Podcasts about Reperfusion

Here's another great podcast from early '24. This was a great conversation and finished the year at #3. In this episode of the PFC podcast, Dennis and Doug delve into the complexities of crush syndrome, discussing the importance of scene safety, initial assessment, and the management of casualties in dynamic environments. They explore the application of tourniquets, fluid resuscitation strategies, and the monitoring of potential complications such as reperfusion injury and electrolyte imbalances. The conversation emphasizes the need for a structured approach to treatment, including the use of sodium bicarbonate and calcium, as well as the critical role of wound management and antibiotics in ensuring positive patient outcomes. Takeaways Scene safety is crucial for rescuers. Crush syndrome patients may have multiple traumatic injuries. Tourniquets should be applied before freeing the casualty. Fluid resuscitation is essential for managing crush syndrome. Monitoring for complications is vital after initial treatment. Reperfusion injury can occur hours after the event. Electrolyte imbalances, especially potassium, must be managed. Sodium bicarbonate can help stabilize patients in shock. Calcium administration is important for cardiac stability. Wound management and antibiotics are key in crush injuries. Chapters 00:00 Introduction to Crush Syndrome 02:50 Scene Safety in Dynamic Environments 05:55 Initial Assessment and Triage 09:01 Tourniquet Application and Management 12:08 Fluid Resuscitation Strategies 15:00 Monitoring and Managing Complications 18:10 Reperfusion Injury and Its Implications 20:48 Electrolyte Management in Crush Syndrome 23:55 Sodium Bicarbonate and Calcium Administration 27:10 Wound Management and Antibiotic Use 30:04 Final Thoughts and Summary Thank you to Delta Development Team for in part, sponsoring this podcast. ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠deltadevteam.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ For more content go to ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠www.prolongedfieldcare.org⁠⁠⁠⁠⁠⁠ ⁠⁠⁠⁠ Consider supporting us: ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠patreon.com/ProlongedFieldCareCollective⁠⁠⁠⁠⁠⁠ or ⁠⁠⁠⁠⁠⁠www.lobocoffeeco.com/product-page/prolonged-field-care

CME credits: 0.50 Valid until: 02-10-2025 Claim your CME credit at https://reachmd.com/programs/cme/unveiling-the-reperfusion-paradox/26976/ Expert faculty discuss the critical role of cardiac and inflammatory biomarkers in assessing myocardial damage, predicting risk, and monitoring treatment response. The program also explores emerging therapeutic strategies aimed at mitigating ischemia-reperfusion injury (IRI) and reducing the risk of adverse cardiovascular events. Join Drs. Manesh Patel and Deepak Bhatt as they address the long-term consequences of IRI, including the development of heart failure and increased cardiovascular mortality. By providing a comprehensive overview of IRI, this program aims to enhance understanding and inform clinical practice.

Commentary by Dr. Valentin Fuster

In this episode, Dennis interviews John and Paul about the Abdominal Aortic and Junctional Tourniquet (AAJT). They discuss the background and reasons for inventing the AAJT, including the need to control bleeding in the pelvis. They also talk about the first application of the AAJT and the positive results seen in combat situations. The conversation then moves on to study data and research on the device, including some negative studies that have been conducted. They also discuss the pressure levels used with the AAJT and the potential for extending the application time. Finally, they address the negative consequences of high pressure and the comfort level of wearing the device. The conversation explores the application and function of the Abdominal Aortic Junctional Tourniquet (AAJT) and its potential use in pre-hospital care. It discusses the challenges of prolonged application and the risks associated with it. The conversation also delves into alternative techniques and future developments in the field. The importance of reperfusion and monitoring is highlighted, along with the impact of the AAJT on breathing and inspiratory pressure. The discussion touches on the considerations for reducing pressure during reperfusion and the duration of application. The risk-benefit analysis of heroic interventions is examined, emphasizing the need for rapid hemorrhage control. The limitations and risks of Roboa are discussed, and a cadaveric study on the AHAT is presented. The conversation concludes with the role of the AHAT in preparing for future wars and its potential use in traumatic cardiac arrest. Takeaways The AAJT was invented to control bleeding in the pelvis and junctional areas. The device has been successfully used in combat situations and has saved lives. There have been several studies conducted on the AAJT, with mixed results. The device applies pressure to occlude blood flow, but the pressure levels are safe and well-tolerated. The Abdominal Aortic Junctional Tourniquet (AAJT) is a fielded device that can be used for rapid hemorrhage control in non-compressible torso hemorrhage. Prolonged application of the AAJT should be avoided, and it is important to consider the risks and benefits of its use. Alternative techniques and future developments, such as foams, are being explored for the treatment of non-compressible torso hemorrhage. Reperfusion and monitoring are crucial considerations when using the AAJT, and the pressure can be reduced during transfusion to mitigate ischemic change. The AAJT has shown promising results in traumatic cardiac arrest and can be a valuable tool in pre-hospital care. Thank you to Delta Development Team for in part, sponsoring this podcast. ⁠⁠⁠⁠deltadevteam.com⁠⁠⁠⁠ For more content go to ⁠⁠⁠⁠www.prolongedfieldcare.org⁠⁠⁠⁠ Consider supporting us: ⁠⁠⁠⁠patreon.com/ProlongedFieldCareCollective or www.lobocoffeeco.com/product-page/prolonged-field-care

The latest episode of "The Dairy Podcast Show" enters the fascinating world of dairy science with Dr. Benjamin Renquist. This episode touches on key areas such as the metabolic consequences of obesity in dairy animals, strategies for optimizing milk production, and the impact of heat stress on dairy cattle. Dr. Renquist's insights into the intersection of animal science and human biomedicine, particularly in the context of fatty liver disease and insulin resistance, provide a nuanced understanding of these complex topics. For anyone engaged in the dairy industry, this episode is a must-listen for its valuable perspectives on enhancing productivity and health within the dairy sector."Food production is key, and animals make up a huge part of the food consumed globally."What you'll learn:(00:00) Highlight(01:14) Introduction(02:29) Obesity epidemic and nutrition(06:16) Addressing obesity and dietary choices(08:13) Research on fatty liver and GABA(16:45) Heat impact on milk production(23:00) Arginine vasopressin and food intake(23:46) Changes in gut permeability and blood flow(27:59) Reperfusion and oxidative stress(30:26) Feed efficiency technology(37:27) Advice for junior scientists(41:00) Closing remarksMeet the guest: Meet Dr. Benjamin Renquist, a visionary researcher committed to translating academic lab discoveries into advancements for human health and animal agriculture. His focus on metabolic pathways is reshaping our understanding and practices in animal production, marking a significant impact on the dairy industry and beyond. Dr. Renquist's work exemplifies the seamless integration of scientific research with real-world applications.The Dairy Podcast Show is trusted and supported by innovative companies like:* Adisseo- Phibro- Protekta- dsm-firmenich- smaXtec- Evonik- ICC- Berg + Schmidt- Diamond V

Contributor: Dylan Luyten MD Educational Pearls: What is a Bradyarrhythmia? Also known as a bradyarrhythmia, it is an irregular heart rate that is also slow (below 60 beats per minute). What can cause it? Complete heart block AKA third-degree AV block; identified on ECG by a wide QRS, and complete dissociation between the atrial and ventricular rhythms with the ventricular being much slower. Treat with a pacemaker. Medication overdose, especially beta blockers. Many other drugs can slow the heart as well including: opioids, clonidine, digitalis, amiodarone, diltiazem, and verapamil to name a few. Electrolyte abnormalities, specifically hyperkalemia. Hypokalemia, hypocalcemia, and hypomagnesemia can also cause bradyarrhythmias. Myocardial infarction. Either by damaging the AV node or the conduction system itself or by triggering a process called Reperfusion Bradycardia. Hypothermia. Bradycardia is generally a sign of severe or advanced hypothermia. References Jurkovicová O, Cagán S. Reperfúzne arytmie [Reperfusion arrhythmias]. Bratisl Lek Listy. 1998 Mar-Apr;99(3-4):162-71. Slovak. PMID: 9919746. Simmons T, Blazar E. Synergistic Bradycardia from Beta Blockers, Hyperkalemia, and Renal Failure. J Emerg Med. 2019 Aug;57(2):e41-e44. doi: 10.1016/j.jemermed.2019.03.039. Epub 2019 May 30. PMID: 31155316. Wung SF. Bradyarrhythmias: Clinical Presentation, Diagnosis, and Management. Crit Care Nurs Clin North Am. 2016 Sep;28(3):297-308. doi: 10.1016/j.cnc.2016.04.003. Epub 2016 Jun 22. PMID: 27484658. Summarized by Jeffrey Olson MS2 | Edited by Meg Joyce & Jorge Chalit, OMSII  

Myocardial infarction (MI), commonly known as a heart attack, is a serious medical condition that always requires comprehensive and targeted care to facilitate optimal recovery. In recent years, medical science has made significant strides in the development of innovative therapies, including peptide therapy Among these, GLP-1 agonists (glucagon-like peptide-1 agonists) have emerged as a promising avenue for post-MI care. In this podcast, we'll talk about the important role of GLP-1 agonists in the context of post-MI management and how these peptides are revolutionizing cardiovascular treatment strategies. What are GLP-1 Agonists? GLP-1 agonists are a class of medications initially designed to manage type 2 diabetes. They mimic the action of glucagon-like peptide-1, a natural hormone that regulates blood sugar levels. In recent years, researchers have discovered that these agonists offer benefits that extend beyond glycemic control. They have been shown to suppress appetite aiding in significant weight loss and have shown remarkable cardioprotective properties, making them valuable therapeutic options, especially in the post-MI period. What are the cardioprotective effects of GLP-1 Agonist? Improving Cardiac Function: GLP-1 agonists have been found to enhance cardiac function by improving the heart's pumping ability and reducing the workload on the cardiovascular system. This effect is particularly helpful after a heart attack when the heart muscle needs support to recover and function efficiently. It is also helpful for those who have heart failure. Reducing Inflammation: Inflammation plays a big role in the progression of heart damage after a heart attack. GLP-1 agonists have anti-inflammatory properties, reducing inflammation within the cardiovascular system. By mitigating inflammation, these medications aid in preventing further damage to the heart tissue, helping the healing process. Promoting Vasodilation: GLP-1 agonists promote vasodilation, which means they relax blood vessels, reducing blood pressure and improving blood flow. This effect is vital post-heart attack as it helps reduce the strain on the heart and prevents complications related to high blood pressure. Mitigating Oxidative Stress: Oxidative stress is caused by an imbalance between free radicals and antioxidants in the body. This can exacerbate heart damage post-heart attack. GLP-1 agonists have antioxidant properties, helping prevent ischemia and reperfusion injury. This is important for many reasons. Ischemia occurs when the blood supply to a specific part of the body is reduced or completely blocked, leading to oxygen and nutrient deprivation. Reperfusion injury, on the other hand, happens when the blood supply is restored after a period of ischemia. Surprisingly, the reintroduction of oxygen-rich blood can exacerbate tissue damage due to the production of free radicals and inflammatory responses, leading to further cellular injury and dysfunction. Anti-atherosclerotic: Atherosclerosis is a condition where these plaques build up, narrowing the arteries and restricting blood flow. This narrowing can lead to various cardiovascular problems, including heart attacks and strokes. GLP-1 agonists help reduce the overall amount of plaque on the inner walls of the heart's arteries, decreasing the risk of heart attack or stroke.  Individualizing Treatment in Post-MI Care: It's important to note that the use of GLP-1 agonists in post-MI care should be individualized. Healthcare providers carefully assess patients' overall health, existing conditions, and medical history to determine the safety of these medications.  And remember, while GLP-1 agonists offer significant benefits, they are just one component of a comprehensive post-MI treatment plan. Lifestyle modifications, such as a heart-healthy diet, regular exercise, and smoking cessation, are equally vital in ensuring a holistic approach to recovery. When you have a heart attack, you'll need immediate emergency medical care and procedures to help stabilize and save your heart. Typical medications used in the hospital are oxygen, pain relievers like nitroglycerin and morphine, blood thinners like heparin to stop clots from forming, beta-blockers like metoprolol to help reduce how hard your heart is working, cholesterol medications like Lipitor (statin) to help prevent further plaque build-up and ACE-inhibitors like lisinopril to help lower your blood pressure. Once your heart attack has passed, you'll likely need long-term medications to help prevent you from having another heart attack. These include medications like blood thinners, blood pressure medications, beta-blockers, and cholesterol medications.  In some cases, your healthcare provider might prescribe a GLP-1 agonist like semaglutide or liraglutide. If you've been prescribed semaglutide or liraglutide, you'll start at a low dose to help your body get used to the medication and avoid stomach-related side effects like nausea, diarrhea, and constipation. Semaglutide will be dosed once weekly and liraglutide will be dosed daily.  Thanks again for listening to The Peptide Podcast, we love having you as part of our community. If you love this podcast, please share it with your friends and family on social media, and have a happy, healthy week! Pro Tips We're huge advocates of using daily greens in your routine to help with gut, skin, nail, bone, and joint health. We take AG1 (athletic greens) every day. Not only does it have vitamins, minerals, and a diverse range of whole-food sourced ingredients, but it also has probiotics to promote a healthy gut microbiome and adaptogens to help with focus and mood balance. It's vegan, paleo, and keto-friendly.

#AskDrJohnWatts Different questions related to baldness, hair grafts, hair loss, hair transplant procedures and medical treatments for hair loss are being raised by patients now and then, including the followers of Dr John Watts, who keep flooding his series of hugely popular educational videos on his popular YouTube channel with queries related to different hair issues. In this video session, Hyderabad's noted dermatologist & trichologist and one of the Best Hair Transplant Surgeons in Hyderabad, Dr John Watts answers a specific query on the working of Minoxidil. Minoxidil is generally used to promote hair growth but how does one be sure that it is working? Is there any testing method? This is quite a common query of many hair loss patients who are using Minoxidil. He also explains alternative solutions for a hair loss patient in case Minoxidil does not show the desired results. So far, Dr John Watts has performed over 2000+ hair transplant surgeries successfully. Hamdam Fazza asks: Sir, I know that Minoxidil is prescribed for promoting hair growth but how do we know if it is working or not. Is there any test to find out whether it is working for my scalp? Please explain. Minoxidil is a well-known FDA-approved hair growth-promoting medication that is used to treat hair loss. However, it is important to know how to determine if it is working effectively or not. In response to the above query, Dr John Watts said that one must first start using Minoxidil as a first step to finding out if it is working by observing the following steps carefully. “Though are no specific testing methods to determine the effectiveness of Minoxidil, there are some signs to look out for,” explained Dr John Watts. 1. In general, 15–20 days after using Minoxidil, the hair falls due to a phenomenon called reperfusion injury. This leads to temporary hair loss and there is nothing to be alarmed. If one notices this phenomenon, then one can conclude that Minoxidil is working. Reperfusion injury is a temporary shedding of hair that may occur when starting Minoxidil treatment. This happens because the hair follicles are being stimulated to grow new hair. 2. In the next 2–3 months after using Minoxidil, hair fall comes under control and new hair growth starts. When this phenomenon is noted, one can safely conclude it as evidence that Minoxidil is working. 3. If even after 6–8 months of Minoxidil usage, there is no result, then one needs to evaluate their condition with a hair transplant surgeon or dermatologist and explore some other alternative treatment options, including a hair transplant procedure. “If Minoxidil is not effective after several months of use, it is an indication that it is not working for you. Hence, it may be necessary to explore other treatment options, such as hair transplant surgery,” advised Dr John Watts. Trichos provides state-of-the-art treatment for various hair loss conditions and offers advanced hair transplant solutions. Call us Today for a Life-Changing Experience.

