POPULARITY
2 episodes with prostacyclin
2 episodes with prostacyclin
3 episodes with prostacyclin
2 episodes with prostacyclin
2 episodes with prostacyclin
In this episode, we dive into the early therapies and how our understanding of vascular physiology drastically changed the management of pulmonary hypertension. Intro 0:12 In this episode 0:18 Recap of part 1 & 2 0:31 What part 3 is about 2:31 WHO conference in 1975: Treating pulmonary hypertension 3:48 The Discovery of Non-Steroidal Anti-inflammatory Drugs (NSAIDs), Part 1 5:20 Epoprostenol 6:18 Prostacyclin 10:37 Endothelin antagonists 11:41 Phosphodiesterase type 5 (PDE5) inhibitors 14:08 Interaction of nerves and blood vessels 15:06 The Soups VS the Sparks 17:36 A dreamed experiment 19:06 Acetylcholine 23:23 Enter “the calabar bean” 24:45 Acetylcholine and vasodilation: 1976 26:01 Rabbit aorta 27:45 Nitric oxide 29:38 Why are we using nitric oxide to treat pulmonary hypertension? 31:31 Tachyphylaxis 33:48 TNT factories 35:09 Nitrous oxide and tachyphylaxis 36:52 Pfizer in the 1980s 38:06 Understanding the trigger of pulmonary hypertension 40:53 PDE5 and nitric oxide and pulmonary hypertension 43:07 The end of the ripping yarns 44:20 Coming up in part 4 46:17 Thanks for listening 47:29 We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum. References: Bernard C. C R Soc Biol. 1851;3:163-164. Furchgott RF, et al. Nature. 1980;doi:10.1038/288373a0. Galiè N, et al. N Engl J Med. 2005;doi:10.1056/NEJMoa050010. Ghofrani HA, et al. Nat Rev Drug Discov. 2006;doi:10.1038/nrd2030. Giordano D, et al. Biochim Biophys Acta. 2001;doi:10.1016/s0167-4889(01)00086-6. Guthrie F. Q J Chem Soc. 1859;doi:10.1039/QJ8591100245. Higenbottam T, et al. Lancet. 1984;doi:10.1016/s0140-6736(84)91452-1. Marsh N, et al. Clin Exp Pharmacol Physiol. 2000;doi:10.1046/j.1440-1681.2000.03240.x. Montastruc JL, et al. Clin Auton Res. 1996;doi:10.1007/BF02281906. Nejad SH, et al. Future Cardiol. 2024;doi:10.1080/14796678.2024.2367390. Tansey EM. C R Biol. 2006;doi:10.10116/j.crvi.2006.03.012. Warren JV. Trans Am Clin Climatol Assoc. 1988;99:10-6. Disclosures: Brown reports no relevant financial disclosures.
In this week's episode we'll see how targeting the prostacyclin receptor is a promising strategy for regulating hemostasis and thrombosis. Then, we'll learn how new evidence indicates that the progression rate is low in MRD-negative myeloma patients who discontinue post-transplant lenalidomide and dexamethasone maintenance therapy after 2 years. Finally we'll discuss how amphiregulin from leptin receptor-positive niche cells in the bone marrow mediates crosstalk between the niche and hematopoietic stem cells under conditions of DNA repair deficiency and aging.
JAMA Pediatrics Editors' Summary by Dimitri A. Christakis, MD, MPH, Editor in Chief, and Alison A. Galbraith, MD, MPH, Associate Editor, for the June 6, 2023, issue. Related Content: Cost-effectiveness and Return on Investment of a Nationwide Case-Finding Program for Familial Hypercholesterolemia in Children in the Netherlands Association Between Early Prostacyclin Therapy and Extracorporeal Life Support Use in Patients With Congenital Diaphragmatic Hernia
Pär Johansson from Copenhagen joins Rob Mac Sweeney to discuss the fascinating phase II COMBAT-COVID trial, investigating prostacyclin in intubated patients with COVID-19 and severe endotheliopathy. The trial was published in the American Journal of Respiratory and Critical Care Medicine in November 2021.
A panel of experts discuss prostacyclin therapies for the treatment of PAH and how to effectively implement them in clinical practice. Credit available for this activity expires: [03/26/22] Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/948191?src=mkm_podcast_addon_948191
Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension with Oral Prostacyclin Pathway Agents Vallerie V McLaughlin, MD, FACC, FCCP; Richard Channick, MD; Teresa De Marco, MD, FACC, FHFSA; Harrison W Farber, MD, FCCP; Sean Gaine, MD, PhD; Nazzareno Galié, MD; Richard A Krasuski, MD; Ioana Preston, MD; Rogerio Souza, MD, PhD; J Gerry Coghlan, MD; Robert P. Frantz, MD; Anna Hemnes, MD; Nick H Kim, MD; Irene M Lang, MD; David Langleben, MD; Mengtao Li, MD; Olivier Sitbon MD, PhD; Victor Tapson, MD; Adaani Frost, MD Funding was provided by Actelion to support the use of independent providers of Delphi methodology expertise and nominal group technique, survey creation, data analysis, medical communication, and meeting management. The authors were not paid an honorarium for their participation. Actelion played no role in the literature search and analysis, development of surveys used to gather consensus, or data analysis; and no Actelion employee was present at the meeting during which consensus statements were finalized. The manuscript was drafted, critically reviewed, and edited solely by the authors with support from an independent professional medical communications agency. Actelion Pharmaceuticals reviewed the final manuscript only to ensure accuracy of UPTRAVI® (selexipag) background ...
Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension with Oral Prostacyclin Pathway Agents Vallerie V McLaughlin, MD, FACC, FCCP; Richard Channick, MD; Teresa De Marco, MD, FACC, FHFSA; Harrison W Farber, MD, FCCP; Sean Gaine, MD, PhD; Nazzareno Galié, MD; Richard A Krasuski, MD; Ioana Preston, MD; Rogerio Souza, MD, PhD; J Gerry Coghlan, MD; Robert P. Frantz, MD; Anna Hemnes, MD; Nick H Kim, MD; Irene M Lang, MD; David Langleben, MD; Mengtao Li, MD; Olivier Sitbon MD, PhD; Victor Tapson, MD; Adaani Frost, MD Funding was provided by Actelion to support the use of independent providers of Delphi methodology expertise and nominal group technique, survey creation, data analysis, medical communication, and meeting management. The authors were not paid an honorarium for their participation. Actelion played no role in the literature search and analysis, development of surveys used to gather consensus, or data analysis; and no Actelion employee was present at the meeting during which consensus statements were finalized. The manuscript was drafted, critically reviewed, and edited solely by the authors with support from an independent professional medical communications agency. Actelion Pharmaceuticals reviewed the final manuscript only to ensure accuracy of UPTRAVI® (selexipag) background ...
Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension with Oral Prostacyclin Pathway Agents Vallerie V McLaughlin, MD, FACC, FCCP; Richard Channick, MD; Teresa De Marco, MD, FACC, FHFSA; Harrison W Farber, MD, FCCP; Sean Gaine, MD, PhD; Nazzareno Galié, MD; Richard A Krasuski, MD; Ioana Preston, MD; Rogerio Souza, MD, PhD; J Gerry Coghlan, MD; Robert P. Frantz, MD; Anna Hemnes, MD; Nick H Kim, MD; Irene M Lang, MD; David Langleben, MD; Mengtao Li, MD; Olivier Sitbon MD, PhD; Victor Tapson, MD; Adaani Frost, MD Funding was provided by Actelion to support the use of independent providers of Delphi methodology expertise and nominal group technique, survey creation, data analysis, medical communication, and meeting management. The authors were not paid an honorarium for their participation. Actelion played no role in the literature search and analysis, development of surveys used to gather consensus, or data analysis; and no Actelion employee was present at the meeting during which consensus statements were finalized. The manuscript was drafted, critically reviewed, and edited solely by the authors with support from an independent professional medical communications agency. Actelion Pharmaceuticals reviewed the final manuscript only to ensure accuracy of UPTRAVI® (selexipag) background ...
Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension with Oral Prostacyclin Pathway Agents Vallerie V McLaughlin, MD, FACC, FCCP; Richard Channick, MD; Teresa De Marco, MD, FACC, FHFSA; Harrison W Farber, MD, FCCP; Sean Gaine, MD, PhD; Nazzareno Galié, MD; Richard A Krasuski, MD; Ioana Preston, MD; Rogerio Souza, MD, PhD; J Gerry Coghlan, MD; Robert P. Frantz, MD; Anna Hemnes, MD; Nick H Kim, MD; Irene M Lang, MD; David Langleben, MD; Mengtao Li, MD; Olivier Sitbon MD, PhD; Victor Tapson, MD; Adaani Frost, MD Funding was provided by Actelion to support the use of independent providers of Delphi methodology expertise and nominal group technique, survey creation, data analysis, medical communication, and meeting management. The authors were not paid an honorarium for their participation. Actelion played no role in the literature search and analysis, development of surveys used to gather consensus, or data analysis; and no Actelion employee was present at the meeting during which consensus statements were finalized. The manuscript was drafted, critically reviewed, and edited solely by the authors with support from an independent professional medical communications agency. Actelion Pharmaceuticals reviewed the final manuscript only to ensure accuracy of UPTRAVI® (selexipag) background ...
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 Greg Hundley, Associate Editor of Circulation and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article is going to focus on trastuzumab-induced cardiac dysfunction in breast cancer patients. We will discuss with Stanford investigators their use of pluripotent stem cells that are differentiated to cardiomyocytes and subsequently exposed to toxins to determine an individual's susceptibility to cardio-toxicity from cancer treatment. But before we get to that, Carolyn, do you have a paper that you'd like to discuss? Dr Carolyn Lam: Well, the first paper deals with cardiac biomarkers and asks the questions, can these biomarkers be useful for the diagnosis and risk stratification of syncope?" Now, this paper is from Dr Mueller and colleagues from University of Hospital Basel in Switzerland. They evaluated the diagnostic and prognostic accuracy of BNP, NT-proBNP, high-sensitivity cardiac troponin T, and high-sensitivity cardiac troponin I concentrations, alone and against the ones of clinical assessments in more than 1,500 patients presented with syncope to the emergency department in a prospective, diagnostic multi-center study. Now, cardiac syncope was adjudicated in 234 or 15% of patients. What they found was that the diagnostic accuracy from cardiac syncope, as quantified by the area under curve, was 0.77 to 0.78 for all four biomarkers. That was superior to that of the syncope-specific diagnostic score, EGSYS. Now, combining the four biomarkers further improved diagnostic accuracy to an area under curve of 0.81. Furthermore, using the four biomarkers at cutoffs achieved predefined thresholds for sensitivity and specificity and allowed rule-in or rule-out of 30% of all patients. Finally, the biomarkers predicted adverse cardiac outcomes with moderate to good prognostic accuracy and better than some of the existing syncope risk-prediction scores. Dr Greg Hundley: Very interesting, Carolyn. Do you think we can now use this clinically? Should we be drawing these biomarkers on patients with syncope? Dr Carolyn Lam: These results really do imply that these biomarkers look like useful tools for the early rule-out and/or rule-in of cardiac syncope in the emergency department. After all, these biomarkers are readily available, inexpensive, and results of this study suggest that they have potential to simplify diagnosis and to risk stratify in challenging presentations. However, before embracing the concept of ordering cardiac biomarkers routinely for syncope presentation, we really need to read the editorial by Dr Sandhu and Sheldon, in which important perspectives are presented, such as considerations of the certainty of the diagnosis of syncope, the usefulness of the comparative scores, the timing of testing, the potential unintended adverse consequences of testing. These editorialists concluded that, although promising, further work is needed to determine how the use of cardiac biomarkers should be incorporated into a risk-stratification algorithm. Dr Greg Hundley: Wow, Carolyn. It sounds like we'd get a lot out of that particular editorial. I'm going to switch over and talk about NT-proBNP in patients with pulmonary hypertension. This is a paper from Dr Kelly Chin from UT Southwestern, and the study evaluated the utility of end terminal pro BNP level thresholds and assessing prognosis in pulmonary hypotension using the GRIPHON study. So GRIPHON is a global double blind, randomized placebo control event driven phase 3 study which assesses the safety and efficacy or a Prostacyclin agonist that promotes pulmonary arterial vasodilation. They performed the study in patients that were 18 to 75 years old with a diagnosis of idiopathic pulmonary hypertension, heritable hypertension or pulmonary hypertension associated with connective tissue disease, repaired congenital systemic pulmonary shunts, HIV infection, drug use or toxin exposure; and the diagnosis of pulmonary hypertension was confirmed by right heart catheterization and by a reduced 6-minute walk distance of 50 to 450 meters. Eligible patients were permitted to take their other therapies including Endothelin receptor agonists and phosphodiesterase type-5 inhibitors. The patients were categorized into low, medium and high in terminal BNP level subgroups according to two thresholds. First, by just the tertiles within the study overall and the secondly by the ESC guideline cutoff ranges. Dr Carolyn Lam: Nice, so what did they find Greg? Dr Greg Hundley: Well first of all both thresholds either the tertile one of the ESC in follow-up NT-proBNP categories were highly prognostic for future morbidity and mortality. And their time dependent analysis the risk of experience a morbidity or mortality even was 92% and 83% lower in the treated patients with a low and medium NT Pro BNP level. And 90% and 56% lower in placebo treated patients with low and medium NT-proBNP levels. So both, whether you're taking that drug of not, the NT-proBNP levels were prognostically valuable. More pronounced treatment benefit of selexipag was seen in the medium and low proBNP groups. There was a positive value for the interaction term. Dr Carolyn Lam: Wow, sounds like two really important findings. Dr Greg Hundley: Yes, exactly Carolyn. So first, NT-proBNP levels are highly prognostic for pulmonary arterial hypertension progression. And having NT-proBNP in the low range, by improving to or maintaining low NT-proBNP levels is a clinically relevant treatment goal for those with pulmonary artery hypertension. And of course as we described this was a very diverse well represented group of many different types of patients with pulmonary hypertension. Then second, while selexipag the