591-024-02802-4, https://www.nature.com/articles/s41591-024-02802-4

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  • Enzyme released by immune cells may play role in depression

    Enzyme released by immune cells may play role in depression

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    Mount Sinai researchers have shown for the first time that immune cells called monocytes, derived in the bone marrow and released into the bloodstream, can be drawn during stress into sites in the brain that control emotional behaviors. There, they release an enzyme called matrix metalloproteinase 8 (MMP8) that breaks down proteins and restructures the brain to alter the function of neurons and, ultimately, impair social behavior and reward.

    These data establish a novel mechanism by which the immune system can affect central nervous system function and behavior in the context of stress, potentially opening the door to novel therapeutic targets for stress-related disorders. The study appears in the February 7 issue of Nature.

    Psychosocial stress is a major factor for developing major depressive disorder and post-traumatic stress disorder (PTSD) and has been shown to have profound effects on the body, including the immune system and the brain. These data are the first to show that immune cells derived in the bone marrow-;and not the brain-;can be recruited during stressful circumstances to the brain, setting off a cascade of other mechanisms that alter brain function and behavior.”


    Flurin Cathomas, MD, lead author, Instructor of Neuroscience and member of the Brain-Body Research Center at Mount Sinai

    To explore these mechanisms, the research team performed comparative cross-species analyses in mice and humans and found that MMP8 is elevated in the serum of study subjects with major depressive disorder, as well as in stress-susceptible mice following chronic social defeat stress, a model of social trauma. Studies in mice confirmed that peripheral MMP8 enters the brain through damaged blood vessels to restructure the brain’s extracellular tissue matrix, which leads to altered function of neurons that ultimately impairs social behavior and reward.

    Prior to this work, most hypotheses about the role of the immune system in stress disorders such as depression have centered on mechanisms related to the brain’s resident immune cells, called microglia, and their ability to release pro-inflammatory molecules such as interleukins to control neural function and behavior.

    Using single-cell RNA sequencing to look at gene expression profiles in circulating monocytes as compared to microglia, the team found that, contrary to popular belief, the microglia did not exhibit a pro-inflammatory gene signature. The team found no evidence that they upregulate genes that code for interleukins. This is in stark contrast to circulating monocytes found within the blood vessel lining of brain regions that control mood and emotion.

    “There are no existing medications to target MMP8, and while it’s not yet clear if such treatments will ultimately be effective in treating depression, my hope is that this study will lead to renewed effort in developing such drugs,” said Scott Russo, PhD, Mount Sinai Professor in Affective Neuroscience, Leon Levy Director of the Brain-Body Research Center, and Center for Affective Neuroscience at Mount Sinai. “It’s also possible that non-pharmacological ‘lifestyle’ strategies to promote positive immune health might be helpful in treating these stress-related disorders.”

    The disturbances in the immune system identified in this study were only found in a subset of patients, which highlights the heterogeneous nature of such illnesses in terms of etiology. Additionally, the studies performed in human subjects were purely correlative, so the team does not yet know if treatments targeting monocytes or MMP8 directly will be effective for human stress disorders. Importantly, there are several additional MMPs that can be derived directly in the brain and it remains unclear whether they play complementary or opposing roles.

    “The brain and the body are unequivocally connected and we are really at the precipice of a markedly deeper understanding of how the connections between the brain and peripheral organ systems like the immune system, cardiovascular system, and others can affect a person’s health,” said Dr. Russo. “Our work suggests that strategies to promote immune health can benefit one’s emotional well-being and possibly prevent stress-related illnesses like depression and PTSD. Additional research for continued understanding and potential treatment development is warranted.”

    The Mount Sinai research team is currently testing therapeutic strategies to inhibit MMP8 as novel antidepressants. They are also investigating MMP8 as a novel immune biomarker for depression patients.

    Source:

    Mount Sinai Health System

    Journal reference:

    Cathomas, F., et al. (2024). Circulating myeloid-derived MMP8 in stress susceptibility and depression. Nature. doi.org/10.1038/s41586-023-07015-2.

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  • Study discovers a direct connection between the brain and its surrounding environment

    Study discovers a direct connection between the brain and its surrounding environment

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    In a recent study of the brain’s waste drainage system, researchers from Washington University in St. Louis, collaborating with investigators at the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institute of Health (NIH), discovered a direct connection between the brain and its tough protective covering, the dura mater. These links may allow waste fluid to leave the brain while also exposing the brain to immune cells and other signals coming from the dura. This challenges the conventional wisdom which has suggested that the brain is cut off from its surroundings by a series of protective barriers, keeping it safe from dangerous chemicals and toxins lurking in the environment.

    Waste fluid moves from the brain into the body much like how sewage leaves our homes. In this study, we asked the question of what happens once the ‘drain pipes’ leave the ‘house’-;in this case, the brain-;and connect up with the city sewer system within the body.”


    NINDS’s Daniel S. Reich, M.D., Ph.D

    Reich’s group worked jointly with the lab of Jonathan Kipnis, Ph.D., a professor at Washington University in St. Louis.

    Reich’s lab used high-resolution magnetic resonance imaging (MRI) to observe the connection between the brain and body’s lymphatic systems in humans. Meanwhile Kipnis’s group was independently using live-cell and other microscopic brain imaging techniques to study these systems in mice.