Commentary by Dr. Valentin Fuster

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.21.537835v1?rss=1 Authors: Wu, Z., Huang, W., He, X., Dutta, S., Paul, C., Fan, G.-C., Kanisicak, O., Xu, M., Liang, J., Wang, Y. Abstract: Ischemia-reperfusion (I/R) injury is a common occurrence in various surgical procedures used to treat heart diseases. However, the role of insulin-like growth factor 2 receptor (IGF2R) during the process of myocardial I/R remains unclear. Therefore, this study aims to investigate the expression, distribution, and functionality of IGF2R in various I/R-associated models (such as reoxygenation, revascularization, and heart transplant). Loss-of-function studies (including myocardial conditional knockout and CRISPR interference) were performed to clarify the role of IGF2R in I/R injuries. Following hypoxia, IGF2R expression increased, but this effect was reversed upon restoration of oxygen levels. Loss of myocardial IGF2R was found to enhance the cardiac contractile functions, and reduced cell infiltration or cardiac fibrosis of I/R mouse models compared to the genotype control. CRISPR-inhibition of IGF2R decreased cell apoptotic death under hypoxia. RNA sequencing analysis indicated that myocardial IGF2R played a critical role in regulating the inflammatory response, innate immune response, and apoptotic process following I/R. Integrated analysis of the mRNA profiling, pulldown assays, and mass spectrometry identified granulocyte-specific factors as potential targets of myocardial IGF2R in the injured heart. In conclusion, myocardial IGF2R emerges as a promising therapeutic target to ameliorate inflammation or fibrosis following I/R injuries. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.25.529915v1?rss=1 Authors: Binder, N., El Amki, M., Glueck, C., Middleham, W., Reuss, A. M., Bertolo, A., Thurner, P., Deffieux, T., Handelsmann, H.-L., Baumgartner, P., Orset, C., Bethge, P., Kulcsar, Z., Aguzzi, A., Tanter, M., Vivien, D., Wyss, M. T., Luft, A., Weller, M., Weber, B., Wegener, S. Abstract: Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet unknown functions. Utilizing a thrombin-based mouse model of stroke and the gold standard fibrinolytic treatment rt-PA, we here show that LMCs play a critical role in preserving vascular function in ischemic territories. We applied laser speckle contrast imaging, ultrafast ultrasound, and two-photon microscopy, to show that after thrombolysis, LMCs allow for gradual reperfusion resulting in small infarcts. On the contrary, in mice with poor LMCs, distal segments of recanalized arteries collapse and deleterious hyperemia causes hemorrhage and mortality. Accordingly, in stroke patients with poor collaterals undergoing thrombectomy, rapid reperfusion resulted in hemorrhagic transformation and unfavorable recovery. Thus, we identify LMCs as key components regulating reperfusion after stroke. Future therapeutic interventions should aim to enhance collateral function, allowing for gradual reperfusion of ischemic tissues after stroke. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529463v1?rss=1 Authors: Ran, X., Ruan, H., Li, S.-s., Wu, R., Luo, A., Zhang, Q. Abstract: Objective:Endothelial cells (ECs) are considered more sensitive to cardiac ischemia/reperfusion (I/R) injury compared to cardiomyocytes. However, current research is mainly focused on molecular mechanisms and preventive strategies targeting cardiomyocyte I/R injury, whereas insufficient attention is placed on protecting endothelial function. Approach and Results: In this study, we established an interlink among ulinastatin (UIT; a serine protease inhibitor), the kallikrein-kinin system (KKS), and EC injury in response to cardiac reperfusion for the first time, using in vitro and in vivo experiments, and bioinformatic analysis. Our data indicated that UTI affected I/R by inhibiting the activation of KKS and simultaneously down-regulating both bradykinin receptor 1 (Bdkrb1) and bradykinin receptor 2 (Bdkrb2) related signaling such as extracellularsignal-regulated kinase (ERK)/inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS), thereby reducing infarct size, attenuating inflammation and edema, and improving cardiac function and mortality. Interestingly, UIT significantly suppressed KLK1 activity but did not down-regulate the KKS in normal conditions, suggesting inhibition of KLK1 might be the crucial mechanism for UIT-induced cardioprotection in reperfusion injury. Moreover, knockdown of Bdkrb1 in reperfusion-induced cardiac endothelial cells (MCECs) injury significantly prevented ERK translocation into the nucleus, reducing apoptosis, junction disruption, and expression levels of cytokines, whereas Bdkrb2 deletion could not protect MCECs against I/R injury. Conclusion:Our findings imply that inhibition of KLK1/Bdkrb1 is a critical target for UIT in the treatment of reperfusion-induced cardiac endothelial inflammation, apoptosis, and leakage and might be a potential therapeutic strategy for cardiac reperfusion injury. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.08.527688v1?rss=1 Authors: Robillard, S., Tran, K., Brazeau, T., Boisvert, E., Lizotte, F., Auger-Messier, M., Boudreault, P.-L., Marsault, E., Geraldes, P. Abstract: Objective: Peripheral artery disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients caused by an insufficient angiogenic response. Unfortunately, therapeutic angiogenesis using growth factors, such as the vascular endothelial growth factor (VEGF), are ineffective in diabetic conditions due to diabetes-induced growth factor resistance. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment has been shown to improve revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. Thus, this study explored the impact of Pyr-apelin-13 in endothelial cell function and diabetic mouse model of hindlimb ischemia. Approach and Results: Nondiabetic and diabetic mice underwent femoral artery ligation to induce lower limb ischemia. A group of diabetic mice was implanted subcutaneously with osmotic pumps delivering Pyr-apelin-13 for 28 days. Blood flow reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed in individual cages with voluntary wheels. In vitro, BAECs were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration, proliferation and tube formation assays were performed following either VEGF or Pyr-apelin-13 stimulation. Following limb ischemia, blood flow reperfusion, functional recovery of the limb and vascular density were improved in diabetic mice receiving Pyr-apelin-13 compared to untreated diabetic mice. In cultured BAECs, exposure to HG concentrations and hypoxia reduced VEGF proangiogenic actions, whereas apelin proangiogenic effects remained unaltered. Pyr-apelin-13 induced its proangiogenic actions through Akt/AMPK/eNOS and RhoA/ROCK signaling pathways under both NG or HG concentrations and hypoxia exposure. Conclusion: Pyr-apelin-13 promoted endothelial cell function and angiogenesis in the ischemic limb despite diabetes and HG level exposure. Therefore, our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