study drug was beneficial in all NT-proBNP categories, the treatment effect was greater in those with low and medium categories versus the very high. Suggesting that earlier selexipag treatment may be of greater benefit. But very interesting biomarker study that follows up on yours Carolyn. Dr Carolyn Lam: Indeed! Dr Greg Hundley: Carolyn what about your next paper? Dr Carolyn Lam: Well I want to switch tracks now and talk about iron. And the question is, how does intravenous iron repletion augment exercise capacity in chronic heart failure? Even if hemoglobin doesn't change. So, first some background right, now, besides hemoglobin it's important to recognize that iron is an obligate component of the mitochondrial enzymes that generate cellular energy in the form of adenosine triphosphate and phosphocreatine. So dynamic phosphorous magnetic resonance spectroscopy is a noninvasive tool that can really quantify the in vivo muscle energetics by measuring the kinetics of phosphocreatine recovery after exertion. These authors use this technique, and these are Dr Okonko from King's College, London British Heart Foundation sender of excellence, school of cardiovascular medicine and sciences. The James Black Center in London and colleagues. And what they did was they tested the hypothesis that intravenous iron repletion in chronic heart failure would enhance skeletal muscle energetics as reflected by a shorter phosphocreatine recovery halftime on phosphorous magnetic resonance spectroscopy imagining of the skeletal muscles. And they looked at 40 patients with chronic heart failure with reduced deduction and iron deficiency in a randomized double blind placebo controlled ferric iron and heart failure trial. Dr Greg Hundley: So, what did they find? Dr Carolyn Lam: They found that a single total dose infusion of intravenous iron repleted iron stores and augmented skeletal muscle energetics at 2 weeks post infusion. Enhancements in the skeletal muscle energetics which implied better mitochondrial function were accompanies by improved symptoms despite no change in hemoglobin at 2 weeks. So, this trial really provides mechanistic support for iron repletion in patients with chronic heart failure and its very importantly discussed in an editorial by Peter van der Meer, Haye van der Wal, and Vojtech Melenovsky. And I really suggest that everybody read that. Dr Greg Hundley: Well, I'm going to talk a little bit about dietary omega-6 fatty acids and the incidence of cardiovascular disease and mortality. And this paper is from Matti Marklund from the Georgia Institute for Global Health and the University of New South Wales in Sydney, Australia. The study focuses on linoleic acid which is an omega-6 polyunsaturated fatty acid that we get from pumpkin seeds, flax seeds, walnuts, soybean oil, canola oil and grapeseed. It's been associated with a decrease in cardiovascular risk, but others have worried about an effect of consumption mainly the downstream production of arachidonic acid which can give rise to eicosanoids that are both pro inflammatory and pro thrombotic. And it's interesting Carolyn, several organizations suggest replacing saturated fat and carbohydrates with linoleic acid. So this study was really performed to address whether consumption of linoleic acid is associated with future cardiovascular events. In the study, investigators measured linoleic acid as well as arachidonic acid levels and from a global consortium across 30 perspective observational studies from 13 countries they performed multi variable adjusted associations of circulating an adipose tissue linoleic and arachidonic acid biomarkers with incident total cardiovascular disease and subtypes of cardiovascular disease including, coronary heart disease, ischemic stroke and cardiovascular mortality and this was all done as pre-specified analytic plan. Dr Carolyn Lam: Wow, so what did they find? Dr Greg Hundley: Well did I put you to sleep discussing all of that? Dr Carolyn Lam: No! You have to tell me what they found. I'm seriously so interested in this topic because being vegetarian I actually get my source of omega fatty acids exactly from these sources. Dr Greg Hundley: Okay, so Carolyn, higher levels of linoleic acid were associated with lower risk of total cardiovascular disease, ischemic stroke, cardiovascular mortality. While arachidonic acid was not associated with cardiovascular risks. And so, the clinical implications of the results support the potential benefits of main dietary omega- 6 fatty acid. That is linoleic acid for cardiovascular disease prevention. Now, while the trial is not randomized so we don't have definitive answers, the results do not support any theorized cardiovascular harms of consuming omega-6 fatty acids. And there is an excellent review on polyunsaturated versus saturated fat intake by Thomas Sanders from King's College, London as an editorial to this piece. So Carolyn I think we're safe right now in consuming linoleic acid. So how about a transition to our featured article and learn a little bit more about trastuzumab-induced cardiac dysfunction. Dr Carolyn Lam: Absolutely! Dr Greg Hundley: Great. Welcome everybody, we have a fantastic paper to discuss. We're going to review human induced pluripotent stem cell derived cardiomyocytes and how they can be used to identify individuals at risk of trastuzumab-induced cardiac dysfunction after treatment for breast cancer. We have today Nazish Sayed and also Dr Joseph Wu, both from Stanford University in California. Welcome gentlemen. Dr Joseph Wu: Thank you for inviting us. Dr Nazish Sayed: Thank you. Dr Greg Hundley: Nazish tell us a little bit about what are these human induced pluripotent stem cells and then also describe your experiment and what were your results? Dr Nazish Sayed: So, induced pluripotent stem cells is about 10 years ago I knew technology where you can actually turn back the clock by you taking human fiber blast or blood cells and then you can test full reprogramming factors and turn back differentiated cells to pluripotent stem cells will mimic like catalytic stem cells. The catalytics include self-renewal, pluripotency and the most important that they can be differentiated to any cell type in the body. For example, cardiomyocytes or endothelial cells the neuron and kind of mimic these differentiated cells from the same individual from where the IPSCs were derived from. So, what we did in our study is we used this platform to derive these pluripotent stem cells from patients and then differentiated them into a cardiomyocyte to understand what would these human cardiomyocytes behave in a dish when treated with a Herceptin or trastuzumab and then kind of determine the underlying mechanism for this cardiac dysfunction. It seemed really difficult to model trastuzumab and use cardiac dysfunction as a heart which is the receptor for the trastuzumab is expressed only in humans. People have usually relied on animal model and for the first time what we did is we used these ideas of cardiomyocytes to model this dysfunction in a dish. Our results were pretty straightforward. We found that the IPSCs cardiomyocytes when treated with the chemotherapy agent showed cardiac dysfunction in the case of decrease contractility. The contraction velocity of these each individual cardiomyocytes is significantly reduced. More with this was also confirmed by having impaired calcium cycling which is very important for the contractility of these cardiomyocytes. But I think the most important thing which we determined from the study is that individuals who are treated with trastuzumab have a metabolic impairment in these cardiomyocytes which is convenient but however have a severe impact on this contractility and calcium handling in these cardiomyocytes. And that was one of the gist of these papers to figure out the metabolic impairment could be a target where we can improve this cardiac dysfunction in these patients. Dr Greg Hundley: And so, after you discovered this, I noticed you also did some work with AMPK activators and perhaps would reverse some of the dysfunction. Could you describe a little bit what are AMPK activators and then how did they reverse the dysfunction that you observed? Dr Nazish Sayed: In our study we characterized these IPS cardiomyocytes from these individuals and then we ran a