    Using MRI, the researchers scanned the brains of a group of healthy volunteers who had received injections of gadobutrol, a magnetic dye used to visualize disruptions in the blood brain barrier or other kinds of blood vessel damage. Large veins are known to pass through the arachnoid barrier carrying blood away from the brain, and these were clearly observed on the MRI scans. As the scan progressed, a ring of dye appeared around those large veins that slowly spread out over time, suggesting that fluid could make its way through the space around those large veins where they pass through the arachnoid barrier on their way into the dura.

    Kipnis’s lab was making similar observations in mice. His group injected mice with light-emitting molecules. Like with the MRI experiments, fluid containing these light-emitting molecules was seen to slip through the arachnoid barrier where blood vessels passed through.

    Together, the labs found a “cuff” of cells that surround blood vessels as they pass through the arachnoid space. These areas, which they called arachnoid cuff exit (ACE) points, appear to act as areas where fluid, molecules, and even some cells can pass from the brain into the dura and vice versa, without allowing complete mixing of the two fluids. In some disorders like Alzheimer’s disease, impaired waste clearance can cause disease-causing proteins to build up. Continuing the sewer analogy, Kipnis explained the possible connection to ACE points:

    “If your sink is clogged, you can remove water from the sink or fix the faucet, but ultimately you need to fix the drain,” he said. “In the brain, clogs at ACE points may prevent waste from leaving. If we can find a way to clean these clogs, its possible we can protect the brain.”

    One implication of ACE points is that they are areas where the immune system can be exposed to and react to changes occurring in the brain. When mice in Dr. Kipnis’s lab were induced to have a disorder where the immune system attacks the myelin in their brain and spinal cord, immune cells could be seen around ACE points and even between the blood vessel wall and the cuff cells; this led over time to a breakdown of the ACE point itself. When the ability of immune cells to interact directly with ACE points was blocked, the severity of infection was reduced.

    “The immune system uses molecules to communicate that cross from the brain into the dura mater,” said Kipnis. “This crossing needs to be tightly regulated, otherwise detrimental effects on brain function can occur.”

    Reich and his team also observed an interesting connection between the participants’ age and the leakiness of ACE points. In older participants, more dye leaked into the surrounding fluid and space around the blood vessels.

    “This might point to a slow breakdown of the ACE points over the course of aging,” said Reich, “and this could be consequential in that the brain and immune system can now interact in ways that they’re not supposed to.”

    The connection to aging and the disruption of a barrier separating the brain and immune system fits with what has been observed in aging mice and in autoimmune disorders like multiple sclerosis. This newfound link between the brain and immune system could also help explain why our risk for developing neurodegenerative diseases increases as we get older, but more research is needed to confirm this connection.

    This study was supported by the NINDS Intramural Research Program, the National Institute on Aging (AG034113, AG057496, AG078106), and the Cure Alzheimer’s Fund BEE Consortium.

    Source:

    NIH/National Institute of Neurological Disorders and Stroke

    Journal reference:

    Smyth, L. C. D., et al. (2024). Identification of direct connections between the dura and the brain. Nature. doi.org/10.1038/s41586-023-06993-7.

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  • New inhibitor drug shows promise in preventing diabetic eye and kidney disease

    New inhibitor drug shows promise in preventing diabetic eye and kidney disease

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    New research has shown a new type of inhibitor drug could prevent microvascular diabetic complications, such as diabetic eye and kidney disease. The University of Bristol-led research is published in Cardiovascular Diabetology.

    Diabetes, a disease which results in uncontrolled blood glucose levels, is estimated to affect one in 11 adults worldwide. Even when managed, this common disease can result in life-altering complications, impacting the small blood vessels of the body, known as the microvasculature.

    While treatments are available for patients who develop microvascular complications, such as diabetic eye and kidney disease, these treatments do not fully delay progression. Eventually they may result in blindness and kidney failure in patients.

    The research team was interested in the protective lining of all blood vessels, called the glycocalyx. This lining is known to be damaged in diabetes. The researchers showed in two mouse models that by preventing damage to this protective layer, the development of diabetic eye and kidney disease could be stopped.

    This is achieved using a ‘heparanase inhibitor’. Heparanase acts likes a pair of scissors, damaging the glycocalyx lining. Heparanase inhibitors stop this damage from happening. The research team has developed a novel class of these drugs, which could be successfully developed as a medication to treat patients.

    Dr Rebecca Foster, Associate Professor of Microvascular Medicine in the Bristol Medical School: Translational Health Sciences (THS), and senior author of the study, said: “Our findings are exciting as we have shown that one type of medication might be able to prevent different diabetic complications, which is a global health problem for adults living with diabetes.”

    We are currently conducting research to advance our novel class of inhibitors to clinical use. With over 8% of the global adult population currently living with diabetes, we hope patients could benefit from our findings in the future.”

    Dr Monica Gamez, Research Associate in the Bristol Medical School (THS) and corresponding author

    The study was funded by the Medical Research Council [MRC].

    Source:

    Journal reference:

    Gamez, M., et al. (2024) Heparanase inhibition as a systemic approach to protect the endothelial glycocalyx and prevent microvascular complications in diabetes. Cardiovascular Diabetology. doi.org/10.1186/s12933-024-02133-1.

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