On Episode 23 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the December 2022 issue of Stroke: “Direct, Indirect, and Combined Extracranial-to-Intracranial Bypass for Adult Moyamoya Disease” and “Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States.” She also interviews Drs. Koji Tanaka and Andrew Demchuk about article “Significance of Baseline Ischemic Core Volume on Stroke Outcome After EVT in Patients Age ≥75 Years.” Dr. Negar Asdaghi:         Let's start with some questions. 1) Is direct bypass better than indirect bypass in preventing the future risk of vascular events in adult patients with moyamoya disease? 2) What is the contemporary incidence of cerebral venous sinus thrombosis in the pediatric population? 3) And finally, is endovascular therapy beneficial for patients presenting with a large ischemic core? We have the answers and much more in today's podcast. You're listening to the Stroke Alert Podcast, and this is the best in Stroke. Stay with us. Welcome back to another issue of the Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine and your host for the monthly Stroke Alert Podcast. In our final podcast for the year, I'm thrilled to announce that Drs. Nastajjia Krementz and Eric Goldstein have joined our podcast as assistant editors to help us cover the latest and the best in the field of cerebrovascular disorder. And together, here's our article selection to close the year. As part of our Advances in Stroke, in the article titled "Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation," we get an update on current evidence from randomized controlled trials on the use of direct oral anticoagulants or vitamin K antagonists in patients with valvular heart disease that are mechanical valves, moderate to severe mitral stenosis, or bioprosthetic valves from the perspective of stroke physicians. What that means is that data from randomized trials was analyzed based on whether the patient had a prior history of stroke or TIA. In this review, we learned that direct oral anticoagulants may be used in patients with bioprosthetic valves who have atrial fibrillation, although DOACs have never been shown to be superior over vitamin K antagonists. We also learned that vitamin K antagonists should be used in patients with rheumatic moderate to severe mitral valve stenosis or patients with mechanical valves with or without atrial fibrillation and, of course, sometimes during the first few months after either surgical or transcatheter aortic valve replacement in patients without atrial fibrillation. And finally, patients with bioprosthetic valves without AFib don't have any other indications to be treated with anticoagulants should be treated with antiplatelet monotherapy in the long run. In a separate article in this issue of the journal, from Dr. Yang and colleagues from China, we learn about the pathophysiology of radiation-induced brain injury with special attention to radiation-induced vasculopathy. These investigators show that hyperactivity of notch signaling pathway that in normal state is essential in vascular morphogenesis and maintenance of arterial identity actually results in abnormal accumulation and disturbance of vascular smooth muscle cells, resulting in arterial muscularization and arterial dysfunction seen in radiation-induced vasculopathy. What's interesting is that inhibition of the notch signaling pathway in their study resulted not only in a measurable reduction in radiation induced vasculopathy, but also an overall improvement in radiation-induced brain injury as measured by the cognitive function of the mice exposed to radiation in their study. This study takes us a step closer to possible therapeutic options for radiation-induced vasculopathy and radiation-induced brain injury using compounds that can potentially inhibit the notch signaling pathway. As always, I encourage you to review these articles in detail in addition to listening to our podcast. For our interview today, I have a special guest who's not only a prominent researcher and a pioneer in the field of acute stroke therapies, but also, he's an experienced educator who has trained many of the current leaders in the field of vascular neurology and has been influential in shaping the careers of many vascular neurology fellows over the years. Take a listen. Dr. Andrew Demchuk:   I've had the privilege of training fellows. I've been the director since 2004, and we've trained close to 100 fellows in Calgary over 20-some years now. Really, it's frankly an honor and privilege to be able to do that. These individuals come from all over the world. They're here to dedicate themselves to learning a subspecialty really, really well, and it's just a fantastic experience to interact with them all and all their cultures to help them learn those things, and doing it in a fun, enjoyable, comprehensive way. Dr. Negar Asdaghi:         And those are the words of Dr. Andrew Demchuk, who's incidentally my own vascular fellowship director as well. Andrew joins me all the way from Canada to talk about his latest paper on the very hot topic of outcomes of endovascular therapy in patients presenting with a large ischemic core. And true to form, he's accompanied by one of his current vascular fellows. The interview is definitely worth the wait after we review these two articles. Most of us have heard of the term "moyamoya." First described in Japan in 1950s, the term refers to occlusion or stenosis of the terminal portion of the internal carotid artery and is associated with dilated collateral vessels of the proximal middle cerebral artery. These collaterals have a hazy appearance on angiography resembling the puff of smoke, which is Japanese for "moyamoya." Moyamoya is categorized into two broad categories of moyamoya syndrome and moyamoya disease. Syndrome refers to the situations where the occlusion occurs due to another condition. Conditions such as Down syndrome, sickle cell disease, neurofibromatosis type one have all been recognized as associated with moyamoya syndrome. Of course, moyamoya syndrome can occur due to a secondary insult to the blood vessels, anything from radiation vasculopathy, as we reviewed earlier in the podcast, to autoimmune vasculitis, or even good old advanced intracranial atherosclerosis involving the distal ICA region can cause moyamoya syndrome. Now, in contrast to moyamoya syndrome, the term "moyamoya disease" is reserved for individuals with no vascular risk factors or known moyamoya predisposing conditions other than, of course, some potential genetic factors. The most recognized genetic association for moyamoya disease is polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17. But we also have to keep in mind that the majority of moyamoya disease patients have no identified genetic abnormalities. So, moyamoya is truly a complex condition, and the physicians have to navigate the many possible etiologies that may cause or be associated with this condition. But when it comes to treatment options, we're really limited here. Antiplatelets are generally used and have been shown to reduce mortality in both moyamoya disease and syndrome, and especially cilostazol, which is the favorite antiplatelet therapy of our own assistant editor, Eric, has been shown to be significantly associated with increased survival rate in patients with moyamoya disease. Eric really wanted me to talk about a recently published study out of Korea, which included over 9,000 patients, and that showed that patients treated with cilostazol had a better survival rate than any other antiplatelet therapies. Apart from antiplatelet therapies, medical treatment includes optimizing all other vascular risk factors, which, as we mentioned, are rarely present in this population. So, it all comes down to most cases, at some point, needing surgical treatment, with bypass surgery being the most commonly surgical intervention for this population. Three flavors of bypass are used: indirect, direct, or combination of the two. Indirect bypasses are kind of like long-term investments where the surgeon moves vascular tissue to the surface of the brain in hopes of promoting angiogenesis. Several procedures, such as performing multiple burr holes, pial synangiosis, dural inversion, or omental transposition, among other methods, are used. And broadly speaking, we can think of indirect procedures as angiogenesis-dependent methods, the effect of which takes months to recognize and, in general, are thought to be more efficacious in the pediatric population than the adult population. The direct bypass, in contrast, commonly referred to as extracranial-to-intracranial, or ECIC, bypass, is more of an immediate reward where the surgeon stitches a vessel directly from a donor extracranial branch, typically the superficial temporal artery, to a recipient artery, typically the middle cerebral artery, to provide a direct anastomosis between the two vessels. There are technical variations, of course, especially with regards to the number of donors and recipient arteries used, but essentially this method is an angiogenesis-independent method that results in a quicker revascularization, but it's unclear if this strategy is long lasting. A combination of direct and indirect bypass can also be used. So, the question is, which method is better, especially in the adult population? In this issue of the journal, in the study titled "Direct, Indirect, and Combined ECIC Bypass for Adult Moyamoya Disease," Dr. Nickalus Khan and colleagues report on a meta-analysis and systematic review of those with adult moyamoya disease who underwent either direct, indirect, or a combination bypass. The main study question was whether there's a difference in the rates of early ischemic or hemorrhagic strokes, defined as strokes occurring within 30 days of bypass, or late strokes, defined as strokes occurring after 30 days of bypass, in this population when comparing the different surgical techniques. They also compared the "favorable" outcome rate; however, this outcome was defined in each study between the various broad techniques of direct, indirect, and combined bypass. So, with that, let's take a very quick look at their methodology. They screened more than 4,000 articles and identified 143 articles for their pooled analysis, the majority of articles being from Eastern Asian-based regions, and they had close to 4,000 combined, 4,000 direct, and 4,000 indirect bypass procedures for this analysis. And they had an average follow-up of over three and a half years. So, this is a great sample size for this large, pooled analysis. But they also performed a smaller meta-analysis where they were much more stringent with article selection, excluding pediatric papers, excluding articles containing only one surgical modality, or articles with insufficient outcome data. So, for that meta-analysis, they only had 43 articles qualified and were included in that meta-analysis. So, what did they find? In the larger pooled analysis, a significant benefit in favor of both direct and combined bypass techniques were noted in reduction of early and late ischemic strokes and late intracerebral hemorrhage. Also, a higher rate of that sort of vague favorable outcome was noted with both the direct or combined methods as compared to when indirect bypass techniques were used alone. So, everything in the large, pooled analysis pointed towards the direct bypass or combined technique performing better than all indirect bypass techniques, with only one exception, which was a lower incidence of early intracerebral hemorrhage rate in indirect bypass cases. So, that's one point to keep in mind. The second point was when they compared combined techniques to direct bypass. Overall, these procedures had more or less the same outcomes with the exception that the rate of late ischemic stroke was lower in the combined group than the direct bypass group. So, this is sort of the overall summary of what they found in that large, pooled analysis. When they were much more stringent with their selection criteria, focusing on the smaller meta-analysis portion of the study, what they found was that in the short term, there were no differences in outcomes of any type of stroke between any of these methods. So, basically, people, regardless of the type of bypasses they received, did the same with regards to the risk of intracerebral hemorrhage and ischemic stroke recurrence within the first 30 days after the bypass. But for the late stroke outcomes, whether ischemic or hemorrhagic, those with indirect bypass were nearly twofold more likely to develop late stroke after 30 days compared to those who've undergone the direct bypass. A similar pattern was found comparing combined bypass versus indirect bypass, in general, beyond the 30 days, with combined bypass doing better. Comparing direct versus combined bypass showed no difference regardless of timeframe. So, in summary, overall, it appears that combined or direct bypasses may be the best surgical strategies for treatment of adult patients with moyamoya disease. This study, of course, has many limitations, as does any meta-analysis, but most importantly, the authors focused on moyamoya disease in their analysis. It is presumed, but really unclear if patients with moyamoya syndrome would respond similarly to these different techniques. So, the question is, what surgical procedure are you using at your institution for treatment of adult moyamoya disease patients? And, of course, Eric wanted me to ask if your antiplatelet of choice is cilostazol for this population, yes or no. Leave us your comments, and let us know. Venous sinus thrombosis, or CVST, is a less common form of stroke most commonly affecting women and young individuals. In our past podcast, we've covered many aspects of CVST, especially when it comes to therapy with anticoagulation, anticoagulant of choice, and duration of therapy. In the October podcast, we reviewed a systematic review and meta-analysis comparing direct oral anticoagulants to vitamin K antagonists in the adult patients with CVST. But there are many aspects of this disease that we have not yet covered. For instance, you may ask, how common is this relatively uncommon condition? In the adult population, the incidence of CVST varies depending on the age of individuals studied, and ranges between 1.3 to 2.7 per 100,000 in women between the ages of 31 to 50, which is the adult population at highest risk for this disease. But the incidence of CVST, for instance, in the pediatric population is largely unknown. Some studies suggested an incidence rate of 0.67 per 100,000 in the pediatric population. That's roughly less than half the incidence rate in young female adults, but these reports are from the 1990s and are likely very outdated. Nowadays, many of the pediatric conditions, especially infectious conditions, that can predispose children to CVST are more readily diagnosed and treated. On the other hand, we now perform a lot more imaging than 30 years ago. Our neuroimaging modalities are more accurate, so we are more likely to diagnose CVST than before. So, the question is, what is the contemporary incidence of pediatric cerebral venous sinus thrombosis? In this issue of the journal, in the study titled "Contemporary Incidence and Burden of Cerebral Venous Sinus Thrombosis in Children of the United States," Dr. Fadar Otite and colleagues conducted a retrospective analysis of the New York State Inpatient Database, or SID, from 2006 to 2018, and the National Kids Inpatient Database, referred to as KID, from 2006 to 2019, for all hospitalized CVST cases. KID is the largest publicly-available pediatric inpatient care database in the United States, containing about 3 million pediatric discharges. They included over 700 hospitalized CVST cases from the SID database and 6,100 hospitalizations from the national KID database for the current analysis. And here's what they found. Number one, in terms of significant risk factors associated with CVST, congenital circulatory system anomalies, infections, head trauma, dehydration, and anemia were amongst the top CVST risk factors in the pediatric population. So that's very good to know. Number two, in terms of presentation, seizures were the most common presentation among all pediatric age groups, with close to half of infants with CVST presenting with seizures. Number three, in terms of outcomes, the rate of mortality was twice higher in the infants group as compared to all other age groups. And finally, the overall incidence of CVST, which was the main question of the paper, in this population was 1.1 per 100,000 per year, with a peak incidence during infancy of 6.4 per 100,000 per year. Interestingly, incident admissions also increased annually by 3.8% throughout the study period, which was close to 15 years in this paper. And the national burden of hospitalization dramatically and exponentially grew during the study period. So, here are the top three points from this study. Point one: Girls included less than half of all admissions nationally and statewide, and the overall burden of CVST was higher in boys than girls. That's a dramatic difference between the pediatric and adult populations. Point two: Incidence of CVST in infants was higher than five times that of other age groups at 6.4 per 100,000 compared to overall incidence in children, which was 1.1 per 100,000 people per year. Mortality was also two times higher in infants than in any other age group. And finally, point 3, incident admissions and national burden of hospitalization have dramatically increased over time, but it remains unclear whether true incidence has been on the rise or if simply more cases are recognized nowadays due to heightened awareness of this condition and our advanced neuroimaging capabilities. This study, of course, has some limitations. Data was only obtained on patients admitted, so many patients that may have had CVST but not admitted are not captured in this database. So, in summary, CVST can have catastrophic consequences in children and lead to long-term neurological deficits. Having a high clinical suspicion and early recognition remain crucial for prompt treatment and improved outcomes in this population. Dr. Negar Asdaghi:         Endovascular treatment, or EVT, is an effective method to achieve recanalization and to improve clinical outcomes in ischemic stroke patients with a target vessel occlusion. Both advanced age and having a large infarct volume at the time of presentation are negative predictors of beneficial outcomes post-EVT. Despite this, the neurological benefits of EVT seem to persist across the spectrum of age, and the same has been observed for a range of ischemic core volumes. But it's important to note that, in general, patients presenting with large ischemic core volumes were excluded from the original thrombectomy studies, and currently there's several ongoing trials to determine whether EVT is beneficial for the large core population. Now, the question that everyone is interested in answering is whether there is an actual ischemic core volume beyond which endovascular therapy is either futile or potentially even harmful, and if this magic futile core volume is the same for all patients, or does it differ depending on the age and other factors. In a previous podcast, in an interview with Dr. Osama Zaidat, we learned about that important interaction between the presenting ischemic core volume as measured by ASPECTS score and advanced age in an analysis of patients enrolled in the STRATIS registry. In that study, no one over the age of 75 achieved functional independence post-EVT if the presenting ASPECTS score was under 5 regardless of the angiographic outcomes. In that interview, we also discussed the limitations of STRATIS registry as a non-randomized, single-arm study, and the issues surrounding using ASPECTS score to define ischemic core. In today's podcast, we're going to revisit the important interaction between the presenting ischemic core volume and age while reviewing a pooled analysis of seven endovascular clinical trials in the paper titled "Significance of Baseline Ischemic Core Volume on Stroke Outcome After Endovascular Therapy in Patients Age 75 Years or Older." I'm delighted to be joined today by the first and senior authors of this paper, Drs. Koji Tanaka and Andrew Demchuk. Dr. Tanaka is an Assistant Professor of Neurology at Kyushu University in Japan. With his experience working at the leading center for conducting stroke clinical trials in Osaka, he has now joined the Calgary Stroke Program as a research fellow. And he's accompanied today by his fellowship director, Dr. Demchuk. Dr. Demchuk, of course, needs no introduction to our Stroke readership and our podcast audience. He's a Professor of Neurology at the University of Calgary Cumming School of Medicine. He's a stroke neurologist and a leader in the field of cerebrovascular research who has been involved in multiple clinical studies and randomized trials, including the seminal studies that led to the approval of EVT as the standard of care for treatment of stroke. And, of course, he's a very special guest of this podcast this morning as he was my very own fellowship director. Top of the morning to you both, Andrew and Koji. Welcome to the podcast. Dr. Andrew Demchuk:   Thanks, Negar. It's great to be here. Dr. Koji Tanaka:               Thank you very much for your invitation. That is a great honor to be here. Dr. Negar Asdaghi:         Thank you both. Andrew, let's start with you. Can you please provide us some background on the pooled analysis and the HERMES collaboration, please? Dr. Andrew Demchuk:   Yeah, HERMES is a really, it's been a really fun journey. Years back, when these trials all came out roughly at the same time, right? There was a real quick succession of trials, the MR CLEAN trial was obviously first, and ESCAPE and others quickly followed it. It became very clear to us that it just made total sense to collaborate. And so we got together as a group and decided we will pool the data. We'll do it in a very careful scientific way with basically an independent statistical analysis, and develop a core imaging lab, and really actually share the workload amongst us. I remember one of the really interesting tidbits about HERMES is when we got together, in order, I think, to really build trust in the group, one of the important things we decided early was we were going to have a snake draft. If you don't know what a snake draft is, Negar, it's essentially where you take turns selecting a topic through each of the trials. So, every trialist got an opportunity to pick a topic, and we just went down the list until everyone had their turn, and then we'd start over again and do it again. And I think that really worked very well to be as democratic as possible with this, and as fair. And it really allowed for a lot to get done because whoever was motivated in the collaboration was able to do an analysis. Dr. Negar Asdaghi:         So, what a great summary of this collaboration. So, it's true collaboration between the trialists that basically gave us those seven original randomized trials. Andrew, can I just stay with you, and can you tell us a little bit about the patient population that were enrolled in those trials? Dr. Andrew Demchuk:   Yeah, I think one of the important things to know, and I think a limitation for any kind of analysis like this, is the trials generally were small core trials, right? I mean there are some, MR CLEAN was certainly a more generalized population, but many other trials, including