whole sequencing of them after treatment where trastuzumab to see which of the pathways which could be down regulated or dysfunction when compared to the control patients which are not treated with trastuzumab. And one of the most significant pathways which we found was in PK pathways which was down regulated in the trastuzumab treated IPSC cardiomyocytes. So knowing that the AMPK activators are used for metabolic diseases, for example being diabetes and metabolic dysfunction, we thought that this same thing could be used in a dish where we can take these AMPK activators and simultaneously cotreat cardiomyocytes with Herceptin or trastuzumab to see if we can rescue the phenotype and indeed you can see in our paper we used 4 different AMPK activators with metformin which is a commonly used diabetic drug. Showing the best rescue for that trastuzumab induced cardiac dysfunction. Dr Greg Hundley: Very intriguing because it looks like you've been able to harvest cells from individuals and then pre-treat them, understand the mechanism of dysfunction, understand who's at risk of dysfunction and then offer therapeutic interventions to perhaps prevent that dysfunction in this patient population. Joe, turning to you now, this is really revolutionary technology it seems to me. Can you describe how long does this process take? Is this something that we see might come into clinical medicine soon? Dr Joseph Wu: We're really excited about this technology that Nazish has described. I think as you know we've been working on this platform for the past 10+ years. In terms of the timeline, right now it takes us about a month to generate the induced pluripotent stem cells. It takes us another month to expand, propagate the IP itself. It takes us another month to generate the IPS cardiomyocytes. And it will take us probably another month to do all the phenotypic characterization in terms of using these IPS cardiomyocytes to expose them to various chemotherapy drugs and see how the chemotherapy drugs have an effect on these cardiomyocytes. So, I would say the total timeline is 12 months at this moment. Is it possible that the timeline could be crunched, could be shrunk over time? Yes that's possible, I think the technology is improving month by month, week by week because there are many different labs trying to work on this platform trying to improve the whole process. But right now one of the limitations that as you pointed out is this 4 month time period. And also the cost that's associated with this. But we're hopeful that over time that both the time, the costs can go down so that we can offer this type of platform to help patients diagnosed with cancer, find out what kind of chemotherapy is safe to use, what kind of chemotherapy is not safe to use. Dr Greg Hundley: So, we're working towards clinical applications but at this point in time it looks like a fantastic platform for understanding, diagnoses and understanding pathways that for patients particularly as they are treated for cancer will experience cardiovascular dysfunction. So, switching a little bit and asking a related question. Patients that receive trastuzumab often also receive doxorubicin. Especially the breast cancer patients. If you looked at this technology trying to understand, and certainly those more at risk for trastuzumab associated left ventricular dysfunction, are the patients that previously received doxorubicin. Have you and your group looked at patients that have also received doxorubicin and then went on to receive trastuzumab relative to those that received trastuzumab alone? Dr Joseph Wu: I think for these two populations for this particular study, we tried to keep them clean. Meaning that we're looking mostly for trastuzumab treated patients, otherwise it's hard for us to piece out whether the toxicity was due to one medication or the other medication. But what you are asking is very important because as you pointed out many of these patients received both and I think for future studies we should be able to model both medications, meaning that take some IPS cardiomyocytes treated with doxorubicin, treated with Herceptin by itself and treated with both the medications. In previous studies we have studied using IPS cardiomyocytes the effects of doxorubicin induced cardiac toxicity. In just the assessment, doxorubicin is a very common effective chemotherapy for breast cancer medications and just like Herceptin, the clinicians struggled with the issue, as we cannot predict which patient will develop toxicity. And then granted the doxorubicin induced toxicity has a slight different mechanism compared to perception induced mild cardiac dysfunction that this Nazish had mentioned about. But these are kind of the studies that we're very excited because now for the first time we have a way to model this. Otherwise they alternative would be not possible, for example it would not be possible for us to biopsy breast cancer patients woman's heart to study the cells. Especially in the case of perception. The receptor that's being studied is not present in animal model cells. For example not present in mouse cardiomyocytes and therefore it would be very difficult to understand the mechanism and this is the reason why the patient specific and disease specific IPS cardiomyocytes become so useful. Dr Greg Hundley: Do you find another emerging therapy in this entire realm is the immunotherapies? Do you think this technology will be applied to determine susceptibility to immune mediated toxicity? Dr Joseph Wu: This is a very good question as well Greg. We've been thinking about studying that and as you know, it's a more complicated system because it involves patients’ immune response, the myocardial, to inflammatory infiltrates that happens. So we have a couple projects going on. One is to study direct effect of the immunotherapy on the cardiomyocytes and then the second angle is to take patients who are in full myocarditis and collect their patients urine samples, blood samples and to see if we could expose these IPS cardiomyocytes to the patients urine samples to see what is the effect. For these IPS cardiomyocytes for future studies we're also trying to make it more complicated by generating not just the cardiomyocytes by itself, but generating what we call engineered heart tissues. In which it's a chunk of human heart muscles that would have the patients cardiomyocytes, patients fibroblast, patients endothelial cells and expose them to the patients serum. But that kind of study would take much longer period of time because the number of people who have these types of immunotherapy induced myocarditis it's relatively low compared to patients who have Herceptin or doxorubicin induced cardio toxicity. This is also part of the reason why we're very much interested in collaborating with big centers throughout the country like York Center to see if we could understand this process better as a team. Dr Greg Hundley: Excellent. I want to thank both of you for this really elegant discussion and perfect work moving forward. In summary, you've illustrated an ability to withdraw human pluripotent stem cells, differentiate them to cardiomyocytes and then perform tests on them to forecast susceptibility to various treatments used commonly for women with breast cancer. And in this study identifying mechanisms for trastuzumab toxicity. And then perhaps therapeutic interventions using again human cells which has a marked leap as you've identified over doing mouse studies, particularly for studying trastuzumab when the receptors the HER2 receptors in mirroring models differ substantially to those in human subjects. Dr Joseph Wu: Thank you Greg. And we want to also express our thanks to our collaborators, our colleagues who contributed to the study and most importantly to the patients who helped us with these studies. Dr Greg Hundley: I want to thank both Nazish and Dr Wu from Stanford and Carolyn and I wish you the best for the coming week and we look forward to speaking with you again next week. Dr Carolyn Lam: This program is copyright American Heart Association 2019.
Marin H. Kollef, MD, FCCP, and Eddy Fan, MD, PhD, FCCP, join CHEST Podcast Editor, D. Kyle Hogarth, MD, FCCP, to debate if persistent or worsening ARDS refractory to optimized ventilation and proning deserves a trial of prostacyclin.
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. Is there a unique lipoprotein profile for incident peripheral artery disease as opposed to coronary or cerebral vascular disease? Well, you're just gonna have to wait for our feature discussion to find out. That's coming right up after these summaries. Our first original paper this week tells us that gene variance known to be associated with idiopathic and peripartum cardiomyopathy are also associated with preeclampsia. First and corresponding author Dr Gammill from University of Washington and colleagues studied 181 participants with confirmed preeclampsia from the Preeclampsia Registry in BioBank. Saliva samples were collected for DNA isolation and whole exome sequencing was performed to detect rare variants in 43 genes known to be associated with cardiomyopathy. Results were compared with data from two controlled groups, unrelated women with a gynecological disorder, sequence using the same methods and instruments, as well as published variant data from 33,000 subjects in the Exome Aggregation Consortium. The results showed that women who developed preeclampsia are more likely to carry protein altering mutations in genes associated with cardiomyopathy, particularly, the TTN gene which encodes the sarcomeric protein titin. Thus, detecting these gene variants may allow more specific diagnosis, classification, counseling and management of women at risk. Prior trials have shown that nonsteroidal anti-inflammatory drugs or NSAIDS confer cardiovascular risk. Now this has been postulated to be due to enhanced formation of methyl arginines in the kidney that would limit the action of nitric oxide throughout the vasculature. However, the next original paper in this week's journal suggests that this may not be correct. First author, Dr Ricciotti, corresponding author, Dr FitzGerald from University of Pennsylvania Perelman School of Medicine and colleagues, used multiple genetic and pharmacological approaches to disrupt the COX 2 pathway in mice and analyze plasma from patients taking NSAIDS. However, they did not observe an increase in methyl arginines. In contrast, they did observe an increase in plasma asymmetric dimethylarginine or EDMA in mice-rendered hypertensive by infusion of angiotensin II at a dose that also caused renal impairment. After a four week washout period following the infusion of angiotensin II, blood pressure, creatinine, and ADMA levels all fell back to normal levels. Celecoxib-treated mice also exhibited increased ADMA and plasma creatinine in response to infusion of angiotensin II and their levels also returned to normal thereafter. Thus, it seems likely that the previous reported elevations in ADMA reflected renal dysfunction rather than a direct consequence of COX 2 deletion or inhibition. The authors end by suggesting that the most plausible mechanism by which NSAIDS confer a cardiovascular risk, is by suppression of COX 2 derived cardioprotective prostaglandins such as Prostacyclin rather than by enhanced formation of methyl arginines. The next original paper identifies new targets with the potential to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia. Co-corresponding authors, Dr Ola and Eichmann from Yale University School of Medicine and colleagues looked at SMAD4, which is a downstream effector of transforming growth factor-beta/bone morphogenetic protein family ligands that signal via activin-like kinase receptors. The authors generated a tamoxifen inducible postnatal endo-fetal specific SMAD for a mutant mouse and showed that SMAD4 prevented flow-induced arterial venous malformations by inhibiting casein kinase II. The uncovered pathways provided novel targets for the treatment of vascular lesions in hereditary hemorrhagic telangiectasia related juvenile polyposis patients carrying SMAD4 mutations. The next original paper provides important data for the accurate diagnosis of long QT syndrome. Long QT syndrome can be a challenging diagnosis partly because the optimal method for QT assessment is not unequivocally established. QT experts advocate manual measurements with a tangent or threshold method. In today's paper, first and corresponding author, Dr Vink from Academic Medical Center University of Amsterdam and colleagues, aimed to assess similarities and differences between these two methods of QT interval analysis among 1,484 patients with a confirmed pathogenic variant in either KCNQ1, KCNH2 or SNC5A genes from 265 families. Both QT measurement methods yielded a high inter and intra reader validity and a high diagnostic accuracy. Using the same current guideline cutoff of QTC interval 480 milliseconds, both methods had similar specificity but yielded a different sensitivity. QTC interval cutoff values for the QT measured by the tangent method was lower compared to that measured by the threshold method. Plus, values were different depending on the correction for heart rate, age, and sex. The authors provided an adjusted cutoff values specified for method, correction formula, age, and sex. In addition, a freely accessible online probability calculator for long QT syndrome at www.QTcalculator.org has been made available as an aid in the interpretation of the QT interval. The next original paper demonstrates for the first time that thrombin mediated signaling may play a role in diet-induced atherogenesis. Co-first authors, Dr Raghavan and Singh, corresponding author Dr Rao from University of Tennessee Health Science Center and colleagues, used a mouse model of diet-induced atherosclerosis and molecular biological approaches and explored the role of thrombin and its G protein coupled receptor signaling in diet-induced atherosclerosis. They found that thrombin-induced CD36 expression and foam cell formation required protease activated receptor 1, G alpha 12, Pyk2, GAB 1, and protein kinase C theta dependent activating transcription factor 2 activation. Thus, inhibition of thrombin G protein coupled receptor signaling could be a promising target for the development of new drugs in reducing the risk of diet-induced atherogenesis. The next study provides insights into the long- term association of LDL cholesterol with coronary heart disease mortality in individuals at low tenure risks of atherosclerotic cardiovascular disease. First and corresponding author, Dr Abdullah, from VA North Texas Medical Center and UT Southwestern Medical Center and colleagues studied more than 36,000 subjects in the Cooper Clinic Longitudinal Study cohort who are at low tenure estimated risk of atherosclerotic cardiovascular disease. In other words, a low tenure risk of less than 7.5%. They've followed these patients for more than two decades. Results showed that LDL cholesterol and non-HDL cholesterol at or above 160 milligrams per deciliter were independently associated with a 50 to 80% increased relative risk of cardiovascular disease mortality. The associations between LDL cholesterol and cardiovascular disease mortality were more robust when follow up was extended beyond the traditional 10 year estimated risk period. The associations remain significant in those with an estimated tenure atherosclerotic cardiovascular disease risk of less than 5%. These data suggests that LDL cholesterol levels at or above 160 milligrams per deciliter in individuals deemed to be at low tenure atherosclerotic cardiovascular risk are associated with worse long term cardiovascular disease mortality. These findings, along with other observational data and data extrapolated from clinical trials, support further consideration of appropriate LDL cholesterol thresholds for lipid lowering interventions in individuals categorized as low short-term risk. The final paper this week uncovers a novel therapeutic target for the prevention and treatment of thoracic aortic aneurysms. First author, Dr Nogi, corresponding author Dr Shimokawa from Tohoku University Graduate School of Medicine and colleagues, used genetically modified mice to show a pathogenic role of the small GTP binding protein, GDP dissociation stimulator in the development of angiotensin 2 induced thoracic aortic aneurysms and dissection. Down regulation of this protein contributed to dysfunction of aortic smooth muscle cells and hence oxidative stress, and matrix metalloproteinase activities in the pathogenesis of thoracic aortic aneurysms and dissection. Local over expression of this small GTB binding protein GDP dissociation stimulator around the thoracic aorta inhibited aortic dilatation and rupture in deficient mice. And that wraps it up for this week's summaries. Now for our feature discussion. Atherosclerosis has been considered a systemic process, meaning that when we see a disease in one vascular bed, we assume that that's a risk marker for disease in other vascular territories, and that they share pathophysiology, they share risk factors. However, if we think about it, the prior studies have all been sort of focusing on coronary and cerebral vascular disease, but today's feature paper changes that a bit because it addresses a key knowledge gap in peripheral artery disease risk, and interestingly suggests that there may be a unique lipid profile that's related to peripheral artery disease. This is gonna be an exciting discussion and I have the first author, Dr Aaron Aday from Vanderbilt University Medical Center currently. We have our editorialist, Dr Parag Joshi from UT Southwestern, and our associate editor, Dr Anand Rohatgi from UT Southwestern. Welcome gentlemen and Aaron, could we start with you sharing about your study? Dr Aaron Aday: So, as you mentioned, a lot of the previous epidemiologic data on atherosclerosis have been primarily in coronary artery disease and stroke, and when we looked at peripheral artery disease or PAD, there seemed to be some subtle differences. So for instance, total cholesterol on HTL cholesterol seemed to be the strongest risk factors for future peripheral artery disease and in terms of LDL cholesterol, the data are somewhat mixed. Some have found a weak association, some have actually found no association. And so building on that, we wanted to see if using nuclear magnetic