ESCAPE, I mean the "S" and the "C" in ESCAPE is "small core," right? And so a lot of these trials were small core. So, we don't have a lot of data in larger core patients. But, as you can imagine when you do core lab analysis, you realize that some of the stroke patients weren't as small core as we thought they were when we enrolled them. So, there is some sufficient data to hypothesize. I would consider this paper very much hypothesis-generating. So, yeah, it is a limitation to be considered here. I mean, our sample size isn't very large in the big core patients. Dr. Negar Asdaghi:         Perfect. Thank you, Andrew. So, again, a recap for our listeners, that we are looking at pooled analysis of seven original trials of thrombectomy, but keeping in mind that those patients that were enrolled in the trials had, generally speaking, small presenting ischemic core. So, now, Koji, on to you. Can you walk us please through the current study, and what was the premise of it, and who was actually included in this study? Dr. Koji Tanaka:               Yes. In this study, we aimed to evaluate association between baseline ischemic core volume and the benefit of endovascular therapy over the best medical treatment on functional outcomes. Patients were categorized age over 75 years, and less than 75 years old. The primary outcome of interest was a modified Rankin Scale of three or less, and we included 899 patients who underwent this baseline ischemic core volume measurement, which corresponds to 51% of our patients in the HERMES collaboration dataset. Dr. Negar Asdaghi:         All right. So, just a quick recap of what you said. Thank you for this. So, we have 899 patients. Those patients were all included in the HERMES collaboration, but, of course, these are patients in whom we had presenting ischemic core measurements. And that will get me, actually, Koji, to my second question. Can you please walk us through how you did analysis of ischemic core volume measurements in this study? Dr. Koji Tanaka:               In this study, ischemic core volume was measured by CT perfusion in 591 patients and by diffusion-weighted imaging in 309 patients. We defined the ischemic core volume as a relative cerebral blood flow of less than 30% in CT perfusion and diffusion coefficient of less than 620 square micrometers per second in diffusion-weighted imaging. Previous studies showed ASPECTS moderately correlate with ischemic core volume in both CT perfusion and diffusion-weighted imaging. For example, ASPECTS of eight can be considered as ischemic core volume of 20 milliliters. But underlying [inaudible 00:28:21] were different between CT perfusion and diffusion-weighted imaging, and previous studies suggested CT perfusion occasionally overestimates the ischemic core volume was on diffusion-weighted imaging. In this study, the results did not change when analyzing CT perfusion and diffusion-weighted imaging separately. Dr. Andrew Demchuk:   Yeah, that's a really important point Koji makes, is that because we had sort of a, not quite a 50/50 split, we had a 60/40 split of CTP and DWI, we did analyze them separately, and the odds ratios of treatment effect were pretty similar at different core thresholds. So, they're fairly similar when you separate them out, but obviously the methodology is a little different between a CTP and a diffusion. And to Koji's point, he's absolutely right, the CTP has a tendency to slightly overestimate core when you compare to diffusion. Dr. Negar Asdaghi:         Yeah, and thank you. I think you already sort of alluded to what I was going to ask you and Koji, because, in reality, we have different ways of measuring core. We have the ASPECTS score, which is just a quick and dirty way of estimating or guesstimating core, and then we have CT perfusion, and we also have diffusion that sometimes is available to us, but not always. And the question is, in the heat of it, how we're going to measure the volume. With post-processing softwares, with CT perfusion, we get a quick potential ischemic core volume, but we don't have that capability with diffusion even if we did get diffusion. So, I think it's important to know that what Koji mentioned, an ASPECTS of eight can, more or less, in a quick fashion, be thought of as about 20 cc of core. And the other point that Koji raised was that CTP, again, this is sort of ballpark, can tend to overestimate ischemic core if you were to compare that with diffusion-weighted data. So, with that, now we have a study in which we have core volumes, and we're going to look at outcomes from endovascular thrombectomies compared to best medical management and see whether there is a correlation or interaction between ischemic core presentation, especially age. So, my next question would be to Andrew, can you walk us please through the main findings of the paper? Dr. Andrew Demchuk:   The whole goal of this paper was really to understand, are there thresholds in the older patients? When we looked at overall, and Bruce Campbell and the team wrote an important paper with HERMES and the CTP cohort overall, and the sort of message there was if you looked at shift analysis, there wasn't actually a core threshold found at all in HERMES for lack of benefit. There was a benefit across all the core volumes, but, of course, that's all ages. So, we were really interested in looking at the older patients because we felt there's more likelihood the core volume will matter in the elderly than in the younger patient. We know the younger population, it benefits overwhelmingly with EVT, it's hard to even find a core volume threshold. So, that was a premise. Essentially, we had 247 patients over 75 in the overall cohort, of which 98 had EVT. So, it was a decent population, and not a huge sample, but a decent sample. And so we looked at various things. The first thing that was interesting we found was that infarct volumes, the average infarct volume to achieve an mRS three or less, was lower in the older patients, significantly lower, was 23.9 for younger patients under 75 and 10.7 for the older patients. You tend to have much smaller infarcts to achieve good outcome. And so that was kind of interesting, and I think that's been shown by others. Then we got into the weeds to try to figure out, OK, what are these thresholds? And if there's one figure that matters, Negar, you know me to always point out that there's always one figure or table in a paper that's kind of where the money is, where the real learning is, and that's Figure 2 on this paper in my opinion, beautiful figure with four figure A, B, C, and D. And it really sort of nicely highlights these issues and these cutoffs. But what we saw is that in the older patients who received EVT, around 50 mils seemed to be a threshold to achieve zero three, you had to, to see treatment effect, you had to have a baseline infarct volume less than 50 mils for a zero three outcome advantage. For zero four, it was 85 mils. And then we looked at this issue of what we called futility, true futility. And that's a very controversial thing. What is futility, or how do you measure futility? And really, I think, we even had a debate about this as a HERMES group when we were designing the analysis, and we sort of landed on mRS five six. A 90% chance of mRS five six, right? That's quite the bar, right, to say true futility because some people argue mRS four is still not a horrible outcome. Culturally, that is an OK outcome in some situations. But when we did use that five six 90% threshold, it was 132 mils. So, you're getting up to these really large volumes. But here's the catcher in the whole thing, and Koji will probably speak to this a bit more. I don't want to steal his thunder too much, but this issue of reperfusion seemed to matter in this. And we'll come back to that maybe with another question. Reperfusion matters a lot when you think about these thresholds. Dr. Negar Asdaghi:         OK, so, Andrew, a lot of information, I don't know if I need a recap myself to recap, but basically what you mentioned is that for the older patients who received EVT, if we keep our eyes on the outcome of mRS of zero to three, it seems to be the magic core volume for that outcome post-endovascular therapy that it lands on the magic volume of 50 cc core. Did I get that right? Dr. Andrew Demchuk:   That's correct. Dr. Negar Asdaghi:         Then if you're still a bit more lenient with the definitions of what is favorable outcome, what outcomes we're looking at and so on, so forth, for an mRS of five to six, then when we talk about futility of endovascular thrombectomy, the volume that you mentioned, and again I want to ask you this, this volume is for elderly over the age of 75, is 130 mil. Dr. Andrew Demchuk:   132, but yeah, absolutely. But there's a real catcher here, and we need to really emphasize the catcher in this. Dr. Negar Asdaghi:         Okay. I will ask you one more question before I go to Koji, which I'm sure is going to tell us more about that catcher. Andrew, can you please tell us about the factor of time? I feel like that is something that we need to discuss, as well. Your study included patients early on in their stroke onset, but we're talking about an important interaction. The question is, do you think the results of this interaction would be different or impacted by the value of time? Dr. Andrew Demchuk:   Hypothetically? It must, right? I think that that must be the case. We don't have any data specific to this. That would be an interesting Aurora analysis to do. Now, of course, the challenge with late window analysis is, we are really small core in our late window trials, we probably have even a much smaller proportion of large cores. So, to be able to even tackle that question in the late window is, I don't know if we have the data yet, to be honest. But it makes sense that you would expect the thresholds to be a bit lower the later you are in the window. But that is a hypothetical opinion. Dr. Negar Asdaghi:         Right, so, I want to take that and come to Koji. I want to digress a little bit to Koji and see how we can understand the finding of this current analysis of this paper. So, small core patients early on into their onset, we're looking at the interaction between age and their core volume and coming up with numbers 50 cc for the elderly population. If you're looking at the outcome of zero to three or 132, as Andrew pointed out, for an MRS of much higher, four or five. Dr. Andrew Demchuk:   Actually five, six, 90% chance of five, six. So, it's there. It's like almost everybody got five, six, took 132 mils to get there. So, it's like this extreme outcome. Dr. Negar Asdaghi:         Right, so, exactly, and I have to correct it, again, mRS of five or six or dead or almost dead mRS basically. Dr. Andrew Demchuk:   In 90% of patients. Dr. Negar Asdaghi:         90% of patients. So, we have these important numbers here, and I want us to basically understand these numbers in these volumes in the context of the recently published RESCUE-Japan LIMIT study. Can you tell us a little bit about that study and how we can make sense of these volumes in the setting of that paper? Dr. Koji Tanaka:               In the recent RESCUE-Japan LIMIT trial, the median ASPECTS was lower, and baseline ischemic core volume was greater than those in our study. And surprisingly, the median ischemic core volume in that trial was close to our threshold to predict less than 10% of patients achieve a modified Rankin Scale of four or less after endovascular therapy. We thought this is due to much higher complete reperfusion rate in HERMES patient. We have much interest in their additional analysis for outcomes in elderly patients by reperfusion status. This potential benefit of endovascular therapy in the area is promising for the future clinical trials. Dr. Andrew Demchuk:   I think just to add to that, it was actually really interesting, Negar, because when we were analyzing all of this and then the trial came up and it was actually really nice because we're like, OK, how does our data relate to their data? And that's where Table 2 comes in, and it would almost be worth putting on the pod, whatever, I don't know if you have on your podcast website, you have one figure that you can sit there with as you listen to the podcast, because that would be the figure. Dr. Negar Asdaghi:         We'll work on that Andrew, but tell us a little bit more because, really, when I read the trial results, the way I understand it is that people enrolled in RESCUE-Japan that were older than 75, and these are all large core patients, benefited more from endovascular therapy than their younger counterpart. How do I understand that? I don't know how to wrap my head around that finding. Dr. Andrew Demchuk:   You want to try to answer that, and then I'll add? Dr. Koji Tanaka:               As I mentioned previously, we want to know about the exact patient population just only for elderly patients, whether they have a exactly larger ischemic core volume or as well as their functional outcome. How many patients achieved modified Rankin Scale four or less or three or less, or more than five or six? Dr. Andrew Demchuk:   Koji's point's very important. We actually don't have the breakdown of the mRS, so we don't know if they created a lot of fours, or threes, or what. So, that's one issue. But I think that the key to this whole thing is to understand that this is a 2022 trial. HERMES data is essentially a 2015 equivalent where we're looking at a number of clinical trials who roughly ended between 2014, 2016. So, the technology, the technique, the operators, are just at a different level back then than now. And quite frankly, EVT is an improving treatment. We probably don't even fully understand how much, I mean, we're just getting better at it. And I think what's happened here is the reperfusion rates have improved. And our HERMES reperfusion rates, remind me, Koji, I think they're about half, we think, in HERMES, than like the TICI 2bs, threes, are half in HERMES what they got in RESCUE-Japan LIMIT. So, when you achieve successful reperfusion, what were the numbers here? TICI 3 was 43% in the Japan RESCUE LIMIT, and 8.6% in HERMES. Okay, TICI 3s were not ... Now that may be slight differences in core lab interpretation, but we were just starting to get good at 3s. We were getting a lot of 2bs and some 2cs, but we weren't getting a massive number of 3s back in 2015. Well, voilà, now we are, right? We're hitting home runs when we didn't before. And I think that has really shifted the goalposts on the large core. If you open the vessel, they can still do well if they're elderly, but you've got to really open that vessel. And in HERMES, we only did that in a small portion of patients. So, these thresholds are sort of representative of 2015 skill. Dr. Negar Asdaghi:         Golden points, Andrew and Koji, both of you. I want to recap what you mentioned here. A note to all of our audience and listeners that we are looking at an analysis with RESCUE-Japan, an analysis of a 2022 study. And the patient population that were enrolled were also treated much later in terms of time than the patient population that was enrolled in the HERMES collaboration and in all of the trials that contributed to HERMES. So, we've got to remember that EVT is this fluid, ongoing, everyday-improving therapy, from our techniques to everything else, you know, how fast we get patients to the angiosuite. And the point that you raise, I want to repeat that, the percentage or the odds of achieving a perfect reperfusion was, in RESCUE-Japan, was 43% odds of TICI 3 reperfusion, whereas only 8.6%. So, when we're talking about all of these predictive modeling or predictive factors that will tell us who's going to do well, who's not going to do well, it also is predicated on the angiographic success. And perhaps in the earlier trials or even the early study that we covered as part of the STRATIS registry, we put everybody, TICI 3s with TICI 2b or better, whereas nowadays we accept the best, TICI 3s, and maybe that improved percentage in the most recent trial, the RESCUE-Japan, really did what it had to be done for the elderly population to keep that in mind. And Andrew, before we end our interview, I want us to get your top two takeaway messages from this paper. Dr. Andrew Demchuk:   Clearly, elderly patients do better when their strokes are smaller, that we know, compared to younger patients. But it's all about hitting the home run. It's all about hitting the home run. Figure 2C and 2D, you can see that if you achieve that high TICI score, a significant proportion of elderly patients potentially could still benefit, 30–40% reasonable outcomes with bigger cores if you get those high TICI scores. So, it is about hitting the home run in reperfusion in the elderly. You need to go for it, and hopefully you're successful, because if reperfusion isn't successful, then generally the outcomes are not ideal and they certainly worsen as the core volumes become larger, bigger. Dr. Negar Asdaghi:         Before I ended the interview, given Andrew's tremendous experience as a longtime fellowship director and seeing that he was flanked by two of his fellows, one past, myself, and one present, Koji, I had to ask him one final question of what his philosophy is as an educator. Dr. Andrew Demchuk:   I have a sort of philosophy on life with fellows. I always look for the special power in a fellow. I realized a long time ago we're all, we're not perfect, nobody's perfect, I'm not perfect, but there's usually a special power in people, and if you spend the time to get to know them, you identify that special power, and you really help harness it because you know that if they can harness it when they go back to their faculty job, they're going to really contribute something special to their team, right? You can imagine six special powers from six different people in a team. Now you've got a real team, right? If you know what your power is, you know your limitations, but you know where your strengths you can add to the group, and that's what we try to do here when we can. It's not always, you know, special powers, you have to kind of seek them out. But they're there in most people, and that's really important for career down the line. Dr. Negar Asdaghi:         And this concludes our podcast for the December 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including our very interesting Stroke Images series. In this month, we have a case of progressive cervical myelopathy secondary to a dural AV fistula supplied by the anterior inferior cerebellar artery. We also have a separate case of carotid rete mirabile imaged with a four-dimensional flow MRI study. And with these cases, we bring our 2022 Stroke Alert Podcast series to an end. Over the past 12 months, we've ended our podcasts with various inspirational tales. From the moving account of the American runner Steve Prefontaine and the remarkable journey of the Syrian refugee and Olympian swimmer Yusra Mardini, to the discovery of positron and Commander Armstrong's landing on the moon, our podcast stories have but one thing in common, which is the story of human perseverance and consistency in the face of hardship. So, as we end 2022 to start 2023 anew, Andrew's comments on finding that special power in each of us resonate with our resolution to stay alert with Stroke Alert. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.04.515245v1?rss=1 Authors: Hu, J., Zuo, L., Qu, W., He, H., Bao, J., Zhang, W., Zhang, Y., Zhu, M., Li, T. Abstract: Objective: Based on network pharmacology, the response of Qing-tong-hua-yu Decoction (QTHY) to the regulation of EGFR/MAPK signaling cascade in cerebral ischemia-reperfusion injury was discussed and the possible mechanism of the protective effect of QTHY on the cerebral ischemia-reperfusion injury was studied. Methods: A compound-target disease-function-pathway network was established and analyzed based on the network pharmacology approach used in Chinese medicine. The correlation, which is between effect of the components of QTHY Decoction against CI/RI with EGFR/MAPK signalling cascade response, was observed. And then the degree of neurological deficits in each group was assessed after cerebral ischemia for 2 hours and reperfusion for 3 hours, 24 hours, 3 days and 7 days. Expression levels of EGFR and p44/42MAPK in ischemic brain tissue at different time points in various groups of rats were tested by Western bolt (WB), real-time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC). Results: Network pharmacology analysis revealed that QTHY-mediated treatment involved 439 key targets, in which the effect of QTHY groups against CI/RI was associated with EGFR/MAPK signaling cascade. QTHY treatment reduced neurological deficit scores and improved ischemic changes in rats. In addition, QTHY promoted EGFR and p44/42MAPK expression in the SVZ through the EGFR/MAPK signaling cascade, with varying degrees of improvement at different time points. Conclusion: QTHY can better improve cerebral ischemia injury in CI / RI rats and exert the neuroprotective effect of cerebral ischemia-reperfusion injury. This may be related to the potential of QTHY to activate the EGFR / MAPK signaling cascade, which is consistent with the results of network pharmacology analysis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.05.506665v1?rss=1 Authors: Torteli, A., Toth, R., Berger, S. D., Samardzic, S., Bari, F., Menyhart, A., Farkas, E. Abstract: Background: Despite successful recanalization to treat acute ischemic stroke, reperfusion failure associated with poor functional outcomes develops in half of the patients. The cause of reperfusion failure remains the subject of intensive research. Here, we explore the possibility that spreading depolarization (SD), a potent ischemic injury mechanism is a significant contributor and reliable predictor of reperfusion failure. Methods: Young adult male and female C57BL/6 mice (n=69) were anesthetized with isoflurane (0.6-0.9%) and prepared for transcranial optical imaging. After 10 min of baseline, incomplete global forebrain ischemia was induced by transient (45 min) bilateral common carotid artery (CCA) occlusion, followed by 75 min reperfusion. SD and cerebral blood flow (CBF) changes were visualized with intrinsic optical signal imaging and laser speckle contrast imaging. To block SD, the irreversible NMDA receptor antagonist MK801 was applied (0.3 mg/kg, i.p., n=29). Neurological deficit was evaluated at baseline and post-ischemia with a composite Garcia Neuroscore scale. Collaterals of the circle of Willis were examined after loading the vasculature with carbon black ink. Ischemic neuronal injury was evaluated in hematoxylin-eosin-stained brain sections. Results: SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1+-4.6 vs. 33.6+-4.4 %, SD vs. no SD). The failure of later reperfusion (44.4+-12.5 %) was invariably linked to previous ischemic SD. In contrast, reperfusion was adequate (98.9+-7.4 %) in hemispheres devoid of SD during ischemia. CBF reduced below the perfusion threshold of SD, when the P1 segment was absent in the circle of Willis. SD occurrence and the linked reperfusion failure were associated with poor neurologic function, and greater neuronal necrosis. The inhibition of SD with MK801 significantly improved reperfusion. Conclusions: SD occurrence during ischemia impairs later reperfusion, prognosticating poor functional outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Commentary by Dr. Valentin Fuster