resonance spectroscopy, we could elucidate more details about the litho protein pathways associated with peripheral artery disease. And we did this in the women's health study which is a prospective cohort study of women free of cardiovascular disease, the baseline, they were aged 45 and older. And what we've found in terms of the standards with their profiles, we again found that there was no association between LDL cholesterol and future peripheral artery disease, whereas certain standard lipid measures like HDL cholesterol were strongly associated with PAD, and then using the Endemol spectroscopy tool, we found that actually, small LDL particles and total LDL particles were concentrations of both of those markers, were strong risk factors for future PAD and other measures like total HDL particle concentration were even more strongly associated with future PAD than coronary artery disease. So essentially the signature associated with future peripheral artery disease, had some important differences than that for a composite of coronary artery disease and stroke. Dr Carolyn Lam: Aaron thanks for that. That's beautifully described and just so intriguing. Parag, could you tell us how should we be thinking about results like this? Dr Parag Joshi: It's a great paper and it really highlights a new and unique approach in that we ... Peripheral artery disease as an isolated incident event is fairly understudied I guess we could say and so, this is a really nice paper to start choosing out some of the risk factors for that. I think overall, when we think of peripheral arterial disease in general, I think historically, we've thought of it as similar pathophysiology, you know LDL particles and perhaps other particles depositing in the arterial space. But this does highlight some important differences that might exist and I think one of those seems to be that maybe this is more a signature of elevated remnant lipoproteins or triglyceride rich remnant lipoproteins, small dent LDL particles, low HDL, that sort of metabolic syndrome type patterns that we look at as a high risk factor that may be more contributory to peripheral artery disease than coronary disease, or at least more specific to peripheral artery disease. I guess one of my main questions about that from your work Aaron is, how can we be sure this isn't just a pre-clinical marker of diabetic patients which we know have this type of pattern? Dr Aaron Aday: Sure, it's certainly a possibility. I think what's notable in the cohort, at least a time enrollment. And there was a very little diabetes and actually there was a much greater prevalent of metabolic syndrome. So in my mind, it may be more of a metabolic syndrome specific marker rather than necessarily down the diabetes pathway, but it's certainly something that needs to be explored further. Dr Parag Joshi: I wonder whether women's health studies such a healthy cohort that I wonder if this is picking up some signal before the answer to diabetes or as you said, metabolic syndrome, you know which certainly suggests an insulin resistance pattern and we know the association of diabetes with peripheral artery disease is stronger and so I wonder if this may be a sort of earlier way of picking that up. Dr Aaron Aday: It may be. I think one thing to notice is the outcome of peripheral artery disease that we're using. So it is symptomatic disease. So, we're not picking up a lot of ulcers that are developing in the future, it's more the claudication and then people who've undergone revascularization. Certainly diabetics have both of those as well but I think that may suggest it's not fully unexplained by developing diabetes than peripheral artery disease further down the line. Dr Parag Joshi: Yeah that's a great point. Dr Carolyn Lam: Yeah great questions, great thoughts. Anand, what about you? Did you have questions too? Dr Anand Rohatgi: I think from my perspective and thinking about it for circulation and its readership, we found this really interesting for several reasons. Number one, I think is, as you all have discussed, peripheral arterial disease just is not as well characterized and you can see that here in over 25,000 people, add about a 100 a bed, so I think in younger folk, it takes a lot of people to study, to be able to really understand kind of the pathophysiology of peripheral arterial disease. The other thing that they think they really shed some light on is how this is happening in women in particular and in women, of course as we know have been understudied in all cardiovascular diseases, but in particular, diseases like this which are less common. It's really insightful to see that these lipid abnormalities in women are contributing to peripheral arterial disease more so than your typical LDL cholesterol management and interestingly enough, most of the women who had PAD events in this study, did not have other cardiovascular events. They really just had PAD events exclusively and I thought that was really intriguing, and the use of this advanced lipoprotein testing, this NMR modality has been very useful in terms of biology and research, and I think that's the case here where we really go under the hood Carolyn, as you said, and get kind of deep dive, the lipid metalobles on abnormalities. And I think Parag and Aaron hit the nail in the head that this is really capturing an insulin resistance of phenotype and what I really liked about this is, instead of studying people who are 70, 80 years old and a lot of things are sort of clustering, a lot of diseases are clustering and they're manifesting all at the same time, it's very hard to tease apart the effective age. Here, we captured women in their 50s and middle aged, just as they have kind of gone through menopause and this adverse metabolite's phenotype starts to rise in women. And then we could follow them over time and see what the natural history of that is, and the women who have this phenotype go on to have this devastating consequence, this peripheral arterial disease. One of the questions I had then, Aaron for you is, what do you think the implications are from these findings? Does it mean that in terms of diagnostics, we should be doing more advanced testings looking at LDL and HDL type particles with NMR or some other mortality? Does it change therapies with new therapies beings studies right now? What do you think the implications are from your work? Dr Aaron Aday: That's important right. I think you mentioned this and I see the inter marked tool in this study, is really a way to try to dig further into the biology of peripheral artery disease as a form of atherosclerosis. I think that we already know patients who are extremely high risk or PAD, those are patients with diabetes, smoking history, metabolic syndrome et cetera., and as you can see in a patient population in 28,000 middle aged women who are pretty healthy, we only had just over a 100 PAD events. So, I think even if you were to scale this up in terms of cost, I'm not sure that that would necessarily be a viable option for patients, but I think it does suggest that truly focusing on LDL in a very high-risk patient population, meaning patients with PAD, or we may not be fully addressing their risk. And so I think this is a need to highlight that important gap, think about other therapeutic options and we'll soon have ongoing trials, triglyceride low in therapy that may be particularly beneficial in this patient population and so that's how I see this being used. Dr Anand Rohatgi: That makes a lot of sense and particular because in middle aged women like this, your standard risk score algorithms will not really capture that they're at increased risk, even if they smoke, just because they're women and they're younger and so, I think this really is a call to arms to more refined risk assessment in these women. Dr Parag Joshi: Aaron, do you think there's actually a difference in the biology in the peripheral arteries compared to the coronary and cerebral vascular beds, or is there data to kind of look at that or maybe histopathological data to look at that? Dr Aaron Aday: We know there's a lot of overlaps, so I don't wanna suggest that PAD is not a former atherosclerosis. I think one limitation is that the primary animal model for PAD is the hyperCKemia model. That doesn't fully recapitulate what's happening in a limb with PAD and so I think that has been one limitation in understanding the biology. But I think what we're starting to see in some clinical trials that have come out in the last couple of years or starting to see a somewhat different signal for therapies in patients with PAD so for instance, in 48, we actually saw that there was a greater benefit to LDL lower [inaudible 00:21:00] inhibitors than for coronary disease. We now have the compass trial results, again, more events, higher risk among these patients but for their benefit, add on River Oxodine therapy, we've seen lymph events or lymph signals in the SGLP2 inhibitor trials. So, I think we're starting to get a sense that there may be something else on top of the traditional ascariasis biology that may be a potential target on down the road. Dr Parag Joshi: I think it's really a fascinating biological question of how these different territories might actually differ in their pathophysiology. I think it's a really a nice time to look at this. Also I think, Anand and Aaron both mentioned ongoing trials. The omega 3 fatty acid trials I think reduce it, will be soon to be presented and hopefully published in the next month or so. It would be nice to see if they evaluate peripheral events in that group, I'm sure they will. Dr Carolyn Lam: Indeed, these have been just such great thoughts and discussion. Nothing really much to add there. I suppose I could say something cheeky like for the first time, and I never thought I'd say it on the podcast, I feel kind of bad that there are no men included in this trial but anyway, I just learnt so much from this. I just wanna thank you gentlemen for a great discussion. Thank you, listeners, for joining us today and don't forget to tune in again next week to Circulation on the Run.
Today's Neuroscience, Tomorrow's History - Professor Salvador Moncada
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 07/19
Vaskuläre Erkrankungen sind als Ursache für Mortalität und Morbidität führend in westlichen Industrieländern. Es gibt zunehmend Hinweise darauf, dass oxLDL eine herausragende Rolle bei der Atheroskleroseinduktion bzw. -progression zukommt. Die initiale Wirkung von im Blut zirkulierendem oxLDL findet auf der Ebene der Interaktion mit dem vaskulären Endothel statt und resultiert in der endothelialen Dysfunktion. Da die Zellfunktion durch die Integrität der Endothelzellschicht bzw. deren interzelluläre Kommunikation mitbestimmt ist, wäre es denkbar, dass für die oxLDL-induzierten Veränderungen im Endothel u. a. die Beeinflussung der Zell-Zell-Kommunikation via Gap Junctions eine Rolle spielt. Bislang war jedoch wenig darüber bekannt, welchen Einfluss oxLDL auf die interzelluläre Kommunikation über Gap Junctions in Endothelzellen ausübt. Außerdem war es nicht geklärt, inwiefern diese Veränderungen in der Zell-Zell-Kommunikation die Induktion und den Schweregrad der oxLDL-induzierten Apoptose beeinflussen. Ziele der Studie waren daher i) zu analysieren, ob und über welche Mechanismen oxLDL einen Einfluss auf die interzelluläre Kommunikation über Gap Junctions in Endothelzellen ausübt, ii) zu untersuchen, welche Bedeutung der interzellulären Kommunikation über Gap Junctions bzw. einzelnen Connexinen bei der Induktion der Apoptose zukommt. Mittels der Dye-Transfer-Methode nach Farbstoffinjektion in eine einzelne Zelle konnten wir zeigen, dass oxLDL eine signifikante Steigerung der interzellulären Kommunikation über Gap Junctions in HUVEC induziert. Dieser Effekt ist dosisabhängig: er zeigte sich nur bei geringen oxLDL-Konzentrationen (15 bzw. 26 μg/ml) und wurde bei weiterer Erhöhung der Konzentration bis auf 100 μg/ml wiederum aufgehoben. Die durch oxLDL verstärkte Zell-Zell-Kommunikation wurde in Endothelzellen durch einen cAMP/PKA abhängigen Mechanismus vermittelt, wobei die cAMP-Freisetzung durch ein Cyclooxygenaseprodukt, wahrscheinlich Prostacyclin, getriggert wurde. Mittels immunhistochemischer Färbungen für Cx37 und Cx43 konnten wir nicht bestätigen, dass die oxLDL-induzierte Verstärkung der Zell-Zell-Kommunikation infolge einer Hochregulation der Connexin-Expression auftritt. Im zweiten Teil der Studie wurde der Einfluss von oxLDL auf die Apoptoseinduktion analysiert. Die Apoptose wurde mittels der Annexin V - Propidium Iodid Färbung bzw. durch Nachweis des Mitochondrienmembranpotentials durchflusszytometrisch erfasst. OxLDL verursachte einen signifikanten Anstieg der Apoptoserate in HUVEC. Zur Aufklärung der Rolle bestimmter Connexine wurden weitere Experimenten in Cx-transfizierten HeLa-Zellen durchgeführt. In diesen Zellen erhöhen einzelne Connexine die Apoptoserate in unterschiedlichem Ausmaß: Cx43 > Cx40 > Cx37. Um zu prüfen, ob die bloße Anwesenheit der Connexine dafür von Bedeutung war oder ob von Connexinen gebildete Gap Junctions dafür von Bedeutung waren, wurden weitere Experimente durchgeführt. Dafür wurden in einem neuen Versuchsansatz Zellen in Suspension (keine Zell-Zell-Kontakte) sowie adhärente Zellen im Monolayer (bestehende Zell-Zell- Kontakte) einer proapoptotischen Stimulation durch Streptonigrin unterzogen. Die Zellen in Suspension wiesen erst zu einem deutlich späteren Zeitpunkt apoptotische Veränderungen auf. Das deutet auf eine Beteiligung der Gap Junctions bei der Apoptoseinduktion hin. Diese Interpretation wurde durch Befunde einer weiteren Versuchsreihe bestätigt. Bei Inkubation von apoptotischen Cx43-positiven Zellen mit intakten Zellen wurde die Apoptoserate der Letzteren nur dann signifikant erhöht, wenn diese ebenfalls Connexin 43 exprimierten und funktionelle Gap Junctions mit den bereits apoptotischen Zellen de novo bilden konnten. Somit demonstriert diese Arbeit, dass Gap Junctions eine wichtige Rolle bei der Apoptoseinduktion spielen. In nachfolgenden Studien soll in Atherosklerose-Modellen überprüft werden, ob und inwiefern die hier beschriebenen Mechanismen auch unter den In-Vivo-Bedingungen bei den oxLDL-assoziierten Gefäß/Endothelschäden eine Rolle spielen.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 01/19
Die Anpassung der Gewebsdurchblutung an die unterschiedlichen Bedarfssituationen, setzt ein koordiniertes Verhalten der Gefäße im mikrovaskulären Gefäßnetz voraus. Diese Koordination der vasomotorischen Reaktionen im mikrovaskulären Gefäßsystem, ist möglicherweise auf die interzelluläre Kommunikation der Endothelzellen angewiesen. Die Endothelzellen und glattten Muskelzellen der Blutgefäße sind über Gap Junctions gekoppelt, auch eine myoendotheliale Kopplung wird diskutiert. Dadurch können Signale in Form von Ionen (und damit Änderungen des Membranpotentials) oder kleinen Moleküle über solche interzellulären Kanäle entlang der Endothelzellschicht weitergegeben werden. Völlig unbekannt ist aber, ob die Permeabilität dieser endothelialen Gap Junctions reguliert wird. Deshalb wurde in dieser Arbeit untersucht, ob vom Endothel gebildete lokal wirksame Gewebshormone (Autakoide, wie NO und Prostacyclin) die Durchlässigkeit der Gap Junctions beeinflussen. Hierzu wurde in konfluenten Kulturen von humanen umbilikalvenösen Endothelzellen (n=190) die Ausbreitung der Farbstoffe Carboxyfluoresein und Calcein nach Injektion in eine einzelne Endothelzelle in die benachbarten Endothelzellen untersucht. Es konnte gezeigt werden, daß der injizierte Farbstoff tatsächlich nur über interzelluläre Kanäle von einer Zelle zur nächsten gelangt. Diese Kanäle werden von Connexinen gebildet, denn ein Peptid, das das Aneinanderdocken der