Commentary by Dr. Valentin Fuster

This month on Episode 30 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the October 29 and November 12 issues of Circulation Research. This episode also features a conversation with Dr Elisa Klein from the University of Maryland about her study, Laminar Flow on Endothelial Cells Suppresses eNOS O-GlcNAcylation to Promote eNOS Activity.   Article highlights:   Subramani, et al. CMA of eNOS in Ischemia-Reperfusion Liu, et al. Macrophage MST1 Regulates Cardiac Repair Van Beusecum, et al. GAS6/Axl Signaling in Hypertension Pati, et al. Exosomes Promote Efferocytosis and Cardiac Repair   Cindy St. Hilaire:        Hi and welcome to Discover CircRes, the podcast of the American Heart Association's Journal Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh and today I'll be highlighting articles presented in our October 29th and November 12th issues of Circulation Research. I also will speak with Dr Elisa Klein from the University of Maryland about her study, Laminar Flow on Endothelial Cells Suppresses eNOS O-GlcNAcylation to Promote eNOS Activity.   Cindy St. Hilaire:        The first article I want to share is titled, Chaperone-Mediated Autophagy of eNOS in Myocardial Ischemia Reperfusion Injury. The first author is Jaganathan Subramani and the corresponding author is Kumuda Das from Texas Tech University Health Sciences Center. Reestablishing blood flow to ischemic heart muscle after myocardial infarction is critical for restoring muscle function but the return of flow itself can cause damage, a so-called reperfusion injury. The generation of reactive oxygen species or ROS and loss of nitric oxide or NO both contribute to reperfusion injury.                                       Reperfusion injury is exacerbated when the NO producing enzyme, endothelial nitric oxide synthase or eNOS, produces damaging super oxide anions instead of NO. This switch in eNOS function is caused by glutathionylation of the enzyme, termed SG-eNOS. But how long this modification lasts and how it is fixed is unclear. This group used an in vitro model of ischemia reperfusion where human endothelial cells are exposed to several hours of hypoxia followed by reoxygenation. In this model, they found the level of SG-eNOS steadily increases for 16 hours and then sharply decreases. By blocking several different cellular degradation pathways, they discovered that this decrease in S-G eNOS was due to chaperone mediated autophagy with the chaperone protein, HSC70, being responsible for SG-eNOS destruction. Importantly, this team went on to show that pharmacological D-glutathionylation of eNOS in mice promoted NO production and reduced reperfusion injury, suggesting this approach may be of clinical benefit after myocardial infarction.   Cindy St. Hilaire:        The second article I want to share is titled Macrophage MST1/2 Disruption Impairs Post-Infarction Cardiac Repair via LTB4. The first author is Mingming Liu and the corresponding author is Ding Ai and they're from Tianjin Medical University. Myocardial infarction injures the heart muscle. These cells are unable to regenerate and instead a non-contractile scar forms and that fibrotic scar can lead to heart failure.                                     Cardiomyocytes specific inhibition of the kinase MST1 can prevent infarction induced death of the cells and preserve the heart function, suggesting that it may have clinical utility. However, MST1 also has anti-inflammatory properties in macrophages. So inhibition of MST1 in macrophages may delay inflammation resolution after MI and impair proper healing. Thus, targeting this enzyme for therapy is not a straightforward process. This study examined mice lacking MST1 in macrophages and found that after myocardial infarction, the inflammatory mediator leukotriene B4 was upregulated in macrophages and the animal's heart function was reduced compared to that of wild type controls. Blocking the action of leukotriene B4 in mice reduced infarction injuries in the hearts of MST1-lacking animals and enhanced repair in the injured hearts of wild type animals given an MST1 inhibitor. The results suggest that if MST1 inhibition is used as a future post infarction regenerative therapy, then leukotriene B4 blockade may prevent its inflammatory side effects.   Cindy St. Hilaire:        The next article I want to share is titled Growth Arrest Specific-6 and Axl Coordinate Inflammation and Hypertension. The first author is Justin Beusecum and the corresponding author is David Harrison and they're from Vanderbilt University. Inflammation contributes to hypertension pathology but the links of this relationship are unclear. It's thought one trigger of inflammation may be the hypertension-induced mechanical stretch of vascular endothelial cells. Mechanical stretch causes endothelial cells to release factors that convert circulating monocytes into inflammatory cells. And one such factor is the recently identified Axl and Siglec-6 positive dendritic cells, also called AS DCs.                                       AS DCs produce a large amount of inflammatory cytokines but little is known about the role of AS DCs or their cytokines in hypertension. This group found elevated levels of AS DCs in hypertensive people compared to normal tensive individuals. Mechanical stretch of human endothelial cells promoted the release of GAS6, which is an activator of the AS DC cell surface kinase, Axl. This stretch induced GAS6 release also promoted conversion of co-cultured monocytes to AS DCs. Inhibition of GAS6 or Axl in the co-cultured system prevented conversion of monocytes to AS DCs. This team went on to show that hypertensive humans and mice have elevated levels of plasma GAS6 and that blocking Axl activity in mice attenuated experimentally induced hypertension and the associated inflammation. This work highlights a new signaling pathway, driving hypertension associated inflammation and identifies possible targets to treat it.   Cindy St. Hilaire:        The last article I want to share is titled Novel Mechanisms of Exosome- Mediated Phagocytosis of Dead Cells in Injured Heart. The first author is Mallikarjun Patil and Sherin Saheera and the corresponding author is Prasanna Krishnamurthy from the University of Alabama, Birmingham. After myocardial infarction inflammation must quickly be attenuated to avoid excessive scarring and loss of muscle function. Macrophage mediated efferocytosis of dead cells is a critical part of this so-called inflammation resolution process. And resolution depends in part on the protein. MFGE8. MFGE8 helps macrophages engage with eat me signals on the dead cells and loss of macrophage MFGE8 delays inflammation resolution in mice. Because stem cell-derived exosomes promote cardiac repair after infarction and are anti-inflammatory and express MFGE8, this group hypothesized that perhaps part of a stem-cell derived exosomes proresolven activity may be due to boosting macrophage efferocytosis.                                     They showed that stem cell derived exosomes did indeed boost efferocytosis of apoptotic cardiomyocytes in vitro and in vivo. An in vitro experiments showed that if exosomes lacked MFGE8 then efferocytosis by macrophages was reduced. Furthermore, after myocardial infarction in mice, treatment with MFGE8 deficient exosomes did not reduce infarct size and did not improve heart function compared to control exosomes. These results suggest MFGE8 is important for the cardioprotective effects of stem cell-derived exosomes. And that this protein may be of interest for boosting efferocytosis after myocardial infarction and in other pathologies where inflammation is not readily resolved.   Cindy St. Hilaire         So today, Dr Elisa Klein from the Department of Biomedical Engineering at the University of Maryland is with me to discuss her study Laminar Flow on Endothelial Cells Suppresses eNOS O-GlcNAcylation to Promote eNOS Activity and this article is in our November 12th issue of Circulation Research. So Dr Klein, thank you so much for joining me today.   Elisa Klein:                 Thank you for having me.   Cindy St. Hilaire:        Yeah. So broadly your study is investigating how blood flow patterns specifically, kind of, laminar and oscillatory flow, how those blood flow patterns impact protein modifications and activity. So before we, kind of, get to the details of the paper, I was wondering if you could just introduce for us the concept of blood flow patterns, how they change in the body naturally but then how they might influence or contribute to disease pathogenesis in the vessels?   Elisa Klein:                 Sure. So obviously we have blood flow through all of our vessels and since we are complex human beings, we have complex vascular beds that turn and that split or bifurcate. And so every place we get one of these bifurcations or a turn in a vessel, the blood flow can't quite make that turn or split perfectly. So you get a little area where the flow is a oscillatory or what we call disturbed. There's lots of different kinds of disturbed flow. And the reason why that's important is because you tend to develop atherosclerotic plaques at locations where the blood flow is disturbed. So in my lab, we look a lot at what it is about that disturbed flow that makes the endothelial cells there dysfunctional and that leads to the atherosclerotic plaque development.   Cindy St. Hilaire:        That is so interesting. So I can picture how this is happening in a mouse at the bifurcation of different arteries but how are you able to model this in vitro? Can you describe the setup and then also how that setup can mirror the physiological parameters?   Elisa Klein:                 Sure. So we have a couple of different systems we can use to model this and they all have their advantages and disadvantages, right? So a few years ago we made a system that's a parallel plate flow chamber. So you basically have your cells that you see that on a microscope slide and you use a gasket that's a given shape and that either drives the flow… Usually it drives the flow straight across the cells. So that's a nice laminar steady flow. And we see that the cells align and they produce nitric oxide in that type of flow which are measures that they are responding to the flow in vitro. So, a few years ago we made a device that actually makes the flow zigzag as it goes across the endothelial cells. And that creates these little pockets of disturbed flow and we did that in our parallel plate flow chamber.                                       And that parallel plate flow chamber is really good for visualizing the cells. So you can stick it on a microscope. You can see what's happening, we can label for specific markers but it's not good for doing the things that we did in this Circ Research paper, where we want it to measure metabolism, because you need a lot more cells to measure metabolism and we needed a better media to cell ratio, so less media and more cells. So for this one, we designed and built a cone-and-plate device. So what it is, it's a cone and you spin that cone on top of a dish of endothelial cells and that cone produces flow. So it's going around in a circle. And if we just make it go around in a circle, it'll produce a steady laminar flow but if we oscillated it, so basically we kind of turn it back and forth, it'll make this oscillating disturbed flow. And then we have our dish of cells.                                     We do this in a 60-millimeter dish and then we have a small amount of media in there and a lot of cells. And we can culture the cells in there for a while.                                     Cindy St. Hilaire:        That is so neat. And so I'm assuming that then your cone system is very tuneable. You could either speed it up, slow it down or change that oscillatory rate with different, I guess, shifts of it? Elisa Klein:                 Yeah, that's exactly right. So we can do all those things. It's programmable with a motor and so we can run whatever type of flow we want. Cindy St. Hilaire:        That's great. So before your study, what was known regarding this link between hemodynamics and endothelial cell dysfunction and also endothelial cell metabolism? Because I feel like that's a really interesting space that a lot of people look at, kind of, metabolism and EC dysfunction or they just look at shear stress and EC dysfunction and you're, kind of, combining the three. So what was kind of the knowledge gap that you were hoping to investigate? Elisa Klein:                 Yeah, so we're really interested in macrovascular endothelial cell dysfunction. So this pro atherosclerotic phenotype that you can get in endothelial cells. And most of the work on endothelial cell metabolism had actually been done in the context of angiogenesis. So how much energy and how do cells get their energy to make new blood vessels? And that's more of a microvascular thing. So there was a study that came out before ours, actually, before we started this study, that was looking at how steady laminar flow could decrease endothelial cell glycolysis. And so that was after 72 hours of flow and they showed some gene expression changes at that time. Our study is shorter than that and we were still able to see a decrease in glycolysis in our cells in laminar flow. Before we started this study, no one had really looked at disturbed flow. So in the meantime, there are a few other papers that came out showing that the cells don't decrease glycolysis when they're in disturbed flow but not so much connecting them back to this function of making nitric oxide. Cindy St. Hilaire:        So we were kind of dancing to the topic of O linked N acetylglucosamine or how do you say it? Elisa Klein:                 GlcNAC. Cindy St. Hilaire:        GlcNAC? O- GlcNAC. So, O- GlcNAC is a sugar drive modification and I think it's added to Syrian and three Indian residues and proteins. Elisa Klein:                 Yup, that's right. Cindy St. Hilaire:        Okay, good. And that modification, it does help dictate a protein's function. And you were investigating the role of this moiety on endothelial nitric oxide synthase or eNOS and so what exactly does this GlcNAC do for eNOS' function and under what conditions or disease states is this modification operative? Elisa Klein:                 Yeah. So there's some really important studies from a little bit ago that showed that eNOS gets GlcNAcylated in animals with diabetes, right? So if you have constantly high sugar levels, you get this modification of eNOS. The thought was that eNOS gets GlcNAcylated at the same site where it gets phosphorylated. But a more recent study came out and said, well, maybe that's not the case but it definitely gets GlcNAcylated somewhere where it affects this phosphorylation site. So it may be near it and prevent the folding or prevent the phosphorylation site availability. So if the eNOS gets GlcNAcylated, the thought is that it can't get phosphorylated and therefore it can't make nitric oxide. Cindy St. Hilaire:        And so an interesting thing about this GlcNAcylation, which is probably the hardest thing I've ever said on this podcast, is that it's integrated with lots of different things. Obviously you need glycolysis and the substrates from the breakdown of sugars to make that substrate but also the enzymes that make that substrate are required. And so what's known about that balance in endothelial cells? Is there much known regarding the metabolic rate of the cells and this N-Glcynation? Elisa Klein:                 Yeah. So endothelial cells are thought to be highly glycolytic in terms of how they use glucose but they definitely take up glutamine to fuel the tricarboxylic acid or TCA cycle. And another paper came out a few years ago showing that quiescent and endothelial cells metabolize a lot of fatty acids. So they're fueling their energy needs that way. So there wasn't a lot known about GlcNAcylation in endothelial cells.                                     A lot of this work has been done in cancer cells, which are also highly glycolytic but their metabolism actually seems like it's maybe more diverse than people have thought for a long time. So the weird thing about GlcNAcylation, which if you're used to working with phosphorylation there's a thousand different enzymes that can phosphorolate right. But with GlcNAcylation there's one enzyme that's known to put the GlcNAC on and one enzyme that's known to take it off. And so they're global, right? So in our studies, if we say, okay, we're going to knock down that enzyme, you're effecting every single protein in the cell that's GlcNAcylated. And obviously ourselves in particular, we're not a big fan of that. Especially once you put them in flow, they were, like, nope, we're not going to make it. Cindy St. Hilaire:        Well, and that's a perfect segue to my next question because your results show that this flow really did not alter the expression of these enzymes that either add or subtract to the moiety. And rather it was the Hexosamine Biosynthetic Pathway that was decreased itself. So can you maybe give us a quick primer on what that is exactly and how that pathway feeds into the glycosylation... I think you wrote in the paper of over 4,000 proteins? So how would that fit in and why eNOS then? Elisa Klein:                 Yeah, so the Hexosamine Biosynthetic Pathway is one of these branch pathways that comes off glycolysis and there are these numbers sometimes there are these pathways out there and people say for the HBP in particular, 2% to 5% of the glucose that's going down through glycolysis gets shunted off into the HBP. We've done a lot of looking to try and figure out exactly where that 2% to 5%- Cindy St. Hilaire:        Yeah, what exact percentage? Elisa Klein:                 Yeah, but some percentage of it comes down and we really thought there were going to be changes in these enzymes that do the GlcNacylation, we thought there might be changes in the localization of the proteins and it's possible that those things do occur. We just couldn't detect them in our cells. And in the end, what we showed was the main thing was that when you have cells and steady laminar flow, you just decreased glycolysis. And therefore, that 2% to 5% goes down. So you seem to make less of this UDP- GlcNAC, which is the substrate that gets put on to eNOS in this case. The really strange thing that we could not explain despite a lot of work and obviously we don't get to put all of our experiments that didn't work in the paper- Cindy St. Hilaire:        The blood, sweat and tears gets left out. So- Elisa Klein:                 Exactly. So we tried really hard to figure out why it was eNOS specifically, right? Because in steady laminar flow, you see a lot of these like GlcNAcylated  proteins and a lot of them didn't change but eNOS changed hugely, essentially this GlcNAcylation just went away for the cells and steady laminar flow. So we couldn't quite answer that. We're still working on that part of the question and looking at some of the other proteins that maybe get GlcNAcylated more in this case and trying to figure out what they are. Cindy St. Hilaire:        I thought one of the cool results in your paper was one of the last ones. It was the one in healthy mice. In that you looked at healthy mice, just normal C57 black 6 mice that were 10 weeks old. So they just, kind of, reached maturity but you looked at their kind of these bifurcations and you looked at the inner aortic arch where there is more disturbed flow and you saw, similar to your in vitro studies, that there was this higher level of O-GlcNAcylation compared to the outer arch in the descending order. So my question is, these are healthy mice that are relatively young, they're not even full adults yet. That takes a couple more months. And so what are your thoughts about the role of this O-GlcNAcylation specifically on eNOS in driving atherogenesis. Where do you think this is happening in the disease process? It appears if it's in these wild type mice, it's already happening early. So where do you think this is most operative in the disease pathogenesis? Elisa Klein:                 I mean, I think it's very early, the effects of disturbed flow on endothelial cells. I can't imagine that there's a time when it's not having an effect on the cells. So I teach college students and I tell them all the time you think you're invincible now but these choices you're making today are going to affect your cardiovascular future in 50 years, which is very hard to accept. So I think it's very early in the process and I think it's only made worse by the things that we eat, in particular, that changed our blood sugar and our blood fatty acids and things like that. And our lab is looking into this more to try and see how when you change your blood metabolites then how does that then also affect this GlcNAcylation and the endothelial cell metabolism and then how does that affect endothelial cell function? Cindy St. Hilaire:        Yeah. And it's funny, it's really making me think of those, kinds of, extreme diets like keto diets and things like that where you're just like depleting sugar. And obviously there's lots of controversy in that field, but if you just think about the sugar aspect what is that doing to those EC cells? Why do you think endothelial cells have this response? Meaning why do you think it is that they've adapted to induce a metabolic shift in response to disturbed flow? Because, obviously it's not going to be perfect laminar flow everywhere. So what do you think it is that provides some sort of advantage in the shift? Elisa Klein:                 That's a really good question. I haven't thought about the advantage that it might provide. There are a lot of things that are going on in this area of disturbed flow. So there is the shear stress, the differential shear stress that the cells are experiencing. There's also transport issues, right? So if you have this area of disturbed flow, you have blood and the contents of the blood, including the white blood cells and the red blood cells, everything else that's, kind of, sitting around in that area and not getting washed downstream as quickly. So it is possible that maintaining glycolysis provides energy for repair or for protecting the endothelial cell from some sort of inflammatory insult or something like that, that's happening in the area of disturbed flow. And I feel like I just read something recently, it was in a different genre but... if they stopped the increased glycolysis or stop the metabolic shifts, it actually was worse.                                     Right? So I also believe that we treat humans for a single metabolic change, right? So if you have diabetes, I'm going to give you this drug and if you have high triglycerides, I'm going to give you this drug. But it's possible that if you have this metabolic abnormality, your body shifts the rest of your metabolism to protect the cells because of that metabolic abnormality. And so part of what we do as engineers is try and build computational models or we can take into account some of this complexity. So that's a really interesting question and my guess is that there are some protective aspects of this maintenance of high glycolysis and disturbed flow. Cindy St. Hilaire:        Yeah, maybe it would be perfectly fine until we get athero and then it all goes awry. So in terms of... obviously it's early days and I know you're a bioengineer but in terms of translational potential, what do you think your findings suggest about future potential therapies or future targets for which we can use to develop therapies? Is modulating this O-GlcNAcylation itself, a viable option? Elisa Klein:                 I don't think that modulating it is a super viable option, right? Because as I said, when we tried to change those enzymes ourselves did not enjoy going through flow or anything else. So it's very hard to change it overall. What I think is these things that are coming out about how metabolism may shift for endothelial cells when they're activated versus when they're quiescent, right? So when laminar flow or cells are quiescent, they decrease glycolysis, they increase fatty acid oxidation. Those things are important to take into consideration when you are treating a person who has a metabolic disorder. So that's the biggest translational piece that I think is, how do we give therapies that modify the metabolism of a cell holistically instead of trying to hit one pathway in particular.                                     We have done some studies where we tried to give endothelial cells something to inhibit a specific metabolic pathway and you see the cell shifts its entire metabolism to account for that. So we're starting to look at some of these other drugs like statins or metformin that do change endothelial cell metabolism, possibly even the SGLT2 inhibitors and trying to see not just how they change glycolysis but how they change metabolism as a whole and how that then affects endothelial cell function. Cindy St. Hilaire:        So what are you going to do next on this project? Elisa Klein:                 So on this project, so we have some stuff in the works like I said on statins and how statins work together. And one of our big goals is to sort of build a comprehensive metabolic model of the endothelial cell. So this study really focused on glucose but there are other things that endothelial cells metabolize, glutamine, and fatty acids, and trying to look at some of those and then seeing how changes in the glycolytic pathway may affect some of those other pathways. We also have some really nice mass spec data part of which is in this paper but part of which is going to go into our next work, which is looking at how laminar flow impacts some of the other side branch pathways that are in metabolism and coming off of glycolysis as well as the TCA cycle, right? So we don't think of endothelial cells as being big mitochondrial energy producers but they do use their mitochondria. And so we think it's really interesting and part of our goal of building an endothelial cell model and then hopefully a model of the complexity of the whole vascular wall. Cindy St. Hilaire:        Wow. That would be amazing. Well, Dr Elisa Klein from the University of Maryland, thank you so much for joining me today. This is an amazing study and I'm looking forward to seeing hopefully more of your future work. Elisa Klein:                 Thank you so much. It was a pleasure. Cindy St. Hilaire:        That's it for the highlights the from October 29th and November 12th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes or #DiscoverCircRes. Thank you to our guest, Dr Elisa Klein. This podcast is produced by Asahara Ratnayaka, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries and basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers on this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, visit AHAjournals.org.

Article discussed in today's episode: Obesity-related IL-18 Impairs Treg Function and Promotes Lung Ischemia-reperfusion Injury

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Miriam Cortese-Krott and Associate Editor Charles Lowenstein as they discuss the article "Red Blood Cell and Endothelial eNOS Independently Regulate Circulating Nitric Oxide Metabolites and Blood Pressure." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-host I'm Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature paper is one of those really, really landmark papers that really advance our understanding of Nitric oxide signaling. And it's about red blood cell and Endothelial eNOS, and how they independently regulate circulating nitric oxide, metabolites, and blood pressure. A real, real must, but let's go on and look at the other papers in this issue first. Greg, you want to go first? Dr. Greg Hundley: You bet, Carolyn. Better grab a cup of coffee. And my first paper is from professor Nathan Mewton from Hôpital Louis Pradel Hospices Civils de Lyon. Carolyn, these authors hypothesized that Colchicine a potent anti-inflammatory agent may reduce infarct size in left ventricular remodeling at the acute phase of STEMI. And so to address this hypothesis, they performed a double-blind multi-center trial and randomly assigned patients admitted for a first episode of STEMI referred for primary PTCA to receive oral Colchicine two-milligram loading dose followed by 0.5 milligrams twice a day, or matching placebo from admission to day five and the primary efficacy outcome was infarct size determined by cardiovascular magnetic resonance imaging at five days. And the relative left ventricular end-diastolic volume change at three months and infarct size at three months was also assessed by cardiac MRI. And these were secondary outcomes. Dr. Carolyn Lam: Nice. Okay. So what were the results? Dr. Greg Hundley: Right, Carolyn. So 192 patients were enrolled. 101 in the Colchicine group and 91 in the controls. And as a result of this trial, the oral administration of high dose Colchicine at the time of Reperfusion. And for five days thereafter did not reduce infarct size assessed by cardiac MRI. And so Carolyn, the clinical implications of these results suggest that other studies exploring the timing, pharma kinetics, and dose-response of Colchicine, as well as other anti-inflammatory agents are needed to identify an effective method to reduce infarct size and limit remodeling in this group of patients. Dr. Carolyn Lam: Wow, it's just such a rich field done with all this about Colchicine. Well, our next paper is a pre-specified sub-analysis of the randomized EAST-AFNET 4 Trial and the sub-analysis assess the effect of systematic early rhythm control therapy that is using Antiarrhythmic drugs or catheter ablation compared to usual care, which means allowing rhythm control therapy to improve symptoms in patients with heart failure. And this was defined in the sub-analysis as the presence of heart failure symptoms of New York Heart Association status two to three or a left ventricular ejection fraction of less than 50%. Dr. Carolyn Lam: Now, the authors led by Dr. Kirchhof at University Heart and Vascular Center UKE in Hamburg, Germany included 798 patients in this sub-analysis of whom 442 had HFpEF, 211 had heart failure with mid-range ejection fraction and 132 had HF-rEF over a median of 5.1 years of follow-up the composite primary outcome of cardiovascular death stroke or hospitalization for worsening heart failure, or for acute coronary syndrome occurred less often in patients randomized to early rhythm control therapy compared with patients randomized to usual care. And this was not altered by heart failure status with an interaction P-value of 0.6. Left ventricular function, symptoms, and quality of life improved equally in both treatment strategies. Dr. Greg Hundley: Wow, Carolyn, a lot of information here. So what can we take away from this? Dr. Carolyn Lam: Well, let's remember that this is a sub-analysis, albeit pre-specified of that randomized trial of the EAST-AFNET 4 Trial, but nonetheless, the data supports a treatment strategy of rhythm control therapy with Antiarrhythmic drugs or ablation within a year of diagnosing atrial fibrillation in patients with signs and symptoms of heart failure to reduce cardiovascular outcomes. Dr. Greg Hundley: Very nice, Carolyn. So, Carolyn, my next paper pertains to Alarmin Interleukin-1 Alpha, and it comes to us from Dr. Thimoteus Speer at Saarland University. So, Carolyn, Alarmin Interleukin-1 Alpha is expressed in a variety of cell types, promoting sterile systemic inflammation. And the aim of the present study was to examine the role of Alarmin Interleukin-1 Alpha in mediating inflammation in the setting of acute myocardial infarction and chronic kidney disease. Dr. Carolyn Lam: Wow, sterile inflammation. It's a really hot topic now. So what did these authors find? Dr. Greg Hundley: Right, Carolyn. So we're going to call Alarmin Interleukin-1 Alpha. Let's just call it IL-1 Alpha and so increased IL-1 Alpha surface expression on monocytes from patients with acute myocardial infarction in patients with chronic kidney disease was found to be associated with cardiovascular events. Next, IL-1 Alphas itself served as an adhesion molecule, mediating leukocyte-endothelial adhesion, and finally, abrogation of IL-1 alpha prevented inflammation after myocardial infarction and ameliorated chronic kidney disease in Vivo. Dr. Carolyn Lam: Wow. So what does this mean clinically? Dr. Greg Hundley: Right, Carolyn, so perhaps targeted therapeutic inhibition of IL-1 Alpha might represent a novel anti-inflammatory treatment strategy in patients with myocardial infarction and in patients with chronic kidney disease. Dr. Carolyn Lam: Amazing. Thanks, Greg. Well, in today's issue, there's also an exchange of letters between doctors Lother and Filippatos on Finerenone and risk of hyperkalemia in CKD and type two diabetes. There's an On My Mind paper by Dr. Sattler on the single-cell immunology and cardiovascular METs in, do we know yet what we don't know? Dr. Greg Hundley: And then Carolyn, from the mailbag, a Research Letter from Professor Wehrens entitled “Atrial Specific LK Beta One Knockdown Represents a Novel Mouse Model of Atrial Cardiomyopathy with Spontaneous Atrial Fibrillation.” Well, Carolyn, how about we turn our attention to those red blood cells and endothelial nitric oxide synthase. Dr. Carolyn Lam: Yeah. Can't wait. Dr. Mercedes Carnethon: Well, welcome to this episode of Circulation on the Run. Our podcasts, where we have an opportunity to speak with authors of important papers that are appearing in the journal of circulation. I'm pleased to introduce myself. My name is Mercedes Carnethon, professor and vice-chair of preventive medicine at the Northwestern University Feinberg School of Medicine. And I'm pleased today to invite our guest author, Miriam Cortese-Krott, who is the faculty of the University of Duesseldorf, and a guest professor at the Karolinska Institute in Stockholm. And we have with us as well the other associate editor who handled the piece for circulation, Dr. Charlie Lowenstein from Johns Hopkins University. So welcome to each of you this morning. Miriam Cortese-krott: Thank you. Dr. Charles Lowenstein : Thanks for having me. Dr. Mercedes Carnethon: Well, thank you. I'm really excited to jump right into this piece, Miriam, can you tell me a little bit about the rationale for carrying out the study, why you pursued it? Professor Miriam Cortese-Krott: The reason is because when I was working as a post-doc, I had to isolate an enzyme from red blood cells, which is a very, very difficult. And if you know, this enzyme is endothelial nitric oxide synthase, which produce nitric oxide, and actually, the red blood cell is full of the worst enemy of nitric oxide, which is hemoglobin. So actually, when I was talking about my project, everybody was asking, "Why are you doing that?" And I was actually able to isolate the enzyme and look at activity and be sure that the enzyme was fine, but the function of this enzyme was absolutely unknown. Professor Miriam Cortese-Krott: And the only way to study proteins in red blood cells is to make modification in the bone marrow of the mice. So in the Erythroid cells, because you can not, of course, if there are cells without nucleus you don't have any chance to modify them in culture, something like that. So the only way was to generate mice with modification specifically in the red blood cells. And I had the chance to create, to generate red cell-specific eNOS knockout mice. And of course, as a control endothelial-specific eNOS knockout mice by using the Cre-loxP technology. And with this technology, I could really understand what's happening to the physiology of the mouse if you remove this protein from the red blood cells. And so this was the whole idea. Dr. Mercedes Carnethon: Thank you so much. It was really exciting for me to read this piece. We are on opposite ends of the scientific inquiry spread as I'm an epidemiologist who does things at the population level, and you're identifying things at the basic science level. I thought the paper was extremely well-written and that encouraged people to dig in, even if you're unfamiliar, and in part that's because you provided such a great explanation of how your findings are used and how they're relevant to the process. Do you mind sharing a little bit about your findings and how you expect that they will be used by our scientific community? Professor Miriam Cortese-Krott: I think the main finding of this paper is that if you remove eNOS from the red blood cells if the mice are hypertensive, have hypertension, and this is completely something that you actually will not expect, as I told you that indeed red cells are full of the enemy of nitric oxide that remove it immediately. So you can ask yourself how it is possible. But I think the key finding here in this paper was that I also generated the opposite model. So I created the model a conditional eNOS Knockout model where you can decide in which tissue you want to have your enzyme. And of course, I applied for red blood cells. And what you see in this model is that you start from a global knockout mouse with hypertension, you reintroduce the eNOS just in the red blood cells, you have normal tension. So this means, this is the main finding. You have a switch in the red blood cells, which is the enzyme eNOS, which it's behaving in a completely different way clearly as compared to the vessel wall eNOS and still regulating blood pressure. Dr. Mercedes Carnethon: Well, thank you so much. I think this is the point at which I like to turn to the associate editor who handled the piece. Charlie, you and I don't get to talk as often given the diversity of work that we each pursue, but Charlie, tell me a little bit about what excited you about this piece? Dr. Charles Lowenstein: Thanks, Mercedes. So I love this piece. I thought Miriam, your article is so great. So a couple of thoughts. One is nitric oxide and nitric oxide synthase are so important in biology and medicine, nitric oxide regulates blood pressure. It regulates neurotransmission. It regulates inflammation. And this is true, not only in the lab, looking at cells in mice, but also in the human. So genetic variance in the endothelial nitric oxide synthase gene or NOS3 are associated with risks for diseases like coronary artery disease. So eNOS is just so important in biology and medicine. And now some ancient history. When I was a cardiology fellow, about a hundred years ago, I worked in the lab that first purified nitric oxide synthase proteins, and we cloned two of the nitric oxide synthase genes that was in the lab of Dr. Solomon Snyder at Johns Hopkins back in the 1700s. Dr. Charles Lowenstein: So when we cloned the nitric oxide synthase genes, when we and others did, we made a huge mistake. We chose the names for these isoforms from the tissue where they were first isolated. So we called the brain nitric oxide synthase nNOS, because it's a neurons, macrophages MCnos we called it MCnos and in endothelial cells, we called it the nitric oxide synthase eNOS or endothelial NOS. But in the last 20 years, lots of investigators have found these isoforms are in other cells, not just the original cells at discovery. And so Miriam's question is just so important, which cells make endothelial NOS also called NOS3. That's the history. Now what Miriam has discovered is just so important. I was so fascinated by her work because as she just said, she made two amazing discoveries. One, red blood cells make endothelial nitric oxide synthase. Dr. Charles Lowenstein: And that's been a controversy for a long time. Some people have said, "Yes." Some, "No." And Miriam made the definitive answer. Yes, red blood cells make eNOS, and secondly, she has discovered so much about the physiology of ENO coming from red blood cells, the nitric oxide that's made inside red blood cells regulates blood pressure. What a magical, interesting, and important finding. That's a little bit about the history. Nitric oxide and NOS are important in medicine. The people who originally cloned and purified the nitric oxide synthase isoforms named them after the tissue in which they discovered. And Miriam has made a major discovery that it's not only endothelial cells that make nitric oxide but also red blood cells. Dr. Mercedes Carnethon: Thank you so much for that summary. And I guess, I would have thought perhaps this was something of an Elixir of youth because if you've been working in this area for 200 plus years and Miriam, you started working on this as part of your dissertation work, you both have a lot of insight and background on where we've been and what the advances are. Miriam, can you tell me a little bit about how you'd like to see these findings used by the scientific community? Professor Miriam Cortese-Krott: I think I would like that the scientific community would use my mice first because I think, as Charles has said, it's not only red cells that express eNOS and it's not only endothelial cells. There are other cells producing eNOS and the function in the other cells is not known even in leukocytes, even when they have iNOS of course, but also have eNOS. So you can use my mice since it's a flux model. You can choose whatever you want, what cell you want, and then knock it in and knock it out. So this is one thing that I think the community could really do. I cannot do everything. So I'm happy to give my mice away. Professor Miriam Cortese-Krott: And the second thing is I would like too that in particular, the clinical community would see this link between Emathology and cardiovascular disease. This is something that was started, of course, there are studies looking at anemia and cardiovascular disease, but these studies have sometimes some issues I of course cannot speak as a basic scientist. I cannot speak about huge clinical trials, but I think this link exists and exists at the molecular level and it can be a target for pharmacological therapy. So I think this is what I would like to transport with this study to the clinical community and the basic science community. Dr. Mercedes Carnethon: Yeah. I think this is the point at which Charlie, I turn it to you because you really stand at the intersection of both of those communities. What questions do you have for Miriam going forward, as you think about spreading the word on this important work? Dr. Charles Lowenstein: So Miriam's discovery is just so important and she now has the tools to help answer really, really important questions. How is nitric oxide made in red blood cells? How is it stored in red blood cells? How is it transported throughout the body in red blood cells? What is the chemistry of nitric oxide, when it is stored, when it combines with oxygen when it forms nitrite and nitrate, how is it released from red blood cells? How is it targeted from a red blood cell to the vasculature? So there're these great basic science questions that Miriam and her colleagues are now poised to answer. So there's the science part of it. Then there's the medicine part of it because Miriam's mice and her great discovery have really huge implications for medicine. And so the question is, how can we use ENO? How can we deliver it? How can we target ENO to human tissues? Dr. Charles Lowenstein: How can we turn on erythrocyte, nitric oxide synthase? How can we turn it off? Because there are all these medical diseases where too much nitric oxide is bad, like in sepsis or inadequate amounts, don't protect the vasculature like atherosclerosis. Then there are all these other interesting questions. When we transfuse red blood cells, sometimes if you transfuse aged red blood cells, it's not good. You can harm people. Maybe we can load up or activate eNOS in stored red blood cells and then help deliver more ENO to patients who need red blood cells. So there are all these fascinating medical questions that we can look at based on Miriam's really important discovery. Dr. Mercedes Carnethon: Well, thank you so much. We're coming to the end of this wonderful and informative podcast. And I guess, I'd just ask Miriam, do you have anything else you'd like our listeners to know about your work and about the findings from this study? Professor Miriam Cortese-Krott: I would like people know that hard work help a lot, and that you have to believe in what you are doing and the quality of your science at the end would bring their true discoveries. So I think it's important specifically, for the young women in science that having this message too. So the science per se must be excellent and to proceed, you need a lot of work, but then the work goes to a good end. Dr. Mercedes Carnethon: Miriam, thank you so much for that inspirational note. The hard work that scientists need, the persistence across one's career and building from earlier discoveries, and bringing those forward through one's career are always critically important. And so I hope everyone has really enjoyed this episode and this opportunity to hear from Dr. Cortese-Krott. Miriam, you've done such wonderful work, and thank you as well, Charlie, for your insights about the intersection of this work with clinical care and basic science. Professor Miriam Cortese-Krott: Thank you. Dr. Charles Lowenstein: Thank you. Dr. Mercedes Carnethon: Thank you all very much for joining us today in this episode of Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

Vol 214, Issue 7: 12 April 2021. Dr Elly Redwood is a Basic Physician Trainee at Prince of Wales Hospital and Community Health Services. Professor David Brieger is an interventional cardiologist and Professor of Cardiology at Concord Repatriation General Hospital. They talk about the importance of ambulance transport to hospital in the event of ST-elevated myocardial infarction. With MJA news and online editor, Cate Swannell.

Interview with Ateev Mehrotra, MD, author of Reperfusion Treatment and Stroke Outcomes in Hospitals With Telestroke Capacity

Interview with Ateev Mehrotra, MD, author of Reperfusion Treatment and Stroke Outcomes in Hospitals With Telestroke Capacity

This Beat episode, featuring Joel Dunning, MD, focuses on survivors' longitudinal functional status of ECMO after COVID-19, a trial on advanced reperfusion strategies, an analysis on the decrease in all adult surgeries, and results of robotically-assisted congenital cardiac surgery. For more information on this episode's topics, links are provided:What Does Survival Look Like After ECMO for COVID-19? Small registry highlights need to analyze survivors' longitudinal functional statushttps://www.medpagetoday.com/meetingcoverage/sts/90972Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trialhttps://www.thelancet.com/article/S0140-6736(20)32338-2/fulltextAn analysis of national data revealed a 53% decrease in all adult heart surgeries, including a 40% decline in non-elective heart surgeries and a 65% drop in elective heart surgeries during the pandemic, compared to 2019.https://consumer.healthday.com/b-2-2-pandemic-has-cut-heart-surgeries-in-half-and-more-patients-are-dying-2650177681.html   https://www.ctsnet.org/article/totally-endoscopic-transaortic-septal-myectomy-hypertrophic-cardiomyopathyEarly Results of Robotically Assisted Congenital Cardiac Surgery: Analysis of 242 Patients : JANS postinghttps://www.ctsnet.org/jans/early-results-robotically-assisted-congenital-cardiac-surgery-analysis-242-patients

Commentary by Dr. Valentin Fuster

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.31.275438v1?rss=1 Authors: Milliken, A. S., Kulkarni, C., Brookes, P. S. Abstract: Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane {Delta}pH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]). We show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by {Delta}pH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed. Copy rights belong to original authors. Visit the link for more info