Connexine verhindert, reduzierte die Ausbreitung des fluoreszierenden Farbstoffs. Daher kann mit dieser Methode tatsächlich die Kopplung der Zellen über Gap Junctions untersucht werden. Die erhobenen Daten zeigen, daß die Anzahl der fluoreszierenden Zellen nach Hemmung der NO-Synthase mit Nw-nitro-L-Arginin (L-NA, 30µmol/L) um bis zu 29% zunahm, während die anschließende erneute Freisetzung von NO durch zwei differente NO-Donoren (SNAP bzw. SNP, 1 µmol/L) die Zahl der fluoreszierenden Zellen wieder auf den Ausgangswert reduzierte oder sogar unterhalb den, der unbehandelten Kontrollzellen senkte. Diese durch NO hervorgerufene Wirkung blieb in Anwesenheit des Hemmstoffes der löslichen Guanylatcyclase ODQ (10 µmol/L) oder der Radikalfänger Tiron und Superoxiddismutase unverändert. Dies weist daraufhin, daß es sich bei dieser durch NO hervorgerufenen Hemmung um einen direkten Effekt von NO handelt, der weder über die Bildung von cGMP noch über eine gesteigerte Peroxynitritproduktion vermittelt wird. Auch eine Hyperpolarisation der Endothelzellen durch den Aktivator von KATP-Kanälen HOE234 (1 µmol/L) hatte keinen Einfluß auf die Kopplung der Zellen. Im Gegensatz dazu hatte NO in Anwesenheit der Hemmstoffe der Tyrosinphosphatase Orthovanadat (100 µmol/L) und Phenylarsinoxid (1 µmol/L) keinen Einfluß mehr auf die endotheliale Kommunikation via Gap Junctions. Dagegen führte die Behandlung der Zellen mit dem Tyrosinkinase Inhibitor Genistein (100 µmol/L) zu einer deutlichen Reduktion der endothelialen Kopplung (-14%), die mit der Wirkung von NO vergleichbar war. Daraus läßt sich schließen, daß die durch NO hervorgerufene Wirkung auf die interzelulläre Kommunikation über eine Verminderung der Tyrosinphosphorylierung vermittelt zu werden scheint. Außerdem zeigen diese Daten, daß Prostacyclin die endotheliale Kopplung signifikant steigert, und das diese Wirkung über das gebildete cAMP vermittelt wird. Denn nicht nur das Prostacyclin Analogon Iloprost (1 µmol/L), sondern auch der Aktivator der Adenylatcyclase Forskolin (30 µmol/L), verbesserte die Ausbreitung des Farbstoffes signifikant . Schließlich zeigen die Ergebnisse auch, daß die beiden vom Endothel gebildeten Substanzen sich gegenseitig in ihrer Wirkung auf die endothelialen Gap Junctions beeinflussen können. Die erhobenen Daten zeigen erstmals eine Rolle von NO und Prostacyclin in der Regulation der Permeabilität endothelialer Gap Junctions. Diese Regulationsmöglichkeit und die Auswirkungen einer vermehrten oder verminderten Kopplung der Endothelzellen wirft zahlreiche neue Fragestellungen auf z. B. hinsichtlich der Pathophysiologie der coronaren Herzkrankheit oder auch des arteriellen Hypertonus und bietet damit auch die Möglichkeit zur Entwicklung neuer Therapiemöglichkeiten.
Today, the technique to directly administer vasodilators via the airway to treat pulmonary hypertension and to improve pulmonary gas exchange is widely accepted among clinicians. The flood of scientific work focussing on this new therapeutic concept had been initiated by a fundamental new observation by Pepke-Zaba {[}1] and Frostell in 1991 {[}2]: Both scientists reported, that inhalation of exogenous nitric oxide (NO) gas selectively dilates pulmonary vessels without a concomittant systemic vasodilation. No more than another decade ago NO was identified as an important endogenous vasodilator {[}3] while having merely been regarded an environmental pollutant before that time. Although inhaled NO proved to be efficacious, alternatives were sought-after due to NO's potential side-effects. In search for the ideal inhaled vasodilator another group of endogenous mediators - the prostanoids - came into the focus of interest. The evidence for safety and efficacy of inhaled prostanoids is - among a lot of other valuable work - based on a series of experimental and clinical investigations that have been performed or designed at the Institute for Surgical Research under the guidance and mentorship of Prof. Dr. med. Dr. h.c. mult. K. Messmer {[}4-19]. In the following, the current and newly emerging clinical applications of inhaled prostanoids and the experimental data which they are based on, will be reviewed. Copyright (C) 2002 S. Karger AG, Basel.
Thu, 1 Sep 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/9792/1/9792.pdf Linz, Wolfgang; Schölkens, Bernward A.; Wohlfart, Paulus; Korth, Petra; Fink, Edwin; Wiemer, Gabriele
Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-3',5' monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time- dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation.
Sat, 1 Jan 1994 12:00:00 +0100 https://epub.ub.uni-muenchen.de/9203/1/9203.pdf Messmer, Konrad; Zwißler, Bernhard; Welte, M. ddc:610, Medizin
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.15.039842v1?rss=1 Authors: Womack, T., Vollert, C., Nwoko, O., Schmitt, M., Montazari, S., Beckett, T., Mayerich, D., Murphy, M. P., Eriksen, J. L. Abstract: Alzheimer's disease (AD) is an incurable neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that the use of anti-inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid disease pathologies. Mice overexpressing both amyloid and PGI2exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2control mice. PGI2overexpression accelerated the development of amyloid accumulation in the brain and selectively increased the production of soluble amyloid-{beta} 42. PGI2 damaged the microvasculature through alterations in vascular length and branching; amyloid expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype. Copy rights belong to original authors. Visit the link for more info
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