Today’s episode discusses issues pertaining to the management of ST-elevation myocardial infarction in low and middle-income countries. Dr Carolyn Lam and Dr Greg Hundley also discuss the following: Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation by Sadek et al. Autoantibody Signature in Cardiac Arrest by Li et al. Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults by Kim et al. TRANSCRIPT Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article this week is a little bit different from what we've done in the past with original manuscripts, we're going to focus on issues pertaining to the management of ST-elevation myocardial infarction in low- and middle-income countries. Oh my Carolyn, there's so many different things to consider. There are knowledge gaps, how we manage patients, how we get from one center to another, even just defining those centers. And this could be a very nice blueprint for future governments to use in managing these patients. But before we get to that feature, how about we have a little bit of a chat on some of the other articles in the issue? Dr Carolyn Lam: You bet, Greg. Now, have you ever wondered why do some but not all patients with severe aortic stenosis develop otherwise unexplained reduced systolic function? Dr Greg Hundley: Yes, I have Carolyn. And I wonder if it happens to do with one of our favorite magnetic resonance spectroscopy measurements, including creatine kinase. Dr Carolyn Lam: You are just too smart, Greg Hundley! Dr Greg Hundley: I had the opportunity to manage this one through the whole editorial board review. Dr Carolyn Lam: Well, Dr Ryder and colleagues from University of Oxford hypothesized that reduce creatine kinase capacity and or flux would be associated with the transition to reduce systolic function in severe aortic stenosis. So they looked at 102 participants recruited into five groups. One, those with moderate stenosis. Two, severe aortic stenosis with ejection fraction above 55%. Three, severe aortic stenosis with ejection fraction less than 55%. Four, healthy volunteers with non-hypertrophied hearts with normal systolic function. And five, patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function who are undergoing cardiac surgery and donating left ventricular biopsies. Now, all these groups underwent CMR, cardiac magnetic resonance imaging, and 31 phosphorous magnetic resonance spectroscopy from myocardial energetics. And they also had left ventricular biopsies. So Greg, I know you know what they found, and so let me lunge right into it. They found that total creatine kinase capacity was reduced in severe aortic stenosis with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting creatine kinase flux suggested that ATP delivery was reduced earlier at the moderate aortic stenosis stage, but where left ventricular functions still remain preserved. These findings thus suggest that significant energetic impairment is already established in moderate aortic stenosis and a fall in creatine kinase flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with aortic stenosis severity, this could increase susceptibility to systolic failure. As such, targeting creatine kinase capacity and our flux may be a new therapeutic strategy to prevent or treat systolic failure in aortic stenosis. Dr Greg Hundley: Very nice, Carolyn. That is a very challenging explanation. And boy, you walked us through it just perfectly. And I'm so glad you're here as an expert in heart failure and transplantation to get us through this next quiz. So Carolyn, can you name several of the primary causes of heart transplant related mortality? Dr Carolyn Lam: All right. Rejection, infection, malignancy and allograph vasculopathy, of course. Dr Greg Hundley: Thank you very much, Carolyn. What a wonderful job. So this paper comes from Dr Alexandra Loupy, and the study focused on the etiology of transplant related vasculopathy, the last one that you just named, from a population-based perspective. So 1,310 heart transplant recipients from four academic centers spread across Europe and the United States underwent prospective protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical histological and immunological parameters. The main outcome was prediction for cardiac allograph vasculopathy trajectory. Dr Carolyn Lam: Interesting. So what did they find? Dr Greg Hundley: So Carolyn, over a median follow-up post-transplant of about six and a half years, 4,710 coronary angiograms were analyzed, and four distinct profiles for allograph vasculopathy trajectories were observed. These four trajectories were characterized by one, patients without allograph vasculopathy at one year and non-progression over time. And that was about 56% of the patients. Second, patients without allograph vasculopathy at one year and late onset slow allograph vasculopathy progression. And that was about seven and a half percent of patients. Third, patients with mild allograph vasculopathy at one year and mild progression over time. And that was about 23% of patients. And finally, a fourth category, patients with mild allograph vasculopathy at one year and accelerated progression. And that was about 13% of patients. Dr Carolyn Lam: Huh? So what most predictive? Dr Greg Hundley: Well Carolyn, six early independent predictors of these trajectories were identified. One, donor age. Second, donor male gender. Third, if the donor used tobacco. Fourth, recipient dyslipidemia. Fifth, class two anti-HLA donor-specific antibodies. And finally, acute cellular rejection greater than 2R. The four allograft trajectories manifested consistently in the US independent cohort with similar discrimination, and in different clinical scenarios, and showed gradients for all caused mortality. Dr Carolyn Lam: Wow. Okay. So what's the take home message, Greg? Dr Greg Hundley: Well, because this study identified these four trajectories and their respective independent predictive variables, they provide the basis for a trajectory-base assessment of heart transplant patients for early risk stratification. And therefore, we might be able to develop monitoring strategies and form clinical trials around those to determine the efficacy of perhaps these predictive models. Dr Carolyn Lam: Thanks. Okay. Well, this next paper focuses on Tet-methylcytosine dioxygenase 2, or TET2. Dr Greg Hundley: Carolyn, what is that? Dr Carolyn Lam: Well, I'm glad you asked me before I asked you. So TET2 is a key enzyme in DNA demethylation. And the gene TET2 encodes an epigenetic regulator that demethylates cytosine. Somatic mutations of TET2 occur in cardiovascular disease and are associated with clonal hematopoiesis inflammation and at first vascular remodeling. The current paper by Dr Archer from Queens University Kingston in Ontario, Canada, and colleagues, is novel because it's the first to examine the role of TET2 in pulmonary arterial hypertension. And they did this by evaluating exome sequencing data from the largest PAH cohort assembled to date, including 2,572 patients in the PAH Biobank. Unlike prior genetic studies, the biobank includes patients with associated PAH. Now, this is important. This is the category that includes patients with connective tissue disease such as scleroderma. This biobank also included non-European ancestry. So these are the novel aspects. The authors performed gene-specific rare variant association analyses using up to 1,832 cases of European origin from the PAH Biobank, and transcriptomic analysis in an independent cohort to assess TET2 expression. Dr Greg Hundley: Carolyn, so what did they find regarding to TET2? Dr Carolyn Lam: In the entire cohort, they identified 12 predicted deleterious variants of TET2 novel to PAH. 75% predicted germline and 25% predicted somatic variants. None of the variant carriers were responsive to acute vasodilator challenge. Now, this is the first time that putative germline TET2 mutations have been associated with a human disease. They also identify ubiquitous downregulation of the expression of TET2 in the peripheral blood mononuclear cells of idiopathic PAH and associated PAH patients. Finally, they evaluated TET2 depleted mice and demonstrated that they spontaneously developed inflammation, pulmonary vascular obliteration and pulmonary hypertension, thus providing biological plausibility that disorders in this pathway can indeed cause PAH. This is discussed in an editorial by Dr Soubrier from INSERM, entitled, TET2: A Bridge Between DNA Methylation and Vascular Inflammation. Dr Greg Hundley: Oh wow, Carolyn. Well, let me tell you about a couple other articles in our issue. First, Dr Amr Abbas has a letter to the editor regarding actuarial versus echocardiographic outcomes following TAVR, evaluating gradients, leaks, areas and mortality with responses by Flavin Vincent and from Laurent Fauchier. We have Dr Miguel A. Arias again presenting another EKG challenge for us. Next, professor Giovanni Esposito has a research letter involving PCI rates for ACS during this COVID-19 pandemic. Next, Dan Roden from Vanderbilt has a consensus report related to QTC prolongation during the coronavirus pandemic. And finally, professor Marco Roffi has an on my mind piece related to STEMI and COVID-19 pandemics. Dr Carolyn Lam: Oh, there is a series of on my mind papers in this week's issue. “The Future of Cardiovascular Prevention: Unprecedented Times,” by Laurence Sperling. “Primary and Secondary Prevention Of Cardiovascular Disease in the Era of Coronavirus Pandemic,” by Erin Michos. “Reperfusion of STEMI in the COVID-19 Era: Is it Business as Usual?” by Dharam Kumbhani. And finally, we also have a research letter by Dr Lili Jong, addressing immune checkpoint inhibitors which are increasingly applied to a broader range of cancers and their potential toxicity causing myocarditis. And this letter describes the association of timing and dose of cortical steroids in immune checkpoint inhibitor associated myocarditis and cardiac outcomes. Dr Greg Hundley: How about we discuss how we might want to manage ST-elevation myocardial infarctions in low- and middle-income countries? Dr Carolyn Lam: You bet. Let's go, Greg. Dr Greg Hundley: Well listeners, now we get to turn to our feature article. And we're very privileged today to have Dr Chandrashekhar from The University of Minnesota. And he and a large group of authors have put together a paper discussing the resources and infrastructure really necessary to manage ST-elevation myocardial infarction in low- and middle-income countries. Welcome Chandra. So we're going to call him Chandra for short as he is known internationally. Chandra, can you tell us a little bit about this prevalence of STEMI in low- and middle-income countries, and then also about the constitution of your writing group and what you were trying to do to address this issue? Dr Chandrashekhar: The issue we are trying to address is, as you know, the low- and middle-income countries, there are about 80 plus countries constituting this group, and they account for something like 5.8 billion people around the world. And it's so interesting that 80% of the MIs that happen on the face of this earth are probably happening there, in areas which don't have resources to effectively deal with this condition, unlike the US or European countries and developed countries. So this group got together to create some outlines of how to optimize care in low- and middle-income countries. And we got together groups which have extensive experience in dealing with this problem. It was a coalition of frontline clinicians as well as major organizations, including the Indian Council of Medical Research, the premier research body in India, a public health foundation of India which is a nongovernmental organization extensively involved in this, The Population Health Research Institute in Canada, the Latin America Telemedicine Infarct Network called LATIN, The Pan African Society of Cardiology and The South African Society of Cardiac Interventions, and an NGO in India called STEMI India. So we took experienced people from a number of different countries and created this group. Dr Greg Hundley: Very good. Now, were there knowledge gaps or implementation gaps, maybe help distinguish those two terms for us, that you had to address when just starting your effort? Dr Chandrashekhar: Yeah, absolutely. So let's start with the knowledge gap. As you know, there are excellent guidelines both in the United States, as well as Europe. Of course, there are STEMI guidelines in the UK and Australia and New Zealand, but these guidelines are not very applicable to low and middle income countries due to a number of reasons, due to porosity of resources, due to poverty, overcrowding, lack of infrastructure, and a bunch of other reasons that you can imagine. So if we recommend somebody needs total balloon time under certain threshold, it's nearly impossible to meet this in most places in the low- and middle-income countries. And so there is a significant amount of implementation gap as well as knowledge gap, because the guidelines that are tailored to Western societies don't fit very easily in low- and middle-income countries. It's like fitting a round peg in a square hole. So that's why we thought we should create something very focused, right? And there are implementation gaps in the sense infrastructure-based as well as resource-based. And knowledge gaps, for example, we don't know what the dose of dual antiplatelet therapy is optimal in these patients, for example, ticagrelor may have a higher effect in some Asian populations with small body habitus. Similarly, as you know, statin doses, especially in the far east are much lower than what are prescribed here. So these are the kinds of challenges that we are applying and try to suggest some solutions. Dr Greg Hundley: It sounds like definitions could differ, management strategies could differ, pharmacologic versus invasive, even centers that would manage the patients. Can you describe some of those issues for us? Dr Chandrashekhar: Right. So that was the biggest challenge we had. So we had to create some resource infrastructure appropriate management paradigms for low- and middle-income countries. To give you an example, primary PCI, which is something we take for granted within our milieu, if you think about it, you and I probably didn't give thrombolytic therapy in the last 15 years. So this is a day-to-day thing in low- and middle-income countries. Most of the patients either they come so late that they don't get any reperfusion therapy for STEMI, or if they do, thrombolytic therapy is are very common mode of treatment there. And so we had to create a way for them to get the optimized care. And so we divided the localities into different levels, from level one to level five. Level one being the most remote area and five being the one which is most equipped and can implement all the Western standards and guidelines. And so we suggest a system of hub and spoke to transfer people from the smaller centers to the big centers, and outline what therapies need to be done at what stage. And one of the things that we emphasize so much is called pharmaco-invasive therapy, where you give thrombolytic therapy if you cannot reach a PCI center in time, and then in the next three to 24 hours, you transport the patient to a center where they can do PCI. And this has been studied in a number of trials showing that it's a very effective strategy. And so these are the kinds of solutions that we try to emphasize. Dr Greg Hundley: And how about the patients themselves and the doctors that would implement, in terms of education, does your document cover how to reach out to both patients and physicians in these countries to emphasize these new protocols that you and your group have developed? Dr Chandrashekhar: Absolutely. That's the crucial issue, right? No matter how many guidelines we create, if we can't implement it, they're useless, right? And so we have two parts to this guideline. There's a section devoted to governmental agencies as well as NGOs interested in improving care, STEMI care in low and middle income countries, as well as a section for frontline clinicians, which includes very focused flashcards with definitions and what exactly each level of this center in the hub and spoke model should be doing and how do they transport patients and how do they ensure that adequate pharmacotherapy is instituted? And so we keep repeating this and we also provide some other options of how to communicate with the hub facilities, from the spoke facilities, including use of mobile and social media apps like WhatsApp. Dr Greg Hundley: Do you have certain recommendations that physicians in the field and patients at home should be aware of, for example, administration of aspirin and things like that? Dr Chandrashekhar: Absolutely. These are all codified in flashcards, which are going to be printed for distribution to the frontline physicians. And they are also created as wall posters and plastered in this peripheral health centers where essentially the only thing they may have is an old EKG machine and a few drugs like aspirin. And so we have tried to cater to each of this, both in the informational material and what basic pharmacotherapies and equipment these centers should be having. And that's where the governmental part comes. So when governments have to decide how they invest their scarce dollars, they can divide it appropriately based on these recommendations. Dr Greg Hundley: I like that last statement, it sounds like in addition to physicians and patients that your document may even be useful for governments and organizations delivering the care in these countries, do you want to talk a little bit about where you think this document may go next in that regard? Dr Chandrashekhar: The best use of this document would be for agencies in different parts of the countries to take this up. And at the last count, there are at least five or six governments which are actively looking at the blueprint that is provided from this document, and to see what parts of this are locally implementable within their environment. And eventually, if it appears that it's applicable to multiple jurisdictions, then perhaps something like WHO could take this and modify it suitably for different localities. We see a lot of potential in this. Dr Greg Hundley: Well, we are very privileged to have the opportunity to publish this important work. And I wonder here, just in closing, on behalf of your entire author group, are there any words you'd like to leave us with regarding this just monumental effort? Dr Chandrashekhar: The thing that we can say is we should thank Circulation and its editorial board for working with us. It went through, I think, three revisions and it really made the document much better. And we really thank all of you for allowing us this platform. As you know, this is going to reach a huge part of the medical establishment as an open access article. And hopefully it will help us implement some progressive changes in healthcare in the low- and middle-income countries. And so we really thank Circulation for providing us this platform. Dr Greg Hundley: Well, listeners, we're going to wrap up here and we're most appreciative to Chandra from The University of Minnesota and his entire author group. On behalf of Carolyn and myself, we wish you a great week and look forward to chatting with you next week. This program is copyright to The American Heart Association, 2020.  

The thrombolysis in cerebral infarction scale otherwise known as the (TICI) scale is an important outcome measure to evaluate the quality of endovascular stroke therapy. The TICI scale is ordinal and observer dependent, so this means it may not result in the best prediction of patient outcome and can also provide an inconsistent reperfusion grading.  Carmen Lahiff Jenkins Managing Editor of the International Journal of Stroke spoke to Drs Haryadi Prasetya and Manon Kappelhof from Amsterdamn University Medical Centre two of the author group who submitted the article qTICI: Quantitative assessment of brain tissue reperfusion on digital subtraction angiograms of acute ischemic stroke patients. In this podcast we look at the authors investigations into  qTICI and eTICI using image processing techniques based on the TICI methodology to develop better quality reperfusion grading.  The International Journal of Stroke is the flagship publish of the World Stroke Organisation  qTICI: Quantitative assessment of brain tissue reperfusion on digital subtraction angiograms of acute ischemic stroke patients 

Commentary by Dr. Valentin Fuster

Credits: 0.25 AMA PRA Category 1 Credits™ Claim CME/CE credit: https://www.pri-med.com/online-education/podcast/frankly-speaking-cme-142 Overview: There has been increasing interest in the use of endovascular reperfusion for patients who have suffered an ischemic stroke. The American Heart Association (AHA) and the American Stroke Association (ASA) have jointly developed a nationwide registry to evaluate the benefits of these techniques on stroke outcomes. During this episode we will review a recent retrospective cohort study of almost 7,000 patients presenting with an acute ischemic stroke that demonstrates a significant benefit to endovascular reperfusion, even several hours after the onset of symptoms. Guest: Robert A. Baldor, MD, FAAFP Music Credit: Richard Onorato

Credits: 0.25 AMA PRA Category 1 Credits™ Claim CME/CE credit: https://www.pri-med.com/online-education/podcast/frankly-speaking-cme-142 Overview: There has been increasing interest in the use of endovascular reperfusion for patients who have suffered an ischemic stroke. The American Heart Association (AHA) and the American Stroke Association (ASA) have jointly developed a nationwide registry to evaluate the benefits of these techniques on stroke outcomes. During this episode we will review a recent retrospective cohort study of almost 7,000 patients presenting with an acute ischemic stroke that demonstrates a significant benefit to endovascular reperfusion, even several hours after the onset of symptoms. Guest: Robert A. Baldor, MD, FAAFP Music Credit: Richard Onorato

July 16, 2019 edition of the weekly JAMA Editors' Summary

The coronary reperfusion package is arguably the most influential clinical intervention on patient outcomes.  Today we look at this package, and how we go about delivering it well.   It comes down to three principles of excellence.  Accuracy, Efficiency, Safety.

Dr. Graham Wong discussed the 2019 ST-Elevation Myocardial Infraction Focused Update on Regionalization and Reperfusion in this February 2019 CJC podcast. CJC article: https://www.onlinecjc.ca/article/S0828-282X(18)31225-X/fulltext Guest Twitter handle: https://twitter.com/Realgrahamcwong

Welcome to HBOT in Wound Care Episode 5: Reperfusion Injury Click Here to Download Audio  

Liver transpl: Reperfusion effect effect; Liver transpl: Electrolyte disturbances; Liver transpl: Hypocalcemia etiology; Hypocalcemia: ECG effects 

Out-of-hospital cardiac arrest (OHCA) is common and carries a high mortality rate. In Victoria, Australia approximately 50% of patients with an initial cardiac rhythm of VF achieve a return of spontaneous circulation (ROSC) and 30% overall survive to hospital discharge. Currently, OHCA patients who have achieved ROSC but who remain unconscious routinely receive 100% oxygen for several hours in the ambulance, ED, cardiac catheterisation laboratory until admission to ICU. However, there is now evidence from laboratory studies and preliminary observational clinical studies that the administration of 100% oxygen during the first few hours following resuscitation may increase both cardiac and neurological injury. Clinical trials are underway to test whether titrated oxygen to a target oxygen saturation of 90-94% in the immediate hours after ROSC results in improved outcomes compared with 100% oxygen.

Is Suspended Animation only in the realms of science fiction, or is this a realsitic treatment option? Mervyn Singer questions if we can prevent secondary reperfusion injury following cerbral ischaemia.

Die Herztransplantation stellt, trotz der großen Fortschritte in der Therapie terminaler Herzerkrankungen, häufig noch immer die letzte Therapieoption dieser Erkrankungen dar. Aufgrund des enormen Spendermangels sind geeignete Organe allerdings sehr knapp. Die xenogene Herztransplantation, im Speziellen die Transplantation von Schweineherzen an den Menschen, könnte dieses Problem lösen. Allerdings ist die Xenotransplantation noch weit von der klinischen Implementierung entfernt. Das Hauptproblem dabei stellt die Beherrschung der xenogenen Abstoßungsreaktion dar. Zwar kann die hyperakute Abstoßungsreaktion durch gentechnisch veränderte Spenderschweine inzwischen relativ gut beherrscht werden, bei der akut vaskulären (humoralen) Abstoßung hingegen ist dies noch nicht der Fall. Die pathophysiologischen Vorgänge während der xenogenen Abstoßungsreaktion sind noch nicht vollständig verstanden. Vorliegende Daten deuten aber auf eine ausgeprägte Koagulopathie mit einer Störung der Mikrozirkulation und Thrombosen im Rahmen der hyperakuten und akut humoralen Abstoßungsreaktion hin. Es ist unabdingbar notwendig die Mechanismen der xenogenen Abstoßungsreaktion genau zu kennen, damit man gezielt eingreifen kann. Um die zugrundeliegenden Mechanismen dieser Abstoßungsreaktion besser zu verstehen, war das Ziel dieser Arbeit ein neues Kleintiermodell zu etablieren, anhand dessen die Mikrozirkulation in vivo mittels Intravitalmikroskopie direkt am schlagenden Herzen sowohl quantitativ als auch qualitativ untersucht werden kann. Um dies zu erreichen wurden Herzen von Syrischen Goldhamstern heterotop an die Halsgefäße von Lewis-Ratten transplantiert. In drei Versuchsgruppen wurde nun die xenogene Abstoßungsreaktion untersucht. In Gruppe 1 wurde mittels Intravitalmikroskopie die subepikardiale Mikrozirkulation nach Reperfusion über dem rechten Ventrikel des Hamsterherzens untersucht. Die Ratten in Versuchsgruppe 2 wurden sieben Tage vor der xenogenen Herztransplantation mit Hamsterblut sensibilisiert, um die Bildung von xenoreaktiven Antikörpern zu induzieren und so eine hyperakute Abstoßung zu provozieren. Bei den Tieren aus Versuchsgruppe 3 wurde ohne vorherige Sensibilisierung nach der Transplantation das Operationsgebiet wieder verschlossen, um die Dynamik und Kinetik bis zur vollständigen Transplantatabstoßung zu untersuchen. In allen Versuchsgruppen wurden außerdem histologischen Analysen sowie Analysen des Blutbildes, Gerinnungsstatus und der Myokardmarker durchgeführt. Die in dieser Arbeit vorliegenden Daten zeigen, dass die Herzen der ersten und dritten Versuchsgruppe akut vaskulär (humoral) abgestoßen werden, bei einer durchschnittlichen Zeit bis zur vollständigen Abstoßung von 3,2 ± 0,2 Tagen. Die Hamsterherzen aus der zweiten Versuchsgruppe wurden hingegen nach vorheriger Sensibilisierung hyperakut in 14,8 ± 2,8 Sekunden vollständig abgestoßen. Die Analyse der Mikrozirkulation mittels Intraviralmikroskopie zeigte einen Anstieg des Blutflusses in den Spenderherzen, welcher als reaktive Hyperämie nach Reperfusion zu deuten ist. Des Weiteren ist eine sehr hohe endotheliale Leakage auffällig, die für eine bereits sehr frühe Endothelaktivierung im Rahmen der akut humoralen Abstoßung spricht. Bezüglich der Zell-Endothel-Interaktion könnte weder bei den Leukozyten noch bei den Thrombozyten eine signifikante Veränderung zwischen 30 und 90 Minuten nach Reperfusion gefunden werden. Gleichwohl wurden aber ein Anstieg der Interaktion der Leukozyten mit dem Gefäßendothel sowie einen Abfall der Thrombozyten-Endothel-Interaktion gefunden, welche ebenfalls für eine Endothelzellaktivierung im Rahmen der ablaufenden akuten Abstoßungsreaktion sprechen. Auch die Blutwerte bestätigten die Annahmen über die ablaufende Abstoßungsreaktion. So waren in allen Gruppen die sog. Myokardmarker deutliche erhöht, was für einen myokardialen Schaden sowohl durch das operative Trauma, als auch durch die Abstoßungsreaktion spricht. Des Weiteren wurde in Versuchsgruppe 2, also der Gruppe die das Hamsterherz nach ca. 3 Tagen akut vaskulär (humoral) abgestoßen hat, ein deutlicher Anstieg des Leukozytenwertes sowie eine Verlängerung des Quick-Wertes gefunden, was unter anderem für eine starke Stimulation des Immunsystems und eine Koagulopathie im Rahmen der akut xenogenen Transplantatabstoßung spricht. Ebenso deckten sich die Histologien der drei Versuchsgruppen mit diesen Annahmen und den Ergebnissen anderer Forschungsgruppen zu diesem Thema. Die Herzen, die die akut vaskuläre (humorale) Abstoßungsreaktion unterliefen, zeigten bereits 90 Minuten nach Reperfusion (Versuchsgruppe 1) erste Anzeichen der Transplantatabstoßung, wie beginnende Nekrosen und Einblutungen. Nach vollständiger Transplantatabstoßung (Versuchsgruppe 3) waren hingegen flächenhafte Nekrosen sowie Hämorrhagien und perivaskulär Infiltrate mononuklearer Zellen vorhanden. Die hyperakut abgestoßenen Hamsterherzen (Versuchsgruppe 2) zeigten im Vergleich zu den akut abgestoßenen Herzen ein ähnliches, wenn auch weniger ausgeprägtes Bild der Transplantatzerstörung mit Nekrosen, Hämorrhagien und Infiltraten mononuklearer Zellen. Thrombotische Gefäßverschlüsse konnten sowohl bei den hyperakut als auch bei den akut vaskulär (humoral) abgestoßenen Herzen vereinzelt gefunden werden. Zusammenfassend konnte erstmals die mikrovaskulären Mechanismen und die Koagulopathie während der akut vaskulären (humoralen) Abstoßungsreaktion sowohl qualitativ als auch quantitativ ausgewertet werden. Hierbei deckten sich die Ergebnisse dieser Arbeit mit den Daten anderer Forschungsgruppen weitestgehend. Somit wurde dieses Kleintiermodell erfolgreich etabliert. Insbesondere eignet sich dieses Modell zur Erforschung verschiedenster Strategien zur Verhinderung der xenogenen Abstoßungsreaktion und deren mikrovaskulären Einflüsse.

The efficacy of hypothermia as a neuroprotectant has yet to be demonstrated in acute ischemic stroke. Researchers at Emory University School of Medicine conducted a phase I pilot study to assess the feasibility and safety of performing intravascular hypothermia after definitive intra-arterial reperfusion therapy (IAT), and in this podcast co-author Rishi Gupta tells Rob Tarr what they found.Read the full paper:Endovascular Reperfusion and Cooling in Cerebral Acute Ischemia (ReCCLAIM I) http://goo.gl/yiNQKk

Die Manifestation der Artherosklerose an den Herzkranzarterien ist die koronare Herzerkrankung (KHK), ein pathologischer Prozess dessen Auswirkungen in Industrieländern die Krankheits- und Todesursachenstatistiken anführen1. Der Myokardinfarkt mit thrombotischem Verschluss einer Koronararterie ist dabei eine der häufigsten Komplikationen. Die zeitnahe Revaskularisation ist die wichtigste therapeutische Maßnahme zur Reduzierung des postischämischen Myokardschadens, wobei auch durch die Reperfusion selbst eine Schädigung der Myozyten und des Endothels stattfindet. Mit Wiedereröffnung der verschlossenen Herzkranzgefäße setzt eine gesteigerte inflammatorische Reaktion ein, begleitet von erhöhter Leukozytenmigration in myokardiales Gewebe. Der Rezeptor der advanced glycation end products (RAGE) wurde in verschiedenen Vorarbeiten im Kontext der myokardialen Ischämie und Reperfusion beschrieben. In dieser Arbeit wurden die postischämische Interaktion von RAGE und Leukozyten und deren funktionelle Relevanz in einem Mausmodell analysiert. Tiere, die defizient für das endotheliale Adhäsionsmolekül ICAM-1 oder für RAGE sind, sowie doppeldefiziente Tiere wurden einer 20-minütigen Okklusion der LAD unterzogen. Nach einer darauf folgenden 15-minütigen Reperfusion wurde die Leukozytenrekrutierung mittels Rhodamin-G6 Infusion fluoreszenzmikroskopisch untersucht. Außerdem wurde in WT und in ICAM-1/RAGE-defizienten Tieren die linksventrikuläre Funktion nach 45 Minuten myokardialer Ischämie und 24 Stunden Reperfusion mittels invasiver intrakardialer Druckmessung untersucht. In RAGE- oder ICAM-1-defizienten Tieren kam es zu einer gleichwertigen Verminderung der Leukozytenrekrutierung (Abb. 8) im Vergleich zu Wildtyp-Tieren. In ICAM-1/RAGE-/- Tieren kam es zu einer additiven Reduktion. Ebenso zeigten RAGE/ICAM-1-/-Tiere eine verbesserte postischämische LV-Funktion im Vergleich zu WT-Kontrollen. Um zwischen endothelial und leukozytär exprimiertem RAGE zu differenzieren, wurden Knochenmark-Chimären mit WT und ICAM-1/RAGE-/- Tieren generiert. Hierzu wurden Wildtyp-Mäusen nach Bestrahlung Knochenmark von ICAM-1/RAGE-defizienzenten Tieren transplantiert, um Mäuse mit leukozytärer ICAM-1/RAGE-Defizienz zu generieren. Umgekehrt wurde ICAM-1/RAGE-defizienten Tieren Knochenmark von Wildtyp-Tieren transplantiert. Dadurch erhielten wir Mäuse mit ausschließlich auf dem Endothel fehlender ICAM-1/RAGE-Expression. In diesen Knochenmarkschimären konnten wir zeigen, dass das Fehlen des endothelialen RAGE zu einer deutlichen Reduktion der Leukozytenadhäsion führt, das Fehlen von leukozytärem RAGE hingegen kaum zu einer Änderung der Leukozytenadhäsion. Somit konnten wir zeigen, dass nicht das leukozytäre sondern endotheliales RAGE einen redundanten Effekt für die Leukozytenrekrutierung darstellt. Wir konnten nachweisen, dass diese ICAM-1/RAGE-Defizienz zu einer signifikanten Verbesserung der linksventrikulären Funktion führt. Ein möglicher Mechanismus ist die Interaktion zwischen leukozytärem Mac-1 und endothelialem RAGE. Die reduzierte inflammatorische Reaktion ist verantwortlich für die verbesserte linksventrikuläre Funktion und könnte als neuartiger therapeutischer Ansatz von Nutzen sein.

Thu, 5 Dec 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16415/ https://edoc.ub.uni-muenchen.de/16415/7/Kronas_Nils.pdf Kronas, Nils ddc:610, ddc:600, Medizinische Faku

Non-pharmacological reperfusion for acute ischemic stroke: Carlos Molina

Alistair Lindsay talks to Declan O’Regan about assessing reperfusion injury using cardiac MRI in patients with acute MI.See also;Assessment of severe reperfusion injury with T2* cardiac MRI in patients with acute myocardial infarction http://bit.ly/14MsaUf

Michael Marber (professor of Cardiology at King’s College London) discusses reperfusion injury with Michel Ovize (professor at the Hôpitaux de Lyon).See also:Postconditioning and protection from reperfusion injury: where do we stand?http://bit.ly/15EmdIyWebcasts from all the sessions at the British Cardiovascular Society Conference 2012 http://bit.ly/ZMGmUE

Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts.

Die Ischämie-Reperfusion in der Niere führt zur Aktivierung des angeborenen Immunsystems mit nachfolgender steriler Entzündungsreaktion und Gewebeschädigung der Niere, das v.a. das Tubulussystem betrifft. Es werden v.a. residente dendritische Zellen aktiviert, die die größte Immunzellpopulation in der Niere darstellen.In der weiteren Signaltransduktion sind v.a. TLR2 und TLR4 involviert, die über MyD88 proinflammatorischen Zytokinen/Chemokinen induzieren. Die proinflammatorische Wirkung wird dabei u.a. über IRF5 bewirkt, das an MyD88 andockt. Diese Funktion wird von IRF4 gehemmt, das als kompetitiver Faktor IRF5 von seiner Bindungsstelle verdrängt. Die negativ regulatorische Wirkung von IRF4 schützt die Niere vor zu starker Entzündung und dadurch vor zu starker Gewebeschädigung. Dadurch wird das Ausmaß des aktuen Nierenversagens reduziert. IRF4 wird durch Sauerstoffradikale im Rahmen der Ischämie-Reperfusion induziert. Nach der Gewebeschädigung und Induktion einer Entzündung wird IRF4 erst verzögert exprimiert, um die Entzündung wieder zu begrenzen.

Einleitung: Viele operative Eingriffe werden unter Blutsperre durchgeführt. Postoperativ kommt es gehäuft zu Komplikationen an Muskeln und Knochen, als Post-Tourniquet-Syndrom zusammengefasst. In ihrer Pathogenese spielen wahrscheinlich hämodynamische Veränderungen während der Reperfusion eine bedeutende Rolle. Ziel der vorliegenden Studie war es, die Dynamik der Reperfusion der langen Röhrenknochen und Muskeln nach Ischämie zu klären. Die Blutflussmessung wurde mittels fluoreszierender Mikrosphären durchgeführt. Methodik: 13 Kaninchen wurde eine Blutsperre angelegt und für 60 bzw. 120 Minuten belassen. Die Tiere erhielten in Narkose linksventrikuläre Injektionen von fluoreszierenden Mikrosphären 1, 5, 15, 30, 60 und 90 Minuten nach Lösen der Blutsperre. Beide Femora, Tibiae und Tali sowie Mm. gastrocnemicae und tibialis anteriores wurden nach einem festgelegten Dissektionsschema in Proben aufgeteilt und die Fluoreszenz automatisiert gemessen. Hiermit konnte der Blutfluss errechnet werden. Ergebnisse: Im Knochen und in der Muskulatur trat nach Entfernen der Blutsperre eine sofortige Hyperämie auf. Nach 120 Minuten Ischämiezeit war die Mehrdurchblutung höher und hielt länger an als nach 60 Minuten Ischämiezeit. Im Knochen war der maximale Blutfluss auf das 1,4 fache, im Muskel sogar auf das 6 fache erhöht. Nach einer Stunde Ischämiezeit war der Blutfluss 15 Minuten erhöht und nach 2 Stunden 90 Minuten. Regionale Unterschiede in der Knochendurchblutung nach Ischämie fanden sich nicht. Schlussfolgerung: Diese Ergebnisse belegen die Abhängigkeit der Knochen- und Muskeldurchblutung während der Reperfusion von der Ischämiezeit. Es ergeben sich Unterschiede in der Dynamik und im Ausmaß der Durchblutungsänderung. Dieser Zusammenhang kann zur Klärung der Pathogenese postoperativer Komplikationen nach Blutsperre beitragen.